Publications
The FePsy project produced 315 peer-reviewed publications, book chapters and conference contributions (years 1989–2026). Use the search and filters to narrow the list; click an entry to reveal its abstract.
315 matches
2026
- Koutsouleris N, Vetter C, Buciuman M, Neuner LM, Weyer C, Urquijo-Castro MF, et al. Biosignatures of cognitive basic symptoms mark a distinct neurodevelopmental pathway to schizophrenia. Brain: A Journal of Neurology. 2026 Mar;awag100.
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Efforts to predict schizophrenia risk using biological data have been hampered by the heterogeneity of current "clinical-high-risk" (CHR-P) criteria, which pool phenomenologically and biologically distinct syndromes under a single label. In particular, the field has focused almost exclusively on ultra-high-risk (UHR) symptoms, while cognitive basic symptoms (COGDIS)-despite their close alignment with schizophrenia's core features such as formal thought disorder-have remained underutilised. To date, no study has directly compared brain signatures of different CHR-P definitions with respect to their similarity to schizophrenia and their diagnostic, biopsychosocial, and prognostic profiles. We applied machine learning to structural MRI data from 1,425 patients (CHR-P subgroups, recent-onset psychosis, depression) and 907 healthy controls to derive and compare diagnostic brain signatures for Cognitive Disturbances (COGDIS), Ultra-High-Risk (UHR), their overlap (MIXED), and schizophrenia. The MIXED and UHR signatures lacked diagnostic separability and similarity with schizophrenia. Contrarily, the COGDIS signature distinguished patients from controls (BAC=69%, P < .001) and aligned with the schizophrenia signature (r = 0.60), involving shared fronto-parieto-perisylvian volume reductions. UHR was characterised by volume enlargements, whereas MIXED exhibited a mixed pattern of reductions and enlargements relative to healthy controls. COGDIS and schizophrenia signature expressions were predictable with 12%-21% variance explained based on polygenic, cognitive, and exposomal factors both in a transdiagnostic patient cohort and in healthy controls. Their expressions increased from health to schizophrenia. MIXED signature expression was also predictable from biopsychosocial data, but with higher explained variance in patient samples (21%) than in healthy controls (3%). UHR signature expression showed no significant biopsychosocial predictability in either group. Cell-enriched polygenic risk profiles differed across signatures, with COGDIS and schizophrenia showing enrichment patterns implicated in neurodevelopmental processes, while MIXED being associated with immune- and blood-brain-barrier-related enrichments. Longitudinally, COGDIS and schizophrenia brain scores stratified patients with functional disability, while UHR scores predicted better outcomes. Together, these findings indicate that psychosis-risk syndromes differ markedly in the diagnostic specificity, biopsychosocial informativeness and prognostic value of their underlying brain signatures. UHR symptoms are linked to a weak and diagnostically unspecific brain pattern, while the MIXED phenotype is characterised by a dimensional, transdiagnostic signature enriched across early psychotic and affective disease states. In contrast, COGDIS aligns with a neurodevelopmentally grounded vulnerability pattern that converges with schizophrenia's cognitive-disorganisation dimension. These distinctions support a biologically informed reconceptualization of psychosis risk, with cognitive basic symptoms capturing a core liability dimension of schizophrenia, while other risk states reflecting more transient processes underlying psychotic symptom expression.
- Buciuman MO, Haas SS, Antonucci LA, Sarisik E, Khuntia A, Lichtenstein T, et al. From Snapshots to Stable Outcomes: Resting-State Functional Magnetic Resonance Imaging-Based Prognosis of Functioning in Patients With Psychosis Risk or Recent-Onset Depression. Biological Psychiatry. 2026 Apr;99(8):692–705.
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BACKGROUND: Early recovery of functioning is critical for favorable outcomes in psychotic and affective disorders. Transdiagnostic brain activity patterns may capture pathways for poor outcomes before clinical manifestation, thereby supporting timely prevention and intervention. METHODS: Using machine learning, we evaluated the transdiagnostic prognostic value of resting-state functional magnetic resonance imaging fractional amplitude of low-frequency fluctuations (fALFF) (slow-5 and slow-4 sub-bands) for functional outcomes in patients at clinical high risk for psychosis (n = 217) or with recent-onset depression (n = 198) from the multisite PRONIA (Prognostic Tools for Early Psychosis Management) study. Leave-site-out cross-validation assessed the geographic generalizability of models across disability and symptom domains, with outcomes defined as snapshots at 9- or 18-month follow-up or across both time points. We examined diagnosis-specific performance, generalization to recent-onset psychosis (n = 140), and negative symptoms and the added value of fALFF over clinical prognostication. RESULTS: Transdiagnostic models predicting stable good functioning across follow-ups showed up to 10% higher balanced accuracy (BAC) than snapshot models. Decreased slow-5 fALFFs in the default mode network, executive control network (ECN), and dorsal attentional network (DAN) and increased fALFF in the salience network, ECN, and DAN predicted impairment with BAC = 67% (sensitivity = 65%, specificity = 70%, p < .001). This model generalized to recent-onset psychosis (BAC = 62%, sensitivity = 64%, specificity = 59%, p < .001) and predicted (BAC = 65%, sensitivity = 66%, specificity = 65%, p < .001) and was mediated by negative symptoms. Slow-5-based models improved prognostic accuracy over expert ratings in disability (BACraters = 66%, BACraters+slow-5 = 75%, W = 1680, p < .001) and symptom (BACraters = 61%, BACraters+slow-5 = 71%, W = 1444, p < .001) domains. CONCLUSIONS: We highlighted the prognostic value of fALFF for functional impairment in psychosis risk and early depression. Leveraging trajectorial information, we identified candidate imaging biomarkers to improve prognostication, thereby supporting personalized prevention and recovery strategies.
2025
- Tognin S, Catalan A, Aymerich C, Richter A, Kempton MJ, Modinos G, et al. Association between Adverse Childhood Experiences and long-term outcomes in people at Clinical High-Risk for Psychosis. Schizophrenia. 2025 Feb;11(1):23.
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Adverse childhood experiences (ACEs) are common in people at clinical high-risk for psychosis (CHR), however, the relationship between ACEs and long-term clinical outcomes is still unclear. This study examined associations between ACEs and clinical outcomes in CHR individuals. 344 CHR individuals and 67 healthy controls (HC) were assessed using the Childhood Trauma Questionnaire (CTQ), the Bullying Questionnaire and the Childhood Experience of Care and Abuse (CECA). CHR were followed up for up to 5 years. Remission from the CHR state, transition to psychosis (both defined with the Comprehensive Assessment of an At Risk Mental State), and level of functioning (assessed with the Global Assessment of Functioning) were assessed. Stepwise and multilevel logistic regression models were used to investigate the relationship between ACEs and outcomes. ACEs were significantly more prevalent in CHR individuals than in HC. Within the CHR cohort, physical abuse was associated with a reduced likelihood of remission (OR = 3.64, p = 0.025). Separation from a parent was linked to an increased likelihood of both remission (OR = 0.32, p = 0.011) and higher level of functioning (OR = 1.77, p = 0.040). Death of a parent (OR = 1.87, p = 0.037) was associated with an increased risk of transitioning to psychosis. Physical abuse and death of a parent are related to adverse long-term outcomes in CHR. The counter-intuitive association between separation from a parent and outcomes may reflect the removal of a child from an adverse environment. Future studies should investigate whether interventions targeting the effect of specific ACEs might help to improve outcomes in this population.
- Schlögelhofer M, Lin A, Markulev C, Schäfer MR, McGorry PD, Nelson B, et al. Association between non-adherence to fish oil or placebo as a risk factor of transition to psychosis in ultra-high-risk individuals in the NEURAPRO study. The Australian and New Zealand Journal of Psychiatry. 2025 Oct;59(10):888–96.
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OBJECTIVE: Non-adherence is an important factor in clinical trials, which has not been investigated in people at ultra-high risk (UHR) of developing a first episode of psychosis. METHODS: Exploratory analysis of data from NEURAPRO, a multicenter, placebo-controlled trial of long-chain omega-3 polyunsaturated fatty acids (omega-3 PUFAs) in 304 individuals at UHR. We examined correlates of non-adherence with study medication (omega-3 PUFAs or placebo), including patient, illness and treatment factors, plus transition to psychosis. Non-adherence was defined as <75% study medication intake over 6 months and, post hoc, by the number of returned pills. RESULTS: Of 285 randomized participants with baseline fatty acid data, 163 (57.2%) were non-adherent. In univariate analyses, non-adherence was associated with baseline omega-3 index, pre-baseline duration of untreated symptoms, smoking, cannabis use, lower baseline Social and Occupational Functioning Assessment Scale, Global Functioning: Social and Role Scale scores and transition to psychosis. Transition to psychosis risk was significantly lower in the adherent than non-adherent group (4.2%, 95% CI = 0.7-7.7% vs 17.3%, 95% CI = 10.4-24.2%), Kaplan-Meier Log-rank test, chi-square = 10.675, p = 0.001), independent of omega-3 PUFA treatment status. Similarly, Cox regression analysis, covarying for the aforementioned factors significantly associated with non-adherence, also revealed non-adherence as an independent predictor of transition to psychosis (B = 1.452, p = 0.005). Finally, non-adherence was also significantly associated with transition to psychosis, even when defining non-adherence by number of returned pills. CONCLUSION: Non-adherence predicted a higher risk of progressing to psychosis in UHR individuals. Further studies are needed to better understand factors contributing to non-adherence and how non-adherence is related to transition to psychosis.
- Hu Y, Frisman M, Andreou C, Avram M, Riecher-Rössler A, Borgwardt S, et al. Brain Fractal Dimension and Machine Learning can predict first-episode psychosis and risk for transition to psychosis. Computers in Biology and Medicine. 2025 Jul;193:110333.
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Although there are notable structural abnormalities in the brain associated with psychotic diseases, it is still unclear how these abnormalities relate to clinical presentation. However, the fractal dimension (FD), which offers details on the complexity and irregularity of brain microstructures, may be a promising feature, as demonstrated by neuropsychiatric disorders such as Parkinson's and Alzheimer's. It may offer a possible biomarker for the detection and prognosis of psychosis when paired with machine learning. The purpose of this study is to investigate FD as a structural magnetic resonance imaging (sMRI) feature from individuals with a high clinical risk of psychosis who did not transit to psychosis (CHR_NT), clinical high risk who transit to psychosis (CHR_T), patients with first-episode psychosis (FEP) and healthy controls (HC). Using a machine learning approach that ultimately classifies sMRI images, the goals are (a) to evaluate FD as a potential biomarker and (b) to investigate its ability to predict a subsequent transition to psychosis from the high-risk clinical condition. We obtained sMRI images from 194 subjects, including 44 HCs, 77 FEPs, 16 CHR_Ts, and 57 CHR_NTs. We extracted the FD features and analyzed them using machine learning methods under five classification schemas (a) FEP vs. HC, (b) FEP vs. CHR_NT, (c) FEP vs. CHR_T, (d) CHR_NT vs. CHR_T, (d) CHR_NT vs. HC and (e) CHR_T vs. HC. In addition, the CHR_T group was used as external validation in (a), (b) and (d) comparisons to examine whether the progression of the disorder followed the FEP or CHR_NT patterns. The proposed algorithm resulted in a balanced accuracy greater than 0.77. This study has shown that FD can function as a predictive neuroimaging marker, providing fresh information on the microstructural alterations triggered throughout the course of psychosis. The effectiveness of FD in the detection of psychosis and transition to psychosis should be established by further research using larger datasets.
- Wannan C, Scott I, Dwyer D, Clark SR, Hartmann S, Ye RR, et al. Characterizing the Clinical Trajectory and Predicting Persistence and Deterioration of Attenuated Psychotic Symptoms in Ultra-High-Risk Individuals. Schizophrenia Bulletin. 2025 Nov;51(6):1592–605.
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BACKGROUND: Almost 40% of individuals at ultra-high risk (UHR) for psychosis experience persistent attenuated psychotic symptoms (APS) yet it is unclear (1) whether they share overlapping clinical and functional outcomes compared to individuals who transition to psychosis, (2) when symptom and functioning trajectories begin to diverge between UHR individuals with different clinical outcomes, and (3) whether non-remission (persistent APS or transition) can be predicted using baseline and/or longitudinal data. STUDY DESIGN: Participants were drawn from 2 randomized clinical trials: Neurapro (n = 220; discovery sample) and STEP (n = 180; external validation sample). First, 12-24 month symptoms and functioning were compared between UHR individuals with persistent APS, sustained remission, or transition to psychosis. Next, short-term changes in symptoms and functioning were compared between groups to determine timepoints at which trajectories began to diverge. Finally, we used support vector machines to predict non-remission (persistent APS or transition) vs sustained remission using data from baseline, 6-month follow-up, and combined baseline and 6-month follow-up. RESULTS: Individuals with persistent APS had substantially poorer outcomes compared to those who remitted, and more closely resembled individuals who later transitioned to psychosis. Despite few baseline differences between groups, clinical and functional trajectories of the persistent APS and transition groups rapidly diverged from those who remitted. Prediction of non-remission was poor using baseline data but improved substantially when using 6-month follow-up or combined baseline-6-month data. CONCLUSIONS: Ultra-high-risk individuals with persistent APS display similar clinical and functional trajectories to transitioned cases, suggesting that more intensive and sustained intervention is required for this subgroup. However, prospective identification of individuals with poor clinical outcomes (ie, persistence or deterioration of attenuated psychotic symptoms) may require longitudinal monitoring of symptom and functioning trajectories for several months.
- Gifford G, Avila A, Kempton MJ, Fusar-Poli P, McCutcheon RA, Coutts F, et al. Do Cognitive Subtypes Exist in People at Clinical High Risk for Psychosis? Results From the EU-GEI Study. Schizophrenia Bulletin. 2025 Jul;51(4):1019–29.
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BACKGROUND AND HYPOTHESIS: Cognition has been associated with socio-occupational functioning in individuals at Clinical High Risk for Psychosis (CHR-P). The present study hypothesized that clustering CHR-P participants based on cognitive data could reveal clinically meaningful subtypes. STUDY DESIGN: A cohort of 291 CHR-P subjects was recruited through the multicentre EU-GEI high-risk study. We explored whether an underlying cluster structure was present in the cognition data. Clustering of cognition data was performed using k-means clustering and density-based spatial clustering of applications with noise. Cognitive subtypes were validated by comparing differences in functioning, psychosis symptoms, transition outcome, and grey matter volume between clusters. Network analysis was used to further examine relationships between cognition scores and clinical symptoms. STUDY RESULTS: No underlying cluster structure was found in the cognitive data. K-means clustering produced "spared" and "impaired" cognition clusters similar to those reported in previous studies. However, these clusters were not associated with differences in functioning, symptomatology, outcome, or grey matter volume. Network analysis identified cognition and symptoms/functioning measures that formed separate subnetworks of associations. CONCLUSIONS: Stratifying patients according to cognitive performance has the potential to inform clinical care. However, we did not find evidence of cognitive clusters in this CHR-P sample. We suggest that care needs to be taken in inferring the existence of distinct cognitive subtypes from unsupervised learning studies. Future research in CHR-P samples could explore the existence of cognitive subtypes across a wider range of cognitive domains.
- Riecher-Rössler A. Editorial 1/25. Archives of Women’s Mental Health. 2025 Aug;28(4):721.
- Vetter CS, Bender A, Dwyer DB, Montembeault M, Ruef A, Chisholm K, et al. Exploring the predictive value of structural covariance networks for the diagnosis of schizophrenia. Frontiers in Psychiatry. 2025;16:1570797.
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INTRODUCTION: Schizophrenia is a psychiatric disorder hypothesized to result from disturbed brain connectivity. Structural covariance networks (SCN) describe the shared variation in morphological properties emerging from coordinated neurodevelopmental processes, This study evaluates the potential of SCNs as diagnostic biomarker for schizophrenia. METHODS: We compared the diagnostic value of two SCN computation methods derived from regional gray matter volume (GMV) in 154 patients with a diagnosis of first episode psychosis or recurrent schizophrenia (PAT) and 366 healthy control individuals (HC). The first method (REF-SCN) quantifies the contribution of an individual to a normative reference group's SCN, and the second approach (KLS-SCN) uses a symmetric version of Kulback-Leibler divergence. Their diagnostic value compared to regional GMV was assessed in a stepwise analysis using a series of linear support vector machines within a nested cross-validation framework and stacked generalization, all models were externally validated in an independent sample (NPAT=71, NHC=74), SCN feature importance was assessed, and the derived risk scores were analyzed for differential relationships with clinical variables. RESULTS: We found that models trained on SCNs were able to classify patients with schizophrenia and combining SCNs and regional GMV in a stacked model improved training (balanced accuracy (BAC)=69.96%) and external validation performance (BAC=67.10%). Among all unimodal models, the highest discovery sample performance was achieved by a model trained on REF-SCN (balanced accuracy (BAC=67.03%). All model decisions were driven by widespread structural covariance alterations involving the somato-motor, default mode, control, visual, and the ventral attention networks. Risk estimates derived from KLS-SCNs and regional GMV, but not REF-SCNs, could be predicted from clinical variables, especially driven by body mass index (BMI) and affect-related negative symptoms. DISCUSSION: These patterns of results show that different SCN computation approaches capture different aspects of the disease. While REF-SCNs contain valuable information for discriminating schizophrenia from healthy control individuals, KLS-SCNs may capture more nuanced symptom-level characteristics similar to those captured by PCA of regional GMV.
- Si S, See C, Hedges EP, Tognin S, Modinos G, de Haan L, et al. Gray Matter Volume Abnormalities and the Association with the Trajectory of Symptoms and Functioning in Individuals at Clinical High Risk of Psychosis. Schizophrenia Bulletin. 2025 Dec;sbaf231.
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BACKGROUND: Brain volume alterations in those at clinical high risk (CHR) of psychosis have been reported in many studies. However, the association between these alterations and the longitudinal trajectory of changes in symptoms and functioning remains unexplored. STUDY DESIGN: T1-weighted magnetic resonance imaging (MRI) scans were acquired from 226 CHR and 65 healthy controls (HC) recruited from the EU-GEI high-risk study. Five a priori regions of interest were examined and segmented using FreeSurfer: total gray matter (GM) volume, anterior cingulate cortex (ACC), hippocampus, fusiform gyri, and insula. Brain volumes in the CHR and HC groups were compared at baseline. In the CHR group, linear mixed models were used to investigate the association between baseline brain volume and longitudinal changes in positive symptoms, negative symptoms, and functioning over a 2-year follow-up period. We also compared CHR participants who later transitioned to psychosis (CHR-T, n = 48) and those who did not (CHR-NT, n = 178) in terms of their trajectory of symptoms and functioning. STUDY RESULTS: Compared with HC, CHR participants had lower total GM and fusiform volume at baseline. Lower total GM and hippocampus volume at baseline were associated with higher levels of positive symptoms at baseline and follow-up in CHR individuals, and lower baseline hippocampus volume also predicted future transition. CHR-T and CHR-NT individuals demonstrated distinct symptoms and functioning trajectories over time. CONCLUSION: Our findings suggest that CHR individuals show baseline differences in brain structure compared to HC, which may also predict changes in positive symptoms over the subsequent 2 years.
- Sprüngli-Toffel E, Studerus E, Curtis L, Conchon C, Alameda L, Bailey B, et al. Individualized pretest risk estimates to guide treatment decisions in patients with clinical high risk for psychotic disorders. Spanish Journal of Psychiatry and Mental Health. 2025;18(2):133–40.
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INTRODUCTION: Clinical high risk for psychosis (CHR) states are associated with an increased risk of transition to psychosis. However, the predictive value of CHR screening interviews is dependent on pretest risk enrichment in referred patients. This poses a major obstacle to CHR outreach campaigns since they invariably lead to risk dilution through enhanced awareness. A potential compensatory strategy is to use estimates of individual pretest risk as a 'gatekeeper' for specialized assessment. We aimed to test a risk stratification model previously developed in London, UK (OASIS) and to train a new predictive model for the Swiss population. METHOD: The sample was composed of 513 individuals referred for CHR assessment from six Swiss early psychosis detection services. Sociodemographic variables available at referral were used as predictors whereas the outcome variable was transition to psychosis. RESULTS: Replication of the risk stratification model developed in OASIS resulted in poor performance (Harrel's c=0.51). Retraining resulted in moderate discrimination (Harrel's c=0.67) which significantly differentiated between different risk groups. The lowest risk group had a cumulative transition incidence of 6.4% (CI: 0-23.1%) over two years. CONCLUSION: Failure to replicate the OASIS risk stratification model might reflect differences in the public health care systems and referral structures between Switzerland and London. Retraining resulted in a model with adequate discrimination performance. The developed model in combination with CHR assessment result, might be useful for identifying individuals with high pretest risk, who might benefit most from specialized intervention.
- Koutsouleris N, Buciuman MO, Vetter C, Bajrić A, Weyer C, Perdomo ST, et al. Multimodal biological profiles of symptom-based subgroups in recent-onset psychosis. Research Square. 2025 Oct;rs.3.rs-7867983.
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Symptom diversity in psychoses complicates the search for biological markers. Using Positive and Negative Symptom Scale data from 362 recent-onset patients in the multicenter PRONIA study, we identified four subgroups with dominant symptom patterns: motor/cognitive, positive, social withdrawal, and affective. Subgroups were compared against each other and to 338 healthy controls across neurocognition, brain imaging, and genetic risk. Patient subgroups shared a profile of impaired processing speed and altered functional connectivity, with increased coupling in sensorimotor networks and reduced connectivity within and between default-mode, salience, and control networks. Variations in modality-specific neurobiological underpinnings differentiated subgroups, with fronto-temporal gray-matter loss characterizing the motor/cognitive and positive subgroups, and elevated genetic risk best separating the positive subgroup from the rest. The motor/cognitive group showed the most severe alterations across modalities, reaching the highest multimodal separability from controls (Balanced Accuracy=82.1%, sensitivity=74.9%, specificity=89.3%). Our findings support a framework of shared biological dysfunction with modality-selective vulnerabilities shaping symptom heterogeneity in early-stage psychotic disorders.
- Howard LM, Wilson CA, Reilly TJ, Moss KM, Mishra GD, Coupland-Smith E, et al. Women’s reproductive mental health: currently available evidence and future directions for research, clinical practice and health policy. World Psychiatry: Official Journal of the World Psychiatric Association. 2025 Jun;24(2):196–215.
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Sex and gender differences in the epidemiology of mental disorders are well documented. Less well understood are the drivers of these differences. Reproductive health represents one of the gendered determinants of mental health that may affect women throughout their life course. In this paper, we review common reproductive events that may be associated with mental ill health, including menstruation (with premenstrual dysphoric disorder appearing for the first time in recent classifications of mental disorders), contraception, abortion, sexual dysfunction, hypersexuality, sexual violence, reproductive coercion, infertility and associated gynaecological conditions, and menopause. Such reproductive events may differentially affect women globally via a range of potential biological and psychosocial mechanisms. These include, for example, vulnerability to the physiological changes in hormone levels across the menstrual cycle; side effects of treatment of mental disorders; inflammation underpinning endometriosis and polycystic ovarian syndrome as well as mental disorders such as depression; intersections with gender disadvantage manifesting, for example, as structural barriers in accessing menstrual products and sanitation, contraception and abortion, underscoring the broader social determinants impacting women's mental health. Greater understanding of these mechanisms is guiding the development of effective interventions, which are also reviewed here. However, key evidence gaps remain, partly as a result of the historic gender bias in mental health research, and the neglect of reproductive health in clinical practice. Furthermore, while several women's health strategies have recently been proposed internationally, they do not usually include a focus on mental health across the life course, particularly for women with severe mental illness. Integrating co-designed reproductive health interventions into primary and secondary mental health care settings, providing tailored care, increasing the evidence base on effective interventions, and empowering women to make informed choices about their reproductive health, could improve not only reproductive health but also women's mental health across the life course.
2024
- Formica MJC, Fuller-Tyszkiewicz M, Reininghaus U, Kempton M, Delespaul P, de Haan L, et al. Associations between disturbed sleep and attenuated psychotic experiences in people at clinical high risk for psychosis. Psychological Medicine. 2024 Jul;54(9):2254–63.
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BACKGROUND: Pre-diagnostic stages of psychotic illnesses, including 'clinical high risk' (CHR), are marked by sleep disturbances. These sleep disturbances appear to represent a key aspect in the etiology and maintenance of psychotic disorders. We aimed to examine the relationship between self-reported sleep dysfunction and attenuated psychotic symptoms (APS) on a day-to-day basis. METHODS: Seventy-six CHR young people completed the Experience Sampling Methodology (ESM) component of the European Union Gene-Environment Interaction Study, collected through PsyMate® devices, prompting sleep and symptom questionnaires 10 times daily for 6 days. Bayesian multilevel mixed linear regression analyses were performed on time-variant ESM data using the brms package in R. We investigated the day-to-day associations between sleep and psychotic experiences bidirectionally on an item level. Sleep items included sleep onset latency, fragmentation, and quality. Psychosis items assessed a range of perceptual, cognitive, and bizarre thought content common in the CHR population. RESULTS: Two of the seven psychosis variables were unidirectionally predicted by previous night's number of awakenings: every unit increase in number of nightly awakenings predicted a 0.27 and 0.28 unit increase in feeling unreal or paranoid the next day, respectively. No other sleep variables credibly predicted next-day psychotic symptoms or vice-versa. CONCLUSION: In this study, the relationship between sleep disturbance and APS appears specific to the item in question. However, some APS, including perceptual disturbances, had low levels of endorsement amongst this sample. Nonetheless, these results provide evidence for a unidirectional relationship between sleep and some APS in this population.
- Pinto da Costa M, Galderisi S, Herrman H, Riecher-Rössler A, Wasserman D. Breaking barriers in the career development of women in academic psychiatry. BJPsych open. 2024 Nov;10(6):e208.
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Academic psychiatry is essential for advancing mental health understanding and treatments. However, women encounter more obstacles hindering their progress in academia than men. This Editorial aims to highlight these obstacles and propose strategies to address them, advocating for a more supportive environment for women psychiatrists' ongoing growth and development. The importance of supportive environments, fair access to opportunities and structural changes, including initiatives for mentorship, funding and flexible work arrangements, are crucial. Collaboration among governments, institutions and organisations is needed to enhance research infrastructure and promote gender equality. Encouraging and recognising women's contributions in research fosters inclusivity and innovation. Prioritising these efforts is vital for the existence, well-being and success of women in academic psychiatry.
- Hartmann S, Dwyer D, Cavve B, Byrne EM, Scott I, Gao C, et al. Development and temporal validation of a clinical prediction model of transition to psychosis in individuals at ultra-high risk in the UHR 1000+ cohort. World Psychiatry: Official Journal of the World Psychiatric Association. 2024 Oct;23(3):400–10.
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The concept of ultra-high risk for psychosis (UHR) has been at the forefront of psychiatric research for several decades, with the ultimate goal of preventing the onset of psychotic disorder in high-risk individuals. Orygen (Melbourne, Australia) has led a range of observational and intervention studies in this clinical population. These datasets have now been integrated into the UHR 1000+ cohort, consisting of a sample of 1,245 UHR individuals with a follow-up period ranging from 1 to 16.7 years. This paper describes the cohort, presents a clinical prediction model of transition to psychosis in this cohort, and examines how predictive performance is affected by changes in UHR samples over time. We analyzed transition to psychosis using a Cox proportional hazards model. Clinical predictors for transition to psychosis were investigated in the entire cohort using multiple imputation and Rubin's rule. To assess performance drift over time, data from 1995-2016 were used for initial model fitting, and models were subsequently validated on data from 2017-2020. Over the follow-up period, 220 cases (17.7%) developed a psychotic disorder. Pooled hazard ratio (HR) estimates showed that the Comprehensive Assessment of At-Risk Mental States (CAARMS) Disorganized Speech subscale severity score (HR=1.12, 95% CI: 1.02-1.24, p=0.024), the CAARMS Unusual Thought Content subscale severity score (HR=1.13, 95% CI: 1.03-1.24, p=0.009), the Scale for the Assessment of Negative Symptoms (SANS) total score (HR=1.02, 95% CI: 1.00-1.03, p=0.022), the Social and Occupational Functioning Assessment Scale (SOFAS) score (HR=0.98, 95% CI: 0.97-1.00, p=0.036), and time between onset of symptoms and entry to UHR service (log transformed) (HR=1.10, 95% CI: 1.02-1.19, p=0.013) were predictive of transition to psychosis. UHR individuals who met the brief limited intermittent psychotic symptoms (BLIPS) criteria had a higher probability of transitioning to psychosis than those who met the attenuated psychotic symptoms (APS) criteria (HR=0.48, 95% CI: 0.32-0.73, p=0.001) and those who met the Trait risk criteria (a first-degree relative with a psychotic disorder or a schizotypal personality disorder plus a significant decrease in functioning during the previous year) (HR=0.43, 95% CI: 0.22-0.83, p=0.013). Models based on data from 1995-2016 displayed good calibration at initial model fitting, but showed a drift of 20.2-35.4% in calibration when validated on data from 2017-2020. Large-scale longitudinal data such as those from the UHR 1000+ cohort are required to develop accurate psychosis prediction models. It is critical to assess existing and future risk calculators for temporal drift, that may reduce their utility in clinical practice over time.
- Riecher-Rössler A. Development of the PSYCHS - A great step forward! Early Intervention in Psychiatry. 2024 Apr;18(4):286–7.
- Koutsouleris N, Buciuman MO, Vetter CS, Weyer CFC, Zhutovsky P, Perdomo ST, et al. Distinct multimodal biological and functional profiles of symptom-based subgroups in recent-onset psychosis. Research Square. 2024 Mar;rs.3.rs-3949072.
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Symptom heterogeneity characterizes psychotic disorders and hinders the delineation of underlying biomarkers. Here, we identify symptom-based subtypes of recent-onset psychosis (ROP) patients from the multi-center PRONIA (Personalized Prognostic Tools for Early Psychosis Management) database and explore their multimodal biological and functional signatures. We clustered N = 328 ROP patients based on their maximum factor scores in an exploratory factor analysis on the Positive and Negative Syndrome Scale items. We assessed inter-subgroup differences and compared to N = 464 healthy control (HC) individuals regarding gray matter volume (GMV), neurocognition, polygenic risk scores, and longitudinal functioning trajectories. Finally, we evaluated factor stability at 9- and 18-month follow-ups. A 4-factor solution optimally explained symptom heterogeneity, showing moderate longitudinal stability. The ROP-MOTCOG (Motor/Cognition) subgroup was characterized by GMV reductions within salience, control and default mode networks, predominantly throughout cingulate regions, relative to HC individuals, had the most impaired neurocognition and the highest genetic liability for schizophrenia. ROP-SOCWD (Social Withdrawal) patients showed GMV reductions within medial fronto-temporal regions of the control, default mode, and salience networks, and had the lowest social functioning across time points. ROP-POS (Positive) evidenced GMV decreases in salience, limbic and frontal regions of the control and default mode networks. The ROP-AFF (Affective) subgroup showed GMV reductions in the salience, limbic, and posterior default-mode and control networks, thalamus and cerebellum. GMV reductions in fronto-temporal regions of the salience and control networks were shared across subgroups. Our results highlight the existence of behavioral subgroups with distinct neurobiological and functional profiles in early psychosis, emphasizing the need for refined symptom-based diagnosis and prognosis frameworks.
- Riecher-Rössler A. Oestrogens and Mental Health. Archives of Women’s Mental Health. 2024 Dec;27(6):869–70.
- Iseli GC, Ulrich S, Stämpfli P, Studerus E, Coynel D, Riecher-Rössler A, et al. Parsing heterogeneity in global and local white matter integrity at different stages across the psychosis continuum. Schizophrenia. 2024 Nov;10(1):106.
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Psychosis progresses along a continuum. While heterogeneity is evident across the continuum, it remains unknown whether this is also reflected in white matter (WM) heterogeneity and whether parsing WM heterogeneity may reveal subgroups with more pronounced clinical features. This analysis included 212 participants consisting of healthy controls (HC, n = 59), individuals with high schizotypy (SPT, n = 27), at-risk mental state (ARMS, n = 35), and patients with first episode psychosis (FEP, n = 50) and schizophrenia (SZ, n = 41). Fractional anisotropy (FA) and mean diffusivity (MD) were derived from diffusion tensor imaging (DTI), and fibre density (FD), a non-tensor-derived diffusion marker, was computed. The Person-Based-Similarity Index (PBSI) and Coefficient of Variation Ratio (CVR) were computed to assess global and local heterogeneity. ANOVAs were performed to determine whether people with deviating PBSIs exhibit more pronounced clinical features. Global heterogeneity for all diffusion parameters significantly differed across groups, with greatest difference in heterogeneity between SZ and HC. Results further indicate that FA deviators exhibit lower global functioning and higher negative symptoms. Local FA heterogeneity was greater in FEP relative to ARMS and HC in almost all WM tracts, while SZ patients specifically showed greater heterogeneity in the right thalamic radiation and the left uncinate compared to HCs. Group differences in WM heterogeneity might be indicative of symptom specificity and duration. While these findings offer valuable insights into the neurobiological variability of psychosis, they are primarily hypothesis-generating. Future large-scale studies are warranted to test the robustness of diffusion markers and their clinical relevance.
- Byrne JF, Healy C, Föcking M, Susai SR, Mongan D, Wynne K, et al. Proteomic Biomarkers for the Prediction of Transition to Psychosis in Individuals at Clinical High Risk: A Multi-cohort Model Development Study. Schizophrenia Bulletin. 2024 Apr;50(3):579–88.
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Psychosis risk prediction is one of the leading challenges in psychiatry. Previous investigations have suggested that plasma proteomic data may be useful in accurately predicting transition to psychosis in individuals at clinical high risk (CHR). We hypothesized that an a priori-specified proteomic prediction model would have strong predictive accuracy for psychosis risk and aimed to replicate longitudinal associations between plasma proteins and transition to psychosis. This study used plasma samples from participants in 3 CHR cohorts: the North American Prodrome Longitudinal Studies 2 and 3, and the NEURAPRO randomized control trial (total n = 754). Plasma proteomic data were quantified using mass spectrometry. The primary outcome was transition to psychosis over the study follow-up period. Logistic regression models were internally validated, and optimism-corrected performance metrics derived with a bootstrap procedure. In the overall sample of CHR participants (age: 18.5, SD: 3.9; 51.9% male), 20.4% (n = 154) developed psychosis within 4.4 years. The a priori-specified model showed poor risk-prediction accuracy for the development of psychosis (C-statistic: 0.51 [95% CI: 0.50, 0.59], calibration slope: 0.45). At a group level, Complement C8B, C4B, C5, and leucine-rich α-2 glycoprotein 1 (LRG1) were associated with transition to psychosis but did not surpass correction for multiple comparisons. This study did not confirm the findings from a previous proteomic prediction model of transition from CHR to psychosis. Certain complement proteins may be weakly associated with transition at a group level. Previous findings, derived from small samples, should be interpreted with caution.
- See CRZ, Si S, Hedges E, Tognin S, Modinos G, van der Gaag M, et al. The effects of recent stressful life events on outcomes in individuals at clinical high risk for psychosis: results from the longitudinal EU-GEI high-risk study. Psychological Medicine. 2024 Dec;54(16):4768–78.
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BACKGROUND: Recent stressful life events (SLE) are a risk factor for psychosis, but limited research has explored how SLEs affect individuals at clinical high risk (CHR) for psychosis. The current study investigated the longitudinal effects of SLEs on functioning and symptom severity in CHR individuals, where we hypothesized CHR would report more SLEs than healthy controls (HC), and SLEs would be associated with poorer outcomes. METHODS: The study used longitudinal data from the EU-GEI High Risk study. Data from 331 CHR participants were analyzed to examine the effects of SLEs on changes in functioning, positive and negative symptoms over a 2-year follow-up. We compared the prevalence of SLEs between CHR and HCs, and between CHR who did (CHR-T) and did not (CHR-NT) transition to psychosis. RESULTS: CHR reported 1.44 more SLEs than HC (p < 0.001), but there was no difference in SLEs between CHR-T and CHR-NT at baseline. Recent SLEs were associated with poorer functioning and more severe positive and negative symptoms in CHR individuals (all p < 0.01) but did not reveal a significant interaction with time. CONCLUSIONS: CHR individuals who had experienced recent SLEs exhibited poorer functioning and more severe symptoms. However, as the interaction between SLEs and time was not significant, this suggests SLEs did not contribute to a worsening of symptoms and functioning over the study period. SLEs could be a key risk factor to becoming CHR for psychosis, however further work is required to inform when early intervention strategies mitigating against the effects of stress are most effective.
2023
- Korda AI, Andreou C, Avram M, Frisman M, Aliqadri M, Riecher-Rössler A, et al. Chaos analysis of the cortical boundary for the recognition of psychosis. Journal of psychiatry & neuroscience: JPN. 2023;48(2):E135–42.
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BACKGROUND: Structural MRI studies in people with first-episode psychosis (FEP) and those in the clinical high-risk (CHR) state have consistently shown volumetric abnormalities that depict changes in the structural complexity of the cortical boundary. The aim of the present study was to employ chaos analysis in the identification of people with psychosis based on the structural complexity of the cortical boundary and subcortical areas. METHODS: We performed chaos analysis of the grey matter distribution on structural MRIs. First, the outer boundary points for each slice in the axial, coronal and sagittal view were calculated for grey matter maps. Next, the distance of each boundary point from the centre of mass in the grey matter was calculated and stored as spatial series, which was further analyzed by extracting the Largest Lyapunov Exponent (lambda [λ]), a feature depicting the structural complexity of the cortical boundary. RESULTS: Structural MRIs were acquired from 77 FEP, 73 CHR and 44 healthy controls. We compared λ brain maps between groups, which resulted in statistically significant differences in all comparisons. By matching the λ values extracted in axial view with the Morlet wavelet, differences on the surface relief are observed between groups. LIMITATIONS: Parameters were selected after experimentation on the examined sample. Investigation of the effectiveness of the method in a larger data set is needed. CONCLUSION: The proposed framework using spatial series verifies diagnosis-relevant features and may contribute to the identification of structural biomarkers for psychosis.
- Tognin S, Catalan A, Kempton MJ, Nelson B, McGorry P, Riecher-Rössler A, et al. Impact of adverse childhood experiences on educational achievements in young people at clinical high risk of developing psychosis. European Psychiatry: The Journal of the Association of European Psychiatrists. 2023 Jan;66(1):e16.
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BACKGROUND: Adverse childhood experiences (ACE) can affect educational attainments, but little is known about their impact on educational achievements in people at clinical high risk of psychosis (CHR). METHODS: In total, 344 CHR individuals and 67 healthy controls (HC) were recruited as part of the European Community's Seventh Framework Programme-funded multicenter study the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI). The brief version of the Child Trauma Questionnaire was used to measure ACE, while educational attainments were assessed using a semi-structured interview. RESULTS: At baseline, compared with HC, the CHR group spent less time in education and had higher rates of ACE, lower rates of employment, and lower estimated intelligence quotient (IQ). Across both groups, the total number of ACE was associated with fewer days in education and lower level of education. Emotional abuse was associated with fewer days in education in HC. Emotional neglect was associated with a lower level of education in CHR, while sexual abuse was associated with a lower level of education in HC. In the CHR group, the total number of ACE, physical abuse, and neglect was significantly associated with unemployment, while emotional neglect was associated with employment. CONCLUSIONS: ACE are strongly associated with developmental outcomes such as educational achievement. Early intervention for psychosis programs should aim at integrating specific interventions to support young CHR people in their educational and vocational recovery. More generally, public health and social interventions focused on the prevention of ACE (or reduce their impact if ACE occur) are recommended.
- Chester LA, Valmaggia LR, Kempton MJ, Chesney E, Oliver D, Hedges EP, et al. Influence of cannabis use on incidence of psychosis in people at clinical high risk. Psychiatry and Clinical Neurosciences. 2023 Sep;77(9):469–77.
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AIMS: Evidence for case-control studies suggests that cannabis use is a risk factor for the development of psychosis. However, there have been limited prospective studies and the direction of this association remains controversial. The primary aim of the present study was to examine the association between cannabis use and the incidence of psychotic disorders in people at clinical high risk of psychosis. Secondary aims were to assess associations between cannabis use and the persistence of psychotic symptoms, and with functional outcome. METHODS: Current and previous cannabis use were assessed in individuals at clinical high risk of psychosis (n = 334) and healthy controls (n = 67), using a modified version of the Cannabis Experience Questionnaire. Participants were assessed at baseline and followed up for 2 years. Transition to psychosis and persistence of psychotic symptoms were assessed using the Comprehensive Assessment of At-Risk Mental States criteria. Level of functioning at follow up was assessed using the Global Assessment of Functioning disability scale. RESULTS: During follow up, 16.2% of the clinical high-risk sample developed psychosis. Of those who did not become psychotic, 51.4% had persistent symptoms and 48.6% were in remission. There was no significant association between any measure of cannabis use at baseline and either transition to psychosis, the persistence of symptoms, or functional outcome. CONCLUSIONS: These findings contrast with epidemiological data that suggest that cannabis use increases the risk of psychotic disorder.
- Stainton A, Chisholm K, Griffiths SL, Kambeitz-Ilankovic L, Wenzel J, Bonivento C, et al. Prevalence of cognitive impairments and strengths in the early course of psychosis and depression. Psychological Medicine. 2023 Oct;53(13):5945–57.
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BACKGROUND: Studies investigating cognitive impairments in psychosis and depression have typically compared the average performance of the clinical group against healthy controls (HC), and do not report on the actual prevalence of cognitive impairments or strengths within these clinical groups. This information is essential so that clinical services can provide adequate resources to supporting cognitive functioning. Thus, we investigated this prevalence in individuals in the early course of psychosis or depression. METHODS: A comprehensive cognitive test battery comprising 12 tests was completed by 1286 individuals aged 15-41 (mean age 25.07, s.d. 5.88) from the PRONIA study at baseline: HC (N = 454), clinical high risk for psychosis (CHR; N = 270), recent-onset depression (ROD; N = 267), and recent-onset psychosis (ROP; N = 295). Z-scores were calculated to estimate the prevalence of moderate or severe deficits or strengths (>2 s.d. or 1-2 s.d. below or above HC, respectively) for each cognitive test. RESULTS: Impairment in at least two cognitive tests was as follows: ROP (88.3% moderately, 45.1% severely impaired), CHR (71.2% moderately, 22.4% severely impaired), ROD (61.6% moderately, 16.2% severely impaired). Across clinical groups, impairments were most prevalent in tests of working memory, processing speed, and verbal learning. Above average performance (>1 s.d.) in at least two tests was present for 40.5% ROD, 36.1% CHR, 16.1% ROP, and was >2 SDs in 1.8% ROD, 1.4% CHR, and 0% ROP. CONCLUSIONS: These findings suggest that interventions should be tailored to the individual, with working memory, processing speed, and verbal learning likely to be important transdiagnostic targets.
- Mondelli V, Blackman G, Kempton MJ, Pollak TA, Iyegbe C, Valmaggia LR, et al. Serum immune markers and transition to psychosis in individuals at clinical high risk. Brain, Behavior, and Immunity. 2023 May;110:290–6.
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Individuals at clinical high risk (CHR) for psychosis have been found to have altered cytokine levels, but whether these changes are related to clinical outcomes remains unclear. We addressed this issue by measuring serum levels of 20 immune markers in 325 participants (n = 269 CHR, n = 56 healthy controls) using multiplex immunoassays, and then followed up the CHR sample to determine their clinical outcomes. Among 269 CHR individuals, 50 (18.6 %) developed psychosis by two years. Univariate and machine learning techniques were used to compare levels of inflammatory markers in CHR subjects and healthy controls, and in CHR subjects who had (CHR-t), or had not (CHR-nt) transitioned to psychosis. An ANCOVA identified significant group differences (CHR-t, CHR-nt and controls) and post-hoc tests indicated that VEGF levels and the IL-10/IL-6 ratio were significantly higher in CHR-t than CHR-nt, after adjusting for multiple comparisons. Using a penalised logistic regression classifier, CHR participants were distinguished from controls with an area-under the curve (AUC) of 0.82, with IL-6 and IL-4 levels the most important discriminating features. Transition to psychosis was predicted with an AUC of 0.57, with higher VEGF level and IL-10/IL-6 ratio the most important discriminating features. These data suggest that alterations in the levels of peripheral immune markers are associated with the subsequent onset of psychosis. The association with increased VEGF levels could reflect altered blood-brain-barrier (BBB) permeability, while the link with an elevated IL-10/IL-6 ratio points to an imbalance between anti- and pro-inflammatory cytokines.
- Buciuman MO, Oeztuerk OF, Popovic D, Enrico P, Ruef A, Bieler N, et al. Structural and Functional Brain Patterns Predict Formal Thought Disorder’s Severity and Its Persistence in Recent-Onset Psychosis: Results From the PRONIA Study. Biological Psychiatry Cognitive Neuroscience and Neuroimaging. 2023 Dec;8(12):1207–17.
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BACKGROUND: Formal thought disorder (FThD) is a core feature of psychosis, and its severity and long-term persistence relates to poor clinical outcomes. However, advances in developing early recognition and management tools for FThD are hindered by a lack of insight into the brain-level predictors of FThD states and progression at the individual level. METHODS: Two hundred thirty-three individuals with recent-onset psychosis were drawn from the multisite European Prognostic Tools for Early Psychosis Management study. Support vector machine classifiers were trained within a cross-validation framework to separate two FThD symptom-based subgroups (high vs. low FThD severity), using cross-sectional whole-brain multiband fractional amplitude of low frequency fluctuations, gray matter volume and white matter volume data. Moreover, we trained machine learning models on these neuroimaging readouts to predict the persistence of high FThD subgroup membership from baseline to 1-year follow-up. RESULTS: Cross-sectionally, multivariate patterns of gray matter volume within the salience, dorsal attention, visual, and ventral attention networks separated the FThD severity subgroups (balanced accuracy [BAC] = 60.8%). Longitudinally, distributed activations/deactivations within all fractional amplitude of low frequency fluctuation sub-bands (BACslow-5 = 73.2%, BACslow-4 = 72.9%, BACslow-3 = 68.0%), gray matter volume patterns overlapping with the cross-sectional ones (BAC = 62.7%), and smaller frontal white matter volume (BAC = 73.1%) predicted the persistence of high FThD severity from baseline to follow-up, with a combined multimodal balanced accuracy of BAC = 77%. CONCLUSIONS: We report the first evidence of brain structural and functional patterns predictive of FThD severity and persistence in early psychosis. These findings open up avenues for the development of neuroimaging-based diagnostic, prognostic, and treatment options for the early recognition and management of FThD and associated poor outcomes.
- Theisen C, Rosen M, Meisenzahl E, Koutsouleris N, Lichtenstein T, Ruhrmann S, et al. The heterogeneity of attenuated and brief limited psychotic symptoms: association of contents with age, sex, country, religion, comorbidities, and functioning. Frontiers in Psychiatry. 2023;14:1209485.
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INTRODUCTION: The Attenuated Psychosis Symptoms (APS) syndrome mostly represents the ultra-high-risk state of psychosis but, as does the Brief Intermittent Psychotic Symptoms (BIPS) syndrome, shows a large variance in conversion rates. This may be due to the heterogeneity of APS/BIPS that may be related to the effects of culture, sex, age, and other psychiatric morbidities. Thus, we investigated the different thematic contents of APS and their association with sex, age, country, religion, comorbidity, and functioning to gain a better understanding of the psychosis-risk syndrome. METHOD: A sample of 232 clinical high-risk subjects according to the ultra-high risk and basic symptom criteria was recruited as part of a European study conducted in Germany, Italy, Switzerland, and Finland. Case vignettes, originally used for supervision of inclusion criteria, were investigated for APS/BIPS contents, which were compared for sex, age, country, religion, functioning, and comorbidities using chi-squared tests and regression analyses. RESULT: We extracted 109 different contents, mainly of APS (96.8%): 63 delusional, 29 hallucinatory, and 17 speech-disorganized contents. Only 20 contents (18.3%) were present in at least 5% of the sample, with paranoid and referential ideas being the most frequent. Thirty-one (28.5%) contents, in particular, bizarre ideas and perceptual abnormalities, demonstrated an association with age, country, comorbidity, or functioning, with regression models of country and obsessive-compulsive disorders explaining most of the variance: 55.8 and 38.3%, respectively. Contents did not differ between religious groups. CONCLUSION: Psychosis-risk patients report a wide range of different contents of APS/BIPS, underlining the psychopathological heterogeneity of this group but also revealing a potential core set of contents. Compared to earlier reports on North-American samples, our maximum prevalence rates of contents were considerably lower; this likely being related to a stricter rating of APS/BIPS and cultural influences, in particular, higher schizotypy reported in North-America. The various associations of some APS/BIPS contents with country, age, comorbidities, and functioning might moderate their clinical severity and, consequently, the related risk for psychosis and/or persistent functional disability.
- Kilic O, Riecher-Rössler A, Galderisi S, Gorwood P, Frangou S, Pinto da Costa M. The role of gender as a barrier to the professional development of psychiatrists. European Psychiatry: The Journal of the Association of European Psychiatrists. 2023 Oct;66(1):e89.
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BACKGROUND: Despite efforts toward greater gender equality in clinical and academic psychiatry in recent years, more information is needed about the challenges in professional development within psychiatry, and how these may vary with gender. METHODS: A cross-sectional 27-item online survey was conducted with psychiatrists and psychiatric trainee members of the European Psychiatric Association. RESULTS: A total of 561 psychiatrists and psychiatric trainees from 35 European countries participated representing a response rate of 52.8% for women and 17.7% for men from a total sample of 1,580. The specific challenges that women face in their professional development fall into two categories. One comprised women's negative attitudes concerning their abilities in self-promotion and networking. The other identified environmental barriers related to lack of opportunity and support and gender discrimination. Compared to men, women reported higher rates of gender discrimination in terms of professional advancement. Women were less likely to agree that their institutions had regular activities promoting inclusion, diversity, and training to address implicit gender bias. Working in high-income countries compared to middle-income countries relates to reporting institutional support for career progression. CONCLUSIONS: These findings are an open call to hospital leaders, deans of medical schools, and department chairs to increase efforts to eradicate bias against women and create safer, inclusive, and respectful environments for all psychiatrists, a special call to women psychiatrists to be aware of inner tendencies to avoid self-promotion and networking and to think positively and confidently about themselves and their abilities.
2022
- Dwyer DB, Buciuman MO, Ruef A, Kambeitz J, Sen Dong M, Stinson C, et al. Clinical, Brain, and Multilevel Clustering in Early Psychosis and Affective Stages. JAMA psychiatry. 2022 Jul;79(7):677–89.
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IMPORTANCE: Approaches are needed to stratify individuals in early psychosis stages beyond positive symptom severity to investigate specificity related to affective and normative variation and to validate solutions with premorbid, longitudinal, and genetic risk measures. OBJECTIVE: To use machine learning techniques to cluster, compare, and combine subgroup solutions using clinical and brain structural imaging data from early psychosis and depression stages. DESIGN, SETTING, AND PARTICIPANTS: A multisite, naturalistic, longitudinal cohort study (10 sites in 5 European countries; including major follow-up intervals at 9 and 18 months) with a referred patient sample of those with clinical high risk for psychosis (CHR-P), recent-onset psychosis (ROP), recent-onset depression (ROD), and healthy controls were recruited between February 1, 2014, to July 1, 2019. Data were analyzed between January 2020 and January 2022. MAIN OUTCOMES AND MEASURES: A nonnegative matrix factorization technique separately decomposed clinical (287 variables) and parcellated brain structural volume (204 gray, white, and cerebrospinal fluid regions) data across CHR-P, ROP, ROD, and healthy controls study groups. Stability criteria determined cluster number using nested cross-validation. Validation targets were compared across subgroup solutions (premorbid, longitudinal, and schizophrenia polygenic risk scores). Multiclass supervised machine learning produced a transferable solution to the validation sample. RESULTS: There were a total of 749 individuals in the discovery group and 610 individuals in the validation group. Individuals included those with CHR-P (n = 287), ROP (n = 323), ROD (n = 285), and healthy controls (n = 464), The mean (SD) age was 25.1 (5.9) years, and 702 (51.7%) were female. A clinical 4-dimensional solution separated individuals based on positive symptoms, negative symptoms, depression, and functioning, demonstrating associations with all validation targets. Brain clustering revealed a subgroup with distributed brain volume reductions associated with negative symptoms, reduced performance IQ, and increased schizophrenia polygenic risk scores. Multilevel results distinguished between normative and illness-related brain differences. Subgroup results were largely validated in the external sample. CONCLUSIONS AND RELEVANCE: The results of this longitudinal cohort study provide stratifications beyond the expression of positive symptoms that cut across illness stages and diagnoses. Clinical results suggest the importance of negative symptoms, depression, and functioning. Brain results suggest substantial overlap across illness stages and normative variation, which may highlight a vulnerability signature independent from specific presentations. Premorbid, longitudinal, and genetic risk validation suggested clinical importance of the subgroups to preventive treatments.
- Schirmbeck F, van der Ven E, Boyette LL, McGuire P, Valmaggia LR, Kempton MJ, et al. Differential trajectories of tobacco smoking in people at ultra-high risk for psychosis: Associations with clinical outcomes. Frontiers in Psychiatry. 2022;13:869023.
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OBJECTIVE: People at ultra-high risk (UHR) for psychosis have a high prevalence of tobacco smoking, and rates are even higher among the subgroup that later develop a psychotic disorder. However, the longitudinal relationship between the course of tobacco smoking and clinical outcomes in UHR subjects is unknown. METHODS: We investigated associations between tobacco smoking and clinical outcomes in a prospective study of UHR individuals (n = 324). Latent class mixed model analyses were used to identify trajectories of smoking severity. Mixed effects models were applied to investigate associations between smoking trajectory class and the course of attenuated psychotic symptoms (APS) and affective symptoms, as assessed using the CAARMS. RESULTS: We identified four different classes of smoking trajectory: (i) Persistently High (n = 110), (ii) Decreasing (n = 29), (iii) Persistently Low (n = 165) and (iv) Increasing (n = 20). At two-year follow-up, there had been a greater increase in APS in the Persistently High class than for both the Persistently Low (ES = 9.77, SE = 4.87, p = 0.046) and Decreasing (ES = 18.18, SE = 7.61, p = 0.018) classes. There were no differences between smoking classes in the incidence of psychosis. There was a greater reduction in the severity of emotional disturbance and general symptoms in the Decreasing class than in the High (ES = -10.40, SE = 3.41, p = 0.003; ES = -22.36, SE = 10.07, p = 0.027), Increasing (ES = -11.35, SE = 4.55, p = 0.014; ES = -25.58, SE = 13.17, p = 0.050) and Low (ES = -11.38, SE = 3.29, p = 0.001; ES = -27.55, SE = 9.78, p = 0.005) classes, respectively. CONCLUSIONS: These findings suggests that in UHR subjects persistent tobacco smoking is associated with an unfavorable course of psychotic symptoms, whereas decrease in the number of cigarettes smoked is associated with improvement in affective symptoms. Future research into smoking cessation interventions in the early stages of psychoses is required to shine light on the potential of modifying smoking behavior and its relation to clinical outcomes.
- Nelson B, Yuen HP, Amminger GP, Berger G, Chen EYH, de Haan L, et al. Distress Related to Attenuated Psychotic Symptoms: Static and Dynamic Association With Transition to Psychosis, Nonremission, and Transdiagnostic Symptomatology in Clinical High-Risk Patients in an International Intervention Trial. Schizophrenia Bulletin Open. 2022 Jan;3(1):sgaa006.
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This study examined whether distress in relation to attenuated psychotic symptoms (DAPS) is associated with clinical outcomes in an ultra-high risk (UHR) for psychosis sample. We also investigated whether DAPS is associated with cognitive style (attributional style and cognitive biases) and whether amount of psychosocial treatment provided is associated with reduction in DAPS. The study was a secondary analysis of the "Neurapro" clinical trial of omega-3 fatty acids. Three hundred and four UHR patients were recruited across 10 early intervention services. Data from baseline assessment, regular assessments over 12 months, and medium term follow-up (mean = 3.4 years) were used for analysis. Findings indicated: a positive association between DAPS assessed over time and transition to psychosis; a significant positive association between baseline and longitudinal DAPS and transdiagnostic clinical and functional outcomes; a significant positive association between baseline and longitudinal DAPS and nonremission of UHR status. There was no relationship between severity of DAPS and cognitive style. A greater amount of psychosocial treatment (cognitive-behavioral case management) was associated with an increase in DAPS scores. The study indicates that UHR patients who are more distressed by their attenuated psychotic symptoms are more likely to have a poorer clinical trajectory transdiagnostically. Assessment of DAPS may therefore function as a useful marker of risk for a range of poor outcomes. The findings underline the value of repeated assessment of variables and incorporation of dynamic change into predictive modeling. More research is required into mechanisms driving distress associated with symptoms and the possible bidirectional relationship between symptom severity and associated distress.
- Riecher-Rössler A. Editorial. Archives of Women’s Mental Health. 2022 Dec;25(6):1005.
- Barth C, Blokland GAM, Riecher-Rössler A. Editorial: Sex and the Suffering Brain - A Call for Sex-Stratified Analyses in Psychiatric Research. Frontiers in Psychiatry. 2022;13:849009.
- Riecher-Rössler A. Editorial: Women and the Pandemic. Archives of Women’s Mental Health. 2022 Apr;25(2):255–6.
- Cheng N, McLaverty A, Nelson B, Markulev C, Schäfer MR, Berger M, et al. Effects of omega-3 polyunsaturated fatty acid supplementation on cognitive functioning in youth at ultra-high risk for psychosis: secondary analysis of the NEURAPRO randomised controlled trial. BJPsych open. 2022 Sep;8(5):e165.
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BACKGROUND: Cognitive impairments are well-established features of psychotic disorders and are present when individuals are at ultra-high risk for psychosis. However, few interventions target cognitive functioning in this population. AIMS: To investigate whether omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementation improves cognitive functioning among individuals at ultra-high risk for psychosis. METHOD: Data (N = 225) from an international, multi-site, randomised controlled trial (NEURAPRO) were analysed. Participants were given omega-3 supplementation (eicosapentaenoic acid and docosahexaenoic acid) or placebo over 6 months. Cognitive functioning was assessed with the Brief Assessment of Cognition in Schizophrenia (BACS). Mixed two-way analyses of variance were computed to compare the change in cognitive performance between omega-3 supplementation and placebo over 6 months. An additional biomarker analysis explored whether change in erythrocyte n-3 PUFA levels predicted change in cognitive performance. RESULTS: The placebo group showed a modest greater improvement over time than the omega-3 supplementation group for motor speed (ηp2 = 0.09) and BACS composite score (ηp2 = 0.21). After repeating the analyses without individuals who transitioned, motor speed was no longer significant (ηp2 = 0.02), but the composite score remained significant (ηp2 = 0.02). Change in erythrocyte n-3 PUFA levels did not predict change in cognitive performance over 6 months. CONCLUSIONS: We found no evidence to support the use of omega-3 supplementation to improve cognitive functioning in ultra-high risk individuals. The biomarker analysis suggests that this finding is unlikely to be attributed to poor adherence or consumption of non-trial n-3 PUFAs.
- Susai SR, Healy C, Mongan D, Heurich M, Byrne JF, Cannon M, et al. Evidence that complement and coagulation proteins are mediating the clinical response to omega-3 fatty acids: A mass spectrometry-based investigation in subjects at clinical high-risk for psychosis. Translational Psychiatry. 2022 Oct;12(1):454.
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Preliminary evidence indicates beneficial effects of omega-3 polyunsaturated fatty acids (PUFAs) in early psychosis. The present study investigates the molecular mechanism of omega-3 PUFA-associated therapeutic effects in clinical high-risk (CHR) participants. Plasma samples of 126 CHR psychosis participants at baseline and 6-months follow-up were included. Plasma protein levels were quantified using mass spectrometry and erythrocyte omega-3 PUFA levels were quantified using gas chromatography. We examined the relationship between change in polyunsaturated PUFAs (between baseline and 6-month follow-up) and follow-up plasma proteins. Using mediation analysis, we investigated whether plasma proteins mediated the relationship between change in omega-3 PUFAs and clinical outcomes. A 6-months change in omega-3 PUFAs was associated with 24 plasma proteins at follow-up. Pathway analysis revealed the complement and coagulation pathway as the main biological pathway to be associated with change in omega-3 PUFAs. Moreover, complement and coagulation pathway proteins significantly mediated the relationship between change in omega-3 PUFAs and clinical outcome at follow-up. The inflammatory protein complement C5 and protein S100A9 negatively mediated the relationship between change in omega-3 PUFAs and positive symptom severity, while C5 positively mediated the relationship between change in omega-3 and functional outcome. The relationship between change in omega-3 PUFAs and cognition was positively mediated through coagulation factor V and complement protein C1QB. Our findings provide evidence for a longitudinal association of omega-3 PUFAs with complement and coagulation protein changes in the blood. Further, the results suggest that an increase in omega-3 PUFAs decreases symptom severity and improves cognition in the CHR state through modulating effects of complement and coagulation proteins.
- Schirmbeck F, van der Burg NC, Blankers M, Vermeulen JM, McGuire P, Valmaggia LR, et al. Impact of Comorbid Affective Disorders on Longitudinal Clinical Outcomes in Individuals at Ultra-high Risk for Psychosis. Schizophrenia Bulletin. 2022 Jan;48(1):100–10.
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INTRODUCTION: Diagnoses of anxiety and/or depression are common in subjects at Ultra-High Risk for Psychosis (UHR) and associated with extensive functional impairment. Less is known about the impact of affective comorbidities on the prospective course of attenuated psychotic symptoms (APS). METHOD: Latent class mixed modelling identified APS trajectories in 331 UHR subjects assessed at baseline, 6, 12, and 24 months follow-up. The prognostic value of past, baseline, and one-year DSM-IV depressive or anxiety disorders on trajectories was investigated using logistic regression, controlling for confounders. Cox proportional hazard analyses investigated associations with transition risk. RESULTS: 46.8% of participants fulfilled the criteria for a past depressive disorder, 33.2% at baseline, and 15.1% at one-year follow-up. Any past, baseline, or one-year anxiety disorder was diagnosed in 42.9%, 37.2%, and 27.0%, respectively. Participants were classified into one of three latent APS trajectory groups: (1) persistently low, (2) increasing, and (3) decreasing. Past depression was associated with a higher risk of belonging to the increasing trajectory group, compared to the persistently low (OR = 3.149, [95%CI: 1.298-7.642]) or decreasing group (OR = 3.137, [1.165-8.450]). In contrast, past (OR = .443, [.179-1.094]) or current (OR = .414, [.156-1.094]) anxiety disorders showed a trend-level association with a lower risk of belonging to the increasing group compared to the persistently low group. Past depression was significantly associated with a higher risk of transitioning to psychosis (HR = 2.123, [1.178-3.828]). CONCLUSION: A past depressive episode might be a particularly relevant risk factor for an unfavorable course of APS in UHR individuals. Early affective disturbances may be used to advance detection, prognostic, and clinical strategies.
- Hochstrasser L, Studerus E, Riecher-Rössler A, Schimmelmann BG, Lambert M, Lang UE, et al. Latent state-trait structure of BPRS subscales in clinical high-risk state and first episode psychosis. Scientific Reports. 2022 Apr;12(1):6652.
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To investigate the longitudinal latent state-trait structure of the different dimensions of psychosis symptoms in clinical high-risk state (CHRS) and first episode psychosis (FEP) individuals over a one year time-span. This paper examines if the symptom clusters Positive Symptoms, Negative Symptoms, Affectivity, Resistance, Activation, and Excitement according to the Brief Psychiatric Rating Scale (BPRS) differ in their trait and state characters in 196 CHRS and 131 FEP individuals. Statistical analysis was performed using latent state-trait analysis. On average, trait differences accounted for 72.2% of Positive Symptoms, 81.1% of Negative Symptoms, 57.0% of Affectivity, and 69.2% of Activation, whereas 15.0% of the variance of Resistance and 13.2% of the variance of Excitement were explained by trait differences. Explorative analyses showed a trait components' increase of 0.408 in Positive Symptoms from baseline up to the 9th month and an increase of 0.521 in Affectivity from baseline up to the 6th month. Negative Symptoms had the highest trait component levels of all subscales between baseline and 6 months. The finding that an increasing proportion of psychosis symptoms is persisting over time underlines the importance of early intervention programs in individuals with psychotic disorders.
- Susai SR, Mongan D, Healy C, Cannon M, Cagney G, Wynne K, et al. Machine learning based prediction and the influence of complement - Coagulation pathway proteins on clinical outcome: Results from the NEURAPRO trial. Brain, Behavior, and Immunity. 2022 Jul;103:50–60.
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BACKGROUND: Functional outcomes are important measures in the overall clinical course of psychosis and individuals at clinical high-risk (CHR), however, prediction of functional outcome remains difficult based on clinical information alone. In the first part of this study, we evaluated whether a combination of biological and clinical variables could predict future functional outcome in CHR individuals. The complement and coagulation pathways have previously been identified as being of relevance to the pathophysiology of psychosis and have been found to contribute to the prediction of clinical outcome in CHR participants. Hence, in the second part we extended the analysis to evaluate specifically the relationship of complement and coagulation proteins with psychotic symptoms and functional outcome in CHR. MATERIALS AND METHODS: We carried out plasma proteomics and measured plasma cytokine levels, and erythrocyte membrane fatty acid levels in a sub-sample (n = 158) from the NEURAPRO clinical trial at baseline and 6 months follow up. Functional outcome was measured using Social and Occupational Functional assessment Score (SOFAS) scale. Firstly, we used support vector machine learning techniques to develop predictive models for functional outcome at 12 months. Secondly, we developed linear regression models to understand the association between 6-month follow-up levels of complement and coagulation proteins with 6-month follow-up measures of positive symptoms summary (PSS) scores and functional outcome. RESULTS AND CONCLUSION: A prediction model based on clinical and biological data including the plasma proteome, erythrocyte fatty acids and cytokines, poorly predicted functional outcome at 12 months follow-up in CHR participants. In linear regression models, four complement and coagulation proteins (coagulation protein X, Complement C1r subcomponent like protein, Complement C4A & Complement C5) indicated a significant association with functional outcome; and two proteins (coagulation factor IX and complement C5) positively associated with the PSS score. Our study does not provide support for the utility of cytokines, proteomic or fatty acid data for prediction of functional outcomes in individuals at high-risk for psychosis. However, the association of complement protein levels with clinical outcome suggests a role for the complement system and the activity of its related pathway in the functional impairment and positive symptom severity of CHR patients.
- Lalousis PA, Schmaal L, Wood SJ, Reniers RLEP, Barnes NM, Chisholm K, et al. Neurobiologically Based Stratification of Recent-Onset Depression and Psychosis: Identification of Two Distinct Transdiagnostic Phenotypes. Biological Psychiatry. 2022 Oct;92(7):552–62.
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BACKGROUND: Identifying neurobiologically based transdiagnostic categories of depression and psychosis may elucidate heterogeneity and provide better candidates for predictive modeling. We aimed to identify clusters across patients with recent-onset depression (ROD) and recent-onset psychosis (ROP) based on structural neuroimaging data. We hypothesized that these transdiagnostic clusters would identify patients with poor outcome and allow more accurate prediction of symptomatic remission than traditional diagnostic structures. METHODS: HYDRA (Heterogeneity through Discriminant Analysis) was trained on whole-brain volumetric measures from 577 participants from the discovery sample of the multisite PRONIA study to identify neurobiologically driven clusters, which were then externally validated in the PRONIA replication sample (n = 404) and three datasets of chronic samples (Centre for Biomedical Research Excellence, n = 146; Mind Clinical Imaging Consortium, n = 202; Munich, n = 470). RESULTS: The optimal clustering solution was two transdiagnostic clusters (cluster 1: n = 153, 67 ROP, 86 ROD; cluster 2: n = 149, 88 ROP, 61 ROD; adjusted Rand index = 0.618). The two clusters contained both patients with ROP and patients with ROD. One cluster had widespread gray matter volume deficits and more positive, negative, and functional deficits (impaired cluster), and one cluster revealed a more preserved neuroanatomical signature and more core depressive symptomatology (preserved cluster). The clustering solution was internally and externally validated and assessed for clinical utility in predicting 9-month symptomatic remission, outperforming traditional diagnostic structures. CONCLUSIONS: We identified two transdiagnostic neuroanatomically informed clusters that are clinically and biologically distinct, challenging current diagnostic boundaries in recent-onset mental health disorders. These results may aid understanding of the etiology of poor outcome patients transdiagnostically and improve development of stratified treatments.
- Sanfelici R, Ruef A, Antonucci LA, Penzel N, Sotiras A, Dong MS, et al. Novel Gyrification Networks Reveal Links with Psychiatric Risk Factors in Early Illness. Cerebral Cortex. 2022 Apr;32(8):1625–36.
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Adult gyrification provides a window into coordinated early neurodevelopment when disruptions predispose individuals to psychiatric illness. We hypothesized that the echoes of such disruptions should be observed within structural gyrification networks in early psychiatric illness that would demonstrate associations with developmentally relevant variables rather than specific psychiatric symptoms. We employed a new data-driven method (Orthogonal Projective Non-Negative Matrix Factorization) to delineate novel gyrification-based networks of structural covariance in 308 healthy controls. Gyrification within the networks was then compared to 713 patients with recent onset psychosis or depression, and at clinical high-risk. Associations with diagnosis, symptoms, cognition, and functioning were investigated using linear models. Results demonstrated 18 novel gyrification networks in controls as verified by internal and external validation. Gyrification was reduced in patients in temporal-insular, lateral occipital, and lateral fronto-parietal networks (pFDR < 0.01) and was not moderated by illness group. Higher gyrification was associated with better cognitive performance and lifetime role functioning, but not with symptoms. The findings demonstrated that gyrification can be parsed into novel brain networks that highlight generalized illness effects linked to developmental vulnerability. When combined, our study widens the window into the etiology of psychiatric risk and its expression in adulthood.
- Catalan A, Tognin S, Kempton MJ, Stahl D, Salazar de Pablo G, Nelson B, et al. Relationship between jumping to conclusions and clinical outcomes in people at clinical high-risk for psychosis. Psychological Medicine. 2022 Jun;52(8):1569–77.
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BACKGROUND: Psychosis is associated with a reasoning bias, which manifests as a tendency to 'jump to conclusions'. We examined this bias in people at clinical high-risk for psychosis (CHR) and investigated its relationship with their clinical outcomes. METHODS: In total, 303 CHR subjects and 57 healthy controls (HC) were included. Both groups were assessed at baseline, and after 1 and 2 years. A 'beads' task was used to assess reasoning bias. Symptoms and level of functioning were assessed using the Comprehensive Assessment of At-Risk Mental States scale (CAARMS) and the Global Assessment of Functioning (GAF), respectively. During follow up, 58 (16.1%) of the CHR group developed psychosis (CHR-T), and 245 did not (CHR-NT). Logistic regressions, multilevel mixed models, and Cox regression were used to analyse the relationship between reasoning bias and transition to psychosis and level of functioning, at each time point. RESULTS: There was no association between reasoning bias at baseline and the subsequent onset of psychosis. However, when assessed after the transition to psychosis, CHR-T participants showed a greater tendency to jump to conclusions than CHR-NT and HC participants (55, 17, 17%; χ2 = 8.13, p = 0.012). There was a significant association between jumping to conclusions (JTC) at baseline and a reduced level of functioning at 2-year follow-up in the CHR group after adjusting for transition, gender, ethnicity, age, and IQ. CONCLUSIONS: In CHR participants, JTC at baseline was associated with adverse functioning at the follow-up. Interventions designed to improve JTC could be beneficial in the CHR population.
- Susai SR, Mongan D, Healy C, Cannon M, Nelson B, Markulev C, et al. The association of plasma inflammatory markers with omega-3 fatty acids and their mediating role in psychotic symptoms and functioning: An analysis of the NEURAPRO clinical trial. Brain, Behavior, and Immunity. 2022 Jan;99:147–56.
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There is increasing evidence that dysregulation of polyunsaturated fatty acids (FAs) mediated membrane function plays a role in the pathophysiology of schizophrenia. Even though preclinical findings have supported the anti-inflammatory properties of omega-3 FAs on brain health, their biological roles as anti-inflammatory agents and their therapeutic role on clinical symptoms of psychosis risk are not well understood. In the current study, we investigated the relationship of erythrocyte omega-3 FAs with plasma immune markers in a clinical high risk for psychosis (CHR) sample. In addition, a mediation analysis was performed to examine whether previously reported associations between omega-3 FAs and clinical outcomes were mediated via plasma immune markers. Clinical outcomes for CHR participants in the NEURAPRO clinical trial were measured using the Brief Psychiatric Rating Scale (BPRS), Schedule for the Scale of Assessment of Negative Symptoms (SANS) and Social and Occupational Functioning Assessment Scale (SOFAS) scales. The erythrocyte omega-3 index [eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA)] and plasma concentrations of inflammatory markers were quantified at baseline (n = 268) and 6 month follow-up (n = 146) by gas chromatography and multiplex immunoassay, respectively. In linear regression models, the baseline plasma concentrations of Interleukin (IL)-15, Intercellular adhesion molecule (ICAM)-1 and Vascular cell adhesion molecule (VCAM)-1 were negatively associated with baseline omega-3 index. In addition, 6-month change in IL-12p40 and TNF-α showed a negative association with change in omega-3 index. In longitudinal analyses, the baseline and 6 month change in omega-3 index was negatively associated with VCAM-1 and TNF-α respectively at follow-up. Mediation analyses provided little evidence for mediating effects of plasma immune markers on the relationship between omega-3 FAs and clinical outcomes (psychotic symptoms and functioning) in CHR participants. Our results indicate a predominantly anti-inflammatory relationship of omega-3 FAs on plasma inflammatory status in CHR individuals, but this did not appear to convey clinical benefits at 6 month and 12 month follow-up. Both immune and non-immune biological effects of omega-3 FAs would be resourceful in understanding the clinical benefits of omega-3 FAs in CHR papulation.
- Tognin S, Richter A, Kempton MJ, Modinos G, Antoniades M, Azis M, et al. The Relationship Between Grey Matter Volume and Clinical and Functional Outcomes in People at Clinical High Risk for Psychosis. Schizophrenia Bulletin Open. 2022 Jan;3(1):sgac040.
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OBJECTIVE: To examine the association between baseline alterations in grey matter volume (GMV) and clinical and functional outcomes in people at clinical high risk (CHR) for psychosis. METHODS: 265 CHR individuals and 92 healthy controls were recruited as part of a prospective multi-center study. After a baseline assessment using magnetic resonance imaging (MRI), participants were followed for at least two years to determine clinical and functional outcomes, including transition to psychosis (according to the Comprehensive Assessment of an At Risk Mental State, CAARMS), level of functioning (according to the Global Assessment of Functioning), and symptomatic remission (according to the CAARMS). GMV was measured in selected cortical and subcortical regions of interest (ROI) based on previous studies (ie orbitofrontal gyrus, cingulate gyrus, gyrus rectus, inferior temporal gyrus, parahippocampal gyrus, striatum, and hippocampus). Using voxel-based morphometry, we analysed the relationship between GMV and clinical and functional outcomes. RESULTS: Within the CHR sample, a poor functional outcome (GAF < 65) was associated with relatively lower GMV in the right striatum at baseline (P < .047 after Family Wise Error correction). There were no significant associations between baseline GMV and either subsequent remission or transition to psychosis. CONCLUSIONS: In CHR individuals, lower striatal GMV was associated with a poor level of overall functioning at follow-up. This finding was not related to effects of antipsychotic or antidepressant medication. The failure to replicate previous associations between GMV and later psychosis onset, despite studying a relatively large sample, is consistent with the findings of recent large-scale multi-center studies.
- Allott K, Schmidt SJ, Yuen HP, Wood SJ, Nelson B, Markulev C, et al. Twelve-Month Cognitive Trajectories in Individuals at Ultra-High Risk for Psychosis: A Latent Class Analysis. Schizophrenia Bulletin Open. 2022 Jan;3(1):sgac008.
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Understanding longitudinal cognitive performance in individuals at ultra-high risk for psychosis (UHR) is important for informing theoretical models and treatment. A vital step in this endeavor is to determine whether there are UHR subgroups that have similar patterns of cognitive change over time. The aims were to: i) identify latent class trajectories of cognitive performance over 12-months in UHR individuals, ii) identify baseline demographic and clinical predictors of the resulting classes, and iii) determine whether trajectory classes were associated with transition to psychosis or functional outcomes. Cognition was assessed using the Brief Assessment of Cognition in Schizophrenia (BACS) at baseline, 6- and 12-months (N = 288). Using Growth Mixture Modeling, a single unimpaired improving trajectory class was observed for motor function, speed of processing, verbal fluency, and BACS composite. A two-class solution was observed for executive function and working memory, showing one unimpaired and a second impaired class. A three-class solution was found for verbal learning and memory: unimpaired, mildly impaired, and initially extremely impaired, but improved ("caught up") to the level of the mildly impaired. IQ, omega-3 index, and premorbid adjustment were associated with class membership, whereas clinical variables (symptoms, substance use), including transition to psychosis, were not. Working memory and verbal learning and memory trajectory class membership was associated with functioning outcomes. These findings suggest there is no short-term progressive cognitive decline in help-seeking UHR individuals, including those who transition to psychosis. Screening of cognitive performance may be useful for identifying UHR individuals who may benefit from targeted cognitive interventions.
- Hedges EP, Dickson H, Tognin S, Modinos G, Antoniades M, van der Gaag M, et al. Verbal memory performance predicts remission and functional outcome in people at clinical high-risk for psychosis. Schizophrenia Research Cognition. 2022 Jun;28:100222.
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Robust deficits in cognitive functioning are present in people with psychosis and are evident in the early stages of the disorder. Impairments in verbal memory and verbal fluency are reliably seen in individuals at clinical high-risk for psychosis (CHR) compared to healthy populations. As previous studies have shown a relationship between cognition and longer-term outcomes in schizophrenia, the aim of this paper was to explore whether verbal memory and verbal fluency performance predicted outcomes in a large CHR sample recruited as part of the EU-GEI High Risk Study. Participants included 316 CHR individuals, 90.8% of whom were not currently on antipsychotic medication, and 60 healthy controls. Verbal memory and verbal fluency performance were measured at baseline. At two-year follow-up, CHR individuals were assessed by three different outcome measures, those who did and did not (1) transition to psychosis, (2) experience burdening impairment or disabilities, or (3) remit clinically from CHR status. Individuals with CHR displayed significant verbal memory and verbal fluency deficits at baseline compared to healthy controls (Hedges' g effect size = 0.24 to 0.66). There were no significant differences in cognitive performance of those who did and did not transition to psychosis. However, impaired immediate verbal recall predicted both functional disability and non-remission from the CHR state. Results remained significant when analyses were restricted to only include antipsychotic-free CHR participants. These findings may inform the development of early interventions designed to improve cognitive deficits in the early stages of psychosis.
2021
- van der Heijden HS, Schirmbeck F, McGuire P, Valmaggia LR, Kempton MJ, van der Gaag M, et al. Association between tobacco use and symptomatology in individuals at ultra-high risk to develop a psychosis: A longitudinal study. Schizophrenia Research. 2021 Oct;236:48–53.
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BACKGROUND: The high prevalence rates and impact of tobacco smoking in individuals with a psychotic disorder have become an increasing interest. Little is known about tobacco smoking in individuals at ultra-high risk of psychosis (UHR). METHODS: We studied 345 UHR individuals of the high-risk study of the European network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI). Smoking status and the number of cigarettes per day were assessed at multiple moments using the CIDI. Symptom severity at each time point was assessed using CAARMS. Linear mixed-effects analyses were conducted to examine the multi-cross-sectional and prospective associations between (change in) smoking behaviour and symptomatology. FINDINGS: At baseline, 175 individuals (53%) smoked tobacco with an average of 12.4 (SD = 9.0) cigarettes per day. Smokers did not significantly differ in symptom severity from non-smokers on general, positive, negative, emotional, cognitive, behavioural, or motor symptoms across time. However, associations were found between the number of cigarettes and the severity of general psychopathology (estimate 0.349, SE 0.146, p = 0.017). Change in the number of cigarettes had no significant effect on change in general symptom severity (estimate 0.330, SE 0.285, p = 0.248). INTERPRETATION: Smoking prevalence in UHR individuals is high. Cigarette consumption was associated with higher levels of general symptoms. However, we observed no association between change in number of cigarettes and symptom severity. Given the fact that smoking is associated with poorer health and worse outcomes in people with psychosis, the clinical high-risk phase offers a window of opportunity for prevention and cessation interventions.
- Sandini C, Zöller D, Schneider M, Tarun A, Armando M, Nelson B, et al. Characterization and prediction of clinical pathways of vulnerability to psychosis through graph signal processing. eLife. 2021 Sep;10:e59811.
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Causal interactions between specific psychiatric symptoms could contribute to the heterogenous clinical trajectories observed in early psychopathology. Current diagnostic approaches merge clinical manifestations that co-occur across subjects and could significantly hinder our understanding of clinical pathways connecting individual symptoms. Network analysis techniques have emerged as alternative approaches that could help shed light on the complex dynamics of early psychopathology. The present study attempts to address the two main limitations that have in our opinion hindered the application of network approaches in the clinical setting. Firstly, we show that a multi-layer network analysis approach, can move beyond a static view of psychopathology, by providing an intuitive characterization of the role of specific symptoms in contributing to clinical trajectories over time. Secondly, we show that a Graph-Signal-Processing approach, can exploit knowledge of longitudinal interactions between symptoms, to predict clinical trajectories at the level of the individual. We test our approaches in two independent samples of individuals with genetic and clinical vulnerability for developing psychosis. Novel network approaches can allow to embrace the dynamic complexity of early psychopathology and help pave the way towards a more a personalized approach to clinical care.
- Pollak TA, Kempton MJ, Iyegbe C, Vincent A, Irani SR, Coutinho E, et al. Clinical, cognitive and neuroanatomical associations of serum NMDAR autoantibodies in people at clinical high risk for psychosis. Molecular Psychiatry. 2021 Jun;26(6):2590–604.
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Serum neuronal autoantibodies, such as those to the NMDA receptor (NMDAR), are detectable in a subgroup of patients with psychotic disorders. It is not known if they are present before the onset of psychosis or whether they are associated with particular clinical features or outcomes. In a case-control study, sera from 254 subjects at clinical high risk (CHR) for psychosis and 116 healthy volunteers were tested for antibodies against multiple neuronal antigens implicated in CNS autoimmune disorders, using fixed and live cell-based assays (CBAs). Within the CHR group, the relationship between NMDAR antibodies and symptoms, cognitive function and clinical outcomes over 24 month follow-up was examined. CHR subjects were not more frequently seropositive for neuronal autoantibodies than controls (8.3% vs. 5.2%; OR = 1.50; 95% CI: 0.58-3.90). The NMDAR was the most common target antigen and NMDAR IgGs were more sensitively detected with live versus fixed CBAs (p < 0.001). Preliminary phenotypic analyses revealed that within the CHR sample, the NMDAR antibody seropositive subjects had higher levels of current depression, performed worse on the Rey Auditory Verbal Learning Task (p < 0.05), and had a markedly lower IQ (p < 0.01). NMDAR IgGs were not more frequent in subjects who later became psychotic than those who did not. NMDAR antibody serostatus and titre was associated with poorer levels of functioning at follow-up (p < 0.05) and the presence of a neuronal autoantibody was associated with larger amygdala volumes (p < 0.05). Altogether, these findings demonstrate that NMDAR autoantibodies are detectable in a subgroup of CHR subjects at equal rates to controls. In the CHR group, they are associated with affective psychopathology, impairments in verbal memory, and overall cognitive function: these findings are qualitatively and individually similar to core features of autoimmune encephalitis and/or animal models of NMDAR antibody-mediated CNS disease. Overall the current work supports further evaluation of NMDAR autoantibodies as a possible prognostic biomarker and aetiological factor in a subset of people already meeting CHR criteria.
- Velthorst E, Mollon J, Murray RM, de Haan L, Germeys IM, Glahn DC, et al. Cognitive functioning throughout adulthood and illness stages in individuals with psychotic disorders and their unaffected siblings. Molecular Psychiatry. 2021 Aug;26(8):4529–43.
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Important questions remain about the profile of cognitive impairment in psychotic disorders across adulthood and illness stages. The age-associated profile of familial impairments also remains unclear, as well as the effect of factors, such as symptoms, functioning, and medication. Using cross-sectional data from the EU-GEI and GROUP studies, comprising 8455 participants aged 18 to 65, we examined cognitive functioning across adulthood in patients with psychotic disorders (n = 2883), and their unaffected siblings (n = 2271), compared to controls (n = 3301). An abbreviated WAIS-III measured verbal knowledge, working memory, visuospatial processing, processing speed, and IQ. Patients showed medium to large deficits across all functions (ES range = -0.45 to -0.73, p < 0.001), while siblings showed small deficits on IQ, verbal knowledge, and working memory (ES = -0.14 to -0.33, p < 0.001). Magnitude of impairment was not associated with participant age, such that the size of impairment in older and younger patients did not significantly differ. However, first-episode patients performed worse than prodromal patients (ES range = -0.88 to -0.60, p < 0.001). Adjusting for cannabis use, symptom severity, and global functioning attenuated impairments in siblings, while deficits in patients remained statistically significant, albeit reduced by half (ES range = -0.13 to -0.38, p < 0.01). Antipsychotic medication also accounted for around half of the impairment in patients (ES range = -0.21 to -0.43, p < 0.01). Deficits in verbal knowledge, and working memory may specifically index familial, i.e., shared genetic and/or shared environmental, liability for psychotic disorders. Nevertheless, potentially modifiable illness-related factors account for a significant portion of the cognitive impairment in psychotic disorders.
- Mongan D, Föcking M, Healy C, Susai SR, Heurich M, Wynne K, et al. Development of Proteomic Prediction Models for Transition to Psychotic Disorder in the Clinical High-Risk State and Psychotic Experiences in Adolescence. JAMA psychiatry. 2021 Jan;78(1):77–90.
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IMPORTANCE: Biomarkers that are predictive of outcomes in individuals at risk of psychosis would facilitate individualized prognosis and stratification strategies. OBJECTIVE: To investigate whether proteomic biomarkers may aid prediction of transition to psychotic disorder in the clinical high-risk (CHR) state and adolescent psychotic experiences (PEs) in the general population. DESIGN, SETTING, AND PARTICIPANTS: This diagnostic study comprised 2 case-control studies nested within the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) and the Avon Longitudinal Study of Parents and Children (ALSPAC). EU-GEI is an international multisite prospective study of participants at CHR referred from local mental health services. ALSPAC is a United Kingdom-based general population birth cohort. Included were EU-GEI participants who met CHR criteria at baseline and ALSPAC participants who did not report PEs at age 12 years. Data were analyzed from September 2018 to April 2020. MAIN OUTCOMES AND MEASURES: In EU-GEI, transition status was assessed by the Comprehensive Assessment of At-Risk Mental States or contact with clinical services. In ALSPAC, PEs at age 18 years were assessed using the Psychosis-Like Symptoms Interview. Proteomic data were obtained from mass spectrometry of baseline plasma samples in EU-GEI and plasma samples at age 12 years in ALSPAC. Support vector machine learning algorithms were used to develop predictive models. RESULTS: The EU-GEI subsample (133 participants at CHR (mean [SD] age, 22.6 [4.5] years; 68 [51.1%] male) comprised 49 (36.8%) who developed psychosis and 84 (63.2%) who did not. A model based on baseline clinical and proteomic data demonstrated excellent performance for prediction of transition outcome (area under the receiver operating characteristic curve [AUC], 0.95; positive predictive value [PPV], 75.0%; and negative predictive value [NPV], 98.6%). Functional analysis of differentially expressed proteins implicated the complement and coagulation cascade. A model based on the 10 most predictive proteins accurately predicted transition status in training (AUC, 0.99; PPV, 76.9%; and NPV, 100%) and test (AUC, 0.92; PPV, 81.8%; and NPV, 96.8%) data. The ALSPAC subsample (121 participants from the general population with plasma samples available at age 12 years (61 [50.4%] male) comprised 55 participants (45.5%) with PEs at age 18 years and 61 (50.4%) without PEs at age 18 years. A model using proteomic data at age 12 years predicted PEs at age 18 years, with an AUC of 0.74 (PPV, 67.8%; and NPV, 75.8%). CONCLUSIONS AND RELEVANCE: In individuals at risk of psychosis, proteomic biomarkers may contribute to individualized prognosis and stratification strategies. These findings implicate early dysregulation of the complement and coagulation cascade in the development of psychosis outcomes.
- Dickens AM, Sen P, Kempton MJ, Barrantes-Vidal N, Iyegbe C, Nordentoft M, et al. Dysregulated Lipid Metabolism Precedes Onset of Psychosis. Biological Psychiatry. 2021 Feb;89(3):288–97.
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BACKGROUND: A key clinical challenge in the management of individuals at clinical high risk for psychosis (CHR) is that it is difficult to predict their future clinical outcomes. Here, we investigated if the levels of circulating molecular lipids are related to adverse clinical outcomes in this group. METHODS: Serum lipidomic analysis was performed in 263 CHR individuals and 51 healthy control subjects, who were then clinically monitored for up to 5 years. Machine learning was used to identify lipid profiles that discriminated between CHR and control subjects, and between subgroups of CHR subjects with distinct clinical outcomes. RESULTS: At baseline, compared with control subjects, CHR subjects (independent of outcome) had higher levels of triacylglycerols with a low acyl carbon number and a double bond count, as well as higher levels of lipids in general. CHR subjects who subsequently developed psychosis (n = 50) were distinguished from those that did not (n = 213) on the basis of lipid profile at baseline using a model with an area under the receiver operating curve of 0.81 (95% confidence interval = 0.69-0.93). CHR subjects who became psychotic had lower levels of ether phospholipids than CHR individuals who did not (p < .01). CONCLUSIONS: Collectively, these data suggest that lipidomic abnormalities predate the onset of psychosis and that blood lipidomic measures may be useful in predicting which CHR individuals are most likely to develop psychosis.
- Salokangas RKR, Hietala J, Armio RL, Laurikainen H, From T, Borgwardt S, et al. Effect of childhood physical abuse on social anxiety is mediated via reduced frontal lobe and amygdala-hippocampus complex volume in adult clinical high-risk subjects. Schizophrenia Research. 2021 Jan;227:101–9.
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BACKGROUND: Childhood adverse experiences (CAE) are associated with clinical psychiatric disorders and symptoms, and with volumetric abnormalities in the amygdala-hippocampus complex (AmHiC) and frontal lobe (FroL) in adulthood. AIM: To study whether CAE are associated with reduced AmHiC and FroL and whether these structures mediate the effect of CAE on social anxiety and depression. METHOD: In seven European centres, 374 patients with recent onset of psychosis (n = 127), clinical high-risk to psychosis (n = 119) or recent onset of depression (n = 128) were scanned with MRI and their FroL and AmHiC volumes were measured. They all completed self-report scales for assessment of CAE, social anxiety and depression. RESULTS: Of the CAE domains, physical abuse was associated specifically with reduced grey and white matter volumes of FroL and AmHiC in psychotic and high-risk patients. After controlling intracranial volume, PhyAb associated significantly with FroL and its grey matter volume in high-risk patients only. In mediation analyses, the effect of physical abuse on social anxiety was mediated via reduced FroL grey mater volume in high-risk patients. In them, when the effects of AmHiC and depression were controlled, the effect of physical abuse on social anxiety was mediated via FroL grey matter volume reduction. CONCLUSIONS: Childhood physical abuse is associated with reduced frontal lobe and amygdala-hippocampus complex volume in adult subjects with psychotic symptoms. Reduced frontal lobe and amygdala-hippocampus complex volume mediate the effect of physical abuse on social anxiety in high-risk patients. The effect of physical abuse on depression-independent social anxiety is mediated via reduced frontal lobe.
- Koutsouleris N, Dwyer DB, Degenhardt F, Maj C, Urquijo-Castro MF, Sanfelici R, et al. Multimodal Machine Learning Workflows for Prediction of Psychosis in Patients With Clinical High-Risk Syndromes and Recent-Onset Depression. JAMA psychiatry. 2021 Feb;78(2):195–209.
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IMPORTANCE: Diverse models have been developed to predict psychosis in patients with clinical high-risk (CHR) states. Whether prediction can be improved by efficiently combining clinical and biological models and by broadening the risk spectrum to young patients with depressive syndromes remains unclear. OBJECTIVES: To evaluate whether psychosis transition can be predicted in patients with CHR or recent-onset depression (ROD) using multimodal machine learning that optimally integrates clinical and neurocognitive data, structural magnetic resonance imaging (sMRI), and polygenic risk scores (PRS) for schizophrenia; to assess models' geographic generalizability; to test and integrate clinicians' predictions; and to maximize clinical utility by building a sequential prognostic system. DESIGN, SETTING, AND PARTICIPANTS: This multisite, longitudinal prognostic study performed in 7 academic early recognition services in 5 European countries followed up patients with CHR syndromes or ROD and healthy volunteers. The referred sample of 167 patients with CHR syndromes and 167 with ROD was recruited from February 1, 2014, to May 31, 2017, of whom 26 (23 with CHR syndromes and 3 with ROD) developed psychosis. Patients with 18-month follow-up (n = 246) were used for model training and leave-one-site-out cross-validation. The remaining 88 patients with nontransition served as the validation of model specificity. Three hundred thirty-four healthy volunteers provided a normative sample for prognostic signature evaluation. Three independent Swiss projects contributed a further 45 cases with psychosis transition and 600 with nontransition for the external validation of clinical-neurocognitive, sMRI-based, and combined models. Data were analyzed from January 1, 2019, to March 31, 2020. MAIN OUTCOMES AND MEASURES: Accuracy and generalizability of prognostic systems. RESULTS: A total of 668 individuals (334 patients and 334 controls) were included in the analysis (mean [SD] age, 25.1 [5.8] years; 354 [53.0%] female and 314 [47.0%] male). Clinicians attained a balanced accuracy of 73.2% by effectively ruling out (specificity, 84.9%) but ineffectively ruling in (sensitivity, 61.5%) psychosis transition. In contrast, algorithms showed high sensitivity (76.0%-88.0%) but low specificity (53.5%-66.8%). A cybernetic risk calculator combining all algorithmic and human components predicted psychosis with a balanced accuracy of 85.5% (sensitivity, 84.6%; specificity, 86.4%). In comparison, an optimal prognostic workflow produced a balanced accuracy of 85.9% (sensitivity, 84.6%; specificity, 87.3%) at a much lower diagnostic burden by sequentially integrating clinical-neurocognitive, expert-based, PRS-based, and sMRI-based risk estimates as needed for the given patient. Findings were supported by good external validation results. CONCLUSIONS AND RELEVANCE: These findings suggest that psychosis transition can be predicted in a broader risk spectrum by sequentially integrating algorithms' and clinicians' risk estimates. For clinical translation, the proposed workflow should undergo large-scale international validation.
- Hauke DJ, Schmidt A, Studerus E, Andreou C, Riecher-Rössler A, Radua J, et al. Multimodal prognosis of negative symptom severity in individuals at increased risk of developing psychosis. Translational Psychiatry. 2021 May;11(1):312.
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Negative symptoms occur frequently in individuals at clinical high risk (CHR) for psychosis and contribute to functional impairments. The aim of this study was to predict negative symptom severity in CHR after 9 months. Predictive models either included baseline negative symptoms measured with the Structured Interview for Psychosis-Risk Syndromes (SIPS-N), whole-brain gyrification, or both to forecast negative symptoms of at least moderate severity in 94 CHR. We also conducted sequential risk stratification to stratify CHR into different risk groups based on the SIPS-N and gyrification model. Additionally, we assessed the models' ability to predict functional outcomes in CHR and their transdiagnostic generalizability to predict negative symptoms in 96 patients with recent-onset psychosis (ROP) and 97 patients with recent-onset depression (ROD). Baseline SIPS-N and gyrification predicted moderate/severe negative symptoms with significant balanced accuracies of 68 and 62%, while the combined model achieved 73% accuracy. Sequential risk stratification stratified CHR into a high (83%), medium (40-64%), and low (19%) risk group regarding their risk of having moderate/severe negative symptoms at 9 months follow-up. The baseline SIPS-N model was also able to predict social (61%), but not role functioning (59%) at above-chance accuracies, whereas the gyrification model achieved significant accuracies in predicting both social (76%) and role (74%) functioning in CHR. Finally, only the baseline SIPS-N model showed transdiagnostic generalization to ROP (63%). This study delivers a multimodal prognostic model to identify those CHR with a clinically relevant negative symptom severity and functional impairments, potentially requiring further therapeutic consideration.
- Ong HL, Isvoranu AM, Schirmbeck F, McGuire P, Valmaggia L, Kempton MJ, et al. Obsessive-Compulsive Symptoms and Other Symptoms of the At-risk Mental State for Psychosis: A Network Perspective. Schizophrenia Bulletin. 2021 Jul;47(4):1018–28.
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BACKGROUND: The high prevalence of obsessive-compulsive symptoms (OCS) among subjects at Ultra-High Risk (UHR) for psychosis is well documented. However, the network structure spanning the relations between OCS and symptoms of the at risk mental state for psychosis as assessed with the Comprehensive Assessment of At Risk Mental States (CAARMS) has not yet been investigated. This article aimed to use a network approach to investigate the associations between OCS and CAARMS symptoms in a large sample of individuals with different levels of risk for psychosis. METHOD: Three hundred and forty-one UHR and 66 healthy participants were included, who participated in the EU-GEI study. Data analysis consisted of constructing a network of CAARMS symptoms, investigating central items in the network, and identifying the shortest pathways between OCS and positive symptoms. RESULTS: Strong associations between OCS and anxiety, social isolation and blunted affect were identified. Depression was the most central symptom in terms of the number of connections, and anxiety was a key item in bridging OCS to other symptoms. Shortest paths between OCS and positive symptoms revealed that unusual thought content and perceptual abnormalities were connected mainly via anxiety, while disorganized speech was connected via blunted affect and cognitive change. CONCLUSIONS: Findings provide valuable insight into the central role of depression and the potential connective component of anxiety between OCS and other symptoms of the network. Interventions specifically aimed to reduce affective symptoms might be crucial for the development and prospective course of symptom co-occurrence.
- McLaverty A, Allott KA, Berger M, Hester R, McGorry PD, Nelson B, et al. Omega-3 fatty acids and neurocognitive ability in young people at ultra-high risk for psychosis. Early Intervention in Psychiatry. 2021 Aug;15(4):874–81.
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BACKGROUND: Neurocognitive impairments are core early features of psychosis and are observed in those at ultra-high risk (UHR) for psychosis. The aim of the present study was to explore whether neurocognition is associated with polyunsaturated fatty acids (PUFAs), as has been observed in other clinical populations. METHOD: Erythrocyte levels of total omega-3-and omega-6 PUFAs the omega-3/omega-6 ratio, were measured in 265 UHR individuals. Six domains of neurocognition as well a Composite Score, were assessed using the Brief Assessment of Cognition in Schizophrenia. Pearson's correlations were used to assess the relationship between PUFAs and neurocognition. All analyses were controlled for tobacco smoking. RESULTS: Verbal Fluency correlated positively with eicosapentaenoic acid (P = .024) and alpha-linolenic acid (P = .01), and negatively with docosahexanoic acid (P = .007) and Working Memory positively correlated with omega-3/omega-6 ratio (P = .007). CONCLUSIONS: The current results provide support for a relationship between Verbal Fluency and omega-3 PUFAs in UHR. Further investigation is required to elucidate whether these biomarkers are useful as risk markers or in understanding the biological underpinning of neurocognitive impairment in this population.
- Kirschner M, Schmidt A, Hodzic-Santor B, Burrer A, Manoliu A, Zeighami Y, et al. Orbitofrontal-Striatal Structural Alterations Linked to Negative Symptoms at Different Stages of the Schizophrenia Spectrum. Schizophrenia Bulletin. 2021 Apr;47(3):849–63.
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Negative symptoms such as anhedonia and apathy are among the most debilitating manifestations of schizophrenia (SZ). Imaging studies have linked these symptoms to morphometric abnormalities in 2 brain regions implicated in reward and motivation: the orbitofrontal cortex (OFC) and striatum. Higher negative symptoms are generally associated with reduced OFC thickness, while higher apathy specifically maps to reduced striatal volume. However, it remains unclear whether these tissue losses are a consequence of chronic illness and its treatment or an underlying phenotypic trait. Here, we use multicentre magnetic resonance imaging data to investigate orbitofrontal-striatal abnormalities across the SZ spectrum from healthy populations with high schizotypy to unmedicated and medicated first-episode psychosis (FEP), and patients with chronic SZ. Putamen, caudate, accumbens volume, and OFC thickness were estimated from T1-weighted images acquired in all 3 diagnostic groups and controls from 4 sites (n = 337). Results were first established in 1 discovery dataset and replicated in 3 independent samples. There was a negative correlation between apathy and putamen/accumbens volume only in healthy individuals with schizotypy; however, medicated patients exhibited larger putamen volume, which appears to be a consequence of antipsychotic medications. The negative association between reduced OFC thickness and total negative symptoms also appeared to vary along the SZ spectrum, being significant only in FEP patients. In schizotypy, there was increased OFC thickness relative to controls. Our findings suggest that negative symptoms are associated with a temporal continuum of orbitofrontal-striatal abnormalities that may predate the occurrence of SZ. Thicker OFC in schizotypy may represent either compensatory or pathological mechanisms prior to the disease onset.
- Berendsen S, Kapitein P, Schirmbeck F, van Tricht MJ, McGuire P, Morgan C, et al. Pre-training inter-rater reliability of clinical instruments in an international psychosis research project. Schizophrenia Research. 2021 Apr;230:104–7.
- Polari A, Yuen HP, Amminger P, Berger G, Chen E, deHaan L, et al. Prediction of clinical outcomes beyond psychosis in the ultra-high risk for psychosis population. Early Intervention in Psychiatry. 2021 Jun;15(3):642–51.
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AIM: Several prediction models have been introduced to identify young people at greatest risk of transitioning to psychosis. To date, none has examined the possibility of developing a clinical prediction model of outcomes other than transition. The aims of this study were to examine the association between baseline clinical predictors and outcomes including, but not limited to, transition to psychosis in young people at risk for psychosis, and to develop a prediction model for these outcomes. METHODS: Several evidence-based variables previously associated with transition to psychosis and some important clinical comorbidities experienced by ultra-high risk (UHR) individuals were identified in 202 UHR individuals. Secondary analysis of the Neurapro clinical trial were conducted to investigate the associations between these variables and favourable (remission and recovery) or unfavourable (transition to psychosis, no remission, any recurrence and relapse) clinical outcomes. Logistic regression, best subset selection, Akaike Information Criterion and receiver operating characteristic curves were used to seek the best prediction model for clinical outcomes from all combinations of possible predictors. RESULTS: When considered individually, only higher general psychopathology levels (P = .023) was associated with the unfavourable outcomes. Prediction models suggest that general psychopathology and functioning are predictive of unfavourable outcomes. CONCLUSION: The predictive performance of the resulting models was modest and further research is needed. Nonetheless, when designing early intervention centres aiming to support individuals in the early phases of a mental disorder, the proper assessment of general psychopathology and functioning should be considered in order to inform interventions and length of care provided.
- Studerus E, Ittig S, Beck K, Del Cacho N, Vila-Badia R, Butjosa A, et al. Relation between self-perceived stress, psychopathological symptoms and the stress hormone prolactin in emerging psychosis. Journal of Psychiatric Research. 2021 Apr;136:428–34.
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BACKGROUND: Psychosocial stress and the stress hormone prolactin are assumed to play an important role in the pathogenesis of schizophrenia and related psychoses, and have been frequently observed to be increased in antipsychotic-naïve patients with a clinical high risk for psychosis (CHR-P) or first episode of psychosis (FEP). The aim of this study was to further elucidate the relationships between self-perceived stress, psychopathological symptoms and prolactin levels in these patients. METHODS: In this cross-sectional study, 45 healthy controls, 31 CHR-P patients and 87 FEP patients were recruited from two different study centers. Prolactin was measured under standardized conditions between 8 and 10 am. All patients were antipsychotic-naïve and not taking any prolactin influencing medication. Self-perceived stress during the last month was measured with the perceived stress scale (PSS-10) immediately before blood taking. RESULTS: Both CHR-P and FEP patients showed significantly higher levels of self-perceived stress and prolactin than controls. Hyperprolactinemia (i.e. prolactin levels above the reference range) was observed in 26% of CHR-P and 45% of FEP patients. Self-perceived stress was significantly positively associated with affective symptoms, but not with other symptoms. There was no significant association between self-perceived stress and prolactin levels. CONCLUSION: Our results confirm that CHR-P and FEP patients have higher stress levels than healthy controls and frequently have hyperprolactinemia, independent of antipsychotic medication. However, although it is well established that prolactin increases in response to stress, our results do not support the notion that increased prolactin levels in these patients are due to stress.
- O’Donoghue B, Geros H, Sizer H, Addington J, Amminger GP, Beaden CE, et al. The association between migrant status and transition in an ultra-high risk for psychosis population. Social Psychiatry and Psychiatric Epidemiology. 2021 Jun;56(6):943–52.
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PURPOSE: Migrant status is one of the most replicated and robust risk factors for developing a psychotic disorder. This study aimed to determine whether migrant status in people identified as Ultra-High Risk for Psychosis (UHR) was associated with risk of transitioning to a full-threshold psychotic disorder. METHODS: Hazard ratios for the risk of transition were calculated from five large UHR cohorts (n = 2166) and were used to conduct a meta-analysis using the generic inverse-variance method using a random-effects model. RESULTS: 2166 UHR young people, with a mean age of 19.1 years (SD ± 4.5) were included, of whom 221 (10.7%) were first-generation migrants. A total of 357 young people transitioned to psychosis over a median follow-up time of 417 days (I.Q.R.147-756 days), representing 17.0% of the cohort. The risk of transition to a full-threshold disorder was not increased for first-generation migrants, (HR = 1.08, 95% CI 0.62-1.89); however, there was a high level of heterogeneity between studies The hazard ratio for second-generation migrants to transition to a full-threshold psychotic disorder compared to the remainder of the native-born population was 1.03 (95% CI 0.70-1.51). CONCLUSIONS: This meta-analysis did not find a statistically significant association between migrant status and an increased risk for transition to a full-threshold psychotic disorder; however, several methodological issues could explain this finding. Further research should focus on examining the risk of specific migrant groups and also ensuring that migrant populations are adequately represented within UHR clinics.
2020
- Wong TY, Radua J, Pomarol-Clotet E, Salvador R, Albajes-Eizagirre A, Solanes A, et al. An overlapping pattern of cerebral cortical thinning is associated with both positive symptoms and aggression in schizophrenia via the ENIGMA consortium. Psychological Medicine. 2020 Sep;50(12):2034–45.
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BACKGROUND: Positive symptoms are a useful predictor of aggression in schizophrenia. Although a similar pattern of abnormal brain structures related to both positive symptoms and aggression has been reported, this observation has not yet been confirmed in a single sample. METHOD: To study the association between positive symptoms and aggression in schizophrenia on a neurobiological level, a prospective meta-analytic approach was employed to analyze harmonized structural neuroimaging data from 10 research centers worldwide. We analyzed brain MRI scans from 902 individuals with a primary diagnosis of schizophrenia and 952 healthy controls. RESULTS: The result identified a widespread cortical thickness reduction in schizophrenia compared to their controls. Two separate meta-regression analyses revealed that a common pattern of reduced cortical gray matter thickness within the left lateral temporal lobe and right midcingulate cortex was significantly associated with both positive symptoms and aggression. CONCLUSION: These findings suggested that positive symptoms such as formal thought disorder and auditory misperception, combined with cognitive impairments reflecting difficulties in deploying an adaptive control toward perceived threats, could escalate the likelihood of aggression in schizophrenia.
- Surbeck W, Hanggi J, Scholtes F, Viher PV, Schmidt A, Stegmayer K, et al. Anatomical integrity within the inferior fronto-occipital fasciculus and semantic processing deficits in schizophrenia spectrum disorders. Schizophrenia research. 2020 Jan;
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The core symptoms of schizophrenia spectrum disorders (SSD) include abnormal semantic processing which may rely on the ventral language stream of the human brain. Thus, structural disruption of the ventral language stream may play an important role in semantic deficits observed in SSD patients. Therefore, we compared white matter tract integrity in SSD patients and healthy controls using diffusion tensor imaging combined with probabilistic fiber tractography. For the ventral language stream, we assessed the inferior fronto-occipital fasciculus [IFOF], inferior longitudinal fasciculus, and uncinate fasciculus. The arcuate fasciculus and corticospinal tract were used as control tracts. In SSD patients, the relationship between semantic processing impairments and tract integrity was analyzed separately. Three-dimensional tract reconstructions were performed in 45/44 SSD patients/controls (”Bern sample“) and replicated in an independent sample of 24/24 SSD patients/controls (”Basel sample“). Multivariate analyses of fractional anisotropy, mean, axial, and radial diffusivity of the left IFOF showed significant differences between SSD patients and controls (p < 0.001, η = 0.23) in the Bern sample. Axial diffusivity (AD) of the left UF was inversely correlated with semantic impairments (r = -0.454, p = 0.035). In the Basel sample, significant group differences for the left IFOF were replicated (p < .01, η = 0.29), while the correlation between AD of the left IFOF and semantic processing decline (r = -0.376, p = .09) showed a statistical trend. No significant effects were found for the dorsal language stream. This is direct evidence for the importance of the integrity of the ventral language stream, in particular the left IFOF, in semantic processing deficits in SSD.
- Modinos G, Kempton MJ, Tognin S, Calem M, Porffy L, Antoniades M, et al. Association of Adverse Outcomes With Emotion Processing and Its Neural Substrate in Individuals at Clinical High Risk for Psychosis. JAMA psychiatry. 2020 Feb;77(2):190–200.
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IMPORTANCE: The development of adverse clinical outcomes in patients with psychosis has been associated with behavioral and neuroanatomical deficits related to emotion processing. However, the association between alterations in brain regions subserving emotion processing and clinical outcomes remains unclear. OBJECTIVE: To examine the association between alterations in emotion processing and regional gray matter volumes in individuals at clinical high risk (CHR) for psychosis, and the association with subsequent clinical outcomes. DESIGN, SETTING, AND PARTICIPANTS: This naturalistic case-control study with clinical follow-up at 12 months was conducted from July 1, 2010, to August 31, 2016, and collected data from 9 psychosis early detection centers (Amsterdam, Basel, Cologne, Copenhagen, London, Melbourne, Paris, The Hague, and Vienna). Participants (213 individuals at CHR and 52 healthy controls) were enrolled in the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) project. Data were analyzed from October 1, 2018, to April 24, 2019. MAIN MEASURES AND OUTCOMES: Emotion recognition was assessed with the Degraded Facial Affect Recognition Task. Three-Tesla magnetic resonance imaging scans were acquired from all participants, and gray matter volume was measured in regions of interest (medial prefrontal cortex, amygdala, hippocampus, and insula). Clinical outcomes at 12 months were evaluated for transition to psychosis using the Comprehensive Assessment of At-Risk Mental States criteria, and the level of overall functioning was measured through the Global Assessment of Functioning [GAF] scale. RESULTS: A total of 213 individuals at CHR (105 women [49.3%]; mean [SD] age, 22.9 [4.7] years) and 52 healthy controls (25 women [48.1%]; mean [SD] age, 23.3 [4.0] years) were included in the study at baseline. At the follow-up within 2 years of baseline, 44 individuals at CHR (20.7%) had developed psychosis and 169 (79.3%) had not. Of the individuals at CHR reinterviewed with the GAF, 39 (30.0%) showed good overall functioning (GAF score, ≥65), whereas 91 (70.0%) had poor overall functioning (GAF score, <65). Within the CHR sample, better anger recognition at baseline was associated with worse functional outcome (odds ratio [OR], 0.88; 95% CI, 0.78-0.99; P = .03). In individuals at CHR with a good functional outcome, positive associations were found between anger recognition and hippocampal volume (ze = 3.91; familywise error [FWE] P = .02) and between fear recognition and medial prefrontal cortex volume (z = 3.60; FWE P = .02), compared with participants with a poor outcome. The onset of psychosis was not associated with baseline emotion recognition performance (neutral OR, 0.93; 95% CI, 0.79-1.09; P = .37; happy OR, 1.03; 95% CI, 0.84-1.25; P = .81; fear OR, 0.98; 95% CI, 0.85-1.13; P = .77; anger OR, 1.00; 95% CI, 0.89-1.12; P = .96). No difference was observed in the association between performance and regional gray matter volumes in individuals at CHR who developed or did not develop psychosis (FWE P < .05). CONCLUSIONS AND RELEVANCE: In this study, poor functional outcome in individuals at CHR was found to be associated with baseline abnormalities in recognizing negative emotion. This finding has potential implications for the stratification of individuals at CHR and suggests that interventions that target socioemotional processing may improve functional outcomes.
- Walger H, Antonucci LA, Pigoni A, Upthegrove R, Salokangas RKR, Lencer R, et al. Basic Symptoms Are Associated With Age in Patients With a Clinical High-Risk State for Psychosis: Results From the PRONIA Study. Frontiers in Psychiatry. 2020;11:552175.
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In community studies, both attenuated psychotic symptoms (APS) and basic symptoms (BS) were more frequent but less clinically relevant in children and adolescents compared to adults. In doing so, they displayed differential age thresholds that were around age 16 for APS, around age 18 for perceptive BS, and within the early twenties for cognitive BS. Only the age effect has previously been studied and replicated in clinical samples for APS. Thus, we examined the reported age effect on and age thresholds of 14 criteria-relevant BS in a patient sample at clinical-high risk of psychosis (N = 261, age 15-40 yrs.), recruited within the European multicenter PRONIA-study. BS and the BS criteria, "Cognitive Disturbances" (COGDIS) and "Cognitive-perceptive BS" (COPER), were assessed with the "Schizophrenia Proneness Instrument, Adult version" (SPI-A). Using logistic regressions, prevalence rates of perceptive and cognitive BS, and of COGDIS and COPER, as well as the impact of social and role functioning on the association between age and BS were studied in three age groups (15-18 years, 19-23 years, 24-40 years). Most patients (91.2%) reported any BS, 55.9% any perceptive and 87.4% any cognitive BS. Furthermore, 56.3% met COGDIS and 80.5% COPER. Not exhibiting the reported differential age thresholds, both perceptive and cognitive BS, and, at trend level only, COPER were less prevalent in the oldest age group (24-40 years); COGDIS was most frequent in the youngest group (15-18 years). Functional deficits did not better explain the association with age, particularly in perceptive BS and cognitive BS meeting the frequency requirement of BS criteria. Our findings broadly confirmed an age threshold in BS and, thus, the earlier assumed link between presence of BS and brain maturation processes. Yet, age thresholds of perceptive and cognitive BS did not differ. This lack of differential age thresholds might be due to more pronounced the brain abnormalities in this clinical sample compared to earlier community samples. These might have also shown in more frequently occurring and persistent BS that, however, also resulted from a sampling toward these, i.e., toward COGDIS. Future studies should address the neurobiological basis of CHR criteria in relation to age.
- Mallawaarachchi SR, Amminger GP, Farhall J, Bolt LK, Nelson B, Yuen HP, et al. Cognitive functioning in ultra-high risk for psychosis individuals with and without depression: Secondary analysis of findings from the NEURAPRO randomized clinical trial. Schizophrenia Research. 2020 Apr;218:48–54.
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Neurocognitive impairments are well established in both ultra-high risk (UHR) for psychosis and major depressive disorder (MDD). Despite this understanding, investigation of neurocognitive deficits in UHR individuals with MDD and its association with MDD within this population, has been scarce. Hence, this study aimed to examine any differences in neurocognition at baseline between those with MDD at baseline and those with no history of MDD, as well as determine whether neurocognitive variables are significantly associated with meeting criteria for MDD at follow-up, while controlling for relevant clinical variables, within a UHR cohort. Data analysis was conducted on 207 participants whose baseline neurocognition was assessed using Brief Assessment of Cognition for Schizophrenia, as part of a trial of omega-3 fatty acids (NEURAPRO) for UHR individuals. While baseline MDD was the strongest predictor, poorer verbal memory and higher verbal fluency were significantly associated with MDD at 12 months (p = .04 and 0.026, respectively). Further, higher processing speed was significantly associated with MDD at medium-term follow-up (p = .047). These findings outline that neurocognitive skills were independently associated with meeting criteria for MDD at follow-up within UHR individuals, with novel findings of better verbal fluency and processing speed being linked to MDD outcomes. Hence, neurocognitive performance should be considered as a marker of risk for MDD outcomes and a target for management of MDD in UHR.
- Alqarni A, Mitchell TW, McGorry PD, Nelson B, Markulev C, Yuen HP, et al. Comparison of erythrocyte omega-3 index, fatty acids and molecular phospholipid species in people at ultra-high risk of developing psychosis and healthy people. Schizophrenia Research. 2020 Dec;226:44–51.
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People classified as ultra-high risk (UHR) of developing psychosis have reduced cellular membrane omega-3 and omega-6 polyunsaturated fatty acids (PUFA). We aimed to compare omega-3 index, fatty acids and molecular phospholipid species from erythrocytes of people with UHR (n = 285) with age-matched healthy controls (n = 120) assessed by mass spectrometry. Lower proportions of PUFA were observed in the UHR group compared to healthy controls; specifically, eicosapentaenoic acid (EPA) was 29.3% lower, docosahexaenoic acid (DHA) was 27.2% lower, arachidonic acid (AA) was 15.8% lower and the omega-3 index was 26.9% lower. The AA to EPA ratio was higher in the UHR group compared to the healthy group. Smoking status had no significant effect on PUFA levels in healthy or the UHR groups. BMI was associated with PUFA levels in the UHR group only and the statistical model only explains 2% of the variance of the PUFA levels. The proportion of nervonic acid was 64.4% higher in the UHR group compared to healthy controls. At a lipid class level, the UHR group had 16% higher concentrations of sphingomyelin (SM) and 46% lower concentrations phosphatidylethanolamine (PE) compared to healthy group. Of the 49 individual molecular phospholipids, twenty-seven phospholipid species were lower in the UHR group. In conclusion, there are clear differences in the proportions of erythrocyte fatty acids and phospholipids between UHR and healthy controls and UHR had higher concentrations of SM and lower concentrations of PE. These differences may represent a promising prodromal risk biomarker in the UHR population to aid clinical diagnosis.
- Berger M, Nelson B, Markulev C, Yuen HP, Schäfer MR, Mossaheb N, et al. Corrigendum: Relationship Between Polyunsaturated Fatty Acids and Psychopathology in the NEURAPRO Clinical Trial. Frontiers in Psychiatry. 2020;11:514.
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[This corrects the article DOI: 10.3389/fpsyt.2019.00393.].
- Hadar H, Zhang H, Phillips LJ, Amminger GP, Berger GE, Chen EYH, et al. Do schizotypal or borderline personality disorders predict onset of psychotic disorder or persistent attenuated psychotic symptoms in patients at high clinical risk? Schizophrenia Research. 2020 Jun;220:275–7.
- Riecher-Rössler A. Editorial. Archives of Women’s Mental Health. 2020 Dec;23(6):739–40.
- Mackintosh AJ, Borgwardt S, Studerus E, Riecher-Rössler A, de Bock R, Andreou C. EEG Microstate Differences in Medicated vs. Medication-Naïve First-Episode Psychosis Patients. Frontiers in Psychiatry. 2020;11:600606.
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There has been considerable interest in the role of synchronous brain activity abnormalities in the pathophysiology of psychotic disorders and their relevance for treatment; one index of such activity are EEG resting-state microstates. These reflect electric field configurations of the brain that persist over 60-120 ms time periods. A set of quasi-stable microstates classes A, B, C, and D have been repeatedly identified across healthy participants. Changes in microstate parameters coverage, duration and occurrence have been found in medication-naïve as well as medicated patients with psychotic disorders compared to healthy controls. However, to date, only two studies have directly compared antipsychotic medication effects on EEG microstates either pre- vs. post-treatment or between medicated and unmedicated chronic schizophrenia patients. The aim of this study was therefore to directly compare EEG resting-state microstates between medicated and medication-naïve (untreated) first-episode (FEP) psychosis patients (mFEP vs. uFEP). We used 19-channel clinical EEG recordings to compare temporal parameters of four prototypical microstate classes (A-D) within an overall sample of 47 patients (mFEP n = 17; uFEP n = 30). The results demonstrated significant decreases of microstate class A and significant increases of microstate class B in mFEP compared to uFEP. No significant differences between groups were found for microstate classes C and D. Further studies are needed to replicate these results in longitudinal designs that assess antipsychotic medication effects on neural networks at the onset of the disorder and over time during illness progression. As treatment response and compliance in FEP patients are relatively low, such studies could contribute to better understand treatment outcomes and ultimately improve treatment strategies.
- de Bock R, Mackintosh AJ, Maier F, Borgwardt S, Riecher-Rössler A, Andreou C. EEG microstates as biomarker for psychosis in ultra-high-risk patients. Translational Psychiatry. 2020 Aug;10(1):300.
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Resting-state EEG microstates are brief (50-100 ms) periods, in which the spatial configuration of scalp global field power remains quasi-stable before rapidly shifting to another configuration. Changes in microstate parameters have been described in patients with psychotic disorders. These changes have also been observed in individuals with a clinical or genetic high risk, suggesting potential usefulness of EEG microstates as a biomarker for psychotic disorders. The present study aimed to investigate the potential of EEG microstates as biomarkers for psychotic disorders and future transition to psychosis in patients at ultra-high-risk (UHR). We used 19-channel clinical EEG recordings and orthogonal contrasts to compare temporal parameters of four normative microstate classes (A-D) between patients with first-episode psychosis (FEP; n = 29), UHR patients with (UHR-T; n = 20) and without (UHR-NT; n = 34) later transition to psychosis, and healthy controls (HC; n = 25). Microstate A was increased in patients (FEP & UHR-T & UHR-NT) compared to HC, suggesting an unspecific state biomarker of general psychopathology. Microstate B displayed a decrease in FEP compared to both UHR patient groups, and thus may represent a state biomarker specific to psychotic illness progression. Microstate D was significantly decreased in UHR-T compared to UHR-NT, suggesting its potential as a selective biomarker of future transition in UHR patients.
- Tognin S, Catalan A, Modinos G, Kempton MJ, Bilbao A, Nelson B, et al. Emotion Recognition and Adverse Childhood Experiences in Individuals at Clinical High Risk of Psychosis. Schizophrenia Bulletin. 2020 Jul;46(4):823–33.
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OBJECTIVE: To investigate the association between facial affect recognition (FAR) and type of adverse childhood experiences (ACEs) in a sample of clinical high risk (CHR) individuals and a matched sample of healthy controls (HCs). METHODS: In total, 309 CHR individuals and 51 HC were recruited as part of an European Union-funded multicenter study (EU-GEI) and included in this work. During a 2-year follow-up period, 65 CHR participants made a transition to psychosis (CHR-T) and 279 did not (CHR-NT). FAR ability was measured using a computerized version of the Degraded Facial Affect Recognition (DFAR) task. ACEs were measured using the Childhood Experience of Care and Abuse Questionnaire, the Childhood Trauma Questionnaire, and the Bullying Questionnaire. Generalized regression models were used to investigate the relationship between ACE and FAR. Logistic regressions were used to investigate the relationship between FAR and psychotic transition. RESULTS: In CHR individuals, having experienced emotional abuse was associated with decreased total and neutral DFAR scores. CHR individuals who had experienced bullying performed better in the total DFAR and in the frightened condition. In HC and CHR, having experienced the death of a parent during childhood was associated with lower DFAR total score and lower neutral DFAR score, respectively. Analyses revealed a modest increase of transition risk with increasing mistakes from happy to angry faces. CONCLUSIONS: Adverse experiences in childhood seem to have a significant impact on emotional processing in adult life. This information could be helpful in a therapeutic setting where both difficulties in social interactions and adverse experiences are often addressed.
- Leanza L, Studerus E, Mackintosh AJ, Beck K, Seiler L, Andreou C, et al. Predictors of study drop-out and service disengagement in patients at clinical high risk for psychosis. Social Psychiatry and Psychiatric Epidemiology. 2020 May;55(5):539–48.
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PURPOSE: Study drop-out during follow-up and service disengagement frequently occur in patients at clinical high risk for psychosis (CHR-P). However, little is known about their predictors. Therefore, we aimed to analyze the rate and reasons for drop-out and service disengagement in CHR-P patients and investigate their sociodemographic and clinical predictors. METHODS: Data from 200 patients of the prospective Früherkennung von Psychosen (FePsy) study were analyzed with competing risks survival models, considering drop-out and transition to psychosis as competing events. To investigate whether symptoms changed immediately before drop-out, t tests were applied. RESULTS: Thirty-six percent of patients dropped out within 5 years. Almost all drop-outs also disengaged from our service. Hence, study drop-out was used as a proxy for service disengagement. Patients with more severe baseline disorganized symptoms and a late inclusion into the study were significantly more likely to disengage. Immediately before disengagement, there was significant improvement in negative symptoms only. CONCLUSION: A considerable proportion of CHR-P patients disengaged from our clinical study and service. Patients who were included during a later study period with more assessments disengaged more often, which might have been due to more frequent invitations to follow-up assessments and thereby increasing participation burden. Hence, our study provides a cautionary note on high-frequency follow-up assessments. Larger-scale studies evaluating predictors on multiple domains would help to further elucidate drop-out and disengagement.
- Menghini-Müller S, Studerus E, Ittig S, Valmaggia LR, Kempton MJ, Gaag M van der, et al. Sex differences in cognitive functioning of patients at-risk for psychosis and healthy controls: Results from the European Gene-Environment Interactions study. European psychiatry : the journal of the Association of European Psychiatrists. 2020 Mar;63(1).
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BACKGROUND.: Sex differences in cognitive functioning have long been recognized in schizophrenia patients and healthy controls (HC). However, few studies have focused on patients with an at-risk mental state (ARMS) for psychosis. Thus, the aim of the present study was to investigate sex differences in neurocognitive performance in ARMS patients compared with HC. METHODS.: The data analyzed in this study were collected within the multicenter European Gene-Environment Interactions study (11 centers). A total of 343 ARMS patients (158 women) and 67 HC subjects (33 women) were included. All participants completed a comprehensive neurocognitive battery. Linear mixed effects models were used to explore whether sex differences in cognitive functioning were present in the total group (main effect of sex) and whether sex differences were different for HC and ARMS (interaction between sex and group). RESULTS.: Women performed better in social cognition, speed of processing, and verbal learning than men regardless of whether they were ARMS or HC. However, only differences in speed of processing and verbal learning remained significant after correction for multiple testing. Additionally, ARMS patients displayed alterations in attention, current IQ, speed of processing, verbal learning, and working memory compared with HC. CONCLUSIONS.: Findings indicate that sex differences in cognitive functioning in ARMS are similar to those seen between healthy men and women. Thus, it appears that sex differences in cognitive performance may not be specific for ARMS, a finding resembling that in patients with schizophrenic psychoses.
- Alqarni A, Mitchell TW, McGorry PD, Nelson B, Markulev C, Yuen HP, et al. Supplementation with the omega-3 long chain polyunsaturated fatty acids: Changes in the concentrations of omega-3 index, fatty acids and molecular phospholipids of people at ultra high risk of developing psychosis. Schizophrenia Research. 2020 Dec;226:52–60.
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Omega-3 long chain polyunsaturated fatty acids (n-3 LCPUFA) are necessary for optimum mental health, with recent studies showing low n-3 LCPUFA in people at ultra-high risk (UHR) of developing psychosis. Furthermore, people at UHR of psychosis had increased erythrocyte sphingomyelin (SM) and reduced phosphatidylethanolamine (PE) concentrations as well as 27 erythrocyte phospholipid species that differed when compared to erythrocytes from age matched people not at UHR of psychosis. The aim of this analysis was to evaluate the effect of n-3 supplementation on the different erythrocyte lipid species (including SM and PE concentrations) in people at UHR of psychosis. Participants were randomly assigned to fish oil (containing 840 mg EPA and 560 mg DHA per day) or placebo (paraffin oil) for 6 months. Fasted blood samples were taken at baseline and post intervention. Mass spectrometry was used to analyse the molecular phospholipids and fatty acid composition of erythrocytes for both groups. The n-3 index was significantly increased from 3.0% to 4.12% after 6 months of receiving n-3 capsules. Fish oil capsules increased the phospholipid molecular species containing n-3 LCPUFA, and concomitant decreases in n-6 LCPUFA species. SM species did not show any significant changes in n-3 LCPUFA group however, three SM species (SM 16:0, SM 18:0, SM 18:1) significantly increased after 6 months of supplementation with placebo. N-3 supplementation for 6 months led to higher n-3 incorporation into erythrocytes, at the expense of n-6 PUFA across all phospholipid classes analyzed and may have prevented the increase in SM seen in the placebo group.
- Amminger GP, Nelson B, Markulev C, Yuen HP, Schäfer MR, Berger M, et al. The NEURAPRO Biomarker Analysis: Long-Chain Omega-3 Fatty Acids Improve 6-Month and 12-Month Outcomes in Youths at Ultra-High Risk for Psychosis. Biological Psychiatry. 2020 Feb;87(3):243–52.
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BACKGROUND: NEURAPRO was a multicenter, placebo-controlled trial of long-chain omega-3 polyunsaturated fatty acids (n-3 PUFAs) (fish oil) in 304 individuals at ultra-high risk for psychotic disorders. The study failed to show benefits of n-3 PUFAs over placebo. Although the randomized controlled trial design is placed at the top of the evidence hierarchy, this methodology has limitations in fish oil randomized controlled trials, as not only is the test agent present in the intervention group, but also n-3 fats are present in the diet and the body tissue of all participants. METHODS: Analysis of biomarker data (eicosapentaenoic acid [EPA], docosahexaenoic acid [DHA], n-3 index, EPA+DHA) collected as part of NEURAPRO was conducted on 218 participants with longitudinal biomarker data to determine if n-3 PUFAs measured in erythrocytes at baseline and month 6 predicted clinical outcomes. RESULTS: Increases of the n-3 index, EPA, and DHA predicted less severe psychopathology and better functioning at both follow-up time points. Higher baseline levels and increases of n-3 index also predicted overall clinical improvement at month 6 (n-3 index baseline: adjusted odds ratio [95% confidence interval (CI)] = 1.79 [1.30-2.48]; n-3 PUFA increase: adjusted odds ratio [95% CI] = 1.43 [1.16-1.76]) and at month 12 (n-3 index baseline: adjusted odds ratio [95% CI] = 2.60 [1.71-3.97]; n-3 PUFA increase: adjusted odds ratio [95% CI] = 1.36 [1.06-1.74]). CONCLUSIONS: These data suggest that n-3 PUFAs can exert therapeutic effects in ultra-high-risk individuals. This finding has implications for early intervention and treatment guidelines, as n-3 PUFA supplementation can easily and safely be used in a wide variety of settings, from primary care to specialist services.
- Hartmann JA, Schmidt SJ, McGorry PD, Berger M, Berger GE, Chen EYH, et al. Trajectories of symptom severity and functioning over a three-year period in a psychosis high-risk sample: A secondary analysis of the Neurapro trial. Behaviour Research and Therapy. 2020 Jan;124:103527.
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The Ultra-High Risk (UHR) for psychosis group is known to be heterogeneous with diverse outcomes. This study aimed to: 1. Identify subclasses of UHR individuals based on trajectories of symptomatic and functional change over time, 2. Identify predictors of these trajectories. A sample of 304 UHR individuals participating in the Neurapro trial were followed over an average of 40 months. All participants received cognitive-behavioural case management (CBCM). Symptomatic and functional profiles were investigated using latent class growth analysis. Multinomial regression was employed to investigate predictors of classes. Identified trajectories showed mostly parallel slopes (i.e. improving symptoms/functioning over time), which were primarily distinct regarding the severity of symptomatology/level of functioning at baseline (i.e. the intercept). Higher symptomatic/lower functioning classes were predicted by higher substance use, older age, female gender, and lower cognitive functioning. No divergent trajectories were identified as all classes improved over time. This may reflect effective treatment through CBCM, natural illness course, or effective engagement with mental health services. Nonetheless, classes highest in symptoms/lowest in functioning still showed considerable impairment during follow-up, highlighting the need for targeted intervention in these subgroups. The study emphasizes the need for more clinical attention directed towards UHR patients being female or using substances.
2019
- Bykowsky O, Harrisberger F, Schmidt A, Smieskova R, Hauke DJ, Egloff L, et al. Association of antidepressants with brain morphology in early stages of psychosis: an imaging genomics approach. Scientific reports. 2019 Jun;9(1).
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Depressive symptoms in subjects at Clinical High Risk for Psychosis (CHR-P) or at first-episode psychosis (FEP) are often treated with antidepressants. Our cross-sectional study investigated whether brain morphology is altered by antidepressant medication. High-resolution T-weighted structural MRI scans of 33 CHR-P and FEP subjects treated with antidepressants, 102 CHR-P and FEP individuals without antidepressant treatment and 55 controls, were automatically segmented using Freesurfer 6.0. Linear mixed-effects modelling was applied to assess the differences in subcortical volume, surface area and cortical thickness in treated, non-treated and healthy subjects, taking into account converted dosages of antidepressants. Increasing antidepressant dose was associated with larger volume of the pallidum and the putamen, and larger surface of the left inferior temporal gyrus. In a pilot subsample of separately studied subjects of known genomic risk loci, we found that in the right postcentral gyrus, the left paracentral lobule and the precentral gyrus antidepressant dose-associated surface increase depended on polygenic schizophrenia-related-risk score. As the reported regions are linked to the symptoms of psychosis, our findings reflect the possible beneficial effects of antidepressant treatment on an emerging psychosis.
- Youn S, Phillips LJ, Amminger GP, Berger G, Chen EYH, Haan L de, et al. Basic symptoms in young people at ultra-high risk of psychosis: Association with clinical characteristics and outcomes. Schizophrenia research. 2019 Dec;
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There has been limited research into the predictive value of basic symptoms and their relationship with other psychopathology in patients identified using the 'ultra high risk' (UHR) for psychosis approach. The current study investigated whether basic symptoms, specifically cognitive disturbances (COGDIS), were associated with a greater risk of transition to psychotic disorder and persistent attenuated psychotic symptoms (APS) at medium term follow-up (mean = 3.4 years) in UHR patients, as well as with general psychopathology at baseline. The sample included 304 UHR participants (mean age = 19.12 years) involved in an international multicenter trial of omega-3 fatty acids. UHR individuals who also met the COGDIS criteria (basic symptoms risk criteria) did not have a greater risk of transition than those who met the UHR criteria alone. However, meeting COGDIS risk criteria was associated with a greater likelihood of meeting the UHR attenuated psychotic symptoms risk group (i.e., having persistent attenuated psychotic symptoms) at 12-month follow-up (odds ratio = 1.85; 95% CI = 1.03, 3.32). Greater severity of cognitive basic symptoms was also independently associated with more severe general psychopathology at study entry. The findings do not support the notion that combined risk identification approaches (UHR and basic symptoms) aid in the identification of individuals at greatest risk of psychosis, although this interpretation is limited by the modest transition to psychosis rate (13%) and the time of follow up. However, the findings indicate that basic symptoms may be a clinically useful marker of more severe general psychopathology in UHR groups and risk for persistent attenuated psychotic symptoms.
- Princewill CW, Wangmo T, Jegede AS, Riecher-Rössler A, Elger BS. Bride price payment and women’s autonomy: Findings from qualitative interviews from Nigeria. Women & Health. 2019 Aug;59(7):775–88.
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Marriage involving a man and a woman is a universal social institution, but its practices vary among cultures. In Nigeria, a marriage is recognized after gifts are given, and a bride price is paid by the groom's family to the bride's family. Understanding the bride price will reduce the challenges women face in their marital homes. Women's autonomy is important for them to address matters affecting their health. We examined married Ikwerre women's perspectives on bride price and its impact on their autonomy using qualitative methods. From December 2014 to March 2015, 34 in-depth interviews and six focus group discussions were conducted with married Ikwerre women. Participants reported that patriarchy and a culture of absolute respect for men, not the bride price, was the reason for women's diminished autonomy. Participants noted that payment of the bride price was critical for validating marriage to give women respectable status in society as wives. Patriarchal rule and the demand for absolute respect for men need to be addressed in the Ikwerre culture. A woman's capability to address her health needs and use health care is largely dependent on her ability to act autonomously. Thus, educational interventions to enable women's decision-making are critical.
- Beck K, Andreou C, Studerus E, UlrikeHeitz, Ittig S, Leanza L, et al. Clinical and functional long-term outcome of patients at clinical high risk (CHR) for psychosis without transition to psychosis: A systematic review. Schizophrenia Research. 2019;
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Background Research on patients at clinical high risk (CHR) for psychosis has so far mainly focused on those with transition to frank psychosis (CHR-T patients). However, the majority of CHR patients do not transition (CHR-NT patients) and relatively little information is available on their clinical and functional outcome. Methods We conducted a systematic review on clinical and functional long-term outcome of CHR-NT patients. Studies were included if they had an average follow-up period of at least 24”¯months and reported on long-term outcome of CHR-NT patients in one or more of the following domains: (non-)remission from CHR, prevalence of clinical symptoms and/or clinical diagnoses (axis I and II), and psychosocial functioning. Results Ten publications from seven different single or multicenter studies with average follow-up durations of 2–7.5”¯years could be included. At the last follow-up assessment 28–71% of CHR-NT patients were not remitted from their CHR and 22–82% still had at least one clinical diagnosis. Approximately half of CHR-NT patients presented with poor psychosocial outcome at 2-year and 6-year follow-up. Conclusions The results suggest that, in the long-term, the majority of CHR-NT patients are not in full clinical remission and seem to suffer from one or more clinical disorders and psychosocial impairments. Since relatively few studies could be identified, further research is required to better understand the trajectories and clinical needs of CHR-NT patients.
- Beck K, Studerus E, Andreou C, Egloff L, Leanza L, Simon AE, et al. Clinical and functional ultra-long-term outcome of patients with a clinical high risk (CHR) for psychosis. European psychiatry : the journal of the Association of European Psychiatrists. 2019 Sep;62:30–7.
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Background Few studies have followed up patients with a clinical high risk (CHR) for psychosis for more than 2–3 years. We aimed to investigate the rates and baseline predictors for remission from CHR and transition to psychosis over a follow-up period of up to 16 years. Additionally, we examined the clinical and functional long-term outcome of CHR patients who did not transition. Methods We analyzed the long-term course of CHR patients that had been included in the longitudinal studies “Früherkennung von Psychosen” (FePsy) or “Bruderholz” (BHS). Those patients who had not transitioned to psychosis during the initial follow-up periods (2/5 years), were invited for additional follow-ups. Results Originally, 255 CHR patients had been included. Of these, 47 had transitioned to psychosis during the initial follow-ups. Thus, 208 were contacted for the long-term follow-up, of which 72 (34.6%) participated. From the original sample of 255, 26%, 31%, 35%, and 38% were estimated to have transitioned after 3, 5, 10, and 16 years, respectively, and 51% had remitted from their high risk status at the latest follow-up. Better psychosocial functioning at baseline was associated with a higher rate of remission. Of the 72 CHR patients re-assessed at long-term follow-up, 60 had not transitioned, but only 28% of those were fully recovered clinically and functionally. Conclusions Our study shows the need for follow-ups and clinical attention longer than the usual 2–3 years as there are several CHR patients with later transitions and only a minority of CHR those without transition fully recovers.
- Studerus E, Beck K, Fusar-Poli P, Riecher-Rössler A. Development and Validation of a Dynamic Risk Prediction Model to Forecast Psychosis Onset in Patients at Clinical High Risk. Schizophrenia bulletin. 2019 Jul;
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The prediction of outcomes in patients at Clinical High Risk for Psychosis (CHR-P) almost exclusively relies on static data obtained at a single snapshot in time (ie, baseline data). Although the CHR-P symptoms are intrinsically evolving over time, available prediction models cannot be dynamically updated to reflect these changes. Hence, the aim of this study was to develop and internally validate a dynamic risk prediction model (joint model) and to implement this model in a user-friendly online risk calculator. Furthermore, we aimed to explore the prognostic performance of extended dynamic risk prediction models and to compare static with dynamic prediction. One hundred ninety-six CHR-P patients were recruited as part of the ”Basel Früherkennung von Psychosen“ (FePsy) study. Psychopathology and transition to psychosis was assessed at regular intervals for up to 5 years using the Brief Psychiatric Rating Scale-Expanded (BPRS-E). Various specifications of joint models were compared with regard to their cross-validated prognostic performance. We developed and internally validated a joint model that predicts psychosis onset from BPRS-E disorganization and years of education at baseline and BPRS-E positive symptoms during the follow-up with good prognostic performance. The model was implemented as online risk calculator (http://www.fepsy.ch/DPRP/). The use of extended joint models slightly increased the prognostic accuracy compared to basic joint models, and dynamic models showed a higher prognostic accuracy than static models. Our results confirm that extended joint modeling could improve the prediction of psychosis in CHR-P patients. We implemented the first online risk calculator that can dynamically update psychosis risk prediction.
- Kulkarni J, Butler S, Riecher-Rössler A. Estrogens and SERMS as adjunctive treatments for schizophrenia. Frontiers in neuroendocrinology. 2019 Mar;
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More than thirty years have passed since sex and gender differences were noted in the age of onset, course and outcomes for schizophrenia. The 'estrogen hypothesis“ was coined in the 1990's to describe neuroprotective effects of estrogen. Intervention studies in schizophrenia patients with estradiol and selective estrogen receptor modulators (SERMs) are promising but psychiatrists and other health practitioners do not generally take up this useful adjunctive treatment for their female patients with schizophrenia. The reasons for this are manifold, but overall a cultural shift in the practice of psychiatry is needed to recognise the specific needs of women with schizophrenia and tailor treatments, such as hormone adjuncts to improve the outcomes for this significant population. The two main aims of this article are to review the evidence and theory of estrogen treatments in schizophrenia and to recommend translation of adjunctive estrogen treatment into clinical practice for women with schizophrenia.
- Menghini-Müller S, Studerus E, Ittig S, Heitz U, Egloff L, Andreou C, et al. Gender differences of patients at-risk for psychosis regarding symptomatology, drug use, comorbidity and functioning - Results from the EU-GEI study. European psychiatry : the journal of the Association of European Psychiatrists. 2019 May;59:52–9.
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BACKGROUND: Gender differences in symptomatology in chronic schizophrenia and first episode psychosis patients have often been reported. However, little is known about gender differences in those at risk of psychotic disorders. This study investigated gender differences in symptomatology, drug use, comorbidity (i.e. substance use, affective and anxiety disorders) and global functioning in patients with an at-risk mental state (ARMS) for psychosis. METHODS: The sample consisted of 336 ARMS patients (159 women) from the prodromal work package of the EUropean network of national schizophrenia networks studying Gene-Environment Interactions (EU-GEI; 11 centers). Clinical symptoms, drug use, comorbidity and functioning were assessed at first presentation to an early detection center using structured interviews. RESULTS: In unadjusted analyses, men were found to have significantly higher rates of negative symptoms and current cannabis use while women showed higher rates of general psychopathology and more often displayed comorbid affective and anxiety disorders. No gender differences were found for global functioning. The results generally did not change when corrected for possible cofounders (e.g. cannabis use). However, most differences did not withstand correction for multiple testing. CONCLUSIONS: Findings indicate that gender differences in symptomatology and comorbidity in ARMS are similar to those seen in overt psychosis and in healthy controls. However, observed differences are small and would only be reliably detected in studies with high statistical power. Moreover, such small effects would likely not be clinically meaningful.
- Maric NP, Petrovic SA, Rojnic-Kuzman M, Riecher-Rössler A. Implementation of early detection and intervention services for psychosis in Central and Eastern Europe: Current status. Early intervention in psychiatry. 2019 Mar;
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Unequal development of early detection (ED) and early intervention (EI) programs/services for psychosis has been shown across Europe. The present report aims to fill in the knowledge gap regarding the implementation and several other important aspects of ED/EI services in Central and Eastern Europe (CEE), a region with highly underdeveloped mental health service research.
- Malda A, Boonstra N, Barf H, Jong S de, Aleman A, Addington J, et al. Individualized Prediction of Transition to Psychosis in 1,676 Individuals at Clinical High Risk: Development and Validation of a Multivariable Prediction Model Based on Individual Patient Data Meta-Analysis. Frontiers in psychiatry. 2019 May;10.
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The Clinical High Risk state for Psychosis (CHR-P) has become the cornerstone of modern preventive psychiatry. The next stage of clinical advancements rests on the ability to formulate a more accurate prognostic estimate at the individual subject level. Individual Participant Data Meta-Analyses (IPD-MA) are robust evidence synthesis methods that can also offer powerful approaches to the development and validation of personalized prognostic models. The aim of the study was to develop and validate an individualized, clinically based prognostic model for forecasting transition to psychosis from a CHR-P stage. A literature search was performed between January 30, 2016, and February 6, 2016, consulting PubMed, Psychinfo, Picarta, Embase, and ISI Web of Science, using search terms (”ultra high risk“ OR ”clinical high risk“ OR ”at risk mental state“) AND [(conver* OR transition* OR onset OR emerg* OR develop*) AND psychosis] for both longitudinal and intervention CHR-P studies. Clinical knowledge was used to select predictors: age, gender, CHR-P subgroup, the severity of attenuated positive psychotic symptoms, the severity of attenuated negative psychotic symptoms, and level of functioning at baseline. The model, thus, developed was validated with an extended form of internal validation. Fifteen of the 43 studies identified agreed to share IPD, for a total sample size of 1,676. There was a high level of heterogeneity between the CHR-P studies with regard to inclusion criteria, type of assessment instruments, transition criteria, preventive treatment offered. The internally validated prognostic performance of the model was higher than chance but only moderate [Harrell's C-statistic 0.655, 95% confidence interval (CIs), 0.627-0.682]. This is the first IPD-MA conducted in the largest samples of CHR-P ever collected to date. An individualized prognostic model based on clinical predictors available in clinical routine was developed and internally validated, reaching only moderate prognostic performance. Although personalized risk prediction is of great value in the clinical practice, future developments are essential, including the refinement of the prognostic model and its external validation. However, because of the current high diagnostic, prognostic, and therapeutic heterogeneity of CHR-P studies, IPD-MAs in this population may have an limited intrinsic power to deliver robust prognostic models.
- Bolt LK, Amminger GP, Farhall J, McGorry PD, Nelson B, Markulev C, et al. Neurocognition as a predictor of transition to psychotic disorder and functional outcomes in ultra-high risk participants: Findings from the NEURAPRO randomized clinical trial. Schizophrenia research. 2019 Apr;206:67–74.
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BACKGROUND: Neurocognitive impairments experienced by individuals at ultra-high risk (UHR) for psychosis are potential predictors of outcome within this population, however there is inconsistency regarding the specific neurocognitive domains implicated. This study aimed to examine whether baseline neurocognition predicted transition to psychosis, or functional outcomes, at medium-term (mean”¯=”¯3.4”¯years) follow-up, while controlling for other clinical/treatment variables associated with transition to psychosis. METHOD: Analysis of data collected as part of a multi-centre RCT of omega-3 fatty acids and cognitive-behavioural case management (NEURAPRO) for UHR individuals was conducted on the 294 participants (134 males, 160 females) who completed neurocognitive assessment (Brief Assessment of Cognition for Schizophrenia) at baseline. Transition to psychosis was determined using the Comprehensive Assessment of At-Risk Mental States (CAARMS), and functioning was measured with the Global Functioning: Social and Role Scales. RESULTS: Mean baseline z-scores indicated that UHR participants performed a quarter to half a standard deviation below normative means in all domains (range mean z”¯=”¯-0.24 to -0.47), except for executive functioning (mean z”¯=”¯0.16). After adjusting for covariates, poorer Executive (p”¯=”¯.010) and Motor (p”¯=”¯.030) functions were predictive of transition to psychosis. Processing Speed and Verbal Fluency were significant predictors of role functioning at 12”¯months (p”¯=”¯.004), and social functioning at medium-term follow-up (p”¯=”¯.015), respectively. CONCLUSIONS: Neurocognitive abilities are independent predictors of both transition to psychosis and functional outcomes within the UHR population. Further research is needed to determine the best combination of risk variables in UHR individuals for prediction of psychosis transition, functioning and other psychopathology outcomes
- Egloff L, Lenz C, Studerus E, Heitz U, Harrisberger F, Smieskova R, et al. No associations between medial temporal lobe volumes and verbal learning/memory in emerging psychosis. The European journal of neuroscience. 2019 Apr;
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Gray matter (GM) volume alterations have been repeatedly demonstrated in patients with first episode psychosis (FEP). Some of these neuroanatomical abnormalities are already evident in the at-risk mental state (ARMS) for psychosis. Not only GM alterations but also neurocognitive impairments predate the onset of frank psychosis with verbal learning and memory (VLM) being among the most impaired domains. Yet, their interconnection with alterations in GM volumes remains ambiguous. Thus, we evaluated associations of different subcortical GM volumes in the medial temporal lobe with VLM performance in antipsychotic-naïve ARMS and FEP patients. Data from 59 ARMS and 31 FEP patients, collected within the prospective Früherkennung von Psychosen study, were analysed. Structural T1-weighted images were acquired using a 3 Tesla magnetic resonance imaging scanner. VLM was assessed using the California Verbal Learning Test and its factors Attention Span, Learning Efficiency, Delayed Memory and Inaccurate Memory. FEP patients showed significantly enlarged volumes of hippocampus, pallidum, putamen and thalamus compared to ARMS patients. A significant negative association between amygdala and pallidum volume and Attention Span was found in ARMS and FEP patients combined, which however did not withstand correction for multiple testing. Although we found significant between-group differences in subcortical volumes and VLM is among the most impaired cognitive domains in emerging psychosis, we could not demonstrate an association between low performance and subcortical GM volumes alterations in antipsychotic-naïve patients. Hence, deficits in this domain do not appear to stem from alterations in subcortical structures. This article is protected by copyright. All rights reserved.
- Berger M, Nelson B, Markulev C, Yuen HP, Schafer MR, Mossaheb N, et al. Relationship Between Polyunsaturated Fatty Acids and Psychopathology in the NEURAPRO Clinical Trial. Frontiers in psychiatry. 2019 Jun;10.
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Deficiencies in membrane polyunsaturated fatty acids (PUFA) such as omega-3 (n-3) fatty acids are thought to contribute to the pathophysiological processes underlying psychotic disorders. Emerging evidence suggests that the levels of PUFA are related to clinical symptoms but significant heterogeneity exists between studies. Here, we investigated associations of membrane PUFA with clinical symptoms and functioning in a large sample of individuals at ultra-high risk (UHR) for psychosis. A total of 285 participants of the NEURAPRO clinical trial were investigated for erythrocyte PUFA levels, including the n-3 index, n-6/n-3 PUFA ratio, docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA). Severity of general psychopathology [Brief Psychiatric Rating Scale (BPRS)], psychotic symptoms (BPRS psychosis subscale), negative symptoms [Scale for the Assessment of Negative Symptoms (SANS)], manic symptoms [Young Mania Rating Scale (YMRS)], depressive symptoms [Montgomery Asberg Depression Rating Scale (MADRS)], and functioning [Social and Occupational Functioning Scale (SOFAS), Global Functioning Social (GF-S) and Role (GF-R) scales] were assessed concurrently. Partial correlation taking into account the effects of gender, age, and smoking was used to examine the relationship between PUFAs and symptoms severity. The n-3 index negatively correlated with the severity of general psychopathology, psychotic symptoms, depressive symptoms, and manic symptoms. The n-6/n-3 PUFA ratio positively correlated with severity of psychotic and depressive symptoms. The n-3 PUFA DHA negatively correlated with the severity of general psychopathology, positive, manic, and depressive symptoms. EPA negatively correlated with manic symptoms. Nervonic acid, an n-9 monounsaturated fatty acid, positively correlated with general psychopathology, positive and negative symptoms, depressive symptoms, and manic symptoms. The long-chain saturated fatty acid tetracosanoic acid positively correlated with general psychopathology, positive, manic, and depressive symptoms. Partially consistent with a previous study, psychotic symptoms, depressive symptoms, and symptoms of mania were associated with several classes of FAs in the present study. These findings support the relevance of membrane fatty acids for the onset of psychotic symptoms and indicate that FAs should be further evaluated as biomarkers in the UHR for psychosis group. ANZCTR, identifier: 12608000475347.
- van Erp TGM, Walton E, Hibar DP, Schmaal L, Jiang W, Glahn DC, et al. Reply to: New Meta- and Mega-analyses of Magnetic Resonance Imaging Findings in Schizophrenia: Do They Really Increase Our Knowledge About the Nature of the Disease Process? Biological Psychiatry. 2019 Apr;85(7):e35–9.
- Thibaut F, Chagraoui A, Buckley L, Gressier F, Labad J, Lamy S, et al. WFSBP * and IAWMH ** Guidelines for the treatment of alcohol use disorders in pregnant women. The World Journal of Biological Psychiatry: The Official Journal of the World Federation of Societies of Biological Psychiatry. 2019 Jan;20(1):17–50.
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OBJECTIVES: These practice guidelines for the treatment of alcohol use disorders during pregnancy were developed by members of the International Task Force of the World Federation of Societies of Biological Psychiatry and the International Association for Women's Mental Health. METHODS: We performed a systematic review of all available publications and extracted data from national and international guidelines. The Task Force evaluated the data with respect to the strength of evidence for the efficacy and safety of each medication. RESULTS AND DISCUSSION: There is no safe level of alcohol use during pregnancy. Abstinence is recommended. Ideally, women should stop alcohol use when pregnancy is planned and, in any case, as soon as pregnancy is known. Detecting patterns of alcohol maternal drinking should be systematically conducted at first antenatal visit and throughout pregnancy. Brief interventions are recommended in the case of low or moderate risk of alcohol use. Low doses of benzodiazepines, for the shortest duration, may be used to prevent alcohol withdrawal symptoms when high and chronic alcohol intake is stopped and hospitalisation is recommended. Due to the low level of evidence and/or to low benefit/risk ratio, pharmacological treatment for maintenance of abstinence should not be used during pregnancy. At birth, foetal alcohol spectrum disorders must be searched for, and alcohol metabolites should be measured in meconium of neonates in any doubt of foetal alcohol exposure.
2018
- Studerus E, Corbisiero S, Mazzariello N, Ittig S, Leanza L, Egloff L, et al. Can neuropsychological testing facilitate differential diagnosis between at-risk mental state (ARMS) for psychosis and adult attention-deficit/hyperactivity disorder (ADHD)? European psychiatry : the journal of the Association of European Psychiatrists. 2018 Mar;52:38–44.
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Patients with an at-risk mental state (ARMS) for psychosis and patients with attention-deficit/hyperactivity disorder (ADHD) have many overlapping signs and symptoms and hence can be difficult to differentiate clinically. The aim of this study was to investigate whether the differential diagnosis between ARMS and adult ADHD could be improved by neuropsychological testing. 168 ARMS patients, 123 adult ADHD patients and 109 healthy controls (HC) were recruited via specialized clinics of the University of Basel Psychiatric Hospital. Sustained attention and impulsivity were tested with the Continuous Performance Test, verbal learning and memory with the California Verbal Learning Test, and problem solving abilities with the Tower of Hanoi Task. Group differences in neuropsychological performance were analyzed using generalized linear models. Furthermore, to investigate whether adult ADHD and ARMS can be correctly classified based on the pattern of cognitive deficits, machine learning (i.e. random forests) was applied. Compared to HC, both patient groups showed deficits in attention and impulsivity and verbal learning and memory. However, in adult ADHD patients the deficits were comparatively larger. Accordingly, a machine learning model predicted group membership based on the individual neurocognitive performance profile with good accuracy (AUC”¯=”¯0.82). Our results are in line with current meta-analyses reporting that impairments in the domains of attention and verbal learning are of medium effect size in adult ADHD and of small effect size in ARMS patients and suggest that measures of these domains can be exploited to improve the differential diagnosis between adult ADHD and ARMS patients.
- Das T, Borgwardt S, Hauke DJ, Harrisberger F, Lang UE, Riecher-Rössler A, et al. Disorganized Gyrification Network Properties During the Transition to Psychosis. JAMA psychiatry. 2018 Apr;
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IMPORTANCE: There is urgent need to improve the limited prognostic accuracy of clinical instruments to predict psychosis onset in individuals at clinical high risk (CHR) for psychosis. As yet, no reliable biological marker has been established to delineate CHR individuals who will develop psychosis from those who will not. OBJECTIVES: To investigate abnormalities in a graph-based gyrification connectome in the early stages of psychosis and to test the accuracy of this systems-based approach to predict a transition to psychosis among CHR individuals. DESIGN, SETTING, AND PARTICIPANTS: This investigation was a cross-sectional magnetic resonance imaging (MRI) study with follow-up assessment to determine the transition status of CHR individuals. Participants were recruited from a specialized clinic for the early detection of psychosis at the Department of Psychiatry (Universitäre Psychiatrische Kliniken [UPK]), University of Basel, Basel, Switzerland. Participants included individuals in the following 4 study groups: 44 healthy controls (HC group), 63 at-risk mental state (ARMS) individuals without later transition to psychosis (ARMS-NT group), 16 ARMS individuals with later transition to psychosis (ARMS-T group), and 38 antipsychotic-free patients with first-episode psychosis (FEP group). The study dates were November 2008 to November 2014. The dates of analysis were March to November 2017. MAIN OUTCOMES AND MEASURES: Gyrification-based structural covariance networks (connectomes) were constructed to quantify global integration, segregation, and small-worldness. Group differences in network measures were assessed using functional data analysis across a range of network densities. The extremely randomized trees algorithm with repeated 5-fold cross-validation was used to delineate ARMS-T individuals from ARMS-NT individuals. Permutation tests were conducted to assess the significance of classification performance measures. RESULTS: The 4 study groups comprised 161 participants with mean (SD) ages ranging from 24.0 (4.7) to 25.9 (5.7) years. Small-worldness was reduced in the ARMS-T and FEP groups and was associated with decreased integration and increased segregation in both groups (Hedges g range, 0.666-1.050). Using the connectome properties as features, a good classification performance was obtained (accuracy, 90.49%; balanced accuracy, 81.34%; positive predictive value, 84.47%; negative predictive value, 92.18%; sensitivity, 66.11%; specificity, 96.58%; and area under the curve, 88.30%). CONCLUSIONS AND RELEVANCE: These findings suggest that there is poor integration in the coordinated development of cortical folding in patients who develop psychosis. These results further suggest that gyrification-based connectomes might be a promising means to generate systems-based measures from anatomical data to improve individual prediction of a transition to psychosis in CHR individuals.
- Yuen HP, Mackinnon A, Hartmann J, Amminger GP, Markulev C, Lavoie S, et al. Dynamic prediction of transition to psychosis using joint modelling. Schizophrenia research. 2018 Dec;202:333–40.
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Considerable research has been conducted seeking risk factors and constructing prediction models for transition to psychosis in individuals at ultra-high risk (UHR). Nearly all such research has only employed baseline predictors, i.e. data collected at the baseline time point, even though longitudinal data on relevant measures such as psychopathology have often been collected at various time points. Dynamic prediction, which is the updating of prediction at a post-baseline assessment using baseline and longitudinal data accumulated up to that assessment, has not been utilized in the UHR context. This study explored the use of dynamic prediction and determined if it could enhance the prediction of frank psychosis onset in UHR individuals. An emerging statistical methodology called joint modelling was used to implement the dynamic prediction. Data from the NEURAPRO study (n”¯=”¯304 UHR individuals), an intervention study with transition to psychosis study as the primary outcome, were used to investigate dynamic predictors. Compared with the conventional approach of using only baseline predictors, dynamic prediction using joint modelling showed significantly better sensitivity, specificity and likelihood ratios. As dynamic prediction can provide an up-to-date prediction for each individual at each new assessment post entry, it can be a useful tool to help clinicians adjust their prognostic judgements based on the unfolding clinical symptomatology of the patients. This study has shown that a dynamic approach to psychosis prediction using joint modelling has the potential to aid clinicians in making decisions about the provision of timely and personalized treatment to patients concerned.
- Egloff L, Studerus E, Zimmermann R, Heitz U, Menghini-Müller S, Ittig S, et al. Evaluating verbal learning and memory in patients with an at-risk mental state or first episode psychosis using structural equation modelling. PloS one [Internet]. 2018 May;13(5). Available from: http://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0196936&type=printable
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Verbal learning and memory are impaired not only in patients with a first episode of psychosis (FEP) but also–to a lower extent–in those with an at-risk mental state for psychosis (ARMS). However, little is known about the specific nature of these impairments. Hence, we aimed to study learning and memory processes in ARMS and FEP patients by making use of structural equation modelling. Verbal learning was assessed with the California Verbal Learning Test (CVLT) in 98 FEP patients, 126 ARMS patients and 68 healthy controls (HC) as part of the Basel early detection of psychosis (FePsy) study. The four-factorial CFA model of Donders was used to estimate test performance on latent variables of the CVLT and growth curve analysis was used to model the learning curve. The latter allows disentangling initial recall, which is strongly determined by attentional processes, from the learning rate. The CFA model revealed that ARMS and FEP patients were impaired in Attention Span, Learning Efficiency and Delayed Memory and that FEP patients were additionally impaired in Inaccurate Memory. Additionally, ARMS-NT, but not ARMS-T, performed significantly worse than HC on Learning Efficiency. The growth curve model indicated that FEP patients were impaired in both initial recall and learning rate and that ARMS patients were only impaired in the learning rate. Since impairments were more pronounced in the learning rate than the initial recall, our results suggest that the lower scores in the CVLT reported in previous studies are more strongly driven by impairments in the rate of learning than by attentional processes.
- Peralta D, Studerus E, Andreou C, Beck K, Ittig S, Leanza L, et al. Exploring the predictive power of the unspecific risk category of the Basel Screening Instrument for Psychosis. Early intervention in psychiatry. 2018 Jul;
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AIM: Ultrahigh risk (UHR) criteria, consisting of brief limited intermittent psychotic symptoms (BLIPS), attenuated psychotic symptoms (APS) and genetic risk and deterioration (GRD) syndrome are the most widely used criteria for assessing the clinical high-risk state for psychosis (CHR-P). The Basel Screening Instrument for Psychosis (BSIP) includes a further risk category, the unspecific risk category (URC). However, little is known about the predictive power of this risk category compared to other risk categories. METHODS: Two hundred CHR-P patients were detected as part of the Früherkennung von Psychosen (FePsy) study using the BSIP. Transition to psychosis was assessed in regular intervals for up to 7 years. RESULTS: Patients meeting only the URC criterion (n = 40) had a significantly lower risk of transition to psychosis than the UHR group (including BLIPS, APS and GRD) (HR 0.19 [0.05; 0.80] (P = 0.024). Furthermore, the URC only risk group had a lower transition risk than the APS without BLIPS group (P = 0.015) and a trendwise lower risk than the BLIPS group (P = 0.066). However, despite the lower transition risk in the URC only group, there were still two patients (5%) in this group with a later transition to psychosis. CONCLUSIONS: The URC includes patients who have a lower risk of transition than those included by the UHR categories and thereby increases the sensitivity of the BSIP. This offers the possibility of a stratified intervention, with these subjects receiving low intensity follow-up and treatment.
- Harrisberger F, Smieskova R, Egli T, Simon AE, Riecher-Rössler A, Fusar-Poli P, et al. Impact on the Onset of Psychosis of a Polygenic Schizophrenia-Related Risk Score and Changes in White Matter Volume. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology. 2018 Jul;48(3):1201–14.
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BACKGROUND: Reductions in the volume of brain white matter are a common feature in schizophrenia and bipolar disorder while the association between white matter and polygenic schizophrenia-related risk is unclear. To look at the intermediate state between health and the full-blown disorder, we investigated this aspect in groups of patients before and after the onset of psychosis. METHODS: On a 3 Tesla scanner, total and regional white matter volumes were investigated by structural magnetic resonance imaging (MRI) in the following groups: 37 at-risk mental state patients (ARMS), including 30 with no transition to psychosis (ARMS-NT) and 7 with a transition to psychosis (ARMS-T) pooled with 25 first episode psychosis (FEP) patients. These T1-weighted images were automatically processed with the FreeSurfer software and compared with an odds-ratio-weighted polygenic schizophrenia-related risk score (PSRS) based on the publicly available top white matter single-nucleotide polymorphisms. RESULTS: We found no association, only a trend, between PSRS and white matter volume over all groups (β = 0.24, p = 0.07, 95% confidence interval = [-0.02 - 0.49]). However, a higher PSRS was significantly associated with a higher probability of being assigned to the ARMS-T + FEP group rather than to the ARMS-NT group (β = 0.70, p = 0.02, 95% confidence interval = [0.14 - 1.33]); there was no such association with white matter volume. Additionally, a positive association was found between PSRS and the Brief Psychiatric Rating Scale (BPRS) total score for the pooled ARMS-NT/ARMS-T+FEP sample and for the ARMS-T + FEP group also, but none for the ARMS-NT group only. CONCLUSION: These findings suggest that at-risk mental state patients with a transition and first-episode psychosis patients have a higher genetic risk for schizophrenia than at-risk mental state patients with no transition to psychosis; this risk was associated with psychopathological symptoms. Further analyses may allow polygenic schizophrenia-related risk scores to be used as biomarkers to predict psychosis.
- Nelson B, Amminger GP, Yuen HP, Markulev C, Lavoie S, Schafer MR, et al. NEURAPRO: a multi-centre RCT of omega-3 polyunsaturated fatty acids versus placebo in young people at ultra-high risk of psychotic disorders-medium-term follow-up and clinical course. NPJ schizophrenia. 2018 Jun;4(1).
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This study reports a medium-term follow-up of a randomised, double-blind, placebo-controlled trial of omega-3 polyunsaturated fatty acids (PUFA) in ultra-high risk for psychosis (UHR) patients. Primary outcomes of interest were transition to psychosis and symptomatic and functional outcome. A secondary aim was to investigate clinical predictors of medium-term outcome. Three hundred four UHR participants were recruited across 10 specialised early psychosis services in Australia, Asia, and Europe. The intervention consisted of 1.4 g/daily of omega-3 PUFA or placebo, plus up to 20 sessions of cognitive-behavioural case management (CBCM), over the 6-month study period, with participants receiving further CBCM sessions on basis of need between months 6-12. Mean time to follow-up was 3.4 (median = 3.3; SD = 0.9) years. There was a modest increase in transitions between 12-month and medium-term follow-up (11-13%) and substantial improvement in symptoms and functioning between baseline and follow-up, with no differences between the treatment groups. Most improvement had been achieved by end of the intervention. 55% of the sample received mental health treatment between end of intervention and follow-up. Omega-3 PUFA did not provide additional benefits to good quality psychosocial intervention over the medium term. Although most improvement had been achieved by end of intervention the substantial rates of post-intervention mental health service use indicate longer-term clinical need in UHR patients. The post-intervention phase treatment or the longer-term effect of CBCM, or a combination of the two, may have contributed to maintaining the gains achieved during the intervention phase and prevented significant deterioration after this time.
- Heitz U, Papmeyer M, Studerus E, Egloff L, Ittig S, Andreou C, et al. Plasma and serum brain-derived neurotrophic factor (BDNF) levels and their association with neurocognition in at-risk mental state, first episode psychosis and chronic schizophrenia patients. The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry. 2018 Jun;1–10.
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OBJECTIVES: Brain-derived neurotrophic factor (BDNF) is involved in numerous cognitive processes. Since cognitive deficits are a core feature of psychotic disorders, the investigation of BDNF levels in psychosis and their correlation with cognition has received increased attention. However, there are no studies investigating BDNF levels in individuals with an at-risk mental state (ARMS) for psychosis. Hence, the aims of the present study were: (1) assessing peripheral BDNF levels across different (potential) stages of psychosis; (2) investigating their association with cognition. METHODS: Plasma and serum BDNF levels and neuropsychological performance were assessed in 16 ARMS, six first-episode psychosis (FEP), and 11 chronic schizophrenia (CS) patients. Neuropsychological assessment covered intelligence, verbal memory, working memory, attention and executive functioning. RESULTS: Both plasma and serum BDNF levels were highest in CS, intermediate in FEP and lowest in ARMS. Multiple regression analysis revealed a significant positive association of plasma BDNF levels with planning ability across all groups. CONCLUSIONS: The lower peripheral BDNF levels in ARMS compared to FEP and CS might point towards an important drop of this neurotrophin prior to the onset of frank psychosis. The associations of peripheral BDNF with planning-abilities match previous findings.
- Koutsouleris N, Kambeitz-Ilankovic L, Ruhrmann S, Rosen M, Ruef A, Dwyer DB, et al. Prediction Models of Functional Outcomes for Individuals in the Clinical High-Risk State for Psychosis or With Recent-Onset Depression: A Multimodal, Multisite Machine Learning Analysis. JAMA psychiatry. 2018 Sep;
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IMPORTANCE: Social and occupational impairments contribute to the burden of psychosis and depression. There is a need for risk stratification tools to inform personalized functional-disability preventive strategies for individuals in at-risk and early phases of these illnesses. OBJECTIVE: To determine whether predictors associated with social and role functioning can be identified in patients in clinical high-risk (CHR) states for psychosis or with recent-onset depression (ROD) using clinical, imaging-based, and combined machine learning; assess the geographic, transdiagnostic, and prognostic generalizability of machine learning and compare it with human prognostication; and explore sequential prognosis encompassing clinical and combined machine learning. DESIGN, SETTING, AND PARTICIPANTS: This multisite naturalistic study followed up patients in CHR states, with ROD, and with recent-onset psychosis, and healthy control participants for 18 months in 7 academic early-recognition services in 5 European countries. Participants were recruited between February 2014 and May 2016, and data were analyzed from April 2017 to January 2018. AIN OUTCOMES AND MEASURES: Performance and generalizability of prognostic models. RESULTS: A total of 116 individuals in CHR states (mean [SD] age, 24.0 [5.1] years; 58 [50.0%] female) and 120 patients with ROD (mean [SD] age, 26.1 [6.1] years; 65 [54.2%] female) were followed up for a mean (SD) of 329 (142) days. Machine learning predicted the 1-year social-functioning outcomes with a balanced accuracy of 76.9% of patients in CHR states and 66.2% of patients with ROD using clinical baseline data. Balanced accuracy in models using structural neuroimaging was 76.2% in patients in CHR states and 65.0% in patients with ROD, and in combined models, it was 82.7% for CHR states and 70.3% for ROD. Lower functioning before study entry was a transdiagnostic predictor. Medial prefrontal and temporo-parieto-occipital gray matter volume (GMV) reductions and cerebellar and dorsolateral prefrontal GMV increments had predictive value in the CHR group; reduced mediotemporal and increased prefrontal-perisylvian GMV had predictive value in patients with ROD. Poor prognoses were associated with increased risk of psychotic, depressive, and anxiety disorders at follow-up in patients in the CHR state but not ones with ROD. Machine learning outperformed expert prognostication. Adding neuroimaging machine learning to clinical machine learning provided a 1.9-fold increase of prognostic certainty in uncertain cases of patients in CHR states, and a 10.5-fold increase of prognostic certainty for patients with ROD. CONCLUSIONS AND RELEVANCE: Precision medicine tools could augment effective therapeutic strategies aiming at the prevention of social functioning impairments in patients with CHR states or with ROD.
- Egloff L, Lenz C, Studerus E, Harrisberger F, Smieskova R, Schmidt A, et al. Sexually dimorphic subcortical brain volumes in emerging psychosis. Schizophrenia research. 2018 Mar;
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BACKGROUND: In schizophrenic psychoses, the normal sexual dimorphism of the brain has been shown to be disrupted or even reversed. Little is known, however, at what time point in emerging psychosis this occurs. We have therefore examined, if these alterations are already present in the at-risk mental state (ARMS) for psychosis and in first episode psychosis (FEP) patients. METHODS: Data from 65 ARMS (48 (73.8%) male; age=25.1±6.32) and 50 FEP (37 (74%) male; age=27±6.56) patients were compared to those of 70 healthy controls (HC; 27 (38.6%) male; age=26±4.97). Structural T1-weighted images were acquired using a 3 Tesla magnetic resonance imaging (MRI) scanner. Linear mixed effects models were used to investigate whether subcortical brain volumes are dependent on sex.RESULTS: We found men to have larger total brain volumes (p<0.001), and smaller bilateral caudate (p=0.008) and hippocampus volume (p<0.001) than women across all three groups. Older subjects had more GM and WM volume than younger subjects. No significant sex×group interaction was found. CONCLUSIONS: In emerging psychosis there still seem to exist patterns of normal sexual dimorphism in total brain and caudate volume. The only structure affected by reversed sexual dimorphism was the hippocampus, with women showing larger volumes than men even in HC. Thus, we conclude that subcortical volumes may not be primarily affected by disrupted sexual dimorphism in emerging psychosis.
- Maric NP, Petrovic SA, Raballo A, Rojnic-Kuzman M, Klosterkotter J, Riecher-Rössler A. Survey of the European Psychiatric Association on the European status and perspectives in early detection and intervention in at-risk mental state and first-episode psychosis. Early intervention in psychiatry. 2018 Jun;
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AIM: Early detection/early intervention (ED/EI) programmes have been inconsistently implemented throughout Europe. We evaluated the ED/EI service distribution in European Psychiatric Association (EPA) member countries, considering indicators of socio-economic development, human and financial resources allocated in mental health (MH) as well as presence of a national branch of the Early Intervention in MH (IEPA). Contextually, we evaluated the duration of untreated psychosis (DUP) in relation to ED/EI service implementation. METHODS: EPA section “Prevention of Mental Disorders” conducted the cross-sectional survey administering the 16-item questionnaire to the representatives of its National Psychiatric Associations (NPAs). The survey addressed the Service status and profile, national guidelines, education and policy, DUP and IEPA national branch status. The data were analysed in relation to the indices of economic parameters and MH resources. RESULTS: Neither the national economic parameters, nor indices of MH financial resources were significantly associated with variables related to ED/EI implementation. However, more MH human resources per country were associated with shorter DUP. In comparison to countries without a national branch of IEPA, all of these with the branch had more MH human resources, ED/EI chapters in the national guidelines and services involving both adolescents and adults. CONCLUSIONS: An unequal development of ED/EI services and related academic activities appears throughout Europe. The current results, besides providing a useful starting point to set the agenda for harmonizing ED/EI services, reveal that their implementation was more likely to be influenced by the IEPA membership status, rather than by country-specific financial and human resources allocated to MH.
- Pflueger MO, Calabrese P, Studerus E, Zimmermann R, Gschwandtner U, Borgwardt S, et al. The neuropsychology of emerging psychosis and the role of working memory in episodic memory encoding. Psychology research and behavior management. 2018 May;11:157–68.
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BACKGROUND: Episodic memory encoding and working memory (WM) deficits are among the first cognitive signs and symptoms in the course of schizophrenia spectrum disorders. However, it is not clear whether the deficit pattern is generalized or specific in nature. We hypothesized that encoding deficits at an early stage of the disease might be due to the more fundamental WM deficits. METHODS: We examined episodic memory encoding and WM by administering the California Verbal Learning Test, a 2-back task, and the Wisconsin Card Sorting Test in 90 first-episode psychosis (FE) patients and 116 individuals with an at-risk mental state for psychosis (ARMS) compared to 57 healthy subjects. RESULTS: Learning progress, but not span of apprehension, was diminished to a similar extent in both the ARMS and the FE. We showed that this was due to WM impairment by applying a structural equation approach. CONCLUSION: Thus, we conclude that verbal memory encoding deficits are secondary to primary WM impairment in emerging psychosis.
- Leanza L, Egloff L, Studerus E, Andreou C, Heitz U, Ittig S, et al. The relationship between negative symptoms and cognitive functioning in patients at clinical high risk for psychosis. Psychiatry research. 2018 Jun;268:21–7.
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Negative symptoms and neurocognitive performance have been reported to be negatively associated in patients with emerging psychosis. However, most previous studies focused on patients with frank psychosis and did not differentiate between subdomains of negative symptoms. Hence, we aimed to elucidate the specific relationship between negative symptoms and cognitive functioning in patients at clinical high risk (CHR) for psychosis. Data from 154 CHR patients collected within the prospective Früherkennung von Psychosen (FePsy) study were analyzed. Negative symptoms were assessed with the Scale for the Assessment of Negative Symptoms (SANS) and cognitive functioning with an extensive neuropsychological test battery. Regression analyses revealed significant negative associations between negative symptoms and cognitive functioning, particularly in the domains of nonverbal intelligence and verbal fluency. When analyzing each negative symptom domain separately, alogia and asociality/anhedonia were significantly negatively associated with nonverbal intelligence and alogia additionally with verbal fluency. Overall, our results in CHR patients are similar to those reported in patients with frank psychosis. The strong negative association between verbal fluency and negative symptoms may be indicative of an overlap between these constructs. Verbal fluency might have a strong influence on the clinical impression of negative symptoms (particularly alogia) and vice versa.
- Huber CG, Widmayer S, Smieskova R, Egloff L, Riecher-Rössler A, Stieglitz RD, et al. Voxel-Based Morphometry Correlates of an Agitated-Aggressive Syndrome in the At-Risk Mental State for Psychosis and First Episode Psychosis. Scientific reports. 2018 Nov;8(1).
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There are mixed reports on structural neuroimaging correlates of aggression in schizophrenia with weak evidence due to cohort overlaps and lack of replications. To our knowledge, no study examined volumetric neuroimaging correlates of aggression in early stages of psychosis. An agitated-aggressive syndrome is present in at-risk mental state (ARMS) and in first-episode psychosis (FEP) - it is unclear whether this syndrome is associated with structural brain abnormalities in early stages of psychosis. Using three-dimensional magnetic resonance imaging and a whole brain voxel-based morphometry approach, we examined 56 ARMS patients, 55 FEP patients and 25 healthy controls. We operationalized aggression using the Excited Component of the Brief Psychiatric Rating Scale (BPRS-EC) and dichotomized our patient group by median split into “BPRS-EC high” (n = 49) and “BPRS-EC low” groups (n = 62). The “BPRS-EC high” group had significantly smaller left lingual gyrus volume than HC. This finding was not present in the “BPRS-EC low” group. In addition, grey matter volume in the left lingual gyrus showed a negative linear correlation with BPRS-EC over all subjects (ρ = -0.318; p = 0.0001) and in the patient group (ρ = -0.202; p = 0.033). These findings provide first hints on structural brain abnormalities associated with an agitated-aggressive syndrome in ARMS and FEP patients.
2017
- Ramyead A, Kometer M, Studerus E, Andreou C, Ward LM, Riecher-Rössler A. Abnormal brain connectivity during error-monitoring in the psychosis high-risk state. Schizophrenia research. 2017 Jul;
- Dukart J, Smieskova R, Harrisberger F, Lenz C, Schmidt A, Walter A, et al. Age-related brain structural alterations as an intermediate phenotype of psychosis. Journal of psychiatry & neuroscience : JPN. 2017 May;42(4).
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There is only limited agreement with respect to location, directionality and functional implications of brain structural alterations observed in patients with schizophrenia. Additionally, their link to occurrence of psychotic symptoms remains unclear. A viable way of addressing these questions is to examine populations in an at-risk mental state (ARMS) before the transition to psychosis. We tested for structural brain alterations in individuals in an ARMS compared with healthy controls and patients with first-episode psychosis (FEP) using voxel-based morphometry and measures of cortical thickness. Furthermore, we evaluated if these alterations were modified by age and whether they were linked to the observed clinical symptoms. Our sample included 59 individuals with ARMS, 26 healthy controls and 59 patients with FEP. We found increased grey matter volume and cortical thickness in individuals with ARMS and a similar pattern of structural alterations in patients with FEP. We further found stronger age-related reductions in grey matter volume and cortical thickness in both patients with FEP and individuals with ARMS, linking these alterations to observed clinical symptoms. The ARMS group comprised subgroups with heterogeneous levels of psychosis risk and medication status. Furthermore, the cross-sectional nature of our study and the reduced number of older patients limit conclusions with respect to observed interactions with age. Our findings on consistent structural alterations in individuals with ARMS and patients with FEP and their link to clinical symptoms have major implications for understanding their time of occurrence and relevance to psychotic symptoms. Interactions with age found for these alterations may explain the heterogeneity of findings reported in the literature.
- Ramyead A, Kometer M, Studerus E, Baumeler D, Rotz R von, Riecher-Rössler A. Alpha Oscillations underlie Working Memory Abnormalities in the Psychosis High-risk State. Biological psychology. 2017 Apr;
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Working memory (WM) functioning, known to be modulated by neural oscillations, is impaired in schizophrenic psychoses. It remains unclear whether in the psychosis high-risk state, WM encoding is altered or whether patients are impaired at shielding their WM against distractors. We employed single-trial analyses of neurophysiological and behavioral data recorded during a WM paradigm, designed to include predictable distractors, on 18 patients with an at-risk mental state for psychosis (ARMS,26.1+/-5.45years) and 21 healthy controls(HCs,25.5+/-3.95years). Strong distractors were associated with reduced WM accuracy(p=0.036), but only ARMS patients required more processing time for strong distractors(p=0.002). Increased parieto-occipital alpha amplitude preceding distractor presentations was associated with enhanced accuracy only in HCs(p=0.009). During encoding, increased intertrial alpha phase locking values were associated with increased performance. Reduced shielding mechanisms against distractors in ARMS patients could lead to defective WM maintenance, which may result in significant confusion that may contribute to the formation of psychotic symptoms.
- Rapp C, Canela C, Studerus E, Walter A, Aston J, Borgwardt S, et al. Duration of untreated psychosis/illness and brain volume changes in early psychosis. Psychiatry research. 2017 Jun;255:332–7.
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The time period during which patients manifest psychotic or unspecific symptoms prior to treatment (duration of untreated psychosis, DUP, and the duration of untreated illness, DUI) has been found to be moderately associated with poor clinical and social outcome. Equivocal evidence exists of an association between DUP/DUI and structural brain abnormalities, such as reduced hippocampus volume (HV), pituitary volume (PV) and grey matter volume (GMV). Thus, the goal of the present work was to examine if DUP and DUI are associated with abnormalities in HV, PV and GMV. Using a region of interest (ROI) based approach, we present data of 39 patients from the Basel FePsy (Früherkennung von Psychosen, early detection of psychosis) study for which information about DUP, DUI and HV, PV and GMV data could be obtained. Twenty-three of them were first episode psychosis (FEP) and 16 at-risk mental state (ARMS) patients who later made the transition to frank psychosis. In unadjusted analyses, we found a significant positive correlation between DUP and PV in FEP patients. However, when adjusted for covariates, we found no significant correlation between DUP or DUI and HV, PV or GMV anymore. There only was a trend for decreasing GMV with increasing DUI in FEP. Our results do not comprehensively support the hypothesis of a “toxic” effect of the pathogenic mechanism underlying untreated psychosis on brain structure. If there is any effect, it might rather occur very early in the disease process, during which patients experience only unspecific symptoms.
- Heitz U, Studerus E, Menghini-Müller S, Papmeyer M, Egloff L, Ittig S, et al. Gender differences in first self-perceived signs and symptoms in patients with an at-risk mental state and first-episode psychosis. Early intervention in psychiatry. 2017 Dec;
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AIM: Gender differences in the current symptomatology of patients with psychotic disorders have previously been described in the literature. However, it has not yet been investigated whether gender differences exist in the very first self-perceived signs or symptoms of illness onset. The aim of this study was to investigate this aspect in at-risk mental state (ARMS) and first-episode psychosis (FEP) patients. METHODS: ARMS and FEP were recruited via the early detection of psychosis (FePsy) clinic Basel, Switzerland. The Basel Interview for Psychosis (BIP) was used to retrospectively assess the first 3 self-perceived signs and symptoms at illness onset. Differences between gender and patient groups on single item and symptom cluster levels were analysed using logistic regression models. RESULTS: One-hundred-thirty six ARMS (91 men, 45 women) and 89 FEP patients (63 men, 26 women) could be recruited for this study. On a single item level, women more frequently reported “unusual anxiety, fears” and men (at a trend level) “social withdrawal” as being among their 3 first self-perceived symptoms, independent of diagnostic group. On the symptom cluster level, women more frequently reported “increased worrying/anxiety” and (sub-threshold) “hallucinations”, independent of diagnostic group. Problems with “thinking, concentration” were reported more frequently by men in the ARMS group only. CONCLUSION: Our results suggest that only few and relatively small gender differences exist in the first self-perceived signs and symptoms. While men initially mainly notice negative/cognitive symptoms, women first notice (sub-threshold) positive and affective symptoms.
- Zarogianni E, Storkey AJ, Borgwardt S, Smieskova R, Studerus E, Riecher-Rössler A, et al. Individualized prediction of psychosis in subjects with an at-risk mental state. Schizophrenia research. 2017 Sep;
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Early intervention strategies in psychosis would significantly benefit from the identification of reliable prognostic biomarkers. Pattern classification methods have shown the feasibility of an early diagnosis of psychosis onset both in clinical and familial high-risk populations. Here we were interested in replicating our previous classification findings using an independent cohort at clinical high risk for psychosis, drawn from the prospective FePsy (Fruherkennung von Psychosen) study. The same neuroanatomical-based pattern classification pipeline, consisting of a linear Support Vector Machine (SVM) and a Recursive Feature Selection (RFE) achieved 74% accuracy in predicting later onset of psychosis. The discriminative neuroanatomical pattern underlying this finding consisted of many brain areas across all four lobes and the cerebellum. These results provide proof-of-concept that the early diagnosis of psychosis is feasible using neuroanatomical-based pattern recognition.
- Hartmann JA, McGorry PD, Schmidt SJ, Amminger GP, Yuen HP, Markulev C, et al. Opening the Black Box of Cognitive-Behavioural Case Management in Clients with Ultra-High Risk for Psychosis. Psychotherapy and psychosomatics. 2017 Sep;86(5):292–9.
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BACKGROUND: Cognitive-behavioural therapy (CBT) is the first-choice treatment in clients with ultra-high risk (UHR) for psychosis. However, CBT is an umbrella term for a plethora of different strategies, and little is known about the association between the intensity and content of CBT and the severity of symptomatic outcome. METHODS: A sample of 268 UHR participants received 6 months of CBT with case management (CBCM) in the context of the multi-centre NEURAPRO trial with monthly assessments of attenuated psychotic symptoms (APS). Using multilevel regressions and controlling for the initial severity of APS, the associations between (1) number of CBCM sessions received and severity of APS and (2) specific CBCM components and severity of APS were investigated. RESULTS: In month 1, a higher number of sessions and more assessment of symptoms predicted an increase in APS, while in month 3, a higher number of sessions and more monitoring predicted a decrease in the level of APS. More therapeutic focus on APS predicted an overall increase in APS. CONCLUSIONS: Our findings indicate that the association between intensity/content of CBCM and severity of APS in a sample of UHR participants depends on the length of time in treatment. CBCM may positively impact the severity of APS later in the course of treatment. Therefore, it would seem important to keep UHR young people engaged in treatment beyond this initial period. Regarding the specific content of CBCM, a therapeutic focus on APS may not necessarily be beneficial in reducing the severity of APS, a possibility in need of further investigation.
- Papmeyer M, Aston J, Everts-Graber J, Heitz U, Studerus E, Borgwardt SJ, et al. Outcome of individuals “not at risk of psychosis” and prognostic accuracy of the Basel Screening Instrument for Psychosis (BSIP). Early intervention in psychiatry. 2017 Apr;
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BACKGROUND: We aimed to determine the prognostic accuracy of the Basel Screening Instrument for Psychosis (BSIP) in terms of specificity, sensitivity, positive and negative predictive value by following up individuals that were initially not considered to be at increased risk of psychosis based on the BSIP. Moreover, clinical characteristics of these individuals were examined given the relative lack of such information in the literature. METHODS: As part of the “Früherkennung von Psychosen” (FePsy) study, 87 individuals were screened with the BSIP. Of these, 64 were classified at baseline as being in an at-risk mental state (ARMS+) for psychosis using the BSIP and followed up at regular time intervals for at least 2 years to determine a putative transition to psychosis. Twenty-three individuals were classified at baseline as not being in an at-risk mental state (ARMS-) using the BSIP and re-assessed after 4 years. Sensitivity, specificity, positive and negative predictive value of the BSIP were computed. Clinical characteristics of the ARMS- group were analysed descriptively. RESULTS: During the follow-up period, none of the ARMS- individuals, but 21 of ARMS+ had developed psychosis. Sensitivity of the BSIP was 1.0, specificity was 0.35. The majority of ARMS- individuals showed depressive disorders or anxiety disorders and varying levels of functioning. CONCLUSIONS: The BSIP has good prognostic accuracy for detecting the prodromal phase of psychosis with an excellent sensitivity and a specificity similar to other risk instruments and the advantage of a relatively short duration. Depressive and anxiety symptoms commonly develop in ARMS- individuals.
- Riecher-Rössler A, Studerus E. Prediction of conversion to psychosis in individuals with an at-risk mental state: a brief update on recent developments. Current opinion in psychiatry. 2017 Feb;
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PURPOSE OF REVIEW: So far, only little more than one-third of individuals classified as being at-risk for psychosis have been shown to actually convert to frank psychosis during follow-up. There have therefore been enormous efforts to improve the accuracy of predicting this transition. We reviewed the most recent studies in the field with the aim to clarify whether accuracy of prediction has been improved by the different research endeavors and what could be done to further improve it, and/or what alternative goals research should pursue. RECENT FINDINGS: A total of 56 studies published between May 2015 and December 2016 were included, of which eight were meta-analyses. New meta-analytical evidence confirms that established instruments for checking clinical risk criteria have an excellent clinical utility in individuals referred to high-risk services. Within a such identified group of ultra-high-risk (UHR) individuals, especially Brief Limited Intermittent Psychotic Symptoms and Attenuated Psychotic Symptoms seem to predict transition. Further assessments should be performed within the UHR individuals, as risk of transition seems particularly high in those with an even higher severity of certain symptoms such as suspiciousness or anhedonia, in those with lower global or social functioning, poor neurocognitive performance or cannabis abuse. Also, electroencephalography, neuroimaging and blood biomarkers might contribute to improving individual prediction. The most promising approach certainly is a staged multidomain assessment. Risk calculators to integrate all data for an individualized prediction are being developed. SUMMARY: Prediction of psychosis is already possible with an excellent prognostic performance based on clinical assessments. Recent studies show that this accuracy can be further improved by using multidomain approaches and modern statistics for individualized prediction. The challenge now is the translation into the clinic with a broad clinical implementation.
- Studerus E, Ramyead A, Riecher-Rössler A. Prediction of transition to psychosis in patients with a clinical high risk for psychosis: a systematic review of methodology and reporting. Psychological medicine. 2017 Jan;1–16.
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To enhance indicated prevention in patients with a clinical high risk (CHR) for psychosis, recent research efforts have been increasingly directed towards estimating the risk of developing psychosis on an individual level using multivariable clinical prediction models. The aim of this study was to systematically review the methodological quality and reporting of studies developing or validating such models. A systematic literature search was carried out (up to 14 March 2016) to find all studies that developed or validated a clinical prediction model predicting the transition to psychosis in CHR patients. Data were extracted using a comprehensive item list which was based on current methodological recommendations. A total of 91 studies met the inclusion criteria. None of the retrieved studies performed a true external validation of an existing model. Only three studies (3.5%) had an event per variable ratio of at least 10, which is the recommended minimum to avoid overfitting. Internal validation was performed in only 14 studies (15%) and seven of these used biased internal validation strategies. Other frequently observed modeling approaches not recommended by methodologists included univariable screening of candidate predictors, stepwise variable selection, categorization of continuous variables, and poor handling and reporting of missing data. Our systematic review revealed that poor methods and reporting are widespread in prediction of psychosis research. Since most studies relied on small sample sizes, did not perform internal or external cross-validation, and used poor model development strategies, most published models are probably overfitted and their reported predictive accuracy is likely to be overoptimistic.
- Ittig S, Studerus E, Heitz U, Menghini-Müller S, Beck K, Egloff L, et al. Sex differences in prolactin levels in emerging psychosis: Indication for enhanced stress reactivity in women. Schizophrenia research. 2017 Feb;
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BACKGROUND: Hyperprolactinemia is a known side effect of antipsychotics. In recent reports it has also been shown in antipsychotic-naïve at-risk mental state (ARMS) and first-episode psychosis (FEP) patients. Prolactin is not only involved in reproduction and lactation, but is also synthesized in response to stress. As stress is thought to play an important role in the onset and relapse of schizophrenia, the aim of this study was to further elucidate the influence of prolactin in emerging psychosis. METHODS: The data analysed in this study were collected within the prospective Früherkennung von Psychosen (FePsy) study. Blood sample collection took place under standardized conditions between 8 and 10am after an overnight fast and 30minutes of rest. All patients were antipsychotic-naïve and did not take any prolactin influencing medication. RESULTS: Our sample consisted of 116 antipsychotic-naïve ARMS and 49 FEP patients. Hyperprolactinemia was shown in 32% of ARMS and 35% of FEP patients. After correction for the normal biological variation between the sexes, we still found higher average prolactin levels in female than in male patients (β=0.42; t=2.47; p=0.01) but no difference in prolactin levels between ARMS and FEP patients (β=-0.05; t=-0.30; p=0.76). The survival analysis revealed no significant predictive value for prolactin levels to predict transition to psychosis. CONCLUSION: Our findings support a possible role of prolactin in emerging psychosis and it could be speculated that stress, which can induce hyperprolactinemia, has a stronger effect on women than on men in emerging psychosis.
- Uttinger M, Studerus E, Ittig S, Heitz U, Schultze-Lutter F, Riecher-Rössler A. The Frankfurt Complaint Questionnaire for self-assessment of basic symptoms in the early detection of psychosis-Factor structure, reliability, and predictive validity. International journal of methods in psychiatric research. 2017 Dec;
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OBJECTIVES: Patients with schizophrenia often experience subtle disturbances in several domains of information processing-so-called basic symptoms (BS). BS are already present before onset of frank psychosis and can be assessed by interviews but also by the self-administered Frankfurt Complaint Questionnaire (FCQ). We investigated the factor structure, reliability, and predictive validity for transition to psychosis of the FCQ, comparing previously proposed factor solutions containing 1, 2, 4, and 10 factors. METHODS: Confirmatory factor analysis was used in a sample of 117 at-risk mental state and 92 first-episode psychosis participants of the Basel FePsy (early detection of psychosis) study. RESULTS: Although all factor models fitted to the data, the 2- or 4-factor solutions performed best among the models that used at least half of the FCQ items, suggesting the covariance between FCQ items is best explained by 2 to 4 underlying factors. No FCQ-scale predicted transition to psychosis. CONCLUSION: We could confirm a 2- to 4-factor structure of the FCQ in a sample of at-risk mental state and first-episode psychosis patients using confirmatory factor analysis. Contrary to interview-assessed cognitive-perceptive BS, self-assessed BS do not seem to improve prediction of psychosis. This result reinforces reports of poor correspondence between interview- and questionnaire-assessed BS.
2016
- Harrisberger F, Buechler R, Smieskova R, Lenz C, Walter A, Egloff L, et al. Alterations in the hippocampus and thalamus in individuals at high risk for psychosis. NPJ Schizophrenia. 2016;
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Reduction in hippocampal volume is a hallmark of schizophrenia and already present in the clinical high-risk state. Nevertheless, other subcortical structures, such as the thalamus, amygdala and pallidum can differentiate schizophrenia patients from controls. We studied the role of hippocampal and subcortical structures in clinical high-risk individuals from two cohorts. High-resolution T1-weighted structural MRI brain scans of a total of 91 clinical high-risk individuals and 64 healthy controls were collected in two centers. The bilateral volume of the hippocampus, the thalamus, the caudate, the putamen, the pallidum, the amygdala, and the accumbens were automatically segmented using FSL-FIRST. A linear mixed-effects model and a prospective meta-analysis were applied to assess group-related volumetric differences. We report reduced hippocampal and thalamic volumes in clinical high-risk individuals compared to healthy controls. No volumetric alterations were detected for the caudate, the putamen, the pallidum, the amygdala, or the accumbens. Moreover, we found comparable medium effect sizes for group-related comparison of the thalamus in the two analytical methods. These findings underline the relevance of specific alterations in the hippocampal and subcortical volumes in the high-risk state. Further analyses may allow hippocampal and thalamic volumes to be used as biomarkers to predict psychosis.
- Walter A, Suenderhauf C, Smieskova R, Lenz C, Harrisberger F, Schmidt A, et al. Altered Insular Function during Aberrant Salience Processing in Relation to the Severity of Psychotic Symptoms. Frontiers in Psychiatry. 2016;7(189).
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There is strong evidence for abnormal salience processing in patients with psychotic experiences. In particular, there are indications that the degree of aberrant salience processing increases with the severity of positive symptoms. The aim of the present study was to elucidate this relationship by means of brain imaging. Functional magnetic resonance imaging was acquired to assess hemodynamic responses during the Salience Attribution Test, a paradigm for reaction time that measures aberrant salience to irrelevant stimulus features. We included 42 patients who were diagnosed as having a psychotic disorder and divided them into two groups according to the severity of their positive symptoms. Whole brain analysis was performed using Statistical Parametric Mapping. We found no significant behavioral differences with respect to task performance. Patients with more positive symptoms showed increased hemodynamic responses in the left insula corresponding to aberrant salience than in patients with less positive symptoms. In addition, left insula activation correlated negatively with cumulative antipsychotic medication. Aberrant salience processing in the insula may be increased in psychosis, depending on the severity of positive symptoms. This study indicates that clinically similar psychosis manifestations share the same functional characteristics. In addition, our results suggest that antipsychotic medication can modulate insular function.
- Schmidt A, Palaniyappan L, Smieskova R, Simon A, Riecher-Rössler A, Lang UE, et al. Dysfunctional insular connectivity during reward prediction in patients with first-episode psychosis. J Psychiatry Neurosci. 2016;41(6):367–76.
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Increasing evidence indicates that psychosis is associated with abnormal reward processing. Imaging studies in patients with first-episode psychosis (FEP) have revealed reduced activity in diverse brain regions, including the ventral striatum, insula and anterior cingulate cortex (ACC), during reward prediction. However, whether these reductions in local brain activity are due to altered connectivity has rarely been explored. We applied dynamic causal modelling and Bayesian model selection to fMRI data during the Salience Attribution Task to investigate whether patients with FEP showed abnormal modulation of connectivity between the ventral striatum, insula and ACC induced by rewarding cues and whether these changes were related to positive psychotic symptoms and atypical antipsychotic medication. The model including reward-induced modulation of insula-ACC connectivity was the best fitting model in each group. Compared with healthy controls (n = 19), patients with FEP (n = 29) revealed reduced right insula-ACC connectivity. After subdividing patients according to current antipsychotic medication, we found that the reduced insula-ACC connectivity relative to healthy controls was observed only in untreated patients (n = 17), not in patients treated with antipsychotics (n = 12), and that it correlated negatively with unusual thought content in untreated patients with FEP. The modest sample size of untreated patients with FEP was a limitation of our study. This study indicates that insula-ACC connectivity during reward prediction is reduced in untreated patients with FEP and related to the formation of positive psychotic symptoms. Our study further suggests that atypical antipsychotics may reverse connectivity between the insula and the ACC during reward prediction
- Riecher-Rössler A, McGorry P. Early Detection and Intervention in Psychosis. In: Riecher-Rössler A, McGorry P, editors. Early Detection and Intervention in Psychosis - State of the Art and Future Perspectives. Basel: Karger; 2016. p. 179–89.
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As this volume shows, early detection of and intervention in psychosis is a rapidly evolving and highly promising field of psychiatry. Starting with the early detection of frank psychosis and building up services for these patients, the field has in the meantime developed much further and deeper. There is now clear and accumulating evidence that early detection is also possible before transition to frank psychosis in the early prodromal and subthreshold psychotic states, i.e. in the sense of risk-assessment. Moreover, there is a large body of evidence regarding early intervention. However, it is also clear that there are still some unsolved problems and questions, and a lot has still to be done.
- Riecher-Rössler A, McGorry P, editors. Early Detection and Intervention in Psychosis - State of the Art and Future Perspectives. Basel: Karger; 2016. (Key Issues in Mental Health).
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This new volume reviews early detection approaches and possible subsequent interventions for psychosis. After introductory chapters, various methods for early detection not only in adults, but also adolescents are described. In this context, the validity of the psychosis high-risk state is debated along with whether early detection is indeed helpful, or actually stigmatizing, for the patient. Further contributions review neuroimaging, including structural and functional MRI, as well as pattern recognition methods and measurement of connectivity abnormalities. Neurocognitive and neurophysiological assessments are also discussed in detail. The last part focuses on early intervention for emerging psychosis, including psychological methods, non-pharmacological substances and pharmacological treatments. Overall conclusions and future perspectives are provided in a final chapter. This book is a state-of-the-art review of current options. It is important reading for researchers and clinicians faced with recognizing and treating psychosis in the most timely and effective manner possible.
- Uttinger M, Papmeyer M, Riecher-Rössler A. Early Detection of Psychosis - Helpful or Stigmatizing Experience for Those Concerned? In: Riecher-Rössler A, McGorry P, editors. Early Detection and Intervention in Psychosis - State of the Art and Future Perspectives. Basel: Karger; 2016. p. 69–82.
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This chapter provides an overview of the literature on early detection of psychosis concerning stigma and discrimination in individuals with an at-risk mental state (ARMS) for psychosis. Extended surveys about stigma and psychosis/schizophrenia show that these patients belong to the most stigmatized patient groups. Therefore, ARMS individuals are conceivably affected by stigma and its consequences. In response to the recent scientific debate concerning potential stigma associated with an ARMS for psychosis, a small but growing number of studies on the topic have been carried out. The following two questions are addressed in this chapter: (1) do ARMS individuals experience stigma - and if so, what kind of stigma, and (2) are early detection centers contributing to stigma in any form or is the support offered rather experienced as helpful? Special emphasis is placed on the subjective perspective of ARMS individuals. Research reviewed in this chapter suggests that ARMS individuals fear stigma rather than having experienced it. They suffer from fear of negative reactions from peers, leading to concealment of mental issues, social withdrawal and delayed help-seeking. According to the literature reviewed, early detection services help individuals coping with symptoms, social isolation and potential stigma instead of enhancing or causing the latter. More emphasis should be placed on the subjective experiences and perspectives of those concerned in future research. Potential stigma including self-stigmatization should be assessed and included into treatment recommendations for individuals with an ARMS.
- Andreou C, Moritz S. Editorial: Non-pharmacological Interventions for Schizophrenia - How Much Can Be Achieved and How? Frontiers in Psychology. 2016;7:1289.
- McGorry PD, Nelson B, Markulev C, Yuen HP, Schafer MR, Mossaheb N, et al. Effect of ω-3 Polyunsaturated Fatty Acids in Young People at Ultrahigh Risk for Psychotic Disorders: The NEURAPRO Randomized Clinical Trial. JAMA Psychiatry. 2016;
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IMPORTANCE: A promising treatment to prevent onset and improve outcomes in patients at ultrahigh risk for psychosis is dietary supplementation with long-chain ω-3 polyunsaturated fatty acids (PUFAs). OBJECTIVE: To determine whether treatment with ω-3 PUFAs in combination with a high-quality psychosocial intervention (cognitive behavioral case management [CBCM]) is more effective than placebo plus CBCM. DESIGN, SETTING, AND PARTICIPANTS: NEURAPRO, a double-blind, placebo-controlled, randomized clinical trial, was conducted from March 1, 2010, to September 30, 2014, in 10 specialized early psychosis treatment services in Australia, Asia, and Europe. The primary analysis used the intention-to-treat approach. INTERVENTIONS: A daily dose of 1.4 g of ω-3 PUFAs or placebo (paraffin oil), plus 20 or fewer sessions of CBCM over the 6-month study period. MAIN OUTCOMES AND MEASURES: The primary outcome was transition to psychosis status at 6 months. The secondary outcomes were general levels of psychopathology and functioning, as assessed by the Brief Psychiatric Rating Scale (BPRS) (range, 24-168), Scale for the Assessment of Negative Symptoms (SANS) (range, 0-125), Montgomery-Åsberg Depression Rating Scale (MADRS) (range, 0-60), Young Mania Rating Scale (YMRS) (range, 0-44), Social and Occupational Functioning Assessment Scale (SOFAS) (range, 0-100), and the Global Functioning: Social and Role scale (range, 0-10). For SOFAS and Global Functioning: Social and Role scale, higher scores were better; for other measures, lower scores were better. RESULTS: In this study of 304 adults at ultrahigh risk for psychotic disorders, 153 (50.3%) received ω-3 PUFAs and 151 (49.7%) received placebo. In all, 139 (45.7%) were male; mean (SD) age was 19.1 (4.6) years. The Kaplan-Meier-estimated 6-month transition rates were 5.1% (95% CI, 1.3%-8.7%) in the control group and 6.7% (95% CI, 2.3%-10.8%) in the ω-3 PUFA group. At 12 months, the rates were 11.2% (95% CI, 5.5%-16.7%) in the control group and 11.5% (95% CI, 5.8%-16.9%) in the ω-3 PUFA group. No significant difference was observed between the transition rates of both groups (hazard ratio, 1.1; 95% CI, 0.55-2.23; P = .76, stratified log-rank test). CONCLUSIONS AND RELEVANCE: This trial clearly failed to replicate the findings of the original single-center trial. The most likely explanation is that ω-3 PUFAs lack efficacy under these conditions. However, the lower-than-expected transition rate may have prevented a test of the main hypothesis. Given the substantial symptomatic and functional improvement in both groups, the other treatments received (ie, CBCM and antidepressants) likely produced a ceiling effect beyond which ω-3 PUFAs, even if effective, could not be shown to confer additional benefits. Nevertheless, the main conclusion is that ω-3 PUFAs are not effective under conditions where good quality, evidence-based psychosocial treatment is available.
- Franke I, Thier S, Riecher-Rössler A. Effects of an electronic reminder system on guideline-concordant treatment of psychotic disorders : Results from a pilot feasibility trial. Neuropsychiatrie. 2016;
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Adherence to evidence-based guidelines is essential for the treatment outcome of psychotic disorders. Previous studies showed that IT-supported pathways are able to increase guideline adherence in psychiatric care. This paper describes a pilot study on the development of an electronic recall-reminder-system (RRS) for supporting guideline-adherent treatment in outpatient care of patients with chronic psychotic disorders and analyses its feasibility. Guidelines were integrated in the RRS software M.E.M.O.R.E.S. Software training for the staff was provided. We compared the number of conducted vs. guideline-recommended interventions 6 months before and after implementation. Subsequently both the caregivers' and the patients' satisfaction with the RRS was evaluated. Guideline adherence in general was low and the RRS was barely used. After its implementation a significant increase was observed in chemogram-check-ups and diagnostics regarding cardiovascular risks (esp. ECG). Both patients and professionals described problems with integrating the RRS in their daily routine and questioned the usefulness of the guidelines for chronically ill, although they basically approved its importance and usefulness. Participants appreciated the idea of supporting guideline adherence with an IT-system, but there seemed to be major obstacles to implementation: caregivers appear to be concerned of being exposed or questioned, technical difficulties might lead to avoidance, and there seems to be a lack of knowledge and awareness about the health risks for individuals with psychotic disorders. Possibly guidelines adapted for the chronically ill would find more acceptance. Technical simplifications and better information should be considered prior to further attempts to implement IT-supported guidelines in order to increase acceptance.
- Fusar-Poli P, Cappucciati M, Borgwardt S, Woods S, Addington J, Nelson B, et al. Heterogeneity of Psychosis Risk Within Individuals at Clinical High Risk : A Meta-analytical Stratification. JAMA Psychiatry [Internet]. 2016 Feb;73(2):113–20. Available from: http://view.ncbi.nlm.nih.gov/pubmed/26719911
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Individuals can be classified as being at clinical high risk (CHR) for psychosis if they meet at least one of the ultra-high-risk (UHR) inclusion criteria (brief limited intermittent psychotic symptoms [BLIPS] and/or attenuated psychotic symptoms [APS] and/or genetic risk and deterioration syndrome [GRD]) and/or basic symptoms [BS]. The meta-analytical risk of psychosis of these different subgroups is still unknown. To compare the risk of psychosis in CHR individuals who met at least one of the major inclusion criteria and in individuals not at CHR for psychosis (CHR-). Electronic databases (Web of Science, MEDLINE, Scopus) were searched until June 18, 2015, along with investigation of citations of previous publications and a manual search of the reference lists of retrieved articles. We included original follow-up studies of CHR individuals who reported the risk of psychosis classified according to the presence of any BLIPS, APS and GRD, APS alone, GRD alone, BS, and CHR-. Independent extraction by multiple observers and random-effects meta-analysis of proportions. Moderators were tested with meta-regression analyses (Bonferroni corrected). Heterogeneity was assessed with the I2 index. Sensitivity analyses tested robustness of results. Publication biases were assessed with funnel plots and the Egger test. The proportion of each subgroup with any psychotic disorder at 6, 12, 24, 36, and 48 or more months of follow-up. Thirty-three independent studies comprising up to 4227 individuals were included. The meta-analytical proportion of individuals meeting each UHR subgroup at intake was: 0.85 APS (95%CI, 0.79-0.90), 0.1 BLIPS (95%CI, 0.06-0.14), and 0.05 GRD (95%CI, 0.03-0.07). There were no significant differences in psychosis risk at any time point between the APS and GRD and the APS-alone subgroups. There was a higher risk of psychosis in the any BLIPS greater than APS greater than GRD-alone subgroups at 24, 36, and 48 or more months of follow-up. There was no evidence that the GRD subgroup has a higher risk of psychosis than the CHR- subgroup. There were too few BS or BS and UHR studies to allow robust conclusions. There is meta-analytical evidence that BLIPS represents separate risk subgroup compared with the APS. The GRD subgroup is infrequent and not associated with an increased risk of psychosis. Future studies are advised to stratify their findings across these different subgroups. The CHR guidelines should be updated to reflect these differences.
- Riecher-Rössler A, Studerus E. High time for a paradigm shift in psychiatry. World Psychiatry. 2016 Jun;15(2):131–3.
- Harrisberger F, Smieskova R, Vogler C, Egli T, Schmidt A, Lenz C, et al. Impact of polygenic schizophrenia-related risk and hippocampal volumes on the onset of psychosis. Translational psychiatry. 2016 Aug;6(8).
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Alterations in hippocampal volume are a known marker for first-episode psychosis (FEP) as well as for the clinical high-risk state. The Polygenic Schizophrenia-related Risk Score (PSRS), derived from a large case-control study, indicates the polygenic predisposition for schizophrenia in our clinical sample. A total of 65 at-risk mental state (ARMS) and FEP patients underwent structural magnetic resonance imaging. We used automatic segmentation of hippocampal volumes using the FSL-FIRST software and an odds-ratio-weighted PSRS based on the publicly available top single-nucleotide polymorphisms from the Psychiatric Genomics Consortium genome-wide association study (GWAS). We observed a negative association between the PSRS and hippocampal volumes (β=-0.42, P=0.01, 95% confidence interval (CI)=(-0.72 to -0.12)) across FEP and ARMS patients. Moreover, a higher PSRS was significantly associated with a higher probability of an individual being assigned to the FEP group relative to the ARMS group (β=0.64, P=0.03, 95% CI=(0.08-1.29)). These findings provide evidence that a subset of schizophrenia risk variants is negatively associated with hippocampal volumes, and higher values of this PSRS are significantly associated with FEP compared with the ARMS. This implies that FEP patients have a higher genetic risk for schizophrenia than the total cohort of ARMS patients. The identification of associations between genetic risk variants and structural brain alterations will increase our understanding of the neurobiology underlying the transition to psychosis.
- Vogel T, Smieskova R, Schmidt A, Walter A, Harrisberger F, Eckert A, et al. Increased superior frontal gyrus activation during working memory processing in psychosis : Significant relation to cumulative antipsychotic medication and to negative symptoms. Schizophrenia Research [Internet]. 2016 Apr; Available from: http://view.ncbi.nlm.nih.gov/pubmed/27102424
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Impairment in working memory (WM) is a core symptom in schizophrenia. However, little is known about how clinical features influence functional brain activity specific to WM processing during the development of first-episode psychosis (FEP) to schizophrenia (SZ). We compared functional WM-specific brain activity in FEP and SZ patients, including the effects of the duration of illness, psychopathological factors and antipsychotic medication. Cross-sectional study of male FEP (n=22) and SZ (n=20) patients performing an n-back task when undergoing functional magnetic resonance imaging (fMRI). Clinical features were collected by semi-structured interviews and medical records. The SZ group performed significantly worse than the FEP group in the 2-back condition. The SZ group also showed significantly higher activation in the left superior frontal gyrus in the 2-back versus 0-back condition (2-back>0-back). This frontal activation correlated positively with negative symptoms and with cumulative antipsychotic medication during the year before the fMRI examination. There were no significant correlations between activation and duration of illness. There was greater frontal neural activation in SZ than in FEP. This indicated differences in WM processing, and was significantly related to cumulative antipsychotic exposure and negative symptoms, but not to the duration of illness. Copyright © 2016 Elsevier B.V. All rights reserved.
- Ramyead A, Studerus E, Kometer M, Heitz U, Gschwandtner U, Fuhr P, et al. Neural Oscillations in Antipsychotic-Naïve Patients with a First Psychotic Episode. The World Journal of Biological Psychiatry [Internet]. 2016 Jun;17(4):296–307. Available from: http://view.ncbi.nlm.nih.gov/pubmed/26899507
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In chronic schizophrenic psychoses, oscillatory abnormalities predominantly occur in prefrontal cortical regions and are associated with reduced communication across cortical areas. Nevertheless, it remains unclear whether similar alterations can be observed in patients with a first-episode of psychosis (FEP), a state characterized by pathological features occurring in both late prodromal patients and initial phases of frank schizophrenic psychoses. We assessed resting-state EEG data of 31 antipsychotic-naïve FEP patients and 29 healthy-controls (HC). We investigated the 3-dimensional current-source density (CSD) distribution and lagged phase synchronization (LPS) of oscillations across small-scale and large-scale brain networks. We additionally investigated LPS relationships with clinical symptoms using linear mixed-effects models. Compared to HC, FEP patients demonstrated abnormal CSD distributions in frontal areas of the brain; while decreased oscillations were found in the low frequencies, an increase was reported in the high frequencies (p<0.01). Patients also exhibited deviant LPS in the high frequencies, whose dynamics changed over increasing 3D cortico-cortical distances and increasing psychotic symptoms. These results indicate that in addition to prefrontal cortical abnormalities, altered synchronized neural oscillations are also present, suggesting possible disruptions in cortico-cortical communications. These findings provide new insights into the pathophysiological mechanisms of emerging schizophrenic psychoses.
- Studerus E, Papmeyer M, Riecher-Rössler A. Neurocognition and Motor Functioning in the Prediction of Psychosis. In: Riecher-Rössler A, McGorry P, editors. Early Detection and Intervention in Psychosis - State of the Art and Future Perspectives. Basel: Karger; 2016. p. 116–32.
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Meta-analyses suggest that - among help-seeking individuals - only about one third of those meeting internationally established criteria for an at-risk mental state (ARMS) for psychosis will later develop psychosis, and about one third will have a clinical remission within two years. Hence, further risk stratification among ARMS individuals is urgently needed to improve the cost-benefit ratio of preventive interventions. Cognitive and motor functioning deficits are promising candidates for improving the prediction of psychosis in ARMS individuals because they are hallmark features of schizophrenic psychoses, they precede the onset of frank psychosis by many years, and they can be assessed at relatively low costs. In this chapter, we critically evaluate the potential of cognitive and motor functioning parameters for improving the prediction of psychosis in ARMS individuals. We first summarize current evidence on cognitive and motor functioning differences between ARMS individuals who later developed psychosis and those who did not, and then address the question of whether cognitive and motor functioning variables are independently associated with transition to psychosis. Specifically, we review all available studies that included cognitive and/or motor functioning variables into prediction models integrating variables from multiple domains and thereby evaluate their added predictive value. Finally, we provide a detailed discussion of methodological issues in the current research and give recommendations for improvements.
- Riecher-Rössler A. Oestrogens, prolactin, hypothalamic-pituitary-gonadal axis, and schizophrenic psychoses. Lancet Psychiatry. 2016;
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Interest is growing in the potential effect of gonadal hormones, prolactin, and the hypothalamic-pituitary-gonadal axis in schizophrenic psychoses. Many studies from clinical, epidemiological, and fundamental research have confirmed that oestradiol, the main component of oestrogens, can have protective effects in schizophrenic psychoses. Furthermore, many patients with schizophrenic psychoses-even in the untreated prodromal stages-have hyperprolactinaemia and gonadal dysfunction, with oestrogen deficiency in women and testosterone deficiency in men. The understanding of the pathogenetic mechanisms underlying these findings could contribute to a better understanding of the aetiopathogenesis of schizophrenic psychoses and improve therapeutic approaches. In this Series paper, we aim to review methodologically sound studies in this area, propose a theory to explain these findings in the context of psychosis, and suggest therapeutic strategies and implications for further research.
- Riecher-Rössler A. Sex and gender differences in mental disorders. Lancet Psychiatry. 2016;
- Schmidt A, Crossley NA, Harrisberger F, Smieskova R, Lenz C, Riecher-Rössler A, et al. Structural Network Disorganization in Subjects at Clinical High Risk for Psychosis. Schizophrenia bulletin. 2016 Aug;
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Previous network studies in chronic schizophrenia patients revealed impaired structural organization of the brain's rich-club members, a set of highly interconnected hub regions that play an important integrative role for global brain communication. Moreover, impaired rich-club connectivity has also been found in unaffected siblings of schizophrenia patients, suggesting that abnormal rich-club connectivity is related to familiar, possibly reflecting genetic, vulnerability for schizophrenia. However, no study has yet investigated whether structural rich-club organization is also impaired in individuals with a clinical risk syndrome for psychosis. Diffusion tensor imaging and probabilistic tractography was used to construct structural whole-brain networks in 24 healthy controls and 24 subjects with an at-risk mental state (ARMS). Graph theory was applied to quantify the structural rich-club organization and global network properties. ARMS subjects revealed a significantly altered structural rich-club organization compared with the control group. The disruption of rich-club organization was associated with the severity of negative psychotic symptoms and led to an elevated level of modularity in ARMS subjects. This study shows that abnormal structural rich-club organization is already evident in clinical high-risk subjects for psychosis and further demonstrates the impact of rich-club disorganization on global network communication. Together with previous evidence in chronic schizophrenia patients and unaffected siblings, our findings suggest that abnormal structural rich-club organization may reflect an endophenotypic marker of psychosis.
- Fusar-Poli P, Schultze-Lutter F, Cappucciati M, Rutigliano G, Bonoldi I, Stahl D, et al. The Dark Side of the Moon : Meta-analytical Impact of Recruitment Strategies on Risk Enrichment in the Clinical High Risk State for Psychosis. Schizophrenia Bulletin [Internet]. 2016 May;42(3):732–43. Available from: http://view.ncbi.nlm.nih.gov/pubmed/26591006
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The individual risk of developing psychosis after being tested for clinical high-risk (CHR) criteria (posttest risk of psychosis) depends on the underlying risk of the disease of the population from which the person is selected (pretest risk of psychosis), and thus on recruitment strategies. Yet, the impact of recruitment strategies on pretest risk of psychosis is unknown. Meta-analysis of the pretest risk of psychosis in help-seeking patients selected to undergo CHR assessment: total transitions to psychosis over the pool of patients assessed for potential risk and deemed at risk (CHR+) or not at risk (CHR-). Recruitment strategies (number of outreach activities per study, main target of outreach campaign, and proportion of self-referrals) were the moderators examined in meta-regressions. 11 independent studies met the inclusion criteria, for a total of 2519 (CHR+: n = 1359; CHR-: n = 1160) help-seeking patients undergoing CHR assessment (mean follow-up: 38 months). The overall meta-analytical pretest risk for psychosis in help-seeking patients was 15%, with high heterogeneity (95% CI: 9%-24%, I (2) = 96, P < .001). Recruitment strategies were heterogeneous and opportunistic. Heterogeneity was largely explained by intensive (n = 11, β = -.166, Q = 9.441, P = .002) outreach campaigns primarily targeting the general public (n = 11, β = -1.15, Q = 21.35, P < .001) along with higher proportions of self-referrals (n = 10, β = -.029, Q = 4.262, P = .039), which diluted pretest risk for psychosis in patients undergoing CHR assessment. There is meta-analytical evidence for overall risk enrichment (pretest risk for psychosis at 38monhts = 15%) in help-seeking samples selected for CHR assessment as compared to the general population (pretest risk of psychosis at 38monhts=0.1%). Intensive outreach campaigns predominantly targeting the general population and a higher proportion of self-referrals diluted the pretest risk for psychosis. © The Author 2015. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.
- Papmeyer M, Wursch I, Studerus E, Stieglitz RD, Riecher-Rössler A. The role of vulnerability factors in individuals with an at-risk mental state of psychosis. Neuropsychiatrie [Internet]. 2016 Mar; Available from: http://view.ncbi.nlm.nih.gov/pubmed/26969465
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Several indicators of heightened vulnerability to psychosis and relevant stressors have been identified. However, it has rarely been studied prospectively to what extent these vulnerability factors are in fact more frequently present in individuals with an at-risk mental state for psychosis. Moreover, it remains unknown whether any of these contribute to the prediction of psychosis onset in at-risk mental state individuals. There were 28 healthy controls, 86 first-episode psychosis patients and 127 at-risk mental state individuals recruited within the Basel “Früherkennung von Psychosen” project. Relative frequencies of selected vulnerability factors for psychosis were compared between healthy controls, psychosis patients, those at-risk mental state individuals with subsequent psychosis onset (n = 31) and those without subsequent psychosis onset (n = 55). Survival analyses were applied to determine associations between time to transition to psychosis and vulnerability factors in all 127 at-risk mental state individuals. The vulnerability factors/indicators such as “difficulties during school education or vocational training”, “difficulties during employment”, “being single”, “difficulties with intimate relationships” and “being burdened with specific stressful situations” were more commonly found in the at-risk mental state and first-episode psychosis group than in healthy controls. At-risk mental state and first-episode psychosis individuals more frequently present with vulnerability factors. Individual vulnerability factors appear, however, not to be predictive for an onset of psychosis.
- Laprevote V, Heitz U, Patrizio PD, Studerus E, Ligier F, Schwitzer T, et al. Why and how to treat psychosis earlier? Presse Med. 2016 Nov;45(11):992–1000.
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Chronic psychosis, as for instance schizophrenia, usually begins in young adulthood and may cause severe disability. It causes a mean loss of life expectancy of 22 years. Actual models of psychosis do not trace the beginning of psychosis to the first franc psychotic episode only, but to earlier symptoms. In a classical health system only considering the first psychotic episode, the mean duration of untreated illness (DUI) can last several years. Yet this DUI has a direct impact on the prognosis of the disease. Actual international recommendations prescribe to early detect and treat at risk mental states of psychosis, thus reducing DUI. Such an attitude also helps the patient to integrate care in a moment where she/he is fully in condition to consent and to adhere. Generalist practitioners are crucial actors of early detection. We describe here simple and standardized tools helping early detection of high-risk mental states of psychosis in primary care and the appropriate attitude to do it properly. Numerous countries have developed early detection and treatment centers for psychosis. It has been established that such interventions clearly decrease the risk of transition towards chronic psychosis and improve the prognosis. These recent data about early detection and intervention in psychosis are a major step forward in psychiatry practice. It is now necessary to largely develop such actions in France.
2015
- Riecher-Rössler A, Ackermann T, Uttinger M, Ittig S, Koranyi S, Rapp C, et al. [The Basel Interview for Psychosis (BIP) : Structure, Reliability and Validity]. Fortschritte der Neurologie-Psychiatrie [Internet]. 2015 Feb;83(2):99–108. Available from: http://view.ncbi.nlm.nih.gov/pubmed/25723774
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Although several instruments have been developed to identify patients with an at-risk mental state (ARMS) for psychosis and first episode of psychosis (FEP), up to now there were no instruments for a detailed assessment of risk factors and indicators of emerging psychosis and the temporal development of psychiatric symptoms over the whole life span in these patients. We therefore developed the Basle Interview for Psychosis (BIP). The aim of this study is to describe the development of the BIP and to report about its psychometric properties. The BIP is a comprehensive semi-structured interview that was developed for the Basel early detection of psychoses (FePsy) study. Its items were derived from the most important risk factors and indicators of psychosis described in the literature and from several existing instruments. It contains the following six sections: 1) social and physical development and family, 2) signs and symptoms, 3) vulnerability, 4) help-seeking behavior, 5) illness insight, 6) evaluation of the interview. To estimate the inter-rater reliabilities of the items of sections 2 and 3, 20 interviews were conducted and rated by 8 well-trained raters. The factorial structure of the BIP section “signs and symptoms” was explored in a sample of 120 ARMS and 77 FEP patients. On the basis of the discovered factorial structure, we created new subscales and assessed their reliabilities and validities. Of the 153 studied items of sections 2 and 3, 150 (98”Š%) were rated with sufficiently high agreement (inter-rater reliability >”Š0.4). The items of section “signs and symptoms” could be grouped into 5 subscales with predominantly good to very good internal consistencies, homogeneities, and discriminant and convergent validities. Predictive validities could be demonstrated for the subscales “Positive Psychotic Symptoms”, “Disturbance of Thinking” and the total score. The BIP is the first interview for comprehensively assessing risk factors and indicators of emerging psychosis and the temporal development of psychiatric symptoms over the whole life span, which has been validated in ARMS and FEP patients. We could show that the BIP has excellent psychometric properties. © Georg Thieme Verlag KG Stuttgart · New York.
- Fusar-Poli P, Cappucciati M, Rutigliano G, Schultze-Lutter F, Bonoldi I, Borgwardt S, et al. At risk or not at risk? : A meta-analysis of the prognostic accuracy of psychometric interviews for psychosis prediction. World Psychiatry [Internet]. 2015 Oct;14(3):322–32. Available from: http://view.ncbi.nlm.nih.gov/pubmed/26407788
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An accurate detection of individuals at clinical high risk (CHR) for psychosis is a prerequisite for effective preventive interventions. Several psychometric interviews are available, but their prognostic accuracy is unknown. We conducted a prognostic accuracy meta-analysis of psychometric interviews used to examine referrals to high risk services. The index test was an established CHR psychometric instrument used to identify subjects with and without CHR (CHR+ and CHR-). The reference index was psychosis onset over time in both CHR+ and CHR- subjects. Data were analyzed with MIDAS (STATA13). Area under the curve (AUC), summary receiver operating characteristic curves, quality assessment, likelihood ratios, Fagan's nomogram and probability modified plots were computed. Eleven independent studies were included, with a total of 2,519 help-seeking, predominately adult subjects (CHR+: N=1,359; CHR-: N=1,160) referred to high risk services. The mean follow-up duration was 38 months. The AUC was excellent (0.90; 95% CI: 0.87-0.93), and comparable to other tests in preventive medicine, suggesting clinical utility in subjects referred to high risk services. Meta-regression analyses revealed an effect for exposure to antipsychotics and no effects for type of instrument, age, gender, follow-up time, sample size, quality assessment, proportion of CHR+ subjects in the total sample. Fagan's nomogram indicated a low positive predictive value (5.74%) in the general non-help-seeking population. Albeit the clear need to further improve prediction of psychosis, these findings support the use of psychometric prognostic interviews for CHR as clinical tools for an indicated prevention in subjects seeking help at high risk services worldwide. © 2015 World Psychiatric Association.
- Schmidt A, Lenz C, Smieskova R, Harrisberger F, Walter A, Riecher-Rössler A, et al. Brain Diffusion Changes in Emerging Psychosis and the Impact of State-Dependent Psychopathology. Neuro-Signals [Internet]. 2015;23(1):71–83. Available from: http://view.ncbi.nlm.nih.gov/pubmed/26682550
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Previous diffusion tensor imaging (DTI) studies have shown microstructural changes in the brain white matter of at-risk mental state (ARMS) subjects for psychosis and patients with first-episode psychosis (FEP). However, only a few studies have been conducted in clinical high-risk samples and findings in both groups are inconsistent, in particular along the superior longitudinal fasciculus (SLF). This DTI study used tract-based spatial statistics (TBSS) to compare fractional anisotropy (FA) and mean diffusivity (MD) between ARMS subjects, untreated and antipsychotic-treated FEP patients and healthy controls (HC) across the whole brain and the SLF. Compared to HC, ARMS and FEP patients showed increased FA and decreased MD in diverse regions across the whole brain including the SLF. FA in the SLF was positively correlated with positive psychotic symptoms in ARMS and FEP individuals. Furthermore, untreated but not treated FEP patients showed increased FA in the left inferior longitudinal fasciculus and right SLF. This study revealed increased FA and decreased MD in early stages of psychosis in widespread white matter tracts including the SLF. Our findings further suggest that microstructural changes in the SLF are probably related to state-dependent psychopathology. © 2015 The Author(s) Published by S. Karger AG, Basel.
- Bendfeldt K, Smieskova R, Koutsouleris N, Kloppel S, Schmidt A, Walter A, et al. Classifying individuals at high-risk for psychosis based on functional brain activity during working memory processing. NeuroImage Clinical [Internet]. 2015;9:555–63. Available from: http://view.ncbi.nlm.nih.gov/pubmed/26640767
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The psychosis high-risk state is accompanied by alterations in functional brain activity during working memory processing. We used binary automatic pattern-classification to discriminate between the at-risk mental state (ARMS), first episode psychosis (FEP) and healthy controls (HCs) based on n-back WM-induced brain activity. Linear support vector machines and leave-one-out-cross-validation were applied to fMRI data of matched ARMS, FEP and HC (19 subjects/group). The HC and ARMS were correctly classified, with an accuracy of 76.2% (sensitivity 89.5%, specificity 63.2%, p = 0.01) using a verbal working memory network mask. Only 50% and 47.4% of individuals were classified correctly for HC vs. FEP (p = 0.46) or ARMS vs. FEP (p = 0.62), respectively. Without mask, accuracy was 65.8% for HC vs. ARMS (p = 0.03) and 65.8% for HC vs. FEP (p = 0.0047), and 57.9% for ARMS vs. FEP (p = 0.18). Regions in the medial frontal, paracingulate, cingulate, inferior frontal and superior frontal gyri, inferior and superior parietal lobules, and precuneus were particularly important for group separation. These results suggest that FEP and HC or FEP and ARMS cannot be accurately separated in small samples under these conditions. However, ARMS can be identified with very high sensitivity in comparison to HC. This might aid classification and help to predict transition in the ARMS.
- Spitz A, Studerus E, Koranyi S, Rapp C, Ramyead A, Ittig S, et al. Correlations between self-rating and observer-rating of psychopathology in at-risk mental state and first-episode psychosis patients : influence of disease stage and gender. Early Intervention in Psychiatry [Internet]. 2015 Oct; Available from: http://dx.doi.org/10.1111/eip.12270
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Research findings on the correlations between self-rating and observer-rating of schizophrenic psychopathology are inconsistent and have rarely considered first-episode psychosis (FEP) and at-risk mental state (ARMS) for psychosis patients. This study investigates these correlations in ARMS and FEP patients and how they are moderated by disease stage and gender. Methods In the Basel Früherkennung von Psychosen (FePsy) study, positive and negative psychotic and affective symptoms were rated in 126 ARMS and 94 FEP patients using two observer- and three self-rating scales. The agreement between self-rating and observer-rating and the moderating influence of disease stage and gender was quantified using Pearson correlation and multiple regression models. Results Correlations between self- and observer-rated subscales covering the same symptom dimension were low and mostly non-significant except for one correlation of positive and one of negative symptoms. There was no moderating influence of disease stage and gender on the correlations between self-rating and observer-rating except for one higher association in positive symptoms in FEP compared to ARMS and in women compared to men. However, these significant interaction effects did not withstand correction for multiple testing. Conclusions This study suggests that the agreement between self-rating and observer-rating in FEP and ARMS patients is rather low, similar across symptom dimensions, and only partially dependent on disease stage and gender. However, low correlations between self-rating and observer-rating do not necessarily indicate that these patients have difficulties reporting their symptoms. They could also have occurred because the scales did not exactly cover the same symptom dimensions.
- Uttinger M, Koranyi S, Papmeyer M, Fend F, Ittig S, Studerus E, et al. Early detection of psychosis : helpful or stigmatizing experience? A qualitative study. Early Intervention in Psychiatry [Internet]. 2015 Sep; Available from: http://view.ncbi.nlm.nih.gov/pubmed/26362478
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Despite the large scientific debate concerning potential stigmatizing effects of identifying an individual as being in an at-risk mental state (ARMS) for psychosis, studies investigating this topic from the subjective perspective of patients are rare. This study assesses whether ARMS individuals experience stigmatization and to what extent being informed about the ARMS is experienced as helpful or harmful. Eleven ARMS individuals, currently participating in the follow-up assessments of the prospective Basel Früherkennung von Psychosen (FePsy; English: Early”…Detection of”…Psychosis) study, were interviewed in detail using a semistructured qualitative interview developed for this purpose. Data were analysed using Interpretative Phenomenological Analysis. Most individuals experiencing first symptoms reported sensing that there was 'something wrong with them' and felt in need of help. They were relieved that a specific term was assigned to their symptoms. The support received from the early detection centre was generally experienced as helpful. Many patients reported stigmatization and discrimination that appeared to be the result of altered behaviour and social withdrawal due to the prepsychotic symptoms they experienced prior to contact with the early detection clinic. The results suggest that early detection services help individuals cope with symptoms and potential stigmatization rather than enhancing or causing the latter. More emphasis should be put on the subjective experiences of those concerned when debating the advantages and disadvantages of early detection with regard to stigma. There was no evidence for increased perceived stigma and discrimination as a result of receiving information about the ARMS. © 2015 Wiley Publishing Asia Pty Ltd.
- Schultze-Lutter F, Michel C, Schmidt SJ, Schimmelmann BG, Maric NP, Salokangas RK, et al. EPA guidance on the early detection of clinical high risk states of psychoses. European Psychiatry [Internet]. 2015 Mar;30(3):405–16. Available from: http://view.ncbi.nlm.nih.gov/pubmed/25735810
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The aim of this guidance paper of the European Psychiatric Association is to provide evidence-based recommendations on the early detection of a clinical high risk (CHR) for psychosis in patients with mental problems. To this aim, we conducted a meta-analysis of studies reporting on conversion rates to psychosis in non-overlapping samples meeting any at least any one of the main CHR criteria: ultra-high risk (UHR) and/or basic symptoms criteria. Further, effects of potential moderators (different UHR criteria definitions, single UHR criteria and age) on conversion rates were examined. Conversion rates in the identified 42 samples with altogether more than 4000 CHR patients who had mainly been identified by UHR criteria and/or the basic symptom criterion 'cognitive disturbances' (COGDIS) showed considerable heterogeneity. While UHR criteria and COGDIS were related to similar conversion rates until 2-year follow-up, conversion rates of COGDIS were significantly higher thereafter. Differences in onset and frequency requirements of symptomatic UHR criteria or in their different consideration of functional decline, substance use and co-morbidity did not seem to impact on conversion rates. The 'genetic risk and functional decline' UHR criterion was rarely met and only showed an insignificant pooled sample effect. However, age significantly affected UHR conversion rates with lower rates in children and adolescents. Although more research into potential sources of heterogeneity in conversion rates is needed to facilitate improvement of CHR criteria, six evidence-based recommendations for an early detection of psychosis were developed as a basis for the EPA guidance on early intervention in CHR states. Copyright © 2015 Elsevier Masson SAS. All rights reserved.
- Schmidt SJ, Schultze-Lutter F, Schimmelmann BG, Maric NP, Salokangas RK, Riecher-Rössler A, et al. EPA guidance on the early intervention in clinical high risk states of psychoses. European Psychiatry [Internet]. 2015 Mar;30(3):388–404. Available from: http://view.ncbi.nlm.nih.gov/pubmed/25749390
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This guidance paper from the European Psychiatric Association (EPA) aims to provide evidence-based recommendations on early intervention in clinical high risk (CHR) states of psychosis, assessed according to the EPA guidance on early detection. The recommendations were derived from a meta-analysis of current empirical evidence on the efficacy of psychological and pharmacological interventions in CHR samples. Eligible studies had to investigate conversion rate and/or functioning as a treatment outcome in CHR patients defined by the ultra-high risk and/or basic symptom criteria. Besides analyses on treatment effects on conversion rate and functional outcome, age and type of intervention were examined as potential moderators. Based on data from 15 studies (n=1394), early intervention generally produced significantly reduced conversion rates at 6- to 48-month follow-up compared to control conditions. However, early intervention failed to achieve significantly greater functional improvements because both early intervention and control conditions produced similar positive effects. With regard to the type of intervention, both psychological and pharmacological interventions produced significant effects on conversion rates, but not on functional outcome relative to the control conditions. Early intervention in youth samples was generally less effective than in predominantly adult samples. Seven evidence-based recommendations for early intervention in CHR samples could have been formulated, although more studies are needed to investigate the specificity of treatment effects and potential age effects in order to tailor interventions to the individual treatment needs and risk status. Copyright © 2015 Elsevier Masson SAS. All rights reserved.
- Riecher-Rössler A. Früherkennung und Frühintervention bei beginnenden Psychosen. NeuroTransmitter. 2015 Jan;26(1):50–4.
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Die Bedeutung der frühzeitigen Erkennung und Therapie psychotischer Erkrankungen wurde in den letzten Jahren zunehmend akzeptiert. Wenn schizophrene Psychosen rechtzeitig erkannt und behandelt werden, können viele Patienten zumindest wieder ein „normales“ Leben unter Wahrnehmung ihrer verschiedenen sozialen Rollen führen.
- Bernasconi R, Smieskova R, Schmidt A, Harrisberger F, Raschle NM, Lenz C, et al. Hippocampal volume correlates with attenuated negative psychotic symptoms irrespective of antidepressant medication. NeuroImage Clinical [Internet]. 2015;8:230–7. Available from: http://view.ncbi.nlm.nih.gov/pubmed/26110110
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Individuals with at-risk mental state for psychosis (ARMS) often suffer from depressive and anxiety symptoms, which are clinically similar to the negative symptomatology described for psychosis. Thus, many ARMS individuals are already being treated with antidepressant medication. To investigate clinical and structural differences between psychosis high-risk individuals with or without antidepressants. We compared ARMS individuals currently receiving antidepressants (ARMS-AD; n = 18), ARMS individuals not receiving antidepressants (ARMS-nonAD; n = 31) and healthy subjects (HC; n = 24), in terms of brain structure abnormalities, using voxel-based morphometry. We also performed region of interest analysis for the hippocampus, anterior cingulate cortex, amygdala and precuneus. The ARMS-AD had higher 'depression' and lower 'motor hyperactivity' scores than the ARMS-nonAD. Compared to HC, there was significantly less GMV in the middle frontal gyrus in the whole ARMS cohort and in the superior frontal gyrus in the ARMS-AD subgroup. Compared to ARMS-nonAD, the ARMS-AD group showed more gray matter volume (GMV) in the left superior parietal lobe, but less GMV in the left hippocampus and the right precuneus. We found a significant negative correlation between attenuated negative symptoms and hippocampal volume in the whole ARMS cohort. Reduced GMV in the hippocampus and precuneus is associated with short-term antidepressant medication and more severe depressive symptoms. Hippocampal volume is further negatively correlated with attenuated negative psychotic symptoms. Longitudinal studies are needed to distinguish whether hippocampal volume deficits in the ARMS are related to attenuated negative psychotic symptoms or to antidepressant action.
- Koutsouleris N, Meisenzahl E, Borgwardt S, Riecher-Rössler A, Frodl T, Kambeitz J, et al. Individualized differential diagnosis of schizophrenia and mood disorders using neuroanatomical biomarkers. Brain: A Journal of Neurology [Internet]. 2015 May;138(Pt 7):2059–73. Available from: http://view.ncbi.nlm.nih.gov/pubmed/25935725
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Magnetic resonance imaging-based markers of schizophrenia have been repeatedly shown to separate patients from healthy controls at the single-subject level, but it remains unclear whether these markers reliably distinguish schizophrenia from mood disorders across the life span and generalize to new patients as well as to early stages of these illnesses. The current study used structural MRI-based multivariate pattern classification to (i) identify and cross-validate a differential diagnostic signature separating patients with first-episode and recurrent stages of schizophrenia (n = 158) from patients with major depression (n = 104); and (ii) quantify the impact of major clinical variables, including disease stage, age of disease onset and accelerated brain ageing on the signature's classification performance. This diagnostic magnetic resonance imaging signature was then evaluated in an independent patient cohort from two different centres to test its generalizability to individuals with bipolar disorder (n = 35), first-episode psychosis (n = 23) and clinically defined at-risk mental states for psychosis (n = 89). Neuroanatomical diagnosis was correct in 80% and 72% of patients with major depression and schizophrenia, respectively, and involved a pattern of prefronto-temporo-limbic volume reductions and premotor, somatosensory and subcortical increments in schizophrenia versus major depression. Diagnostic performance was not influenced by the presence of depressive symptoms in schizophrenia or psychotic symptoms in major depression, but earlier disease onset and accelerated brain ageing promoted misclassification in major depression due to an increased neuroanatomical schizophrenia likeness of these patients. Furthermore, disease stage significantly moderated neuroanatomical diagnosis as recurrently-ill patients had higher misclassification rates (major depression: 23%; schizophrenia: 29%) than first-episode patients (major depression: 15%; schizophrenia: 12%). Finally, the trained biomarker assigned 74% of the bipolar patients to the major depression group, while 83% of the first-episode psychosis patients and 77% and 61% of the individuals with an ultra-high risk and low-risk state, respectively, were labelled with schizophrenia. Our findings suggest that neuroanatomical information may provide generalizable diagnostic tools distinguishing schizophrenia from mood disorders early in the course of psychosis. Disease course-related variables such as age of disease onset and disease stage as well alterations of structural brain maturation may strongly impact on the neuroanatomical separability of major depression and schizophrenia. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
- Smieskova R, Roiser J, Chaddock C, Schmidt A, Harrisberger F, Bendfeldt K, et al. Modulation of motivational salience processing during the early stages of psychosis. Schizophrenia Research [Internet]. 2015 May;166(1–3):17–23. Available from: http://dx.doi.org/10.1016/j.schres.2015.04.036
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BACKGROUND: Deficits in motivational salience processing have been related to psychotic symptoms and disturbances in dopaminergic neurotransmission. We aimed at exploring changes in salience processing and brain activity during different stages of psychosis and antipsychotic medication effect. METHODS: We used fMRI during the Salience Attribution Task to investigate hemodynamic differences between 19 healthy controls (HCs), 34 at-risk mental state (ARMS) individuals and 29 individuals with first-episode psychosis (FEP), including a subgroup of 17 FEP without antipsychotic medication (FEP-UM) and 12 FEP with antipsychotic medication (FEP-M). Motivational salience processing was operationalized by brain activity in response to high-probability rewarding cues (adaptive salience) and in response to low-probability rewarding cues (aberrant salience). RESULTS: Behaviorally, adaptive salience response was not accelerated in FEP, although they correctly distinguished between trials with low and high reward probability. In comparison to HC, ARMS exhibited a lower hemodynamic response during adaptive salience in the right inferior parietal lobule and FEP-UM in the left dorsal cingulate gyrus. The FEP-M group exhibited a lower adaptive salience response than HC in the right insula and than ARMS in the anterior cingulate gyrus. In unmedicated individuals, the severity of hallucinations and delusions correlated negatively with the insular- and anterior cingulate hemodynamic response during adaptive salience. We found no differences in aberrant salience processing associated with behavior or medication. CONCLUSION: The changes in adaptive motivational salience processing during psychosis development reveal neurofunctional abnormalities in the somatosensory and premotor cortex. Antipsychotic medication seems to modify hemodynamic responses in the anterior cingulate and insula.
- Markulev C, McGorry P, Nelson B, Yuen HP, Schaefer M, Yung A, et al. NEURAPRO-E study protocol : a multicentre randomized controlled trial of omega-3 fatty acids and cognitive-behavioural case management for patients at ultra high risk of schizophrenia and other psychotic disorders. Early Intervention in Psychiatry [Internet]. 2015 Aug; Available from: http://view.ncbi.nlm.nih.gov/pubmed/26279065
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Recent research has indicated that preventative intervention is likely to benefit patients 'at-risk' for psychosis, both in terms of symptom reduction and delay or prevention of onset of threshold psychotic disorder. The strong preliminary results for the effectiveness of omega-3 polyunsaturated fatty acids (PUFAs), coupled with the falling transition rate in ultra high-risk (UHR) samples, mean that further study of such benign, potentially neuroprotective interventions is clinically and ethically required. Employing a multicentre approach, enabling a large sample size, this study will provide important information with regard to the use of omega-3 PUFAs in the UHR group. This trial is a 6-month, double-blind, randomized placebo-controlled trial of 1.4 g day(-1) omega-3 PUFAs in UHR patients aged between 13 and 40 years. The primary hypothesis is that UHR patients receiving omega-3 PUFAs plus cognitive-behavioural case management (CBCM) will be less likely to transition to psychosis over a 6-month period compared to treatment with placebo plus CBCM. Secondary outcomes will examine symptomatic and functional changes, as well as examine if candidate risk factors predict response to omega-3 PUFA treatment in the UHR group. This is the protocol of the NeuraproE study. Utilizing a large sample, results from this study will be important in informing indicated prevention strategies for schizophrenia and other psychotic disorders, which may be the strongest avenue for reducing the burden, stigmatization, disability and economic consequences of these disorders. © 2015 Wiley Publishing Asia Pty Ltd.
- Ramyead A, Studerus E, Kometer M, Uttinger M, Gschwandtner U, Fuhr P, et al. Prediction of psychosis using neural oscillations and machine learning in neuroleptic-naïve at-risk patients. The World Journal of Biological Psychiatry [Internet]. 2015 Oct;1–11. Available from: http://view.ncbi.nlm.nih.gov/pubmed/26453061
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This study investigates whether abnormal neural oscillations, which have been shown to precede the onset of frank psychosis, could be used towards the individualised prediction of psychosis in clinical high-risk patients. We assessed the individualised prediction of psychosis by detecting specific patterns of beta and gamma oscillations using machine-learning algorithms. Prediction models were trained and tested on 53 neuroleptic-naïve patients with a clinical high-risk for psychosis. Of these, 18 later transitioned to psychosis. All patients were followed up for at least 3 years. For an honest estimation of the generalisation capacity, the predictive performance of the models was assessed in unseen test cases using repeated nested cross-validation. Transition to psychosis could be predicted from current-source density (CSD; area under the curve [AUC] = 0.77), but not from lagged phase synchronicity data (LPS; AUC = 0.56). Combining both modalities did not improve the predictive accuracy (AUC = 0.78). The left superior temporal gyrus, the left inferior parietal lobule and the precuneus most strongly contributed to the prediction of psychosis. Our results suggest that CSD measurements extracted from clinical resting state EEG can help to improve the prediction of psychosis on a single-subject level.
- Ittig S, Studerus E, Papmeyer M, Uttinger M, Koranyi S, Ramyead A, et al. Sex differences in cognitive functioning in at-risk mental state for psychosis, first episode psychosis and healthy control subjects. European Psychiatry [Internet]. 2015 Feb;30(2):242–50. Available from: http://view.ncbi.nlm.nih.gov/pubmed/25555341
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Several sex differences in schizophrenia have been reported including differences in cognitive functioning. Studies with schizophrenia patients and healthy controls (HC) indicate that the sex advantage for women in verbal domains is also present in schizophrenia patients. However, findings have been inconsistent. No study focused on sex-related cognitive performance differences in at-risk mental state for psychosis (ARMS) individuals yet. Thus, the aim of the present study was to investigate sex differences in cognitive functioning in ARMS, first episode psychosis (FEP) and HC subjects. We expected a better verbal learning and memory performance of women in all groups. The neuropsychological data analysed in this study were collected within the prospective Früherkennung von Psychosen (FePsy) study. In total, 118 ARMS, 88 FEP individuals and 86 HC completed a cognitive test battery covering the domains of executive functions, attention, working memory, verbal learning and memory, IQ and speed of processing. Women performed better in verbal learning and memory regardless of diagnostic group. By contrast, men as compared to women showed a shorter reaction time during the working memory task across all groups. The results provide evidence that women generally perform better in verbal learning and memory, independent of diagnostic group (ARMS, FEP, HC). The finding of a shorter reaction time for men in the working memory task could indicate that men have a superior working memory performance since they responded faster during the target trials, while maintaining a comparable overall working memory performance level. Copyright © 2014 Elsevier Masson SAS. All rights reserved.
2014
- Ramyead A, Kometer M, Studerus E, Koranyi S, Ittig S, Gschwandtner U, et al. Aberrant Current Source-Density and Lagged Phase Synchronization of Neural Oscillations as Markers for Emerging Psychosis. Schizophrenia Bulletin [Internet]. 2014 Sep; Available from: http://dx.doi.org/10.1093/schbul/sbu134
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Background: Converging evidence indicates that neural oscillations coordinate activity across brain areas, a process which is seemingly perturbed in schizophrenia. In particular, beta (13-30 Hz) and gamma (30–50 Hz) oscillations were repeatedly found to be disturbed in schizophrenia and linked to clinical symptoms. However, it remains unknown whether abnormalities in current source density (CSD) and lagged phase synchronization of oscillations across distributed regions of the brain already occur in patients with an at-risk mental state (ARMS) for psychosis. Methods: To further elucidate this issue, we assessed resting-state EEG data of 63 ARMS patients and 29 healthy controls (HC). Twenty-three ARMS patients later made a transition to psychosis (ARMS-T) and 40 did not (ARMS-NT). CSD and lagged phase synchronization of neural oscillations across brain areas were assessed using eLORETA and their relationships to neurocognitive deficits and clinical symptoms were analyzed using linear mixed-effects models. Results: ARMS-T patients showed higher gamma activity in the medial prefrontal cortex compared to HC, which was associated with abstract reasoning abilities in ARMS-T. Furthermore, in ARMS-T patients lagged phase synchronization of beta oscillations decreased more over Euclidian distance compared to ARMS-NT and HC. Finally, this steep spatial decrease of phase synchronicity was most pronounced in ARMS-T patients with high positive and negative symptoms scores. Conclusions: These results indicate that patients who will later make the transition to psychosis are characterized by impairments in localized and synchronized neural oscillations providing new insights into the pathophysiological mechanisms of schizophrenic psychoses and may be used to improve the prediction of psychosis.
- Schmidt A, Smieskova R, Simon A, Allen P, Fusar-Poli P, McGuire P, et al. Abnormal effective connectivity and psychopathological symptoms in the psychosis high-risk state. Journal of Psychiatry & Neuroscience [Internet]. 2014 Feb;39(1). Available from: http://view.ncbi.nlm.nih.gov/pubmed/24506946
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Recent evidence has revealed abnormal functional connectivity between the frontal and parietal brain regions during working memory processing in patients with schizophrenia and first-episode psychosis. However, it still remains unclear whether abnormal frontoparietal connectivity during working memory processing is already evident in the psychosis high-risk state and whether the connection strengths are related to psychopathological outcomes. Healthy controls and antipsychotic-naive individuals with an at-risk mental state (ARMS) performed an n-back working memory task while undergoing functional magnetic resonance imaging. Effective connectivity between frontal and parietal brain regions during working memory processing were characterized using dynamic causal modelling. Our study included 19 controls and 27 individuals with an ARMS. In individuals with an ARMS, we found significantly lower task performances and reduced activity in the right superior parietal lobule and middle frontal gyrus than in controls. Furthermore, the working memory-induced modulation of the connectivity from the right middle frontal gyrus to the right superior parietal lobule was significantly reduced in individuals with an ARMS, while the extent of this connectivity was negatively related to the Brief Psychiatric Rating Scale total score. The modest sample size precludes a meaningful subgroup analysis for participants with a later transition to psychosis. This study demonstrates that abnormal frontoparietal connectivity during working memory processing is already evident in individuals with an ARMS and is related to psychiatric symptoms. Thus, our results provide further insight into the pathophysiological mechanisms of the psychosis high-risk state by linking functional brain imaging, computational modelling and psychopathology.
- Koutsouleris N, Davatzikos C, Borgwardt S, Gaser C, Bottlender R, Frodl T, et al. Accelerated brain aging in schizophrenia and beyond : a neuroanatomical marker of psychiatric disorders. Schizophrenia Bulletin [Internet]. 2014 Sep;40(5):1140–53. Available from: http://dx.doi.org/10.1093/schbul/sbt142
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Structural brain abnormalities are central to schizophrenia (SZ), but it remains unknown whether they are linked to dysmaturational processes crossing diagnostic boundaries, aggravating across disease stages, and driving the neurodiagnostic signature of the illness. Therefore, we investigated whether patients with SZ (N = 141), major depression (MD; N = 104), borderline personality disorder (BPD; N = 57), and individuals in at-risk mental states for psychosis (ARMS; N = 89) deviated from the trajectory of normal brain maturation. This deviation was measured as difference between chronological and the neuroanatomical age (brain age gap estimation [BrainAGE]). Neuroanatomical age was determined by a machine learning system trained to individually estimate age from the structural magnetic resonance imagings of 800 healthy controls. Group-level analyses showed that BrainAGE was highest in SZ (+5.5 y) group, followed by MD (+4.0), BPD (+3.1), and the ARMS (+1.7) groups. Earlier disease onset in MD and BPD groups correlated with more pronounced BrainAGE, reaching effect sizes of the SZ group. Second, BrainAGE increased across at-risk, recent onset, and recurrent states of SZ. Finally, BrainAGE predicted both patient status as well as negative and disorganized symptoms. These findings suggest that an individually quantifiable “accelerated aging” effect may particularly impact on the neuroanatomical signature of SZ but may extend also to other mental disorders. © The Author 2013. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.
- Riecher-Rössler A. Basler Projekt zur Früherkennung von Psychosen (FePsy) feiert 15-jähriges Jubiläum. Schweizerische Ärztezeitung. 2014;95(33):1202–3.
- Koutsouleris N, Riecher-Rössler A, Meisenzahl E, Smieskova R, Studerus E, Kambeitz-Ilankovic L, et al. Detecting the Psychosis Prodrome Across High-risk Populations Using Neuroanatomical Biomarkers. Schizophrenia Bulletin [Internet]. 2014 Jun;41(2):471–82. Available from: http://dx.doi.org/10.1093/schbul/sbu078
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To date, the MRI-based individualized prediction of psychosis has only been demonstrated in single-site studies. It remains unclear if MRI biomarkers generalize across different centers and MR scanners and represent accurate surrogates of the risk for developing this devastating illness. Therefore, we assessed whether a MRI-based prediction system identified patients with a later disease transition among 73 clinically defined high-risk persons recruited at two different early recognition centers. Prognostic performance was measured using cross-validation, independent test validation, and Kaplan-Meier survival analysis. Transition outcomes were correctly predicted in 80% of test cases (sensitivity: 76%, specificity: 85%, positive likelihood ratio: 5.1). Thus, given a 54-month transition risk of 45% across both centers, MRI-based predictors provided a 36%-increase of prognostic certainty. After stratifying individuals into low-, intermediate-, and high-risk groups using the predictor’s decision score, the high- vs low-risk groups had median psychosis-free survival times of 5 vs 51 months and transition rates of 88% vs 8%. The predictor’s decision function involved gray matter volume alterations in prefrontal, perisylvian, and subcortical structures. Our results support the existence of a cross-center neuroanatomical signature of emerging psychosis enabling individualized risk staging across different high-risk populations. Supplementary results revealed that (1) potentially confounding between-site differences were effectively mitigated using statistical correction methods, and (2) the detection of the prodromal signature considerably depended on the available sample sizes. These observations pave the way for future multicenter studies, which may ultimately facilitate the neurobiological refinement of risk criteria and personalized preventive therapies based on individualized risk profiling tools.
- Huber C, Smieskova R, Schroeder K, Studerus E, Harrisberger F, Aston J, et al. Evidence for an agitated-aggressive syndrome predating the onset of psychosis. Schizophrenia Research [Internet]. 2014 Jul;157(1–3):26–32. Available from: http://dx.doi.org/10.1016/j.schres.2014.06.014
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Aggression and suicidality prior to the initiation of treatment are frequent phenomena in psychosis patients. Increased scores in the Brief Psychiatric Rating Scale Excited Component (BPRS-EC) have been shown to predict involuntary treatment, aggression, and suicide in first-episode psychosis (FEP) patients. However, it is unclear if an agitated-aggressive syndrome as measured with the BPRS-EC is already present in at-risk mental state (ARMS). BPRS-EC scores from 43 ARMS patients, 50 FEP patients, and 25 healthy controls (HC) were analyzed. Multivariate analyses were performed to review if group differences were mediated by potential confounders. In addition, the association of BPRS-EC scores with clinical variables was examined. BPRS-EC scores were significantly different across diagnostic groups (H(2)=22.1; p<.001), and post-hoc analyses showed significantly higher BPRS-EC scores for ARMS (p=.001) and for FEP patients (p<.001) compared to HC. Differences remained significant after controlling for gender, years of education, and intelligence. No significant differences emerged between ARMS and FEP patients. BPRS-EC was significantly correlated with lower intelligence (r=-.27; p=.008), reduced level of functioning (r=-.44; p<.001), and with smoking behavior (r=.22; p=.019). ARMS and FEP patients in our sample had significantly higher BPRS-EC scores compared to HC. This may constitute a correlate of an agitated-aggressive syndrome and an increased risk for aggression and suicidality. Copyright © 2014 Elsevier B.V. All rights reserved.
- Soguel-dit Piquard F, Papmeyer M, Studerus E, Riecher-Rössler A. Früherkennung von Psychosen - was der Hausarzt wissen muss. HAUSARZT PRAXIS. 2014 Nov;9(11):47–52.
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Ein möglichst frühes Erkennen einer beginnenden Psychose ist von grosser Bedeutung, da eine frühe Hilfestellung negative Folgen bis hin zur Chronifizierung der Erkrankung verhindern kann. Auf Früherkennung spezialisierte Zentren spielen eine wichtige Rolle, aber auch Erstversorger können Frühsymptome erkennen, darauf rechtzeitig und adäquat reagieren und somit Verlauf und Prognose entscheidend verbessern.
- Gonzalez-Rodriguez A, Studerus E, Spitz A, Bugra H, Aston J, Borgwardt S, et al. Gender Differences in the Psychopathology of Emerging Psychosis. The Israel Journal of Psychiatry and Related Sciences. 2014 Sep;21(2):85–93.
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Background: Gender differences have often been found in psychopathological symptoms among chronic schizophrenia and first-episode psychosis (FEP) patients. However, many of these studies suffer from methodological problems and show inconsistent results. Furthermore, very few studies have investigated gender differences in individuals with an at-risk mental state (ARMS) for psychosis. Methods: Psychopathological symptoms were assessed in 117 ARMS and 87 FEP patients by two observer rated scales, namely, the expanded version of the Brief Psychiatric Rating Scale (BPRS) and the Scale for the Assessment of Negative Symptoms (SANS), and by one self-report scale, the Frankfurt Complaint Questionnaire (FCQ). Gender differences were investigated by applying Analyses of Variance using the BPRS, SANS and FCQ subscales as dependent variables, and group and sex as between-subject factors - in a second step by including age, antipsychotic, antidepressant and cannabis use as covariates. Results: There were no significant gender × patient group interactions, suggesting that gender effects did not differ between patient groups. Women had higher scores in positive psychotic symptoms (BPRS Psychosis/Thought Disturbance) while men had higher scores in negative symptoms (BPRS negative symptoms, SANS total score, as well as subscales Affective Flattening, Avolition-Apathy and Asociality-Anhedonia). However, the differences did not withstand correction for multiple testing. The results did not change when corrected for potential confounders. Conclusions: There do not seem to be any gender differences in psychopathology, neither in ARMS nor in FEP patients, as regards self-reported or observerrated symptoms, when corrected for multiple testing and potential confounders.
- EU-GE IEN of NN studying GEI in in. Identifying Gene-Environment Interactions in Schizophrenia : Contemporary Challenges for Integrated, Large-scale Investigations. Schizophrenia Bulletin [Internet]. 2014 Jul;40(4):729–36. Available from: http://dx.doi.org/10.1093/schbul/sbu069
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Recent years have seen considerable progress in epidemiological and molecular genetic research into environmental and genetic factors in schizophrenia, but methodological uncertainties remain with regard to validating environmental exposures, and the population risk conferred by individual molecular genetic variants is small. There are now also a limited number of studies that have investigated molecular genetic candidate gene-environment interactions (G × E), however, so far, thorough replication of findings is rare and G × E research still faces several conceptual and methodological challenges. In this article, we aim to review these recent developments and illustrate how integrated, large-scale investigations may overcome contemporary challenges in G × E research, drawing on the example of a large, international, multi–center study into the identification and translational application of G × E in schizophrenia. While such investigations are now well underway, new challenges emerge for G × E research from late-breaking evidence that genetic variation and environmental exposures are, to a significant degree, shared across a range of psychiatric disorders, with potential overlap in phenotype.
- Walter A, Studerus E, Smieskova R, Tamagni C, Rapp C, Borgwardt S, et al. Pituitary gland volume in at-risk mental state for psychosis : a longitudinal MRI analysis. CNS Spectrums [Internet]. 2014 Mar;1–8. Available from: http://dx.doi.org/10.1017/s109285291400011x
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Introduction Pituitary enlargement has been reported in individuals with schizophrenic psychosis or an at-risk mental state for psychosis (ARMS). In a previous study, our group could show pituitary volume increase in first episode and ARMS patients with later transition to psychosis (ARMS-T). However, there are no longitudinal studies on this issue so far. We therefore examined longitudinally whether transition to psychosis would be accompanied by a further increase of pituitary volume in antipsychotic-naïve ARMS patients. Magnetic resonance imaging (MRI) data were acquired from 23 antipsychotic-naïve individuals with an ARMS. Ten subjects developed psychosis (ARMS-T) and 13 did not (ARMS-NT). ARMS-T were re-scanned after the onset of psychosis, and ARMS-NT were re-scanned at the end of the study period. There was no significant difference of the pituitary volume between ARMS-T and ARMS-NT in our sample, and there were no significant pituitary volume changes over time. Discussion Longitudinally, we could not detect any further volumetric changes in the pituitary volume with transition to psychosis. This, together with the result of our previous study, could indicate that the perceived level of stress in ARMS patients is constantly high from very early onward.
- Tognin S, Riecher-Rössler A, Meisenzahl EM, Wood SJ, Hutton C, Borgwardt SJ, et al. Reduced parahippocampal cortical thickness in subjects at ultra-high risk for psychosis. Psychological Medicine [Internet]. 2014 Feb;44(3):489–98. Available from: http://dx.doi.org/10.1017/s0033291713000998
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Grey matter volume and cortical thickness represent two complementary aspects of brain structure. Several studies have described reductions in grey matter volume in people at ultra-high risk (UHR) of psychosis; however, little is known about cortical thickness in this group. The aim of the present study was to investigate cortical thickness alterations in UHR subjects and compare individuals who subsequently did and did not develop psychosis. We examined magnetic resonance imaging data collected at four different scanning sites. The UHR subjects were followed up for at least 2 years. Subsequent to scanning, 50 UHR subjects developed psychosis and 117 did not. Cortical thickness was examined in regions previously identified as sites of neuroanatomical alterations in UHR subjects, using voxel-based cortical thickness. At baseline UHR subjects, compared with controls, showed reduced cortical thickness in the right parahippocampal gyrus (p < 0.05, familywise error corrected). There were no significant differences in cortical thickness between the UHR subjects who later developed psychosis and those who did not. These data suggest that UHR symptomatology is characterized by alterations in the thickness of the medial temporal cortex. We did not find evidence that the later progression to psychosis was linked to additional alterations in cortical thickness, although we cannot exclude the possibility that the study lacked sufficient power to detect such differences.
2013
- Riecher-Rössler A, Aston J, Borgwardt S, Bugra H, Fuhr P, Gschwandtner U, et al. [Prediction of Psychosis by Stepwise Multilevel Assessment - The Basel FePsy (Early Recognition of Psychosis)-Project]. Fortschritte der Neurologie-Psychiatrie [Internet]. 2013 May;81(5):265–75. Available from: http://dx.doi.org/10.1055/s-0033-1335017
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Background: We have conducted various studies in Basel with the aim of improving the methods for the early detection of psychosis (Früherkennung von Psychosen, FePsy).Methods: From 1.3.2000 to 29.2.2004 234 individuals were screened using the Basel Screening Instrument for Psychosis (BSIP). 106 patients were identified as at risk for psychosis; out of these 53 remained in follow-up for up to 7 years (mean 5.4 years). The assessments were done with a specifically developed instrument for history taking, various scales for the psychopathology, assessments of neuropsychology and fine motor functioning, clinical and quantitative EEG, MRI of the brain, laboratory etc.Results: Based on the BSIP alone, a relatively reliable prediction was possible: 21 (39.6 %) of the individuals identified as at risk developed psychosis within the follow-up time. Post-hoc prediction could be improved to 81 % by weighting psychopathology and including neuropsychology. Including the other domains obviously allows further improvements of prediction.Conclusions: The risk for psychosis should be assessed in a stepwise procedure. In a first step, a clinically oriented screening should be conducted. If an at-risk status is found, further assessments in various domains should be done in a specialised centre. © Georg Thieme Verlag KG Stuttgart · New York.
- Tamagni C, Studerus E, Gschwandtner U, Aston J, Borgwardt S, Riecher-Rössler A. Are neurological soft signs pre-existing markers in individuals with an at-risk mental state for psychosis? Psychiatry research [Internet]. 2013 Jul;210(2):427–31. Available from: http://dx.doi.org/10.1016/j.psychres.2013.06.016
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Neurological soft signs (NSS) are more common in schizophrenic psychoses and in genetically high-risk individuals than in healthy controls. But nothing is known so far regarding individuals with a clinical at-risk mental state (ARMS). The goals of our study therefore were (a) to compare the NSS frequency in ARMS individuals to that of first-episode psychosis (FEP) patients and (b) to test whether NSS could predict the transition to psychosis. Neurological soft signs were assessed using a shortened version of the Neurological Evaluation Scale (NES). Fifty-three ARMS individuals (16 with later transition to psychosis=ARMS-T, and 37 without transition=ARMS-NT) and 27 FEP patients were recruited through the Basel Early Detection Clinic FePsy. Of the FEP patients 37% showed NSS. We found no significant differences between FEP and ARMS-T patients or between ARMS-NT and ARMS-T. Our findings of NSS being present already before transition to psychosis to the same extent as after transition provide further support to the neurodevelopmental hypothesis of schizophrenic psychoses. Furthermore, our findings might indicate that ARMS-NT individuals also suffer from some sort of neurodevelopmental abnormalities.
- Schmidt A, Smieskova R, Aston J, Simon A, Allen P, Fusar-Poli P, et al. Brain Connectivity Abnormalities Predating the Onset of Psychosis : Correlation With the Effect of Medication. JAMA psychiatry [Internet]. 2013 Jul;70(9):903–12. Available from: http://dx.doi.org/10.1001/jamapsychiatry.2013.117
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IMPORTANCE Brain imaging studies have identified robust changes in brain structure and function during the development of psychosis, but the contribution of abnormal brain connectivity to the onset of psychosis is unclear. Furthermore, antipsychotic treatment can modulate brain activity and functional connectivity during cognitive tasks. OBJECTIVES To investigate whether dysfunctional brain connectivity during working memory (WM) predates the onset of psychosis and whether connectivity parameters are related to antipsychotic treatment. DESIGN Dynamic causal modeling study of functional magnetic resonance imaging data. SETTING Participants were recruited from the specialized clinic for the early detection of psychosis at the Department of Psychiatry, University of Basel, Basel, Switzerland. PARTICIPANTS Seventeen participants with an at-risk mental state (mean [SD] age, 25.24 [6.3] years), 21 individuals with first-episode psychosis (mean [SD] age, 28.57 [7.2] years), and 20 healthy controls (mean [SD] age, 26.5 [4] years). MAIN OUTCOME AND MEASURE Functional magnetic resonance imaging data were recorded while participants performed an N-back WM task. Functional interactions among brain regions involved in WM, in particular between frontal and parietal brain regions, were characterized using dynamic causal modeling. Bayesian model selection was performed to evaluate the likelihood of alternative WM network architectures across groups, whereas bayesian model averaging was used to examine group differences in connection strengths. RESULTS We observed a progressive reduction in WM-induced modulation of connectivity from the middle frontal gyrus to the superior parietal lobule in the right hemisphere in healthy controls, at-risk mental state participants, and first-episode psychosis patients. Notably, the abnormal modulation of connectivity in first-episode psychosis patients was normalized by treatment with antipsychotics. CONCLUSIONS AND RELEVANCE Our findings suggest that the vulnerability to psychosis is associated with a progressive failure of functional integration of brain regions involved in WM processes, including visual encoding and rule updating, and that treatment with antipsychotics may have the potential to counteract this.
- Schulze C, Zimmermann R, Gschwandtner U, Pflueger M, Rapp C, Studerus E, et al. Can cognitive deficits facilitate differential diagnosis between at-risk mental state for psychosis and depressive disorders? Early intervention in psychiatry [Internet]. 2013 Nov;7(4):381–90. Available from: http://dx.doi.org/10.1111/eip.12004
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AIM: Many studies have provided evidence of cognitive deficits in individuals in an 'At Risk Mental State' (ARMS) for psychosis, which makes neuropsychology potentially useful in the early detection of psychosis. As depression is an important differential diagnosis in prodromal states of psychosis, the specificity of neurocognitive deficits in ARMS individuals as compared with non-psychotic depressive disorders is investigated. METHODS: Neurocognitive performance of four groups was analysed: 22 ARMS individuals with later transition to psychosis (ARMS-T), 25 ARMS individuals without later transition to psychosis (ARMS-NT), 34 controls with depressive disorders and 76 healthy controls. The subjects were assessed with a neurocognitive test battery covering the domains' intelligence, executive function and attention/ working memory. MANOVAs, ANOVAs and Tukey's tests were applied after adjustment for confounding factors. RESULTS: ARMS-T showed significant cognitive deficits in working memory and in certain executive function tasks compared with healthy controls as well as with controls with depression. Controls with depression were only impaired in time per move in the tower of Hanoi test when compared with healthy controls. CONCLUSIONS: The psychosis prodrome seems to be associated with cognitive deficits in the domains of working memory and executive function. In contrast, depressive patients showed no cognitive deficits, but slowing in one executive function task. Neurocognitive testing might therefore contribute to the differential diagnosis between prodromal psychosis and depressive disorders. © 2012 Wiley Publishing Asia Pty Ltd.
- Rapp C, Walter A, Studerus E, Bugra H, Tamagni C, Rothlisberger M, et al. Cannabis use and brain structural alterations of the cingulate cortex in early psychosis. Psychiatry research [Internet]. 2013 Sep;214(2):102–8. Available from: http://dx.doi.org/10.1016/j.pscychresns.2013.06.006
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As cannabis use is more frequent in patients with psychosis than in the general population and is known to be a risk factor for psychosis, the question arises whether cannabis contributes to recently detected brain volume reductions in schizophrenic psychoses. This study is the first to investigate how cannabis use is related to the cingulum volume, a brain region involved in the pathogenesis of schizophrenia, in a sample of both at-risk mental state (ARMS) and first episode psychosis (FEP) subjects. A cross-sectional magnetic resonance imaging (MRI) study of manually traced cingulum in 23 FEP and 37 ARMS subjects was performed. Cannabis use was assessed with the Basel Interview for Psychosis. By using repeated measures analyses of covariance, we investigated whether current cannabis use is associated with the cingulum volume, correcting for age, gender, alcohol consumption, whole brain volume and antipsychotic medication. There was a significant three-way interaction between region (anterior/posterior cingulum), hemisphere (left/right cingulum) and cannabis use (yes/no). Post-hoc analyses revealed that this was due to a significant negative effect of cannabis use on the volume of the posterior cingulum which was independent of the hemisphere and diagnostic group and all other covariates we controlled for. In the anterior cingulum, we found a significant negative effect only for the left hemisphere, which was again independent of the diagnostic group. Overall, we found negative associations of current cannabis use with grey matter volume of the cingulate cortex, a region rich in cannabinoid CB1 receptors. As this finding has not been consistently found in healthy controls, it might suggest that both ARMS and FEP subjects are particularly sensitive to exogenous activation of these receptors. © 2013 Elsevier Ireland Ltd. All rights reserved.
- Bugra H, Studerus E, Rapp C, Tamagni C, Aston J, Borgwardt S, et al. Cannabis use and cognitive functions in at-risk mental state and first episode psychosis. Psychopharmacology (Berl) [Internet]. 2013 Jun;230(2):299–308. Available from: http://dx.doi.org/10.1007/s00213-013-3157-y
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Background Meta-analyses suggest that schizophrenia patients with a history of cannabis use have less impaired cognitive functioning compared to patients without cannabis use. Aims The objective of this study was to assess the association between recency and frequency of cannabis use and cognitive functioning in at-risk mental state for psychosis (ARMS) and first episode psychosis (FEP) individuals. Methods One hundred thirty-six participants completed a cognitive test battery and were assessed for current and past cannabis use. Analyses of covariance models were applied to evaluate the main effects of cannabis use and patient group (ARMS vs. FEP) as well as their interactions on cognitive functioning. Results No differences were observed in cognitive performance between current, former, and never users, and there were no significant interactions between cannabis use and patient group. Furthermore, within the group of current cannabis users, the frequency of cannabis use was not significantly associated with cognitive functioning. Conclusion The results of the present study do not support the notion that FEP patients and ARMS individuals with a history of cannabis use have less impaired cognitive functioning compared to those without cannabis use.
- Smieskova R, Fusar-Poli P, Marmy J, Schmidt A, Bendfeldt K, Riecher-Rössler A, et al. Do subjects at clinical high risk for psychosis differ from those with a genetic high risk?–A systematic review of structural and functional brain abnormalities. Current medicinal chemistry [Internet]. 2013 Nov;20(3):467–81. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3580804/
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Introduction: Pre-psychotic and early psychotic characteristics are investigated in the high-risk (HR) populations for psychosis. There are two different approaches based either on hereditary factors (genetic high risk, G-HR) or on the clinically manifested symptoms (clinical high risk, C-HR). Common features are an increased risk for development of psychosis and similar cognitive as well as structural and functional brain abnormalities. Methods: We reviewed the existing literature on longitudinal structural, and on functional imaging studies, which included G-HR and/or C-HR individuals for psychosis, healthy controls (HC) and/or first episode of psychosis (FEP) or schizophrenia patients (SCZ). Results: With respect to structural brain abnormalities, vulnerability to psychosis was associated with deficits in frontal, temporal, and cingulate regions in HR, with additional insular and caudate deficits in C-HR population. Furthermore, C-HR had progressive prefrontal deficits related to the transition to psychosis. With respect to functional brain abnormalities, vulnerability to psychosis was associated with prefrontal, cingulate and middle temporal abnormalities in HR, with additional parietal, superior temporal, and insular abnormalities in C-HR population. Transition-to-psychosis related differences emphasized prefrontal, hippocampal and striatal components, more often detectable in C-HR population. Multimodal studies directly associated psychotic symptoms displayed in altered prefrontal and hippocampal activations with striatal dopamine and thalamic glutamate functions. Conclusion: There is an evidence for similar structural and functional brain abnormalities within the whole HR population, with more pronounced deficits in the C-HR population. The most consistent evidence for abnormality in the prefrontal cortex reported in structural, functional and multimodal studies of HR population may underlie the complexity of higher cognitive functions that are impaired during HR mental state for psychosis.
- Rapp C, Studerus E, Bugra H, Aston J, Tamagni C, Walter A, et al. Duration of untreated psychosis and cognitive functioning. Schizophrenia research [Internet]. 2013 Feb;145:43–9. Available from: http://dx.doi.org/10.1016/j.schres.2012.12.016
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BACKGROUND: Studies examining the influence of duration of untreated psychosis (DUP) or duration of untreated illness (DUI) on cognition vary with regard to results and methods. This study is the first in this field to include an at risk mental state with later transition to psychosis (ARMS-T) sample and to analyse how the DUI relates to their cognitive functioning. Because methodological operationalization of cognitive functioning in previous studies is highly heterogeneous, we aimed to compare different approaches. METHOD: 60 first episode psychosis (FEP) patients and 24 ARMS-T patients were examined. Associations between DUP, DUI and neurocognitive performance were tested by three different operationalizations of cognition: as the raw outcome measure of different neuropsychological tests, as outcome scores which were normed on a sample of 75 healthy participants, and as the deterioration index (DI). RESULTS: There were no significant correlations between DUP or DUI and outcome of neuropsychological tests in both normed and raw scores. When adjusted for covariates, DUP and DUI also did not significantly predict any cognitive performance. There was no significant relationship between DUP or DUI and the DI index. However, longer DUP and DUI were significantly associated with stronger negative symptoms. CONCLUSIONS: This study could not confirm an association between duration of untreated psychosis or duration of untreated illness and neurocognitive performance in the ARMS-T and FEP samples. This could be because schizophrenic psychoses are neurodevelopmental disorders in which most cognitive deficits exist long before the onset of psychiatric symptoms. Copyright © 2013 Elsevier B.V. All rights reserved.
- Fridgen G, Aston J, Gschwandtner U, Pflueger M, Zimmermann R, Studerus E, et al. Help-seeking and pathways to care in the early stages of psychosis. Social psychiatry and psychiatric epidemiology [Internet]. 2013 Jul;48(7):1033–43. Available from: http://dx.doi.org/10.1007/s00127-012-0628-0
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PURPOSE: Delay in the treatment of a first psychotic episode can have a negative influence on the future course of the disease. In this context, it is important to examine pathways to care to understand factors contributing to delay in access to adequate care. METHODS: Using the Basel Interview for Psychosis, we examined the help-seeking behaviour of 61 individuals with an at-risk mental state for psychosis and 37 patients with a first episode of psychosis in a low threshold health care system as part of the Basel early detection of psychosis study. RESULTS: The median duration of untreated illness was 3.4 years, of untreated psychosis 12 months. Eighty-six percent of all individuals sought help of some kind before reaching our specialised early detection outpatient clinic, with a mean number of help-seeking contacts of 1.5 prior to referral. The most frequent first help-seeking contacts were family members or relatives n = 24 (26.7 %), close friends n = 17 (17.9 %), psychiatrists in private practice n = 13 (14.4 %) or general practitioners n = 11 (12.2 %). Most patients consulted other health professionals in the early course of the illness before reaching our specialised service; help-seeking with non-medical institutions was rare. Women had more help-seeking contacts than men before contact with our early detection clinic. CONCLUSIONS: Family, close friends and medical professionals play an important role in help-seeking leading to specialised psychiatric care. Men seek help less often; specific strategies for encouraging young, at-risk men to seek help should be developed.
- Riecher-Rössler A, Rybakowski JK, Pflueger MO, Beyrau R, Kahn RS, Malik P, et al. Hyperprolactinemia in antipsychotic-naive patients with first-episode psychosis. Psychological medicine [Internet]. 2013 Apr;43(12):2571–82. Available from: http://dx.doi.org/10.1017/s0033291713000226
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BACKGROUND: Hyperprolactinemia is frequent in patients with schizophrenic psychoses. It is usually regarded as an adverse effect of antipsychotics but has recently also been shown in patients without antipsychotic medication. Our objective was to test whether hyperprolactinemia occurs in antipsychotic-naive first-episode patients (FEPs). Method In the framework of the European First Episode Schizophrenia Trial (EUFEST), 249 out of 498 FEPs were eligible for this study, of whom 74 were antipsychotic naive. All patients were investigated regarding their serum prolactin levels with immunoassays standardized against the 3rd International Reference Standard 84/500. RESULTS: Twenty-nine (39%) of the 74 antipsychotic-naive patients showed hyperprolactinemia not explained by any other reason, 11 (50%) of 22 women and 18 (35%) of 52 men. CONCLUSIONS: Hyperprolactinemia may be present in patients with schizophrenic psychoses independent of antipsychotic medication. It might be stress induced. As enhanced prolactin can increase dopamine release through a feedback mechanism, this could contribute to explaining how stress can trigger the outbreak of psychosis.
- Pfluger MO, Riecher-Rössler A, Calabrese P. Schizophrene Psychosen. In: Calabrese P, Markowitsch HJ, editors. Kognitive Störungen in Neurologie und Psychiatrie: Grundlagen, Krankheitsbilder, Diagnostik. Bad Honnef, Germany: Hippocampus Verlag; 2013. p. 141–61.
- Simon A, Riecher-Rössler A, Lang U, Borgwardt S. The attenuated psychosis syndrome in DSM-5. Schizophrenia research [Internet]. 2013 Oct;151(1–3):295. Available from: http://dx.doi.org/10.1016/j.schres.2013.09.019
- Fusar-Poli P, Borgwardt S, Bechdolf A, Addington J, Riecher-Rössler A, Schultze-Lutter F, et al. The Psychosis High-Risk State : A Comprehensive State-of-the-Art Review. Archives of general psychiatry [Internet]. 2013 Jan;701(1):107–20. Available from: http://dx.doi.org/10.1001/jamapsychiatry.2013.269
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CONTEXT During the past 2 decades, a major transition in the clinical characterization of psychotic disorders has occurred. The construct of a clinical high-risk (HR) state for psychosis has evolved to capture the prepsychotic phase, describing people presenting with potentially prodromal symptoms. The importance of this HR state has been increasingly recognized to such an extent that a new syndrome is being considered as a diagnostic category in the DSM-5. OBJECTIVE To reframe the HR state in a comprehensive state-of-the-art review on the progress that has been made while also recognizing the challenges that remain. DATA SOURCES Available HR research of the past 20 years from PubMed, books, meetings, abstracts, and international conferences. STUDY SELECTION AND DATA EXTRACTION Critical review of HR studies addressing historical development, inclusion criteria, epidemiologic research, transition criteria, outcomes, clinical and functional characteristics, neurocognition, neuroimaging, predictors of psychosis development, treatment trials, socioeconomic aspects, nosography, and future challenges in the field. DATA SYNTHESIS Relevant articles retrieved in the literature search were discussed by a large group of leading worldwide experts in the field. The core results are presented after consensus and are summarized in illustrative tables and figures. CONCLUSIONS The relatively new field of HR research in psychosis is exciting. It has the potential to shed light on the development of major psychotic disorders and to alter their course. It also provides a rationale for service provision to those in need of help who could not previously access it and the possibility of changing trajectories for those with vulnerability to psychotic illnesses.
2012
- Bugra H, Rapp C, Studerus E, Aston J, Borgwardt S, Riecher-Rössler A. [Can cannabis use increase the risk for schizophrenic psychoses?]. Fortschritte der Neurologie-Psychiatrie [Internet]. 2012 Nov;80(11):635–43. Available from: http://dx.doi.org/10.1055/s-0032-1325415
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Background: In recent years, cannabis has been increasingly discussed as one of the most important environmental risk factors for developing schizophrenic psychoses. This is mainly due to the following observations. (i) Cannabis at high doses can cause acute transient psychotic symptoms even in healthy individuals. (ii) Patients with schizophrenia abuse cannabis more often than age-matched healthy controls. Objectives: It is still controversial whether cannabis use can cause schizophrenic psychoses that would not have occurred otherwise. In our review, we have critically evaluated the evidence for a causal link between cannabis use and schizophrenic psychoses.Methods: A systematic literature review in PubMed, ISI Web of Science and PsycINFO was carried out using the following keywords: cannabis, marijuana, THC, hashish, psychosis, schizophrenia. Conclusions: We have concluded that although a causal relationship between cannabis use and schizophrenic psychoses cannot be definitely proven, the available evidence strongly supports its plausibility. Furthermore, the results of the review indicate that cannabis might cause psychosis especially in individuals with a predisposition for schizophrenia and in adolescents with an early onset of cannabis use. © Georg Thieme Verlag KG Stuttgart · New York.
- Rothlisberger M, Riecher-Rössler A, Aston J, Fusar-Poli P, Radu EW, Borgwardt SJ. Cingulate Volume Abnormalities in Emerging Psychosis. Current Pharmaceutical Design [Internet]. 2012 Jan;18(4):495–504. Available from: http://view.ncbi.nlm.nih.gov/pubmed/22239580
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Background: Neuroanatomical abnormalities, including cingulate cortex volume abnormalities, are a common feature in psychosis. However, the extent to which these are related to a vulnerability to psychosis, as opposed to the disorder per se, is less certain. Aim und Hypotheses: The aim of the present study is to compare cingulate gray matter volumes in different stages of psychosis. We reviewed previous studies of subjects in a prodromal stage of psychosis and tested of cingulate volume changes during the transition to psychosis. Methods: A cross-sectional MRI study of manually traced cingulate gray-matter volumes in 37 individuals with an At Risk Mental State (ARMS) for psychosis, 23 individuals with First-Episode Psychosis (FEP), and 22 Healthy Controls (HC) was performed using a 1.5T MRI-Scanner. 16 of 37 ARMS individuals (43 %) developed psychosis during follow up (ARMS-T), whereas 21 did not (ARMS-NT). The mean duration of follow up in ARMS was 25.1 months. 8 cingulate subregionswere analysedin a region-of-interest analysis. Results: Compared to HC, subjects with an ARMS had significantly reduced left caudal anterior cingulate cortex volume (p<0.027). This finding was also evident at a trend level (p: 0.069) in FEP patients. Within the ARMS, ARMS-T group showed significantly reduced whole right cingulate cortex (p: 0.036), right subgenual cingulate cortex (p: 0.036) and right posterior cingulate cortex (p: 0.012) compared to ARMS-NT. Discussion: These results suggest that theat-risk mental state is associated with cingulate volume reductions in particular in the left caudal anterior cingulate cortex (CACC). These abnormalities do not only seem to occur with transition to psychosis, but may be a correlate of an increased vulnerability to psychosis.
- Spitz A, Rapp C, Bugra H, Riecher-Rössler A. Das Basler FePsy Projekt zur Früherkennung von Psychosen. Kerbe. 2012 Oct;(4):20–3.
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Schizophrene Psychosen beginnen meist schleichend und atypisch, wodurch sie oft lange unerkannt und unbehandelt bleiben. Dies verschlechtert die Prognose deutlich. Im Rahmen des Basler FePsy Projektes (Früherkennung von Psychosen) wollen wir die Frühdiagnose und Einschätzung des Psychoserisikos verbessern. Eine Aufklärung der Betrofffenen über ihr Risiko mit anschliessender Begleitung, wenn nötig auch symptomatische Behandlung, sollten in diesem Falle unbedingt erfolgen. Vor allem muss mit dem Patienten/der Patientin in diesem Stadium eine vertrauensvolle Beziehung aufgebaut werden, um bei tatsächlichem Übergang in eine Psychose auch eine spezifische Behandlung einleiten zu können.
- Smieskova R, Allen P, Simon A, Aston J, Bendfeldt K, Drewe J, et al. Different duration of at-risk mental state associated with neurofunctional abnormalities. A multimodal imaging study. Human Brain Mapping [Internet]. 2012 Oct;33(10):2281–94. Available from: http://dx.doi.org/10.1002/hbm.21360
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Objectives: Neurofunctional alterations are correlates of vulnerability to psychosis, as well as of the disorder itself. How these abnormalities relate to different probabilities for later transition to psychosis is unclear. We investigated vulnerability- versus disease-related versus resilience biomarkers of psychosis during working memory (WM) processing in individuals with an at-risk mental state (ARMS). Experimental design: Patients with “first-episode psychosis” (FEP, n = 21), short-term ARMS (ARMS-ST, n = 17), long-term ARMS (ARMS-LT, n = 16), and healthy controls (HC, n = 20) were investigated with an n-back WM task. We examined functional magnetic resonance imaging (fMRI) and structural magnetic resonance imaging (sMRI) data in conjunction using biological parametric mapping (BPM) toolbox. Principal observations: There were no differences in accuracy, but the FEP and the ARMS-ST group had longer reaction times compared with the HC and the ARMS-LT group. With the 2-back > 0-back contrast, we found reduced functional activation in ARMS-ST and FEP compared with the HC group in parietal and middle frontal regions. Relative to ARMS-LT individuals, FEP patients showed decreased activation in the bilateral inferior frontal gyrus and insula, and in the left prefrontal cortex. Compared with the ARMS-LT, the ARMS-ST subjects showed reduced activation in the right inferior frontal gyrus and insula. Reduced insular and prefrontal activation was associated with gray matter volume reduction in the same area in the ARMS-LT group. Conclusions: These findings suggest that vulnerability to psychosis was associated with neurofunctional alterations in fronto-temporo-parietal networks in a WM task. Neurofunctional differences within the ARMS were related to different duration of the prodromal state and resilience factors. Hum Brain Mapp, 2011. © 2011 Wiley-Liss, Inc. Copyright © 2011 Wiley-Liss, Inc.
- Koutsouleris N, Borgwardt S, Meisenzahl E, Bottlender R, Moller HJ, Riecher-Rössler A. Disease Prediction in the At-Risk Mental State for Psychosis Using Neuroanatomical Biomarkers : Results From the FePsy Study. Schizophrenia bulletin [Internet]. 2012 Nov;38(6):1234–46. Available from: http://dx.doi.org/10.1093/schbul/sbr145
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Background: Reliable prognostic biomarkers are needed for the early recognition of psychosis. Recently, multivariate machine learning methods have demonstrated the feasibility to predict illness onset in clinically defined at-risk individuals using structural magnetic resonance imaging (MRI) data. However, it remains unclear whether these findings could be replicated in independent populations. Methods: We evaluated the performance of an MRI-based classification system in predicting disease conversion in at-risk individuals recruited within the prospective FePsy (Früherkennung von Psychosen) study at the University of Basel, Switzerland. Pairwise and multigroup biomarkers were constructed using the MRI data of 22 healthy volunteers, 16/21 at-risk subjects with/without a subsequent disease conversion. Diagnostic performance was measured in unseen test cases using repeated nested cross-validation. Results: The classification accuracies in the “healthy controls (HCs) vs converters,” “HCs vs nonconverters,” and “converters vs nonconverters” analyses were 92.3%, 66.9%, and 84.2%, respectively. A positive likelihood ratio of 6.5 in the converters vs nonconverters analysis indicated a 40% increase in diagnostic certainty by applying the biomarker to an at-risk population with a transition rate of 43%. The neuroanatomical decision functions underlying these results particularly involved the prefrontal perisylvian and subcortical brain structures. Conclusions: Our findings suggest that the early prediction of psychosis may be reliably enhanced using neuroanatomical pattern recognition operating at the single-subject level. These MRI-based biomarkers may have the potential to identify individuals at the highest risk of developing psychosis, and thus may promote informed clinical strategies aiming at preventing the full manifestation of the disease.
- Borgwardt S, Koutsouleris N, Aston J, Studerus E, Smieskova R, Riecher-Rössler A, et al. Distinguishing Prodromal From First-Episode Psychosis Using Neuroanatomical Single-Subject Pattern Recognition. Schizophrenia Bulletin [Internet]. 2012 Sep; Available from: http://dx.doi.org/10.1093/schbul/sbs095
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Background: The at-risk mental state for psychosis (ARMS) and the first episode of psychosis have been associated with structural brain abnormalities that could aid in the individualized early recognition of psychosis. However, it is unknown whether the development of these brain alterations predates the clinical deterioration of at-risk individuals, or alternatively, whether it parallels the transition to psychosis at the single-subject level. Methods: We evaluated the performance of an magnetic resonance imaging (MRI)-based classification system in classifying disease stages from at-risk individuals with subsequent transition to psychosis (ARMS-T) and patients with first-episode psychosis (FE). Pairwise and multigroup biomarkers were constructed using the structural MRI data of 22 healthy controls (HC) , 16 ARMS-T and 23 FE subjects. The performance of these biomarkers was measured in unseen test cases using repeated nested cross-validation. Results: The classification accuracies in the HC vs FE, HC vs ARMS-T, and ARMS-T vs FE analyses were 86.7%, 80.7%, and 80.0%, respectively. The neuroanatomical decision functions underlying these discriminative results particularly involved the frontotemporal, cingulate, cerebellar, and subcortical brain structures. Conclusions:Our findings suggest that structural brain alterations accumulate at the onset of psychosis and occur even before transition to psychosis allowing for the single-subject differentiation of the prodromal and first-episode stages of the disease. Pattern regression techniques facilitate an accurate prediction of these structural brain dynamics at the early stage of psychosis, potentially allowing for the early recognition of individuals at risk of developing psychosis.
- Riecher-Rössler A. E-Learning-Modul Schizophrenie : Früherkennung und Frühintervention [Internet]. 2012. Available from: http://www.fepsy.ch/FEPSY.material/Infomaterial_Teil_Fachpersonen/E-Learing-Modul_Schizophrenie.pdf
- Rapp C, Bugra H, Riecher-Rössler A, Borgwardt S. Effects of cannabis use on human brain structure in psychosis : a systematic review combining in vivo structural neuroimaging and post mortem studies. Current pharmaceutical design [Internet]. 2012 Jun;18(32):5070–80. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3474956/
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It is unclear yet whether cannabis use is a moderating or causal factor contributing to grey matter alterations in schizophrenia and the development of psychotic symptoms. We therefore systematically reviewed structural brain imaging and post mortem studies addressing the effects of cannabis use on brain structure in psychosis. Studies with schizophrenia (SCZ) and first episode psychosis (FEP) patients as well as individuals at genetic (GHR) or clinical high risk for psychosis (ARMS) were included. We identified 15 structural magnetic resonance imaging (MRI) (12 cross sectional / 3 longitudinal) and 4 post mortem studies. The total number of subjects encompassed 601 schizophrenia or first episode psychosis patients, 255 individuals at clinical or genetic high risk for psychosis and 397 healthy controls. We found evidence for consistent brain structural abnormalities in cannabinoid 1 (CB1) receptor enhanced brain areas as the cingulate and prefrontal cortices and the cerebellum. As these effects have not consistently been reported in studies examining non-psychotic and healthy samples, psychosis patients and subjects at risk for psychosis might be particularly vulnerable to brain volume loss due to cannabis exposure.
- Aston J, Bull N, Gschwandtner U, Pfluger MO, Borgwardt SJ, Stieglitz RD, et al. First Self-perceived Signs and Symptoms in Emerging Psychosis Compared to Depression. Early Intervention in Psychiatry [Internet]. 2012 Mar;6(4):455–9. Available from: http://dx.doi.org/10.1111/j.1751-7893.2012.00354.x
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Aim: To investigate differences between the early symptoms of schizophrenia and depressive disorders. Methods: Sixty-one individuals with an at-risk mental state (ARMS), 17 of whom later made the transition to psychosis (ARMS-T), 37 patients with a first episode of psychosis (FE) and 16 controls with depressive disorders (DC) were interviewed about first self-perceived signs and symptoms. Results: In ARMS and FE, on average, first self-perceived signs or symptoms had occurred about 5-6 years before referral. In ARMS, including ARMS-T, “loss of energy” and “difficulties concentrating” were the most frequently recalled first signs. FE most frequently mentioned “depression” and “irritability”, DC “depression” and “social isolation”. As compared to ARMS, DC significantly more often recalled “depression” and “social isolation” as the very first signs of disease.
- Simon A, Riecher-Rössler A. Früherkennung von Psychosen ist matchentscheidend. Synapse. 2012 Apr;2:8–10.
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Wie unterscheidet man einen normativen, entwicklungsspezifischen Prozess von einer eigentlichen psychotischen Entwicklung? Das «Netzwerk Früherkennung Psychosen Nordwestschweiz» bietet anderen medizinischen Fachrichtungen – insbesondere den Hausärzten - Unterstützung bei der Diagnose an.
- Walter A, Studerus E, Smieskova R, Kuster P, Aston J, Lang U, et al. Hippocampal volume in subjects at high risk of psychosis : A longitudinal MRI study. Schizophrenia research [Internet]. 2012 Dec;142(1–3):217–22. Available from: http://dx.doi.org/10.1016/j.schres.2012.10.013
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INTRODUCTION: The hippocampal formation has been studied extensively in schizophrenic psychoses and alterations in hippocampal anatomy have been consistently reported. Chronic schizophrenia seems to be associated with bilateral hippocampal volume (HV) reduction, while in patients with an at-risk mental state (ARMS) there are contradictory results. This is the first region of interest (ROI) based follow-up MRI study of hippocampal volume comparing ARMS individuals with and without transition to psychosis. The aim was to investigate the timing of HV changes in ARMS in the early phase of psychosis. METHODS: Magnetic resonance imaging data from 18 antipsychotic-naïve individuals with an ARMS were collected within the FePsy-clinic for early detection of psychoses. During follow-up 8 subjects transitioned to psychosis (ARMS-T) and 10 did not (ARMS-NT). Subjects were re-scanned after the onset of psychosis or at the end of the follow-up if they did not develop psychosis. RESULTS: Across both groups there was a significant decrease in HV over time (p<0.05). There was no significant difference in progression between ARMS-T and ARMS-NT. Antipsychotic medication at follow up was associated with increased HV (p<0.05). CONCLUSIONS: We found a decrease of HV over time in subjects with an ARMS, independently of clinical outcome. We may speculate that the decrease of HV over time might reflect brain degeneration processes. Copyright © 2012 Elsevier B.V. All rights reserved.
- Smieskova R, Fusar-Poli P, Aston J, Simon A, Bendfeldt K, Lenz C, et al. Insular volume abnormalities associated with different transition probabilities to psychosis. Psychological Medicine [Internet]. 2012 Aug;42(8):1613–25. Available from: http://dx.doi.org/10.1017/s0033291711002716
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BACKGROUND: Although individuals vulnerable to psychosis show brain volumetric abnormalities, structural alterations underlying different probabilities for later transition are unknown. The present study addresses this issue by means of voxel-based morphometry (VBM).MethodWe investigated grey matter volume (GMV) abnormalities by comparing four neuroleptic-free groups: individuals with first episode of psychosis (FEP) and with at-risk mental state (ARMS), with either long-term (ARMS-LT) or short-term ARMS (ARMS-ST), compared to the healthy control (HC) group. Using three-dimensional (3D) magnetic resonance imaging (MRI), we examined 16 FEP, 31 ARMS, clinically followed up for on average 3 months (ARMS-ST, n=18) and 4.5 years (ARMS-LT, n=13), and 19 HC. RESULTS: The ARMS-ST group showed less GMV in the right and left insula compared to the ARMS-LT (Cohen's d 1.67) and FEP groups (Cohen's d 1.81) respectively. These GMV differences were correlated positively with global functioning in the whole ARMS group. Insular alterations were associated with negative symptomatology in the whole ARMS group, and also with hallucinations in the ARMS-ST and ARMS-LT subgroups. We found a significant effect of previous antipsychotic medication use on GMV abnormalities in the FEP group. CONCLUSIONS: GMV abnormalities in subjects at high clinical risk for psychosis are associated with negative and positive psychotic symptoms, and global functioning. Alterations in the right insula are associated with a higher risk for transition to psychosis, and thus may be related to different transition probabilities.
- Smieskova R, Fusar-Poli P, Riecher-Rössler A, Borgwardt S. Neuroimaging and resilience factors–staging of the at-risk mental state? Current Pharmaceutical Design [Internet]. 2012;18(4):416–21. Available from: http://view.ncbi.nlm.nih.gov/pubmed/22239572
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Over the past decade, vulnerability- and psychosis-associated structural and functional brain abnormalities in a population at high clinical risk to develop psychosis were intensively studied. We reviewed the results from studies comparing at-risk mental state (ARMS) individuals with and without subsequent transition to psychosis. Additionally, we introduced a new concept of splitting ARMS population according to the duration of the psychosis risk syndrome and their probability to develop psychosis. Studying the ARMS individuals still vulnerable to psychosis but with lower risk to transit can disclose the possible protective-resilience factors or characteristics. Resilience, understood as ability to recover from change, can be thus applied in the early intervention for high clinical risk for psychosis individuals.
- Riecher-Rössler A, editor. Psychische Erkrankungen in Schwangerschaft und Stillzeit. Basel: Karger; 2012.
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Psychische Erkrankungen während oder nach einer Schwangerschaft bleiben oft unerkannt und damit unbehandelt. Dieser multidisziplinäre Leitfaden beschreibt praxisorientiert Prophylaxe, Diagnose und Therapie von Depression, Angst- oder Abhängigkeitserkrankungen aus verschiedenen Perspektiven. Er beantwortet gleichzeitig wichtige Fragen, die sich in der Praxis immer wieder stellen: Was ist zu beachten, wenn bei oder nach psychischen Erkrankungen eine Schwangerschaft geplant wird? Was, wenn die Schwangerschaft ungeplant eintritt? Was ist eine optimale Betreuung für Mutter und Kind während Schwangerschaft, Geburt und Stillzeit? Welche Psychopharmaka dürfen eingesetzt werden? Welche neuen Möglichkeiten der Psychotherapie gibt es? Welche alternativen Verfahren? Wie ist das Selbsterleben der Mütter, aber auch der Väter? Wie kann die Mutter-Kind-Beziehung gefördert und wie die junge Familie unterstützt werden? Schliesslich: Wie können die Beteiligten zum Wohl von Mutter und Kind besser kooperieren? Hierzu werden Modelle zur Verbesserung der interdisziplinären Kooperation und der Prävention vorgestellt. Alle, die sich in diesem Bereich engagieren, werden in diesem Buch wertvolle Hinweise für ihre tägliche Arbeit finden.
- Riecher-Rössler A. Psychische Erkrankungen in Schwangerschaft und Stillzeit. In: Riecher-Rössler A, editor. Psychosen in Schwangerschaft und Stillzeit. Basel: Karger; 2012. p. 34–42.
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Bei Psychosen handelt es sich wohl um die schwerwiegendsten psychischen Erkrankungen in der Schwangerschaft und Postpartalzeit. Mütter mit Psychosen sind besonders stigmatisiert und haben große Ängste, die sie oft von einer adäquaten Behandlung fernhalten. Dies kann schwerwiegende Konsequenzen für Mutter und Kind haben. Nach wie vor bestehen auch eklatante Versorgungsmängel für diese Mütter und ihre Neugeborenen. Mütter mit psychotischer Symptomatik sollten stationär aufgenommen werden. Stationär wie ambulant sollte den betroffenen (werdenden) Müttern mit ihren Kindern ein integriertes psychiatrisch-psychotherapeutisches Angebot gemacht werden mit Medikation, Beratung, Psychoedukation, Einzeltherapie sowie sozialarbeiterischen und anderen Hilfen, Hausbesuchen durch speziell geschulte Psychiatriepflegekräfte und bei Bedarf auch Aufnahme in spezialisierte Mutter-Kind-Einheiten. Großer Wert ist auf ein sorgfältiges «parenting assessment» und ein gutes «parenting training» sowie eine langfristige unterstützende Begleitung zu legen. Eine enge interdisziplinäre Zusammenarbeit zwischen Psychiaterinnen, Gynäkologinnen, Hebamme, Pädiaterinnen, Kinderpsychiaterinnen, Hausärztinnen usw. ist zum Wohl dieser Mütter und Kinder unbedingt anzustreben.
- Yung A, Woods S, Ruhrmann S, Addington J, Schultze-Lutter F, Cornblatt B, et al. Whither the attenuated psychosis syndrome? Schizophrenia bulletin [Internet]. 2012 Nov;38(6):1130–4. Available from: http://dx.doi.org/10.1093/schbul/sbs108
2011
- Riecher-Rössler A, Kulkarni J. Estrogens and Gonadal Function in Schizophrenia and Related Psychoses Biological Basis of Sex Differences in Psychopharmacology. In: Neill J, Kulkarni J, editors. Biological Basis of Sex Differences in Psychopharmacology [Internet]. Berlin Heidelberg: Springer; 2011. p. 155–71. Available from: http://dx.doi.org/10.1007/7854_2010_100
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Recent research has increasingly pointed to the importance of estrogens and the hypothalamic–pituitary–gonadal axis in schizophrenia. Specifically, there is mounting evidence from clinical, epidemiological, and basic research that estradiol, the main component of estrogens, exerts protective effects in schizophrenia and related psychoses. Possible modes of action of this hormone in the brain have been suggested, and clinical intervention studies have reported the first positive results. Furthermore, there are an increasing number of reports on gonadal dysfunction and states of estrogen deficiency in women with schizophrenia. These findings could have important implications for clinicians and researchers alike.
- Mechelli A, Riecher-Rössler A, Meisenzahl E, Tognin S, Wood S, Borgwardt S, et al. Neuroanatomical Abnormalities That Predate the Onset of Psychosis. Archives of General Psychiatry [Internet]. 2011 May;68(5):489–95. Available from: http://dx.doi.org/10.1001/archgenpsychiatry.2011.42
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People experiencing possible prodromal symptoms of psychosis have a very high risk of developing the disorder, but it is not possible to predict, on the basis of their presenting clinical features, which individuals will subsequently become psychotic. Recent neuroimaging studies suggest that there are volumetric differences between individuals at ultra-high risk (UHR) for psychosis who later develop psychotic disorder and those who do not. However, the samples examined to date have been small, and the findings have been inconsistent. To assess brain structure in individuals at UHR for psychosis in a larger and more representative sample than in previous studies by combining magnetic resonance imaging data from 5 different scanning sites. Case-control study. Multisite. A total of 182 individuals at UHR and 167 healthy controls. Participants were observed clinically for a mean of 2 years. Forty-eight individuals (26.4%) in the UHR group developed psychosis and 134 did not. Magnetic resonance images were acquired from each participant. Group differences in gray matter volume were examined using optimized voxel-based morphometry. The UHR group as a whole had less gray matter volume than did controls in the frontal regions bilaterally. The UHR subgroup who later developed psychosis had less gray matter volume in the left parahippocampal cortex than did the UHR subgroup who did not. Individuals at high risk for psychosis show alterations in regional gray matter volume regardless of whether they subsequently develop the disorder. In the UHR population, reduced left parahippocampal volume was specifically associated with the later onset of psychosis. Alterations in this region may, thus, be crucial to the expression of illness. Identifying abnormalities that specifically predate the onset of psychosis informs the development of clinical investigations designed to predict which individuals at high risk will subsequently develop the disorder.
- Malik P, Kemmler G, Hummer M, Riecher-Rössler A, Kahn R, Fleischhacker W, et al. Sexual dysfunction in first-episode schizophrenia patients : results from European First Episode Schizophrenia Trial. Journal of clinical psychopharmacology [Internet]. 2011 Jun;31(3):274–80. Available from: http://dx.doi.org/10.1097/jcp.0b013e3182199bcc
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Sexual dysfunctions (SDs) occur frequently in schizophrenia patients and have a huge impact on quality of life and compliance. They are often associated with antipsychotic medication. Nicotine consumption, negative or depressive symptoms, and physical illness are also discussed as contributing factors. Data on SD in first-episode schizophrenia patients are scarce.As part of the European First Episode Schizophrenia Trial, first-episode schizophrenia patients were randomly assigned to 5 medication groups. We assessed SD by analyzing selected items from the Udvalg for Kliniske Undersugelser at baseline and at 5 following visits.Differences between antipsychotics were small for all SDs, and fairly little change in the prevalence of SDs was seen over the course of the study. A significantly larger increase of amenorrhea and galactorrhea was seen with amisulpride than with the other medications. In men, higher age, more pronounced Positive and Negative Syndrome Scale general psychopathology symptoms, and higher plasma prolactin levels predicted higher rates of erectile and ejaculatory dysfunctions. Positive and Negative Syndrome Scale negative symptoms and higher age were predictors for decreased libido.In women, higher prolactin plasma levels were identified as a predictor of amenorrhea. Positive and Negative Syndrome Scale negative symptoms predicted decreased libido.All evidence taken together underscores the influence of the disease schizophrenia itself on sexual functioning. In addition, there is a strong correlation between the prolactin-increasing properties of amisulpride and menstrual irregularities.
- Simon A, Schmeck K, Gallo AD, Borgwardt SJ, Aston J, Roth B, et al. Zur Bedeutung der frühen Erkennung und Behandlung von Psychosen. Swiss Med Forum. 2011 Dec;49(11):913–8.
2010
- Aston J, Keck M. Beginnende schizophrene Erkrankungen - Wie erkennen und behandeln? Ars Medici [Internet]. 2010 Dec;25/26:1051–5. Available from: http://www.rosenfluh.ch/rosenfluh/issues/view/180
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Sowohl klinische als auch quantitative EEG-Untersuchungen können zur Früherkennung von Psychosen beitragen. Des Weiteren ist eine neuro psychologische Abklärung bei Patienten mit Verdacht auf eine beginnende Psychose empfehlenswert. Sie kann zur Einschätzung des tatsächlichen Psychoserisiko beitragen, und sie ist auch wichtig zur Beurteilung des kognitiven Verlaufs der Erkrankung, der sozialen und beruflichen Integrationsfähigkeit sowie zur gezielten Planung eines kognitiven Trainings.
- Zimmermann R, Gschwandtner U, Wilhelm F, Pfluger M, Riecher-Rössler A, Fuhr P. EEG spectral power and negative symptoms in at-risk individuals predict transition to psychosis. Schizophrenia research [Internet]. 2010 Nov;123(2–3):208–16. Available from: http://dx.doi.org/10.1016/j.schres.2010.08.031
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EEG power in the delta, theta and beta1 bands has been shown to be positively correlated with negative symptoms in first episode psychotic patients. The present study investigates this correlation in an “at risk mental state for psychosis” (ARMS) with the aim to improve prediction of transition to psychosis. Thirteen ARMS patients with later transition to psychosis (ARMS-T) and fifteen without (follow-up period of at least 4 years) (ARMS-NT) were investigated using spectral resting EEG data (of 8 electrodes over the fronto-central scalp area placed according to the 10-20 system) and summary score of the Scale for the Assessment of Negative Symptoms (SANS). Linear regressions were used to evaluate the correlation of SANS and EEG power in seven bands (delta, theta, alpha1, alpha2, beta1, beta2, beta3) in both ARMS groups and logistic regressions were used to predict transition to psychosis. Potentially confounding factors were controlled. ARMS-T and ARMS-NT showed differential correlations of EEG power and SANS in delta, theta, and beta1 bands (p<.05): ARMS-T showed positive and ARMS-NT negative correlations. Logistic regressions showed that neither SANS score nor EEG spectral power alone predicted transition to psychosis. However, SANS score in combination with power in the delta, theta, beta1, and beta2 bands, respectively, predicted transition significantly (p<.03). ARMS-T and ARMS-NT show differential correlations of SANS summary score and EEG power in delta, theta, and beta bands. Prediction of transition to psychosis is possible using combined information from a negative symptom scale and EEG spectral data. Copyright © 2010 Elsevier B.V. All rights reserved.
- Boter H, Derks E, Fleischhacker W, Davidson M, Kahn R, Group ES. Generalizability of the results of efficacy trials in first-episode schizophrenia : comparisons between subgroups of participants of the European First Episode Schizophrenia Trial (EUFEST). The Journal of Clinical Psychiatry [Internet]. 2010 Jan;71(1):58–65. Available from: http://dx.doi.org/10.4088/jcp.08m04506yel
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Most randomized drug trials in schizophrenia exclude patients with comorbidities such as suicidality or substance use, which may limit the generalizability of the results. We aimed to evaluate the generalizability of the results of these trials in participants of a randomized clinical trial with broad inclusion criteria. In 50 sites in 14 countries, 498 patients with first-episode psychosis (DSM-IV schizophrenia, schizoaffective disorder, or schizophreniform disorder) were recruited between December 2002 and January 2006 in an open, randomized clinical drug trial with 12 months of follow-up. Baseline characteristics and follow-up data were compared between patients with versus patients without baseline suicidality and/or substance use. Of the 489 participants with data on baseline suicidality and substance use, 153 (31%) patients were suicidal and/or using substances. Groups differed on only a few of the many baseline characteristics tested: comorbid patients were younger (25.1 vs 26.5 years of age; P < .01), less often female (25% vs 47%; P < .001) or married (4% vs 17%; P < .001), had fewer years of education (11.8 vs 12.8; P < .001), and experienced lower levels of overall psychosocial functioning (Global Assessment of Functioning; 38.4 vs 40.8; P <or= .05) and higher levels of depression (Calgary Depression Scale for Schizophrenia; 6.1 vs 4.6; P < .001). At follow-up, comorbid patients showed shorter time to (re)hospitalization and reported higher levels of depression than patients without comorbidity (hazard ratio = 2.02, P = .004; chi(2)(7) = 17.25, P = .016, respectively), without differences on other outcome measures. Although it appears that the generalizability of antipsychotic treatment trials in first-episode patients is not seriously affected by the exclusion of patients with suicidal symptoms and/or substance use, researchers should be cautious about the exclusion of such patients. controlled-trials.com Identifier: ISRCTN68736636. ©Copyright 2010 Physicians Postgraduate Press, Inc.
- Borgwardt S, Smieskova R, Bendfeldt K, Buhlmann E, Berger G, Aston J, et al. Hippocampal volume reduction specific for later transition to psychosis or substance-associated effects? Journal of Psychiatry & Neuroscience [Internet]. 2010 May;35(3). Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2861138/
- Buhlmann E, Berger G, Aston J, Gschwandtner U, Pfluger M, Borgwardt S, et al. Hippocampus abnormalities in at risk mental states for psychosis? : A cross-sectional high resolution region of interest magnetic resonance imaging study. Journal of psychiatric research [Internet]. 2010 May;44(7):447–53. Available from: http://dx.doi.org/10.1016/j.jpsychires.2009.10.008
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Hippocampal volume (HV) reduction is well documented in schizophrenia. However, it is still unclear whether this change is a pre-existing vulnerability factor, a sign of disease progression, a consequence of environmental factors, such as drug use, antipsychotic medication, or malnutrition. The timing of HV changes is not well established, but a lack of macrostructural hippocampal brain abnormalities before disease onset would rather support a neuroprogressive illness model. To investigate the timing of HV changes in emerging psychosis. A cross-sectional MRI study of manually traced HVs in 37 individuals with an At Risk Mental State (ARMS) for psychosis, 23 individuals with First-Episode Psychosis (FEP), and 22 Healthy Controls (HC) was performed. We compared left and right HVs corrected for whole brain volume across groups using analysis of covariance (ANCOVA) with gender as a covariate. Sixteen of 37 ARMS individuals developed a psychotic disorder during follow up (ARMS-T). The mean duration of follow up in ARMS was 25.1months. The overall ANCOVA model comparing left HVs across FEP, ARMS and HC indicated a significant general group effect (p<.05) with largest volumes in ARMS and smallest in FEP. ARMS-T subjects had significantly larger left HVs compared to FE but no HV differences compared to HC (p<0.05). Over all groups, we found an asymmetry between the left and right mean HVs and a strong effect of sex. The present study suggests that macrostructural hippocampal abnormalities probably occur in the context of the first psychotic breakdown. Copyright 2009 Elsevier Ltd. All rights reserved.
- Aston J, Rechsteiner E, Bull N, Borgwardt S, Gschwandtner U, Riecher-Rössler A. Hyperprolactinaemia in early psychosis-not only due to antipsychotics. Progress in neuro-psychopharmacology & biological psychiatry [Internet]. 2010 Oct;34(7):1342–4. Available from: http://dx.doi.org/10.1016/j.pnpbp.2010.02.019
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Hyperprolactinaemia is often found in patients with schizophrenia and usually considered a consequence of antipsychotics. Prolactin levels were measured in 43 At-Risk Mental State individuals (ARMS) and 26 patients with First Episode Psychosis (FEP). Hyperprolactinaemia was found in 25.6% of ARMS and 46.2% of FEP. Within 60 antipsychotic-naïve ARMS and FEP, hyperprolactinaemia was found in 26.7%. Hyperprolactinaemia may be pre-existing in a subgroup of patients with schizophrenia.
- Smieskova R, Fusar-Poli P, Allen P, Bendfeldt K, Stieglitz RD, Drewe J, et al. Neuroimaging predictors of transition to psychosis - a systematic review and meta-analysis. Neuroscience and biobehavioral reviews [Internet]. 2010 Jul;34(8):1207–22. Available from: http://dx.doi.org/10.1016/j.neubiorev.2010.01.016
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In early stage psychosis research the identification of neurobiological correlates of vulnerability to schizophrenia is an important hurdle. We systematically reviewed the neuroimaging publications on high-risk subjects with subsequent transition to psychosis (HR-T) and conducted a meta-analysis calculating the effect size Cohen's d. Out of 30 identified studies 25 met the inclusion criteria. Structural (s)MRI studies showed small to medium effect sizes of decreased prefrontal, cingulate, insular and cerebellar gray matter volume in HR-T compared to high-risk subjects without transition (HR-NT). Meta-analysis revealed relatively larger whole brain volumes in HR-T compared to HR-NT subjects (mean Cohen's d 0.36, 95% CI 0.27-0. 46). Compared to HR-NT, HR-T subjects showed in functional imaging studies reduced brain activation in prefrontal cortex, reduced neuronal density, and increased membrane turnover in frontal and cingulate cortex with medium to large effect sizes. Despite methodological differences between studies, structural and neurochemical abnormalities in prefrontal, anterior cingulate, medial temporal and cerebellar cortex might be predictive for development of psychosis within HR subjects.
- Buschlen J, Berger G, Borgwardt S, Aston J, Gschwandtner U, Pfluger M, et al. Pituitary volume increase during emerging psychosis. Schizophrenia Research [Internet]. 2010 Nov; Available from: http://dx.doi.org/10.1016/j.schres.2010.09.022
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Morphologic abnormalities of the pituitary gland volume (PV) have been reported in schizophrenia, but at what point in time they occur remains unclear. This study determines PV across different stages of emerging psychotic disorders compared to healthy controls. We compared PV of 36 individuals with an at-risk mental state (ARMS) for psychosis, 23 patients with a first episode psychosis (FEP) and 20 healthy controls (HC). Transition to psychosis was monitored using the BPRS transition criteria according to Yung et al. (Yung, A.R. et al., 1998. Prediction of psychosis. A step towards indicated prevention of schizophrenia. Br. J. Psychiatry Suppl. 172 (33), 14–20). Applying these transition criteria, 16 of the 36 ARMS individuals made the transition to psychosis (ARMS-T) and 20 did not (ARMS-NT). We traced PV manually on 1 mm slices of magnetic resonance images in three dimensions (coronal, sagittal and axial) blind to group status. We used univariate analysis of covariance (ANCOVA) with PV as dependent variable, group and sex as between-subject factors and whole brain volume as covariate. PV increased from HC to ARMS-NT to ARMS-T/FEP. ANCOVA revealed a significant effect of group (F3,78 = 3.0; p = .036) and a sex × group interaction (F3,78 = 6.5; p = .001). Over all groups, women had considerably larger PV than men (F1,78 = 9.8; p = .003). Our findings provide further evidence that PV is increased in emerging psychotic disorders, and suggest that this is due to a stress-associated activation of the pituitary gland.
- Riecher-Rössler A. Prospects for the classification of mental disorders in women. European psychiatry : the journal of the Association of European Psychiatrists [Internet]. 2010 May;25(4):189–96. Available from: http://dx.doi.org/10.1016/j.eurpsy.2009.03.002
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Many mental disorders show marked gender differences as regards prevalence, symptomatology, risk factors or course. Other disorders do per definition only occur in women - e.g. premenstrual dysphoric disorder (PMDD) - or are markedly influenced by female specific factors such as hormonal changes over the life cycle or during reproductive processes. Current classification systems have tried to take into account these gender aspects, but some problems will certainly have to be discussed again with the next revisions of the ICD and DSM. As regards gender differences in prevalence and symptomatology questions of gender bias in diagnostic instruments and diagnostic criteria will have to be readdressed. New findings from unselected epidemiological samples, which were analysed by gender, will have to be taken into account as well as new findings from research into gender specific personality traits, which can influence the symptomatology of mental disorders. Decisions will have to be taken whether to revise existing diagnostic criteria and provide alternative diagnostic thresholds for men and women or even to develop alternative criteria sets in certain disorders, or rather to enhance the gender neutrality of criteria. A further question to be addressed will be that of gender specific diagnoses versus diagnostic specifiers. In the whole discussion two main aims of classification should be given priority: the research aim of identifying genuine entities with a common aetiology, which means we should be able to identify specific diagnostic entities with descriptive, construct, and predictive validity quite independently of the influences of gender; and the clinical aim to improve treatment and care for men and women, which often means to offer gender-specific approaches. (c) 2009 Elsevier Masson SAS. All rights reserved.
- Borgwardt S, Aston J, Bugra H, Pfluger M, Rapp C, Smieskova R, et al. Schwerwiegende Krankheitsfolgen verhindern - Früherkennung und Frühbehandlung von Psychosen. Info Neurologie & Psychiatrie. 2010;8(5):6–10.
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Dank verbesserter Diagnose- und Therapiemöglichkeiten hat sich der Verlauf psychotischer Erkrankungen in den letzten Jahrzehnten bei vielen Patienten erheblich gebessert. Die Frühdiagnose in spezialisierten Früherkennungs- und Behandlungszentren für Psychosen (z.B. Basler FePsy Projekt) verbessert die Behandlungsmöglichkeiten weiter und damit die Prognose psychotischer Erkrankungen. Neue medikamentöse und psychotherapeutische Behandlungsverfahren haben dazu geführt, dass die meisten Patienten - wenn ihre Erkrankung früh erkannt und behandelt wird - geheilt werden oder zumindest wieder ein weitgehend normales Leben führen können.
- Muller M, Vetter S, Buchli-Kammermann J, Stieglitz RD, Stettbacher A, Riecher-Rössler A. The Self-screen-Prodrome as a short screening tool for pre-psychotic states. Schizophrenia research [Internet]. 2010 Nov;123(2–3):217–24. Available from: http://dx.doi.org/10.1016/j.schres.2010.08.018
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Early detection of psychosis is an important issue in current research. Early intervention helps to improve the outcome of the disorder. Therefore, a comprehensive examination in large populations, necessary as it might be, is economically almost not feasible. A screening via self-report is more practicable as it helps focus on individuals with high symptom loads. To examine aspects of validity of the Self-screen-Prodrome (SPro) as a new screening tool for prodromal states of psychosis in a military sample. 938 Swiss conscripts were assessed with the SPro, the Eppendorf Schizophrenia-Inventory (ESI) and the Symptom-Checklist-90-Revised (SCL-90-R). Conscripts with potential psychosis-like pathology (T-transformed Severity Index of the SCL-90-R-subscales Psychoticism [PSYC] and Paranoid Ideation [PARA]≥63) were compared with those not meeting the criteria of this condition (non-cases). Both groups (cases and non-cases) showed significant differences in their mean scores on SPro and ESI, although only the SPro had satisfactory effect sizes. In hierarchic logistic regression models the SPro turned out to be highly predictive for caseness while ESI-scales were not significant. A cut-off score of ≥2 on the SPro subscale for psychotic risk (SPro-Psy-Risk) was found to identify caseness best with a sensitivity of 74% and a specificity of 61%. The SPro has proven to be a valid and very economic screening tool for general and prodromal pathology in large populations. Copyright © 2010 Elsevier B.V. All rights reserved.
- Pfluger MO, Gschwandtner U, Kalin A, Riecher-Rössler A, Fuhr P. Was kann das EEG zur Vorhersage von schizophrenen Psychosen leisten? neuro aktuell - Informationsdienst für Neurologen und Psychiater [Internet]. 2010;01:30–5. Available from: http://www.zora.uzh.ch/41474/
2009
- Kammermann J, Stieglitz RD, Riecher-Rössler A. [“Self-screen prodrome”–self-rating for the early detection of mental disorders and psychoses]. Fortschritte der Neurologie-Psychiatrie [Internet]. 2009 May;77(5):278–84. Available from: http://dx.doi.org/10.1055/s-0028-1109227
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In the past years, the significance of early detection of psychoses has been increasingly recognized. Screening for the onset of disorders should focus on individuals seeking treatment in an outpatient setting and should preferably operate stepwise. Within a prospective study for the early detection of psychoses (FePsy = Früh Erkennung von PSYchosen) the self-rating instrument “Self-screen Prodrome” was developed to differentiate between healthy individuals, individuals with psychosis or an at-risk mental state for psychosis and patients with other ICD-10 diagnoses. The “Self-screen Prodrome” was developed by taking established risk factors and early signs of disease into account. In particular, prodromes and pre-psychotic symptoms were captured. A total score and a subscale were analyzed with regard to validity and reliability. The total score “Self-screen Prodrome” distinguished between outpatients with a mental disorder and healthy individuals (Cut-off > or = 6; sensitivity: 85 % specificity: 91 %). Additionally the subscale distinguished between psychosis-(risk)-individuals and outpatients with other ICD-10 psychiatric diagnoses (Cut-off > or = 2; sensitivity: 85 % specificity: 39 %). The “Self-screen Prodrome” is a useful instrument that a) separates mentally ill patients from healthy individuals and b) filters individuals with a risk of developing psychoses from patients with other ICD-10 diagnoses for further screening. The next step in the early detection of psychoses for identified individuals should be a detailed psychiatric exploration by experts.
- Riecher-Rössler A, Schmid C, Bleuer S, Birkhauser M. [Antipsychotics and hyperpolactinaemia : pathophysiology, clinical relevance, diagnosis and therapy]. Neuropsychiatrie [Internet]. 2009;23(2):71–83. Available from: http://view.ncbi.nlm.nih.gov/pubmed/19573500
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Hyperprolactinaemia is a frequent but often neglected side effect of typical, but also of many atypical antipsychotics such as amisulpiride, risperidone or ziprasidone. Besides galactorrhoea, potential consequences are suppression of the hypothalamic-pituitary-gonadal axis with hypogonadism, sexual dysfunction, infertility and in women also irregularities of the menstrual cycle and amenorrhoea. Potential long term consequences are mainly osteopenia and osteoporosis with an enhanced risk of fractures. Hyperprolactinaemia, if not clearly caused by a prolactin inducing antipsychotic, should always be thoroughly investigated. Ideally, prolactin should be measured before starting a patient on a new antipsychotic. Furthermore, before neuroleptic treatment is begun, and also in regular intervals after that, patients should be asked about potential clinical signs of hyperprolactinaemia. Hyperprolactinaemia which is clearly due to antipsychotics but without clinical symptoms only requires regular controls of bone mineral density. However, if clinical symptoms occur, switching to a prolactin sparing antipsychotic may be necessary. In these cases fertility is often regained and the women concerned have to be informed about the enhanced risk of pregnancy and counselled regarding contraception. If switching is not possible, estradiol has to be substituted in women. Also in men with hypogonadism hormonesubstitution (with testosterone) is usually indicated. Generally hyperprolactinaemia in psychiatric patients should be taken more seriously in the future.
- Haller S, Borgwardt SJ, Schindler C, Aston J, Radu E, Riecher-Rössler A. Can cortical thickness asymmetry analysis contribute to detection of at-risk mental state and first-episode psychosis? : A pilot study. Radiology [Internet]. 2009 Jan;250(1):212–21. Available from: http://dx.doi.org/10.1148/radiol.2501072153
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To investigate whether cortical thickness analysis in individuals with an at-risk mental state (ARMS) might contribute to early detection of psychosis. Ethics committee approval and written informed consent were obtained. Cortical thickness was analyzed because early disease-related morphometric changes were expected to be most pronounced in the cerebral cortex. With the assumption of progressive change in cortical thickness from control subjects, to those with an ARMS, and then to those who have had a first episode (FE) of psychosis, the brain regions that substantially differ between those with FE psychosis and control subjects were identified. Whether these regions help discriminate between the ARMS group and control subjects was tested. Because normal interindividual variation of cortical thickness, even for control subjects, may exceed that expected with early disease-related changes, intraindividual cortical thickness asymmetry was analyzed. Twenty age- and sex-matched individuals for each group (ARMS group, FE group, and control subjects) were recruited within a prospective early-detection study. High-spatial-resolution magnetization-prepared rapid gradient-echo magnetic resonance (MR) brain images were acquired with a 1.5-T MR imager. Cortical thickness asymmetry was analyzed in 41 anatomic regions corresponding to the Talairach standard brain atlas. Direct cortical thickness analysis did not help distinguish between groups. Cortical thickness asymmetry analysis helped distinguish between groups (P = .007); variability increased from control subjects, to the ARMS group, and then to the FE group in seven anatomic regions (P < .0001). Cortical thickness asymmetry in these regions helped distinguish the FE group from control subjects (P = .0006; sensitivity, 70.0%; specificity, 85.0%) and showed a trend toward helping to distinguish the ARMS group from control subjects (P = .06; sensitivity, 75.0%; specificity, 65.0%). Cortical thickness asymmetry analysis is more accurate than direct cortical thickness measurement in distinguishing the control from the FE group and might contribute to early detection of an ARMS. (c) RSNA, 2009.
- Davidson M, Galderisi S, Weiser M, Werbeloff N, Fleischhacker W, Keefe R, et al. Cognitive effects of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder : a randomized, open-label clinical trial (EUFEST). The American journal of psychiatry [Internet]. 2009 Jun;166(6):675–82. Available from: http://dx.doi.org/10.1176/appi.ajp.2008.08060806
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Cognitive impairment, manifested as mild to moderate deviations from psychometric norms, is present in many but not all schizophrenia patients. The purpose of the present study was to compare the effect of haloperidol with that of second-generation antipsychotic drugs on the cognitive performance of patients with schizophreniform disorder or first-episode schizophrenia. Subjects were 498 patients with schizophreniform disorder or first-episode schizophrenia who were randomly assigned to open-label haloperidol (1 to 4 mg/day [N=103]), amisulpride (200 to 800 mg/day [N=104]), olanzapine (5 to 20 mg/day [N=105]), quetiapine (200 to 750 mg/day [N=104]), or ziprasidone (40 to 160 mg/day [N=82]). The Rey Auditory Verbal Learning Test, Trail Making Test Part A and Part B, WAIS Digit Symbol Test, and Purdue Pegboard Test were administered at baseline and the 6-month follow-up evaluation. Compared with scores at baseline, composite cognitive test scores improved for all five treatment groups at the 6-month follow-up evaluation. However, there were no overall differences among the treatment groups. In addition, there was a weak correlation between the degree of cognitive improvement and changes in Positive and Negative Syndrome Scale scores. Treatment with antipsychotic medication is associated with moderate improvement in the cognitive test performance of patients who have schizophreniform disorder or who are in their first episode of schizophrenia. The magnitude of improvement does not differ between treatment with haloperidol and treatment with second-generation antipsychotics. Moreover, cognitive improvement is weakly related to symptom change.
- Galderisi S, Davidson M, Kahn R, Mucci A, Boter H, Gheorghe M, et al. Correlates of cognitive impairment in first episode schizophrenia : the EUFEST study. Schizophrenia research [Internet]. 2009 Dec;115(2–3):104–14. Available from: http://dx.doi.org/10.1016/j.schres.2009.09.022
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Profile and correlates of cognitive deficits in first episode (FE) schizophrenia patients are still debated. The present study is aimed to clarify in a large sample of FE patients the extent of impairment in key cognitive domains and its relationships with demographic and clinical variables. The European First Episode Schizophrenia Trial collected demographic, clinical and neurocognitive baseline data in 498 FE patients with minimal or no prior exposure to antipsychotics. Two-hundred-twenty healthy subjects (HS) were also evaluated. Neurocognitive assessment included the Rey Auditory Verbal Learning Test; Trail Making A and B, Purdue Pegboard and Digit-Symbol Coding. Patients performed worse than HS on all tests (effect sizes from -0.88 to -1.73). Correlations with psychopathological dimensions were weak and involved reality distortion and disorganization. The duration of untreated psychosis (DUP) was not associated with cognitive impairment. Subjects living alone had a better neurocognitive performance, while the occupation status did not reveal any association with cognition. A moderate/severe impairment of processing speed, motor dexterity, verbal memory and cognitive flexibility was found in the largest sample of FE patients analyzed so far. The impairment was largely independent from psychopathology and not associated with DUP.
- Gschwandtner U, Pfluger M, Semenin V, Gaggiotti M, Riecher-Rössler A, Fuhr P. EEG : a helpful tool in the prediction of psychosis. European archives of psychiatry and clinical neuroscience [Internet]. 2009 Aug;259(5):257–62. Available from: http://dx.doi.org/10.1007/s00406-008-0854-3
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EEG investigation in patients with an at risk mental state (ARMS) for psychosis and patients with a first episode of psychosis (FE) in comparison to healthy controls (HC) in a clinical follow up study of Early Detection of Psychosis. Seventy-three patients (42 ARMS, 31 FE) and 35 HC were investigated. ARMS patients were followed up in order to monitor transition to psychosis. Psychopathology was assessed with respect to positive and negative symptoms. At study baseline EEG was recorded using the 10/20 system. Two blinded neurologists analyzed the EEGs visually for presence of generalized or focal slowing and epileptiform discharges. EEG data were controlled for medication and substance abuse. For statistical analyses we used chi(2)-tests, logistic regression, ANOVA, and receiver operating characteristics. Patients showed significantly more pathological EEG abnormalities than HC (P < 0.05), located more frequently in temporal or fronto-temporal regions (P < 0.01) of the brain, with twice as many pathologies in ARMS than in FE patients. The specificity of the prediction of psychosis could be increased from 59 to 73% by considering EEG pathology in addition to psychopathology alone. In contrast, sensitivity of prediction remained unchanged. These results show that EEG investigation in patients at risk for psychosis can add to the identification of those patients who will not develop psychosis later on.
- Boter H, Peuskens J, Libiger J, Fleischhacker W, Davidson M, Galderisi S, et al. Effectiveness of antipsychotics in first-episode schizophrenia and schizophreniform disorder on response and remission : an open randomized clinical trial (EUFEST). Schizophrenia research [Internet]. 2009 Dec;115(2–3):97–103. Available from: http://dx.doi.org/10.1016/j.schres.2009.09.019
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Predefined response and remission criteria may hold more clinical relevance than mean scores on rating scales. We compared the effectiveness of low doses of haloperidol and regular doses of second generation antipsychotics (SGAs) on >or=50% response and remission. In an open randomized clinical trial in 14 countries, 498 unselected first-episode patients with schizophrenia were assigned to haloperidol (1-4 mg/d; n=103), amisulpride (200-800 mg/d; n=104), olanzapine (5-20mg/d; n=105), quetiapine (200-750 mg/d; n=104), or ziprasidone (40-160 mg/d; n=82). Primary outcomes were >or=50% response and remission within 12 months, as measured with the Positive and Negative Syndrome Scale. Analysis was by intention-to-treat. Within 12 months, the proportions of patients with >or=50% response were 37% for haloperidol, 67% for amisulpride, 67% for olanzapine, 46% for quetiapine, and 56% for ziprasidone. Comparisons with haloperidol showed a higher likelihood for >or=50% response with amisulpride (hazard ratio [HR] 2.27, [95% CI 1.51-3.42]), olanzapine (HR 2.07 [1.38-3.10]), and ziprasidone (HR 1.62 [1.02-2.56]). Within 12 months, the proportions of patients in remission were 17% for haloperidol, 40% for amisulpride, 41% for olanzapine, 24% for quetiapine, and 28% for ziprasidone. Comparisons with haloperidol showed a better chance for remission on amisulpride (HR 2.49, [95% CI 1.43-4.35]), olanzapine (HR 2.58 [1.48-4.48]), quetiapine (HR 1.96 [1.06-3.64]), and ziprasidone (HR 2.03 [1.07-3.87]). Substantial proportions of first-episode patients with schizophrenia showed clinically meaningful response and remission rates within 12 months. The proportions of response and remission were higher for most SGAs as compared to haloperidol.
- Riecher-Rössler A, Pfluger M, Aston J, Borgwardt S, Brewer W, Gschwandtner U, et al. Efficacy of using cognitive status in predicting psychosis : a 7-year follow-up. Biological psychiatry [Internet]. 2009 Dec;66(11):1023–30. Available from: http://dx.doi.org/10.1016/j.biopsych.2009.07.020
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Despite extensive early detection research in schizophrenic psychoses, methods for identifying at-risk individuals and predicting their transition to psychosis are still unreliable. Moreover, there are sparse data on long-term prediction. We therefore investigated long-term psychosis transition in individuals with an At Risk Mental State (ARMS) and examined the relative efficacy of clinical and neuropsychological status in optimizing the prediction of transition. Sixty-four individuals with ARMS for psychosis were identified from all referrals to our early detection clinic between March 1, 2000 and February 29, 2004. Fifty-three (83%) were followed up for up to 7 (mean 5.4) years. Twenty-one of the 53 staying in follow-up developed psychosis, corresponding to a transition rate of .34 (Kaplan-Meier estimates). Median time to transition was 10 months (range <1-55). Six of all transitions (29%) occurred only after 12 months from referral. Best transition predictors within this population were selected attenuated psychotic symptoms (suspiciousness), negative symptoms (anhedonia/asociality), and cognitive deficits (reduced speed of information processing). With these predictors in an integrated model for predicting transition to psychosis, the overall predictive accuracy was 80.9% with a sensitivity of 83.3% and a specificity of 79.3%. Follow-up of ARMS subjects should exceed the usual 12 months. Prediction of transitions could be improved by a stronger weighting of certain early symptoms and by introducing neurocognitive tests into a stepwise risk assessment. Confirmatory research will hopefully further improve risk algorithm, including psychopathology and neuropsychological performance, for clinical application in early detection clinics.
- McGorry P, Nelson B, Amminger P, Bechdolf A, Francey S, Berger G, et al. Intervention in individuals at ultra-high risk for psychosis : a review and future directions. The Journal of clinical psychiatry [Internet]. 2009 Sep;70(9):1206–12. Available from: http://dx.doi.org/10.4088/jcp.08r04472
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Over the last 15 years, a focus on early intervention in psychotic disorders has emerged. Initially, the early psychosis movement focused on timely recognition and phase-specific treatment of first-episode psychosis. However, early psychosis researchers suspected that pushing the point of intervention even further back to the prodromal phase of psychotic disorders may result in even better outcomes. This article reviews intervention research in the ultra-high-risk phase of psychotic disorders. A literature search of intervention trials with ultra-high-risk cohorts published after 1980 was conducted on PubMed with the search terms prodrome and intervention. All published intervention trials with ultra-high-risk cohorts. The first generation of intervention trials indicated that both pharmacologic and psychological intervention strategies may be of value in terms of symptom reduction and delay or prevention of onset of threshold psychotic disorder. Further controlled intervention trials with larger sample sizes are required in order to confirm and extend these findings. We argue that the clinical staging model provides a framework for the rationale and design of such studies, with simpler, safer, and more benign interventions being better candidates for first-line treatment, while more complex and potentially harmful treatments should be reserved for those cases in which response has failed to occur. Recent evidence indicates that neuroprotective agents, such as essential fatty acids, may be a suitable form of intervention for the ultra-high-risk phase of psychotic disorders, with a positive risk-benefit balance. Ethical aspects have become more salient given the recently observed declining transition rate in ultra-high-risk samples. We outline the key questions for the next generation of ultra-high-risk intervention trials. Copyright 2009 Physicians Postgraduate Press, Inc.
- Gschwandtner U, Zimmermann R, Pfluger M, Riecher-Rössler A, Fuhr P. Negative symptoms in neuroleptic-naïve patients with first-episode psychosis correlate with QEEG parameters. Schizophrenia research [Internet]. 2009 Dec;115(2–3):231–6. Available from: http://dx.doi.org/10.1016/j.schres.2009.06.013
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While several studies have shown an association of QEEG band power with negative symptoms in patients with schizophrenia, this has not yet been investigated in a sample with neuroleptic-naïve first-episode patients (NNFE) up to now. From literature we hypothesized delta (0.5-4Hz) and theta (4-8Hz) power to be augmented and alpha (8-12Hz) power to be decreased with increased negative symptoms in NNFE. The sample consisted of 27 NNFE. Psychopathology was rated with the Scale for the Assessment of Negative Symptoms (SANS). EEG was recorded from 21 electrodes according to the 10/20 system. Spectral analysis was performed on mean power of 8 electrodes in seven frequency bands after artefact removal. Linear regressions were calculated with log transformed power as dependent and psychopathology as independent variable. We controlled for medication, drugs, age, sex, education and day time of EEG recording. A positive correlation of SANS global score with power in delta and theta frequency bands could be confirmed in NNFE. In the alpha1 (8-10Hz) band we found no significant correlation with negative symptoms and in the alpha2 (10-12Hz) band there was a positive correlation with SANS (p=0.069). Beta1 (12-15Hz) power also correlated positively with SANS. The present results confirm the correlation of negative symptoms with power of slow frequency bands. In addition to previous studies in chronic schizophrenia patients, the effect was shown in NNFE, which is compatible with augmented slow wave power being a marker for negative symptoms in psychosis.
- Muller M, Riecher-Rössler A, Kammermann J, Stieglitz RD, Stettbacher A, Vetter S. Prediction of caseness for mental pathology in Swiss conscripts : the Self-Screen Prodrome. Military medicine [Internet]. 2009 Dec;174(12):1270–5. Available from: http://view.ncbi.nlm.nih.gov/pubmed/20055067
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Basic military training (BMT) is an environment of higher stress levels than are encountered in civilian life. It may trigger mental disorders in predisposed individuals. To reduce BMT attrition because of mental problems a psychiatric assessment is part of the Swiss recruitment process. An initial screening survey that identifies vulnerable individuals will be useful to save both cost and effort when dealing with large populations, such as military draftees. Aims of this investigation are to verify the psychometric properties of the Self-Screen Prodrome (SPro), a newly developed, short screening tool for psychopathology, and to validate it against the Symptom Checklist-90-Revised (SCL-90-R), a well-established self-assessment instrument. A sample of 12,380 male conscripts from the year 2003 were administered both the SPro and the SCL-90-R. Vulnerability was operationalized using the “caseness” definition of the SCL-90-R. Factor analysis demonstrated unidimensional scaling of the SPro, and this was supported by high internal reliability. Scores of nine or more symptoms on the SPro scale were found to successfully discriminate between SCL-90-R positive and negative cases. It is thus an adequate measure of general psychopathology (caseness). The association of p = 0.77 between the SPro and the SCL-90-R Global Severity Index (GSI) clearly supports concurrent validity. Our data also demonstrated that the SPro can distinguish individuals with self-reported mental health problems from those with no or few reported symptoms (cutoff > or = 9; sensitivity 89.3%; specificity 84.9%; AUC 0.942; CI 95% 0.935-0.948). Though replication and further research are needed, the SPro scale may currently be a useful screening tool for initial screening in a two-stage process of early detection of psychopathology.
- Borgwardt SJ, Riecher-Rössler A, Smieskova R, McGuire P, Fusar-Poli P. Superior temporal gray and white matter changes in schizophrenia or antipsychotic related effects? Schizophrenia research [Internet]. 2009 Aug;113(1):109–10. Available from: http://dx.doi.org/10.1016/j.schres.2009.05.028
- Borgwardt SJ, Smieskova R, Fusar-Poli P, Bendfeldt K, Riecher-Rössler A. The effects of antipsychotics on brain structure : what have we learnt from structural imaging of schizophrenia? Psychological medicine [Internet]. 2009 Nov;39(11):1781–2. Available from: http://dx.doi.org/10.1017/s0033291709006060
- Smieskova R, Fusar-Poli P, Allen P, Bendfeldt K, Stieglitz RD, Drewe J, et al. The effects of antipsychotics on the brain : what have we learnt from structural imaging of schizophrenia?–a systematic review. Current pharmaceutical design [Internet]. 2009 Aug;15(22):2535–49. Available from: http://view.ncbi.nlm.nih.gov/pubmed/19689326
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Despite a large number of neuroimaging studies in schizophrenia reporting subtle brain abnormalities, we do not know to what extent such abnormalities reflect the effects of antipsychotic treatment on brain structure. We therefore systematically reviewed cross-sectional and follow-up structural brain imaging studies of patients with schizophrenia treated with antipsychotics. 30 magnetic resonance imaging (MRI) studies were identified, 24 of them being longitudinal and six cross-sectional structural imaging studies. In patients with schizophrenia treated with antipsychotics, reduced gray matter volume was described, particularly in the frontal and temporal lobes. Structural neuroimaging studies indicate that treatment with typical as well as atypical antipsychotics may affect regional gray matter (GM) volume. In particular, typical antipsychotics led to increased gray matter volume of the basal ganglia, while atypical antipsychotics reversed this effect after switching. Atypical antipsychotics, however, seem to have no effect on basal ganglia structure.
2008
- Riecher-Rössler A, Aston J, Ventura J, Merlo M, Borgwardt SJ, Gschwandtner U, et al. [The Basel Screening Instrument for Psychosis (BSIP) : development, structure, reliability and validity]. Fortschritte der Neurologie-Psychiatrie [Internet]. 2008 Apr;76(4):207–16. Available from: http://dx.doi.org/10.1055/s-2008-1038155
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Early detection of psychosis is of growing clinical importance. So far there is, however, no screening instrument for detecting individuals with beginning psychosis in the atypical early stages of the disease with sufficient validity. We have therefore developed the Basel Screening Instrument for Psychosis (BSIP) and tested its feasibility, interrater-reliability and validity. Aim of this paper is to describe the development and structure of the instrument, as well as to report the results of the studies on reliability and validity. The instrument was developed based on a comprehensive search of literature on the most important risk factors and early signs of schizophrenic psychoses. The interraterreliability study was conducted on 24 psychiatric cases. Validity was tested based on 206 individuals referred to our early detection clinic from 3/1/2000 until 2/28/2003. We identified seven categories of relevance for early detection of psychosis and used them to construct a semistructured interview. Interrater-reliability for high risk individuals was high (Kappa .87). Predictive validity was comparable to other, more comprehensive instruments: 16 (32 %) of 50 individuals classified as being at risk for psychosis by the BSIP have in fact developed frank psychosis within an follow-up period of two to five years. The BSIP is the first screening instrument for the early detection of psychosis which has been validated based on transition to psychosis. The BSIP is easy to use by experienced psychiatrists and has a very good interrater-reliability and predictive validity.
- Borgwardt SJ, McGuire P, Fusar-Poli P, Radu EW, Riecher-Rössler A. Anterior cingulate pathology in the prodromal stage of schizophrenia. NeuroImage [Internet]. 2008 Jan;39(2):553–4. Available from: http://dx.doi.org/10.1016/j.neuroimage.2007.08.047
- Kahn R, Fleischhacker W, Boter H, Davidson M, Vergouwe Y, Keet I, et al. Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder : an open randomised clinical trial. Lancet [Internet]. 2008 Mar;371(9618):1085–97. Available from: http://dx.doi.org/10.1016/s0140-6736(08)60486-9
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Second-generation antipsychotic drugs were introduced over a decade ago for the treatment of schizophrenia; however, their purported clinical effectiveness compared with first-generation antipsychotic drugs is still debated. We aimed to compare the effectiveness of second-generation antipsychotic drugs with that of a low dose of haloperidol, in first-episode schizophrenia. We did an open randomised controlled trial of haloperidol versus second-generation antipsychotic drugs in 50 sites, in 14 countries. Eligible patients were aged 18-40 years, and met diagnostic criteria for schizophrenia, schizophreniform disorder, or schizoaffective disorder. 498 patients were randomly assigned by a web-based online system to haloperidol (1-4 mg per day; n=103), amisulpride (200-800 mg per day; n=104), olanzapine (5-20 mg per day; n=105), quetiapine (200-750 mg per day; n=104), or ziprasidone (40-160 mg per day; n=82); follow-up was at 1 year. The primary outcome measure was all-cause treatment discontinuation. Patients and their treating physicians were not blinded to the assigned treatment. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN68736636. The number of patients who discontinued treatment for any cause within 12 months was 63 (Kaplan-Meier estimate 72%) for haloperidol, 32 (40%) for amisulpride, 30 (33%) for olanzapine, 51 (53%) for quetiapine, and 31 (45%) for ziprasidone. Comparisons with haloperidol showed lower risks for any-cause discontinuation with amisulpride (hazard ratio [HR] 0.37, [95% CI 0.24-0.57]), olanzapine (HR 0.28 [0.18-0.43]), quetiapine (HR 0.52 [0.35-0.76]), and ziprasidone (HR 0.51 [0.32-0.81]). However, symptom reductions were virtually the same in all the groups, at around 60%. This pragmatic trial suggests that clinically meaningful antipsychotic treatment of first-episode of schizophrenia is achievable, for at least 1 year. However, we cannot conclude that second-generation drugs are more efficacious than is haloperidol, since discontinuation rates are not necessarily consistent with symptomatic improvement.
- Borgwardt SJ, Fusar-Poli P, Radu EW, Riecher-Rössler A. Insular pathology in the at-risk mental state. European archives of psychiatry and clinical neuroscience [Internet]. 2008 Jun;258(4):254–5. Available from: http://dx.doi.org/10.1007/s00406-007-0794-3
- Borgwardt SJ, McGuire P, Aston J, Gschwandtner U, Pfluger M, Stieglitz RD, et al. Reductions in frontal, temporal and parietal volume associated with the onset of psychosis. Schizophrenia research [Internet]. 2008 Dec;106(2–3):108–14. Available from: http://dx.doi.org/10.1016/j.schres.2008.08.007
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Volumetric MRI abnormalities similar to those evident in schizophrenia are also evident in people at very high risk of psychosis. Which volumetric abnormalities are related to psychotic illness, as opposed to vulnerability to psychosis is unclear. The aim of the study was to compare regional gray matter volume in people before and after the onset of psychosis using a within-subject prospective design. MRI data were acquired from individuals when they presented with an at-risk mental state (ARMS, n=20). Over the following 3 years, 10 subjects developed psychosis and 10 did not. Subjects were re-scanned after the onset of psychosis or at the end of follow-up if they did not become psychotic. Images were processed and analyzed using voxel-based morphometry (SPM5). In subjects who developed psychosis there were longitudinal volume reductions in the orbitofrontal, superior frontal, inferior temporal, medial and superior parietal cortex, and in the cerebellum. There were no longitudinal changes in subjects who did not develop psychosis. The onset of psychosis was associated with a reduction in gray matter volume in frontal, temporal and parietal cortex. These abnormalities may be particularly associated with psychotic illness, as opposed to a vulnerability to psychosis.
2007
- Riecher-Rössler A. [Early detection of schizophrenic psychoses in men and women]. Therapeutische Umschau Revue thérapeutique [Internet]. 2007 Jun;64(6):337–43. Available from: http://view.ncbi.nlm.nih.gov/pubmed/17877211
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The early detection and treatment of schizophrenic psychoses is of decisive importance in order to improve the course of this disorder, which so far often is a chronic one leading to early invalidity. Women on average fall ill about 4-5 years later than men, often even only after the 40th year of life. These “late onset schizophrenias”, which account for as much as 20% of all schizophrenias, should not be overlooked. Prodromi and other early signs of the disorder are very similar in women and men as is the delay of diagnosis and therapy. Due to the fact that women get the disorder only at a higher age, they are usually already much better established regarding their different social roles. However there obviously is a danger to neglect professional (re-)integration in women. Early detection, early intervention and early rehabilitation therefore should also be gender sensitive.
- Rossler W, Riecher-Rössler A. Akute Psychose. In: Hewer W, Rossler W, editors. Akute psychische Erkrankungen (Second Edition) - Management und Therapie. Munich: Elsevier; 2007. p. 133–44.
- Yildiz M, Pfluger M, Riecher-Rössler A, Berger G. Aneurysms of pericallosal cerebral artery haemorrhage with consecutive psychosis. The Australian and New Zealand journal of psychiatry [Internet]. 2007 Jun;41(6). Available from: http://dx.doi.org/10.1080/00048670701341939
- Borgwardt SJ, Radu EW, Riecher-Rössler A. Cavum septum pellucidum in patients with first episode psychosis and individuals at high risk of psychosis. European psychiatry : the journal of the Association of European Psychiatrists [Internet]. 2007 May;22(4). Available from: http://dx.doi.org/10.1016/j.eurpsy.2006.11.005
- Berger G, Yildiz M, Aston J, Gschwandtner U, Riecher-Rössler A. Früherkennung psychotischer Störungen. Ein praktischer Leitfaden. The Medical Journal (TMJ) [Internet]. 2007;2:29–32. Available from: http://bibnet.org/vufind/Record/ccmed951966609
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Psychotische Störungen umfassen eine Gruppe von Erkrankungen, die in den meisten Fällen in der Jugend oder im frühen Erwachsenenalter beginnen. Erste Symptome wie eine Wesensveränderung, eine veränderte Wahrnehmung der Gefühle und Umgebung oder eine Einschränkung der Leistungsfähigkeit treten häufig Jahre vor der ersten psychotischen Episode auf. Dieser Beitrag gibt praktische Hinweise zur Früherkennung beginnender psychotischer Erkrankungen.
- Pfluger M, Gschwandtner U, Stieglitz RD, Riecher-Rössler A. Neuropsychological deficits in individuals with an at risk mental state for psychosis - working memory as a potential trait marker. Schizophrenia research [Internet]. 2007 Dec;97(1–3):14–24. Available from: http://dx.doi.org/10.1016/j.schres.2007.09.003
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To investigate the neuropsychological profile of individuals with an at risk mental state for psychosis (ARMS, N=60) compared to healthy controls (HC, N=51) and to identify those cognitive domains which discriminate best between groups. Study subjects and controls were compared using a neuropsychological test battery covering the domains of intelligence (LPS3, MWT-A), executive functions (ToH, WCST, TAP - Go/NoGo), working memory (Tests for Attentional Performance (TAP) - Working Memory), and attention (CPT-OX). A multivariate analysis of variance (MANOVA) comparing ARMS subjects with HC was conducted. A stepwise logit regression procedure was performed in order to determine the subset of measures which best distinguish ARMS subjects from HC. ARMS subjects revealed deficiencies in intelligence, executive functions, working memory and attention. Verbal intelligence, executive functions, and, in particular, working memory discriminated best between the groups. Individuals with an at risk mental state for psychosis already show impairment of neuropsychological functions prior to the onset of the first psychotic episode and can best be distinguished from healthy controls on the basis of working memory.
- Riecher-Rössler A, Gschwandtner U. Pro Früherfassung und Frühbehandlung von schizophrenen Psychosen. Schweizer Zeitschrift für Psychiatrie & Neurologie. 2007;2:8–12.
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Früherkennung von Psychose ist notwendig, allerdings benötigen wir mehr Forschungsanstrengungen auf diesem Gebiet, um das Risiko noch zuverlässiger einschätzen zu können. Eine vorschnelle medikamentöse Behandlung sollte ebenso vermieden werden wie eine zu lange Verzögerung der (Verdachts-)Diagnose, mit der Konsequenz der verspäteten Hilfe für Patienten und Familien. Dagegen sind psychotherapeutische Unterstützung und sozialarbeiterische Massnahmen oft schon indiziert lange bevor sich der Verdacht auf eine Psychose erhärtet und sollten integraler Bestandteil einer Früherkennungssprechstunde sein.
- Rossler W, Riecher-Rössler A, Angst J, Murray R, Gamma A, Eich D, et al. Psychotic experiences in the general population : a twenty-year prospective community study. Schizophrenia research [Internet]. 2007 May;92(1–3):1–14. Available from: http://dx.doi.org/10.1016/j.schres.2007.01.002
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Recent work suggested that psychosis might be expressed at subclinical levels. However, the determinants of subclinical psychotic symptoms, the degree of continuity over the life span, and the impact on functioning remain unclear. Thus we analyzed the prevalence, determinants, patterns and impact of subclinical psychotic symptoms in a community cohort over a 20-year period. The Zurich Study - a longitudinal community study - started in 1979 with a sample of 591 participants aged 20/21 years. Follow-up interviews were conducted at age 23, 28, 30, 35 and 41. Symptoms were assessed with a semi-structured interview and the SCL90-R. In this analysis, items of the SCL90-R symptom dimensions “paranoid ideation” and “psychoticism” were examined. Two distinct symptom dimensions of subclinical psychosis became evident, one representing schizophrenia nuclear symptoms, the other representing schizotypal signs. Cannabis use in adolescence was associated specifically with schizophrenia nuclear symptoms, whereas childhood adversity as well as chronic physical or mental disorders in parents contributed to schizotypal signs. Individuals with a persistently high level of either of the two identified symptom dimensions over 20 years experienced significant deficiencies in social achievement and functioning. Expression of psychotic symptoms in populations is continuous and characterized by differing levels of severity and persistence. A small group of individuals displays persistence of subclinical psychotic symptoms over a period of 20 years. The causes of and pathways to clinical psychotic disorder can be studied long before the disorder becomes clinically relevant.
- Borgwardt SJ, Riecher-Rössler A, Dazzan P, Chitnis X, Aston J, Drewe M, et al. Regional gray matter volume abnormalities in the at risk mental state. Biological psychiatry [Internet]. 2007 May;61(10):1148–56. Available from: http://dx.doi.org/10.1016/j.biopsych.2006.08.009
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Individuals with an At Risk Mental State (ARMS) have a very high risk of developing a psychotic disorder but the basis of this risk is unclear. We addressed this issue by studying gray matter volume in this group with magnetic resonance imaging (MRI). Thirty-five individuals with an ARMS, 25 patients with first episode schizophrenia, and 22 healthy volunteers were studied using a 1.5T MRI scanner. Twelve (34%) of the ARMS group developed schizophrenia in the 2 years subsequent to scanning. There were significant volumetric differences between the three groups in the left insula, superior temporal gyrus, cingulate gyrus and precuneus. In these regions, the volume in the ARMS group was smaller than in volunteers but not significantly different from that in the first episode (FE) group. Direct comparison of the ARMS and control groups revealed additional areas of reduced volume in the left medial temporal cortex. Within the ARMS group, those subjects who later developed psychosis had less gray matter than subjects who did not in the right insula, inferior frontal and superior temporal gyrus. The ARMS was associated with reductions in gray matter volume in areas that are also reduced in schizophrenia, suggesting that these are a correlate of an increased vulnerability to psychosis. Volumetric differences within the ARMS group may be related to the subsequent onset of schizophrenia in a subset of those at high risk.
- Riecher-Rössler A, Rossler W. Schizophrenie und verwandte Erkrankungen (Second Edition). In: Hewer W, Rossler W, editors. Akute psychische Erkrankungen - Management und Therapie. Munich: Elsevier; 2007. p. 293–313.
- Borgwardt SJ, McGuire P, Aston J, Berger G, Dazzan P, Gschwandtner U, et al. Structural brain abnormalities in individuals with an at-risk mental state who later develop psychosis. The British journal of psychiatry Supplement [Internet]. 2007 Dec;51. Available from: http://dx.doi.org/10.1192/bjp.191.51.s69
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Neuroanatomical abnormalities are a well-established feature of schizophrenia. However, the timing of their emergence and the extent to which they are related to vulnerability to the disorder as opposed to psychotic illness itself is unclear. To assess regional grey matter volume in the at-risk individuals who subsequently developed psychosis. Magnetic resonance imaging data from at-risk individuals who developed psychosis (n=12) within the following 25 months were compared with data from healthy volunteers (n=22) and people with first-episode psychosis (n=25). Compared with healthy volunteers, individuals who subsequently developed psychosis had smaller grey matter volume in the posterior cingulate gyrus, precuneus, and paracentral lobule bilaterally and in the left superior parietal lobule, and greater grey matter volume in a left parietal/posterior temporal region. Compared with first-episode patients, they had relatively greater grey matter volume in the temporal gyrus bilaterally and smaller grey matter volume in the right lentiform nucleus. Some of the structural brain abnormalities in individuals with an at-risk mental state may be related to an increased vulnerability to psychosis, while others are associated with the development of a psychotic illness.
- Riecher-Rössler A, Gschwandtner U, Aston J, Borgwardt SJ, Drewe M, Fuhr P, et al. The Basel early-detection-of-psychosis (FEPSY)-study–design and preliminary results. Acta psychiatrica Scandinavica [Internet]. 2007 Feb;115(2):114–25. Available from: http://dx.doi.org/10.1111/j.1600-0447.2006.00854.x
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Early detection and therapy of schizophrenic psychoses have become broadly accepted aims in psychiatry, recently even in very early stages of the disorder when clear diagnostic criteria are not yet fulfilled. However, reliable and widely applicable methods do not yet exist. This study aims at contributing to the improvement of the early assessment of psychosis. Method: Individuals potentially at risk are identified by a newly developed stepwise screening procedure. Identified subjects are then examined extensively and followed-up for at least 5 years to detect actual transition to psychosis. RESULTS: Of 50 subjects who have been followed up for 1-5 years by now, 16 have progressed to frank psychosis, 12 of them during the first 12 months of follow-up. CONCLUSION: At this stage, our approach seems to be promising for the early detection of psychosis. Further results from this ongoing study will hopefully permit us to optimize the assessment procedure.
2006
- Riecher-Rössler A, Gschwandtner U, Borgwardt SJ, Aston J, Pfluger MO, Rossler W. Early detection and treatment of schizophrenia : how early? Acta Psychiatrica Scandinavica [Internet]. 2006 Jan;113(429):73–80. Available from: http://dx.doi.org/10.1111/j.1600-0447.2005.00722.x
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Objective: Whereas early detection and therapy of schizophrenic psychoses until some time ago concentrated on frank schizophrenia, during the last years some centres have also started to treat patients even before a clear diagnosis could be established. This paper attempts to discuss if and when this is justified in the light of recent research. Method: Mini review of literature. Results: The rationale for early detection and treatment of schizophrenia is based on several observations: diagnosis and treatment of schizophrenia are often seriously delayed. Consequences of the disease are severe already in the early undiagnosed phase of the disorder and early treatment seems to improve the course of the disease. It can therefore be stated quite safely that patients should be treated as early as possible. However, the question of how early has not been sufficiently answered up to now. Conclusion: We are at the moment in an ethical dilemma between either diagnosing and treating this disorder too late or too early. The only way and prerequisite for solving this dilemma is a more reliable identification of individuals at risk and the beginning disease process.
- Gschwandtner U, Pfluger M, Aston J, Borgwardt S, Drewe M, Stieglitz RD, et al. Fine motor function and neuropsychological deficits in individuals at risk for schizophrenia. European archives of psychiatry and clinical neuroscience [Internet]. 2006 Jun;256(4):201–6. Available from: http://dx.doi.org/10.1007/s00406-005-0626-2
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Deficits in fine motor function and neuropsychological performance have been described as risk factors for schizophrenia. In the Basel FEPSY study (Früherkennung von Psychosen; English: Early Detection of Psychosis) individuals at risk for psychosis were identified in a screening procedure (Riecher-Rössler et al. 2005). As a part of the multilevel assessment, 40 individuals at risk for psychosis and 42 healthy controls matched for age, sex and handedness were investigated with a fine motor function test battery and a neuropsychological test battery. Individuals at risk showed lower performances in all subtests of the fine motor function tests, predominantly in dexterity and velocity (wrist/fingers and arm/hand). In the neuropsychological test battery, individuals at risk performed less well compared to healthy controls regarding sustained attention, working memory and perseveration. The combined evaluation of the two test batteries (neuropsychological and fine motor function) separates the two groups into individuals at risk and healthy controls better than each test battery alone. A multilevel approach might therefore be a valuable contribution to detecting beginning schizophrenia.
- Riecher-Rössler A, Rechsteiner E, D’Souza M, Castelmur E von, Aston J. Frühdiagnostik und Frühbehandlung schizophrener Psychosen - ein Update. Swiss Medical Forum [Internet]. 2006;(6):603–9. Available from: http://bibnet.org/vufind/Record/ccmed951882608
- Hafner H, Ehrenreich H, Gattaz W, Louza M, Riecher-Rössler A, Kulkarni J. Oestrogen-A Protective Factor in Schizophrenia? Current Psychiatry Reviews [Internet]. 2006 Aug;2(3):339–52. Available from: http://dx.doi.org/10.2174/157340006778018120
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Gender differences in schizophrenia, in the age of onset, course, lifetime risk, age distribution of onsets over the life cycle and clinical symptoms will be reviewed from the literature and our own studies. Also, the pre- and postmenopausal course of illness in women will be explored. Explanations for the gender differences using “normal” behavioural sex differences and the protective oestrogen hypothesis will be discussed. The hypothesis of the “protective” effect of oestrogen is based on findings from animal experiments, epidemiological and clinical studies. Oestrogen acts similarly on D2, 5-HTA2 and NMDA receptors in both the neurochemical and genomic domains. The neuroprotective effects of oestrogen on a genomic and cellular level might also favourably affect degenerative processes in schizophrenia. The lack of a gender difference in age of onset in familial schizophrenia due to a lower age of onset in pre-menopausal, genetically predisposed women strongly suggests an antagonistic balance between predisposition to the illness and the oestrogen effect. Oestrogen treatment plus antipsychotic therapy, compared with antipsychotic therapy alone, accelerates symptom remission in both women and men, thus corroborating the antipsychotic properties of oestrogen. Oestrogen is the only known substance with preventive potential in schizophrenia. However, health risks associated with long-term oestrogen treatment require careful weighing up of risks and benefits for patients. Future efforts to develop oestrogen-like compounds which do not affect breast and uterine tissue must be strongly encouraged.
- Borgwardt SJ, Radu EW, Gotz K, Aston J, Drewe M, Gschwandtner U, et al. Radiological findings in individuals at high risk of psychosis. Journal of neurology, neurosurgery, and psychiatry [Internet]. 2006 Feb;77(2):229–33. Available from: http://dx.doi.org/10.1136/jnnp.2005.069690
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To assess the prevalence of radiological magnetic resonance imaging (MRI) findings in individuals at high risk of schizophrenia. MRI scans from individuals at high risk of schizophrenia (HR; n = 37) were assessed by a radiologist blind to group status and compared with scans from patients with first episode psychosis (FE; n = 30), depressive controls (DC; n = 17), and healthy controls (HC; n = 26). There was a significantly higher proportion of radiological findings in individuals at high risk of schizophrenia (35%) and patients with first-episode psychosis (40%) than in patients with depression (18%) or healthy controls (12%). These differences were specific to findings regarded as potentially clinically significant as opposed to normal variants; however, there was no indication for medical treatment. The results suggest that a large proportion of those at high risk of psychosis have radiological findings on MRI scanning, and that the prevalence of radiological findings in this group is similar to that in patients with first episode psychosis.
2005
- Hafner H. Gender differences in schizophrenia. In: Bergemann N, Riecher-Rössler A, editors. Estrogen Effects in Psychiatric Disorders. Vienna: Springer; 2005. p. 53–94.
- Hayeems RZ, Seeman MV. Puberty and schizophrenia onset. In: Bergemann N, Riecher-Rössler A, editors. Estrogen Effects in Psychiatric Disorders. Vienna: Springer; 2005. p. 95–106.
- Rossler W, Joachim H, Os J van, Riecher-Rössler A. Size of burden of schizophrenia and psychotic disorders. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology [Internet]. 2005 Aug;15(4):399–409. Available from: http://dx.doi.org/10.1016/j.euroneuro.2005.04.009
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Schizophrenia is a severe mental disorder characterised by fundamental disturbances in thinking, perception and emotions. More than 100 years of research have not been able to fully resolve the puzzle that schizophrenia represents. Even if schizophrenia is not a very frequent disease, it is among the most burdensome and costly illnesses worldwide. It usually starts in young adulthood. Life expectancy is reduced by approximately 10 years, mostly as a consequence of suicide. Even if the course of the illness today is considered more favourable than it was originally described, it is still only a minority of those affected, who fully recover. The cumulative lifetime risk for men and women is similar, although it is higher for men in the age group younger than 40 years. According to the Global Burden of Disease Study, schizophrenia causes a high degree of disability, which accounts for 1.1% of the total DALYs (disability-adjusted life years) and 2.8% of YLDs (years lived with disability). In the World Health Report [The WHO World Health Report: new understanding, new hope, 2001. Geneva], schizophrenia is listed as the 8th leading cause of DALYs worldwide in the age group 15-44 years. In addition to the direct burden, there is considerable burden on the relatives who care for the sufferers. The treatment goals for the moment are to identify the illness as early as possible, treat the symptoms, provide skills to patients and their families, maintain the improvement over a period of time, prevent relapses and reintegrate the ill persons into the community so that they can lead as normal a life as possible.
- Fleischhacker W, Keet I, Kahn R, Committee ES. The European First Episode Schizophrenia Trial (EUFEST) : rationale and design of the trial. Schizophrenia research [Internet]. 2005 Oct;78(2–3):147–56. Available from: http://dx.doi.org/10.1016/j.schres.2005.06.004
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Most studies comparing second generation antipsychotics with classical neuroleptics have been conducted in more or less chronic schizophrenia patients. Such studies were usually conducted in highly selected samples, and were generally designed and financed by the manufacturer of the drug tested. These and other facts have stimulated discussions regarding the effectiveness of the new generation of antipsychotics. The aim of the European First Episode Schizophrenia Trial (EUFEST) is to compare treatment with amisulpride, quetiapine, olanzapine and ziprasidone to a low dose of haloperidol in an unselected sample of first episode schizophrenia patients with minimal prior exposure to antipsychotics. 500 patients between the ages of 18-40 meeting DSM-IV criteria for schizophrenia, schizoaffective disorder or schizophreniform disorder are randomly allocated to one year of treatment with one of the drugs under study. The primary outcome measure is retention in treatment, defined as time to discontinuation of study drug. Loss of retention can be the result of insufficient clinical effect, or lack of tolerability or acceptance. Secondary measures include changes in different dimensions of psychopathology, side effects, compliance, social needs, quality of life, substance abuse and cognitive functions. At present, more than 400 patients have been recruited and randomized in the following countries: Austria, Belgium, Bulgaria, Czech Republic, Germany, France, Israel, Italy, the Netherlands, Poland, Rumania, Spain, Sweden and Switzerland: The study should be finished by the end of 2006 and it is expected that results will yield relevant clinical information with regard to the effectiveness of the second generation antipsychotics. This effort represents the first independently designed trans-European schizophrenia treatment trial.
2004
- Drewe M, Drewe J, Riecher-Rössler A. Cannabis and risk of psychosis. Swiss medical weekly [Internet]. 2004 Nov;134(45–46):659–63. Available from: http://view.ncbi.nlm.nih.gov/pubmed/15611887
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Legalization of cannabis use in Switzerland has recently been debated by the Swiss Parliament. Although legalization has not yet been decided upon, it is still the subject of impassioned public discussion. If cannabis use is legalized, an increase in consumption is to be expected. One of the manifold negative consequences for mental health will probably be an increase in the prevalence of psychoses – not only acute, toxic psychosis but also chronic psychoses. Schizophrenic psychoses are expected to be triggered at an earlier age and to be negatively influenced in their course. This eventuality could have deleterious consequences not only for many currently healthy individuals predisposed to psychosis, but also for the disability pension.
- Gschwandtner U, Borgwardt SJ, Aston J, Drewe M, Radu EW, Riecher-Rössler A. Chronisch subdurales Hämatom bei einem Patienten mit Verdacht auf Prodromalstadium einer Schizophrenie. Der Nervenarzt [Internet]. 2004 Jul;75(7):691–3. Available from: http://dx.doi.org/10.1007/s00115-003-1636-9
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Zusammenfassung Bei einem Patienten, der mit psychoseverdächtigen „Prodromal-Symptomen“ der Früherkennungssprechstunde für Psychosen zugewiesen wurde, konnte mittels MRI ein chronisch subdurales Hämatom festgestellt werden. Anhand dieses Falles soll aufgezeigt werden, dass bei Patienten mit auffälligen Wesensänderungen, sozialem Rückzug, Aggressivität und Misstrauen neben einer beginnenden Schizophrenie auch an hirnorganische Ursachen gedacht werden muss. Die Diagnostik bei Erstmanifestation und Prodromalstadium einer Schizophrenie sollte daher—neben Anamnese sowie psychopathologischem und körperlichem Befund—obligat medizinische Zusatzuntersuchungen (EEG, cCT oder MRI) umfassen, um organische Ursachen frühzeitig zu erkennen und Fehldiagnosen zu vermeiden.
- Riecher-Rössler A. Die Frau mit einer schizophrenen Psychose. In: Riecher-Rössler A, Bitzer J, editors. Frauengesundheit Ein Leitfaden für die ärztliche und psychotherapeutische Praxis. Munich: Elsevier; 2004. p. 229–42.
- Riecher-Rössler A. Früherkennung schizophrener Psychosen. In: Riecher-Rössler A, Bitzer J, editors. Frauengesundheit Ein Leitfaden für die ärztliche und psychotherapeutische Praxis. Munich: Elsevier; 2004. p. 522–33.
- Riecher-Rössler A. Früherkennung und Frühbehandlung schizophrener Psychosen in der Hausarztpraxis. Med pharm drog hosp. 2004;5:21–4.
- Riecher-Rössler A. Geschlechtsunterschiede bei Schizophrenie - eine integrative bio-psycho-soziale Sichtweise ist notwendig. In: Fleischhacker WW, Hummer M, editors. Schizophrene Störungen /State of the Art 3: Entwicklung, Bewertung und Effizienz neuer pharmakologischer Therapien. Innsbruck: Verlag Integrative Psychiatrie; 2004. p. 161–74.
2003
- Riecher-Rössler A. Geschlechtsspezifische Aspekte der Schizophrenie und mögliche therapeutische Konsequenzen. In: Machleidt W, Garlipp P, Haltenhof H, editors. Schizophrenie: Behandlungspraxis zwischen speziellen Methoden und integrativen Konzepten. Schattauer Verlag; 2003. p. 41–8.
- Hafner H, Loffler W, Maurer K, Riecher-Rössler A, Stein A. IRAOS - Interview for the retrospective assessment of the onset and course of schizophrenia and other psychoses - Interview and Manual. Hafner H, editor. Göttingen: Hogrefe & Huber; 2003.
- Riecher-Rössler A, Hafner H, Hafner-Ranabauer W, Loffler W, Reinhard I. Late-onset schizophrenia versus paranoid psychoses : a valid diagnostic distinction? The American journal of geriatric psychiatry [Internet]. 2003 Nov;11(6):595–604. Available from: http://view.ncbi.nlm.nih.gov/pubmed/14609799
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The authors tested the validity of the diagnostic distinction between schizophrenia and delusional disorder of late onset. Authors examined hospital case registers. A clear distinction between these diagnostic groups is not possible, irrespective of whether a descriptive, predictive, or construct-based approach is taken. There is a relatively high overlap between the two groups. Clinical diagnosis seems to be influenced more by the age of the patients than by symptomatology. Furthermore, the slight differences observed in symptomatology can partly be explained by “pathoplastic” factors that influence symptomatology, such as age, sex, previous treatment, or somatic comorbidity. Since clear and etiologically meaningful differentiation between these diagnostic categories is not possible, they should not be separated by artificial diagnostic criteria for research purposes. Rather, the whole “schizo-paranoid” spectrum should always be analyzed. As long as classification is based on differences in symptomatology, the influences of pathoplastic factors should be taken into account.
- Borgwardt SJ, Riecher-Rössler A. Multidisziplinäre Früherkennung von Psychosen im Kantonsspital Basel - die Basler FEPSY - FrühErkennung von PSYchosen Sprechstunde. Synapse [Internet]. 2003;8:10–2. Available from: http://www.aerzte-bl.ch/fileadmin/media-extern/pdf/synapse/2003-8.pdf
- Gschwandtner U, Aston J, Borgwardt SJ, Drewe M, Feinendegen C, Lacher D, et al. Neuropsychological and neurophysiological findings in individuals suspected to be at risk for schizophrenia : preliminary results from the Basel early detection of psychosis study - Früherkennung von Psychosen (FEPSY). Acta psychiatrica Scandinavica [Internet]. 2003 Aug;108(2):152–5. Available from: http://dx.doi.org/10.1034/j.1600-0447.2003.00157.x
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Our study aims to establish a scientific basis for the very early detection of patients at risk for schizophrenia during the nonspecific prodromal phase of the disorder and to predict its outbreak. A multidomain approach is used. After screening, approved psychopathological, neurophysiological, neuropsychological and neuroradiological investigations are used to assess a sample of individuals suspected to be at risk for schizophrenia. Neuropsychological and fine motor functioning tests as well as eye movement measurements showed statistically significant differences (P<0.01) between individuals suspected to be at risk for schizophrenia and healthy controls. Individuals suspected to be at risk for schizophrenia show specific impairments in various investigations including neuropsychological and fine motor functioning tests as well as eye movement measurements. A set of methods sensitive to even subtle changes in normal functioning may prove useful in predicting the subsequent outbreak of schizophrenia.
- Riecher-Rössler A. Östrogene und gonadale Achse Implikationen für die Therapie von Frauen mit Schizophrenien. Der Nervenarzt [Internet]. 2003 May;74(5):398–405. Available from: http://view.ncbi.nlm.nih.gov/pubmed/12966813
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Estrogens significantly influence the mental states of women and probably modulate many mental diseases. Concerning schizophrenic psychoses, there is increasing evidence for a protective effect of estrogens on the one hand and gonadal dysfunction and hypoestrogenism in many women with schizophrenia on the other. This results in the urgent need to pay more attention to the gonadal axis and estrogen status in women with schizophrenia, both in research and in practice.
- Riecher-Rössler A. Spät beginnende schizophrene und paranoide Psychosen. In: Forstl H, editor. Lehrbuch der Gerontopsychiatrie und -psychotherapie: Grundlagen - Klinik - Therapie. Stuttgart: Thieme; 2003. p. 414–23.
2002
- Aston J, Gschwandtner U, Riecher-Rössler A. Screening zur Früherfassung von schizophrenen Psychosen in der Hausarztpraxis. Schweiz Med Forum [Internet]. 2002 Oct;(41):971–4. Available from: http://www.medicalforum.ch/pdf/pdf_d/2002/2002-41/2002-41-112.PDF
2001
- Rossler W, Riecher-Rössler A. Comprehensive care of the schizophrenics - end of the revolving-door psychiatry? In: Brenner HD, Boker W, Genner R, editors. The Treatment of Schizophrenia: Status and Emerging Trends. Hogrefe & Huber; 2001. p. 195–209.
- Riecher-Rössler A. Geschlechtsunterschiede bei Schizophrenen und mögliche therapeutische Implikationen. In: Riecher-Rössler A, Rohde A, editors. Psychische Erkrankungen bei Frauen - Für eine geschlechtersensible Psychiatrie und Psychotherapie. Basel: Karger; 2001. p. 73–91.
2000
- Riecher-Rössler A, Hafner H. Gender aspects in schizophrenia : bridging the border between social and biological psychiatry. Acta psychiatrica Scandinavica Supplementum [Internet]. 2000;(407):58–62. Available from: http://view.ncbi.nlm.nih.gov/pubmed/11261642
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This paper tries to show that gender differences in mental diseases are a valuable paradigm for research into the interplay between biological and psychosocial factors–not only regarding pathogenetic mechanisms, but also concerning therapeutic approaches. Based on relevant literature, this topic is highlighted using schizophrenia as an example. Schizophrenic disorders show a later age of onset in women and a slightly better course, especially in young women. As to pathogenesis, there is some evidence that the age difference might be due at least partly to the female sex hormone oestradiol being a protective factor. Differences in course might also have to do with this biological factor, but at the same time with the psychosocial advantages of a higher age of onset and other psychosocial factors. Concerning therapy, these gender differences have important implications for pharmacotherapy, but also psychotherapy and social measures. A gender-sensitive approach in psychiatry improves our understanding of mental illness and our therapeutic strategies and at the same time illustrates that comprehensive psychiatry cannot be practised in artificially separated 'drawers' called 'biological psychiatry', on one hand, and 'social psychiatry' on the other.
1999
- Riecher-Rössler A. Die beginnende Schizophrenie als “Knick in der Lebenslinie.” In: Schneider H, editor. Lieben und Arbeiten Der junge Erwachsene und der Ernst des Lebens. Mattes Verlag; 1999. p. 23–40.
- Riecher-Rössler A. Gibt es eine Spätschizophrenie? Extracta psychiatrica. 1999;(9):23–6.
- Riecher-Rössler A. Late onset schizophrenia : the German concept and literature. In: Howard R, Rabins PV, Castle DJ, editors. Late Onset Schizophrenia. Wrightson Biomedical Publishing Ltd; 1999. p. 3–16.
- Riecher-Rössler A, Hafner H. Validity of late onset schizophrenia : a European view. In: Howard R, Rabins PV, Castle DJ, editors. Late Onset Schizophrenia. Wrightson Biomedical Publishing Ltd; 1999. p. 55–78.
1998
- Hafner H, Heiden W an der, Behrens S, Gattaz W, Hambrecht M, Loffler W, et al. Causes and Consequences of the Gender Difference in Age at Onset of Schizophrenia. Schizophrenia Bulletin [Internet]. 1998 Jan;24(1):99–113. Available from: http://schizophreniabulletin.oxfordjournals.org/content/24/1/99.abstract
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The ABC (age, beginning, course) schizophrenia study was commenced in 1987 to generate and test hypotheses about pathogenic aspects of schizophrenia. One of the main branches of the study focused on how gender influences the age distribution of onset, symptomatology, illness behavior, and early course in schizophrenia. Proceeding from one of the rare, strikingly deviating, consistent findings—the gender difference in age at first admission—we launched a systematic search for explanations by generating and testing hypotheses in a series of substudies. We moved from the epidemiological to the neurobiological and finally to the clinical level. The present article is an attempt to provide a brief overview of the individual stages of the ABC study and the different levels of investigation involved in formulating and testing the estrogen hypothesis in animal experiments and in demonstrating its applicability to human schizophrenia. From these results, three hypotheses were formulated and tested on data from an ABC study sample of 232 first-episode cases of schizophrenia. The analyses described here represent the latest stages of the ABC study.
- Riecher-Rössler A, Rossler W. Der Verlauf schizophrener Erkrankungen. Wien Med Wochenschr. 1998;148(11–12):259–65.
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There is only a limited amount of safe knowledge on the course of schizophrenic psychoses, although 100 years have passed since their first description as “Dementia praecox”. 2 main reasons may account for this: On the one hand most studies suffer from more or less serious methodological shortcomings, which do not allow to generalize the results. On the other hand schizophrenic psychoses are possibly not one homogeneous disease with one uniform etiology and a relatively uniform course, but rather a group of diseases with hetereogenous causes and therefore hetereogenous courses as well.
- Hafner H, Hambrecht M, Loffler W, Munk-Jorgensen P, Riecher-Rössler A. Is schizophrenia a disorder of all ages? : A comparison of first episodes and early course across the life-cycle. Psychological Medicine [Internet]. 1998 Mar;28(2):351–65. Available from: http://view.ncbi.nlm.nih.gov/pubmed/9572092
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The heterogeneity of schizophrenic and delusional syndromes by age of onset has frequently been discussed. The age distribution of symptoms and 5 year course was studied in a population-based first-episode sample admitted to 10 psychiatric hospitals before the age of 60 (N = 232) and in a clinical sample without age limit of consecutive first admissions to a single hospital (N = 1109), both samples with broadly diagnosed schizophrenia. Early-onset patients, particularly men, presented more non-specific symptoms and higher PSE-CATEGO total scores than late-onset patients. In men, symptom severity decreased with increasing age of onset. In women, it remained stable except for an increase of negative symptoms with late-onset. Only a few symptoms changed markedly with age: disorganization decreased, while paranoid and systematic delusions increased steeply across the whole age of onset range. Pronounced age- and sex-differences emerged in illness behaviour, socially negative behaviour and substance abuse. Within the group of late-onset psychoses there were continuous transitions in symptom profiles and no discrimination between schizophrenia and paranoid psychosis or late paraphrenia. The main determinant of social course was onset level of social development. Early-onset patients did not improve in social status, while late-onset patients, prior to retirement, suffered considerable decline in social status. Gender differences in age at onset and in age trends in symptom severity support the hypothesis of a mild protective effect of oestrogen. Social course results from an interplay between biological factors (age at onset and functional impairment) and development factors (level of social development at onset and illness behaviour).
- Rossler W, Riecher-Rössler A. Neue Versorgungsstrategien Schizophrener - Ende der Drehtür-Psychiatrie? In: Fleischhacker WW, Hinterhuber H, Meise U, editors. State of the Art II, Ursachen - Behandlung - Verlauf. Verlag Integrative Psychiatrie; 1998. p. 216–32.
- Hafner H, Maurer K, Loffler W, Heiden an der, Munk-Jorgensen P, Hambrecht M, et al. The ABC Schizophrenia Study : a preliminary overview of the results. Social psychiatry and psychiatric epidemiology [Internet]. 1998 Aug;33(8):380–6. Available from: http://view.ncbi.nlm.nih.gov/pubmed/9708025
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The ABC Schizophrenia Study, a large-scale epidemiological and neurobiological research project commenced in 1987, initially pursued two aims: (1) to elucidate the possible causes of the sex difference in age at first admission for schizophrenia and (2) to analyse the early course of the disorder from onset until first contact and its implications for further course and outcome. First, transnational case-register data (for Denmark and Germany) were compared, second, a population-based sample of first-episode cases of schizophrenia (n = 232) were selected and third, the results obtained were compared with data from the WHO Determinants of Outcome Study by using a systematic methodology. A consistent result was a 3-4 years higher age of onset for women by any definition of onset, which was not explainable by social variables, such as differences in the male-female societal roles. A sensitivity-reducing effect of oestrogen on central D2 receptors was identified as the underlying neurobiological mechanism in animal experiments. Applicability to humans with schizophrenia was established in a controlled clinical study. A comparison of familial and sporadic cases showed that in cases with a high genetic load, the sex difference in age of onset disappeared due to a clearly reduced age of onset in women, whereas in sporadic cases it increased. To analyse early course retrospectively, a semistructured interview, IRAOS, was developed. The early stages of the disorder were reconstructed in comparison with age- and sex-matched controls from the same population of origin. The initial signs consisted mainly of negative and affective symptoms, which accumulated exponentially until the first episode, as did the later emerging positive symptoms. Social disability appeared 2-4 years before first admission on average. In early-onset cases, social course and outcome, studied prospectively over 5 years, was determined by the level of social development at onset through social stagnation. In late-onset cases, decline from initially high social statuses occurred. Socially negative illness behaviour contributed to the poor social outcome of young men. Symptomatology and other proxy variables of the disorder showed stable courses and no sex differences. Further aspects tested were the sequence of onset and the influence of substance abuse on the course of schizophrenia, primary and secondary negative symptoms, structural models and symptom clusters from onset until 5 years after first admission.
- Riecher-Rössler A, Rossler W. The course of schizophrenic psychoses : what do we really know? A selective review from an epidemiological perspective. European archives of psychiatry and clinical neuroscience [Internet]. 1998;248(4):189–202. Available from: http://view.ncbi.nlm.nih.gov/pubmed/9810482
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There is only a limited amount of definite knowledge on the course of schizophrenic psychoses, although 100 years have passed since they were first described by Kraepelin as “Dementia praecox”. The main reason for this is that most studies done thus far suffer from more or less serious methodological shortcomings: samples were often highly selective; investigations were often not direct, not prospective and almost never continuous, which would be of utmost importance in an episodic disease such as schizophrenia; assessments in older studies were neither standardized nor tested for validity or reliability; in more recent studies they were often not conducted by experienced psychiatrists; patients who refused to participate or who died during the study period were widely neglected. Nevertheless, we have learned that schizophrenic psychoses do not have a steadily deteriorating course ending in “dementia”. On the contrary, the course of these psychoses seems very heterogeneous. Due to their methodological shortcomings, studies done thus far even seem to have underestimated heterogeneity by partly neglecting patients with very good outcome, on the one hand, and very poor outcome, on the other hand.
1997
- Hambrecht M, Hafner H. “Weiche” Drogen : Eine Ursache für Schizophrenie? In: Helmchen H, Hippius H, editors. Psychiatrie für die Praxis. MMV Medizin Verlag; 1997. p. 310–3.
- Riecher-Rössler A. 50 Jahre nach Manfred Bleuler Was wissen wir heute über die Spätschizophrenie(n)? Der Nervenarzt [Internet]. 1997 Mar;68(3):159–70. Available from: http://dx.doi.org/10.1007/s001150050111
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Seit Manfred Bleuler vor nunmehr über 50 Jahren erstmals das Krankheitsbild der Spätschizophrenie beschrieb, blieb umstritten, ob es gerechtfertigt ist, dieses als valide, eigenständige Entität von der Gruppe der klassischen, im frühen Alter beginnenden Schizophrenien abzugrenzen. Auch heute noch läßt sich diese Frage – wie vorliegende Literaturübersicht zeigt – nicht eindeutig beantworten. Vielmehr ist festzustellen, daß wir unser Wissen bezüglich dieses Krankheitsbilds seit Manfred Bleulers umfassendem Beitrag weder entscheidend vermehren noch auf eine methodisch sehr viel solidere Basis stellen konnten. Ursachen hierfür sind zum einen die konzeptuelle und begriffliche Konfusion, die sich international bezüglich dieser Krankheitsgruppe entwickelt hat, zum anderen die methodischen Limitierungen der empirischen Studien, die bisher zu diesem Krankheitsbild vorliegen.
- Riecher-Rössler A, Loffler W, Munk-Jorgensen P. What do we really know about late-onset schizophrenia? European archives of psychiatry and clinical neuroscience [Internet]. 1997;247(4):195–208. Available from: http://view.ncbi.nlm.nih.gov/pubmed/9332902
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Actual knowledge on classical late-onset schizophrenia, i.e. the schizophrenic disorders with onset after age 40 years, is reviewed regarding incidence, symptomatology and course. As is shown, sound empirical knowledge is scarce. Reasons for this are, on the one hand, the conceptual and terminological confusion which has occurred internationally regarding this illness group, and, on the other hand, the methodological limitations of the empirical studies conducted on this clinical picture thus far. If we only draw on classical late-onset schizophrenia, as originally defined by Bleuler, and primarily on methodologically sound studies, as well as on own studies, we can nevertheless conclude that the term “late-onset schizophrenia” could be omitted. Late-onset schizophrenia does not seem to be a distinct entity, but instead seems to belong to the same illness group as classical schizophrenia with earlier onset. Slight differences in symptomatology and course are probably due to unspecific influences of age. The markedly higher proportion of women among late-onset cases, as well as our finding that symptomatology and course of late-onset women are comparably poor, could possibly be explained by an effect of the female sex hormone oestradiol.
1996
- Riecher-Rössler A. Spätschizophrenie. Münchener Medizinische Wochenschrift. 1996;138:816–9.
- Hambrecht M, Hafner H, Riecher-Rössler A. Weiche Drogen : Eine Ursache von Schizophrenie. Münchener Medizinische Wochenschrift. 1996;138(25):430–1.
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Substanzmissbrauch ist unter Patienten mit Schizophrenie weit verbreitet. Wie die Mannheimer ABC-Schizophrenie-Studie ergab, weisen ersterkrankte Patienten mit Schizophrenie doppelt so häufig eine Drogenanamnese auf wie entsprechende Vergleichspersonen aus der Allgemeinbevölkerung (14% gegenüber 7%). Betroffen sind vor allem junge Männer. In erster Linie werden Cannabis, zunehmend auch Amphetamine konsumiert. Etwa gleichviele Patienten begannen den Drogenmissbrauch vor, gleichzeitig mit bzw. nach den ersten Schizophrenie-Symptomen. Ein Teil der Patienten konsumiert Drogen demnach zur Linderung schizophrener Symptome (v. a. von Minussymptomatik). Fehlende Unterschiede in der schizophrenen Kernsymptomatik zwischen Patienten mit und ohne Drogenanamnese sprechen für ein Vulnerabilitätskonzept, bei dem Drogen dann die Erkrankung auslösen, wenn eine entsprechende Disposition vorliegt.
1995
- Rossler W, Loffler W, Fatkenheuer B, Riecher-Rössler A. Case management for schizophrenic patients at risk for rehospitalization : a case control study. European archives of psychiatry and clinical neuroscience [Internet]. 1995;246(1):29–36. Available from: http://view.ncbi.nlm.nih.gov/pubmed/8773216
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In many countries deinstitutionalization of psychiatric patients is accompanied by fragmentation of care, giving responsibility to an array of different services and providers. One of the possible side effects of this is an increased rehospitalization rate and length of stay. The need to coordinate the services involved for the benefit of individuals has led to the conceptual development of case management. However, despite an apparent belief in the effectiveness of case management, there is only limited scientific evidence to support this assumption. In the case control study presented we compared a group of 97 schizophrenic patients in the aftercare of case management services with a group of patients who received no outpatient care by case management services after discharge from hospital. Each patient in the case-managed group was exactly matched with a control patient with regard to diagnosis and known risk factors for rehospitalization. Additionally, we considered influencing factors that result from general health system conditions such as regional differences and different types of hospital care. Our analyses demonstrate that, during an observation period of 2.5 years, case management had neither a significant effect on the risk of rehospitalization nor on the length of time in hospital in the event of rehospitalization.
- Riecher-Rössler A, Rossler W. Der Verlauf psychogener Psychosen - was wissen wir 100 Jahre nach Kraepelin? In: Hinterhuber H, Fleischhacker WW, Meise U, editors. Die Behandlung der Schizophrenien. Verlag Integrative Psychiatrie; 1995. p. 19–51.
- Riecher-Rössler A, Rossler W, Forstl H, Meise U. Late-onset schizophrenia and late paraphrenia. Schizophrenia Bulletin [Internet]. 1995;21(3). Available from: http://dx.doi.org/10.1093/schbul/21.3.345
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The term “late-onset schizophrenia” was first coined by Manfred Bleuler (1943) to describe a form of schizophrenia with an onset between the ages of 40 and 60. This concept has been adopted by German psychiatry. Until recently, British and American psychiatrists had little interest in this patient group. However, they often used the term “late-onset schizophrenia” interchangeably with late paraphrenia or as a generic term for both these diseases, even though the concept of late paraphrenia is quite different from that of late-onset schizophrenia. Late paraphrenia is a British concept that includes all delusional disorders starting after age 60. This confusion of terms and concepts is even more important now, because recent neuroimaging and neuropsychological studies suggest that an organic substrate probably exists in most cases of late paraphrenia, while only minor organic abnormalities can be found in late-onset schizophrenia. We believe it is of utmost importance to establish a clear boundary between late-onset schizophrenia and other delusional disorders in middle and old age, because the confusion in terminology and concepts is a serious impediment to comparative international research.
- Hafner H, Maurer K, Loffler W, Bustamante S, Heiden W an der, Riecher-Rössler A, et al. Onset and early course of schizophrenia. In: Hafner H, Gattaz WF, editors. Search for the Causes of Schizophrenia - Volume III. Springer Verlag; 1995. p. 43–66.
- Lutzhoft JH, Skadhede S, Fatkenheuer B, Hafner H, Loffler W, Riecher-Rössler A, et al. Symptom assessment in casenotes and the clinical diagnosis of schizophrenia. Psychopathology [Internet]. 1995;28(3):131–9. Available from: http://view.ncbi.nlm.nih.gov/pubmed/7675998
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It is well known from several international studies that the incidence rates for schizophrenia, based on first-admission samples, are low in Denmark, especially in females, compared with other countries. This might be due to special diagnostic traditions in Denmark. To analyze how Danish psychiatrists reach a diagnosis of schizophrenia, a stratified subsample of 122 cases out of all 1,259 patients, aged between 12 and 64 years, with a first hospital admission in 1976 under the diagnosis of schizophrenia, paranoid psychosis, acute reactive paranoid psychosis, or casus limitaris was selected. For this subsample, psychopathological symptoms, as documented in the clinical casenotes, were rated by PSE-9 symptom lists for subsequent CATEGO analysis. The core syndrome of schizophrenia, as defined by the CATEGO class S+, showed no association with the clinical schizophrenia diagnosis compared with the other diagnoses mentioned. Also, positive symptoms of schizophrenia did not determine the diagnosis, but for typical negative symptoms such associations were indicated. Some negative symptoms also seemed to be linked to a depressive state. Furthermore, the present work indicates that using first-admission data leads to a higher age at schizophrenia onset and a lower first-admission rate in Denmark compared with Germany.
1994
- Riecher-Rössler A, Hafner H, Stumbaum M, Maurer K, Schmidt R. Can estradiol modulate schizophrenic symptomatology? Schizophrenia Bulletin [Internet]. 1994;20(1):203–14. Available from: http://dx.doi.org/10.1093/schbul/20.1.203
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Using epidemiologic data, in an earlier study we formulated the hypothesis that estrogens can delay the onset of schizophrenia in females by raising the vulnerability threshold for this disease. In animal experiments, Häfner and colleagues found evidence that chronic estradiol treatment reduces the sensitivity of dopamine (D2) receptors in the brain. In the clinical study presented in this article, as a further step we examined the antipsychotic properties of estradiol in human females by testing whether schizophrenic symptomatology varies with estradiol serum levels throughout the menstrual cycle. We examined 32 acutely admitted female schizophrenia patients (Present State Examination/CATEGO diagnosis, ICD-9) with a history of regular menstrual cycles, ages 18 to 43 (mean = 30.5), during their hospital stays (3-8 weeks), analyzing hormonal parameters and applying various rating scales for psychopathology every 7 days. In all patients, estradiol serum levels were markedly reduced as compared with the normal population, and fluctuations throughout the cycle were dampened. Nevertheless, a significant association emerged between estradiol levels, on the one hand, and psychopathology scores, on the other–that is, the psychiatric symptomatology as assessed by the clinical psychiatrist (Brief Psychiatric Rating Scale, p < or = 0.01), behavior on the ward as assessed by the nursing staff (Nurses' Observation Scale for Inpatient Evaluation p < or = 0.01), paranoid tendencies and general well-being as assessed by the patients themselves (Paranoid-Depressivitäts-Skala paranoid score p < or = 0.05; Befindlichkeits-Skala p < or = 0.05). Psychopathology seems to improve when estradiol levels rise, and vice versa. These findings can be interpreted as further evidence for a protective effect of estrogens in schizophrenia, possibly due to the known anti-dopaminergic activities of these hormones.
- Riecher-Rössler A. Die Spätschizophrenie - eine valide Entität? : Eine empirische Studie zu Risikofaktoren, Krankheitsbild und Verlauf. Habilitationsschrift, Universität Heidelberg-Mannheim. 1994;
- Riecher-Rössler A, Hafner H, Dutsch-Strobel A, Oster M, Stumbaum M, Gulick-Bailer M van, et al. Further evidence for a specific role of estradiol in schizophrenia? Biological Psychiatry [Internet]. 1994 Oct;36(7):492–4. Available from: http://view.ncbi.nlm.nih.gov/pubmed/7811850
- Patton GC, Riecher-Rössler A. Gender differences in schizophrenia - do computer tomography findings provide an explanation? New trends in experimental and clinical psychiatry [Internet]. 1994;10(3):121–6. Available from: http://psycnet.apa.org/psycinfo/1995-21552-001
- Hambrecht M, Riecher-Rössler A, Fatkenheuer B, Louza MR, Hafner H. Higher morbidity risk for schizophrenia in males : fact or fiction? Comprehensive psychiatry [Internet]. 1994 Jan;35(1):39–49. Available from: http://view.ncbi.nlm.nih.gov/pubmed/8149728
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Male to female ratios in published annual incidence rates for schizophrenia range from 0.70 to 3.47. These variations between studies are attributed to differences in sampling, diagnostic criteria, design characteristics, and methods of calculation, which limit the quality of the studies. In an effort to overcome these shortcomings, we collected a comprehensive sample of 392 consecutive first admissions with a diagnosis of schizophrenia or a similar disorder out of a population of 1.5 million in a central region of western Germany. In this large representative sample, no significant gender differences in the incidence of schizophrenia could be detected regardless of different diagnostic definitions.
- Hafner H, Maurer K, Loffler W, Fatkenheuer B, Heiden an der, Riecher-Rössler A, et al. The epidemiology of early schizophrenia. Influence of age and gender on onset and early course. The British journal of psychiatry Supplement [Internet]. 1994 Apr;(23):29–38. Available from: http://view.ncbi.nlm.nih.gov/pubmed/8037899
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For the investigation of the early course of schizophrenia starting from onset, the standardised Interview for the Retrospective Assessment of the Onset of Schizophrenia was developed and validated. In a representative sample of 267 first-admitted German schizophrenics of a broad diagnosis from a population of 1.5 million, the age at which different diagnostic and onset definitions were satisfied, the symptoms at the time of the interview, and the accumulation of positive and negative symptoms until first admission were assessed. Comparison between the two sexes and three age groups yielded hardly any differences in the accumulation of symptoms and their course until first admission, except for a slightly shorter period of negative symptoms in young males and a slightly longer one in older women–which contradicts prevailing opinion. At the time of the interview, no significant sex differences were found with respect to the core symptoms of schizophrenia (negative and first-rank symptoms), but clear and substantial differences emerged in disease behaviour. The significantly higher age at first onset in women is explained, on the basis of animal experiments and a clinical study, by the neuromodulatory effect of oestrogen on D2 receptors and by a higher vulnerability threshold in women.
- Loffler W, Hafner H, Fatkenheuer B, Maurer K, Riecher-Rössler A, Lutzhoft JH, et al. Validation of Danish case register diagnosis for schizophrenia. Acta psychiatrica Scandinavica [Internet]. 1994 Sep;90(3):196–203. Available from: http://view.ncbi.nlm.nih.gov/pubmed/7810343
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The ABC schizophrenia study aims at investigating sex differences in age of onset, symptoms and course of schizophrenic and paranoid disorders. For this purpose, we used case register data from Denmark and Mannheim and a directly examined sample of first admissions (ABC sample). The Danish case register sample included less clinical diagnoses of schizophrenia and more schizophrenia-related disorders (acute paranoid reaction, paranoid states and borderline schizophrenia) than the Mannheim data (case register and ABC sample). The problem therefore was whether the two datasets are comparable and the results are valid. For this reason a randomized, stratified sample of 116 patients was drawn from the Danish case register sample. The case notes of these 116 patients were requested from the hospitals where the patients had been treated and analyzed by means of a scoring sheet based on the Interview for the Retrospective Assessment of the Onset of Schizophrenia (IRAOS). The use of operationalized diagnoses of the CATEGO program, based on PSE items, which are integrated in IRAOS, demonstrated that the samples of the Danish and the Mannheim case registers and the directly investigated ABC sample have comparable diagnostic distributions. Possible explanations for the differences between the clinical and the CATEGO diagnoses in the Danish case register may be the frequent use of diagnoses of borderline schizophrenia and reactive psychoses (previously called psychogenic psychoses), and above all a more narrow concept of schizophrenia; in Denmark, schizophrenia is diagnosed relatively late, i.e., after the presence of enduring negative symptoms, and thus mostly after the appearance of residual state.(ABSTRACT TRUNCATED AT 250 WORDS)
- Riecher-Rössler A, Hafner H, Stumbaum M, Schmidt R. Wirken Östrogene antipsychotisch? Fortschritte der Neurologie · Psychiatrie [Internet]. 1994;62(01):22–8. Available from: http://dx.doi.org/10.1055/s-2007-996653
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Within the framework of our ABC study, an epidemiological study on schizophrenia (Hafner et al., 1989, 1991 a; Riecher et al., 1991), we were able to show that the mean age at onset of the disease is 3-4 years higher in women than in men and that women have a second peak of onsets after 45 years of age. In a systematic analysis we developed and tested different psychosocial and biological explantory hypotheses. The oestrogen hypothesis could be identified in the course of this analysis as the most plausible one. According to this hypothesis (Hafner, 1987) female sex hormones enhance the vulnerability threshold for schizophrenia. In this case women from puberty to (pre-)menopause would be protected from the outbreak of the disease to a certain extent by their high physiological oestradiol production; they would, however, later “draw level” in respect of morbidity risk. Animal experiments conducted to test this hypothesis and to explain the underlying pathophysiological mechanism implied that oestradiol can modulate the sensitivity of dopamine-D2-receptors in the brain (Hafner et al., 1991 b; Gattaz et al., 1992). In the clinical study presented, we examined the validity of the oestrogen hypothesis in humans. We tested, whether the acute symptomatology of schizophrenic patients fluctuates with oestradiol serum levels during the female menstrual cycle. We examined 32 acutely admitted schizophrenic women during their hospital stay by analysing hormonal parameters and applying various rating scales for psychopathology on certain days of the cycle. A significant association emerged between oestradiol levels on the one hand, and psychiatric symptomatology, behaviour on ward, paranoid tendencies and general well-being, on the other.
1993
- Hafner H, Heiden an der, Hambrecht M, Riecher-Rössler A, Maurer K, Loffler W, et al. [A chapter in systematic schizophrenia research–the search for causal explanations for sex differences in age of onset]. Der Nervenarzt [Internet]. 1993 Nov;64(11):706–16. Available from: http://view.ncbi.nlm.nih.gov/pubmed/8278011
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With the aim of detecting causal processes contributing to the onset of schizophrenic symptoms a systematic search strategy was worked out. One of the few epidemiological findings on schizophrenia consistently diverging from expected values, the sex difference in age at first admission, was taken as a basis and replicated on data from the Danish and the Mannheim case registers by controlling for selection and diagnostic artefacts. Danish psychiatrists turned out to have underdiagnosed schizophrenia to a considerable extent at least in 1976, the year from which the analysed case-register data dated. After the exclusion of alternative explanations, the time when symptoms appeared for the first time and the first acute episode occurred was determined for a representative sample of 267 first-admitted cases with a diagnosis of non-affective functional disorder by using the IRAOS interview designed for this purpose. At any of the definitions of first onset applied the mean age of females was significantly higher than that of males, the difference ranging from 3.2 to 4.1 years. The distribution of onsets across the female life cycle showed a clearly delayed increase at young age and a second, lower peak of onsets at the age of 45-54, whereas the cumulative incidence up to the age of 60 years was equal for males and females. On assessing the plausibility of psychosocial versus biological explanations it was hypothesized that due to the effect of estrogens the vulnerability threshold for schizophrenia is raised in females until the menopause. Animal experiments and postmortem analysis showed that chronic estrogen applications significantly shortened dopamine-induced behaviour and reduced D2 receptor sensitivity in the brain. The applicability of this pathophysiological mechanism on human schizophrenia was tested on acutely schizophrenic females with normal menstrual cycles. A significant negative correlation was found between measures of symptomatology and plasma estrogen levels. Apparently, the manifestation of schizophrenic symptoms is influenced by a sufficiently sensitive D2 receptor system in the brain, blocked by neuroleptics and modulated by estrogens.
- Zedlick D, Maurer K. Der Frühverlauf der Schizophrenie und seine Beziehung zu Alter, Geschlecht und Diagnose bei stationärer Erstaufnahme. Neuropsychiatrie. 1993;7:183–96.
- Hafner H, Riecher-Rössler A, Heiden W an der, Maurer K, Fatkenheuer B, Loffler W. Generating and testing a causal explanation of the gender difference in age at first onset of schizophrenia. Psychological Medicine [Internet]. 1993 Nov;23(4):925–40. Available from: http://view.ncbi.nlm.nih.gov/pubmed/8134516
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Motivated by the lack of knowledge of the pathophysiological processes underlying the manifestation of symptoms in schizophrenia, we have worked out a systematic search strategy. Since epidemiological distribution patterns consistently deviating from expected values provide valuable indications of causal relationships, we chose the higher age of females at first admission for schizophrenia, first reported by Kraepelin and since then confirmed in over 50 studies, as the basis for our study. This unexplained epidemiological finding was replicated on Danish and Mannheim case-register data by systematically controlling for selection and diagnostic artefacts and by testing alternative explanations at the individual stage of the study. To check whether the difference in age at first admission was determined by a difference in age at onset, a representative sample of 267 first-admitted patients with non-affective functional psychosis was examined by using an interview for the retrospective assessment of the onset of schizophrenia (IRAOS) designed for this purpose. Any of the definitions of first-ever onset applied–first sign of mental disorder, first psychotic symptom, first acute episode–led to a significant age difference of 3.2 to 4.1 years between the sexes. The distribution of onsets across the life cycle showed a later increase and a second, lower peak between the ages of 45 and 54 years among females compared with males. The lifetime risk for schizophrenia was equal for males and females. After testing the plausibility of psychosocial versus biological explanations we hypothesized that due to the effect of oestrogens the vulnerability threshold for schizophrenia is elevated in females until the menopause. Animal experiments and post mortem analyses showed that chronic oestrogen applications significantly shortened dopamine-induced behaviour and reduced D2 receptor sensitivity in the brain. The applicability of this pathophysiological mechanism to human schizophrenia was tested on acutely schizophrenic females with normal menstrual cycles. A significant negative correlation was found between measures of symptomatology and plasma oestrogen levels. The manifestation of symptoms in schizophrenia appears to be influenced by a sufficiently sensitive D2 receptor system in the brain, blocked by neuroleptics and modulated by oestrogens.
- Hafner H, Maurer K, Loffler W, Riecher-Rössler A. The influence of age and sex on the onset and early course of schizophrenia. The British journal of psychiatry : the journal of mental science [Internet]. 1993 Jan;162:80–6. Available from: http://view.ncbi.nlm.nih.gov/pubmed/8425144
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A new standardised interview for the retrospective assessment of onset and early course of schizophrenia (IRAOS) was used to study the influence of age and sex on time of onset and psychopathology before first admission in 267 schizophrenic patients admitted for the first time. Mean age at onset, according to various operationalised definitions, differed by three to four years between the sexes. The age distribution at the earliest sign of mental disorder showed an early and steep increase until the age of 25 in males, and a delayed and smaller increase in females, with a second peak in women aged 45-79. Schizophrenia began with negative symptoms in 70% of cases, appearing two to six years before admission, and all positive symptoms appearing up to two years before. Both positive and negative symptoms accumulated exponentially. The early course of the disease was similar across age groups, except there was a longer period of negative symptoms before first admission in late-onset schizophrenia in women. The few significant age differences in symptoms were presumably due to general age-dependent reaction patterns like anxiety and depression or the cognitive development of personality, as indicated by an increase in fully elaborated positive symptoms, especially systematised paranoid delusions, with age.
1992
- Hafner H, Riecher-Rössler A, Maurer K, Fatkenheuer B, Loffler W. First onset and early symptomatology of schizophrenia. A chapter of epidemiological and neurobiological research into age and sex differences. European archives of psychiatry and clinical neuroscience [Internet]. 1992;242(2–3):109–18. Available from: http://view.ncbi.nlm.nih.gov/pubmed/1486099
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In the frame of the ABC (Age, Beginning and Course) Schizophrenia Project we studied the influence of age and sex on first-ever onset, symptom manifestation and early course up to first admission in schizophrenia by using a large, representative sample of first-admitted schizophrenic patients. The results showed that the two variables had surprisingly little bearing upon the core symptoms, particularly on negative and other most frequent symptoms and on first-rank symptoms. In 70% of the cases schizophrenia started solely with negative symptoms, in 20% with negative and positive and in 10% with positive symptoms only. In most of the cases symptoms accumulated exponentially up to the first acute episode with positive symptoms appearing considerably later. The age differences observed concerned secondary phenomena associated with developmental factors. Such phenomena, i.e. anxiety, depression and the cognitive formation of delusions, can be interpreted as responses to the psychosis. Also the sex differences, which culminated in far more frequent socially negative disease behaviour in males, were limited to secondary phenomena. This positive and negative core symptomatology of schizophrenia seems to be astonishingly uniform and fairly independent of age and sex at this early stage of the disease. The only remarkable difference was a three to four years higher mean age of onset in females. We were able to show in animal experiments and to confirm in a clinical study that this finding is attributable to a neuromodulatory effect of estrogens on the sensitivity of D2 receptors in the brain. Apparently, estrogens raise the vulnerability threshold until menopause and have a slight neuroleptic-like effect on the symptomatology in acute schizophrenic episodes.
- Hafner H, Riecher-Rössler A, Hambrecht M, Maurer K, Meissner S, Schmidtke A, et al. IRAOS : an instrument for the assessment of onset and early course of schizophrenia. Schizophrenia research [Internet]. 1992 Mar;6(3):209–23. Available from: http://view.ncbi.nlm.nih.gov/pubmed/1571314
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Since Kraepelin's first description of dementia praecox in 1889 many data and theories have been published on the onset and course of schizophrenia. Until now studies on these topics had to rely on first admission data and on the subsequent course of the disease. However, first hospitalisation is preceded by a wide variety of patterns and duration of the early course. Items taken from the pre-admission phase of the disease are often incorrectly used as premorbid characteristics, understandably preceding the subsequent course and outcome of schizophrenia with high predictive power. In relation to our interest to study the beginning of schizophrenia, systematically, paying special attention to the age and gender distribution of true onset and the symptomatology and pattern of the early and later course, we developed an 'Interview for the Retrospective Assessment of the Onset of Schizophrenia (IRAOS)'. It allows an objective, reliable, and valid assessment of the symptoms, psychological impairments, demographic and social characteristics as well as the referring points in time of the early course of psychosis. The instrument is administered as a semi-structured interview with both the patient and a key informant. The obtained information is extended by a systematic examination of the clinician's case notes. Some results derived from an ongoing study on age and gender differences in onset and patterns of early course are added to demonstrate the use of the instrument.
- Riecher-Rössler A, Fatkenheuer B, Loffler W, Maurer K, Hafner H. Is age of onset in schizophrenia influenced by marital status? : Some remarks on the difficulties and pitfalls in the systematic testing of a “simple” question. Social psychiatry and psychiatric epidemiology [Internet]. 1992 May;27(3):122–8. Available from: http://view.ncbi.nlm.nih.gov/pubmed/1621136
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Schizophrenia is a disease characterized by a distinctly higher age at onset and at first admission in females than in males. In a systematic study on gender differences in schizophrenia we have confirmed this finding using different sets of data, in particular through the examination of a large and representative sample of first-admitted patients. The question addressed in this paper is whether marital status influences this sex-specific age difference. Assuming that marriage or a stable relationship is a protective factor in schizophrenia, delaying the onset of the disease or first hospitalization, the hypothesis was formulated that the later age of onset in women is at least partly explained by their generally earlier age of marriage. Testing this hypothesis illustrates some of the methodological problems that often occur when a causal analysis of social data is attempted. The problems emerge especially when both the dependent variable (age of onset/first admission) and the independent variable (marital status) are essentially related to age. First results appearing to indicate an influence of marital status on age at first admission did not bear a critical interpretation.
1991
- Loffler W, Fatkenheuer B, Hambrecht M, Maurer K, Riecher-Rössler A, Hafner H. [A computer algorithm for diagnostic assessment with DSM-III in the early course of schizophrenic diseases]. Schweizer Archiv für Neurologie und Psychiatrie (Zurich, Switzerland : 1985) [Internet]. 1991;142(5):423–37. Available from: http://view.ncbi.nlm.nih.gov/pubmed/1721238
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The purpose of the computer algorithm described here is the evaluation of diagnostic criteria according to DSM-III for schizophrenia and schizophreniform disorders. It also dates the first time point of the assessment of these diagnoses. The necessary information comes from a semistructured interview, called IRAOS (Interview for the Retrospective Assessment of the Onset of Schizophrenia). With this interview early indicators of a beginning schizophrenia can be evaluated in their chronological order and their type of course. The algorithm was first used in a sample of patients admitted for the first time with a diagnosis of either schizophrenia or paranoid psychosis. One third of these patients fulfills the DSM-III-criterion of a duration of at least six months. The other patients fulfill criterion B of a schizophreniform disorder. To strengthen the validity of a diagnosis including the criteria A up to E successively, the sample is reduced to 70%. The average time point of the first assessment of the diagnosis by the computer algorithm is about 1.5 years before the index-admission. Together with the IRAOS the computer algorithm allows an operationalized assessment of the real onset of schizophrenia.
- Hafner H, Fatkenheuer B, Heiden W an der, Loffler W, Maurer K, Munk-Jorgensen P, et al. [Sex differences in age of onset, symptomatology and evolution of schizophrenia]. Santé mentale au Québec [Internet]. 1991 Jun;16(1):77–98. Available from: http://view.ncbi.nlm.nih.gov/pubmed/1932426
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Gender differences in age at onset, symptomatology and course of schizophrenia are examined by analyzing case register data and by direct investigation of a representative sample of first-admitted patients. The main finding that males fall ill at an earlier age than females can be confirmed even after ruling out other interpretations due to sample bias, different time span between real onset and first hospital admission, gender differences in symptom development or other confounding factors. When looking for causes of these gender differences it seems that disturbances in early social development must be understood as a consequence of beginning schizophrenia rather than a prerequisite. The need for explanatory models is stressed that allow for the empirical testing of hypotheses concerning gender specific development of schizophrenia.
- Riecher-Rössler A, Rossler W. Die Schizophrenie. Aktueller Kenntnisstand über eine weit verbreitete psychiatrische Krankheit. Deutsche Krankenpflegezeitschrift [Internet]. 1991 Oct;44(3):721–5. Available from: http://tematicas.es/salud/articulo/die-schizophrenie-aktueller-kenntnisstand-uber-eine-weit-verbreitete-psychiatrische-krankheit/
- Riecher-Rössler A, Rossler W, Loffler W, Fatkenheuer B. Factors influencing compulsory admission of psychiatric patients. Psychological Medicine [Internet]. 1991 Feb;21(1):197–208. Available from: http://dx.doi.org/10.1017/S0033291700014781
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From 1 January 1984 until 30 June 1986 all 517 compulsorily admitted psychiatric patients of a well-defined mixed rural-urban catchment area in Baden-Württemberg, a southern State of the German Federal Republic, were compared with all 10,232 voluntarily admitted patients. Because of the very low frequency of compulsory admissions this population can be regarded as a 'core group' of committed patients. In a logit analysis the characteristics distinguishing involuntary from voluntary patients can be reduced to three main factors: the diagnosis 'schizophrenia/paranoid disorder', 'masculine gender' and the compound indicator 'not owning a home', the latter being mainly associated with youth, masculine gender and low occupational status. The strong association of these characteristics with the criteria 'severity of disease' and 'danger to oneself and others', both pre-requisites for compulsory admission according to the laws of most countries, is discussed.
- Riecher A, Maurer K, Loffler W, Fatkenheuer B, Heiden W an der, Munk-Jorgensen P, et al. Gender differences in age at onset and course of schizophrenic disorders. In: Hafner H, Gattaz WF, editors. Search for the Causes of Schizophrenia - Volume II. Springer; 1991. p. 14–33.
- Hafner H, Riecher A, Maurer K, Fatkenheuer B. Geschlechtsunterschiede bei schizophrenen Erkrankungen. Fortschr Neurol Psychiatr [Internet]. 1991;59(9):343–60. Available from: http://dx.doi.org/10.1055/s-2007-1000709
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Geschlechtsunterschiede bei schizophrenen Erkrankungen sind ein lange beobachtetes, aber auch lange vernachlässigtes Phänomen in der psychiatrisch-epidemiologischen Forschung, obwohl sie u. E. wichtige Hinweise auf pathogene Faktoren bei dieser in ihrer Ätiologie noch ungeklärten Krankheitsgruppe geben könnten. Wir haben deshalb umfangreiche Untersuchungen zu diesem Thema begonnen. Die vorliegende Arbeit referiert einige erste Ergebnisse, basierend auf Daten des Mannheimer und des Nationalen dänischen Fallregisters sowie unserer eigenen Schizophreniestudie, einer repräsentativen Erhebung von 392 Erstaufnahmen aus dem Rhein-Neckar-Raum und der östlichen Pfalz. Zunächst wurden Geschlechtsunterschiede im Ersterkrankungsalter unter sorgfältiger Kontrolle von Artefakten und anderen, meist vernachlässigten methodischen Fehlerquellen untersucht Bestätigt werden konnte der Unterschied im durchschnittlichen Alter der Geschlechter bei Erstaufnahmen und mit Hilfe eines eigens dafür entwickelten Instruments auch bei Erkrankungsbeginn. Männer sind demnach auch beim Auftreten der ersten großenteils unspezifischen Krankheitszeichen und der ersten schizophrenen Symptome etwa 3 bis 4 Jahre jünger als Frauen. Dagegen scheint das kumulative Lebenszeitrisiko - berechnet bis zum Alter von 60 Jahren - für beide Geschlechter gleich zu sein . Geschlechtsunterschiede in der Krankheitssymptomatik zum Zeitpunkt der Erstaufnahme bestehen offenbar nicht, und zwar sowohl was die häufigsten, aber auch was die charakteristischen Symptome betrifft. Signifikante, wenn auch quantitativ nicht sehr große Unterschiede zeigten sich beim Krankheitsverhalten, das bei Frauen etwas häufiger sozial positive, bei Männern deutlich häufiger sozial negative Züge erkennen läßt. Hinsichtlich des Krankheitsverlaufs konnten wir - allerdings vorerst auf der Grundlage der dänischen Fallregisterdaten und nur unter Zugrundelegen von Kriterien des Behandlungsverlaufs wie Zahl und Dauer stationärer Aufenthalte - über 10 Jahre nach Erstaufnahme keine deutlichen Geschlechtsunterschiede finden.
- Hafner H, Maurer K, Loffler W, Riecher-Rössler A. Schizophrenie und Lebensalter. Nervenarzt [Internet]. 1991;62(9):536–48. Available from: http://psycnet.apa.org/psycinfo/1993-86813-001
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The association of age with time of onset, symptomatology and early course of schizophrenia was studied on a large, representative sample of first-admitted patients with a diagnosis of schizophrenia (nuclear and related diagnoses) from a total population of about 1.5 million by using a semi-structured interview (IRAOS) developed specifically for this purpose. As a result an age distribution differing between men and women was obtained when the appearance of the first sign of a mental disturbance was studied. 61.6% of the men and 47.4% of the women fell ill prior to the age of 25. Negative symptoms and the early course of the disease turned out to be relatively independent of age at onset. The few age differences observed with positive and unspecific symptoms seem to be accounted for by factors not specific for schizophrenia, such as slightly increased anxiety at young age, slightly increased depressiveness in early adulthood and slightly increased paranoid delusions later in adulthood. At young age delusional symptoms, probably as an expression of immature personality, are less stable, less differentiated and less systematized, whereas fully developed delusions of persecution become more frequent at higher age. An unexpected finding was a comparatively high proportion of lengthy phases characterized by negative symptoms prior to first admission in late-onset schizophrenia in females. Hence, beginning schizophrenia seems to be a fairly uniform pattern of response at all ages, female sex appearing to be the only factor independent of the disease that influences it to any significant extent by delaying onset.
1989
- Hafner H, Riecher A, Maurer K, Loffler W, Munk-Jorgensen P, Stromgren E. How does gender influence age at first hospitalization for schizophrenia? : A transnational case register study. Psychological Medicine [Internet]. 1989 Nov;19(4):903–18. Available from: http://view.ncbi.nlm.nih.gov/pubmed/2594886
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Numerous studies have reported a lower mean age at first hospitalization for schizophrenia in males than in females. For this finding not only a gender difference in age at first onset of schizophrenia, but also other factors can be responsible. With the aim of providing a comprehensive analysis of gender differences in onset, symptomatology and course of schizophrenia, we started by testing the hypothesis postulating a gender difference in mean age at first hospitalization. By using the Danish and the Mannheim psychiatric case registers we analysed all hospital admissions for schizophrenia and related diagnoses and all previous admissions for other diagnoses of the Danish population in 1976 and those of the inhabitants of the German city of Mannheim in the period of 1978-80. Artefacts were controlled for systematically. The impact of intervening variables such as selection factors as well as the influence of gender on the ascription of a diagnosis of schizophrenia for the first time were assessed. We found a mean difference of 5 to 6 years in age at first hospitalization between males and females in both countries when a broad definition of the diagnosis was used and of 4 to 5 years when a restrictive definition was applied. The higher mean age at first hospitalization among females is not attributable to artefacts, diagnostic procedures or to any essential extent to gender differences in help-seeking behaviour or occupational status. When a distinction was made between 'single' and 'married', the significant difference in age at first hospitalization between the sexes disappeared in singles. With case register data and without knowing the chronological order of marriage and onset of the disease, it remains an open question whether this finding can be explained by purely correlative associations between sex, marital status and age of onset or by causal effects.
- Riecher A, Maurer K, Loffler W, Fatkenheuer B, Heiden an der, Hafner H. Schizophrenia–a disease of young single males? : Preliminary results from an investigation on a representative cohort admitted to hospital for the first time. European archives of psychiatry and neurological sciences [Internet]. 1989;239(3):210–2. Available from: http://dx.doi.org/10.1007/BF01739655
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The later age at onset of schizophrenia in females, reported in the literature, led to a study of transnational case register data and of a cohort of all patients admitted to hospital for the first time with a non-affective functional psychosis from a defined catchment area. The preliminary analysis of the first representative sample of 86 patients showed that at the time of first admission with a diagnosis of schizophrenia (according to different diagnostic definitions) as well as at the time of onset of the disease (operationalized on different levels) females were on average 5 years older than males. Singles, and even more so young single males, were clearly overrepresented among those first hospitalized in comparison to the population of the same age. To remain single seems to be in most cases a consequence of the disease or of premorbid characteristics in those predisposed to schizophrenia.