Prevention of First-Episode Psychosis in People at Clinical High Risk: A Randomized Controlled, Multicentre Trial Comparing Cognitive-Behavioral Therapy and Clinical Management Plus Low-Dose Aripiprazole or Placebo (PREVENT).

BACKGROUND: There is limited knowledge of whether cognitive-behavioral therapy (CBT) or second-generation antipsychotics (SGAs) should be recommended as the first-line treatment in individuals at clinical high risk for psychosis (CHRp). HYPOTHESIS: To examine whether individual treatment arms are superior to placebo and whether CBT is non-inferior to SGAs in preventing psychosis over 12 months of treatment. STUDY DESIGN: PREVENT was a blinded, 3-armed, randomized controlled trial comparing CBT to clinical management plus aripiprazole (CM + ARI) or plus placebo (CM + PLC) at 11 CHRp services. The primary outcome was transition to psychosis at 12 months. Analyses were by intention-to-treat. STUDY RESULTS: Two hundred eighty CHRp individuals were randomized: 129 in CBT, 96 in CM + ARI, and 55 in CM + PLC. In week 52, 21 patients in CBT, 19 in CM + ARI, and 7 in CM + PLC had transitioned to psychosis, with no significant differences between treatment arms (P = .342). Psychopathology and psychosocial functioning levels improved in all treatment arms, with no significant differences. CONCLUSIONS: The analysis of the primary outcome transition to psychosis at 12 months and secondary outcomes symptoms and functioning did not demonstrate significant advantages of the active treatments over placebo. The conclusion is that within this trial, neither low-dose aripiprazole nor CBT offered additional benefits over clinical management and placebo.

Bridging the phenomenological gap between predictive basic-symptoms and attenuated positive symptoms: a cross-sectional network analysis.

Attenuated positive symptoms (APS), transient psychotic-like symptoms (brief, limited intermittent psychotic symptoms, BLIPS), and predictive cognitive-perceptive basic-symptoms (BS) criteria can help identify a help-seeking population of young people at clinical high-risk of a first episode psychosis (CHRp). Phenomenological, there are substantial differences between BS and APS or BLIPS. BS do not feature psychotic content as delusion or hallucinations, and reality testing is preserved. One fundamental problem in the psychopathology of CHRp is to understand how the non-psychotic BS are related to APS. To explore the interrelationship of APS and predictive BS, we fitted a network analysis to a dataset of 231 patients at CHRp, aged 24.4 years (SD = 5.3) with 65% male. Particular emphasis was placed on points of interaction (bridge symptoms) between the two criteria sets. The BS 'unstable ideas of reference' and "inability to discriminate between imagination and reality" interacted with attenuated delusional ideation. Perceptual BS were linked to perceptual APS. Albeit central for the network, predictive cognitive basic BS were relatively isolated from APS. Our analysis provides empirical support for existing theoretical accounts that interaction between the distinct phenomenological domains of BS and APS is characterized by impairments in source monitoring and perspective-taking. Identifying bridge symptoms between the symptom domains holds the potential to empirically advance the etiological understanding of psychosis and pave the way for tailored clinical interventions.

[Obsessive-compulsive symptoms in psychotic disorders: pathogenesis and treatment]. / Zwangssymptome bei psychotischen Störungen: Pathogenese und Therapie.

BACKGROUND: Comorbid disorders often occur in psychoses from the schizophrenia spectrum and are an additional burden for patients' quality of life, render treatment and rehabilitation prognosis more difficult and can also contribute to suicidal ideation. Specifically, obsessive-compulsive syndrome (OCS) and OC disorder (OCD) have been reported. OBJECTIVE: What is known about the epidemiology and pathogenesis and which conclusions can be drawn regarding the diagnostics and treatment? MATERIAL AND METHODS: This review evaluated current reports on comorbid OCS during different stages of psychotic disorders, starting with the at-risk mental state (ARMS) via the first manifestation and up to chronic courses. The focus was on pharmacological and psychotherapeutic consequences. RESULTS: Patients with ARMS suffer much more often from OCS than the general population. The prevalence is even higher in patients with a first manifestation of psychosis. During the chronic courses ca. 30% of patients are affected by comorbid OCS and 12% fulfill the diagnostic criteria of a OCD. The pathogenesis can most likely be explained by a genetic disposition in the glutamatergic system, shared structural and functional abnormalities of cortical and subcortical structures, pharmacological influences and psychosocial stressors. CONCLUSION: Clozapine and other antipsychotics may induce or aggravate OCS in a dose-dependent manner. In order to alleviate symptoms clozapine should be reduced to a minimally sufficient level. This can be attempted through combination, for example with dopaminergic antipsychotics. In general, serotonergic antidepressants can be added. Cognitive behavioral therapy should be offered to every patient with comorbid OCS. For future research multimodal longitudinal studies investigating the efficacy of interventions and aimed at the subjective level will be important.

Amisulpride and olanzapine combination treatment versus each monotherapy in acutely ill patients with schizophrenia in Germany (COMBINE): a double-blind randomised controlled trial.

BACKGROUND: Combining antipsychotics is common in schizophrenia treatment, despite evidence-based guidelines generally not recommending such practice. Otherwise, evidence remains inconclusive, especially regarding specific combinations. The trial aimed to test whether a combination of amisulpride plus olanzapine is more effective than either intervention as a monotherapy. METHODS: A multicentre, 16-week, randomised, double-blind, controlled trial was done at 16 psychiatric in-patient centres throughout Germany. Inclusion criteria were adults aged 18-65 years with non-first episode schizophrenia or schizoaffective disorder and with a Positive and Negative Syndrome Scale (PANSS) total score of at least 70 and at least two items of the positive symptoms subscale rated at least 4. Patients were randomly assigned to receive 16 weeks of treatment with either amisulpride plus olanzapine, amisulpride plus placebo, or olanzapine plus placebo (1:1:1), and block randomisation was stratified by study site. To keep patients and investigators masked throughout the duration of the trial, amisulpride, olanzapine, and placebo were administered as identical capsules. Flexibly dosed monotherapy of oral amisulpride (amisulpride plus placebo, 200-800 mg per day) or olanzapine (olanzapine plus placebo, 5-20 mg per day) was compared with a combination of amisulpride plus olanzapine. The primary outcome was symptom reduction measured by the PANSS total score after 8 weeks, in the modified intention-to-treat population (all patients randomly assigned to an intervention and receiving at least one study drug dose). As determined a priori, group differences were examined by t tests (Bonferroni-Holm-adjustment) followed by pre-planned Bayesian analyses as well as imputation methods based on mixed models to account for missing values and post-hoc ANCOVA adjusting for PANSS baseline scores. The study was registered on ClinicalTrials.gov, NCT01609153; the German Clinical Trials Register, DRKS00003603; and the European Union Drug Regulating Authorities Clinical Trials Database, EudraCT-No. 2011-002463-20. FINDINGS: Between June 15, 2012, and Dec 15, 2018, 13 692 patients were assessed for eligibility. 13 364 patients were excluded (including for not meeting inclusion criteria, declining to participate, or inappropriate reasons for changing pharmacological treatment), and 328 were then randomly assigned to an intervention group. 112 patients were randomly assigned to receive amisulpride plus olanzapine, 109 were randomly assigned to receive amisulpride plus placebo, and 107 were randomly assigned to receive olanzapine plus placebo. 321 patients were analysed for the primary outcome in the modified intention-to-treat population after exclusion of screening failures and patients who did not receive the intervention (110 for amisulpride plus olanzapine, 109 for amisulpride plus placebo, and 102 for olanzapine plus placebo). Among the 321 patients who were randomly assigned to intervention groups and analysed for the primary outcome, 229 (71%) were male, 92 (29%) were female; the mean age was 40·2 years (SD 11·7); and 296 (92%) were White and 25 (8%) were classified as other ethnicity. PANSS total score improved significantly more at 8 weeks in the amisulpride plus olanzapine group (-29·6 [SD 14·5]) than in the olanzapine plus placebo group (-24·1 [13·4], p=0·049, Cohen's d=0·396). A significant difference was not observed in reduction of PANSS total score between the amisulpride and olanzapine group compared with the amisulpride and placebo group (-25·2 [SD 15·9], p=0·095, Cohen's d=0·29). After 8 weeks and 16 weeks, sexual dysfunction, weight, and waist circumference increase were significantly higher for patients receiving amisulpride plus olanzapine than for those receiving amisulpride plus placebo, with no differences in serious adverse events. Two patients died during study participation; one randomly assigned to the amisulpride plus olanzapine group, and one assigned to the olanzapine plus placebo group (both assessed with no relation to treatment). INTERPRETATION: The advantages of amisulpride plus olanzapine have to be weighed against a higher propensity for side-effects. The use of this specific combination therapy could be an alternative to monotherapy in certain clinical situations, but side-effects should be considered. FUNDING: German Federal Ministry of Education and Research.

App-based maintenance treatment for alcohol use disorder after acute inpatient treatment: Study protocol for a multicentre randomized controlled trial.

BACKGROUND: Alcohol use disorder, a prevalent and disabling mental health problem, is often characterized by a chronic disease course. While effective inpatient and aftercare treatment options exist, the transferal of treatment success into everyday life is challenging and many patients remain without further assistance. App-based interventions with human guidance have great potential to support individuals after inpatient treatment, yet evidence on their efficacy remains scarce. OBJECTIVES: To develop an app-based intervention with human guidance and evaluate its usability, efficacy, and cost-effectiveness. METHODS: Individuals with alcohol use disorder (DSM-5), aged 18 or higher, without history of schizophrenia, undergoing inpatient alcohol use disorder treatment (N = 356) were recruited in eight medical centres in Bavaria, Germany, between December 2019 and August 2021. Participants were randomized in a 1:1 ratio to either receive access to treatment as usual plus an app-based intervention with human guidance (intervention group) or access to treatment as usual plus app-based intervention after the active study phase (waitlist control/TAU group). Telephone-based assessments are conducted by diagnostic interviewers three and six weeks as well as three and six months after randomization. The primary outcome is the relapse risk during the six months after randomization assessed via the Timeline Follow-Back Interview. Secondary outcomes include intervention usage, uptake of aftercare treatments, AUD-related psychopathology, general psychopathology, and quality of life. DISCUSSION: This study will provide further insights into the use of app-based interventions with human guidance as maintenance treatment in individuals with AUD. If shown to be efficacious, the intervention may improve AUD treatment by assisting individuals in maintaining inpatient treatment success after returning into their home setting. Due to the ubiquitous use of smartphones, the intervention has the potential to become part of routine AUD care in Germany and countries with similar healthcare systems.

Lower Emotion Regulation Competencies Mediate the Association between Impulsivity and Craving during Alcohol Withdrawal Treatment.

There is evidence that craving mediates the relationship between Impulsive Personality Traits (IPTs) and relapse during the treatment of an Alcohol Use Disorder (AUD). To provide tailored interventions, a deeper understanding of the relation between IPTs and craving, namely mediating processes, is important. Based on previous literature, we proposed that lower emotion regulation competencies mediate the relation between attentional as well as non-planning IPTs and craving. To investigate these interrelations, we used data from the baseline assessment (n = 320) of the SmartAssistEntz project (pre-registered in the German Clinical Trials Register [DRKS00017700]). Inpatients with a primary AUD diagnosis were interviewed using standardized self-report measures (IPTs: BIS-15, emotion regulation competencies: ERSQ, craving: OCDS-G short version) during their withdrawal treatment. Indirect effects were calculated using the SPSS macro PROCESS v3.5. Attentional as well as non-planning, but not motor, IPTs were associated with craving. Emotion regulation competencies mediated the relationship between attentional as well as non-planning IPTs and craving. Given their mediating role in the present study, it is interesting to investigate if addressing emotion regulation competencies can mitigate the negative influences of attentional and non-planning IPTs. The direct effect of attentional IPTs implicates alternate mediating processes, which should also be investigated in future research.

Association of impulsivity with quality of life and well-being after alcohol withdrawal treatment.

OBJECTIVES: Impulsivity is related to a higher risk of relapse in alcohol use disorders. However, besides drinking behavior, other recovery outcomes like physical and mental health-related quality of life are at least as important. The present study aimed to fill a research gap regarding the association of different impulsivity facets with health-related quality of life and well-being in alcohol use disorder. METHODS: Individuals with a primary alcohol use disorder diagnosis (n = 167) were interviewed with standardized self-report measures at the progressed stage of their withdrawal treatment and 6 weeks thereafter. Multiple regression models were calculated to examine the association of impulsivity, craving, and drinking patterns with health-related quality of life and well-being 6 weeks after withdrawal treatment, as well as the predictive role of impulsivity assessed during withdrawal for these two outcomes. RESULTS: Craving was associated with health-related quality of life and well-being 6 weeks after withdrawal. Likewise, non-planning and attentional impulsivity were associated with well-being 6 weeks after withdrawal. Motor impulsivity during withdrawal treatment predicted health-related quality of life 6 weeks thereafter. CONCLUSION: Impulsivity seems to be negatively related to health-related quality of life and well-being in the first weeks after alcohol withdrawal treatment, probably to a higher extent than drinking patterns, but differentiating between its facets seems to be important. These findings emphasize the importance of treatment approaches aiming at reduced impulsivity in the early recovery process.

[Validity of the "Structured Inventory of Malingered Symptomatology" [SIMS] in the Assessment of Healthy Individuals and Patients with Psychiatric Disorders Outside the Forensic Context]. / Validität des "Strukturierten Fragebogens Simulierter Symptome" [SIMS] bei gesunden Probanden und Patienten mit psychiatrischen Erkrankungen außerhalb eines forensischen Kontexts.

OBJECTIVE: Assessment of the rate of false-positive results of the Structured Inventory of Malingered Symptomatology (SIMS) in healthy controls and authentic patients outside the forensic or rehabilitative context. METHODS: Beyond the SIMS scores, further variables (PANSS, Hamilton scale, MMSE) were obtained. SIMS scores of healthy individuals were compared with the SIMS scores of the different groups of patients. Additionally, correlations between the SIMS scores and other variables were investigated. RESULTS: Patients with psychotic disorders (n=30) or depressive episodes (n=32) more frequently achieved SIMS scores >16 as compared to healthy controls. In comparison, patients with amnestic disorders (n=15) had inconspicuous SIMS scores. Depressed patients with positive SIMS results were significantly more likely to be diagnosed with another psychiatric disorder and the scores of these patients on the Hamilton scale were correlated with positive results on 2 subscales of the SIMS (NI, AF). CONCLUSION: If this instrument is to applied in clinical practice in the future, further validation of the SIMS is necessary. The specificity of the SIMS seems to be context-related.

[Acute Psychotic Disorders]. / Akute psychotische Störungsbilder.

Acute psychotic disorders (APS) are characterized by an acute onset as well as a wide array of symptoms including affective, psychotic, and psychomotor symptoms. They occur independently of substance use or organic disorders. In most cases, patients recover fully and without residues within a short period of time. However, APS tend to show a relapsing course, and transitions into other psychiatric disorders (schizophrenia, bipolar disorder) may occur.

Stressful experiences affect the course of co-occurring obsessive-compulsive and psychotic symptoms: A focus on within-subject processes.

OBJECTIVE: Obsessive-compulsive symptoms (OCS) frequently occur in patients with psychotic disorders and are associated with higher burden and poorer prognosis. This study prospectively investigated the effect of stressful experiences on the severity of OCS and co-occurring psychotic and affective symptoms, with a focus on within-subject processes. METHOD: Monthly assessments over 6 months in patients with a psychotic disorder (n = 56) and unaffected siblings (n = 49) resulted in 309 and 277 observations, respectively. Linear mixed-effects models investigated the disaggregated effects of within-subject changes and between-subject differences in stressful events on OCS, positive, negative and depressive symptoms. Subsequently, moderating effects of coping strategies and dysfunctional metacognitive beliefs were assessed. Mediation analyses investigated direct and indirect effects of stressful events on OCS four weeks later. RESULTS: Stressful experiences were associated with severity in almost all symptom domains on the between- and within-subject levels. Dysfunctional coping and metacognitive beliefs moderated these associations. Patients and siblings with a tendency for passive coping showed higher within-subject increase in depressive symptoms, whereas passive coping and dysfunctional beliefs moderated the association between stressful experiences and severity of positive symptoms and OCS on the between-subject level. Effects of stressful experiences on OCS four weeks later were partially mediated by depressive and positive symptoms in patients and siblings. CONCLUSIONS: Findings suggest that severity and variability of co-occurring psychopathology can partly be explained by recent stressful events and the way individuals cope with these experiences. The implementation of coping-oriented interventions could possibly help to prevent development and/or aggravation of co-occurring symptom severity.

A randomized double-blind controlled trial to assess the benefits of amisulpride and olanzapine combination treatment versus each monotherapy in acutely ill schizophrenia patients (COMBINE): methods and design.

This report presents the rationale and design of a multi-center clinical trial that examines the efficacy and safety of antipsychotic combination treatment in acutely ill schizophrenia patients compared to antipsychotic monotherapy. Antipsychotic combination treatment is common in clinical practice worldwide, despite clinical guidelines generally not recommending such practice due to lacking evidence for its efficacy and safety. Olanzapine has a related chemical structure and comparable receptor-binding profile as clozapine, which demonstrated superior efficacy in combination studies, but has a more unfavorable side-effect profile compared to olanzapine. Amisulpride and olanzapine have shown promising therapeutic efficacy in meta-analyses in monotherapy for people with schizophrenia. Combining amisulpride and olanzapine, complementary receptor-binding properties may enhance efficacy and possibly reduce (or at least not augment) side effects due to the different receptor profiles and metabolization pathways. Accordingly, we hypothesize that patients treated with amisulpride plus olanzapine show greater improvement on the Positive and Negative Syndrome Scale total score after 8 weeks versus either monotherapy. A randomized, double-blind controlled trial is performed at 16 German centers comparing flexibly dosed monotherapy of oral amisulpride (400-800 mg/day), and olanzapine (10-20 mg/day) and amisulpride-olanzapine co-treatment. Sample size was calculated to be n = 101 per treatment arm, assuming an effect size of 0.500 and a two-sided alpha = 0.025 and beta = 0.90. Recruitment for this trial started in June 2012. Until December 2018, 328 patients have been randomized. Trial conduct has been extended to reach the projected sample size. Publication of the study results is expected in 2019 informing an evidence-based recommendation regarding specific antipsychotic combination treatment.

Can the Positive and Negative Syndrome scale (PANSS) differentiate treatment-resistant from non-treatment-resistant schizophrenia? A factor analytic investigation based on data from the Pattern cohort study.

Treatment-Resistant Schizophrenia (TRS) and Non-Treatment-Resistant Schizophrenia (NTRS) may represent different subtypes of schizophrenia. However, few studies have investigated their PANSS symptom dimensions by Exploratory (EFA) or Confirmatory (CFA). Data from the present study are derived from 1429 patients of the Pattern study. TRS was defined by the use of clozapine in the previous year whereas NTRS by the use of non-clozapine antipsychotics ("by proxy"). Factors were chosen based on the Kaiser criterion and considered valid when loadings were greater than or equal to 0.5. The fit to the data was evaluated by CFA in comparison with well-established PANSS models, using fit indexes. The EFA yielded similar five-factor model in both groups: Negative, Positive, Anxiety/Depression, Cognitive and Excited. CFA showed a satisfactory, but not perfect, fit to the data, as compared with the previous PANSS factor analytic models. Despite the limitations regarding the 'by proxy' definition of TRS, the results of the present study show that there are no differences in the factorial structure of PANSS in patients with TRS and NTRS.

Brain Heterogeneity in Schizophrenia and Its Association With Polygenic Risk.

Importance: Between-individual variability in brain structure is determined by gene-environment interactions, possibly reflecting differential sensitivity to environmental and genetic perturbations. Magnetic resonance imaging (MRI) studies have revealed thinner cortices and smaller subcortical volumes in patients with schizophrenia. However, group-level comparisons may mask considerable within-group heterogeneity, which has largely remained unnoticed in the literature. Objectives: To compare brain structural variability between individuals with schizophrenia and healthy controls and to test whether respective variability reflects the polygenic risk score (PRS) for schizophrenia in an independent sample of healthy controls. Design, Setting, and Participants: This case-control and polygenic risk analysis compared MRI-derived cortical thickness and subcortical volumes between healthy controls and patients with schizophrenia across 16 cohorts and tested for associations between PRS and MRI features in a control cohort from the UK Biobank. Data were collected from October 27, 2004, through April 12, 2018, and analyzed from December 3, 2017, through August 1, 2018. Main Outcomes and Measures: Mean and dispersion parameters were estimated using double generalized linear models. Vertex-wise analysis was used to assess cortical thickness, and regions-of-interest analyses were used to assess total cortical volume, total surface area, and white matter, subcortical, and hippocampal subfield volumes. Follow-up analyses included within-sample analysis, test of robustness of the PRS threshold, population covariates, outlier removal, and control for image quality. Results: A comparison of 1151 patients with schizophrenia (mean [SD] age, 33.8 [10.6] years; 68.6% male [n = 790] and 31.4% female [n = 361]) with 2010 healthy controls (mean [SD] age, 32.6 [10.4] years; 56.0% male [n = 1126] and 44.0% female [n = 884]) revealed higher heterogeneity in schizophrenia for cortical thickness and area (t = 3.34), cortical (t = 3.24) and ventricle (t range, 3.15-5.78) volumes, and hippocampal subfields (t range, 2.32-3.55). In the UK Biobank sample of 12 490 participants (mean [SD] age, 55.9 [7.5] years; 48.2% male [n = 6025] and 51.8% female [n = 6465]), higher PRS was associated with thinner frontal and temporal cortices and smaller left CA2/3 (t = -3.00) but was not significantly associated with dispersion. Conclusions and Relevance: This study suggests that schizophrenia is associated with substantial brain structural heterogeneity beyond the mean differences. These findings may reflect higher sensitivity to environmental and genetic perturbations in patients, supporting the heterogeneous nature of schizophrenia. A higher PRS was associated with thinner frontotemporal cortices and smaller hippocampal subfield volume, but not heterogeneity. This finding suggests that brain variability in schizophrenia results from interactions between environmental and genetic factors that are not captured by the PRS. Factors contributing to heterogeneity in frontotemporal cortices and hippocampus are key to furthering our understanding of how genetic and environmental factors shape brain biology in schizophrenia.

Reproducible grey matter patterns index a multivariate, global alteration of brain structure in schizophrenia and bipolar disorder.

Schizophrenia is a severe mental disorder characterized by numerous subtle changes in brain structure and function. Machine learning allows exploring the utility of combining structural and functional brain magnetic resonance imaging (MRI) measures for diagnostic application, but this approach has been hampered by sample size limitations and lack of differential diagnostic data. Here, we performed a multi-site machine learning analysis to explore brain structural patterns of T1 MRI data in 2668 individuals with schizophrenia, bipolar disorder or attention-deficit/ hyperactivity disorder, and healthy controls. We found reproducible changes of structural parameters in schizophrenia that yielded a classification accuracy of up to 76% and provided discrimination from ADHD, through it lacked specificity against bipolar disorder. The observed changes largely indexed distributed grey matter alterations that could be represented through a combination of several global brain-structural parameters. This multi-site machine learning study identified a brain-structural signature that could reproducibly differentiate schizophrenia patients from controls, but lacked specificity against bipolar disorder. While this currently limits the clinical utility of the identified signature, the present study highlights that the underlying alterations index substantial global grey matter changes in psychotic disorders, reflecting the biological similarity of these conditions, and provide a roadmap for future exploration of brain structural alterations in psychiatric patients.

Reduced activity and connectivity of left amygdala in patients with schizophrenia treated with clozapine or olanzapine.

Obsessive-compulsive symptoms (OCS) in patients with schizophrenia are a common co-occurring condition, often associated with additional impairments. A subgroup of these patients develops OCS during treatment with second-generation antipsychotics (SGAs), most importantly clozapine and olanzapine. So far, little is known about possible neural mechanism of these SGAs, which seem to aggravate or induce OCS. To investigate the role of SGA treatment on neural activation and connectivity during emotional processing, patients were stratified according to their monotherapy into two groups (group I: clozapine or olanzapine, n = 20; group II: amisulpride or aripiprazole, n = 20). We used an fMRI approach, applying an implicit emotion recognition task. Group comparisons showed significantly higher frequency and severity of comorbid OCS in group I than group II. Task specific activation was attenuated in group I in the left amygdala. Furthermore, functional connectivity from left amygdala to right ventral striatum was reduced in group I. Reduced amygdala activation was associated with OCS severity. Recent literature suggests an involvement of an amygdala-cortico-striatal network in the pathogenesis of obsessive-compulsive disorder. The observed differential activation and connectivity pattern of the amygdala might thus indicate a neural mechanism for the development of SGA-associated OCS in patients with schizophrenia. Further neurobiological research and interventional studies are needed for causal inferences.

Obsessive-compulsive symptoms in psychotic disorders: longitudinal associations of symptom clusters on between- and within-subject levels.

Obsessive-compulsive symptoms (OCS) are frequently reported in patients with schizophrenia and have been associated with subjective distress and higher impairment. Recent studies suggest fluctuation in co-occurring OCS and associations with the course of psychotic symptoms. Current evidence is limited by few studies with long assessments intervals and a sole focus on between-subject comparisons. The aim of this study was to specifically investigate co-variation of symptom domains over time within individuals. Patients with a psychotic disorder (n = 56) and un-affected siblings (n = 49) completed monthly assessments of clinical and subclinical symptoms over 6 months. Mixed-model multilevel analyses examined the variability and relationship between OCS and positive, negative, and depressive symptoms on the between- and within-subject level. Symptom domains were associated across subjects and assessment times, in patients and siblings, with the strongest association between OCS and (subclinical) positive symptoms. Within-subjects, substantial variability and co-variation of all symptom domains was found. Particularly, between-subject differences in positive symptoms and within-subject change in depressive symptoms predicted subsequent OCS in patients 1 months later. This is the first prospective study disaggregating between and within-subject associations between co-occurring OCS and symptom cluster of psychosis. Differences on these two levels suggest different underlying mechanisms. The association between depressive symptoms and subsequent increase/decrease of OCS within patients may have important treatment implications.

Response to Agomelatine Treatment is Independent of Smoking Status and Dosage: Results From the AGOPSYCH Study.

INTRODUCTION: Cigarette smoking influences response to antidepressant treatment. It accelerates the metabolism of several cytochrome P450 (CYP) subtypes, including CYP1A2, and therefore bears the risk of pharmacokinetic interactions with psychotropic drugs using that pathway. Agomelatine is a substrate of CYP1A2; the association between nicotine use and agomelatine dosage, however, has never been studied before. METHODS: Smoking habits were correlated with agomelatine doses and treatment outcomes in a sample of 27 patients with lifetime diagnoses within the schizophrenia spectrum who received agomelatine treatment in addition to their stable antipsychotic treatment regimen because of depressive symptoms. RESULTS: No interactions were found between smoking status and agomelatine dosage, and treatment outcomes did not differ between smokers and nonsmokers. DISCUSSION: Agomelatine efficacy appears to be independent of dosage and smoking status, pointing toward mechanisms beyond mere dose-response relationships. Further research will be necessary to validate these findings.

Correlation of Health-Related Quality of Life in Clinically Stable Outpatients with Schizophrenia.

BACKGROUND: Generic health-related quality of life (HRQoL) scales are increasingly being used to assess the effects of new treatments in schizophrenia. The objective of this study is to better understand the usefulness of generic and condition specific HRQoL scales in schizophrenia by analyzing their correlates. METHODS: Data formed part of the Pattern study, an international observational study among 1379 outpatients with schizophrenia. Patients were evaluated with the Mini International Neuropsychiatric Inventory, the Clinical Global Impression-Schizophrenia (CGI-SCH) Scale and the Positive and Negative Syndrome Scale (PANSS) and reported their HRQoL using the Schizophrenia Quality of Life Scale (SQLS), the Short Form-36 (SF-36), and the EuroQol-5 Dimension (EQ-5D). The two summary values of the SF-36 (the Mental Component Score and the Physical Component Score, SF-36 MCS and SF-36 PCS) were calculated. RESULTS: Higher PANSS positive dimension ratings were associated with worse HRQoL for the SQLS, EQ-5D VAS, SF-36 MCS, and SF-36 PCS. Higher PANSS negative dimension ratings were associated with worse HRQoL for the EQ-5D VAS, SF-36 MCS, and SF-36 PCS, but not for the SQLS or the EQ-5D tariff. PANSS depression ratings were associated with lower HRQoL in all the scales. There was a high correlation between the HRQoL scales. However, in patients with more severe cognitive/disorganized PANSS symptoms, the SQLS score was relatively higher than the EQ-5D tariff and SF-36 PCS scores. CONCLUSION: This study has shown substantial agreement between three HRQoL scales, being either generic or condition specific. This supports the use of generic HRQoL measures in schizophrenia. CLINICALTRIALSGOV IDENTIFIER: NCT01634542 (July 6, 2012, retrospectively registered).

Understanding the course of persistent symptoms in schizophrenia: Longitudinal findings from the pattern study.

The Pattern study was conducted to provide longitudinal observational data for individual patients with persistent symptoms of schizophrenia. Pattern is an international, multicenter, non-interventional, prospective cohort study of schizophrenia outpatients who were not considered to be in recovery. In the longitudinal phase reported herein, patients were assessed over 1 year using different clinical rating scales. Patient management followed routine local clinical practice. Primary outcome was disease state, defined by the Positive and Negative Syndrome Scale (PANSS), Negative Symptom Factor Score (NSFS), Positive Symptom Factor Score (PSFS), and Personal and Social Performance (PSP) Scale. In total, 1344 protocol-compliant patients (70.9% male) were included. Patients showed a high stability in disease state between consecutive study visits. Persistent negative persistent symptoms and symptomatic remission were the most prevalent and stable disease states. Patients in relapse generally transitioned to negative persistent symptoms or to symptomatic remission. PANSS, PSP, and quality of life ratings remained relatively stable. Relapses occurred in 10% of patients; probability of relapse was associated with younger age, extra-pyramidal symptoms, and more antipsychotic medications. Despite treatment, schizophrenia symptoms tend to remain stable over time, without overall improvement. One of the greatest challenges in schizophrenia is attainment of full symptom remission.