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Background: Antipsychotic polypharmacy (APP) is frequently prescribed for schizophrenia-spectrum disorders. Despite the inconsistent findings on efficacy, APP may be beneficial for subgroups of psychotic patients. This meta-analysis of individual patient data investigated moderators of efficacy and tolerability of APP in adult patients with schizophrenia-spectrum disorders., Design: We searched PubMed, EMBASE, and the Cochrane Central Register of Randomized Trials until September 1, 2022, for randomized controlled trials comparing APP with antipsychotic monotherapy. We estimated the effects with a one-stage approach for patient-level moderators and a two-stage approach for study-level moderators, using (generalized) linear mixed-effects models. Primary outcome was treatment response, defined as a reduction of 25 % or more in the Positive and Negative Syndrome Scale (PANSS) score. Secondary outcomes were study discontinuation, and changes from baseline on the PANSS total score, its positive and negative symptom subscale scores, the Clinical Global Impressions Scale (CGI), and adverse effects., Results: We obtained individual patient data from 10 studies (602 patients; 31 % of all possible patients) and included 599 patients in our analysis. A higher baseline PANSS total score increased the chance of a response to APP (OR = 1.41, 95 % CI 1.02; 1.94, p = 0.037 per 10-point increase in baseline PANSS total), mainly driven by baseline positive symptoms. The same applied to changes on the PANSS positive symptom subscale and the CGI severity scale. Extrapyramidal side effects increased significantly where first and second-generation antipsychotics were co-prescribed. Study discontinuation was comparable between both treatment arms., Conclusions: APP was effective in severely psychotic patients with high baseline PANSS total scores and predominantly positive symptoms. This effect must be weighed against potential adverse effects., Competing Interests: Declaration of competing interest Dr. Anıl Yağcıoğlu has served as a speaker/advisory board member for Janssen, Abdi İbrahim Otsuka, Boehringer Ingelheim, Santa Farma, Nobel and has been an investigator for Janssen, Boehringer Ingelheim. Dr. Kasper served in the past 3 years as a consultant or on advisory boards for Angelini, Biogen, Boehringer, Esai, Janssen, IQVIA, Mylan, Recordati, Rovi, Sage and Schwabe; and he has served on speakers bureaus for Angelini, Aspen Farmaceutica S.A., Biogen, Janssen, Recordati, Schwabe, Servier, Sothema, and Sun Pharma. Dr. R.E. Nielsen has received funding for research or has been an investigator for H. Lundbeck, Otsuka Pharmaceuticals, Compass, Boehringer Ingelheim and Janssen-Cilag. Furthermore, REN has received speakers fee from Bristol-Meyers Squibb, Astra Zeneca, Janssen-Cilag, Lundbeck, Servier, Otsuka Pharmaceuticals, Teva and Eli Lilly. Dr. Remington has received research support from the Canadian Institutes of Health Research (CIHR), University of Toronto, and HLS Therapeutics Inc. Dr. Schmidt-Kaepelin is patent holder of patent No.: 102020106962, and has received speakers honoraria by Boehringer Ingelheim. Dr. Correll has been a consultant and/or advisor to or has received honoraria from: AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Biogen, Boehringer-Ingelheim, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Denovo, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Jamjoom Pharma, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Neurelis, Newron, Noven, Novo Nordisk, Otsuka, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Sage, Seqirus, SK Life Science, Sumitomo Pharma America, Sunovion, Sun Pharma, Supernus, Takeda, Teva, Tolmar, Vertex, and Viatris. He provided expert testimony for Janssen and Otsuka. He served on a Data Safety Monitoring Board for Compass Pathways, Denovo, Lundbeck, Relmada, Reviva, Rovi, Supernus, and Teva. He has received grant support from Janssen and Takeda. He received royalties from UpToDate and is also a stock option holder of Cardio Diagnostics, Kuleon Biosciences, LB Pharma, Mindpax, and Quantic. Lochmann van Bennekom, IntHout, Gijsman, Akdede, Barnes, Galling, Gueorguieva, Kreinin, J. Nielsen, Repo-Tiihonen, Shafti, Xiao and Verkes reported no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Extensive research has been undertaken to predict treatment response (TR) to antipsychotics. Most studies address TR to antipsychotics in general and as monotherapy, however, it is unknown whether patients might respond favourably to a combination of antipsychotics., Aims: This study aimed to identify differential predictors for TR to monotherapy with amisulpride or olanzapine compared to a combination of antipsychotics., Methods: Post-hoc analysis was conducted of data collected from the COMBINE-study, a double-blind, randomized, controlled trial. Demographic and disease-related measures were gathered at baseline to predict TR after eight weeks defined by the Positive and Negative Syndrome Scale. Missing values were accounted for by a random replacement procedure. Attrition effects and multicollinearity were analysed and sets of logistic regression models were calculated for different treatment groups., Results: Of the 321 randomized patients, 201 completed procedures until week eight and 197 were included in the analyses. For all treatment groups, early TR after two weeks and high subjective well-being under antipsychotics at baseline were robust predictors for TR. The propensity for early side effects also indicated a higher risk of later non-response. Specific parameter estimates were rather similar between treatment groups., Conclusion: Early TR, drug-related subjective well-being, and early side effect propensity evolved as predictors for later TR whether to monotherapy or combination strategy. Accordingly, due to a lack of differential predictors, early and close monitoring of targeted and unwanted effects is indicated to guide respective treatment decisions., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Hypothesis: Meta-analyses have shown that the majority of patients with schizophrenia who have not improved after 2 weeks of treatment with an antipsychotic drug are unlikely to fully respond later. We hypothesized that switching to another antipsychotic with a different receptor binding profile is an effective strategy in such a situation., Study Design: In total, 327 inpatients with an acute exacerbation of schizophrenia were randomized to double-blind treatment with either olanzapine (5-20 mg/day) or amisulpride (200-800 mg/day). Those patients who had not reached at least 25% Positive-and-Negative-Syndrome-Scale (PANSS) total score reduction from baseline after 2 weeks (the "non-improvers") were rerandomized double-blind to either staying on the same compound ("stayers") or to switching to the other antipsychotic ("switchers") for another 6 weeks. The primary outcome was the difference in the number of patients in symptomatic remission between the combined "switchers" and the "stayers" after 8 weeks of treatment, analyzed by logistic regression., Study Results: A total of 142 nonimprovers were rerandomized at week two. 25 (45.5 %) of the 'stayers' compared to 41 (68.3 %) of the "switchers" reached remission at endpoint (p = .006). Differences in secondary efficacy outcomes were not significant, except for the PANSS negative subscore and the Clinical-Global-Impression-Scale. "Switchers" and "stayers" did not differ in safety outcomes., Conclusions: Switching "non-improvers" from amisulpride to olanzapine or vice-versa increased remission rates and was safe. The superiority in the primary outcome was, however, not paralleled by significant differences in most secondary efficacy outcomes and the effect was only apparent at the last visit making replications of longer duration necessary., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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.

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., Competing Interests: Declaration of interests CUC has been a consultant and advisor to or has received honoraria from AbbVie, Acadia, Alkermes, Allergan, Angelini, Axsome, Gedeon Richter, IntraCellular Therapies, Janssen Pharmaceuticals, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Medscape, Merck, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Noven, Otsuka, Pfizer, Recordati, Rovi, Seqirus, Servier, Sumitomo Dainippon, Sunovion, Supernus, Takeda, Teva, and Viatris. He has provided expert testimony for Bristol-Myers Squibb, Janssen, and Otsuka. He served on a Data Safety Monitoring Board for Boehringer-Ingelheim, Lundbeck, Rovi, Supernus, and Teva. He received royalties from UpToDate and grant support from Janssen and Takeda. He is also a shareholder of LB Pharma. MK received honoraria from Roche, Servier, and Tromssdorff and a travel grant from Janssen Cilag. MZ received scientific grants from the German Research Foundation and Servier; and speaker and travel grants from Otsuka, Lundbeck, Roche, Recordati, Ferrer and Trommsdorff. BL received honoraria and speaker's fees from ANM, AstraZeneca, Autifony Therapeutics, Desyncra, Lundbeck, Merz, MagVenture, Neurolite, Neuromod, Novartis, Pfizer, and Servier; research funding from the Tinnitus Research Initiative, the German Research Foundation, the German Bundesministerium für Bildung und Forschung, the American Tinnitus Association, AstraZeneca, and cerbomed; funding for equipment from MagVenture and Deymed Diagnostic; and travel and accommodation payments from Eli Lilly, Lundbeck, Servier, and Pfizer. TBP has served as a consultant for Rovi and received travel compensation from AstraZeneca and Pfizer. GG has served as a consultant for Allergan, Boehringer Ingelheim, Institute for Quality and Efficiency in Health Care, Janssen-Cilag, Lundbeck, Otsuka, Recordati, ROVI, Sage, and Takeda. He has served on the speakers' bureau of Gedeon Richter, Janssen Cilag, Lundbeck, Otsuka, Recordati. He has received grant support from Boehringer Ingelheim, Lundbeck and Saladax. He is co-founder or shareholder, or both, of Mind and Brain Institute GmbH, Brainfoods GmbH, OVID Health Systems GmbH, and MIND Foundation gGmbH. AH was on the advisory board of Janssen-Cilag, Lunbeck, Roche, and Otsuka and has accepted paid speaking engagements for Janssen-Cilag, Lunbeck, and Otsuka. SL has received honoraria as a consultant or advisor, or for lectures, from Alkermes, Angelini, Eisai, Gedeon Richter, Janssen, Lundbeck, Lundbeck Institute, Merck Sharpp and Dome, Otsuka, Recordati, Rovi, Sanofi Aventis, TEVA, Medichem, and Mitshubishi. JC was a member of an advisory board of Roche; accepted travel or hospitality not related to a speaking engagement from Servier; received support for symposia from Inomed, Localite, Magventure, Roche, Mag & More, NeuroConn, Syneika, FBI Medizintechnik, Spitzer Arzneimittel and Diamedic; and was involved in research and participated in studies funded by the German Research Foundation and the German Bundesministerium für Bildung und Forschung, Foundation European Group for Research In Schizophrenia, ACADIA Pharmaceuticals, Boehringer Ingelheim Pharma GmbH KG, Otsuka Pharmaceutical Europe, and EnVivo Pharmaceuticals. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Antipsychotics are the cornerstone in the treatment of schizophrenia and are primarily recommended as monotherapy by evidence-based guidelines. Nevertheless, antipsychotic polypharmacy (APP) is prevalent in routine practice and APP is also used as a quality indicator since 2016 in quality management programs., Objective: Based on routine data of nine psychiatric hospitals of the Landschaftsverband Rheinland (LVR)/Germany the prevalence of APP was determined and correlated with factors of routine healthcare in order to monitor the adoption of APP and to discuss its feasibility as a quality indicator., Materials and Methods: All cases with schizophrenia (ICD-10 F20.x; ≥ 18 years) discharged between June 1st, 2016, and June 1st, 2017, (in-patient and day clinic) were extracted from an established research database shared by all nine hospitals and analyzed regarding APP prevalence at the time of discharge., Results: Based on 6,788 cases, the prevalence of APP was 55.5 % with an average of 2.4 antipsychotics (SD = 0.6) administered simultaneously. In multivariate analyses, significant predictors for APP were: gender (male > female), the number of days in hospital (long > short), involuntary treatment (no > yes) and the location of the hospital., Conclusions: We found a high proportion of polypharmacy in inpatient schizophrenia patients and significant differences between hospitals. The use of the results as a quality indicator (criteria ≥ 2 antipsychotics) remains dependent on the background of the individual treatment courses, which cannot be adequately represented by the existing routine data. The LVR has been using the quality indicator of ≥ 3 antipsychotics since 2018, which is discussed as a more appropriate approach for future evaluations., Competing Interests: Bei MB, JC, CE, SE, EGM, MG, CSK, MK, IL, EML, JM, RM, MR, SR, ATS und JV besteht kein Interessenkonflikt. NS hat für Tätigkeiten in Advisory Boards, Vortragstätigkeit, Erstellung von Manuskripten sowie Erstellung von Weiterbildungsmaterial Honorare von den Firmen AbbVie, Camurus, Hexal, Janssen-Cilag, Lundbeck, MSD, Medice, Mundipharma, Reckitt-Benckiser/Indivior und Sanofi-Aventis erhalten. Er hat in den letzten 3 Jahren an Medikamentenprüfungen teilgenommen, die von der pharmazeutischen Industrie finanziert wurden. JZ erhielt finanzielle Unterstützung der Deutschen Gesellschaft für Psychiatrie, Psychotherapie, Psychosomatik und Nervenheilkunde (DGPPN) zur Vorbereitung des DGPPN-Kongresses., (Thieme. All rights reserved.)

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.

Objective: It is well established that long-term hypothyroidism is associated with cognitive deficits. Based on recent literature, we hypothesized that pharmacologically induced euthyroidism would lead to improved cognitive performance compared to a hypothyroid state., Methods: We analyzed data from 14 nondepressed thyroidectomized female patients after differentiated thyroid carcinoma during hypothyroidism (due to a four-week withdrawal of thyroid hormone, T1) and euthyroidism brought about by substitution with L-thyroxine (T2). At both measurement points, patients completed a cognitive test battery as our dependent measure and Beck’s Depression Inventory to control depressive states., Results: A Wilcoxon signed-rank tests revealed a significant improvement in the Rey–Osterrieth complex figure test (cognitive reproduction), Z = −3.183, p = 0.001, and the D2 concentration score, Z = −1.992, p = 0.046 in euthyroidism compared to hypothyroidism., Conclusions: Our results confirm that hormone replacement therapy with L-thyroxine promotes cognitive reproduction and concentration in thyroidectomized female patients after differentiated thyroid carcinoma.

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.

Background: Psychotropic drugs are the cornerstone of schizophrenia treatment, often requiring lifelong treatment. Data on pharmacotherapy in inpatient settings are lacking., Methods: Prescription data of schizophrenic inpatients within the time period 2000-2015 were obtained from the database of the Drug Safety Program in Psychiatry (AMSP). Data were collected at 2 index dates per year; the prescription patterns and changes over time were analyzed., Results: Among 30 908 inpatients (mean age 41.6 years, 57.8% males), the drug classes administered most often were antipsychotics (94.8%), tranquilizers (32%), antidepressants (16.5%), antiparkinsonians (16%), anticonvulsants (14.1%), hypnotics (8.1%), and lithium (2.1%). The use of second-generation antipsychotics significantly increased from 62.8% in 2000 to 88.9% in 2015 (P < .001), whereas the prescription of first-generation antipsychotics decreased from 46.6% in 2000 to 24.7% in 2015 (P < .001). The administration of long-acting injectable antipsychotics decreased from 15.2% in 2000 to 11.7% in 2015 (P = .006). Clopazine was the most often used antipsychotic, having been used for 21.3% of all patients. Polypharmacy rates (≥5 drugs) increased from 19% in 2000 to 26.5% in 2015. Psychiatric polypharmacy (≥3 psychotropic drugs) was present in 44.7% of patients., Conclusions: Combinations of antipsychotics and augmentation therapies with other drug classes are frequently prescribed for schizophrenic patients. Though treatment resistance and unsatisfactory functional outcomes reflect clinical necessity, further prospective studies are needed on real-world prescription patterns in schizophrenia to evaluate the efficacy and safety of this common practice., (© The Author(s) 2019. Published by Oxford University Press on behalf of CINP.)

Purpose/background: The present study was conducted to investigate the difference in attitudes toward psychiatric drugs, long-term medication, and depot formulations between psychiatric patients and patient-related groups and the German general public., Methods/procedures: Different groups (n = 50 patients, n = 34 relatives of patients, n = 42 psychiatrists, n = 70 medical students, and n = 58 psychiatric nursing professionals) were surveyed using a questionnaire to investigate their attitude toward depot medication and compared with matched participants from the German general public., Findings/results: Patients did not differ from their matched controls regarding their attitude toward potential reasons to reject a depot, whereas psychiatrists (P = 0.002) and nursing staff (P = 0.003) were more concerned about patients fearing an injection than their matched controls., Implications/conclusions: Psychiatrists and psychiatric nurses were significantly more concerned about giving an (intragluteal) injection because of concerns about patients' fears of this administration method than their matched controls. In contrast, patients' concerns about receiving an injection did not differ from their matched controls. Furthermore, we found that psychiatrists tended to believe that giving an injection might be time-consuming than giving oral medication. These results may emphasize the fact that the low rate of depot medication use is derived from subjective reservations of medical staff rather than actual negative attitudes or fears of patients.

Background: Treatment of schizophrenia with depot medication has advantages compared with oral medication, and among these include an improved compliance. Despite such advantages, prescription rates in many European countries are lower than 20%. The aim of this survey was to study the attitudes toward depot medication among the German general population. To the best of our knowledge, only selective samples have been investigated up until now., Methods: A representative sample of 754 people were interviewed via telephone by a professional market research and polling organization. The questionnaire queried demographic characteristics, experience with medication, and the treatment of mental disorders. Subjects' attitudes toward medication in general, long-term medication, and depot medication were surveyed., Results: Most (66.7%) of the subjects stated that they would be willing to receive depot medication. Subjects who experienced the treatment of mental disorders were more likely to be willing to receive depot medication. Among the reasons for not using depot medication, "fear of injection" (66.3%) and "more self-control when taking medication as tablets" (48.9%) were stated as the most frequent reasons., Conclusions: This study found a good acceptance of antipsychotic depot medication among the German general population in terms of willingness to receive such treatment. We argue that the clinical practitioners' assumptions that depot formulations would be refused by many patients are unsubstantiated.

Objectives Polypharmacy in the treatment of severe psychiatric disorders may include promising treatment options, yet may also be subject to additional side effects and interactions. In patients with severe depression, the prevalence of antidepressive (AD) combination treatment has not been thoroughly assessed yet. Methods We assessed the prevalence of antidepressive combination treatment in a sample of hospital patients at the LVR-Clinic in Düsseldorf, Germany in 2012. Results 1.198 residential or semi-residential patients were diagnosed with severe depressive episode and were treated with at least one antidepressant. 25.1 % of those received a combination of at least two antidepressants. The most frequent combination approaches were tri- and tetracyclic AD with selective serotonin reuptake inhibitors (SSRI) yet various other combination approaches were observed. Conclusions Combination treatment is a common strategy. Future trends could be monitored via electronic prescription software, yet prospective confirmatory trials are needed to assess the rationale of different combination treatment approaches., Competing Interests: Interessenkonflikt: Die Autoren erklären, dass folgende wirtschaftliche oder persönliche Beziehungen bestehen: Christian Schmidt-Kraepelin und Eva Horstkötter: keine Interessenkonflikte; Jürgen Zielasek: Autorenhonorar für einen Reviewartikel durch die Firma Servier; Marina Otten: keine Interessenkonflikte; Joachim Cordes: Mitglied des Advisory Boards von Roche, Unterstützung Reisekosten für Vortragstätigkeit von Servier, Unterstützung der DGHP-Tagung durch Inomed, Localite, Magventure, Roche, Magalore, NeuroConn, Syneika, FBI Medizintechnik, Spitzer Arzneimittel, Diamedic., (© Georg Thieme Verlag KG Stuttgart · New York.)

Metabolic Syndrome (MetS) is one of the most common factors underlying the high rate of mortality observed in patients with schizophrenia. Recent research on this topic revealed that many of the patients studied were, in fact, in a medicated state. As such, it is unclear whether MetS is causally associated with the disorder itself or the medication used to treat it. In this study, patients with a clinically high risk of expressing first episode psychosis (CHR) were examined regarding the prevalence of MetS. N=144 unmedicated and antipsychotic-naïve CHR patients, aged between 18 and 42years and suffering from unmanifested prodromal symptoms, were compared with a cohort of N=3995 individuals from the "German Metabolic and Cardiovascular Risk Study" (GEMCAS). A slightly higher prevalence of individual MetS criteria was observed in the CHR group compared to the GEMCAS sample; specifically, the following were noted: a higher blood pressure (35.0% vs. 28.0%), increased waist circumference (17.6% vs. 15.1%), and increased fasting blood glucose (9.4% vs. 4.0%) in CHR patients. Additionally, the rate of reduced HDL cholesterol concentrations was lower in the control group (20.2% vs. 13.3%)., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objectives: This study was designed to investigate whether a preventive weight management program (WMP) reduces weight gain during olanzapine (OLZ) treatment. Moreover, we examined the effects of intervention on metabolic parameters., Methods: Patients (N = 100) with schizophrenia or schizoaffective disorder (DSM-IV) who had commenced treatment with OLZ were recruited. Following a run-in period of 4 weeks, 74 patients who had gained at least 1.5 kg body weight were randomized to receive either 12 bi-weekly WMP sessions (prevention group (PG), n = 36), or usual care (control group (CG), n = 38). Anthropometric and metabolic parameters were assessed after the 24-week intervention phase and a 24-week follow-up., Results: Forty-two percent of 74 participants (PG: 36.1%, CG: 47.4%) finished the 24-week intervention phase while 34% of them (PG: 30.6%, CG: 36.8%) completed the 48-week study. There was no significant difference in weight gain between groups (PG: + 3.4 ± 4.2 kg vs. CG: + 4.5 ± 6.1 kg, P = 0.184) after 24 weeks. Nevertheless, PG showed a significantly smaller increase in waist circumference than CG (PG: + 4.6 ± 8.3 cm, CG: + 10.1 ± 7.3 cm, P = 0.019) after 48 weeks. Furthermore, PG showed a significantly smaller increase in fasting glucose (P = 0.031) and 2-h glucose after oral glucose load (P = 0.018) than CG., Conclusions: These results suggest that preventive WMP may reduce the risk of abdominal obesity and deterioration of glucose metabolism in OLZ-treated patients.

Objectives: Although guidelines usually recommend monotherapy, in clinical practice, antipsychotic polypharmacy is common especially with chronically ill patients. We therefore assessed the current practice of antipsychotic polypharmacy in "high-utilising" patients with schizophrenia in Germany., Methods: Antipsychotic medication was assessed using a representative sample of 638 patients with schizophrenia from two multi-centre studies., Results: Antipsychotic combination treatment was administered to 43.9 % of the patients. Combination treatment not including clozapine was apparent in 36.2 %., Conclusions: Antipsychotic polypharmacy is prevalent in the treatment of patients with schizophrenia showing high service use also when excluding such combinations with clozapine. Differences between the study samples indicate possible influences linked with therapy resistance or treatment setting., (© Georg Thieme Verlag KG Stuttgart · New York.)

Central nervous system (CNS) monoamine deficits have been linked to a number of pathological conditions such as major depressive disorder. Individual biological variations in 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) might account for the variation in responses of neurotransmitter systems observed after the administration of clomipramine. The prolactin response to clomipramine has been widely used to assess CNS functioning. This open label study investigates the prolactin response induced by clomipramine in the plasma of healthy volunteers and whether it is related to changes in monoamine metabolites. The effects of clomipramine challenge on prolactin, 5-HIAA, HVA and MHPG were measured in 12 healthy volunteers. Samples were drawn directly before and 50 min after clomipramine infusion. A statistically significant increase in serum prolactin concentrations was measured in women 50 min after CMI infusion, but not in men. We found no significant increases in the serum monoamine metabolite concentrations 50 min after CMI infusion. Changes in HVA and 5-HIAA correlated statistically significantly and positively with the amount of prolactin release in the whole sample. Furthermore, positive correlations were found between ∆(50-0 min) 5-HIAA and ∆(50-0 min) HVA, although we did not find a correlation between ∆(50-0 min) prolactin and ∆(50-0 min) MHPG after clomipramine challenge. The pronounced prolactin release in healthy adult women might indicate a higher physiological sensitivity. Correlations between intra-individual changes in HVA, 5-HIAA and serum prolactin might indicate a central nervous effect of clomipramine on monoamine turnover. We conclude that monoamine changes in relation to prolactin response after clomipramine challenge may be suitable for characterizing the relationship between central serotonergic and dopaminergic function.

The aim of this project was to improve treatment processes and results in acutely ill inpatients within a network of nine psychiatric state hospitals of the Landschaftsverband Rheinland by introducing a benchmarking process. The project was based upon pre-existing measures of quality management. Patient groups were selected that were characterised by a severe clinical development or a high demand for mental health care services (alcohol abuse, depression of the elderly, schizophrenia). Room for improvement concerning specific hospitals and the overall hospital network were identified. The project was conducted with two patient cohorts before and after a quality-related intervention. Interventions were implemented for specific hospitals and the overall hospital network. Overall treatment documentations of 1,696 patients (1(st) cohort n=1,856, 2(nd) cohort n=1,696) were completed. Although there was no constant quantifiable statistically significant improvement of quality within the three patient groups (and certainly not with respect to the overall network), there was successful improvement of essential treatment processes for certain hospitals and the overall network under benchmarking. This was especially relevant where treatment recommendations were concerned. Future projects should focus on the conformance with treatment guidelines by defining both structural and process measures as a starting point and evaluation criterion., (Copyright © 2011. Published by Elsevier GmbH.)

The goal of this study was to prevent rehospitalizations and thus to optimize satisfaction with treatment and quality of life in patients suffering by schizophrenia or schizoaffective disorder. A complex intervention with improved cooperation between in- and outpatient services was applied to 46 "high utilizing" patients after discharge from inpatient care during an intervention phase of 6 months. The study was controlled by a matched group of 47 patients receiving treatment as usual. The intervention was based on a computerized decision support module. Eight psychiatrists in private practices were supplied with this software to obtain guideline-based recommendations according to current psychopathology and clinical state. Suggested complex interventions by the software included psychoeducation, social competence group therapy, integrated psychological therapy, computer-based cognitive training, coping skills training, sociotherapy, nursing care, home visits, social-worker care, assistance to family members, and the use of an emergency call-in line. A local hospital project team arranged specifically suggested interventions. We intended to accomplish a reduction of rehospitalization rates by 50% in the intervention group within a 12-month follow-up phase. Satisfaction with treatment, subjective quality of life, and treatment costs in terms of daily inpatient costs were compared between both groups. Moderator variables such as socio-demographical aspects or influences of certain interventions to rehospitalization rate were analyzed. The sample included patients more seriously ill than originally expected. Subjects in the control group (CG) were older (46 years) than those subjects in the intervention group (IG) (40 years). Other sociodemographical aspects (sex, family status, level of education, and number of former hospitalizations) showed no differences between both groups. The rehospitalization rate and the mean length of inpatient treatment were reduced to nearly 50% in the intervention group. The rate of readmissions increased in the control group, leading to a difference of 23% between both groups. The most important factor to favorably influence rehospitalization rates was the participation in coping skills training. There was an increase in patient satisfaction with treatment, while the subjective quality of life remained constant. Since these improvements were accomplished with lower costs (in terms of inpatient care), cost effectiveness was higher in the IG than in the CG. The most important single factor to favorably influence rehospitalization rates was the participation in coping skills training. Only the guideline consistent complex therapies as common intervention caused the significant overall result. Thereby, satisfaction with treatment increased considerably during the 6 months of intervention and remained constant during 12 months of follow up. The model project described is an important step to gain evidence and experience with integrated care for patients with schizophrenia.

Schizophrenic patients present deficits in executive control functions. The Stroop test requires executive control functions, in particular response inhibition. So far only one study has employed the high temporal resolution of electrophysiological methods to investigate the neural correlates of the Stroop effect in schizophrenia. This study investigated medicated patients with schizophrenia or schizoaffective disorder (n=15) and healthy controls (n=15) using event-related potentials. The analyses of the P1 and N1 components revealed no differences between the groups indicating intact sensory processing in schizophrenia during the Stroop test. We found greater negativity in the incongruent as compared to the congruent and neutral conditions between 350 and 450 ms over prefrontal scalp areas in healthy subjects but not in schizophrenic patients. Later on, a sustained positivity was observed over parietal scalp regions in healthy subjects. This later sustained potential was attenuated in patients but only in the first block. This suggests that following practice patients show similar parietal effects as healthy subjects. The total errors in the incongruent condition in patients correlated negatively with the difference in mean activity between incongruent and congruent conditions over the left parietal area (time window 600-1000 ms). In other words the more errors were made by patients, the more attenuated was the Stroop related electrophysiological effect. This suggests that the parietal activity is related to successful resolution of the Stroop conflict in schizophrenic patients. Furthermore, the absence of the frontal deflection in patients reflects dysfunctional neural processes associated with executive control.