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Introduction The neural correlates of the cognitive dysfunction in first-episode psychosis (FEP) are still unclear. The present review and meta-analysis provide an update of the location of the abnormalities in the fMRI-measured brain response to cognitive processes in individuals with FEP. Methods Systematic review and voxel-based meta-analysis of cross-sectional fMRI studies comparing neural responses to cognitive tasks between individuals with FEP and healthy controls (HC) according to PRISMA guidelines. Results Twenty-six studies were included, comprising 598 individuals with FEP and 567 HC. Individual studies reported statistically significant hypoactivation in the dorsolateral prefrontal cortex (6 studies), frontal lobe (8 studies), cingulate (6 studies) and insula (5 studies). The meta-analysis showed statistically significant hypoactivation in the left anterior insula, precuneus and bilateral striatum. Conclusions While the studies tend to highlight frontal hypoactivation during cognitive tasks in FEP, our meta-analytic results show that the left precuneus and insula primarily display aberrant activation in FEP that may be associated with salience attribution to external stimuli and related to deficits in perception and regulation.

Although schizophrenia is associated with increased presynaptic dopamine function in the striatum, it remains unclear if neuromelanin levels, which are thought to serve as a biomarker for midbrain dopamine neuron function, are increased in patients with schizophrenia. We conducted a systematic review and meta-analysis of magnetic resonance imaging (MRI) and postmortem studies comparing neuromelanin (NM) levels between patients with schizophrenia and healthy controls (HCs). Standard mean differences were calculated to assess group differences in NM accumulation levels between patients with schizophrenia and HCs. This study included 7 articles in total. Five studies employed NM-sensitive MRI (NM-MRI) and two were postmortem brain studies. The patient group (n = 163) showed higher NM levels in the substantia nigra (SN) than HCs (n = 228) in both the analysis of the seven studies and the subgroup analysis of the 5 NM-MRI studies. This analysis suggest increased NM levels in the SN may be a potential biomarker for stratifying schizophrenia, warranting further research that accounts for the heterogeneity of this disorder.

Background: The drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a drug-induced hypersensitivity reaction. Aims: Aim was to review reports of clozapine-related reactions fulfilling the registry of severe cutaneous adverse reaction (RegiSCAR) criteria for DRESS syndrome reported as such or otherwise, to provide a descriptive overview of demographic patterns, clinical manifestations, and DRESS course and investigate associations between demographic, DRESS parameters, and clinical outcomes. Methods: This review was conducted following preferred reporting items for systematic reviews and meta-analyses guidelines and registered with PROSPERO (registration number CRD42020156385). We searched PubMed/Embase/PsychInfo/Cochrane for reports of clozapine-related reactions meeting RegiSCAR criteria. Associations between RegiSCAR scores and time-to-recovery with demographic/clinical variables were assessed. Demographic/clinical characteristics of patients with versus without reported DRESS were compared using non-parametrical tests. Results: We identified 26 reports of 27 patients meeting RegiSCAR criteria. Males ( n = 19, 70.4%) and patients with schizophrenia ( n = 18, 66.7%) were mainly affected. Twelve patients (44.4%) received clozapine-monotherapy. DRESS symptoms manifested within a month after clozapine initiation ( n = 24, 88.9%). Lungs and liver were the most common organs involved ( n = 12, 44.4%; n = 11, 40.7%), with a mean time to recovery of 33.75 days. Clozapine rechallenge led to DRESS recurrence in four patients. Death rate was 7.4%. No associations were detected between RegiSCAR criteria or days to recovery with any demographic/clinical variables. No differences between patients with versus without reported DRESS were detected. Conclusions: Clozapine-related DRESS may be rare, but also underreported. Clinicians need to be aware of it even in patients under clozapine-monotherapy or without skin rash.

Objective To quantify the risk and predictors of relapse among individuals with schizophrenia randomly withdrawn from antipsychotic maintenance treatment. Methods We re-analyzed time-to-event and baseline predictors from placebo arms in five placebo-controlled randomized trials of antipsychotics (n = 688 individuals; 173 stabilized on oral antipsychotic [OAP] and 515 on long-acting injectables [LAI]) for relapse-prevention available in the Yale Open Data Access repository. Using a survival and Cox-proportional hazards regression analyses, we estimated survival rates of “relapse-free” individuals by the end of follow-up (median = 118 days, IQR = 52.0–208.0), the rate of study-confirmed relapse, and adjusted hazard ratios (aHR, 95% confidence intervals [CI]) associated with baseline predictors. We also estimated these parameters for individuals followed for >5 half-lives of the stabilizing antipsychotic, and studied predictors of “rebound psychosis” in OAP-stabilized participants, defined as occurring within 30 days of antipsychotic withdrawal. Results 29.9% (95%CI = 23.2–38.5) remained relapse-free by the end of follow-up, 11.1% (95%CI = 5.65–21.9) among those OAP-stabilized, 36.4% (95%CI = 28.4–46.7) among those LAI-stabilized. The study-confirmed relapse rate was 45.2%, 62.4% among those OAP-stabilized and 39.4% among those LAI-stabilized. Predictors of relapse included smoking (aHR = 1.54, 95%CI = 1.19–2.00), female sex (aHR = 1.37, 95%CI = 1.08–1.79), and having been stabilized on OAPs vs LAIs (aHR = 3.56, 95%CI = 2.68–4.72). Greater risk of relapse on OAP persisted even after sufficient time had elapsed to clear antipsychotic plasma level among LAI-stabilized (aHR = 5.0, 95%CI = 3.5–7.1). “Rebound psychosis” did not show predictors. Conclusions and relevance Our results corroborate the high relapse risk following antipsychotic withdrawal after symptom stabilization with limited patient-related predictors of safe treatment discontinuation. Stabilization with LAIs reduces the short-/medium-term relapse risk.

Objective Clozapine is the only approved strategy for treatment-resistant schizophrenia, although it is highly underutilized. We aim to generate practical and actionable evidence-based recommendations for the use of this drug considering prescription barriers. Method Narrative review. Results A consistent body of evidence supports the efficacy of clozapine reducing morbidity and mortality in schizophrenia. The main obstacles to its use are the lack of experience by prescribers and perceived treatment burden. Systematic screening of eligibility, utilization of available resources for consultation, developing a professional network with other stakeholders, as well as optimizing how clozapine is presented to patients is discussed. Furthermore, specific evidence-based recommendations for initiation, maintenance, and safety monitoring with clozapine are provided. Conclusion Clozapine prescription is one of the areas in psychiatry with the greatest mismatch between efficacy and utilization in clinical practice. Although multiple barriers to the use of clozapine exist, some of these may be overcome by updates of routine clinical practice.

OBJECTIVE Neuroleptic malignant syndrome (NMS) is a potentially fatal, idiosyncratic reaction to antipsychotics. Due to low incidence of NMS, research on risk factors of mortality associated with NMS is limited. METHODS Two authors independently searched Medline/Embase/Cochrane/CINAHL/PsychINFO databases for case reports with author-defined NMS published in English until 05/30/2020. Demographic, clinical, treatment, and outcome data were independently extracted following PRISMA guidelines. NMS severity was rated using the Francis-Yacoub scale. Mortality risk factors were identified using a multivariable regression analysis including all characteristics that were significantly different between NMS cases resulting vs. not resulting in death. RESULTS 683 cases with NMS were analyzed (median age = 36 years, males = 62.1%). In a multivariable model, independent predictors of NMS mortality were lack of antipsychotic discontinuation (odds ratio (OR) = 4.39 95% confidence interval (CI) = 2.14-8.99; p < 0.0001), respiratory problems (OR = 3.54 95%CI = 1.71-7.32; p = 0.0004), severity of hyperthermia (Unit-OR = 1.30, 95%CI = 1.16-1.46; p < 0.0001), and older age (Unit-OR = 1.05, 95%CI = 1.02-1.07; p = 0.0014). Even in univariate, patient-level analyses, antipsychotic formulation was not related to death (oral antipsychotic (OAP): n = 39/554 (7.0%) vs. long-acting injectable (LAI): n = 13/129 (10.1%); p = 0.2413). Similarly, death with NMS was not related to antipsychotic class (first-generation antipsychotic: n = 38/433 (8.8%) vs. second-generation antipsychotic: n = 8/180 (4.4%); p = 0.0638). Non-antipsychotic co-treatments were not associated with NMS mortality. CONCLUSION Despite reliance on case reports, these findings indicate that presence of respiratory alterations, severity of hyperthermia, and older age should alert clinicians to a higher NMS mortality risk, and that antipsychotics should be stopped to reduce mortality, yet when NMS arises on LAIs, mortality is not increased vs. OAPs.

Schizophrenia often requires long-term treatment with antipsychotic medication. This study aims to measure the continuity of antipsychotic treatment over the course of illness in schizophrenia, as well as factors involved in the interruption of treatment. For this, we followed up a national cohort of first-episode psychosis patients in Finland for up to 18 years. Stratified Cox proportional hazards regressions were conducted for “within-participant” risk of discontinuation of subsequent treatments compared to the first, and by specific antipsychotic compared to oral olanzapine, the most prescribed antipsychotic in this cohort. Adjusted hazard ratios (aHRs) and 95% confidence intervals (95% CIs) were calculated. Among 3343 participants followed up for a mean of 8 years (SD = 4.93), the median number of continuous treatment episodes was 6 (interquartile range [IQR] = 3–11) with a median duration of 11.4 months (IQR = 5.3–25.6). In the first year after diagnosis, the incidence rate of treatment discontinuation was 30.12 (95% CI = 29.89–30.35) events per 100 participant-years, decreasing to 8.90 (95% CI = 8.75–9.05) in the 10th year. The risk of discontinuation progressively decreased over successive treatment episodes (aHR = 0.30; 95% CI = 0.20–0.46 for episodes after the 15th compared to the first). Individuals were 67% less likely to interrupt treatment with long-acting injectable than oral antipsychotics (aHR = 0.33; 95% CI = 0.27–0.41). Treatment for schizophrenia over the long term is often characterized by recurrent cycles of interruptions and reintroductions of antipsychotic medication, which is typically not recommended by management guidelines. Greater utilization of long-acting injectable formulations earlier in the course of illness may facilitate the continuity of antipsychotic treatment in schizophrenia.

Introduction Long-acting injectable antipsychotics (LAIs) are associated with multiple positive outcomes in psychosis, but it is unclear whether LAIs are associated with worse outcomes if neuroleptic malignant syndrome (NMS), a potentially lethal adverse effect, occurs. Methods We used nationwide and nationally representative databases of healthcare encounters in Finland to study the incidence and outcome predictors of NMS in patients diagnosed with schizophrenia/schizoaffective disorder between January 01, 1972 and December 31, 2017. Using a nested case-control design, we also explored differences by antipsychotic formulation (LAI vs oral antipsychotic [OAP]) and class (first-generation antipsychotic [FGA] vs second-generation antipsychotic [SGA]). Results One hundred seventy-two NMS cases and 1441 sex-, age-, and diagnosis-matched controls were included (age = 58.8 ± 13.1 years, males = 59.9%). Incidence of NMS was 1.99 (1.98–2.00) per 10 000 person-years. The likelihood of developing NMS did not differ by antipsychotic formulation (adjusted odds ratio [aOR]: 0.89, 95% confidence intervals [95% CI]: 0.59–1.33, for LAIs vs OAPs) or class (FGA-OAP vs SGA-OAP [aOR: 1.08, 95% CI: 0.66–1.76], FGA-LAI [aOR: 0.89, 95% CI: 0.52–1.53], SGA-LAI [aOR: 1.35, 95% CI: 0.58–3.12]). NMS risk factors included antipsychotic treatment change: increased number (odds ratios [OR]: 5.00, 95% CI: 2.56–9.73); decreased number/switch (OR: 2.43, 95% CI: 1.19–4.96); higher antipsychotic dose (>2DDDs–OR: 3.15, 95% CI: 1.61–6.18); co-treatment with anticholinergics (OR: 2.26, 95% CI: 1.57–3.24), lithium (OR: 2.16, 95% CI: 1.30–3.58), benzodiazepines (OR: 2.02, 95% CI: 1.44–3.58); and comorbid cardiovascular disease (OR: 1.73, 95% CI: 1.22–2.45). Within 30 days, 4.7% of cases with NMS died (15.1% within 1 year) without differences by antipsychotic formulation. NMS reoccurred in 5 of 119 subjects (4.2%), after a median = 795 (range = 77–839) days after rechallenge with antipsychotics. Conclusion NMS remains a potentially life-threatening risk, yet these results should further contribute to mitigate concerns about LAI safety regarding NMS onset or outcomes, including mortality.

Most individuals with psychotic disorders relapse over their course of illness, yet the neural processes that may lead to symptom worsening are poorly understood. Importantly, such processes could be potentially affected by antipsychotic adherence status upon relapse (i.e., relapse despite ongoing antipsychotic maintenance vs following antipsychotic discontinuation), reflecting distinct mechanisms. As a first foray into this question, we aim to compare the striatal connectivity index (SCI), a biomarker derived from striatal resting state functional connectivity predictive of treatment response, by adherence status upon relapse. In order to confirm adherence status upon relapse, we compared individuals treated with long-acting injectable antipsychotics upon relapse (i.e., breakthrough psychosis) (n = 23), with individuals who had decided to interrupt antipsychotic treatment and then relapsed (n = 27), as well as healthy controls (n = 26). We acquired for each individual >10 min of resting state fMRI, to generate functional connectivity maps. Region of interest (ROI) analyses were conducted to calculate SCI values for each participant. These values were entered as dependent variable in a linear regression adjusted for sex and age for which adherence status was the independent variable. Individuals in the breakthrough psychosis group had significantly lower SCI values than healthy controls (Cohen's d = 0.99, p < 0.001), and non-adherent individuals upon relapse (Cohen's d = 0.58, p = 0.032), whereas non-adherent individuals had also trend level lower SCI values than healthy controls (Cohen's d = 0.44, p = 0.09). These results suggest the hypothesis that striatal functional connectivity may be aberrant in psychosis relapse, and that this dysfunction may be greater among individuals who developed relapse despite ongoing antipsychotic treatment.

Background: Schizophrenia often requires long-term treatment with antipsychotic medication. This study aims to measure the continuity of antipsychotic treatment over the course of illness in schizophrenia, as well as factors involved in the interruption of treatment. Methods: Cohort study of individuals in Finland recently diagnosed with schizophrenia, and followed up between 2000 and 2018. Stratified Cox proportional hazards regressions were conducted for “within-participant” risk of discontinuation of subsequent treatments compared to the first, and by specific antipsychotic compared to oral olanzapine, the most commonly prescribed antipsychotic. Adjusted Hazards Ratios (aHR), 95% Confidence Intervals (95%CI) were calculated. Outcomes: Among 3,343 participants followed up for a mean of 8 years (Standard Deviation (SD)=4·93), the median number of continuous treatment episodes was 6 (Inter Quartile Range [IQR]=3-11) with a median duration of 11·4 months (IQR=5·3-25·6). In the first year after diagnosis, the incidence rate of treatment discontinuation was 30·12 (95%CI=29·89-30·35) events per 100 participant-years, decreasing to 8·90 (95%CI=8·75-9·05) in the tenth year. The risk of discontinuation progressively decreased over successive treatment episodes (aHR= 0·30; 95% CI=0·20-0·46 for episodes after the 15th compared to the 1st). Individuals were 67% less likely to interrupt treatment with long-acting injectable than oral antipsychotics (aHR=0·33; 95% CI=0·27-0·41). Interpretation: Treatment for schizophrenia over the long-term is often characterized by recurrent cycles of interruptions and reintroductions of antipsychotic medication, which is typically not recommended by management guidelines. Interventions in the early phase of illness and greater utilization of long-acting injectable formulations may facilitate the continuity of antipsychotic treatment in schizophrenia. Funding Statement: This study was funded with departmental support of the Zucker Hillside Hospital (Glen Oaks, NY), the Department of Clinical Neuroscience, Karolinska Institutet (Stockholm, Sweden), and the Academy of Finland (Grants: 315969, 320107, for HT). Declaration of Interests: Dr Rubio has been a consultant or has received speaker/consulting honoraria from: Lundbeck, Teva, Medscape. He has also received royalties from UpToDate, and grant support from Alkermes. Dr Taipale reports personal fees from Janssen-Cilag. Dr. Correll has been a consultant and/or advisor to or has received honoraria from: Acadia, Alkermes, Allergan, Angelini, Axsome, Gedeon Richter, Gerson Lehrman Group, IntraCellular Therapies, Janssen/JJ is a member of advisory board for Lundbeck, and has received grants from the Stanley Foundation and Sigrid Juselius Foundation. Dr. Tiihonen, Dr. Tanskanen and Dr. Taipale have participated in research projects funded by grants from Janssen-Cilag and Eli Lilly to their employing institution. Ethics Approval Statement: Permissions were granted by pertinent institutional authorities at the Finnish National Institute for Health and Welfare (permission THL/847/5.05.00/2015), the Social Insurance Institution of Finland (65/522/2015), and Statistics Finland (TK53-1042-15).

Coordinated specialty care (CSC) has become the standard of care for first-episode psychosis (FEP). The gap between CSC best practices and the actual care delivered is unknown. This longitudinal study aimed to measure that gap by using a large Medicaid claims database and 10 quality indicators (QIs) reflecting aspects of CSC and to study the relationship between these QIs and future health care utilization.Individuals with FEP were identified in a Missouri Medicaid claims database. Participants were required to have been eligible for Medicaid benefits for at least 10 months in the year prior to and the year after their first episode of psychosis and to have had no evidence of a prior psychosis diagnosis. Descriptive statistics were generated for each of the QIs, and a stratified Cox regression was used to identify predictors of subsequent health care utilization.Data were obtained for 6,246 participants, and follow-up lasted a mean of 4.24 years. Significant practice gaps were found in the use and monitoring of antipsychotic medications. Of those prescribed antipsychotic medication, 5% received prescriptions above recommended daily doses, 16% received two or more antipsychotics, and 20% were treated with olanzapine or clozapine. Among the QIs, lack of monitoring for smoking (hazard ratio [HR]=2.71, 95% confidence interval [CI]=2.47-2.97) and lack of integrated care delivery in treatment (HR=2.00, 95% CI=1.92-2.08) were most associated with psychiatric hospitalization.In most cases, treatment was far from meeting CSC recommendations, suggesting that implementation of CSC requires substantial modifications to delivery of care for individuals with FEP.

Most individuals with psychotic disorders relapse over their course of illness. Relapse pathophysiology is generally not well captured in studies that do not account for antipsychotic non-adherence, which is common and often unnoticed in schizophrenia. This study was explicitly designed to understand relapse in patients with guaranteed antipsychotic delivery. We compared individuals with psychosis breakthrough on antipsychotic maintenance medication (BAMM, n=23), for whom antipsychotic adherence prior to relapse was confirmed by using long acting injectable antipsychotics, and individuals who at the time of relapse were antipsychotic free (APF, n=27), as they had declared treatment non-adherence. Resting state functional MRI was acquired to conduct a region of interest (ROI) analyses. We generated functional connectivity maps to calculate striatal connectivity index (SCI) values, a prognostic biomarker of treatment response in first episode schizophrenia. Group differences in SCI values (BAMM vs APF) were compared in a linear regression model. We hypothesized that individuals in the BAMM group would have greater aberrant striatal function, thus lower SCI values, than in individuals in the APF group. Furthermore, we conducted exploratory group comparisons at the ROI level. As predicted, the BAMM group had significantly lower SCI values (ß=0.95, standard error=0.378, p=0.013). Group comparisons at the ROI level indicate differences in functional connectivity of dorsal striatum, and greater decoupling in striato-cerebellar connections among the BAMM group. A prognostic biomarker of treatment response in first episode psychosis showed differences by antipsychotic exposure upon relapse, suggesting that relapse during continued antipsychotic treatment may be characterized by aberrant striatal function.

The Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome is a severe, multiorganic, and potentially life-threatening drug-induced hypersensitivity reaction, linked to several common drugs, including antiepileptics, antibiotics, and several psychotropic drugs, including clozapine. Due to the importance of clozapine in the management of treatment-resistant schizophrenia, a systematic review and characterization of clozapine-related DRESS syndrome is long overdue.This systematic review was conducted following PRISMA guidelines. PubMed, Embase, PsychINFO, and the Cochrane Library databases were independently reviewed up to 1 November 2019 for articles reporting clozapine-related DRESS syndrome cases. The RegiSCAR score system was applied to systematically characterize the clinical presentations of selected studies.Clozapine-related DRESS syndrome was reported in six patients from four articles. Five patients received polypharmacy. Skin rash and liver involvement with elevated liver enzymes were very common. No fatal cases were found. Treatment mainly included clozapine discontinuation and immunosuppression. The mismatch between incidences of DRESS with other responsible drugs, the common misdiagnosis of this syndrome, and the fact that an extensive literature search only identified six cases suggests that clozapine-related DRESS may be overlooked. It is, therefore, necessary to optimize diagnostic strategies to identify immune-related side effects of clozapine.

Summary Background Most individuals with schizophrenia-spectrum disorders have relapses, which increase the risk of morbidity and mortality. Because non-adherence to antipsychotic maintenance treatment could affect more than half of individuals with schizophrenia-spectrum disorders, psychosis relapse can often be confounded by unnoticed treatment interruption. Research of relapse during confirmed antipsychotic exposure has basic clinical and neurobiological implications, but data are scarce. We aimed to generate reliable estimates of incidence and predictors of relapse during assured antipsychotic treatment. Methods We did a systematic review and individual participant data (IPD) meta-analysis of clinical trials of long-acting injectable antipsychotics (LAIs) for psychosis relapse-prevention, following IPD-PRISMA guidelines. Datasets were identified by searching relevant repositories from inception to Aug 1, 2019. Each LAI group was reanalysed as a separate cohort, further identifying subcohorts of individuals with and without prospectively determined symptom remission (PSR). Summary incidence rate of relapse, incidence rate ratios (IRRs) of relapse between individuals with and without PSR, hazard ratios (HRs) of covariates on risk of relapse, and standardised mean difference (SMDs) in changes in overall functioning associated with relapse were generated by pooling results from the harmonised reanalysis of each study. This study is registered with PROSPERO, number CRD42019137439. Findings 19 treatment cohorts consisting of 5130 individuals (2938 with PSR, 2192 without PSR), with 3959·53 observed participant-years, were meta-analysed. Pooled incidence of relapse was 22·97 per 100 participant-years (14·76 per 100 participant-years for the PSR subcohort, 31·51 per 100 participant-years for the non-PSR subcohort), with an IRR of 0·19 (95% CI 0·07 to 0·54). Relapse was associated with functional decline (overall SMD −0·76, 95% CI −1·14 to −0·37; PSR SMD −0·52, 95% CI −0·80 to −0·21; non-PSR SMD −0·72, 95% CI −1·18 to −0·26). The strongest predictor of relapse was tardive dyskinesia at treatment onset (HR 2·39, 95% CI 1·05 to 5·42). Interpretation Despite the established efficacy of antipsychotics in preventing relapse, these data indicate that these drugs might not prevent subsequent exacerbations for a proportion of individuals whose illness is stabilised on continuous antipsychotic treatment. Tardive dyskinesia in particular might have pathophysiological implications for relapse. Funding Northwell Health.

The long-term benefit-to-risk ratio of sustained antipsychotic treatment for schizophrenia has recently been questioned. In this paper, we critically examine the literature on the long-term efficacy and effectiveness of this treatment. We also review the evidence on the undesired effects, the impact on physical morbidity and mortality, as well as the neurobiological correlates of chronic exposure to antipsychotics. Finally, we summarize factors that affect the risk-benefit ratio. There is consistent evidence supporting the efficacy of antipsychotics in the short term and mid term following stabilization of acute psychotic symptoms. There is insufficient evidence supporting the notion that this effect changes in the long term. Most, but not all, of the long-term cohort studies find a decrease in efficacy during chronic treatment with antipsychotics. However, these results are inconclusive, given the extensive risk of bias, including increasing non-adherence. On the other hand, long-term studies based on national registries, which have lower risk of bias, find an advantage in terms of effectiveness during sustained antipsychotic treatment. Sustained antipsychotic treatment has been also consistently associated with lower mortality in people with schizophrenia compared to no antipsychotic treatment. Nevertheless, chronic antipsychotic use is associated with metabolic disturbance and tardive dyskinesia. The latter is the clearest undesired clinical consequence of brain functioning as a potential result of chronic antipsychotic exposure, likely from dopaminergic hypersensitivity, without otherwise clear evidence of other irreversible neurobiological changes. Adjunctive psychosocial interventions seem critical for achieving recovery. However, overall, the current literature does not support the safe reduction of antipsychotic dosages by 50% or more in stabilized individuals receiving adjunctive psychosocial interventions. In conclusion, the critical appraisal of the literature indicates that, although chronic antipsychotic use can be associated with undesirable neurologic and metabolic side effects, the evidence supporting its long-term efficacy and effectiveness, including impact on life expectancy, outweighs the evidence against this practice, overall indicating a favorable benefit-to-risk ratio. However, the finding that a minority of individuals diagnosed initially with schizophrenia appear to be relapse free for long periods, despite absence of sustained antipsychotic treatment, calls for further research on patient-level predictors of positive outcomes in people with an initial psychotic presentation.

Objective This systematic review and pooled, patient-level analysis of neuroleptic malignant syndrome (NMS) case reports and series compared NMS characteristics and outcomes during long-acting injectable antipsychotic (LAI) versus oral antipsychotic (OAP) treatment. Data sources Two authors independently searched MEDLINE, Embase, Cochrane, CINAHL, and PsycINFO databases for articles in English from database inception until October 9, 2018. Study selection Case reports with author-defined NMS during ongoing antipsychotic treatment or within 1 injection interval of LAIs in adults aged 18-65 years. Data extraction Demographic, clinical, treatment and outcome data were independently extracted following PRISMA guidelines. NMS severity was rated using the Francis-Yacoub scale. Characteristics and outcomes of NMS were compared when occurring during LAI versus OAP treatment, adjusting for significant between-group differences. Results Of 662 reported cases (median age = 36 years, male = 61.2%), 122 (18.4%) involved LAIs (second-generation antipsychotic [SGA] LAIs [SGA-LAIs] = 10, 1.5%), whereas 540 (81.6%) involved OAPs (SGA-OAPs = 159, 24.0%). The 2 groups did not differ in age, illness duration, comorbidities, or presence or severity of NMS symptoms (median Francis-Yacoub score: LAIs = 26 vs OAPs = 23, P = .8276). Antipsychotic formulation was not significantly associated with longer duration of hospitalization (LAIs = 5.0 weeks vs OAPs = 3.8 weeks, P = .8322), post-NMS sequelae (LAIs = 8.8% vs OAPs = 7.0%, P = .7489), or death (LAIs = 10.7% vs OAPs = 6.7%, P = .0861). When different, post hoc confounder-adjusted models were used, duration of NMS (but not hospitalization for NMS) was longer with LAIs than with OAPs (median = 2.6 vs 1.8 weeks, P = .0339), driven by FGAs rather than SGAs. Conclusions These data, plus the fact that only 10 published NMS cases exist with SGA-LAIs, should mitigate safety concerns regarding LAIs, but results should be interpreted cautiously since they are based on case reports.

Background: Most individuals with schizophrenia-spectrum disorders experience relapses, which increases the risk of morbidity and mortality. Since non-adherence with antipsychotic maintenance treatment may affect up to half of individuals, psychosis relapse can often be confounded by unnoticed treatment interruption. Research of relapse during confirmed antipsychotic exposure has basic clinical and neurobiological implications, yet data are limited. Methods: Systematic review and individual participant data meta-analysis (IPDMA) of clinical trials of long-acting injectable antipsychotics (LAIs) for psychosis relapse-prevention, following IPD-PRISMA guidelines. Datasets were identified by searching relevant repositories up to August/01/2019. Each LAI arm was re-analyzed as a separate cohort, further identifying sub-cohorts of individuals with and without prospectively determined symptom remission (PSR). Pooled incidence rates, incidence rate ratios (IRRs) and hazard ratios (HRs) were derived from within-cohort Poisson, Kaplan-Meyer and Cox regression analyses. Outcomes: Nineteen treatment cohorts (n=5,111), of which 2,938 had PSR, while 2,173 did not (non-PSR), with 3,959·53 actual observed participant years were meta-analyzed. Pooled incidence of relapse was 22·97 per 100 patient-years, being 14·76 per 100 patient-years for the PSR sub-cohort and 31·51 per 100 patient-years for the non-PSR sub-cohort (IRR=0·39, 95%CI=0.29-0·53). The strongest predictors of relapse were having tardive dyskinesia (HR=2·39, 95%CI=1·05-5·42) and comorbid substance use disorder (HR=1·55, 95%CI=1·15-2·10) at treatment onset. Predictors were similar between the PSR and non-PSR sub-cohorts, except for greater impact of substance use disorder in PSR (p

BackgroundThere is uncertainty about the incidence of breakthrough psychosis in treatment adherent patients, and the role that factors, such as cumulative antipsychotic exposure, play in this phenomenon.MethodsIn a nationwide cohort of individuals treated for schizophrenia-spectrum disorders in Finland between 1 January 1996 and 31 December 2015, ‘Breakthrough Psychosis on Antipsychotic Maintenance Medication’ (BAMM) was defined as hospitalization for psychosis despite ongoing continuous treatment with long-acting injectable antipsychotics (LAIs) or oral antipsychotics (OAPs) for ⩾8 weeks. Incidence rates, survival curves, and risk factors were presented.ResultsIn a cohort of 16 031 continuous LAI treatment episodes with virtually assured adherence [median duration = 441 days, interquartile range (IQR) = 155–1277], BAMM incidence was 31.5%. For 42 867 OAPs treatment episodes (median duration = 483 days, IQR = 167–1491), for whom adherence was modeled by the PRE2DUP method, BAMM incidence was 31.1%. Factors related to illness instability at treatment onset were associated with BAMM, although median time to BAMM was 291 days (IQR = 121–876) for LAIs and 344 days (IQR = 142–989) for OAPs, and 27.4% (N= 1386) of the BAMM events in the LAI, and 32.9% (N= 4378) in the OAP group occurred despite >1 year since last hospitalization at treatment onset. Cumulative antipsychotic exposure was not a consistent risk factor.ConclusionBAMM was relatively common even when adherence was confirmed with LAIs. Illness instability at treatment onset accounted for most cases, but relapse after years of continuous treatment was still prevalent. There was insufficient evidence to support causality between cumulative antipsychotic exposure and BAMM. Future research needs to address the role of symptom severity and neurobiology in BAMM.

Schizophrenia is a chronic disorder that often requires long-term relapse-prevention treatment. This treatment is effective for most individuals, yet approximately 20–30 % of them may still relapse despite confirmed adherence. Alternatively, for about 15 % it may be safe to discontinue medications over the long term, but since there are no means to identify who those individuals will be, the recommendation is that all individuals receive long-term relapse-prevention treatment with antipsychotic maintenance. Thus, the current approach to prevent relapse in schizophrenia may be suboptimal for over one third of individuals, either by being insufficient to protect against relapse, or by unnecessarily exposing them to medication side effects. There is great need to identify biomarkers of relapse in schizophrenia to stratify treatment according to the risk and develop therapeutics targeting its pathophysiology. In order to develop a line of research that meets those needs, it is necessary to create a framework by identifying the challenges to this type of study as well as potential areas for biomarker identification and development. In this manuscript we review the literature to create such a framework.

Background Most individuals with schizophrenia experience relapse over the course of the illness, yet unfortunately the mechanisms of this phenomenon are poorly understood. This research is often confounded by non-adherence with antipsychotic drugs. We propose to study relapse in individuals treated with long acting injectable antipsychotics (LAIs), for whom treatment adherence is confirmed. Since striatal resting state functional connectivity (RSFC) has been shown to reflect pathophysiological aspects of antipsychotic treatment response, we aim to study striatal RSFC in relapse in individuals treated with LAIs to identify potential mechanisms. In particular, we will compare striatal RSFC between individuals who relapse while treated with LAIs, individuals who are not on LAIs and are non-adherent with antipsychotics at the time of relapse, and healthy controls, to generate a hypothesis about the role of striatal functioning in psychosis relapse. Methods Subjects with a psychotic disorder treated with LAI antipsychotics and history of clinical response to that trial confirmed by collateral, presenting with acute psychotic symptoms at the time of the scan (defined as ≥4 in BPRS in at least one of the psychotic items) (n=16) were compared with subjects also with a psychotic disorder presenting with acute psychotic symptoms who were non-adherent with antipsychotic drugs demonstrated by negative plasma level (n=16), and healthy controls (n=18). Participants were scanned using fMRI and data was pre-processed using the HCP pipeline with the ICA-FIX procedure, removing motion artifacts and nuisance variables. Connectivity maps were generated for 6 bilateral (12 total) striatal regions of interest as in Di Martino et al. 2007, which were compared between groups (cluster threshold p< .05, voxel threshold p Results We found no significant differences in sex or age between any of the 2 patient groups or the healthy controls, nor of psychopathology between the patient groups. For patients treated with LAIs upon relapse, striatal RSFC was significantly lower in an area in posterior cingulate, whereas it was higher in an area in the middle temporal gyrus, inferior temporal gyrus, and precentral gyrus, compared with healthy controls. When the LAI-treated individuals’ striatal RSFC was compared with that of individuals who were non-adherent with antipsychotic drugs at the time of relapse, it was significantly higher in the posterior parietal cortex, whereas it was lower in the pulvinar (thalamus) and primary and associative cortex. The SCI values for individuals who relapsed despite assured antipsychotic exposure were significantly lower than for non-LAI individuals who had relapsed due to non-adherence (p=0.049), and than healthy controls (p=0.01). Discussion Despite a relatively small sample, these results indicate differences in striatal functional connectivity depending on antipsychotic exposure at the time of relapse. The finding of significantly lower SCI values for LAI treated individuals at the time of relapse compared with non-adherent individuals with relapse and healthy controls suggests the hypothesis that relapse occurring despite assured antipsychotic exposure may result from aberrant striatal functional connectivity which is insufficiently engaged by antipsychotic drugs.

Study Objective To compare operative and postoperative results of ovarian cortex retrieval by conventional laparoscopy (1cm umbilical site and 3 accessory 5-mm-reusable working ports) (HASS) versus single site laparoscopy (SSL). Design Prospective cohort study. Setting Fertility Preservation Programme at La Fe University Hospital-University of Valencia, Valencia, Spain, 2011 to 2012. Fertility Preservation Programme at La Fe University Hospital of Valencia, Valencia, Spain. Patients Twenty-one patients with cancer (breast cancer: n = 17; Hodgkin's lymphoma: n = 3; and non-Hodgkin's lymphoma: n = 1). Intervention Ovarian cortex retrieval either by conventional laparoscopy using an umbilical Hasson port and 3 accessory ports (HASS group: n = 11) or by SSL (SSL group: n = 10). Measurements and Main Results Operative length, blood loss, postoperative pain (visual analog scale for pain at 6, 24, and 48 hours), need of additional analgesia, quality of life (European Quality of Life-5 Dimensions), cosmesis of the scar, and patient's self-perception were assessed at 24 and 48 hours and 3 months after surgery. Baseline characteristics were similar between groups. Estimated blood loss, operative length, and postoperative pain did not differ between groups. The start of chemotherapy was not delayed in either group, and cosmesis and image self-perception were also similar. Conclusion The SSL approach can be considered a safe option compared with the classic multisite approach.

This study presents data on the association of intimate partner violence (IPV) perpetration and rates of psychiatric disorders, and other correlates. Data were drawn from Wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), a nationally representative sample of adults in the United States, 18 years and older, residing in households and group quarters. The sample comprised adults who reported being in a relationship within the past 12 months (N = 25,631). Of these, 1,677 individuals reported perpetrating IPV (4.2% in men, 7.0% in women). Compared to non-IPV perpetrators, IPV perpetrators had greater odds of having any psychiatric disorder, 42.0% and 67.7%, respectively, OR = 2.89, 95% CI [2.51, 3.32]. After adjusting for the effects of nuisance variables, being younger, having an alcohol use disorder, a personality disorder, low levels of social support, and low income were associated with perpetration. Across a wide range of factors, IPV victimization itself had the strongest association with perpetration, AOR = 66.12, 95% CI [55.01, 79.48]. Mental health assessments of IPV perpetrators might offer an opportunity to identify and treat psychiatric disorders and improve the clinical course of conditions that can be affected by ongoing acts of violence.

IMPORTANCE: Limited treatment responses in schizophrenia prompted the testing of combining an antipsychotic drug treatment with a second psychotropic medication. A comprehensive evaluation of the efficacy of multiple medication combinations is missing. OBJECTIVE: To summarize and compare the meta-analytically determined efficacy of pharmacologic combination strategies of antipsychotic drugs in adults with schizophrenia. DATA SOURCES: Systematic search of PubMed and PsycInfo until May 13, 2016. STUDY SELECTION: Meta-analyses of randomized clinical trials comparing the efficacy of antipsychotic drugs combined with other antipsychotic or nonantipsychotic medications vs placebos or antipsychotic monotherapy among adults with schizophrenia. DATA EXTRACTION AND SYNTHESIS: Independent reviewers extracted the data and assessed the quality of the methods of the included meta-analyses using A Measurement Tool to Assess Systematic Reviews (AMSTAR), adding 6 new items to rate their quality. Effect sizes, expressed as standardized mean difference /Hedges g or risk ratio, were compared separately for combinations with any antipsychotic drug and for combinations with clozapine. MAIN OUTCOMES AND MEASURES: The primary outcome was total symptom reduction. Secondary outcomes included positive and negative symptoms, treatment recommendations by authors, study-defined inefficacies, cognitive and depressive symptoms, discontinuation of treatment because of any cause, and inefficacies or intolerabilities. RESULTS: Of 3397 publications, 29 meta-analyses testing 42 combination strategies in 381 individual trials and among 19 833 participants were included. For total symptom reductions, 32 strategies that augmented any antipsychotic drug and 5 strategies that augmented clozapine were examined. Fourteen combination treatments outperformed controls (standard mean difference/Hedges g, −1.27 [95% CI, −2.35 to −0.19] to −0.23 [95% CI, −0.44 to −0.02]; P = .05). No combination strategies with clozapine outperformed controls. The quality of the methods of the meta-analyses was generally high (mean score, 9 of a maximum score of 11) but the quality of the meta-analyzed studies was low (mean score, 2.8 of a maximum score of 8). Treatment recommendations correlated with the effect size (correlation coefficient, 0.22; 95% CI, 0.35-0.10; P

Cross-sectional studies indicate that mental disorders are inversely associated with quality of life (QoL) and that the magnitude of the negative correlation varies across disorders. The aims of this study were to examine whether QoL decreases after new onset of psychiatric disorders and to characterize variations across disorders. Data were drawn from a longitudinal study representative of the adult US population. Changes were examined in QoL, as measured by the Short Form-12 version 2, after incidence of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), disorders at wave 2 in individuals without the given disorder at wave 1. A subanalysis examined change of QoL after incidence of mental disorders in individuals without a history of any mental disorder. With the exception of alcohol abuse, new incidence of each examined DSM-IV disorder was associated with a decrement in QoL, being the largest for major depressive disorder and generalized anxiety disorder. Incidence of these disorders was associated with a decrease in QoL even in individuals without history or presence of any other mental disorder. Although the incidence of most DSM-IV disorders is associated with a decrement in QoL, mood and anxiety disorders have the largest impact.

Anxiety disorders and major depressive disorder (MDD) are among the most common mental disorders in the United States,[1] with high individual and societal burden derived from their considerable associated work and social impairment.[2,3] Decreasing the burden of anxiety disorders and MDD is an important public health priority. Anxiety disorders often co-occur with each other and with MDD[4,5] suggesting the existence of a latent structure that may parsimoniously explain these patterns of comorbidity[6–9]. Several studies have examined the genetic liability of anxiety disorders and MDD, and consistently concluded that most of this genetic liability is exerted at the level of the latent variable,[8, 10–13] rather than at the disorder-specific level. Because anxiety disorders and MDD share a broad range of other risk factors,[14–24] an essential step in the development of more effective treatment and prevention interventions is to determine whether those factors exert their effect through the common latent variable, directly on each disorder, or through a combination of effects at both levels.[14, 16, 25] We sought tsreo address this gap in knowledge by drawing on data from a large, nationally representative survey to compare the common and the specific contribution of a set of observable risk factors to risk of anxiety disorders and MDD. We followed a conceptual model of risk factors, which was initially developed by Kendler and colleagues to examine the prevalence of MDD,[26, 27] but seems to be applicable to other internalizing disorders.[28] Because anxiety disorders often co-occur with each other and with MDD and seem to have a partially shared liability,[8, 13, 14] prior to our analyses, we hypothesized that the comorbidity structure of anxiety disorders and MDD would be well described by a single latent variable and that the risk factors postulated in Kendler’s model would exert part of their effect through this latent variable. However, because the prevalence and course of the different anxiety disorder and MDD does not fully overlap[29–31] and they also have nonshared variance, we also hypothesized that the risk factors would also partially exert their effect directly on the individual disorders.

BACKGROUND: Although antipsychotic drugs are highly efficacious in preventing psychosis relapse, (1) approximately 15% of treatment adherent patients relapse during the maintenance phase. (2) This phenomenon is known as “breakthrough psychosis on antipsychotic maintenance medication” (BAMM). (3) The biological mechanisms of psychotic relapse in treatment adherent individuals are poorly understood. Recent data from our own and other groups indicate that individuals with poor treatment response demonstrate greater striatal functional connectivity than those who respond to antipsychotic drugs, suggesting that failure to respond to antipsychotic drugs may be mediated through extra-striatal mechanisms. (4–6) The BAMM Study aims to generate data about the role of striatal function in individuals with psychosis who have a history of response to antipsychotics yet fail to maintain such response despite confirmed continuous treatment with long acting injectable (LAI) antipsychotics. METHODS: Subjects with a psychotic disorder treated with LAI antipsychotics and history of clinical response to antipsychotic medication and sustained response on LAI’s who presented with acute psychosis (BPRS≥4 in >1 psychotic items)(i.e., BAMM) were compared with subjects with a psychotic disorder and history of treatment response to antipsychotics who were treatment non-adherent and acutely psychotic (BPRS≥4 in >1 psychotic items)(i.e. Controls). Drug exposure for the BAMM group was confirmed by serum level and dates of LAI administration. We studied group differences in functional connectivity maps of striatal seeds as in Di Martino et al.(7). Data were preprocessed using the Human Connectome Project pipeline and cleaned with the ICA-FIX procedure, which removed motion artifacts and nuisance variables (white matter and CSF signal), but not global signal. Outputs from this procedure underwent band-pass filtering (0.1-0.01Hz). Time-series for each striatal seed were extracted and correlated with those of voxels in the whole brain. The resulting z-transformed maps for each subject were then used in the group analyses (voxelwise z=2.53, cluster threshold p=0.05). RESULTS: Subjects included in the BAMM group had a defined daily dose of 1.36 (ref=1), had been treated continuously >3 months and received the last LAI a mean of 11.19 days prior to the scan. BAMM (n=12)Controls (n=10) P Value Mean (SD)Mean (SD) Age37.3 (12.3)34.7 (11.2)0.62 Male sex (N,%) 4 (40%)4 (33.3%)1.0 Previous hospit 5.1 (2.7)3.1 (1.8)0.07 Duration of 12.4 (9.4) 9.2 (5.2) 0.37 illness (years) CGI4.8 (0.9)4.9 (0.6)0.87 BPRS total score45.5 (9.4)42.2 (5.9)0.36 PSx rating12.6 (3.4)15.4 (3.2)0.06 The BAMM group had significantly greater striatal functional connectivity than controls in the following regions: left dorsal caudate: postcentral gyrus (peak z=3.47) and precuneus (peak z=4.00); right dorso-rostral putamen: a region spanning orbitofrontal cortex, insula and inferior frontal gyrus (peak z=3.56); left superior ventral striatum: postcentral gyrus (peak z=4.25), supplementary motor cortex (peak z=3.72) and postcentral gyrus (peak z=3.70); and right superior ventral striatum: postcentral gyrus (peak z=3.73). DISCUSSION: The preliminary analyses of the first 22 participants indicate that relapse may have different mechanisms depending on whether or not it occurred despite antipsychotic exposure. These pilot data suggest the hypothesis that non-striatal mechanisms may be involved in the failure to maintain antipsychotic drug response. Longitudinal studies using extra-striatal seeds should be conducted to confirm this hypothesis. This research is relevant to better understand the mechanisms of relapse and treatment resistance.

Background Chronic major depressive disorder (CMDD) is highly prevalent and associated with high personal and societal cost. Identifying risk factors for persistence and remission of CMDD may help in developing more effective treatment and prevention interventions. Methods Prospective cohort study of individuals participating in the National Epidemiologic Survey on Alcohol and Related Conditions (Wave 1; n =43,093) and its 3-year follow-up (Wave 2; n =34,653) who met a diagnosis of CMDD at the Wave 1 assessment. Results Among the 504 respondents who met criteria for present CMDD at Wave 1, only 63 (11.52%) of them continued to meet criteria of CMDD. A history of childhood sexual abuse, earlier onset of MDD, presence of comorbidity and a history of treatment-seeking for depression predicted persistence of CMDD three years after the baseline evaluation. Limitations Our sample is limited to adults, our follow-up period was only three-years and the diagnosis of CMDD at baseline was retrospective. Conclusions CMDD shows high rates of remission within three years of baseline assessment, although some specific risk factors predict a persistent course. Given the high personal and societal cost associated with CMDD, there is a need to develop and disseminate effective interventions for CMDD.

Generalized anxiety disorder (GAD) and major depressive disorder (MDD) are highly prevalent, disabling conditions associated with considerable personal and societal burden.(1) Because MDD and GAD have high symptom overlap(2) and often co-occur,(3) there is considerable controversy regarding their separation as distinct diagnostic entities. Some studies and meta-analyses have suggested that MDD and several anxiety disorders have a modest familial aggregation and moderate levels of cross heritability,(4) but other studies have found mixed evidence for shared familial risk.(5) Other studies have found distinguishable patterns of comorbidity between GAD and MDD,(6) although whether co-occurrence of MDD and GAD has any influence on these differences is unknown. Several twin studies have also examined the relationship between MDD and GAD in large population samples.(7) The Virginia Adult Twin Study of Psychiatric and Substance Use Disorders (VATSPSUD) found that the correlation for environmental risk factors between MDD and GAD was 0.51, indicating that environmental risk factors for these disorders are moderately correlated. The VATSPSUD estimated the genetic correlation between MDD and GAD to be 1, indicating a very strong relationship between the genetic risk factors for both disorders.(7) Data from the Australian and Dutch Twins and Siblings Study also suggest considerable overlap in genetic risk factors for GAD and MDD,(8) and data from the Swedish Twin Registry(9) indicate that GAD and MDD share the same genetic factors but their environmental determinants are mostly distinct. Three large prospective epidemiological studies have also indicated that the developmental risk factors for GAD and MDD do not fully overlap,(10-12) suggesting that despite their similarities, the etiological pathways of these two disorders may differ. Application of latent variable techniques to three large community surveys in which psychiatric diagnoses were used as indicators have suggested that MDD and GAD may be part of an underlying factor named “anxious misery”,(13-16) but other studies have found divergent results.(17) In addition, a recent meta-analysis of the relationship between anxiety sensitivity and internalizing disorders found that anxiety sensitivity is more strongly correlated with agoraphobia, GAD and posttraumatic stress than with depression, raising new questions regarding the relationship between GAD and MDD.(18) The present study seeks to build on existing knowledge by examining data from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), a large, nationally representative sample of US adults. The specific goals of our study were: 1) to compare the sociodemographic characteristics and comorbidity patterns of individuals with GAD, MDD, and those with both disorders (GAD-MDD); and, 2) to determine the factor structure of the individual DSM-IV criteria for GAD and MDD.

Background Childhood and adolescence represent the periods during which hallucinatory experiences occur at the greatest prevalence, and also constitute a critical window of vulnerability for the pathogenesis of psychotic disorders. The longitudinal course of hallucinatory experiences during late childhood and adolescence, as well as their relationship to psychotic disorders, has never been the subject of review. Methods We followed the PRISMA guidelines for conducting systematic reviews and combined the use of electronic and manual systematic search methods. Data were extracted upon pre-defined requested items and were analyzed using several epidemiological measures. The interpretation of the results was conducted in relation to the study design variables. Results A total of 11 datasets (6 epidemiological and 5 clinical) were reviewed. The baseline prevalence of hallucinatory experiences ranged from 4.9% to 9%. Discontinuation occurred in between 58.7% and 94.5% of the cases, and person–year discontinuation rates ranged from 3% to 40.7% and appeared to be related to the duration of follow-up. Despite low person–year incidence rate, incident cases constituted between 27.7% and 83.3% of outcome samples. 2 of 3 studies showed evidence to predict transition to psychosis with likelihood ratios of 2.5 and 6.6. Conclusions Hallucinatory experiences are a common experience during childhood and adolescence. A review of the current literature suggests that there is a considerable turnover of incident-discontinuing cases and that most cases discontinue in the short term. A subset of the cases was at risk for persistence or transition to psychosis, probably related to indicators of severity of the hallucinatory experience.

Background: Burden related to major depressive disorder (MDD) derives mostly from long-term occurrence of symptoms. This study aims to examine the prevalence, sociodemographic correlates, patterns of 12-month and lifetime psychiatric comorbidity, lifetime risk factors, psychosocial functioning, and mental health service utilization of chronic major depressive disorder (CMDD) compared to nonchronic major depressive disorder. Methods: Face-to-face interviews were conducted in the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions (n = 43,093). Results: The 12-month and lifetime prevalence of CMDD within the population meeting criteria for MDD was 26.5% and 24.0%, respectively. Individuals reporting a chronic course of MDD were socioeconomically and educationally disadvantaged, tended to be older, report loss of spouse or history of divorce, live in rural areas, have public assistance, low self-esteem, worse overall health and more likely to report comorbidities, most importantly dysthymia, generalized anxiety disorder, avoidant, and dependant personality disorder. Individuals with chronic MDD were more likely to report familial but not childhood onset risk factors for MDD. Those suffering CMDD were more likely to seek and receive mental health care than other forms of MDD, even though it took longer to start treatment. Conclusion: Chronic course of MDD is related to still worse socioeconomic conditions, educational achievement, more comorbidities, and family risk factors, although other courses of MDD carried greater risk of unmet treatment. Depression and Anxiety, 2011. © 2011 Wiley-Liss, Inc. Language: en

Commentary on: Tiihonen J, Mittendorfer-Rutz E, Majak M, et al. Real-world effectiveness of antipsychotic treatments in a nationwide cohort of 29 823 patients with schizophrenia. JAMA Psychiatry 2017;74:686–693. It is essential to identify differences in efficacy and effectiveness between antipsychotic options to inform treatment decisions in schizophrenia. Presence or absence of superiority has recently been particularly controversial for clozapine and long-acting injectable antipsychotics (LAIs), triggered by contrasting positive, negative and inconsistent meta-analyses of randomised controlled trials (RCTs).1–4 These inconsistencies may have been largely the result of selection bias since patients enrolled in RCTs may have a less severe illness, more insight, greater adherence and an overall better prognosis.4 This selection bias may be particularly important for clozapine and LAIs, which may be most effective in treatment-resistant patients and those with greater likelihood of non-adherence-related poor outcomes. The authors conducted a cohort study of all the patients with a diagnosis of schizophrenia between 1 July 2006 and 31 December 2013 in Sweden, studying separately the cohort of patients who received a new diagnosis of schizophrenia during the study period.5 The intervention was the prescribed pharmacological treatment, obtained from …

Antipsychotics are the cornerstone of treatment for schizophrenia, but they have limited effectiveness, as most patients require subsequent strategies at some point of their treatment. Despite being widely used, the efficacy of pharmacologic augmentation of antipsychotics is controversial and no combination treatment has been approved for schizophrenia. We conducted a systematic review in PubMed and PsycInfo on June 1st 2015 and a random effects meta-analysis of meta-analyses of short-term, placebo-controlled studies of pharmacological augmentation strategies of antipsychotics in schizophrenia. Methodological quality of meta-analyses was measured using the AMSTAR, plus 6 additional items developed to rate the content quality of the meta-analyzed trials. Out of 3062 publications, we identified 36 eligible augmenting strategies. For total symptom reduction, 25 strategies augmenting antipsychotics and 5 strategies augmenting clozapine were eligible and examined. Eleven strategies were more efficacious than placebo, none of them augmenting clozapine. Significant effect sizes ranged between SMD −1.03 and −0.23. Efficacy was not correlated with the quality of the meta-analyses. Only the meta-analysis for NSAIDs augmentation had a score greater than half of the possible points for content quality. Only antipsychotics, azapirones, antidepressants and lithium were less discontinued than placebo. Serotonin-3-receptor antagonists, lamotrigine, mirtazapine/mianserine, minocycline and estrogens had large effect sizes augmenting antipsychotics. However the quality of the content of most meta-analyses was low. The NSAIDs augmentation meta-analysis had the best content quality, yet with a low effect size for efficacy. The evidence for short-term augmentation strategies of antipsychotics in schizophrenia is inconclusive, due to the limited quality of the available trials.Disclosure of interestThe authors have not supplied their declaration of competing interest.

FROM: Tiihonen J, Mittendorfer-Rutz E, Torniainen M et al. Mortality and cumulative exposure to antipsychotics, antidepressants, and benzodiazepines in patients with schizophrenia: an observational follow-up study. Am J Psychiatry 2016;173:600–6.[OpenUrl][1] Individuals with schizophrenia die ∼15–20 years prematurely compared to the general population, mostly due to cardiovascular disease, obesity-related cancer, diabetes and chronic obstructive pulmonary disease.1 Owing to the known metabolic effects of antipsychotics,2 clarifying their role in increased mortality is important. Paradoxically, prior studies in schizophrenia have suggested a relative decrement in mortality with moderate antipsychotic doses compared to no antipsychotic exposure. Cohort studies have indicated an elevated mortality risk with benzodiazepines in several populations, but adjustment for other treatment variables has been limited. A cohort of 21 492 individuals aged 17–65 years old who lived in Sweden in 2005 and who received treatment for schizophrenia prior to the beginning of 2006 was followed for 5 years. This cohort was derived from nationwide registers representing all contacts with healthcare in Sweden during the study period. The cumulative prescription of antipsychotics, benzodiazepines and … [1]: {openurl}?query=rft.jtitle%253DAm%2BJ%2BPsychiatry%26rft.volume%253D173%26rft.spage%253D600%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx

OBJECTIVE Although psychiatric disorders are associated with decreased health-related quality of life, it is unknown whether symptom remission is associated with its improvement or normalization. METHOD Data were derived from the National Epidemiologic Survey on Alcohol and Related Conditions, a large national sample of the United States population. A total of 34,653 adults 18 years and older residing in households completed 2 waves (2001-2002 and 2004-2005) of face-to-face surveys. DSM-IV psychiatric diagnoses of mood, anxiety, and substance use disorders were based on the Alcohol Use Disorder and Associated Disabilities Interview Schedule-DSM-IV Version. Health-related quality of life was assessed with the Short Form-12 Health Survey, Version 2 (SF-12). RESULTS Remission from alcohol dependence, major depressive disorder, bipolar disorder, dysthymia, social anxiety disorder, and generalized anxiety disorder was associated with significant improvement in SF-12 scores compared to nonremission (ranging from β = 7.28 in dysthymia to β = 3.16 in social anxiety disorder, all P < .05). However, with the exception of alcohol abuse, individuals who had remitted from all other disorders had lower SF-12 scores than individuals without lifetime history of the disorder. Furthermore, remission of alcohol abuse, cannabis use disorder, nicotine dependence, panic disorder, and specific phobia was not associated with significant improvement in SF-12 scores. CONCLUSIONS The relationship between psychiatric disorders and health-related quality of life is complex and differs across disorders. Although remission of several psychiatric disorders was associated with significant improvements, remission was generally not associated with full restoration of health-related quality of life, even among those without comorbid disorders.

THE TIMING OF ADMINISTRATION OF LETROZOLE SIGNIFICANTLYAFFECTS THE OOCYTE RECOVERY RATE IN BREAST CANCER PATIENTS UNDERGOING CONTROLLED OVARIAN STIMULATION FOR FERTILITY PRESERVATION. C. Diaz-Garcia, J. Domingo, A. Romero, M. Martinez, J. M. Rubio, J. A. Garcia-Velasco, A. Pellicer. Woman’s Health Area, La Fe University Hospital, Valencia, Spain; IVI-Las Palmas, Las Palmas de Gran Canaria, Spain; IVIMadrid,Madrid, Spain; La Fe University Hospital, Valencia, Spain; IVI-Valencia, Valencia, Spain.