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Competing Interests: W. Honer has received consulting fees or sat on paid advisory boards for the Canadian Agency for Drugs and Technology in Health, AlphaSights, Guidepoint, In Silico, Translational Life Sciences, Otsuka, Lundbeck and Newron. S. Clark has recieved an investigator-initated grant, participated in an advisory and an educational board and recieved speakers fees from Lundbeck-Otsuka Australia and received an investigator-initiated grant from Janssen-Cilag Australia. He has received speakers fees from Servier Australia. C. 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/J&J, LB Pharma, Lundbeck, MedAvante-ProPhase, Medscape, Neurocrine, Noven, Otsuka, Pfizer, Recordati, Rovi, Sumitomo Dainippon, Sunovion, Supernus, Takeda and Teva. He has provided expert testimony for Janssen and Otsuka. He served on a data safety monitoring board for Lundbeck, Rovi, Supernus and Teva. He has received grant support from the Berlin Institute of health, Janssen, the National Institute of Mental Health, Patient Centered Outcomes Research Institute, Takeda and the Thrasher Foundation. He has received royalties from UpToDate and is a stock option holder of LB Pharma. A. Hasan has been on the advisory boards and has received speaker fees from Janssen, Lundbeck and Otsuka. O. Howes reports receiving speaker fees, participating on advisory boards, and/or receiving investigator-initiated funding from manufacturers of antipsychotics, including clozapine. J. Kane declares consulting fees/honoraria from Acadia, Alkermes, Allergan, Eli Lilly, Forum, Genentech, Dainippon Sumitomo, H. Lundbeck, Intracellular Therapies, Janssen Pharmaceutical, Jazz Pharma, Johnson & Johnson, LB Pharmaceuticals, Merck, Minerva, Neurocrine, Otsuka, Pierre Fabre, Reviva, Roche, Sunovion, Takeda and Teva, as well as grant support from Otsuka, Lundbeck and Janssen. He is also a shareholder in Vanguard Research Group and LB Pharmaceuticals, Inc. D. Kelly has served as a consultant for Lundbeck, HLS Therapeutics and Alkermes, and is a joint holder of a patent for analytical microdevices for mental health treatment monitoring (US9581536B2). J. MacCabe has received research grants from, and acted as an unpaid consultant to Lundbeck and Saladax Biomedical. D. Taylor has received research funding from Janssen and Sunovion and lecture payments form Janssen, Lundbeck, Otsuka and Recordati. O. Freudenreich has received a grant from Avanir for a clinical trial involving patients taking clozapine and royalties from UpToDate for the entry on clozapine. No other authors declared competing interests.

Competing Interests: W. Honer has received consulting fees or sat on paid advisory boards for the Canadian Agency for Drugs and Technology in Health, AlphaSights, Guidepoint, In Silico, Translational Life Sciences, Otsuka, Lundbeck and Newron. S. Clark has recieved an investigator-initated grant, participated in an advisory andan educational board and recieved speakers fees from Lundbeck-OtsukaAustralia and received an investigator-initiated grant fromJanssen-CilagAustralia. He has received speakers fees from ServierAustralia. C. Correll has been a consultant and/or advisor to or hasreceived honoraria from Acadia, Alkermes, Allergan, Angelini, Axsome,Gedeon Richter, Gerson Lehrman Group, IntraCellularTherapies,Janssen/J&J, LB Pharma, Lundbeck, MedAvante-ProPhase,Medscape, Neurocrine, Noven, Otsuka, Pfizer, Recordati, Rovi,SumitomoDainippon, Sunovion, Supernus, Takeda and Teva. Hehas provided expert testimony for Janssen and Otsuka. He served ona data safety monitoring board for Lundbeck, Rovi, Supernus andTeva. He has received grant support from the Berlin Institute ofhealth, Janssen, the National Institute of Mental Health, Patient CenteredOutcomes Research Institute, Takeda and the Thrasher Foundation.He has received royalties from UpToDate and is a stock optionholder of LB Pharma. A. Hasan has been on the advisory boardsand has received speaker fees from Janssen, Lundbeck and Otsuka.O. Howes reports receiving speaker fees, participating on advisoryboards, and/or receiving investigator-initiated funding from manufacturersof antipsychotics, including clozapine. J. Kane declares consultingfees/honoraria from Acadia, Alkermes, Allergan, Eli Lilly,Forum, Genentech, Dainippon Sumitomo, H. Lundbeck, IntracellularTherapies, Janssen Pharmaceutical, Jazz Pharma, Johnson & Johnson,LB Pharmaceuticals, Merck, Minerva, Neurocrine, Otsuka, PierreFabre, Reviva, Roche, Sunovion, Takeda and Teva, as well as grantsupport from Otsuka, Lundbeck and Janssen. He is also a shareholderin Vanguard Research Group and LB Pharmaceuticals, Inc.D. Kelly has served as a consultant for Lundbeck, HLS Therapeuticsand Alkermes, and is a joint holder of a patent for analytical microdevicesfor mental health treatment monitoring (US9581536B2).J. MacCabe has received research grants from, and acted as an unpaidconsultant to Lundbeck and Saladax Biomedical. D. Taylor has receivedresearchfunding from Janssen and Sunovion and lecture paymentsform Janssen, Lundbeck, Otsuka and Recordati. O. Freudenreich hasreceived a grant from Avanir for a clinical trial involving patientstaking clozapine and royalties from UpToDate for the entry on clozapine.No other authors declared competing interests.

Objectives: To explore the impact upon estimation of drug effect as a result of applying exclusion criteria in randomized-controlled trials (RCT) measuring the efficacy of antipsychotics (AP) in schizophrenia., Methods: Three characteristics which may act as effect-modifiers of AP, while also common exclusion criteria in RCTs, were identified through literature review: schizophrenia duration, substance use disorder and poor adherence. The SOHO cohort was used to estimate the effect of initiating antipsychotic drugs "A", "B" or "C" (pooled) upon symptom evolution at 3months from baseline (CGI-S scale). "Estimated effectiveness" and "estimated efficacy" were drawn from the "SOHO" and "RCT-like" (patients with none of the above-listed exclusion criteria) samples, respectively. Effect-modification and impact of each exclusion criterion on AP effect estimates were explored using non-adjusted statistics., Results: The "SOHO sample" included 8250 patients initiating drug A, B or C at baseline, whose AP "estimated effectiveness" was ΔCGI-S=-0.78 (95% CI=-0.80, -0.76). The "RCT-like" sub-sample included 5348 (65%) patients whose AP "estimated efficacy" was ΔCGI-S=-0.73 (95% CI=-0.75, -0.70). Patients with short illness duration (≤3years since first AP; n=2436) experienced significant symptom improvement (ΔCGI-S=-0.89; 95%CI=-0.93, -0.85) compared to patients with duration >3years (mean ΔCGI-S=-0.73; 95%CI=-0.76, -0.71). Excluding patients with short illness duration led to a change in AP effect estimates but this was not the case for substance use disorder or poor adherence., Conclusion: Using certain exclusion criteria in RCTs may impact the drug's effect estimate, particularly when exclusion criteria are AP effect-modifiers representing frequent characteristics among patients with schizophrenia., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Purpose: A case study was conducted, exploring methods to identify drugs effects modifiers, at a health care center level., Patients and Methods: Data were drawn from the Schizophrenia Outpatient Health Outcome cohort, including hierarchical information on 6641 patients, recruited from 899 health care centers from across ten European countries. Center-level characteristics included the following: psychiatrist's gender, age, length of practice experience, practice setting and type, countries' Healthcare System Efficiency score, and psychiatrist density in the country. Mixed multivariable linear regression models were used: 1) to estimate antipsychotic drugs' effectiveness (defined as the association between patients' outcome at 3 months - dependent variable, continuous - and antipsychotic drug initiation at baseline - drug A vs other antipsychotic drug); 2) to estimate the similarity between clustered data (using the intra-cluster correlation coefficient); and 3) to explore antipsychotic drug effects modification by center-related characteristics (using the addition of an interaction term)., Results: About 23% of the variance found for patients' outcome was explained by unmeasured confounding at a center level. Psychiatrists' practice experience was found to be associated with patient outcomes ( p =0.04) and modified the relative effect of "drug A" ( p <0.001), independent of center- or patient-related characteristics., Conclusion: Mixed models may be useful to explore how center-related characteristics modify drugs' effect estimates, but require numerous assumptions., Competing Interests: Disclosure Lucien Abenhaim is the chairman of LASER Analytica, and Clementine Nordon has been employed by LASER Analytica, a research and consultancy company collaborating with virtually all pharmaceutical companies. LASER has no commercial interests in any of the products studied. Members of the LASER network have no interest in a drug or other factors studied. Josef Maria Haro works at the Sant Joan de Déu Health Park in Barcelona, Spain. Mark Belger is an employee of Eli Lilly and Company Limited. Helene Verdoux is a clinician at Bordeaux University Hospital. Constance Battin and Tjeerd van Staa report no conflicts of interest in this work.

To explore whether prenatal exposure to diethylstilbestrol (DES) is associated with increased risk of poor psychological outcome independently of the occurrence of major somatic complications related to DES exposure. Data on health outcome were collected in women prenatally exposed to DES (n = 2566) and unexposed women (n = 2967) recruited in a French national survey. Women prenatally exposed to DES were 1.7 times more likely to have consulted a mental health specialist compared to unexposed women (adjusted odds ratio = 1.69, 95% confidence interval 1.47-1.96), independently of demographic characteristics, poor gynecological or obstetrical outcome, or history of cancer. Frequency of consultation with a mental health specialist in persons with a history of gynecological complications or cancer was comparable in women prenatally exposed to DES and unexposed women. Findings regarding psychological outcome obtained in the high-risk group of women prenatally exposed to DES may contribute to improving identification of psychological needs of all women presenting with gynecological abnormalities.

Background: The relationship between depression and heart failure is neither coincidental nor trivial, since depression is a powerful predictor of re-hospitalization and mortality. We prospectively studied the prevalence and impact of depression on the clinical outcomes of patients attending for cardiac resynchronization therapy (CRT). We specifically examined whether patients with depression have a different rate of response to CRT and whether CRT has an effect on depressive symptoms., Methods: Sixty-eight recipients of CRT systems were included. The depressive status was evaluated before implant and after 6 months by a structured diagnostic interview measuring Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria of major depression and by a self-report questionnaire (Center for Epidemiological Studies Depression Scale, CES-D). The CRT response was assessed at 6 months by a clinical composite score., Results: At inclusion, DSM-IV criteria of major depression were identified in 41% of the population, while using the self-report questionnaire 65% were observed to have mild to major depressive symptoms (CES-D ≥ 16). Only 4 patients were taking antidepressants. At 6 months, 75% were considered responders to CRT. Response to CRT did not differ between those with and without depression at baseline. The rate of patients with depression at 6 months was significantly lower in responders to CRT compared with nonresponders., Conclusions: We found a high prevalence of depressive symptoms in patients receiving CRT systems. Patients with depression should not be excluded from CRT, because they demonstrate a similar rate of response than the persons without depression and the responders are less likely to be depressed at 6 months., (© 2012 Wiley Periodicals, Inc.)

Objective: The primary aim of this study was to compare the impact of risperidone long-acting injectable (R-LAI) to other antipsychotics on rates of hospitalisation in real-life settings., Method: The Cohort for the General study of Schizophrenia (CGS) followed 1859 patients diagnosed with schizophrenia (DSM-IV) from 177 psychiatric wards of public and private hospitals across France over a mean period of 12months. These patients were ambulatory or had been hospitalised for less than 93days at study entry. Recruitment was stratified for long-acting second-generation antipsychotic use. A multivariate Poisson regression adjusted for confounding with propensity scores and allowing for autocorrelation was used for the calculation of relative rates of hospitalisation with 95% confidence intervals., Results: The mean age of participants was 37.65years, 68.3% were male and 36.7% were hospitalised for less than 93days at study entry. Altogether, participants accumulated 796 hospital stays (53.4 per 100 person-years). R-LAI patients were slightly younger and had been hospitalised more often in the past 12months compared to non-R-LAI users. The adjusted Poisson regression analysis showed R-LAI use to be associated with a lower rate of future hospitalisation: 0.66 [0.46-0.96] compared to non-R-LAI use, and 0.53 [0.32-0.88] compared to use of other LAIs., Conclusion: Use of R-LAI was associated with lower rates of hospitalisation compared to non-use of R-LAI., (Copyright © 2011. Published by Elsevier B.V.)

Objective: The authors investigated the association between death of older people and use of psychotropic drugs before and during the Western European August 2003 heatwave., Method: A retrospective population-based case-control study was conducted using the French social security insurance national database. Exposure to psychotropic drugs in cases aged 70-100 years who died before (N = 2,093) and during (N = 9,531) the August 2003 heatwave was compared with those of survivors matched for age, gender, and presence of chronic illness, by using conditional logistic regressions., Results: The association between death and psychotropic drug use was modified by level of external temperature (Wald chi(2) = 13.1, degree of freedom = 1, p <0.001). Use of any psychotropic drug was associated with a 30% increased risk of death during the heatwave, with a significant dose-response relationship between the number of psychotropic drugs and the risk of death (adjusted odds ratio [aOR] for linear trend 1.25, 95% confidence interval [95% CI]: 1.21-1.29). During the heatwave, therapeutic classes independently associated with an increased risk of death were antidepressants (aOR 1.71, 95% CI: 1.57-1.86) and antipsychotics (aOR 2.09, 95% CI: 1.89-2.35), whereas exposure to anxiolytics/hypnotics use (aOR 0.85, 0.79-0.91) was associated with a decreased risk. Findings remained unchanged after adjustment on cardiotropic, antidementia, or anti-parkinsonian drug use., Conclusion: Our findings suggest that a causal relationship may exist between psychotropic drug use during a heatwave and increased risk of death in older people. The risk/benefit ratio of antidepressant and antipsychotic drugs should be carefully assessed in older people during a heatwave.

Background: As a large number of persons are exposed to prescribed psychotropic drugs, their utilisation and impact should be further explored at the population level., Aims: To illustrate the interest of pharmacoepidemiological studies of psychotropic drugs by selected examples of major public health issues., Method: Selective review of the literature., Results: Many questions remain unsolved regarding the behavioural teratogenicity of prenatal exposure to psychotropic drugs, the impact of their increasing use in children, the long-term cognitive consequences of exposure to benzodiazepines, and the risks associated with extension of indications of antipsychotic drugs., Conclusion: Pharmacoepidemiological studies need to be further developed owing to the large number of public health questions raised by the extensive and expanding use of psychotropic drugs.

Background: The quality of the relationship between patient and therapist can be considered a cornerstone of psychiatric practice. Nonadherence is one of the leading problems affecting antipsychotic effectiveness in schizophrenic patients and represents a poor prognostic factor for schizophrenia. Among the factors influencing adherence, the clinician's style of communication and the therapeutic relationship (TR) are recognized as key points. The measures of TR have been broadly explored in psychotherapy process but have received little attention in the treatment of severe mental illness in the context of routine mental health. Our objective was to build a self-rating scale easy to use in clinical psychiatric practice to assess TR, including drug-taking aspects and the relationship with the clinician on a day-to-day basis. A secondary objective was to assess the scale's validity and the association between TR and adherence., Methods: The study was conducted with 92 consenting inpatients who met specified criteria for schizophrenia and schizoaffective disorders (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition). Assessments of TR were obtained by the 4-Point ordinal Alliance Self-report and an 8-cm visual analog scale completed by the patient 1 week before discharge, after the remission of acute symptomatology. Adherence behavior was estimated with a new valid and reliable questionnaire called the Medication Adherence Rating Scale. Factor analysis was performed., Results: Internal consistency was assessed by calculating Cronbach alpha, which revealed a highly satisfactory value (alpha = .91). After oblique rotation was run, 2 understandable factors were extracted that we termed empathy experienced and psychoeducation., Conclusions: Therapeutic relationship with the clinician can be considered a prerequisite for positive treatment course and outcome. The detection of subpopulations characterized by determinants of poor TR could be the first step toward improving schizophrenia prognosis linked to poor adherence.

Objective: To investigate whether measurement of plasma levels can predict tolerance to oxcarbazepine (OXC)., Methods: We reviewed medical records to identify all inpatients consecutively treated by OXC at the University Department of Psychiatry in Bordeaux. Adverse effects were rated before treatment onset, at day 3, then every week and at discharge or at discontinuation. Residual hydroxy-OXC concentrations were measured on blood samples at the same periods., Results: OXC was prescribed to 20 patients with bipolar (n=18) or schizoaffective bipolar-type disorder (n=2). Reported side effects were transient and occurred mostly at the beginning of the treatment. Three patients stopped OXC because of severe cutaneous side effects. Residual hydroxy-OXC plasma levels were similar in patients with or without occurrence of side effects at all times of assessment., Conclusion: Our data suggest that the occurrence of severe side-effects is relatively high with OXC. Measurement of plasma OXC levels does not appear to be of interest in clinical practice since plasma concentrations are not predictive of the occurrence of side effects.

Background: Prenatal exposure to diethylstilboestrol (DES) may induce neurodevelopmental disturbances potentially mediating an increased risk of psychiatric disorders in exposed subjects. Most findings of an increased prevalence of psychiatric disorders in men and women prenatally exposed to DES are not easy to interpret because of selection biases., Method: Information on hormonal treatment during pregnancy and on offspring's medical outcome was collected from women participating in the Etude Epidemiologique de femmes de la Mutuelle Générale de l'Education Nationale (E3N) prospective cohort who completed consecutive postal questionnaires on a range of medical events since 1990. Information on hormonal treatment during pregnancy was collected in 1992 and on offspring's medical outcome in 2004. The psychiatric outcome of subjects prenatally exposed to DES was compared to that of their unexposed siblings., Results: A total of 1352 mothers with DES treatment for at least one pregnancy provided information on 1680 exposed children and 1447 unexposed siblings. After adjustment for duration of follow-up, educational level, history of obstetric complication, prenatal exposure to progestagen drugs or other hormones and parental history of psychiatric hospitalization, no association was found between prenatal exposure to DES and occurrence of strictly defined serious psychiatric outcome (suicide or psychiatric hospitalization) [adjusted odds ratio (OR) 0.8, 95% confidence interval (CI) 0.5-1.2], or of broadly defined serious psychiatric outcome (same events plus psychiatric or psychological consultation) (adjusted OR 1.0, 95% CI 0.8-1.2)., Conclusions: These findings suggest that the impact of prenatal DES exposure on foetal brain development, if any, is unlikely to increase the risk of serious psychiatric disorders.

The aims of the present study were to assess the prevalence and comorbidity of psychiatric disorders in subjects with intentional drug overdose and to explore whether there were gender differences in prevalence and comorbidity. A standardized psychiatric evaluation was performed in 100 randomly selected subjects, 18 years old and older, with intentional drug overdose referred to an emergency department. The prevalences of psychiatric morbidity and comorbidity were very high in both genders: 88% presented with at least one psychiatric diagnosis, and three-quarters presented with comorbid psychiatric disorders. Affective and anxiety disorders were the most prevalent diagnoses. One patient out of three presented with alcohol or substance misuse. Compared to females, males suffered five times more often from substance misuse and three times more often from psychotic syndrome and were three times less likely to present with anxiety disorder. When subjects are referred to hospital for intentional drug overdose, medical management should systematically involve a psychiatric assessment in order to identify not only affective and anxiety disorders, but also alcohol and substance misuse, due to the high prevalence of these disorders, especially in male subjects.

Background: A major public health issue is to determine whether long-term benzodiazepine use may induce cognitive deficits persisting after withdrawal. The aim of the present review was to examine findings from prospective studies carried out in general population samples exploring whether exposure to benzodiazepines is associated with an increased risk of incident cognitive decline., Method: Using a MEDLINE search and a hand-search of related references in selected papers, we retrieved original studies published in peer-reviewed journals that explored in general population samples the association between benzodiazepine exposure and change in cognitive performance between baseline and follow-up assessment., Results: Six papers met the inclusion criteria. Two studies reported a lower risk of cognitive decline in former or ever users, two found no association whatever the category of user, and three found an increased risk of cognitive decline in benzodiazepine users., Conclusions: The discrepant findings obtained by studies examining the link between benzodiazepine exposure and risk of cognitive decline may be due to methodological differences, especially regarding the definitions of exposure and cognitive outcome. As a large proportion of subjects are exposed to benzodiazepines, a small increase in the risk of cognitive decline may have marked deleterious consequences for the health of the general population. This issue needs to be explored further by pharmaco-epidemiological studies.

Objective: The nature of the link between cannabis use and psychosis remains to be clarified., Method: The paper reviews the evidence suggesting that cannabis may be a risk factor for psychosis onset., Results: Cross-sectional and retrospective epidemiological studies show that individuals with psychosis use cannabis more often than other individuals in the general population. It has long been considered that this association is explained by the self-medication hypothesis, postulating that cannabis is used to self-medicate psychotic symptoms. This hypothesis has been recently challenged by several prospective studies carried out in population-based samples, showing that cannabis exposure is associated with an increased risk of psychosis, possibly by interacting with a pre-existing vulnerability for these disorders. A dose-response relationship was found between cannabis exposure and risk of psychosis, and this association was independent from potential confounding factors such as exposure to other drugs and pre-existence of psychotic symptoms. However, the diagnostic specificity is weak, as cannabis exposure may be a risk factor for the occurrence of a large spectrum of psychiatric disorders, ranging from schizophrenia to mood and anxiety disorders., Conclusion: Considering the growing number of adolescents exposed to cannabis, the impact of this substance on the population mental health should be further explored.

Objective: The putative role of neuroleptics in the known excess mortality of subjects with schizophrenia remains disputed. The aim of this study was to assess the link between mortality and the class of neuroleptic., Method: Causes of death (suicide, cardiovascular, etc.) and exposure to neuroleptics were studied in a cohort of 3474 patients with schizophrenia followed from 1993 to 1997., Results: From 1993 to 1997, 178 patients died. The risk of all-cause death (OR=1.59; 95% CI 1.02-2.50; p=0.04), and suicide (OR=2.22; 95% CI 1.24-3.97; p=0.006) were increased in users of thioxanthenes (alone or associated with other drugs), and increased risk of "other causes" of death was associated with use of atypical neuroleptics (OR=2.06; 95% CI 1.15-3.70; p=0.0016)., Conclusion: Our findings suggest the existence of association between certain classes of neuroleptics and death, all cause or specific. This could be related to the drug itself or to patient selection.