Optimal Doses of Specific Antipsychotics for Relapse Prevention in a Nationwide Cohort of Patients with Schizophrenia

Background and Hypothesis Optimal doses of most antipsychotics in the maintenance treatment of schizophrenia are unknown. We aimed to study the risk of severe relapse indicated by rehospitalization for different dose categories of 15 most frequently used antipsychotics in monotherapy in Finland. Study Methods We studied the risk of rehospitalization (Adjusted Hazard Ratio, aHR) associated with six antipsychotic monotherapy dose categories (as time-varying dose, measured in defined daily dose, DDDs/day) in a nationwide cohort of persons diagnosed with schizophrenia (n = 61 889), using within-individual analyses to eliminate selection bias. Study Results Among the 15 most widely used antipsychotics, 13 had a U- or J-shaped dose-response curve, showing the lowest risks of relapse for doses of 0.6-0.9 DDD/day, and especially at 1.4-Peer reviewe

Persistence of Antipsychotic Use After Clozapine Discontinuation:A Real-World Study Across Antipsychotics

Although clozapine treatment is often discontinued due to limited efficacy or low tolerability, there is a lack of guidelines and evidence on treatment options after discontinuation of clozapine in patients with schizophrenia. Persistence has proven to be an adequate indicator for treatment effectiveness in patients with schizophrenia. The aim of this study was, therefore, to compare persistence of antipsychotic use between antipsychotic treatment options in patients after stopping clozapine treatment. Registry data from a prescription database representative of the Dutch population (1996-2017) was collected to investigate persistence in patients with schizophrenia who had been using clozapine for >= 90 days. Persistence with antipsychotics after clozapine discontinuation was analyzed using Cox-proportional hazard regression models. Our study population consisted of 321 participants, of whom 138 re-initiated clozapine and 183 started some other antipsychotic in the year after clozapine discontinuation (N = 518 antipsychotic use periods, N = 9,178 months). Second-generation antipsychotics (SGAs) as a group were associated with better persistence compared to first-generation antipsychotics (adjusted hazard ratio (aHR), 0.73; 95% confidence interval (CI) 0.57-0.93; P = 0.011). Compared with other antipsychotics, the following oral monotherapy antipsychotics were associated with significantly better persistence: restarting clozapine (aHR 0.48; 95% CI 0.32-0.71; P <0.001) and switching to risperidone (aHR 0.52; 95% CI 0.32-0.84; P = 0.008) or olanzapine (aHR 0.55; 95% CI 0.35-0.87; P = 0.010). Sensitivity analyses confirmed the results. In conclusion, oral SGAs are associated with better persistence than alternative antipsychotic treatment options in patients discontinuing clozapine for undefined reasons. Especially clozapine (except in those with previous serious adverse reactions to clozapine), olanzapine and risperidone should be considered as oral monotherapy for these patients

Associations between genetic liabilities to smoking behavior and schizophrenia symptoms in patients with a psychotic disorder, their siblings and healthy controls

It is unknown how smoking behavior polygenic scores (PRS) relate to psychosis and psychotic symptoms. To elucidate this, genotype and phenotype data were collected from patients with schizophrenia, their unaffected siblings, and healthy controls in a six-year follow-up prospective cohort study. Associations between smoking behaviors, PRS and schizophrenia symptoms were explored using linear mixed-effect models. The mean number of cigarettes smoked per day were 18 for patients, 13 for siblings and 12 for controls. In the overall sample, PRSs-smoking initiation (i.e., ever smoking as a binary phenotype, PRS-SI) were positively associated with positive symptoms, negative symptoms, and depressive symptoms, whereas PRSs-AI (age at regular smoking initiation) were negatively associated with all symptom dimensions, with similar effect sizes. When considering groups separately, PRS were only associated with psychotic symptoms in siblings and controls. In conclusion, unaffected siblings show smoking behaviors at an intermediate level between patients and healthy controls. Additionally, PRS-SI and PRS-AI are associated with all symptom dimensions only in unaffected siblings and healthy controls, possibly owing to the dominant role of other (genetic) risk factors in patients. Future studies may examine mechanisms via which genetic risk for smoking affects mental health symptoms.</p

Polygenetic risk scores and phenotypic constellations of obsessive–compulsive disorder in clozapine-treated schizophrenia

Obsessive–compulsive symptoms (OCS) are frequently observed in individuals with schizophrenia (SCZ) treated with clo- zapine (CLZ). This study aimed to analyze prevalence of OCS and obsessive–compulsive disorder (OCD) in this subgroup and find possible correlations with different phenotypes. Additionally, this is the first study to examine polygenetic risk scores (PRS) in individuals with SCZ and OCS. A multicenter cohort of 91 individuals with SCZ who were treated with CLZ was recruited and clinically and genetically assessed. Symptom severity was examined using the Positive and Negative Symptom Scale (PANSS), Clinical Global Impression Scale (CGI), the Calgary Depression Scale for Schizophrenia (CDSS), Global Assessment of Functioning Scale (GAF) and Yale–Brown Obsessive–Compulsive Scale (Y-BOCS). Participants were divided into subgroups based on phenotypic OCS or OCD using Y-BOCS scores. Genomic-wide data were generated, and PRS analyses were performed to evaluate the association between either phenotypic OCD or OCS severity and genotype-predicted predisposition for OCD, SCZ, cross-disorder, and CLZ/norclozapine (NorCLZ) ratio, CLZ metabolism and NorCLZ metabo- lism. OCS and OCD were frequent comorbidities in our sample of CLZ-treated SCZ individuals, with a prevalence of 39.6% and 27.5%, respectively. Furthermore, the Y-BOCS total score correlated positively with the duration of CLZ treatment in years (r = 0.28; p = 0.008) and the PANSS general psychopathology subscale score (r = 0.23; p = 0.028). A significant cor- relation was found between OCD occurrence and PRS for CLZ metabolism. We found no correlation between OCS severity and PRS for CLZ metabolism. We found no correlation for either OCD or OCS and PRS for OCD, cross-disorder, SCZ, CLZ/NorCLZ ratio or NorCLZ metabolism. Our study was able to replicate previous findings on clinical characteristics of CLZ-treated SCZ individuals. OCS is a frequent comorbidity in this cohort and is correlated with CLZ treatment dura- tion in years and PANSS general psychopathology subscale score. We found a correlation between OCD and PRS for CLZ metabolism, which should be interpreted as incidental for now. Future research is necessary to replicate significant findings and to assess possible genetic predisposition of CLZ-treated individuals with SCZ to OCS/OCD. Limitations attributed to the small sample size or the inclusion of subjects on co-medication must be considered. If the association between OCD and PRS for CLZ metabolism can be replicated, it should be further evaluated if CYP1A2 alteration, respectively lower CLZ plasma level, is relevant for OCD development

Analysis of shared common genetic risk between amyotrophic lateral sclerosis and epilepsy

Peer reviewe

Phenome-wide and genome-wide analyses of quality of life in schizophrenia

This article has been published in a revised form in BJPsych Open [http://doi.org/10.1192/bjo.2020.140]. This version is free to view and download for private research and study only. Not for re-distribution or re-use. © copyright holder.Background Schizophrenia negatively affects quality of life (QoL). A handful of variables from small studies have been reported to influence QoL in patients with schizophrenia, but a study comprehensively dissecting the genetic and non-genetic contributing factors to QoL in these patients is currently lacking. Aims We adopted a hypothesis-generating approach to assess the phenotypic and genotypic determinants of QoL in schizophrenia. Method The study population comprised 1119 patients with a psychotic disorder, 1979 relatives and 586 healthy controls. Using linear regression, we tested >100 independent demographic, cognitive and clinical phenotypes for their association with QoL in patients. We then performed genome-wide association analyses of QoL and examined the association between polygenic risk scores for schizophrenia, major depressive disorder and subjective well-being and QoL. Results We found nine phenotypes to be significantly and independently associated with QoL in patients, the most significant ones being negative (β = −1.17; s.e. 0.05; P = 1 × 10–83; r2 = 38%), depressive (β = −1.07; s.e. 0.05; P = 2 × 10–79; r2 = 36%) and emotional distress (β = −0.09; s.e. 0.01; P = 4 × 10–59, r2 = 25%) symptoms. Schizophrenia and subjective well-being polygenic risk scores, using various P-value thresholds, were significantly and consistently associated with QoL (lowest association P-value = 6.8 × 10–6). Several sensitivity analyses confirmed the results. Conclusions Various clinical phenotypes of schizophrenia, as well as schizophrenia and subjective well-being polygenic risk scores, are associated with QoL in patients with schizophrenia and their relatives. These may be targeted by clinicians to more easily identify vulnerable patients with schizophrenia for further social and clinical interventions to improve their QoL.Dutch Health Research Council; Lundbeck; AstraZeneca; Eli Lilly; Janssen Cilag;Amsterdam: Academic Psychiatric Centre of the Academic Medical Center and the mental health institutions at Geestelijke Gezondheidszorg (GGZ) Ingeest; Arkin; Dijk en Duin; GGZ Rivierduinen; Erasmus Medical Centre and GGZ Noord Holland Noord; Groningen: University Medical Center Groningen and the mental health institutions at Lentis; GGZ Friesland; GGZ Drenthe; Dimence; Mediant; GGNet Warnsveld; Yulius Dordrecht and Parnassia Psycho-Medical Center The Hague; Maastricht: Maastricht University Medical Centre and the mental health institutions at GGZ Eindhoven en De Kempen; GGZ Breburg; GGZ Oost-Brabant; Vincent van Gogh voor Geestelijke Gezondheid; Mondriaan; Virenze riagg; Zuyderland GGZ; MET ggz; Universitair Centrum Sint-Jozef Kortenberg; Collaborative Antwerp Psychiatric Research Institute University of Antwerp; Psychiatrisch Centrum Ziekeren Sint-Truiden; Psychiatrisch Ziekenhuis Sancta Maria Sint-Truiden; GGZ Overpelt and Openbaar Psychiatrisch Zorgcentrum Rekem; Utrecht: University Medical Center Utrecht and the mental health institutions Altrecht; GGZ Centraal and Delt

Raloxifene augmentation in men and women with a schizophrenia spectrum disorder:A study protocol

Although acute psychotic symptoms are often reduced by antipsychotic treatment, many patients with schizophrenia are impaired in daily functioning due to the persistence of negative and cognitive symptoms. Raloxifene, a Selective Estrogen Receptor Modulator (SERM) has been shown to be an effective adjunctive treatment in schizophrenia. Yet, there is a paucity in evidence for raloxifene efficacy in men and premenopausal women. We report the design of a study that aims to replicate earlier findings concerning the efficacy of raloxifene augmentation in reducing persisting symptoms and cognitive impairment in postmenopausal women, and to extend these findings to a male and peri/premenopausal population of patients with schizophrenia. The study is a multisite, placebo-controlled, double-blind, randomised clinical trial in approximately 110 adult men and women with schizophrenia. Participants are randomised 1:1 to adjunctive raloxifene 120 mg or placebo daily during 12 weeks. The treatment phase includes measurements at three time points (week 0, 6 and 12), followed by a follow-up period of two years. The primary outcome measure is change in symptom severity, as measured with the Positive and Negative Syndrome Scale (PANSS), and cognition, as measured with the Brief Assessment of Cognition in Schizophrenia (BACS). Secondary outcome measures include social functioning and quality of life. Genetic, hormonal and inflammatory biomarkers are measured to assess potential associations with treatment effects. If it becomes apparent that raloxifene reduces psychotic symptoms and/or improves cognition, social functioning and/or quality of life as compared to placebo, implementation of raloxifene in clinical psychiatric practice can be considered