Search

Altered emotional experiences in response to antipsychotics may increase the burden of disease in patients with schizophrenia. In a large cross-sectional study, patients with schizophrenia completed the Subjects Reaction to Antipsychotics questionnaire (SRA) to assess whether they attributed altered emotional experiences (flattened affect or depressive symptoms) to their antipsychotics. Association with antipsychotic D2 receptor affinity and occupancy was examined using logistic regression. We compared antipsychotic-attributed emotional experiences between patients using antipsychotic monotherapy and combination therapy. Of the 1298 included patients, 23% attributed flattened affect to their antipsychotics and 16% attributed depressive symptoms to their antipsychotics, based on the SRA. No differences were observed between antipsychotics in patients on monotherapy. We discuss that within these patients' relatively low dose range, altered emotional experiences did not appear to relate to the level of D2 receptor affinity of antipsychotic monotherapy. Patients using antipsychotic combination therapy (22%) were more likely to attribute depressive symptoms to their antipsychotics than patients using antipsychotic monotherapy (OR [95%CI]=1.443 [1.033-2.015]); possibly due to higher D2 receptor occupancies as estimated by dose equivalents., (Copyright © 2016. Published by Elsevier Ireland Ltd.)

Background: Evidence is limited regarding the most effective pharmacological treatment for psychotic depression: combination of an antidepressant plus an antipsychotic, monotherapy with an antidepressant or monotherapy with an antipsychotic. This is an update of a review first published in 2005 and last updated in 2009., Objectives: 1. To compare the clinical efficacy of pharmacological treatments for patients with an acute psychotic depression: antidepressant monotherapy, antipsychotic monotherapy and the combination of an antidepressant plus an antipsychotic, compared with each other and/or with placebo.2. To assess whether differences in response to treatment in the current episode are related to non-response to prior treatment., Search Methods: A search of the Cochrane Central Register of Controlled Trials and the Cochrane Depression, Anxiety and Neurosis Group Register (CCDANCTR) was carried out (to 12 April 2013). These registers include reports of randomised controlled trials from the following bibliographic databases: EMBASE (1970-), MEDLINE (1950-) and PsycINFO (1960-). Reference lists of all studies and related reviews were screened and key authors contacted., Selection Criteria: All randomised controlled trials (RCTs) that included participants with acute major depression with psychotic features, as well as RCTs consisting of participants with acute major depression with or without psychotic features, that reported separately on the subgroup of participants with psychotic features., Data Collection and Analysis: Two review authors independently extracted data and assessed risk of bias in the included studies, according to the criteria of the Cochrane Handbook for Systematic Reviews of Interventions. Data were entered into RevMan 5.1. We used intention-to-treat data. For dichotomous efficacy outcomes, the risk ratio (RR) with 95% confidence intervals (CIs) was calculated. For continuously distributed outcomes, it was not possible to extract data from the RCTs. Regarding the primary outcome of harm, only overall dropout rates were available for all studies., Main Results: The search identified 3659 abstracts, but only 12 RCTs with a total of 929 participants could be included in the review. Because of clinical heterogeneity, few meta-analyses were possible. The main outcome was reduction of severity (response) of depression, not of psychosis.We found no evidence for the efficacy of monotherapy with an antidepressant or an antipsychotic.However, evidence suggests that the combination of an antidepressant plus an antipsychotic is more effective than antidepressant monotherapy (three RCTs; RR 1.49, 95% CI 1.12 to 1.98, P = 0.006), more effective than antipsychotic monotherapy (four RCTs; RR 1.83, 95% CI 1.40 to 2.38, P = 0.00001) and more effective than placebo (two identical RCTs; RR 1.86, 95% CI 1.23 to 2.82, P = 0.003).Risk of bias is considerable: there were differences between studies with regard to diagnosis, uncertainties around randomisation and allocation concealment, differences in treatment interventions (pharmacological differences between the various antidepressants and antipsychotics) and different outcome criteria., Authors' Conclusions: Psychotic depression is heavily understudied, limiting confidence in the conclusions drawn. Some evidence indicates that combination therapy with an antidepressant plus an antipsychotic is more effective than either treatment alone or placebo. Evidence is limited for treatment with an antidepressant alone or with an antipsychotic alone.

Background: Evidence is limited regarding the most effective pharmacological treatment for psychotic depression: combination of an antidepressant plus an antipsychotic, monotherapy with an antidepressant or monotherapy with an antipsychotic. This is an update of a review first published in 2005 and last updated in 2009., Objectives: 1. To compare the clinical efficacy of pharmacological treatments for patients with an acute psychotic depression: antidepressant monotherapy, antipsychotic monotherapy and the combination of an antidepressant plus an antipsychotic, compared with each other and/or with placebo.2. To assess whether differences in response to treatment in the current episode are related to non-response to prior treatment., Search Methods: A search of the Cochrane Central Register of Controlled Trials and the Cochrane Depression, Anxiety and Neurosis Group Register (CCDANCTR) was carried out (to 12 April 2013). These registers include reports of randomised controlled trials from the following bibliographic databases: EMBASE (1970-), MEDLINE (1950-) and PsycINFO (1960-). Reference lists of all studies and related reviews were screened and key authors contacted., Selection Criteria: All randomised controlled trials (RCTs) that included participants with acute major depression with psychotic features, as well as RCTs consisting of participants with acute major depression with or without psychotic features, that reported separately on the subgroup of participants with psychotic features., Data Collection and Analysis: Two review authors independently extracted data and assessed risk of bias in the included studies, according to the criteria of the Cochrane Handbook for Systematic Reviews of Interventions. Data were entered into RevMan 5.1. We used intention-to-treat data. For dichotomous efficacy outcomes, the risk ratio (RR) with 95% confidence intervals (CIs) was calculated. For continuously distributed outcomes, it was not possible to extract data from the RCTs. Regarding the primary outcome of harm, only overall dropout rates were available for all studies., Main Results: The search identified 3659 abstracts, but only 12 RCTs with a total of 929 participants could be included in the review. Because of clinical heterogeneity, few meta-analyses were possible. The main outcome was reduction of severity (response) of depression, not of psychosis.We found no evidence for the efficacy of monotherapy with an antidepressant or an antipsychotic.However, evidence suggests that the combination of an antidepressant plus an antipsychotic is more effective than antidepressant monotherapy (three RCTs; RR 1.49, 95% CI 1.12 to 1.98, P = 0.006), more effective than antipsychotic monotherapy (four RCTs; RR 1.83, 95% CI 1.40 to 2.38, P = 0.00001) and more effective than placebo (two identical RCTs; RR 1.86, 95% CI 1.23 to 2.82, P = 0.003).Risk of bias is considerable: there were differences between studies with regard to diagnosis, uncertainties around randomisation and allocation concealment, differences in treatment interventions (pharmacological differences between the various antidepressants and antipsychotics) and different outcome criteria., Authors' Conclusions: Psychotic depression is heavily understudied, limiting confidence in the conclusions drawn. Some evidence indicates that combination therapy with an antidepressant plus an antipsychotic is more effective than either treatment alone or placebo. Evidence is limited for treatment with an antidepressant alone or with an antipsychotic alone.

Pharmacogenetic studies have demonstrated significant associations between several candidate genes (DRD2, DRD3, 5HTR2A and 5HTR2C, COMT and MTHFR) and antipsychotic drug response. The present study investigates the effect of nine polymorphisms in these genes for an association with antipsychotic treatment response. 329 Caucasian patients with a non-affective psychotic disorder using antipsychotics were included. All patients participated in the longitudinal GROUP-study in The Netherlands. We genotyped 9 SNPs in 6 candidate genes (DRD2: TaqI_A, -141C; DRD3: Ser9Gly; HTR2A: 102-T/C, His452Tyr; HTR2C: Cys23Ser; COMT: Val158Met; MTHFR: 677-C/T) using standard protocols. Polymorphisms were based on previous studies showing associations with positive symptoms treatment response. The Clinical Global Impression - Improvement (CGI-I) scale was used to assess improvement in positive psychotic symptoms since the start of current antipsychotic treatment. Ordinal regression was used for association analyses. Ninety percent of the patients used second generation antipsychotics, with olanzapine (28%) and risperidone (29%) being the most prescribed drugs. Ser9Gly of the dopamine D3 receptor gene (P value 0.034) and 677-C/T of MTHFR (P value 0.019) were tested statistically significant. Gly-carriers and T-carriers, respectively, showed more clinical improvement on the CGI-I. The other polymorphisms did not show a statistically significant association (P values>0.10). In conclusion, we replicated two out of nine of the previously reported associations between polymorphisms and treatment response. The direction and magnitude of the associations presented here in DRD3 (Ser9Gly) and MTHFR (677-C/T) are in line with previous association studies in Caucasian patients. These polymorphisms may be of value for predicting clinical response., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Rationale: Pharmacogenetic studies on antipsychotic-induced movement disorders (MD) in schizophrenia so far have focused mainly on tardive dyskinesia. Only a few examined the more acute antipsychotic-induced MD such as parkinsonism and akathisia. Notably, all MD relate to deregulation of the dopamine system., Objective: This study aimed to replicate previously reported associations in candidate genes for acute and tardive antipsychotic-induced MD in a young Caucasian sample., Methods: In 402 patients (median age 26 years), a total of 13 polymorphisms were genotyped in eight dopamine-related candidate genes selected a priori from the literature (regarding dopamine and serotonin receptors, dopamine degradation, and free radicals scavenging enzymes pathways)., Results: Patients with MD used on average a higher haloperidol dose equivalent when compared to those without MD. The prevalence of MD was high and did not differ between first- and second-generation antipsychotics. Significant associations were found between (a) the TaqI_D polymorphism and akathisia (OR = 2.3, p = 0.001 for each extra C-allele) and (b) the -141C polymorphism and tardive dyskinesia (OR = 0.20, p = 0.001 for each extra Del allele). The other polymorphisms were not significantly associated with an MD., Conclusions: Two associations were found between genetic variation TaqI_D and the -141C polymorphisms in the DRD2 gene and antipsychotic-induced MD; one with acute akathisia and one with tardive dyskinesia. These were previously reported to be associated with tardive dyskinesia and acute parkinsonism, respectively. These results suggest that the contribution of these DRD2 gene variants in the vulnerability of antipsychotic-induced MD takes place in a more general or pleiotropic way.

Background: Weight gain is one of the major problems in patients using antipsychotic medication, leading to relevant morbidities and reduced compliance to pharmacotherapy. Recently, an association has been reported between a single nucleotide polymorphism (rs1455832) of the roundabout axon guidance receptor, homolog 1 (ROBO1) gene and body mass index (BMI) in persons younger than 30 years. The aim of this study is to investigate the association between BMI and rs1455832 in patients with a psychotic disorder using antipsychotics., Methods: A cross-sectional design was used in a pooled sample of Caucasian psychiatric patients obtained from three comparable Dutch psychiatric populations. Patients were eligible for inclusion in this study if they met the Diagnostic and Statistical Manual of Mental Disorders-IV criteria for a nonaffective psychotic disorder, were 18 years or older, and used one or more antipsychotics. Genotyping was performed according to standard protocols. Linear (for BMI) and logistic (for obesity, defined as BMI > 30) regression analyses, corrected for age and sex, were applied in the statistical analyses., Results: A total of 435 patients were included in this association analyses. The rs1455832 polymorphism studied was significantly associated with BMI and obesity in female patients. Female patients had a statistically significant (P = 0.025) decrease of 1.76 kg/m in BMI values per C allele. In contrast to female patients, this association was not exhibited in male patients., Conclusion: The rs1455832 polymorphism may play a role in inducing obesity in female patients using antipsychotics.

Rationale: Antipsychotic affinity for the histamine H1 receptor and the muscarinic M3 receptor have been associated with the side effects weight gain, and development of diabetes, respectively., Objectives: We investigated polymorphisms of the histamine H1 (HRH1) and muscarinic acetylcholine receptor M3 (CHRM3) receptor genes for an association with body mass index (BMI) and glycated hemoglobin (HbA1c)., Methods: We included 430 Caucasian patients with a non-affective psychotic disorder using antipsychotics for at least 3 months. Primary endpoints of the study were cross-sectionally measured BMI and HbA1c; secondary endpoints were obesity and hyperglycaemia. Two single-nucleotide polymorphisms (SNPs) in the HRH1 gene, rs346074 and rs346070, and one SNP in the CHRM3 gene, rs3738435, were genotyped. Our primary hypothesis in this study was an interaction between genotype on BMI and antipsychotic affinity for the H1 and M3 receptor., Results: A significant association of interaction between haplotype rs346074-rs346070 and BMI (p value 0.025) and obesity (p value 0.005) in patients using high-H1 affinity antipsychotics versus patients using low-H1 affinity antipsychotics was found. There was no association of CHRM3 gene variant rs3738435 with BMI, and we observed no association with HbA1c or hyperglycaemia in any of the variants., Conclusions: This study, for the first time, demonstrates a significant association between HRH1 variants and BMI in patients with a psychotic disorder using antipsychotics. In future, genotyping of HRH1 variants may help predicting weight gain in patients using antipsychotics.

Objective: To assess the effect of withdrawal of antipsychotic treatment on relapse risk in remitted first-episode schizophrenia patients., Methods: First-episode 1-year stable and remitted outpatients with a schizophrenic disorder were randomly allocated to continuation of their antipsychotic regimen for at least 6 months (N = 9), or gradual withdrawal (N = 11). Primary outcome was the difference in cumulative relapse-free survival at 9 months., Results: Recruitment was terminated prematurely on 26 October 2005. The cumulative relapse-free survival was 88% (SE = 0.12) in the continuation and 18% (SE = 0.12) in the discontinuation group (P = 0.001) at 9 months follow-up., Conclusions: Discontinuation of antipsychotic medication markedly increases the risk of relapse in stable remitted first-episode schizophrenia patients. In future studies the topics of safety monitoring and sampling of patients should receive extra attention.

The influence of antipsychotic medication on brain morphology in schizophrenia may confound interpretation of brain changes over time. We aimed to assess the effect of discontinuation of atypical antipsychotic medication on change in brain volume in patients. Sixteen remitted, stable patients with first-episode schizophrenia, schizoaffective or schizophreniform disorder and 20 healthy controls were included. Two magnetic resonance imaging brain scans were obtained from all subjects with a 1-year interval. The patients either discontinued (n = 8) their atypical antipsychotic medication (olanzapine, risperidone, or quetiapine) or did not (n = 8) discontinue during the follow-up period. Intracranial volume and volumes of total brain, cerebral gray and white matter, cerebellum, third and lateral ventricle, nucleus caudatus, nucleus accumbens, and putamen were obtained. Multiple linear regression analyses were used to assess main effects for group (patient-control) and discontinuation (yes-no) for brain volume (change) while correcting for age, sex, and intracranial volume. Decrease in cerebral gray matter and caudate nucleus volume over time was significantly more pronounced in patients relative to controls. Our data suggest decreases in the nucleus accumbens and putamen volumes during the interval in patients who discontinued antipsychotic medication, whereas increases were found in patients who continued their antipsychotics. We confirmed earlier findings of excessive gray matter volume decrements in patients with schizophrenia compared with normal controls. We found evidence suggestive of decreasing volumes of the putamen and nucleus accumbens over time after discontinuation of medication. This might suggest that discontinuation reverses effects of atypical medication.

Rationale, Aims and Objectives: Antipsychotics are approved treatment for severe conditions and have serious side effects. Antipsychotics are often prescribed off-label. Although a substantial proportion of antipsychotics are prescribed in primary care, it is largely unknown what motivates the general practitioner (GP) to initiate antipsychotic treatment. Therefore, we sought to examine the relation between pre-defined, licensed as well as off-label, reasons for antipsychotic treatment and the initiation of this treatment by the GP as well as report registration and incidence of antipsychotic treatment in general practice., Methods: In a case-control study, 723 patients selected from an electronic database and with a new antipsychotic prescription were compared with 3615 controls receiving any other new prescription. Using logistic regression, six pre-defined categories of International Classification of Primary Care (ICPC) codes ('psychosis', 'depression and anxiety', 'sleeping disorders', 'acute stress and surmenage', 'dementia' and 'somatic indications') were associated with initiating antipsychotic treatment., Results: All, including off-label, categories were significantly related to initiating antipsychotic treatment. The incidence of initiating antipsychotic therapy was 1.28 per 1000 persons per year (95% confidence interval: 1.09, 1.48). GPs registered an ICPC code in 50% and prescribed typical antipsychotics in 90% of the cases. Prescription of atypical antipsychotics increased almost threefold over the study period., Conclusions: The results suggest that GPs prescribe antipsychotics off-label. Despite serious side effects and relatively infrequent occurrence in Dutch general practices, GPs seem imprecise in underpinning and registrating the initiation of antipsychotic treatment. GPs increasingly prescribe atypical antipsychotics although the prescription of typical antipsychotics still dominates., (© 2010 Blackwell Publishing Ltd.)

Background: Data about follow-up after acute pharmacological treatment of psychotic depression are scarce., Methods: A 4 month open follow-up was done, preferentially with same medication as during acute treatment, of patients (n=59) with DSM-IV-TR major depressive disorder with psychotic features, aged 18 to 65 years, who had completed as responders an acute double-blind 7 week trial with imipramine, venlafaxine or venlafaxine plus quetiapine. Main outcome measures were Hamilton Rating Scale for Depression and Clinical Global Impression Scale., Results: Six patients dropped out during the 4 month follow-up. Almost all patients (86.4%; 51/59) remained responder while remission rate increased from 59.3% (35/59) to 86.8% (46/53), independent of treatment. Relapse rate was low (3.8%; 2/53). Tolerability was good. Weight increased with all treatments., Limitations: Limitations were the limited sample size and consequent limited statistical power. The treatment during follow-up was not double-blind., Conclusions: Continuation treatment with the same medication that was effective in the acute treatment trial, remained effective during the 4 month follow-up in many patients leading to further improvement, and was well tolerated., (Copyright 2009 Elsevier B.V. All rights reserved.)

Background: Risperidone long-acting injectable (RLAI), the first second-generation depot antipsychotic, has extensively been studied before introduction. Thereafter, questions about the type of patients actually treated with RLAI in daily practice remain to be answered for making valid antipsychotic treatment comparisons involving RLAI in observational studies., Objective: We aimed to determine in chronic antipsychotic users who switched treatment, predictors for the prescription of (1) depot versus oral antipsychotics and (2) RLAI versus first-generation antipsychotics (FGAs) depot., Methods: We used pharmacy dispensing data from 53 community pharmacies in the northeast of the Netherlands containing approximately 500,000 persons. Chronic antipsychotic users were defined and followed up for a switch in antipsychotic treatment within the first period that RLAI was on the market. Multivariable analysis was performed to relate patient, prescriber, and medication characteristics to prescription of a new antipsychotic drug., Results: Predictors for switching to depot versus oral antipsychotics were male sex, previous use of depot antipsychotics, recent anticholinergic drug use, and a gap in antipsychotic dispensation history. Predictors for switching to RLAI versus FGA depot were previous use of depot and consulting a specialist., Conclusions: The results suggest that, compared with oral antipsychotics, patients receiving a depot are less compliant users, with more extrapyramidal side effects. Compared with FGA depot, patients receiving RLAI tend to be more severely ill patients. We conclude that RLAI may be partly channeled to patients as a last resort, which may have important consequences for the interpretation of observational effectiveness comparisons between RLAI and other antipsychotics in daily practice.

The article focuses on a study which investigated the effectiveness of adjuvant treatment with aspirin (acetylsalicylic acid) in patients with schizophrenia spectrum disorders. The study included 70 patients with schizophrenia spectrum disorders who received antipsychotic drugs in the Netherlands between May 2004 and August 2007, and were randomized to receive either aspirin or placebo. Study authors concluded that adjuvant treatment with aspirin reduces the symptoms of schizophrenia spectrum disorders.