Internalized stigma, hope and depressive symptoms are important variables in the recovery process of people with schizophrenia spectrum disorders, but little is known about their stability or relationship among each other over time. This study aims to unravel the longitudinal stability and relationships of these variables. 99 participants were included in this prospective study assessing internalized stigma, hope and depressive symptoms at baseline, with a first follow-up after three months and a second follow-up after six months. Multilevel models examined if the variables changed over time and a correlation coefficient was conducted to show their relationship to each other. Hope stayed stable over time, whereas internalized stigma and depressive symptoms significantly decreased over the study period. The correlation coefficient showed that internalized stigma and depressive symptoms influenced each other moderately over time. Thus, while hope was a stable construct over time, internalized stigma and depressive symptoms changed significantly and were correlated to each other positively. This implies that participants may adjust to their chronic condition over time, and recovery focused interventions should target both psychological dimensions at the same time.

Although antipsychotics are widely prescribed, their effect of on improving poor illness insight in schizophrenia has seldom been investigated and therefore remains uncertain. This paper examines the effects of low dose haloperidol, amisulpride, olanzapine, quetiapine, and ziprasidone on insight in first-episode schizophrenia, schizoaffective disorder, or schizophreniform disorder. The effects of five antipsychotic drugs in first episode psychosis on insight were compared in a large scale open randomized controlled trial conducted in 14 European countries: the European First-Episode Schizophrenia Trial (EUFEST). Patients with at least minimal impairments in insight were included in the present study (n=455). Insight was assessed with item G12 of the Positive and Negative Syndrome Scale (PANSS), administered at baseline and at 1, 3, 6, 9, and 12 months after randomization. The use of antipsychotics was associated with clear improvements in insight over and above improvements in other symptoms. This effect was most pronounced in the first three months of treatment, with quetiapine being significantly less effective than other drugs. Effects of spontaneous improvement cannot be ruled out due to the lack of a placebo control group, although such a large spontaneous improvement of insight would seem unlikely.

Impulsivity in schizophrenia is a risk factor for suicide, drug abuse, and other risk-taking behaviors. This exploratory, multicenter, randomized, double-blind, functional magnetic resonance imaging (fMRI) study assessed the effects of brexpiprazole on brain regions that control impulsive behavior. Thirty-eight outpatients with stable schizophrenia and impulsivity symptoms were randomized to 6 weeks of brexpiprazole 2 or 4 mg/day. The prespecified outcome measure was blood oxygen-level dependent (BOLD) activation in the right ventrolateral prefrontal cortex (VLPFC) during performance of tasks associated with inhibition/control of impulsivity: the go/no-go task and stop-signal task. Secondary objectives evaluated the efficacy, safety and tolerability of brexpiprazole. Over 6 weeks, patients receiving brexpiprazole had no statistically significant change in right VLPFC BOLD activation during the go/no-go task, but showed a significant decrease in right VLPFC BOLD activation during the stop-signal task. Brexpiprazole was also associated with significantly improved stop-signal reaction time (SSRT). No worsening of psychiatric symptoms, functioning, or impulsivity occurred in these patients. No unexpected safety or tolerability concerns were identified. In conclusion, brexpiprazole treatment among patients with schizophrenia and impulsivity was associated with decreased right VLPFC activation and decreased SSRT, supportive of a benefit of brexpiprazole on inhibition-related brain activation and behavior. ClinicalTrials.gov identifier: NCT02194933.

To evaluate functional outcomes of aripiprazole once-monthly (ARI-OM) 400 mg (ARI-OM-400) versus a sub-therapeutic dose of ARI-OM (50 mg; ARI-OM-50), oral aripiprazole (ARI), and placebo, in two trials of stable patients with schizophrenia. Detailed study designs have been reported previously. Results are reported for the double-blind, randomized phase of each study. ARI-OM is an extended-release injectable suspension given at 400 mg in the gluteal muscle. Functional outcome was measured using the Personal and Social Performance scale (PSP) and statistically analyzed using analysis of covariance with last observation carried forward. A total of 403 patients were randomized to ARI-OM-400 (n=269) or placebo (n=134) in the first (246) trial. PSP scores at endpoint significantly worsened with placebo (-6.2) versus ARI-OM-400 (-1.7; p=0.0002). In the second study (247), 662 patients were randomized to: ARI-OM-400 (n=265); ARI (n=266); or ARI-OM-50 (n=131). PSP scores with sub-therapeutic ARI-OM-50 significantly worsened (-2.39) versus ARI-OM-400 (+0.45; p=0.03). Similar functional stability was observed with ARI (+0.08). Patient functioning, as assessed by PSP, was maintained with ARI-OM in both studies but deteriorated in patients randomized to either sub-therapeutic doses or placebo, confirming the benefits of adequately dosed antipsychotic therapy in preserving functional stability in long-term management of schizophrenia.

Generalised anxiety disorder is a disease that can be associated with substantial dysfunction. Pharmacological treatment is often the first choice for clinicians because of the cost and resource constraints of psychological alternatives, but there is a paucity of comparative information for the multiple available drug choices.A systematic review and network meta-analysis was performed on randomised trials in adult outpatients with generalised anxiety disorder identified from MEDLINE, Web of Science, Cochrane Library, ClinicalTrials.gov, Chinese National Knowledge Infrastructure (CNKI), Wanfang data, [email protected] and commercial pharmaceutical registries. Placebo and active control trials were included. Data were extracted from all manuscripts and reports. Primary outcomes were efficacy (mean difference [MD] in change in Hamilton Anxiety Scale Score) and acceptability (study discontinuations for any cause). We estimated summary mean treatment differences and odds ratios using network meta-analyses with random effects. This study is registered with PROSPERO, number CRD42018087106.Studies were published between Jan 1, 1994 and Aug 1, 2017, in which 1992 potential studies were screened for inclusion. This analysis is based on 89 trials, which included 25 441 patients randomly assigned to 22 different active drugs or placebo. Duloxetine (MD −3·13, 95% credible interval [CrI] −4·13 to −2·13), pregabalin (MD −2·79, 95% CrI −3·69 to −1·91), venlafaxine (MD −2·69, 95% CrI −3·50 to −1·89), and escitalopram (MD −2·45, 95% CrI −3·27 to −1·63) were more efficacious than placebo with relatively good acceptability. Mirtazapine, sertraline, fluoxetine, buspirone, and agomelatine were also found to be efficacious and well tolerated but these findings were limited by small sample sizes. Quetiapine (MD −3·60 95% CrI −4·83 to −2·39) had the largest effect on HAM-A but it was poorly tolerated (odds ratio 1·44, 95% CrI 1·16–1·80) when compared with placebo. Likewise, paroxetine and benzodiazepines were effective but also poorly tolerated when compared with placebo. Risk of reporting bias was considered low, and when possible all completed studies were included to avoid publication bias.To our knowledge, this is the largest contemporary review of pharmacological agents for the treatment of generalised anxiety disorder by use of network analysis. There are several effective treatment choices for generalised anxiety disorder across classes of medication. The failure of initial pharmacological therapy might not be a reason to abandon a pharmacological treatment strategy.No funding was received for this research.

The Side Effects of Drugs Annuals is a series of volumes in which the adverse effects of drugs and adverse reactions to them are surveyed. The series supplements the contents of Meyler's Side Effects of Drugs: The International Encyclopedia of Adverse Drug Reactions and Interactions. This review of publications on adverse reactions to antipsychotic drugs from January 2015 to December 2015 covers amisulpride; aripiprazole; asenapine; blonanserin; brexpiprazole; cariprazine; chlorpromazine; clozapine; droperidol; flupenthixol; haloperidol; iloperidone; loxapine; lurasidone; olanzapine; paliperidone; prochlorperazine; quetiapine; risperidone; sertindole; ziprasidone; levomepromazine; chlorprothixene; clotiapine.

ObjectiveEvaluate the efficacy and long-term safety of investigational aripiprazole once-monthly (ARI-OM) for maintenance treatment in schizophrenia.MethodsPatients requiring chronic treatment for schizophrenia, not on aripiprazole monotherapy, were cross-titrated from other antipsychotic(s) to aripiprazole in an oral conversion phase (Phase 1). All patients entered an oral aripiprazole stabilization phase (Phase 2). Patients meeting stability criteria entered an ARI-OM stabilization phase (Phase 3), with coadministration of oral aripiprazole for the first 2 weeks. Patients meeting stability criteria were randomized to ARI-OM or placebo once-monthly (placebo-OM) during a 52-week, double-blind maintenance phase (Phase 4). Primary endpoint was time-to-impending relapse. Safety and tolerability were also assessed.Results710 patients entered Phase 2, 576 Phase 3 and 403 Phase 4 (ARI-OM=269, placebo-OM=134). The study was terminated early because efficacy was demonstrated by a pre-planned interim analysis. Time-to-impending relapse was significantly delayed with ARI-OM vs. placebo-OM (p< 0.0001, log-rank test). Discontinuations due to treatment-emergent adverse events (AEs) were: Phase 1, 3.8% (n=24/632); Phase 2, 3.0% (n=21/709); Phase 3, 4.9% (n=28/576); Phase 4, 7.1% (n=19/269). Most AEs were mild or moderate. Insomnia was the only AE >5% incidence in any phase. Headache, somnolence, and nausea had a peak first onset within the first 4 weeks of treatment. There were no unusual shifts in all phases in laboratory values, fasting metabolic parameters, weight, or objective scales of movement disorders.ConclusionsARI-OM significantly delayed time-to-impending relapse compared with placebo-OM and was well tolerated as maintenance treatment in schizophrenia1.

Background Hyperprolactinemia is frequent in patients with schizophrenic psychoses. It is usually regarded as an adverse effect of antipsychotics but has recently also been shown in patients without antipsychotic medication. Our objective was to test whether hyperprolactinemia occurs in antipsychotic-naive first-episode patients (FEPs). Method In the framework of the European First Episode Schizophrenia Trial (EUFEST), 249 out of 498 FEPs were eligible for this study, of whom 74 were antipsychotic naive. All patients were investigated regarding their serum prolactin levels with immunoassays standardized against the 3rd International Reference Standard 84/500. Results Twenty-nine (39%) of the 74 antipsychotic-naive patients showed hyperprolactinemia not explained by any other reason, 11 (50%) of 22 women and 18 (35%) of 52 men. Conclusions Hyperprolactinemia may be present in patients with schizophrenic psychoses independent of antipsychotic medication. It might be stress induced. As enhanced prolactin can increase dopamine release through a feedback mechanism, this could contribute to explaining how stress can trigger the outbreak of psychosis.

ObjectiveEvaluate the effectiveness of investigational aripiprazole once-monthly (ARI-OM) for maintenance treatment in schizophrenia.MethodsDetailed methodology has been published previously1. Briefly, the study consisted of 4 phases: oral conversion to aripiprazole (Phase 1); oral aripiprazole stabilization (Phase 2); ARI-OM stabilization (Phase 3), with co-administration of oral aripiprazole for the first 2 weeks; and an ARI-OM maintenance phase (Phase 4). Effectiveness assessments included Investigator's Assessment Questionnaire (IAQ) scores, a scale that evaluates effectiveness of current treatment vs. pre-trial medication, where a negative change in score signals improvement, and Personal and Social Performance (PSP) scale scores, where negative change in score signals worsening.Results710 patients entered Phase 2, 576 Phase 3 and 403 Phase 4 (ARI-OM=269, placebo once-monthly [placebo- OM]=134). Mean IAQ Total scores remained stable in Phase 2 (31.3) and Phase 3 (30.6). During Phase 4, the mean change in IAQ Total score was +1.3 for ARI-OM vs. +3.8 for placebo-OM (p< 0.0001). Mean changes in PSP Total scale scores showed improvement during Phase 2 (3.0) and Phase 3 (2.6). Mean change in PSP scores during Phase 4 showed greater functional stability with ARI-OM (−1.7) compared with placebo-OM (−6.2) (p=0.0002 vs. placebo-OM).ConclusionsImprovements in effectiveness, as assessed by the IAQ and PSP Total scale scores, in the Phases 2 & 3 were maintained in Phase 4 for ARI-OM compared with placebo-OM. Treatment with ARI-OM improved symptoms, overall response to treatment and functioning.

Studies and meta-analyses investigating the influence of substance use disorder (SUD) (substance abuse or dependence) on psychopathology and neurocognitive function in schizophrenia patients have revealed controversial results. Most studies did only have small samples and did not focus exclusively on first-episode schizophrenia patients.Method: In a post-hoc analysis of the European First Episode Schizophrenia Trial (EUFEST) psychopathology and cognitive performances of patientswith (FE-SUD, N = 119, consisting of N = 88 patientswith persisting SUD at baseline and N = 31 patients with previous SUD) and without SUD (FE-non-SUD, N = 204) were compared at baseline and 6 months follow-up. Neurocognitive assessment included the Rey Auditory Verbal Learning Test (RAVLT); Trail Making Tests A and B (TMT), Purdue Pegboard and Digit-Symbol Coding.Results: In total 31.1% of patients reported SUD, and 22.2% of patients used cannabis. There were no significant differences between patients with and without SUD concerning PANSS scores, extrapyramidal motor symptoms or neurocognitive measures except better performance in psychomotor speed (TMT-A, p = 0.033, Cohen's d = 0.26) in patients with SUD at 6 months follow-up. Interestingly, SUD patients with ongoing substance use at follow-up showed elevated positive symptoms (PANSS positive score, p = 0.008, Cohen's d = 0.84) compared to those who abstained. PANSS scores at baseline were increased in patients with an onset of SUD before the age of 16 years. In addition we found a correlation between longer duration of cannabis use and higher cognitive performance as well as reduced symptom improvement and more extrapyramidal motor symptoms in patients with higher frequency of cannabis consumption.Conclusions: FE-SUD and FE-non-SUD show similar psychopathology and neuropsychological performances at baseline and during the first 6 months of antipsychotic treatment. (C) 2013 Elsevier B. V. All rights reserved.

The population with schizophrenia is characterised by a leftward shift in handedness—sinistrality. However, findings are inconsistent in chronic patients, and familial sinistrality (FS), defined as the presence of left-handed close relatives, might contribute to the discrepancies. Therefore the aim of this study was to investigate the strength of manual lateralisation in patients with first episode schizophrenia, taking into account familial sinistrality. The Edinburgh Inventory (EI) allowed us to categorise 179 patients from the EUFEST study and 189 controls presenting “strong handedness” (SH: EI absolute value between ∣81∣ and ∣100∣) or “weak-handedness” (WH: EI value between −80 and +80). The nominal logistic regression did not show an FS effect, but a nearly significant interaction between illness and FS (p =.07). There were fewer participants without FS presenting SH among patients (99/151: 65.6%) than among controls (134/164: 81.7%, p =.001). In contrast, the number of participants with FS presenting SH was similar between controls (68%) and patients (75%, p =.57). The presence of left-handed relatives (FS + ) tended to reduce manual lateralisation, but only in controls. This supports the notion that reduced manual lateralisation in schizophrenia is related to the illness rather than to familial left-handedness.

BackgroundThis study aimed to identify the course of unmet needs by patients with a first episode of schizophrenia and to determine associated variables.MethodWe investigated baseline assessments in the European First Episode Schizophrenia Trial (EUFEST) and also follow-up interviews at 6 and 12 months. Latent class growth analysis was used to identify patient groups based on individual differences in the development of unmet needs. Multinomial logistic regression determined the predictors of group membership.ResultsFour classes were identified. Three differed in their baseline levels of unmet needs whereas the fourth had a marked decrease in such needs. Main predictors of class membership were prognosis and depression at baseline, and the quality of life and psychosocial intervention at follow-up. Depression at follow-up did not vary among classes.ConclusionsWe identified subtypes of patients with different courses of unmet needs. Prognosis of clinical improvement was a better predictor for the decline in unmet needs than was psychopathology. Needs concerning social relationships were particularly persistent in patients who remained high in their unmet needs and who lacked additional psychosocial treatment.

Background A cross-sectional study was conducted in participants with schizophrenia to explore a potential association between the patients' remission status and neurocognitive functioning and to examine whether these factors have an impact on functional outcome. Method Psychopathological symptoms were rated by means of the Positive and Negative Syndrome Scale with symptom remission being assessed by applying the severity component of the recently proposed remission criteria. Tests for the cognitive battery were selected to cover domains known to be impaired in patients with schizophrenia. Next to pre-morbid intelligence, attention performance, executive functioning, verbal fluency, verbal learning and memory, working memory and visual memory were assessed. The joint effect of remission status and neurocognitive functioning on treatment outcome was investigated by logistic regression analysis. Results Out of 140 patients included in the study, 62 were symptomatically remitted. Mean age, education and sex distribution were comparable in remitted and non-remitted patients. Remitted patients showed significantly higher values on tests of verbal fluency, alertness and optical vigilance. Both symptomatic remission as well as performance on tests of working memory and verbal memory had a significant effect on the patients' employment status. Conclusions In the present study neuropsychological measures of frontal lobe functioning were associated with symptomatic remission from schizophrenia. In addition, both symptomatic remission and performance on tests of working memory and verbal memory had a significant effect on the patients' employment status. Longitudinal follow-up data are needed to determine how the associations of these determinants of functional outcome interact and change over time.