Antidepressive Effectiveness of Amisulpride, Aripiprazole, and Olanzapine in Patients With Schizophrenia Spectrum Disorders: A Secondary Outcome Analysis of a Pragmatic, Randomized Trial (BeSt InTro).

BACKGROUND: Depressive symptoms are frequent in schizophrenia and associated with a poorer outcome. Currently, the optimal treatment for depressive symptoms in schizophrenia remains undetermined. Amisulpride, aripiprazole, and olanzapine all have antidepressive pharmacodynamic properties, ranging from serotonergic affinities to limbic dopaminergic selectivity. Consequently, in a 12-month pragmatic, randomized clinical trial, we aimed to investigate differences in antidepressive effectiveness among amisulpride, aripiprazole, and olanzapine as a secondary outcome, measured by change in the Calgary Depression Scale for Schizophrenia sum score in patients within the schizophrenia spectrum. METHODS: Psychotic patients within the schizophrenia spectrum were included, and effectiveness was analyzed with latent growth curve modeling. RESULTS: Of the 144 patients, 51 (35%) were women, the mean age was 31.7 (SD 12.7), and 39% were antipsychotic naive. At inclusion, 68 (47%) participants had a Calgary Depression Scale for Schizophrenia sum score >6, indicating severe depressive symptoms. Across the 12-month follow-up, there was a depressive symptom reduction in all medication groups, but no statistically significant differences between the study drugs. Separate analyses of the subcohort with elevated depressive symptoms at inclusion also failed to find differences in depressive symptom reduction between study drugs. The reduction in depressive symptoms mainly occurred within 6 weeks after randomization. CONCLUSIONS: There was a reduction in depressive symptoms under treatment with amisulpride, aripiprazole, and olanzapine in acutely psychotic patients with schizophrenia spectrum disorder, but no differences between the drugs.

High Scores on the Montgomery-Åsberg Depression Rating Scale and Psychotic Symptoms Predict Suicide: A Prospective Cohort Study of Psychiatric Acute Ward Patients.

Objective: To investigate the role of depression severity in suicide risk by studying the predictive value of psychotic symptoms and depression scale scores, controlled for suicidal behavior and gender.Methods: We conducted a prospective cohort study of consecutive psychiatric acute ward admissions between 2005 and 2014 from a Norwegian catchment area. Inclusion criteria were an ICD-10 diagnosis of unipolar or bipolar depression with a current depressive episode (n = 1,846); depression severity was measured by the Montgomery-Åsberg Depression Rating Scale (MADRS). Patients were assessed for suicidal ideation/planning, self-harm, and recent suicide attempts on admission. Mean follow-up time was 5.5 years (minimum/maximum: 0/10.6 years). We used Cox regression analyses and Kaplan-Meier analyses to explore potential predictors and time to suicide.Results: During the follow-up period, 46 patients died by suicide, 30 (65%) of these within the year following admission. Psychotic depression (P = .014), admission MADRS score (P = .006), suicide attempts (P = .021), and male sex (P = .043) significantly predicted suicide. Suicidal ideation and self-harm did not predict suicide. The cumulative suicide risk in psychotic depression was 1.7% after 12 weeks and 3.0% after 52 weeks.Conclusions: Depression severity as measured with the MADRS or a diagnosis of psychotic depression independently predicted suicide. More suicides may be prevented by implementing intensive treatment and post-discharge follow-up for patients who present to psychiatric acute wards with severe depressive episodes and recent suicide attempts, regardless of self-reported suicidal ideation, suicide plans, and self-harm.

The association between cytokines and psychomotor speed in a spectrum of psychotic disorders: A longitudinal study.

BACKGROUND: In schizophrenia, impaired psychomotor speed is a common symptom predicting worse functional outcome. Inflammation causes changes in white matter integrity, which may lead to reduced psychomotor speed. Therefore, we wanted to investigate if peripheral inflammation assessed with cytokines affected performance on psychomotor speed in patients with a spectrum of psychotic disorders. METHODS: The current study is a prospective cohort study, including participants from a pragmatic, randomised controlled trial comparing three atypical antipsychotics in patients with a spectrum of psychotic disorders. For the purposes of this sub-study, we analysed drug treatment groups collectively. Psychomotor speed was assessed at baseline, and at weeks 6, 12, 26 and 52 of follow-up, using the neuropsychological tests trail making test (TMT) A and B, and symbol coding. Serum concentration of the following cytokines were measured: interleukin (IL)-ß, IL-2, IL-4, IL-6, IL-10, IL12 p70, IL-17a, interferon (IFN)-γ and tumor necrosis factor (TNF)-α. Blood samples were collected at baseline and after 1, 3, 6, 12, 26, 39 and 52 weeks. We analysed the effect of cytokines levels on psychomotor speed over time in linear mixed effects models. RESULTS: In our linear mixed effects models controlling for possible confounders, IFN-γ had a significant negative effect on TMT-A and symbol coding performance. None of the other tests for psychomotor speed were significantly associated with cytokines. Overall psychomotor speed performance increased significantly across the study period while cytokine levels remained stable. CONCLUSION: Our study indicates a negative association between IFN-γ and psychomotor speed, which might be of importance when understanding the mechanisms behind psychomotor deviations in psychotic disorders.

Cognitive change and antipsychotic medications: Results from a pragmatic rater-blind RCT.

Cognitive impairment is a core aspect of psychotic disorders and difficult to treat. Atypical antipsychotics (AAs) might have differential effects on cognitive impairment, but rigid study designs and selective sampling limit the generalizability of existing findings. This pragmatic, semi-randomized, industry-independent study aimed to investigate and compare the effect of amisulpride, aripiprazole and olanzapine on cognitive performance in psychosis over a 12-month period controlling for diagnostic group. This sub study of the BeSt InTro study recruited adults with ongoing psychosis in the schizophrenia spectrum of disorders (ICD-10 diagnoses F20-F23, F25, F28 or F29; n = 104) from Bergen and Stavanger, Norway; and Innsbruck, Austria. Participants were randomized to amisulpride, aripiprazole, or olanzapine and they completed neuropsychological assessments at baseline, 6 weeks, 6 and 12 months. The test battery targeted working memory, verbal ability, and processing speed. We used Longitudinal mixed effect (LME) models to assess cognitive change for intention to treat (ITT) and per protocol (PP) medication groups, as well as comparing cognitive performance between F20 and non-F20 participants. The sample baseline global cognitive performance t-score was 42.20. Global performance improved significantly to every follow-up, including for the F20 group. There were however no significant differences in cognitive change over time between neither ITT nor PP medication groups.

Amisulpride, aripiprazole, and olanzapine in patients with schizophrenia-spectrum disorders (BeSt InTro): a pragmatic, rater-blind, semi-randomised trial.

BACKGROUND: Amisulpride, aripiprazole, and olanzapine are first-line atypical antipsychotics that have not previously been compared head-to-head in a pragmatic trial. We aimed to compare the efficacy and safety of these agents in a controlled trial. METHODS: This pragmatic, rater-blind, randomised controlled trial was done in three academic centres of psychiatry in Norway, and one in Austria. Eligible patients were aged 18 years or older, met ICD-10 criteria for schizophrenia-spectrum disorders (F20-29), and had symptoms of active psychosis. Eligible patients were randomly assigned to receive oral amisulpride, aripiprazole, or olanzapine. Treatment allocation was open to patients and staff, and starting dose, treatment changes, and adjustments were left to the discretion of the treating physician. Computer-generated randomisation lists for each study centre were prepared by independent statisticians. Patients were followed up for 52 weeks after random assignment, during which assessments were done 8 times by researchers masked to treatment. The primary outcome was reduction of the Positive And Negative Syndrome Scale (PANSS) total score at 52 weeks, and primary analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01446328. FINDINGS: Between Oct 20, 2011, and Dec 30, 2016, we assessed 359 patients for eligibility. 215 patients were excluded (107 did not meet inclusion criteria, 82 declined to participate, 26 other reasons). 144 patients (mean baseline PANSS total estimated score 78·4 [SD 1·4]) were randomly assigned 1:1:1 to receive amisulpride (44 patients), aripiprazole (48 patients) or olanzapine (52 patients). After 52 weeks, the patients allocated to amisulpride had a PANSS total score reduction of 32·7 points (SD 3·1) compared with 21·9 points reduction with aripiprazole (SD 3·9, p=0·027) and 23·3 points with olanzapine (2·9, p=0·025). We observed weight gain and increases of serum lipids and prolactin in all groups. 26 serious adverse events (SAEs) among 20 patients were registered (four [9%] of 44 patients allocated to amisulpride, ten [21%] of 48 patients allocated to aripiprazole, and six [12%] of 52 patients allocated to olanzapine), with no statistically significant differences between the study drugs. 17 (65%) of the 26 SAEs occurred during the use of the study drug, with readmission or protracted hospital admission accounting for 13 SAEs. One death by suicide, one unspecified death, and one life-threatening accident occurred during follow-up, after cessation of treatment. INTERPRETATION: Amisulpride was more efficacious than aripiprazole or olanzapine for reducing the PANSS total scores in adults with schizophrenia-spectrum disorders. Side-effect differences among the groups were generally small. This study supports the notion that clinically relevant efficacy differences exist between antipsychotic drugs. Future research should aim to compare first-line antipsychotics directly in pragmatic clinical trials that reflect everyday clinical practice. FUNDING: The Research Council of Norway, the Western Norway Regional Health Trust, and participating hospitals and universities.

Cognitive Profile in Ultra High Risk for Psychosis and Schizophrenia: A Comparison Using Coordinated Norms.

Background: Cognitive impairment is not only a core aspect of schizophrenia but also commonly observed in help-seeking youth at ultra high risk for psychosis (UHR), with potential implications for prognosis and individualized treatment. However, there is no consensus on the cognitive profile in the UHR state, partly due to lack of valid comparisons of performance in established schizophrenia and UHR. Objectives: To compare the cognitive functioning and profile of UHR subjects to a sample with schizophrenia, they were split into two groups based on duration of illness. Comparisons were made using coordinated norms based on healthy controls reflecting the younger UHR age spectrum. Methods: Participants for UHR (n = 51) and schizophrenia groups (n = 19 and n = 22) were included from the Prevention of Psychosis and Bergen Psychosis 2 projects. All subjects completed a comprehensive neurocognitive test battery aiming to measure speed of processing, working memory, verbal learning, reasoning, and problem solving, as well as visual problem solving. Cognitive functioning was compared between groups based on coordinated norms using z-scores derived by regression modeling from an age-matched healthy control group (n = 61). Results: UHR subjects showed significantly impaired speed of processing (p < 0.001) working memory (p = 0.042) and verbal learning, reasoning, and problem solving (p = 0.007) as compared to the control group. Visual problem-solving skills appeared unimpaired. UHR subjects significantly outperformed the schizophrenia group with duration of illness >3 years for speed of processing and working memory (both p < 0.001). There were no significant differences in performance between the UHR group and the group with duration of schizophrenia <3 years. Conclusion: Cognitive performance is impaired in UHR subjects as compared to healthy controls and should thus be monitored when a person is deemed at high risk of psychotic illness. Spatial skills, as measured by tests using physical objects, appear less affected than other domains. The pattern of impairment is similar to that of a group with recent onset schizophrenia but is less severe than in a group with duration of illness <3 years.

Public attitudes towards involuntary admission and treatment by mental health services in Norway.

PURPOSE: The role of compulsory treatment of serious mental disorders has been the topic of ongoing public debate involving among others mental health professionals, service providers, service user advocates, relatives of service users, media commentators and politicians. However, relatively little is known about general public attitudes towards involuntary admission and compulsory treatment of people with various mental disorders. This article examines the attitudes in a representative sample of Norway's population towards the use of involuntary admission and treatment, and under which circumstances does the general public consider compulsory treatment to be justified in the Norwegian mental health care services. METHOD: Data were collected from a representative sample of the population in Norway aged 18 and older. The sample was stratified for gender, geographical region and age distribution (n=2001). The survey was performed in the months of May 2009 (n=1000) and May 2011 (n=1001), using Computer Assisted Telephone Interviews (CATI) by an independent polling company. All respondents were provided a general definition of coercive intervention before the interview was conducted. ANALYSIS: Univariate descriptions and bivariate analyses were performed by means of cross-tabulation, analysis of variance (one-way ANOVA) and comparing of group of means. Cohen's d was used as the measure for effect size. RESULTS: Between 87% and 97% of those surveyed expressed strong or partial agreement with the use of involuntary admissions or compulsory treatment related to specified cases and situations. The majority of interviewees (56%) expressed the opinion that overall, current levels are acceptable. A further, 34% were of the opinion that current levels are too low, while only 9.9% of respondents supported a reduction in the level of involuntary treatment. Lower levels of education were associated with a more positive attitude towards involuntary admission and treatment. There was stronger support for admission to prevent suicide than the possibility of violence by the mentally ill. CONCLUSION: The Norwegian adult population largely supports current legislation and practices regarding involuntary admission and compulsory treatment in the mental health services.

The Course of Neurocognitive Changes in Acute Psychosis: Relation to Symptomatic Improvement.

INTRODUCTION: Cognitive impairment is a core aspect of psychosis, but the course of cognitive functioning during acute psychosis remains poorly understood, as does the association between symptom change and neurocognitive change. Some studies have found cognitive improvement to be related to improvement in negative symptoms, but few have examined cognitive changes in the early acute phase, when clinical improvement mainly happens. This study's aim was to investigate the relation between cognitive and symptomatic change in clinically heterogeneous patients during the early acute phase of psychosis. METHOD: Participants (n = 84), including both first-episode and previously ill patients, were recruited from consecutive admissions to the acute psychiatric emergency ward of Haukeland University Hospital, Bergen, Norway, as part of the Bergen Psychosis Project (BPP). The RBANS neurocognitive test battery was administered on admission and again at discharge from the acute ward (mean time 4.1 weeks, SD 1.86 weeks). Symptomatic change was measured by PANSS. RESULTS: The proportion of subjects with cognitive impairment (t < 35) was 28.6% in the acute phase and 13.1% at follow-up. A sequential multiple linear regression model with RBANS change as the dependent variable found PANSS negative symptoms change to significantly predict total RBANS performance improvement (beta = -.307, p = .016). There was no significant difference between subjects with schizophrenia and those with other psychotic disorders in terms of cognitive change. CONCLUSION: The proportion of subjects with mild to moderate impairment in cognitive test performance is reduced across the acute phase of psychosis, with improvement related to amelioration of negative symptoms.

"Everyone Needs a Friend Sometimes" - Social Predictors of Long-Term Remission In First Episode Psychosis.

Background: Predictors of long-term symptomatic remission are crucial to the successful tailoring of treatment in first episode psychosis. There is lack of studies distinguishing the predictive effects of different social factors. This prevents a valid evaluating of their independent effects. Objectives: To test specific social baseline predictors of long-term remission. We hypothesized that first, satisfaction with social relations predicts remission; second, that frequency of social interaction predicts remission; and third, that the effect of friend relationship satisfaction and frequency will be greater than that of family relations satisfaction and frequency. Material and Methods: A sample of first episode psychosis (n = 186) completed baseline measures of social functioning, as well as clinical assessments. We compared groups of remitted and non-remitted individuals using generalized estimating equations analyses. Results: Frequency of social interaction with friends was a significant positive predictor of remission over a two-year period. Neither global perceived social satisfaction nor frequency of family interaction showed significant effects. Conclusions: The study findings are of particular clinical importance since frequency of friendship interaction is a possibly malleable factor. Frequency of interaction could be affected through behavioral modification and therapy already from an early stage in the course, and thus increase remission rates.

Visual Hallucinations in First-Episode Psychosis: Association with Childhood Trauma.

BACKGROUND: Hallucinations are a core diagnostic criterion for psychotic disorders and have been investigated with regard to its association with childhood trauma in first-episode psychosis samples. Research has largely focused on auditory hallucinations, while specific investigations of visual hallucinations in first-episode psychosis remain scarce. OBJECTIVES: The aims of this study were to describe the prevalence of visual hallucinations, and to explore the association between visual hallucination and childhood trauma in a first-episode psychosis sample. METHODS: Subjects were included from TIPS-2, a first episode psychosis study in south Rogaland, Norway. Based on the medical journal descriptions of the Positive and Negative Symptoms Scale (PANSS), a separate score for visual and auditory hallucinations was created (N = 204). Patients were grouped according to hallucination severity (none, mild, and psychotic hallucinations) and multinomial logistic regression was performed to identify factors associated with visual hallucination group. RESULTS: Visual hallucinations of a psychotic nature were reported by 26.5% of patients. The experience of childhood interpersonal trauma increased the likelihood of having psychotic visual hallucinations. CONCLUSION: Visual hallucinations are common in first-episode psychosis, and are related to childhood interpersonal trauma.

Verbal working memory deficits predict levels of auditory hallucination in first-episode psychosis.

BACKGROUND: Auditory verbal hallucinations are a characteristic symptom in schizophrenia. Recent causal models of auditory verbal hallucinations propose that cognitive mechanisms involving verbal working memory are involved in the genesis of auditory verbal hallucinations. Thus, in the present study, we investigate the hypothesis that verbal working memory is a specific factor behind auditory verbal hallucinations. METHODS: In the present study, we investigated the association between verbal working memory manipulation (Backward Digit Span and Letter-Number Sequencing) and auditory verbal hallucinations in a population study (N=52) of first episode psychosis. The degree of auditory verbal hallucination as reported in the P3-subscale of the PANSS interview was included as dependent variable using sequential multiple regression, while controlling for age, psychosis symptom severity, executive cognitive functions and simple auditory working memory span. RESULTS: Multiple sequential regression analyses revealed verbal working memory manipulation to be the only significant predictor of verbal hallucination severity. CONCLUSIONS: Consistent with cognitive data from auditory verbal hallucinations in healthy individuals, the present results suggest a specific association between auditory verbal hallucinations, and cognitive processes involving the manipulation of phonological representations during a verbal working memory task.