Does drug use affect the efficacy of amisulpride, aripiprazole and olanzapine in patients with schizophrenia spectrum disorders? Results from a pragmatic, randomised study.

OBJECTIVES: Drug use is prevalent in patients with schizophrenia spectrum disorders (SSD) but there is limited knowledge about the influence of drug use on the effectiveness of antipsychotic medication. This secondary explorative study compared the effectiveness of three antipsychotics in patients with SSD, with and without drug use. METHODS: The BeSt InTro multi-centre, head to head, rater-blinded randomised study compared amisulpride, aripiprazole and olanzapine over a 1-year follow-up period. All patients (n = 144) were aged ≥18 years and met the ICD-10 criteria for SSD (F20-29). Clinical symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS). The primary outcome was reduction of a PANSS positive subscale score. RESULTS: At baseline, 38% of all patients reported drug use in the last 6 months before inclusion, with cannabis as the main drug (85%), followed by amphetamine-type stimulants (45%), sedatives (26%), hallucinogens (19%), cocaine (13%), opiates (4%), GHB (4%), solvents (4%), analgesics (4%) and anabolic steroids (2%). The predominant pattern was the use of several drugs. There were no significant overall differences in the PANSS positive subscale score reduction for the three studied antipsychotics among patients either with or without drug use. In the drug use group, older patients treated with amisulpride showed a greater PANSS positive subscale score reduction during the treatment period compared to younger patients. CONCLUSION: The current study showed that drug use does not appear to affect the overall effectiveness of amisulpride, aripiprazole and olanzapine in patients with SSD. However, amisulpride may be a particularly suitable choice for older patients with drug use.

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.

Depression trajectories and cytokines in schizophrenia spectrum disorders - A longitudinal observational study.

Depression occurs frequently in all phases of schizophrenia spectrum disorders. Altered activity in the immune system is seen in both depression and schizophrenia. We aimed to uncover depressive trajectories in a sample of 144 adult individuals with schizophrenia spectrum disorders followed for one year, in order to identify possible cytokine profile differences. Patients were assessed longitudinally with the Positive and Negative Syndrome Scale (PANSS) and the Calgary Depression Scale for Schizophrenia (CDSS), where a score above 6 predicts depression. The serum cytokine concentrations for tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, interleukin (IL)-1beta, IL-2, IL-4, IL-6, IL-10, IL-12p70 and IL-17A were measured using immunoassays. Latent growth curve models, multilevel models and latent class growth analysis (LCGA) were applied. The LCGA model supported three latent classes (trajectories) with differing CDSS profiles during the one-year follow-up: a high CDSS group (40.8 % of participants), a moderate CDSS group (43.9 %) and a low CDSS group (15.3 %). Five single PANSS items predicted affiliation to depressive trajectory: hallucinations, difficulty in abstract thinking, anxiety, guilt feelings and tension. In the high CDSS group, despite diminishing psychotic symptoms, depressive symptoms persisted throughout one year. The pro-inflammatory cytokines IFN-γ, IL-1ß and TNF-α were differentially distributed between the depressive trajectories, although levels remained remarkably stable throughout 12 months. Significant changes were found for the anti-inflammatory cytokine IL-10 at baseline with an accompanying difference in change over time. More research is required to optimize future treatment stratification and investigate the contribution of inflammation in depressed patients with schizophrenia spectrum disorders.

Association between C-reactive protein levels and antipsychotic treatment during 12 months follow-up period after acute psychosis.

BACKGROUND: A potential role of inflammatory pathways in the pathology of schizophrenia has been suggested for at least a subgroup of patients. Elevated levels of the inflammatory marker C-reactive protein (CRP) have been observed, with associations to pathogenesis and symptoms. The current evidence regarding effects of antipsychotics on CRP levels is ambiguous. OBJECTIVES: To examine and compare the influence on CRP levels of three pharmacologically diverse new generation antipsychotics during a one-year follow-up in schizophrenia spectrum disorder. METHODS: In a multicenter, pragmatic and rater-blinded randomized trial, the effects of amisulpride, aripiprazole and olanzapine were compared in 128 patients with schizophrenia spectrum disorder. All had positive symptoms of psychosis at study entry. Clinical and laboratory assessments including the measurement of CRP levels were conducted at baseline, and 1, 3, 6, 12, 26, 39, and 52 weeks thereafter. RESULTS: For all antipsychotic drugs analysed together, there was an increase in CRP levels during the one-year follow-up. Aripiprazole, as opposed to amisulpride and olanzapine, was associated with a reduced CRP level after one week, after which the CRP level caught up with the other drugs. Compared to those previously exposed to antipsychotic drugs, antipsychotic-naïve patients had lower CRP levels at all follow-up time points, but with the same temporal patterns of change. CONCLUSION: Treatment with amisulpride, aripiprazole and olanzapine showed different effects on CRP levels in patients with schizophrenia spectrum disorders, modified by previous antipsychotics exposure status. This finding suggests that antipsychotic drugs may vary with respect to their influence on pro-inflammatory pathways. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT01446328; URL: http://www. CLINICALTRIALS: gov/.

Differential Effectiveness of Atypical Antipsychotics on Hallucinations: A Pragmatic Randomized Controlled Trial.

BACKGROUND: Most studies investigating antipsychotic effectiveness report either total psychopathology or symptom cluster findings. Studies focusing on a separate symptom, such as hallucinations, a hallmark symptom in schizophrenia, are scarce.Therefore, the current study aims to compare the antihallucinatory effectiveness of 3 pharmacologically different antipsychotics: olanzapine, amisulpride, and aripiprazole. METHODS: The present study is part of the Bergen-Stavanger-Innsbruck-Trondheim study, a 12-month prospective, randomized, pragmatic antipsychotic drug trial in active-phase schizophrenia spectrum disorders. The primary outcome of the present study was change of hallucinations as measured by item P3 (hallucinatory behavior) from the Positive and Negative Syndrome Scale in the subgroup with hallucinations at baseline. Primary analyses were intention to treat. RESULTS: A total of 144 participants were included in the study, where 105 (72%) had a score of 3 or more on the Positive and Negative Syndrome Scale P3 item at baseline, indicating the presence of hallucinations (HALL subgroup).In the HALL subgroup, a significantly less reduction of hallucinations was revealed for participants using olanzapine in weeks 12, 26, 39, and 52 when compared with amisulpride and in weeks 26 and 52 when compared with aripiprazole. In subanalyses for participants never exposed to antipsychotic drugs (antipsychotic-naive) and those who had used antipsychotics before entering the study, antihallucinatory differences were revealed only in the latter group. CONCLUSIONS: A differential antihallucinatory effect of the 3 study drugs was present. The inferior effect of olanzapine seems to be driven by the subgroup of participants exposed to antipsychotic treatment before entering the study.

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.

Associations between C-reactive protein levels and cognition during the first 6 months after acute psychosis.

OBJECTIVE: Inverse relationships between the C-reactive protein (CRP) levels and cognitive performance in acute psychosis have been demonstrated. We aimed to investigate how the serum level and initial change of CRP in acutely admitted patients with psychosis was correlated with cognitive performance during a 6-months follow-up period. METHODS: The study is part of a pragmatic, randomised trial comparing four different second-generation antipsychotic drugs, and consists of 208 acute phase patients recruited at admittance for psychosis. This study reports data for all groups collectively, and does not compare treatment groups. Measurements of CRP and cognitive performance were conducted at baseline (T1) and after 4 weeks on average after inclusion (T2). Cognition was also assessed after 3 months (T3) and 6 months (T4) of follow-up. RESULTS: Global cognition improved during the follow-up period of 6 months, especially in the T1-T2 interval. The different cognitive subdomains showed different time-dependent profiles of improvement, with memory and attention improving significantly also in the later phases. Reduction of the CRP level during the initial follow-up interval (T1-T2) was associated with increased overall cognitive performance in the T2-T4 interval, but not in the T1-T2 interval. For the cognitive subdomains, we found an inverse association between change in CRP level and verbal abilities (T2-T4 interval), and attention (T2-T3 interval). CONCLUSION: These findings indicate that initial changes in the serum level of CRP in the acute phase of psychosis may predict cognitive function in later phases of the disease.

The serum level of C-reactive protein (CRP) is associated with cognitive performance in acute phase psychosis.

BACKGROUND: Inflammatory processes have been implicated in the etiology of schizophrenia and related psychoses, in which cognitive deficits represent core symptoms. The aim of the present study was to investigate possible associations between the level of the inflammation marker C-reactive protein (CRP) and cognitive performance in patients through the acute phase of psychosis. METHODS: A total of 124 patients were assessed at admittance to hospital and 62 patients were retested at discharge or after 6 weeks at the latest, with measurements of the CRP levels and alternative forms of the Repeatable Battery for the Assessment of Neuropsychological Status. RESULTS: There was an inverse relationship between overall cognitive performance and CRP level at admittance. The association increased in sub-analyses including only patients with schizophrenia. In cognitive subdomain analyses statistically significant inverse associations were found between the CRP level and Delayed memory and Attention, respectively. No associations were found between CRP level and other measures of psychopathology including psychosis symptoms, depression, or functioning. At follow-up the association between CRP level and cognition was no longer present. There was a significant increase in cognitive performance between baseline and follow-up. There was a stronger increase in overall cognition scores in patients with higher baseline CRP levels. CONCLUSIONS: The findings indicate that signs of inflammation may serve as a state-dependent marker of cognitive dysfunctions in acute psychosis. TRIAL REGISTRATION: ClinicalTrials.gov ID; NCT00932529 , registration date: 02.07.2009.