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Summary 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.

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. publishedVersion

Supplemental digital content is available in the text., 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.

ObjectiveInverse 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.MethodsThe 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.ResultsGlobal 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).ConclusionThese 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.

Childhood trauma (CT) is a risk factor for schizophrenia spectrum disorders (SSDs), and cognitive impairment is a core feature and a vulnerability marker of SSDs. Studies of the relationship between CT and cognitive impairment in SSDs are inconclusive. In addition, few studies have examined differential effects of CT subtypes, e.g. physical, sexual or emotional abuse/neglect, on cognitive functioning. The present study therefore aimed to examine the effects of CT and CT subtypes on cognitive impairment in SSD. Participants (n = 78) with SSDs completed a comprehensive neuropsychological test battery and the Childhood Trauma Questionnaire Short-Form (CTQ-SF). We compared global cognitive performance as well as scores in seven subdomains (verbal abilities, visuospatial abilities, learning, memory, attention/working memory, executive abilities and processing speed) between participants reporting no CT and those reporting CT experiences using independent samples t-tests as well as linear regression analyses to control for possible confounders. CT subtype physical neglect was associated with attention and working memory after controlling for positive and negative psychosis symptoms, years of education, antipsychotics, gender and age, and adjustment of multiple testing. Our results indicate that the observed heterogeneity in cognitive impairment in SSDs, especially attention/working memory abilities, may in part be associated with childhood physical neglect., Highlights • Research on childhood trauma and cognitive impairment in SSDs is inconclusive • Few studies investigated if CT subtypes (abuse and neglect) could explain the heterogeneity in cognitive impairment in SSDs • CT subtype physical neglect was associated with impairment in attention/working memory abilities • The observed heterogeneity in cognitive impairment in SSDs may in part be associated with CT subtypes

BACKGROUND: Schizophrenia spectrum disorders (SSDs) are characterized by cognitive impairment. However, not all patients with SSDs show cognitive impairments, and the explanation for the possible heterogeneity in cognitive functioning in SSDs is not clear. Studies have found high levels of childhood trauma (CT) in SSDs. It has been shown that CT has a detrimental effect on brain development and cognitive function. Accordingly, CT could influence the level of cognitive impairment in individuals with SSDs. Research on whether CT is associated with cognitive impairment in SSDs is inconclusive – some studies report impaired cognitive functioning, whereas other studies have found no cognitive impairment in SSDs reporting CT. Few studies have investigated if overall CT and CT subtypes, i.e. physical, sexual, emotional abuse, and physical and emotional neglect, could explain the observed variation in cognitive functioning, which was the aim of the present study. METHODS: We included 75 patients with SSDs (i.e. ICD-10 diagnoses F20-29) who completed a comprehensive neuropsychological test battery and the Childhood Trauma Questionnaire Short-Form (CTQ-SF), measuring five subtypes of CT. We divided the sample into two groups and compared patients reporting no CT (0 moderate to severe CT) to those reporting CT (1 – 5 moderate to severe CT) in relation to cognitive impairment (general cognitive functioning and seven cognitive domains: verbal abilities; visuospatial abilities; learning; memory; attention/working memory; executive abilities, and processing speed) by means of independent t-tests. CTQ-SF subscale scores and the relation to cognitive impairment were investigated by means of multiple regression analyses. RESULTS: Thirty-six (48 %) patients reported 0 (moderate - severe) CT and 39 (52 %) reported 1 – 5 (moderate – severe) CT. Preliminary results indicate that the group of patients reporting 1 – 5 CT showed impaired verbal abilities compared to the SSDs patients reporting 0 CT. Further, the CTQ-SF subscales as predictors in the regression models were examined, and we found a differential effect of CT subtypes on cognitive impairment. The effect sizes (R2) were small to moderate, ranging from .06 to .25. Comprehensive results will be presented. DISCUSSION: In our sample of patients with SSDs, the patients reporting moderate to severe CT may show impaired verbal abilities compared to the patients without CT. Further, CT subtypes may exert a differential effect on cognitive impairment.

Background Inflammatory processes have been implicated in the pathophysiology of schizophrenia and related psychosis and could be particularly relevant to the associated cognitive deficits. The C-reactive protein (CRP) serves as a general marker of inflammation, and inverse relationships between CRP levels and cognitive performance in acute psychosis have been demonstrated. Here we aimed to investigate how the serum level and initial change of CRP in acutely admitted patients with psychosis were correlated with cognitive performance during a 6-months follow-up period. Methods The study is part of a pragmatic, randomized trial comparing four different second-generation antipsychotic drugs, and consists of 208 acute phase patients recruited at admittance for psychosis (schizophrenia, schizoaffective disorder, acute and transient psychotic disorder, delusional disorder, drug-induced psychosis, bipolar disorder except for manic psychosis, or major depressive disorder with psychotic features). The present study reports data for all treatment groups collectively, and does not compare treatment groups. Measurements of CRP and cognitive performance were conducted at baseline (T1) and after an average of 4 weeks after inclusion (T2). Cognition was 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 learning (T1–T2 interval), verbal abilities (T2–T4 interval), and attention (T2–T3 interval). Discussion The main finding of the present study was that the global cognitive performance continued to improve from the initial phase (baseline to 4 weeks) of acute psychosis to the later phase (4 weeks–6 months), and was predicted by the change in CRP level that was observed during the initial phase (baseline–4 weeks) of the treatment. These findings might indicate a prolonged effect of inflammatory processes on cognition in acute psychosis, stretching beyond the initial phase. There is substantial evidence that inflammatory processes are involved in the cognitive performance in psychosis. CRP levels have been associated with cognitive impairment in patients with schizophrenia. Conclusions These findings indicate that initial changes in the serum level of CRP in the acute phase of psychosis may predict cognitive functioning in later phases of the disease.

Background Cognitive impairment is a core feature of schizophrenia spectrum disorders (SSDs). Exposure to childhood trauma (CT), defined as physical, sexual and emotional abuse, and physical and emotional neglect, has been associated with SSDs across study designs and populations. Possibly, there is a relationship between exposure to CT and cognitive impairment in individuals with SSDs. Research has shown that a history of CT may be related to decline in cognitive performance in the general population, as well as in SSDs, whereas other studies have failed to find evidence for an association between CT and cognitive impairments in patients with SSDs. Findings on the relation between CT and cognitive impairment in individuals with SSDs is not conclusive, and a minority of the studies to date have examined the effects of frequency and severity of CT subtypes in SSDs and the relation to cognitive abilities. We hypothesize that there will be a negative relationship between the frequency and severity of CT and cognitive functioning, possibly in a dose dependent matter. CT subtypes may influence this relationship. Methods The present study is part of the Bergen Psychosis project 2 (BP2), Haukeland University Hospital, Norway. Patients were recruited at the Medical University in Innsbruck, Innsbruck, Austria; Stavanger University Hospital, Stavanger, Norway; and Haukeland University Hospital, Bergen, Norway, and gave informed consent to participate. To be included, patients had to meet ICD-10 criteria for SSDs (F20-F29), be > 16 years of age, and score ≥ 4 on at least one of the psychosis items on the Positive and Negative Syndrome Scale (PANSS). Childhood trauma (physical, emotional, sexual abuse, and physical, emotional neglect) was measured by the Childhood Trauma Questionnaire Short-Form (CTQ-SF). Cognitive functioning was examined by means of a comprehensive neuropsychological test battery. The following cognitive domains were assessed: verbal and visuospatial abilities, learning, memory, attention and working memory, executive functioning, and processing speed. The assessments were completed within three months of inclusion to the study. Results The relationship between the frequency and severity of CT and cognition will be examined, in addition to the possible influence of CT subtypes. Preliminary findings will be reported. Discussion The clinical implications of our findings will be discussed.

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 publishedVersion

Background: Mounting evidence shows that immunological pathways including inflammatory mechanisms are involved in the pathophysiology, and possible also in the etiology of schizophrenia spectrum disorders. Underpinnings for this hypotheses stem from different studies of patients with schizophrenia vs healthy controls; eg, from findings in genetic studies (Schizophrenia Working Group of the Psychiatric Genomics, 2014; Hwang et al, 2013), postmortem studies of brain tissue, and from findings of modestly elevated proinflammatory cytokines in peripheral blood: interleukin (IL)-1β, IL-6, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α (Upthegrove et al, 2014). Also their soluble and circulating receptors, eg, TNFsR1 and IL1sR1, which also are known to have an anti-inflammatory role, are used to assess peripheral inflammation, together with additional cytokines as IL-2, IL-4, and Il-10. Antipsychotic treatment has been found to reduce proinflammatory cytokines (Miller et al, 2011; Tourjman et al, 2013), the studies reviewed by Miller et al had a mean duration of 53 days. However, also conflicting evidence of the effects of antipsychotic treatment on cytokines has been found (Baumeister et al, 2016), and the purpose of the study was to evaluate the influence of antipsychotic treatment on peripheral cytokines early in the antipsychotic treatment periode.