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Abstract Background Auditory verbal hallucinations, which frequently involve negative emotions, are reliable symptoms of schizophrenia. Brain asymmetries have also been linked to the condition, but the relevance of asymmetries within the amygdala, which coordinates all emotional signals, to the content of and response to auditory verbal hallucinations has not been explored. Methods We evaluated the performance of two asymmetry biomarkers that were recently introduced in literature: the distance index, which captures global asymmetries, and a revised version of the laterality index, which captures left–right local asymmetries. We deployed random forest regression models over values computed with the distance index and with the laterality index over amygdala nuclei volumes (lateral, basal, accessory-basal, anterior amygdaloid area, central, medial, cortical, cortico-amygdaloid area, and paralaminar) for 71 patients and 71 age-matched controls. Results Both biomarkers made successful predictions for the 35 items of the revised version of the Belief About Voices Questionnaire, such that hallucination severity increased with increasing local asymmetries and with decreasing global asymmetries of the amygdala. Conclusions Our findings highlight a global reorganization of the amygdala, where left and right nuclei volumes differ pairwise but become proportionally more similar as hallucinations increase in severity. Identifying asymmetries in particular brain structures relevant to specific symptoms could help monitor the evolution and outcome of psychopathological conditions.

Abstract Background Antipsychotic treatment may improve clinical insight. However, previous studies have reported inconclusive findings on whether antipsychotics improve insight over and above the reduction in symptoms of psychosis. These studies assessed homogeneous samples in terms of stage of illness. Randomised studies investigating a mixed population of first- and multiepisode schizophrenia spectrum disorders might clarify this disagreement. Methods Our data were derived from a pragmatic, rater-blinded, semi-randomised trial that compared the effectiveness of amisulpride, aripiprazole and olanzapine. A sample of 144 patients with first- or multiepisode schizophrenia spectrum disorders underwent eight assessments during a 1-year follow-up. Clinical insight was assessed by item General 12 from the Positive and Negative Syndrome Scale (PANSS). We analysed latent growth curve models to test if the medications had a direct effect on insight that was over and above the reduction in total psychosis symptoms. Furthermore, we investigated whether there were differences between the study drugs in terms of insight. Results Based on allocation analysis, all three drugs were associated with a reduction in total psychosis symptoms in the initial phase (weeks 0–6). Amisulpride and olanzapine were associated with improved insight over and above what was related to the reduction in total psychosis symptoms in the long-term phase (weeks 6–52). However, these differential effects were lost when only including the participants that chose the first drug in the randomisation sequence. We found no differential effect on insight among those who were antipsychotic-naïve and those who were previously medicated with antipsychotics. Conclusions Our results suggest that antipsychotic treatment improves insight, but whether the effect on insight surpasses the effect of reduced total psychosis symptoms is more uncertain. Trial registration ClinicalTrials.gov Identifier: NCT01446328, 05.10.2011.

Abstract Current guidelines for patients with schizophrenia spectrum disease do not take sex differences into account, which may result in inappropriate sex-specific treatment. In the BeSt InTro study, a total of 144 patients (93 men and 51 women) with a schizophrenia spectrum diagnosis and ongoing psychosis were included and randomized to amisulpride, aripiprazole, or olanzapine in flexible dose. This trial is registered with ClinicalTrials.gov (NCT01446328). Primary outcomes were sex differences in dose, dose-corrected serum levels, efficacy, and tolerability. Dosing was higher for men than for women in the aripiprazole group (p = 0.025) and, at trend level, in the olanzapine group (p = 0.056). Dose-corrected serum levels were 71.9% higher in women than in men for amisulpride (p = 0.019) and 55.8% higher in women than in men for aripiprazole (p = 0.049). In the amisulpride group, men had a faster decrease in psychotic symptoms than women (p = 0.003). Moreover, amisulpride was more effective than the other medications in men but not in women. Prolactin levels were higher in women than in men, especially for amisulpride (p

Background: Auditory verbal hallucinations (AVH) have been linked to aberrant interhemispheric connectivity between the left and the right superior temporal gyrus (STG), labeled the interhemispheric miscommunication theory. The present study investigated if interhemispheric miscommunication is modulated at the neurochemical level by glutamate (Glu) and gamma-aminobutyric acid (GABA) concentrations in temporal and prefrontal lobe areas, as proposed by the theory.Methods: We combined resting-state fMRI connectivity with MR spectroscopy (MRS) in a sample of 81 psychosis patients, comparing patients with high hallucination severity (high-AVH) and low hallucination severity (low-AVH) groups. Glu and GABA concentrations were acquired from the left STG and the anterior cingulate cortex (ACC), an area of cognitive control that has been proposed to modulate STG functioning in AVH.Results: Functional connectivity showed significant interaction effects between AVH Group and ACC-recorded Glu and GABA metabolites. Follow-up tests showed that there was a significant positive association for Glu concentration and interhemispheric STG connectivity in the high-AVH group, while there was a significant negative association for GABA concentration and interhemispheric STG connectivity in the low-AVH group.Conclusion: The results show neurochemical modulation of STG interhemispheric connectivity, as predicted by the interhemispheric miscommunication hypothesis. Furthermore, the findings are in line with an excitatory/inhibitory imbalance model for AVH. By combining different neuroimaging modalities, the current results provide a more comprehensive insight into the neural correlates of AVH.

There is a wealth of evidence showing aberrant functional connectivity (FC) in schizophrenia but with considerable variability in findings across studies. Dynamic FC is an extension of traditional static FC, in that such analyses allow for explorations of temporal changes in connectivity. Thereby they also provide more detailed information on connectivity abnormalities in psychiatric disorders such as schizophrenia. The current study investigated dynamic FC in a sample of 80 schizophrenia patients and 80 matched healthy control subjects, replicating previous findings of aberrant dwell times in specific FC states, and further supporting a role for default mode network (DMN) dysfunction. Furthermore, relationships with hallucinations, a core symptom of schizophrenia, were explored. Two measures of hallucinations were used, one measure of current hallucination severity assessed on the day of scanning, and one trait-measure where hallucinations were assessed repeatedly over the course of 1 year. Current hallucination severity did not show a significant relationship with dynamic FC. However, the trait-measure of hallucination proneness over 1 year showed a significant relationship with dynamic FC. Patients with high hallucination proneness spent less time in connectivity states characterized by strong anti-correlation between the DMN and task-positive networks. The findings support theoretical models of hallucinations which have proposed an instability of the DMN and impaired cognitive control in patients with hallucinations. Furthermore, the results point to hallucination proneness as a potential marker for identifying distinct subgroups of schizophrenia patients.

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

Schizophrenia is considered a syndrome comprised by several disease phenotypes, covering a range of underlying pathologies. One of these disease mechanisms seems to involve immune dysregulation and neuroinflammation. While the current dopamine receptor-blocking antipsychotic drugs decrease psychotic symptoms and prevent relapse in the majority of patients with schizophrenia, there is a huge need to explore new treatment options that target other pathophysiological pathways. Such studies should aim at identifying robust biomarkers in order to diagnose and monitor the immune biophenotype in schizophrenia and develop better selection procedures for clinical trials with anti-inflammatory and immune-modulating drugs. In this focused review, we describe available methods to assess inflammatory status and immune disturbances in vivo. We also outline findings of immune disturbances and signs of inflammation at cellular, protein, and brain imaging levels in patients with schizophrenia. Furthermore, we summarize the results from studies with anti-inflammatory or other immune-modulating drugs, highlighting how such studies have dealt with participant selection. Finally, we propose a strategy to construct an immune signature that may be helpful in selecting and monitoring participants in studies with immune modulating drugs and also applicable in regular clinical work.

There is a high prevalence of cannabis use reported in non-affective psychosis. Early prospective longitudinal studies conclude that cannabis use is a risk factor for psychosis, and neurochemical studies on cannabis have suggested potential mechanisms for this effect. Recent advances in the field of neuroscience and genetics may have important implications for our understanding of this relationship. Importantly, we need to better understand the vulnerability x cannabis interaction to shed light on the mediators of cannabis as a risk factor for psychosis. Thus, the present study reviews recent literature on several variables relevant for understanding the relationship between cannabis and psychosis, including age of onset, cognition, brain functioning, family history, genetics and neurological soft signs (NSS) in non-affective psychosis. Compared with non-using non-affective psychosis, the present review shows that there seem to be fewer stable cognitive deficits in patients with cannabis use and psychosis, in addition to fewer NSS and possibly more normalized brain functioning, indicating less neurobiological vulnerability for psychosis. There are, however, some familiar and genetic vulnerabilities present in the cannabis psychosis group which may influence the cannabis pathway to psychosis by increasing sensitivity to cannabis. Furthermore, an earlier age of onset suggests a different pathway to psychosis in the cannabis-using patients. Two alternative vulnerability models are presented to integrate these seemingly paradoxical findings.

QTc interval prolongation is a side effect of several antipsychotic drugs, with associated risks of torsade de pointes arrhythmias and sudden cardiac death. There is an ongoing debate of whether or not electrocardiogram (ECG) assessments should be mandatory in patients starting antipsychotic drugs. To investigate QTc prolongation in a clinically relevant patient group 171 adult patients acutely admitted to an emergency ward for psychosis were consecutively recruited. ECGs were recorded at baseline and then at discharge or after 6 weeks at the latest (discharge/6 weeks), thus reflecting the acute phase treatment period. The mean QTc interval was 421.1 (30.4) ms at baseline and there was a positive association between the QTc interval and the agitation score whereas the QTc interval was inversely associated with the serum calcium level. A total of 11.6% had abnormally prolonged QTc intervals and another 14.3% had borderline prolongation. At discharge/6 weeks, the corresponding proportions were reduced to 4.2% and 5.3%, respectively. The reduction of the proportion with prolonged QTc intervals reached statistical significance (chi-square exact test: P=0.046). The finding of about one-quarter of the patients with borderline or prolonged QTc intervals could indicate mandatory ECG recordings in this population. This trial is registered with ClinicalTrials.gov ID: NCT00932529.

Priapism is a rare but important side effect of antipsychotic drugs which may evolve into a urological emergency. Most antipsychotic drugs are alpha-1 adrenergic antagonists, which is thought to be the principal mechanism involved in antipsychotic-induced priapism. Other aetiologies exist, however. A case is presented with multiple episodes of priapism during the use of several different antipsychotic drugs. The case is representative of many patients treated with antipsychotic drugs, as there were hyperprolactinemia, and illicit drug use, which are known causes of priapism. Moreover, the patient used combinations of antipsychotic drugs. The case thus illustrates the etiological complexity which could delay a diagnosis of antipsychotic-induced priapism, and the problem of establishing a link between priapism and one particular ingredient of a drug combination. The case presents how a treatment regimen was finally established balancing antipsychotic efficacy to acceptable side effects and offers guidance to physicians regarding how antipsychotic-induced priapism may be resolved.

Abstract Background Efficacy studies indicate anti-depressive effects of at least some second generation antipsychotics (SGAs). The Bergen Psychosis Project (BPP) is a 24-month, pragmatic, industry-independent, randomized, head-to-head comparison of olanzapine, quetiapine, risperidone and ziprasidone in patients acutely admitted with psychosis. The aim of the study is to investigate whether differential anti-depressive effectiveness exists among SGAs in a clinically relevant sample of patients acutely admitted with psychosis. Methods Adult patients acutely admitted to an emergency ward for psychosis were randomized to olanzapine, quetiapine, risperidone or ziprasidone and followed for up to 2 years. Participants were assessed repeatedly using the Positive and Negative Syndrome Scale - Depression factor (PANSS-D) and the Calgary Depression Scale for Schizophrenia (CDSS). Results A total of 226 patients were included. A significant time-effect showing a steady decline in depressive symptoms in all medication groups was demonstrated. There were no substantial differences among the SGAs in reducing the PANSS-D score or the CDSS sum score. Separate analyses of groups with CDSS sum scores > 6 or ≤6, respectively, reflecting degree of depressive morbidity, revealed essentially identical results to the primary analyses. There was a high correlation between the PANSS-D and the CDSS sum score (r = 0.77; p < 0.01). Conclusions There was no substantial difference in anti-depressive effectiveness among olanzapine, quetiapine, risperidone or ziprasidone in this clinically relevant sample of patients acutely admitted to hospital for symptoms of psychosis. Based on our findings we can make no recommendations concerning choice of any particular SGA for targeting symptoms of depression in a patient acutely admitted with psychosis. Trial Registration ClinicalTrials.gov ID; URL: http://www.clinicaltrials.gov/: NCT00932529

Abstract Background No clear recommendations exist regarding which antipsychotic drug should be prescribed first for a patient suffering from psychosis. The primary aims of this naturalistic study were to assess the head-to-head effectiveness of first-line second-generation antipsychotics with regards to time until drug discontinuation, duration of index admission, time until readmission, change of psychopathology scores and tolerability outcomes. Methods Patients ≥ 18 years of age admitted to the emergency ward for symptoms of psychosis were consecutively randomized to risperidone (n = 53), olanzapine (n = 52), quetiapine (n = 50), or ziprasidone (n = 58), and followed for up to 2 years. Results A total of 213 patients were included, of which 68% were males. The sample represented a diverse population suffering from psychosis. At admittance the mean Positive and Negative Syndrome Scale (PANSS) total score was 74 points and 44% were antipsychotic drug naïve. The primary intention-to-treat analyses revealed no substantial differences between the drugs regarding the times until discontinuation of initial drug, until discharge from index admission, or until readmission. Quetiapine was superior to risperidone and olanzapine in reducing the PANSS total score and the positive subscore. Quetiapine was superior to the other drugs in decreasing the PANSS general psychopathology subscore; in decreasing the Clinical Global Impression - Severity of Illness scale score (CGI-S); and in increasing the Global Assessment of Functioning - Split version, Functions scale score (GAF-F). Ziprasidone was superior to risperidone in decreasing the PANSS positive symptoms subscore and the CGI-S score, and in increasing the GAF-F score. The drugs performed equally with regards to most tolerability outcomes except a higher increase of hip-circumference per day for olanzapine compared to risperidone, and more galactorrhoea for risperidone compared to the other groups. Conclusions Quetiapine appears to be a good starting drug candidate in this sample of patients admitted to hospital for symptoms of psychosis. Trial Registration ClinicalTrials.gov ID; URL: http://www.clinicaltrials.gov/: NCT00932529

Abstract Background Surveys on prescription patterns for antipsychotics in the Scandinavian public health system are scarce despite the prevalent use of these drugs. The clinical differences between antipsychotic drugs are mainly in the areas of safety and tolerability, and international guidelines for the treatment of schizophrenia offer rational strategies to minimize the burden of side effects related to antipsychotic treatment. The implementation of treatment guidelines in clinical practice have proven difficult to achieve, as reflected by major variations in the prescription patterns of antipsychotics between different comparable regions and countries. The objective of this study was to evaluate the practice of treatment of schizophrenic patients with antipsychotics at discharge from acute inpatient settings at a national level. Methods Data from 486 discharges of patients from emergency inpatient treatment of schizophrenia were collected during a three-month period in 2005; the data were collected in a large national study that covered 75% of Norwegian hospitals receiving inpatients for acute treatment. Antipsychotic treatment, demographic variables, scores from the Global Assessment of Functioning and Health of the Nation Outcome Scales and information about comorbid conditions and prior treatment were analyzed to seek predictors for nonadherence to guidelines. Results In 7.6% of the discharges no antipsychotic treatment was given; of the remaining discharges, 35.6% were prescribed antipsychotic polypharmacy and 41.9% were prescribed at least one first-generation antipsychotic (FGA). The mean chlorpromazine equivalent dose was 450 (SD 347, range 25–2800). In the multivariate regression analyses, younger age, previous inpatient treatment in the previous 12 months before index hospitalization, and a comorbid diagnosis of personality disorder or mental retardation predicted antipsychotic polypharmacy, while previous inpatient treatment in the previous 12 months also predicted prescription of at least one FGA. Conclusion Our national survey of antipsychotic treatment at discharge from emergency inpatient treatment revealed antipsychotic drug regimens that are to some degree at odds with current guidelines, with increased risk of side effects. Patients with high relapse rates, comorbid conditions, and previous inpatient treatment are especially prone to be prescribed antipsychotic drug regimens not supported by international guidelines.