Search

Background The symptom severity of a substantial group of schizophrenia patients (30–40%) does not improve through pharmacotherapy with antipsychotic medication, indicating a clear need for new treatment options to improve schizophrenia outcome. Meta-analyses, genetic studies, randomized controlled trials, and post-mortem studies suggest that immune dysregulation plays a role in the pathophysiology of schizophrenia. Some anti-inflammatory drugs have shown beneficial effects on the symptom severity of schizophrenia patients. Corticosteroids are effective in various chronic inflammatory and autoimmune disorders. Prednisolone, a potent glucocorticosteroid, has minor mineral-corticosteroid potencies and can adequately pass the blood–brain barrier and its side effects and safety profile are well known. Therefore, the effect of prednisolone can be studied as a proof of concept for immune modulation as a treatment for schizophrenia. Methods/design In total, 90 subjects aged 18–70 years and diagnosed with schizophrenia, schizoaffective disorder, or schizophreniform disorder (Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) 295.x) or psychosis not otherwise specified (NOS; 298.9) will be included. The time interval between the onset of psychosis and study entry should not exceed 7 years. Patients will be randomized 1:1 to either prednisolone or placebo daily for a period of 6 weeks in addition to a stable dose of antipsychotic medication. Study medication will be initiated at 40 mg for 3 days, after which it will be tapered down within 6 weeks after initiation, following inflammatory bowel diseases treatment guidelines. Primary outcome is change in symptom severity, expressed as change in total score on the Positive and Negative Symptom Scale (PANSS) from baseline to end of treatment. Cognitive functioning (measured through the Brief Assessment of Cognition in Schizophrenia (BACS)) and change in Global Assessment Functioning (GAF) and depressive symptoms as measured with the Calgary Depression Scale for Schizophrenia (CDS) will be assessed, in addition to various immunological biomarkers. Secondary outcomes are a 4- and 6-month follow-up assessment of PANSS, BACS, and GAF scores and immunological biomarkers. Additionally, a subgroup of patients will be included in the magnetic resonance imaging (MRI) part of the study where MR spectroscopy and structural, functional, and diffusion MRI will be conducted. Discussion It is expected that prednisolone addition to current antipsychotic medication use will reduce symptom severity and will improve cognition when compared to placebo. Trial registration ClinicalTrials.gov, NCT02949232 and NCT03340909. Registered 31 October 2016 and 14 November 2017. EudraCT-number 2014–000520-14 and 2017–000163-32.

Background Remission in schizophrenia is difficult to achieve. Antipsychotic drugs are critical in the treatment of schizophrenia. International guidelines for the pharmacological treatment of schizophrenia recommend a 3-step algorithm with clozapine being the third-line antipsychotic agent. This study investigated the 1-year outcome and the application of the guidelines for the pharmacological treatment of nonremitted first-episode schizophrenia (FES) patients during the first year of follow-up. Methods A sample of 78 FES patients from the Norwegian TIPS (Early Treatment and Intervention in Psychosis) 2 study was assessed at the end of the first year of follow-up. The symptom remission criteria were those defined by the Remission in Schizophrenia Working Group. The adherence to the pharmacological guidelines was assessed by reading the medical files and by a digital search of the words “clozapine,” “klozapin,” and “Leponex” in the hospital electronic data system. Results The majority (n = 53, 67.9%) of the patients included were nonremitted at the 1-year follow-up. The majority of the nonremitted patients received either none (7.5%), one (56.6%), or 2 types (15.1%) of antipsychotic drugs during the first year of follow-up. Only 2 (3.8%) received treatment with clozapine, and 3 (5.7%) in total were offered it. Conclusions For our FES sample, there was a low 1-year remission rate and a poor adherence to the pharmacological guidelines. Higher adherence to treatment guidelines with a more intensified antipsychotic treatment, which in some cases will include clozapine, will enhance the quality of treatment and may enhance the rates of remission for schizophrenia. publishedVersion

BACKGROUND: Schizophrenia (SZ) and bipolar disorder (BD) share substantial neurodevelopmental components affecting brain maturation and architecture. This necessitates a dynamic lifespan perspective in which brain aberrations are inferred from deviations from expected lifespan trajectories. We applied machine learning to diffusion tensor imaging (DTI) indices of white matter structure and organization to estimate and compare brain age between patients with SZ, patients with BD, and healthy control (HC) subjects across 10 cohorts.METHODS: We trained 6 cross-validated models using different combinations of DTI data from 927 HC subjects (18-94 years of age) and applied the models to the test sets including 648 patients with SZ (18-66 years of age), 185 patients with BD (18-64 years of age), and 990 HC subjects (17-68 years of age), estimating the brain age for each participant. Group differences were assessed using linear models, accounting for age, sex, and scanner. A meta-analytic framework was applied to assess the heterogeneity and generalizability of the results.RESULTS: Tenfold cross-validation revealed high accuracy for all models. Compared with HC subjects, the model including all feature sets significantly overestimated the age of patients with SZ (Cohen's d = -20.29) and patients with BD (Cohen's d = 0.18), with similar effects for the other models. The meta-analysis converged on the same findings. Fractional anisotropy-based models showed larger group differences than the models based on other DTI-derived metrics.CONCLUSIONS: Brain age prediction based on DTI provides informative and robust proxies for brain white matter integrity. Our results further suggest that white matter aberrations in SZ and BD primarily consist of anatomically distributed deviations from expected lifespan trajectories that generalize across cohorts and scanners.

Individuals diagnosed with borderline personality disorder (BPD) often struggle with chronic suicidal thoughts and behaviors and have frequent acute psychiatric admissions. Prevention of serial admissions and disruptions in long-term treatment strategies is needed. This study explored predictors of how frequently and how quickly patients diagnosed with BPD are readmitted after an index psychiatric admission. The authors identified self-harming behavior as a predictor of readmission frequency, whereas depression and hallucinations and delusions predicted time elapsed between the index admission and the first readmission. The authors recommend that predictors of readmissions should be carefully monitored and treated following index admission.

The arcuate fasciculus (AF) has been implicated in the pathology behind schizophrenia and auditory verbal hallucinations (AVHs). White matter tracts forming the arcuate fasciculus can be quantified and visualized using diffusion tensor imaging (DTI) tractography. Although there have been a number of studies on this topic, the results have been conflicting. Studying the underlying white matter structure of the AF could shed light on functional connectivity between temporal and frontal language areas in AVHs. The participants were 66 patients with a schizophrenia diagnosis, where AVHs were defined from the Positive and Negative Syndrome Scale (PANSS), and compared with a healthy control group. DTI was performed on a 3T MR scanner, and tensor estimation was done using deterministic streamline tractography. Statistical analysis of the data showed significantly longer tracts along the AF in patients with severe and frequent AVHs, as well as an overall significant asymmetry with longer fibers on the left side. In addition, there were significant positive correlations between PANSS scores and tract length, tract volume, and number of streamlines for the posterior AF segment on the left side. It is concluded that the present structural results complement previous functional findings of fronto-temporal connectivity in AVH patients.

Background: The symptom severity of a substantial group of schizophrenia patients (30-40%) does not improve through pharmacotherapy with antipsychotic medication, indicating a clear need for new treatment options to improve schizophrenia outcome. Meta-analyses, genetic studies, randomized controlled trials and post-mortem studies suggest that immune dysregulation plays a role in the pathophysiology of schizophrenia. Some anti-inflammatory drugs have shown beneficial effects on the symptom severity of schizophrenia patients.. Corticosteroids are effective in various chronic inflammatory and auto-immune disorders. From the group of glucocorticosteroids, prednisolone has minor mineral-corticosteroid potencies, can adequately pass the blood-brain barrier (BBB) and its side-effects and safety profile are well known. Therefore, a study into treatment with prednisolone can provide as a proof of concept for immune modulation as a treatment for schizophrenia. Method: In total 90 subjects, aged 18-70 years, diagnosed with schizophrenia, schizoaffective or schizophreniform disorder (Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) 295.*) or psychosis NOS (not otherwise specified) (298.9) will be included. The time interval between the onset of psychosis and study entry should not exceed seven years. Patients will be randomized 1:1 to either prednisolone or placebo daily for a period of 6 weeks. Study medication will be initiated at 40 mg for three days, after which it will be tapered down within 6 weeks after initiation, following current treatment guidelines. Primary outcome is change in symptom severity, expressed as change in total score on the Positive and Negative Symptom Scale (PANSS) from baseline to end of treatment. Cognitive functioning (measured through the Brief Assessment of Cognition in Schizophrenia; BACS) and change in Global Assessment Functioning (GAF) will be assessed, in addition to various immunological biomarkers. Secondary outcomes are a 4- and 6-month follow-up assessment of PANSS, BACS, GAF scores and immunological biomarkers. Additionally, a subgroup of patients can participate in the magnetic resonance imaging (MRI) part of the study where MR spectroscopy, structural, functional and diffusion MRI will be conducted. Discussion: It is expected that prednisolone addition to current antipsychotic medication use will reduce symptom severity and will improve cognition when compared to placebo. Trial registration: ClinicalTrails.gov NCT02949232 registered at 31 October 2016, retrospectively registered https://clinicaltrials.gov/ct2/show/NCT02949232?term=corticosteroid&cond=schizophrenia&rank=3 ; EudraCT-number 2014-000520-14 and 2017-000163-32.

BackgroundSchizophrenia (SZ) and bipolar disorders (BD) share substantial neurodevelopmental components affecting brain maturation and architecture. This necessitates a dynamic lifespan perspective in which brain aberrations are inferred from deviations from expected lifespan trajectories. We applied machine learning to diffusion tensor imaging (DTI) indices of white matter structure and organization to estimate and compare brain age between patients with SZ, BD, and healthy controls across 10 cohorts.MethodsWe trained six cross-validated models using different combinations of DTI data from 927 healthy controls (HC, 18-94 years), and applied the models to the test sets including 648 SZ (18-66 years) patients, 185 BD patients (18-64 years), and 990 HC (17-68 years), estimating brain age for each participant. Group differences were assessed using linear models, accounting for age, sex, and scanner. A meta-analytic framework was applied to assess the heterogeneity and generalizability of the results.Results10-fold cross-validation revealed high accuracy for all models. Compared to controls, the model including all feature sets significantly over-estimated the age of patients with SZ (d=-.29) and BD (d=.18), with similar effects for the other models. The meta-analysis converged on the same findings. Fractional anisotropy (FA) based models showed larger group differences than the models based on other DTI-derived metrics.ConclusionsBrain age prediction based on DTI provides informative and robust proxies for brain white matter integrity. Our results further suggest that white matter aberrations in SZ and BD primarily consist of anatomically distributed deviations from expected lifespan trajectories that generalize across cohorts and scanners.

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.

AIM To investigate whether differential influence on the QTc interval exists among four second generation antipsychotics (SGAs) in psychosis. METHODS Data were drawn from a pragmatic, randomized head-to-head trial of the SGAs risperidone, olanzapine, quetiapine, and ziprasidone in acute admissions patients with psychosis, and with follow-up visits at discharge or maximally 6-9 wk, 3, 6, 12 and 24 mo. Electrocardiograms were recorded on all visits. To mimic clinical shared decision-making, the patients were randomized not to a single drug, but to a sequence of the SGAs under investigation. The first drug in the sequence defined the randomization group, but the patient and/or clinician could choose an SGA later in the sequence if prior negative experiences with the first one(s) in the sequence had occurred. The study focuses on the time of, and actual use of the SGAs under investigation, that is until treatment discontinuation or change, in order to capture the direct medication effects on the QTc interval. Secondary intention-to-treat (ITT) analyses were also performed. RESULTS A total of 173 patients, with even distribution among the treatment groups, underwent ECG assessments. About 70% were males and 43% had never used antipsychotic drugs before the study. The mean antipsychotic doses in milligrams per day with standard deviations (SD) were 3.4 (1.2) for risperidone, 13.9 (4.6) for olanzapine, 325.9 (185.8) for quetiapine, and 97.2 (42.8) for ziprasidone treated groups. The time until discontinuation of the antipsychotic drug used did not differ in a statistically significant way among the groups (Log-Rank test: P = 0.171). The maximum QTc interval recorded during follow-up was 462 ms. Based on linear mixed effects analyses, the QTc interval change per day with standard error was -0.0030 (0.0280) for risperidone; -0.0099 (0.0108) for olanzapine; -0.0027 (0.0170) for quetiapine, and -0.0081 (0.0229) for ziprasidone. There were no statistically significant differences among the groups in this regard. LME analyses based on ITT groups (the randomization groups), revealed almost identical slopes with -0.0063 (0.0160) for risperidone, -0.0130 (0.0126) for olanzapine, -0.0034 (0.0168) for quetiapine, and -0.0045 (0.0225) for ziprasidone. CONCLUSION None of the SGAs under investigation led to statistically significant QTc prolongation. No statistically significant differences among the SGAs were found.

Background: Childhood trauma (CT) is a potential risk factor in psychosis, and the prevalence of CT may be higher in patients with psychosis compared to other mental health disorders. The aim of the study was to investigate the potential specificity of CT in psychosis.Methods: The sample consisted of 52 patients with schizophrenia spectrum disorders and 52 matched patients with other mental health disorders. CT was measured by the CTQ-SF. The groups were compared on CTQ-SF sum and subscale scores indicating rates of CT, in addition to rates of none/low vs. moderate/severe levels of CT.Results: The psychosis group had significantly higher CTQ-SF sum scores, and reported significantly higher levels of, and more severe, physical and sexual abuse and physical neglect. Also, 67.3% of the psychosis group reported ≥ 1 CT above the cut-off, compared to 38.5% in the non-psychosis group. No patients in the non-psychosis group reported ≥ 4 CT, compared to 9.6% in the psychosis group.Conclusions: Patients wit...

The arcuate fasciculus (AF) has been implicated in the pathology behind schizophrenia and auditory verbal hallucinations (AVHs). White matter tracts forming the arcuate fasciculus can be quantified and visualized using diffusion tensor imaging (DTI) tractography. Although there have been a number of studies on this topic, the results have been conflicting. Studying the underlying white matter structure of the AF could shed light on the constrains for interaction between temporal and frontal language areas in AVHs. The participants were 66 patients with a schizophrenia diagnosis, where AVHs were defined from the Positive and Negative Syndrome Scale (PANSS), and compared with a healthy control group. DTI was performed on a 3T MR scanner, and tensor estimation was done using deterministic streamline tractography. Statistical analysis of the data showed significantly longer reconstructed tracks along the AF in patients with severe and frequent AVHs, as well as an overall significant asymmetry with longer tracks in the left compared to the right side. In addition, there were significant positive correlations between PANSS scores and track length, track volume, and number of track streamlines for the posterior AF segment on the left side. It is concluded that the present DTI results may have implications for interpretations of functional imaging results. publishedVersion

Objective Hallucinations are highly prevalent in schizophrenia and related disorders. Antipsychotics are generally effective in treating hallucinations, but major inter-individual differences in treatment response exist. Previous studies have identified heterogeneity of over-all antipsychotic response patterns in schizophrenia. The aim of this study was to explore the heterogeneity in the response of hallucinations to antipsychotic drug treatment in a representative sample of patients acutely admitted for psychosis. Methods 226 adult patients with symptoms of active psychosis were included in a randomized pragmatic trial of second-generation antipsychotics and followed for 27 weeks. Latent-mixture and latent growth curve models were conducted to analyze heterogeneity of treatment response for hallucinations to second-generation antipsychotics. Results We found five different trajectories of treatment response for patients with hallucinations at baseline. These included two groups of “dramatic responders” who had rapid reduction followed by extinction of hallucinations during the first four weeks of treatment, then groups of “gradual responders”, “temporal responders” and “non-responders”. Most responders, 80% of those with hallucinations at baseline, were dramatic responders. Patients who showed no response in the early weeks remained non-responders also after longer follow-up. Conclusions The study suggests the existence of differential response patterns of hallucinations to antipsychotic treatment, and that a significant subgroup are dramatic responders. Hallucinations generally respond quickly to antipsychotic treatment. With no improvement in the very first weeks an early change of treatment should be considered.

Glutamate (Glu), gamma amino-butyric acid (GABA), and excitatory/inhibitory (E/I) imbalance have inconsistently been implicated in the etiology of schizophrenia. Elevated Glu levels in language regions have been suggested to mediate auditory verbal hallucinations (AVH), the same regions previously associated with neuronal hyperactivity during AVHs. It is, however, not known whether alterations in Glu levels are accompanied by corresponding GABA alterations, nor is it known if Glu levels are affected in brain regions with known neuronal hypo-activity. Using magnetic resonance spectroscopy (MRS), we measured Glx (Glu+glutamine) and GABA+ levels in the anterior cingulate cortex (ACC), left and right superior temporal gyrus (STG), and left inferior frontal gyrus (IFG), in a sample of 77 schizophrenia patients and 77 healthy controls. Two MRS-protocols were used. Results showed a marginally significant positive correlation in the left STG between Glx and AVHs, whereas a significant negative correlation was found in the ACC. In addition, high-hallucinating patients as a group showed decreased ACC and increased left STG Glx levels compared to low-hallucinating patients, with the healthy controls in between the 2 hallucinating groups. No significant differences were found for GABA+ levels. It is discussed that reduced ACC Glx levels reflect an inability of AVH patients to cognitively inhibit their “voices” through neuronal hypo-activity, which in turn originates from increased left STG Glu levels and neuronal hyperactivity. A revised E/I-imbalance model is proposed where Glu-Glu imbalance between brain regions is emphasized rather than Glu-GABA imbalance within regions, for the understanding of the underlying neurochemistry of AVHs.

Background Auditory hallucinations have been linked to aberrant functioning of the left superior temporal gyrus (STG) and are associated with impaired cognitive control regulated by areas in the prefrontal cortex. However, the mechanisms behind these dysfunctions are still unclear. Methods The current study combined resting state connectivity fMRI with MR spectroscopy (MRS) in a sample of 81 psychosis patients to explore how neurochemical correlates of auditory hallucinations modulate left STG functioning. The analyses were focused on glutamate (Glu) and gamma-aminobutyric acid (GABA), two neurotransmitters with excitatory and inhibitory functions, respectively, since these have previously been implicated in psychosis. Results Glu and GABA showed differential relationships with left STG connectivity in patients with and without hallucinations. Specifically, Glu concentration in the anterior cingulate cortex (ACC) was positively related to functional connectivity between the left and right temporal lobe in hallucinating patients only. In contrast, GABA concentration in the ACC was negatively related to connectivity between the left and right temporal lobe in non-hallucinating patients only. Discussion These findings support a recently proposed model of interhemispheric temporal lobe miscommunication in auditory hallucinations and indicate prefrontal neurochemical modulation as a potential underlying mechanism. The results can further be integrated with previously suggested excitatory/inhibitory imbalances as neurochemical modulators in AVH.

Background Genetic findings imply a role of the immune system in the complex psychopathology of schizophrenia, and elevated serum levels of pro-inflammatory cytokines have been found in patients. Altered levels of cytokines are linked to severe depression and cognitive dysfunction, both of which are common among patients suffering from schizophrenia. Depression is important to diagnose in this patient population as consequences of untreated depression can be severe. In this study we will investigate if the level and change of immune markers in blood are related to depression in patients with schizophrenia spectrum disorders. Methods The study is part of the Bergen-Stavanger-Innsbruck-Trondheim study (BestIntro) which is a multicenter randomized controlled trial comparing treatment with amisulpride, aripirazole and olanzapine. The study included patients with schizophrenia spectrum disorders (ICD-10 F20-F29) above 18 years with a score of 4 or more one of the following items on the Positive and Negative Syndrome scale (PANSS): Delusions, hallucinations, grandiosity, suspiciousness/persecution and unusual thought content. Participants were followed throughout one year, and for this sub-study participants from all treatment arms were analyzed together. Blood samples were drawn at week 0, 1, 3, 6, 12, 26, 39 and 52. Depression was measured with the Calgary Depression Scale (CDSS) which distinguishes depression from negative symptoms. A panel of 9 immune markers were analyzed: interferon gamma (IFN-γ), interleukin 1-β (IL-1β), interleukin 10 (IL-10), interleukin 12p70 (IL-12p70), interleukin 17A (IL-17A), interleukin 2 (IL-2), interleukin 4 (IL-4), interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α). We examined whether the level and change in inflammation parameters could be predicted by latent classes describing CDSS trajectories. Results The preliminary results suggest three different CDSS trajectories: high, moderate and low level of depression. In the three class model, the different groups were found to be related to some differences in level and change in the inflammation parameters. Baseline differences were found with higher IL-10 in the high depression group. In the 0–1 week interval, the low depression trajectory group reduced their IL1-beta, while the other two groups did not. Discussion Different courses of change in depression were identified suggesting that trajectories exist. With regard to temporal patterns of inflammatory parameters, findings point in the opposite direction of the established links between pro-inflammatory cytokines and depression. Further studies should explore if cytokine alterations in schizophrenia per se can explain this difference, or if depression in schizophrenia differs in its underlying biology from regular depressive states.

Cognitive impairment is a core feature of schizophrenia, which is predictive for functional outcomes and is, therefore, a treatment target in itself. Yet, literature on efficacy of different pharmaco-therapeutic options is inconsistent. This quantitative review provides an overview of studies that investigated potential cognitive enhancers in schizophrenia. We included pharmacological agents, which target different neurotransmitter systems and evaluated their efficacy on overall cognitive functioning and seven separate cognitive domains. In total, 93 studies with 5630 patients were included. Cognitive enhancers, when combined across all different neurotransmitter systems, which act on a large number of different mechanisms, showed a significant (yet small) positive effect size of 0.10 (k = 51, p = 0.023; 95% CI = 0.01 to 0.18) on overall cognition. Cognitive enhancers were not superior to placebo for separate cognitive domains. When analyzing each neurotransmitter system separately, agents acting predominantly on the glutamatergic system showed a small significant effect on overall cognition (k = 29, Hedges’ g = 0.19, p = 0.01), as well as on working memory (k = 20, Hedges’ g = 0.13, p = 0.04). A sub-analysis of cholinesterase inhibitors (ChEI) showed a small effect on working memory (k = 6, Hedges’ g = 0.26, p = 0.03). Other sub-analyses were positively nonsignificant, which may partly be due to the low number of studies we could include per neurotransmitter system. Overall, this meta-analysis showed few favorable effects of cognitive enhancers for patients with schizophrenia, partly due to lack of power. There is a lack of studies involving agents acting on other than glutamatergic and cholinergic systems, especially of those targeting the dopaminergic system.

Aims: The aim of this study was to investigate time trends in dosing and prevalence of antipsychotic prescriptions in Scandinavia. Methods: We retrieved data on antipsychotic use between 2006 and 2016 from Danish, Norwegian and Swedish national prescription registers. For each antipsychotic, we calculated prevalence of use and mean doses, overall and for specific age groups (young, adults and elderly). Results: Antipsychotic use in Scandinavia increased from 16.5 to 17.2 users/1000 inhabitants between 2006 and 2016 (+2.4%, annual change: 0.07 users/1000 inhabitants/year, 95% CI: 0.02–0.20, P = 0.02). In 2006, chlorprothixene and levomepromazine were the most commonly used antipsychotics. By 2016, quetiapine was the most used antipsychotic in all three countries and across all age groups, with an overall 1-year prevalence of 4.05–9.97 users/1000 inhabitants (annual change: 0.57 users/1000 inhabitants/year, 95% CI: 0.54–0.60, P

Background Measuring patient satisfaction in mental health care potentially provides valuable information, but studies in acutely admitted psychosis patients are scarce. Aims The aims were to assess satisfaction among patients acutely admitted with psychosis, to compare satisfaction in voluntarily versus involuntarily admitted patients, and to assess the influence of symptom load and insight. Methods The UKU Consumer Satisfaction Rating Scale (UKU-ConSat) was used. A total of 104 patients completed the UKU-ConSat at discharge/follow-up (between 6-11 weeks after admittance if not discharged earlier) (mean duration of stay 4 weeks), thus corresponding to the end of the acute treatment phase. Results A total of 88.4% had total scores above zero (satisfied). Only three of the eight single items were statistically significantly different among patients admitted voluntarily versus involuntarily, and only the information item score remained significantly different in adjusted analyses. Insight level at admittance, and an increasing level of insight during the acute phase were positively associated with patient satisfaction, whereas levels and changes in positive and negative psychosis symptoms were indirectly related to satisfaction via this process of insight. Conclusions The vast majority of the acutely admitted patients were satisfied with treatment. There were few differences between the involuntarily and voluntarily admitted patient groups, except that the involuntary care group was clearly less satisfied with the information provided. Poor insight had a major negative impact on treatment satisfaction in psychosis. The provision of sufficient and adequate information is an important target for mental health care service improvement.

Background Patients with schizophrenia spectrum disorders and substance use may have an earlier onset of illness compared to those without substance use. Most previous studies have, however, too small samples to control for confounding variables and the effect of specific types of substances. The present study aimed to examine the relationship between substance use and age at onset, in addition to the influence of possible confounders and specific substances, in a large and heterogeneous multisite sample of patients with schizophrenia spectrum disorders. Methods The patients (N = 1119) were recruited from catchment areas in Oslo, Stavanger and Bergen, Norway, diagnosed according to DSM-IV and screened for substance use history. Linear regression analysis was used to examine the relationship between substance use and age at onset of illness. Results Patients with substance use (n = 627) had about 3 years earlier age at onset (23.0 years; SD 7.1) than the abstinent group (n = 492; 25.9 years; SD 9.7). Only cannabis use was statistically significantly related to earlier age at onset. Gender or family history of psychosis did not influence the results. Conclusion Cannabis use is associated with 3 years earlier onset of psychosis.

We investigated whether posttraumatic stress disorder (PTSD) was predictor of suicidal behavior even when adjusting for comorbid borderline personality disorder (BPD) and other salient risk factors. To study this, we randomly selected 308 patients admitted to a psychiatric hospital because of suicide risk. Baseline interviews were performed within the first days of the stay. Information concerning the number of self-harm admissions to general hospitals over the subsequent 6 months was retrieved through linkage with the regional hospital registers. A censored regression analysis of hospital admissions for self-harm indicated significant associations with both PTSD (β = .21, p < .001) and BPD (β = .27, p < .001). A structural model comprising two latent BPD factors, dysregulation and relationship problems, as well as PTSD and several other variables, demonstrated that PTSD was an important predictor of the number of self-harm admissions to general hospitals(B = 1.52, p < .01). Dysregulation predicted self-harm directly (B = 0.28, p < .05), and also through PTSD [corrected]. These results suggested that PTSD and related dysregulation problems could be important treatment targets for a reduction in the risk of severe self-harm in high-risk psychiatric patients.

This is a (1)H MR spectroscopy (MRS) study of glutamate (Glu), measured as Glx, levels in temporal and frontal lobe regions in patients with schizophrenia compared with a healthy control group with the objective of revealing aspects of the underlying neurochemistry of auditory hallucinations. We further compared and correlated Glu(Glx) levels for the patients-only against frequency and severity of auditory hallucinations and the sum of Positive symptoms, and also for frequency and severity of emotional withdrawal, and sum of Negative symptoms. The sample included 23 patients with an ICD-10 and DSM-IV diagnosis of schizophrenia, and 26 healthy control subjects without any known psychiatric or neurological disorders. Symptom scores were obtained from the Positive and Negative Syndrome Scale (PANSS). (1)H MRS data were acquired on a 3T MR scanner from two temporal and two frontal voxels, using standard sequences and analysis parameters. The results showed that schizophrenia patients as a group had reduced Glu(Glx) levels in the voxels of interest compared to the healthy control subjects, while increased levels were found for patients with frequent and severe auditory hallucinations, relative to patients with less frequent and severe hallucination. We further found significant positive correlations between frequency and severity of auditory hallucinations, and for sum Positive symptoms, and Glu(Glx) levels in all regions, not seen when the analysis was done for negative symptoms. It is concluded that the results show for the first time that glutamate may be a mediating factor in auditory hallucinations in schizophrenia.

Background: The specificity of childhood trauma (CT) in psychosis is not known, since CT may occur in other disorders, especially substance abuse disorders (SUDs). The aim of the study was to examine the severity and frequency of CT in schizophrenia spectrum disorders as compared to SUDs. In order for CT to be specific for psychosis, one would expect more frequent and severe CT when compared to other disorders also associated with CT, such as SUDs. Methods: The sample consisted of 57 patients with schizophrenia spectrum disorders and 57 patients with SUDs, matched by age and gender. The groups were compared on the Childhood Trauma Questionnaire Short-Form (CTQ-SF) sum score and subscale scores, as well as the number of patients reporting CT at a cut-off of moderate/severe levels. Results: There were no statistically significant differences for the CTQ-SF sum scores between the psychosis group (M = 45.55, Mdn = 43) and substance abuse group (M = 43.85, Mdn = 43; U = 1587.5, P = .83) or for the CTQ-SF subscale scores (sexual, physical and emotional abuse, and physical and emotional neglect). When investigating whether the patients met the cut-off of moderate/severe levels of CT, we found no statistically significant differences between the groups. The groups were also compared on the number of patients in each group who reported 0–5 subtypes above the cut-off. In the psychosis group, 64.9 % (n = 37) reported ≥1 CT above cut-off as compared to 64.9 % (n = 37) in the substance abuse group. Almost 9% (n = 5) in the psychosis group reported ≥ 4 CT above the cut-off compared to 1.75 % (n = 1) in the substance abuse group. This difference was nonsignificant χ2 (1) = .240, P = .62. Conclusion: The results indicate similar frequency and severity of CT when comparing schizophrenia spectrum disorders and SUDS, a comparison that to the author’s best knowledge has not previously been researched. The similarities in levels of CT might have implications for etiological models of CT in these disorders. More research is needed to understand the differential pathways of CT; how and why do some individuals develop psychosis whereas others develop SUDs after childhood trauma.

Illicit drug use may influence cognition in non-affective psychosis. Previous studies have shown better cognition in psychosis with illicit drug use as compared to psychosis only. Possibly, illicit drug using patients have more transient drug-related cognitive deficits. Thus, the aim of the present study was to examine cognitive change the first weeks after admission to a psychiatric emergency ward, expecting more cognitive improvement at follow-up in the illicit drug group as compared to psychosis only. Patients with acute non-affective psychosis with (26%) and without illicit drug use were examined at baseline (n=123) and follow-up (n=67), with alternative forms of the Repeatable Battery for the Assessment of Neuropsychological Status. Latent Growth Curve models, controlling for cognition at baseline and age differences between the groups, were used to analyze cognitive change. The illicit drug using patients showed the largest improvement in cognition, especially among the youngest patients. Younger patients with non-affective psychosis and illicit drug use showed more cognitive improvement the first weeks after acute psychosis as compared to psychosis only. This suggests that the illicit drug users constitute a sub-group with less stable cognitive deficits and less cognitive vulnerability. publishedVersion

Background The aim of this study is to examine the one-year outcome in a cohort of patients with a first-episode core schizophrenia diagnosis (schizophrenia, schizophreniform psychosis, schizoaffective disorder) and the use of clozapine in the non-remitted patients at one-year control. Methods The population studied is the patients who were included with a first-episode psychosis in the TIPS project in the period 01.01.2002-31.12.2010 and had a core schizophrenia diagnosis. We divided the patients into two groups according to their remission status at one-year follow up and compared their main characteristics. We then performed a digital search in the hospitaĹs journal of the non-remitted group for the words “clozapine” and “Leponex”. Results Out of the 78 patients with first-episode core schizophrenia diagnosis included in the TIPS project during the examined period, 53 were continuously psychotic at one-year follow up. The one-year remission rate for our sample was therefore 32%. All of the non-remitted patients during the first year could be eligible for clozapine, but clozapine was considered to only 3 of them (5.7 %) and only two of them were offered clozapine. The mean number of periods with antipsychotic treatment in this group was four (4). Discussion The findings in our study show firstly a surprisingly low one-year remission rate for first-episode schizophrenia (32 %). This is much lower than what corresponding studies of the last years show. Our results also prove the underutilization of clozapine in non-remitted patients with a first-episode core schizophrenia diagnosis. Therefore, the clinicians did not follow the recommended guidelines for the treatment of schizophrenia. The possible reasons for this low use of clozapine will be discussed, but it was not possible to verify them as there was not found any relevant information in the patients’ files.

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 The gamma-aminobutyric acid (GABA)-glutamate hypothesis of schizophrenia suggests a neurotransmitter imbalance – reduced GABA and increased glutamate - which causes disruption of the modulation between inhibitory GABAergic interneurons and excitatory glutamatergic neurons. In the left superior temporal gyrus (STG) both hyperactivation and increased glutamate levels have previously been associated with auditory hallucinations in schizophrenia patients. However, the STG GABA-glutamate imbalance by simultaneously measuring GABA and glutamate in the same subjects has not previously been tested, and was therefore the aim of the present study. We hypothesized reduced GABA and increased glutamate in the patients relative to controls. Furthermore, reduced GABA and elevated glutamate in STG should be related to severity of auditory hallucinations in these patients. Methods The current study tested 23 schizophrenia patients (18 hallucinating and 5 non-hallucinating) and 53 healthy controls. The sample included both female and male participants above the age of 18. All patients were on medication, and they were tested at different times relative to the treatment onset. Magnetic resonance spectroscopy (MRS) was used to acquire data from voxels in the right and left superior temporal gyrus (Heschl’s gyri) with a 3T GE 750 Discovery MR scanner. PRESS and MEGA-PRESS sequences were applied to measure glutamate and GABA, respectively. Voxel tissue water was used as reference for glutamate and GABA. Scores on the Positive and Negative Syndrome Scale (PANSS) were also collected, and used to differentiate hallucinating from non-hallucinating patients. Results Separate 2(Group) x 2(Hemisphere) ANOVAs were estimated for GABA and glutamate. No main or interaction effects came out significant for GABA (All F(1,73)0.1, η2

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.

Schizophrenia is characterized by cognitive impairment, especially in relation to executive functions. Brain structural abnormalities are also often seen in schizophrenia although little is known of the relationship between cognitive impairment and structural brain changes. Our aim was therefore to investigate this relationship further using MRI and a dichotic listening (DL) task with simple speech sounds and with instructions to focus attention and report only from the left or right ear stimulus. When instructed to focus attention on the left ear syllable a cognitive conflict is induced requiring the allocation of executive resources to be resolved. Grey matter (GM) volume was measured with MRI from four volumes of interests (VOIs), left and right frontal and temporal cortex, respectively, and correlated with DL performance. The results showed significant differences between the groups in their ability to focus attention on and report the left ear stimulus, which was accompanied by reduced GM volume in the left frontal and right temporal lobe VOIs. There was also a significant positive correlation between left frontal GM volume and performance on the DL task, for the groups combined. The results did not support a conclusion that an impairment in cognitive function in schizophrenia was driven by an corresponding impairment in brain structure, since there were no significant correlations when the groups were analyzed separately. It is however concluded that patients with schizophrenia are impaired in executive functions and that they also show reduced GM volumes in left frontal and right temporal lobe areas, compared to healthy controls.

This naturalistic study investigated longitudinal and cross-sectional symptomatic and neurocognitive correlates of social cognition indexed by emotion perception. Participants were 31 persons admitted to a psychiatric emergency ward due to acute psychosis. Positive and negative (i.e., affective blunting and avolition) symptoms were assessed at baseline and 12-month follow-up using the Positive and Negative Syndrome Scale. Participants completed neuropsychological assessments with alternative versions of the Repeatable Battery for the Assessment of Neuropsychological Status at baseline and at 12-month follow-up. Emotion perception was measured using the Face/Voice Emotion Test at 12-month follow-up. Correlational analyses (Spearman's rho) revealed strong and statistically significant associations between neurocognition and emotion perception (baseline r = 0.58, follow-up r = 0.43). Associations between positive symptoms and emotion perception were weak or non-existent (baseline r = 0.13, follow-up r = -0.01). Emotion perception was moderately, but not significantly, associated with affective blunting at follow-up (r = 0.33), but not at baseline (r = 0.21). The association with avolition was non-existent (baseline r = -0.05, follow-up r = 0.01). This study supports the notion that emotion perception has neurocognitive correlates. The cross-sectional trend level association with affective blunting suggests that the ability to perceive emotions might be related to, but dissociable from the ability to express emotions.

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.

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

Schizophrenia and bipolar disorder are often highly debilitating with chronic courses, and psychotropic drugs represent cornerstones in the treatment. The primary aim of the review was to summarize the latest evidence with regards to the efficacy and effectiveness of drug treatment of schizophrenia and the manic phases of bipolar disorder. Schizophrenia systematic reviews conclude that antipsychotic drugs are effective in treating overall symptoms of psychosis and in preventing relapse. Some of the newer agents, the second-generation antipsychotics (SGAs), have demonstrated superiority compared with the older first-generation drugs and other SGAs but side-effect differences among the drugs are of a greater magnitude than effect differences. The pragmatic randomized trials of effectiveness have shown a longer time until treatment discontinuation for olanzapine compared with other antipsychotics. Cohort studies have found superiority for the long-acting injection formulations compared with the oral formulations of the drugs, and lower total mortality risk in users of antipsychotics compared with non-users. In bipolar mania SGAs have shown superior antimanic efficacy compared with other mood-stabilizing drugs. In conclusion antipsychotics, in particular some of the SGAs, seem to be drugs of first choice for both schizophrenia and bipolar mania. This perspective review focused on mean effects but the group means may not always be particularly useful as schizophrenia and bipolar mania are biologically heterogeneous disorders with large inter-individual variations in drug response and tolerance. In patients with a prior drug history the different pharmacological and clinical profiles may be exploited in subsequent choices of drugs.

Antipsychotic polytherapy (APT) has evolved as a common treatment strategy at odds with recommendations from schizophrenia treatment guidelines. The literature on combinations with clozapine as a means to enhance efficacy and with aripiprazole to reduce side effects was reviewed. No solid evidence supporting antipsychotic combinations with clozapine for treatment-resistant patients with schizophrenia was identified. The reason for this may be that most combinations with clozapine increase the D(2)-receptor blockade, and this strategy is probably not efficient for patients with treatment-resistant schizophrenia. Some basic and clinical evidence for the addition of aripiprazole to lower prolactin levels was identified. In conclusion, there is very limited support in the evidence for the feasibility of rational APT.

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.

Background Patient satisfaction is a complex phenomenon, and relations between patient satisfaction, symptom load, insight, side effects and depression have been shown in patients treated for psychosis. However, few studies on patient satisfaction in psychosis discriminate between persons previously treated with antipsychotic drugs and those who are antipsychotic drug naïve. Our aim was to test whether predictors for treatment satisfaction differ between previously medicated with antipsychotics (PM) and those who were antipsychotic naïve (AN) at admission. Methods In total 226 consecutive patients were included when admitted to hospital due to symptoms of active psychosis (≥4 on in one or more items of PANSS positive subscale), and were candidates for oral antipsychotic medication. At baseline PANSS, CDSS and Clinical Global Impression- Severity of Illness scale (CGI-S) were conducted. A total of 104 patients were assessed at discharge or follow up after a maximum of 11 weeks (mean 28.5 days, SD 14.1). In addition to the baseline assessments, patient satisfaction was assessed by the UKU Consumer Satisfaction Rating scale and the UKU Side Effect Rating Scale. For statistics structural equation modelling was performed to test multi sample growth models. Results Patients assessed at baseline were found to be statistically similar to those also assessed at discharge/follow-up, with the exception of a slightly higher PANSS negative subscale score in those assessed at baseline only (independent samples t-test: p = 0.023, mean difference 2.3, 95% confidence interval of the mean difference 0.3–4.3). There was a general improvement in function between baseline and follow-up, reflected in the CGI-S score reduction from 5.17 (SD .619) to 3.70 (SD 1.09) and symptom reduction in PANSS positive: mean change - 6.68 (SD 5.00). For PM patients (N =55), satisfaction was predicted by level of insight (b = - 2.21, β = - 0.42, p = 0.000), and positive symptom reduction (b = -0.56, β = -0.39, p = 0.012). The most satisfied patients had high level of insight at baseline, and the steepest decline in positive symptoms. For AN patients (N =49), satisfaction was predicted by level and change of insight (respectively: b= - 2.21, β = - 0.46, p = 0.000; b = - 1.53, β = - 0.32, p = 0.032), change in depression (b = -0.37, β = -0.26, p = 0.025), and side effects (b = -0.15, β = -0.30, p = 0.033). The most satisfied patients had high level of insight at baseline, most improvement in insight, the steepest decline in the CDSS score, and the lowest level of side effects. Discussion The consecutive inclusions of patients make these finding relevant and generalizable to everyday practice in similar clinical settings. Our findings suggest that reducing positive symptoms and side effects are important, but not solely sufficient to enhance patient satisfaction, and that differences exist among drug naïve and previously medicated patients. Improving insight and reducing depression are key processes to enhance satisfaction, particularly for antipsychotic naïve patients. Being drug naïve may be considered a proxy for First Episode Psychosis (FEP). Symptoms of depression seem to be particularly prevalent in FEP patients (1), and might dominate the experienced distress relative to symptoms of psychosis in these patients. Furthermore, FEP patients are more sensitive to the side effects of antipsychotic drugs. Another key target for improving satisfaction is to keep antipsychotic drug treatment at the lowest effective doses, as most side effects are dose-related. References 1. Cotton SM, Lambert M, Schimmelmann BG, Mackinnon A, Gleeson JFM, Berk M, et al. Depressive symptoms in first episode schizophrenia spectrum disorder. Schizophrenia research. 2012;134(1):20–6.

Background Cognitive impairment is a core feature of schizophrenia, which is predictive for functional outcomes and should therefore be one of the main treatment targets. Pharmacological enhancement of cognition has been a main field of research in the last decades, investigating almost all neurotransmitter systems and reporting positive as well as negative findings. The pathophysiology of cognitive dysfunctions in schizophrenia is complex and many different neurotransmitter systems are involved. This quantitative review provides an overview of studies of pharmacological agents targeting neurotransmitter systems relevant for cognitive deficits in schizophrenia. Methods In our systematic search we included pharmacological agents targeting glutamatergic, cholinergic, serotonergic, dopaminergic, GABAergic and noradrenergic neurotransmitter systems, and also a miscellaneous group of agents, including modafinil/armodafinil. We evaluated the effects of cognitive enhancers on overall cognitive functioning as well as on seven cognitive domains, including attention/vigilance, processing speed, reasoning, verbal learning and memory, visual learning and memory, working memory, and verbal fluency. Results In total, 93 studies with 5630 patients were suitable for inclusion in the meta-analysis. The mean sample size was 28.73 (SD=27.13, range=4–203), mean age of the participants was 44.15 years (SD=6.36, as reported by 91 study samples), 68.54% of the sample were men (as reported by 87 study samples), and average illness duration was 15.57 years (SD=6.47, as reported by 63 study samples). Combining all cognitive enhancers across different neurotransmitter systems for the effect on overall cognitive functioning resulted in fifty-one study samples, with a total of 3635 patients. Cognitive enhancers showed a small but significant positive effect size of 0.10 over placebo treatment (p=.023; 95%CI=0.01 to 0.18). Overall, cognitive enhancers showed no positive effects as compared to placebo for the separate domains. When analysing each neurotransmitter system separately, agents acting predominantly on the glutamatergic system showed a small but significant effect size on overall cognitive functioning (Hedges’ g=0.19, p=.01), as well as on working memory (Hedges’ g=0.13, p=.04). A sub-analysis of acetylcholinesterase inhibitors (AChEI) within cholinergic system showed a small effect on working memory (Hedges’ g=0.26, p=.03). No other positive effects of cognitive enhancers as compared to placebo were revealed. Discussion The current meta-analysis showed very few favorable effects of cognitive enhancers for patients with schizophrenia spectrum disorders. The overall analysis showed small difference between cognitive enhancers and placebo. Most studies were on agents acting on the glutamatergic and the cholinergic system. There is some evidence of positive effects on cognitive functioning for agents acting on glutamatergic system and acetylcholinesterase inhibitors within cholinergic system. There is still a major lack of studies involving agents acting on other systems. Important issues such as dose, treatment duration, including a younger population and subtyping heterogeneous samples should be taken into account for future studies.

We investigated whether posttraumatic stress disorder (PTSD) was predictor of suicidal behavior even when adjusting for comorbid borderline personality disorder (BPD) and other salient risk factors. To study this, we randomly selected 308 patients admitted to a psychiatric hospital because of suicide risk. Baseline interviews were performed within the first days of the stay. Information concerning the number of self-harm admissions to general hospitals over the subsequent 6 months was retrieved through linkage with the regional hospital registers. A censored regression analysis of hospital admissions for self-harm indicated significant associations with both PTSD (β = .21, p.001) and BPD (β = .27, p.001). A structural model comprising two latent BPD factors, dysregulation and relationship problems, as well as PTSD and several other variables, demonstrated that PTSD was an important predictor of the number of self-harm admissions to general hospitals(B = 1.52, p.01). Dysregulation predicted self-harm directly (B = 0.28, p.05), and also through PTSD [corrected]. These results suggested that PTSD and related dysregulation problems could be important treatment targets for a reduction in the risk of severe self-harm in high-risk psychiatric patients.

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 × 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. publishedVersion

Previous studies have shown that auditory verbal hallucinations (AVHs) in psychosis are associated with reduced verbal auditory attention. Whether this is an effect of ongoing AVH or reflects a more stable cognitive vulnerability also present after treating the AVH is unknown. The aim of this study was to follow patients with acute psychosis with and without AVH, and to test their auditory attention in a more stabilised clinical phase.Fifty patients (35 males and 15 females) were examined when admitted to an acute psychiatry ward and tested three months later with a dichotic listening test with attention instructions. The patients were divided into a frequent (n = 33) and non-frequent (n = 17) AVH group based on their score on the Positive and Negative Syndrome Scale item hallucinatory behaviour (≥4 and ≤3, respectively) at baseline.A significant interaction emerged between AVH group and attention instruction condition; the frequent AVH group failed to control their auditory attention as opposed to the non-frequent AVH group.Patients with frequent AVH in an acute psychotic state showed impaired auditory attention three months after their AVH had been treated, indicating a stable cognitive vulnerability factor for experiencing AVH.

Schizophrenia is characterized by impaired cognitive functioning, and brain regions involved in cognitive control processes show marked glutamatergic abnormalities. However, it is presently unclear whether aberrant neuronal response is directly related to the observed deficits at the metabolite level in schizophrenia. Here, 17 medicated schizophrenia patients and 17 matched healthy participants underwent functional magnetic resonance imaging (fMRI) when performing an auditory cognitive control task, as well as proton magnetic resonance spectroscopy (1H-MRS) in order to assess resting-state glutamate in the anterior cingulate cortex. The combined fMRI–1H-MRS analysis revealed that glutamate differentially predicted cortical blood-oxygen level-dependent (BOLD) response in patients and controls. While we found a positive correlation between glutamate and BOLD response bilaterally in the inferior parietal lobes in the patients, the corresponding correlation was negative in the healthy control participants. Further, glutamate levels predicted task performance in patients, such that lower glutamate levels were related to impaired cognitive control functioning. This was not seen for the healthy controls. These findings suggest that schizophrenia patients have a glutamate-related dysregulation of the brain network supporting cognitive control functioning. This could be targeted in future research on glutamatergic treatment of cognitive symptoms in schizophrenia., Highlights • Neuronal processing of cognitive control is different in schizophrenia patients (SZ). • Cingulum glutamate levels predict the degree of parietal neuronal response. • Lower glutamate predicts poorer cognitive control abilities in SZ. • SZ have a glutamate-related neuronal dysregulation of cognitive control processing.

Background:Few studies have examined rate and predictors of self-harm in discharged psychiatric patients.Aims:To investigate the rate, coding, timing, predictors and characteristics of self-harm induced somatic admission after discharge from psychiatric acute admission.Method:Cohort study of 2827 unselected patients consecutively admitted to a psychiatric acute ward during three years. Mean observation period was 2.3 years. Combined register linkage and manual data examination. Cox regression was used to investigate covariates for time to somatic admission due to self-harm, with covariates changing during follow-up entered time dependently.Results:During the observation period, 10.5% of the patients had 792 somatic self-harm admissions. Strongest risk factors were psychiatric admission due to non-suicidal self-harm, suicide attempt and suicide ideation. The risk was increased throughout the first year of follow-up, during readmission, with increasing outpatient consultations and in patients diagnosed with recurrent depression, personality disorders, substance use disorders and anxiety/stress-related disorders. Only 49% of the somatic self-harm admissions were given hospital self-harm diagnosis.Conclusions:Self-harm induced somatic admissions were highly prevalent during the first year after discharge from acute psychiatric admission. Underdiagnosing of self-harm in relation to somatic self-harm admissions may cause incorrect follow-up treatments and unreliable register data.

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.

Experiencing auditory verbal hallucinations is a prominent symptom in schizophrenia that also occurs in subjects at enhanced risk for psychosis and in the general population. Drug treatment of auditory hallucinations is challenging, because the current understanding is limited with respect to the neural mechanisms involved, as well as how CNS drugs, such as antipsychotics, influence the subjective experience and neurophysiology of hallucinations. In this article, the authors review studies of the effect of antipsychotic medication on brain activation as measured with functional MRI in patients with auditory verbal hallucinations. First, the authors examine the neural correlates of ongoing auditory hallucinations. Then, the authors critically discuss studies addressing the antipsychotic effect on the neural correlates of complex cognitive tasks. Current evidence suggests that blood oxygen level-dependant effects of antipsychotic drugs reflect specific, regional effects but studies on the neuropharmacology of auditory hallucinations are scarce. Future directions for pharmacological neuroimaging of auditory hallucinations are discussed.

Auditory verbal hallucinations (AVHs) are speech perceptions that lack an external source, phenomenologically experienced as "hearing voices". A perceptual origin of an AVH experience in patients with schizophrenia can however not explain why the "voices" drain the attentional and cognitive capacity of the patients, making them unable to direct attention away from the "voices" and to cognitively suppress the experience. We recently reported how AVHs interfere with the perception of speech sounds, using a dichotic listening experimental paradigm. We now extend this finding by reporting on the interference caused by AVHs on attention and cognitive control, using a slight variation of the same dichotic listening paradigm. The patients (N=148) were instructed to pay attention to and report from either the right or left ear syllable of the dichotic pair. We then correlated their PANSS score for the hallucination item (P3) with the performance score on the dichotic listening task. The results showed that AVHs interfered with the ability to report the right ear syllable when instructed to pay attention to the right side, which is a marker of inability to attend to an external speech stimulus. When instructed to pay attention to the left side, AVHs interfered with the ability to report the left ear syllable, which is a marker of inability to use cognitive control to suppress attending to the "voices". The corresponding correlations for the emotional withdrawal (N2) negative symptom were all non-significant. The correlations were substantiated in an ANOVA with corresponding significant group differences between high versus low symptom score groups. The results thus extend our previous findings of a perceptual origination for AVHs by showing that AVHs interfere with the ability to attend to the outer world around the patient, and the ability to inhibit, or suppress, the "voices" once they occur. Future research should pin down the neuronal basis of both the origination and the attentional and cognitive control aspects of AVHs.

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.

We report evidence that auditory verbal hallucinations (AVH) in schizophrenia patients are perceptual distortions lateralized to the left hemisphere. We used a dichotic listening task with repeated presentations of consonantvowel syllables, a different syllable in the right and left ear. This task produces more correct reports for the right ear syllable in healthy individuals, indicative of left hemisphere speech processing focus. If AVHs are lateralized to the left hemisphere language receptive areas, then this should interferewith correct right ear reports in the dichotic task, which would result in significant negative correlations with severity of AVHs. We correlated the right and left ear correct reportswith the PANSS hallucination symptom, and a randomly selected negative symptom, in addition to the sum total of the positive and negative symptoms, in 160 patients with schizophrenia. The results confirmed the predictions with significant negative correlations for the right ear scoreswith the PANSS hallucination item, and for the sum total of positive symptoms, while all other correlationswere close to zero. The results are unambiguous evidence for AVHs as aberrant speech perceptions originating in the left hemisphere. (C) 2012 Elsevier B. V. All rights reserved.

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