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Background and Hypotheses Auditory verbal hallucinations (AVHs) is not only a common symptom in schizophrenia but also observed in individuals in the general population. Despite extensive research, AVHs are poorly understood, especially their underlying neuronal architecture. Neuroimaging methods have been used to identify brain areas and networks that are activated during hallucinations. A characteristic feature of AVHs is, however, that they fluctuate over time, with varying frequencies of starts and stops. An unanswered question is, therefore, what neuronal events co-occur with the initiation and inhibition of an AVH episode. Study Design We investigated brain activation with fMRI in 66 individuals who experienced multiple AVH-episodes while in the scanner. We extracted time-series fMRI-data and monitored changes second-by-second from 10 s before to 15 s after participants indicated the start and stop of an episode, respectively, by pressing a hand-held response-button. Study Results We found a region in the ventromedial prefrontal cortex (VMPFC) which showed a significant increase in activation initiated a few seconds before participants indicated the start of an episode, and a corresponding decrease in activation initiated a few seconds before the end of an episode. Conclusions The consistent increase and decrease in activation in this area in advance of the consciously experienced presence or absence of the “voice” imply that this region may act as a switch in turning episodes on and off. The activation is unlikely to be confounded by motor responses. The findings could have clinical implications for brain stimulation treatments, like transcranial magnetic stimulation.

Objective:Akathisia is among the most unpleasant side effects related to antipsychotic drug (AP) use, and possible associations between akathisia and agitation, depression and suicidal behaviour, respectively, have been described in previous literature. New generation antipsychotics are however regarded less prone to induce this particular adverse effect compared to older drugs, but evidence is incomplete and in need of confirmation from clinically relevant samples and settings. We, therefore, aim to investigate akathisia at hospital discharge for patients consecutively admitted with acute-phase psychosis and treated with atypical antipsychotics according to guideline-concordant clinical practice.Methods:This exploratory study is part of a naturalistic randomised controlled study in patients admitted with acute phase psychosis (N = 109). We report cross-sectional data at discharge/first follow-up after acute psychiatric hospital admission for patients with schizophrenia and related psychotic disorders.Results:There were statistically significant positive associations between akathisia and the following; suicidality in men (Beta 0.306, p = 0.048), but not in women; agitation in those previously unexposed to antipsychotics (Beta 0.288, p = 0.047) and depression in those exposed to antipsychotics before hospital admittance (Beta 0.375, p = 0.031).Conclusion:Main findings were that akathisia is still a prevalent side effect in a clinically relevant sample of patients treated with atypical antipsychotics. Our results suggest that akathisia is significantly associated with depression, suicidality and agitation in different subgroups of patients receiving APs. Akathisia can be detrimental and the relations between akathisia and depression, suicidality and agitation should be investigated further in prospective, hypothesis-testing studies with larger samples.

Antipsychotic drugs remain the mainstay of schizophrenia treatment; however, their effectiveness has been questioned, and it is not possible to predict the response to a specific antipsychotic drug in an individual patient. Thus, it is important to compare the effectiveness of the various antipsychotics and search for possible response predictors.To investigate the effectiveness of antipsychotic drugs, we examined response trajectories and predictors for belonging to different trajectory groups.The Bergen-Stavanger-Innsbruck-Trondheim (BeSt InTro) trial compared the effectiveness of three atypical antipsychotics-amisulpride, aripiprazole, and olanzapine-in a prospective, semirandomized, rater-blind, head-to-head design. Adult participants with a schizophrenia spectrum disorder diagnosis, according to international classification of diseases, Tenth Revision (ICD-10) F20-29, were included. Participants were followed for a period of 12 mo, with assessments at baseline; after one, three and six weeks; and after three, six, nine and 12 mo. A latent class mixed model was fitted to our data. The three-trajectory model based on the Positive and Negative Syndrome Scale (PANSS) total score reduction was found to have adequate fit, and the study drugs, as well as various demographic and clinical parameters, were tested as predictors for belonging to the different trajectory groups.Overall, 144 participants were included, and 41% completed the 12-mo study period. The largest trajectory group, consisting of 74% of participants, showed a PANSS total score reduction of 59% from baseline to 12 mo (Good response group). A trajectory group comprising 13% of participants had their PANSS total score reduced by 82.5% at 12 mo (Strong response group), while the last response trajectory group comprising 13% of the participants had a PANSS total score reduction of 13.6% (Slight response group). The largest part of the total reduction for the Good and Strong response groups occurred at six weeks of treatment, amounting to 45% and 48% reductions from baseline, respectively. The use of amisulpride predicted belonging to the Strong response group, while unemployment, depression, and negative psychotic symptoms at baseline increased the chance of belonging to the Slight response group, indicating a poor response to antipsychotic drug treatment.Most of the participants (87%) had a good outcome after one year. Amisulpride users, more often than aripiprazole and olanzapine users, belonged to the response trajectory group with a strong response.

Background and Hypothesis Gut microbiota alterations have been reported in severe mental illness (SMI) but fewer studies have probed for signs of gut barrier disruption and inflammation. We hypothesized that gut leakage of microbial products due to intestinal inflammation could contribute to systemic inflammasome activation in SMI. Study Design We measured plasma levels of the chemokine CCL25 and soluble mucosal vascular addressin cell adhesion molecule-1 (sMAdCAM-1) as markers of T cell homing, adhesion and inflammation in the gut, lipopolysaccharide binding protein (LBP) and intestinal fatty acid binding protein (I-FABP) as markers of bacterial translocation and gut barrier dysfunction, in a large SMI cohort (n = 567) including schizophrenia (SCZ, n = 389) and affective disorder (AFF, n = 178), relative to healthy controls (HC, n = 418). We assessed associations with plasma IL-18 and IL-18BPa and leukocyte mRNA expression of NLRP3 and NLRC4 as markers of inflammasome activation. Study Results Our main findings were: (1) higher levels of sMAdCAM-1 (P = .002), I-FABP (P = 7.6E−11), CCL25 (P = 9.6E−05) and LBP (P = 2.6E−04) in SMI compared to HC in age, sex, BMI, CRP and freezer storage time adjusted analysis; (2) the highest levels of sMAdCAM-1 and CCL25 (both P = 2.6E−04) were observed in SCZ and I-FABP (P = 2.5E−10) and LBP (3) in AFF; and (3), I-FABP correlated with IL-18BPa levels and LBP correlated with NLRC4. Conclusions Our findings support that intestinal barrier inflammation and dysfunction in SMI could contribute to systemic inflammation through inflammasome activation.

Background: Transcranial direct current stimulation (tDCS) is used as treatment for auditory verbal hallucinations (AVH). The theory behind the treatment is that tDCS increases activity in prefrontal cognitive control areas, which are assumed to be hypoactive, and simultaneously decreases activity in temporal speech perception areas, which are assumed to be hyperactive during AVH. We tested this hypofrontal/hypertemporal reversal theory by investigating anatomical, neurotransmitter, brain activity, and network connectivity changes over the course of tDCS treatment. Methods: A double-blind, randomized controlled trial was conducted with 21 patients receiving either sham or real tDCS treatment (2 mA) twice daily for 5 days. The anode was placed over the left dorsolateral prefrontal cortex (DLPFC) and the cathode over the left temporo-parietal cortex (TPC). Multimodal neuroimaging as well as clinical and neurocognitive functioning assessment were performed before, immediately after, and three months after treatment. Results: We found a small reduction in AVH severity in the real tDCS group, but no corresponding neuroimaging changes in either DLPFCD or TPC. Limitations: The study has a small sample size. Conclusion: The results suggest that the currently leading theory behind tDCS treatment of AVH may need to be revised, if confirmed by studies with larger N. Tentative findings point to the involvement of Broca’s area as a critical structure for tDCS treatment. publishedVersion

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

Background Cell adhesion molecules (CAMs) orchestrate leukocyte trafficking and could link peripheral and neuroinflammation in patients with severe mental illness (SMI), by promoting inflammatory and immune-mediated responses and mediating signals across blood-brain barrier. We hypothesized that CAMs would be dysregulated in SMI and evaluated plasma levels of different vascular and neural CAMs. Dysregulated CAMs in plasma were further evaluated in vivo in leukocytes and brain tissue and in vitro in induced pluripotent stem cells. Methods We compared plasma soluble levels of different vascular (VCAM-1, ICAM-1, P-SEL) and neural (JAM-A, NCAD) CAMs in circulating leukocytes in a large SMI sample of schizophrenia (SCZ) spectrum disorder (n = 895) and affective disorder (n = 737) and healthy control participants (n = 1070) controlling for age, sex, body mass index, C-reactive protein, and freezer storage time. We also evaluated messenger RNA expression of ICAM1 and related genes encoding ICAM-1 receptors in leukocytes using microarray (n = 842) and in available RNA sequencing data from the CommonMind Consortium (CMC) in postmortem samples from the dorsolateral prefrontal cortex (n = 474). The regulation of soluble ICAM-1 in induced pluripotent stem cell–derived neurons and astrocytes was assessed in patients with SCZ and healthy control participants (n = 8 of each). Results Our major findings were 1) increased soluble ICAM-1 in patients with SMI compared with healthy control participants; 2) increased ITGB2 messenger RNA, encoding the beta chain of the ICAM-1 receptor, in circulating leukocytes from patients with SMI and increased prefrontal cortex messenger RNA expression of ICAM1 in SCZ; and 3) enhanced soluble ICAM-1 release in induced pluripotent stem cell–derived neurons from patients with SCZ. Conclusions Our results support a systemic and cerebral dysregulation of soluble ICAM-1 expression in SMI and especially in patients with SCZ.

Background Evidence is limited for the associations between use of psychotropic medications and overactive, aggressive, disruptive or agitated behavior (OADA)1 in clinical practice. Aims To investigate the associations between risk of readmission with OADA and use of antipsychotics, antidepressants, mood stabilizers and benzodiazepines in patients with schizophrenia. Method A consecutive total cohort diagnosed with schizophrenia (N = 663) after admission to the Haukeland University Hospital psychiatric acute unit in Bergen, Norway, was followed from discharge over a 10-year period. At every following readmission, the level of OADA was assessed using the first item of the Health of the Nation Outcome Scale (HoNOS). Periods of use versus non-use of antipsychotics, antidepressants, mood stabilizers and benzodiazepines were recorded as time-dependent variables in each patient and compared using Cox multiple regression analyses. Results A total of 161 (24.3 %) patients were readmitted with OADA, and the mean (SD) and median times in years to readmission with OADA were 2.8 (2.6) and 2.1, respectively. We found that the risk of readmission with OADA was negatively associated with use of antipsychotics (adjusted hazard ratio (AHR) = 0.33, p < 0.01, CI: 0.24–0.46) and antidepressants (AHR = 0.57, p = 0.03, CI: 0.34–0.95), positively associated with use of benzodiazepines (AHR = 1.95, p < 0.01, CI: 1.31–2.90) and not significantly associated with use of mood stabilizers. Conclusions Use of antipsychotics and antidepressants is associated with reduced risk of readmission with OADA whereas benzodiazepines are associated with an increased risk of readmission with OADA in patients with schizophrenia. publishedVersion

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

Purpose: Little is known about the impact of different psychotropic drugs on acute readmission risk, when used concomitantly in a real-life setting. We aimed to investigate the association between acute readmission risk and use of antipsychotic drugs, antidepressants, mood stabilizers, and benzodiazepines in patients with schizophrenia. Methods: A cohort study included all patients diagnosed with schizophrenia admitted to a psychiatric acute unit at Haukeland University Hospital in Bergen, Norway, during a 10-year period (N = 663). Patients were followed from discharge until first readmission or censoring. Cox multiple regression analyses were conducted using antipsychotic drugs, antidepressants, mood stabilizers, and benzodiazepines as time-dependent variables, and periods of use and nonuse were compared within individual patients. Adjustments were made for sex, age at index admission, and excessive use of alcohol and illicit substances. Results: A total of 410 patients (61.8%) were readmitted during follow-up, and the mean and median times in days to readmission were 709 and 575, respectively. Compared with nonuse, the use of antipsychotic drugs was associated with reduced risk of readmission (adjusted hazards ratio, 0.20; P < 0.01; confidence interval, 0.16–0.24), and the use of benzodiazepines was associated with increased risk of readmission (adjusted hazards ratio, 1.51; P < 0.01; confidence interval, 1.13–2.02). However, no relation to readmission risk was found for the use of antidepressants and mood stabilizers. Conclusions: We found that use of benzodiazepines and antipsychotic drugs are inversely associated with acute readmission risk in schizophrenia. publishedVersion

Background: Treatment satisfaction predicts treatment adherence and long-term outcome for patients with psychosis. It is therefore important to understand the underpinnings of patient satis...

Background: Psychosis is associated with a high prevalence of substance use, leading to worsened prognosis. Less is known about how comorbid substance abuse may influence the effectiveness of antip...

Side effects restrict the optimal use of antipsychotics. Little is known about the influence of substance use on side effects. The aim of this study was to compare antipsychotic side effects in patients with psychosis with and without substance use, while also taking medication history and diagnosis into consideration.All patients (At baseline, 30% of the patients used substances, 54% were diagnosed with SSD, and 47% were antipsychotic naïve. The occurrence of side effects in total was not different in patients with substance use compared to without after 4-weeks of treatment, nor in the follow-up period. At 4-weeks there were some group differences in relation to substance use, diagnosis, and medication history for single side effects. Patients with substance use showed more increased dream activity, less reduced salivation, and more gynecomastia. Patients with SSD showed less neurological side effects, orgasm dysfunction, and tension/inner unrest. The medication naïve patients showed increased hypokinesia/akinesia.Substance use alone does not influence the general magnitude of side effects of antipsychotic medication and does not indicate a different prescription practice in patients with psychosis and substance use.

BackgroundSchizophrenia (SCZ) and bipolar disorder (BD) are severe mental illnesses (SMI) that are part of a psychosis continuum, and dysregulated innate immune responses have been suggested to be involved in their pathophysiology. However, disease-specific immune mechanisms in SMI are not known yet. Recently, dyslipidemia has been linked to systemic inflammasome activation, and elevated atherogenic lipid ratios have been shown to correlate with circulating levels of inflammatory biomarkers in SMI. It is, however, not yet known if increased systemic cholesterol load leads to inflammasome activation in these patients.MethodsWe tested the hypothesis that patients with SCZ and BD display higher circulating levels compared to healthy individuals of key members of the IL-18 system using a large patient cohort (n=1632; including 737 SCZ and 895 BD), and healthy controls (CTRL; n=1070). In addition, we assessed associations with coronary artery disease risk factors in SMI, focusing on relevant inflammasome-related, neuroendocrine, and lipid markers.ResultsWe report higher baseline levels of circulating IL-18 system components (IL-18, IL-18BPA) as well as increased expression of inflammasome-related genes (NLRP3 and NLRC4) in the blood of patients relative to CTRL. We demonstrate a cholesterol dyslipidemia pattern in psychotic disorders, and report correlations between levels of blood cholesterol species and the expression of inflammasome system elements in SMI.ConclusionsBased on these results, we suggest a link between systemic inflammasome activation/dysregulation and cholesterol load in SMI. Our findings further the understanding of possible underlying inflammatory and metabolic mechanisms and may expose important therapeutic targets in SMI.

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

Background In schizophrenia, impaired psychomotor speed is a common symptom predicting worse functional outcome. Inflammation causes changes in white matter integrity, which may lead to reduced psychomotor speed. Therefore, we wanted to investigate if peripheral inflammation assessed with cytokines affected performance on psychomotor speed in patients with a spectrum of psychotic disorders. Methods The current study is a prospective cohort study, including participants from a pragmatic, randomised controlled trial comparing three atypical antipsychotics in patients with a spectrum of psychotic disorders. For the purposes of this sub-study, we analysed drug treatment groups collectively. Psychomotor speed was assessed at baseline, and at weeks 6, 12, 26 and 52 of follow-up, using the neuropsychological tests trail making test (TMT) A and B, and symbol coding. Serum concentration of the following cytokines were measured: interleukin (IL)-β, IL-2, IL-4, IL-6, IL-10, IL12 p70, IL-17a, interferon (IFN)-γ and tumor necrosis factor (TNF)-α. Blood samples were collected at baseline and after 1, 3, 6, 12, 26, 39 and 52 weeks. We analysed the effect of cytokines levels on psychomotor speed over time in linear mixed effects models. Results In our linear mixed effects models controlling for possible confounders, IFN-γ had a significant negative effect on TMT-A and symbol coding performance. None of the other tests for psychomotor speed were significantly associated with cytokines. Overall psychomotor speed performance increased significantly across the study period while cytokine levels remained stable. Conclusion Our study indicates a negative association between IFN-γ and psychomotor speed, which might be of importance when understanding the mechanisms behind psychomotor deviations in psychotic disorders., Highlights • The cytokine interferon (IFN) – γ is related to psychomotor speed in patients with psychotic disorders. • For majority of cytokines, we found no significant association with psychomotor speed. • Cytokines remained stable during the study period of 52 weeks.

The relation between auditory verbal hallucinations (AVH) and white matter has been studied, but results are still inconsistent. This inconsistency may be related to having only a single time-point of AVH assessment in many studies, not capturing that AVH severity fluctuates over time. In the current study, AVH fluctuations were captured by utilizing a longitudinal design and using repeated (Positive and Negative Symptoms Scale) PANSS questionnaire interviews over a 12 month period. We used a Magnetic Resonance Diffusion Tensor Imaging (MR DTI) sequence and tract-based spatial statistics (TBSS) to explore white matter differences between two subtypes of schizophrenia patients, 44 hallucinating (AVH+) and 13 non-hallucinating (AVH&minus, ), compared to 13 AVH&minus, matched controls and 44 AVH+ matched controls. Additionally, we tested for hemispheric fractional anisotropy (FA) asymmetry between the groups. Significant widespread FA-value reduction was found in the AVH+ group in comparison to the AVH&minus, group. Although not significant, the extracted FA-values for the control group were in between the two patient groups, for all clusters. We also found a significant difference in FA-asymmetry between the AVH+ and AVH&minus, groups in two clusters, with significantly higher leftward asymmetry in the AVH&minus, group. The current findings suggest a possible qualitative difference in white matter integrity between AVH+ and AVH&minus, patients. Strengths and limitations of the study are discussed.

Background In society at large, it is debated whether use of antipsychotic drugs is associated with increased or decreased mortality among patients with schizophrenia. Large register studies have demonstrated an increased mortality risk associated with non-use of antipsychotic drugs, but prospective studies are missing. Aims To investigate the association between mortality and non-use of antipsychotics in patients with schizophrenia. Method An open cohort study included and followed all patients with a discharge-diagnosis of schizophrenia consecutively admitted to a psychiatric acute unit at Haukeland University Hospital, Bergen, Norway during a 10 year period (n = 696). Cox multiple regression analyses were conducted with use of antipsychotic drugs as a time dependent variable, and periods of use and non-use were compared within individual patients. Adjustments were made for gender, age at index admission, number of acute psychiatric hospital admissions, excessive use of alcohol and illicit substances and use of benzodiazepines and antidepressants. Results A total of 68 (9.8%) deaths were registered during follow-up. Of these, 40 (59%) had natural causes, whereas 26 (38%) had unnatural causes. Non-use of antipsychotics was associated with 2.15 (p = .01, CI: 1.24–3.72) times higher mortality risk compared to use of antipsychotics. The difference in mortality risk between use and non-use of antipsychotic drugs was age dependent, with the largest risk difference in young patients. Conclusions Non-use of antipsychotic drugs was associated with twofold increased mortality risk in patients with schizophrenia.

Background The prevalence of new psychoactive substances (NPS) in acute psychotic patients has not been investigated systematically. We applied a highly sensitive and specific mass spectrometry method for detection of NPS as well as traditional drugs of abuse (including illicit or prescription substances) in order to assess their prevalence and associations with symptom severity. Identification of these substances is useful in both the diagnostic process and evaluation of treatment effects. Methods Demographic data, results from the Positive and Negative Syndrome Score (PANSS) and Calgary Depression Scale for Schizophrenia (CDSS) and urine samples from admission were collected from 53 patients recruited into a clinical study of psychosis during 2014-2017. Urine samples were analysed with liquid chromatography high resolution mass spectrometry (LC-QTOF-MS), through both highly specific detection of 191 substances using internal standards and untargeted screening by means of pre-defined libraries. PANSS and CDSS scores in patients with or without drugs of abuse were compared. Results Potential drugs of abuse, i.e. drugs that could be used in a controlled therapeutic or a non-prescribed manner, were detected in samples from 20 of the 53 patients. Seven samples contained illicit drugs, but no NPS were detected. In this small patient subgroup, PANSS total score and CDSS score were significantly higher than in patients with negative urine sample results. Conclusion Drug screening could play an important role in the differential diagnostic evaluation of patients admitted with psychotic symptoms. Although no NPS were detected in the study population, we found other substances that were associated with psychotic and depressive symptoms.

BackgroundBoth neurodegenerative and neurodevelopmental abnormalities have been suggested to be part of the etiopathology of severe mental illness (SMI). Neuron-specific enolase (NSE), mainly located in the neuronal cytoplasm, may indicate the process as it is upregulated after neuronal injury while a switch from non-neuronal enolase to NSE occurs during neuronal maturation.MethodsWe included 1132 adult patients with SMI [schizophrenia (SZ) or bipolar spectrum disorders], 903 adult healthy controls (HC), 32 adolescent patients with SMI and 67 adolescent HC. Plasma NSE concentrations were measured by enzyme immunoassay. For 842 adults and 85 adolescents, we used total grey matter volume (TGMV) based on T1-weighted magnetic resonance images processed in FreeSurfer v6.0. We explored NSE case-control differences in adults and adolescents separately. To investigate whether putative case-control differences in NSE were TGMV-dependent we controlled for TGMV.ResultsWe found significantly lower NSE concentrations in both adult (p < 0.001) and adolescent patients with SMI (p = 0.007) compared to HC. The results remained significant after controlling for TGMV. Among adults, both patients with SZ spectrum (p < 0.001) and bipolar spectrum disorders (p = 0.005) had lower NSE than HC. In both patient subgroups, lower NSE levels were associated with increased symptom severity. Among adults (p < 0.001) and adolescents (p = 0.040), females had lower NSE concentrations than males.ConclusionWe found lower NSE concentrations in adult and adolescent patients with SMI compared to HC. The results suggest the lack of progressive neuronal injury, and may reflect abnormal neuronal maturation. This provides further support of a neurodevelopmental rather than a neurodegenerative mechanism in SMI.

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.

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

Background The common recommendation that adults with onset of mental illness after the age of 65 should receive specialised psychogeriatric treatment is based on limited evidence. Aims To compare factors related to psychiatric acute admission in older adults who have no previous psychiatric history (NPH) with that of those who have a previous psychiatric history (PPH). Method Cross-sectional cohort study of 918 patients aged ≥65 years consecutively admitted to a general adult psychiatric acute unit from 2005 to 2014. Results Patients in the NPH group (n = 526) were significantly older than those in the PPH group (n = 391) (77.6 v. 70.9 years P < 0.001), more likely to be men, married or widowed and admitted involuntarily. Diagnostic prevalence in the NPH and PPH groups were 49.0% v. 8.4% (P < 0.001) for organic mental disorders, 14.6% v. 30.4% (P < 0.001) for psychotic disorders, 30.2% v. 55.5% (P < 0.001) for affective disorders and 20.7% v. 13.3% (P = 0.003) for somatic disorders. The NPH group scored significantly higher on the Health of the Nation Outcome Scale (HoNOS) items agitated behaviour; cognitive problems; physical illness or disability and problems with activities of daily living, whereas those in the PPH group scored significantly higher on depressed mood. Although the PPH group were more likely to report suicidal ideation, those in the NPH group were more likely to have made a suicide attempt before the admission. Conclusions Among psychiatric patients >65 years, the subgroup with NPH were characterised by more physical frailty, somatic comorbidity and functional and cognitive impairment as well as higher rates of preadmission suicide attempts. Admitting facilities should be appropriately suited to manage their needs.

Introduction: Psychosis is a multifaceted clinical phenomenon in which the various symptoms may show a differential response to treatment. Important information may be lost when heterogeneous sympt...

SummaryAuditory verbal hallucinations, or “hearing voices”, is a remarkable state of the mind, occurring in psychiatric and neurological patients, and in a significant minority of the general population. An unexplained characteristic of this phenomenon is that it transiently fluctuates, with coming and going of episodes with time. We monitored neural activity with BOLD-fMRI second-by-second before and after participants indicated the start and end of a transient hallucinatory episode during the scanning session by pressing a response-button. We show that a region in the ventro-medial frontal cortex is activated in advance of conscious awareness of going in or out of a transient hallucinatory state. There was an increase in activity initiated a few seconds before the button-press for onsets, and a corresponding decrease in activity initiated a few seconds before the button-press for offsets. We identified the time between onset and offset button-presses, extracted the corresponding BOLD time-courses from nominated regions-of-interest, and analyzed changes in the signal from 10 seconds before to 15 seconds after the response-button was pressed, which identified onset and offset events. We suggest that this brain region act as a switch to turn on and off a hallucinatory episode. The results may have implications for new interventions for intractable hallucinations.

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

Depression is common in schizophrenia and associated with negative outcomes. Previous studies have identified heterogeneity in treatment response in schizophrenia. We aimed to investigate different trajectories of depression in patients suffering from psychosis and predictors of change in depressive symptoms during antipsychotic treatment. Two hundred and twenty-six patients18 years acutely admitted due to psychosis were consecutively included and the follow-up was 27 weeks. The Calgary Depression Scale for Schizophrenia (CDSS) sum score was the primary outcome. Latent growth curve (LGCM) and Growth Mixture Models (GMM) were conducted. Predictors were the Positive sum score of the Positive and Negative Syndrome Scale for Schizophrenia (PANSS), Schizophrenia spectrum/non-spectrum psychoses, gender and being antipsychotic naive at inclusion. We found support for three depression-trajectories, including a high- (14.7%), a low depression-level (69.6%) class and a third depressed class quickly decreasing to a low level (15.7%). Change in CDSS was associated with change in PANSS positive score in all time intervals (4 weeks: b = 0.18, p 0.001, 3 months: 0.21, p 0.023, 6 months: 0.43, p 0.001) and with a diagnosis within schizophrenia spectrum but not with antipsychotic naivety or gender. The schizophrenia-spectrum patients had less depressive symptoms at inclusion (-2.63, p 0.001). In conclusion, an early responding and a treatment refractory group were identified. The treatment-refractory patients are candidates for enhanced anti-depressive treatment, for which current evidence is limited. The post-psychotic depression group was characterized by depressive symptoms in the acute phase as well. We could not identify differentiating characteristics of the depression trajectories.

The prevalence of childhood trauma (CT) in schizophrenia spectrum disorders (SSDs) and substance abuse disorders (SUDs) is high. Direct comparisons of CT in these disorders are lacking, and it is not known whether there are differences in self-reported CT in SSDs as compared to SUDs. We aimed to compare the frequency, severity and types of CT in SDDs and SUDs. Patients with SSDs (n = 57) and SUDs (n = 57) were matched for age and gender. Overall levels of CT and CT subtypes were measured retrospectively by the Childhood Trauma Questionnaire Short-Form (CTQ-SF), and grouped into none/low and moderate/severe levels of CT. Group differences in CTQ-SF sum score and subscale scores, as well as differences in the severity of overall CT and CT subtypes were all non-significant. In both groups, 64.9% reported ≥ 1 subtypes of CT above cut-off. Of those who reported CT above the cut-off, 13.5% in the psychosis group reported ≥ 4 subtypes, as compared to 2.7% in the substance abuse group. We did not find statistically significant differences between SSDs and SUDs in terms of exposure to CT frequency or severity, all effect sizes were small (r < 0.15).

Hallucinated voices are common across psychiatric and non-clinical groups. The predominant cognitive theory about the impact of voices posits that beliefs about voice power (‘Omnipotence’) and voice intent (‘Malevolence’/‘Benevolence’) play a key role in determining emotional and behavioral reactions. The revised Beliefs about Voices Questionnaire (BAVQ-R) was designed to assess these constructs, together with two styles of responding (Engagement and Resistance). The BAVQ-R is widely used in clinical and research settings, yet it has not received validation of its constructs and factor structure. This study examined the factor structure of the BAVQ-R by combining datasets from five study centers, comprising 450 participants (belief constructs) and 269 participants (response styles), and using confirmatory and exploratory factor analysis. Findings failed to support a three factor belief model, instead showing a two-factor structure (‘Persecutory beliefs’ combining Omnipotence and Malevolence constructs, and a Benevolent construct). Emotional and behavioral items did not separate. Overall, results showed that (i) a two-factor model of beliefs (Persecutory and Benevolent beliefs) provides a better fit to the data than a three-factor model, and (ii) emotional and behavioral modes of responding items should not be separated. Theoretical implications of this finding are discussed in relation to the research and therapy., Highlights • The BAVQ-R was designed to measure beliefs about voices and reactions to voices. • Despite widespread use, the factor structure of the BAVQ-R has not been established. • A two-factor model of beliefs (Persecutory and Benevolent) provided the best fit. • A two-factor model of reactions (Engagement and Resistance) provided the best fit.

Background 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. Methods The current study investigated dynamic FC in a sample of 80 schizophrenia patients and 80 matched healthy control subjects. Furthermore, relationships with auditory verbal hallucinations (AVH), a core symptom of schizophrenia, were explored. Two measures of AVH were used, one measure of current AVH severity assessed on the day of scanning, and one trait-measure where AVH were assessed repeatedly over the course of one year. Results Compared to healthy controls, schizophrenia patients showed increased dwell times in states with high connectivity within the default mode network (DMN). Current AVH severity did not show a significant relationship with dynamic FC. However, the trait-measure of AVH proneness over one year showed a significant relationship with dynamic FC. Patients with high AVH proneness spent less time in connectivity states characterized by strong anti-correlation between the DMN and task-positive networks. Discussion The results provide further evidence for a DMN dysfunction in schizophrenia, which could be linked to thought disturbances in relation to an increased internal focus of cognitive processing. The effects of AVH proneness on dynamic FC support theoretical models of AVH which have proposed an instability of the DMN and impaired cognitive control in AVH patients. The results also point to AVH proneness as a potential marker for identifying distinct subgroups of schizophrenia patients.

Background Impaired insight is common among patients with schizophrenia, and a major obstacle for treatment adherence and improvement. Previous studies have investigated the effect of antipsychotics on insight, but findings are indecisive due to small or homogeneous samples, non-randomized design or short follow- up. The aim of this study was to investigate if there were differential effects on insight among different antipsychotic medications, and whether the effect was directly related to improvement in insight or indirectly through reduction of psychosis symptoms. Methods Data was derived from the Bergen-Stavanger-Innsbruck-Trondheim study (BestIntro). This is a randomized, rater-blinded, naturalistic study with a head- to head comparison of three antipsychotic medications: amisulpride, aripiprazole and olanzapine. Inclusion criteria were adults with a F20-F29 ICD-10 diagnosis being actively psychotic defined as a score of ≥4 on items P1, P3, P5, P6, or G9 on the Positive And Negative Syndrome Scale (PANSS). Insight was measured by PANSS item G12. We used a modified version of PANSS to assess psychosis symptoms (PANSS total score minus item G12, mPANSS). Level and change in insight and psychosis symptoms were estimated in latent growth curve models. The pattern of change indicated a piecewise model with the initial phase from baseline to week six and the long-term phase from week six to one year. The study drugs were used as predictors. Results A total of 144 participants were included, 35% female and 61% had previously used antipsychotic medication. Mean insight score at baseline was 3.36. Preliminary findings show differential effects on insight among the three medications, where aripiprazole was the least effective drug. The effect on insight was related to improvement in psychosis symptoms for all study drugs. In addition, we found a direct effect on insight in the long-term phase for amisulpride and olanzapine. In the same phase, the aripiprazole group showed a slight increase in impaired insight. Discussion This is the first randomized study with a heterogeneous sample to find an effect of antipsychotics on insight that exceeds the contribution of reduction of psychosis symptoms. Although we have not investigated the association between increased insight and medication adherence, our results imply that patients with impaired insight will benefit from antipsychotic treatment. More specifically, treatment with amisulpride or olanzapine may be more helpful in improving insight over time.

Background Schizophrenia is a serious illness and treatment with antipsychotic drugs remains one of the most effective types of treatment. The course of schizophrenia, however, is highly heterogeneous and currently it is not possible to predict which patient will respond adequately to which antipsychotic drug. The aim of our study was to define trajectories regarding response to antipsychotic drug treatment in patients with schizophrenia spectrum disorders. A second aim was to evaluate demographic factors and antipsychotic drugs as predictors for the different trajectories. Methods Best Intro is a randomized, rater-blind, head-to-head comparison of amisulpride, aripiprazole and olanzapine. Adult patients with a diagnosis in the schizophrenia spectrum (ICD-10 diagnoses F20-29) were included. Participants had symptoms of ongoing psychosis as determined by a score of four or more on at least one of the following PANSS (Positive and Negative Syndrome Scale) items: P1 (delusions), P3 (hallucinations), P5 (grandiosity), P6 (suspiciousness/persecution) or G9 (unusual thought content). Patients were followed over a period of 52 weeks and the assessment points were at baseline, after one week, three weeks, six weeks, three months, six months, nine months, and 12 months. Totally 359 patients were assessed for eligibility, and 144 of them were enrolled and randomized to one of the study drugs. We used the R statistical program to define trajectories of antipsychotic response. Results We identified three different trajectories regarding the reduction of PANSS total score, with Bayesian information criterion (BIC) = 6157 (BIC for two groups=6164 and for four groups=6171). A large group of patients (N=106, 74%) showed a trajectory of good improvement in PANSS total score over the first 26 weeks of follow-up and maintained it after one year with a total of 35% reduction in PANSS total score (Good response group). A second group of patients (N=19, 13%) followed a trajectory of quick response (already at one week) and a large reduction of PANSS total score (Strong response group). After one year, the reduction of PANSS total score was 58%. There was a difference in the starting point for PANSS total score in these two groups with a higher value at baseline in the Strong response group, but the ending point was quite similar. A third group of patients (N= 19, 13%) followed a trajectory of poor improvement and a 9% reduction in PANSS total score over the studied period (Slight response group). The demographic variables age, sex, civil status and living alone, or drug naivety did not predict participants grouping in the various trajectories. Furthermore, we examined the predictive value of different antipsychotic drug treatment for the different trajectories with the “Intention to treat” method. There was a statistically significant difference in favor of amisulpride treatment for belonging to the Strong response group, while olanzapine strongly predicted the belonging to the Slight response group. There was no significant difference among the antipsychotic drugs regarding the Good response group. Discussion Most patients (74%) with a schizophrenia spectrum diagnosis showed a good response during the one year follow-up and another 13% showed a remarkable strong improvement. That means that a total of 87% of patients had a satisfactory course of illness during the first year. Use of amisulpride predicts a better course compared to aripiprazole and olanzapine. This finding can be useful for clinicians when selecting antipsychotic drugs for their patients.

Background Antipsychotic associated akathisia is a highly relevant clinical phenomenon. The common side effect can be stigmatizing, cause subjective distress and depression, lead to medication noncompliance and be potentially disabling for patients with psychosis. Associations between akathisia and both suicide, depression and agitation has been suggested in research literature, but inconsistently. This study investigates the level of akathisia at hospital discharge/first follow-up for consecutively admitted patients with acute phase psychosis, comparing four atypical antipsychotics (AAPs) regarding the presence of akathisia, and explores possible associations between akathisia and both suicidality, depression and agitation. Methods This study is a sub-study of the Bergen Psychosis Project (BPP), a pragmatic, rater-blind, randomized trial comparing head-to-head ziprasidone, olanzapine, risperidone and quetiapine. The present study reports cross-sectional data at discharge/first follow-up after acute admission to hospital for patients with psychosis. Patients were assessed with The Positive And Negative Syndrome Scale (PANSS). We applied the validated PANSS Excited Component (PANSS-EC) factor to assess agitation. The PANSS-EC consists of the five PANSS items: P4 Excitement, P7 Hostility, G4 Tension, G8 Uncooperativeness and G14 Poor impulse control. To assess depression in general and suicidality specifically we used the validated Calgary Depression Scale for Schizophrenia (CDSS).Furthermore the Clinical Global Impression – Severity Scale (CGI-S), and the patient-administered version of the UKU Side Effect Self-Rating Scale (UKU SERS Pat). Results A total of 109 patients were included of which 35 (32.1 %) were females, mean age was 34.0 (12.4). The mean total PANSS score was 54.9 (14.4), the mean CGI-S was 3.7 (1.1) and the mean total CDSS score was 3.9 (4.0). Our preliminary results show that a total of 58 (53.3%) patients had used antipsychotics before entering the study. Some level of akathisia was reported by ¼ of the patients, meaning a score of 1 or more on the UKU SERS Pat. There was a statistically significant difference between ziprasidone and olanzapine, with higher akathisia level in the ziprasidone group. Furthermore, there were statistically significant correlations between akathisia and suicidality and between akathisia and depression. We found no significant correlation between akathisia and the PANSS-EC factor or between akathisia and the PANSS general item G14 Poor impulse control. Statistical details will be presented on the poster. Discussion Our study shows that akathisia is a prevalent side effect in a clinically relevant sample of patients with acute phase psychosis treated with atypical antipsychotics. The prevalence of antipsychotic associated akathisia ranges widely across studies due to, among others, methodological heterogeneities and varieties in measurement tools. In our study, akathisia was significantly associated with both depression and suicidality. The finding of a significant correlation between akathisia and suicidality supports a previous finding that even a mild to moderate experience of akathisia in first episode patients had an increase in the likelihood to be suicidal. We found no relationship with agitation in our study. As akathisia may go unrecognized in clinical practice and may contribute to medication noncompliance, systematic assessment for symptoms of akathisia is warranted. Conclusion Akathisia is still a prevalent phenomenon in a substantial proportion of patients treated with atypical antipsychotics. Special attention is called for regarding the association towards suicidality.