Lower levels of the glial cell marker TSPO in drug-naive first-episode psychosis patients as measured using PET and [11C]PBR28.

Abstract Several lines of evidence are indicative of a role for immune activation in the pathophysiology of schizophrenia. Nevertheless, studies using positron emission tomography (PET) and radioligands for the translocator protein (TSPO), a marker for glial activation, have yielded inconsistent results. Whereas early studies using a radioligand with low signal-to-noise in small samples showed increases in patients, more recent studies with improved methodology have shown no differences or trend-level decreases. Importantly, all patients investigated thus far have been on antipsychotic medication, and as these compounds may dampen immune cell activity, this factor limits the conclusions that can be drawn. Here, we examined 16 drug-naive, first-episode psychosis patients and 16 healthy controls using PET and the TSPO radioligand [11C]PBR28. Gray matter (GM) volume of distribution (VT) derived from a two-tissue compartmental analysis with arterial input function was the main outcome measure. Statistical analyses were performed controlling for both TSPO genotype, which is known to affect [11C]PBR28 binding, and gender. There was a significant reduction of [11C]PBR28 VT in patients compared with healthy controls in GM as well as in secondary regions of interest. No correlation was observed between GM VT and clinical or cognitive measures after correction for multiple comparisons. The observed decrease in TSPO binding suggests reduced numbers or altered function of immune cells in brain in early-stage schizophrenia

Reply to: New Meta- and Mega-analyses of Magnetic Resonance Imaging Findings in Schizophrenia: Do They Really Increase Our Knowledge About the Nature of the Disease Process?

This work was supported by National Institute of Biomedical Imaging and Bioengineering Grant No. U54EB020403 (to the ENIGMA consortium)

Cortical brain abnormalities in 4474 individuals with schizophrenia and 5098 control subjects via the enhancing neuro Imaging genetics through meta analysis (ENIGMA) Consortium

BACKGROUND: The profile of cortical neuroanatomical abnormalities in schizophrenia is not fully understood, despite hundreds of published structural brain imaging studies. This study presents the first meta-analysis of cortical thickness and surface area abnormalities in schizophrenia conducted by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Schizophrenia Working Group. METHODS: The study included data from 4474 individuals with schizophrenia (mean age, 32.3 years; range, 11-78 years; 66% male) and 5098 healthy volunteers (mean age, 32.8 years; range, 10-87 years; 53% male) assessed with standardized methods at 39 centers worldwide. RESULTS: Compared with healthy volunteers, individuals with schizophrenia have widespread thinner cortex (left/right hemisphere: Cohen's d = -0.530/-0.516) and smaller surface area (left/right hemisphere: Cohen's d = -0.251/-0.254), with the largest effect sizes for both in frontal and temporal lobe regions. Regional group differences in cortical thickness remained significant when statistically controlling for global cortical thickness, suggesting regional specificity. In contrast, effects for cortical surface area appear global. Case-control, negative, cortical thickness effect sizes were two to three times larger in individuals receiving antipsychotic medication relative to unmedicated individuals. Negative correlations between age and bilateral temporal pole thickness were stronger in individuals with schizophrenia than in healthy volunteers. Regional cortical thickness showed significant negative correlations with normalized medication dose, symptom severity, and duration of illness and positive correlations with age at onset. CONCLUSIONS: The findings indicate that the ENIGMA meta-analysis approach can achieve robust findings in clinical neuroscience studies; also, medication effects should be taken into account in future genetic association studies of cortical thickness in schizophrenia

Schizophrenia as a systemic disorder : studies of peripheral and central biological functions

Psychiatric disturbances with an onset in adulthood may show subtle signs in childhood and school age. This is particularly applicable to patients with schizophrenia. A plasma membrane disturbance has been proposed as a common denominator responsible for both the central nervous system abnormalities and the changes in peripheral organs in patients with schizophrenia. The aim of the present thesis was to investigate central (neuropsychological, neurological and psychomotor) and peripheral (neuromuscular, tyrosine transport across the cell membrane) functions in schizophrenia with tyrosine kinetics as an indicator of membrane function. Another aim was to study possible familial transmission(s) of central and peripheral biological changes by investigating the occurrences of such abnormalities in unaffected first-degree relatives to the patients. Patients with schizophrenia (n = 39) their first degree- relatives (n = 44) and healthy controls (n = 55) were investigated according to the below listed studies. I. Clinical neurological investigation of neurological signs were performed. Psychomotor functions were investigated using the finger tapping, Purdue pegboard and pronation-supination tests, hand grasp strength, and gait. II. Histopathological examination of the skeletal muscle fibre was performed. The electrophysiological properties of the motor unit was studied in patients with schizophrenia and controls using the macro electromyographical (EMG) technique III. Investigation of the muscle fibre histology and electrophysiology was performed as in study II in unaffected first-degree relatives to patients with schizophrenia. IV. Tyrosine transport (Km and Vmax) across the cell membrane was investigated in vitro using cultivated fibroblasts from patient with schizophrenia and healthy controls. V. Cognitive functions in patients with schizophrenia, their first-degree relatives and controls were assessed using an extensive battery of neuropsychological tests Patients with schizophrenia exhibited neurological abnormalities and aberrant psychomotor performance to a significantly greater extent than healthy controls. Neuromuscular changes were found significantly more often in patients with schizophrenia and their unaffected first-degree relatives compared to controls. The most frequent histopathological finding in patients was muscle fibre atrophies, affecting both type I and type II fibres. Increased amplitude and area of the motor unit action potentials were found in the macro EMG recordings from patients and relatives but not in that from controls. The patients exhibited aberrant tyrosine transport kinetics with significantly lower Vmax (indicating lower tyrosine transport) and Km (indicating higher affinity) compared to controls. Finally, the patients performed significantly worse than their first-degree relatives and the controls in most of the neuropsychological tests and this significantly correlated with a lower level of functioning. Biological and clinical changes have been demonstrated deriving both from the central nervous system and peripheral organs indicating that schizophrenia is a systemic disease. Furthermore, the type of macro EMG findings and tyrosine transport aberrations indicate a membrane dysfunction. These results entail a different perspective on the ethiology of schizophrenia

Predicting 5-year outcome in first-episode psychosis: Construction of a prognostic rating scale

Objective: The aim of this study was to construct a rating scale to predict long-term outcome on the basis of clinical and sociodemographic characteristics in patients with symptoms of psychosis who seek psychiatric help for the first time. Method: Patients (N = 153) experiencing their first episode of psychosis (DSM-IV schizophrenia, schizophreniform disorder, schizoaffective disorder, brief psychotic episode, delusional disorder, affective psychosis with mood-incongruent delusions, or psychotic disorder not otherwise specified or being actively psychotic) were consecutively recruited from 17 psychiatric clinics in Sweden from January 1996 through December 1997 (24 months). Baseline characteristics were assessed with an extensive battery of psychiatric rating scales; duration of untreated psychosis, premorbid characteristics, and cognitive functioning were also assessed. The relationship between baseline characteristics and the 5-year outcome was analyzed using a stepwise logistic regression model. Results: In the logistic regression analysis, 5 variables were found to have unique contributions in the prediction of outcome. In order of magnitude of the odds ratios, these variables were Global Assessment of Functioning (GAF) score during the year before first admission, education level, actual GAF score at first admission, gender, and social network. The sensitivity, i.e., correctly identified cases (poor outcome), was 0.84, and the specificity, i.e., the correctly identified non-cases (good outcome), was 0.77. Conclusion: To initiate adequate interventions, it is crucial to identify patients experiencing their first episode of psychosis who are likely to have an unfavorable long-term outcome. The predictive rating scale described here is a feasible tool for early detection of these patients

Meta-analysis of cognitive performance in drug-naive patients with schizophrenia

Cognitive deficits represent a significant characteristic of schizophrenia. However, a majority of the clinical studies have been conducted in antipsychotic drug treated patients. Thus, it remains unclear if significant cognitive impairments exist in the absence of medication. This is the first meta-analysis of cognitive findings in drug-na ve patients with schizophrenia. Cognitive data from 23 studies encompassing 1106 patients and 1385 controls published from 1992 to 2013 were included. Tests were to a large extent ordered in cognitive domains according to the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) battery. Analysis was performed with STATA using the random-effects model and heterogeneity as well as Egger's publication bias was assessed. Overall the results show that patients performed worse than healthy controls in all cognitive domains with medium to large effect sizes. Verbal memory, speed of processing and working memory were three of the domains with the greatest impairments. The pattern of results is in line with previous meta-analytic findings in antipsychotic treated patients. The present meta-analysis confirms the existence of significant cognitive impairments at the early stage of the illness in the absence of antipsychotic medication

Effect of Brief Admission to Hospital by Self-referral for Individuals Who Self-harm and Are at Risk of Suicide. A Randomized Clinical Trial

Importance To our knowledge, there is no consensus regarding when individuals who repeatedly self-harm and are at risk of suicide should be hospitalized. To evaluate a new alternative, we examined the effects of brief admission (BA) to hospital by self-referral.Objectives To determine the effects of BA on inpatient service use and on secondary outcomes of daily life functioning, nonsuicidal self-injuries, and attempted suicide among individuals who self-harm and are at risk of suicide.Design, Setting, and ParticipantsThe single-masked Brief Admission Skåne Randomized Clinical Trial was conducted from September 2015 to June 2018 at 4 psychiatric health care facilities in southern Sweden. Data were collected 6 months retrospectively at baseline and at 6-month and 12-month follow-ups. Participants were randomized to either BA and treatment as usual (BA group) or treatment as usual (control group). The sample was a referral population, with the most important inclusion criteria being current episodes of self-harm and/or recurrent suicidality, at least 3 diagnostic criteria for borderline personality disorder, and hospitalization in the last 6 months.Interventions Self-referred BA was offered for 12 months, with standard limits for duration and frequency, after the negotiation of a contract outlining the intervention.Main Outcomes and Measures Prespecified main outcome measures were days admitted to the hospital, including voluntary admission, BA, and compulsory admission.ResultsThe 125 participants had a mean (SD) age of 32.0 (9.4) years, 106 (84.8%) were women, and 63 were randomized to the BA group and 62 to the control group. No significant advantage was observed in the number of days in the hospital for the BA group compared with the control group. Within-group analyses demonstrated significant decreases in both groups regarding days admitted to the hospital (BA group: χ2 = 22.71; P < .001; control group: χ2 = 23.01; P < .001) and visits to the emergency department (BA group: χ2 = 13.95; P < .001; control group: χ2 = 21.61; P < .001), but only the BA group showed a reduction in days with compulsory admission (χ2 = 7.67; P = .02) and nonsuicidal self-injuries (χ2 = 6.13; P = .047). The BA group showed significantly greater improvements in the mobility domain of daily life functioning (z = −2.39; P = .02) and significant within-group improvements in 3 other domains (cognition: F = 9.02; P < .001; domestic responsibilities: F = 3.23; P = .049; and participation: F = 3.79; P = .03).Conclusions and Relevance Brief admission appears no more efficacious in reducing use of inpatient services than usual care for individuals who self-harm and are at risk of suicide. Future studies should explore other possible beneficial effects

No association between cortical dopamine D2 receptor availability and cognition in antipsychotic-naive first-episode psychosis

Cognitive impairment is an important predictor of disability in schizophrenia. Dopamine neurotransmission in cortical brain regions has been suggested to be of importance for higher-order cognitive processes. The aim of this study was to examine the relationship between extrastriatal dopamine D2-R availability and cognitive function, using positron emission tomography and the high-affinity D2-R radioligand [C-11]FLB 457, in an antipsychotic-naive sample of 18 first-episode psychosis patients and 16 control subjects. We observed no significant associations between D2-R binding in the dorsolateral prefrontal cortex or hippocampus (beta = 0.013-0.074, partial r= -0.037-0.273, p = 0.131-0.841). Instead, using Bayesian statistics, we found moderate support for the null hypothesis of no relationship (BFH0:H1 = 3.3-8.2). Theoretically, our findings may suggest a lack of detrimental effects of D2-R antagonist drugs on cognition in schizophrenia patients, in line with clinical observations

What are the effects of implementing patient-controlled admissions in inpatient care? : A study protocol of a large-scale implementation and naturalistic evaluation for adult and adolescent patients with severe psychiatric conditions throughout Region Stockholm

Introduction Patient-controlled admissions (PCAs) represent a change in psychiatric inpatient care where patients are allowed to decide for themselves when hospitalisation might be required. Prior research has demonstrated that PCA increase the number of admissions, but decrease days in inpatient care, while both the admissions to and days in involuntary care decrease. However, investigations have been restricted to specific patient groups arid have not examined other possible benefits, such as effects on symptoms, quality of life and autonomy. Methods and analysis This study explores the implementation process and effects of PCA in Region Stockholm, who is currently introducing PCA for all patients with severe psychiatric conditions and extensive healthcare utilisation. In total, the study comprises approximately 45 inpatient wards, including child and adolescent psychiatry. In a naturalistic evaluation, patients assigned PCA will be followed up to 36 months, both with regard to hospitalisation rates and self-reported outcomes. In addition, qualitative studies will explore the experiences of patients, caregivers of adolescents and healthcare providers. Ethics and dissemination Approval has been granted by the Swedish Ethical Review Authority (Dnr: 2020-06498). The findings from this study will be disseminated via publications in international peer-reviewed journals, at scientific conferences, as part of two doctoral theses, and through the Swedish Partnership for Mental Health