Exploring causal mechanisms of psychosis risk.

Robust epidemiological evidence of risk and protective factors for psychosis is essential to inform preventive interventions. Previous evidence syntheses have classified these risk and protective factors according to their strength of association with psychosis. In this critical review we appraise the distinct and overlapping mechanisms of 25 key environmental risk factors for psychosis, and link these to mechanistic pathways that may contribute to neurochemical alterations hypothesised to underlie psychotic symptoms. We then discuss the implications of our findings for future research, specifically considering interactions between factors, exploring universal and subgroup-specific factors, improving understanding of temporality and risk dynamics, standardising operationalisation and measurement of risk and protective factors, and developing preventive interventions targeting risk and protective factors.

PsyCog: A computerised mini battery for assessing cognition in psychosis.

Despite the functional impact of cognitive deficit in people with psychosis, objective cognitive assessment is not typically part of routine clinical care. This is partly due to the length of traditional assessments and the need for a highly trained administrator. Brief, automated computerised assessments could help to address this issue. We present data from an evaluation of PsyCog, a computerised, non-verbal, mini battery of cognitive tests. Healthy Control (HC) (N = 135), Clinical High Risk (CHR) (N = 233), and First Episode Psychosis (FEP) (N = 301) participants from a multi-centre prospective study were assessed at baseline, 6 months, and 12 months. PsyCog was used to assess cognitive performance at baseline and at up to two follow-up timepoints. Mean total testing time was 35.95 min (SD = 2.87). Relative to HCs, effect sizes of performance impairments were medium to large in FEP patients (composite score G = 1.21, subtest range = 0.52-0.88) and small to medium in CHR patients (composite score G = 0.59, subtest range = 0.18-0.49). Site effects were minimal, and test-retest reliability of the PsyCog composite was good (ICC = 0.82-0.89), though some practice effects and differences in data completion between groups were found. The present implementation of PsyCog shows it to be a useful tool for assessing cognitive function in people with psychosis. Computerised cognitive assessments have the potential to facilitate the evaluation of cognition in psychosis in both research and in clinical care, though caution should still be taken in terms of implementation and study design.

Association of Complement and Coagulation Pathway Proteins With Treatment Response in First-Episode Psychosis: A Longitudinal Analysis of the OPTiMiSE Clinical Trial.

BACKGROUND AND HYPOTHESIS: Treatment response to specific antipsychotic medications is difficult to predict on clinical grounds alone. The current study hypothesizes that the baseline complement pathway activity predicts the treatment response and investigates the relationship between baseline plasma biomarkers with treatment response to antipsychotic medications. STUDY DESIGN: Baseline plasma samples were collected from first episode of psychosis patients (n = 243) from a multi-center clinical trial. The participants were treated with amisulpride for 4 weeks. Levels of complement and coagulation proteins at baseline were measured using both data-dependent and data-independent mass spectrometry approaches. The primary outcome was remission status at 4 weeks and the secondary outcomes included change in psychotic and functional symptoms over the period of treatment. In addition, immunoassays were performed at baseline for complement C1R, as well as for activation markers C4a and sC5b-9. STUDY RESULTS: The plasma level of complement variant C4A was significantly associated with remission at 4 weeks. Moreover, higher levels of several complement and coagulation pathway proteins were associated with a reduction in psychotic symptoms and an improvement in functioning. Immunoassays showed an association of baseline levels of C1R and C4a as well as complement activation marker sC5b-9 levels with treatment response. CONCLUSION: The results demonstrated that the response to antipsychotic treatment might be related to pre-treatment levels of plasma complement and coagulation pathway proteins. This is consistent with independent evidence associating immune dysfunction with the pathophysiology of psychosis. Moreover, these results inform the development of novel therapeutic approaches that target the complement system for psychosis.

Integrated metastate functional connectivity networks predict change in symptom severity in clinical high risk for psychosis.

The ability to identify biomarkers of psychosis risk is essential in defining effective preventive measures to potentially circumvent the transition to psychosis. Using samples of people at clinical high risk for psychosis (CHR) and Healthy controls (HC) who were administered a task fMRI paradigm, we used a framework for labelling time windows of fMRI scans as 'integrated' FC networks to provide a granular representation of functional connectivity (FC). Periods of integration were defined using the 'cartographic profile' of time windows and k-means clustering, and sub-network discovery was carried out using Network Based Statistics (NBS). There were no network differences between CHR and HC groups. Within the CHR group, using integrated FC networks, we identified a sub-network negatively associated with longitudinal changes in the severity of psychotic symptoms. This sub-network comprised brain areas implicated in bottom-up sensory processing and in integration with motor control, suggesting it may be related to the demands of the fMRI task. These data suggest that extracting integrated FC networks may be useful in the investigation of biomarkers of psychosis risk.

Neural Circuitry of Novelty Salience Processing in Psychosis Risk: Association With Clinical Outcome.

Psychosis has been proposed to develop from dysfunction in a hippocampal-striatal-midbrain circuit, leading to aberrant salience processing. Here, we used functional magnetic resonance imaging (fMRI) during novelty salience processing to investigate this model in people at clinical high risk (CHR) for psychosis according to their subsequent clinical outcomes. Seventy-six CHR participants as defined using the Comprehensive Assessment of At-Risk Mental States (CAARMS) and 31 healthy controls (HC) were studied while performing a novelty salience fMRI task that engaged an a priori hippocampal-striatal-midbrain circuit of interest. The CHR sample was then followed clinically for a mean of 59.7 months (~5 y), when clinical outcomes were assessed in terms of transition (CHR-T) or non-transition (CHR-NT) to psychosis (CAARMS criteria): during this period, 13 individuals (17%) developed a psychotic disorder (CHR-T) and 63 did not. Functional activation and effective connectivity within a hippocampal-striatal-midbrain circuit were compared between groups. In CHR individuals compared to HC, hippocampal response to novel stimuli was significantly attenuated (P = .041 family-wise error corrected). Dynamic Causal Modelling revealed that stimulus novelty modulated effective connectivity from the hippocampus to the striatum, and from the midbrain to the hippocampus, significantly more in CHR participants than in HC. Conversely, stimulus novelty modulated connectivity from the midbrain to the striatum significantly less in CHR participants than in HC, and less in CHR participants who subsequently developed psychosis than in CHR individuals who did not become psychotic. Our findings are consistent with preclinical evidence implicating hippocampal-striatal-midbrain circuit dysfunction in altered salience processing and the onset of psychosis.

Resting state fMRI based multilayer network configuration in patients with schizophrenia.

Novel methods for measuring large-scale dynamic brain organisation are needed to provide new biomarkers of schizophrenia. Using a method for modelling dynamic modular organisation (Mucha et al., 2010), evidence suggests higher 'flexibility' (switching between multilayer network communities) to be a feature of schizophrenia (Braun et al., 2016). The current study compared flexibility between 55 patients with schizophrenia and 72 controls (the COBRE Dataset). In addition, novel methods of 'between resting state network synchronisation' (BRSNS) and the probability of transition from one community to another were used to further describe group differences in dynamic community structure. There was significantly higher schizophrenia group flexibility scores in cerebellar (F (1124) = 9.33, p (FDR) = 0.017), subcortical (F (1124) = 13.14, p (FDR) = 0.005), and fronto-parietal task control (F (1124) = 7.19, p (FDR) = 0.033) resting state networks (RSNs), as well as in the left thalamus (MNI XYZ: -2, -13, 12; F(1, 124) = 17.1, p (FDR) < 0.001) and the right crus I (MNI XYZ: 35, -67, -34; F (1, 124) = 19.65, p (FDR) < 0.001). Flexibility in the left thalamus reflected transitions between communities covering default mode and sensory-somatomotor RSNs. BRSNS scores suggested altered dynamic inter-RSN modular configuration in schizophrenia. This study suggests less stable community structure in a schizophrenia group at an RSN and node level and provides novel methods of exploring dynamic community structure. Mediation of group differences by mean time window correlation did however suggest flexibility to be no better as a schizophrenia biomarker than simpler measures and a range of methodological choices affected results.

Can We Reduce the Duration of Untreated Psychosis? A Systematic Review and Meta-Analysis of Controlled Interventional Studies.

Reduction of duration of untreated psychosis (DUP) is the key strategy of early interventions for improving the outcomes of first-episode psychosis. Although several controlled interventional studies have been conducted with the aim of reducing DUP, the results are highly inconsistent and conflicting. The current study systematically searches Web of Science and Ovid for English original articles investigating interventions adopted to reduce DUP, compared to a control intervention, up to April 6, 2017. Sixteen controlled interventional studies were retrieved, including 1964 patients in the intervention arm and 1358 in the control arm. The controlled intervention studies were characterized by standalone first episode psychosis services, standalone clinical high risk services, community interventions, healthcare professional training, and multifocus interventions. Random effects meta-analyses were conducted. There was no summary evidence that available interventions are successful in reducing DUP during the first episode of psychosis (Hedges' g = -0.12, 95% CI = -0.25 to 0.01). Subgroup analyses showed no differences within each subgroup, with the exception of clinical high risk services (Hedges' g = -0.386, 95% CI = -0.726 to -0.045). These negative findings may reflect a parceled research base in the area, lack of prospective randomized controlled trials (only 2 randomized cluster designed studies were present) and small sample sizes. There was substantial heterogeneity (I2 = 66.4%), most of which was accounted by different definitions of DUP onset (R2 = .88). Psychometric standardization of DUP definition, improvement of study design, and implementation of preventative strategies seem the most promising avenues for reducing DUP and improving outcomes of first-episode psychosis.

Using neuroimaging to help predict the onset of psychosis.

The aim of this review is to assess the potential for neuroimaging measures to facilitate prediction of the onset of psychosis. Research in this field has mainly involved people at 'ultra-high risk' (UHR) of psychosis, who have a very high risk of developing a psychotic disorder within a few years of presentation to mental health services. The review details the key findings and developments in this area to date and examines the methodological and logistical challenges associated with making predictions in an individual subject in a clinical setting.