Objective The primary aim was to compare the impact of NAVIGATE, a comprehensive, multidisciplinary, team-based treatment approach for first episode psychosis designed for implementation in the U.S. healthcare system, to Community Care on quality of life. Methods Thirty-four clinics in 21 states were randomly assigned to NAVIGATE or Community Care. Diagnosis, duration of untreated psychosis and clinical outcomes were assessed via live, two-way video by remote, centralized raters masked to study design and treatment. Participants (mean age 23) with schizophrenia and related disorders and ≤6 months antipsychotic treatment (N=404) were enrolled and followed for ≥2 years. The primary outcome was the Total Score of the Heinrichs-Carpenter Quality of Life Scale, a measure that includes sense of purpose, motivation, emotional and social interactions, role functioning and engagement in regular activities. Results 223 NAVIGATE recipients remained in treatment longer, experienced greater improvement in quality of life, psychopathology and involvement in work/school compared to 181 Community Care participants. The median duration of untreated psychosis=74 weeks. NAVIGATE participants with duration of untreated psychosis <74 weeks had greater improvement in quality of life and psychopathology compared with those with longer duration of untreated psychosis and those in Community Care. Rates of hospitalization were relatively low compared to other first episode psychosis clinical trials and did not differ between groups. Conclusions Comprehensive care for first episode psychosis can be implemented in U.S. community clinics. and improves functional and clinical outcomes. Effects are more pronounced for those with shorter duration of untreated psychosis.

It has long been recognized that generalized deficits in cognitive ability represent a core component of schizophrenia, evident prior to full illness onset and independent of medication. The possibility of genetic overlap between risk for schizophrenia and cognitive phenotypes has been suggested by the presence of cognitive deficits in first-degree relatives of patients with schizophrenia; however, until recently, molecular genetic approaches to test this overlap have been lacking. Within the last few years, large-scale genome-wide association studies (GWAS) of schizophrenia have demonstrated that a substantial proportion of the heritability of the disorder is explained by a polygenic component consisting of many common SNPs of extremely small effect. Similar results have been reported in GWAS of general cognitive ability. The primary aim of the present study is to provide the first molecular genetic test of the classic endophenotype hypothesis, which states that alleles associated with reduced cognitive ability should also serve to increase risk for schizophrenia. We tested the endophenotype hypothesis by applying polygenic SNP scores derived from a large-scale cognitive GWAS meta-analysis (~5000 individuals from 9 non-clinical cohorts comprising the COGENT consortium) to four schizophrenia case-control cohorts. As predicted, cases had significantly lower cognitive polygenic scores compared to controls. In parallel, polygenic risk scores for schizophrenia were associated with lower general cognitive ability. Additionally, using our large cognitive meta-analytic dataset, we identified nominally significant cognitive associations for several SNPs that have previously been robustly associated with schizophrenia susceptibility. Results provide molecular confirmation of the genetic overlap between schizophrenia and general cognitive ability, and may provide additional insight into pathophysiology of the disorder.

Objective Clinical response to antipsychotic drug treatment is highly variable, yet prognostic biomarkers are lacking. The authors recently demonstrated that successful antipsychotic drug treatment alters resting-state functional connectivity of the striatum. The goal of the present study was to test whether intrinsic striatal connectivity patterns provide prognostic information and can serve as a potential biomarker of treatment response to antipsychotic drugs. Method The authors used resting-state functional MRI (fMRI) to develop a prognostic index in a discovery cohort of 41 first-episode schizophrenia patients, then tested this index in an independent cohort of 40 newly hospitalized chronic patients with acute psychosis. In the discovery cohort, patients underwent resting-state fMRI scanning at the initiation of randomized controlled treatment with a second-generation antipsychotic. Whole-brain functional connectivity maps were generated for each subject from striatal seed regions. A stringent measure of clinical response was calculated that required sustained improvement over two consecutive study visits. Clinical response was entered into a survival analysis, and Cox regression was applied to the functional connectivity data. A striatal connectivity index was created, comprising functional connections of the striatum that predicted treatment response. This striatal connectivity index was tested on a generalizability cohort of patients with psychotic disorders who were hospitalized for an acute psychotic episode. Results A total of 91 regions functionally connected with the striatum provided significant prognostic information. Connectivity in these regions was used to create a baseline striatal connectivity index that predicted response to antipsychotic treatment with high sensitivity and specificity in both the discovery and generalizability cohorts. Conclusions These results provide evidence that individual differences in striatal functional connectivity predict response to antipsychotic drug treatment in acutely psychotic patients. With further development, this has the potential to serve as a prognostic biomarker with clinical utility and to reduce the overall burden associated with psychotic illnesses.

The augmentation of clozapine with ECT is a safe and effective treatment option. Further research is required to determine the persistence of the improvement and the potential need for maintenance treatments.