Implicating particular genes in the generation of complex brain and behavior phenotypes requires multiple lines of evidence. The rarity of most high impact genetic variants typically precludes the possibility of accruing statistical evidence that they are associated with a given trait. We show here that the enrichment of a rare Chromosome 22q11.22 deletion in a recently expanded Northern Finnish sub-isolate enables the detection of association between TOP3β and both schizophrenia and cognitive impairment. Biochemical analysis of TOP3β revealed that this topoisomerase is a component of cytosolic messenger ribonucleoproteins (mRNPs) and is catalytically active on RNA. The recruitment of TOP3β to mRNPs was independent of RNA cis-elements and was coupled to the co-recruitment of FMRP, the disease gene product in fragile X mental retardation syndrome (FXS). Thus, we uncover a novel role for TOP3β in mRNA metabolism and provide several lines of evidence implicating it in neurodevelopmental disorders.

By meta-analyzing rare coding variants in whole-exome sequences of 4,133 schizophrenia cases and 9,274 controls, de novo mutations in 1,077 trios, and copy number variants from 6,882 cases and 11,255 controls, we show that individuals with schizophrenia carry a significant burden of rare damaging variants in 3,488 genes previously identified as having a near-complete depletion of loss-of-function variants. In schizophrenia patients who also have intellectual disability, this burden is concentrated in risk genes associated with neurodevelopmental disorders. After excluding known neurodevelopmental disorder risk genes, a significant rare variant burden persists in other loss-of-function intolerant genes, and while this effect is notably stronger in schizophrenia patients with intellectual disability, it is also seen in patients who do not have intellectual disability. Together, our results show that rare damaging variants contribute to the risk of schizophrenia both with and without intellectual disability, and support an overlap of genetic risk between schizophrenia and other neurodevelopmental disorders.

Objective: Although mortality related to psychotropic medications has received much attention in recent years, little is known about the relationship between risk of death and cumulative antipsychotic load, and even less about the relationship between mortality and cumulative exposure to antidepressants or benzodiazepines. The authors examined these relationships using nationwide databases. Method:The authors used prospectively collected nationwide databases to identify all individuals 16-65 years of age with a schizophrenia diagnosis (N=21,492) in Sweden. All-cause and cause-specific mortality rates were calculated as a function of cumulative low, moderate, and high exposure to antipsychotics, antidepressants, and benzodiazepines from 2006 through 2010.Results: Compared with no exposure, both moderate (adjusted hazard ratio=0.59, 95% CI=0.49-0.70) and high (adjusted hazard ratio=0.75, 95% CI=0.63-0.89) antipsychotic exposures were associated with substantially lower overall mortality. Moderate antidepressant exposure was associated with a lower mortality (adjusted hazard ratio=0.85, 95% CI=0.73-0.98), and high exposure, even lower (adjusted hazard ratio=0.71, 95% CI=0.59-0.86). Exposure to benzodiazepines showed a dose-response relationship with mortality (hazard ratios up to 1.74 [95% CI=1.50-2.03]).Conclusions: Moderate and high-dose antipsychotic and antidepressant use were associated with 15%-40% lower overall mortality, whereas chronic high-dose use of benzodiazepines was associated with up to a 70% higher risk of death compared with no exposure. Since patients with anxiety and depressive symptoms may have a higher intrinsic risk of death, the finding for benzodiazepines may be attributable to some extent to residual confounding.

Among patients with schizophrenia, the cumulative antipsychotic exposure displays a U-shaped curve for overall mortality, revealing the highest risk of death among those patients with no antipsychotic use. These results indicate that both excess overall and cardiovascular mortality in schizophrenia is attributable to other factors than antipsychotic treatment when used in adequate dosages.

No abstract

The present study aimed to compare population-based familial samples of patients with schizophrenia (n = 218) and schizoaffective disorder (n = 62) and a healthy control group (n = 123). Patients with schizoaffective disorder outperformed patients with schizophrenia in verbal ability, processing speed, visual working memory, and verbal memory. When compared with controls, patients with schizoaffective disorder also had a generalized cognitive impairment. Adjusting for clinical characteristics removed significant differences between the patient groups. Irrespective of the diagnosis, patients with the most severe negative symptoms and highest dose of antipsychotics had the most severe cognitive impairments, whereas mood symptoms were not related to cognitive performance. In conclusion, people with schizoaffective disorder have severe cognitive impairments, but the impairments are milder than in schizophrenia. Mood symptoms may not explain the difference between the diagnostic groups in cognitive functions, but the difference may be related to differences in the severity of negative symptoms.

No abstract

First-episode psychosis (FEP) is associated with inflammatory and brain structural changes, but few studies have investigated whether systemic inflammation associates with brain structural changes in FEP. Thirty-seven FEP patients (median 27 days on antipsychotic medication), and 19 matched controls were recruited. Serum levels of 38 chemokines and cytokines, and cardiovascular risk markers were measured at baseline and 2 months later. We collected T1- and diffusion-weighted MRIs with a 3 T scanner from the patients at baseline. We analyzed the association of psychosis-related inflammatory markers with gray and white matter (WM) volume using voxel-based morphometry and WM diffusion using tract-based spatial statistics with whole-brain and region-of-interest (ROI) analyses. FEP patients had higher CCL22 and lower TGFα, CXCL1, CCL7, IFN-α2 and ApoA-I than controls. CCL22 decreased significantly between baseline and 2 months in patients but was still higher than in controls. The association between inflammatory markers and FEP remained significant after adjusting for age, sex, smoking and BMI. We did not observe a correlation of inflammatory markers with any symptoms or duration of antipsychotic treatment. Baseline CCL22 levels correlated negatively with WM volume and positively with mean diffusivity and radial diffusivity bilaterally in the frontal lobes in ROI analyses. Decreased serum level of ApoA-I was associated with smaller volume of the medial temporal WM. In whole-brain analyses, CCL22 correlated positively with mean diffusivity and radial diffusivity, and CXCL1 associated negatively with fractional anisotropy and positively with mean diffusivity and radial diffusivity in several brain regions. This is the first report to demonstrate an association between circulating chemokine levels and WM in FEP patients. Interestingly, CCL22 has been previously implicated in autoimmune diseases associated with WM pathology. The results suggest that an altered activation of innate immunity may contribute to WM damage in psychotic disorders.