Psychosis, even in its early stages, ranks highly among the causes of disability worldwide, resulting in an increased focus on improved recovery of social and occupational functioning. This study ...aimed to provide an estimate of the effectiveness of psychosocial interventions for improving functioning in early psychosis. We also sought evidence of superiority between intervention approaches.
An electronic search was conducted using PubMed and PsycINFO to identify original articles reporting on trials of psychosocial interventions in early-stage psychosis, published up to December 2020 and is reported following PRISMA guidelines. Data were extracted on validated measures of functioning from included studies and pooled standardised mean difference (SMD) was estimated.
In total, 31 studies involving 2811 participants were included, focusing on: cognitive behavioural therapy for psychosis (CBTp), family-based therapy, supported employment, cognitive remediation training (CRT) and multi-component psychosocial interventions. Across interventions, improved function was observed (SMD = 0.239; 95% confidence interval 0.115-0.364,
< 0.001). Effect sizes varied by intervention type, stage of illness, length and duration of treatment and outcome measure used. In particular, interventions based on CRT significantly outperformed symptom-focused CBT interventions, while multi-component interventions were associated with largest gains.
Psychosocial interventions, particularly when provided as part of a multi-component intervention model and delivered in community-based settings are associated with significant improvements in social and occupational function. This review underscores the value of sensitively tracking and targeting psychosocial function as part of the standard provided by early intervention services.
Social environmental stress, including childhood abuse and deprivation, is associated with increased rates of psychiatric disorders such as schizophrenia and depression. However, the neural ...mechanisms mediating risk are not completely understood. Functional magnetic resonance imaging (MRI) studies have reported effects of social environmental stress on a variety of brain regions, but interpretation of results is complicated by the variety of environmental risk factors examined and different methods employed.
We examined brain regions consistently showing differences in blood oxygen level-dependent (BOLD) response in individuals exposed to higher levels of environmental stress by performing a coordinate-based meta-analysis on 54 functional MRI studies using activation likelihood estimation (ALE), including an overall sample of 3044 participants. We performed separate ALE analyses on studies examining adults (mean age ⩾18 years) and children/adolescents (mean age <18 years) and a contrast analysis comparing the two types of study.
Across both adult and children/adolescent studies, ALE meta-analysis revealed several clusters in which differences in BOLD response were associated with social environmental stress across multiple studies. These clusters incorporated several brain regions, among which the right amygdala was most frequently implicated.
These findings suggest that a variety of social environmental stressors is associated with differences in the BOLD response of specific brain regions such as the right amygdala in both children/adolescents and adults. What remains unknown is whether these environmental stressors have differential effects on treatment response in these brain regions.
Genetic variants associated with increased risk for schizophrenia (SZ) are hypothesized to be more penetrant at the level of brain structure and function than at the level of behavior. However, to ...date the relative sensitivity of imaging vs cognitive measures of these variants has not been quantified. We considered effect sizes associated with cognitive and imaging studies of 9 robust SZ risk genes (DAOA, DISC1, DTNBP1, NRG1, RGS4, NRGN, CACNA1C, TCF4, and ZNF804A) published between January 2005-November 2011. Summary data was used to calculate estimates of effect size for each significant finding. The mean effect size for each study was categorized as small, medium, or large and the relative frequency of each category was compared between modalities and across genes. Random effects meta-analysis was used to consider the impact of experimental methodology on effect size. Imaging studies reported mostly medium or large effects, whereas cognitive investigations commonly reported small effects. Meta-analysis confirmed that imaging studies were associated with larger effects. Effect size estimates were negatively correlated with sample size but did not differ as a function of gene nor imaging modality. These observations support the notion that SZ risk variants show larger effects, and hence greater penetrance, when characterized using indices of brain structure and function than when indexed by cognitive measures. However, it remains to be established whether this holds true for individual risk variants, imaging modalities, or cognitive functions, and how such effects may be mediated by a relationship with sample size and other aspects of experimental variability.
The regional distribution of white matter (WM) abnormalities in schizophrenia remains poorly understood, and reported disease effects on the brain vary widely between studies. In an effort to ...identify commonalities across studies, we perform what we believe is the first ever large-scale coordinated study of WM microstructural differences in schizophrenia. Our analysis consisted of 2359 healthy controls and 1963 schizophrenia patients from 29 independent international studies; we harmonized the processing and statistical analyses of diffusion tensor imaging (DTI) data across sites and meta-analyzed effects across studies. Significant reductions in fractional anisotropy (FA) in schizophrenia patients were widespread, and detected in 20 of 25 regions of interest within a WM skeleton representing all major WM fasciculi. Effect sizes varied by region, peaking at (d=0.42) for the entire WM skeleton, driven more by peripheral areas as opposed to the core WM where regions of interest were defined. The anterior corona radiata (d=0.40) and corpus callosum (d=0.39), specifically its body (d=0.39) and genu (d=0.37), showed greatest effects. Significant decreases, to lesser degrees, were observed in almost all regions analyzed. Larger effect sizes were observed for FA than diffusivity measures; significantly higher mean and radial diffusivity was observed for schizophrenia patients compared with controls. No significant effects of age at onset of schizophrenia or medication dosage were detected. As the largest coordinated analysis of WM differences in a psychiatric disorder to date, the present study provides a robust profile of widespread WM abnormalities in schizophrenia patients worldwide. Interactive three-dimensional visualization of the results is available at www.enigma-viewer.org.
Intelligence is highly heritable
and a major determinant of human health and well-being
. Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence
, but ...much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer's disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.
Schizophrenia (SZ) and autism spectrum disorders (ASDs) are complex neurodevelopmental disorders that may share an underlying pathology suggested by shared genetic risk variants. We sequenced the ...exonic regions of 215 genes in 147 ASD cases, 273 SZ cases and 287 controls, to identify rare risk mutations. Genes were primarily selected for their function in the synapse and were categorized as: (1) Neurexin and Neuroligin Interacting Proteins, (2) Post-synaptic Glutamate Receptor Complexes, (3) Neural Cell Adhesion Molecules, (4) DISC1 and Interactors and (5) Functional and Positional Candidates. Thirty-one novel loss-of-function (LoF) variants that are predicted to severely disrupt protein-coding sequence were detected among 2 861 rare variants. We found an excess of LoF variants in the combined cases compared with controls (P=0.02). This effect was stronger when analysis was limited to singleton LoF variants (P=0.0007) and the excess was present in both SZ (P=0.002) and ASD (P=0.001). As an individual gene category, Neurexin and Neuroligin Interacting Proteins carried an excess of LoF variants in cases compared with controls (P=0.05). A de novo nonsense variant in GRIN2B was identified in an ASD case adding to the growing evidence that this is an important risk gene for the disorder. These data support synapse formation and maintenance as key molecular mechanisms for SZ and ASD.
Schizophrenia is a serious psychiatric disorder with a broadly undiscovered genetic etiology. Recent studies of de novo mutations (DNMs) in schizophrenia and autism have reinforced the hypothesis ...that rare genetic variation contributes to risk. We carried out exome sequencing on 57 trios with sporadic or familial schizophrenia. In sporadic trios, we observed a ~3.5-fold increase in the proportion of nonsense DNMs (0.101 vs 0.031, empirical P=0.01, Benjamini-Hochberg-corrected P=0.044). These mutations were significantly more likely to occur in genes with highly ranked probabilities of haploinsufficiency (P=0.0029, corrected P=0.006). DNMs of potential functional consequence were also found to occur in genes predicted to be less tolerant to rare variation (P=2.01 × 10(-)(5), corrected P=2.1 × 10(-)(3)). Genes with DNMs overlapped with genes implicated in autism (for example, AUTS2, CHD8 and MECP2) and intellectual disability (for example, HUWE1 and TRAPPC9), supporting a shared genetic etiology between these disorders. Functionally CHD8, MECP2 and HUWE1 converge on epigenetic regulation of transcription suggesting that this may be an important risk mechanism. Our results were consistent in an analysis of additional exome-based sequencing studies of other neurodevelopmental disorders. These findings suggest that perturbations in genes, which function in the epigenetic regulation of brain development and cognition, could have a central role in the susceptibility to, pathogenesis and treatment of mental disorders.
We review studies of whether cortisol levels following psychosocial stress exposure differ between patients with psychosis and healthy control subjects.
Original research published between 1993 and ...February 2019 was included in the literature search. Studies that used experimentally induced psychosocial stress and reported stress response measures of plasma or saliva cortisol levels in patients at any stage of illness (i.e. high risk, first episode and chronic phase) were included.
A total of 17 studies were included. Although there was evidence of inconsistencies in measures, we observed moderate evidence of an association with stress-induced cortisol blunting response across studies.
This review highlights recent evidence of blunting of cortisol response following experimentally induced psychosocial stress. While there was some evidence of this blunted response across illness types and stages, the strongest evidence was observed for those with chronic schizophrenia. Due to the low number of studies, in particular in bipolar disorder, much work is still needed to accurately characterise the biological effects of stress in psychosis.
The complex nature of human cognition has resulted in cognitive genomics lagging behind many other fields in terms of gene discovery using genome-wide association study (GWAS) methods. In an attempt ...to overcome these barriers, the current study utilized GWAS meta-analysis to examine the association of common genetic variation (~8M single-nucleotide polymorphisms (SNP) with minor allele frequency ⩾1%) to general cognitive function in a sample of 35 298 healthy individuals of European ancestry across 24 cohorts in the Cognitive Genomics Consortium (COGENT). In addition, we utilized individual SNP lookups and polygenic score analyses to identify genetic overlap with other relevant neurobehavioral phenotypes. Our primary GWAS meta-analysis identified two novel SNP loci (top SNPs: rs76114856 in the CENPO gene on chromosome 2 and rs6669072 near LOC105378853 on chromosome 1) associated with cognitive performance at the genome-wide significance level (P<5 × 10
). Gene-based analysis identified an additional three Bonferroni-corrected significant loci at chromosomes 17q21.31, 17p13.1 and 1p13.3. Altogether, common variation across the genome resulted in a conservatively estimated SNP heritability of 21.5% (s.e.=0.01%) for general cognitive function. Integration with prior GWAS of cognitive performance and educational attainment yielded several additional significant loci. Finally, we found robust polygenic correlations between cognitive performance and educational attainment, several psychiatric disorders, birth length/weight and smoking behavior, as well as a novel genetic association to the personality trait of openness. These data provide new insight into the genetics of neurocognitive function with relevance to understanding the pathophysiology of neuropsychiatric illness.
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