Centre for Addiction and Mental Health

Hand grip strength (HGS) is a predictor of cognitive decline in aging. To understand the direct and indirect mechanisms underlying this association, we performed integrative analyses of genetic, cognitive, and autopsy data. A polygenic risk score for HGS (PRSHGS) was calculated in two independent studies of aging (total n = 25,227). Cross-sectional and longitudinal modeling, including mediation with physical activity, assessed the effects of PRSHGS on cognitive performance and postmortem neuropathology. In both cohorts, higher PRSHGS predicted better global cognitive performance (p = 7.77 × 10-4 and p = 0.025) and improved the predictive performance of an Alzheimer's disease PRS (likelihood ratio test p = 2.5 × 10-5 and p = 0.007). PRSHGS was not associated with levels of any postmortem neuropathology. PRSHGS effects on cognition were only partially and inconsistently mediated by physical activity. Genetic predisposition for greater HGS predicts better cognitive performance in late life, independent from Alzheimer's disease-related neuropathology.

In this Perspective, we summarize the evidence to date around the use of the Camouflaging Autistic Traits Questionnaire (CAT-Q) as a tool in research and clinical settings, and offer suggestions for its future use. We highlight that the CAT-Q is a useful measure of camouflaging/masking for research purposes, although questions remain regarding sociocultural variation in camouflaging experiences, and its specificity regarding autistic camouflaging compared with impression management more generally. With respect to clinical practice, we note that very little research has examined the use of the CAT-Q in clinical settings to date, and we encourage clinicians to be mindful of this limited evidence base and to refrain from using CAT-Q scores in diagnostic decision-making or as an intervention monitoring/outcome tool.

International audience

Some individuals interpret persistent depression and anxiety, alongside the exhaustion of standard treatment options, as leading to a desperate need for relief. While desperation may shape how people assess treatment options, its role in psychedelic self-treatment and its relevance for emerging clinical models of psychedelic treatment remain underexplored. We collected discussion threads from two online substance use communities on Reddit.com and investigated how members interpreted desperation in relation to their decisions to self-treat depression and anxiety with psychedelics (including microdosing and macrodosing). Using constructivist grounded theory, we compared posts across 108 threads (173,229 words) from members who expressed desperation (n=50) and those who did not (n=68). Members described mounting frustration with standard treatments and worsening mental health that culminated in a tipping point interpreted as desperation for relief. They redefined their need to relieve depression and anxiety as urgent, which contributed to how they made sense of rapid, unplanned self-treatment with available psychedelics, without researching these options or implementing harm reduction and despite acknowledged risks. While some interpreted outcomes as relieving distress, others constructed worsening mental health as linked to multiple desperation-driven decisions to relieve distress. Our findings show how desperation shaped meaning-making around psychedelic self-treatment for depression and anxiety in online communities. These interpretations may be relevant to clinical models, where access is often granted after other treatments fail, and where similar urgency and expectations may shape engagement, decision-making, and outcome interpretations.

Cannabis use disorder (CUD) is common in youth, with elevated rates among youth with bipolar disorder (BD). Cannabis use among youth is also associated with anomalous neurostructural phenotypes. While neurophysiological mechanisms associated with cannabis use may contribute to these differences, genetic predisposition to CUD may also be contributory. Given the lack of prior studies on this topic, we examined polygenic risk scores for CUD (CUD-PRS) in relation to brain structure among youth with and without BD. T1-weighted magnetic resonance imaging (MRI) was collected for 114 participants ages 13-20 (n = 67 BD, n = 47 healthy controls (HC)). CUD-PRS was calculated using PRS-CS-auto, based on summary statistics from a genome-wide association study conducted in adults. Covariate-adjusted vertex-wise analyses examined the association of CUD-PRS with cortical volume, surface area (SA), and thickness in the whole sample, and within BD and HC. In the whole sample, higher CUD-PRS was associated with significantly lower volume and SA in the right superior frontal gyrus (β = -0.31, p < 0.01; β = -0.33, p < 0.01), and with significantly lower SA in the left paracentral lobule (β = -0.37, p = 0.0002). Within HC, higher CUD-PRS was associated with significantly lower volume and SA in the left and right superior frontal gyrus (β = -0.78, p < 0.002; β = -0.66, p < 0.028; β = -0.79, p < 0.0001; β = -0.68, p < 0.0001). There were no significant within-BD results. Present findings demonstrate a consistent pattern of higher CUD-PRS corresponding with lower regional brain structure, even in the absence of CUD. Future studies are needed to understand the mechanisms, developmental trajectories, and diagnosis-related differences in the observed findings.

Advances in gene–environment (GE) research underscore the need for novel statistical methods to clarify how social stress and genetic liability jointly influence Alcohol Use Disorder (AUD). This study examined the effect of Stressful Life Events (SLEs) on past-year DSM-5 AUD severity using propensity score matching and tested whether Polygenic Risk Scores (PRS) moderated the association between stress exposure and AUD severity. A secondary analysis was performed using the data from National Epidemiologic Survey on Alcohol and Related Conditions III (NESARC III; N = 36,309) and the newly available NESARC III genomic dataset (N = 22,848). Of 10,775 self-reported White subjects, individuals in the high-stress group (i.e., more than two stressors) (N = 4436) were matched to those in the low-stress group (N = 5048) using propensity score matching. Further, a moderation analysis was conducted to evaluate the interaction between PRS and SLE. Exposure to two or more SLEs in the past year significantly increased the odds of AUD severity after covariate adjustment (estimate: 0.37; 95%CI: 0.27–0.48; t-value: 6.96; p < 0.001). PRS was independently associated with higher AUD criteria counts after adjustment (estimate: 0.23; 95%CI: 0.07–0.39; t-value: 2.87; p = 0.01). PRS significantly moderated the relationship between the stress exposure and the AUD severity (interaction effect = 0.30; 95% CI: 0.06–0.54; t = 2.47; p = 0.01), indicating stronger stress-related effects among individuals with higher genetic risk. Additional sensitivity analyses suggested that PRS moderation by stress exposure is small and sensitive to model specification. This novel GE interaction model provides evidence that polygenic risk can potentiate the effects of high-stress exposure on the severity of AUD, thereby advancing post-GWAS modeling efforts and support precise identification of high-risk subpopulations for targeted prevention and intervention. Not applicable.