METHODS: Thirty-one patients with OCD and 29 healthy volunteers performed a decision-making task requiring them to decide whether 2 perceptually similar visual representations were the same or different under a high-uncertainty condition without feedback. Both groups underwent 7T magnetic resonance spectroscopy scans on the same day. Correlations between out-of-scanner experimental measures of checking and the glutamate/GABA (gamma-aminobutyric acid) ratio in the anterior cingulate cortex, supplementary motor area, and occipital cortex were assessed. Their relationship with subjective ratings of doubt, anxiety, and confidence was also investigated.
RESULTS: Patients with OCD exhibited excessive and dysfunctional checking, which was significantly correlated with changes in the glutamate/GABA ratio within the anterior cingulate cortex. No behavioral/neurochemical relationships were evident for either the supplementary motor area or occipital cortex. The excessive checking observed in patients was negatively correlated with their confidence levels and positively related to doubt, anxiety, and compulsivity traits.
CONCLUSIONS: We conclude that experimental measures of excessive and dysfunctional checking in OCD, which have been linked to increased doubt, anxiety, and lack of confidence, are related to an imbalance between excitatory and inhibitory neural activity within the anterior cingulate cortex. This study adds to our understanding of the role of this region in OCD by providing a laboratory model of the possible development of compulsive checking.
METHODS: Genome-wide analysis of remission (n remit = 1852, n nonremit = 3299) and percentage improvement (n = 5218) was performed. Single nucleotide polymorphism-based heritability was estimated using genome-wide complex trait analysis. Genetic covariance with eight mental health phenotypes was estimated using polygenic scores/AVENGEME. Out-of-sample prediction of antidepressant response polygenic scores was assessed. Gene-level association analysis was performed using MAGMA and transcriptome-wide association study. Tissue, pathway, and drug binding enrichment were estimated using MAGMA.
RESULTS: Neither genome-wide association study identified genome-wide significant associations. Single nucleotide polymorphism-based heritability was significantly different from zero for remission (h 2 = 0.132, SE = 0.056) but not for percentage improvement (h 2 = -0.018, SE = 0.032). Better antidepressant response was negatively associated with genetic risk for schizophrenia and positively associated with genetic propensity for educational attainment. Leave-one-out validation of antidepressant response polygenic scores demonstrated significant evidence of out-of-sample prediction, though results varied in external cohorts. Gene-based analyses identified ETV4 and DHX8 as significantly associated with antidepressant response.
CONCLUSIONS: This study demonstrates that antidepressant response is influenced by common genetic variation, has a genetic overlap schizophrenia and educational attainment, and provides a useful resource for future research. Larger sample sizes are required to attain the potential of genetics for understanding and predicting antidepressant response.