Jingyi TONG
Psychiatry and Clinical Psychopharmacology - 2026;36(3):285-292
Background: Several observational studies have identified mood disorders as a risk factor for psychosomatic disorders, and mood stabilizers like lamotrigine are hypothesized to have disease-modifying effects. This Mendelian randomization (MR) study aimed to 1) investigate the causal association between mood disorders and 4 psychosomatic disorders (diabetes, hypertension, sleep duration disorder, thyroid problems) and 2) evaluate the potential impact of 14 drug targets of lamotrigine on these psychosomatic disorders. Methods: Fourteen lamotrigine drug targets (CACNA1E, SCN11A, ADORA1, ADORA2A, ADRA1A, ADRA2A, ADRB1, DRD2, HRH1, OPRK1, CHRNA1, HTR2A, HTR3A, GRIA1) and 4 psychosomatic disorders were included. Two-sample MR analysis (primary: inverse variance weighted method) with sensitivity tests (MR-Egger, weighted median, MR-PRESSO) was conducted using public summary-level data (e.g., UK Biobank mood swings dataset: 325 480 European-ancestry individuals; DIAGRAM diabetes dataset: ~900 000 participants). Summary data-based MR (SMR) explored target gene expression-psychosomatic disorder links, and Bayesian colocalization verified result robustness. Results: Only the lamotrigine target DRD2 showed significant associations with 3 psychosomatic disorders: hypertension (OR=1.23, 95% CI=1.09-1.39, P=1.34x10???) and sleep disorders (OR=2.45, 95% CI=1.67-3.61, P=4.89x10???), with consistent results in the validation dataset. In the validation dataset, DRD2 showed only a nominal association with diabetes (IVW OR=3.59; 95% CI, 1.15-11.23; P=.02), which did not meet the Bonferroni-corrected threshold. Conclusion: While primary MR analysis suggested an association between the lamotrigine target DRD2 and diabetes, hypertension, or sleep duration disorder, this was not validated by SMR or colocalization. Thus, lamotrigine's direct impact on these psychosomatic disorders remains unconfirmed, and cautious interpretation is needed for its potential off-label use in comorbid physical conditions. These findings highlight the value of multi-method genetic analyses to validate MR results and guide future clinical research.
