Understanding the Causal Relationships Between Opioid Dependence and Risk of Mental Disorders: A Comprehensive Two-Sample Mendelian Randomization Study

Observational studies have reported positive associations between opioid dependence and major mental disorders. However, the causal relationships and causal mechanisms between opioid dependence and mental disorders remain unknown due to potential confounding bias and reverse causality. In this study, we aim to investigate the causal associations and possible mediating mechanisms between opioid dependence and mental disorders via Mendelian randomization. Comprehensive bidirectional Mendelian randomization (MR) studies were conducted between opioid dependence and major mental disorders, including schizophrenia, bipolar disorder, major depressive disorder, panic disorder, anorexia, obsessive–compulsive disorder, post-traumatic stress disorder, and insomnia. Inverse variance weighted approach was adopted as the primary analytic method with series of sensitivity analyses. Mediation effects of chronic pain along the opioid dependence–mental disorders causal pathway were assessed by multivariate MR and two-step MR. Forward MR identified significant positive causal effects of opioid dependence on insomnia (OR = 1.03, 95% CI = (1.01, 1.05), p = 0.005), while reverse MR showed significant positive causal effects of schizophrenia on opioid dependence (OR = 1.20, 95% CI = (1.07, 1.34), p = 0.002). No significant causal associations were found between opioid dependence and other mental disorders. Neither opioid dependence on insomnia nor schizophrenia on opioid dependence causal pathway was significantly mediated by chronic pain. Higher risks of genetically predicted opioid dependence may lead to higher risks of insomnia, while higher risks of genetically predicted schizophrenia may lead to higher risks of developing opioid dependence. The majority of causal effects were acted directly rather than via chronic pain.