A Comprehensive Mendelian Randomization Study of Bidirectional Causal Relationships Between Pain and Mental Disorders.

Background: Pain and mental disorders frequently co-occur, yet the direction and specificity of their relationship remain uncertain due to limitations of observational studies. Mendelian randomization (MR) provides an opportunity to clarify causal links between distinct pain phenotypes and psychiatric outcomes. Methods: We performed a comprehensive bidirectional MR analysis to investigate causal relationships between multiple pain conditions and mental and personality disorders. Multivariable MR was applied to assess the independence of these associations while accounting for common comorbidities. Robustness was evaluated using complementary sensitivity analyses. Results: Forward analyses showed that several pain phenotypes - including back pain, headaches, neck or shoulder pain, stomach or abdominal pain, migraine, and trigeminal neuralgia-were associated with increased risk of specific mental disorders. Reverse analyses indicated that mental disorders also predispose individuals to certain pain conditions. Most associations remained robust after multivariable adjustment, although some were attenuated by obesity or substance use. Conclusion: These findings demonstrate structured, pain - type - specific bidirectional relationships between pain and mental disorders. Clinically, they support phenotype-informed screening and management strategies, including targeted assessment of depression and anxiety in patients with high-risk pain conditions and proactive evaluation of pain symptoms in patients with mental disorders, to facilitate earlier risk stratification and integrated care.