Exploring the Potential Bidirectional Relationship Between Migraine and Depression: A Narrative Review

Background: Migraine and depression frequently coexist, increasing disability and reducing quality of life. This review evaluated evidence on the direction and mechanisms of their relationship. Methods: A critical narrative review used targeted searches of PubMed, Scopus, and Google Scholar for English-language publications from January 2016 to June 2026, supplemented by landmark studies. Evidence was synthesised qualitatively according to study design and its ability to inform association, temporal direction, or causality. Results: Cross-sectional studies consistently associate migraine with depressive symptoms or reported depression. Prospective studies show temporal associations in both directions but do not establish causal bidirectionality. Mendelian randomisation has more often yielded estimates consistent with a potential influence of genetic liability to major depressive disorder on migraine risk than with the reverse pathway. Shared polygenic susceptibility and alterations in pain- and emotion-related neural systems, neurotransmitter and inflammatory signalling, stress regulation, sleep, anxiety, and functional impairment may contribute, but direct mechanistic evidence in clinically diagnosed comorbidity is limited. In a placebo-controlled trial, fremanezumab reduced monthly migraine days and depressive symptom scores in participants with a DSM-5-defined history of major depressive disorder and active symptoms; whether mood improvement was independent of reduced migraine burden remains uncertain. Conclusions: Reciprocal assessment and coordinated management are reasonable, although their comparative effectiveness remains unproven. CGRP-targeted prevention may improve migraine burden and depressive symptoms in selected patients but should not replace targeted depression treatment. Research should use verified diagnoses, clarify mechanisms and causal direction, and test whether treating either disorder modifies the other.