Therapeutic Overlap Between Bipolar Disorder and Migraine: A Systematic Review of Pharmacological Trials

Background/Objectives: Migraine is markedly more prevalent among individuals with bipolar disorder (BD) than in the general population. The two disorders share overlapping pathophysiological mechanisms, including neuroinflammation, oxidative stress, and genetic vulnerability. However, the potential bidirectional efficacy of pharmacological agents approved for one condition on the other remains unclear. This study aimed to evaluate cross-disorder pharmacological efficacy between migraine and bipolar disorder. Methods: We systematically searched Medline and the Cochrane Central Register of Controlled Trials (PROSPERO registration: CRD420251130780) for randomized controlled trials (RCTs) assessing (1) concurrent treatment effects in comorbid BD–migraine samples, (2) efficacy of migraine treatments in BD, or (3) efficacy of BD treatments in migraine. Searches included guideline-recommended drugs for either disorder, without language or date restrictions. Results: A total of 32 RCTs met the inclusion criteria. Fifteen studies evaluated migraine drugs in BD, and sixteen evaluated BD drugs in migraine. No RCTs were identified that simultaneously assessed both conditions within the same sample. Valproate was the only agent demonstrating consistent, replicated efficacy in both conditions, supporting true cross-disorder benefit. Haloperidol and chlorpromazine showed limited evidence for acute anti-migraine efficacy, based solely on placebo-controlled studies, whereas all other guideline-recommended BD drugs lacked evidence of benefit for migraine. Conversely, topiramate, while effective for migraine, was inferior to valproate in BD outcomes, and lamotrigine was effective for BD only when compared with placebo. Conclusions: Valproate remains the sole pharmacological agent with robust evidence of bidirectional efficacy in migraine and BD. Most other guideline-recommended medications show disorder-specific effects, highlighting the need for integrative trials addressing pharmacological overlap in comorbid migraine–BD samples.