Fremanezumab for the Treatment of Patients With Migraine and Comorbid Major Depressive Disorder: The UNITE Randomized Clinical Trial.

IMPORTANCE

Migraine and major depressive disorder are frequently comorbid; however, evidence evaluating the efficacy of preventive migraine therapy in patients with both diseases is limited.

OBJECTIVE

To evaluate the efficacy and safety of fremanezumab in adults with migraine and comorbid major depressive disorder.

DESIGN, SETTING, AND PARTICIPANTS: The UNITE study was a double-blind, placebo-controlled, parallel-group, randomized clinical trial consisting of a 4-week screening period, 12-week double-blind period, and 12-week open-label extension (OLE), conducted between July 9, 2020, and August 31, 2022. The trial was conducted at 55 centers across 12 countries. Eligible patients were adults with episodic migraine (EM) or chronic migraine (CM), history of major depressive disorder according to Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) criteria for 12 or more months before screening, and active symptoms of depression (9-item Patient Health Questionnaire score of 10 or more) at screening.

INTERVENTIONS

Patients were randomized 1:1 to receive monthly fremanezumab (225 mg) or matched placebo. All patients in the OLE received quarterly fremanezumab (675 mg).

MAIN OUTCOMES AND MEASURES

The primary end point was the mean change from baseline in monthly migraine days during the 12-week double-blind period.

RESULTS

Of the 540 patients screened for the study, 353 patients (mean [SD] age, 42.9 [12.3] years; 310 female [88%]; EM, 48%; CM, 52%) were eligible and randomized to receive fremanezumab (n = 175) or placebo (n = 178). Mean (SE) change from baseline in monthly migraine days during the 12-week double-blind period was -5.1 (0.50; 95% CI, -6.09 to -4.13) for fremanezumab and -2.9 (0.49; 95% CI, -3.89 to -1.96) for placebo (P <.001). Mean (SE) change from baseline in the Hamilton Depression Rating Scale-17 Items score at week 8 was -6.0 (0.55; 95% CI, -7.10 to -4.95) for fremanezumab and -4.6 (0.54; 95% CI, -5.66 to -3.55) for placebo (least squares mean [SE] difference: -1.4 [0.61]; 95% CI, -2.61 to -0.22; P = .02). Adverse events were consistent with other fremanezumab trials. Results were maintained throughout the OLE.

CONCLUSIONS AND RELEVANCE

Treatment with fremanezumab compared with placebo resulted in significant reductions in monthly migraine days and depressive symptoms. No new safety concerns were observed. To the authors' knowledge, this was the first placebo-controlled, randomized clinical trial, specifically designed to assess patients with migraine and comorbid depressive disorder, to demonstrate significant improvements in migraine and depressive symptoms with a single pharmacological intervention.

TRIAL REGISTRATION

ClinicalTrials.gov Identifier: NCT04041284.