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

Abstract

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.

Figure 1.. Flow of Patients

Figure 2.. Change From Baseline in Monthly Migraine Days and Patients With 50% or Greater Reduction in Monthly Migraine Days From Baseline at Week 4, 8, and 12

A, Change in monthly migraine days from baseline. B, Patients with a 50% or greater reduction in monthly migraine days from baseline. P values are shown for the difference between the placebo and fremanezumab groups.

Figure 3.. Change in Questionnaire Scores From Baseline at Week 4, 8, and 12

A, Hamilton Depression Rating Scale–17 Items (HAM-D 17). B, Clinical Global Impression Severity of Illness (CGI-S). C, 6-Item Headache Impact Test (HIT-6). D, 9-Item Patient Health Questionnaire (PHQ-9). P values are shown for the difference in mean change from baseline values between the placebo and fremanezumab groups. ^aReductions of 2 or more points from baseline, or a score of 3 or greater indicates a clinically meaningful minimal change. ^bReductions of 8 or more points indicate a clinically meaningful minimal change.