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.
| Discipline Area | Score |
|---|---|
| Physician |  |
Physician rater
I'm not convinced that a statistical significance is a clinically meaningful difference when the difference between days/month migraine-free is less than 2 compared with placebo. Also, I can't imagine a monoclonal Ab medication is going to be low cost. I suspect this will be more of interest to headache specialists.
Physician rater
This is an important study for those suffering from migraines and major depressive disorder.
Physician rater
This paper clearly shows the benefit of a pharmacological agent in people with migraine and comorbid depression. It is useful for me as a psychiatrist to know this information even if this would not be prescribed by psychiatrists.
Physician rater
The question remains about whether the differences in depression reach clinical significance. Interestingly the difference seems to increase over the 12-wk period. Results from a longer follow-up would be interesting to know.
Physician rater
This study provides new treatment options with fremanezumab for patients with migraine and depressive disorder. However, both fremanezumab and placebo achieved clinically meaningful changes in the depression scores PHQ-9 and HAMD-7 (statistically favoring fremanezumab). The authors did not report the number of patients who achieved a remission of major depressive disorder based on the scores of PHQ-9 and HAMD-D-17. There was no statistically significant difference in the CGI-ratings (clinical global impression severity of illness) between fremanezumab and placebo. Therefore, we should not overestimate the effects of fremanezumab on depressive symptoms in patients with migraine and major depressive disorder and acknowledge the power of unspecific effects such as positive patient expectations and close clinical monitoring (which are parts of the so-called placebo response) in the effectiveness of a medication.
, McMaster University