Fremanezumab Demonstrates Dual Benefits in Adults with Migraine and Depression

New research suggests fremanezumab is effective in treating a difficult clinical population with migraine and comorbid major depressive disorder (MDD), potentially alleviating psychiatric comorbidities.¹

The latest data from the randomized, double-blind, placebo controlled UNITE clinical trial (NCT04041284) showed that treatment with fremanezumab for 12 weeks led to significant reductions in monthly migraine days compared to placebo in people with migraine and comorbid MDD.¹

“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,” corresponding author Richard B. Lipton, MD, of the Albert Einstein College of Medicine in New York, NY, and colleagues wrote in the study published online May 5, 2025, in JAMA Neurology.¹

Migraine and depression are commonly co-occurring, with each condition increasing the risk of the other, complicating treatment strategies. Currently, traditional antidepressants such as tricyclics and venlafaxine are first-line treatments but often carry tolerability issues and limited efficacy.¹

“Newer migraine-preventive drugs that target the calcitonin gene-related peptide (CGRP) pathway have proven efficacy as convenient, effective, and well-tolerated treatments in various populations with migraine,” Lipton and colleagues wrote.¹ “However, limited data are available on the efficacy of migraine-preventive therapy in patients with migraine and psychiatric comorbidities or the impact of those therapies on the psychiatric comorbidity itself.”

Fremanezumab is a humanized monoclonal antibody that selectively targets CGRP that was FDA-approved for migraine prevention in January 2020.² Lipton and coauthors conducted the current open-label extension trial of the UNITE study to assess the long-term safety, tolerability, and efficacy of fremanezumab in patients with both migraine and comorbid MDD. The UNITE trial enrolled 353 patients from 12 countries, with a mean age of 42.9 years, and was conducted from July 2020 to August 2022.¹

In the current study, participants were randomized to receive monthly 225 mg doses of fremanezumab or placebo for 12 weeks. The primary outcome was the change in monthly migraine days, while secondary outcomes included depressive symptom improvement, measured by the Hamilton Depression Rating Scale–17 Items (HAM-D 17) and the Patient Health Questionnaire (PHQ-9).¹

Results showed that patients in the fremanezumab group had a significantly greater reduction in monthly migraine days (mean change: -5.1 days) compared to the placebo group (-2.9 days, P<.001). A higher proportion of patients in the fremanezumab group achieved a 50% or greater reduction in monthly migraine days (33% vs. 13%, P<.001). At week 12, 40% of fremanezumab-treated patients experienced a 50% reduction in migraine days compared to 25% in the placebo group (P= .002).¹

In terms of depressive symptoms, fremanezumab also led to a greater reduction in the HAM-D 17 score at week 8 (-6.0) versus placebo (-4.6, P=.02). The treatment effect was maintained throughout the open-label extension (OLE) phase, with significant reductions in depressive symptom scores observed at week 12 and continued improvements through week 24. Furthermore, fremanezumab showed a significant improvement in the 6-Item Headache Impact Test (HIT-6) scores, which measure headache-related disability (P<.001).¹

The safety profile of fremanezumab was consistent with previous studies, with the most common adverse events being mild-to-moderate infections and injection site reactions. A total of 40% of patients in the fremanezumab group reported one or more adverse events, compared with 27% in the placebo group. Serious adverse events were rare, and no suicidality risks were identified during the study period.¹

“It is important to note that further studies are required to evaluate the effectiveness of fremanezumab at alleviating depressive symptoms compared with standard preventive migraine treatments for patients with comorbid depression,” investigators concluded.¹

References:

1. Lipton RB, Ramirez Campos V, Roth-Ben Arie Z, et al. Fremanezumab for the treatment of patients with migraine and comorbid major depressive disorder: the UNITE randomized clinical trial. JAMA Neurol. Published online May 5, 2025. doi:10.1001/jamaneurol.2025.0806
2. Halsey G. Consider CGRP Inhibitors as a First-Line Option for Preventive Treatment of Migraine: New American Headache Society Consensus Statement. Patient Care Online. April 12, 2024. https://www.patientcareonline.com/view/cgrp-inhibitors-a-first-line-option-for-preventive-treatment-of-migraine