Overview

Migraine and major depressive disorder frequently occur together (comorbid conditions), creating significant challenges for patients - including making migraine and migraine overuse/adaptation headache more difficult to treat. Until now, evidence evaluating preventive migraine therapy in this population has been limited. The UNITE study is the first placebo-controlled randomized clinical trial specifically designed to assess the efficacy of fremanezumab (Ajovy®), a calcitonin gene-related peptide (CGRP) monoclonal antibody, in patients with both conditions.

Study Design and Participants

The UNITE study was a 28-week, multicenter, double-blind, placebo-controlled, parallel-group randomized clinical trial conducted between July 2020 and August 2022 at 55 centers across 12 countries. It included a 4-week screening period, 12-week double-blind treatment period, and 12-week open-label extension.

A total of 353 patients (mean age: 42.9 years; 88% female) were randomized 1:1 to receive either monthly fremanezumab (225 mg) or matched placebo via subcutaneous injection. Of these, 48% had episodic migraine and 52% had chronic migraine.

Importantly, 64% of participants were taking a stable-dose antidepressant medication that was continued throughout the study, making the sample representative of real-world patients with these comorbidities.

Key Findings: Migraine Days

The primary endpoint of the study was the mean change from baseline in monthly migraine days during the 12-week double-blind period. Results showed significant improvement with fremanezumab treatment.

"Compared with placebo, patients treated with fremanezumab experienced significant reductions in monthly migraine days during the 12-week double-blind period, which were sustained and became numerically larger in the open-label extension."

Key Findings: Depression Outcomes

A key secondary endpoint was the change in depressive symptoms as measured by the Hamilton Depression Rating Scale–17 Items (HAM-D 17) at week 8. Here too, fremanezumab showed significant benefit.

Patients in both groups demonstrated a clinically meaningful response in depressive symptoms. However, the statistically significant benefit of fremanezumab over placebo suggests its superior effect on reducing depression symptoms.

"Although treatment with fremanezumab and placebo both resulted in clinically meaningful reductions in depressive symptoms, fremanezumab achieved statistical significance vs placebo at week 8."

Other Patient-Reported Outcomes

The study also evaluated several other patient-reported outcomes that provide additional context for the quality-of-life impact of treatment.

Safety Profile

Fremanezumab was generally well-tolerated with a safety profile consistent with previous clinical trials, despite the clinical complexity of this population.

It is important to note that this study occurred during the COVID-19 pandemic, and all COVID-19 infections were recorded as adverse events, which may have influenced the overall adverse event rate.

Potential Biological Mechanisms

The study's results raise interesting questions about the relationship between migraine and depression, and how CGRP-targeted therapy may affect both conditions.

"The results of the UNITE study suggest that fremanezumab was effective in a difficult to treat clinical population with migraine and comorbid major depressive disorders and may also be effective in alleviating psychiatric comorbidities, therefore reducing the cumulative burden on patients."

Clinical Implications

The findings from this study have important implications for clinical practice, particularly for patients who struggle with both migraine and depression.

Historically, patients with migraine and comorbid depression have been treated with tricyclic antidepressants or venlafaxine. While these treatments can address both conditions, they sometimes have limited efficacy for migraine and poor tolerability profiles. The results of this study provide evidence for an alternative approach.