Fremanezumab Reduces Migraine Days and Depressive Symptoms in Adults With MDD

In adult patients with migraine and comorbid major depressive disorder (MDD), treatment with fremanezumab is associated with significant reductions in both monthly migraine days (MMDs) and depressive symptoms, according to study results published in JAMA Neurology.

In the UNITE trial (ClinicalTrials.gov Identifier: NCT04041284), a multicenter, double-blind study, researchers evaluated the efficacy and safety of fremanezumab, a calcitonin gene-related peptide (CGRP) monoclonal antibody, in adults with episodic or chronic migraine and active symptoms of MDD over the course of 28 weeks. Eligible participants were aged 18 to 70 years with a diagnosis of migraine based on International Classification of Headache Disorders–3 criteria and MDD for at least 1 year prior to screening based on The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria. Patients also required a Patient Health Questionnaire-9 (PHQ-9) score of ≥10 at baseline to confirm active depressive symptoms.

Following a 4-week screening period, 353 patients (mean age, 42.9 years; women, 88%) were randomly assigned in a 1:1 ratio to receive either monthly subcutaneous fremanezumab 225 mg (n=175) or matched placebo (n=178) over a 12-week double-blind period, followed by a 12-week open-label extension in which all participants received quarterly fremanezumab 675 mg.

The primary endpoint was the mean change from baseline in MMDs during the double-blind phase. Secondary endpoints included changes in depressive symptoms assessed by the Hamilton Depression Rating Scale–17 Items (HAM-D 17) and the proportion of patients achieving a ≥50% reduction in migraine days.

At week 12, compared with placebo, fremanezumab significantly reduced MMDs (–5.1 vs –2.9 days; mean difference, –2.2; P <.001). Moreover, a greater proportion of patients in the fremanezumab group achieved a ≥50% reduction in migraine days (33% vs 13%; P <.001).

Fremanezumab also yielded greater improvements in depressive symptoms. At week 8, the mean reduction in HAM-D 17 scores was –6.0 with fremanezumab and –4.6 with placebo (least squares mean difference, –1.4; 95% CI, –2.61 to –0.22; P =.02). These improvements were sustained through week 24 in both treatment arms following open-label treatment.

Adverse events were reported in both groups (40% vs 27%, fremanezumab vs placebo, respectively), but were generally mild or moderate in severity. The most common events included injection site reactions and mild infections.

While fremanezumab and placebo both produced clinically meaningful improvements in depressive symptoms, the statistically significant advantage with fremanezumab on HAM-D 17 supports a potential direct or indirect effect on MDD symptoms in patients with migraine. However, the study was not powered to distinguish whether reductions in depressive symptoms were independent of migraine improvements.

The study’s limitations include the exclusion of patients with certain psychiatric conditions, the homogenous study population, and unexamined interactions between treatments.

“… [F]remanezumab 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,” the researchers concluded.

Multiple study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.