Fremanezumab tackles migraine, depression at the same time

Fremanezumab appears to provide a two-for-one benefit in patients with migraine and comorbid depressive disorder, with data from the UNITE study showing that the drug helped reduce migraine days and lift mood.

In the 12-week double-blind period, mean monthly migraine days decreased by 5.1 days (95 percent confidence interval [CI], −6.09 to −4.13) in the fremanezumab arm vs −2.9 days (95 percent CI, −3.89 to −1.96) in the placebo arm (p<0.001). At week 12, 40 percent of fremanezumab-treated patients achieved at least a 50-percent reduction in monthly migraine days as opposed to only 25 percent of placebo-treated patients (p=0.002). [JAMA Neurol 2025;82:560-569]

Additionally, while mean Hamilton Depression Rating Scale–17 Items (HAM-D 17) scores at week 8 dropped in both treatment arms, the change was significantly greater with fremanezumab (–6.0 vs –4.6 points; difference, −1.4 points, 95 percent CI, −2.61 to −0.22; p=0.02).

“Overall, fremanezumab was well tolerated, with no new safety signals observed,” the investigators said.

Adverse events (AEs) occurred in 40 percent of patients in the fremanezumab arm and in 27 percent in the placebo arm. The most common AEs were mild or moderate infections and infestations or injection site reactions, documented mostly in the fremanezumab arm. However, the investigators pointed out that the study was still being conducted during the COVID-19 pandemic, and all COVID-19 infections were recorded as AEs. None of the patients in either treatment arm died during the study, and no suicidality risks were identified.

Difficult-to-treat cohort

These findings are encouraging for patients with both migraine and depression—which represent a particularly challenging cohort—and their clinicians, given that the co-occurrence of depression is considered a negative predictor of treatment response for migraine, and major depressive disorder itself carries heightened cardiovascular and metabolic risks, as the investigators pointed out. [Pharmaceuticals (Basel) 2023;16:934; Neuropsychiatr Dis Treat 2020;16:81-86]

“The comorbidity of migraine and depression has been shown to predict migraine chronification, increase the likelihood of medication overuse, headache-related disability, and medical costs, and decrease quality of life… Historically, recommendations have focused on treating patients with migraine and comorbidities with a single drug to address both, as this approach appears to simplify management, reduce costs, minimize potential AEs, and eliminate potential drug interactions,” they explained. 

In light of the results of UNITE, the investigators believed that fremanezumab may provide an “effective and well-tolerated preventive treatment option” for this difficult-to-treat patient population.

However, they also acknowledged that the improvements in depressive symptoms occurred in both treatment arms, and depressive symptoms were not measured weekly. Therefore, they were not able to establish whether the decrease in monthly migraine days preceded or followed the reductions in depression.

“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,” the investigators said.

Conducted at 55 centres across 12 countries, UNITE 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).

A total of 353 patients (mean age 42.9 years, 88 percent female) were randomly assigned to receive a monthly dose of fremanezumab 225 mg (n=175) or placebo (n=178) during the double-blind phase. In the OLE, all patients received a quarterly dose of fremanezumab 675 mg.

The reductions in migraine days and HAM-D 17 scores were sustained throughout the OLE.