Fremanezumab eases migraine and depressive symptoms

Treatment with fremanezumab – an anticalcitonin gene-related peptide (CGRP) – reduces depressive symptoms in patients with migraine and comorbid major depressive disorder (MDD) in the UNITE trial.

Given as a subcutaneous injection, fremanezumab is US FDA-approved for migraine prevention in adults, but not for depression.

“We’ve known for a long time that migraine is comorbid with a number of illnesses,” said study investigator Professor Richard Lipton from the Albert Einstein College of Medicine and director of the Montefiore Headache Center in New York City, New York, US. “One of the most common is depression.”

The question any physician would face in the clinic is, “Do I treat the migraine and the depression independently, or do I treat both?” he continued.

When a migraine presents with MDD

Adults with migraine (n=330) who were diagnosed with moderate-to-severe MDD – defined as nine-criteria Patient Health Questionnaire (PHQ-9) score ≥10 – were randomly assigned to receive fremanezumab 225 mg given subcutaneously monthly (n=164) or placebo (n=166) for 12 weeks. The trial continued as an open-label trial for another 12 weeks. [AHS 2023, abstract IO-05]

Those treated with fremanezumab had a significant reduction in both the 17-item Hamilton Depression Rating Scale (HAMD-17) and the PHQ-9 scores compared with matched controls on placebo. Both tools assessed the severity of depression.

During the double-blind phase, the mean change from baseline in the HAMD-17 score was –6.0 with fremanezumab at week 8 (p=0.0205) and –6.7 at week 12 (p=0.0228) vs  –4.6 at week 8 and –5.4 at week 12 with placebo.

The change from baseline in PHQ-9 total score at week 8 was –7.1 with fremanezumab and –5.8 with placebo. At week 12, the change was greater at –7.8 with fremanezumab vs –6.3 with placebo. The reductions in depression severity were maintained throughout the 12-week open-label period. 

Lipton said the results have several implications. “If the patient has migraine and depression and you treat with fremanezumab, both disorders get better to a statistically significant degree. That’s critically important,” he continued.

But what Lipton finds most interesting about the results is that fremanezumab does not cross the blood–brain barrier. There are many antimigraine therapies that do, for example, tricyclic antidepressants. “They make the migraine and the depression better, but you do not know if the benefit in depression comes from the improvement in migraine because the drugs work for both conditions.”

“My interpretation is that the depression got better because the migraine got better,” he shared.

What other experts think

Dr Huma Sheikh from NY Neurology Medicine PC in New York City, New York, US said the study is important as it confirms the strong association between migraine and depression, which have similar underlying neurobiological pathophysiology.

“If you are impacting one area in the brain with the CGRP inhibitors, you might also be targeting some of the receptors or pathways that are involved in depression,” Sheikh said.

Although the relationship is generally viewed as bidirectional, “I still do not think I would assume that any drug that reduces migraine would reduce depression,” commented Dr Elizabeth Loder, professor of neurology at Harvard Medical School, Boston, Massachusetts, US.