New Clinical Trial Results: Anti-CGRP Treatment Improves Migraine and Comorbid Depression

The first study of its kind shows that fremanezumab could be an effective drug to manage this common comorbidity of migraine.

Many people with migraine also struggle with depression – a comorbidity that can complicate migraine diagnosis and treatment. However, clinical research has historically excluded migraine patients with depression and other comorbidities from drug trials.

Now, a new randomized clinical trial has found that fremanezumab, a monoclonal antibody that targets calcitonin gene-related peptide (CGRP) for the treatment of migraine, also reduces comorbid depressive symptoms in people with migraine.

The research, from Richard Lipton, Albert Einstein College of Medicine, Bronx, US, and colleagues, reported improvement in various outcome measures both during the 12-week double-blind study period, as well as during a 12-week open-label extension period.

The trial is the first of its kind specifically designed to test whether a migraine medication could help both migraine and depression in patients with these comorbid conditions. And it suggests that perhaps some of the adverse consequences of the comorbidity – including an increased risk of migraine chronification, medication overuse, and disability, among others – could be prevented.

“Some of the most common comorbidities for migraine are things like depression and anxiety,” said Juliana VanderPluym, a neurologist at the Mayo Clinic in Scottsdale, Arizona, US, who was not involved with the study. “The fact that this trial focused on people who have migraine and who have comorbid major depression is really important, because these are populations that we’re actually seeing in the clinic.”

The study appeared in the June 2025 issue of JAMA Neurology.

“Fellow travelers”
Researchers have suspected that migraine might be related to depression for over a century. Still, it wasn’t until researchers conducted large-scale epidemiological studies in the 1990s that the connection between migraine and depression was finally confirmed. This research also suggested that the relationship was bidirectional: Migraine increased the risk of depression, and depression increased the risk of migraine.

Researchers now estimate that depression occurs in about 30% of all patients with chronic migraine (people with 15 or more migraine days a month) and 15% of patients with episodic migraine (those with 14 or fewer migraine days a month), said Lipton. These numbers are roughly twice as high as the national average, with 8% of all American adults expected to have at least one major depressive episode in their lifetimes.

“Migraine has many fellow travelers,” including anxiety and insomnia, said Lipton. But despite the frequency of depression and other mental health issues in migraine, patients with both conditions are frequently kept out of new drug trials.

That’s because investigators organizing migraine clinical trials worry that including people with depression can complicate study results and might even impact the effectiveness of a drug, said VanderPluym. That leaves doctors treating migraine without reliable information as to how new therapies might impact migraine patients with comorbidities.

Alleviating headache…
In 2021, Lipton and his colleagues published an analysis of data collected as part of a drug trial for fremanezumab, which was then being developed by the pharmaceutical company Teva. Their results suggested that taking fremanezumab may have helped reduce symptoms of depression in some patients.

When fremanezumab received FDA approval for migraine prevention in 2018, Lipton and others secured funding from Teva to conduct a larger study to see whether the drug could also treat comorbid depression in migraine patients.

To test this, the researchers included 353 patients with either chronic or episodic migraine from 12 countries, mainly in Europe, but also Israel and the United States. These patients all met the criteria for major depressive disorder according to a psychiatric assessment based on symptoms listed in the Diagnostic and Statistical Manual of Mental Disorders (DSM)-5. About 88% of participants were female, and 97% were white.

During a four-week baseline period, the researchers gathered data on average monthly migraine days and depression severity. Study participants were then randomized to receive either a 225 mg dose of subcutaneous fremanezumab or a placebo. They received the drug at baseline, and at the end of week four and week eight, with a final assessment taking place at week 12. The investigators also conducted a 12-week open-label extension after the double-blind period.

As expected, patients who received fremanezumab saw a greater overall reduction in migraine days than patients who received the placebo: The fremanezumab group showed an average reduction of 5.1 migraine days per month compared to a reduction of 2.9 days in the placebo group, a statistically significant result. The team also found that 40% of people who received fremanezumab reported a 50% or greater reduction in migraine days over the study period, but only 25% of those who received the placebo reported a similar drop.

…and depression
The drop in migraine days was in line with previous clinical studies. But the researchers also looked at the impact of fremanezumab on symptoms of depression, assessing overall depression severity using the Hamilton Depression Rating Scale-17 Items score. The score reflects how often patients recall experiencing symptoms of depression, such as a lack of interest in normal activities and sadness.

Baseline estimates placed both treatment groups at an average score of 16.2, indicating moderate to severe depression. While both groups reported a decline in depression severity over the next 12 weeks, the fremanezumab group scored 6 points lower, compared to 4.6 points lower in the placebo group, at 8 weeks. The authors wrote that this was a clinically meaningful result. The greater reduction in the depression score in the fremanezumab versus placebo group was also statistically significant at week 8. Depression severity continued to decline over the next four weeks, though by less than 1 point in both cases.

The improvements in depression, and migraine, were maintained during the open-label extension period. Finally, adverse events observed in the trial were similar to those seen in previous trials of fremanezumab.

The study is the first trial of its kind to show that a migraine medication can reduce both migraine and depressive symptoms in migraine patients. That makes the finding “exciting, but there’s a lot more for us to understand,” said VanderPluym. For instance, it’s unclear whether other drugs targeting the CGRP system will have a similar effect. Also, the research did not address whether fremanezumab acted on depression directly, or whether patients were less depressed because their headaches were less frequent.

Lipton suspects it was the latter. “Broadly speaking, I think that effective migraine treatment in general often results in reduced depression,” he said. Plus, he saw that the reduction in migraine days preceded the drop in depressive symptoms, which supports the hypothesis.

However, he said it’s “plausible” that anti-CGRP treatment could have direct antidepressant effects, given that a previous study found that a CGRP receptor antagonist had antidepressant qualities in a post-stroke depression rat model.

Lipton said he now preferentially uses fremanezumab when treating migraine patients with depression. Historically, doctors prescribed antidepressants to migraine patients in the hopes of treating both conditions.

“The ideal situation would be having one medicine that treats both depression and migraine with minimal side effects,” VanderPluym  said. However, “we really need more research before we can say that these new medicines should become the first choice for treating depression. We’re just not there yet.”

Freda Kreier is a freelance science journalist based in Washington, DC.

Reference
Fremanezumab for the treatment of patients with migraine and comorbid major depressive disorder: The UNITE randomized clinical trial.
Lipton et al.
JAMA Neurol. 2025 Jun 1;82(6):560-9.

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