CGRP Offers Relief From Migraine and Comorbid Depression

Treatment with the anticalcitonin gene-related peptide (CGRP) fremanezumab (Ajovy, Teva Pharmaceuticals Inc) reduces depressive symptoms in patients with migraine and comorbid major depressive disorder (MDD), new research shows.

Patients with both conditions who were randomly assigned to receive fremanezumab showed a statistically significant reduction in both the 17-item Hamilton Depression Rating Scale (HAMD-17) and the nine-criteria Patient Health Questionnaire (PHQ-9) scores compared with matched controls who received placebo.

The results from the UNITE trial were presented June 17 at the American Headache Society (AHS) Annual Meeting 2023.

Long-Standing Questions

“It’s been well known for a long time that migraine is comorbid with a number of illnesses, and one of the most common is depression,” study investigator Richard B. Lipton, a professor of neurology at Albert Einstein College of Medicine and the director of the Montefiore Headache Center in New York City, told Medscape Medical News.

“Do you treat the depression? Do you treat the migraine? Do you independently treat both? Those have been long-standing questions for clinicians,” Lipton said.

Investigators randomly assigned 330 adults with migraine who were diagnosed with moderate-to-severe MDD (defined as a PHQ-9 score of 10 or greater) to receive 225 mg subcutaneous monthly fremanezumab (n = 164) or placebo (n = 166) for 12 weeks.

The trial continued as an open-label trial for another 12 weeks.

During the double-blind phase of the study, the mean change from baseline in the HAMD-17 score with placebo was –4.6 at week 8 and –5.4 at week 12, compared with –6.0 with fremanezumab at week 8 (P = .0205) and –6.7 at week 12 (P = .0228).

The change from baseline in PHQ-9 total score at week 8 was –5.8 for placebo and –7.1 for fremanezumab (P = .0283). At week 12, the change was –6.3 for placebo vs –7.8 for fremanezumab (P = .0108).

These reductions were maintained throughout the open-label period of the trial.

The beneficial effect on depression and migraine demonstrated in the study is interesting on several levels, Lipton said.

“One, it tells us that 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 said.

“The other thing, and this is actually what I find most interesting about this study, is that fremanezumab doesn’t get into the brain. There are many antimigraine therapies that do, so you can treat a patient with migraine and depression with a tricyclic antidepressant.

“It may make the migraine better and the depression better, but you don’t know if the benefit in depression comes from the improvement in migraine, because of course the antidepressant works for both conditions. Maybe there are people who would disagree with this, but my interpretation [of the trial results] is that the depression got better because the migraine got better,” he added.

The link between migraine and depression is well established, Lipton added.

Longitudinal studies have shown that people with depression but without migraine develop migraine at increased rates compared with people with no depression. Conversely, people with migraine but no depression develop depression at increased rates.

“Both disorders may have a common substrate, but I also think many forms of chronic pain lead to depression, and that’s the part we’re making better,” he said.

If fremanezumab has this dual effect on migraine and depression, it is possible that other anti-CGRP drugs will have a similar effect, Lipton said.

“Honestly, my hope is that other companies that make effective drugs will do similar studies to see if other monoclonal antibodies that target CGRP have the same effect. My guess is that all of them work but until the studies are done, I’m going to use fremanezumab, the one that has been studied, in my patients.”

He added that depression is an important comorbidity of migraine and represents a huge challenge for clinicians, Lipton said.

“A lot of headache patients want to know what to do about comorbid anxiety or comorbid depression. I run a headache center in a specialty practice and when people come in with migraine, they almost always come in with migraine and depression or anxiety or another pain disorder, or something else, and one of the great challenges in the practice is managing these comorbidities,” he said.

A Bidirectional Relationship

The overlap between migraine and depression and anxiety has been known for quite a while, agreed Elizabeth W. Loder, MD, MPH, vice chair of academic affairs, Department of Neurology, Brigham and Women’s Hospital, and professor of neurology at Harvard Medical School, Boston, Massachusetts.

“I think the relationship is generally viewed as bidirectional and causality is uncertain. I still do not think I would assume that any drug that reduces migraine would reduce depression,” Loder told Medscape Medical News.

However, she added, the fremanezumab study data are interesting.

“The effects of any drug on depression could be due to improvement of migraine or it could be due to some other effect of the treatment on depression. That is what makes these results so intriguing. If the findings are borne out by other studies, it could mean that these treatments would be preferred to those older ones in patients with depression,” Loder said.

Also commenting on the findings, Huma Sheikh, MD, CEO of NY Neurology Medicine PC in New York City, said the study is important because it confirms the strong association between migraine and depression.

“Both conditions have similar underlying neurobiological pathophysiologies, and 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.

The study was funded by Teva Pharmaceuticals. Lipton reported financial relationships with Teva and multiple other pharmaceutical companies. Loder and Sheikh have disclosed no relevant financial relationships.

American Headache Society (AHS) Annual Meeting 2023: Abstract #IO-05. Presented June 17, 2023.

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