Ajovy clinical trial shows little improvement over placebo in migraine and depression

Albert Einstein College of Medicine and Teva Pharmaceuticals, in collaboration with multiple international institutions, report findings on the efficacy of fremanezumab (sold as Ajovy by Teva) in reducing migraine frequency and depressive symptoms among patients with comorbid major depressive disorder.

Significant reductions in monthly migraine days and depressive symptoms were observed in both fremanezumab and placebo. Fremanezumab did not demonstrate clinically meaningful effects on depression and headache-related disability when compared to placebo.

Migraine presents a substantial burden, often leading to moderate or severe disability and disruption to daily life, interpersonal relationships, and financial stability. Previous studies have documented a bidirectional relationship between migraine and depression, with each condition increasing the risk of onset for the other.

Emerging migraine-preventive therapies targeting the calcitonin gene-related peptide (CGRP) pathway, such as fremanezumab, have shown promise in reducing headache frequency, duration, and severity in broader migraine populations. Limited data exist regarding the efficacy of these therapies specifically for individuals with comorbid psychiatric conditions.

In the study, “Fremanezumab for the Treatment of Patients With Migraine and Comorbid Major Depressive Disorder: The UNITE Randomized Clinical Trial,” published in JAMA Neurology, researchers conducted a 28-week, multicenter, double-blind, placebo-controlled, parallel-group randomized clinical trial to evaluate the efficacy and safety of fremanezumab in adults with migraine and comorbid major depressive disorder.

Cohort enrollment across 61 centers in 12 countries included 353 adults aged 18–70 years with a diagnosis of episodic or chronic migraine and major depressive disorder. Participants were randomized in a 1:1 ratio to receive either monthly fremanezumab (225 mg) or placebo administered via subcutaneous injection at baseline, week four, and week eight. All patients in the open-label extension (OLE) received quarterly fremanezumab (675 mg).

Outcome measures included changes in monthly migraine days, depressive symptoms as assessed by the Hamilton Depression Rating Scale–17 Items (HAM-D 17), and Patient Health Questionnaire-9 (PHQ-9). Additional assessments included the Clinical Global Impression–Severity of Illness (CGI-S) and the 6-Item Headache Impact Test (HIT-6).

At week eight, mean HAM-D-17 scores (0 to 52 scale) decreased by 6.0 points with fremanezumab versus 4.6 points with placebo. Although statistically significant, this 1.4-point gap falls below the trial’s predefined minimal clinically important difference of a 3-point reduction, indicating the additional benefit over placebo is not clinically meaningful.

Reported data on PHQ-9 (0 to 29 scale) were described as “Both treatment groups” (fremanezumab and placebo) “…demonstrated a clinically meaningful change from baseline in PHQ-9 score at each timepoint.”

Specific PHQ-9 values were not provided in the primary results, yet a provided visual graph illustrates a reduction of 7.0 points for fremanezumab and approximately 5.8 points for placebo by week 8, with a net reduction of around 1.2 points. A 5-point reduction in PHQ-9 score is considered clinically meaningful for depressive symptoms.

By week 12, CGI-S patients on fremanezumab rated themselves about 1.1 points better on the 1–7 severity scale versus a 0.8-point improvement with placebo, leaving a 0.3-point gap, well below the 2-point change considered meaningful.

The Headache Impact Test (HIT-6) (36 to 78 scale) specifically assesses the impact of headaches on daily functioning, including social, role, cognitive, and psychological aspects. HIT-6 scores at week 12 showed a reduction of 8.8 points in the fremanezumab group and 5.2 points in the placebo group, representing a net effect of 3.6 points.

An 8-point reduction is considered clinically meaningful for headache-related disability, indicating that the observed effect size did meet the clinical threshold for significant change from baseline, though not in additional benefit over placebo.

Of note, a visual graph seems to indicate a week 12 HIT-6 score of around -7.8, not the -8.8 reported elsewhere. It is unclear which result is the correct one.

Participants receiving fremanezumab reported a mean reduction of 5.1 monthly migraine days compared to a reduction of 2.9 days in the placebo group. According to the results, fremanezumab clearly adds an effect beyond placebo, just not a clinically meaningful therapeutic benefit for migraine and major depressive disorder in a cohort where patients experience both.

Given that Teva makes fremanezumab, which is currently prescribed for the prevention of migraines, and that the study was sponsored by Teva and conducted by multiple Teva employees—conflicting presentations of the data hitting or missing the clinically meaningful 8-point reduction mark on the headache impact test is intriguing— though to be fair, incorporating accurate graphics into a research paper is always a bit of a headache.

© 2025 Science X Network

Albert Einstein College of Medicine and Teva Pharmaceuticals, in collaboration with multiple international institutions, report findings on the efficacy of fremanezumab (sold as Ajovy by Teva) in reducing migraine frequency and depressive symptoms among patients with comorbid major depressive disorder.

Significant reductions in monthly migraine days and depressive symptoms were observed in both fremanezumab and placebo. Fremanezumab did not demonstrate clinically meaningful effects on depression and headache-related disability when compared to placebo.

Migraine presents a substantial burden, often leading to moderate or severe disability and disruption to daily life, interpersonal relationships, and financial stability. Previous studies have documented a bidirectional relationship between migraine and depression, with each condition increasing the risk of onset for the other.

Emerging migraine-preventive therapies targeting the calcitonin gene-related peptide (CGRP) pathway, such as fremanezumab, have shown promise in reducing headache frequency, duration, and severity in broader migraine populations. Limited data exist regarding the efficacy of these therapies specifically for individuals with comorbid psychiatric conditions.

In the study, “Fremanezumab for the Treatment of Patients With Migraine and Comorbid Major Depressive Disorder: The UNITE Randomized Clinical Trial,” published in JAMA Neurology, researchers conducted a 28-week, multicenter, double-blind, placebo-controlled, parallel-group randomized clinical trial to evaluate the efficacy and safety of fremanezumab in adults with migraine and comorbid major depressive disorder.

Cohort enrollment across 61 centers in 12 countries included 353 adults aged 18–70 years with a diagnosis of episodic or chronic migraine and major depressive disorder. Participants were randomized in a 1:1 ratio to receive either monthly fremanezumab (225 mg) or placebo administered via subcutaneous injection at baseline, week four, and week eight. All patients in the open-label extension (OLE) received quarterly fremanezumab (675 mg).

Outcome measures included changes in monthly migraine days, depressive symptoms as assessed by the Hamilton Depression Rating Scale–17 Items (HAM-D 17), and Patient Health Questionnaire-9 (PHQ-9). Additional assessments included the Clinical Global Impression–Severity of Illness (CGI-S) and the 6-Item Headache Impact Test (HIT-6).

At week eight, mean HAM-D-17 scores (0 to 52 scale) decreased by 6.0 points with fremanezumab versus 4.6 points with placebo. Although statistically significant, this 1.4-point gap falls below the trial’s predefined minimal clinically important difference of a 3-point reduction, indicating the additional benefit over placebo is not clinically meaningful.

Reported data on PHQ-9 (0 to 29 scale) were described as “Both treatment groups” (fremanezumab and placebo) “…demonstrated a clinically meaningful change from baseline in PHQ-9 score at each timepoint.”

Specific PHQ-9 values were not provided in the primary results, yet a provided visual graph illustrates a reduction of 7.0 points for fremanezumab and approximately 5.8 points for placebo by week 8, with a net reduction of around 1.2 points. A 5-point reduction in PHQ-9 score is considered clinically meaningful for depressive symptoms.

By week 12, CGI-S patients on fremanezumab rated themselves about 1.1 points better on the 1–7 severity scale versus a 0.8-point improvement with placebo, leaving a 0.3-point gap, well below the 2-point change considered meaningful.

The Headache Impact Test (HIT-6) (36 to 78 scale) specifically assesses the impact of headaches on daily functioning, including social, role, cognitive, and psychological aspects. HIT-6 scores at week 12 showed a reduction of 8.8 points in the fremanezumab group and 5.2 points in the placebo group, representing a net effect of 3.6 points.

An 8-point reduction is considered clinically meaningful for headache-related disability, indicating that the observed effect size did meet the clinical threshold for significant change from baseline, though not in additional benefit over placebo.

Of note, a visual graph seems to indicate a week 12 HIT-6 score of around -7.8, not the -8.8 reported elsewhere. It is unclear which result is the correct one.

Participants receiving fremanezumab reported a mean reduction of 5.1 monthly migraine days compared to a reduction of 2.9 days in the placebo group. According to the results, fremanezumab clearly adds an effect beyond placebo, just not a clinically meaningful therapeutic benefit for migraine and major depressive disorder in a cohort where patients experience both.

Given that Teva makes fremanezumab, which is currently prescribed for the prevention of migraines, and that the study was sponsored by Teva and conducted by multiple Teva employees—conflicting presentations of the data hitting or missing the clinically meaningful 8-point reduction mark on the headache impact test is intriguing— though to be fair, incorporating accurate graphics into a research paper is always a bit of a headache.

© 2025 Science X Network