This randomized clinical trial investigates if treatment with fremanezumab compared with placebo leads to improvements in migraine and depressive symptoms in patients with migraine and comorbid major depressive disorder.
Key Points
Question
Does treatment with fremanezumab compared with placebo lead to improvements in both migraine and depressive symptoms in patients with migraine and comorbid major depressive disorder?
Findings
In this 28-week, multicenter, randomized clinical trial including 353 patients, treatment with fremanezumab compared with placebo significantly reduced the mean number of monthly migraine days and depressive symptoms in patients with migraine and comorbid major depressive disorder.
Meaning
Findings from UNITE, a study to evaluate the efficacy and safety of fremanezumab for the preventive treatment of migraine in patients with major depressive disorder, suggest that fremanezumab was effective in alleviating migraine and comorbid major depressive disorder in patients with both conditions.
Abstract
Importance
Migraine and major depressive disorder are frequently comorbid; however, evidence evaluating the efficacy of preventive migraine therapy in patients with both diseases is limited.
Objective
To evaluate the efficacy and safety of fremanezumab in adults with migraine and comorbid major depressive disorder.
Design, Setting, and Participants
The UNITE study 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), conducted between July 9, 2020, and August 31, 2022. The trial was conducted at 55 centers across 12 countries. Eligible patients were adults with episodic migraine (EM) or chronic migraine (CM), history of major depressive disorder according to Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) criteria for 12 or more months before screening, and active symptoms of depression (9-item Patient Health Questionnaire score of 10 or more) at screening.
Interventions
Patients were randomized 1:1 to receive monthly fremanezumab (225 mg) or matched placebo. All patients in the OLE received quarterly fremanezumab (675 mg).
Main Outcomes and Measures
The primary end point was the mean change from baseline in monthly migraine days during the 12-week double-blind period.
Results
Of the 540 patients screened for the study, 353 patients (mean [SD] age, 42.9 [12.3] years; 310 female [88%]; EM, 48%; CM, 52%) were eligible and randomized to receive fremanezumab (n = 175) or placebo (n = 178). Mean (SE) change from baseline in monthly migraine days during the 12-week double-blind period was −5.1 (0.50; 95% CI, −6.09 to −4.13) for fremanezumab and −2.9 (0.49; 95% CI, −3.89 to −1.96) for placebo (P <.001). Mean (SE) change from baseline in the Hamilton Depression Rating Scale–17 Items score at week 8 was −6.0 (0.55; 95% CI, −7.10 to −4.95) for fremanezumab and −4.6 (0.54; 95% CI, −5.66 to −3.55) for placebo (least squares mean [SE] difference: −1.4 [0.61]; 95% CI, −2.61 to −0.22; P = .02). Adverse events were consistent with other fremanezumab trials. Results were maintained throughout the OLE.
Conclusions and Relevance
Treatment with fremanezumab compared with placebo resulted in significant reductions in monthly migraine days and depressive symptoms. No new safety concerns were observed. To the authors’ knowledge, this was the first placebo-controlled, randomized clinical trial, specifically designed to assess patients with migraine and comorbid depressive disorder, to demonstrate significant improvements in migraine and depressive symptoms with a single pharmacological intervention.
Trial Registration
ClinicalTrials.gov Identifier: NCT04041284
Introduction
Migraine causes significant burden to those affected; it can often lead to moderate or severe disability as well as disruption to interpersonal relationships, financial stability, and family life.1,2,3,4,5 An additional burden is added by the large number of conditions comorbid with migraine.6,7 Depression is one of the most common psychiatric diseases comorbid with migraine, and the association between the 2 has been investigated in numerous cross-sectional and longitudinal studies.8,9,10,11,12,13,14 A bidirectional association between migraine and depression has also been demonstrated, with each disease increasing the risk of the first occurrence of the other.11,15,16
Historically, patients with migraine and major depressive disorder were treated with tricyclic antidepressants or venlafaxine. These, and other antidepressants, are not uniformly effective for migraine17,18 and are sometimes associated with a poor tolerability profile.19 Newer migraine-preventive drugs that target the calcitonin gene-related peptide (CGRP) pathway have proven efficacy as convenient, effective, and well-tolerated treatments in various populations with migraine.20,21,22,23 However, limited data are available on the efficacy of migraine-preventive therapy in patients with migraine and psychiatric comorbidities or the impact of those therapies on the psychiatric comorbidity itself.
Fremanezumab is a humanized monoclonal antibody (mAb) that selectively targets CGRP, approved for the preventive treatment of episodic migraine (EM) and chronic migraine (CM) in adults.24,25 The superiority of fremanezumab over placebo in reducing headache frequency, severity, and duration, along with other patient-related outcome measures, has been demonstrated in a series of phase 3 randomized clinical trials.26,27,28,29 Post hoc analysis of the HALO CM study showed that, compared with placebo, patients with migraine and comorbid depression treated with fremanezumab experienced statistically significant reductions in monthly migraine days and migraine-related disability, and improvements in quality of life (QOL) measures.30 Patients also experienced reductions in depressive symptoms. These data, and the bidirectional relationship of migraine and psychiatric comorbidities, suggest that fremanezumab could reduce cumulative burden of CM and depression. However, this post hoc analysis only evaluated a small number of patients with moderate to severe depressive symptoms at baseline, rather than those meeting diagnostic criteria for major depressive disorder.
The aim of the UNITE trial was to evaluate the efficacy and safety of fremanezumab in adults with migraine and comorbid major depressive disorder (as diagnosed by Diagnostic and Statistical Manual of Mental Disorders [Fifth Edition, DSM-5] criteria).31 We sought to test the hypothesis that fremanezumab treatment would improve both migraine and major depressive disorder outcomes, compared with placebo. Herein, we report outcomes from the 12-week double-blind period, and selected outcomes from when patients either continued to receive fremanezumab or switched from placebo to fremanezumab in the open-label extension (OLE).
Methods
Study Design and Patients
This was a 28-week, multicenter, double-blind, placebo-controlled, parallel-group randomized clinical trial to evaluate the efficacy and safety of fremanezumab for migraine prevention in adults with migraine and major depressive disorder. The trial protocol is available in Supplement 1. The trial consisted of a 4-week baseline period from screening to randomization, a 12-week double-blind period, a 12-week OLE, and an end-of-treatment visit approximately 12 weeks after the final dose of fremanezumab (eFigure in Supplement 2).
The trial was conducted at 61 centers, 55 of which randomized 1 or more patients, in 12 countries (Czech Republic, France, Germany, Greece, Italy, Israel, Poland, Russia, Spain, UK, Ukraine, and US) between July 9, 2020, and August 31, 2022 (eTable 1 in Supplement 2). All written and oral information provided during the study was in a language understandable to all patients. Written informed consent was obtained from all patients before the start of the study. The trial was performed in full accordance with the International Conference on Harmonisation Good Clinical Practice Consolidated Guideline and approved by ethics committees and institutional review boards according to national or local regulations. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guidelines.
Eligible patients were adults (aged 18-70 years) with a diagnosis of EM or CM as defined by the International Classification of Headache Disorders 3rd Edition (ICHD-3) criteria,32 with disease onset at 50 years or younger and 12 or more months before screening, confirmed by a study physician with expertise in migraine diagnosis. CM was defined as headache occurring on 15 or more days per month for more than 3 months, with 8 or more of those days having features of migraine or use of specific acute migraine treatment. EM was defined as headache occurring on greater than 4 to 14 days per month, with 4 or more of those days having features of migraine or use of specific acute migraine treatment. All patients were diagnosed with major depressive disorder (according to DSM-5 criteria)31 12 or more months before screening, confirmed by an on-site psychiatrist. Patients were required to have active symptoms of depression at screening as assessed by a 9-item Patient Health Questionnaire (PHQ-9) score of 10 or higher and cognitive function in the normal range based on a Mini-Mental State Examination score of 26 or higher.33,34 PHQ-9 was chosen as a screening tool as it aligns closely with the DSM-5 criteria for major depressive disorder.35 During the baseline period, patients were required to have had attacks qualifying as migraine on 4 or more days and demonstrate compliance with an electronic headache diary by entering data on a minimum cumulative 21 days. Patients self-reported the following races and ethnicities: American Indian or Alaska Native, Asian, Black or African American, Hispanic or Latino, not Hispanic or Latino, White, other (which included Middle Eastern), or unknown. Race and ethnicity were included to assess diversity among the patients included in this study, including disparities in medication utilization and response to treatment.
A single preventive medication for the treatment of migraine was permitted in up to 35% of patients if the dose was stable for 8 weeks before screening. No other migraine preventive medications were permitted. A single concomitant medication prescribed for depression was permitted if the dose had been stable for 8 or more weeks before screening and was expected to remain at the stable dose during the study. Psychotherapy was documented at enrollment, and changes in antidepressant medication, psychotherapy, or physiotherapy were recorded until week 24/end of treatment. All concomitant medications were recorded, including over-the-counter medications, natural products, vitamins, and prescription medications. Details on the documentation of prior and concomitant medications, and exclusion criteria are listed in the eMethods in Supplement 2.
Patients were randomized 1:1 to receive either a monthly fremanezumab (225 mg) dose or matched placebo via subcutaneous injection at baseline and at the end of week 4 and week 8. Randomization was performed by interactive response technology and stratified according to sex, country, migraine type (CM or EM), and baseline PHQ-9 score category (10-14, 15-19, and ≥20). After 12 weeks, all patients who completed the double-blind period were invited to enter the OLE where they received a quarterly dose of fremanezumab (675 mg). Patients kept a daily electronic headache diary to record headache characteristics and other end points. On each day, patients were asked to record diary data for the previous 24-hour period for specified end points.
Depressive symptoms were measured using the Hamilton Depression Rating Scale–17 Items (HAM-D 17) and PHQ-9.36,37,38,39,40,41 HAM-D 17 is a standard efficacy outcome in antidepressant clinical trials and is widely used by psychiatrists to assess depressive symptoms.42,43 The HAM-D 17 was administered and recorded by a qualified staff member (ie, the site investigator). A psychiatrist was a member of the site study team and was consulted as appropriate. Other patient reported outcomes (PROs) were assessed using the Clinical Global Impression–Severity of Illness (CGI-S) and 6-Item Headache Impact Test (HIT-6).44,45 Details of these outcome measures are in the eMethods in Supplement 2.
Outcomes
The primary end point was mean change from baseline in the average number of monthly migraine days from baseline during the 12-week double-blind period after the first dose of fremanezumab. Secondary end points were: mean change from baseline in depressive symptoms at week 8 as measured by HAM-D 17, in line with US Food and Drug Administration guidelines for clinical trials in patients with MDD46; number of patients with 50% or greater reduction from baseline in monthly migraine days over 12 weeks; mean change from baseline in PROs scores at weeks 4 and 8 (CGI-S) and week 12 (CGI-S and HIT-6); safety and tolerability as assessed by occurrence of adverse events (AEs), and measurement of vital signs, body weight, hypersensitivity, anaphylaxis, discontinuation rate, suicidal ideation, and behavior. Key exploratory end points included change from baseline in depressive symptoms at week 4 (PHQ-9 and HAM-D 17), week 8 (PHQ-9), week 12 (PHQ-9 and HAM-D 17), and week 24 (HAM-D 17).
Statistical Analysis
Multiplicity was controlled by a predefined hierarchical testing procedure; the primary end point was tested first, followed by each secondary end point in the prespecified order listed previously. A 2-sided P value of <.05 was considered statistically significant when all preceding end points in the hierarchy were statistically significant. For end points outside of the hierarchy, statistical significance is not claimed.
The intention-to-treat (ITT) analysis set included all randomized patients. The double-blind, modified ITT (mITT) analysis set included only patients who received at least 1 dose of study drug and had 10 or more days of postrandomization assessment on the primary end point during the double-blind period.
The double-blind safety analysis set included patients who received at least 1 dose of study drug during the double-blind period. The OLE mITT analysis set included only patients who received at least 1 dose of study drug during the OLE and had 10 or more days of diary entries during the OLE. All efficacy analyses were performed in the mITT analysis sets. Details of the sample size calculation and statistical analysis methods are provided in the eMethods in Supplement 2. Data analysis was performed using SAS software, version 9.4 or later (SAS Institute).
Results
Participant Disposition and Baseline Characteristics
The study was conducted between July 2020 and August 2022. Of 540 patients assessed for eligibility, 353 patients (mean [SD] age, 42.9 [12.3] years; 310 female [88%]; 43 male [12%]; EM, 48%; CM, 52%) were randomized to monthly fremanezumab (n = 175) or placebo (n = 178). Patients self-reported the following races and ethnicities: 2 American Indian or Alaska Native (1%), 8 Black or African American (2%), 11 Hispanic or Latino (3%), 341 not Hispanic or Latino (97%), 342 White (97%), 1 other race (<1%), and 1 unknown ethnicity (<1%). All randomized patients were included in the mITT set. Overall, 10% of patients (37 of 353) had less than 75% diary compliance during the double-blind period. A total of 164 of 175 patients (94%) in the fremanezumab group and 166 of 178 patients (93%) in the placebo group completed the double-blind period and entered the OLE (placebo-fremanezumab, n = 165; fremanezumab-fremanezumab, n = 165). Withdrawal by patients (fremanezumab, 4 of 175 [2%]; placebo, 6 of 178 [3%]) and protocol deviations (fremanezumab, 3 of 175 [2%]; placebo, 3 of 178 [2%]) were the most common reasons for discontinuation during the double-blind period (Figure 1).
Figure 1. Flow of Patients.
Demographic and other baseline characteristics were similar between treatment groups (Table 1). In total, 98% of patients in each treatment group (fremanezumab, 173 of 176; placebo, 173 of 177) used 1 or more concomitant medications during the double-blind period (eTable 2 in Supplement 2). Approximately 76% of patients (268 of 353) had prior use of medications to treat depression, and approximately 64% (225) had been using a single medication to treat depression at a stable dose for 8 or more weeks before screening and continued this medication during the study.
Table 1. Baseline Demographics and Clinical Characteristics, and Prior and Concomitant Medication Use.
| ITT analysis set | Placebo | Fremanezumab | Total population |
|---|---|---|---|
| No. | 178 | 175 | 353 |
| Age, mean (SD), y | 42.3 (12.6) | 43.5 (12.0) | 42.9 (12.3) |
| Sex, No. (%) | |||
| Female | 156 (88) | 154 (88) | 310 (88) |
| Male | 22 (12) | 21 (12) | 43 (12) |
| Race, No. (%) | |||
| American Indiana | 2 (1) | 0 | 2 (1) |
| Asian | 0 | 0 | 0 |
| Black or African American | 4 (2) | 4 (2) | 8 (2) |
| White | 172 (97) | 170 (97) | 342 (97) |
| Otherb | 0 | 1 (<1) | 1 (<1) |
| Ethnicity, No. (%) | |||
| Hispanic or Latino | 6 (3) | 5 (3) | 11 (3) |
| Not Hispanic or Latino | 171 (96) | 170 (97) | 341 (97) |
| Unknown | 1 (<1) | 0 | 1 (<1) |
| Weight, mean (SD), kg | 71.1 (14.8) | 71.3 (15.7) | 71.2 (15.2) |
| BMI, mean (SD)c | 25.4 (4.7) | 25.2 (4.5) | 25.3 (4.6) |
| Time since migraine diagnosis, mean (SD), y | 19.9 (13.8) | 21.6 (13.7) | 20.7 (13.8) |
| Migraine classification, No. (%) | |||
| CM | 92 (52) | 93 (53) | 185 (52) |
| EM | 86 (48) | 82 (47) | 168 (48) |
| Monthly No. of migraine days, mean (SD) | 14.4 (6.2) | 15.1 (6.4) | 14.8 (6.3) |
| Region, No. (%) | |||
| US | 27 (15) | 26 (15) | 53 (15) |
| EU | 112 (63) | 114 (65) | 226 (64) |
| Others | 39 (22) | 35 (20) | 74 (21) |
| PHQ-9, mean (SD) | 15.2 (3.7) | 15.8 (3.8) | 15.5 (3.8) |
| PHQ-9 band, No. (%) | |||
| 10-14 | 79 (44) | 71 (41) | 150 (42) |
| 15-19 | 71 (40) | 75 (43) | 146 (41) |
| ≥20 | 28 (16) | 29 (17) | 57 (16) |
| HAM-D 17, mean (SD) | 16.2 (6.5) | 16.2 (6.3) | 16.2 (6.4) |
| HIT-6, mean (SD) | 65.4 (4.1) | 66.0 (4.8) | 65.7 (4.5) |
| CGI-S rating, mean (SD) | 3.5 (1.2) | 3.6 (1.2) | 3.5 (1.2) |
| Prior medication for migraine/headache, No. (%)d | 177 (>99) | 174 (>99) | 351 (>99) |
| Double-blind safety analysis set | |||
| No. | 177 | 176 | NA |
| Concomitant medication for migraine/headache, No. (%)d | 170 (96) | 169 (96) | NA |
Abbreviations: BMI, body mass index; CGI-S, Clinical Global Impression Severity of Illness; CM, chronic migraine; EM, episodic migraine; EU, European Union; HAM-D 17, Hamilton Depression Rating Scale–17 Items; HIT-6, 6-Item Headache Impact Test; ITT, intention to treat; NA, not applicable; PHQ-9, 9-item Patient Health Questionnaire.
Or Alaska Native.
Other race includes Middle Eastern.
Calculated as weight in kilograms divided by height in meters squared.
Based on medications received with the indication of migraine/headache.
Primary End Point
Baseline mean (SD) monthly migraine days were 15.1 (6.4) and 14.4 (6.2) days in the fremanezumab and placebo treatment groups, respectively. Mean (SE) change from baseline in monthly migraine days during the double-blind period was −5.1 (0.50; 95% CI, −6.09 to −4.13) for fremanezumab and –2.9 (0.49; 95% CI, −3.89 to −1.96) for placebo (P < .001) (eTable 3 in Supplement 2). Mean changes from baseline in monthly migraine days at each time point are shown in Figure 2A.
Figure 2. Change From Baseline in Monthly Migraine Days and Patients With 50% or Greater Reduction in Monthly Migraine Days From Baseline at Week 4, 8, and 12.
A, Change in monthly migraine days from baseline. B, Patients with a 50% or greater reduction in monthly migraine days from baseline. P values are shown for the difference between the placebo and fremanezumab groups.
Secondary End Points
Baseline HAM-D 17 score was 16.2 in both treatment groups (mean [SD], fremanezumab, 16.2 [6.3]; placebo, 16.2 [6.5]), indicating moderate to severe depression. Mean (SE) change from baseline in HAM-D 17 at week 8 was −6.0 (0.55; 95% CI, −7.10 to −4.95) for fremanezumab and −4.6 (0.54; 95% CI, −5.66 to −3.55) for placebo, indicating that both groups achieved a clinically meaningful response. Compared with placebo, the fremanezumab group had a statistically significant greater reduction in HAM-D 17 scores at week 8 (least squares [LS] mean [SE] difference: −1.4 [0.61]; 95% CI, −2.61 to −0.22; P = .02) (eTable 3 in Supplement 2 and Figure 3A).
Figure 3. Change in Questionnaire Scores From Baseline at Week 4, 8, and 12.
A, Hamilton Depression Rating Scale–17 Items (HAM-D 17). B, Clinical Global Impression Severity of Illness (CGI-S). C, 6-Item Headache Impact Test (HIT-6). D, 9-Item Patient Health Questionnaire (PHQ-9). P values are shown for the difference in mean change from baseline values between the placebo and fremanezumab groups.
aReductions of 2 or more points from baseline, or a score of 3 or greater indicates a clinically meaningful minimal change.
bReductions of 8 or more points indicate a clinically meaningful minimal change.
A significantly higher proportion of patients achieved a 50% or greater reduction from baseline in monthly migraine days during the 12-week double-blind period with fremanezumab compared with placebo (33% [57 of 175] vs 13% [24 of 178]; 95% CI, 1.89-5.62; P <.001) (eTable 3 in Supplement 2). At week 12, 40% of patients (70 of 175) in the fremanezumab group achieved a 50% or greater reduction in monthly migraine days, compared with 25% of patients (44 of 178) in the placebo group (95% CI, 1.33-3.38). Response rate was maintained from week 4 through to week 12 (Figure 2B).
Mean (SD) baseline CGI-S ratings were 3.6 (1.2) and 3.5 (1.2) for fremanezumab and placebo, respectively. Mean change from baseline in CGI-S ratings at each time point is shown in Figure 3B. At week 4, mean (SE) change in CGI-S rating from baseline was −0.6 (0.10; 95% CI, −0.80 to −0.42) for fremanezumab compared with −0.4 (0.10; 95% CI, −0.62 to −0.24) for placebo (LS mean difference: −0.2; 95% CI, −0.39 to 0.03; P = .09). Given that this P value did not achieve statistical significance, the hierarchical testing procedure was stopped (eTable 3 in Supplement 2).
Mean (SD) baseline HIT-6 scores were 66.0 (4.8) in the fremanezumab group and 65.4 (4.1) in the placebo group. At week 12, mean (SE) change from baseline in HIT-6 score was −8.8 (0.73; 95% CI, −10.20 to −7.34) for fremanezumab, indicating a clinically meaningful response and −5.2 (0.71; 95% CI, −6.62 to −3.81) for placebo (LS mean [SE] difference: −3.6 [0.81]; 95% CI, −5.14 to −1.96) (eTable 3 in Supplement 2). Mean change from baseline in HIT-6 score at each time point is shown in Figure 3C.
Exploratory End Points
Exploratory end points assessed outcomes at different time points across the double-blind period and OLE.
Mean (SE) change from baseline in HAM-D 17 score was −3.7 (0.51; 95% CI, −4.70 to −2.70) for fremanezumab and −3.2 (0.50; 95% CI, −4.23 to −2.25) for placebo at week 4, and −6.7 (0.54; 95% CI, −7.76 to −5.66) for fremanezumab and −5.4 (0.53; 95% CI, −6.4 to −4.32) for placebo at week 12 (Figure 3A). Baseline mean (SD) PHQ-9 scores were 15.8 (3.8) and 15.2 (3.7) for fremanezumab and placebo, respectively. Both treatment groups demonstrated a clinically meaningful change from baseline in PHQ-9 score at each time point (Figure 3D).
Reductions in monthly migraine days were sustained throughout the OLE, with an overall mean (SD) change from baseline of −6.9 (5.52; n = 297) at week 24. Reductions were observed in both the fremanezumab-fremanezumab (mean [SD], −6.9 [5.56]; n = 145) and placebo-fremanezumab (−7.0 [5.50]; n = 152) groups. Reductions in HAM-D 17 score were also sustained, with a mean (SD) change from baseline of −8.0 (7.03; n = 316) for all patients, −7.7 (7.21; n = 155) for the fremanezumab-fremanezumab group, and −8.3 (6.86; n = 161) for the placebo-fremanezumab group at week 24.
Adverse Events
A total of 70 of 176 patients (40%) in the fremanezumab group and 48 of 177 patients (27%) in the placebo group reported 1 or more AEs during the double-blind period, most of which were mild or moderate in severity (Table 2). Further details on AEs are provided in the eResults in Supplement 2.
Table 2. Adverse Events (AEs) Reported in the 12-Week Double-Blind Period.
| Event | No. (%) | |
|---|---|---|
| Placebo (n = 177) | Fremanezumab (n = 176) | |
| All events | ||
| ≥1 AE | 48 (27) | 70 (40) |
| ≥1 Severe AEa | 1 (<1) | 4 (2) |
| ≥1 Treatment-related AE | 8 (5) | 15 (9) |
| ≥1 Serious AE | 1 (<1) | 2 (1) |
| Any AE leading to discontinuationb | 0 | 3 (2) |
| Blood and lymphatic system disorders | 3 (2) | 0 |
| Gastrointestinal disorders | 5 (3) | 13 (7) |
| Constipation | 2 (1) | 5 (3) |
| Nausea | 0 | 4 (2) |
| General disorders and administration site conditions | 8 (5) | 20 (11) |
| Injection site pain | 3 (2) | 7 (4) |
| Injection site erythema | 1 (<1) | 5 (3) |
| Injection site pruritus | 0 | 5 (3) |
| Infections and infestations | 17 (10) | 27 (15) |
| COVID-19 | 4 (2) | 7 (4) |
| Nasopharyngitis | 3 (2) | 6 (3) |
| Urinary tract infection | 3 (2) | 3 (2) |
| Investigations | 5 (3) | 7 (4) |
| Metabolism and nutrition disorders | 2 (1) | 5 (3) |
| Musculoskeletal and connective tissue disorders | 5 (3) | 4 (2) |
| Nervous system disorders | 5 (3) | 5 (3) |
| Psychiatric disorders | 4 (2) | 5 (3) |
| Kidney and urinary disorders | 3 (2) | 1 (<1) |
| Respiratory, thoracic, and mediastinal disorders | 3 (2) | 2 (1) |
| Skin and subcutaneous tissue disorders | 1 (<1) | 4 (2) |
| Vascular disorders | 3 (2) | 0 |
Severe AEs included a severe case of COVID-19 from day 22, increased C-reactive protein (ongoing from day 84), 3 days of severe abdominal pain (from day 5), 1 day of severe hiatal hernia (from day 5), and 8 days of severe injection site erythema and injection site pruritus (from day 55).
AEs leading to treatment discontinuation included mild depression from day 11; 37 days of moderate severity injection site pain, erythema, and swelling (from day 36); and a severe case of COVID-19 from day 22.
Discussion
Results from this 28-week, multicenter, double-blind, placebo-controlled, parallel-group randomized clinical trial demonstrate that fremanezumab was efficacious in reducing both migraine and major depression outcomes in patients with migraine and moderate to severe comorbid major depressive disorder. Compared with placebo, patients treated with fremanezumab experienced significant reductions in monthly migraine days during the 12-week double-blind period, which were sustained and became numerically larger in the OLE. Furthermore, a significantly higher proportion of patients in the fremanezumab group achieved a 50% or greater reduction in monthly migraine days, compared with placebo, during the 12-week double-blind period.
Overall, fremanezumab was well tolerated, with no new safety signals observed. The most common AEs reported were mild or moderate infections and infestations or injection site reactions, which occurred with greater incidence with fremanezumab than with placebo. It is important to note that this study occurred during the COVID-19 pandemic, and all COVID-19 infections were recorded as AEs. No deaths occurred in either treatment group, and no suicidality risks were identified.
The presence of depression with migraine is considered a negative predictor of response to treatment, and major depressive disorder is associated with increased cardiovascular and metabolic risks.47,48 However, the efficacy and safety profiles of fremanezumab, as well as the low discontinuation rates observed, were consistent with previous pivotal trials26,27,28,29 despite enrollment of patients in this study with long and complex treatment histories.
Although treatment with fremanezumab and placebo both resulted in clinically meaningful reductions in depressive symptoms (3-8 point reduction in HAM-D 17 score at week 8, which was sustained throughout the OLE), fremanezumab achieved statistical significance vs placebo at week 8. Although hierarchical testing failed after week 8, clinically meaningful reductions were observed with fremanezumab in HIT-6 scores at week 12, as well as in PHQ-9 scores from week 8. Reductions in depressive symptom scores may be due to an indirect effect of active treatment on migraine frequency, although further analyses are required to understand this association. It has long been suggested that CGRP is implicated in the pathophysiology of depression, as increased CGRP activity in the brain has been demonstrated in patients with major depressive disorder but not in patients with schizophrenia or healthy controls.49 In a recent study50 of patients with migraine, CGRP-targeted mAb treatment was associated with improvements in depressive symptoms independent of migraine reduction, suggesting a possible direct effect of CGRP-targeted vs CGRP pathway mAbs on depression symptoms. Interestingly, central infusion of a CGRP receptor antagonist has been shown to produce antidepressant effects in rats with CGRP-induced poststroke depression, which is a subtype of vascular depression.51 Because mAbs are thought to not cross the blood-brain barrier, mechanisms remain to be explored. In vivo mouse model studies have shown a link between depressionlike behavior and CGRP. An investigation of gestational environmental stressors found that stressed-reared mice exhibit depressionlike behaviors in tests and increased hippocampal expression of CGRP gene transcripts.52 Future research could include a comparative investigation on the effect of CGRP pathway mAbs on major depressive disorder in patients with and without headache comorbidity.
Clinical Implications
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 QOL; thus, it is crucial that comorbid depression be considered when treating patients with migraine.7,8,9,10,11,15,34,53,54 Both migraine frequency and depression are known risk factors of migraine progression and medication overuse, which raises the possibility that fremanezumab may reduce the risk of migraine chronification and medication overuse in patients with comorbid depression.8,9,54,55 This hypothesis needs to be tested in studies specifically designed to prevent migraine progression.56
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.21 Therefore, patients with migraine and comorbid depression that require migraine prevention have been treated first-line with tricyclic antidepressants or venlafaxine.21,22 However, when started on antidepressants, long-term persistence in patients with CM is low as AEs and insufficient efficacy often lead to discontinuation.23,57 Although polypharmacy is an option for patients who do not respond to antidepressants, this comes at an extra financial cost, complicates management, and increases the risk of AEs and drug interactions.21 The results of this study suggest that fremanezumab may provide an effective and well-tolerated preventive treatment option for this patient population. It is important to note that 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.
Strengths and Limitations
This study has several strengths. Randomized clinical trials focusing on the treatment of migraine and a common comorbidity are rare. To the best of our knowledge, the UNITE trial was the first study to assess the effects of a migraine-specific preventive treatment in patients with migraine and comorbid major depressive disorder, and the first placebo-controlled study to demonstrate significant improvement in both migraine and major depressive disorder with a single pharmacological intervention. Furthermore, the population enrolled in this study was highly complex, having had migraine and major depressive disorder for at least 1 year, with an average of 20.7 years since migraine diagnosis and moderate to severe depressive symptoms at baseline. Additionally, a high proportion of patients (64%) received concomitant antidepressant medication, making the sample representative of the real-world population of patients with migraine and psychiatric comorbidities.
There are also limitations to this study. Patients with a history of uncontrolled psychiatric disorder and bipolar disorder were excluded, which may limit generalizability across the full spectrum of patients with migraine and major depressive disorder. Inclusion of patients receiving concomitant antidepressants improves the generalizability of our findings. However, part of the treatment effect observed in the study may result from an interaction of fremanezumab with an antecedent antidepressant. Further, the proportion of patients who had their antidepressant dose adjusted during the study was not recorded.
There were improvements in indicators of depression in both the fremanezumab and placebo groups in the study. More specifically, the mean changes from baseline in PHQ-9 scores were clinically meaningful for both treatment groups at all time points.41 Trials involving patients with depression are often associated with a large placebo effect size,58 regardless of treatment modality.59 Thus, it is important to consider the possibility that the clinically meaningful change in PHQ-9 scores was due to a placebo effect; however, the statistically significant benefit of fremanezumab over placebo on HAM-D 17 score suggests that fremanezumab was superior to placebo in reducing depressive symptoms. Given that major depressive disorder has a profound impact on quality of life, a treatment that can achieve both clinically meaningful reductions in depressive symptoms and statistical improvement over placebo has relevance, even if the benefit over placebo is small.
In addition, as depressive symptoms were not measured weekly, it was not possible to assess whether the reduction in monthly migraine days precedes or follows reductions in depression, and therefore understand the relationship between the two. Lastly, migraine has a total prevalence of 15.3% in the US, and there are differences across races and ethnicities, whereas 97% of patients enrolled in the UNITE trial were White, potentially limiting the generalizability of the results.60
Conclusions
In the UNITE randomized clinical trial, treatment with monthly doses of fremanezumab (225 mg) for 12 weeks led to significant reductions in monthly migraine days, compared with placebo, in adult patients with migraine and comorbid major depressive disorder. These reductions were in line with those observed in previous pivotal trials of fremanezumab, despite the clinical complexity of this population, and were sustained throughout the OLE. In addition to improvements in migraine, patients treated with fremanezumab experienced significant and/or clinically meaningful reductions in depressive symptom scores and PROs, compared with placebo. The safety and tolerability profile of fremanezumab was also comparable with previous pivotal trials of fremanezumab, with no new safety signals observed. The results of the UNITE study suggest that fremanezumab was effective in a difficult to treat clinical population with migraine and comorbid major depressive disorders and may also be effective in alleviating psychiatric comorbidities, therefore reducing the cumulative burden on patients.
Trial Protocol.
eMethods.
eResults.
eReferences.
eFigure. UNITE Study Design
eTable 1. Principal Investigators and Affiliations
eTable 2. Concomitant Medications by Therapeutic Class and WHO Drug PT
eTable 3. Efficacy Outcomes
Data Sharing Statement.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial Protocol.
eMethods.
eResults.
eReferences.
eFigure. UNITE Study Design
eTable 1. Principal Investigators and Affiliations
eTable 2. Concomitant Medications by Therapeutic Class and WHO Drug PT
eTable 3. Efficacy Outcomes
Data Sharing Statement.