Monthly fremanezumab reduced migraine days and depressive symptoms vs placebo in adults with migraine and comorbid major depressive disorder, with a favorable safety profile.

Background

Migraine and major depressive disorder (MDD) frequently co-occur and bidirectionally increase each other’s risk and burden. Traditional antidepressants used for migraine prevention have variable efficacy and tolerability. Fremanezumab, a calcitonin gene–related peptide (CGRP)–targeting monoclonal antibody, is effective for migraine prevention, but dedicated evidence in patients with comorbid MDD has been limited.

Patients

• N: 353 randomized (fremanezumab 175; placebo 178)
• Age: Mean 42.9 years; Sex: 88% female
• Migraine type: 48% episodic migraine (EM), 52% chronic migraine (CM)
• MDD: DSM-5 diagnosis ≥12 months; active symptoms (PHQ-9 ≥10) at screening; MMSE ≥26
• Concomitant therapy: Single stable antidepressant allowed (used by ~64%); up to 35% could use one stable migraine preventive
• Sites: 55 centers in 12 countries

Intervention

• Fremanezumab 225 mg subcutaneous monthly (baseline, week 4, week 8) during 12-week double-blind period
• Open-label extension (OLE): All patients received fremanezumab 675 mg quarterly for 12 additional weeks

Control

• Matched placebo subcutaneous injections on the same schedule during the 12-week double-blind period

Outcome

• Primary: Mean change from baseline in monthly migraine days (MMDs) over the 12-week double-blind period
• Secondary (key):
  • Change from baseline in Hamilton Depression Rating Scale–17 items (HAM-D17) at week 8
  • Proportion achieving ≥50% reduction in MMDs over 12 weeks
  • Patient-reported outcomes: Clinical Global Impression–Severity (CGI-S) and Headache Impact Test–6 (HIT-6)
  • Safety and tolerability

Study Design

28-week, multicenter, double-blind, placebo-controlled, parallel-group randomized clinical trial (UNITE), including a 4-week screening/baseline, 12-week double-blind treatment, and 12-week open-label extension. Randomization 1:1 stratified by sex, country, migraine type (EM/CM), and PHQ-9 category.

Level of Evidence

Level I (randomized controlled trial)

Follow up period

• Blinded efficacy and safety: 12 weeks
• Total follow-up including OLE: 24 weeks

Results

• Primary outcome (MMDs, over 12 weeks):
  • Fremanezumab: −5.1 days (SE 0.50; 95% CI −6.09 to −4.13) from baseline
  • Placebo: −2.9 days (SE 0.49; 95% CI −3.89 to −1.96) from baseline
  • Between-group difference (approx.): −2.2 days favoring fremanezumab
• Secondary outcomes:
  • Depressive symptoms (HAM-D17, week 8): Fremanezumab −6.0 (SE 0.55; 95% CI −7.10 to −4.95) vs placebo −4.6 (SE 0.54; 95% CI −5.66 to −3.55); LS mean difference −1.4 (95% CI −2.61 to −0.22)
  • ≥50% MMD responder rate (over 12 weeks): 33% (57/175) with fremanezumab vs 13% (24/178) with placebo; reported 95% CI for odds ratio 1.89–5.62
    • Absolute risk difference: 20%
    • NNT: 5 (over 12 weeks)
  • ≥50% MMD responder rate (week 12 timepoint): 40% vs 25% (NNT ≈ 7)
  • Headache impact (HIT-6, week 12): −8.8 (SE 0.73; 95% CI −10.20 to −7.34) with fremanezumab vs −5.2 (SE 0.71; 95% CI −6.62 to −3.81); LS mean difference −3.6 (95% CI −5.14 to −1.96)
• Open-label extension (week 24):
  • MMD change from baseline: −6.9 days overall (sustained in both initial fremanezumab and crossover groups)
  • HAM-D17 change from baseline: −8.0 overall (sustained)
• Safety:
  • Any adverse event: 40% fremanezumab vs 27% placebo; mostly mild to moderate
  • Serious adverse events: 1%–2%; no deaths; low discontinuation due to AEs (2% fremanezumab, 0% placebo)
  • More injection-site reactions with fremanezumab; infections (including COVID-19) occurred in both groups
  • No new safety concerns identified

Limitations

• Excluded patients with uncontrolled psychiatric disorders and bipolar disorder, limiting generalizability
• Predominantly White cohort (~97%), potentially reducing external validity
• Many patients used concomitant antidepressants; dose changes during the study were not captured, and interaction effects cannot be excluded
• Hierarchical testing stopped after a nonsignificant CGI-S endpoint; some later endpoints were not formally multiplicity-controlled
• Depression measures were not collected weekly, limiting assessment of temporal relationships between migraine and mood improvements
• Study conducted during COVID-19; related AEs recorded and may affect AE profiles

Funding

Sponsored by Teva Pharmaceutical Industries. Medical writing support by Ashfield MedComms (Inizio), funded by Teva.

Citation

Lipton RB, Ramirez Campos V, Roth-Ben Arie Z, et al. Fremanezumab for the Treatment of Patients With Migraine and Comorbid Major Depressive Disorder: The UNITE Randomized Clinical Trial. JAMA Neurology. 2025;82(6):560-569. doi:10.1001/jamaneurol.2025.0806. ClinicalTrials.gov: NCT04041284.