Comparative efficacy and safety of tricyclic antidepressants vs. serotonin-norepinephrine reuptake inhibitors for migraine prophylaxis: A systematic review and meta-analysis

Sep 14, 2025Clinical neurology and neurosurgery

Effectiveness and safety of older antidepressants versus newer serotonin-norepinephrine drugs for preventing migraines

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Abstract

A total of 333 patients were included in the analysis comparing tricyclic antidepressants and serotonin-norepinephrine reuptake inhibitors for migraine prevention.

Both tricyclic antidepressants (TCAs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) were effective in reducing monthly migraine days compared to baseline.
There was no significant difference in the reduction of monthly migraine days between the two medication groups.
SNRIs resulted in a marginally greater reduction in migraine attack duration compared to TCAs.
The incidence of adverse events was significantly lower in the SNRI group than in the TCA group.

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INTRODUCTION: Migraine is a leading cause of global disability, yet research on prophylactic interventions remains limited due to unclear underlying mechanisms. We performed a systematic review and meta-analysis to evaluate the comparative efficacy and safety of tricyclic antidepressants (TCAs) versus serotonin-norepinephrine reuptake inhibitors (SNRIs) for migraine prophylaxis.

METHODS: A systematic review was executed in accordance with PRISMA guidelines. PubMed, Embase, and Cochrane Central databases were searched from inception to December, 2024 for randomized controlled trials (RCTs) comparing selective norepinephrine reuptake inhibitors (SNRIs) with tricyclic antidepressants (TCAs) in migraine patients. Two independent reviewers screened studies, extracted data, and assessed risk of bias using the RoB 2 tool. A random-effects model was applied to pool effect estimates, reporting mean differences (MD) and risk ratios (RR) with 95 % confidence intervals (CIs), using Review Manager v.5.4.

RESULTS: Out of 4253 screened articles, a total of three randomized trials met the inclusion criteria, encompassing 333 patients (mean age 32.4 years, 68 % female) with a mean follow-up of 10 weeks. Both SNRI and TCA groups reduced monthly migraine days (MMD) compared to baseline, with no significant difference between them (MD = -0.03, 95 % CI: -0.67-0.61; p = 0.93). However, SNRIs demonstrated a marginally greater reduction in migraine attack duration (MD = -0.71, 95 % CI: -1.41 to -0.01; p = 0.05) and a significantly lower incidence of adverse events compared to TCAs (RR = 0.68, 95 % CI: 0.51-0.91; p = 0.009).

CONCLUSION: SNRIs demonstrated comparable efficacy to TCAs in reducing monthly migraine days, with shorter attack duration and fewer adverse events.

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Comparative efficacy and safety of tricyclic antidepressants vs. serotonin-norepinephrine reuptake inhibitors for migraine prophylaxis: A systematic review and meta-analysis

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