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Long-Term Psychiatric Outcomes in Adult Patients With Migraine on Prophylactic Adjunctive Amitriptyline vs. Duloxetine: A Retrospective Cohort TriNetX Study
Journal article   Open access   Peer reviewed

Long-Term Psychiatric Outcomes in Adult Patients With Migraine on Prophylactic Adjunctive Amitriptyline vs. Duloxetine: A Retrospective Cohort TriNetX Study

Manasa Mula, Zachary Li, Taylor M Gong and Eduardo D Espiridion
Curēus (Palo Alto, CA), v 18(4), e107916
28 Apr 2026
DOI: https://doi.org/10.7759/cureus.107916
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Abstract

Migraine, a primary headache disorder, is a prevalent and debilitating chronic neurologic disorder. Migraine headaches are bidirectionally related to psychiatric conditions, such as anxiety and depression. Given these associations, further investigation into how medications used for migraine prophylaxis are associated with long-term psychiatric outcomes is warranted. Our study aims to examine, among patients with migraine, whether the use of adjunctive antidepressants (duloxetine or amitriptyline) in combination with topiramate is associated with differences in the incidence of long-term psychiatric outcomes, such as anxiety and depression. A retrospective cohort study with a five-year follow-up period was performed using TriNetX, a global federated health research network, and included patients aged ≥18 years with migraine who were started on either topiramate + duloxetine or topiramate + amitriptyline within one month on or after the first instance of documented migraine diagnosis in their electronic health record. After propensity score matching, both groups comprised 1241 patients. We found that patients on prophylactic topiramate + duloxetine had significantly greater five-year risks of anxiety disorder (unspecified), bipolar disorder, depressive episode, major depressive disorder, panic disorder, and post-traumatic stress disorder compared to patients on prophylactic topiramate + amitriptyline (p<0.05). In contrast, the risk of generalized anxiety disorder did not significantly differ between the two groups. There is limited data comparing duloxetine and amitriptyline when used for migraine prophylaxis in relation to subsequent psychiatric outcomes. Our study helps address this gap using real-world observational evidence. Our study may help inform future randomized clinical trials directly comparing these antidepressants for migraine prophylaxis, as well as provide a basis for future research on treatment selection, considering patients’ severity of neurological symptoms, psychiatric risk factors, tolerability of adverse effects, and potential treatment benefits.

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