# Genetic Basis of the Negative Response to the Use of Triptans for the Treatment of Migraine—A Systematic Review and Meta‐Analysis

## TL;DR

This study reviews genetic factors that may explain why some people do not respond well to triptans, a common migraine treatment.

## Contribution

The study identifies specific genes linked to triptan nonresponse and highlights the potential for personalized migraine treatment.

## Key findings

- SLC6A4, 5-HT1B, and COMT polymorphisms show significant associations with triptan nonresponse.
- CALCA and PRDM16 have moderate evidence, while GRIA1 and SCN1A show limited evidence for nonresponse.
- Polygenic risk scores and multi-omics approaches may improve personalized migraine therapy.

## Abstract

Migraine is a widespread and disabling neurological disorder, and triptans are a primary treatment for acute episodes. However, around 40% of patients are non‐responsive. Genetic polymorphisms can influence drug effectiveness, and several association studies exist. This systematic review consolidates findings from etiological studies, which may provide greater certainty about their use in predicting the risk of low response to triptans.

This study followed COSMOS‐E guidelines and employed databases like PubMed, Web of Science, and Embase until 2023. The Newcastle–Ottawa Scale (NOS) was used to assess quality, and statistical meta‐analysis was performed.

A comprehensive literature search identified 1421 articles from which 30 met eligibility for full‐text review, and 9 studies were included in the final analysis. Although the overall analysis did not confirm a statistically significant association, subgroup analyses demonstrated significant relationships between SLC6A4, 5‐HT1B, and COMT polymorphisms and triptan nonresponse, while CALCA and PRDM16 had moderate evidence, and GRIA1 and SCN1A polymorphisms exhibited limited evidence for non‐response. While our analysis revealed that genetic polymorphisms are an essential cause of heterogeneity in response to triptans, the included studies showed substantial variability and methodological inconsistency. Polygenic risk scores (PRS) and combined genetic approaches, including prospective clinical trials and multi‑omics integration, can help stratify triptan nonresponders and inform decision‑making in precision and personalized medicine (PPM).

These results underscore the potential utility of these genetic associations in tailored migraine therapy and reinforce the involvement of serotonergic and dopaminergic pathways in triptan efficacy. Future studies with larger and more homogeneous cohorts are essential to validate these associations. Still, clinical implementation of polygenic risk score (PRS) may offer a more effective pathway for applying PPM in migraine care.

To systematize the genetic basis correctly associated with nonresponse to triptan, we revised etiological studies on Web of Science, Embase, and PubMed until 2023. We found that only polymorphisms in the SLC6A4, 5‐HT1B, and COMT genes have a stronger association with this condition. More robust studies are needed to increase this certainty.