Poster Presentation GENEMAPPERS 2026

The influence of CYP2C19 and CYP2D6 polymorphisms on amitriptyline response in chronic pain a retrospective study from the Australian Genetics of Depression Study (#63)

Bade Uckac 1 2 , Natalia S. Ogonowski 1 3 , Santiago Diaz-Torres 1 3 , Dale R. Nyholt 2 , Nicholas G. Martin 1 , Miguel E. Renteria 1 2 3 , Giovanni Ferreira 4 5
  1. QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
  2. School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Queensland, Australia
  3. School of Biomedical Sciences, Faculty of Health,Medicine and Behavioural Sciences, The University of Queensland, Brisbane, Queensland, Australia
  4. Institute for Musculoskeletal Health, Sydney Local Health District, Sydney, New South Wales, Australia
  5. Sydney School of Public Health, The University of Sydney, Sydney, New South Wales, Australia

Introduction

Chronic pain is a leading reason for off-label antidepressant use, affecting one in three adults. Tricyclic antidepressants (TCAs), particularly amitriptyline, are widely prescribed, yet treatment response and tolerability remain variable and difficult to predict. Polymorphisms in CYP2C19 and CYP2D6 influence its metabolism, but their impact on pain-related outcomes is unclear. This study examined the influence of functional genetic variation in CYP2C19 and CYP2D6 on self-reported effectiveness and tolerability of amitriptyline, aiming to inform personalised pharmacotherapy in chronic pain.

Methods

Participants were drawn from the Australian Genetics of Depression Study who reported multisite chronic pain (≥2 sites for >3 months). Amitriptyline effectiveness was rated as “very well,” “moderately well,” or “not very well,” and discontinuation due to side effects (“yes/no”) was a secondary outcome. Genotypes were translated into metaboliser phenotypes using PharmCAT and grouped into ordered activity clusters to address complex diplotype combinations. Logistic regression and Cochran–Armitage tests assessed associations and linear trends, adjusting for age and sex.

Results

We evaluated 1,147 participants, most of whom reported limited benefit. Effectiveness results were not statistically significant; however, CYP2D6 showed a significant trend toward improved response with increasing metabolic activity (Z = +2.56, p = 0.0116), while CYP2C19 showed negligible trends. CYP2D6 poor/intermediate metabolisers had borderline higher discontinuation (OR 1.47, 95% CI 0.996–2.19; p = 0.052), suggesting reduced tolerability. In contrast, CYP2C19 poor/intermediate metabolisers had significantly lower discontinuation (OR 0.47, 95% CI 0.27–0.82; p = 0.008), indicating greater tolerability.

Conclusion

Pharmacogenetic metaboliser status influenced tolerability, with weaker effects on effectiveness. Integrating automated genotype translation and clustering provides scalable, reproducible tools for resolving complex diplotypes and metabolic heterogeneity. These findings support the potential for more precise, personalised pharmacogenetic-guided prescribing in chronic pain and comorbid psychiatric disorders, where interindividual variability in treatment response is high.

 

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