Antidepressant-Associated Treatment Emergent Mania: A Meta-Analysis to Guide Risk Modeling Pharmacogenomic Targets of Potential Clinical Value

Nicolas A. Nuñez, Brandon J. Coombes, Lindsay Melhuish Beaupre, Francisco Romo-Nava, Manuel Gardea-Resendez, Aysegul Ozerdem, Marin Veldic, Balwinder Singh, Jorge A. Sanchez Ruiz, Alfredo Cuellar-Barboza, Jonathan G. Leung, Miguel L. Prieto, Susan L. McElroy, Joanna M. Biernacka, Mark A. Frye*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Background The purpose of this study was to review the association between the SLC6A4 5-HTTLPR polymorphism and antidepressant (AD)-associated treatment emergent mania (TEM) in bipolar disorder alongside starting a discussion on the merits of developing risk stratification models to guide when not to provide AD treatment for bipolar depression. Methods Studies that examined the association between clinical and genetic risk factors, specifically monoaminergic transporter genetic variation, and TEM were identified. A meta-analysis was performed using the odds ratio to estimate the effect size under the Der-Simonian and Laird model. Results Seven studies, referencing the SLC6A4 5-HTTLPR polymorphism and TEM (total N = 1578; TEM+ =594, TEM- = 984), of 142 identified articles were included. The time duration between the start of the AD to emergence of TEM ranged from 4 to 12 weeks. There was a nominally significant association between the s allele of the 5-HTTLPR polymorphism and TEM (odds ratio, 1.434; 95% confidence interval, 1.001-2.055; P = 0.0493; I2 = 52%). No studies have investigated norepinephrine or dopamine transporters. Conclusion Although the serotonin transporter genetic variation is commercially available in pharmacogenomic decision support tools, greater efforts, more broadly, should focus on complete genome-wide approaches to determine genetic variants that may contribute to TEM. Moreover, these data are exemplary to the merits of developing risk stratification models, which include both clinical and biological risk factors, to guide when not to use ADs in bipolar disorder. Future studies will need to validate new risk models that best inform the development of personalized medicine best practices treating bipolar depression.

Original languageEnglish
Pages (from-to)428-433
Number of pages6
JournalJournal of Clinical Psychopharmacology
Issue number5
StatePublished - 1 Sep 2023

Bibliographical note

Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.


  • antidepressant induced mania
  • antidepressants
  • bipolar depression
  • risk factors of TEM
  • serotonin transporter
  • treatment emergent mania
  • Pharmacogenetics
  • Humans
  • Bipolar Disorder/drug therapy
  • Polymorphism, Genetic/genetics
  • Antidepressive Agents/adverse effects
  • Serotonin Plasma Membrane Transport Proteins/genetics
  • Mania


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