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

J Clin Psychopharmacol. 2023 Sep-Oct;43(5):428-433. doi: 10.1097/JCP.0000000000001747.


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.

Publication types

  • Meta-Analysis
  • Review

MeSH terms

  • Antidepressive Agents / adverse effects
  • Bipolar Disorder* / chemically induced
  • Bipolar Disorder* / drug therapy
  • Bipolar Disorder* / genetics
  • Humans
  • Mania*
  • Pharmacogenetics
  • Polymorphism, Genetic / genetics
  • Serotonin Plasma Membrane Transport Proteins / genetics


  • Antidepressive Agents
  • Serotonin Plasma Membrane Transport Proteins
  • SLC6A4 protein, human