Pharmacogenomics of antidepressant induced mania: A review and meta-analysis of the serotonin transporter gene (5HTTLPR) association

Joanna M. Biernacka, Susan L. McElroy, Scott Crow, Alexis Sharp, Joachim Benitez, Marin Veldic, Simon Kung, Julie M. Cunningham, Robert M. Post, David Mrazek, Mark A. Frye

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22 Scopus citations


Background: Antidepressants can trigger a rapid mood switch from depression to mania. Identifying genetic risk factors associated with antidepressant induced mania (AIM) may enable individualized treatment strategies for bipolar depression. This review and meta-analysis evaluates the evidence for association between the serotonin transporter gene promoter polymorphism (5HTTLPR) and AIM. Methods: Medline up to November 2009 was searched for key words bipolar, antidepressant, serotonin transporter, SLC6A4, switch, and mania. Results: Five studies have evaluated the SLC6A4 promoter polymorphism and AIM in adults (total N = 340 AIM+ cases, N = 543 AIM- controls). Although a random effects meta-analysis showed weak evidence of association of the S allele with AIM+ status, a test of heterogeneity indicated significant differences in estimated genetic effects between studies. A similar weak association was observed in a meta-analysis based on a subset of three studies that excluded patients on mood stabilizers; however the result was again not statistically significant. Limitations: Few pharmacogenomic studies of antidepressant treatment of bipolar disorder have been published. The completed studies were underpowered and often lacked important phenotypic information regarding potential confounders such as concurrent use of mood stabilizers or rapid cycling. Conclusions: There is insufficient published data to confirm an association between 5HTTLPR and antidepressant induced mania. Pharmacogenomic studies of antidepressant induced mania have high potential clinical impact provided future studies are of adequate sample size and include rigorously assessed patient characteristics (e.g. ancestry, rapid cycling, concurrent mood stabilization, and length of antidepressant exposure).

Original languageEnglish (US)
Pages (from-to)e21-e29
JournalJournal of Affective Disorders
Issue number1-2
StatePublished - Jan 2012

Bibliographical note

Funding Information:
Dr. Biernacka, Alexis Sharp, Dr. Benitez, Dr. Veldic, Dr. Kung, and Dr. Cunningham, and Dr. Post declare no conflicts of interest. Dr. McElroy is employed by the Lindner Center of Hope and the University of Cincinnati College of Medicine. She is part of the Bipolar Collaborative Network. She is also a consultant to, or member of the scientific advisory boards of AstraZeneca, Eli Lilly and Co., and Schering-Plough. Dr. McElroy has received research support from Abbott Laboratories, AstraZeneca, Bristol-Myers Squibb, Cephalon, Eli Lilly and Company, Forest Labs, GlaxoSmithKline, Jazz Pharmaceuticals, Inc., National Institute of Mental Health, OREXIGEN Therapeutics, Inc., Pfizer, and Takeda Pharmaceutical Company Limited. Dr. McElroy is also inventor on United States Patent No. 6,323,236 B2, Use of Sulfamate Derivatives for Treating Impulse Control Disorders, and, along with the patent's assignee, University of Cincinnati, Cincinnati, OH, has received payments from Johnson & Johnson Pharmaceutical Research & Development, L.L.C., which has exclusive rights under the patent. Dr. Crow is employed by the University of Minnesota and has received research support from Novartis. Dr. Mrazek is employed by the Mayo Clinic. A team of researchers, including Dr. Mrazek, has developed intellectual property which has been exclusively licensed by AssureRx. Dr. Frye is employed by the Mayo Clinic and is part of the Bipolar Collaborative Network. He is a consultant for Bristol-Myers Squibb, Cephalon, Dainippon Sumittomo Pharma, Medtronic, Ortho McNeil/Janssen Pharmaceuticals, Johnson & Johnson, Schering Plough, Sepracor, and Pfizer. Dr. Frye has recieved research support from Pfizer, National Alliance for Schizophrenia and Depression (NARSAD), National Institute of Mental Health (NIMH), National Institute of Alcohol Abuse and Alcoholism (NIAAA), and Mayo Foundation. Dr. Frye has also received CME supported activity from Astra-Zeneca, Bristol-Myers Squibb, Eli Lilly and Co., GlaxoSmithKline, Otsuka Pharmaceuticals, Pfizer, and Schering-Plough.

Funding Information:
Supported by Mayo Clinic and a Generous Gift from the Marriott Family . We thank Ms. Jessica Weldon for her assistance in the preparation of this manuscript.


  • Antidepressant
  • Bipolar disorder
  • Pharmacogenomics
  • SLC6A4


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