Common Selective Serotonin Reuptake Inhibitor Side Effects in Older Adults Associated with Genetic Polymorphisms in the Serotonin Transporter and Receptors: Data from a Randomized Controlled Trial Lauren D. Garfield, Ph.D., M.P.H., David Dixon, Ph.D., Petra Nowotny, Ph.D., Francis E. Lotrich, M.D., Ph.D., Bruce G. Pollock, M.D., Ph.D., Sean D. Kristjansson, Ph.D., Peter M. Dor e, M.A., Eric J. Lenze, M.D. Objective: Antidepressant side effects are a significant public health issue, associated with poor adherence, premature treatment discontinuation, and, rarely, significant harm. Older adults assume the largest and most serious burden of medication side effects. We investigated the association between antidepressant side effects and genetic variation in the serotonin system in anxious, older adults participating in a randomized, placebo-controlled trial of the selective serotonin reuptake inhibitor (SSRI) escitalopram. Methods: Adults (N ¼ 177) aged  60 years were randomized to active treatment or placebo for 12 weeks. Side effects were assessed using the Udvalg fur Kliniske Undersøgelser side-effect rating scale. Genetic polymorphisms were putative functional variants in the promoters of the serotonin transporter and 1A and 2A receptors (5-HTTLPR [L/S þ rs25531], HTR1A rs6295, HTR2A rs6311, respec- tively). Results: Four significant drugeplacebo side-effect differences were found: increased duration of sleep, dry mouth, diarrhea, and diminished sexual desire. Analyses using putative high- versus low-transcription genotype groupings revealed six pharmacogenetic effects: greater dry mouth and decreased sexual desire for the low- and high-expressing serotonin transporter genotypes, respectively, and greater diarrhea with the 1A receptor low-transcription genotype. Diminished sexual desire was experienced significantly more by high-expressing genotypes in the serotonin transporter, 1A, or 2A receptors. There was not a significant relationship between drug concentration and side effects nor a mean difference in drug concentration between low- and high-expressing genotypes. Conclusion: Genetic variation in the serotonin system may predict who develops common SSRI side effects and why. More work is needed to further characterize this genetic modulation and to translate Received October 1, 2012; revised July 1, 2013; accepted July 8, 2013. From the Department of Psychiatry (LDG, DD, PN, SDK, PMD, EJL), Washington University School of Medicine, St. Louis, MO; Western Psychiatric Institute and Clinic (FEL), University of Pittsburgh, Pittsburgh, PA; and Campbell Family Mental Health Research Institute-Centre for Addiction and Mental Health (BGP), University of Tor- onto, Toronto, Canada. Presented at the 11th annual Pharmacogenetics in Psychiatry Meeting, New York, NY, March 30e31, 2012. Send correspondence and reprint requests to Lauren D. Garfield, Ph.D., M.P.H., Washington University School of Medicine, 660 South Euclid Ave., Campus Box 8134, St. Louis, MO 63110. e-mail: garfiell@psychiatry.wustl.edu Supplemental digital content is available for this article in the HTML and PDF versions of this article on the journal’s Web site (www. ajgponline.org). Ó 2013 American Association for Geriatric Psychiatry http://dx.doi.org/10.1016/j.jagp.2013.07.003 Am J Geriatr Psychiatry -:-, - 2013 1