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

Am J Geriatr Psychiatry. 2014 Oct;22(10):971-9. doi: 10.1016/j.jagp.2013.07.003. Epub 2013 Sep 8.


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 = 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 + rs25531], HTR1A rs6295, HTR2A rs6311, respectively).

Results: Four significant drug-placebo 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 research findings into strategies useful for more personalized patient care.

Keywords: SSRI; older adults; pharmacogenetic; serotonin; side effects.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Antidepressive Agents / adverse effects*
  • Antidepressive Agents / therapeutic use
  • Anxiety Disorders / drug therapy
  • Anxiety Disorders / genetics*
  • Citalopram / adverse effects*
  • Citalopram / blood
  • Citalopram / therapeutic use
  • Double-Blind Method
  • Female
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Polymorphism, Genetic*
  • Promoter Regions, Genetic / genetics
  • Receptor, Serotonin, 5-HT1A / genetics*
  • Receptor, Serotonin, 5-HT2A / genetics*
  • Serotonin Plasma Membrane Transport Proteins / genetics*
  • Serotonin Uptake Inhibitors / adverse effects*
  • Serotonin Uptake Inhibitors / blood
  • Serotonin Uptake Inhibitors / therapeutic use


  • Antidepressive Agents
  • Receptor, Serotonin, 5-HT2A
  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin Uptake Inhibitors
  • Citalopram
  • Receptor, Serotonin, 5-HT1A