Effects of the serotonin transporter gene promoter polymorphism on mirtazapine and paroxetine efficacy and adverse events in geriatric major depression

Arch Gen Psychiatry. 2004 Nov;61(11):1163-9. doi: 10.1001/archpsyc.61.11.1163.


Background: The "long/short"polymorphism (5HTTLPR) in the promoter of the serotonin transporter gene (SLC6A4) has been proposed as a pharmacogenetic marker for antidepressant efficacy. Some but not all studies have found that the short form of 5HTTLPR (S allele) results in decreased efficacy of selective serotonin reuptake inhibitors.

Objective: To determine if the 5HTTLPR polymorphism influences the efficacy and tolerability of mirtazapine and paroxetine hydrochloride, 2 frequently prescribed antidepressants with differing pharmacologic profiles, in geriatric depression.

Design: Double-blind, randomized 8-week study.

Setting: Eighteen academic and private outpatient clinics.

Patients: We evaluated 246 cognitively intact patients 65 years or older with major depression.

Interventions: Antidepressant therapy with 15 to 45 mg/d of mirtazapine (n = 124) or 20 to 40 mg/d of paroxetine (n = 122).

Main outcome measures: The Hamilton Depression Rating Scale-17 and Geriatric Depression Scale, severity of adverse events and dosing compliance indexes, and discontinuations due to adverse events. Outcome measures were stratified according to 5HTTLPR genotypes.

Results: Geriatric Depression Scale scores indicated that S allele carriers treated with paroxetine showed a small impairment in antidepressant response. Among mirtazapine-treated patients, there was little indication that the 5HTTLPR genotype affected antidepressant efficacy. However, the 5HTTLPR polymorphism had a dramatic effect on adverse events. Among paroxetine-treated subjects, S allele carriers experienced more severe adverse events during the course of the study, achieved significantly lower final daily doses, and had more discontinuations at days 14, 21, 28, 42, and 49. Surprisingly, among mirtazapine-treated subjects, S allele carriers had fewer discontinuations due to adverse events, experienced less severe adverse events, and achieved higher final daily doses.

Conclusions: These results support the hypothesis that the S allele of 5HTTLPR at the SLC6A4 locus is associated with a poor outcome after treatment with selective serotonin reuptake inhibitors. However, the major effect was on the tolerability of these drugs rather than efficacy. Results from mirtazapine-treated patients indicate that the effect of this polymorphism on outcome may depend on the mechanism of antidepressant action.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic alpha-Antagonists / administration & dosage
  • Adrenergic alpha-Antagonists / therapeutic use*
  • Aged
  • Ambulatory Care
  • Depressive Disorder, Major / drug therapy*
  • Depressive Disorder, Major / genetics
  • Female
  • Genetic Markers
  • Genotype
  • Humans
  • Male
  • Membrane Glycoproteins / genetics*
  • Membrane Transport Proteins / genetics*
  • Mianserin / administration & dosage
  • Mianserin / analogs & derivatives*
  • Mianserin / therapeutic use*
  • Mirtazapine
  • Nerve Tissue Proteins / genetics*
  • Paroxetine / administration & dosage
  • Paroxetine / therapeutic use*
  • Pharmacogenetics
  • Polymorphism, Genetic
  • Proportional Hazards Models
  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin Uptake Inhibitors / administration & dosage
  • Serotonin Uptake Inhibitors / therapeutic use*
  • Treatment Outcome


  • Adrenergic alpha-Antagonists
  • Genetic Markers
  • Membrane Glycoproteins
  • Membrane Transport Proteins
  • Nerve Tissue Proteins
  • SLC6A4 protein, human
  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin Uptake Inhibitors
  • Mianserin
  • Paroxetine
  • Mirtazapine