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.