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.
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.
Double-blind, randomized 8-week study.
Eighteen academic and private outpatient clinics.
We evaluated 246 cognitively intact patients 65 years or older with
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
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.
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.