Allelic Variation in the Serotonin Transporter Promoter Affects Onset of Paroxetine Treatment Response in Late-Life Depression

Abstract

The relationship of the serotonin transporter gene promoter region polymorphism Variability in response to antidepressant treatment may be dependent on interindividual differences in drug concentration or drug targets. The serotonin transporter gene (SLC6A4) promoter region (5-HTTLPR) insertion/ deletion polymorphism is known to affect transporter expression and function . A long ( l , 528 bp) and a short ( s , 484 bp) form affect the expression and function of the serotonin transporter. Those with the s variant, approximately 42% of Caucasians, have reduced transcription of the 5-HTT gene promoter, resulting in decreased 5-HTT expression and an approximate 50% reduction in serotonin uptake Collier et al. 1996). We hypothesized that the initial pharmacologic impact of a selective serotonin reuptake inhibitor (SSRI) was likely to be proportionately greater for those patients with enhanced serotonin reuptake (i.e., those possessing the ll genotype). These patients would thus be expected to respond earlier to an SSRI than those with one or two copies of the dominant s allele. Because inhibition of serotonin reuptake by a SSRI is believed to be only the initial step in a complex 23 , NO . 5 adaptive process, we further hypothesized that final outcome, for those receiving paroxetine, would not differ between the transporter promoter genotypes and that the acute response of patients treated with nortriptyline, an antidepressant affecting predominately reuptake of norepinephrine, would not be affected by this polymorphism. METHODSThis study was conducted in the geriatric inpatient units and the outpatient Late Life Depression Clinic of Western Psychiatric Institute and Clinic as previously described (Mulsant et al. 1999). Study participants were evaluated with the Structured Clinical Interview for DSM-IV Axis-I Disorders (SCID-IV; First et al. 1997) and several rating scales, including the 17-item Hamilton Rating Scale for Depression (HRSD; Hamilton 1967) and the MiniMental State Examination (MMSE; Folstein et al. 1975). Written informed consent was obtained from each subject after the procedures had been fully explained.For inclusion in the study, patients had to meet the following criteria: age 60 years or older; DSM-IV major depressive episode with neither psychotic features nor history of bipolar or schizoaffective disorder; baseline HRSD score of 15 or above; MMSE score of 18 or above; no history of alcohol or other substance abuse or dependency during at least the past year; and no specific medical condition contraindicating treatment with either nortriptyline or paroxetine (e.g., QRS longer than 120 ms or bradychardia with heart rate below 50). Ninety-six subjects (mean age: 72.0 Ϯ 7.9 years) were randomized under double-blind conditions to treatment with either nortriptyline ( n ϭ 45) or paroxetine ( n ϭ 51) after a washout of all psychotropic medications except for lorazepam. Patients received initial doses of 25 mg of nortriptyline, or 20 mg of paroxetine. Nortriptyline doses were adjusted weekly until...

Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with selective serotonin reuptake inhibitor efficacy in depressed patients

“…Indeed some evidence suggest that the association between 5-HTTLPR and treatment response is due to acceleration, more than overall response rate. 24,32,46 The results of our study suggest the period of assessment could be an important factor to evaluate the response rate, while on the other hand the remission rate seemed less influenced by the period of assessment because our results showed no heterogeneity in all remission comparison. This could be due to the fact that remission was evaluated in a longer length of observation: only two studies within 4 weeks.…”

Obsessive-Compulsive Disorder, 5-HTTLPR polymorphism and treatment response

“…[20][21][22] Moreover 5-HTTLPR seems also to be associated with the prophylactic efficacy of lithium in mood disorders. 27 Our data do not seem to correlate the different 5-HTTLPR genotypes with YBOCS total score variation.…”

“…19 Since the 5-HTT is the primary target of action for SRIs, it is possible to hypothesize that allelic variation of 5-HTTLPR could be an important factor in conferring susceptibility to OCD, and also influence the individual response to these drugs, as in mood disorders. Different studies report that ll homozygotes show a more prompt 20 and better antidepressant response than ls and ss individuals. 21,22 On the contrary, a Korean study by Kim et al reports a better antidepressant response in ss homozygotes, while they report that allelic variation of a VNTR (Variable Number of Tandem Repeats) in intron 2 of the gene coding for the 5-HTT may affect the antidepressant response to SSRI drugs.…”

Serotonergic vulnerability and depression: assumptions, experimental evidence and implications

“…The l-allele of the 5-HTTLPR polymorphism is associated with better SSRI antidepressive effects than the s-allele 49,52,53 and with faster response to several SSRI's. 54,55 Combined treatment with a 5-HT 1A blocker to prevent negative feedback at the somatodendritic level compensated for the worse antidepressant effect of SSRIs in s/s and s/l genotypes, 56 suggesting higher 5-HT 1A negative feedback in s-allele genotypes.…”