Polymorphism within the promoter of the serotonin transporter gene and antidepressant efficacy of fluvoxamine

Abstract

Depression with psychotic features has been shown to respond to selective serotonin reuptake inhibitors (SSRIs). The serotonin transporter (5-HTT) is a prime target for SSRIs. A functional polymorphism within the promoter region of the 5-HTT gene, leading to different transcriptional efficiency, was recently reported. We tested the hypothesis that allelic variation of the 5-HTT promoter could be related to the antidepressant response to fluvoxamine and/or augmentation with pindolol (a serotonin autoreceptors antagonist) which has been suggested as an augmentation therapy for nonresponders. One hundred and two inpatients with major depression with psychotic features were randomly assigned to treatment with a fixed dose of fluvoxamine and either placebo or pindolol for 6 weeks. Depression severity was assessed once a week using the Hamilton Depression Rating Scale. Allelic variation in each subject was determined using a PCR-based method. Data were analyzed with a three-way repeated measures analysis of variance. Both homozygotes for the long variant (l/l) of the 5-HTT promoter and heterozygotes (l/s) showed a better response to fluvoxamine than homozygotes for the short variant (s/s). In the group treated with fluvoxamine plus pindolol all the genotypes acted like l/l treated with fluvoxamine alone. Fluvoxamine efficacy in delusional depression seems to be related to allelic variation within the promoter of the 5-HTT gene. Even though other factors may be implicated, genotyping at 5-HTT promoter may represent a promising tool to individualize the pharmacological treatment of depression.

The moderation by the serotonin transporter gene of environmental adversity in the aetiology of mental illness: review and methodological analysis

“…An initial European investigation showed that among sufferers of major depression, 5-HTTLPR long allele is associated with better response to serotonergic antidepressants. 111 This finding has been followed by several replications in European samples. 112,113 However, findings in Asian and American samples have been inconsistent, including findings of effect in the opposite direction in Korean samples 114,115 and of no association with antidepressant response in a large multicentre USA study.…”

“…169 Given that the 5-HTTLPR polymorphism is in the regulatory promoter region of the serotonin transporter gene, it is likely that dynamic endophenotypes, concerning response to a challenge or a stressor will be of greater value in disentangling the mechanism of this G Â E. Promising examples include response to tryptophan depletion, 90,93,94 HPA activation by stress and response to corticosteroids, 71 and clinical response to serotonin reuptake inhibitors. 111 Exploring the interplay between psychological and biological intermediate phenotypes is one way forward to disentangle and characterise the G Â E.…”

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

“…Hardy-Weinberg equilibrium was examined in studies where genotype frequencies were included. 9,[15][16][17][18][19][20][21][22][23][24][25] Given the lack of unequivocal data for 5-HTTLPR genotype pooling, we tested both dominant and recessive hypotheses: l/l versus l/s-s/s and l/l-l/s versus s/s. Outcome was defined with three phenotypes: remission rate, response rate, and response rate within 4 weeks.…”

“…Our group performed the first studies, and tested the hypothesis that 5-HTTLPR was related to the response to fluvoxamine and/or augmentation with pindolol in 102 inpatients with major depression. 9 The carriers of the long allele showed a better response to fluvoxamine compared to those who were homozygous for the short allelic variant. Following this pilot study, the association between 5-HTTLPR and response in patients with mood disorder has been investigated by a large number of studies, but findings are not always consistent.…”

Further evidence for a possible association between serotonin transporter gene and lithium prophylaxis in mood disorders

“…Finally, another reason for the conflicting results could be due to the fact that the polymorphism investigated is in linkage disequilibrium with a nearby functional one. 81 Recently, the SERTPR polymorphism has been associated with the antidepressant response to certain selective serotonin reuptake inhibitors, such as fluvoxamine [82][83][84][85] and paroxetine. 86,87 A possible common mechanism may therefore underlie SSRI and lithium efficacy even if the exact mechanism of action of lithium activity is largely unknown.…”