In the context of a long term follow-up study, we analysed the possible implication of the 5-HTTLPR polymorphism at the serotonin transporter gene in clinical response and remission of major depressive patients treated with citalopram. The sample consisted of 131 patients, all of Spanish origin, diagnosed according to DSM-IV criteria. A 21-item Hamilton Depression Rating Scale (HDRS) was used to evaluate severity of the symptoms during the follow-up and to determine clinical response and remission condition of the patients at 4th and 12th week, respectively. Our results showed that S/S genotype of the 5-HTTLPR polymorphism was associated with the non-Remission condition at 12th week (χ2 = 8.7, P = 0.013). Moreover, homozygous for the allele S presented three times more risk for non reaching remission of depressive episode after citalopram treatment than patients with any other 5-HTTLPR genotype combination (χ2: 7.29, P = 0.006; OR = 3.23 [95%CI: 1.24-8.5]). In conclusion, our results show that genetic variation of serotonin transporter is involved in clinical remission of major depressive episodes after twelve weeks of citalopram treatment.
Clinical response to drug treatment in depression is a complex psychological and biological phenomenon in which several factors, some of them with a genetic origin, are involved. Selective serotonin re-uptake inhibitors (SSRIs) have been developed as drugs with high selectiveness for their molecule target, and have constituted the most relevant advance for the pharmacological treatment of depression in the general practice setting during the last years. 1 However, SSRIs present some disadvantages, including a delay of 2 or 3 weeks before the first effects in clinical response become evident. 2,3 In this sense, there is consensus that optimal antidepressant-induced improvement of depression symptoms is slow, taking 6-12 weeks to occur. 4,5 Among SSRIs, citalopram has been distinguished by being the most selective inhibitor of the serotonin transporter molecule. 6 Its capability of inhibiting serotonin re-uptake without appreciably inhibiting the uptake of noradrenaline or dopamine makes it a perfect target in pharmacogenetic studies. 7
Pharmacogenetics investigate the individual possible genetic factors involved in the response to clinical drug treatment, including those factors related to drug absorption and metabolism, and those related to number, function and morphology of receptor targets. 8,9 Arranz and colleagues 10 have recently pointed out the importance of these studies in psychiatry. They reported a high level of response prediction (76.86%) to clozapine treatment in schizophrenic patients when they combined different genotype variants of several genes including 5HT2A, 5HT2C and serotonin transporter gene. This study revealed the importance of pharmacogenetic studies as a useful tool for the individualisation of pharmacological treatment in mental disorders.
Recently, some excitement was caused by reports on major depression and serotonin transporter gene (SLC6A4) polymorphisms and their influence on the clinical response to SSRIs antidepressants such as fluvoxamine, fluoxetine or paroxetine 11-17 (see Serretti et al 18 and Mancama et al 19 for extensive reviews). Most of these studies showed that variability on the promoter region of this gene is involved in 6-week clinical response to the aforementioned SSRIs. 11-13,15 Among these, only Pollock et al1 14 and Rausch et al 16 presented data on clinical outcome of patients in a twelve weeks follow up but none of them use the status of remission as a criteria of clinical response. On the other hand, a study on Korean population 17 has shown an association between serotonin transporter and clinical response but in the opposite direction as all the previous studies. These opposite associations may reflect linkage of these polymorphisms to an additional variant important in gene regulation. 20
The serotonin transporter is encoded by a single gene (SLC6A4) on chromosome 17q11.1-17q12. Two common polymorphisms have been described in this gene: a variable number of tandem repeats (VNTR) in intron 2, and an insertion/deletion variant (5-HTTLPR) placed on the promoter region. Both polymorphisms have no influence on the structure of the protein but might have important influence on the regulation of gene expression, particularly the 5-HTTLPR polymorphism, whose short variant, allele 484, reduces the transcriptional efficiency of the gene, resulting in decreased serotonin transporter expression in the neuron. 21 This reduced efficiency of SLC6A4 gene has been considered as a hypothetical factor that could modify the clinical response to drugs that have this receptor as a target protein.
In the present work, we performed a twelve weeks follow up study in a sample of major depressive patients treated with citalopram in order to evaluate the role of the SLC6A4 promoter polymorphism (5-HTTLPR) in clinical response and remission after pharmacological treatment.