Allele Of 5-HTTLPR Research Articles

No association between polymorphism of serotonin transporter gene and depression in Parkinson's disease in Chinese

Depressive symptoms affect 40% to 50% of Parkinson's disease (PD) patients, and adversely impact their quality of life. The decrease of serotonin (5-HT) in the synaptic cleft is commonly considered as the cause of depression. The reuptake of 5-HT released into the synaptic cleft is mediated by the 5-HT transporter (5-HTT). Many studies have focused on the relationship between the 5-HTT-linked polymorphic region (5-HTTLPR) and depression. The present study is to investigate the association between the polymorphisms in the promoter of the 5-HTT gene (including 5-HTTLPR and rs25531), which determine either a higher or lower 5-HT uptake, and risk for depression of PD. Three hundred six idiopathic PD patients were recruited randomly from hospital clinic and the Center for Epidemiological Studies Depression Scale (CES-D) was used as the diagnosis or rating scale for depression. Polymerase Chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used and the patients’ genotypes were divided as L A, L G, S A, and S G. We found no evidence for an association between variants of 5-HTTLPR and rs25531 alleles, and depressive symptoms in Chinese PD patients.

Serotonin transporter promoter region polymorphisms do not influence treatment response to escitalopram in patients with major depression

Several studies and meta-analyses have implicated a polymorphism in the promoter region of the serotonin transporter (5-HTT) gene, 5-HTTLPR in treatment outcomes of selective serotonin re-uptake inhibitors in patients with major depression. In this study we investigated the impact of 5-HTTLPR and a functional SNP rs25531 on the treatment outcomes to escitalopram in depressive patients. The study sample consisted of 135 outpatients with major depressive disorder (mean age 31.1 ± 11.6 years, 68% females) treated with escitalopram 10–20 mg/day for 12 weeks. There were no significant associations between 5-HTT promoter region polymorphisms and response rate or mean change of depressive symptoms during escitalopram treatment. However we showed that patients carrying S allele of 5-HTTLPR may have increased risk for some side effects, including headache, induced by escitalopram medication.

Genetic variation in 5HTTLPR is associated with emotional resilience

Emotional resilience can be defined as the ability to maintain healthy and stable levels of psychological functioning in the wake of stress and trauma. Although genes that contribute to psychopathology (often in interaction with environmental stressors) are being detected with increasing consistency, genes that influence resilience to stress have been less studied. In this study, 423 undergraduate college students completed a psychometrically sound 10-item self-report measure of resilience (CDRISC-10) and provided blood for DNA. Linear and logistic regression analyses were used to model relationships between the serotonin transporter promoter polymorphism (5HTTLPR) and CDRISC-10 scores and categories, respectively. CDRISC-10 scores were normally distributed (mean 26.17, SD 5.88 [range 5-40]). In models adjusting for ancestry proportion scores (to mitigate confounding by population stratification) and other covariates, each copy of the "s" allele of 5HTTLPR was associated with approximately 1-point lower CDRISC-10 score. Each copy of the "s" allele was associated with increased (adjusted OR = 1.53, 95% CI 1.06-2.21, P = 0.024) odds of being in the low resilient category (>1 SD below the mean), compared to being homozygous for the "l" allele. These findings suggest that variation in 5HTTLPR is associated with individual differences in emotional resilience, defined as an individual's ability to withstand and bounce back from stress. This relationship may explain the frequently observed interaction between 5HTTLPR and life stressors in predicting adverse mental health outcomes (e.g., depressive symptoms). Replication is needed, in concert with identification of other genes that influence emotional resilience and related phenotypes.

Psychotic Symptoms in Alzheimer's Disease and 5-HTTLPR Polymorphism of the Serotonin Transporter Gene: Evidence for an Association

The occurrence of psychotic symptoms is common in Alzheimer's disease (AD), configuring a possibly distinguished clinical entity defined "Psychosis in Alzheimer's Disease" (AD-P). In order to investigate demographic clinical and biological variables potentially associated to the occurrence of AD-P, 148 AD patients were selected. Mini-Mental State Examination (MMSE), Activities of Daily Living (ADL), and Instrumental Activities of Daily Living (IADL) scores, socio-economic status and 5-HTTLPR and APOE gene polymorphisms were determined for each subject. AD-P patients were significantly more frequent carriers of the long (L) allele of 5-HTTLPR. The percentage of AD-P increased with the number of copies of the L-allele: 13% among S homozygote; 36% among heterozygotes; 51% among L-homozygotes. No difference resulted between AD-P and non-psychotic AD (AD-NP) in the distribution of the epsilon4 allele of APOE. The risk of AD-P was increased in L/L homozygous (OR = 7.25, p = 0.003) and, to a lesser extent, in heterozygous (OR = 3.91; p = 0.018). Backward logistic regression analysis showed that the risk for AD-P was increased in older subjects (OR = 1.07; p = 0.018) while an increase of MMSE score was protective (OR = 0.90; p = 0.004). The occurrence of AD-P resulted significantly related to age at examination, cognitive status, and to the presence of the 5-HTTLPR L-allele.

Impulsive-disinhibited personality and serotonin transporter gene polymorphisms: Association study in an inmate’s sample

The association between different impulsive-disinhibited personality traits with 5-HTTLPR and 5-HTTVNTR genetic polymorphisms was examined in an imprisoned male sample. Higher scores of the impulsive-disinhibited personality traits tended to be associated with carrying one or two copies of the 5-HTTPLR S allele (S/S homozygous and S/L heterozygous), and carrying two copies of the 5-HTTVNTR 12 allele (12/12 homozygous). Genotype, allele, haplotype and extended genotype distribution between low and high impulsive-disinhibited groups confirmed this association. Allele S and genotypes S/S+S/L at the 5-HTTLPR locus and allele 12 and genotype 12/12 at the 5-HTTVNTR locus were overrepresented in the high scoring group. Accordingly, allele S and allele 12 conferred a trend for risk to be in the high scoring group with an odds ratio (OR) of 1.8 ( p < 0.035) and 1.7 ( p < 0.014), respectively. In addition, extended genotype distribution shows that those S allele carriers (S/S homozygote and S/L heterozygote) that were also 12/12 homozygote, were overrepresented in the high scoring group (OR = 3.2; p < 0.004). The main risk of being in the high scoring group was assigned to those carrying two copies of the S-12 haplotype (OR = 5.7; p < 0.0007). We discuss the possible relationship between the two genetic serotonin polymorphisms and the personality impulsive-disinhibited traits investigated.

S46-02 Influence of the mother’s emotional state on infant irritability is moderated by the 5-HTTLPR polymorphism

The serotonin transporter gene-linked polymorphic region (5-HTTLPR) may moderate an individual's response to stress. This study analyzes how the infant 5-HTTLPR may interact with the level of their mother's emotional state to affect infant irritability.A prospective study was carried out with 314 newborns and their mothers. Infant irritability and the mother emotional state were evaluated at 8 and 32 weeks after childbirth. These variables were correlated with the 5-HTTLPR genotypes of both the infants and their mothers. The irritability score of infants with the s allele of 5-HTTLPR showed a linear relationship with their mother's anxiety at both 8 (P= 0.009) and 32 weeks (P= 0.008). In Infants carrying the ll genotype irritability was independent of their mother's anxiety.This study provided evidence that the promoter 5-HTTLPR polymorphism could moderate the influence of the mother's anxiety on infant irritability.

Association between the serotonin transporter promoter polymorphism (5-HTTLPR) and adult unresolved attachment.

Research on antecedents of organized attachment has focused on the quality of caregiving received during childhood. In recent years, research has begun to examine the influence of genetic factors on quality of infant attachment. However, no published studies report on the association between specific genetic factors and adult attachment. This study examined the link between the 5-HTTLPR promoter polymorphism of the serotonin transporter gene and adult unresolved attachment assessed with the Adult Attachment Interview. Genetic material and information on attachment-related loss or trauma were available for 86 participants. Multivariate regression analyses showed an association between the short 5-HTTLPR allele and increased risk for unresolved attachment. Temperament traits and psychological symptoms did not affect the association between 5-HTTLPR and unresolved attachment. The authors hypothesize that the increased susceptibility to unresolved attachment among carriers of the short allele of 5-HTTLPR is consistent with the role of serotonin in modulation of frontal-amygdala circuitry. The findings challenge current thinking by demonstrating significant genetic influences on a phenomenon previously thought to be largely environmentally driven.

Novel allelic variants in the human serotonin transporter gene linked polymorphism (5-HTTLPR) among depressed patients with suicide attempt

A polymorphism in the serotonin transporter gene (5-HTTLPR) is being extensively studied for association with suicidal behavior. A new allelic variant within the 5-HTTLPR polymorphism was described but it has not been thoroughly analyzed in the recent literature. The SNP functional analysis demonstrated that the A variant of the L allele (L A) produces high levels of mRNA and that the G variant (L G) is equivalent to the S allele. Our aims were to compare the frequency of 5-HTTLPR alleles in 94 depressed patients who attempted suicide compared to 94 controls free of psychiatric disorder, including the embedded SNP rs25531. Using the biallelic classification, our sample contained 62 (33%) LL, 76 (40.4%) LS, and 50 (26.6%) SS individuals. Using the functional classification system, our sample contained 43 (22.5%) L’L’, 84 (44.7%) L'S’, and 61 (32.4%) S'S’ individuals, with no significant differences between cases and controls in genotypic tests in either biallelic ( χ 2 = 2.543; df = 2; p = 0.280) and functional models ( χ 2 = 2.995; df = 2; p = 0.228). The minor allele frequency (MAF) – the S allele – did not show any distributional difference between cases and controls using biallelic classification system 0.51 vs. 0.43, (OR = 1.41; CI95% 0.94 to 2.12; p = 0.121). Also the S’ allele of the functional classification system did not show any distributional difference between the two groups 0.59. vs. 0.51 (OR = 1.35; CI95% 0.90 to 2.03; p = 0.178). This study provided the possibility of a re-analysis of novell 5-HTTLPR functional variants identified within L allele that alters its mRNA production and thus changes its functionality. We could not find any association between both biallelic and functional 5-HTTLPR in depressed patients with suicide attempt, being the small sample size an important limitation for these results. In conclusion, we can suggest that despite the several studies in this issue, the exact effect and role of 5-HTTLPR in genetics of suicide is still unclear and should be better investigated for future studies.

Serotonergic genes and amygdala activity in response to negative affective facial stimuli in Korean women

Serotonergic genes have been implicated in mood disorders, alcoholism and certain personality traits. We investigated the possible relationship between several polymorphisms in the serotonin (5-HT) system and amygdala responses to negative facial stimuli in Korean women using functional magnetic resonance imaging. All participants were genotyped with regard to the following polymorphisms: the serotonin transporter-gene-linked polymorphic region (5-HTTLPR), tryptophan hydroxylase 2 (TPH2) G(-703)T, 5-HT(1A) C(-1019)G and 5-HT(2A) single nucleotide polymorphism (SNP) rs6311. We found increased activations in response to angry facial stimuli in the bilateral amygdala of subjects with the long allele of 5-HTTLPR compared with those with two copies of the short allele. Higher activations in response to sad facial stimuli were found in the bilateral amygdala of subjects with the T/T genotype of 5-HT(2A) SNP rs6311, compared with C allele carriers, and in subjects with the G/G genotype of TPH2 G(-703)T, compared with those with T/T and G/T genotypes. Our results for individuals from an Asian population countered a previous finding for a Caucasian population and identified the moderating role of genetic background in the relationships between these serotonergic gene polymorphisms and amygdala function elicited by negative emotional stimuli.

The Expression of NMDA Receptor Subunit mRNA in Human Chronic Alcoholics

Ethanol is a modulator at the N-methyl-d-aspartate class of glutamate receptors in the brain. In animal studies the receptor adapts to sustained ethanol exposure through altered expression of the subunits that make up the receptor complex. We used real-time RT-PCR normalized to GAPDH to assay NR1, NR2A, and NR2B subunit mRNA in superior frontal and primary motor cortex tissue obtained at autopsy from chronic alcoholics with and without co-morbid cirrhosis of the liver, and from matched controls. The expression of all three subunits was significantly lower in both areas of cirrhotic alcoholics than in the corresponding areas in both controls and alcoholics without co-morbid disease, who did not differ significantly from each other. The decrease was area-dependent when cases were partitioned by the 5-HTTLPR allele. Thus, polymorphisms in one gene can have a significant effect on the expression of a second, unrelated, gene. The expression of the N-methyl-d-aspartate glutamate receptor complex is under multifactorial control.

Seasonal changes in brain serotonin transporter binding in short 5-HTTLPR-allele carriers but not in long-allele homozygotes

AbstractSeveral findings suggest seasonal variations in the serotonin (5-HT) system. We sought evidence for seasonal variation in the serotonin transporter (5-HTT). We found that length of daylight time in minutes correlates negatively with 5-HTT binding in the putamen and the caudate, with a similar tendency in the thalamus, but no such association in the midbrain. In the putamen, an anatomical region with a dense serotonin innervation that is implicated in processing of aversive stimuli, we found a significant gene*daylight effect with a negative correlation between the 5-HTT binding and daylight time in carriers of the short 5-HTTLPR allele, but not in carriers of the long allele. The neurobiological endophenotype identified here directly links activation studies, showing responses on the neural circuit level, with dynamic changes in transporter expression measured in vivo.

Serotonin-System Polymorphisms (5-HTTLPR and -1438G/A) and Responses of Patients With Bulimic Syndromes to Multimodal Treatments

We tested the hypothesis that individuals carrying low-function alleles of the serotonin transporter (5-HTTLPR) and 5-HT(2A) receptor gene (-1438G/A) promoter polymorphisms would show relatively poor treatment responses on indices of bulimic and concurrent symptoms. Participants included 111 women with bulimia-spectrum eating disorders (DSM-IV-TR criteria), 98 of whom were followed through 4- to 8-month spans of specialized multimodal treatment to enable examination of relationships between genotypes and prospective changes in eating and general psychiatric symptoms. Given a hierarchically structured dataset and a desire to control for effects of variations in adjunctive pharmacotherapy, individual therapy, group therapy, or day treatment, we used multilevel modeling techniques. The study was conducted between October 2001 and May 2007. After effects of treatments were removed, 5-HTTLPR low-function allele carriers showed smaller treatment reductions in binge eating (p < .01) and in anxiety and depression (p < .05), whereas low-function -1438G/A G carriers showed smaller reductions in binge eating (p < .01) and impulsivity (p < .05). This study documents an expected association between poorer bulimia-treatment response and low-function alleles of 5-HTTLPR and -1438G/A--and suggests that such effects cannot be attributed to mediating influences of medication or psychotherapy responsiveness alone. A better understanding of hereditary, serotonin-mediated factors affecting bulimic individuals' progress during therapy may facilitate the development of more effective treatments.

Autism and serotonin transporter gene polymorphisms: A systematic review and meta‐analysis

The serotonin transporter gene (5-HTT) plays a crucial role in serotonergic neurotransmission and has been found to be associated, with varying degrees of significance, with many diseases, including autism. Prior association studies of autism have yielded conflicting results regarding the association between two common 5-HTT polymorphisms, the promoter insertion/deletion (5-HTTLPR) and the intron 2 VNTR (STin2 VNTR). We conducted a systematic review and meta-analysis to test the following hypotheses: (i) there is an association between autism and either or both of the 5-HTTLPR and STin2 VNTR polymorphisms, and (ii) the S allele of 5-HTTLPR and/or the STin2.12 allele of the VNTR are the specific risk alleles for autism. All published family-based and population based studies were examined to determine the overall strength of association between 5-HTT polymorphisms and autism. After exclusion of studies with overlapping samples and studies whose data did not allow for calculation of an odds ratio, 16 studies were included for final analyses, all but two of which used a family-based design. The meta-analysis failed to find a significant overall association between either of the 5-HTT polymorphisms examined and autism. Further, no allelic transmission distortion was found when studies of simplex (11 studies) and multiplex (3 studies) family samples were analyzed separately. However, there was significant heterogeneity by ethnicity; family based studies of US mixed population samples showed preferential transmission of the S allele of 5-HTTLPR (S allele:L allele = 247:183), while there was no allelic distortion among the family-based studies of European and Asian samples.

Lack of association between serotonin transporter gene polymorphism 5-HTTLPR and smoking among Polish population: a case-control study

BackgroundA better understanding of the genetic determinants of tobacco smoking might help in developing more effective cessation therapies, tailored to smokers' genotype. Insertion/deletion polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) has been linked to vulnerability to smoking and ability to quit. We aimed to determine whether 5-HTTLPR genotype is associated with smoking behavior in Caucasians from Northern Poland and to investigate other risk factors for tobacco smoking.Methods5-HTTLPR genotypes were determined in 149 ever smokers (66 females; mean age 53.0 years) and 158 gender and ethnicity matched never smoking controls (79 females; mean age 45.0 years) to evaluate the association of this polymorphism with ever smoking status. Analysis of smokers was performed to evaluate the role of 5-HTTLPR in the age of starting regular smoking, the number of cigarettes smoked daily, pack-years, FTND score, duration of smoking, and the mean length of the longest abstinence on quitting. Genotype was classified according to the presence or absence of the short (S) allele vs. the long (L) allele of 5-HTTLPR (i.e., S/S + S/L vs. L/L). Logistic regression analysis was also used to evaluate correlation between ever smoking and several selected variables.ResultsWe found no significant differences in the rates of S allele carriers in ever smokers and never smokers, and no relationship was observed between any quantitative measures of smoking and the polymorphism. Multivariate analysis demonstrated significant association between the older age (OR = 4.03; 95% CI: 2.33–6.99) and alcohol dependence (OR = 10.23; 95% CI: 2.09–50.18) and smoking.Conclusion5-HTTLPR seems to be not a major factor determining cigarette smoking in Poles. Probably, the risk of smoking results from a large number of genes, each contributing a small part of the overall risk, while numerous non-genetic factors might strongly influence these genetic undergrounds of susceptibility to smoking.

Impact of serotonin transporter and catechol- O-methyl transferase genes polymorphism on gastrointestinal dysfunction in Swedish and Japanese familial amyloidotic polyneuropathy patients

Background Differences in the gastrointestinal manifestations have emerged between Swedish and Japanese familial amyloidotic polyneuropathy amyloidogenic transthyretin Valine30Methionine (FAP ATTR Val30Met) patients. To elucidate the cause of the differences, we investigated the associations between serotonin transporter gene-linked polymorphic region (5-HTTLPR) and/or catechol- O-methyl transferase (COMT) gene polymorphism and their gastrointestinal in these patients. Methods Twenty-six Swedish and 24 Japanese patients with gastrointestinal disturbances, in whom genetic material was available, were included in the study. The initial gastrointestinal manifestations of the disease were classified as constipation, constipation alternating with diarrhoea, continuous diarrhoea, and nausea/vomiting. 5-HTTLPR and COMT gene polymorphism were assessed by polymerase chain reaction and enzymatic digestion. Results A significantly higher L A allele frequency of 5-HTTLPR was noted in the Swedish population compared with that of the Japanese. Moreover, the L A allele frequency tended to be lower in the continuous diarrhoea group than in that of the remaining groups of both Swedish and Japanese patients. No association between COMT genotype and initial gastrointestinal symptoms was noted. Conclusion A high expression of serotonin transporter induced by L A allele of 5-HTTLPR may be one of the factors implicated with the inhibition of severe diarrhoea in early stages of Swedish FAP ATTR Val30Met patients.

Polymorphisms in the 3′ UTR of the serotonin transporter are associated with cognitive flexibility in rhesus macaques

The serotonin system is an important neurophysiological mediator of many behavioral phenotypes. Genetic variation within this system is thought to contribute not only to the natural range of behavioral differences, but also to neuropsychiatric pathologies. Cognitive flexibility, the ability to change patterns of response as reward context shifts, is an important trait that underlies many complex social interactions. Environmental manipulations of the serotonin system have been shown to alter performance on tests measuring cognitive flexibility. Variation at the serotonin transporter promoter region (5HTTLPR) has recently been shown to associate with the performance of rhesus monkeys on an object discrimination reversal learning task [Izquierdo et al., 2007]. Here, we demonstrate that functional genetic variation at the serotonin transporter 3' untranslated region, independent of 5HTTLPR, also associates with performance in an object discrimination reversal learning task in rhesus macaques. The polymorphisms comprising the T:G:T haplotype (T1970, G1991, and T2327) were associated with fewer errors on a reversal learning test and greater levels of cognitive flexibility. We have previously demonstrated that the T:G:T haplotype renders lower levels of gene expression in vitro, paralleling the functionality of human 3' UTR haplotypes, as well as the short allele of 5HTTLPR found in both macaques and humans. The 3' UTR haplotypes are independent and in linkage equilibrium with the 5HTTLPR locus. Together, these data lead to the intriguing possibility that differences observed in human cognitive flexibility, whether naturally or in pathological states, may be associated with genetic variation in the serotonin transporter 3' untranslated region also.

Association between brain‐derived neurotrophic factor gene and a severe form of bipolar disorder, but no interaction with the serotonin transporter gene

Recent data suggest that brain-derived neurotrophic factor (BDNF) and the serotonergic system are involved and interact in major depressive disorder and suicidal behavior (SB). Several family and population-based studies have reported associations between the BDNF gene and serotonin-related genes, specifically the serotonin transporter (5HTT) gene, with bipolar disorder (BD) and SB. However, despite the fact that gene-by-gene interaction between BDNF and 5HTT has been demonstrated in monoamine deficiencies in animals, this kind of interaction has never been tested in humans. Our hypothesis is that some BDNF and 5HTT polymorphisms might confer increased risk for BD and SB and that both genes may interact with each other. To test this hypothesis, we genotyped the most common BDNF polymorphisms, G196A (Val66Met), A-633T and BDNF-LCPR, as well as 5HTT (5HTT-LPR), in 447 BD patients and 370 controls. We replicated the association previously reported between BDNF G196A (Val66Met) polymorphism and BD. We also observed a correlation between the number of G196 alleles and short alleles of 5HTT-LPR and the severity of SB in BD. However, we found no significant interaction between these two markers. These results suggest that BDNF G196A as well as 5HTT-LPR polymorphisms confer risk for SB in BD, but we did not observe any evidence for an interaction between them.

Genetic variation in the serotonin transporter modulates neural system‐wide response to fearful faces

A distributed, serotonergically innervated neural system comprising extrastriate cortex, amygdala and ventral prefrontal cortex is critical for identification of socially relevant emotive stimuli. The extent to which a genetic variation of serotonin transporter gene 5-HTTLPR impacts functional connectivity between the amygdala and the other components of this neural system remains little examined. In our study, neural activity was measured using event-related functional magnetic resonance imaging in 29 right-handed, white Caucasian healthy subjects as they viewed mild or prototypical fearful and neutral facial expressions. 5-HTTLPR genotype was classified as homozygous for the short allele (S/S), homozygous for the long allele (L/L) or heterozygous (S/L). S/S showed greater activity than L/L within right fusiform gyrus (FG) to prototypically fearful faces. To these fearful faces, S/S more than other genotype subgroups showed significantly greater positive functional connectivity between right amygdala and FG and between right FG and right ventrolateral prefrontal cortex (VLPFC). There was a positive association between measure of psychoticism and degree of functional connectivity between right FG and right VLPFC in response to prototypically fearful faces. Our data are the first to show that genotypic variation in 5-HTTLPR modulates both the amplitude within and the functional connectivity between different components of the visual object-processing neural system to emotionally salient stimuli. These effects may underlie the vulnerability to mood and anxiety disorders potentially triggered by socially salient, emotional cues in individuals with the S allele of 5-HTTLPR.

New Evidence for the Association of the Serotonin Transporter Gene (SLC6A4) Haplotypes, Threatening Life Events, and Depressive Phenotype

Since the first report of the significant gene-environment interaction (G x E) in depression published by Caspi et al., the literature is considerably contradictory in this field. To clarify this question, we analyzed the interaction between the serotonin transporter gene (SLC6A4) and threatening life events (TLE) on Zung Self-Rating Depression Score (ZSDS). Five markers tagging the whole SLC6A4 gene (5-HTTLPR and 4 single nucleotide polymorphisms: rs2020942, rs140700, rs3798908, rs1042173) were genotyped in 567 nonclinical individuals. Generalized linear models were used to analyze single marker associations, and likelihood ratio tests and score tests were used for haplotype analysis. Haplotype analysis revealed a significant global effect of haplotypes on ZSDS score in high TLE subgroup (p = .008). Besides the 5-HTTLPR, rs140700 tagging the middle region of the gene had significant effects. Subjects carrying the A allele of rs140700 scored lower on ZSDS independently of 5-HTTLPR carrier status. Explained variances for depressive phenotype were 1%, 4%, and 6% when 5-HTTLPR, 5-HTTLPR x TLE and 5-HTTLPR x rs140700 x TLE were included in the model, respectively. Our results demonstrate heterogeneity of individuals carrying S alleles of 5-HTTLPR in association with high TLE providing possible explanation for the inconsistency of previous studies. In addition to the promoter, the middle region of the SLC6A4 gene carries the G x G x E interaction for mood, and this new model provided a higher explained variance. We report the first evidence for the significant effects of haplotypes of the SLC6A4 gene and threatening life events on depressive phenotype.

Serotonin transporter gene and response to lithium augmentation in depression

The serotonin (5-HT) transporter gene-linked polymorphic region (5-HTTLPR) is associated with better response to selective serotonin reuptake inhibitors in Caucasian patients carrying the long (l)-allele. In contrast, augmentation of antidepressant drugs with pindolol has been shown to improve responsiveness to antidepressants in short (s)-allele carriers. Lithium augmentation is a well-established strategy for overcoming treatment resistance. In this study, the 5-HTTLPR allele variant's effect on lithium augmentation was analyzed in antidepressant-nonresponsive patients. We measured remission rates during lithium augmentation in 50 depressed patients genotyped for the 5-HTTLPR. All patients took part in phase II of the German Algorithm Project, a prospective study for the evaluation of a standardized stepwise drug treatment regimen. For statistical analysis, the Cox regression model including several clinical factors besides the 5-HTTLPR was used. Only the genotype of the 5-HTTLPR (P<0.006) showed a signficant influence on remission. Patients homozygous for the s-allele had a more favorable response compared with those heterozygous (hazard ratio=6.9; P=0.005) or homozygous for the l allele (hazard ratio=4.5; P=0.003). The findings support a differential effect of the 5-HTTLPR gene on primary treatment with antidepressants and treatment augmentation. Similar to the observations with pindolol, s/s-allele patients showed a higher benefit from lithium augmentation than did patients carrying other 5-HTTLPR genotypes. Thus, the s/s genotype might predict an individual's risk of antidepressant nonresponsiveness and sensitivity to augmentative drugs such as lithium.