Effects of the serotonin transporter gene promoter polymorphism on mirtazapine and paroxetine efficacy and adverse events in geriatric major depression

BACKGROUND: 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. OBJECTIVE: 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. DESIGN: Double-blind, randomized 8-week study. SETTING: Eighteen academic and private outpatient clinics. PATIENTS: We evaluated 246 cognitively intact patients 65 years or older with major depression. INTERVENTIONS: 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 genotypes. RESULTS: 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. CONCLUSIONS: 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.     

Influence of the serotonin transporter promoter gene polymorphism on susceptibility to posttraumatic stress disorder

Posttraumatic stress disorder (PTSD) is a prevalent anxiety disorder marked by behavioral, physiologic, and hormonal alterations. The etiology of PTSD is unknown, although exposure to a traumatic event constitutes a necessary, but not sufficient, factor. Serotonergic dysfunction has been implicated in PTSD. The present study examined the possible association between the serotonin-transporter-linked polymorphic region (SERTPR) and PTSD. The genotype and allele frequencies of the SERTPR were analyzed in 100 PTSD patients and 197 unrelated healthy controls using a case-control design. The frequency of the s/s genotype was significantly higher in PTSD patients than in normal controls. These findings suggest that the SERTPR s/s genotype is one of the genetic factors for the susceptibility to PTSD. Further investigations are required into the influence of gene polymorphisms on the biological mechanisms of PTSD, its clinical expression, and its response to treatment.     

5-羟色胺转运体基因与注意缺陷多动障碍及其相关症状的关联分析

目的　探讨5- 羟色胺转运体( 5 -HTT)基因启动子区多态性与注意缺陷多动障碍(ADHD)及其相关症状的关系。方法　抽取1 39例ADHD患儿及1 1 5名正常对照,用Achenbach儿童行为调查表(CBCL)来评定患者的临床症状;采用聚合酶链式反应(PCR)、聚丙烯酰胺凝胶电泳结合银染技术,检测ADHD患者和对照组基因型和等位基因的频率。结果　患者组5- HTT启动子区多态性( 5- HTTLPR)的基因型和等位基因的频率与对照组相比无显著性差异(P >0. 0 5) ;但发现S/S基因型个体社会退缩、躯体主诉两行为分量表评分高,S/S基因型个体与S/L +L/L基因型个体间社会退缩、躯体主诉两分量表分有显著性差异(P <0 . 0 5)。结论　本研究结果不支持5- HTTL- PR与ADHD存在关联,但ADHD的某些内化性症状与5 -HTTLPR可能存在关联。     

A functional serotonin transporter promoter gene polymorphism increases ADHD symptoms in delinquents: interaction with adverse childhood environment

Although attention-deficit/hyperactivity disorder (ADHD) is highly heritable, environmental conditions play an important role in its manifestation during childhood development. Here, we report the results of an investigation on the interaction of adverse childhood environment with a functional polymorphism of the serotonin transporter promoter gene (5-HTTLPR) and its impact on ADHD psychopathology in young adult delinquents. Standardized instruments were used to assess childhood and current ADHD and adverse childhood environment in 184 male delinquents. Each subject was genotyped for 5-HTTLPR long (L) and small (S) alleles. Logistic regression analysis revealed independent effects of high childhood environmental adversity and the 5-HTTLPR LL-genotype on self-reported childhood ADHD and on persistent ADHD. In addition, a significant gene by environment interaction was found, indicating that carriers of at least one 5-HTTLPR short allele are more sensitive to childhood environment adversity than carriers of the LL-genotype. The results support prior findings of association between ADHD and 5-HTTLPR LL-genotype and adverse childhood environment, and they underline the need for further investigation of gene by environment interaction with respect to ADHD.     

The interaction of serotonin transporter gene polymorphisms and early adverse life events on vulnerability for major depression

Considerable literature supports the hypothesis of dysfunction in central nervous system serotonergic circuits in the pathophysiology of mood disorders, specifically major depression. Since the development of the selective serotonin (5-HT) reuptake inhibitors, a putative role for the 5-HT transporter (SERT) in the etiology of depression has been explored. The discovery of a functional SERT polymorphism has provided a novel tool to further scrutinize the role of serotonergic neurons in depression. This article reviews the burgeoning evidence of an interaction between early life stress and an SERT polymorphism on vulnerability to depression.     

5-羟色胺转运体启动子区基因多态性与强迫症的关联分析

目的:探索汉族人群中的5-羟色胺转运体启动子区(5-HTTLPR)基因多态性与强迫症的发病关系.方法:对强迫症患者(强迫症组)和正常对照者(对照组)分别采用聚合酶链反应扩增片断长度多态技术测定基因型.结果:强迫症组与对照组5-HTTLPR的基因型频率无显著性差异;两组的等位基因频率有显著性差异.L等位基因与强迫症呈正关联(OR=1.929,P＜0.05).结论:5-HTTLPR基因多态性的L等位基因与强迫症相关联,是强迫症的危险因子.     

强迫症与5-羟色胺转运体基因多态的关联分析

目的 探索汉族人群中5-羟色胺转运体SLC6A4基因多态与强迫症发病的关系。方法采用聚合酶链反应扩增片段长度多态技术测定120例强迫症患者(强迫症组)和130名健康人(对照组)的SLC6A4基因型。结果 强迫症组SLC6A4第2内含子及启动子的基因型多态分布与对照组间的差异有显著性(X2=6.70,P=0.035;X2=6.35,P=0.042);第2内含子等位基因频数分布与对照组之间的差异有非常显著性(X2=7.54,P=0.006);第2内含子的等位基因10,12/10基因型和启动子的L/L基因型与强迫症存在显著正关联[比数比(OR)值分别为2.24,2.12和3.57,P<0.05];强迫症组及对照组内不同性别间基因型分布的差异均无显著性(P>0.05)。结论 在汉族人群中SLC6A4基因可能与强迫症存在遗传关联,第2内含子的等位基因10和12/10基因型、启动子的L/L基因型可能是强迫症的风险因子。     

Association of the serotonin transporter promoter regulatory region polymorphism and obsessive-compulsive disorder.

Although modulation of symptoms of obsessive-compulsive disorder (OCD) by serotonergic agents is well established, it is unclear whether an abnormality in the central serotonergic system is involved in its etiology. The serotonin (5-HT) transporter (5-HTT), which is the key modulator of serotonergic neurotransmission, is the target for serotonin reuptake inhibiting drugs (SRIs) that are uniquely effective in the treatment of OCD. In this preliminary study we report an association of a functional polymorphism in the 5-HTT 5' regulatory-region and OCD. Seventy-five OCD Caucasian patients and 397 ethnically-matched individuals from a non-patient control group were genotyped for the 5-HTTLPR. Population-based association analysis revealed that patients with OCD were more likely to carry two copies of the long allele (l) as compared to controls (46.7% vs 32.3%: chi2 = 5.19, P = 0.023). This finding replicates a recent family-based study of this polymorphism in OCD, and thus indicates that the 5-HTTLPR may be associated with susceptibility to OCD.     

Association of a triallelic serotonin transporter gene promoter region (5-HTTLPR) polymorphism with stressful life events and severity of depression

OBJECTIVE: The lower expressing allele of the serotonin transporter gene 5' promoter region (5-HTTLPR) polymorphism is reported to be associated with susceptibility to depression and suicidality in response to stressful life events. The authors examined the relationship of a triallelic 5-HTTLPR polymorphism to stressful life events, severity of major depression, and suicidality. METHOD: Mood disorder subjects (N=191) and healthy volunteers (N=125), all Caucasian subjects of European origin, were genotyped for the triallelic 5-HTTLPR polymorphism (higher expressing allele: L(A); lower expressing alleles: L(G), S). All subjects underwent structured clinical interviews to determine DSM-IV diagnoses, ratings of psychopathology, stressful life events, developmental history, and suicidal behavior. CSF 5-HIAA was assayed in a subgroup of subjects. RESULTS: Lower expressing alleles independently predicted greater depression severity and predicted greater severity of major depression with moderate to severe life events compared with the higher expressing L(A) allele. No associations with suicidal behavior and CSF 5-HIAA were found. CONCLUSIONS: Lower expressing transporter alleles, directly and by increasing the impact of stressful life events on severity, explain 31% of the variance in major depression severity. The biological phenotype responsible for these effects remains to be elucidated.     

5-羟色胺转运体基因功能性多态与强迫症的关联研究

目的 探讨中国汉族人群中5-羟色胺转运体基因启动子区域多态(5-HTTLPR)功能性3等位基因L_A、L_G和S与强迫症(OCD)的关系.方法 采用聚合酶链反应-限制性片段长度多态技术测定138例OCD患者(OCD组)和199名健康人(对照组)的5-HTTLPR功能性3等位基因多态性.结果 OCD组5-HTTLPR功能性基因型及等位基因频率与对照组间的差异有统计学意义(χ~2=8.396,P＜0.05;χ~2=8.483,P＜0.01);L_A/L_A因型和L_A等位基因与OCD存在显著正关联[比值比分别为3.361(P＜0.05)和1.771(P＜0.01)].结论在中国汉族人群中5-HTTLPR功能性3等位基因可能与OCD存在遗传关联,L_A/L_A基因型和等位基因L_A可能是OCD的风险因子.     

The effect of serotonin transporter gene promoter polymorphism on adolescent and adult ADHD symptoms and educational attainment: A longitudinal study

IntroductionThe purpose of this longitudinal study was to investigate the relationship between the 5-HTTLPR genotype, symptoms of ADHD in adolescence and adulthood, and educational attainment in a population representative sample. Neuroticism, depressive symptoms and general mental abilities were controlled for as possible confounding factors.MethodsADHD symptoms were reported at age 15 and 18 by teachers using the Hyperactivity Scale of af Klinteberg and SNAP-IV, and self-reported at age 25 using the ASRS. Data about education were reported at age 25.ResultsAt age 15, subjects with the l/l genotype had more concentration difficulties compared to s-allele carriers, and they also had more inattention symptoms according to SNAP-IV at age 18. These results were not altered by taking neuroticism or depressive symptoms into account. No 5-HTTLPR genotype effect on self-reported ADHD symptoms at age 25 was found. Inattention symptoms in adolescence were associated with lower education in young adulthood. The proportion of subjects with higher education at age 25 was significantly larger among s/s genotype compared to the l/l or s/l genotype.ConclusionsThe l/l genotype of the 5-HTTLPR is associated with inattentive symptoms during adolescence in the general population, and increases the likelihood of inferior educational level in young adulthood.     

Meta-analysis of the association of serotonin transporter gene polymorphism with obsessive-compulsive disorder

Evidence has supported a role for serotonin system dysfunction in the pathogenesis of the obsessive-compulsive disorder (OCD). Many studies examined the association between OCD and a functional polymorphism of the serotonin transporter gene promoter (5-HTTLPR) but yielded inconsistent results. Current study aimed to determine conclusively whether there is an association by using a meta-analytic method. Over 3000 subjects from 13 independent case-control association studies were included in the analysis. By using random effects model, data from these studies were pooled to compare the genotypes and allelic distribution of the 5-HTTLPR polymorphism between OCD patients and control subjects. In the analysis, OCD was found to be associated with the SS homozygous genotype (OR=1.21, p=0.04), but was inversely associated with the LS heterozygous genotype (OR=0.79, p=0.03). No association with the LL homozygous genotype or the allelic distribution was found. These results suggest that variations of the serotonin transporter gene influence the risk of OCD, but their functional roles in the pathogenesis of OCD need to be elucidated.     

The serotonin transporter gene polymorphism (5-HTTLPR) and affective symptoms among women diagnosed with borderline personality disorder

Gene variants of the serotonin transporter have been associated with vulnerability to affective disorders. In particular, the presence of one or two copies of the short (s) allele of the 5-HTTLPR polymorphism has been associated with reduced serotonin transporter expression and function, and vulnerability to affective disorders. To test for an association between variants of the serotonin transporter gene polymorphism (5-HTTLPR) and relevant clinical features of borderline personality disorder (BPD), a psychiatric disorder with symptoms characteristic for serotonin dysfunction, 77 women with BPD were genotyped in the 5-HTTLPR polymorphism. They rated their subjective experience of borderline-specific, depressive, anxious and obsessive-compulsive symptoms, and were interviewed about lifetime incidence of suicide attempts and self-harming acts. Carriers of two s alleles of the 5-HTTLPR reported more symptoms of borderline, depression, anxiety and obsessive-compulsive behaviours, but not of suicidal and self-injury behaviour, compared to carriers of a long (l) allele. This indicates that the 5-HTTLPR ss homozygous genotype might influence serotonin function affecting susceptibility to both borderline-specific, depressive, anxious and obsessive-compulsive symptoms in BPD, and leading to a more severe symptomatology related to these clinical features. Further, this suggests that 5-HTT gene variants may not be as influential on suicidal and self-injury behaviour in BPD.     

No evidence for in vivo regulation of midbrain serotonin transporter availability by serotonin transporter promoter gene polymorphism.

BACKGROUND: A polymorphism in the serotonin transporter promoter gene region (5-HTTLPR) has been shown to influence the quantity of serotonin transporter expressed in human cell lines: the 5-HTTLPR short allele (s) has been associated with reduced 5-HTT expression when compared to cells carrying the 5-HTTLPR long allele (l). We performed a single photon emission computed tomography (SPECT) study using the ligand [(123)I]-2-beta-carbomethoxy-3-beta-(4-iodophenyl)tropane ([(123)I]-beta-CIT) to measure 5-HTT availability in 16 healthy subjects genotyped for 5-HTTLPR. METHODS: SPECT scans were performed 24 hours after tracer injection, regions of interest anatomically corresponding to the thalamus-hypothalamus and mesencephalon-pons areas were compared to the binding in the cerebellum, representing the nondisplaceable [(123)I]-beta-CIT-binding (results expressed as target activity minus cerebellum activity/cerebellum activity). DNA from peripheral nuclear blood cells was genotyped for 5-HTTLPR using standard polymerase chain reaction methods. RESULTS: Specific binding ratios in the thalamus-hypothalamus were 2.65 +/- 0.4 in subjects with the l/l genotype (n = 3), 2.76 +/- 0.5 in subjects with the l/s genotype (n = 9), and 2.77 +/- 0.4 in subjects with the s/s genotype (n = 4). Binding ratios in the mesencephalon-pons were 1.43 +/- 0.3 (l/l; n = 3), 1.37 +/- 0.3 (l/s; n = 9), and 1.28 +/- 0.3 (s/s; n = 4). None of these differences was statistically significant. CONCLUSIONS: Our data provide no evidence for in vivo functional regulation of 5-HTT availability by 5-HTTLPR in the thalamus-hypothalamus and mesencephalon-pons of healthy subjects.     

Association analysis of serotonin transporter promoter gene polymorphism with ADHD and related symptomatology

Attention deficit hyperactivity disorder (ADHD) is one of the most common childhood behavioral disorders. Genetic factors contribute to the underlying liability to develop attention deficit hyperactivity disorder. Several investigations have reported associations between ADHD and serotonin transporter promoter polymorphisms, but the results have been inconsistent. The present study did not find significant association between ADHD and serotonin transporter promoter polymorphisms, but did find an effect of serotonin transporter promoter polymorphisms on some ADHD symptomatology. Patients homozygous for the short allele showed more Withdrawn or Somatic complaint scores than subjects with the long allele.     

Association study of the serotonin transporter promoter polymorphism and mirtazapine antidepressant response in major depressive disorder

Modulations of serotonergic and noradrenergic systems are thought to be critical to the therapeutic effect of most antidepressants, and their efficacies have been shown to depend on a functional polymorphism within the promoter region of the serotonin transporter gene (5-HTTLPR). Mirtazapine has a dual-action profile, combining the enhancement of the noradrenergic neurotransmitter system with specific actions on particular serotonergic receptor subtypes. The goal of this study was to elucidate whether the 5-HTTLPR polymorphism is associated with the mirtazapine antidepressant response in subjects with major depressive disorder (MDD). One hundred and one MDD patients were evaluated during 4 weeks of mirtazapine treatment. The severity of depression was assessed with the 21-item Hamilton Depression Rating scale, and the 5-HTTLPR genotypes in the patients were determined using the polymerase chain reaction. Our results showed that responses at the 2nd and 4th weeks were significantly better for the s/s genotype of the 5-HTTLPR polymorphism than for l-allele carriers. These results support our hypothesis that the response to noradrenergic and specific serotonergic antidepressants is significantly associated with the 5-HTTLPR polymorphism.     

Serotonin transporter gene promoter polymorphism affects the severity of binge eating in general population

Objective

The s-allele of the 5-HTTLPR has been suggested to lead to the development of less efficient and less flexible 5-HT system and has been associated to different forms of psychopathology. It has also been shown that alterations in serotonergic activity contribute to the pathophysiology of binge eating but it is not clear which changes in 5-HT function observed in eating disorder patients represent trait vs state effect. We investigated the association between the 5-HTTLPR and binge eating in a population-representative sample of women, and tested whether the 5-HTTLPR genotype influences the severity of binge eating.

Methods

The sample was based on women participating in the third wave of the Estonian Children Personality, Behaviour and Health Study. EDI-2 subscales – drive for thinness and bulimia – were used to assess eating behaviour and attitudes. Barratt Impulsiveness Scale (BIS-11) and State and Trait Anxiety Inventory (STAI) were used to measure impulsivity and anxiety. Participants were genotyped for the 5-HTTLPR.

Results

There was no 5-HTTLPR genotype effect on binge eating even after the covarying effect of impulsivity and anxiety was controlled for. However, women prone to binge eating and carrying the s-allele showed significantly higher levels of bulimia scores, and among them, women with s/s genotype had also higher levels of state anxiety and tendency for higher impulsivity.

Conclusions

While the 5-HTTLPR genotype does not predict symptoms of eating disorder in general population, the s-allele, and especially the s/s genotype increases the risk for affective instability and symptom severity.     

5-羟色胺转运体基因启动子区域多态性与汉族强迫症的关联分析

目的探讨5-羟色胺转运体（Serotonin transporter,5-HTT）基因SLC6A4（solute car-rier family6,member4）启动子区域上44个碱基对插入/缺失多态性与汉族强迫症的关系,研究强迫症病理生理机制。方法将符合《疾病及有关健康问题的国际分类》（第10版,ICD-10）诊断标准的23例强迫症患者,及其父母纳入研究。用PCR法检测判定各自的基因型,用传递不平衡检测（transmission disequilibriumtest,TDT）及单体型相对风险检测（haplotype-based haplotype relative risk,HHRR）测其等位基因的传递是否平衡。结果在所收23个核心家系中,共有24个父母为杂和基因型,在24个杂合子父母中,13个传递了‘l’等位基因,11个传递了‘s’等位基因,未发现有传递不平衡存在（χ^2 DT=0.167,P〉0.05;χ^2HRR=0.820,P〉0.05）。结论5-羟色胺转运体基因启动子区域多态性与中国汉族强迫症可能不存在关联。