Serotonin transporter gene influences the time course of improvement of "core" depressive and somatic anxiety symptoms during treatment with SSRIs for recurrent mood disorders

The short variant of the serotonin transporter gene (SERTPR) has been consistently associated with a poorer response to treatment with various selective serotonin reuptake inhibitors (SSRIs). Antidepressant response is not a unitary phenomenon, however, and we here hypothesized that the SERTPR effect could be specific to some types of symptomatology. The sample comprised 281 inpatients affected by mood disorders and treated for major depression with SSRIs. The total depressive scores for all patients were analyzed in previous reports, but symptomatologic clusters were not examined previously. The 21-item Hamilton Rating Scale for Depression (HAM-D) was administered to evaluate depressive symptoms at baseline and weekly over 6 weeks of treatment. All patients were genotyped for the SERTPR polymorphism. Compared with patients with the SERTPR l/l and l/s polymorphisms, s/s patients showed a selective and slower improvement of depressive "core" and somatic anxiety symptoms, but they did not differ from other patients regarding other symptomatologic clusters such as insomnia and motor retardation. These findings support the view that response to SSRIs is not a unitary phenomenon and that improvement of symptomatologic clusters as, at least in part, genetically driven. SERTPR may be hypothesized as concurrently participating to the activity of anatomic brain regions differentially involved in depression and somatic symptoms of anxiety; however, further studies are required to examine these complex interactions.     

Influence of SERTPR and STin2 in the serotonin transporter gene on the effect of selective serotonin reuptake inhibitors in depression: a systematic review

Large differences in clinical response to selective serotonin reuptake inhibitors (SSRIs) are observed in depressive patients with different genotypes. Quantification of these differences is needed to decide if genetic testing prior to antidepressant treatment is useful. We conducted a systematic review of the literature on the influence of polymorphisms in the serotonin transporter gene (SERTPR (or 5-HTTLPR) and STin2) on SSRI response. Studies were identified by the use of MEDLINE, EmBase and PsycINFO, references of articles, reviews and information from pharmaceutical companies. Nine studies assessing the influence of SERTPR or STin2 on treatment response were included. Outcome was expressed as the percentage of decrease in depression score (HAM-D or MADRS) or as the percentage of responders (> or =50% reduction on the depression scale). Both study methodologies and study outcomes showed large heterogeneity. Weighted mean decreases in depression score for patients with the s/s, s/l and l/l genotypes were 35.4, 46.3 and 48.0% at week 4, respectively, and 53.9, 54.6 and 48.3% at week 6. Among Caucasian patients, both mean decrease in depression score and response rate were lowest in the s/s group, while among Asian patients, results were inconsistent. Weighted response rates were 36.1% for the 10/12 genotype of the STin2 polymorphism and 80.7% for the 12/12 genotype (chi2=27.8, P<0.001) (only Asians). The available evidence points to a less favourable response to SSRI treatment among Caucasian patients with the SERTPR s/s genotype and among (Asian) patients with the STin2 10/12 genotype. In view of the scarcity and heterogeneity of the studies, however, current information is insufficiently reliable as a basis for implementing genetic testing in the diagnostic work-up of the depressive patient.     

The serotonin transporter gene and effectiveness of SSRIs

The definition of a genetic liability profile for specific antidepressant treatment will soon be available, offering considerable help in early detection of effective therapy in mood disorders. The search for genetic factors predisposing to drug response or side effects in mood disorders started only in the last few years. The efficacy of antidepressant action was associated with several polymorphisms, located on coding genes of proteins thought to be involved in the different mechanisms of action of antidepressant treatments. Among these, gene variants in sequences of serotonin pathway proteins were candidates, both for the well-known evidence of its involvement in the development of depressive symptoms and for the worldwide use of selective serotonin reuptake inhibitors as first-choice treatment of depression. A polymorphism in the promoter region of the serotonin transporter (SERTPR) was independently associated with efficacy for a range of treatments. This article reviews the pharmacogenetic studies published to date, focusing the attention on the SERTPR.     

Effects of the serotonin type 2A, 3A and 3B receptor and the serotonin transporter genes on paroxetine and fluvoxamine efficacy and adverse drug reactions in depressed Japanese patients

In this study, we tested the influence of the serotonin type 2A, 3A and 3B receptor genes (HTR2A, HTR3A, HTR3B) in addition to a polymorphism in the promoter region of the serotonin transporter (SERTPR), and investigated the different characteristics of clinical responses to paroxetine and fluvoxamine. A total of 100 Japanese patients affected by major recurrent depression were enrolled in a randomized 6-week study. The clinical response was evaluated using the Hamilton Rating Scale for Depression (HAM-D), and adverse drug reactions were assessed at each visit. Patients with the l allele of SERTPR showed a better response to SSRIs than s/s genotype carriers (p = 0.015-0.042), more significantly to fluvoxamine. The -1438G/G genotype of HTR2A was associated with a good response to SSRIs (p = 0.010-0.039), especially to fluvoxamine, and significantly with severe nausea in paroxetine-treated patients (p = 0.013). The 178C/C genotype of the HTR3A was associated with an antidepressant response (p = 0.022-0.042), and more significantly in paroxetine-treated patients (p = 0.002-0.042). These effects were independent of one another. We replicated the finding that the SERPTR polymorphism was associated with a response to SSRIs. We additionally found that HTR2A and HTR3A polymorphisms are associated with the efficacy, and the HTR2A polymorphism is also associated with adverse drug reactions. Furthermore, the effects of these polymorphisms varied from one SSRI to another and thus may depend on the characteristics of each SSRI.     

No association between dopamine D(2) and D(4) receptor gene variants and antidepressant activity of two selective serotonin reuptake inhibitors.

The possible association of the dopamine receptor D(2) (Ser 311Cys) and D(4) exon 3 (48 base pair repeat) gene variants with the antidepressant activity of selective serotonin reuptake inhibitors (SSRIs) was investigated in a sample of 364 inpatients affected by a major depressive episode treated with fluvoxamine, 300 mg/day (n=266), or paroxetine, 20-40 mg/day (n=98). The severity of depressive symptoms was assessed weekly with the Hamilton Rating Scale for Depression. Dopamine receptor D(2) (DRD2) and dopamine receptor D(4) (DRD4) allelic variants were determined in each subject by polymerase chain reaction. We observed that DRD2 and DRD4 variants were not associated with response to SSRI treatment. Possible stratification factors, such as sex, diagnosis, presence of psychotic features, depressive symptoms at baseline, paroxetine and fluvoxamine plasma levels, and pindolol augmentation did not significantly influence the observed results. The investigated DRD2 and DRD4 gene variants therefore do not seem to play a major role in the antidepressant activity of SSRIs, at least in the present sample.     

The influence of Serotonin Transporter Promoter Polymorphism (SERTPR) and other polymorphisms of the serotonin pathway on the efficacy of antidepressant treatments

The definition of a genetic liability profile for specific antidepressant treatment will soon be available offering considerable help in early detection of effective therapy in affective disorders. The search for genetic factors predisposing to drug response or side-effects in affective disorders started only in the last few years. The efficacy of antidepressant action was associated with several polymorphisms, located on coding genes of proteins thought to be involved in the different mechanisms of action of antidepressant treatments. Among these, gene variants in sequences of serotonin pathway proteins were candidate, both for the well known evidence of its involvement in the development of depressive symptomathology and for the wide-world use of selective serotonin reuptake inhibitors as first choice treatment of depression. A polymorphism in the promoter region of the serotonin transporter (SERTPR) was independently associated with efficacy for a range of treatments, other polymorphism located on the tryptophan hydroxylase gene, 5-HT2a receptor and G-protein beta 3 showed some association, while other candidate genes were not associated with treatment efficacy. Possible liability genes controlling at least to some extent both acute and long-term treatment were identified, and the further objective is to identify other candidate genes in order to define individualized treatments according to genetic profile in a future. The present paper reviews the pharmacogenetic studies published to date, focusing the attention on the serotonergic pathway.     

Antidepressant response and intolerance to SSRI is not influenced by G-protein beta3 subunit gene C825T polymorphism in Japanese major depressive patients

The G-protein β3 subunit (GNB3) gene is a key modulator of signal transduction and is a major candidate for SSRIs response. The aim of the present study is to test a possible effect of the C825T polymorphism on the antidepressant response and intolerance to selective serotonin reuptake inhibitors (SSRIs) in 146 Japanese samples with major depression treated with paroxetine or fluvoxamine for 6 weeks. The severity of depression symptom was assessed using the 21-item Hamilton Rating Scale for Depression (HAM-D) and adverse drug reactions were evaluated bi-weekly. No association with SSRIs treatment response was observed in 107 completers also including HAM-D baseline scores, SSRI type or/and 5-HTTLPR variants in the model as covariates. Furthermore, no significant association could be observed with intolerance to SSRIs in the whole subjects. The result suggests that C825T variants of GNB3 cannot play a major role as a predictor of treatment response as well as intolerance to SSRIs in Japanese patients with major depression.     

Association study of paroxetine therapeutic response with SERT gene polymorphisms in patients with major depressive disorder.

We investigated the relationships between LS promoter (SERTPR) and ls intron2 (SERTin2) genetic variants of serotonin transporter (SERT) polymorphisms with treatment response in 130 patients with major depressive disorder (MDD) treated with paroxetine (20 mg/day) for 6 weeks. To assess and evaluate therapeutic response to paroxetine all patients were rated weekly using the HAMD-17 scale. Responders were defined as those subjects with a decrease in HAMD scale by>/=50% at week 6 of treatment. Comparison of genotypes and alleles frequency of the SERTPR between responders and non-responders revealed significant differences among genotypes and overrepresentation of the S allele in the group of non-responders (P=0.0004). SERTin2-ss genotype bearing subjects showed better treatment response compared to ls and ll genotype from the fourth week of treatment (P=0.035). Statistical differences were also found in distributions of the estimated haplotypes between responders and non-responders, while subsequent analysis revealed overrepresentation of S/l haplotype (P=0.006) in the group of non-responders. SERTPR and SERTin2 were found to be in linkage disequilibrium in studied population. These findings identify genetic factors associated with paroxetine treatment response in MDD patients.     

Temperament and character in mood disorders: influence of DRD4, SERTPR, TPH and MAO-A polymorphisms

Gene variants exert a complex range of effects on human normal and abnormal behavior. We previously reported the effect of gene variants in serotoninergic and dopaminergic pathways, in a range of clinical features in mood disorders, such as symptomathology, periodicity, social adjustment and treatment response. In this paper we hypothesized that the same gene variants could influence temperamental traits in mood disorders patients. We focused on genes of the serotoninergic and dopaminergic systems (dopamine receptor D4 gene, DRD4; serotonin transporter gene, promoter region SERTPR; tryptophan hydroxylase gene, TPH; monoamine oxidase A gene, MAO-A). Two hundred and seven euthymic subjects, affected by major depressive disorder (n=73) and bipolar disorder (n=134) were assessed by the Cloninger's Temperament and Character Inventory (TCI) and typed using PCR-based analyses. Possible stratification factors such as demographic, clinical and other temperamental factors were also taken into account. We observed that homozygosity for the short SERTPR allele was associated with low novelty-seeking scores (p=0.006) and genotypes containing the DRD4 long allele were marginally associated with low harm avoidance (p=0.05). Finally, the long MAO-A allele was associated with decreased persistence scores among females (p=0.006). Our observation of a pattern of influence on temperamental dimension exerted by serotonergic and dopaminergic genes suggests that the contribution of these polymorphisms to the clinical presentation of mood disorders could be mediated by an influence on personality differences.     

Monoamine oxidase: A gene polymorphism,tryptophan hydroxylase gene polymorphism and antidepressant response to fluvoxamine in Japanese patients with major depressive disorder

Monoamine oxidase A (MAOA) and tryptophan hydroxylase (TPH) are the staple enzymes in the metabolism of serotonin (5-HT). The genetic polymorphisms of these two enzymes might individually alter the production, release, reuptake or degradation of 5-HT during the treatment of selective serotonin reuptake inhibitors (SSRIs), leading to the individual differences in the antidepressant effects of SSRIs. The authors investigated whether a functional polymorphism in the MAOA gene promoter (MAOA-VNTR) and a TPH gene polymorphism in intron 7 (TPH-A218C) were associated with the antidepressant response to fluvoxamine in 66 Japanese patients with major depressive disorder during a 6-week study with a specific dosage plan. Fifty-four patients completed the study. The present study fails to demonstrate that the genetic polymorphisms of MAOA-VNTR and TPH-A218C affect the antidepressant effect of fluvoxamine in Japanese patients with major depressive disorder.     

Cerebral perfusion response to successful treatment of depression with different serotoninergic agents

In 19 patients with major depressive disorder, effective treatment with selective serotonin reuptake inhibitors (SSRIs) or amesergide (AMSG) was associated with increased cerebral perfusion in anterior cingulate cortex (SSRI and AMSG) and in medial prefrontal cortex (AMSG). Both selective serotonin reuptake inhibitors and AMSG exert antidepressant action through the serotonin (5-HT) system as reuptake inhibitors. Amesergide differs from SSRIs in that it is also a highly selective 5-HT antagonist, which may in part account for differences in cerebral blood flow response to treatment.     

Prolactin response to d-fenfluramine in major depression before and after treatment with serotonin reuptake inhibitors.

BACKGROUND: Central serotonin dysfunction is thought to be involved in the etiology of major depression. Serotonergic challenge studies before and after treatment of depressed patients have yielded conflicting results; however, these studies have not focused on the effect of antidepressant treatment with selective serotonin reuptake inhibitors (SSRIs) on serotonergic challenge studies. METHODS: The authors studied 19 outpatients with major depressive disorder using prolactin response to d-fenfluramine as a measure of central serotonergic functioning. Testing of patients was conducted just before and right after 8 weeks of treatment with either fluoxetine (n = 10) or fluvoxamine (n = 9) as part of a randomized, double-blind treatment trial. Blood samples for prolactin were collected prior to administration of d-fenfluramine (0.5 mg/kg) and then over the next 5 hours. RESULTS: Unlike previous studies in which antidepressant treatment produced an enhanced prolactin response to fenfluramine, in this study there was no increase in prolactin response to d-fenfluramine following SSRI treatment. In fact, prolactin response to d-fenfluramine was significantly diminished after treatment with fluvoxamine but not fluoxetine. CONCLUSIONS: The implications of these findings are discussed with regard to possible mechanisms of action of SSRI treatment.     

Managing epilepsy-associated depression: Serotonin enhancers or serotonin producers?

Depression is one of the major psychiatric comorbidities having a major impact on the quality of life in people with epilepsy (PWE). Selective serotonin reuptake inhibitors (SSRIs) are considered as safest therapy for the treatment of depression in PWE. Although administration of SSRIs increases the synaptic serotonin levels, it decreases the overall serotonin synthesis in the brain. Long-term therapy with SSRIs has been reported to decrease serotonin synthesis, which may be the possible reason for lessening of their antidepressant effect over time as well as elevated seizure outcomes observed in PWE. Thus the present scenario warrants streamlined studies to explore the safety and efficacy of SSRIs as well as approaches beyond SSRIs for treatment of depression in epilepsy. In this review, we outline the approaches which may restore serotonin levels rather than a pseudo enhancement of serotonin with SSRIs. The potential of various anti-inflammatory approaches such as selective cyclooxygenase-2 inhibitors, inflammatory cytokine inhibitors, and indoleamine 2,3-dioxygenase inhibitors pertaining to their serotonin restoring effects is discussed as possible therapy for treatment of depression in epilepsy.     

Are antidepressant drugs that combine serotonergic and noradrenergic mechanisms of action more effective than the selective serotonin reuptake inhibitors in treating major depressive disorder? A meta-analysis of studies of newer agents.

BACKGROUND: Recent studies suggest that the treatment of major depressive disorder (MDD) with newer antidepressant drugs that simultaneously enhance norepinephrine and serotonin neurotransmission might result in higher response and remission rates than the selective serotonin reuptake inhibitors (SSRIs). The goal of our work was to compare response rates among patients with MDD treated with either of these two broad categories of antidepressant drugs. METHODS: Medline/Pubmed, EMBase, clinical trial registries, program syllabi from major psychiatric meetings held since 1995, and documents from relevant pharmaceutical companies were searched for double-blind, randomized trials comparing a newer serotonergic-noradrenergic antidepressant drug (venlafaxine, duloxetine, milnacipran, mirtazapine, mianserin, or moclobemide) with an SSRI for MDD. RESULTS: Ninety-three trials (n = 17,036) were combined using a random-effects model. Treatment with serotonergic + noradrenergic antidepressant drugs was more likely to result in clinical response than the SSRIs (risk ratio [RR] = 1.059; response rates 63.6% versus 59.3%; p = .003). There was no evidence for heterogeneity among studies combined (p = 1.0). Excluding each individual agent did not significantly alter the pooled RR. With the exception of duloxetine (.985), RRs for response for each individual serotonergic + noradrenergic antidepressant drug were within the 95% confidence interval of the pooled RR (1.019-1.101). CONCLUSIONS: Serotonergic-noradrenergic antidepressant drugs seem to have a modest efficacy advantage compared with SSRIs in MDD. With the Number Needed to Treat (NNT) statistic as one indicator of clinical significance, nearly 24 patients would need to be treated with dual-action antidepressant drugs instead of SSRIs in order to obtain one additional responder. This difference falls well below the mark of NNT = 10 suggested by the United Kingdom's National Institute of Clinical Excellence but nonetheless might be of public health relevance given the large number of depressed patients treated with SSRI /serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressant drugs. Further research is needed to examine whether larger differences between classes of antidepressant drugs might exist in specific MDD sub-populations or for specific MDD symptoms.     

Role of COMT, 5-HT(1A) , and SERT genetic polymorphisms on antidepressant response to Transcranial Magnetic Stimulation

Background: Transcranial Magnetic Stimulation (TMS) is an effective technique in the treatment of depression, specifically in drug‐resistant patients. However, there is little data available on the influence of genetic variables on TMS response. Methods: We analyzed the role of three genetic polymorphisms that affected the antidepressant response: serotonin transporter promoter region (SERTPR) polymorphism, 5‐HT_1A serotonergic receptor promoter region polymorphism (rs6295), and the coding region of COMT gene polymorphism (rs4680). Ninety patients with a major depressive drug‐resistant episode due to a Major Depressive Disorder or to a Bipolar Disorder were included in our study. Patients underwent high frequency TMS, focused on the left prefrontal cortex, for 2 weeks. At study completion, the response rate was 45.5%. Effects of gene polymorphisms on clinical improvement were analyzed with an analysis of variance with each gene (SERTPR, 5‐HT_1A, and COMT) as factors and the Hamilton Rating Scale for Depression variation from baseline to the end of the treatment as a dependent variable. Results: We found a significant model in which three factors were not significant (diagnosis, COMT, and SERTPR), whereas factor 5‐HT_1A showed a significant influence on the outcome, with patients with C/C genotype showing a greater improvement than G/G and C/G and no difference between G/G and C/G. Conclusion: According to our data, 5‐HT_1A polymorphism may play a role in influencing TMS response. The effect of COMT and SERTPR did not reach statistical significance. The analysis of these and other candidate genes in larger samples could help explain genetic influence on TMS response. Depression and Anxiety, 2011. © 2011 Wiley‐Liss, Inc.     

Candidate genes for antidepressant response to selective serotonin reuptake inhibitors

Selective serotonin reuptake inhibitors (SSRIs) can safely and successfully treat major depression, although a substantial number of patients benefit only partially or not at all from treatment. Genetic polymorphisms may play a major role in determining the response to SSRI treatment. Nonetheless, it is likely that efficacy is determined by multiple genes, with individual genetic polymorphisms having a limited effect size. Initial studies have identified the promoter polymorphism in the gene coding for the serotonin reuptake transporter as moderating efficacy for several SSRIs. The goal of this review is to suggest additional plausible polymorphisms that may be involved in antidepressant efficacy. These include genes affecting intracellular transductional cascades; neuronal growth factors; stress-related hormones, such as corticotropin-releasing hormone and glucocorticoid receptors; ion channels and synaptic efficacy; and adaptations of monoaminergic pathways. Association analyses to examine these candidate genes may facilitate identification of patients for targeted alternative therapies. Determining which genes are involved may also assist in identifying future, novel treatments.     

Association between the tryptophan hydroxylase-1 gene A218C polymorphism and citalopram antidepressant response in a Korean population

Tryptophan hydroxylase-1 (TPH1) is the rate-limiting enzyme in serotonin biosynthesis, and selective serotonin reuptake inhibitors (SSRIs) exert their activity enhancing the general serotonergic tone. Citalopram is the most selective SSRI, with little or no affinity for a variety of receptor types. The goal of this study was to investigate whether the A218C polymorphism of the TPH1 gene is associated with the citalopram antidepressant response in subjects with major depressive disorder (MDD). All of the patients were evaluated using the 21-item Hamilton Depression Rating Scale before beginning and after 8 weeks of citalopram treatment. Genotyping was performed with the polymerase chain reaction. The remission rate to citalopram treatment was worse in MDD subjects with the TPH1 A/A and A/C genotypes than in those with the TPH1 C/C genotype. Our results suggest that the A218C polymorphism of the TPH1 gene serves as a modulator of antidepressant activity, especially in terms of treatment remission.     

Escitalopram for major depression in Parkinson's disease: an open-label, flexible-dosage study

Depression and antidepressant use are common in Parkinson's disease, but the benefit of selective serotonin reuptake inhibitor (SSRI) treatment in this population has not been established. The authors treated 14 Parkinson's disease patients with major depression with escitalopram in an open-label study. Although treatment was well tolerated and correlated with a significant decrease in Inventory of Depressive Symptomatology score, response and remission rates were only 21% and 14%, respectively. However, half of the subjects met Clinical Global Impression-Improvement criteria for response. In Parkinson's disease, either SSRIs may have limited antidepressant effects, or the use of existing depression diagnostic and rating instruments may be problematic.