Influence of tryptophan hydroxylase and serotonin transporter genes on fluvoxamine antidepressant activity

Serretti, Alessandro; Zanardi, Raffaella; Rossini, David; Cusin, Cristina; Lilli, Roberta; Smeraldi, Enrico

doi:10.1038/sj.mp.4000876

Cited by 154 publications

(104 citation statements)

References 57 publications

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“…The most consistent findings have been of associations between antidepressant treatment response with the insert/delete polymorphism of the upstream regulatory region of the serotonin transporter gene. [39][40][41][42][43][44] Other genes shown to be associated with antidepressant treatment response include tryptophan hydroxylase 45,46 and the serotonin 2 A receptor. 47 Antidepressants act on monoaminergic systems with pharmacological effects that are rapid and biochemically evident within hours of initial drug administration.…”

Section: Discussionmentioning

confidence: 99%

Association of a corticotropin-releasing hormone receptor 1 haplotype and antidepressant treatment response in Mexican-Americans

et al. 2004

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There are well-replicated, independent lines of evidence supporting a role for corticotropinreleasing hormone (CRH) in the pathophysiology of depression. CRH receptor 1 (CRHR1), which we first mapped in the brain in 1994, has been implicated in the treatment of depression and anxiety. We studied the association of CRHR1 genotypes with the phenotype of antidepressant treatment response in 80 depressed Mexican-Americans in Los Angeles who completed a prospective randomized, placebo lead-in, double-blind treatment of fluoxetine or desipramine, with active treatment for 8 weeks. Subjects were included into the study if they had a diagnosis of depression without other confounding medical or psychiatric diagnoses or treatments. All patients were followed weekly and assessed for changes in the Hamilton rating scales for anxiety (HAM-A) and depression (HAM-D). Inclusion criteria in the study included a HAM-D of 18 or higher. Because CRHR1 affects both depression and anxiety. Patients were classified into a high-anxiety (HA) group if their HAM-A score was 18 or higher and in a low-anxiety (LA) group if their HAM-A score was less than 18. Utilizing the haplotype-tag single-nucleotide polymorphisms rs1876828, rs242939 and rs242941, we tested for haplotypic association between CRHR1 and 8-week response to daily antidepressant treatment. In the HA group (n ¼ 54), homozygosity for the GAG haplotype was associated with a relative 70% greater reduction in HAM-A scores compared to heterozygous (63.174.5 vs 37.176.9%, respectively, P ¼ 0.002). For HAM-D, GAG haplotype homozygosity was associated with a 31% greater reduction in scores after treatment compared to heterozygous (67.374.3 vs 51.276.0%, respectively, P ¼ 0.03). In those with loweranxiety levels at screening, there were no associations between CRHR1 genotype and percent change in HAM-A or HAM-D. These findings of increased response to antidepressants in highly anxious patients homozygous for the GAG haplotype of CRHR1 need to be independently validated and replicated. Such work would support the hypotheses that response to antidepressant treatment is heterogeneous and that the CRHR1 gene and possibly other genes in stress-inflammatory pathways are involved in response to antidepressant treatment. These findings also suggest that variations in the CRHR1 gene may affect response to CRHR1 agonists or antagonists. All data are deposited in www.pharmgkb. Keywords: corticotropin-releasing hormone; corticotropin-releasing hormone receptor; MexicanAmerican; Hispanic; depression; anxiety Major depression is a common and complex disorder of gene-environment interactions. 1 The specific genetic substrates and precipitating environmental factors have not yet been elucidated. The disorder affects 10% of males and 20% of females and has a point prevalence of 3%. Its cost to the US economy exceeds 100 billion dollars per year. 2 Over 20 drugs are approved by the US Food and Drug Administration for treatment of depression, each one with efficacy of approximately 60%. Various subgroups ...

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Section: Discussionmentioning

confidence: 99%

Association of a corticotropin-releasing hormone receptor 1 haplotype and antidepressant treatment response in Mexican-Americans

et al. 2004

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“…Several studies have demonstrated that the 5-HTT gene polymorphism plays a role in the antidepressant response. [3][4][5][6][7] In addition, Mundo et al 8 reported a significant association between the 5-HTTLPR and AIM in bipolar patients treated with proserotonergic compounds. However, the interpretation of this study was limited by the absence of a consensus definition of AIM.…”

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confidence: 99%

Antidepressant-induced mania, rapid cycling and the serotonin transporter gene polymorphism

et al. 2003

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The genes involved in the serotonin system are major candidates in association studies on affective disorders and responses to antidepressants. We studied a functional polymorphism of the serotonin transporter (5-HTT) gene (a 44 bp insertion/deletion in the 5-HTT-linked polymorphic region (5-HTTLPR)) and lifetime history of antidepressant-induced mania (AIM) in a population of 305 patients with bipolar affective disorder. AIM was defined using a broad definition and a restrictive definition. No association was found between the 's' allele of the 5-HTTLPR and AIM for either definition. However, we found an association between the 5-HTTLPR and lifetime history of rapid cycling in a subsample of patients (for allele and genotype distributions: exact probability, p ¼ 0.0009 and w 2 ¼ 9.4; df ¼ 1; p ¼ 0.002, respectively). These results may help to explain the conflicting association results obtained with the 5-HTT gene polymorphism, in particular with AIM. Indeed, the precise phenotype associated with the 5-HTT gene is unclear. The association between the 's' allele and rapid cycling may provide further evidence for an association between the 5-HTTLPR 's' allele and a pattern of affective instability.

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“…15 Moreover, we reported a worse response for the 5-HTTLPR*s/s subjects to antidepressant treatments. [34][35][36][37][38] We may therefore hypothesize that a given genetic predisposition (5-HTTLPR*s) may confer susceptibility to anxiety features and a worse antidepressant response in subjects affected by mood disorder. Abnormalities in the serotonin transporter function may in fact confer only a small susceptibility to state conditions, because an adaptatory mechanism may partially compensate, while the dramatic alterations of serotonin turnover observed during antidepressant treatment may evidence partial transporter abnormalities, that lead to a worse antidepressant response.…”

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Serotonin transporter gene (5-HTTLPR) and major psychoses

et al. 2002

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Serotoninergic neurotransmitter systems have been implicated in the pathogenesis of major psychoses. A functional polymorphism (5-HTTLPR) in the upstream regulatory region of the gene (SLC6A4) has been associated with a number of psychiatric disturbances, but conflicting replication followed. The aim of this study was to investigate the possibility that the 5-HTTLPR might be associated with major psychoses. One thousand, eight hundred and twenty inpatients (789 bipolars, 667 major depressives, 66 delusionals, 261 schizophrenics, 37 psychotics not otherwise specified-NOS) and 457 control subjects were included in this study. A subsample of 1235 patients (523 bipolars, 359 major depressives, 259 schizophrenics, 66 delusionals, 28 psychotic NOS) were evaluated for lifetime psychotic symptomatology using the Operational Criteria for Psychotic illness (OPCRIT) checklist. The subjects were also typed for 5-HTTLPR variants using PCR techniques. 5-HTTLPR allele frequencies were not significantly different between controls and bipolars, major depressives, schizophrenics, delusionals and psychotic NOS; genotype analysis also did not show any association. The analysis of symptomatology did not show significant differences. Consideration of possible stratification factors such as sex and age of onset did not significantly influence results. 5-HTTLPR variants are not therefore a liability factor for major psychoses or for major psychoses symptomatology. Molecular Psychiatry ( The serotonin transporter is the major determinant of serotonin inactivation following release at synapses and it is the site of action of most antidepressants. The gene coding for the serotonin transporter (SLC6A4) has been therefore proposed as a possible candidate for involvement in the pathogenesis of major psychoses. The primary structure of the serotonin transporter gene did not prove to be associated with the diagnosis of mood disorders, 1 however, a polymorphic region containing a 17-bp variable number of tandem repeat (VNTR) in the second intron was associated with major depressive disorder 2-4 and a functional polymorphism in the upstream regulatory region of the gene has been associated with both major depressive and bipolar disorders, 5-7 although subsequent studies did not replicate these results. [8][9][10][11][12] The polymorphism in the upstream is a 44-bp deletion/insertion (5-HTTLPR) located exactly at the 5Ј-flanking regulatory region of the serotonin transporter gene on chromosome 17q11.2. In vitro studies evidenced that the basal activity of the long (l) variant was more than twice that of the short (s) form of the 5-HTTLPR, suggesting that serotonin transporter gene transcription is modulated by variants of the 5-HTTLPR with the s allele corresponding to low serotonin uptake activity. 13 The gene also proved to be associated or showed conflicting evidence with a number of other conditions, like anxiety-related traits in normals and in depressed patients, seasonal affective disorder, anxiety disorders, autism, severe alcoholism, sui...

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Influence of tryptophan hydroxylase and serotonin transporter genes on fluvoxamine antidepressant activity

Cited by 154 publications

References 57 publications

Association of a corticotropin-releasing hormone receptor 1 haplotype and antidepressant treatment response in Mexican-Americans

Association of a corticotropin-releasing hormone receptor 1 haplotype and antidepressant treatment response in Mexican-Americans

Antidepressant-induced mania, rapid cycling and the serotonin transporter gene polymorphism

Serotonin transporter gene (5-HTTLPR) and major psychoses

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