Progress in Neuro-Psychopharmacology and Biological Psychiatry
Influence of the serotonin transporter gene-linked polymorphic region on the antidepressant response to fluvoxamine in Japanese depressed patients
Introduction
There is considerable evidence supporting the hypothesis that alterations in the serotonergic neuronal function are involved in the pathophysiology of depression (Owens and Nemeroff, 1994). Serotonin (5-hydroxytryptamine: 5-HT) transporter (5-HTT) plays a critical role in the termination of 5-HT neurotransmission by sodium-dependent uptake into the presynaptic neuron (Rudnick and Clark, 1993). Heils et al. (1996) reported the long (l) and short (s) (44 bp insertion/deletion) variants of the 5-HTT gene-linked polymorphic region (5-HTTLPR). Several investigators have suggested that they are associated with the susceptibility of affective disorders Collier et al., 1996, Furlong et al., 1998, but conflicting results have also been reported Ewald et al., 1998, Ohara et al., 1998. The polymorphism of the 5-HTT gene seems to be associated not only with the susceptibility of affective disorders but also with the treatment response to selective serotonin reuptake inhibitors (SSRIs), because they are thought to exert their effects through binding to 5-HTT and inhibiting 5-HT reuptake.
Zanardi et al. (2000) reported that patients with major depressive disorder who are homozygous for the s variant of the 5-HTTLPR had a significantly poorer response to treatment using paroxetine than others. The frequencies of the s and l alleles are approximately 79% and 21% among Japanese, while 42% and 58% among Caucasians, respectively (Kunugi et al., 1997). If the allelic variation of 5-HTTLPR can be a predictor of an antidepressant response, the antidepressant effect of SSRIs can be not as good in Japanese as in Caucasians. To clarify this issue, the authors first investigated whether the allelic variation of 5-HTTLPR was associated with the antidepressant response to fluvoxamine in Japanese depressed patients. The authors selected fluvoxamine because it has a higher selectivity than fluoxetine and paroxetine for blocking the reuptake of 5-HT (Richelson, 1996).
Section snippets
Subjects and treatment
Sixty-six patients meeting the DSM-IV (American Psychiatric Association, 1994) diagnosis of major depressive disorder, whose score of Montgomery and Åsberg (1979) Depression Rating Scale (MADRS) was more than 20 points, were included in this study. They had no severe medical diseases and other Axis I or Axis II disorders. The patients had to be between 20 and 69 years old and free from psychotropic drugs at least 14 days before their entry into the present study. All patients provided informed
Patient characteristics
Among 66 patients, four patients could not end the 6-week study because of gastrointestinal symptoms such as nausea and vomiting. Five patients had no complaints and stopped visiting our hospital. Fifty-seven patients ended the 6-week study. Three of the patients in the 6-week study were excluded from the present study because at least one of their duplicate plasma samples showed 0 ng/ml of the fluvoxamine level and their compliance was considered to be extremely poor. Subjects who completed
Discussion
The present study showed that fluvoxamine could be more effective in depressive patients carrying the s allele than in ones carrying the l allele. Kim et al. (2000) reported that s/s patients with major depressive disorder showed better response than other groups in Korean patients. Their results were similar to ours in part, but their study had methodological problems. They used two SSRIs (fluoxetine and paroxetine), and their doses were not protocolized. They did not examine the plasma levels
Conclusions
The present study suggests that fluvoxamine is not less effective in depressive patients carrying the s allele than in ones carrying the l allele and it is not less effective in Japanese than in Caucasians. It is difficult to explain the mechanism underlying this racial difference of the antidepressant response. Further studies should be needed to clarify whether the 5-HTTLPR can be a predictor of the antidepressant effect of SSRIs.
Acknowledgements
This study was supported in part by a grant from the Japan Research Foundation for Clinical Pharmacology.
References (20)
- et al.
A functional variant of the serotonin transporter gene in families with bipolar affective disorder
J. Affective Disord.
(1998) - et al.
Expression of serotonin transporter mRNA in human brainstem raphe nuclei
Neuropsychopharmacology
(1996) - et al.
Functional polymorphism in the serotonin transporter promoter at the SLC6A4 locus and mood disorders
Biol. Psychiatry
(1998) - et al.
Allelic variation in the serotonin transporter promoter affects onset of paroxetine treatment response in late-life depression
Neuropsychopharmacology
(2000) - et al.
From synapse to vesicle: the reuptake and storage of biogenic amine neurotransmitters
Biochim. Biophys. Acta
(1993) Diagnostic and Statistical Manual of Mental Disorders
(1994)- et al.
A novel functional polymorphism within the promoter of the serotonin transporter gene: possible role in susceptibility to affective disorders
Mol. Psychiatry
(1996) - et al.
Analysis and meta-analysis of two serotonin transporter gene polymorphisms in bipolar and unipolar affective disorders
Am. J. Med. Genet.
(1998) - et al.
Allelic variation of human serotonin transporter gene expression
J. Neurochem.
(1996) - et al.
Prediction of dopamine transporter binding availability by genotype: a preliminary report
Am. J. Psychiatry
(2000)
Cited by (233)
Pharmacogenetics of selective serotonin reuptake inhibitors (SSRI): A serotonin reuptake transporter (SERT)-based approach
2024, Neurochemistry InternationalGenetics of antidepressant response and treatment-resistant depression
2023, Progress in Brain ResearchPersonalized Pharmacotherapy: A Historical Perspective on the Pharmacogenomics of Depression
2022, Comprehensive PharmacologyPharmacogenetic association of bi- and triallelic polymorphisms of SLC6A4 with antidepressant response in major depressive disorder
2020, Journal of Affective DisordersCitation Excerpt :Besides, one article reported findings from 3 trials with different design and populations and was then considered as 3 independent studies in our analysis (Calabro et al., 2018). Finally, 49 studies were included in present study, of which 46 were for 5-HTTLPR biallelic polymorphism (Arias et al., 2003; Basu et al., 2015; Bousman et al., 2014; Bozina et al., 2008; Calabro et al., 2018; Chang et al., 2014; Dogan et al., 2008; Durham et al., 2004; Gressier et al., 2009; Hong et al., 2006; Hu et al., 2007; Huezo-Diaz et al., 2009; Illi et al., 2011; Joyce et al., 2003; Kang et al., 2007; Kato et al., 2005; Kim et al., 2000; Kim et al., 2006; Kirchheiner et al., 2007; Lee et al., 2010; Manoharan et al., 2016; Maron et al., 2009; Min et al., 2009; Mrazek et al., 2009; Ng et al., 2016; Ng et al., 2006; Poland et al., 2013; Pollock et al., 2000; Rausch et al., 2002; Reimherr et al., 2010; Ruhe et al., 2009; Sahraian et al., 2013; Serretti et al., 2004; Smeraldi et al., 1998; Tatham et al., 2017; Tomita et al., 2014; Umene-Nakano et al., 2010; Wilkie et al., 2009; Yoshida et al., 2002; Yoshida et al., 2004; Yoshimura et al., 2009; Yu et al., 2002; Zanardi et al., 2000; Zanardi et al., 2001) and 10 for 5-HTTLPR/rs25531 triallelic polymorphism (Calabro et al., 2018; Camarena et al., 2019; Dreimuller et al., 2012; Hu et al., 2007; Kato et al., 2013; Manoharan et al., 2016; Maron et al., 2009; Ruhe et al., 2009). The basic characteristics of eligible studies for biallelic and triallelic polymorphism were listed in Table 1 and 2, respectively.
Associations of the serotonin transporter promoter polymorphism (5-HTTLPR) with bipolar disorder and treatment response: A systematic review and meta-analysis
2019, Progress in Neuro-Psychopharmacology and Biological PsychiatryBiomarker-based treatment selection: A precision medicine approach for depression
2019, Neurobiology of Depression: Road to Novel Therapeutics