Effect of Serotonin Receptor 2A Gene Polymorphism on Mirtazapine Response in Major Depression

The 5-HTR2A gene is a candidate gene for influencing the clinical response to treatment with antidepressants. The purpose of this study was to determine the relationship between the -1438A/G polymorphism of the 5-HTR2A gene and the response to mirtazapine in a Korean population with major depressive disorder. Mirtazapine was administered for eight weeks to the 101 patients who completed the study, during which we evaluated the clinical outcome using repeated-measures ANCOVA. A main effect of genotype or an effect of genotype-time interactions on the decrease in HAMD score during the eight-week follow-up was not found, which suggests that the 5-HTR2A -1438A/G polymorphism does not affect the clinical outcome to mirtazapine administration. However, significant effects of genotype and allele carriers on the decrease in the sleep score over the eight weeks were found (genotype: F = 4.093, p = 0.017; allele: F = 4.371, p = 0.037), whereas no effect of genotype-time interactions on the decrease in the HAMD score over the eight-week follow-up was found. These observations suggest that the -1438A/G polymorphism affects the sleep improvement but not the sleep pattern over time. A t-test-based evaluation of the effect of the 5-HTR2A -1438A/G polymorphism on the sleep improvement at each time period revealed significant differences in the sleep scores after two weeks of mirtazapine administration. The sleep scores were lower for carriers of the A+ allele than of the A — allele after two weeks of mirtazapine administration (p = 0.041), which means that the -1438GG genotype is associated with less improvement in sleep, and suggests that the effect of mirtazapine on improving the sleep quality differs with the 5-HTR2A -1438A/G polymorphism within two weeks of mirtazapine treatment. In conclusion, although the -1438A/G polymorphism affects the sleep improvement resulting from the administration of mirtazapine to Korean patients with major depressive disorder, our results do not support the hypothesis that this polymorphism of the 5-HTR2A gene is involved in the therapeutic response to mirtazapine.

[1]  S. Schultz,et al.  Serotonin 2A −1438 G/A and G-Protein Beta3 Subunit C825T Polymorphisms in Patients with Depression and SSRI-Associated Sexual Side-Effects , 2006, Neuropsychopharmacology.

[2]  T. Kinoshita,et al.  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 , 2006, Neuropsychobiology.

[3]  Francis J McMahon,et al.  Variation in the gene encoding the serotonin 2A receptor is associated with outcome of antidepressant treatment. , 2006, American journal of human genetics.

[4]  T. Someya,et al.  Polymorphisms in the 5-Hydroxytryptamine 2A Receptor and CytochromeP4502D6 Genes Synergistically Predict Fluvoxamine-Induced Side Effects in Japanese Depressed Patients , 2006, Neuropsychopharmacology.

[5]  C. Shapiro,et al.  Polysomnographic and Symptomatological Analyses of Major Depressive Disorder Patients Treated with Mirtazapine , 2006, Canadian journal of psychiatry. Revue canadienne de psychiatrie.

[6]  B. Ham,et al.  Serotonin Receptor 2A Gene Polymorphism (–1438A/G) and Short-Term Treatment Response to Citalopram , 2005, Neuropsychobiology.

[7]  R. Kerwin,et al.  The –1438A/G polymorphism in the 5-hydroxytryptamine type 2A receptor gene affects promoter activity , 2004, Biological Psychiatry.

[8]  C. Nemeroff,et al.  Prediction of Antidepressant Response to Milnacipran by Norepinephrine Transporter Gene Polymorphisms , 2004 .

[9]  J. Knowles,et al.  Investigation of serotonin-related genes in antidepressant response , 2004, Molecular Psychiatry.

[10]  A. Schatzberg,et al.  Pharmacogenetics of antidepressant medication intolerance. , 2003, The American journal of psychiatry.

[11]  C. McDougle,et al.  Synergistic Action of 5-HT2A Antagonists and Selective Serotonin Reuptake Inhibitors in Neuropsychiatric Disorders , 2003, Neuropsychopharmacology.

[12]  Tetsuo Shimizu,et al.  Association between -1438G/A Promoter Polymorphism in the 5-HT2A Receptor Gene and Fluvoxamine Response in Japanese Patients with Major Depressive Disorder , 2002, Neuropsychobiology.

[13]  Chih-Chiang Chiu,et al.  Association of risperidone treatment response with a polymorphism in the 5-HT(2A) receptor gene. , 2002, The American journal of psychiatry.

[14]  D. Nutt.  Tolerability and safety aspects of mirtazapine , 2002, Human psychopharmacology.

[15]  C. Thompson.  Onset of action of antidepressants: results of different analyses , 2002, Human psychopharmacology.

[16]  A. Meulemans,et al.  Pharmacological characterization of the 5‐HT receptors mediating contraction and relaxation of canine isolated proximal stomach smooth muscle , 2002, British journal of pharmacology.

[17]  B. Sokolov,et al.  Differential expression of the “C” and “T” alleles of the 5‐HT2A receptor gene in the temporal cortex of normal individuals and schizophrenics , 2002, Journal of neuroscience research.

[18]  C. Cusin,et al.  Influence of monoamine oxidase A and serotonin receptor 2A polymorphisms in SSRI antidepressant activity. , 2002, The international journal of neuropsychopharmacology.

[19]  P. Zwanzger,et al.  Serotonin-2A-receptor and -transporter polymorphisms: Lack of association in patients with major depression , 2001, European Neuropsychopharmacology.

[20]  F. Quitkin,et al.  Does mirtazapine have a more rapid onset than SSRIs? , 2001, The Journal of clinical psychiatry.

[21]  D. Nelson,et al.  LY367265, an inhibitor of the 5-hydroxytryptamine transporter and 5-hydroxytryptamine(2A) receptor antagonist: a comparison with the antidepressant, nefazodone. , 2000, European journal of pharmacology.

[22]  M. Alda,et al.  The implications of genetics studies of major mood disorders for clinical practice. , 2000, The Journal of clinical psychiatry.

[23]  L. Kubin,et al.  Pontomedullary distribution of 5‐HT2A receptor‐like protein in the rat , 2000, The Journal of comparative neurology.

[24]  P. Achermann,et al.  Serotonin-2 Receptors and Human Sleep: Effect of a Selective Antagonist on EEG Power Spectra , 1999, Neuropsychopharmacology.

[25]  P. Liddle,et al.  Decrease in brain serotonin 2 receptor binding in patients with major depression following desipramine treatment: a positron emission tomography study with fluorine-18-labeled setoperone. , 1999, Archives of general psychiatry.

[26]  J. Fawcett,et al.  Review of the results from clinical studies on the efficacy, safety and tolerability of mirtazapine for the treatment of patients with major depression. , 1998, Journal of affective disorders.

[27]  P. Cowen,et al.  Brain 5-HT neurotransmission during paroxetine treatment , 1998, British Journal of Psychiatry.

[28]  S. Kasper,et al.  Efficacy of antidepressants in the treatment of severe depression: the place of mirtazapine. , 1997, Journal of clinical psychopharmacology.

[29]  M. Rietschel,et al.  Systematic screening for mutations in the human serotonin-2A (5-HT2A) receptor gene: Identification of two naturally occurring receptor variants and association analysis in schizophrenia , 1996, Human Genetics.

[30]  C. Montigny,et al.  Noradrenergic modulation of central serotonergic neurotransmission: acute and long-term actions of mirtazapine , 1995, International clinical psychopharmacology.

[31]  C. Montigny,et al.  The Effects of Mirtazapine on the Interactions between Central Noradrenergic and Serotonergic Systems , 1995 .

[32]  G. Ruigt,et al.  The Selective α2-Adrenoceptor Antagonist Mirtazapine (Org 3770) Enhances Noradrenergic and 5-HT1A-Mediated Serotonergic Neurotransmission , 1995 .

[33]  T. de Boer.  The effects of mirtazapine on central noradrenergic and serotonergic neurotransmission , 1995, International clinical psychopharmacology.

[34]  M. J. Arranz,et al.  Association between clozapine response and allelic variation in 5-HT2A receptor gene , 1995, The Lancet.

[35]  T. de Boer,et al.  The α2‐selective adrenoceptor antagonist org 3770 (mirtazapine, Remeron®) enhances noradrenergic and serotonergic transmission , 1995 .

[36]  J. Shih,et al.  The human 5-HT2 receptor is encoded by a multiple intron-exon gene. , 1992, Brain research. Molecular brain research.

[37]  D J Kupfer,et al.  Conceptualization and rationale for consensus definitions of terms in major depressive disorder. Remission, recovery, relapse, and recurrence. , 1991, Archives of general psychiatry.

[38]  R. Kahn,et al.  Monoamines and Abnormal Behaviour a Multi-Aminergic Perspective , 1990, British Journal of Psychiatry.

[39]  K J Rothman,et al.  No Adjustments Are Needed for Multiple Comparisons , 1990, Epidemiology.

[40]  S. Tsai,et al.  Response to fluoxetine and serotonin 1A receptor (C-1019G) polymorphism in Taiwan Chinese major depressive disorder , 2006, The Pharmacogenomics Journal.

[41]  E. Maron,et al.  Serotonin Function in Panic Disorder: Important, But Why? , 2006, Neuropsychopharmacology.

[42]  M. Versiani,et al.  Comparison of the Effects of Mirtazapine and Fluoxetine in Severely Depressed Patients , 2005, CNS drugs.

[43]  Alan A. Wilson,et al.  The effect of paroxetine on 5-HT(2A) receptors in depression: an [(18)F]setoperone PET imaging study. , 2001, The American journal of psychiatry.

[44]  P. Gorwood.  Chapter 2.1.4 Genetic association studies in behavioral neuroscience , 1999 .

[45]  S. Watts,et al.  Mechanisms of 5-hydroxytryptamine(2A) receptor activation of the mitogen-activated protein kinase pathway in vascular smooth muscle. , 1999, The Journal of pharmacology and experimental therapeutics.

[46]  V. Matto,et al.  5-HT2A RECEPTORS MEDIATE THE EFFECT OF ANTIDEPRESSANTS IN THE ELEVATED PLUS-MAZE TEST BUT HAVE A PARTIAL ROLE IN THE FORCED SWIMMING TEST , 1999 .

[47]  M. Owen,et al.  A family based association study of T102C polymorphism in 5HT2A and schizophrenia plus identification of new polymorphisms in the promoter , 1998, Molecular Psychiatry.

[48]  D. Collier,et al.  Evidence for association between polymorphisms in the promoter and coding regions of the 5-HT2A receptor gene and response to clozapine , 1998, Molecular Psychiatry.

[49]  T. de Boer.  The pharmacologic profile of mirtazapine. , 1996, The Journal of clinical psychiatry.

[50]  R. Salomon,et al.  Monoamines and the mechanism of antidepressant action: effects of catecholamine depletion on mood of patients treated with antidepressants. , 1993, Psychopharmacology bulletin.