Elsevier

Brain Research

Volume 1262, 25 March 2009, Pages 1-6
Brain Research

Research Report
Association of the adrenergic alpha 2a receptor − 1291C/G polymorphism with weight change and treatment response to mirtazapine in patients with major depressive disorder

https://doi.org/10.1016/j.brainres.2009.01.013Get rights and content

Abstract

Background: Adrenergic α2a receptors (ADRA2A) are expressed in the central nervous system and peripheral tissues. The primary mechanism of action of mirtazapine is the antagonism of central presynaptic α2 receptors. Mirtazapine is reportedly associated with weight gain. Our objective was to determine whether the ADRA2A − 1291C/G polymorphism is associated with weight gain and treatment response to mirtazapine in patients with major depressive disorder (MDD). Methods: The ADRA2A − 1291C/G polymorphism was analyzed in 314 MDD patients and 162 control subjects. All patients were evaluated using the 21-item Hamilton Depression Rating Scale at the beginning of the study and at 1, 2, 4, and 8 weeks of mirtazapine treatment. Results: No relationship was observed between the ADRA2A − 1291C/G polymorphism and MDD. No significant difference was found between responder and non-responder groups when comparing the ADRA2A genotype distribution with treatment response to mirtazapine. Repeated measures ANOVA with the last observation carry-forward test indicated that after adjusting for baseline body weight, age, and gender, the subjects with the C/C genotype exhibited a greater mean body weight gain than the subjects with the C/G or G/G genotype after 8 weeks of mirtazapine treatment (p = 0.052). Conclusions: The ADRA2A − 1291C/G polymorphism does not appear to be a predictor of treatment response to mirtazapine. This polymorphism was weakly associated with weight change after 8 weeks of mirtazapine treatment. Further investigation is required to determine whether other polymorphisms of this gene influence treatment response and weight change in patients receiving mirtazapine.

Introduction

The neurobiological mechanisms of responses to various drugs involve alterations in the functions of neurotransmitter systems and reinforce the importance of changes in both the serotonergic and noradrenergic systems for successful antidepressant therapy (Blier and de Montigny, 1994, Delgado et al., 1993). The latest development has been the introduction of the noradrenergic and specific serotonergic antidepressant mirtazapine. Its antidepressant effect appears to be related to the dual enhancement of central noradrenergic and serotonergic neurotransmission via the blockade of adrenergic α2 receptors (Herman, 1999, Kasper, 1997, Preskorn, 1997). Several antidepressants such as mianserin and its structural analogs exhibit adrenergic α2 receptor antagonism (Charney et al., 1984).

Previous studies have outlined the functional aspects of α2 receptors in depression, reporting reduced α2 inhibition of platelet adenylate cyclase activity (Siever et al., 1984) and increased adrenergic α2 agonist-induced platelet aggregation in depressed patients (Garcia-Sevilla et al., 1990).

Three genes that encode human adrenergic α2 receptors have been cloned: α2a, α2B, and α2C (Bylund et al., 1994). The adrenergic α2a receptor (ADRA2A) subtype is expressed in the central nervous system and peripheral tissues. The α2B receptor is expressed in the liver and kidneys, and the α2C receptor is expressed exclusively in the brain (Lorenz et al., 1990). According to this classification, the classic α2 receptor studied in mood disorders is the α2a receptor. Although information is available regarding the normal function of these receptors, polymorphism in the promoter or enhancer region may result in altered gene expression and receptor density. A transversion from C to G at position − 1291, upstream of the putative origin of transcription, has been described for the ADRA2A gene (Lario et al., 1997). Many psychiatric diseases, including attention deficit hyperactivity disorder (Deupree et al., 2006), weight gain after olanzapine medication (Park et al., 2006), suicide (Fukutake et al., 2008, Sequeira et al., 2004), and the treatment response to milnacipran (Wakeno et al., 2008), have been associated with this polymorphism.

The adrenergic α2 receptor plays an important role in the mechanism of action of mirtazapine. A few studies on the association between the ADRA2A − 1291C/G polymorphism and major depressive disorder (MDD) have been reported. Based on this evidence, we hypothesized that the α2a receptor gene is involved in the pathophysiology of MDD and the treatment response to mirtazapine. Our aim was to determine whether the ADRA2A − 1291C/G polymorphism is associated with susceptibility to MDD, weight change after mirtazapine administration, and treatment response to mirtazapine in MDD patients.

Section snippets

Demographic data and clinical characteristics

The gender distribution did not differ significantly between control subjects (47 males/114 females) and MDD patients (93 males/279 females; χ2 = 1.02, df = 1, p = 0.31). There was no significant difference in age distribution between control subjects and MDD patients (48.5 ± 18.0 vs. 50.8 ± 14.4 years, respectively; t =  1.58, df = 524, p = 0.12). Age, gender, age at onset, and family history did not differ among the three potential ADRA2A − 1291C/G genotypes in MDD patients (Table 1).

Genetic predisposition to MDD among adrenergic α2a − 1291C/G genotypes

The ADRA2A − 1291C/G

Discussion

Our aim was to determine whether the ADRA2A − 1291C/G polymorphism is associated with susceptibility to MDD, weight change after mirtazapine administration, and treatment response to mirtazapine in MDD patients. Antagonism of the central presynaptic adrenergic α2 receptor is a primary mechanism of action of mirtazapine, and thus the adrenergic α2 receptor may be regarded as a candidate target for research on susceptibility to MDD. Moreover, the ADRA2A − 1291C/G polymorphism appears to have an

Subjects

Between 2005 and 2007, in- and outpatients were recruited by the Pharmacogenomic Research Center for Psychotropic Drugs at the Department of Psychiatry, Korea University College of Medicine. All potential subjects examined by trained psychiatrists using the Structured Clinical Interview for the fourth revision of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (Han and Hong, 2000). The severity of depression was assessed according to the 21-item Hamilton Depression Rating

Acknowledgments

This study was supported by a grant from the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (03-PJ10-PG13-GD01-0002).

References (31)

  • CharneyD.S. et al.

    The effect of mianserin on alpha-2 adrenergic receptor function in depressed patients

    Br. J. Psychiatry

    (1984)
  • ClarkD.A. et al.

    No association between ADRA2A polymorphisms and schizophrenia

    Am. J. Med. Genet. B Neuropsychiatr. Genet.

    (2007)
  • DelgadoP.L. et al.

    Monoamines and the mechanism of antidepressant action: effects of catecholamine depletion on mood of patients treated with antidepressants

    Psychopharmacol. Bull.

    (1993)
  • DeupreeJ.D. et al.

    Possible involvement of alpha-2A adrenergic receptors in attention deficit hyperactivity disorder: radioligand binding and polymorphism studies

    Am. J. Med. Genet. B Neuropsychiatr. Genet.

    (2006)
  • Garcia-SevillaJ.A. et al.

    Alpha 2-adrenoceptor-mediated inhibition of platelet adenylate cyclase and induction of aggregation in major depression. Effect of long-term cyclic antidepressant drug treatment

    Arch. Gen. Psychiatry

    (1990)
  • Cited by (16)

    • Pharmacogenetics of Antidepressant Drugs

      2014, Handbook of Pharmacogenomics and Stratified Medicine
    • Excessive daytime sleepiness and fatigue in depressed patients and therapeutic response of a sedating antidepressant

      2011, Journal of Affective Disorders
      Citation Excerpt :

      As well, mirtazapine blockades postsynaptic 5-HT2 and 5-HT3 receptors. In addition, it has a high affinity to histamine H1 receptors (Lee et al., 2009; Rawlings et al., 2010). This may account for the reduction in sleepiness and fatigue.

    • Genetic Variations of α2-Adrenergic Receptors Illuminate the Diversity of Receptor Functions

      2011, Current Topics in Membranes
      Citation Excerpt :

      With regard to depression itself, a recent study carried out in a Korean sample population found no significant relationship between the α2AAR C-1291G polymorphism and incidence of MDD or response to the anti-α2-adrenergic antidepressant drug mirtazepine in MDD patients. A weak association was, however, found between the weight gain side effect commonly observed with mirtazepine and the C/C genotype at position -1291 (Lee et al., 2009). A separate study in a Japanese sample population uncovered a potential link between C-1291G and treatment response to the antidepressant milnacipran, although these results are preliminary (Wakeno et al., 2008).

    • Precision Medicine in Antidepressants Treatment

      2023, Handbook of Experimental Pharmacology
    View all citing articles on Scopus
    View full text