Research ReportAssociation of the adrenergic alpha 2a receptor − 1291C/G polymorphism with weight change and treatment response to mirtazapine in patients with major depressive disorder
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.
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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)
- et al.
Current advances and trends in the treatment of depression
Trends Pharmacol. Sci.
(1994) - et al.
No influence of adrenergic receptor polymorphisms on schizophrenia and antipsychotic response
Neurosci. Lett.
(2000) - et al.
Association of alpha2A-adrenergic receptor gene polymorphism with susceptibility to suicide in Japanese females
Prog. Neuropsychopharmacol. Biol. Psychiatry
(2008) - et al.
Association study of the serotonin transporter promoter polymorphism and mirtazapine antidepressant response in major depressive disorder
Prog. Neuropsychopharmacol. Biol. Psychiatry
(2007) - et al.
No gene is an island: the flip–flop phenomenon
Am. J. Hum. Genet.
(2007) - et al.
Alpha 2A adrenergic receptor gene and suicide
Psychiatry Res.
(2004) - et al.
Platelet alpha-adrenergic binding and biochemical responsiveness in depressed patients and controls
Psychiatry Res.
(1984) - et al.
Association analysis of polymorphism in the promoter region of the alpha2a-adrenoceptor gene with schizophrenia and clozapine response
Schizophr. Res.
(2001) - et al.
An inventory for measuring depression
Arch. Gen. Psychiatry
(1961) - et al.
International Union of Pharmacology nomenclature of adrenoceptors
Pharmacol. Rev.
(1994)
The effect of mianserin on alpha-2 adrenergic receptor function in depressed patients
Br. J. Psychiatry
No association between ADRA2A polymorphisms and schizophrenia
Am. J. Med. Genet. B Neuropsychiatr. Genet.
Monoamines and the mechanism of antidepressant action: effects of catecholamine depletion on mood of patients treated with antidepressants
Psychopharmacol. Bull.
Possible involvement of alpha-2A adrenergic receptors in attention deficit hyperactivity disorder: radioligand binding and polymorphism studies
Am. J. Med. Genet. B Neuropsychiatr. Genet.
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
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