Association of Mu-Opioid Receptor Variants and Response to Citalopram Treatment in Major Depressive Disorder

Abstract

Objective-Because previous preclinical and clinical studies have implicated the endogenous opioid system in major depression and in the neurochemical action of antidepressants, the authors examined how DNA variation in the μ-opioid receptor gene may influence population variation in response to citalopram treatment. Method-A total of 1,953 individuals from the Sequenced Treatment Alternatives to RelieveDepression (STAR*D) study were treated with citalopram and genotyped for 53 single nucleotide polymorphisms (SNPs) in a 100-kb region of the OPRM1 gene. The sample consisted of NonHispanic Caucasians, Hispanic Caucasians, and African Americans. Population stratification was corrected using 119 ancestry informative markers and principal components analysis. Markers were tested for association with phenotypes for general and specific citalopram response as well as remission.Results-Association between one SNP and specific citalopram response was observed. After Bonferroni correction, the strongest finding was the association between the rs540825 SNP and specific response. The rs540825 polymorphism is a nonsynonymous SNP in the final exon of the μ-opioid receptor-1X isoform of the OPRM1 gene, resulting in a histidine to glutamine change in the intra-cellular domain of the receptor. When Hispanic and Non-Hispanic Caucasians were analyzed separately, similar results in the population-corrected analyses were detected.Conclusions-These results suggest that rates of response to antidepressants and consequent remission from major depressive disorder are influenced by variation in the μ-opioid receptor gene as a result of either an effect on placebo response or true pharmacologic response.Antidepressant response rates in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study averaged <50% for treatment with citalopram (level 1 treatment condition), with only approximately 30% of subjects remitting from major depressive disorder (1).Address correspondence and reprint requests to Dr. Hamilton, University of California, San Francisco, Department of Psychiatry, 401 Parnassus Ave., San Francisco, steveh@lppi.ucsf.edu. Previously presented at the Annual Meeting of the National Institute of Mental Health New Clinical Drug Evaluation Unit, June 11-14, 2007, Boca Raton, Fla.; and the Annual Meeting of Pharmacogenetics in Psychiatry, April 13-14, 2007, New York. Preliminary analyses were also presented in Psychiatric Times (April 15, 2008, vol. 25, no. 5).ClinicalTrials.gov registry number, NCT00021528. NIH Public Access Author ManuscriptAm J Psychiatry. Author manuscript; available in PMC 2010 June 15. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptInterindividual differences, such as genetic distinction, may contribute to this variation in response to antidepressant treatment, and two genes have already been identified in two studies (2,3). In the present study, we add to the findings of these investigations and show that the μ-opioid receptor gene is associated with antidepr...

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“…Indeed, the opioid system may also be important in the pathophysiology and treatment of depression. 55,56 As the search for novel antidepressants continues, researchers have turned towards the opioid system for potential therapeutic targets, with the goal of finding an effective antidepressant compound, sans addiction potential. One such Alkermes compound-ALKS 5461-combines buprenorphine (a μ-opioid receptor partial agonist and functional kappa-opioid receptor antagonist) with samidorphan (a potent μ-opioid receptor antagonist) in an attempt to create a functional kappa receptor antagonist.…”

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“…Some data have shown that opioids produce antidepressant effects and those dual action antidepressants such as venlafaxine and duloxetine can produce analgesic action [45]. Furthermore, mu receptor has also been genetically associated with citalopram response in MDD [46] while antidepressant effects of venlafaxine are abolished in mu opioid receptor knockout mice [47]. Finally, studies in mice model of depression have shown that the combination between classical monoaminergic antidepressants and opioid receptor agonists can produce synergistic antidepressant effects [48].…”

“…The activation of sigma-1 receptors appear to be involved in the enhancement of the prefrontal dopaminergic neurotransmission and in the antidepressant effects mediated by some drugs such as fluvoxamine, fluoxetine, citalopram, sertraline, clorgyline, and imipramine [40][41][42][43][44][45][46][47][48][49][50][51][52][53][54]. In an open study, a small sample of depressed patients was treated with JO-1784, a sigma-1 receptor agonist, which induced a 50% reduction of intensity of depressive symptoms on the Hamilton depression scale.…”

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“…In humans, depressed individuals and healthy comparison subjects exhibited different patterns of mu opioid receptor availability in emotionally neutral and sad states (54), supporting a role for opioids in mood. In addition, polymorphisms in the mu opioid receptor gene were associated with citalopram response in STAR*D (55).…”