The melanocortin 4 receptor is widely distributed in the brain and is involved in:
-regulating food consumption
– energy homeostasis
– sexual arousal
– inflammatory response
– pain modulation
– blood pressure
Also, it interacts with the serotonergic and leptinergic systems (Macneil and Müller, 2016).
Mutations in and near the MC4R gene are involved in congenital and polygenic forms of obesity (Macneil and Müller, 2016).
In one study (Czerwensky et al., 2013A), persons homozygous for the rs17782313 C allele had a higher risk of weight gain after four weeks of treatment with a second-generation antipsychotic.
In the subgroup that was not on any other medications that induced weight gain, those with the T/T genotype gained on average 1.09% of their baseline weight, those with the C/T genotype gained an average of 3.3%, and the few (9 patients only) who had the C/C genotype gained 5.47% (Czerwensky et al., 2013A).
Persons homozygous for the rs489693 A allele were found in one study (Czerwensky et al., 2013) to have a 2.2 times higher weight increase (+2.2 kg) than carriers of the CC genotype (+1 kg) over 4 weeks of treatment with a second-generation antipsychotic.
rs489693 is the polymorphism that is tested by the Genecept® assay under MC4R gene. The Genesight® Psychotropic test does not evaluate for MC4R polymorphisms as of May 2017.
Reviews and meta-analyses
Zhang JP, Lencz T, Zhang RX, Nitta M, Maayan L, John M, Robinson DG, Fleischhacker WW, Kahn RS, Ophoff RA, Kane JM, Malhotra AK, Correll CU. Pharmacogenetic Associations of Antipsychotic Drug-Related Weight Gain: A Systematic Review and Meta-analysis. Schizophr Bull. 2016 Nov;42(6):1418-1437. PubMed PMID: 27217270; PubMed Central PMCID: PMC5049532.
Chowdhury NI, Tiwari AK, Souza RP, Zai CC, Shaikh SA, Chen S, Liu F, Lieberman JA, Meltzer HY, Malhotra AK, Kennedy JL, Müller DJ. Genetic association study between antipsychotic-induced weight gain and the melanocortin-4 receptor gene. Pharmacogenomics J. 2013 Jun;13(3):272-9. PubMed PMID: 22310352.
Czerwensky F, Leucht S, Steimer W. Association of the common MC4R rs17782313 polymorphism with antipsychotic-related weight gain. J Clin Psychopharmacol. 2013A Feb;33(1):74-9. PubMed PMID: 23277235.
Czerwensky F, Leucht S, Steimer W. MC4R rs489693: a clinical risk factor for second generation antipsychotic-related weight gain? Int J Neuropsychopharmacol. 2013B Oct;16(9):2103-9. PubMed PMID: 23920449.
Malhotra AK, Correll CU, Chowdhury NI, Müller DJ, Gregersen PK, Lee AT, Tiwari AK, Kane JM, Fleischhacker WW, Kahn RS, Ophoff RA, Meltzer HY, Lencz T, Kennedy JL. Association between common variants near the melanocortin 4 receptor gene and severe antipsychotic drug-induced weight gain. Arch Gen Psychiatry. 2012 Sep;69(9):904-12. PubMed PMID: 22566560; PubMed Central PMCID: PMC4166499.
MacNeil RR, Müller DJ. Genetics of Common Antipsychotic-Induced Adverse Effects. Mol Neuropsychiatry. 2016 Jul;2(2):61-78. PubMed PMID: 27606321; PubMed Central PMCID: PMC4996009.
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