Table 1.

An overview of genetic variants and candidate genes associated with antidepressants treatment response in patients with MDD

Candidate genes	Coded proteins	Pharmacogenomics of antidepressants (description)
IL1B Interleukin-1 beta	IL1B is one of eight other interleukin-1 family genes that encodes interleukin-1 cytokine proteins. These and other related proteins produced by activated macrophages are important mediators of inflammatory response throughout the body, including in the central nervous system (CNS) [121]	Single nucleotide polymorphisms (SNPs) rs16944 and rs116343 in the IL1B gene and their interaction with childhood maltreatment influences the effect of antidepressants in patients with MDD [25] and increase the risk of non-remission after antidepressant treatment in patients with MDD [8]
FKBP5 FK506 binding protein 5	Encodes a protein that is a member of the immunophilin family proteins involved in immune regulation and related cellular processes. This protein binds to the immunosuppressant proteins such as FK506 and rapamycin [121]	A genetic variant rs1360780 in the FKBP5 gene predicts remission to antidepressant treatment [71] and SNP rs352428 might influence SSRIs treatment outcomes in MDD patients [44]
CNR1 Cannabinoid receptor 1	Encodes cannabinoid receptor-1, one of the two receptors for cannabinoid—psychoactive ingredients of marijuana [121]	The CNR1 gene polymorphisms rs806368 and rs806371 have shown a significant effect on the clinical response to SSRI (citalopram) [114]. An SNP rs1049353 may confer an increased risk to antidepressants treatment resistance [38]
NPY Neuropeptide Y	Encodes a neuropeptide that is widely expressed in the CNS and is involved in several physiological processes, including stress response and circadian rhythms [121]	NPY gene variation rs16147 was associated with a slow response and remission to antidepressant treatment [37]
ABCB1 ATP-binding cassette subfamily B member 1	The protein encoded by the ABCB1 gene is a member of ATP-binding cassette (ABC) transporters—superfamily proteins involved in multidrug resistance. ABC proteins transport molecules across extra- and intra-cellular membranes and functions as a transporter in the blood-brain barrier [121]	In patients with MDD, ABCB1 polymorphisms (rs1045642, rs2032582, and rs1128503) were associated with adjustment to antidepressant dosages to achieve remission [146]. Genotyping for rs2032583 and rs2235015 (TT/GG) may be used for clinical application to optimize antidepressant treatment [19]. Antidepressant treatment outcome was significantly associated with rs203258, rs2235015 [17], rs2032588 [13], and C3435T [83] polymorphisms. Moreover, a significant association was found between SSRIs-related adverse drug effects and SNPs rs2032583 and rs2235040 [33]
BDNF Brain-derived neurotrophic factor	Encodes a member of the nerve growth factor family of proteins that promote neuronal survival in the adult brain. BDNF is involved in stress response and in the biology of mood disorders [121]	Genetic polymorphisms BDNF G196A [168] and rs908867 [61] did influence antidepressant treatment outcome. For example, BDNF G196A polymorphism in part determined the antidepressant effect of both milnacipran and fluvoxamine [168], and the BDNF Val66Met was associated with SSRI treatment resistance [] and may be connected with lithium prophylaxis [137]
GRIK4 Glutamate ionotropic receptor kainate-type subunit 4	Encodes a glutamate-gated ionic channel family protein that collectively functions as excitatory neurotransmitters in the CNS [121]	The GRIK4 SNPs rs12800734 [72] and rs1954787 showed a strong association with antidepressant treatment outcome (remission and/or response) [85]
GNB3 G protein subunit beta 3	Encodes a beta subunit of the G protein beta family of G proteins (guanine nucleotide-binding proteins) that help to integrate signals between receptor and effector proteins [121]	GNB3 C825T polymorphism influences the efficacy of antidepressants in the treatment of MDD [64, 88, 89, 101, 166]
HTR1A 5-hydroxytryptamine receptor 1A	Encodes a receptor for serotonin that belongs to the 5-hydroxytryptamine receptor subfamily [129]. Serotonin is a neurotransmitter with several roles in the brain and body, and it is assumed to regulate feelings of happiness and well-being [121]	Patients with BPD who carries a 5-HT1A*C/C genotype showed a better response to an antidepressant (fluvoxamine) [140]. SNPs rs10042486, rs1364043, and rs6295 within the HTR1A gene were significantly associated with antidepressant response [84]
HTR2A 5-hydroxytryptamine receptor 2A	Encodes one of the receptors for serotonin	Polymorphisms in 5HT-2A receptor rs17288723 [72], rs7997012 [102, 103], rs9534505 [93], rs6311, rs6313, rs7997012, and rs1928040 [91, 102] were significantly associated with therapeutic response or remission to antidepressants [102]
SLC6A4 Solute carrier family 6 member 4	Encodes a membrane protein that transports serotonin from synaptic spaces into presynaptic neurons, and terminates the action of serotonin and recycles it [121]	SNPs within SLC6A4 were associated with antidepressant response [42, 97, 128, 169], 5-HTTLPR pre-treatment genotyping might help to predict treatment remission [125]. Patients with 5-HTTLPR L/L or STin2 12/12 genotype experienced better clinical response to SSRI treatment [113]. A high-affinity antidepressant-binding site was found within the serotonin transporter (hSERT) protein [132]. SNP rs8076005 [108] may be a modulator of antidepressant response. Moreover, the GNB3, HTR2A, and SLC6A4 genes may act in an interactive manner to influence antidepressant treatment outcome [99]
COMT Catechol-O-methyltransferase	Encodes the COMT enzyme protein that breakdowns neurotransmitters, such as dopamine, epinephrine, and norepinephrine. This enzyme might be involved in the metabolism of drugs [121]	The Val (108/158) Met variation of the COMT gene is among the most studied polymorphisms associated with response to antidepressants treatment [10, 13, 151] or electroconvulsive therapy [42] in patients with MDD
CYP2C19 Cytochrome P450 (CYP) family 2 subfamily C member 19	Encodes a member of the CYP superfamily of enzymes (monooxygenases)—known to metabolize several drugs, including psychiatric drugs. The CYP enzymes together with the permeability glycoproteins (PGP) play a role in eliminating drugs from the brain and body [121]	Genetic variants within this gene are associated with variable ability to metabolize drugs- genotyping for these variants may help to classify individuals as poor or extensive drug metabolizers. CYP2C19 contributes to the clearance of many antidepressants [139] and an amino acid residue 72 plays a key role in the metabolism of antidepressants by limiting the binding affinities of CYP2C9 [6]
CYP2D6 Cytochrome P450 family 2 subfamily D member 6	It is a highly polymorphic gene that encodes an enzyme in the CYPsuperfamily [121]	Polymorphisms in the CYP2D6 gene may influence the metabolism and response of antidepressant response [16, 67, 90]. Similar to other CYP enzymes, CYP2D6 may result in a different ability to metabolize drugs (poor or ultrarapid)
MAOA Monoamine oxidase A	It is one of two genes that encode mitochondrial enzymes, which catalyzes the degradation of amines (dopamine, norepinephrine, and serotonin)	Genetic variants of the MAOA gene may influence antidepressant treatment response in patients with MDD [40, 170]