Candidate Genes Encoding Dopamine Receptors as Predictors of the Risk of Antipsychotic-Induced Parkinsonism and Tardive Dyskinesia in Schizophrenic Patients

Abstract

(1) Introduction: Extrapyramidal disorders form the so-called extrapyramidal syndrome (EPS), which is characterized by the occurrence of motor disorders as a result of damage to the basal ganglia and the subcortical-thalamic connections. Often, this syndrome develops while taking medications, in particular antipsychotics (APs). (2) Purpose: To review studies of candidate genes encoding dopamine receptors as genetic predictors of development of AP-induced parkinsonism (AIP) and AP-induced tardive dyskinesia (AITD) in patients with schizophrenia. (3) Materials and Methods: A search was carried out for publications of PubMed, Web of Science, Springer, and e-Library databases by keywords and their combinations over the last 10 years. In addition, the review includes earlier publications of historical interest. Despite extensive searches of these commonly used databases and search terms, it cannot be ruled out that some publications were possibly missed. (4) Results: The review considers candidate genes encoding dopamine receptors involved in pharmacodynamics, including genes DRD1, DRD2, DRD3, and DRD4. We analyzed 18 genome-wide studies examining 37 genetic variations, including single nucleotide variants (SNVs)/polymorphisms of four candidate genes involved in the development of AIP and AITD in patients with schizophrenia. Among such a set of obtained results, only 14 positive associations were revealed: rs1799732 (141CIns/Del), rs1800497 (C/T), rs6275 (C/T), rs6275 (C/T) DRD2; rs167771 (G/A) DRD3 with AIP and rs4532 (A/G) DRD1, rs6277 (C/T), rs6275 (C/T), rs1800497 (C/T), rs1079597 (A/G), rs1799732 (141CIns/Del), rs1045280 (C/G) DRD2, rs6280 (C/T), rs905568 (C/G) DRD3 with AITD. However, at present, it should be recognized that there is no final or unique decision on the leading role of any particular SNVs/polymorphisms in the development of AIP and AITD. (5) Conclusion: Disclosure of genetic predictors of the development of AIP and AITD, as the most common neurological adverse drug reactions (ADRs) in the treatment of patients with psychiatric disorders, may provide a key to the development of a strategy for personalized prevention and treatment of the considered complication of AP therapy for schizophrenia in real clinical practice.

The Gender-Specific Association of DRD2 Polymorphism with Metabolic Syndrome in Patients with Schizophrenia

“…Deletion results in altered DRD2 expression in vitro [ 51 ] and, according to some, in increased DRD2 densities in the striatum [ 52 , 53 , 54 ]. Although the robustness of the findings is best left to be desired [ 55 , 56 ], the rs1799732 polymorphism has been reported to be associated with several side effects of antipsychotics: tardive dystonia [ 57 ], tardive dyskinesia [ 58 ], and parkinsonism [ 58 ], prolactin elevation [ 59 ], weight gain [ 60 ]. Therefore, there is at least some evidence that this is a functional polymorphism.…”

Motor- and cognition-related safety of pimavanserin in patients with Parkinson's disease psychosis

“…Many antipsychotic medications used off label are antagonists at the dopamine D 2 receptor and, therefore, can negatively impact motor function ( 17 , 33 , 34 ). Motor-related AEs associated with antipsychotics can mirror symptoms of PD, including akinesia, bradykinesia, and tremor ( 35 ), complicating management of PD symptoms. Altering dopaminergic medication regimens in patients with PD can be a balancing act in which psychotic symptoms may improve at the cost of worsening motor symptoms ( 14 ).…”

Pathophysiological Mechanisms of Antipsychotic-Induced Parkinsonism

“…Individual differences in susceptibility to haloperidol-induced parkinsonism were explained by individual pharmacokinetic variability associated with the influence of carriage of single nucleotide variants (SNVs) of the CYP3A4 and CYP3A5 genes, which affects the metabolism of haloperidol to its pyridinium ion. While taking haloperidol, pyridinium ion-related toxicity may be observed, which may be exacerbated in patients on polytherapy with antidepressants, as they interact with this system [ 6 , 86 , 113 , 114 , 115 , 116 ].…”

“…In our systematic review, the following positive associations for the risk of developing AIP were noted: rs1799732 (NG_008841.1:g.4750dup), rs1800497 (NG_012976.1:g.17316G>A), rs6275 (NG_008841.1:g.67525T>C) of the DRD2 gene; rs167771 (NG_008842.2:g.46980C>T, NG_008842.2:g.46980C>G, NG_008842.2:g.46980C>A) of the DRD3 gene; rs4680 (NG_011526.1:g.27009G>A) of the COMT gene; rs6311 (NG_013011.1:g.4692G>T, NG_013011.1:g.4692G>A) of the 5HTR2A gene; rs6318 (NG_012082.2:g.152242G>C, NG_012082.2:g.152242G>T) and rs3813929 (NG_012082.2:g.4963C>G, NG_012082.2:g.4963C>T) of the HTR2C gene; rs2179652 (NG_022822.1:g.225C>T), rs2746073 (NG_012800.1:g.6059T>A), rs4606 (NG_012800.1:g.8004C>G, NG_012800.1:g.8004C>T), rs1152746 (NC_000001.11:g.192827775C>G, NC_000001.11:g.192827775C>T), rs1819741 (NC_000001.11:g.192815708T>A, NC_000001.11:g.192815708T>A) and rs1933695 (NC_000001.11:g.192795690G>A) of the RGS2 gene; rs4795390 (NG_030330.1:g.3434G>A, NG_030330.1:g.3434G>C, NG_030330.1:g.3434G>T) of the PPP1R1B gene; rs6265 (NG_011794.1:g.68690G>A) of the BDNF gene; rs12678719 (NG_011723.2:g.189908C>G) of the ZFPM2 gene; rs938112 (NC_000003.12:g.117129003C>A, NC_000003.12:g.117129003C>T) of the LSMAP gene; rs2987902 (NG_012034.1:g.125979A>T) of the ABL1 gene. However, at present, it should be recognized that there is no definitive or single decision on the leading role of any particular SNVs/polymorphisms in AIP development [ 6 , 114 , 116 , 117 ].…”