Single-Nucleotide Polymorphisms as Biomarkers of Antipsychotic-Induced Akathisia: Systematic Review

{"Background": "Antipsychotic-induced akathisia (AIA) is a movement disorder characterized by subjective inner restlessness and an irresistible urge to move, occurring in patients taking antipsychotics (APs). The average worldwide prevalence of AIA among adult schizophrenia patients is approximately 30%, with estimates ranging from 0.85% to 55%. AIA is a multifactorial neurological disorder involving both genetic predisposition and environmental factors. Non-modifiable risk factors include female sex (for tardive AIA), middle age, and genetic predisposition. Modifiable risk factors include long-term AP use, vitamin B6 deficiency, ferritin deficiency, low serum iron, traumatic brain injury, alcohol abuse, autoimmune NMDAR-encephalitis, and cancer. The role of single-nucleotide polymorphisms (SNPs) in AIA pathogenesis has been studied for over 40 years. This systematic review aimed to identify and systematize genetic predictors of AIA in patients with schizophrenia.", "Methods": "The authors searched PubMed, Web of Science, Springer, Google Scholar, and e-Library databases for full-text publications in English and Russian from 1977 to 2022. Keywords included antipsychotic-induced akathisia, drug-induced akathisia, antipsychotics, genes, adverse drug reaction, pharmacogenetics, genetic biomarker, and related terms. Eligible study designs included placebo-controlled studies, cross-sectional studies, case-control studies, case studies, systematic reviews, meta-analyses, and Cochrane reviews. The PRISMA quality scale was used for critical selection. A total of 2,175 articles were initially identified by keywords. After exclusion, 35 articles were analyzed, and only 3 articles met all inclusion criteria. Studies were excluded if data were not statistically significant, SNP data did not match international nomenclature databases, associations with specific alleles/polymorphisms were not indicated, samples included fewer than 100 people, or articles considered associations with other AP-induced extrapyramidal symptoms without differentiation. The review was registered under number CRD42022374137.", "Key Results": "Three studies met the inclusion criteria. (1) Koning et al. studied 402 Northern European patients with mental disorders taking APs for at least one month. They found that the major C allele of rs1800498 (TaqI_D) in the DRD2 gene was associated with AIA risk (p = 0.001), and the minor A allele of rs1800497 (TaqIA) in the DRD2 gene was also associated with AIA risk (p = 0.03). (2) A second study of 234 Australian patients on AP monotherapy for at least one month confirmed that the minor A allele of rs1800497 (TaqIA) was associated with AIA risk according to the Barnes Akathisia Rating Scale (BARS) (p = 0.011). (3) A study of 229 Croatian patients with schizophrenia found that the homozygous TT genotype of rs13212041 in the HTR1B gene was associated with AIA risk according to BARS (p = 0.004). The review also identified candidate genes of interest including GRIN2A, GRIN2B, HSPG2, DRD2, DRD3, DRD4, COMT, HTR2A, HTR2C, PPP1R1B, BDNF, MnSOD (SOD2), and GSTP1, though these did not meet inclusion criteria for confirmed association. Notably, 20 studies were excluded because they showed positive associations with AP-induced movement disorders without differentiating between specific disorders such as AIA, antipsychotic-induced parkinsonism (AIP), or tardive dyskinesia.", "Clinical Implications": "The identification of genetic biomarkers for AIA could enable personalized prevention and treatment strategies for this common adverse neurological drug reaction in schizophrenia patients. AIA significantly reduces quality of life and decreases compliance with psychopharmacotherapy. The DRD2 gene SNPs (rs1800498 and rs1800497) and HTR1B gene SNP (rs13212041) represent potential candidates for a genetic risk panel. However, the authors acknowledge that no definitive conclusion can be drawn about the leading role of any specific SNPs, as only three studies met rigorous inclusion criteria. The review highlights that most research has been conducted in Northern European populations, with no genetic studies of AIA found in Russia or other regions. The authors emphasize the need for larger multicenter studies with standardized designs across diverse racial and ethnic groups. Additionally, the review notes that CYP2D6 and CYP1A2 gene polymorphisms may be relevant to AIA risk through their effects on antipsychotic metabolism, though no studies meeting inclusion criteria specifically addressed this relationship. The clinical translation of these findings requires validation in larger, more diverse populations before genetic testing can be implemented in routine psychiatric practice."}