The polymorphisms of candidate pharmacokinetic and pharmacodynamic genes and their pharmacogenetic impacts on the effectiveness of risperidone maintenance therapy among Saudi children with autism.

BACKGROUND: Antipsychotics, including risperidone (RIS), are frequently indicated for various autism spectrum disorder (ASD) manifestations; however, "actionable" PGx testing in psychiatry regarding antipsychotic dosing and selection has limited applications in routine clinical practice because of the lack of standard guidelines, mostly due to the inconsistency and scarcity of genetic variant data. The current study is aimed at examining the association of RIS effectiveness, according to ABC-CV and CGI indexes, with relevant pharmacokinetics (PK) and pharmacodynamics (PD) genes. METHODS: Eighty-nine ASD children who received a consistent RIS-based regimen for at least 8 weeks were included. The Axiom PharmacoFocus Array technique was employed to generate accurate star allele-predicted phenotypes of 3 PK genes (CYP3A4, CYP3A5, and CYP2D6). Genotype calls for 5 candidate PD receptor genes (DRD1, DRD2, DRD3, HTR2C, and HTR2A) were obtained and reported as wild type, heterozygous, or homozygous for 11 variants. RESULTS: Based on the ABC total score, 42 (47.2%) children were classified as responders, while 47 (52.8%) were classified as nonresponders. Multivariate logistic regression analyses, adjusted for nongenetic factors, suggested nonsignificant impacts of the star allele-predicted phenotypes of all 3 PK genes on improvement in ASD symptoms or CGI scores. However, significant positive or negative associations of certain PD variants involved in dopaminergic and serotonergic pathways were observed with specific ASD core and noncore symptom subdomains. Our significant polymorphism findings, mainly those in DRD2 (rs1800497, rs1799978, and rs2734841), HTR2C (rs3813929), and HTR2A (rs6311), were largely consistent with earlier findings (predictors of RIS effectiveness in adult schizophrenia patients), confirming their validity for identifying ASD children with a greater likelihood of core symptom improvement compared to noncarriers/wild types. Other novel findings of this study, such as significant improvements in DRD3 rs167771 carriers, particularly in ABC total and lethargy/social withdrawal scores, and DRD1 rs1875964 homozygotes and DRD2 rs1079598 wild types in stereotypic behavior, warrant further verification in biochemical and clinical studies to confirm their feasibility for inclusion in a PGx panel. CONCLUSION: In conclusion, we provide evidence of potential genetic markers involved in clinical response variability to RIS therapy in ASD children. However, replication in prospective samples with greater ethnic diversity and sample sizes is necessary.

Appropriateness of anticoagulation level in older adult patients on Warfarin: A multicenter retrospective study.

Warfarin is favored over newer direct oral anticoagulants (DOACs) for many older adults. However, its use necessitates rigorous monitoring due to the fine line between toxic and therapeutic doses. Few studies have evaluated the anticoagulation quality of warfarin among elderly patients in Saudi Arabia. This study aimed to assess and identify factors affecting the anticoagulation quality of warfarin using the time in the therapeutic range (TTR) among older adults attending two hospitals in Saudi Arabia. Additionally, we aimed to evaluate differences in the anticoagulation quality of warfarin when managed by pharmacists or physicians. This cross-sectional study was conducted at King Abdullah bin Abdulaziz University Hospital (KAAUH) and King Fahad Medical City (KFMC) in Riyadh, Saudi Arabia. After calculating the TTR of each patient, the anticoagulation control level was determined using these values: a) good control: >70 %; b) intermediate control: 50-70 %; c) poor control: <50 %. A total of 132 patients prescribed warfarin therapy for different indications were included. Most patients (45.5 %) had poor control with TTRs < 50 %, while 18.2 % had intermediate control, and 36.4 % had good control. Our exploratory findings suggest that having three or more comorbidities was a significant factor associated with a poor TTR [odds ratio (OR) = 3.36; (95 % confidence interval 1.28-8.81); P = 0.014]. Thus, the anticoagulation quality of warfarin among older adult patients was poor in two Saudi Arabian tertiary hospitals, and the number of comorbidities was a potentially poor TTR predictor.