High-risk genetic profiles for Pharmacoresistant Schizophrenia: Insights from Belarusian Patients

Despite antipsychotic drugs being a key treatment for schizophrenia, 20–30% of patients show an inadequate response. This may be due to genetic factors affecting drugs' metabolism, side effects, and efficacy. This study explored links between genetic polymorphisms and pharmacoresistant (PR) schizophrenia in Belarusian patients.

A total of 161 participants were included: 104 with PR schizophrenia (no response after 6–8 weeks of treatment) and 57 responders. All were diagnosed according to the ICD-10 (F20), aged 18–60, gave informed consent, and had no acute physical illnesses. The treatments included clozapine (42.1%) or combined atypical and typical antipsychotics (39.5%). We genotyped 19 polymorphic loci across 15 genes (e.g., CYP2D6, COMT, HTR1A, MDR1) using a Real-Time PCR or Sanger sequencing. The data were analyzed in SPSS 20.0 using ORs and 95% CIs to evaluate the genotype–phenotype associations.

Significant associations with PR were found for the following:

• The A-allele and AG genotype of CYP2D6*4 (rs3892097) (OR=2.159 and CI=1.018-4.578 and OR=2.975 and CI=1.269-6.977, respectively);
• The G-allele of COMT (rs4680, V158) (OR=2.786; CI=1.414-5.489);
• The CC genotype of HTR1A (rs6295) (OR=2.703; CI=1.151-6.348).

Protective effects were noted for the following:

• The GG genotype of CYP2D6 (rs3892097) (OR=0.463; CI=0.218-0.928);
• The G allele of HTR1A (rs6295) (OR=0.367; CI=0.156-0.864);
• The AA genotype (Met/Met) of COMT (rs4680) (OR=0.359; CI=0.182-0.707).

Combined genotypes showed an even greater PR risk, including the following:

• A-/A- (CYP2D6/CYP1A2) (OR = 2.926; 95% CI = 1.206–7.102);
• A-/A-/T- (CYP2D6/CYP1A2/MDR1) (OR = 4.833; 95% CI = 1.753–13.328)
• G-/LL (COMT/SLC6A4) (OR = 6.923; 95% CI = 1.900–25.227);
• CC/T- (HTR1A/MDR1) (OR = 2.564; 95% CI = 1.120–5.873).

In conclusion, variants in CYP2D6, HTR1A, and COMT, especially when combined with variants in CYP1A2, MDR1, and SLC6A4, significantly contribute to the PR schizophrenia risk in Belarus. These findings support the use of pharmacogenetic testing for personalized antipsychotic treatment, already implemented in the Republican Research and Practice Center for Mental Health (Minsk).