COMT-Val158Met polymorphism modulates antipsychotic effects on auditory verbal hallucinations and temporal lobe gray matter volumes in healthy individuals—symptom relief accompanied by worrisome volume reductions

Abstract

Investigation of auditory verbal hallucinations (AVHs) in schizophrenics is complicated by psychiatric symptoms. Investigating healthy individuals with AVHs (H-AVHs) can obviate such confounding factors. The objective of this study was to explore the effects of antipsychotic treatment on AVHs and gray matter volumes (GMVs) in H-AVH subjects and whether such are effects are influenced by COMT-Val158Met genotype. Magnetic resonance imaging (MRI) and genotyping studies were completed for 42 H-AVH subjects and 42 well-matched healthy controls (HCs). COMT-Met/Met homozygotes (158th codon) were identified as COMT-Met genotype; COMT-Met/Val heterozygotes and COMT-Val/Val homozygotes were identified as COMT-Val genotype. Data were compared across groups (H-AVH vs. HC, and between genotypes) with two-sample t-tests. The H-AVH COMT-Met group showed a stronger response to antipsychotic treatment than the H-AVH COMT-Val group (p < 0.001). Both H-AVH genotype groups exhibited temporal lobe GMV reductions after treatment, and relative to their respective genotype-matched HC groups. Antipsychotic treatment effects in H-AVH subjects were influenced by COMT-Val158Met genotype and associated with widespread GMV reductions. These findings provide clues for further exploration of treatment targets for AVHs. Treatment associated GMV reductions, however, raise concerns about use of antipsychotics in H-AVH subjects.

Polymorphisms in Dopaminergic Genes in Schizophrenia and Their Implications in Motor Deficits and Antipsychotic Treatment

“…SNPs may influence the effect of antipsychotics. The COMT Val158Met substitution at the rs4680 loci effectively predicted dopaminergic drug effects, as the COMT inhibitor improved cognitive functions Val homozygotes, whereas the antipsychotics were more effective in Met homozygotes (Zhuo et al, 2019). Protein structure and function studies revealed that Val-Met substitution disrupts enzyme stability, leading to suppressed dopamine clearance and higher dopamine activity (Chen et al, 2004).…”

Association of DRD2, DRD4 and COMT genes variants and their gene-gene interactions with antipsychotic treatment response in patients with schizophrenia

“…The efficacy of antipsychotic drugs in patients with schizophrenia has been indicated to be related to rs4680 SNP in COMT gene; associated with a decreased therapeutic effect, leading to pharmacotherapy resistance. In addition, the COMT interacts with several genes to produce various phenotypes [20][21][22][23][24].…”