Catechol-O-Methyltransferase Val158Met Polymorphism and Clinical Response to Antipsychotic Treatment in Schizophrenia and Schizo-Affective Disorder Patients: a Meta-Analysis

Abstract

Background:The catechol-O-methyltransferase (COMT) enzyme plays a crucial role in dopamine degradation, and the COMT Val158Met polymorphism (rs4680) is associated with significant differences in enzymatic activity and consequently dopamine concentrations in the prefrontal cortex. Multiple studies have analyzed the COMT Val158Met variant in relation to antipsychotic response. Here, we conducted a meta-analysis examining the relationship between COMT Val158Met and antipsychotic response.Methods:Searches using PubMed, Web of Science, and PsycInfo databases (03/01/2015) yielded 23 studies investigating COMT Val158Met variation and antipsychotic response in schizophrenia and schizo-affective disorder. Responders/nonresponders were defined using each study’s original criteria. If no binary response definition was used, authors were asked to define response according to at least 30% Positive and Negative Syndrome Scale score reduction (or equivalent in other scales). Analysis was conducted under a fixed-effects model.Results:Ten studies met inclusion criteria for the meta-analysis. Five additional antipsychotic-treated samples were analyzed for Val158Met and response and included in the meta-analysis (ntotal=1416). Met/Met individuals were significantly more likely to respond than Val-carriers (P=.039, ORMet/Met=1.37, 95% CI: 1.02–1.85). Met/Met patients also experienced significantly greater improvement in positive symptoms relative to Val-carriers (P=.030, SMD=0.24, 95% CI: 0.024–0.46). Posthoc analyses on patients treated with atypical antipsychotics (n=1207) showed that Met/Met patients were significantly more likely to respond relative to Val-carriers (P=.0098, ORMet/Met=1.54, 95% CI: 1.11–2.14), while no difference was observed for typical-antipsychotic-treated patients (n=155) (P=.65).Conclusions:Our findings suggest that the COMT Val158Met polymorphism is associated with response to antipsychotics in schizophrenia and schizo-affective disorder patients. This effect may be more pronounced for atypical antipsychotics.

Overview of pharmacogenomic testing in clinical practice

“…In a 10-study meta-analysis from 2016, met/met patients were much more likely to respond to antipsychotic treatment (greater reduction in positive symptoms) and showed a greater decrease in negative symptoms with increased cognitive function. Another interesting finding from this study was a post hoc analysis demonstrating this response in patients treated with atypical antipsychotics but no difference in patients treated with typical antipsychotics 20. However, 1 study included in the meta-analysis featured patients with the val/val genotype, who were more likely to respond to clozapine and have a reduction in their symptoms 21.…”

DNA methylation of membrane‐bound catechol‐O‐methyltransferase in Malaysian schizophrenia patients

“…3 The most recent meta-analysis indicated that COMT was associated with psychological symptoms and cognitive characteristics as well as antipsychotic response in schizophrenia patients. 4 In addition, COMT has also been found to be associated with positive symptoms, 5,6 negative symptoms, 7,8 manic symptoms, 9 and cognitive deficits in schizophrenia. [10][11][12] In terms of epigenetic studies, investigations into the association between COMT DNA methylation and schizophrenia have focused on two isoforms: the soluble isoform (S-COMT) and the membranebound isoform (MB-COMT).…”

“…Accumulating evidence has suggested the involvement of COMT genotypes in the pathophysiology of schizophrenia . The most recent meta‐analysis indicated that COMT was associated with psychological symptoms and cognitive characteristics as well as antipsychotic response in schizophrenia patients . In addition, COMT has also been found to be associated with positive symptoms, negative symptoms, manic symptoms, and cognitive deficits in schizophrenia …”

The Effect of Dopamine Antagonist Treatment on Auditory Verbal Hallucinations in Healthy Individuals Is Clearly Influenced by COMT Genotype and Accompanied by Corresponding Brain Structural and Functional Alterations: An Artificially Controlled Pilot Study

“…These previous findings converge to indicate that the reciprocal interactions between COMT genotype, dopamine levels, and structural and/or functional alterations in the human brain are related to mental disorder symptoms, such as AVHs (Lu et al., 2007; Kang et al., 2010; Sagud et al., 2010; Gothelf et al., 2011; Edgar et al., 2012; Tian et al., 2013a,b; Li et al., 2015; Huang et al., 2016; Steiner et al., 2018). …”