COMT-Val158Met polymorphism modulates antipsychotic effects on auditory verbal hallucinations and temporal lobe gray matter volumes in healthy individuals\u2014symptom relief accompanied by worrisome volume reductions

Chuanjun Zhuo,Gongying Li,Yong Xu,Li Zhang,Langlang Cheng,Chunhua Zhou,Rixing Jing,Shen Li,Xiaodong Lin

doi:10.1007/s11682-019-00043-5

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.

Highlights

Emprirical studies have indicated that some 0.7% of the general population has experienced auditory verbal hallucinations (AVHs) defined based on Jhons’ strict criteria (Johns et al 2004; Sommer et al 2010; Upthegrove et al 2016)
From a cohort of subjects who participated in a prior pilot study, we recruited healthy control (HC) subjects matched to the healthy individuals with AVHs (H-AVHs) subjects with respect to catechol-o-methyl transferase (COMT) genotype, gender, age, and education level
We demonstrated for the first time that antipsychotic drug effects in H-AVH subjects are influenced by COMT genotype and that this distinction is accompanied by corresponding structural changes in the brain, in the temporal lobes

Summary

Introduction

Emprirical studies have indicated that some 0.7% of the general population has experienced auditory verbal hallucinations (AVHs) defined based on Jhons’ strict criteria (Johns et al 2004; Sommer et al 2010; Upthegrove et al 2016). A convergence of findings indicates that there may be reciprocal interactions between COMT genotype, dopamine levels, and structural/functional brain alterations in relation to neuropsychiatric symptoms, such as AVHs (Edgar et al 2012; Gothelf et al 2011; Huang et al 2016; Kang et al 2010; Li et al 2015; Lu et al 2007; Sagud et al 2010; Steiner et al 2018; Tian et al 2013a; Tian et al 2013b)

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