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. 2021 Oct 18;19(10):1780–1790. doi: 10.2174/1570159X18666201023154049

Association Between the COMT Val158Met Polymorphism and Antipsychotic Efficacy in Schizophrenia: An Updated Meta-Analysis

Jingsong Ma 1,#, Mingzhe Zhao 1,#, Wei Zhou 1,2, Mo Li 1, Cong Huai 1, Lu Shen 1, Ting Wang 1, Hao Wu 1, Na Zhang 1, Zhiruo Zhang 1, Lin He 1, Shengying Qin 1,2,*
PMCID: PMC8977635  PMID: 33100205

Abstract

Background

Catechol-O-methyltransferase (COMT) contributes to the control of synaptic dopamine (DA) transmission by catalyzing DA degradation in the presynaptic space. The COMT Val158Met polymorphism (rs4680) substantially alters enzymatic activity and consequently synaptic DA concentration in the prefrontal cortex and hippocampus. The COMT genotype could, therefore, exert a major influence on antipsychotic treatment response as many of these agents also target dopaminergic transmission.

Objective

The present meta-analysis aimed to test a putative relationship between the COMT Val158Met polymorphism and antipsychotic response across different populations and antipsychotic types.

Methods

Searches of PubMed, Web of Science, EMBASE, OVID, Google Scholar, and Baidu Scholar databases yielded 30 peer-reviewed studies published before January 2020 with a pooled total of 6291 participants. The Lipták-Stouffer Z score method for meta-analysis was applied to combine data. The Z score was also calculated separately for Caucasian and Asian subgroups.

Results

Pooled results indicated a highly significant association between COMT Val158Met and antipsychotic response (Z = 6.709, P = 9.8 × 10-12). Further, this relationship remained significant in subgroup analyses of Caucasian patients (Z = 3.180, P = 7.4 × 10-4) and Asian patients (Z = 4.487, P = 3.6 × 10-6).

Conclusion

Pooled evidence supports the hypothesis that the COMT Val158Met polymorphism influences the antipsychotic response in Caucasian and Asian schizophrenia patient populations. Prediction of antipsychotic response by patient genotyping may warrant closer consideration in randomized clinical trials of efficacy.

Keywords: COMT, Val158Met, polymorphism, antipsychotics, schizophrenia, clinical response

1. INTRODUCTION

Schizophrenia is a severe mental disorder characterized by hallucinations, delusions, disorganized speech and behavior, and social withdrawal that afflicts approximately 1% of the global population [1, 2]. Antipsychotic drugs are the main clinical treatment for schizophrenia, but individual responses to these drugs vary widely [3]. Although anti-psychotics reduce symptoms in many patients, more than half of patients discontinue treatment or demonstrate poor compliance due to lack of efficacy or intolerable side effects, resulting in clinical exacerbation or psychotic relapse leading to rehospitalization [4, 5]. The reasons for interindividual variations in antipsychotic drug response are not entirely understood, and the optimal drug regimen is still established primarily by trial and error in clinical practice. Pharmacogenetic studies suggest that genetic factors influence betweenpatient variations in antipsychotic response [6, 7]. As most antipsychotics act on the dopaminergic system, mutations in dopamine system-related genes, including multiple loci of dopamine receptors (such as DRD2 and DRD3) [8, 9] and catechol-O-methyltransferase (COMT) [10, 11], have been investigated extensively for effects on the primary antipsychotic response.

The COMT gene is located on chromosome 22q11.2, and mutations in this gene are considered an important contribution to the risk for schizophrenia [12, 13]. The enzyme COMT catalyzes the O-methylation of catecholamine neurotransmitters such as dopamine (DA), epinephrine, and norepinephrine [14]. More precisely, the cortical DA could be degraded by the COMT enzyme [15]. A G→A substitution at codon 158 of the COMT gene exon 4 changes a valine (Val) to methionine (Met) (COMT Val158Met, rs4680), resulting in three-fold to four-fold lower enzyme activity and higher DA levels in the synapse due to less effective degradation [16]. A great deal of pharmacogenetics studies investigating the association between COMT and antipsychotic response have focused on the functional variant Val158Met. Numerous studies have found an association between this rs4680 single nucleotide polymorphism (SNP) and psychiatric disorders, as well as with clinical characteristics and the response to antipsychotic treatment. However, studies of the association between COMT Val158Met and antipsychotic response in schizophrenia have yielded mixed results. A number of studies have observed that Met allele carriers exhibit a better antipsychotic response [17-24], as well as faster improvement of negative symptoms [25, 26]. Additionally, the Met allele also influences cognitive abilities, which are strongly associated with negative symptoms [27, 28]. However, other studies either did not replicate these findings or observed the opposite effect, with the Met allele predicting non-response to antipsychotic therapy [29-41].

These discrepant results may be explained by the low statistical power of some studies, methodological differences (e.g., diagnostic and response criteria), and/or population heterogeneity (such as the ethnic origin of patients). To address this uncertainty, we conducted an updated meta-analysis evaluating the influence of COMT genetic variation on clinical response to antipsychotics in schizophrenia patients.

2. MATERIALS AND METHODS

2.1. Study Design

This study was designed and reported in accordance with the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines [42], and the study protocol is registered at PROSPERO (CRD42020151146).

2.2. Search Strategies

PubMed, Web of Science, EMBASE, OVID, Google Scholar, and Baidu Scholar were searched for relevant studies from database inception to January 2020 using the following search terms: “COMT”, “Val158Met”, “rs4860”, “antipsychotics”, “schizophrenia”, and “clinical response”. In addition, prior meta-analyses, review articles, and the references of included studies were examined to identify additional eligible publications.

2.3. Eligibility Criteria

Two authors independently reviewed the retrieved articles for eligibility according to the following inclusion criteria: 1) studies on the association between the COMT Val158Met polymorphism and antipsychotic response; 2) patients diagnosed with schizophrenia according to DSM-III, DSM-IV, DSM-5, or ICD-10 criteria and verified through a standardized structured clinical interview; 3) antipsychotic response estimated based on a standardized clinical rating scale, such as the Brief Psychiatric Rating Scale (BPRS) or the Positive and Negative Syndrome Scale (PANSS). Studies focused on intermediate phenotypes such as cognitive response or structural brain alterations were excluded. Authors of studies meeting inclusion criteria, but without effect sizes were contacted for this data. A total of 30 independent investigations with 6291 study subjects met inclusion criteria.

To investigate whether ethnicity can affect the association between the COMT Val158Met polymorphism and antipsychotic treatment efficacy, separate subgroup analyses were conducted in Caucasian and Asian populations.

2.4. Quality Assessment

Two authors independently evaluated methodological quality according to the Strengthening the Reporting of Genetic Association Studies (STREGA) recommendations derived from the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist used to evaluate methodological quality of genetic association studies [43]. The methodological quality of included studies is described in Supplementary Table 1 (848.5KB, pdf) .

2.5. P Value Extraction

The P values were extracted independently from each included study by two authors without divergence. If a study did not report an exact statistical outcome (e.g., the article stated only P > 0.05), the authors were contacted to obtain more precise values. If that was unsuccessful, a P value of 1 (indicating a lack of outcome) was assigned. In some instances, several P values were reported for different antipsychotic drugs. In such cases, weighted mean P values were used in the analysis. If studies reported multiple P values for different subgroups, the mean P value for each subgroup was incorporated into the overall analysis.

2.6. Statistical Analysis

After combining eligible studies, the Lipták-Stouffer Z-score was calculated to obtain an aggregate value based on the significance level of tests weighted by sample size. The P value was converted to one-tailed metrics where P < 0.50 indicated greater drug sensitivity in Met allele and P > 0.50 greater sensitivity in Val allele carriers. This one-tailed P value was then converted to a Z score, with positive and negative values corresponding to P values less and greater than 0.50, respectively. The Z score was incorporated into the formula

where the weighting factor Wi corresponds to the study sample size, Zi is the study Z score, and k is the total number of studies. Calculated Zw values conformed to a normal distribution, so the corresponding probability was obtained from a standard normal distribution table. This statistical procedure was applied to all studies and to the stratified analysis of Caucasian and Asian patients.

To determine whether any single study had a disproportionate influence on pooled results, sensitivity analysis was conducted by computing Zw after removing each study individually. The fail-safe N, defined as the minimum number of studies with negative results (assigned P = 0.5 and average sample size) required to change the qualitative conclusions, was calculated for overall analysis and for stratified weighted Lipták-Stouffer analysis to gauge publication bias. The ratio of fail-safe N to the number of published studies provides an estimate of publication bias [44].

3. RESULTS

3.1. Literature Search Results

The study selection procedure is illustrated in Fig. (1). A total of 15,735 potentially relevant records were identified through literature searches, of which 4,509 were duplicates. After screening titles and abstracts, 11,104 additional articles were excluded, leaving 122 full-text articles for eligibility assessment. Of these, 30 studies, including a total of 6,291 subjects, met inclusion criteria. The characteristics of these studies are summarized in Table 1.

Fig. (1).

Fig. (1)

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Flow chart of article screening process. (A higher resolution / colour version of this figure is available in the electronic copy of the article).

Table 1.

Characteristics of studies investigating the association between COMT Polymorphism Val158Met and antipsychotic drug response in patients with schizophrenia.

Study Sample Size Ethnicity Study Design Diagnosis Antipsychotic Drug Response Criteria
Escamilla et al., 2018 218 Mixed Prospective DSM-V Various 30% reduction of PANSS total score at 12 weeks
Sagud et al., 2018 931 Caucasian Retrospective DSM-IV Various 20% reduction of PANSS total score at 6 weeks
Kaneko et al., 2018 40 Asian Prospective DSM-IV Aripiprazole CGI-I score of 1 or 2 or 30% reduction of PANSS total score at 6 weeks
Han et al., 2017 690 Asian Prospective CCMD-3 Risperidone PANSS improvement rate at 8 weeks
CalabrÒ et al., 2017 259 Mixed Retrospective DSM-IV Various PANSS improvement rate
Rajagopal et al., 2017 93 Asian Retrospective DSM-IV Clozapine BPRS total score ≤ 35 at 12 weeks
Escamilla et al., 2017 176 Mixed Prospective DSM-V Various 30% reduction of PANSS total score at 12 weeks
Terzić et al., 2016 138 Caucasian Retrospective DSM-IV Various BPRS total score < 45 or PANSS total score ≤ 3 on selected items at 6 weeks
Chen et al., 2015 102 Asian Prospective DSM-IV Amisulpride 25% reduction of PANSS total score at 12 weeks
Xu et al., 2015 995 Asian Prospective DSM-IV Various 50% reduction of PANSS total score at 8 weeks
Bosia et al., 2015 107 Caucasian Prospective DSM-IV Clozapine PANSS scores at 16 weeks
Bishop et al., 2014 61 Mixed Prospective DSM-IV Various BPRS scores at 6 weeks
Zhao et al., 2012 130 Asian Prospective DSM-IV Risperidone 40% reduction of BPRS total score at 8 weeks
Tybura et al., 2012 191 Caucasian Prospective ICD-10 Various PANSS improvement rate at 12 weeks
Gao et al., 2012 83 Asian Prospective DSM-IV Risperidone PANSS scores at 8 weeks
Prata et al., 2012 55 Mixed Prospective No report Various PANSS improvement rate at 4 weeks
Tybura et al., 2011 43 Caucasian Prospective ICD-10 Various PANSS improvement rate at 12 weeks
Gareeva et al., 2011 242 Caucasian Prospective ICD-10 Various 50% reduction of PANSS total score at days 21and 45
Pelayo-Terán et al., 2011 161 Caucasian Prospective DSM-IV Various SANS and SAPS improvement rate at 6 weeks
Chen et al., 2010 224 Asian Retrospective DSM-IV Various PANSS improvement rate
Fijal et al., 2009 143 Mixed RCT No report Risperidone PANSS improvement rate at 12 weeks
Study Sample Size Ethnicity Study Design Diagnosis Antipsychotic Drug Response Criteria
Gupta et al., 2009 398 Asian Prospective DSM-IV Risperidone CGI-I score of 2 or less at 1 year
Porcelli et al., 2009 132 Caucasian Prospective DSM-IV Various PANSS scores at 4 weeks and 8 weeks
Porcelli et al., 2009 90 Caucasian Prospective DSM-IV Clozapine PANSS scores at 4 weeks and 8 weeks
Tybura et al., 2007 72 Caucasian Prospective ICD-10 Various PANSS improvement rate at 12 weeks
Bertolino et al., 2007 59 Caucasian Prospective DSM-IV Olanzapine 30% reduction of PANSS total score at 8 weeks
Molero et al., 2007 207 Caucasian Prospective DSM-IV Various PANSS scores at 6 months
Anttila et al., 2004 94 Caucasian Retrospective DSM-IV Various Response to treatment with typical neuroleptics at 4 weeks
Yamanouchi et al., 2003 73 Asian Prospective DSM-IV Risperidone PANSS improvement rate at 8 weeks
Illi et al., 2002 84 Caucasian Retrospective DSM-IV Various Response to treatment with typical neuroleptics at 4 weeks
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RCT: randomized controlled trial; DSM-V: Diagnostic and Statistical Manual of Mental Disorders, 5th edition; DSM-IV: Diagnostic and Statistical Manual of Mental Disorders, 4th edition; CCMD-3: Chinese Classification of Mental Disorders and Diagnostic Criteria Version 3; ICD-10: International Classification of Diseases, 10th revision; PANSS: Positive and Negative Syndrome Scale; CGI-I: Clinical Global Impressions Scale-Improvement; BPRS: Brief Psychiatric Rating Scale; SANS: Scale for the Assessment of Negative Symptoms; SAPS: Scale for the Assessment of Positive Symptoms.

3.2. Overall Meta-Analysis

The pooled results of all 30 studies revealed a strong association between the COMT Val158Met polymorphism and antipsychotic response in schizophrenia (P < 0.0001) (Fig. 2). A significant effect of Val158Met on positive symptom improvement was observed. Moreover, the association was maintained after removing each individual study (8 × 10−5 < P < 0.04) with the exception of two [22, 36] (Table 2). According to fail-safe N publication bias evaluation, a non-significant result (P ≥ 0.05) in the overall analysis would require more than 864 unpublished or undiscovered studies of average sample size n = 209 showing no association (P = 0.50), corresponding to a fail-safe ratio of 28 studies excluded for every one included.

Fig. (2).

Fig. (2)

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Forest plot of 30 human studies for the association between COMT Val158Met polymorphism and effectiveness of antipsychotic treatment in schizophrenia. The squares mark indicates the one-tailed P value for each study, where lower values denote greater response to treatment of Met allele carriers and higher values correspond to greater response to treatment of Val allele carriers. The size of the box reflects relative sample size. The red triangle indicates the overall result of meta-analysis. Black squares mark studies that indexed mixed ethnicity; Blue indicates Caucasian; and dark red indicates Asian. (A higher resolution / colour version of this figure is available in the electronic copy of the article).

Table 2.

All Studies meta-analysis of the association between COMT Polymorphism Val158Met and antipsychotic drug response.

Study Sample Size 1-Tailed P Value P Value After Study Exclusion
Escamilla et al., 2018 218 2.9 × 10-16 5.2 × 10-2
Sagud et al., 2018 931 0.1375 2.4 × 10-2
Kaneko et al., 2018 40 0.0875 3.2 × 10-2
Han et al., 2017 690 0.0005 4.7 × 10-2
CalabrÒ et al., 2017 259 0.5 2.7 × 10-2
Rajagopal et al., 2017 93 0.2975 3.1 × 10-2
Escamilla et al., 2017 176 0.02 8.9 × 10-5
Terzić et al., 2016 138 0.4235 3.0 × 10-2
Chen et al., 2015 102 0.332 3.0 × 10-2
Xu et al., 2015 995 0.012 3.8 × 10-2
Bosia et al., 2015 107 0.00005 3.5 × 10-2
Bishop et al., 2014 61 0.475 3.1 × 10-2
Zhao et al., 2012 130 0.47 3.0 × 10-2
Tybura et al., 2012 191 0.495 2.8× 10-2
Gao et al., 2012 83 0.014 3.2 × 10-2
Prata et al., 2012 55 0.001 3.3 × 10-2
Tybura et al., 2011 43 0.1515 3.2 × 10-2
Gareeva et al., 2011 242 0.5 1.9× 10-2
Pelayo-Terán et al., 2011 161 0.288 3.0 × 10-2
Chen et al., 2010 224 0.204 3.0 × 10-2
Fijal et al., 2009 143 0.24 3.0 × 10-2
Gupta et al., 2009 398 0.022 3.3 × 10-2
Porcelli et al., 2009 132 0.00025 3.5 × 10-2
Porcelli et al., 2009 90 0.014 3.3× 10-2
Tybura et al., 2007 72 0.325 3.1 × 10-2
Bertolino et al., 2007 59 0.003 3.3× 10-2
Molero et al., 2007 207 0.00095 3.5 × 10-2
Anttila et al., 2004 94 0.0025 3.3 × 10-2
Yamanouchi et al., 2003 73 0.25 3.1 × 10-2
Illi et al., 2002 84 0.5 3.0 × 10-2
Total 6291 - -
Average sample size 209 9.8 × 10-12 -
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3.3. Caucasians

We identified 14 studies involving 2,551 Caucasian subjects. Meta-analysis revealed a highly significant association between the COMT Val158Met polymorphism and antipsychotic response (P = 0.0007) (Fig. 1), and the result remained significant after removing each study individually in sensitivity analysis (1 × 10−6 < P < 0.004) (Table 3). To yield a non-significant overall outcome (P ≥ 0.05), more than 157 unpublished or undiscovered studies with a null effect (P = 0.50) and average sample size of n = 182 would be required. This corresponds to a fail-safe ratio of 11 studies not included for every included study.

Table 3.

Studies included in the Caucasian group meta-analysis.

Study Sample Size 1-Tailed P Value P Value after Study Exclusion
Sagud et al., 2018 931 0.1375 1.2 × 10-6
Terzić et al., 2016 138 0.4235 7.3 × 10-4
Bosia et al., 2015 107 0.00005 2.6 × 10-3
Tybura et al., 2012 191 0.495 6.2 × 10-4
Tybura et al., 2011 43 0.1515 8.4 × 10-4
Gareeva et al., 2011 242 0.5 5.4 × 10-4
Pelayo-Terán et al., 2011 161 0.288 8.7 × 10-4
Porcelli et al., 2009 132 0.00025 2.8 × 10-3
Porcelli et al., 2009 90 0.014 1.3 × 10-3
Tybura et al., 2007 72 0.325 8.0 × 10-4
Bertolino et al., 2007 59 0.003 1.2 × 10-3
Molero et al., 2007 207 0.00095 4.4 × 10-3
Anttila et al., 2004 94 0.0025 1.6 × 10-3
Illi et al., 2002 84 0.5 7.1 × 10-4
Total 2551 - -
Average sample size 182 7.4 × 10-4 -
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3.4. Asians

The pooled results of 10 studies with a total of 2,828 Asian subjects revealed a significant association between the COMT Val158Met polymorphism and antipsychotic response (P < 0.0001) (Fig. 1), and results were still significant after removing each study individually (6 × 10−6 < P < 0.0005) (Table 4). More than 58 unpublished or undiscovered studies with a null effect (P=0.50) and average sample of n = 282 would be required for a non-significant outcome in the stratified analysis (P ≥ 0.05), corresponding to a fail-safe ratio of 5 excluded studies for every study included.

Table 4.

Studies included in the Asian group meta-analysis.

Study Sample Size 1-Tailed P Value P Value after Study Exclusion
Kaneko et al., 2018 40 0.0875 4.3 × 10-6
Han et al., 2017 690 0.0005 5.9 × 10-4
Rajagopal et al., 2017 93 0.2975 4.1 × 10-6
Chen et al., 2015 102 0.332 4.0 × 10-6
Xu et al., 2015 995 0.012 1.0 × 10-5
Zhao et al., 2012 130 0.47 3.4 × 10-6
Gao et al., 2012 83 0.014 6.6 × 10-6
Chen et al., 2010 224 0.204 5.2 × 10-6
Gupta et al., 2009 398 0.022 2.4 × 10-5
Yamanouchi et al., 2003 73 0.25 4.2 × 10-6
Total 2828 - -
Average sample size 282 3.6 × 10-6 -
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4. DISCUSSION

To our knowledge, this is the most comprehensive meta-analysis of the association between the COMT Val158Met polymorphism and antipsychotic treatment response in schizophrenia since 2016 [45]. The overall meta-analysis of 30 studies including 6,291 subjects demonstrated a strong association between COMT Val158Met and antipsychotic response. There was a significant improvement in symptoms in COMT Val158Met patients. More precisely, Met-allele carriers experienced improved response compared with Val-allele carriers. Moreover, this association was maintained in stratified analyses of Caucasian patients (n = 2,551) and Asian patients (n = 2,828).

These primary conclusions are consistent with a previous meta-analysis and with the majority of the included studies despite assessment of different agents such as olanzapine [28], risperidone [20, 23, 46, 47], clozapine [47-51], aripiprazole [21], haloperidol [47], and typical antipsychotics [17, 52, 53]. Moreover, sensitivity analysis confirmed the stability of this association.

The COMT Val158/108Met polymorphism is the most widely studied in psychiatry due to its functional relevance to dopaminergic transmission, the primary target of most antipsychotics [54-56]. The enzyme encoded by the Met allele [47] has lower thermostability and reduced enzymatic activity, which is predicted to increase levels of synaptic dopamine in cortex and hippocampus. The first investigation of this association by Illi et al. [17] suggested that the Met allele predicted a poorer response to typical antipsychotic treatment. However, this group failed to replicate their initial finding [57] and subsequent studies reported a better response to antipsychotic treatment among Met allele carriers compared to other COMT genotypes [18-23]. It was also reported that the Met allele enhanced negative symptom improvement during treatment with olanzapine [25] or risperidone [26]. Additionally, Met allele carriers showed greater improvement in cognitive function relative to Val carriers following treatment with clozapine [27] or olanzapine [28]. On the contrary, a large number of studies have found no association between the Val158/108Met polymorphism and antipsychotic response [29-41], although some of these investigations likely lacked sufficient power to detect a difference due to insufficient sample size.

These inconsistencies may also be explained by genetic background as ethnicity is an important factor for both schizophrenia susceptibility and antipsychotic drug response. Thus, specific populations may require different doses due to enhanced or reduced efficacy [58]. For example, Asian and Hispanic schizophrenia patients may require lower antipsychotic doses than Caucasian patients matching for size and disease severity [59]. Moreover, Emsley and colleagues found that black and mixed descent schizophrenia patients achieved greater improvements in positive and negative symptoms than Caucasian patients within the same dose range [60]. Consistent with a contribution of the COMT Val158Met polymorphism to these ethnic differences in antipsychotic drug response, the effect on enzyme activity is stronger in some ethnic groups than others. Moreover, COMT Val/Met allele frequency differs across the world. In the first global survey, Palmatier et al. [61] genotyped 1,314 individuals from 30 different populations for the COMT Val158Met polymorphism and found higher heterozygosity in Europe (0.48) than in other regions. In a recent meta-analysis of case-control studies, the Val allele was associated with schizophrenia in Caucasians, but not Asians [62]. To further assess this ethnic dependence on the relationship between the COMT Val158Met polymorphism and antipsychotic treatment response, we stratified the included studies according to patient ethnicity. In contrast to the aforementioned meta-analysis, we found a highly significant association in both Caucasians and Asians, and further sensitivity analysis confirmed the stability of the result in both groups. Consistent with our findings, numerous previous studies have found an association of the Val158Met polymorphism with antipsychotic response in both Caucasians [17, 19, 24, 28, 47, 49, 51-53] and Asians [18, 20-21, 46, 48]. However, another previous meta-analysis found no significant association between Val158Met and antipsychotic response in patients of European ancestry. Thus, further stratified meta-analyses are required as additional studies on specific ethnic groups become available.

This meta-analysis has several limitations. First, several of the included studies have limited statistical power due to their small sample size. Second, we combined studies with markedly different P values weighted by sample size. We used this approach to maximize the number of studies meeting inclusion criteria, thereby reducing potential bias and better reflecting the current evidence accrued across the globe. While sensitivity analysis showed that no single small-scale study influenced the results, inclusion of several may have. This meta-analysis method of combining P values could be improved, however, by a matching approach to calculate heterogeneity as in traditional approaches. Lastly, different criteria for clinical response might contribute to the heterogeneity and confound the overall effect sizes.

CONCLUSION

Our meta-analysis provides evidence that COMT Val158Met is strongly associated with antipsychotic treatment response in both Caucasian and Asian schizophrenia patients. Future studies should also include other putative functional COMT variants such as rs4818, rs737865, and rs6267 to obtain a more comprehensive understanding of how COMT activity influences antipsychotic response [63]. Moreover, given the complexity of the antipsychotic response phenotype, it is likely that other genetic, environmental, and even epigenetic factors are involved, which were beyond the scope of this study. Notably, several studies have provided evidence for multiple gene-gene and gene-environment interactions involving COMT, so investigation of these interactions should further improve our understanding of COMT influences on antipsychotic response

ACKNOWLEDGEMENTS

Shengying Qin and Lin He designed and concerted the study. Jingsong Ma, Mingzhe Zhao, Wei Zhou, Mo Li, Cong Huai, Lu Shen managed the literature searches. Ting Wang, Hao Wu, Na Zhang and Zhiruo Zhang extracted the data from the literatures. Mingzhe Zhao, Jingsong Ma, Wei Zhou and Mo Li analyzed and interpreted the data. Jingsong Ma and Mingzhe Zhao drafted the article. All authors contributed to and have approved the final manuscript.

SUPPLEMENTARY MATERIAL

Supplementary material is available on the publisher’s website along with the published article.

CN-19-1780_SD1.pdf (848.5KB, pdf)

CONFLICT OF INTEREST

This work was supported by grants from the National Nature Science Foundation of China (81773818, 81273596, 30900799, 81671326), National key research and development program (2016YFC0905000, 2016YFC0905002, 2016YFC1200200, 2016YFC0906400). The 4th Three-year Action Plan for Public Health of Shanghai (The Project No. 15GWZK0101), Shanghai Pujiang Program (17PJD020), Shanghai Key Laboratory of Psychotic Disorders (13dz2260500). The authors declare that they have no competing interests.

REFERENCES

  • 1.Thaker G.K., Carpenter W.T., Jr Advances in schizophrenia. Nat. Med. 2001;7(6):667–671. doi: 10.1038/89040. [DOI] [PubMed] [Google Scholar]
  • 2.Jufe G.S. Schizophrenia according to DSM-5. Vertex. 2014;25(113):36–42. [PubMed] [Google Scholar]
  • 3.Huber C.G., Naber D., Lambert M. Incomplete remission and treatment resistance in first-episode psychosis: definition, prevalence and predictors. Expert Opin. Pharmacother. 2008;9(12):2027–2038. doi: 10.1517/14656566.9.12.2027. [DOI] [PubMed] [Google Scholar]
  • 4.Ilyas S., Moncrieff J. Trends in prescriptions and costs of drugs for mental disorders in England, 1998-2010. Br. J. Psychiatry. 2012;200(5):393–398. doi: 10.1192/bjp.bp.111.104257. [DOI] [PubMed] [Google Scholar]
  • 5.Lieberman J.A. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia: efficacy, safety and cost outcomes of CATIE and other trials. J. Clin. Psychiatry. 2007;68(2):e04. doi: 10.4088/JCP.0207e04. [DOI] [PubMed] [Google Scholar]
  • 6.Arranz M.J., de Leon J. Pharmacogenetics and pharmacogenomics of schizophrenia: a review of last decade of research. Mol. Psychiatry. 2007;12(8):707–747. doi: 10.1038/sj.mp.4002009. [DOI] [PubMed] [Google Scholar]
  • 7.Pouget J.G., Müller D.J. Pharmacogenetics of antipsychotic treatment in schizophrenia. Methods Mol. Biol. 2014;1175:557–587. doi: 10.1007/978-1-4939-0956-8_14. [DOI] [PubMed] [Google Scholar]
  • 8.Zhang J.P., Lencz T., Malhotra A.K. D2 receptor genetic variation and clinical response to antipsychotic drug treatment: a meta-analysis. Am. J. Psychiatry. 2010;167(7):763–772. doi: 10.1176/appi.ajp.2009.09040598. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Hwang R., Zai C., Tiwari A., Müller D.J., Arranz M.J., Morris A.G., McKenna P.J., Munro J., Potkin S.G., Lieberman J.A., Meltzer H.Y., Kennedy J.L. Effect of dopamine D3 receptor gene polymorphisms and clozapine treatment response: exploratory analysis of nine polymorphisms and meta-analysis of the Ser9Gly variant. Pharmacogenomics J. 2010;10(3):200–218. doi: 10.1038/tpj.2009.65. [DOI] [PubMed] [Google Scholar]
  • 10.Naumovska Z., Nestorovska A.K., Filipce A., Sterjev Z., Brezovska K., Dimovski A., Suturkova L.J. Pharmacogenetics and antipsychotic treatment response. Prilozi (Makedon. Akad. Nauk. Umet. Odd. Med. Nauki) 2015;36(1):53–67. doi: 10.1515/prilozi-2015-0030. [DOI] [PubMed] [Google Scholar]
  • 11.O’Tuathaigh C.M., Desbonnet L., Lee P., Waddington J.L. Catechol-O-methyl transferase as a drug target for schizophrenia. CNS Neurol. Disord. Drug Targets. 2012;11(3):282–291. doi: 10.2174/187152712800672418. [DOI] [PubMed] [Google Scholar]
  • 12.Lewis C.M., Levinson D.F., Wise L.H., DeLisi L.E., Straub R.E., Hovatta I., Williams N.M., Schwab S.G., Pulver A.E., Faraone S.V., Brzustowicz L.M., Kaufmann C.A., Garver D.L., Gurling H.M., Lindholm E., Coon H., Moises H.W., Byerley W., Shaw S.H., Mesen A., Sherrington R., O’Neill F.A., Walsh D., Kendler K.S., Ekelund J., Paunio T., Lönnqvist J., Peltonen L., O’Donovan M.C., Owen M.J., Wildenauer D.B., Maier W., Nestadt G., Blouin J.L., Antonarakis S.E., Mowry B.J., Silverman J.M., Crowe R.R., Cloninger C.R., Tsuang M.T., Malaspina D., Harkavy-Friedman J.M., Svrakic D.M., Bassett A.S., Holcomb J., Kalsi G., McQuillin A., Brynjolfson J., Sigmundsson T., Petursson H., Jazin E., Zoëga T., Helgason T. Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: Schizophrenia. Am. J. Hum. Genet. 2003;73(1):34–48. doi: 10.1086/376549. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Owen M.J., Williams N.M., O’Donovan M.C. The molecular genetics of schizophrenia: new findings promise new insights. Mol. Psychiatry. 2004;9(1):14–27. doi: 10.1038/sj.mp.4001444. [DOI] [PubMed] [Google Scholar]
  • 14.Weinshilboum R.M., Otterness D.M., Szumlanski C.L. Methylation pharmacogenetics: catechol O-methyltransferase, thiopurine methyltransferase, and histamine N-methyltransferase. Annu. Rev. Pharmacol. Toxicol. 1999;39:19–52. doi: 10.1146/annurev.pharmtox.39.1.19. [DOI] [PubMed] [Google Scholar]
  • 15.Lachman H.M., Papolos D.F., Saito T., Yu Y.M., Szumlanski C.L., Weinshilboum R.M. Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics. 1996;6(3):243–250. doi: 10.1097/00008571-199606000-00007. [DOI] [PubMed] [Google Scholar]
  • 16.Chen J., Lipska B.K., Halim N., Ma Q.D., Matsumoto M., Melhem S., Kolachana B.S., Hyde T.M., Herman M.M., Apud J., Egan M.F., Kleinman J.E., Weinberger D.R. Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain. Am. J. Hum. Genet. 2004;75(5):807–821. doi: 10.1086/425589. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Illi A., Mattila K.M., Kampman O., Anttila S., Roivas M., Lehtimäki T., Leinonen E. Catechol-O-methyltransferase and monoamine oxidase A genotypes and drug response to conventional neuroleptics in schizophrenia. J. Clin. Psychopharmacol. 2003;23(5):429–434. doi: 10.1097/01.jcp.0000088916.02635.33. [DOI] [PubMed] [Google Scholar]
  • 18.Gupta M., Bhatnagar P., Grover S., Kaur H., Baghel R., Bhasin Y., Chauhan C., Verma B., Manduva V., Mukherjee O., Purushottam M., Sharma A., Jain S., Brahmachari S.K., Kukreti R. Association studies of catechol-O-methyltransferase (COMT) gene with schizophrenia and response to antipsychotic treatment. Pharmacogenomics. 2009;10(3):385–397. doi: 10.2217/14622416.10.3.385. [DOI] [PubMed] [Google Scholar]
  • 19.Molero P., Ortuño F., Zalacain M., Patiño-García A. Clinical involvement of catechol-O-methyltransferase polymorphisms in schizophrenia spectrum disorders: influence on the severity of psychotic symptoms and on the response to neuroleptic treatment. Pharmacogenomics J. 2007;7(6):418–426. doi: 10.1038/sj.tpj.6500441. [DOI] [PubMed] [Google Scholar]
  • 20.Han J., Li Y., Wang X. Potential link between genetic polymorphisms of catechol-O-methyltransferase and dopamine receptors and treatment efficacy of risperidone on schizophrenia. Neuropsychiatr. Dis. Treat. 2017;13:2935–2943. doi: 10.2147/NDT.S148824. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Kaneko H., Miura I., Kanno-Nozaki K., Horikoshi S., Hino M., Yabe H. COMT Val 108/158 Met polymorphism and treatment response to aripiprazole in patients with acute schizophrenia. Neuropsychiatr. Dis. Treat. 2018;14:1657–1663. doi: 10.2147/NDT.S164647. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Escamilla R., Camarena B., Saracco-Alvarez R., Fresán A., Hernández S., Aguilar-García A. Association study between COMT, DRD2, and DRD3 gene variants and antipsychotic treatment response in Mexican patients with schizophrenia. Neuropsychiatr. Dis. Treat. 2018;14:2981–2987. doi: 10.2147/NDT.S176455. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Prata D.P., Gafoor R., Kay V., Arranz M., Munro J., McGuire P. Dopaminergic genes influence early response to atypical antipsychotics in patients with first presentation of psychosis. J. Clin. Psychopharmacol. 2012;32(4):566–569. doi: 10.1097/JCP.0b013e31825ec2cb. [DOI] [PubMed] [Google Scholar]
  • 24.Sagud M., Tudor L., Uzun S., Perkovic M.N., Zivkovic M., Konjevod M., Kozumplik O., Vuksan Cusa B., Svob Strac D., Rados I., Mimica N., Mihaljevic Peles A., Nedic Erjavec G., Pivac N. Haplotypic and Genotypic Association of Catechol-O-Methyltransferase rs4680 and rs4818 Polymorphisms and Treatment Resistance in Schizophrenia. Front. Pharmacol. 2018;9:705. doi: 10.3389/fphar.2018.00705. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Bertolino A., Caforio G., Blasi G., Rampino A., Nardini M., Weinberger D.R., Dallapiccola B., Sinibaldi L., Douzgou S. COMT Val158Met polymorphism predicts negative symptoms response to treatment with olanzapine in schizophrenia. Schizophr. Res. 2007;95(1-3):253–255. doi: 10.1016/j.schres.2007.06.014. [DOI] [PubMed] [Google Scholar]
  • 26.Kang C.Y., Xu X.F., Shi Z.Y., Yang J.Z., Liu H., Xu H.H. Interaction of catechol-O-methyltransferase (COMT) Val108/158 Met genotype and risperidone treatment in Chinese Han patients with schizophrenia. Psychiatry Res. 2010;176(1):94–95. doi: 10.1016/j.psychres.2009.02.009. [DOI] [PubMed] [Google Scholar]
  • 27.Woodward N.D., Jayathilake K., Meltzer H.Y. COMT val108/158met genotype, cognitive function, and cognitive improvement with clozapine in schizophrenia. Schizophr. Res. 2007;90(1-3):86–96. doi: 10.1016/j.schres.2006.10.002. [DOI] [PubMed] [Google Scholar]
  • 28.Bertolino A., Caforio G., Blasi G., De Candia M., Latorre V., Petruzzella V., Altamura M., Nappi G., Papa S., Callicott J.H., Mattay V.S., Bellomo A., Scarabino T., Weinberger D.R., Nardini M. Interaction of COMT (Val(108/158)Met) genotype and olanzapine treatment on prefrontal cortical function in patients with schizophrenia. Am. J. Psychiatry. 2004;161(10):1798–1805. doi: 10.1176/ajp.161.10.1798. [DOI] [PubMed] [Google Scholar]
  • 29.Rajagopal V.M., Rajkumar A.P., Jacob K.S., Jacob M. Gene-gene interaction between DRD4 and COMT modulates clinical response to clozapine in treatment-resistant schizophrenia. Pharmacogenet. Genomics. 2018;28(1):31–35. doi: 10.1097/FPC.0000000000000314. [DOI] [PubMed] [Google Scholar]
  • 30.Terzić T., Kastelic M., Dolžan V., Plesničar B.K. Genetic polymorphisms in dopaminergic system and treatment-resistant schizophrenia. Psychiatr. Danub. 2016;28(2):127–131. [PubMed] [Google Scholar]
  • 31.Chen C.Y., Yeh Y.W., Kuo S.C., Ho P.S., Liang C.S., Yen C.H., Lu R.B., Huang S.Y. Catechol-O-methyltransferase gene variants may associate with negative symptom response and plasma concentrations of prolactin in schizophrenia after amisulpride treatment. Psychoneuroendocrinology. 2016;65:67–75. doi: 10.1016/j.psyneuen.2015.12.003. [DOI] [PubMed] [Google Scholar]
  • 32.Bishop J.R., Reilly J.L., Harris M.S., Patel S.R., Kittles R., Badner J.A., Prasad K.M., Nimgaonkar V.L., Keshavan M.S., Sweeney J.A. Pharmacogenetic associations of the type-3 metabotropic glutamate receptor (GRM3) gene with working memory and clinical symptom response to antipsychotics in first-episode schizophrenia. Psychopharmacology (Berl.) 2015;232(1):145–154. doi: 10.1007/s00213-014-3649-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Zhao Q.Z., Liu B.C., Zhang J., Wang L., Li X.W., Wang Y., Ji J., Yang F.P., Wan C.L., Xu Y.F., Feng G.Y., He L., He G. Association between a COMT polymorphism and clinical response to risperidone treatment: a pharmacogenetic study. Psychiatr. Genet. 2012;22(6):298–299. doi: 10.1097/YPG.0b013e328358629a. [DOI] [PubMed] [Google Scholar]
  • 34.Fijal B.A., Kinon B.J., Kapur S., Stauffer V.L., Conley R.R., Jamal H.H., Kane J.M., Witte M.M., Houston J.P. Candidate-gene association analysis of response to risperidone in African-American and white patients with schizophrenia. Pharmacogenomics J. 2009;9(5):311–318. doi: 10.1038/tpj.2009.24. [DOI] [PubMed] [Google Scholar]
  • 35.Yamanouchi Y., Iwata N., Suzuki T., Kitajima T., Ikeda M., Ozaki N. Effect of DRD2, 5-HT2A, and COMT genes on antipsychotic response to risperidone. Pharmacogenomics J. 2003;3(6):356–361. doi: 10.1038/sj.tpj.6500211. [DOI] [PubMed] [Google Scholar]
  • 36.Pelayo-Terán J.M., Pérez-Iglesias R., Vázquez-Bourgon J., Mata I., Carrasco-Marín E., Vázquez-Barquero J.L., Crespo-Facorro B. Catechol-O-methyltransferase Val158Met polymorphism and negative symptoms after acute antipsychotic treatment in first-episode non-affective psychosis. Psychiatry Res. 2011;185(1-2):286–289. doi: 10.1016/j.psychres.2010.06.006. [DOI] [PubMed] [Google Scholar]
  • 37.Tybura P., Samochowiec A., Beszlej A., Grzywacz A., Mak M., Frydecka D., Bieńkowski P., Mierzejewski P., Potemkowski A., Samochowiec J. Some dopaminergic genes polymorphisms are not associated with response to antipsychotic drugs in schizophrenic patients. Pharmacol. Rep. 2012;64(3):528–535. doi: 10.1016/S1734-1140(12)70848-4. [DOI] [PubMed] [Google Scholar]
  • 38.Tybura P., Grzywacz A., Samochowiec A., Samochowiec J. Associations between candidate genes with schizophrenia susceptibility and the treatment efficiency. Psychiatr. Pol. 2011;45(6):811–823. [PubMed] [Google Scholar]
  • 39.Tybura P., Grzywacz A., Syrek S., Parus M., Samochowiec J. Association of functional genes polymorphisms of key enzymes in the metabolism of biogenic amines with paranoid schizophrenia susceptibility and the influence of these polymorphisms on PANSS results in antipsychotic treatment. Psychiatr. Pol. 2006;40(5):913–923. [PubMed] [Google Scholar]
  • 40.Calabrò M., Porcelli S., Crisafulli C., Wang S.M., Lee S.J., Han C., Patkar A.A., Masand P.S., Albani D., Raimondi I., Forloni G., Bin S., Cristalli C., Mantovani V., Pae C.U., Serretti A. Genetic Variants Within Molecular Targets of Antipsychotic Treatment: Effects on Treatment Response, Schizophrenia Risk, and Psychopathological Features. J. Mol. Neurosci. 2018;64(1):62–74. doi: 10.1007/s12031-017-1002-1. [DOI] [PubMed] [Google Scholar]
  • 41.Chen C.Y., Lu R.B., Yeh Y.W., Shih M.C., Huang S.Y. Association study of catechol-O-methyltransferase gene polymorphisms with schizophrenia and psychopathological symptoms in Han Chinese. Genes Brain Behav. 2011;10(3):316–324. doi: 10.1111/j.1601-183X.2010.00670.x. [DOI] [PubMed] [Google Scholar]
  • 42.Stroup D.F., Berlin J.A., Morton S.C., Olkin I., Williamson G.D., Rennie D., Moher D., Becker B.J., Sipe T.A., Thacker S.B. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA. 2000;283(15):2008–2012. doi: 10.1001/jama.283.15.2008. [DOI] [PubMed] [Google Scholar]
  • 43.Little J., Higgins J.P., Ioannidis J.P., Moher D., Gagnon F., von Elm E., Khoury M.J., Cohen B., Davey-Smith G., Grimshaw J., Scheet P., Gwinn M., Williamson R.E., Zou G.Y., Hutchings K., Johnson C.Y., Tait V., Wiens M., Golding J., van Duijn C., McLaughlin J., Paterson A., Wells G., Fortier I., Freedman M., Zecevic M., King R., Infante-Rivard C., Stewart A., Birkett N. STrengthening the REporting of Genetic Association Studies (STREGA): an extension of the STROBE statement. PLoS Med. 2009;6(2):e22. doi: 10.1371/journal.pmed.1000022. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Gleser L.J., Olkin I. Models for estimating the number of unpublished studies. 1996. [DOI] [PubMed]
  • 45.Huang E., Zai C.C., Lisoway A., Maciukiewicz M., Felsky D., Tiwari A.K., Bishop J.R., Ikeda M., Molero P., Ortuno F., Porcelli S., Samochowiec J., Mierzejewski P., Gao S., Crespo-Facorro B., Pelayo-Terán J.M., Kaur H., Kukreti R., Meltzer H.Y., Lieberman J.A., Potkin S.G., Müller D.J., Kennedy J.L. Catechol-O-Methyltransferase Val158Met Polymorphism and Clinical Response to Antipsychotic Treatment in Schizophrenia and Schizo-Affective Disorder Patients: a Meta-Analysis. Int. J. Neuropsychopharmacol. 2016;19(5):pyv132. doi: 10.1093/ijnp/pyv132. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Gao S., Hu Z., Cheng J., Zhou W., Xu Y., Xie S., Liu S., Li Z., Guo J., Dong J., Huang M. Impact of catechol-o-methyltransferase polymorphisms on risperidone treatment for schizophrenia and its potential clinical significance. Clin. Biochem. 2012;45(10-11):787–792. doi: 10.1016/j.clinbiochem.2012.04.016. [DOI] [PubMed] [Google Scholar]
  • 47.Porcelli S.B.M., Marino E., Angelone S.M., Smeraldi E., Cavallaro R. Association study of COMT Val108/158Met polymorphism and treatment response to haloperidol, risperidone and clozapine. Eur. Neuropsychopharmacol. 2009;19:S73–S74. doi: 10.1016/S0924-977X(09)70084-7. [DOI] [Google Scholar]
  • 48.Xu Q., Wu X., Li M., Huang H., Minica C., Yi Z., Wang G., Shen L., Xing Q., Shi Y., He L., Qin S. Association studies of genomic variants with treatment response to risperidone, clozapine, quetiapine and chlorpromazine in the Chinese Han population. Pharmacogenomics J. 2016;16(4):357–365. doi: 10.1038/tpj.2015.61. [DOI] [PubMed] [Google Scholar]
  • 49.Bosia M., Lorenzi C., Pirovano A., Guglielmino C., Cocchi F., Spangaro M., Bramanti P., Smeraldi E., Cavallaro R. COMT Val158Met and 5-HT1A-R -1019 C/G polymorphisms: effects on the negative symptom response to clozapine. Pharmacogenomics. 2015;16(1):35–44. doi: 10.2217/pgs.14.150. [DOI] [PubMed] [Google Scholar]
  • 50.Escamilla R.C.B., Fresán A., Saracco R., Hernández S., Aguilar A. Pharmacogenetic Study of Antipsychotic Response To Treatment In Mexican Patients with Schizophrenia: Analysis of Response And Resistance. Eur. Neuropsychopharmacol. 2017;27:S405. doi: 10.1016/j.euroneuro.2016.09.446. [DOI] [Google Scholar]
  • 51.Porcelli S.B.M., Cocchi F., Marino E., Smeraldi E., Cavallaro R. Effect of 5-HT1a and catechol-O-methyltransferase gene polymorphisms on negative symptom response to clozapine. Eur. Neuropsychopharmacol. 2009;19:S546–S547. doi: 10.1016/S0924-977X(09)70870-3. [DOI] [Google Scholar]
  • 52.Anttila S., Illi A., Kampman O., Mattila K.M., Lehtimäki T., Leinonen E. Interaction between NOTCH4 and catechol-O-methyltransferase genotypes in schizophrenia patients with poor response to typical neuroleptics. Pharmacogenetics. 2004;14(5):303–307. doi: 10.1097/00008571-200405000-00005. [DOI] [PubMed] [Google Scholar]
  • 53.Gareeva A.Z.D., Kuznetsov D., Samigullina L., Akhmerova I., Valinurov R., Khusnutdinova E. Genetic polymorphisms in dopamine-related genes and treatment response to typical antipsychotics. Eur. Neuropsychopharmacol. 2011;21:S237. doi: 10.1016/S0924-977X(11)70364-9. [DOI] [Google Scholar]
  • 54.Egan M.F., Goldberg T.E., Kolachana B.S., Callicott J.H., Mazzanti C.M., Straub R.E., Goldman D., Weinberger D.R. Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc. Natl. Acad. Sci. USA. 2001;98(12):6917–6922. doi: 10.1073/pnas.111134598. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Shifman S., Bronstein M., Sternfeld M., Pisanté-Shalom A., Lev-Lehman E., Weizman A., Reznik I., Spivak B., Grisaru N., Karp L., Schiffer R., Kotler M., Strous R.D., Swartz-Vanetik M., Knobler H.Y., Shinar E., Beckmann J.S., Yakir B., Risch N., Zak N.B., Darvasi A. A highly significant association between a COMT haplotype and schizophrenia. Am. J. Hum. Genet. 2002;71(6):1296–1302. doi: 10.1086/344514. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Costas J., Sanjuán J., Ramos-Ríos R., Paz E., Agra S., Ivorra J.L., Páramo M., Brenlla J., Arrojo M. Heterozygosity at catechol-O-methyltransferase Val158Met and schizophrenia: new data and meta-analysis. J. Psychiatr. Res. 2011;45(1):7–14. doi: 10.1016/j.jpsychires.2010.04.021. [DOI] [PubMed] [Google Scholar]
  • 57.Illi A., Kampman O., Hänninen K., Anttila S., Mattila K.M., Katila H., Rontu R., Hurme M., Lehtimäki T., Leinonen E. Catechol-O-methyltransferase val108/158met genotype and response to antipsychotic medication in schizophrenia. Hum. Psychopharmacol. 2007;22(4):211–215. doi: 10.1002/hup.841. [DOI] [PubMed] [Google Scholar]
  • 58.Frackiewicz E.J., Sramek J.J., Herrera J.M., Kurtz N.M., Cutler N.R. Ethnicity and antipsychotic response. Ann. Pharmacother. 1997;31(11):1360–1369. doi: 10.1177/106002809703101114. [DOI] [PubMed] [Google Scholar]
  • 59.Collazo Y., Tam R., Sramek J., Herrera J. Neuroleptic dosing in Hispanic and Asian Inpatients with schizophrenia. Mt. Sinai J. Med. 1996;63(5-6):310–313. [PubMed] [Google Scholar]
  • 60.Emsley R.A., Roberts M.C., Rataemane S., Pretorius J., Oosthuizen P.P., Turner J., Niehaus D.J., Keyter N., Stein D.J. Ethnicity and treatment response in schizophrenia: a comparison of 3 ethnic groups. J. Clin. Psychiatry. 2002;63(1):9–14. doi: 10.4088/JCP.v63n0103. [DOI] [PubMed] [Google Scholar]
  • 61.Palmatier M.A., Kang A.M., Kidd K.K. Global variation in the frequencies of functionally different catechol-O-methyltransferase alleles. Biol. Psychiatry. 1999;46(4):557–567. doi: 10.1016/S0006-3223(99)00098-0. [DOI] [PubMed] [Google Scholar]
  • 62.González-Castro T.B., Hernández-Díaz Y., Juárez-Rojop I.E., López-Narváez M.L., Tovilla-Zárate C.A., Fresan A. The Role of a Catechol-O-Methyltransferase (COMT) Val158Met Genetic Polymorphism in Schizophrenia: A Systematic Review and Updated Meta-analysis on 32,816 Subjects. Neuromolecular Med. 2016;18(2):216–231. doi: 10.1007/s12017-016-8392-z. [DOI] [PubMed] [Google Scholar]
  • 63.Allen N.C., Bagade S., McQueen M.B., Ioannidis J.P., Kavvoura F.K., Khoury M.J., Tanzi R.E., Bertram L. Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database. Nat. Genet. 2008;40(7):827–834. doi: 10.1038/ng.171. [DOI] [PubMed] [Google Scholar]

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