Get to know a gene: COMT
What is COMT?
The COMT gene encodes catechol-O-methyltransferase, an enzyme that breaks down synaptic dopamine (DA) and norepinephrine (NE). The best studied polymorphism of the COMT gene is a single G>A substitution at codon 158 (rs4680), resulting in a valine (Val) to methionine (Met) amino acid change. This Val158Met polymorphism results in a decrease in COMT enzymatic activity, which can be described in a trimodal pattern for three genotypes: high in Val/Val, intermediate in Val/Met, and low in Met/Met.1,2 Reduced COMT activity results in less catecholamine degradation and can lead to increased baseline levels of synaptic DA/NE.
Is there a connection between COMT Val158Met genotype and antidepressant treatment outcomes?
Thirty-one studies and two meta-analyses assessed the relationship between the COMT Val158Met polymorphism and treatment outcomes with antidepressant therapy (Table 1). Four studies (n=624) found better outcomes with the Val allele3-6, and five studies (n=734) found better outcomes with the Met allele7-11. However, twenty-two studies (n=6325) found no relationship between COMT genotype and outcomes with various antidepressants.12-33 A meta-analysis of 4 studies and data from the STAR*D trial (n=2510) demonstrated the lack of association between the COMT Val158Met polymorphism and the likelihood of response/remission with antidepressant therapy (ORresponse=0.88, p=0.40; ORremission=1.01, p=0.96).34 Similarly, a more recent meta-analysis of 8 studies (n=2564) did not find a significant effect of the Val158Met polymorphism on outcomes with antidepressant pharmacotherapy across the three possible genotypes in different genetic models (ORdominant=0.72, p=0.09; ORrecessive=0.90, p=0.70).35 Both meta-analyses noted heterogeneity between studies in factors such as patient populations, assessment scales, treatment modalities, etc.
What does the literature say about COMT Val158Met genotype and the response to antipsychotic therapy?
Thirty-four studies and two meta-analyses assessed the relationship between the COMT Val158Met polymorphism and the likelihood of response with antipsychotic therapy (Table 1). Four studies (n=465) found better outcomes with the Val allele36-39, and five studies (n=938) found better outcomes with the Met allele40-44. However, twenty-five studies (n=5343) found no association between COMT genotype and outcomes with antipsychotic therapy.45-69 Interestingly, despite this distribution of data, two meta-analyses demonstrated improved outcomes with the Met allele.70,71 The first meta-analysis combined data from 10 studies and 5 independent samples (n=1416).70 In this cohort of primarily European patients, those with the Met/Met genotype were significantly more likely to be responders than Val-allele carriers (OR=1.37, p=0.039). However, the authors noted that this association would not be significant after Bonferroni correction for multiple testing. The second meta-analysis combined data from 30 articles (n=6291), which included a mixed cohort of mostly Caucasian and Asian patients, and found improved response with the Met allele compared to the Val allele (OR: not reported, p<0.001). However, this meta-analysis collected data from non-peer reviewed sources including poster sessions and ‘Letters to the Editor’. Therefore, the results of this second meta-analysis should be approached with caution.
How does the COMT Val158Met genotype impact the risk of side effects with antipsychotic therapy?
Twenty-one studies and two meta-analyses assessed the relationship between the COMT Val158Met polymorphism and the risk of antipsychotic-induced side effects (Table 1). One study (n=335) found improved outcomes with the Val allele72, and two studies (n=297) found improved outcomes with the Met allele68,73. Eighteen studies (n=4208) found no association between COMT Val158Met genotype and the risk of adverse events with antipsychotic therapy.74-91 One of these studies combined the results from their trial with data from 6 other studies (n=1520) and found no differential risk (OR=1.38, p=0.10) for developing side effects based on the COMT Val158Met polymorphism81. However, one meta-analysis of five studies (n=1089) found a significantly lower risk of tardive dyskinesia (TD) for Met carriers compared to Val/Val patients in the fixed effects model (OR=0.66, p=0.005).92 Interestingly, further analysis demonstrated significant differences in the risk of developing TD between Val/Val and Val/Met patients (OR=0.63, p=0.004), but not between Val/Val and Met/Met patients (OR=0.73, p=0.157). In contrast, a later meta-analysis of 11 studies (n=2886) did not find an association between COMT Val158Met polymorphism and the risk of side effects with antipsychotic therapy across the three genotypes in different genetic models (ORdominant=0.98, p=0.87; ORrecessive=1.15, p=0.21).93
Is there a connection between COMT Val158Met genotype and response to methylphenidate (MPH)?
Thirteen studies and a meta-analysis assessed the relationship between the COMT Val158Met polymorphism and the efficacy of MPH for treating ADHD (Table 1). Three studies (n=366) found that the Val allele had an improved response to MPH.94-96 Only 1 study (n=126) found that the Met allele was associated with an improved response to MPH.97 In contrast, nine studies (n=1076) found that COMT genotype was not associated with differential outcomes after MPH therapy.98-106 While the meta-analysis (n=699) found that Val/Val patients tended to have improved outcomes compared to Met carriers (OR=1.40, p=0.02), effect sizes were estimated from seven different studies despite the use of different subject assessment scales and high heterogeneity between samples.107
Is there a connection between COMT Val158Met genotype and treatment outcomes with amphetamines (AMP)?
There are currently no pharmacogenetic studies that have investigated the effect of the COMT Val158Met polymorphism on amphetamine therapy in ADHD patients. However, five studies assessed the relationship between the COMT Val158Met polymorphism and AMP response in healthy adults (Table 1). The first two studies (n=187) found better outcomes in patients with the Val allele.108,109 However, three subsequent studies (n=627) found no association between the Val158Met polymorphism and response to amphetamines.110-112 Two of these studies (n=581)110,111 attempted to replicate the results of the two earlier studies (n=187)108,109 with larger sample sizes, but were not able to find a significant association between COMT Val158Met genotype and treatment outcomes with amphetamines.
Table 1. Summary of literature assessing the effect of the COMT Val158Met polymorphism on treatment outcomes with psychotropic medications. α: This number includes 1 meta-analysis. ß: This number includes 2 meta-analyses.
|Treatment||No Association||Better with Val||Better with Met|
|Antipsychotics: Side Effects||19α||1||3α|
- Lachman, H. M. et al. Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics 6, 243-250, doi:10.1097/00008571-199606000-00007 (1996).
- Chen, J. et al. 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 75, 807-821, doi:10.1086/425589 (2004).
- Woo, J. M. et al. The association between panic disorder and the L/L genotype of catechol-O-methyltransferase. J Psychiatr Res 38, 365-370, doi:10.1016/j.jpsychires.2004.01.001 (2004).
- Szegedi, A. et al. The catechol-O-methyltransferase Val108/158Met polymorphism affects short-term treatment response to mirtazapine, but not to paroxetine in major depression. Pharmacogenomics J 5, 49-53, doi:10.1038/sj.tpj.6500289 (2005).
- Hopkins, S. C., Reasner, D. S. & Koblan, K. S. Catechol-O-methyltransferase genotype as modifier of superior responses to venlafaxine treatment in major depressive disorder. Psychiatry Res 208, 285-287, doi:10.1016/j.psychres.2013.04.021 (2013).
- Fawver, J., Flanagan, M., Smith, T., Drouin, M. & Mirro, M. The association of COMT genotype with buproprion treatment response in the treatment of major depressive disorder. Brain Behav 10, e01692, doi:10.1002/brb3.1692 (2020).
- Baune, B. T. et al. Association of the COMT val158met variant with antidepressant treatment response in major depression. Neuropsychopharmacology 33, 924-932, doi:10.1038/sj.npp.1301462 (2008).
- Benedetti, F., Colombo, C., Pirovano, A., Marino, E. & Smeraldi, E. The catechol-O-methyltransferase Val(108/158)Met polymorphism affects antidepressant response to paroxetine in a naturalistic setting. Psychopharmacology (Berl) 203, 155-160, doi:10.1007/s00213-008-1381-7 (2009).
- Tsai, S. J. et al. Sexually dimorphic effect of catechol-O-methyltransferase val158met polymorphism on clinical response to fluoxetine in major depressive patients. J Affect Disord 113, 183-187, doi:10.1016/j.jad.2008.04.017 (2009).
- Spronk, D., Arns, M., Barnett, K. J., Cooper, N. J. & Gordon, E. An investigation of EEG, genetic and cognitive markers of treatment response to antidepressant medication in patients with major depressive disorder: a pilot study. J Affect Disord 128, 41-48, doi:10.1016/j.jad.2010.06.021 (2011).
- Vulink, N. C. et al. Catechol-O-methyltranferase gene expression is associated with response to citalopram in obsessive-compulsive disorder. Int J Psychiatry Clin Pract 16, 277-283, doi:10.3109/13651501.2011.653375 (2012).
- Arias, B. et al. Analysis of COMT gene (Val 158 Met polymorphism) in the clinical response to SSRIs in depressive patients of European origin. J Affect Disord 90, 251-256, doi:10.1016/j.jad.2005.11.008 (2006).
- Perlis, R. H. et al. Variation in catechol-O-methyltransferase is associated with duloxetine response in a clinical trial for major depressive disorder. Biol Psychiatry 65, 785-791, doi:10.1016/j.biopsych.2008.10.002 (2009).
- Benedetti, F. et al. Effect of catechol-O-methyltransferase Val(108/158)Met polymorphism on antidepressant efficacy of fluvoxamine. Eur Psychiatry 25, 476-478, doi:10.1016/j.eurpsy.2009.12.007 (2010).
- Bukh, J. D. et al. No interactions between genetic polymorphisms and stressful life events on outcome of antidepressant treatment. Eur Neuropsychopharmacol 20, 327-335, doi:10.1016/j.euroneuro.2009.11.004 (2010).
- Gudayol-Ferre, E. et al. The role of clinical variables, neuropsychological performance and SLC6A4 and COMT gene polymorphisms on the prediction of early response to fluoxetine in major depressive disorder. J Affect Disord 127, 343-351, doi:10.1016/j.jad.2010.06.002 (2010).
- Illi, A. et al. Catechol-O-methyltransferase val108/158met genotype, major depressive disorder and response to selective serotonin reuptake inhibitors in major depressive disorder. Psychiatry Res 176, 85-87, doi:10.1016/j.psychres.2009.03.010 (2010).
- Kocabas, N. A. et al. The impact of catechol-O-methyltransferase SNPs and haplotypes on treatment response phenotypes in major depressive disorder: a case-control association study. Int Clin Psychopharmacol 25, 218-227, doi:10.1097/YIC.0b013e328338b884 (2010).
- Miguita, K., Cordeiro, Q., Shavitt, R. G., Miguel, E. C. & Vallada, H. Association study between genetic monoaminergic polymorphisms and OCD response to clomipramine treatment. Arq Neuropsiquiatr 69, 283-287, doi:10.1590/s0004-282×2011000300003 (2011).
- Xu, Z. et al. Influence and interaction of genetic polymorphisms in catecholamine neurotransmitter systems and early life stress on antidepressant drug response. J Affect Disord 133, 165-173, doi:10.1016/j.jad.2011.04.011 (2011).
- Ji, Y. et al. Catechol O-methyltransferase pharmacogenomics and selective serotonin reuptake inhibitor response. Pharmacogenomics J 12, 78-85, doi:10.1038/tpj.2010.69 (2012).
- Narasimhan, S., Aquino, T. D., Multani, P. K., Rickels, K. & Lohoff, F. W. Variation in the catechol-O-methyltransferase (COMT) gene and treatment response to venlafaxine XR in generalized anxiety disorder. Psychiatry Res 198, 112-115, doi:10.1016/j.psychres.2011.12.034 (2012).
- Perlis, R. H., Fijal, B., Dharia, S. & Houston, J. P. Pharmacogenetic investigation of response to duloxetine treatment in generalized anxiety disorder. Pharmacogenomics J 13, 280-285, doi:10.1038/tpj.2011.62 (2013).
- Serretti, A. et al. No effect of serotoninergic gene variants on response to interpersonal counseling and antidepressants in major depression. Psychiatry Investig 10, 180-189, doi:10.4306/pi.2013.10.2.180 (2013).
- Chiesa, A. et al. Lack of influence of rs4680 (COMT) and rs6276 (DRD2) on diagnosis and clinical outcomes in patients with major depression. Int J Psychiatry Clin Pract 18, 97-102, doi:10.3109/13651501.2014.894073 (2014).
- Fukui, N. et al. Promoter variation in the catechol-O-methyltransferase gene is associated with remission of symptoms during fluvoxamine treatment for major depression. Psychiatry Res 218, 353-355, doi:10.1016/j.psychres.2014.04.030 (2014).
- Atake, K., Yoshimura, R., Hori, H., Katsuki, A. & Nakamura, J. Catechol-O-methyltransferase Val158Met genotype and the clinical responses to duloxetine treatment or plasma levels of 3-methoxy-4-hydroxyphenylglycol and homovanillic acid in Japanese patients with major depressive disorder. Neuropsychiatr Dis Treat 11, 967-974, doi:10.2147/NDT.S80953 (2015).
- Kautzky, A. et al. The combined effect of genetic polymorphisms and clinical parameters on treatment outcome in treatment-resistant depression. Eur Neuropsychopharmacol 25, 441-453, doi:10.1016/j.euroneuro.2015.01.001 (2015).
- Umehara, H. et al. No association between the COMT Val158Met polymorphism and the long-term clinical response in obsessive-compulsive disorder in the Japanese population. Hum Psychopharmacol 30, 372-376, doi:10.1002/hup.2485 (2015).
- Taranu, A. et al. The Catechol-O-methyltransferase Val(108/158)Met Genetic Polymorphism cannot be Recommended as a Biomarker for the Prediction of Venlafaxine Efficacy in Patients Treated in Psychiatric Settings. Basic Clin Pharmacol Toxicol 121, 435-441, doi:10.1111/bcpt.12827 (2017).
- Calabro, M. et al. Neuroplasticity, Neurotransmission and Brain-Related Genes in Major Depression and Bipolar Disorder: Focus on Treatment Outcomes in an Asiatic Sample. Adv Ther 35, 1656-1670, doi:10.1007/s12325-018-0781-2 (2018).
- Brunoni, A. R. et al. Association of BDNF, HTR2A, TPH1, SLC6A4, and COMT polymorphisms with tDCS and escitalopram efficacy: ancillary analysis of a double-blind, placebo-controlled trial. Braz J Psychiatry 42, 128-135, doi:10.1590/1516-4446-2019-0620 (2020).
- Zou, Z., Huang, Y., Wang, J., Min, W. & Zhou, B. The association between serotonin-related gene polymorphisms and susceptibility and early sertraline response in patients with panic disorder. BMC Psychiatry 20, 388, doi:10.1186/s12888-020-02790-y (2020).
- Niitsu, T., Fabbri, C., Bentini, F. & Serretti, A. Pharmacogenetics in major depression: a comprehensive meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry 45, 183-194, doi:10.1016/j.pnpbp.2013.05.011 (2013).
- Tang, Z., Zhang, S., Guo, D. & Wang, H. Association between COMT gene Val108/158Met and antidepressive treatment response: A meta-analysis. Gene 734, 144333, doi:10.1016/j.gene.2020.144333 (2020).
- Illi, A. et al. Catechol-O-methyltransferase and monoamine oxidase A genotypes and drug response to conventional neuroleptics in schizophrenia. J Clin Psychopharmacol 23, 429-434, doi:10.1097/01.jcp.0000088916.02635.33 (2003).
- Anttila, S. et al. Interaction between NOTCH4 and catechol-O-methyltransferase genotypes in schizophrenia patients with poor response to typical neuroleptics. Pharmacogenetics 14, 303-307, doi:10.1097/00008571-200405000-00005 (2004).
- Bosia, M. et al. COMT Val158Met and 5-HT1A-R -1019 C/G polymorphisms: effects on the negative symptom response to clozapine. Pharmacogenomics 16, 35-44, doi:10.2217/pgs.14.150 (2015).
- Escamilla, R. et al. Association study between COMT, DRD2, and DRD3 gene variants and antipsychotic treatment response in Mexican patients with schizophrenia. Neuropsychiatr Dis Treat 14, 2981-2987, doi:10.2147/NDT.S176455 (2018).
- Woodward, N. D., Jayathilake, K. & Meltzer, H. Y. COMT val108/158met genotype, cognitive function, and cognitive improvement with clozapine in schizophrenia. Schizophr Res 90, 86-96, doi:10.1016/j.schres.2006.10.002 (2007).
- Arts, B., Simons, C. J., Drukker, M. & van Os, J. Antipsychotic medications and cognitive functioning in bipolar disorder: moderating effects of COMT Val108/158 Met genotype. BMC Psychiatry 13, 63, doi:10.1186/1471-244X-13-63 (2013).
- 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 13, 2935-2943, doi:10.2147/NDT.S148824 (2017).
- Kaneko, H. et al. COMT Val 108/158 Met polymorphism and treatment response to aripiprazole in patients with acute schizophrenia. Neuropsychiatr Dis Treat 14, 1657-1663, doi:10.2147/NDT.S164647 (2018).
- Nelson, C. L. M. et al. Beneficial and adverse effects of antipsychotic medication on cognitive flexibility are related to COMT genotype in first episode psychosis. Schizophr Res 202, 212-216, doi:10.1016/j.schres.2018.06.029 (2018).
- Yamanouchi, Y. et al. Effect of DRD2, 5-HT2A, and COMT genes on antipsychotic response to risperidone. Pharmacogenomics J 3, 356-361, doi:10.1038/sj.tpj.6500211 (2003).
- Bertolino, A. et al. Interaction of COMT (Val(108/158)Met) genotype and olanzapine treatment on prefrontal cortical function in patients with schizophrenia. Am J Psychiatry 161, 1798-1805, doi:10.1176/ajp.161.10.1798 (2004).
- Weickert, T. W. et al. Catechol-O-methyltransferase val108/158met genotype predicts working memory response to antipsychotic medications. Biol Psychiatry 56, 677-682, doi:10.1016/j.biopsych.2004.08.012 (2004).
- Molero, P., Ortuno, F., Zalacain, M. & Patino-Garcia, 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 7, 418-426, doi:10.1038/sj.tpj.6500441 (2007).
- Fijal, B. A. et al. Candidate-gene association analysis of response to risperidone in African-American and white patients with schizophrenia. Pharmacogenomics J 9, 311-318, doi:10.1038/tpj.2009.24 (2009).
- Gupta, M. et al. Association studies of catechol-O-methyltransferase (COMT) gene with schizophrenia and response to antipsychotic treatment. Pharmacogenomics 10, 385-397, doi:10.2217/14622418.104.22.1685 (2009).
- Pelayo-Teran, J. M. et al. Catechol-O-methyltransferase Val158Met polymorphism and negative symptoms after acute antipsychotic treatment in first-episode non-affective psychosis. Psychiatry Res 185, 286-289, doi:10.1016/j.psychres.2010.06.006 (2011).
- Rebollo-Mesa, I. et al. COMT (Val(158/108)Met) genotype moderates the impact of antipsychotic medication on verbal IQ in twins with schizophrenia. Psychiatr Genet 21, 98-105, doi:10.1097/YPG.0b013e32834371a7 (2011).
- Gao, S. et al. Impact of catechol-o-methyltransferase polymorphisms on risperidone treatment for schizophrenia and its potential clinical significance. Clin Biochem 45, 787-792, doi:10.1016/j.clinbiochem.2012.04.016 (2012).
- Tybura, P. et al. Some dopaminergic genes polymorphisms are not associated with response to antipsychotic drugs in schizophrenic patients. Pharmacol Rep 64, 528-535, doi:10.1016/s1734-1140(12)70848-4 (2012).
- Vehof, J. et al. Clinical response to antipsychotic drug treatment: association study of polymorphisms in six candidate genes. Eur Neuropsychopharmacol 22, 625-631, doi:10.1016/j.euroneuro.2012.01.006 (2012).
- Zhao, Q. Z. et al. Association between a COMT polymorphism and clinical response to risperidone treatment: a pharmacogenetic study. Psychiatr Genet 22, 298-299, doi:10.1097/YPG.0b013e328358629a (2012).
- Bishop, J. R. et al. 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) 232, 145-154, doi:10.1007/s00213-014-3649-4 (2015).
- Chen, C. Y. et al. Catechol-O-methyltransferase gene variants may associate with negative symptom response and plasma concentrations of prolactin in schizophrenia after amisulpride treatment. Psychoneuroendocrinology 65, 67-75, doi:10.1016/j.psyneuen.2015.12.003 (2016).
- Terzic, T., Kastelic, M., Dolzan, V. & Plesnicar, B. K. Genetic polymorphisms in dopaminergic system and treatment-resistant schizophrenia. Psychiatr Danub 28, 127-131 (2016).
- Xu, Q. et al. Association studies of genomic variants with treatment response to risperidone, clozapine, quetiapine and chlorpromazine in the Chinese Han population. Pharmacogenomics J 16, 357-365, doi:10.1038/tpj.2015.61 (2016).
- Shi, Y. et al. Combined study of genetic and epigenetic biomarker risperidone treatment efficacy in Chinese Han schizophrenia patients. Transl Psychiatry 7, e1170, doi:10.1038/tp.2017.143 (2017).
- Calabro, M. et al. Genetic Variants Within Molecular Targets of Antipsychotic Treatment: Effects on Treatment Response, Schizophrenia Risk, and Psychopathological Features. J Mol Neurosci 64, 62-74, doi:10.1007/s12031-017-1002-1 (2018).
- 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 28, 31-35, doi:10.1097/FPC.0000000000000314 (2018).
- Sagud, M. et al. Haplotypic and Genotypic Association of Catechol-O-Methyltransferase rs4680 and rs4818 Polymorphisms and Treatment Resistance in Schizophrenia. Front Pharmacol 9, 705, doi:10.3389/fphar.2018.00705 (2018).
- Sun, Z. et al. Association between COMT gene polymorphisms, clinical symptoms, and cognitive functions in Han Chinese patients with schizophrenia. Psychiatr Genet 28, 47-54, doi:10.1097/YPG.0000000000000194 (2018).
- Hajj, A. et al. Clinical and Genetic Factors Associated with Resistance to Treatment in Patients with Schizophrenia: A Case-Control Study. Int J Mol Sci 20, doi:10.3390/ijms20194753 (2019).
- Nikolac Perkovic, M. et al. Catechol-O-methyltransferase rs4680 and rs4818 haplotype association with treatment response to olanzapine in patients with schizophrenia. Sci Rep 10, 10049, doi:10.1038/s41598-020-67351-5 (2020).
- Punchaichira, T. J., Kukshal, P., Bhatia, T., Deshpande, S. N. & Thelma, B. K. The effect of rs1076560 (DRD2) and rs4680 (COMT) on tardive dyskinesia and cognition in schizophrenia subjects. Psychiatr Genet 30, 125-135, doi:10.1097/YPG.0000000000000258 (2020).
- Peitl, V. et al. Long acting aripiprazole influences cognitive functions in recent onset schizophrenia. Psychopharmacology (Berl), doi:10.1007/s00213-021-05788-w (2021).
- Huang, E. et al. Catechol-O-Methyltransferase Val158Met Polymorphism and Clinical Response to Antipsychotic Treatment in Schizophrenia and Schizo-Affective Disorder Patients: a Meta-Analysis. Int J Neuropsychopharmacol 19, doi:10.1093/ijnp/pyv132 (2016).
- Ma, J. et al. Association between the COMT Val158Met polymorphism and antipsychotic efficacy in schizophrenia: an updated meta-analysis. Curr Neuropharmacol, doi:10.2174/1570159X18666201023154049 (2020).
- Srivastava, V. et al. Genetic susceptibility to tardive dyskinesia among schizophrenia subjects: IV. Role of dopaminergic pathway gene polymorphisms. Pharmacogenet Genomics 16, 111-117, doi:10.1097/01.fpc.0000184957.98150.0f (2006).
- Doug-Hyun Han, J.-H. L., Young-Sik Lee, Baik-Seok Kee, Kyung Joon Min, Chul Na. The Association between Tardive Dyskinesia Induced by Haloperidol and Polymorphisms in the Serotonin Transporter Gene and Catecholamine-OMethyltransferase Gene in Korean Schizophrenic Patients. Clinical Psychopharmacology and Neuroscience 3, 5 (2005).
- Herken, H., Erdal, M. E., Boke, O. & Savas, H. A. Tardive dyskinesia is not associated with the polymorphisms of 5-HT2A receptor gene, serotonin transporter gene and catechol-o-methyltransferase gene. Eur Psychiatry 18, 77-81, doi:10.1016/s0924-9338(03)00005-1 (2003).
- Inada, T., Nakamura, A. & Iijima, Y. Relationship between catechol-O-methyltransferase polymorphism and treatment-resistant schizophrenia. Am J Med Genet B Neuropsychiatr Genet 120B, 35-39, doi:10.1002/ajmg.b.20023 (2003).
- Matsumoto, C., Shinkai, T., Hori, H., Ohmori, O. & Nakamura, J. Polymorphisms of dopamine degradation enzyme (COMT and MAO) genes and tardive dyskinesia in patients with schizophrenia. Psychiatry Res 127, 1-7, doi:10.1016/j.psychres.2004.03.011 (2004).
- Lai, I. C. et al. Negative association between catechol-O-methyltransferase (COMT) gene Val158Met polymorphism and persistent tardive dyskinesia in schizophrenia. J Neural Transm (Vienna) 112, 1107-1113, doi:10.1007/s00702-004-0252-6 (2005).
- Kang, S. G. et al. Val158Met polymorphism in the catechol-O-methyltransferase (COMT) gene is not associated with tardive dyskinesia in schizophrenia. Neuropsychobiology 57, 22-25, doi:10.1159/000123118 (2008).
- Lafuente, A. et al. Polymorphism of dopamine D2 receptor (TaqIA, TaqIB, and-141C Ins/Del) and dopamine degradation enzyme (COMT G158A, A-278G) genes and extrapyramidal symptoms in patients with schizophrenia and bipolar disorders. Psychiatry Res 161, 131-141, doi:10.1016/j.psychres.2007.08.002 (2008).
- Yasui-Furukori, N. et al. Association between dopamine-related polymorphisms and plasma concentrations of prolactin during risperidone treatment in schizophrenic patients. Prog Neuropsychopharmacol Biol Psychiatry 32, 1491-1495, doi:10.1016/j.pnpbp.2008.05.006 (2008).
- Zai, C. C. et al. The catechol-O-methyl-transferase gene in tardive dyskinesia. World J Biol Psychiatry 11, 803-812, doi:10.3109/15622975.2010.486043 (2010).
- De Luca, V. et al. Genetic interactions in the adrenergic system genes: analysis of antipsychotic-induced weight gain. Hum Psychopharmacol 26, 386-391, doi:10.1002/hup.1219 (2011).
- Bakker, P. R. et al. Candidate gene-based association study of antipsychotic-induced movement disorders in long-stay psychiatric patients: a prospective study. PLoS One 7, e36561, doi:10.1371/journal.pone.0036561 (2012).
- Ellingrod, V. L. et al. Risk factors associated with metabolic syndrome in bipolar and schizophrenia subjects treated with antipsychotics: the role of folate pharmacogenetics. J Clin Psychopharmacol 32, 261-265, doi:10.1097/JCP.0b013e3182485888 (2012).
- Knol, W. et al. Genetic variation and the risk of haloperidol-related parkinsonism in elderly patients: a candidate gene approach. J Clin Psychopharmacol 33, 405-410, doi:10.1097/JCP.0b013e3182902708 (2013).
- Zivkovic, M. et al. The association study of polymorphisms in DAT, DRD2, and COMT genes and acute extrapyramidal adverse effects in male schizophrenic patients treated with haloperidol. J Clin Psychopharmacol 33, 593-599, doi:10.1097/JCP.0b013e31829abec9 (2013).
- Tybura, P. et al. Pharmacogenetics of adverse events in schizophrenia treatment: comparison study of ziprasidone, olanzapine and perazine. Psychiatry Res 219, 261-267, doi:10.1016/j.psychres.2014.05.039 (2014).
- Zhang, Y. et al. Metabolic syndrome in patients taking clozapine: prevalence and influence of catechol-O-methyltransferase genotype. Psychopharmacology (Berl) 231, 2211-2218, doi:10.1007/s00213-013-3410-4 (2014).
- Cote, A. T., Panagiotopoulos, C. & Devlin, A. M. Interaction between the Val158Met catechol-O-methyltransferase gene variant and second-generation antipsychotic treatment on blood pressure in children. Pharmacogenomics J 15, 95-100, doi:10.1038/tpj.2014.35 (2015).
- Fabbri, C. et al. Genetics of psychotropic medication induced side effects in two independent samples of bipolar patients. J Neural Transm (Vienna) 122, 43-58, doi:10.1007/s00702-014-1290-3 (2015).
- Oishi, K. et al. Vulnerable combinations of functional dopaminergic polymorphisms to late-onset treatment resistant schizophrenia. PLoS One 13, e0207133, doi:10.1371/journal.pone.0207133 (2018).
- Bakker, P. R., van Harten, P. N. & van Os, J. Antipsychotic-induced tardive dyskinesia and polymorphic variations in COMT, DRD2, CYP1A2 and MnSOD genes: a meta-analysis of pharmacogenetic interactions. Mol Psychiatry 13, 544-556, doi:10.1038/sj.mp.4002142 (2008).
- Lv, Z. et al. The association between COMT Val158Met gene polymorphism and antipsychotic-induced tardive dyskinesia risk. Int J Neurosci 126, 1044-1050, doi:10.3109/00207454.2015.1089504 (2016).
- Cheon, K. A., Jun, J. Y. & Cho, D. Y. Association of the catechol-O-methyltransferase polymorphism with methylphenidate response in a classroom setting in children with attention-deficit hyperactivity disorder. Int Clin Psychopharmacol 23, 291-298, doi:10.1097/YIC.0b013e328306a977 (2008).
- Kereszturi, E. et al. Catechol-O-methyltransferase Val158Met polymorphism is associated with methylphenidate response in ADHD children. Am J Med Genet B Neuropsychiatr Genet 147B, 1431-1435, doi:10.1002/ajmg.b.30704 (2008).
- Park, S. et al. Catechol-O-methyltransferase Val158-Met polymorphism and a response of hyperactive-impulsive symptoms to methylphenidate: A replication study from South Korea. J Psychopharmacol 28, 671-676, doi:10.1177/0269881114527654 (2014).
- Salatino-Oliveira, A. et al. Catechol-O-methyltransferase valine158methionine polymorphism moderates methylphenidate effects on oppositional symptoms in boys with attention-deficit/hyperactivity disorder. Biol Psychiatry 70, 216-221, doi:10.1016/j.biopsych.2011.03.025 (2011).
- Gruber, R. et al. Sleep and COMT polymorphism in ADHD children: preliminary actigraphic data. J Am Acad Child Adolesc Psychiatry 45, 982-989, doi:10.1097/01.chi.0000220848.48650.10 (2006).
- Sengupta, S. et al. COMT Val108/158Met polymorphism and the modulation of task-oriented behavior in children with ADHD. Neuropsychopharmacology 33, 3069-3077, doi:10.1038/npp.2008.85 (2008).
- McGough, J. J. et al. A candidate gene analysis of methylphenidate response in attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 48, 1155-1164, doi:10.1097/CHI.0b013e3181bc72e3 (2009).
- Froehlich, T. E. et al. Pharmacogenetic predictors of methylphenidate dose-response in attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 50, 1129-1139 e1122, doi:10.1016/j.jaac.2011.08.002 (2011).
- Contini, V. et al. No significant association between genetic variants in 7 candidate genes and response to methylphenidate treatment in adult patients with ADHD. J Clin Psychopharmacol 32, 820-823, doi:10.1097/JCP.0b013e318270e727 (2012).
- Yatsuga, C. et al. No association between catechol-O-methyltransferase (COMT) genotype and attention deficit hyperactivity disorder (ADHD) in Japanese children. Brain Dev 36, 620-625, doi:10.1016/j.braindev.2013.08.006 (2014).
- Unal, D., Unal, M. F., Alikasifoglu, M. & Cetinkaya, A. Genetic Variations in Attention Deficit Hyperactivity Disorder Subtypes and Treatment Resistant Cases. Psychiatry Investig 13, 427-433, doi:10.4306/pi.2016.13.4.427 (2016).
- Pagerols, M. et al. Pharmacogenetics of methylphenidate response and tolerability in attention-deficit/hyperactivity disorder. Pharmacogenomics J 17, 98-104, doi:10.1038/tpj.2015.89 (2017).
- Fageera, W. et al. Association between COMT methylation and response to treatment in children with ADHD. J Psychiatr Res 135, 86-93, doi:10.1016/j.jpsychires.2021.01.008 (2021).
- Myer, N. M., Boland, J. R. & Faraone, S. V. Pharmacogenetics predictors of methylphenidate efficacy in childhood ADHD. Mol Psychiatry 23, 1929-1936, doi:10.1038/mp.2017.234 (2018).
- Mattay, V. S. et al. Catechol O-methyltransferase val158-met genotype and individual variation in the brain response to amphetamine. Proc Natl Acad Sci U S A 100, 6186-6191, doi:10.1073/pnas.0931309100 (2003).
- Hamidovic, A., Dlugos, A., Palmer, A. A. & de Wit, H. Catechol-O-methyltransferase val158met genotype modulates sustained attention in both the drug-free state and in response to amphetamine. Psychiatr Genet 20, 85-92, doi:10.1097/YPG.0b013e32833a1f3c (2010).
- Hart, A. B., de Wit, H. & Palmer, A. A. Candidate gene studies of a promising intermediate phenotype: failure to replicate. Neuropsychopharmacology 38, 802-816, doi:10.1038/npp.2012.245 (2013).
- Wardle, M. C., Hart, A. B., Palmer, A. A. & de Wit, H. Does COMT genotype influence the effects of d-amphetamine on executive functioning? Genes Brain Behav 12, 13-20, doi:10.1111/gbb.12012 (2013).
- Ilieva, I., Boland, J. & Farah, M. J. Objective and subjective cognitive enhancing effects of mixed amphetamine salts in healthy people. Neuropharmacology 64, 496-505, doi:10.1016/j.neuropharm.2012.07.021 (2013).