Search

Background: The μ-opioid receptor (MOR) plays an important role in social bonding behaviors, while it is implicated in the pathophysiology of depression. It is shown that the A118G polymorphism (rs1799971) of the MOR gene (OPRM1) causes amino-acid exchange from Asn to Asp, and that this polymorphism is associated with altered mu-opioid receptor function. Meanwhile, sociotropy/autonomy and interpersonal sensitivity are personality vulnerabilities to depression characterized by distinctive interpersonal styles. The present study tested the hypothesis that the functional A118G OPRM1 polymorphism influences these personality traits., Methods: The subjects were 402 physically and mentally healthy Japanese volunteers. Sociotropy and autonomy were measured by the Sociotropy-Autonomy Scale, and interpersonal sensitivity was evaluated by the Interpersonal Sensitivity Measure. The A118G polymorphism of the OPRM1 was determined by the PCR method., Results: In one factor analysis of covariance, there were differences in scores of sociotropy (uncorrected p < .001, corrected p < .003) and interpersonal sensitivity (uncorrected p = .015, corrected p = .045), but not autonomy, among the A/A, A/G, and G/G genotypes. Post hoc LSD tests showed that sociotropy scores were higher in the A/A group than in the A/G (p = .029) and G/G (p < .001) groups, and higher in the A/G group than in the G/G group (p = .004). Interpersonal sensitivity scores were higher in the A/A group than in the A/G (p = .023) and G/G (p = .009) groups., Conclusion: This study suggests that the A118G OPRM1 polymorphism is associated with sociotropy and interpersonal sensitivity, interpersonal vulnerabilities to depression., (© 2022 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Although thiopurine is a crucial drug for treating acute lymphoblastic leukemia, individual variations in intolerance are observed due to gene polymorphisms. A 3-year-old boy with B-cell precursor acute lymphoblastic leukemia who was administered thiopurine developed mucositis, sepsis, and hemophagocytic lymphohistiocytosis due to prolonged hematologic toxicity, chronic disseminated candidiasis, and infective endocarditis that triggered multiple brain infarctions. The patient was found to harbor 3 gene polymorphisms associated with thiopurine intolerance including homozygous NUDT15 R139C, heterozygous ITPA C94A, and homozygous MTHFR C677T and heterozygous RFC1 G80A. Thus, the combined effect of intolerance via multiple gene polymorphisms should be considered in case of unexpected adverse reactions., Competing Interests: K.K. is a patent holder of UNUM Therapeutics. The remaining authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

GTP cyclohydrolase 1 (GCH1) is the initial and rate-limiting enzyme in the biosynthesis of tetrahydrobiopterin, which is an essential cofactor for biosynthetic enzymes of dopamine, serotonin, and nitric oxide. In the present study, the association of functional polymorphism of the GCH1 gene (C+243T, rs841) with personality traits was examined in 902 healthy Japanese subjects. Personality traits were assessed by the Temperament and Character Inventory (TCI), and the GCH1 genotype was detected by a PCR-RFLP method. There were no significant main effects of the GCH1 genotype on the seven TCI dimension scores, but significant interaction effects between the GCH1 genotype and gender were found on the scores of novelty seeking. Post-hoc analysis revealed that males with the C/C genotype had higher scores of novelty seeking than those with the C/T genotype or those with the T/T genotype, while in females the scores of novelty seeking were not different among the genotype groups. The present study thus suggests that the C+243T polymorphism of the GCH1 gene affects the personality trait of novelty seeking in males., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: We investigated the relationship between a brain-derived neurotrophic factor (BDNF) polymorphism (Val66Met) and the clinical response of patients with major depressive disorder to selective serotonin reuptake inhibitors (SSRIs; here, paroxetine and sertraline). In addition, serum BDNF levels in these patients were considered together with the clinical response., Methods: A total of 132 patients who met the DSM-IV criteria for major depressive disorder were enrolled in the study. 54 of these patients were male and 78 were female (age range, 20-74years; mean±S.D., 51±15). The patients' clinical improvement was evaluated using the 17-item Hamilton Rating Scale for Depression (HAMD-17) before (T0) and at 8weeks after the administration of SSRI treatment (T8). Patients with at least a 50% decrease in the HAMD-17 score were classified as responders., Results: No correlation was observed between the BDNF Val66Met polymorphism and response to SSRIs or between the BDNF Val66Met polymorphism and serum BDNF levels at T0. An inverse correlation was found between serum BDNF levels and HAMD-17 scores at T0., Conclusions: These results suggest that the BDNF Val66Met polymorphism is independent of both the response to SSRI treatment and serum BDNF levels. The findings in the present study reconfirm that the serum BDNF level is a state biomarker for depression., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Dopamine transporter (DAT) plays a major role in terminating dopamine neurotransmission, which may be involved in the characterization of personality traits. Recently, polymorphisms of the promoter region (-67 A/T) and intron 8 (40-bp variable number of tandem repeats, VNTRs) in the DAT gene were reported to affect DAT expression. In the present study, we examined the associations of these polymorphisms with personality traits in 654 healthy Japanese. Personality traits were assessed by the Temperament and Character Inventory (TCI), and the DAT polymorphisms were identified by PCR-based methods. Regarding the -67 A/T promoter polymorphism, the females without the A allele predictive of high DAT activity had lower scores of self-directedness (p=0.005) and cooperativeness (p=0.038) than those with the A allele. In males, none of the TCI scores was different between the two genotype groups. The intron 8 VNTR polymorphism did not affect any TCI score either in males or in females. The present study thus suggests that the -67 A/T promoter polymorphism, but not intron 8 VNTR polymorphism, in the DAT gene affects personality traits of Japanese healthy females.

Dopamine and norepinephrine are implicated in the characterization of personality traits. Dopamine-beta-hydroxylase (DBH) is the enzyme responsible for conversion of dopamine to norepinephrine, and thus plays an important role in controlling dispositions of these neurotransmitters. Previous studies have shown that the -1021C/T polymorphism of the DBH gene promoter influences plasma DBH activity. Therefore, we examined the association between the -1021C/T DBH polymorphism and personality traits in 627 Japanese healthy volunteers. The DBH genotypes were identified by a PCR-RFLP method, and personality traits were assessed by the Temperament and Character Inventory (TCI). In the two-factor analysis of covariance with the DBH genotype and sex as factors and with age as a covariate, there was no main effect of the DBH genotype on any TCI score, while the interaction between the factors was significant in harm avoidance. In the post hoc analysis, the group with the T allele predictive of lower DBH activity had higher scores of harm avoidance than that without the T allele in females (p=0.006), but not in males. The present study suggests that the -1021C/T DBH polymorphism affects the personality trait of harm avoidance in healthy females.

To investigate the biological mechanism of gender identity disorder (GID), five candidate sex hormone-related genes, encoding androgen receptor (AR), estrogen receptors alpha (ERalpha) and beta (ERbeta), aromatase (CYP19), and progesterone receptor (PGR) were analyzed by a case-control association study. Subjects were 242 transsexuals (74 male-to-female patients (MTF) and 168 female-to-male patients (FTM)), and 275 healthy age- and geographical origin-matched controls (106 males and 169 females). The distributions of CAG repeat numbers in exon 1 of AR, TA repeat numbers in the promoter region of ERalpha, CA repeat numbers in intron 5 of ERbeta, TTTA repeat numbers in intron 4 of CYP19, and six polymorphisms (rs2008112, rs508653, V660L, H770H, rs572698 and PROGINS) of PGR were analyzed. No significant difference in allelic or genotypic distribution of any gene examined was found between MTFs and control males or between FTMs and control females. The present findings do not provide any evidence that genetic variants of sex hormone-related genes confer individual susceptibility to MTF or FTM transsexualism.

There have been several studies suggesting that sex hormones are involved in characterization of human mental function and behaviour. Recently, it has been reported that the -34T/C polymorphism of cytochrome P450 17 (CYP17) gene affects sex hormone dispositions. Therefore, it is possible that the CYP17 -34T/C polymorphism affects personality traits. In the present study, the association of this genetic polymorphism with personality traits was examined in 595 healthy Japanese. Personality traits were assessed by the Temperament and Character Inventory (TCI), and the CYP17 -34T/C polymorphism was detected by a PCR-RFLP method. In males, the scores of novelty seeking, cooperativeness, and self-transcendence were higher in the group with the C allele than in that without this allele. In females, none of the seven TCI dimensions was different between the two genotype groups. The present study thus suggests that the -34T/C polymorphism of the CYP17 gene affects personality traits of healthy males, but not females, and this gender-dependent effect may be mediated by the action of sex hormones such as estradiol and testosterone.

It has been demonstrated that the interaction between serotonin transporter (5HTT) and norepinephrine transporter (NET) functions affects each transporter function and behavior in studies using knockout mice model. In the present study, we examined the effects of the 5HTT and NET gene promoter polymorphisms on personality traits in 575 Japanese healthy subjects. The 5HTT (long/short, L/S) and NET (-3081 A/T) genotypes were identified by PCR methods, and personality traits were assessed by the Temperament and Character Inventory (TCI). Neither of the two polymorphisms affected any TCI dimension, but the interaction between them had significant effects on harm avoidance and novelty seeking in females. Subsequent analyses showed that the females with the combination of the SS genotype reducing 5HTT function and the TT genotype reducing NET function had higher harm avoidance and lower novelty seeking. The present study suggests that the combination of 5HTT and NET polymorphisms influences harm avoidance and novelty seeking in females.

There have been several data suggesting that norepinephrine neurotransmission is involved in the characterization of personality traits. Recently, the -3081A/T polymorphism in the promoter region of the norepinephrine transporter (NET) gene affecting promoter activity has been reported. In the present study, we studied the association between this NET polymorphism and personality traits in 553 Japanese healthy subjects. Personality traits were assessed by the Temperament and Character Inventory (TCI), and the NET genotypes were identified by a PCR-RFLP method. Multivariate two-factor analysis of covariance with genotype and gender as factors and with age as a covariate showed no association between the NET genotypes and the TCI dimension scores. The present study thus suggests that the -3081A/T polymorphism in the NET gene promoter is not involved in the characterization of personality traits in healthy subjects.

Catechol-O-methyltransferase (COMT) is one of the major enzymes for the degradation of catecholamines. It has been suggested that catecholaminergic neurotransmission is involved in characterization of personality. Previous studies on the association between the COMT Val158Met polymorphism and personality traits in healthy subjects have produced inconsistent results. Therefore, the relationship between this polymorphism and personality was re-examined in 478 Japanese healthy volunteers. Personality traits were assessed by the Temperament and Character Inventory (TCI), and the COMT genotypes were determined by a PCR-RFLP method. In total, there were no significant differences among the Val/Val, Val/Met, and Met/Met genotypes in seven TCI dimension scores. Similarly, no significant relationship was found between the COMT genotypes and the TCI dimensions when males and females were analyzed separately. The present study thus suggests that the COMT Val158Met polymorphism is not associated with personality traits in Japanese healthy subjects.

Pharmacogenetic studies have shown that several cytochrome P450 (CYP) enzymes exhibit genetic polymorphisms. Several benzodiazepines (BZPs) are metabolized predominantly or partly by polymorphic CYP2C19 and CYP3A4/5. The pharmacokinetics of diazepam, etizolam, quazepam and desmethylclobazam have been shown to be affected by CYP2C19 polymorphism. The CYP3A5 polymorphism has been reported to affect the pharmacokinetics of alprazolam, but its effect on midazolam kinetics has been inconclusive. For etizolam and desmethylclobazam, some data suggest that CYP2C19 deficiency leads to side-effects or toxicity. For the remaining BZPs the clinical significance of the observed pharmacokinetic changes remains unclear. Further studies on the effects of genetic polymorphisms of CYP enzymes on the pharmacokinetics and pharmacodynamics of BZPs are necessary to guide treatment individualization and optimization.

It has been suggested that the central serotonergic activity is implicated in personality traits. Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in serotonin synthesis. In the present study, the association between the TPH A218C polymorphism and personality traits assessed by the Temperament and Character Inventory (TCI) was examined in 345 Japanese healthy subjects. The TPH A218C polymorphism was determined by a PCR-RFLP method. There were no significant differences in the seven dimension scores of TCI among the A/A, A/C, and C/C genotype groups by the one-way ANOVA. There was a significant negative correlation between age and the NS scores. Females showed significantly higher scores of HA, RD, and ST, and significantly lower scores of SD than males. The multiple regression analysis using age, gender, and the TPH genotype as independent variables also showed no significant association between any dimension score and the genotype. The present study thus suggests that the TPH A218C polymorphism does not affect personality traits in Japanese healthy subjects.

It has been suggested that personality traits are heritable. The polymorphic cytochrome P450 (CYP) 2C19 metabolizes sex hormones and 5-hydroxytryptamine, which are involved in multiple brain functions. In the present study, the relationship between the CYP2C19 polymorphism and personality traits was examined in 487 Japanese healthy volunteers. Personality traits were assessed by the Temperament and Character Inventory (TCI), and the two mutated alleles causing absent CYP2C19 activity were identified by a PCR-RFLP method. In females, the scores of reward dependence (p=0.026), cooperativeness (p=0.001), and self-transcendence (ST) (p=0.049) were significantly lower in poor metabolizers (PMs) than in extensive metabolizers (EMs). In males, none of the seven TCI dimensions was significantly different between EMs and PMs. The present study thus suggests that the CYP2C19 polymorphism affects personality traits of Japanese females.

Cocaine- and amphetamine-regulated transcript (CART) was originally discovered as a peptide that increased in the rat striatum after injection of a psychostimulant drug, such as cocaine or amphetamine, and is suggested to play potential roles in drug dependence. We tested the genetic association between the CART gene and methamphetamine (METH) dependence and/or psychosis. The subjects were 203 patients with METH dependence and 239 age- and gender-matched healthy controls. Two single nucleotide polymorphisms (SNPs) of the CART gene, -156A>G and IVS1 + 224G>A, were examined . There were no significant differences in genotype and allele distributions of the polymorphisms between patients with METH dependence and/or psychosis and controls. Neither were significant differences in subgroups of clinical phenotypes, for example, age at first consumption of METH, latency to onset of psychotic symptoms after the first consumption of METH, prognosis of psychosis after therapy, complication of spontaneous relapse to a psychotic state, or multisubstance abuse status, observed. The present findings suggest that the CART gene may not play a pivotal role in the development of METH dependence and psychosis, at least in a Japanese population.

Previous studies have indicated that genetic factors substantially affect development of substance use disorders, including methamphetamine dependence. Prodynorphin (PDYN) is an opioid peptide precursor that yields dynorphins, endogenous kappa opioid-receptor agonists that play important roles in substance abuse. A physiologically active polymorphism of 1-4 repeats of a 68-bp element in the promoter region of the PDYN gene has been identified. We analyzed this polymorphism of the PDYN gene by a case-control association study in 143 patients with methamphetamine dependence and 209 healthy controls in the Japanese population. A 3- or 4-repeat allele in the PDYN gene promoter was found significantly more frequently in patients with methamphetamine dependence than in controls (chi(2)=9.45, p=0.0021). A 3- or 4-repeat allele in the PDYN gene promoter, which was shown to produce significantly higher transcription activity of the PDYN gene than a 1- or 2-repeat allele, is a genetic risk factor for development of methamphetamine dependence (odds ratio: 1.83, 95% CI=1.24-2.68).

Several genetic studies have revealed that bipolar disorders are linked with the chromosomal locus of 15q11-q13, where the gamma-aminobutyric acid (GABA) receptor alpha5 subunit gene (GABRA5) locates. GABA is one of the major neurotransmitters that may be involved in the pathogenesis of bipolar disorder. Five polymorphisms in the GABRA5 gene, -754C>T in the promoter region, IVS1-21G>A, IVS2-26T>A, (*)302C>T in 3'-UTR of exon 5, and a CA repeat polymorphism in the 3' flanking region were examined in a Japanese population. IVS1-21G>A exhibited significant differences in the distribution of the genotype and allele frequency in bipolar I disorder patients but not in bipolar II disorder patients, compared with control subjects. The haplotype analysis showed that IVS1-21G>A/IVS2-26A>T was associated with bipolar I disorder, and the IVS1-21A/IVS2-26T haplotype was a negative risk factor for susceptibility to the disorders (odds ratio: 0.57, 95% confidence interval: 0.44-0.73). These results suggest that the GABRA5 gene may confer susceptibility to bipolar I disorder.

Our previous study has suggested that the TaqI A polymorphism of dopamine D2 receptor gene (DRD2) is associated with the predisposition to neuroleptic malignant syndrome (NMS). However, the specificity of this polymorphism as a predictor of NMS dose not seem to be sufficient enough. Meanwhile, it has been shown that the non-carriers of Del allele of the -141C Ins/Del polymorphism in the promoter region of DRD2 have lower dopamine D2 receptor in the brain than the carriers. In addition, dopamine D3 receptor gene has a Ser(9)Gly polymorphism, which may alter the receptor function. The present study examined the association between these three polymorphisms and the development of NMS to investigate if a combination of these polymorphisms could increase the specificity as markers for NMS. The subjects were 17 psychiatric patients who had developed NMS (13 patients with schizophrenia, 3 with major depression, and 1 with dementia of the Alzheimer's type) and 163 schizophrenic patients who had never developed this syndrome. The frequency of the A1 allele was significantly (P = 0.012) higher in the patients who had developed NMS (59%) than in the patients who had not (35%). The proportion of the A1 carriers was significantly (P = 0.003) higher in the patients with NMS (16/17: 94%) than in those without the syndrome (93/163: 57%). However, no significant differences were found in the allele and genotype frequencies of the other two polymorphisms between the two groups. The present study suggests that only the TaqI A polymorphism is at least partly useful as a predictor of NMS, but the -141 C Ins/Del and Ser(9)Gly polymorphisms are not., (Copyright 2003 Wiley-Liss, Inc.)

Monoamine oxidase A (MAOA) and tryptophan hydroxylase (TPH) are the staple enzymes in the metabolism of serotonin (5-HT). The genetic polymorphisms of these two enzymes might individually alter the production, release, reuptake or degradation of 5-HT during the treatment of selective serotonin reuptake inhibitors (SSRIs), leading to the individual differences in the antidepressant effects of SSRIs. The authors investigated whether a functional polymorphism in the MAOA gene promoter (MAOA-VNTR) and a TPH gene polymorphism in intron 7 (TPH-A218C) were associated with the antidepressant response to fluvoxamine in 66 Japanese patients with major depressive disorder during a 6-week study with a specific dosage plan. Fifty-four patients completed the study. The present study fails to demonstrate that the genetic polymorphisms of MAOA-VNTR and TPH-A218C affect the antidepressant effect of fluvoxamine in Japanese patients with major depressive disorder.

The presence of the long (l) variant of the serotonin (5-hydroxytryptamine: 5-HT) transporter gene-linked polymorphic region (5-HTTLPR) is reported to be associated with a more favorable and faster antidepressant effect of selective serotonin reuptake inhibitors in Caucasians. The frequency of the l allele is lower in Japanese than in Caucasians; therefore, the antidepressant effect of fluvoxamine can be not as good in Japanese as in Caucasians. The authors investigated whether 5-HTTLPR was associated with the antidepressant response to fluvoxamine in 66 Japanese patients with major depressive disorder in a protocolized-dosing 6-week study. The short (s) allele frequency was significantly higher in the responsive individuals than in the nonresponsive ones (P = .010). The present study suggests that fluvoxamine is not less effective in depressive patients carrying the s allele than in the ones carrying the l allele and it is not less effective in Japanese than in Caucasians.

Objective: The pathophysiology of neuroleptic malignant syndrome is mainly explained by a central hypodopaminergic state. The familial occurrence of neuroleptic malignant syndrome suggests the involvement of a genetic mechanism in the predisposition to the syndrome. Therefore, the authors examined the association between the TaqI A polymorphism of the dopamine D(2) receptor gene (DRD(2)), which alters DRD(2) density and function, and the development of neuroleptic malignant syndrome., Method: The subjects were 15 psychiatric patients who had developed neuroleptic malignant syndrome (12 patients with schizophrenia and three with major depression) and 138 patients with schizophrenia who had never developed neuroleptic malignant syndrome. The TaqI A genotypes, A1 and A2 alleles, were determined by the polymerase chain reaction method., Results: The frequency of the A1 allele was significantly higher in the patients who had developed neuroleptic malignant syndrome (56.8%) than in the patients who had not (35.1%). The proportion of the A1 carrier was significantly higher in the patients with neuroleptic malignant syndrome (14 [93.3%] of 15 patients) than in those without the syndrome (79 [57.2%] of 138 patients)., Conclusions: These findings suggest that the TaqI A DRD(2) polymorphism is associated with the predisposition to neuroleptic malignant syndrome.

The dopamine D2 receptor (DRD2) gene has a Taq1 A restriction fragment length polymorphism yielding two alleles, A1 and A2. We have previously shown that female patients with the A1 allele show greater prolactin response to nemonapride, a selective antagonist for D2-like dopamine receptors, in schizophrenic patients. In the present study, the relationship between this polymorphism and prolactin response to bromperidol was investigated in 32 untreated schizophrenic inpatients (16 males, 16 females). The daily dose of bromperidol was fixed at 6 (n = 10), 12 (n = 13), or 18 mg (n = 9) during a 2-week treatment period. Taq1 A genotypes were determined by PCR method. Plasma prolactin concentration was measured by radioimmunoassay. Plasma concentration of bromperidol was measured by HPLC method. The subjects were divided into four subgroups by gender and the genotypes, i.e., 10 males and 11 females with the A1 allele, 6 males and 5 females with no A1 allele. The females with the A1 allele had the highest Delta prolactin (the change from the pretreatment concentration)/bromperidol concentration ratio among the other groups (P < 0.05). The present study thus suggests that female patients with the A1 allele show greater prolactin response to bromperidol, who may have a high risk for adverse effects associated with neuroleptic-induced hyperprolactinemia., (Copyright 2001 Wiley-Liss, Inc.)

Previous studies have shown that subjects without Del alleles of the--141C Ins/Del polymorphism in the promoter region of the dopamine D2 receptor (DRD2) gene have lower DRD2 density that those with one or two Del alleles. The present study aims to investigate the relationship between the -141C Ins/Del polymorphism and extrapyramidal adverse effects of bromperidol and nemonapride, antipsychotic drugs with a selective and potent DRD2 antagonistic property, in schizophrenic inpatients. Twenty-seven patients were treated with bromperidol at a fixed-dose of 6, 12 or 18 mg/day, and 25 patients were treated with nemonapride at a fixed-dose of 18 mg/day. The duration of treatment with these drugs was 3 weeks. The Ins and Del alleles were determined by PCR. Extrapyramidal adverse effects were assessed by the Udvalg for Kliniske Undersøgelser side effects rating scale. The subjects consisted of 38 homozygotes of the Ins allele and 14 heterozygotes of the Ins and Del alleles. There were no significant differences in the incidence or severity of extrapyramidal adverse effects between patients with and without the Del allele. It is possible that this result was due to a lack of statistical power. However, the present study suggests that the--141C Ins/Del polymorphism is not related to the development of extrapyramidal adverse effects during acute-phase treatment with antidopaminergic agents.

1. Previous reports showed that the A1 allele of Taq1 A dopamine D2 receptor polymorphism was associated with lowered density and diminished function of dopamine D2 receptor. In this study, association between Taq1 A dopamine D2 receptor polymorphism and psychopathology of schizophrenia was investigated. 2. The subjects were 61 acutely exacerbated schizophrenic patients who were all Japanese descent and had received no medication for at least one month before this study. Pretreatment psychotic symptoms were assessed by the Brief Psychiatric Rating Scale (BPRS). The Taq1 A genotypes, the A1 and A2 alleles, were determined by polymerase chain reaction method. 3. The patients were divided into three genotype groups; i.e., the patients with A1/A1 allele (n=6), those with A1/A2 allele (n=32) and those with A2/A2 allele (n=23). 4. There was no significant difference in total BPRS, subgrouped symptoms (positive, negative, anxiety-depression, excitement and cognitive symptoms) or any scores of BPRS items among the three Taq1 A genotype groups. 5. The present study suggests that Taq1 A dopamine D2 receptor polymorphism does not play an important role in psychopathological symptoms of schizophrenia.

Previous studies have demonstrated that subjects with one or two A1 alleles of dopamine D2 receptor (DRD2) polymorphism at the Taq1 A locus have lower DRD2 density than those with no A1 allele. The present study aimed to examine whether the Taq1 A DRD2 genotypes are related to therapeutic response to nemonapride, a selective dopamine antagonist, in schizophrenic patients. The subjects were 25 acutely exacerbated schizophrenic inpatients who had received no medication for at least 1 month before the study. The fixed dose (18 mg/day) of nemonapride was administered to each patient for 3 weeks. The clinical status was prospectively monitored by the Brief Psychiatric Rating Scale (BPRS) before, and 3 weeks after, the treatment. The Taq1 A genotypes (A1 and A2 alleles) were determined by the polymerase chain reaction method. Three patients were homozygous for the A1 allele, 11 were heterozygous for the A1 and A2 alleles, and 11 were homozygous for the A2 allele. The patients with one or two A1 alleles (n = 14) showed significantly higher percentage improvement in total BPRS and positive symptoms than those with no A1 allele (n = 11) after 3-week treatment while the percentage improvement in other subgrouped symptoms (negative, anxiety-depression, excitement and cognitive symptoms) was similar between the two genotype groups. The present results suggest that the Taq1 A DRD2 polymorphism is related to early therapeutic response to nemonapride in schizophrenic patients, possibly by modifying the efficiency of DRD2 antagonism of the drug in the central nervous system.