Association between dopamine-related polymorphisms and plasma concentrations of prolactin during risperidone treatment in schizophrenic patients

Hyperprolactinemia is an inevitable consequence of treatment with antipsychotic agents to some extent because prolactin response to antipsychotics is related to dopamine blockade. Recent studies have suggested that polymorphisms of the dopamine receptors are associated with therapeutic response to antipsychotics. Thus, we studied the effects of major polymorphisms of dopamine-related genes on plasma concentration of prolactin. Subjects were 174 schizophrenic patients (68 males, 106 females) receiving 3 mg twice daily of risperidone for at least 4 weeks. Sample collections were conducted 12 h after the bedtime dosing. Five dopamine-related polymorphisms (Taq1A, -141C ins/del for DRD2, Ser9Gly for DRD3, 48 bp VNTR for DRD4, Val158Met for COMT) were identified. The mean (+/-SD) plasma concentration of prolactin in females was significantly higher than males (54.3+/-27.2 ng/ml versus 126.8+/-70.2 ng/ml, p<0.001). No dopamine-related polymorphisms differed the plasma concentration of prolactin in males or females. Multiple regression analyses including plasma drug concentration and age revealed that plasma concentration of prolactin correlated with gender (standardized partial correlation coefficients (beta)=0.551, p<0.001) and negatively with age (standardized beta=-0.202, p<0.01). No correlations were found between prolactin concentration and dopamine-related polymorphisms. These findings suggest that plasma prolactin concentrations in females are much higher than in males but the dopamine-related variants are not predominantly associated with plasma concentration of prolactin.     

The effect of smoking status on the plasma concentration of prolactin already elevated by risperidone treatment in schizophrenia patients

Smoking prevalence for schizophrenic patients is higher than for the general population. Inter-individual variability in hyperprolactinemia induced antipsychotics particularly risperidone can be explained by smoking status to some extent. We therefore studied the effects of smoking status on the plasma concentration of prolactin. Subjects included 154 schizophrenia patients (61 males, 93 females) who had received 3 mg of risperidone twice daily for at least 4 weeks. Sample collections were conducted 12 h after the bedtime dosing. The plasma concentrations of prolactin in the females were significantly higher than in the males (117.6 ± 69.3 ng/ml vs. 52.9 ± 30.7 ng/ml, p < 0.001). The mean (± SD) plasma concentrations of prolactin did not differ between smokers and nonsmokers in the males (59.5 ± 31.2 ng/ml vs. 47.6 ± 29.3 ng/ml, not significant (ns)), but there was a significant difference in the females (100.2 ± 59.1 vs. 134.0 ± 74.6, ng/ml, p < 0.05). Multiple regression analyses including gender, plasma drug concentration and age revealed that the plasma concentration of prolactin positively correlated with gender (standardized beta = 0.452, p < 0.001) and negatively with age (standardized beta = −0.171, p < 0.05) and smoking status (standardized beta = −0.232, p < 0.01). These findings suggest that smoking status has an impact on prolactin concentration during risperidone treatment. However, further study is required to determine whether these findings have clinical implications.     

MDR1 gene polymorphisms and response to acute risperidone treatment

Polymorphic multidrug resistant protein 1 (MDR1) transports drugs against a concentration gradient across the blood–brain barrier and reduces their accumulation in the brain. MDR1 may therefore influence antipsychotic brain availability contributing to inter-individual differences in treatment response and adverse effects, regardless of plasma concentrations. In the present study we investigated the influence of two common MDR1 polymorphisms on the improvement of psychopathological symptoms and occurrence of extrapyramidal side effects (EPS) in Slovenian schizophrenia patients acutely treated with risperidone. A total of 59 clinically well defined patients with first episode schizophrenia spectrum disorders or after tapering their maintenance treatment were genotyped for MDR1 C3435T and G2677T/A. Steady-state plasma concentrations of risperidone active moiety (sum of risperidone and the 9-hydroxyrisperidone) were determined. G2677T/A and C3435T genotypes were not associated to psychopathological symptoms, efficacy of treatment and risk for parkinsonism. Marginal associations with akathisia (p = 0.039 and p = 0.042, respectively) and dystonia (p = 0.013 and p = 0.034, respectively) were observed for both G2677T/A and C3435T genotypes. However, higher AIMS and BARS scores were observed only in heterozygous carriers of G2677T/A and C3435T polymorphisms and there was no tendency of gene–dose effect. The present study does not suggest a major influence of MDR1 G2677T/A and C3435T polymorphisms on treatment response during short-term risperidone therapy in patients with schizophrenia or schizoaffective disorder.     

抑郁症患者多药耐药基因多态性对度洛西汀稳态血药浓度和临床疗效的影响

目的探讨抑郁症患者多药耐药1(multidrug resistance 1,MDR1)基因的G2677T和C3435T位点多态性对度洛西汀稳态血药浓度和临床疗效的影响。方法 120例符合中国精神障碍分类与诊断标准第3版(CC-MD-3)抑郁发作标准的抑郁症患者接受度洛西汀治疗8周。在治疗前后采用汉密尔顿抑郁量表评估患者病情,检测8周时度洛西汀稳态血药浓度。检测患者的MDR1基因的G2677T/C3435T多态性。结果 8周后,MDR1基因的G2677T位点的不同基因型患者组之间度洛西汀稳态血药浓度和疗效的差异均有统计学意义(P<0.05),TT基因型组的度洛西汀稳态血药浓度高于GG和GT基因型组[(34.22±2.41)ng/mL,(31.49±3.32)ng/mL,(32.40±2.89)ng/mL,P<0.05],TT型患者组的疗效评分平均秩次较GG型患者组高(70.38 vs 51.65,P<0.05);C3435T位点的不同基因型患者组之间的度洛西汀稳态血药浓度和疗效差异有统计学意义(P<0.05),TT型的度洛西汀稳态血药浓度较CC型和CT型高[(33.99±2.40)ng/mL,(31.53±3....     

Multidrug resistance in patients undergoing resective epilepsy surgery is not associated with C3435T polymorphism in the ABCB1 (MDR1) gene

PURPOSE: The C3435T polymorphism in the gene coding for P-glycoprotein (ABCB1) has been correlated with drug resistance in patients with epilepsy. However, replication studies have revealed conflicting results and the reason for this is not clear. We investigated the frequency of C3435T polymorphism in epileptic Turkish patients who underwent resective epilepsy surgery and compared our results with healthy controls. METHODS: DNA samples were obtained from 100 healthy controls and 89 consecutive adult patients who underwent resective brain surgery due to refractory seizures at our epilepsy center. Genotypes for the C3435T polymorphism were determined by PCR and restriction analysis. RESULTS: Comparison of drug-resistant patients and healthy controls revealed no significant difference in allele frequency (C vs. T; chi(2)=0.015, p=0.90) and genotype frequency (chi(2)=2.05, p=0.36). The findings in the pure hippocampal sclerosis (HS) group (n=73) were not significantly different from control subjects, either (allele frequency: chi(2)=0.29, p=0.59; genotype frequency: chi(2)=2.14, p=0.34). CONCLUSIONS: Our findings failed to prove an association between C3435T polymorphism and drug resistance in a sample of Turkish patients with refractory epilepsy who underwent resective brain surgery.     

精神分裂症患者多药耐药基因多态性与帕利哌酮和注射用利培酮微球临床疗效的关联研究

目的 探讨中国汉族精神分裂症患者多药耐药基因(multidrug resistance gene 1,MDR1)多态性与帕利哌酮和注射用利培酮微球治疗精神分裂症的临床疗效的关联.方法 对入组的133例精神分裂症患者分别给予帕利哌酮或注射用利培酮微球治疗12周;以阳性与阴性症状量表(PANSS)作为主要疗效评价工具,以治疗结束时临床总体印象-严重程度量表(CGI-S)及人际和社交能力量表(PSP)作为次要疗效评价工具;每2周进行PANSS评定;应用聚合酶链反应-限制性片段长度多态性和DNA测序的方法检测受试者多药耐药基因5个多态性位点的基因型,应用卡方检验和方差分析法分析各基因型与临床疗效的关联性.结果 MDR1基因多态性与主要疗效指标PANSS减分率及有效率的关联分析中未发现差异有统计学意义(P＞0.05);非参数检验分析显示:位点rs1045642 CC基因型携带者在阴性症状条目抽象思维障碍(Z=-2.62,P=0.009)及阳性症状条目夸大(Z=-2.84,P=0.005)有较好疗效;rs2032582位点GG基因型携带者在一般病理学症状条目紧张改善较差(Z=-2.50,P=0.012);rs1202169位点A等位基因携带者在一般病理学条目主动社会回避改善较好(Z=-2.09,P=0.036);rs13233308位点CC基因型携带者在一般病理学条目罪恶观念(Z=-2.09,P=0.036)和交流缺乏自发性和主动性疗效(Z=-2.73,P=0.006)改善不佳,该位点携带TT基因型的个体在紧张条目的 疗效改善较好(Z=-2.54,P=0.011).次要疗效指标分析显示,rs1045642位点C等位基因与PSP评分高度相关(Z=-2.18,P=0.029).结论 多药耐药基因多态性可能并不影响中国汉族精神分裂症患者帕利哌酮和注射用利培酮微球的临床疗效,但与妄想、社交回避的改善可能相关.     

ABCB1 (MDR1) gene polymorphisms are associated with the clinical response to paroxetine in patients with major depressive disorder

Variability in antidepressant response is due to genetic and environmental factors. Among genetic factors, the ones controlling for availability of the drug at the target site are interesting candidates. Multidrug resistance 1 (ABCB1, MDR1) gene encodes a blood-brain barrier transporter P-glycoprotein that plays an important role in controlling the passage of substances between the blood and brain. In the present study, we therefore examined the possible association of 3 functional ABCB1 polymorphisms (C3435T: rs1045642, G2677T/A: rs2032582 and C1236T: rs1128503) with response to paroxetine in a Japanese major depression sample followed for 6 weeks. Analysis of covariance at week 6 with baseline scores included in the model as covariate showed significant association of the non-synonymous SNP G2677T/A with treatment response to paroxetine (p=0.011). Furthermore, the wild variants haplotype (3435C-2677G-1236T) resulted associated with poor response (p=0.006). To our best knowledge, this study is the first suggestion of a possible association of ABCB1 variants with SSRIs response.     

The effects of olanzapine and fluphenazine on plasma cortisol, prolactin and muscle rigidity in schizophrenic patients: a double blind study

Pharmacotherapy of schizophrenia is associated with the stressful side effects. Muscle rigidity causes distress, discomfort and poor compliance. The aim of the study was to determine the relationship between plasma hormones (cortisol and prolactin/PRL) and muscle rigidity in female schizophrenic patients treated with olanzapine or fluphenazine. In a randomized, double-blind 22-weeks study, 12 patients were treated with olanzapine (5-20 mg/day) and 10 patients received fluphenazine (6-21 mg/day). Treatment with olanzapine moderately decreased, while treatment with fluphenazine significantly increased plasma cortisol levels and muscle rigidity. The marked and moderate increase in plasma PRL levels were found in patients treated with fluphenazine and olanzapine, respectively. The results suggested that olanzapine induced moderate neuroendocrine effects and a reduction in rigidity as compared to fluphenazine treatment.     

Association between multidrug resistance 1 (MDR1) gene polymorphisms and therapeutic response to bromperidol in schizophrenic patients: a preliminary study

The drug-transporting P-glycoprotein transports drugs against a concentration gradient across the blood-brain barrier back into the plasma and thereby reduces the bioavailability in the brain. Polymorphisms in the MDR1 gene regulating P-glycoprotein expression can be associated with differences in drug disposition in the brain. The present study was therefore designed to examine whether the major polymorphisms of MDR1 gene, C3435T and G2677T/A are related to therapeutic response to neuroleptics in the treatment of schizophrenia. Subjects consisted of 31 acutely exacerbated schizophrenic inpatients treated with bromperidol (6-18 mg/day). Plasma drug concentrations were monitored and clinical symptoms were evaluated using the Brief Psychiatric Rating Scale (BPRS) before and 3 weeks after the treatment. The C3435T and G2677T/A genotypes were determined by a polymerase chain reaction method. Schizophrenic symptoms were allocated into 5 clusters: positive, excitement, cognitive, negative, and anxiety-depression symptoms. Patients were C/C in 12, C/T in 12 and T/T in 7 cases for C3435T genotype and G/G in 3, G/T or A in 17 and T or A/T or A in 11 cases for G2677T/A genotype. There were a tendency of difference, but not statistically different, in the percentage improvement or the improved scores of 5 sub-grouped symptoms after the 3-week treatment between C3435T genotypes and between G2677T/A genotypes. Multiple regression analyses including age, body weight, gender and drug concentration showed significant correlations between the percentage improvement and the improved scores of cognitive symptoms and C3435T genotypes. The present results suggest that the C3435T polymorphism is associated with some therapeutic response to bromperidol in schizophrenic patients, possibly by different drug concentration in the brain.     

The influence of 5-HT(2C) and MDR1 genetic polymorphisms on antipsychotic-induced weight gain in female schizophrenic patients

We investigated the relationships between functional genetic variants of the 5-HT(2C) receptor and multidrug-resistant protein (MDR1), coding for P-glycoprotein, and second generation antipsychotic (SDA)-induced weight gain among 108 female schizophrenic patients treated with olanzapine or risperidone for up to 4 months. No significant differences in -759C/T allelic and genotype variants of 5-HT(2C) were found between patients who gained more than 7% of their initial weight compared with those who gained less. Haplotype-based analysis of two MDR1 loci, exon 21 G2677T and exon 26 C3435T, revealed a slightly lower representation of the G2677/C3435 haplotype in the >/=7% group. In the subgroup of patients treated with risperidone, we found borderline overrepresentation of 2677T, significant overrepresentation of 3435T variant and borderline overrepresentation of 2677T/3435T haplotype the >/=7% group, whereas G2677/C3435 haplotype was found to be less represented in the >/=7% group. Our data indicate a nonsignificant role of 759C/T 5-HT(2C) in SDA-induced weight gain, and a stronger influence of the MDR1 G2677T and C3435T polymorphisms on risperidone-induced weight gain in female schizophrenic patients. 3435T and 2677T MDR1 variants, both associated with lower P-gp function, might predispose to higher risperidone accessibility to the brain that would lead to stronger effects, including weight gain.     

Lack of association between the C3435T polymorphism in the human multidrug resistance (MDR1) gene and response to antiepileptic drug treatment

PURPOSE: P-glycoprotein (P-gp) has been implicated in the causation of refractory epilepsy. The expression and efflux efficiency of P-gp is influenced by a polymorphism (C3435T) in the encoding gene (MDR1). Recent evidence suggests that the homozygous C-variant, which is associated with higher expression and increased activity of P-gp, is more common in patients with pharmacoresistant epilepsy. We have investigated the prevalence of this polymorphism in a series of patients attending a specialist epilepsy clinic. METHODS: DNA samples were obtained from 400 patients, irrespective of seizure type or drug treatment. Genotype of the C3435T polymorphism was determined by traditional polymerase chain reaction (PCR) followed by restriction digest. Classification of response to treatment was determined in a blinded fashion by an independent physician. Results were expressed as genotype and allele frequencies per response group and compared by logistic regression analysis. RESULTS: In total, 170 patients were classified as responders, with > or =12 months seizure freedom on current treatment. The remaining 230 patients were classified as nonresponders. Comparison of responders and nonresponders revealed no significant difference in allele frequency (C vs. T; odds ratio, 1.03; 95% CI, 0.78-1.37; p = 0.83) or genotype frequency (CC vs TT; odds ratio, 1.07; 95% CI, 0.60-1.91; p = 0.81). Subanalyses of individual seizure types were similarly unremarkable. CONCLUSIONS: This study failed to corroborate a previously reported association between the C3435T polymorphism in the human MDR1 gene and pharmacoresistant epilepsy. Whether the C3435T polymorphism can act as a marker for the natural history of treated epilepsy remains to be determined.     

No association between the brain-derived neurotrophic factor gene Val66Met polymorphism and tardive dyskinesia in schizophrenic patients

OBJECTIVE: This study investigated whether the brain-derived neurotrophic factor (BDNF) gene Val66Met single-nucleotide polymorphism (SNP) is associated with antipsychotic-induced tardive dyskinesia (TD) in schizophrenia. METHODS: Genotyping was performed for the BDNF gene Val66Met SNP in Korean schizophrenic patients with (n=83) and without TD (n=126) who were matched for antipsychotic drug exposure and other relevant variables. RESULTS: The frequencies of genotypes (chi2=2.37, p=0.306) and alleles (chi2=0.03, p=0.867) did not differ significantly between these two groups. CONCLUSION: These findings suggest that the BDNF polymorphism does not play a major role in the susceptibility to TD in schizophrenic patients.     

Is there protective haplotype of dysbindin gene (DTNBP1) 3 polymorphisms for major depressive disorder

Dysbindin gene has been repeatedly associated with psychiatric disorders and schizophrenia in particular. This study aimed to investigate the variants of dysbindin gene in major depressive disorder (MDD). One hundred and eighty eight patients with MDD and 350 controls were investigated for 4 variants within the dysbindin gene (rs3213207 A/G, rs1011313 C/T, rs760761 C/T, and rs2619522 A/C). Haplotype analyses revealed a significant association with MDD (p=0.0007, protective A-C-T-A and A-C-C-C haplotypes), in particular the effect was due to the rs760761 (C/T) and rs2619522 (A/C) haplotype (p=0.000026). These results suggest a protective effect of some dysbindin gene haplotypes on the development of MDD. Coupled with previous findings on schizophrenia, our finding suggests that dysbindin gene variants may have a role in the susceptibility to MDD. Adequately powered further studies in different ethnic groups are warranted.     

Vascular Endothelial Growth Factor (VEGF) serum concentration during electroconvulsive therapy (ECT) in treatment resistant depressed patients

Vascular endothelial growth factor (VEGF) is an angiogenic cytokine, which induces vasopermeability and facilitates neurogenesis and synaptic plasticity in the adult brain. Expression studies in animal models have reported that brain VEGF is regulated by electroconvulsive seizures (ECS), which are used in an experimental paradigm similar to clinical electroconvulsive therapy (ECT) a treatment for drug resistant depressed (TRD) patients. The aim of this study was to investigate putative modulations of ECT on VEGF serum levels in TRD patients.Nineteen patients were enrolled in the study; illness severity and VEGF serum contents were assessed before the treatment (T0), the day after the end of ECT (T1) and one month later the end of ECT (T2).ECT treatment improved depression symptomatology as measured by MADRS scores (p < 0.0001). No changes occurred in serum VEGF between T0 and T1, whereas a significant increase was observed between T0 and T2 (p = 0.042). Moreover a significant correlation was observed between the VEGF increase at T2 and the reduction in MADRS scores (p = 0.049).This study is the first to evaluate putative modulations of serum VEGF induced by ECT in TRD patients.     

Association analysis of serotonin receptor 7 gene (HTR7) and risperidone response in Chinese schizophrenia patients

Several lines of evidence suggest that the human 5-HT₇ receptor may be involved in the pharmacodynamics of risperidone and may influence clinical response of the drug. A pharmocogenetics study of this receptor may therefore be useful in developing individualized therapy. But few studies about it have been done. In this study, we genotyped ten single nucleotide polymorphisms (SNPs) distributed throughout the HTR7 gene and analyzed six of them for association with the reduction of Brief Psychiatric Rating Scale (BPRS) scores in drug-naive Chinese schizophrenia patients, following an eight-week period of risperidone monotherapy. The confounding effects of nongenetic factors were estimated and the baseline symptom score as well as the duration of illness were included as covariates for adjustment. No significant correlation of HTR7 with antipsychotic efficacy was detected in either genotype or haplotype analysis. These results demonstrate that variations in the HTR7 gene may not be good genetic markers for predicting the therapeutic efficacy of risperidone.     

Association of the ADRA1A gene and the severity of metabolic abnormalities in patients with schizophrenia

Patients with schizophrenia have a higher risk of developing metabolic abnormalities and their associated diseases. Some studies found that the accumulative number of metabolic syndrome components was associated with the severity of metabolic abnormalities. The purpose of this study was to examine the roles of the ADRA1A, ADRA2A, ADRB3, and 5HT2A genes in the risk of having more severe metabolic abnormalities among patients with schizophrenia. We studied a sample of 232 chronic inpatients with schizophrenia (120 males and 112 females) to explore the associations between the four candidate genes and the severity of metabolic syndrome by accumulative number of the components. Four single nucleotide polymorphisms in the candidate genes were genotyped, including the Arg347Cys in ADRA1A, the C1291G in ADRA2A, the Try64Arg in ADRB3, and the T102C in 5HT2A. An association between the accumulative number of metabolic syndrome components and the ADRA1A gene was found after adjusting age, sex, and other related variables (p-value = 0.036). Presence of the Arg347 allele in the ADRA1A gene is a risk factor for having more severe metabolic abnormalities. These findings suggest a medical attention of closely monitoring metabolic risks for schizophrenia patients with high-risk genotypes.     

The role of dopamine transporter (SLC6A3) and dopamine D2 receptor/ankyrin repeat and kinase domain containing 1 (DRD2/ANKK1) gene polymorphisms in personality traits

Variations in personality traits are caused by interactions between multiple genes of small effect and environmental factors. To date, gender- and ethnicity-specific variations in personality have been established. In the present study, we aimed to test: 1) the effects of four polymorphisms of dopamine system genes: ANKK1/DRD2 Taq1A, DRD2 rs6275, SLC6A3 40-bp VNTR and rs27072, on personality traits; 2) whether these effects differ between men and women and between Russians and Tatars. A sample of 652 healthy individuals (222 men and 430 women) of Caucasian origin (233 Russians and 419 Tatars) from Russia was subjected to personality traits assessment with Eysenck Personality Inventory (EPI) and Temperament and Character Inventory-125 (TCI-125). The associations between each personality trait and polymorphisms were assessed with regression models adjusted for gender and ethnicity. There were significant effects of ANKK1/DRD2 Taq1A on Neuroticism (p = 0.016) and of SLC6A3 rs27072 on Persistence (p = 0.021) in both genders. The association between ANKK1/DRD2 Taq1A A2/A2-genotype and higher Novelty Seeking and lower Reward Dependence was shown in men only (p for gender interaction = 0.018). In women only, there was a significant association between SLC6A3 10R*G-haplotype and higher Persistence (p = 0.002). Our findings provide evidence for a modifying effect of gender on the associations between dopamine system genes and approach-related traits (in men) and Persistence (in women).     

A possible association between missense polymorphism of the breakpoint cluster region gene and lithium prophylaxis in bipolar disorder

Lithium is one of the most commonly used drugs for the treatment of bipolar disorder. To prescribe lithium appropriately to patients, predictors of response to this drug were explored, and several genetic markers are considered to be good candidates. We previously reported a significant association between genetic variations in the breakpoint cluster region (BCR) gene and bipolar disorder. In this study, we examined a possible relationship between response to maintenance treatment of lithium and Asn796Ser single-nucleotide polymorphism in the BCR gene. Genotyping was performed in 161 bipolar patients who had been taking lithium for at least 1 year, and they were classified into responders for lithium mono-therapy and non-responders. We found that the allele frequency of Ser796 was significantly higher in non-responders than in responders. Further investigation is warranted to confirm our findings.     

Low-activity allele of Catechol-O-Methyltransferase (COMTL) is associated with increased lateral ventricles in patients with first episode non-affective psychosis

BACKGROUND: Structural brain anomalies are present at early phases of psychosis. The objective was to examine the impact of Catechol-O-Methyltransferase (COMT) gene variations on brain morphology in first-episode non-affective psychosis. We hypothesized that the low activity-COMT (COMT(L)) allele would be associated with the presence of structural brain changes as assessed by quantitative magnetic resonance imaging (MRI). METHODS: Fifty-two males and 23 females underwent COMT genotyping and MRI. Patients were categorized into three genetic subgroups: COMT(H/H), COMT(L/H) and COMT(L/L). MRI data were analyzed using BRAINS2. Global and lobar volumes of grey matter (GM) and cerebrospinal fluid (CSF) were compared among the three groups after controlling for total intracranial volume and age of illness onset. RESULTS: COMT(L) carriers showed a significant enlargement of the lateral ventricles (F = 7.13, p = 0.009), right lateral ventricle (F = 5.99, p = 0.017) and left lateral ventricle (F = 6.22, p = 0.015). No other significant differences in any of the brain structures were found among subgroups. CONCLUSIONS: Our findings suggest that genetic variations of COMT can contribute to the enlargement of the lateral ventricles described in early phases of non-affective psychosis.     

Repeated administration of Yokukansan inhibits DOI-induced head-twitch response and decreases expression of 5-hydroxytryptamine (5-HT)2A receptors in the prefrontal cortex

Behavioral and psychological symptoms of dementia (BPSD) are commonly seen in patients with Alzheimer's disease (AD) and other forms of senile dementia. BPSD have a serious impact on the quality of life of dementia patients, as well as their caregivers. However, an effective drug therapy for BPSD has not been established. Recently, the traditional Japanese medicine Yokukansan (YKS, Yi-gan san in Chinese) has been reported to improve BPSD in a randomized, single-blind, placebo-controlled study. Moreover, abnormalities of the serotonin (5-HT) system such as 5-HT2A receptors have been reported to be associated with BPSD of AD patients. In the present study, we investigated the effect of YKS on head-twitch response induced by 2,5-dimethoxy-4-iodoamphetamine (DOI, 5 mg/kg, i.p.) in mice, a behavioral response that is mediated, in part, by 5-HT2A receptors. Acute treatment with YKS (100 and 300 mg/kg, p.o.) had no effect on the DOI-induced head-twitch response, whilst 14 days repeated treatment with YKS (300 mg/kg, p.o.) significantly inhibited this response. Moreover, repeated treatment with YKS (300 mg/kg, p.o.) decreased expression of 5-HT2A receptors in the prefrontal cortex, which is part of the circuitry mediating the head-twitch response. These findings suggest that the inhibition of DOI-induced head-twitch response by YKS may be mediated, in part, by altered expression of 5-HT2A receptors in the prefrontal cortex, which suggests the involvement of the 5-HT system in psychopharmacological effects of YKS.