A 6-week, multicenter, double-blind, double-dummy, chlorpromazine-controlled non-inferiorityrandomized phase iiitrial to evaluate the efficacy and safety of quetiapine fumarate (SEROQUEL) extended-release (XR) in the treatment of patients with schizophrenia and acute episodes.

This study aimed to evaluate the efficacy and safety of quetiapine fumarate extended-release (XR) in the treatment of Chinese patients with acute schizophrenia. Multicenter, double-blind, double-dummy, active-controlled non-inferiority randomized study in Chinese patients (n = 388) with schizophrenia randomly assigned to quetiapine XR or chlorpromazine for 6 weeks. Primary outcome was the change from baseline in Positive and Negative Syndrome Scale (PANSS) total score at the end of treatment. Safety objectives included adverse event (AE) monitoring, laboratory test results, and electrocardiograms. Changes in PANSS total score were -33.4 for quetiapine XR and -35.9 for chlorpromazine (P > 0.05). Least squares mean changes were: positive subscale, -9.9 ± 0.53 and -11.1 ± 0.51; negative subscale, -5.9 ± 0.50 and -6.7 ± 0.48; general psychopathology subscale, -12.9 ± 0.74 and -13.9 ± 0.71; aggression and hostility cluster scores, -4.8 ± 0.33 and -5.4 ± 0.32; and depression cluster scores, -1.8 ± 0.18 and -1.7 ± 0.18, for quetiapine XR and chlorpromazine, respectively. For quetiapine XR, AEs were constipation, dizziness, insomnia, and agitation, and nine patients (4.6%) discontinued due to AEs. For chlorpromazine, AEs were extrapyramidal symptoms, constipation, insomnia, dizziness, and agitation, and 17 patients (8.9%) discontinued due to AEs; two patients reported serious AEs. Quetiapine XR monotherapy was not inferior to chlorpromazine for treating acute schizophrenia in Chinese patients and was well tolerated.

Efficacy and safety of quetiapine extended release monotherapy in bipolar depression: a multi-center, randomized, double-blind, placebo-controlled trial.

RATIONALE: Quetiapine extended release (XR) has been used to treat various psychiatric disorders, including depressive episodes associated with bipolar I and II disorders. Quetiapine XR is the first approved drug in China for the treatment of bipolar disorder. OBJECTIVES: The study evaluated the efficacy and safety of short-term quetiapine XR monotherapy in the treatment of depressive episodes of bipolar I and II disorders. METHODS: This was an 8-week multi-center, randomized, double-blind, placebo-controlled, fixed-dose phase 3 study. The primary endpoint was the mean change of the Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Secondary endpoints included Clinical Global Impressions-Bipolar (CGI-BP) and remission rates. RESULTS: The study recruited 279 adult bipolar I or II patients currently experiencing depression from 11 Chinese provinces. Of these, 139 received quetiapine XR (300 mg/day) and 140 received placebo for 8 weeks. The mean change in the MADRS total score was significantly greater in the quetiapine XR group than in the placebo group (-19.00 ± 7.88 vs. -16.20 ± 9.32; p = 0.004). Adverse events occurred in 96 patients (65.3 %) in the quetiapine XR group and 72 (49.0 %) in the placebo group. The incidence of serious adverse events did not differ significantly between the groups (p = 0.247). CONCLUSIONS: This study, which is the first to evaluate 300 mg/day quetiapine XR monotherapy for depression in Chinese patients with bipolar disorders, found that this drug was superior to the placebo. Quetiapine XR was generally safe and well tolerated (ClinicalTrials.gov number, NCT01256177).

Comparative study of the efficacy and safety between blonanserin and risperidone for the treatment of schizophrenia in Chinese patients: A double-blind, parallel-group multicenter randomized trial.

This randomized, double-blind study compared the efficacy and safety of blonanserin and risperidone to treat Chinese schizophrenia patients aged ≥18 and < 65 years. Patients with Positive and Negative Syndrome Scale (PANSS) total scores ≥70 and ≤ 120 were randomized to receive blonanserin or risperidone using a gradual dose-titration method (blonanserin tablets: 8-24 mg/day; risperidone tablets: 2-6 mg/day), twice daily. Treatment populations consisted of 128 blonanserin-treated patients and 133 risperidone-treated patients. Intention-to-treat analysis was performed using the last observation carried forward method. Reductions of PANSS total scores by blonanserin and risperidone treatment were -30.59 and -33.56, respectively. Risperidone treatment was associated with elevated levels of serum prolactin (67.16% risperidone versus 52.31% blonanserin) and cardiac-related abnormalities (22.39% risperidone versus 12.31% blonanserin), and blonanserin patients were more prone to extrapyramidal side effects (48.46% blonanserin versus 29.10% risperidone). In conclusion, blonanserin was as effective as risperidone for the treatment of Chinese patients with schizophrenia. The overall safety profiles of these drugs are comparable, although blonanserin was associated with a higher incidence of EPS and risperidone was associated with a higher incidence of prolactin elevation and weight gain. Thus, blonanserin is useful for the treatment of Chinese schizophrenia patients.

Efficacy and safety of aripiprazole in Chinese Han schizophrenia subjects: a randomized, double-blind, active parallel-controlled, multicenter clinical trial.

OBJECTIVE: Antipsychotics, such as aripiprazole and risperidone, are often used to treat individuals with schizophrenia. The efficacy as well as safety of aripiprazole in Western populations has been described. The objective of this study is to investigate the efficacy, safety, and tolerability of aripiprazole and risperidone in Chinese Han schizophrenia subjects in mainland China. METHOD: The 6-week, double-blind, randomized, parallel study was conducted in 5 medical centers in mainland China from November 2007 to March 2011. A total of 279 subjects with a primary DSM-IV diagnosis of schizophrenia were randomly assigned (with a randomization ratio of 1:1) to aripiprazole (n=139) or risperidone (n=140). Efficacy measurements included the Positive and Negative Syndrome Scale (PANSS) total, positive, negative and general psychopathology subscale scores, and Clinical Global Impressions-Severity of Illness (CGI-S), and Improvement scale scores. Extrapyramidal symptoms (EPS), weight gain, serum prolactin level, QTc interval, and self-reported adverse events were also assessed as measures of safety and tolerability. RESULTS: Both the aripiprazole and risperidone groups showed statistically significant improvement of PANSS total, positive, negative, general psychopathology subscale scores, and CGI-S scores from baseline to the endpoint (all p<0.01). Significant improvement was noted in the first week for both treatment groups. There were no significant differences in efficacy measurements between the two treatment groups. Mean change of PANSS total scores from baseline to the endpoint was -26.8±18.1 for aripiprazole and -30.0±17.7 for risperidone, (p=0.1475). The responder rate was 71% (n=99) and 76% (n=107) for aripiprazole and risperidone, respectively, (p=0.323). The incidences of EPS were similar in the aripiprazole (25%, n=35) and risperidone groups (24%, n=34), respectively (p=0.757). No clinically meaningful effects on QTc interval, QRS duration, or PR interval were observed in either treatment groups. However, the incidence of clinically significant weight gain (p=0.0118) and hyperprolactinemia (p<0.001) in the aripiprazole group was significantly lower than in the risperidone group. CONCLUSION: The study demonstrated that aripiprazole, as well as risperidone, had rapid and persistent efficacy for psychotic symptoms from the first week of therapy. There may be poor efficacy for aripiprazole compared with risperidone for overall improvement, but there were no significant differences in this study. Aripiprazole showed good tolerability with less weight gain and hyperprolactinemia compared with risperidone. The overall efficacy and safety of aripiprazole in Chinese Han schizophrenia subjects were similar to that reported in Western populations.

A randomized, double-blind, double-dummy, multicenter, controlled trial on brotizolam intervention in outpatients with insomnia.

AIM: To investigate the efficacy and safety of brotizolam in outpatients with insomnia. METHODS: This randomized, double-blind, double-dummy, multicenter, controlled trial recruited 253 outpatients randomized to receive either brotizolam (n = 126) or estazolam (n = 127) for 14 days followed by 1 week of follow-up for rebound detection. Sleep Dysfunction Rating Scale (SDRS) and Clinical General Impression Scale were applied for efficacy evaluation. Safety evaluation was based on data regarding vital signs, physical examination, lab tests, ECG and collection of adverse events. RESULTS: Full Analyses Set (FAS) and Safety Set (SS) included data of 251 subjects, with 126 from brotizolam group and 125 from estazolam group. Per Protocol Set (PPS) analysis included data of 235 subjects, with 121 and 114 from each group. After 14 days of treatment, there was no difference with statistical significance between the two groups regarding SDRS total score change from baseline. FAS and PPS analysis showed that the brotizolam is non-inferior to estazolam in efficacy evaluation. There was also no difference with statistical significance regarding rebound rate between brotizolam and estazolam group in FAS. The rate of adverse event in two groups was with no statistically significant difference in SS. CONCLUSION: Brotizolam is effective and safe in relieving the symptoms of insomnia.

Double-blind comparison of ziprasidone and risperidone in the treatment of Chinese patients with acute exacerbation of schizophrenia.

BACKGROUND: The aim of the study was to evaluate the efficacy and safety of ziprasidone versus risperidone in Chinese subjects with acute exacerbation of schizophrenia. METHODS: In patients meeting the Chinese Classification of Mental Disorders criteria for schizophrenia and with a Positive and Negative Syndrome Scale (PANSS) total score ≥60 were randomly assigned to six weeks of double-blind treatment with ziprasidone 40-80 mg twice daily or risperidone 1-3 mg bid, flexibly dosed. Noninferiority was demonstrated if the upper limit of the two-sided 95% confidence interval (CI) for the difference in PANSS total score improvement from baseline in the evaluable population was smaller than the prespecified noninferiority margin of 10 units. RESULTS: The intent-to-treat population comprised 118 ziprasidone-treated and 121 risperidone-treated subjects. Improvement (reduction) from baseline to week 6 in PANSS total score was (-35.6 [95% CI: -38.6, -32.6]) for ziprasidone and (-37.1 [95% CI: -39.9, -34.4]) for risperidone. Noninferiority was demonstrated in the evaluable population with a difference score of 1.5 [95% CI: -2.5, 5.5]. Mean prolactin levels decreased at week 6 compared with baseline for ziprasidone (-3.5 ng/mL), but significantly increased for risperidone (61.1 ng/mL; P < 0.001). More risperidone-treated subjects (14.9%) than ziprasidone-treated subjects (4.2%) reported weight gain ≥7%. Akathisia and somnolence in the ziprasidone group and akathisia and insomnia in the risperidone group were the most common side effects. Treatment-related/treatment-emergent adverse events were reported by 79.7% and 71.1% of ziprasidone-treated and risperidone-treated subjects, respectively. CONCLUSION: In Chinese subjects, ziprasidone was as effective as risperidone, with less weight gain and less prolactin elevation.

A comparative study of paliperidone palmitate and risperidone long-acting injectable therapy in schizophrenia.

This open-label, rater-blinded, parallel-group study was designed to evaluate noninferiority of paliperidone palmitate (PP), a once-monthly injectable atypical antipsychotic, to once-biweekly risperidone long-acting injectable (RIS-LAI) in adult Chinese patients with acute schizophrenia. Eligible Chinese adults (N=452) with schizophrenia were randomized (1:1) to either PP (N=229; deltoid injections on day 1 [150 mg eq.] and day 8 [100 mg eq.]; then once-monthly deltoid or gluteal injections, flexibly dosed [50, 100, or 150 mg eq.]), or RIS-LAI (N=223; once-biweekly gluteal injections, flexibly dosed [25, 37.5 or 50 mg]). RIS-LAI-treated patients received oral risperidone supplementation (1-6 mg/day) at initiation and with RIS-LAI dose increases. Mean (SD) Positive and Negative Syndrome Scale (PANSS) total score at baseline was 83.2 (12.44). Mean (SD) change from baseline to endpoint in PANSS total scores (primary efficacy measure) was: -23.6 (16.28) for PP group and -26.9 (15.43) for RIS-LAI group. PP was noninferior to RIS-LAI (least squares mean difference [95% CI]: -2.3 [-5.20; 0.63]; predetermined non-inferiority margin: -5.5). Mean (SD) change from baseline to endpoint in Clinical Global Impression-Severity scale score was: -1.5 (1.24; PP group), -1.7 (1.16; RIS-LAI group) and in Personal and Social Performance Scale scores was: 16.8 (14.76; PP group), 18.6 (13.92; RIS-LAI group). The incidence of treatment-emergent adverse events (TEAEs) was similar between the two groups (73% [PP]; 75% [RIS-LAI]). The most common TEAEs were akathisia, tremor, and insomnia. The study demonstrated the noninferiority of PP (50-150 mg eq., flexibly dosed, without oral paliperidone supplementation) to risperidone-LAI (25-50 mg, flexibly dosed, with oral risperidone supplementation) for the treatment of acute schizophrenia in adult Chinese patients. PP injections were generally tolerable, and no new safety signals were detected in this population.

Schizophrenia is not associated with the ERBB3 gene in a Han Chinese population sample: Results from case-control and family-based studies.

ERBB3 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 3), encoding a receptor of neuregulin-1 (NRG1), has been considered a functional candidate gene for schizophrenia susceptibility. In order to investigate a relationship between ERBB3 gene and schizophrenia in the Chinese population, case-control and family-based studies were carried out in 470 cases matched by controls, and in 532 family trios. Our results failed to show any evidence of significant association between the ERBB3 rs2292238 polymorphism and schizophrenia.

Schizophrenia is not associated with the ERBB3 gene in a Han Chinese population sample: results from case-control and family-based studies

ERBB3 (v-erb-b2 erythroblastic leukemia viral oncogene homolog 3), encoding a receptor of neuregulin-1 (NRG1), has been considered a functional candidate gene for schizophrenia susceptibility. In order to investigate a relationship between ERBB3 gene and schizophrenia in the Chinese population, case-control and family-based studies were carried out in 470 cases matched by controls, and in 532 family trios. Our results failed to show any evidence of significant association between the ERBB3 rs2292238 polymorphism and schizophrenia.

Association study of a (TG)n dinucleotide repeat at chromosome 15q13.3 and schizophrenia in the Chinese population.

Linkage studies have suggested that chromosome 15q13-q14 may harbor a susceptibility locus for schizophrenia. In the current study, the association between a (TG)n dinucleotide repeat polymorphism at D15S976 and schizophrenia was investigated using two independent samples from the Han Chinese population. In a population-based study, no significant difference was found between the genotype and allele frequency distributions in schizophrenia patients and control subjects. In a family-based study, no significant transmission disequilibrium from heterozygous parents to affected offspring was observed. Further analysis of the parent-of-origin effect found nominally significant allele-wise transmission disequilibrium through maternal transmissions, while 157bp and 159bp alleles showed significant individual allelic transmission disequilibrium from heterozygous mothers to affected offspring. Our results did not support the hypothesis that the (TG)n dinucleotide repeat polymorphism plays a major role in schizophrenia susceptibility in the Chinese population. Further studies are needed to elucidate the putative parent-of-origin effect and its role in schizophrenia susceptibility.

Lack of association between three serotonin genes and suicidal behavior in Chinese psychiatric patients.

BACKGROUND: Suicide is a significant health problem throughout the world. The serotoninergic system is believed to be involved in suicidal behavior and there is evidence of biological abnormalities of two serotonin receptors (HTR2A, HTR2C) and one serotonin transporter (5HTT) in suicide victims. Rs6313 (T102C) of HTR2A and rs6318 (Cys23Ser) of HTR2C have been investigated in suicide behavior in other studies. METHODS: Here, we investigated rs6313 and rs6318 and other 10 randomly chosen SNPs, of those three genes in a study of 329 psychiatric patients who had never attempted suicide and 297 patients who had attempted suicide. RESULTS: No associations were found for the 12 SNPS. CONCLUSIONS: Our results do not support the involvement of HTR2A, 5HTT or HTR2C in suicidal behavior in Han Chinese subjects.

Response and remission rates in Chinese patients with bipolar mania treated for 4 weeks with either quetiapine or lithium: a randomized and double-blind study.

OBJECTIVE: To assess the efficacy and tolerability of quetiapine in Chinese patients hospitalized with acute bipolar mania. METHODS: This was a 4-week, multicenter, randomized, double-blind, lithium-controlled, parallel-group study. Secondary endpoints in the primary analysis were: response rate (> or = 50% decrease from baseline in YMRS total score) and remission rate as defined using 3 criteria: YMRS total score < or = 12, YMRS total score < or = 12 + MADRS total score < or = 8, and YMRS total score < or = 8. Other measures included: change from baseline at Day 28 in YMRS, PANSS, and MADRS total score. Adverse event (AE) data were collected throughout the study. RESULTS: 73 (94.8%) quetiapine and 62 (80.5%) lithium patients completed the study. Mean (SD) quetiapine doses for the ITT population and responders were 648.2 (111.84)mg/day and 637.5 (118.78)mg/day, respectively, while mean lithium concentrations for the ITT population and responders were 0.80 (0.28)mmol/L and 0.80 (0.22)mmol/L, respectively. Of patients who responded to quetiapine at Day 28, 88.3% were receiving 600-800mg/day. At Day 28 YMRS response rate was significantly greater with quetiapine than lithium (77.9% vs. 59.7%, p = 0.0132), and remission rates using the 3 criteria were significantly greater with quetiapine than lithium: YMRS total score < or = 12 (70.1% vs. 48.1%, p = 0.0071), YMRS < or = 12 + MADRS < or = 8 (70.1% vs. 48.1%; p = 0.0071), and YMRS < or = 8 (51.9% vs. 32.5%; p = 0.0147). Significant decreases were observed in PANSS, YMRS, and MADRS total scores for both groups. The most common AEs experienced by patients receiving quetiapine were constipation, dizziness, diarrhea, alanine aminotransferase increase, palpitations, aspartate aminotransferase increase, pharyngolaryngeal pain, upper respiratory tract infection and dry mouth. In patients receiving lithium, the most common AEs were nausea (16.9%), constipation (13.0%), vomiting (13.0%), nasopharyngitis (11.7%), dizziness (6.5%), diarrhea (6.5%), and upper respiratory tract infection (6.5%). CONCLUSION: Quetiapine was shown to be clinically effective in patients with acute bipolar mania. There were side effects with quetiapine similar to those reported in other studies that included other ethnic populations of patients.

Effects of the dopamine D3 receptor (DRD3) gene polymorphisms on risperidone response: a pharmacogenetic study.

Previous observations of the anatomical distribution and pharmacological profile of the dopamine D(3) receptor (DRD3) have indicated its potential role in antipsychotic drug action. Risperidone, an effective first-line atypical antipsychotic agent, exhibits a relatively high affinity for this receptor. Recent studies have reported an association of the Ser9Gly polymorphism in the DRD3 gene with therapeutic response to risperidone, but the results were inconsistent. We therefore postulated that the Ser9Gly polymorphism might be in linkage disequilibrium with an undetected variant that exerts a direct influence on risperidone efficacy. The present study genotyped eight single nucleotide polymorphisms (SNPs) distributed throughout the DRD3 gene and examined five of these for association with treatment outcome, following an 8-week period of risperidone monotherapy in 130 schizophrenic patients from mainland China. Clinical symptoms were assessed before and after the treatment period, using the Brief Psychiatry Rating Scale (BPRS). The confounding effects of non-genetic factors were estimated and the baseline symptom score was included as a covariate for adjustment. Neither was any association observed between the five polymorphisms and improvement in total BPRS scores nor was any combined effect of these variants detected in the haplotype analysis. The current results indicate that genetic variations within the DRD3 gene may not contribute significantly to interindividual differences in the therapeutic efficacy of risperidone.

[Association study of an (AC)n dinucleotide repeat and schizophrenia in Asian and European populations].

Linkage studies have suggested that chromosome 15q13-q14 may harbor a susceptibility locus for schizophrenia. In the current study, the association between a (AC)n dinucleotide repeat polymorphism at D15S118 and schizophrenia was investigated using three independent samples from the Han Chinese population and the Scotland population. In the population-based study, a significant difference was found between the allele frequency distributions in schizophrenia patients and control subjects in the Scottish samples (P = 0.04), but was not replicated in the Chinese samples. In a family-based study, no significant transmission disequilibrium from heterozygous parents to affected offspring was observed. Overall, our results did not support the hypothesis that the (AC)n dinucleotide repeat polymorphism plays a major role in schizophrenia susceptibility, at least in the Chinese population. Further studies are needed to elucidate its role in schizophrenia susceptibility in European population.

Serum prolactin levels, plasma risperidone levels, polymorphism of cytochrome P450 2D6 and clinical response in patients with schizophrenia.

The object of this study is to assess 1) the relationship between plasma antipsychotic drug concentration, serum prolactin levels and the clinical efficacy of risperidone, 2) the relationship between the CYP2D6 polymorphisms and metabolizing of risperidone and 3) the role of 9-hydroxyrisperidone in elevating prolactin levels. One-hundred and eighteen Chinese schizophrenia patients (40 males, 78 females, age 15-60 years) were given risperidone at dosages ranging from 2-8 mg/day for 8 weeks. Clinical efficacy was determined using the Brief Psychiatric Rating Scores (BPRS). Serum prolactin levels were assayed before and after the 8 week treatment and plasma risperidone and 9-hydroxyrisperidone levels were also measured at the end of the 8-week treatment. The results showed there was no significant correlation between the concentration of active moiety and clinical response. Risperidone treatment significantly increased serum prolactin levels. Furthermore, changes of prolactin levels were not correlated with the clinical response. For the risperidone/ 9-hydroxyrisperidone ratio, there was a statistically significant difference among the CYP2D6*1/*1, *1/*10, *10/*10 genotypes (Kruskal-Wallis test, p = 0.012). No significant differences were found in the concentration of 9-hydroxyrisperidone and active moiety among the genotypes. In addition, the concentration of 9-hydroxyrisperidone was not significantly correlated with the increase of serum prolactin. In conclusion, our study has, for the first time, produced evidence that in Chinese schizophrenic patients, the metabolism of risperidone is dependent on CYP2D6. Neither changes in serum prolactin levels nor plasma concentration of active moiety were significantly correlated with clinical efficacy of risperidone. 9-hydroxyrisperidone may not play a predominant role in elevating serum prolactin level.

Systematic study of association of four GABAergic genes: glutamic acid decarboxylase 1 gene, glutamic acid decarboxylase 2 gene, GABA(B) receptor 1 gene and GABA(A) receptor subunit beta2 gene, with schizophrenia using a universal DNA microarray.

Several studies have suggested the dysfunction of the GABAergic system as a risk factor in the pathogenesis of schizophrenia. In the present study, case-control association analysis was conducted in four GABAergic genes: two glutamic acid decarboxylase genes (GAD1 and GAD2), a GABA(A) receptor subunit beta2 gene (GABRB2) and a GABA(B) receptor 1 gene (GABBR1). Using a universal DNA microarray procedure we genotyped a total of 20 SNPs on the above four genes in a study involving 292 patients and 286 controls of Chinese descent. Statistically significant differences were observed in the allelic frequencies of the rs187269C/T polymorphism in the GABRB2 gene (P=0.0450, chi(2)=12.40, OR=1.65) and the -292A/C polymorphism in the GAD1 gene (P=0.0450, chi(2)=14.64 OR=1.77). In addition, using an electrophoretic mobility shift assay (EMSA), we discovered differences in the U251 nuclear protein binding to oligonucleotides representing the -292 SNP on the GAD1 gene, which suggests that the -292C allele has reduced transcription factor binding efficiency compared with the 292A allele. Using the multifactor-dimensionality reduction method (MDR), we found that the interactions among the rs187269C/T polymorphism in the GABRB2 gene, the -243A/G polymorphism in the GAD2 gene and the 27379C/T and 661C/T polymorphisms in the GAD1 gene revealed a significant association with schizophrenia (P<0.001). These findings suggest that the GABRB2 and GAD1 genes alone and the combined effects of the polymorphisms in the four GABAergic system genes may confer susceptibility to the development of schizophrenia in the Chinese population.

Response of risperidone treatment may be associated with polymorphisms of HTT gene in Chinese schizophrenia patients.

Serotonin transporter (5-HTT) is a key component of the serotonergic neurotransmitter system. Few studies have focused on polymorphisms of the serotonin transporter and antipsychotic response and, in particular, there have so far been no published studies on the association between the serotonin transporter and response to risperidone. This study examined the relationship between two polymorphisms of the serotonin transporter and the efficacy of risperidone treatment in 129 patients with schizophrenia. Our results revealed that patients with l allele of HTTRLP showed a greater improvement than those without l allele on the overall brief psychiatric rating scale (BPRS) (P=0.025). But no such relationship was found for the HTTVNTR. In haplotype analysis, the frequency of L-12 haplotype showed a significant difference between the responder group and the non-responder group (P=0.005). Our study has, for the first time, produced evidence that the potential for therapy in patients with schizophrenia is related to the HTTRLP polymorphism in the HTT gene and haplotype L-12 may help to predict risperidone treatment efficiency.

The DNA methylation profile within the 5'-regulatory region of DRD2 in discordant sib pairs with schizophrenia.

Studies of discordance in monozygotic twins have demonstrated that environmental effects play an important role in the pathogenesis of schizophrenia. DNA microarray analysis has revealed upregulation of the DRD2 gene in peripheral blood lymphocytes of schizophrenic patients. We hypothesized that this expression alteration could involve the DNA (CpG) methylation status that is implicated to the transcription status of the gene and in this study we used bisulfited sequence analysis to determine the DNA methylation status of a typical CpGs island within the 5'-regulatory region of DRD2 in peripheral blood lymphocytes from 48 discordant sib pairs suffering from schizophrenia. We found that the methylated cytosines occurred mainly in three clusters. No statistically significant difference in frequency of site-specific cytosine methylation modification of DRD2 between patients and normal controls was found nor did we find any significant association between sex, age on admission or age at onset of schizophrenia and methylated cytosines of DRD2. Our study did not support the hypothesis that site-specific cytosine methylation of DRD2 plays a role in the psychopathology of schizophrenia.

A family-based association study of kinesin heavy chain member 2 gene (KIF2) and schizophrenia.

Schizophrenia is a multifactorial disease characterized by multiple genetic susceptibility elements. The human KIF2 gene represents an orthologue of the murine Kif2a, which plays an important role in the transport of various membranous organelles and protein complexes on microtubules. To examine whether this gene is involved in schizophrenia etiology, we undertook studies of transmission disequilibrium in a cohort of affected family samples to test for association. Although, we failed to detect any positive results in single markers, a common two-SNP haplotype (rs2289883/rs464058, G/A) showed a significant association with the disease and a four-SNP haplotype (T/G/A/G) with a frequency of 23.4% was identified in parental chromosomes and showed a significant association with the disease (P=0.00795). Our results demonstrate that the KIF2 gene, located at 5q12.1, is a potential schizophrenia susceptibility gene.