Clozapine induces autophagic cell death in non-small cell lung cancer cells.

BACKGROUND/AIMS: Previous studies have shown that patients with schizophrenia have a lower incidence of cancer than the general population, and several antipsychotics have been demonstrated to have cytotoxic effects on cancer cells. However, the mechanisms underlying these results remain unclear. The present study aimed to investigate the effect of clozapine, which is often used to treat patients with refractory schizophrenia, on the growth of non-small cell lung carcinoma cell lines and to examine whether autophagy contributes to its effects. METHODS: A549 and H1299 cells were treated with clozapine, and cell cytotoxicity, cell cycle and autophagy were then assessed. The autophagy inhibitor bafilomycin A1 and siRNA-targeted Atg7 were used to determine the role of autophagy in the effect of clozapine. RESULTS: Clozapine inhibited A549 and H1299 proliferation and increased p21 and p27 expression levels, leading to cell cycle arrest. Clozapine also induced a high level of autophagy, but not apoptosis, in both cell lines, and the growth inhibitory effect of clozapine was blunted by treatment with the autophagy inhibitor bafilomycin A1 or with an siRNA targeting atg7. CONCLUSIONS: Clozapine inhibits cell proliferation by inducing autophagic cell death in two non-small cell lung carcinoma cell lines. These findings may provide insights into the relationship between clozapine use and the lower incidence of lung cancer among patients with schizophrenia.

Assessment and classification of service learning: a case study of CS/EE students.

This study investigates the undergraduate students in computer science/electric engineering (CS/EE) in Taiwan to measure their perceived benefits from the experiences in service learning coursework. In addition, the confidence of their professional disciplines and its correlation with service learning experiences are examined. The results show that students take positive attitudes toward service learning and their perceived benefits from service learning are correlated with their confidence in professional disciplines. Furthermore, this study designs the knowledge model by Bayesian network (BN) classifiers and term frequency-inverse document frequency (TFIDF) for counseling students on the optimal choice of service learning.

Switching from clozapine to zotepine in patients with schizophrenia: a 12-week prospective, randomized, rater blind, and parallel study.

Clozapine is the most effective antipsychotic for patients with treatment-refractory schizophrenia, but many adverse effects are noted. Clinicians usually hesitate to switch from clozapine to other antipsychotics because of the risk of a re-emergence or worsening of the psychosis, although empirical studies are very limited. Zotepine, an atypical antipsychotic with a pharmacologic profile similar to clozapine, was found to be an effective treatment for patients with treatment-resistant schizophrenia in Japan. This 12-week study is the first prospective, randomized, and rater-blind study to investigate the efficacy and tolerability of switching from clozapine to zotepine. Fifty-nine patients with schizophrenia, who had taken clozapine for at least 6 months with a Clinical Global Impression-Severity score of at least 3, were randomly allocated to the zotepine and the clozapine groups. At the end of the study, 52 patients (88%) had completed the trial. The 7 withdrawal cases were all in the zotepine group. The final mean (SD) dose of zotepine and clozapine was 397.1 (75.7) versus 377.1 (62.5) mg/d, respectively. Patients in the zotepine group showed a significant increase in the Brief Psychiatric Rating Scale [mean (SD), 4.7 (8.7) vs -1.3 (6.3); P = 0.005], more general adverse effects as revealed by the Udvalg for Kliniske Undersogelser Rating Scale [mean (SD), 1.74 (3.9) vs -0.2 (2.8); P = 0.039], more extrapyramidal adverse effects as demonstrated by the Simpson and Angus Scale [mean (SD), 1.29 (3.5) vs 0.17 (2.1); P = 0.022], an increased use of propranolol (37.1% vs 0%, P < 0.0001) and anticholinergics (25.7% vs 0%, P = 0.008), and an increased level of prolactin (29.6 vs -3.8 ng/ mL, P < 0.0005), compared with the clozapine group. The results suggested that switching from clozapine to zotepine treatment should be done with caution.

Analysis of genetic variations in the dopamine D1 receptor (DRD1) gene and antipsychotics-induced tardive dyskinesia in schizophrenia.

BACKGROUND: Dyskinesia is a kind of abnormal involuntary movement disorder that increases with age. The pathogenesis of dyskinesia may result from divergent changes in dopamine D1 receptors (DRD1) and dopamine D2 receptors (DRD2) in the brain while aging. Tardive dyskinesia (TD), a kind of dyskinesia, may develop after long-term antipsychotic treatment. Because the prevalence of TD also steadily increased with age, TD has been suggested to be the consequence of an imbalance between DRD1 and DRD2. We supposed that patients who develop TD may have genetic variants of DRD1 that cause the excitatory effects of DRD1 overwhelming the attenuated inhibitory effects of DRD2 after antipsychotic treatment. METHODS: In the present study, schizophrenic inpatients receiving long-term antipsychotic treatment were first assessed using the Abnormal Involuntary Movement Scale (AIMS), and only patients who were either free of any abnormal involuntary movements (non-TD group, AIMS =0) or who showed persistent TD (TD group) were enrolled. Finally, 382 patients were recruited (TD=220, non-TD=162) and three single nucleus polymorphisms (SNPs; rs5326, rs4532 and rs265975) of DRD1 were genotyped for each subject. RESULTS: Genotype frequency (%; AA/AG/GG) of rs4532 (TD: non-TD) was 61.4/35.8/2.8: 74.2/24.5/1.3. After genetic analyses, genotype GG showed significant association with TD (if OR=2.0, power (%)=98.5; if OR=1.5, power (%)=63.7; P=0.033). Haplotype frequency (%) CGC of rs5326-rs4532-rs265975 (TD: non-TD) was 19.0:13.7; and after haplotype-based analyses, haplotype CGC also showed significant association with TD (OR=1.4, permutation P=0.027). CONCLUSION: Our results indicate that the genotypic variants of DRD1 might play a role in the susceptibility of TD. Further replication in other countries or other populations is highly expected.

Finding social phobia patients from the Internet.

Patients with social phobia commonly resist face-to-face assessments, and a number of alternative assessment methods based on the Internet are being developed. The aim of this study was to identify patients with social phobia on the Internet and characterize their condition, using the Social Phobia Inventory (SPIN). In Stage I, this study recruited 1307 participants from the Internet, most of whom were well-educated young females, who had remained unmarried and unemployed. The Internet-based SPIN demonstrated excellent internal consistency (Cronbach's α=0.937) and good test-retest reliability (intraclass correlation coefficient=0.942). In Stage II, we examined the discriminant validity of the SPIN via structured telephone interviews. The area under the receiver operating characteristic curve used to discriminate social phobia was 0.871 with an optimal cut-off point of 24 on the total score for the SPIN. According to the SPIN scores, 919 of Stage I participants (70.3%) reached the threshold of social phobia, 531 of which (57.8%) had never sought professional help. These results suggest that the Internet is a potential avenue through which to find untreated patients with social phobia.

Genetic association between TNF-alpha -308 G>A polymorphism and longitudinal weight change during clozapine treatment.

OBJECTIVE: The aim of the study was to investigate the association between genetic variation in the tumor necrosis factor-alpha (TNF-alpha) gene and longitudinal weight change during long-term clozapine treatment. METHODS: Fifty-five patients with refractory schizophrenia treated with clozapine for 8 years were recruited. Gender, age, treatment response to clozapine in the first 14 months, baseline BMI, clozapine dose, concomitant use of mood stabilizers and other antipsychotics, and -308 G > A polymorphism in the human TNF-alpha gene were analyzed using generalized estimating equations. RESULTS: In addition to having a lower baseline BMI (p = 0.0013) and a longer treatment time (p = 0.050), the -308 GG carriers gained significantly more weight than the -308 A allele carriers (p = 0.0084) during 8 years of clozapine treatment, after controlling for other non-genetic factors. CONCLUSIONS: The -308 G > A genetic variant of the TNF-alpha gene is associated with longitudinal weight change during clozapine treatment. Follow-up duration is an important factor to consider when performing pharmacogenetic study of clozapine-induced weight gain.

Weight gain with clozapine: 8-year cohort naturalistic study among hospitalized Chinese schizophrenia patients.

OBJECTIVE: Clozapine is associated with significant weight gain. However, it is still debatable whether the majority of weight gain occurs in the early phase of treatment or if weight gain is a persistent side effect. The inconsistent results in previous outpatient studies may be due to many confounding factors, such as variations in drug adherence, diet content, activity level and environmental factors. The objective of this study was to investigate long-term weight changes in hospitalized Chinese schizophrenic patients treated with clozapine. METHODS: Patients were admitted at the largest mental hospital in Taiwan and had routine monthly body weight monitoring during the study period. Retrospective chart reviews were conducted to obtain demographic data, age at which clozapine treatment was initiated, and weight changes after the initiation of clozapine treatment. RESULTS: The study sample consisted of 349 hospitalized schizophrenic patients, including 204 males (58.8%), with an average age at clozapine initiation of 38.6+/-9.3 and an average clozapine dosage of 318+/-9.3 mg/day. Body weight increased over time, and reached a plateau at month 42. Younger age at clozapine initiation (P=0.0038) and lower baseline body mass index (BBMI) (P<0.0001) were associated with more weight gain. The patients with BBMI<25 gained significantly more weight (10.98+/-8.48 kg) compared to patients with BBMI>or=25 (1.17+/-13.29 kg) (P=0.004). CONCLUSIONS: Similar to reports on Caucasians, clozapine-associated weight gain in Chinese patients reached a plateau at month 42. Younger patients with normal BBMI were associated with higher risk of weight gain.

Improved body weight and metabolic outcomes in overweight or obese psychiatric patients switched to amisulpride from other atypical antipsychotics.

Switching to a different second-generation antipsychotic (SGA) with a lower risk of weight gain is recommended for overweight or obese psychiatric patients undergoing SGA treatment. However, there have been no complete reports regarding the long-term metabolic effects of switching to amisulpride. In this open-label 1-year study, we investigated the effects on body weight and other metabolic profiles when psychiatric patients treated with another SGA were switched to amisulpride treatment. Forty-six schizophrenia or schizoaffective inpatients with a body mass index greater than 27 kg/m were enrolled in the switch group. These patients were cross-titrated to amisulpride treatment and followed up for 1 year prospectively. Another 46 inpatients matched with the baseline body mass index of those in the switch group were enrolled as the control group retrospectively. The results showed that the switch group had greater weight loss than the control group (7.80 +/- 6.67 vs 2.60 +/- 6.23 kg, respectively; repeated-measure analysis of variance, P < 0.0005). During the treatment course, the amisulpride-treated patients showed significantly decreased fasting triglyceride, total cholesterol, glucose, and insulin resistance levels; decreased diastolic blood pressure and pulse rate; and a significant increase in high-density lipoprotein cholesterol levels after switching to amisulpride (all with a P < 0.05). The prevalence of metabolic syndrome in amisulpride-treated patients also decreased significantly from 65.2% to 30.4% (McNemar test, P < 0.0005). These findings suggest that switching to amisulpride could be an effective treatment of overweight or obese psychiatric patients treated previously with other SGAs.

Analysis of genetic variations in the RGS9 gene and antipsychotic-induced tardive dyskinesia in schizophrenia.

Some patients treated chronically with antipsychotics develop tardive dyskinesia (TD), an abnormal involuntary movement disorder. Typical antipsychotics block D(2) dopamine receptors (D(2)DR) and produce D(2)DR supersensitivity. On contrary, regulators of G-protein signaling (RGS) can enhance the signal termination of G-protein-coupled D(2)DR. Besides, after prolonged inhibition of dopaminergic transmission, dopaminergic agonists induced severe dyskinesia only in RGS9 knock-out mice but not in normal mice. Therefore, variety in the human RGS9 gene may be related to susceptibility to TD. In this study, schizophrenic inpatients receiving long-term antipsychotic treatment were assessed using the Abnormal Involuntary Movement Scale twice over a 3-month interval. Only patients in whom abnormal involuntary movements were absent (non-TD group) and those who showed persistent TD (TD group) were enrolled. There were 407 patients in the study sample (TD = 252; non-TD = 155) and seven single nucleus polymorphisms (SNPs) in the RGS9 gene were genotyped for each subject. Genotype and allelic distributions of SNPs did not differ between the TD and non-TD groups in this study, with the exception that a weak trend of allelic association was seen with rs4790953 (P = 0.0399). In the haplotype analysis, a significant association of the AGG haplotype (rs8077696-rs8070231-rs2292593) of the RGS9 gene was found (permutation P = 0.007), and this is worthy of replication and further study.

Randomized, double-blind, placebo, and risperidone-controlled study of lurasidone in the treatment of schizophrenia: Results of an inconclusive 6-week trial.

OBJECTIVE: The efficacy and safety of lurasidone in schizophrenia has been demonstrated in multiple controlled trials, primarily in US and European populations. The aim of the current study was To evaluate lurasidone for the treatment of schizophrenia among patients in Japan, Korea, and Taiwan. METHODS: Hospitalized patients (N = 460) with schizophrenia were randomized to 6 weeks of fixed-dose lurasidone 40 mg/d, lurasidone 80 mg/d, risperidone 4 mg/d, or placebo. Efficacy was assessed using the Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression-Severity (CGI-S). RESULTS: No significant endpoint differences in PANSS total score were found for lurasidone or risperidone vs placebo. Lurasidone was safe and well tolerated, with minimal effects on weight and metabolic parameters. DISCUSSION: The current study was inconclusive regarding the efficacy of lurasidone in schizophrenia but further confirmed its safety and tolerability.

Association study of HLA-A gene and schizophrenia in Han Chinese from Taiwan.

Dysregulation of the immune response has been proposed as a precipitating factor of schizophrenia, and human leukocyte antigens (HLA) play a critical role in regulating the cascade of immunological reaction. Hence, many studies have investigated the relationship between the HLA system and schizophrenia. HLA is a complex gene family that contains several highly polymorphic genes, while the HLA-A gene is the most often studied gene to be associated with schizophrenia in the literature. A recent study reported that the interaction of the HLA-A10 allele and Chlamydial infection was highly associated with schizophrenia in a German population, which prompted us to investigate whether the HLA-A gene was also associated with schizophrenia in our population. Using a sequencing-based HLA typing method, we determined the HLA-A genotypes in 377 Han Chinese patients with schizophrenia (214 males, 163 females) and 321 non-psychotic Han Chinese control subjects (164 males, 157 females) from Taiwan. In total, 26 DNA-defined HLA-A alleles were identified in this sample. However, no significant differences of these allelic frequencies were found between the patients and the control subjects, suggesting that the HLA-A gene was unlikely a major risk factor of schizophrenia in this sample. As different populations have different HLA polymorphisms, an examination of the relationship of other HLA genes and schizophrenia in our population, with a larger sample size, is warranted in the future.

Association of missense variants of the PRKC, apoptosis, WT1, regulator (PAWR) gene with schizophrenia.

Abnormal dopamine signal transduction is implicated in the pathophysiology of schizophrenia. A recent study showed that prostate apoptosis response 4 protein (Par-4) interacts with dopamine D2 receptor and plays an important role in dopamine signaling. Par-4 knockout mice showed depression-like behavior, suggesting that Par-4 gene may be associated with mental disorders in human. The study was aimed to determine whether the PRKC, apoptosis, WT1, regulator gene (PAWR) that encodes the human homolog of Par-4 protein is a susceptibility gene for schizophrenia. We systematically screened for mutations at the 5' untranslated region (5'UTR) and all the exonic regions of the PAWR gene in a sample of Han Chinese schizophrenic patients from Taiwan. We identified two missense single nucleotide polymorphisms (SNPs) that are in strong linkage in our sample (D'=0.98), i.e. P78R at exon 2 and I199M at exon 3, respectively. SNP- and haplotype-based analysis showed that these two variants are associated with schizophrenia; there is an overrepresentation of RR homozygotes of P78R (OR=2.00, 95% CI=1.05-3.83) and MM homozygotes of I199M (OR=1.81, 95% CI=0.95-3.54) in schizophrenic patients as compared to control subjects. When subjects were divided by gender, the association is specifically with female patients (OR=2.94 for RR and OR=2.7 for MM), but not with male patients. Our results indicate that the PAWR gene is associated with schizophrenia in our population, and this study provides genetic evidence to support the dopamine hypothesis of schizophrenia.

Artificial neural network prediction of clozapine response with combined pharmacogenetic and clinical data.

Although one third to one half of refractory schizophrenic patients responds to clozapine, however, there are few evidences currently that could predict clozapine response before the use of the medication. The present study aimed to train and validate artificial neural networks (ANN), using clinical and pharmacogenetic data, to predict clozapine response in schizophrenic patients. Five pharmacogenetic variables and five clinical variables were collated from 93 schizophrenic patients taking clozapine, including 26 responders. ANN analysis was carried out by training the network with data from 75% of cases and subsequently testing with data from 25% of unseen cases to determine the optimal ANN architecture. Then the leave-one-out method was used to examine the generalization of the models. The optimal ANN architecture was found to be a standard feed-forward, fully-connected, back-propagation multilayer perceptron. The overall accuracy rate of ANN was 83.3%, which is higher than that of logistic regression (LR) (70.8%). By using the area under the receiver operating characteristics curve as a measure of performance, the ANN outperformed the LR (0.821+/-0.054 versus 0.579+/-0.068; p<0.001). The ANN with only genetic variables outperformed the ANN with only clinical variables (0.805+/-0.056 versus 0.647+/-0.066; p=0.046). The gene polymorphisms should play an important role in the prediction. Further validation of ANN analysis is likely to provide decision support for predicting individual response.

Association analysis of polymorphisms in the N-methyl-D-aspartate (NMDA) receptor subunit 2B (GRIN2B) gene and tardive dyskinesia in schizophrenia.

Tardive dyskinesia (TD) is a neurological disorder characterized by irregular, non-rhythmic, choreoathetotic and involuntary movements in single or multiple body regions. Chronic administration of typical antipsychotic agents, which predominantly act on dopamine receptors, implicates the dopamine system in susceptibility to TD. An alternative to this dopaminergic supersensivity hypothesis in understanding the pathogenesis of TD is the glutamatergic neurotoxicity hypothesis, which implicates the N-methyl-D-aspartate (NMDA) receptor in TD pathogenesis. In the present study, the association between three polymorphisms (T-200G, C366G and C2664T) of the GRIN2B gene, which encodes the 2B subunit of the NMDA receptor, and the occurrence and severity of TD were investigated in 273 Chinese schizophrenic patients receiving long-term antipsychotic treatment (TD: 142, non-TD: 133). There was no significant association between patients' genotype and allele frequencies and TD occurrence. Among the TD patients, the differences in the total scores on the Abnormal Involuntary Movement Scale (AIMS) among the three genotypes of each polymorphism were not significant. Because the three studied markers are in weak linkage disequilibrium with each other, haplotype-based association was not carried out. We conclude that genetic variations in the human GRIN2B gene probably do not play a major role in susceptibility to, or severity of TD.

Web-based tools can be used reliably to detect patients with major depressive disorder and subsyndromal depressive symptoms.

BACKGROUND: Although depression has been regarded as a major public health problem, many individuals with depression still remain undetected or untreated. Despite the potential for Internet-based tools to greatly improve the success rate of screening for depression, their reliability and validity has not been well studied. Therefore the aim of this study was to evaluate the test-retest reliability and criterion validity of a Web-based system, the Internet-based Self-assessment Program for Depression (ISP-D). METHODS: The ISP-D to screen for major depressive disorder (MDD), minor depressive disorder (MinD), and subsyndromal depressive symptoms (SSD) was developed in traditional Chinese. Volunteers, 18 years and older, were recruited via the Internet and then assessed twice on the online ISP-D system to investigate the test-retest reliability of the test. They were subsequently prompted to schedule face-to-face interviews. The interviews were performed by the research psychiatrists using the Mini-International Neuropsychiatric Interview and the diagnoses made according to DSM-IV diagnostic criteria were used for the statistics of criterion validity. Kappa (kappa) values were calculated to assess test-retest reliability. RESULTS: A total of 579 volunteer subjects were administered the test. Most of the subjects were young (mean age: 26.2 +/- 6.6 years), female (77.7%), single (81.6%), and well educated (61.9% college or higher). The distributions of MDD, MinD, SSD and no depression specified were 30.9%, 7.4%, 15.2%, and 46.5%, respectively. The mean time to complete the ISP-D was 8.89 +/- 6.77 min. One hundred and eighty-four of the respondents completed the retest (response rate: 31.8%). Our analysis revealed that the 2-week test-retest reliability for ISP-D was excellent (weighted kappa = 0.801). Fifty-five participants completed the face-to-face interview for the validity study. The sensitivity, specificity, positive, and negative predictive values for major depressive disorder were 81.8% and 72.7%, 66.7%, and 85.7% respectively. The overall accuracy was 76.4%. CONCLUSION: The evidence indicates the ISP-D is a reliable and valid online tool for assessing depression. Further studies should test the ISP-D in clinical settings to increase its applications in clinical environments with different populations and in a larger sample size.

Association of initial antipsychotic response to clozapine and long-term weight gain.

OBJECTIVE: The aim of this study was to test whether the initial antipsychotic response to clozapine is related to subsequent weight change. METHOD: This study was an 8-year retrospective chart review of 96 hospitalized patients with schizophrenia. Data on monthly weight change, initial clinical response, age, gender, clozapine dose, and concomitant use of mood stabilizers and other antipsychotics were analyzed. RESULTS: Fifty-five (57.3%) of the patients received clozapine over the entire 8-year period; these subjects experienced an average weight gain of 11.7 kg (SD=1.6). Seventeen of these patients (30.9%) who had a significant initial clinical response (CGI improvement rating of 1 or 2 during the first 14 months) gained significantly more weight (13.8 kg [SD=8.4]) than did the 38 patients without a significant initial response (4.5 kg [SD=12.0]). Multiple linear regression analysis showed significant initial clinical response and lower baseline body mass index were associated with significantly more weight gain. CONCLUSIONS: The results show that initial antipsychotic response to clozapine is associated with subsequent long-term weight gain as measured over 8 years.

Genetic analysis of the human ENTH (Epsin 4) gene and schizophrenia.

Numerous linkage studies suggest that chromosome 5q may be one of the important cytogenetic regions containing risk loci for schizophrenia susceptibility. Recently, genetic variations (rs254664 and rs10046055) in the intron 1 and 5' flanking regions of the ENTH (also known as Epsin 4) gene, which is located in 5q 33.3, have been demonstrated to be significantly associated with schizophrenia. The present study investigates whether this finding could be replicated in a population of Han Chinese, consisting of 269 patients with schizophrenia and 236 normal controls, by analyzing 9 single nucleotide polymorphisms (SNPs) ranging from the 5' upstream region to intron 8 of the ENTH gene and covering 96 kb. The results showed that we failed to identify the associations of rs1186922 and rs10046055 with schizophrenia. Although another genetic variation (rs1186922) showed a weak association with schizophrenia (uncorrected p value for alleles = 0.038), the significance did not survive after Bonferroni correction. This study thus fails to support an association of genetic variations in the ENTH gene and schizophrenia.

Risperidone for pre-existing severe tardive dyskinesia: a 48-week prospective follow-up study.

Atypical antipsychotics can alleviate the severity of tardive dyskinesia, but few studies have monitored their long-term effects. The present study investigated the effect of risperidone on pre-existing severe tardive dyskinesia among 40 patients with chronic schizophrenia over 48 weeks. The total Abnormal Involuntary Movement Scale (AIMS) score decreased in 35 patients (87.5%) and increased in three patients (7.5%). At the end of the 48-week trial, the mean total AIMS score decreased significantly, from 15.7+/-4.7 (baseline) to 10.6+/-4.4 (P<0.001), with a mean risperidone dosage of 3.6+/-1.5 mg/day. Twenty-three patients (57.5%) were responders with an average total AIMS score decrease of 8.0+/-2.7. Multiple logistic regression analysis controlling for age, gender, duration of illness, index hospitalization duration, risperidone dose, anticholinergic concomitant use and dystonia score change revealed that a change in the parkinsonism score was the most significant factor related to responders (odds ratio 3.476, 95% confidence interval 1.173-10.298). A significant improvement observed in tardive dyskinesia was noted at week 8, and this improvement persisted until week 48. The results show that the effect of risperidone on pre-existing tardive dyskinesia may be beneficial.

Association analysis of the dopamine D3 receptor gene ser9gly and brain-derived neurotrophic factor gene val66met polymorphisms with antipsychotic-induced persistent tardive dyskinesia and clinical expression in Chinese schizophrenic patients.

The association between the dopamine D3 receptor (DRD3) ser9gly genetic polymorphism and tardive dyskinesia (TD), a serious adverse motor disorder after long-term antipsychotic treatment, has been studied extensively in recent years. However, the existence of inconsistent reports makes the role of the DRD3 ser9gly polymorphism in TD development questionable. In rodent studies, the DRD3 expression could be controlled by the brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family. In this study, we examined the association between the DRD3 ser9gly and BDNF val66met genetic polymorphisms and TD occurrence in 216 schizophrenic patients (TD/non-TD = 102/114). In addition, we also studied the effects of the DRD3 ser9gly and BDNF val66met genotypes and their gene-gene interaction on the clinical expression of TD in these TD patients. We found that the TD patients who were heterozygous for the BDNF genotypes had significantly higher abnormal involuntary movement scale (AIMS) orofacial scores (corrected p = 0.021, Bonferroni correction), and a trend of higher AIMS total and limb-trunk scores than the combined homozygous analogs. The correlation between the DRD3 ser9gly genotypes and its interaction with the BDNF val66met polymorphism, and the three classes of AIMS scores were not statistically significant. Furthermore, neither the DRD3 nor the BDNF genotypes and alleles were demonstrated to be associated with TD occurrence. We concluded that the BDNF val66met genetic polymorphism may exert its effect on the clinically phenotypic variability after TD has occurred. Further replication studies with larger sample size and stringent definition for TD is necessary.

Association study of a functional catechol-O-methyltransferase-gene polymorphism and cognitive function in healthy females.

Using the Wisconsin Card Sorting Test, it has been determined, that the catechol-O-methyltransferase (COMT) Val158Met genetic polymorphism, a functional polymorphism that may affect dopamine metabolism, is associated with prefrontal cognitive function. This study of a cohort of 120 healthy young Chinese females attempted to utilize P300 event-related potentials to replicate this finding and to test the relationship between this COMT polymorphism and cortical physiology. The results demonstrate that subjects bearing the Met/Met homozygote have significantly lower mean P300 latencies than do analogs bearing the Val allele. A significant association between this COMT polymorphism and perseverative errors was not demonstrated in the Wisconsin Card Sorting Test, however. We suggest that, although the COMT Val158Met genetic polymorphism may play a role in cognitive function, ethnicity and testing method may affect the association. Since statistical relationships between P300 components and both the COMT genetic polymorphism and schizophrenic disorders have been demonstrated, it seems reasonable to suggest that this COMT genetic variant may affect the P300 abnormality in schizophrenia.