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.

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.

Transcranial magnetic stimulation for auditory hallucination in severe schizophrenia: partial efficacy and acute elevation of sympathetic modulation.

Repetitive transcranial magnetic stimulation (rTMS) has been reported to be an effective treatment for auditory hallucination (AH) in schizophrenia patients. The efficacy of rTMS and immediate changes in cardiac autonomic function (CAF) after rTMS in severe schizophrenia patients with AH (n = 8) were investigated. Three patients reported a >or=50% reduction of AH after rTMS. The ratio of low-frequency power to high-frequency power, an index of sympathetic modulation, increased significantly after rTMS. Further replication studies with larger sample sizes are indicated.

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.

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.

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.

Patterns of sleep-related medications prescribed to elderly outpatients with insomnia in Taiwan.

OBJECTIVE: To explore prescription patterns and determinants of sleep-related medications prescribed to elderly outpatients with insomnia in Taiwan. METHODS: This cross-sectional study was based on 2001 annual outpatient claims data released by the Bureau of National Health Insurance in Taiwan. The claims data of each physician consultation were extracted and merged in one claim file. International Classification of Diseases (9th Edition)-Clinical Modification codes, patient's demographics, physician's specialty, the medical institution code and the content of pharmaceutical prescription constituted a file. Patients were included if they were: (i) > or =65 years of age; and (ii) coded as having 'insomnia'. RESULTS: Elderly insomniacs made up 216,994 of the 1,000,193 outpatient claim files we surveyed. Patients had a mean age of 74.33 years, and the sex distribution was nearly equal. Based on the data above, 11.14% of the elderly had been diagnosed as having 'insomnia' for the year 2001. This population preferred primary-care clinics over hospital-ambulatory departments; patients most frequently sought medical help from internal medicine specialists. The most popular sleep medication was lorazepam, followed by zolpidem. The first-choice off-label drug used to treat insomnia was trazodone. Hypnotics, sedatives and anxiolytics were prescribed 12.6 times more frequently than off-label used drugs. When treating insomnia with an off-label drug, physicians usually prescribed a therapeutic dosage much lower than that recommended in the package insert. Choice of sleep medication and off-label drug were most often influenced by physician specialty. Off-label prescriptions were common but not prevalent. Choice of hypnotic or sedative-anxiolytic was related to how long the drug acted and how much it cost; choice of off-label drug was related to physicians' familiarity with specific drugs and patients' characteristics. Concomitant anxiety or depression was significantly associated with higher consumption of hypnotics. CONCLUSIONS: Benzodiazepines and newer non-benzodiazepine hypnotics are still the most frequently used drugs for treating insomnia in the elderly in Taiwan. Elderly patients with concomitant anxiety or depression consumed more hypnotics. Further studies conducted over several years are needed to identify trends in the pharmacological treatment of insomnia.

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 the human partially duplicated alpha7 nicotinic acetylcholine receptor genetic variant with bipolar disorder.

The human alpha7 nicotinic acetylcholine receptor subunit (CHRNA7) gene cluster maps to the chromosome 15q13-q14 and is implicated as a candidate gene for bipolar disorder (BPD) by genetic linkage study. A -2 bp deletion polymorphism has been found in the duplicated CHRNA7 (CHRNA7-like) gene, which is located 1 Mb apart from CHRNA7. We tested the hypothesis that the allelic variant, 2 bp deletion (-2 bp), confers susceptibility to BPD or is related to the psychotic features of BPD. We genotyped the -2 bp polymorphism in 77 patients with BPD and 135 normal controls. The distribution of -2 bp genotypes showed a moderately significant difference between the BPD patients and controls (P=0.044). Three BPD patients carried more than two alleles of the -2 bp deletion genotype, while this genotype was not found in the control group. The -2 bp polymorphism was not associated with age of onset or psychotic features in BPD patients. The results of this study suggest that the -2 bp polymorphism or a nearby polymorphism may play a role in the pathogenesis of BPD. Determination of the functional impact of the -2 bp variant in the nervous system and, in particular, the effect of harboring more than two alleles of the -2 bp deletion needs further exploration.

Risk of stroke associated with inhaled ipratropium bromide in chronic obstructive pulmonary disease: a population-based nested case-control study.

BACKGROUND: Cardiovascular safety concerns about inhaled ipratropium bromide have recently been raised. Nonetheless, the specific stroke risk associated with ipratropium use has not been evaluated thoroughly. METHODS: This was a population-based nested case-control study analyzing data from the National Health Insurance Research Database in Taiwan. A cohort of 15,396 newly-diagnosed chronic obstructive pulmonary disease (COPD) patients was included between 2001 and 2007, in which 1477 cases of incident hospitalization for stroke were identified. Each case was individually matched to four randomly-selected controls based on age, sex, and cohort entry date. Conditional logistic regressions were used to estimate the odds ratio (OR) for risk of stroke-related hospitalization associated with ipratropium use. RESULTS: Any use of ipratropium within the 6 months before the index date was associated with an increased risk of stroke compared with nonuse (adjusted OR, 2.02; 95% CI, 1.71 to 2.41). The observed risk remained significant regardless of accumulated doses. Additionally, use of ipratropium within 30 days before the index date resulted in the greatest risk (adjusted OR, 2.97 95% CI, 2.27 to 3.88). Furthermore, an increased risk of stroke was found for ipratropium regimens involving concomitant use of inhaled short-acting ß(2)-agonists (SABAs; adjusted OR, 2.18; 95% CI, 1.81 to 2.62) or theophyllines (adjusted OR, 1.79; 95% CI, 1.42 to 2.26). CONCLUSIONS: Use of ipratropium is associated with an increased risk of stroke in COPD patients. Clinicians should be alert to that risk when prescribing ipratropium, especially for those receiving ipratropium more recently or those with concomitant use of SABAs or theophyllines.

Genome-wide association study of treatment refractory schizophrenia in Han Chinese.

We report the first genome-wide association study of a joint analysis using 795 Han Chinese individuals with treatment-refractory schizophrenia (TRS) and 806 controls. Three loci showed suggestive significant association with TRS were identified. These loci include: rs10218843 (P = 3.04 × 10(-7)) and rs11265461 (P = 1.94 × 10(-7)) are adjacent to signaling lymphocytic activation molecule family member 1 (SLAMF1); rs4699030 (P = 1.94 × 10(-6)) and rs230529 (P = 1.74 × 10(-7)) are located in the gene nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NFKB1); and rs13049286 (P = 3.05 × 10(-5)) and rs3827219 (P = 1.66 × 10(-5)) fall in receptor-interacting serine/threonine-protein kinase 4 (RIPK4). One isolated single nucleotide polymorphism (SNP), rs739617 (P = 3.87 × 10(-5)) was also identified to be associated with TRS. The -94delATTG allele (rs28362691) located in the promoter region of NFKB1 was identified by resequencing and was found to associate with TRS (P = 4.85 × 10(-6)). The promoter assay demonstrated that the -94delATTG allele had a significant lower promoter activity than the -94insATTG allele in the SH-SY5Y cells. This study suggests that rs28362691 in NFKB1 might be involved in the development of TRS.