The Nudging Effect of a Reminder Letter to Reduce Duplicated Medications: A Randomized Controlled Trial.

BACKGROUND: The increasing trend of multiple chronic conditions across the world has worsened the problem of medication duplication in health care systems without gatekeeping or referral requirement. Thus, to overcome this problem, a reminder letter has been developed in Taiwan to nudge patients to engage in medication management. OBJECTIVE: To evaluate the effect of reminder letter on reducing duplicated medications. RESEARCH DESIGN: A 2-arm randomized controlled trial design. SUBJECTS: Patients with duplicated medications in the first quarter of 2019. MEASURES: The Taiwanese single-payer National Health Insurance Administration identified the eligible patients for this study. A postal reminder letter regarding medication duplication was mailed to the patients in the study group, and no information was provided to the comparison group. Generalized estimation equation models with a difference-in-differences analysis were used to estimate the effects of the reminder letters. RESULTS: Each group included 11,000 patients. Those who had received the reminder letter were less likely to receive duplicated medications in the subsequent 2 quarters (postintervention 1: odds ratio [OR]=0.95, 95% CI=0.87-1.03; postintervention_2: OR=0.99, 95% CI=0.90-1.08) and had fewer days of duplicated medications (postintervention 1: ß=-0.115, P =0.015; postintervention 2 (ß=-0.091, P =0.089) than those who had not received the reminder letter, showing marginal but significant differences. CONCLUSIONS: A one-off reminder letter nudge could mildly decrease the occurrence of duplicated medications. Multiple nudges or nudges incorporating behavioral science insights may be further considered to improve medication safety in health systems without gatekeeping.

Optimization of Ternary InxGa1-xN Quantum Wells on GaN Microdisks for Full-Color GaN Micro-LEDs.

Red, green, and blue light InxGa1-xN multiple quantum wells have been grown on GaN/γ-LiAlO2 microdisk substrates by plasma-assisted molecular beam epitaxy. We established a mechanism to optimize the self-assembly growth with ball-stick model for InxGa1-xN multiple quantum well microdisks by bottom-up nanotechnology. We showed that three different red, green, and blue lighting micro-LEDs can be made of one single material (InxGa1-xN) solely by tuning the indium content. We also demonstrated that one can fabricate a beautiful InxGa1-xN-QW microdisk by choosing an appropriate buffer layer for optoelectronic applications.

A novel 111indium-labeled dual carbonic anhydrase 9-targeted probe as a potential SPECT imaging radiotracer for detection of hypoxic colorectal cancer cells.

Tumor hypoxia is a common feature in colorectal cancer (CRC), and is associated with resistance to radiotherapy and chemotherapy. Thus, a specifically targeted probe for the detection of hypoxic CRC cells is urgently needed. Carbonic anhydrase 9 (CA9) is considered to be a specific marker for hypoxic CRC diagnosis. Here, a nuclear imaging Indium-111 (111In)-labeled dual CA9-targeted probe was synthesized and evaluated for CA9 detection in in vitro, in vivo, and in human samples. The CA9-targeted peptide (CA9tp) and CA9 inhibitor acetazolamide (AAZ) were combined to form a dual CA9-targeted probe (AAZ-CA9tp) using an automatic microwave peptide synthesizer, which then was conjugated with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) for radioisotope (111In) labeling (111In-DOTA-AAZ-CA9tp). The assays for cell binding, stability, and toxicity were conducted in hypoxic CRC HCT15 cells. The analyses for imaging and biodistribution were performed in an HCT15 xenograft mouse model. The binding and distribution of 111In-DOTA-AAZ-CA9tp were detected in human CRC samples using microautoradiography. AAZ-CA9tp possessed good CA9-targeting ability in hypoxic HCT15 cells. The dual CA9-targeted radiotracer showed high serum stability, high surface binding, and high affinity in vitro. After exposure of 111In-DOTA-AAZ-CA9tp to the HCT15-bearing xenograft mice, the levels of 111In-DOTA-AAZ-CA9tp were markedly and specifically increased in the hypoxic tumor tissues compared to control mice. 111In-DOTA-AAZ-CA9tp also targeted the areas of CA9 overexpression in human colorectal tumor tissue sections. The results of this study suggest that the novel 111In-DOTA-AAZ-CA9tp nuclear imaging agent may be a useful tool for the detection of hypoxic CRC cells in clinical practice.

The impact of different patterns of home- and community-based services on nursing home admission: National data from Taiwan.

BACKGROUND: This study had two aims: (a) to identify the different patterns of use of home- and community-based services (HCBS) among older adults in Taiwan, and (b) to examine the effects of the different use patterns on HCBS recipients' use of institutional long-term care services. METHODS: The study analyzed cohort data from Taiwan's first National 10-Year Long-Term Care Plan database and from National Health Insurance Claim Data. We extracted baseline information on older adults who were first evaluated for and prescribed HCBS from 2010 through 2013 (N = 71,260). We used latent class analysis to specify the underlying subgroups of recipients with similar patterns of HCBS use. We used hierarchical multinomial logistic regression to examine the effect of the different use patterns on the risk of institutional (e.g., nursing home) placement from 4 to 15 months after initial HCBS evaluation. RESULTS: Four subgroups of HCBS recipients were identified, with patterns of home-based personal care (PC), home-based personal care and medical care (PC/MC), home-based medical care (MC), and community care services. Compared to the home-based PC/MC group, people in the home-based MC group had lower risk (OR = 0.54) and people in the community care group had higher risk (OR = 1.76) of admission to a nursing home. CONCLUSIONS: Study findings may provide insights for policy makers regarding the usefulness of integrating medical care and other types of long-term care services into adult day care.

Multiple Rare Risk Coding Variants in Postsynaptic Density-Related Genes Associated With Schizophrenia Susceptibility.

OBJECTIVE: Schizophrenia is a chronic debilitating neurobiological disorder of aberrant synaptic connectivity and synaptogenesis. Postsynaptic density (PSD)-related proteins in N-methyl-D-aspartate receptor-postsynaptic signaling complexes are crucial to regulating the synaptic transmission and functions of various synaptic receptors. This study examined the role of PSD-related genes in susceptibility to schizophrenia. METHODS: We resequenced 18 genes encoding the disks large-associated protein (DLGAP), HOMER, neuroligin (NLGN), neurexin, and SH3 and multiple ankyrin repeat domains (SHANK) protein families in 98 schizophrenic patients with family psychiatric history using semiconductor sequencing. We analyzed the protein function of the identified rare schizophrenia-associated mutants via immunoblotting and immunocytochemistry. RESULTS: We identified 50 missense heterozygous mutations in 98 schizophrenic patients with family psychiatric history, and in silico analysis revealed some as damaging or pathological to the protein function. Ten missense mutations were absent from the dbSNP database, the gnomAD (non-neuro) dataset, and 1,517 healthy controls from Taiwan BioBank. Immunoblotting revealed eight missense mutants with altered protein expressions in cultured cells compared with the wild type. CONCLUSION: Our findings suggest that PSD-related genes, especially the NLGN, SHANK, and DLGAP families, harbor rare functional mutations that might alter protein expression in some patients with schizophrenia, supporting contributing rare coding variants into the genetic architecture of schizophrenia.

Genetic variants of microsomal triglyceride transfer protein (MTTP) are associated with metabolic syndrome in schizophrenic patients treated with atypical antipsychotics.

OBJECTIVES: Promoter polymorphisms in microsomal triglyceride transfer protein (MTTP) have been associated with the various traits of metabolic syndrome (MetS) in the general population. This study investigated whether the common variants in MTTP genes were associated with MetS in schizophrenic patients treated with atypical antipsychotics. METHOD: The study included 456 hospitalized patients diagnosed with schizophrenia, who had been treated with clozapine (n = 171), olanzapine (n = 91), or risperidone (n = 194) for at least 3 months. Patients were genotyped for the 10 MTTP single-nucleotide polymorphisms. RESULTS: The prevalence of MetS among all subjects was 22.8%. In single-marker-based analysis, the MTTP rs1800591 (-493G>T) T-allele carriers were at double the risk for MetS relative to G/G homozygotes. In contrast, the T-allele homozygotes had considerably lower fasting high-density lipoprotein levels than that in the heterozygotes or G-allele homozygotes. CONCLUSIONS: Our findings extend and add new information to the existing data regarding the association between MTTP genetic variants and MetS regulation during long-term atypical antipsychotic treatment. The MTTP rs1800591 T allele could be a risk factor for MetS in patients under atypical antipsychotic medication.

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.

Spin reorientation transitions and structures of electrodeposited Ni/Cu(100) ultrathin films with and without Pb additives.

Magnetic properties and surface structures of Ni/Cu(100) ultrathin films are studied by means of magneto-optical Kerr effect and in situ scanning tunneling microscopy in combination with cyclic voltammetry. At the initial stage of Ni deposition on a Cu(100) electrode, nickel atoms attach onto the steps and the surface shows single atomic steps corresponding to a layer-by-layer growth. For thicker Ni/Cu(100) films, nanometer-size clusters are randomly distributed on the surface showing a three-dimensional island growth. For thinner Ni layers in the coherent region, the magnetic anisotropy energy of the Cl-electrolyte/Ni interface is small. The reduction of squareness of the hysteresis loops is related to the inhomogeneous growth of the Ni layers. For thicker Ni layers in the incoherent region, the negative value of interface anisotropy for the Cl-electrolyte/Ni interface has a strong impact on perpendicular magnetic anisotropy and plays an important role on the reduction of the Ni thickness for spin reorientation transition in the electrolyte condition. By adding Pb additives, the deposition of a Pb wetting layer causes a defaceting phenomenon and the hydrogen evolution reaction is reduced. As the Ni thickness increases, the growth of Ni changes from layer-by-layer to quasi-two-dimensional islands with a flat top layer. With a Pb additive, the spin reorientation transitions of the Ni/Cu(100) system are not significantly influenced. However, due to the change of the growth mode by Pb atoms as a surfactant, the squareness of the hysteresis loops is enhanced for all the Ni thicknesses.

Influence of antipsychotic agents on heart rate variability in male WKY rats: implications for cardiovascular safety.

BACKGROUND: Sudden cardiac death is higher among schizophrenic patients and is associated with parasympathetic hypoactivity. Antipsychotic agents are highly suspected to be a precipitating factor. Thus, we aimed to test if the antipsychotics haloperidol, risperidone and clozapine affect cardiac autonomic function, excluding the confounding effect of altered sleep structure by the drugs. METHODS: In this study, haloperidol, risperidone and clozapine were given separately by intraperitoneal injection to male Wistar-Kyoto rats for 5 days. Electroencephalogram (EEG), electromyogram (EMG) and electrocardiographic signals were recorded at baseline and 5 days after drug treatments. Sleep scoring was based on EEG and EMG signals. Cardiac autonomic function was assessed using heart rate variability analysis. RESULTS: Clozapine increased heart rate and suppressed cardiac sympathetic and parasympathetic activity. Cardiac acceleration was more severe during sleep. Haloperidol tended to decrease heart rate while risperidone mildly increased heart rate; however, their effects were less obvious than those of clozapine. There was a significant drug-by-stage interaction on several heart rate variability measures. CONCLUSION: Taking this evidence as a whole, we conclude that haloperidol has a better level of cardiovascular safety than either risperidone or clozapine. Application of this approach to other psychotropic agents in the future will be a useful and helpful way to evaluate the cardiovascular safety of the various psychotropic medications that are in clinical use.

TNF-α -308 G>A polymorphism and weight gain in patients with schizophrenia under long-term clozapine, risperidone or olanzapine treatment.

Atypical or second-generation antipsychotics (SGAs) are associated with excessive body weight gain (BWG) and other components of metabolic syndrome. Among all SGAs, clozapine and olanzapine are known to cause the most significant weight gain, followed by risperidone and quetiapine. The genetic variant of tumor necrosis factor α (TNF-α), -308 G>A polymorphism (rs1800629), has been implicated in clozapine-induced BWG in several studies. We hypothesized that TNF-α -308 G>A polymorphism has a general effect on SGA-induced BWG. The present study was conducted to examine the association between TNF-α -308 G>A polymorphism and BWG during treatment for schizophrenia using a variety of second generation antipsychotics (SGAs). A total of 500 patients with schizophrenia treated with clozapine (n=275), olanzapine (n=79) or risperidone (n=146) for an average of 49.9 months were recruited. Subjects with an increase in weight of more than 7% from the baseline before the current SGA treatment to the weight at the survey point were defined as having BWG. The association between TNF-α -308 G>A polymorphism and BWG was studied, and the effect of non-genetic factors such as baseline BMI, SGA treatment duration and SGA type on the association was controlled by logistic regression. The results revealed that there was no significant association between BWG and TNF-α -308 G>A polymorphism (GG/GA/AA or GG/GA+AA) in each separate SGA group or collectively. These findings suggest that TNF-α -308 G>A polymorphism does not play a major role in SGA-induced weight gain.

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.

Analysis of genetic variations in the human melatonin receptor (MTNR1A, MTNR1B) genes and antipsychotics-induced tardive dyskinesia in schizophrenia.

OBJECTIVES: Antipsychotics-induced tardive dyskinesia (TD) has been suggested to be related to altered dopaminergic neurotransmission in the striatum. Melatonin has a modulating effect on dopaminergic neurotransmission in the brain; therefore, the hypothesis of an association between the melatonin receptor genes (MTNR1A, MTNR1B) and antipsychotics-induced TD was examined in this study. METHODS: Schizophrenic inpatients receiving long-term antipsychotic treatment were assessed using the Abnormal Involuntary Movement Scale, and only patients who were either free of any abnormal involuntary movement (non-TD group) or who demonstrated persistent TD (TD group) were enrolled. Genotyping of six tagging single nucleus polymorphisms (SNPs) in the melatonin receptor genes (MRNR1A, MTNR1B) was then performed for each subject. RESULTS: Four hundred and eighteen inpatients (TD=256, non-TD=162) fitted the study criteria and underwent TD assessment and genotyping. Individual haplotype analysis showed that the haplotype ATG was significantly associated with non-TD (permutation P=0.037), and the association was also found to be significant by global haplotype analyses (permutation P=0.045). CONCLUSIONS: Our results indicated a significant association between the haplotype ATG in the MTNR1A gene and non-TD. Further replication in other countries or other populations is indicated.

Support for the involvement of the ERBB4 gene in schizophrenia: a genetic association analysis.

Cellular, animal and human studies support the involvement of aberrant NRG-ErbB signaling in the pathogenesis of schizophrenia. The aim of the present study was to examine whether genetic variation in the human ERBB4 gene is associated with susceptibility to schizophrenia. Two hundred and twenty-seven unrelated chronic inpatients with schizophrenia were enrolled in the study, and the genetic variation in the polymorphisms of the ERBB4 gene in the patients was compared with that of the control group, which consisted of 223 subjects free of psychiatric illness. The results showed that one coding-synonymous polymorphism (rs3748962, Val1065Val) was in genotypic (p=0.0027) and allelic (p=0.0007) association with schizophrenia. In comparison with subjects of the rs3748962-TT type, those of the rs3748962-CT and rs3748962-CC types were at 1.74- and 2.64-fold greater risk of schizophrenia (CT vs. TT: OR=1.71 (95% CI=1.15-2.53), p=0.0014; CC vs. TT: OR=2.64 (95% CI=1.37-5.23), p=0.0047), which supports the hypothesis of an additive model of transmission (p=0.0006). Furthermore, the frequency of haplotype ATC of rs3791709-rs2289086-rs3748962 was found to be significantly higher in the patients with schizophrenia than in the controls (case vs. control=36.0% vs. 24.4%, permutation p-value=0.0002). The findings support the involvement of the ERBB4 gene in schizophrenia in Han Chinese.

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.

Dopamine receptor D2 gene is associated with weight gain in schizophrenic patients under long-term atypical antipsychotic treatment.

OBJECTIVE: Schizophrenic patients treated with atypical antipsychotics (AAPs) often develop excessive body weight gain (BWG), which may lead to further morbidity and poor treatment compliance. This study examined whether genetic variants in the dopamine receptor D2 (DRD2) gene may be associated with body weight change after AAP treatment. METHODS: The study included 479 schizophrenic patients treated with clozapine (n=239), olanzapine (n=70) or risperidone (n=170) for an average of 48.2+/-27.8 months. BWG was defined as an increase of more than 7% of the baseline body weight during AAP treatment. Thirteen common single nucleotide polymorphisms of the DRD2 gene were chosen as tagging single nucleotide polymorphisms. RESULTS: In single-marker-based analysis, the DRD2 rs4436578-C homozygous genotype was found to be associated with a significantly increased risk of BWG [P=0.001, adjusted odds ratio=3.36 (95% confidence interval=1.62 - 7.00)]. In addition, haplotype analysis further showed that the rs4436578-C-allele-related haplotype was more frequent in those patients with BWG than those without (P=0.01 - 0.00019). CONCLUSION: Our findings confirm the importance of genetic factors in body weight change induced by long-term AAP treatment in patients with schizophrenia and indicate a role of DRD2 in body weight regulation during long-term AAP treatment.

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.

Resequencing and association study of vesicular glutamate transporter 1 gene (VGLUT1) with schizophrenia.

Dysregulation of glutamate neurotransmission is implicated in the pathphysiology of schizophrenia. Vesicular glutamate transporters (VGLUTs) package glutamate into vesicles in the presynaptic terminal and regulate the release of glutamate. Abnormal VGLUT1 expression has been linked to schizophrenia in postmortem brain studies. The purpose of this study was to investigate the involvement of the human VGLUT1 in the susceptibility to schizophrenia. In this study, we searched for genetic variants in the putative core promoter region and 12 exons (including UTR ends) of the VGLUT1 gene using direct sequencing in a sample of Han Chinese schizophrenic patients (n=376) and non-psychotic controls (n=368) from Taiwan, and conducted a case-control association study. We identified two common SNPs (g.-248G>C (ss159695612) and c.2697C>A (rs1043558)) in the VGLUT1 gene. No differences in the allele and genotype frequencies were detected between the patients and control subjects. Besides, we identified eight patient-specific rare variants in 16 out of 376 patients, including two variants (g.-296A>G (ss159695611) and g.-32Cv>T (ss159695613)) at the core promoter region and 5'UTR, two missense variants (L516M (ss159695617) and P551S (ss159695618)) and three silent variants (E24E (ss159695614), L118L (ss159695615), and P133P (ss159695616)) at protein-coding regions, and one variant (c.2201G>A (ss159695619)) at the 3'UTR. No rare variants were found in 368 control subjects (4.3% versus 0, P=1.5x10(-5)). Although the functional significance of these rare variants remains to be characterized, our study may lend support to the multiple rare mutation hypothesis of schizophrenia, and may provide genetic clues to indicate the involvement of the glutamate transmission pathway in the pathogenesis of schizophrenia.

Exomic sequencing of the ionotropic glutamate receptor N-methyl-D-aspartate 3A gene (GRIN3A) reveals no association with schizophrenia.

BACKGROUND: Growing evidence suggests that dysregulation of N-methyl-D-aspartate receptor (NMDAR)-mediated glutamate neurotransmission may be involved in the pathophysiology of schizophrenia. The NMDAR is a heteromeric protein complex consisting of subunits from three subfamilies (NR1, NR2A, 2B, 2C, 2D and NR3A, 3B). The unique ability of NR3A to modulate the NMDAR function makes it an attractive candidate gene of schizophrenia. The purpose of this study was to investigate the involvement of the gene encoding the human NR3A subunit (GRIN3A) in the liability to schizophrenia. METHODS: We searched for genetic variants in the putative core promoter region and all the exons (including UTR ends) of the GRIN3A gene in 333 Han Chinese patients with schizophrenia and 369 control subjects from Taiwan using direct polymerase chain reaction (PCR) autosequencing, and assessed their association with schizophrenia. RESULTS: We identified 22 single nucleotide polymorphisms (SNPs) in the GRIN3A gene in this sample. SNP- and haplotype-based analyses showed no association of these 22 SNPs with schizophrenia. Nevertheless, we identified two missense mutations (D133N and Q1091H), one nonsense mutation (R1024X), and two synonymous mutations (Y873Y and E889E) of the GRIN3A gene in 6 out of 333 (1.8%) patients, while no rare mutations were found in 369 control subjects (p=0.011, Fisher's exact test, one-tailed). In silico analysis showed that the R1024X and Q1091H mutations are possibly damaging. CONCLUSIONS: Although the functional significance of these mutations remains to be characterized, our study indicates that rare mutations in the GRIN3A gene may contribute to the pathogenesis of schizophrenia in certain patients.