Relationship between clozapine exposure and the onset of appendicitis in schizophrenia patients: a retrospective cohort study.

OBJECTIVE: Clozapine may cause serious side effects despite benefits in patients with schizophrenia. Thus, an accurate understanding of the side-effect profile of clozapine is extremely important in the management of its administration to patients with schizophrenia. Our aim was to validate the relationship between clozapine exposure and appendicitis onset in patients with schizophrenia. METHODS: In this study, we retrospectively compared the incidence and cumulative incidence of appendicitis in patients with schizophrenia with and without a history of clozapine exposure. Among the patients with schizophrenia who visited our hospital between June 2009 and August 2021, we extracted those with a history of clozapine treatment. Patients with a history of taking clozapine were defined as the clozapine exposure group, while the others were defined as the clozapine non-exposure group. Patients with a history of appendectomy before their initial visit to our hospital or with a history of clozapine use at other hospitals were excluded. RESULTS: There were 65 patients in the clozapine exposure group and 400 patients in the clozapine non-exposure group who met the inclusion criteria. The exposure group exhibited a remarkably higher incidence of appendicitis during the observation period than the non-exposure group (863 cases vs. 124 cases per 100,000 person-years). In particular, if limited to the period of clozapine exposure, the incidence of appendicitis is extremely high, at 2,086 cases per 100,000 person-years. Moreover, multivariable analysis showed that clozapine exposure was an independent factor contributing to the onset of appendicitis. CONCLUSIONS: Clozapine exposure is associated with appendicitis onset in patients with schizophrenia.

Continuous intrathecal orexin delivery inhibits cataplexy in a murine model of narcolepsy.

Narcolepsy-cataplexy is a chronic neurological disorder caused by loss of orexin (hypocretin)-producing neurons, associated with excessive daytime sleepiness, sleep attacks, cataplexy, sleep paralysis, hypnagogic hallucinations, and fragmentation of nighttime sleep. Currently, human narcolepsy is treated by providing symptomatic therapies, which can be associated with an array of side effects. Although peripherally administered orexin does not efficiently penetrate the blood-brain barrier, centrally delivered orexin can effectively alleviate narcoleptic symptoms in animal models. Chronic intrathecal drug infusion through an implantable pump is a clinically available strategy to treat a number of neurological diseases. Here we demonstrate that the narcoleptic symptoms of orexin knockout mice can be reversed by lumbar-level intrathecal orexin delivery. Orexin was delivered via a chronically implanted intrathecal catheter at the upper lumbar level. The computed tomographic scan confirmed that intrathecally administered contrast agent rapidly moved from the spinal cord to the brain. Intrathecally delivered orexin was detected in the brain by radioimmunoassay at levels comparable to endogenous orexin levels. Cataplexy and sleep-onset REM sleep were significantly decreased in orexin knockout mice during and long after slow infusion of orexin (1 nmol/1 µL/h). Sleep/wake states remained unchanged both quantitatively as well as qualitatively. Intrathecal orexin failed to induce any changes in double orexin receptor-1 and -2 knockout mice. This study supports the concept of intrathecal orexin delivery as a potential therapy for narcolepsy-cataplexy to improve the well-being of patients.

A variant at 9q34.11 is associated with HLA-DQB1*06:02 negative essential hypersomnia.

Essential hypersomnia (EHS) is a lifelong disorder characterized by excessive daytime sleepiness without cataplexy. EHS is associated with human leukocyte antigen (HLA)-DQB1*06:02, similar to narcolepsy with cataplexy (narcolepsy). Previous studies suggest that DQB1*06:02-positive and -negative EHS are different in terms of their clinical features and follow different pathological pathways. DQB1*06:02-positive EHS and narcolepsy share the same susceptibility genes. In the present study, we report a genome-wide association study with replication for DQB1*06:02-negative EHS (408 patients and 2247 healthy controls, all Japanese). One single-nucleotide polymorphism, rs10988217, which is located 15-kb upstream of carnitine O-acetyltransferase (CRAT), was significantly associated with DQB1*06:02-negative EHS (P = 7.5 × 10-9, odds ratio = 2.63). The risk allele of the disease-associated SNP was correlated with higher expression levels of CRAT in various tissues and cell types, including brain tissue. In addition, the risk allele was associated with levels of succinylcarnitine (P = 1.4 × 10-18) in human blood. The leading SNP in this region was the same in associations with both DQB1*06:02-negative EHS and succinylcarnitine levels. The results suggest that DQB1*06:02-negative EHS may be associated with an underlying dysfunction in energy metabolic pathways.

New susceptibility variants to narcolepsy identified in HLA class II region.

Narcolepsy, a sleep disorder characterized by excessive daytime sleepiness, cataplexy and rapid eye movement sleep abnormalities, is tightly associated with human leukocyte antigen HLA-DQB1*06:02. DQB1*06:02 is common in the general population (10-30%); therefore, additional genetic factors are needed for the development of narcolepsy. In the present study, HLA-DQB1 in 664 Japanese narcoleptic subjects and 3131 Japanese control subjects was examined to determine whether HLA-DQB1 alleles located in trans of DQB1*06:02 are associated with narcolepsy. The strongest association was with DQB1*06:01 (P = 1.4 × 10(-10), odds ratio, OR = 0.39), as reported in previous studies. Additional predisposing effects of DQB1*03:02 were also found (P = 2.5 × 10(-9), OR = 1.97). A comparison between DQB1*06:02 heterozygous cases and controls revealed dominant protective effects of DQB1*06:01 and DQB1*05:01. In addition, a single-nucleotide polymorphism-based conditional analysis controlling for the effect of HLA-DQB1 was performed to determine whether there were other independent HLA associations outside of HLA-DQB1. This analysis revealed associations at HLA-DPB1 in the HLA class II region (rs3117242, P = 4.1 × 10(-5), OR = 2.45; DPB1*05:01, P = 8.1 × 10(-3), OR = 1.39). These results indicate that complex HLA class II associations contribute to the genetic predisposition to narcolepsy.

Decline of CSF orexin (hypocretin) levels in Prader-Willi syndrome.

Prader-Willi syndrome is a congenital neurodevelopmental disorder resulting from deletion of the paternal copies of genes within the chromosome region 15q11-q13. Patients with Prader-Willi syndrome often exhibit excessive daytime sleepiness, excessive appetite, and obesity. As is the case in narcolepsy, orexin (hypocretin) may be responsible for these symptoms. However, reports showing cerebrospinal fluid orexin levels in Prader-Willi syndrome patients have been limited. The aim of this study was to examine the relationship between the characteristic symptoms of Prader-Willi syndrome and cerebrospinal fluid orexin levels. We clinically identified 14 Prader-Willi syndrome patients and examined their cerebrospinal fluid orexin levels. A total of 12 patients with a 15q11-q13 deletion and two patients with maternal uniparental disomy of chromosome 15 were identified. A total of 37 narcoleptic patients and 14 idiopathic hypersomnia patients were recruited for comparison. Cerebrospinal fluid orexin levels (median [25-75 percentiles]) in the 14 Prader-Willi syndrome patients were intermediate (192 [161-234.5] pg/ml), higher than in the narcoleptic patients, but lower than in the idiopathic hypersomnia patients. Body mass index of the Prader-Willi syndrome patients was higher than in the narcoleptic and idiopathic hypersomnia patients. There was also a negative correlation between Epworth sleepiness scale scores and orexin levels in Prader-Willi syndrome patients. Decreased cerebrospinal fluid orexin levels in Prader-Willi syndrome may play an important role in severity of obesity and excessive daytime sleepiness.

A polymorphism in CCR1/CCR3 is associated with narcolepsy.

Etiology of narcolepsy-cataplexy involves multiple genetic and environmental factors. While the human leukocyte antigen (HLA)-DRB1*15:01-DQB1*06:02 haplotype is strongly associated with narcolepsy, it is not sufficient for disease development. To identify additional, non-HLA susceptibility genes, we conducted a genome-wide association study (GWAS) using Japanese samples. An initial sample set comprising 409 cases and 1562 controls was used for the GWAS of 525,196 single nucleotide polymorphisms (SNPs) located outside the HLA region. An independent sample set comprising 240 cases and 869 controls was then genotyped at 37 SNPs identified in the GWAS. We found that narcolepsy was associated with a SNP in the promoter region of chemokine (C-C motif) receptor 1 (CCR1) (rs3181077, P=1.6×10(-5), odds ratio [OR]=1.86). This rs3181077 association was replicated with the independent sample set (P=0.032, OR=1.36). We measured mRNA levels of candidate genes in peripheral blood samples of 38 cases and 37 controls. CCR1 and CCR3 mRNA levels were significantly lower in patients than in healthy controls, and CCR1 mRNA levels were associated with rs3181077 genotypes. In vitro chemotaxis assays were also performed to measure monocyte migration. We observed that monocytes from carriers of the rs3181077 risk allele had lower migration indices with a CCR1 ligand. CCR1 and CCR3 are newly discovered susceptibility genes for narcolepsy. These results highlight the potential role of CCR genes in narcolepsy and support the hypothesis that patients with narcolepsy have impaired immune function.

Burden of narcolepsy in Japan: A health claims database study evaluating direct medical costs and comorbidities.

OBJECTIVE: This study aimed to determine the burden of narcolepsy in terms of direct medical costs and comorbidities and compare it with the respective burden of schizophrenia, epilepsy, and ulcerative colitis as controls. METHODS: Patients diagnosed with narcolepsy (at least once based on the International Statistical Classification of Diseases and Related Health Problems, 10th Revision, code G47.4) between April 2017 and March 2022 were identified on the health insurance claims database compiled by JMDC Inc. Patients with schizophrenia (F20), epilepsy (G40), and ulcerative colitis (K51) were matched as controls. Direct medical costs (including inpatient, outpatient, and medication costs) and comorbidities were analyzed. RESULTS: We identified 4,594 patients with narcolepsy (≥18 years), 18,376 with schizophrenia, 18,376 with epilepsy, and 4,594 with ulcerative colitis. The total annual direct medical cost per person with narcolepsy was 349,188 JPY. The cost for narcolepsy was less than that for schizophrenia, epilepsy, and ulcerative colitis. Several comorbidities, such as sleep apnea, attention deficit hyperactivity disorder (ADHD), and obesity were more prevalent in the narcolepsy group. CONCLUSIONS: The total direct cost for narcolepsy was approximately three times higher than the national medical expense for people aged 15-44 years (122,000 JPY in 2020), but lower than the total cost for all control diseases. The patients with narcolepsy were also likely to have comorbidities that affected their burden. These findings can contribute to future discussions on medical expense assistance programs for patients with narcolepsy.

Correction to: Prevalence, incidence, and medications of narcolepsy in Japan: a descriptive observational study using a health insurance claims database.

[This corrects the article DOI: 10.1007/s41105-022-00406-4.].

Exploratory Validation of Sleep-Tracking Devices in Patients with Psychiatric Disorders.

Purpose: Sleep-tracking devices have performed well in recent studies that evaluated their use in healthy adults by comparing them with the gold standard sleep assessment technique, polysomnography (PSG). These devices have not been validated for use in patients with psychiatric disorders. Therefore, we tested the performance of three sleep-tracking devices against PSG in patients with psychiatric disorders. Patients and methods: In total, 52 patients (32 women; 48.1 ± 17.2 years, mean ± SD; 18 patients diagnosed with schizophrenia, 19 with depressive disorder, 3 with bipolar disorder, and 12 with sleep disorder cases) were tested in a sleep laboratory with PSG, along with portable electroencephalography (EEG) device (Sleepgraph), actigraphy (MTN-220/221) and consumer sleep-tracking device (Fitbit Sense). Results: Epoch-by-epoch sensitivity (for sleep) and specificity (for wake), respectively, were as follows: Sleepgraph (0.95, 0.76), Fitbit Sense (0.95, 0.45) and MTN-220/221 (0.93, 0.40). Portable EEG (Sleepgraph) had the best sleep stage-tracking performance. Sleep-wake summary metrics demonstrated lower performance on poor sleep (ice, shorter total sleep time, lower sleep efficiency, longer sleep latency, longer wake after sleep onset). Conclusion: Devices demonstrated similar sleep-wake detecting performance as compared with previous studies that evaluated sleep in healthy adults. Consumer sleep device may exhibit poor sleep stage-tracking performance in patients with psychiatric disorders due to factors that affect the sleep determination algorithm, such as changes in autonomic nervous system activity. However, Sleepgraph, a portable EEG device, demonstrated higher performance in mental disorders than the Fitbit Sense and actigraphy.

Characteristics of hypersomnia due to inflammatory demyelinating diseases of the central nervous system.

Background: Neuromyelitis optica spectrum disorder (NMOSD) diagnostic criteria for inflammatory demyelinating central nervous system diseases included symptomatic narcolepsy; however, no relevant case-control studies exist. We aimed to examine the relationship among cerebrospinal fluid orexin-A (CSF-OX) levels, cataplexy and diencephalic syndrome; determine risk factors for low-and-intermediate CSF-OX levels (≤200 pg/mL) and quantify hypothalamic intensity using MRI. Methods: This ancillary retrospective case-control study included 50 patients with hypersomnia and 68 controls (among 3000 patients) from Akita University, the University of Tsukuba and community hospitals (200 facilities). Outcomes were CSF-OX level and MRI hypothalamus-to-caudate-nucleus-intensity ratio. Risk factors were age, sex, hypersomnolence and MRI hypothalamus-to-caudate-nucleus-intensity ratio >130%. Logistic regression was performed for the association between the risk factors and CSF-OX levels ≤200 pg/mL. Results: The hypersomnia group (n=50) had significantly more cases of NMOSD (p<0.001), diencephalic syndrome (p=0.006), corticosteroid use (p=0.011), hypothalamic lesions (p<0.023) and early treatment (p<0.001). No cataplexy occurred. In the hypersomnia group, the median CSF-OX level was 160.5 (IQR 108.4-236.5) pg/mL and median MRI hypothalamus-to-caudate-nucleus-intensity ratio was 127.6% (IQR 115.3-149.1). Significant risk factors were hypersomnolence (adjusted OR (AOR) 6.95; 95% CI 2.64 to 18.29; p<0.001) and MRI hypothalamus-to-caudate-nucleus-intensity ratio >130% (AOR 6.33; 95% CI 1.18 to 34.09; p=0.032). The latter was less sensitive in predicting CSF-OX levels ≤200 pg/mL. Cases with MRI hypothalamus-to-caudate-nucleus-intensity ratio >130% had a higher rate of diencephalic syndrome (p<0.001, V=0.59). Conclusions: Considering orexin as reflected by CSF-OX levels and MRI hypothalamus-to-caudate-nucleus-intensity ratio may help diagnose hypersomnia with diencephalic syndrome.

Association between neighborhood walkability and social participation in community-dwelling older adults in Japan: A cross-sectional analysis of the keeping active across generations uniting the youth and the aged study.

AIM: This study investigated neighborhood walkability using Walk Score® and social participation in districts within a city among older Japanese adults. METHODS: This study was a cross-sectional study using baseline data of older adults from the Keeping Active across Generations Uniting the Youth and the Aged study. In total, 2750 participants (1361 men and 1389 women, mean age 72.8 ± 6.4 years) were included in the analysis. The questionnaire included socioeconomic status, self-rated health, medical history, depressive symptoms, instrumental activities of daily living and social participation. We used the Walk Score® as neighborhood walkability and a walk score <50 was categorized as a "car-dependent" area and a score ≥50 as a "walkable" area. A Poisson regression analysis stratified by sex was performed to investigate the association of neighborhood walkability with social participation. Prevalence ratios were calculated and their 95% confidence intervals. RESULTS: We found that dwelling in car-dependent areas (prevalence ratio 0.78, 95% confidence interval 0.64-0.94) had a significant negative effect on women's social participation, unlike men. CONCLUSIONS: Our study showed that neighborhood walkability and social participation were associated with older Japanese women after adjusting for the covariates. These findings might provide helpful information for public health interventions targeted to promote social participation among older adults. Geriatr Gerontol Int 2022; 22: 350-359.

Prevalence, incidence, and medications of narcolepsy in Japan: a descriptive observational study using a health insurance claims database.

The objectives of this study were to describe prevalence, incidence, and medications among patients who were diagnosed with narcolepsy in Japan using a claims database. Patients diagnosed with narcolepsy were identified from January 2010 to December 2019 using an employment-based health insurance claims database compiled by JMDC Inc. The prevalence and incidence of narcolepsy were estimated annually in the overall population and by age and sex among employees and their dependents aged < 75 years. Medications, examined for each quarter in the overall population, were modafinil, methylphenidate, pemoline, tricyclic antidepressants, selective serotonin reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors. We identified 1539 patients with narcolepsy. The overall annual prevalence increased from 5.7 to 18.5/100,000 persons in 2010 and 2019, respectively. Large increases were found from 2010 to 2019 in patients aged 20-29 years and 10-19 years, with the highest prevalence in 2019 (9.7-37.5/100,000 persons and 5.0-27.1/100,000 persons). The overall incidence slightly increased from 3.6 to 4.3/100,000 person-year from 2010 to 2019, and the highest incidence was found in patients aged 20-29 years and 10-19 years (5.8-11.3/100,000 person-year, and 3.8-7.4/100,000 person-year from 2010 to 2019, respectively). Methylphenidate and modafinil were commonly prescribed in 2010 (27.3-38.9% and 17.5-45.5%, respectively). Methylphenidate prescriptions declined during the 10 years, whereas modafinil prescriptions increased (15.6-17.1% and 43.8-45.8% in 2019, respectively). The estimated prevalence and incidence of narcolepsy appeared to increase from 2010 to 2019, especially in teenagers and 20-year olds. Supplementary Information: The online version contains supplementary material available at 10.1007/s41105-022-00406-4.

Residual effects of low dose of suvorexant, zolpidem, and ramelteon in healthy elderly subjects: A randomized double-blind study.

INTRODUCTION: Current hypnotic agents have next-day residual effects. The new orexin antagonist, suvorexant, has little muscle relaxation effect on the physical and cognitive function in the following morning and daytime. In this study, the effects of suvorexant, zolpidem, ramelteon and placebo in elderly subjects were evaluated. METHODS: Six men and eight women aged 63-75 years received a single tablet and lights were then turned off. Subjects were instructed to sleep from 23:00-6:00 with an interruption from 4:00-4:30 for evaluations. Suvorexant 10 mg, zolpidem 5 mg, ramelteon 4 mg or placebo was administered single time in a randomized, double-blind and crossover design with a one-week drug holiday in between each drug. Measures of objective parameters and subjective ratings were obtained every 2 h from 4:00 to 16:00. RESULT: No subjects showed serious side effects from physical observations and vital sign checks before and after hypnotics were taken. During the first sleep period, the REM sleep time with suvorexant was especially longer than that with zolpidem. During the second sleep period, suvorexant had shorter sleep latency and longer stage2 sleep time than ramelteon and zolpidem, respectively. During the whole entire sleep, the REM sleep time with suvorexant was longer than zolpidem and placebo. For the body sway test with closed eye, the main effects of the medicines and zolpidem were significantly better than suvorexant and ramelteon. CONCLUSION: The changes of physical and cognitive functions in healthy elderly after taking hypnotics were not remarkable. Therefore, these three hypnotics maybe appropriate for the elderly people with insomnia for single-time low dose administration.

A rare genetic variant in the cleavage site of prepro-orexin is associated with idiopathic hypersomnia.

Idiopathic hypersomnia (IH) is a rare, heterogeneous sleep disorder characterized by excessive daytime sleepiness. In contrast to narcolepsy type 1, which is a well-defined type of central disorders of hypersomnolence, the etiology of IH is poorly understood. No susceptibility loci associated with IH have been clearly identified, despite the tendency for familial aggregation of IH. We performed a variation screening of the prepro-orexin/hypocretin and orexin receptors genes and an association study for IH in a Japanese population, with replication (598 patients and 9826 controls). We identified a rare missense variant (g.42184347T>C; p.Lys68Arg; rs537376938) in the cleavage site of prepro-orexin that was associated with IH (minor allele frequency of 1.67% in cases versus 0.32% in controls, P = 2.7 × 10-8, odds ratio = 5.36). Two forms of orexin (orexin-A and -B) are generated from cleavage of one precursor peptide, prepro-orexin. The difference in cleavage efficiency between wild-type (Gly-Lys-Arg; GKR) and mutant (Gly-Arg-Arg; GRR) peptides was examined by assays using proprotein convertase subtilisin/kexin (PCSK) type 1 and PCSK type 2. In both PCSK1 and PCSK2 assays, the cleavage efficiency of the mutant peptide was lower than that of the wild-type peptide. We also confirmed that the prepro-orexin peptides themselves transmitted less signaling through orexin receptors than mature orexin-A and orexin-B peptides. These results indicate that a subgroup of IH is associated with decreased orexin signaling, which is believed to be a hallmark of narcolepsy type 1.

Genome-wide association study of idiopathic hypersomnia in a Japanese population.

Idiopathic hypersomnia (IH) is a rare sleep disorder characterized by excessive daytime sleepiness, great difficulty upon awakening, and prolonged sleep time. In contrast to narcolepsy type 1, which is a well-recognized hypersomnia, the etiology of IH remains poorly understood. No susceptibility loci for IH have been identified, although familial aggregations have been observed among patients with IH. Narcolepsy type 1 is strongly associated with human leukocyte antigen (HLA)-DQB1*06:02; however, no significant associations between IH and HLA alleles have been reported. To identify genetic variants that affect susceptibility to IH, we performed a genome-wide association study (GWAS) and two replication studies involving a total of 414 Japanese patients with IH and 6587 healthy Japanese individuals. A meta-analysis of the three studies found no single-nucleotide polymorphisms (SNPs) that reached the genome-wide significance level. However, we identified several candidate SNPs for IH. For instance, a common genetic variant (rs2250870) within an intron of PDE9A was suggestively associated with IH. rs2250870 was significantly associated with expression levels of PDE9A in not only whole blood but also brain tissues. The leading SNP in the PDE9A region was the same in associations with both IH and PDE9A expression. PDE9A is a potential target in the treatment of several brain diseases, such as depression, schizophrenia, and Alzheimer's disease. It will be necessary to examine whether PDE9A inhibitors that have demonstrated effects on neurophysiologic and cognitive function can contribute to the development of new treatments for IH, as higher expression levels of PDE9A were observed with regard to the risk allele of rs2250870. The present study constitutes the first GWAS of genetic variants associated with IH. A larger replication study will be required to confirm these associations. Supplementary Information: The online version contains supplementary material available at 10.1007/s41105-021-00349-2.

Induction of narcolepsy-like symptoms by orexin receptor antagonists in mice.

Orexins/hypocretins are hypothalamic neuropeptides that promote and stabilize wakefulness by binding to the orexin receptor type-1 (OX1R) and type-2 (OX2R). Disruption of orexinergic signaling results in the sleep disorder narcolepsy in mice, rats, dogs, and humans. The orexin receptor antagonist suvorexant promotes sleep by blocking both OX1R and OX2R. Whereas suvorexant has been clinically approved for the treatment of insomnia because it is well tolerated in experimental animals as well as in human patients, a logical question remains as to why orexin receptor antagonists do not induce overt narcolepsy-like symptoms. Here we show that acute and chronic suvorexant promotes both rapid eye movement (REM) and non-rapid eye movement (NREM) sleep without inducing cataplexy in mice. Interestingly, chronic suvorexant increases OX2R mRNA and decreases orexin mRNA and peptide levels, which remain low long after termination of suvorexant administration. When mice are chronically treated with suvorexant and then re-challenged with the antagonist after a 1-week washout, however, cataplexy and sleep-onset REM (SOREM) are observed, which are exacerbated by chocolate administration. Heterozygous orexin knockout mice, with lower brain orexin levels, show cataplexy and SOREM after acute suvorexant administration. Furthermore, we find that acute suvorexant can induce cataplexy and SOREM in wild-type mice when co-administered with chocolate under stress-free (temporally anesthetized) conditions. Taken together, these results suggest that suvorexant can inhibit orexin synthesis resulting in susceptibility to narcolepsy-like symptoms in mice under certain conditions.

Severity of Depressive Symptoms is Associated with Venous Thromboembolism in Hospitalized Patients with a Major Depressive Episode.

PURPOSE: A major depressive episode is a risk factor for venous thromboembolism (VTE) in psychiatric inpatients. However, it is unclear whether the severity of depressive symptoms or duration of the current depressive episode is associated with VTE. Further, the VTE prevalence among hospitalized patients with a major depressive episode receiving electroconvulsive therapy is unknown. This retrospective study examined factors associated with VTE among hospitalized patients with a major depressive episode and estimated the prevalence of VTE in such patients who underwent electroconvulsive therapy. PATIENTS AND METHODS: Patients with a major depressive episode hospitalized in the Department of Neuropsychiatry at Akita University Hospital between January 2018 and December 2020 were included. Data from the first week of hospitalization were extracted from medical records. VTE was diagnosed based on the findings of computed tomography. To evaluate whether the severity of depressive symptoms or duration of the current depressive episode was associated with VTE, logistic regression analysis was conducted after adjusting for covariates with known VTE risk factors (antidepressants, antipsychotics, and physical comorbidities). RESULTS: We analyzed 133 patients; of these, 14 were diagnosed with asymptomatic VTE. The severity of depressive symptoms (odds ratio: 1.220, 95% confidence interval: 1.081-1.377, p = 0.001) was significantly associated with VTE. The prevalence of VTE among those receiving electroconvulsive therapy was 35% (7/20). CONCLUSION: The prevalence of VTE was 35% among patients receiving in-hospital electroconvulsive therapy for a major depressive episode. VTE should be considered for hospitalized patients with severe depressive symptoms and patients receiving in-hospital electroconvulsive therapy for a major depressive episode.

Identification of potential therapeutic targets in hypertension-associated bladder dysfunction.

OBJECTIVE: To investigate differential gene expression profiles in the bladder of spontaneously hypertensive rat (SHR), as the underlying mechanisms involved in hypertension-associated bladder dysfunction remain to be clarified. MATERIALS AND METHODS: SHR and normotensive Wistar-Kyoto (WKY) rats were distributed initially in three groups: group 1 received doxazosin (30 mg/kg/day); group 2 received nifedipine (30 mg/kg/day); and group 3 received the vehicle orally for 4 weeks. The alterations in gene expression levels of candidate genes identified by microarray analysis with potential biological relevance were verified by real-time reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Voiding frequency was significantly higher, and mean voided volume was significantly lower in untreated SHRs than untreated WKY rats. Microarray analysis revealed that 25 of the differentially expressed genes in untreated SHRs compared to untreated WKY rats were related to G(s), G(i), G(q) and G(12/13) signalling, calcium handling, ion transport and smooth muscle-related genes. Furthermore, RT-PCR data, in accord with the microarray analysis, indicated that untreated SHRs had lower mRNA expression levels of Adcy2, Adcy3, Rgs2, Rgs3, Rgs4 and Arhgdia, and higher mRNA expression levels of Arhgef1, Arhgef11, Arhgef12, Geft, Rock1 and Rock2 than untreated WKY rats. The differential alterations in the micturition patterns and in the expression of several genes related to G-protein signalling pathway observed in SHRs were attenuated by treatment with doxazosin, but not nifedipine. CONCLUSION: Our data suggest that differential alterations in the expression of several genes related to G(s), G(q) and G(12/13) signalling pathways in the SHR bladder might be important in hypertension-associated bladder dysfunction.