BackgroundIntranasal administration is a convenient route for drug delivery that can be applied for procedural sedation. However, there is currently limited exploration into fixed dosing regimens. This study was to investigate the pharmacokinetics (PK), pharmacodynamics (PD), bioavailability (BA) and safety of dexmedetomidine after fixed doses of intranasal and intravenous administration in healthy male and female subjects.MethodsGroup A subjects received intranasal or intravenous administration in two periods (12 subjects received intranasal dexmedetomidine (Dex) or the intravenous formulation, and four received the corresponding placebo). Groups B to F underwent single-period dose ascending, receiving only the intranasal Dex formulation or the corresponding placebo (the number of subjects receiving the drug/placebo in groups B to F were 12/2, 12/2, 12/2, 10/2, 10/2, respectively), with doses of 75 μg, 125 μg, 150 μg, 175 μg, and 200 μg, respectively. After administration of each group, blood samples were collected to investigate the plasma concentration of dexmedetomidine, adrenaline and noradrenaline using a HPLC-MS/MS method. Ramsay score, blood pressure and heart rate were collected for safety evaluation. Pharmacokinetic parameters (Cmax, Tmax, AUC0-24h, AUC0–∞, and t1/2) of dexmedetomidine were calculated.ResultsA total of 82 subjects were randomized. One subject withdrew for personal reasons before administration and the other subjects completed the entire study process. At a dose of 25 μg, the absolute bioavailability was 59%. Across the dose range of 25 to 200 μg, the median Tmax was similar (0.5–1 h), and the mean elimination half-life was comparable (3.09–4.28 h), with exposure (Cmax and AUC0-t) increasing with dose. The pharmacokinetics after intranasal spray administration exhibited linear characteristics, although Cmax was similar in the higher dose groups (175 μg and 200 μg). PD results showed that ideal sedation effects (Ramsay score of 3 or higher in at least 90% of subjects) could be achieved within 30 min following intranasal administration of 75 μg or higher doses. All the subjects were well tolerated without any serious adverse events (SAEs).ConclusionDexmedetomidine nasal spray was well tolerated and achieved satisfactory sedation in the dose range of 25–200 μg in Chinese healthy male and female subjects.Clinical Trial Registration:http://www.chinadrugtrials.org.cn/, identifier CTR20201650

Ulotaront (SEP-363856), a dual trace animeassociated receptor 1 (TAAR1) and 5-HT1A receptor agonist, is in phase 3 clinical development for the treatment of schizophrenia. This study evaluated the comparative bioequivalence (BE) between tablet and capsule formulations of ulotaront and the food effect (FE) on pharmacokinetics (PK) of tablet form in healthy adult human subjects. The BE study applied an open-label two-period crossover design in 24 healthy volunteers. Subjects were randomly assigned (1:1) to dosing sequence AB or BA (A, 25 mg ulotaront tablet; B, 25 mg ulotaront capsule). The FE study also used an open-label randomized two-period crossover design in 20 healthy volunteers. Subjects were fasted overnight then randomly assigned (1:1) to dosing sequence AB or BA (A, fasted condition; B, fed condition). Dosing periods were separated by 1 week for both studies. Serial plasma samples from each period were collected and analyzed by LC–MS/MS. PK parameters were calculated using Phoenix WinNonlin® software. For the BE study, geometric mean ulotaront Cmax values were 93.28 and 86.98 ng/mL for tablet and capsule, respectively. Cmax ratio was 107.25 significant food effect.

Ulotaront, a trace amine-associated receptor 1 (TAAR1) and serotonin 5-HT1A receptors agonist, has demonstrated efficacy in the treatment of patients with an acute exacerbation of schizophrenia in a 4-week, double-blind, placebo-controlled study. The aim of this 26-week open-label extension study was to evaluate the safety and effectiveness of ulotaront (25/50/75 mg/d) in patients who completed the initial 4-week study. Of the 193 4-week completers, 157 patients (81.3%) continued into the open-label extension study; 66.9% were completers. Among all extension phase patients, treatment with ulotaront was associated with minimal changes in body weight (mean [SD] change from double-blind baseline: −0.3 [3.7] kg), cholesterol (median change, −2.0 mg/dL), triglycerides (median, −5.0 mg/dL), and prolactin (female, median, −3.4 ng/mL; male, median, −2.7 ng/mL). Movement disorder scales showed no extrapyramidal effects. Twenty-six weeks of extension phase treatment was associated with a mean (95% CI) observed change from open-label baseline in the PANSS total score of −22.6 (−25.6, −19.6; effect size, 1.46), and a mean (95% CI) change in the CGI-Severity score of −1.0 (−1.2, −0.8; effect size, 1.07). Long-term treatment with the TAAR1 agonist ulotaront, in the daily dose range of 25–75 mg, was characterized by a relatively high completion rate, an adverse event profile notable for the absence of extrapyramidal-related adverse effects, a low liability for adverse weight and metabolic effects, and no effect on prolactin levels. Additional studies are needed to further confirm the long-term efficacy and safety of ulotaront.

IMPORTANCE Genetic variants of ABCB1 may affect intestinal absorption of clopidogrel bisulfate. However, it is unclear whether ABCB1 polymorphisms are associated with clopidogrel efficacy for minor ischemic stroke or transient ischemic attack (TIA). OBJECTIVES To investigate the association between ABCB1 polymorphisms and clopidogrel efficacy for minor stroke or TIA. DESIGN, SETTING, AND PARTICIPANTS In this prespecified secondary analysis of the Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events (CHANCE) randomized clinical trial, 3010 patients with minor stroke or TIA at 73 sites in China with experience in conducting genetic studies were included from October 1, 2009, to July 30, 2012. The analysis was conducted on March 20, 2018. Four single-nucleotide polymorphisms (ABCB1-154T>C [rs4148727], ABCB13435C>T [rs1045642], CYP2C19*2 [681G>A, rs4244285], and CYP2C19*3 [636G>A, rs4986893]) were genotyped among 2836 patients treated with clopidogrel plus aspirin (n = 1414) or aspirin alone (n = 1422). The association of ABCB1 genetic variants (-154 TC/CC and 3435 CT/TT) with clopidogrel efficacy was evaluated in the context of CYP2C19 status, another gene associated with clopidogrel efficacy. INTERVENTIONS Patients in the CHANCE trial were randomized to treatment with clopidogrel combined with aspirin or to aspirin alone. MAIN OUTCOMES AND MEASURES Primary efficacy outcome was stroke recurrence after 3 months. The safety outcome was any bleeding risk after 3 months. RESULTS Among 2836 patients, the median age was 61.8 years (interquartile range, 54.4-71.1 years) and 1887 patients (66.5%) were male. A total of 2146 (75.7%) patients were carriers of ABCB1-154TC/CC (570 [20.1%]) or 3435 CT/TT (1851 [65.3%]) genotype. Clopidogrel plus aspirin treatment was associated with reduced risk of new stroke in patients with ABCB1-154 TT and 3435 CC genotype (hazard ratio [HR], 0.43; 95% Cl, 0.26-0.71) but not in those with ABCB1 -154 TC/CC or 3435 CT/TT genotype (HR, 0.78; 95% CI, 0.60-1.03) compared with aspirin (P=.04 for interaction). A combined association of ABCB1 and CYP2C19 polymorphisms with new stroke was observed. The risk of bleeding for clopidogrel plus aspirin treatment was not associated with the ABCB1 genotypes (2.3% and 1.3% vs 1.9% and 2.2%; P=.25 for interaction in patients with or without ABCB1-154 TC/CC or 3435 CT/TT genotype) CONCLUSIONS AND RELEVANCE The ABCB1 polymorphism was associated with the reduced efficacy of clopidogrel plus aspirin treatment compared with aspirin among patients with minor ischemic stroke or TIA. Genetic polymorphism of ABCB1 should be considered when prescribing clopidogrel for these patients.

BACKGROUND:Suicidal behaviors are common in major depressive disorder (MDD) and contribute significantly to premature death. The objective of this meta-analysis is to estimate the pooled prevalence of suicidal behaviors in patients with MDD in China.METHODS:The relevant databases in English (PubMed, Embase, PsycINFO and Cochrane Library) and Chinese (Chinese National Knowledge Infrastructure, Wanfang and Chinese Biological Medical Literature) were systematically and independently searched from their inceptions until January 23, 2017. Original studies that reported the prevalence of suicidal behaviors including suicidal ideation (SI), suicide plan (SP), suicide attempt (SA) and completed suicide (CS) were included.RESULTS:Thirty three articles that met the inclusion criteria were analyzed. The pooled lifetime prevalence of SI, SP and SA were 53.1% (95% CI: 42.4-63.4%), 17.5% (95% CI: 5.8-42.3%) and 23.7% (95% CI: 19.9-28.0%), respectively. One-month prevalence of SI and SA were 27.7% (95% CI: 15.4-44.5%) and 20.3% (95% CI: 12.1-32.2%), respectively. The pooled prevalence of SA during hospitalization and after onset of MDD were 17.3% (95% CI: 12.4-23.7%) and 42.1% (95% CI: 26.1-60.0%), respectively. Subgroup analyses revealed significant differences in both lifetime prevalence of SI and SA between genders, and between outpatients and inpatients with MDD.CONCLUSION:Suicidal behaviors are common in MDD patients in China. Regular screening and effective intervention for suicidal behavior in MDD patients are warranted.

PURPOSEThe purpose of the study was to determine the pattern of sleep behavior in schizophrenia patients treated in primary care. DESIGN AND METHODSAltogether 623 schizophrenia patients in 22 primary care services were recruited. Sleep duration and demographic and clinical characteristics were recorded. FINDINGSThe mean expected total sleep time was 8.8 hr (SD 1.8) and the mean actual total sleep time was 8.2 hr (SD 2.1). The frequency of short, medium, and long sleepers was 18.1, 38.4, and 43.5%, respectively. Major medical conditions and any type of insomnia were independently associated with short sleep, while long sleep was associated with unemployment and use of second-generation antipsychotics. PRACTICE IMPLICATIONSMore attention should be paid to sleep duration in this population group.

In China, maintenance treatment for clinically stable patients with schizophrenia is usually provided by primary care physicians. This study examined the quality of life (QOL) in patients with schizophrenia treated in primary care and explored the demographic and clinical characteristics associated with QOL. Altogether, 612 patients with schizophrenia treated in 22 randomly selected primary care services in China formed the study sample. QOL, psychotic and depressive symptoms, extra-pyramidal symptoms and insight were assessed using standardized instruments. Data analyses were conducted with the one sample t-test and multiple linear regression analyses. Compared with the normative data for the Chinese general population, significantly lower scores in physical and mental QOL domains were found in the patient group. Older age, being unemployed, major medical conditions, no smoking, more severe depressive and negative symptoms, more frequent insomnia, and suicidality were independently associated with poor physical QOL. Male gender, more severe depressive and anxiety symptoms, more frequent insomnia, and suicidality were independently associated with poor mental QOL. Patients with schizophrenia treated in primary care had lower level of QOL in comparison with general population. Effective measures need to be implemented to improve their QOL.

目的 系统评价华人精神分裂症吸烟患者首次精神病发作前的吸烟率(病前吸烟率).方法 计算机检索中国知网、万方、维普中文期刊网、台湾电子期刊全文数据库、PubMed、EMbase和PsycINFO,查找华人精神分裂症吸烟患者病前吸烟率的原始文献,检索时间均从建库至2016年12月25日.由两位研究者按纳入与排除标准筛选文献、提取数据并评价纳入研究的方法学质量,采用R 3.1.1进行Meta分析.结果 共17项研究(2 445例精神分裂症吸烟患者)纳入分析,所有研究均为低质量.华人精神分裂症患者的合并病前吸烟率为72.0%(95%CI:61.0%~86.8%,P<0.01);亚组分析结果显示,近年发表(2012年-2016年)文献的病前吸烟率高于早年发表(2002年-2011年)文献(83.0% vs.61.0%,P=0.02),首发精神分裂症患者的病前吸烟率高于非首发患者(88.0% vs.67.0%,P=0.047).结论 大多数华人吸烟精神分裂症患者的吸烟行为发生在首次精神疾病发作之前.

Objective: Maintenance treatment for clinically stable patients with schizophrenia is usually provided by Chinese primary care physicians, but no study has investigated smoking rates in this population. This study investigated the rate of smoking and its associations with sociodemographic and clinical characteristics and quality of life (QOL) in patients with schizophrenia treated in primary care in China.Methods: This was a cross-sectional, community-based survey. A total of 621 schizophrenia patients were recruited from 22 primary care services in Guangzhou, China, in 2013. Patients' sociodemographic and clinical characteristics, smoking status, and QOL were recorded.Results: The frequency of current smoking was 23.8% in the whole sample; 41.5% for men and 2.5% for women. Multiple logistic regression analysis revealed that male gender, married status, alcohol use, older age at onset, fewer major medical conditions, lower education level and more hospitalizations were independently associated with current smoking.Conclusion: The frequency of smoking in Chinese schizophrenia patients treated by primary care physicians is lower than most figures reported from Western and Chinese psychiatric settings. (C) 2015 Elsevier Inc. All rights reserved.

Purpose Little is known about the frequency of electroconvulsive therapy (ECT) use in China. This study examined the frequency of ECT and its relationship with demographic and clinical characteristics in a large psychiatric institution in China. Methods This was a retrospective chart review of all the 19,982 inpatients aged 18 to 59 years treated during the period of 8 years (2007–2013) in a tertiary psychiatric institution in Beijing. Sociodemographic and clinical data were collected from the electronic chart management system for discharged patients. Results The frequency of ECT use was 57.7% in the whole sample, 68.4% in bipolar disorders, 66.3% in major depression, 55.2% in schizophrenia, and 28.6% in other psychiatric disorders. Patients who received ECT (ECT group) had shorter length of hospitalization compared with the non-ECT group. In multiple logistic regression analysis, ECT use was independently associated with age younger than 30 years; higher risk for suicide and aggression at time of admission; mood disorders; lower risk for falls; more treatment with antipsychotics, mood stabilizers, and antidepressants; less health insurance coverage and major medical conditions; as well as non–local residency status. Compared with 2007 (35.5%), ECT use significantly increased in the period of 2008 (49.1%) to 2013 (61.9%). All these significant correlates combined explained 20% of the variance of ECT use (P < 0.001). Conclusions In a major psychiatric center in China, the use of ECT was much more common than the figures reported from most countries around the world. Reasons for this difference and variances in outcomes between settings with higher and lower ECT use should be studied.

OBJECTIVE:Clozapine is frequently used to treat schizophrenia in China. Maintenance treatment for clinically stable patients with schizophrenia is usually provided by Chinese primary care physicians, but no study has investigated the frequency of its use prescribed by primary care physicians. This study described the frequency, demographic and clinical characteristics of clozapine treatment and its impact on insight and quality of life (QOL) of patients with schizophrenia treated in primary care in China.METHOD:A total of 623 patients with schizophrenia treated in 22 primary care services in Guangzhou, China in 2013 formed the study sample. Patients' socio-demographic and clinical characteristics including psychopathology, medication side effects and QOL were recorded using a standardized protocol and data collection.RESULTS:The frequency of clozapine prescription was 35.6% with a mean daily dose of 127.7±88.2 mg. There were no significant differences between the patients with and without clozapine in either of the QOL domains after controlling the confounding factors. Multiple logistic regression analyses revealed that patients on clozapine had younger age of onset, more hospitalizations, more severe extrapyramidal side effects, but better insight and fewer prescriptions of first generation antipsychotics.CONCLUSIONS:Clozapine use was found to be common and associated with better insight in patients with schizophrenia treated in primary care in China. Further examination of the rationale and appropriateness of clozapine in primary care in China is warranted.

PURPOSE:To describe the prevalence and clinical correlates of insomnia in schizophrenia patients treated in primary care.DESIGN AND METHODS:Six hundred and twenty-three schizophrenia patients from 22 primary care services were recruited.FINDINGS:The prevalence of at least one type of insomnia was 28.9% (180/623), while those of difficulty initiating sleep, difficulty maintaining sleep, and early morning wakening were 20.5%, 19.6%, and 17.7%, respectively. Only 53.3% of patients suffering from insomnia received treatment.PRACTICE IMPLICATIONS:Insomnia is common in Chinese patients with schizophrenia treated in primary care and the rate of treatment appears low.

PURPOSE:Sexual dysfunction in schizophrenia patients is common. In China, maintenance treatment for clinically stable patients with schizophrenia is usually provided by primary care physicians. Illness- or treatment-related sexual dysfunction in this patient population has been never studied. This study describes the prevalence and correlates of sexual dysfunction and its impact on quality of life (QOL) in patients with schizophrenia treated in primary care in China. METHOD:A total of 607 patients with schizophrenia treated in 22 randomly selected primary care services in China formed the study sample. Patients' socio-demographic and clinical characteristics including sexual function and QOL were recorded using a standardized protocol and data collection. RESULTS:Sexual dysfunction was present in 69.9% of all patients; 60.7% in males and 80.6% in females. Multiple logistic regression analysis revealed that female gender, being single, older age and use of first-generation antipsychotics were independently and significantly associated with more sexual dysfunction accounting for 23.5% of its variance (P<0.001). Unexpectedly, sexual dysfunction was not associated with lower QOL. CONCLUSIONS:High rate of sexual dysfunction was reported in the majority of patients with schizophrenia treated in primary care in China. Given its negative impact on social adjustment, QOL and treatment adherence, efforts should be made to address sexual dysfunction in this patient population.

BACKGROUND:Developing accurate and time-efficient tools to measure depressive symptoms in schizophrenia is important for research and clinical practice. This study tested the psychometric properties of the Chinese version of the 16-item Quick Inventory of Depressive Symptomatology (QIDS-SR) in depressed schizophrenia patients. METHODS:This study included 337 clinically stable patients with schizophrenia. The severity of depressive symptoms was assessed using the Montgomery-Asberg Depression Rating Scale (MADRS), QIDS-SR at baseline and 2 weeks later. Negative symptoms and extrapyramidal symptoms were measured with the negative symptom score of Brief Psychiatric Rating Scale (BPRS) and the Simpson-Angus Scale of Extrapyramidal Symptoms (SAS), respectively. RESULTS:Internal consistency (Cronbach׳s alpha) was 0.73 and 0.67 for QIDS-SR at the baseline and endpoint, respectively. The intra-class correlation coefficient (ICC) for test-retest reliability over the two weeks was 0.77. Two domains (involvement and energy) at baseline and one domain (energy) at endpoint had the highest item-total correlations. The QIDS-SR total score was significantly correlated with the MADRS total score at baseline (r=0.44, p<0.01). Weak correlations of the QIDS-SR score with the scores of the BPRS negative (r=0.18) and the SAS (r=0.05) indicate good discriminant validity. The QIDS-SR showed unidimensional measurement properties in exploratory factor analysis at both baseline. The main limitation of the study is that only clinically stable schizophrenia patients were included. CONCLUSIONS:The QIDS-SR has acceptable psychometric properties in stable schizophrenia patients and may be useful in both research and clinical practice.

Background Studies from Western countries consistently report very high rates of comorbid Antisocial Personality Disorder (ASPD) among individuals with heroin addiction, but the reported proportion of Chinese individuals with heroin addiction who have co-morbid ASPD varies widely, possibly because Chinese clinicians do not consider personality issues when treating substance abuse problems. Aim Conduct a meta-analysis of studies that assessed the proportion of Chinese individuals with heroin dependence who have comorbid ASPD. Methods We searched for relevant studies in both Chinese databases (China National Knowledge Infrastructure, Wanfang Data Knowledge Service Platform, Taiwan Electronic Periodical Services) and western databases (PubMed, EMBASE, and PsycInfo). Two authors independently retrieved the literature, identified studies that met pre-defined inclusion and exclusion criteria, assessed the quality of included studies, and extracted the data used in the analysis. Statistical analysis was performed using StatsDirect 3.0 and R software. Results The search yielded 15 eligible studies with a total of 3692 individuals with heroin dependence. Only 2 of the studies were rated as high-quality studies. All studies were conducted in rehabilitation centers or hospitals. The pooled lifetime prevalence of ASPD in these subjects was 30% (95%CI: 23%-38%), but the heterogeneity of results across studies was great (I2 =95%, p<0.001). Men had a higher prevalence than women (44% vs. 21%), and injection heroin users had higher prevalence than those who smoked heroin (44% vs. 27%). Studies that were methodologically stronger had higher reported prevalence of ASPD among heroin dependent individuals. Conclusions There are substantial methodological problems in the available literature about ASPD in Chinese individuals receiving treatment for heroin dependence, but we estimate that about one-third of them meet criteria for ASPD. Further work is needed to increase clinicians’ awareness of this issue; to compare the pathogenesis, treatment responsiveness and recidivism of those with and without ASPD; and to develop and test targeted interventions for this difficult-to-treat subgroup of individuals with heroin dependence.

PURPOSETo compare self-reported (SR) and interviewer-rated (IR) oral health between schizophrenia (SZ), bipolar disorder (BP), and major depressive disorder (MDD) patients.DESIGN AND METHODS356 patients with SZ, BP, or MDD underwent assessments of psychopathology, side effects, SR, and IR oral health status.FINDINGS118 patients (33.1%) reported poor oral health; the corresponding proportion was 36.4% in BP, 34.8% in SZ, and 25.5% in MD (p = .21). SR and IR oral health correlated only modestly (r = 0.17-0.36) in each group.PRACTICE IMPLICATIONSPsychiatric patients need to be assessed for both SR and IR oral health.

PURPOSE No study has investigated hyperprolactinemia and its risk factors in Chinese psychiatric patients. This study examined the prevalence of hyperprolactinemia and its relationship with demographic and clinical characteristics in inpatients in a large psychiatric institution in Beijing, China. DESIGN AND METHODS A consecutive sample of 617 psychiatric inpatients formed the study sample. Basic sociodemographic and clinical data including serum prolactin level were collected. FINDINGS The prevalence of hyperprolactinemia was 55.9% in the whole sample, and 56.8% and 43.2% for women and men, respectively. The corresponding figures were 59.6%, 40.0%, 53.6%, and 50.8% in schizophrenia spectrum disorders, major depression, bipolar disorders, and other psychiatric disorders, respectively (p = 0.09). In univariate analyses, patients having hyperprolactinemia were younger, more likely to receive risperidone, amisulpride, and first-generation antipsychotics, but less likely to receive clozapine and aripiprazole. In multiple logistic regression analysis, hyperprolactinemia was independently associated with younger age, more use of risperidone or amisulpride and first-generation antipsychotics, and less use of clozapine and aripiprazole (r(2) = 0.197). PRACTICE IMPLICATIONS Hyperprolactinemia is very common in Chinese psychiatric inpatients. Given the potentially harmful consequences of hyperprolactinemia and its preventable nature, effective measures to lower the frequency hyperprolactinemia in patients with major psychiatric disorders should be implemented in Chinese mental health facilities.

ObjectiveThis study aimed to examine the use of high doses of antipsychotic medications (≥600 mg/day chlorpromazine equivalent) in older Asian patients with schizophrenia and its demographic and clinical correlates.MethodInformation on hospitalized patients with schizophrenia aged ≥50 years was extracted from the database of the Research on Asian Psychotropic Prescription Patterns study (2001–2009). Data on 2203 patients in six Asian countries and territories, including China, Hong Kong, Japan, Korea, Singapore and Taiwan, were analyzed. Socio‐demographic and clinical characteristics and antipsychotic prescriptions were recorded.ResultsThe frequency for high‐dose antipsychotic medications was 36.0% overall, with 38.4% in 2001, 33.3% in 2004 and 36.0% in 2009. Multiple logistic regression analysis of the whole sample showed that compared to patients receiving low‐medium antipsychotic doses, those on high doses had a longer illness duration (odds ratio (OR): 2.0, 95% confidence interval (CI):1.2–3.3, p = 0.008), were more likely in the 50–59‐year group (OR: 0.95, 95% CI: 0.94–0.97, p < 0.001), more often had current positive (OR: 1.5, 95% CI: 1.2–1.8, p < 0.001) or negative symptoms (OR: 1.3, 95% CI: 1.03–1.6, p = 0.03), and more commonly received antipsychotic polypharmacy (OR: 5.3, 95% CI: 4.1–6.7, p < 0.001). Extrapyramidal symptoms (p = 0.25) and tardive dyskinesia (p = 0.92) were not more frequent in the high‐dose group.ConclusionsHigh doses of antipsychotic medications were used in more than one third of older Asian patients with schizophrenia. The reasons for the frequent use of high antipsychotic doses in older Asian patients warrant further investigation. Copyright © 2013 John Wiley & Sons, Ltd.