Although small-scale studies have described the effects of oxytocin on social deficits in autism spectrum disorder (ASD), no large-scale study has been conducted. In this randomized, parallel-group, ...multicenter, placebo-controlled, double-blind trial in Japan, 106 ASD individuals (18-48 y.o.) were enrolled between Jan 2015 and March 2016. Participants were randomly assigned to a 6-week intranasal oxytocin (48IU/day, n = 53) or placebo (n = 53) group. One-hundred-three participants were analyzed. Since oxytocin reduced the primary endpoint, Autism Diagnostic Observation Schedule (ADOS) reciprocity, (from 8.5 to 7.7; P < .001) but placebo also reduced the score (8.3 to 7.2; P < .001), no between-group difference was found (effect size -0.08; 95% CI, -0.46 to 0.31; P = .69); however, plasma oxytocin was only elevated from baseline to endpoint in the oxytocin-group compared with the placebo-group (effect size -1.12; -1.53 to -0.70; P < .0001). Among the secondary endpoints, oxytocin reduced ADOS repetitive behavior (2.0 to 1.5; P < .0001) compared with placebo (2.0 to 1.8; P = .43) (effect size 0.44; 0.05 to 0.83; P = .026). In addition, the duration of gaze fixation on socially relevant regions, another secondary endpoint, was increased by oxytocin (41.2 to 52.3; P = .03) compared with placebo (45.7 to 40.4; P = .25) (effect size 0.55; 0.10 to 1.0; P = .018). No significant effects were observed for the other secondary endpoints. No significant difference in the prevalence of adverse events was observed between groups, although one participant experienced temporary gynecomastia during oxytocin administration. Based on the present findings, we cannot recommend continuous intranasal oxytocin treatment alone at the current dose and duration for treatment of the core social symptoms of high-functioning ASD in adult men, although this large-scale trial suggests oxytocin's possibility to treat ASD repetitive behavior.
Abstract
Delirium develops through a multifactorial process and include multiple subtypes with different pathological factors. To refine the treatment and care for delirium, a more detailed ...examination of these subtypes is needed. Therefore, this study aimed to explore the factors affecting delirium in cases in which hallucinations are conspicuous. In total, 602 delirium cases referred to the psychiatry department at a general hospital between May 2015 and August 2020 were enrolled. The Delirium Rating Scale-revised-98 was used to assess perceptual disturbances and hallucinations in patients with delirium. Multiple regression analysis was applied to determine whether individual factors were associated with the hallucinations. A total of 156 patients with delirium (25.9%) experienced hallucinations, with visual hallucinations being the most common subtype. Alcohol drinking (
p
< 0.0005), benzodiazepine withdrawal (
p
= 0.004), and the use of angiotensin II receptor blockers (
p
= 0.007) or dopamine receptor agonists (
p
= 0.014) were found to be significantly associated with hallucinations in patients with delirium. The four factors detected in this study could all be reversible contributing factors derived from the use of or withdrawal from exogenous substances.
Mental disorders are considered as one of the major healthcare issues worldwide owing to their significant impact on the quality of life of patients, causing serious social burdens. However, it is ...hard to examine the living brain—a source of psychiatric symptoms—at the cellular, subcellular, and molecular levels, which poses difficulty in determining the pathogenesis and pathophysiology of mental disorders. Recently, induced pluripotent stem cell (iPSC) technology has been used as a novel tool for research on mental disorders. We believe that the iPSC‐based studies will address the limitations of other research approaches, such as human genome, postmortem brain study, brain imaging, and animal model analysis. Notably, studies using integrated iPSC technology with genetic information have provided significant novel findings to date. This review aimed to discuss the history, current trends, potential, and future of iPSC technology in the field of mental disorders. Although iPSC technology has several limitations, this technology can be used in combination with the other approaches to facilitate studies on mental disorders.
•A number of genetic variants associated with psychiatric disorders are identified.•Rare variants with large effect sizes are useful for developing disease model.•Integrated model of immune system, ...gut microbiota and genetic risk will be needed.
Recent rapid progress in genome analysis and large-scale consortia has made it possible to discover variants with a variety of allele frequencies and effect sizes associated with psychiatric disorders. Among psychiatric disorder-susceptibility variants, rare variants with large effect sizes detected by sequencing analysis or array comparative genomic hybridization would be particularly useful for elucidating pathophysiology by developing disease models, such as genome-edited mouse or induced pluripotent stem cells. In the last decade, investigations of rare variants with large effect size have revealed an important role of neurodevelopment in the pathogenesis of psychiatric disorders. In future research, integration of recent evidence concerning the contribution of the immune system or gut microbiota will enhance our understanding of psychiatric disorders and facilitate novel drug development.
Identifying both the commonalities and differences in brain structures among psychiatric disorders is important for understanding the pathophysiology. Recently, the ENIGMA-Schizophrenia DTI Working ...Group performed a large-scale meta-analysis and reported widespread white matter microstructural alterations in schizophrenia; however, no similar cross-disorder study has been carried out to date. Here, we conducted mega-analyses comparing white matter microstructural differences between healthy comparison subjects (HCS; N = 1506) and patients with schizophrenia (N = 696), bipolar disorder (N = 211), autism spectrum disorder (N = 126), or major depressive disorder (N = 398; total N = 2937 from 12 sites). In comparison with HCS, we found that schizophrenia, bipolar disorder, and autism spectrum disorder share similar white matter microstructural differences in the body of the corpus callosum; schizophrenia and bipolar disorder featured comparable changes in the limbic system, such as the fornix and cingulum. By comparison, alterations in tracts connecting neocortical areas, such as the uncinate fasciculus, were observed only in schizophrenia. No significant difference was found in major depressive disorder. In a direct comparison between schizophrenia and bipolar disorder, there were no significant differences. Significant differences between schizophrenia/bipolar disorder and major depressive disorder were found in the limbic system, which were similar to the differences in schizophrenia and bipolar disorder relative to HCS. While schizophrenia and bipolar disorder may have similar pathological characteristics, the biological characteristics of major depressive disorder may be close to those of HCS. Our findings provide insights into nosology and encourage further investigations of shared and unique pathophysiology of psychiatric disorders.
Rationale
The effects of hypnotics on automobile driving have been attracting increasing attention. However, few driving simulators (DSs) have been confirmed to have acceptable reliability and ...validity for assessing the next-day residual effects of zopiclone as a positive control on driving performance.
Objective
To investigate whether a new DS could permit detection of the next-day residual effects of zopiclone on driving performance.
Methods
In this double-blind, randomized, placebo-controlled crossover trial, 28 healthy males received zopiclone 7.5 mg at bedtime on days 1 and 8 and placebo on the other days over a period of 16 days. The participants took part in three driving tasks—road-tracking, car-following, and harsh-braking—using a DS on days 2 and 9 at 9-h post-dosing. Scores on the Karolinska Sleepiness Scale and Profile of Mood States-Second Edition were then assessed, as was the serum concentration of zopiclone.
Results
The estimated differences in the standard deviation of lateral position (cm) in the road-tracking task between the zopiclone and placebo groups on days 2 and 9 were 3.75 cm (90% confidence interval (CI): 1.71–5.79) and 4.07 cm (90% CI: 2.02–6.11), respectively. The estimated differences in the distance coefficient of variation in the car-following task and in the brake reaction time in the harsh-braking task between the zopiclone and placebo groups on day 2 were 4.31 (90% CI: 1.94–6.69) and 24.6 ms (90% CI: 12.7–36.4), respectively.
Conclusions
The DS used in this study has sufficient sensitivity to detect the next-day residual effects of zopiclone on driving performance.
Sleep disturbances and cognitive decline are common in older adults. We aimed to investigate the effects of the total sleep time (TST) and sleep-wake rhythm on executive function and working memory ...in older adults. In 63 older participants, we measured the TST, wake after sleep onset (WASO), and sleep timing (midpoint between bedtime and wake-up time) using actigraphy. Executive function was evaluated with the trail making test B (TMT-B) and Wisconsin card sorting test (WCST). The number of back task (N-back task) was used to measure working memory. Participants with a TST ≥ 8 h had a significantly lower percentage of correct answers (% correct) on the 1-back task than those with a TST < 8 h. The % correct on the 1-back task was significantly correlated with the TST, WASO, and sleep timing. Multiple regression analyses revealed that the TST and sleep timing were significant factors of the % correct on the 1-back task. The TMT-B score was significantly correlated with the sleep timing. Category achievement on the WCST was significantly correlated with the standard deviation of the sleep timing. Therefore, a long sleep time and an irregular sleep-wake rhythm could have adverse effects on executive function and working memory in older people.
Environmental stressors during childhood and adolescence influence postnatal brain maturation and human behavioral patterns in adulthood. Accordingly, excess stressors result in adult-onset ...neuropsychiatric disorders. We describe an underlying mechanism in which glucocorticoids link adolescent stressors to epigenetic controls in neurons. In a mouse model of this phenomenon, a mild isolation stress affects the mesocortical projection of dopaminergic neurons in which DNA hypermethylation of the tyrosine hydroxylase gene is elicited, but only when combined with a relevant genetic risk for neuropsychiatric disorders. These molecular changes are associated with several neurochemical and behavioral deficits that occur in this mouse model, all of which are blocked by a glucocorticoid receptor antagonist. The biology and phenotypes of the mouse models resemble those of psychotic depression, a common and debilitating psychiatric disease.
Rationale
Although driving simulators (DS) are receiving increasing attention due to concern over traffic accidents under the influences of drugs, few DS are recognized for their reliability and ...validity. Therefore, the development of an evaluation system using DS for driving performance is urgently needed.
Objectives
To investigate whether the standard deviation of lateral position (SDLP) increases with blood alcohol concentration (BAC) using a DS with reliability and calculate the SDLP threshold from the difference between BAC levels of 0 and 0.05%.
Methods
Twenty healthy Japanese men performed the DS tasks up to 60 min in Study 1 and DS tasks twice at 1-week intervals in Study 2. Twenty-six healthy men conducted the same DS tasks under BAC level (0, 0.025, 0.05, and 0.09%) in double-blind, randomized, crossover trial in Study 3. The primary outcome was SDLP in a road-tracking test. The test–retest reliability of DS data was assessed, and the estimated difference in SDLP between BAC levels of 0 and 0.05% was calculated using a linear regression model.
Results
The cumulative SDLP values at 5-min intervals were stable, and the intraclass correlation coefficient for its values was 0.93. SDLP increased with BAC in a concentration-dependent manner. The predicted ΔSDLP value for the difference between BAC levels of 0 and 0.05% was 9.23 cm. No participants dropped out because of simulator sickness.
Conclusions
The new DS used in these studies has reliability, validity, and tolerability and is considered suitable for evaluating the influence of drugs on driving performance.
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