Unclear Insomnia Concept in Randomized Controlled Trials and Systematic Reviews: A Meta-Epidemiological Study.

There are two possible ways to conceptualize the term "insomnia": insomnia disorder and insomnia symptoms, which are often poorly reported. The purpose of this study was to examine the proportion of randomized controlled trials (RCTs) and systematic reviews (SRs) that mention insomnia in their abstracts and cannot distinguish between insomnia disorder and insomnia symptoms from the abstract. We included RCT and SR articles that included the word "insomnia" in the methods or results sections of their structured abstracts, published after 2010. We searched PubMed using English language restrictions on 10 March 2022. From 1580 PubMed articles, we obtained 100 random samples each for eligible RCTs and SRs. The unclear insomnia concept accounted for 88% of the RCT abstracts and 94% of the SR abstracts. Among the RCT and SR abstracts with unclearness, the concept of insomnia was unclear in 27% of RCTs and 57% of SRs after investigating the full text. The concept of insomnia has been unclear in many RCTs and SRs abstracts. The authors of RCTs and SRs are recommended to state "insomnia disorder" or "insomnia symptoms" in the methods and results sections of their abstracts.

Humour-based interventions for people with schizophrenia.

BACKGROUND: Humour-based interventions are defined as any intervention that promotes health and wellness by stimulating a playful discovery, expression, or appreciation of the absurdity or incongruity of life's situations. Humour-based interventions can be implemented in different settings, including hospitals, nursing homes and day care centres. They have been posed as an adjunct to usual care for people with schizophrenia, but a summary of the evidence is lacking. OBJECTIVES: To examine the effects of humour-based interventions as an add-on intervention to standard care for people with schizophrenia. SEARCH METHODS: On 31 July 2019 and 10 February 2021 we searched the Cochrane Schizophrenia Group's study-based register of trials, which is based on CENTRAL, CINAHL, ClinicalTrials.Gov, Embase, ISRCTN, MEDLINE, PsycINFO, PubMed, and WHO ICTRP. SELECTION CRITERIA: We included all randomised controlled trials comparing humour-based interventions with active controls, other psychological interventions, or standard care for people with schizophrenia. We excluded studies fulfilling our prespecified selection criteria but without useable data from further quantitative synthesis. DATA COLLECTION AND ANALYSIS: Two review authors independently inspected citations, selected studies, extracted data and appraised study quality, following the guidance from the Cochrane Handbook for Systematic Reviews of Interventions. For binary outcomes we calculated risk ratios (RRs) and their 95% confidence intervals (CIs). For continuous outcomes we calculated the mean differences (MDs) and their 95% CIs. We assessed risks of bias for included studies and created summary of findings tables using the GRADE approach. MAIN RESULTS: We included three studies in this review for qualitative synthesis, although one study did not report any relevant outcomes. We therefore include two studies (n = 96) in our quantitative synthesis. No data were available on the following prespecified primary outcomes: clinically-important change in general mental state, clinically-important change in negative symptoms, clinically-important change in overall quality of life, and adverse effects. As compared with active control, humour-based interventions may not improve the average endpoint score of a general mental state scale (Positive and Negative Syndrome Scale (PANSS) total score: MD -1.70, 95% CI -17.01 to 13.61; 1 study, 30 participants; very low certainty of evidence); positive symptoms (PANSS positive symptom score: MD 0.00, 95% CI -2.58 to 2.58; 1 study, 30 participants; low certainty of evidence), negative symptoms (PANSS negative symptom score: MD -0.70, 95% CI -4.22 to 2.82; 1 study, 30 participants; very low certainty of evidence) and anxiety (State-Trait Anxiety Inventory (STAI): MD -2.60, 95% CI -5.76 to 0.56; 1 study, 30 participants; low certainty of evidence). Due to the small sample size, we remain uncertain about the effect of humour-based interventions on leaving the study early as compared with active control (no event, 1 study, 30 participants; very low certainty of evidence). On the other hand, humour-based interventions may reduce depressive symptoms (Beck Depression Inventory (BDI): MD -6.20, 95% CI -12.08 to -0.32; 1 study, 30 participants; low certainty of evidence). Compared with standard care, humour-based interventions may not improve  depressive symptoms (BDI second edition: MD 0.80, 95% CI -2.64 to 4.24; 1 study, 59 participants; low certainty of evidence). We are uncertain about the effect of humour-based interventions on leaving the study early for any reason compared with standard care (risk ratio 0.38, 95% CI 0.08 to 1.80; 1 study, 66 participants; very low certainty of evidence). AUTHORS' CONCLUSIONS: We are currently uncertain whether the evidence supports the use of humour-based interventions in people with schizophrenia. Future research with rigorous and transparent methodology investigating clinically important outcomes is warranted.

Effects of hypnotics on prefrontal cortex activity during a verbal fluency task in healthy male subjects: A near-infrared spectroscopy study.

OBJECTIVE: To assess the effects of hypnotics on prefrontal cortex activity in healthy subjects using near-infrared spectroscopy (NIRS) in a double-blind, placebo-controlled crossover trial. METHODS: Eighteen healthy males received acute doses of ramelteon (8 mg), triazolam (0.125 mg), or placebo in a predetermined randomization schedule, with a washout period of more than 1 week. All subjects performed a verbal fluency task during NIRS assessments at baseline and at 1 and 4 hr post-dose. The number of words correctly generated during the task (behavioral performance) and scores on the Stanford Sleepiness Scale (SSS) were also recorded at each test time. RESULTS: Compared with the placebo, triazolam (0.125 mg) significantly decreased oxyhemoglobin (oxy-Hb) concentration change in NIRS during the posttask period and significantly increased behavioral performance, whereas triazolam (0.125 mg) and ramelteon (8 mg) significantly increased SSS scores. CONCLUSIONS: The differential effects of two types of hypnotics on oxy-Hb change measured by NIRS were observed in acute dosing, suggesting that when assessing brain activity of patients with psychiatric disorders, researchers should consider how certain types of hypnotics can influence brain function. This would also provide useful information to clinicians when prescribing hypnotics suitable for their patients' conditions.

Regional decrease in gray matter volume is related to body dissatisfaction in anorexia nervosa.

Anorexia nervosa (AN) is a psychiatric disorder, in which the prognosis for some patients is poor. The etiology and effective treatments for AN have not been established. We examined morphometric changes in the brain of AN and clarified how the changes were associated with symptoms and pathophysiology. We enrolled 52 participants: 7 with the restrictive type of AN, 13 with the binge-eating/purging type, 3 with eating disorder not otherwise specified, and 29 healthy controls. Participants underwent T1-weighted MRI. Group differences between patients and controls in gray matter volume (GMV) were analyzed using voxel-based morphometry. Age and body mass index (BMI) were considered covariates. Correlations between regional GMVs and drive for thinness and body dissatisfaction were examined. Patients had decreased GMV in the superior/middle temporal gyrus (STG/MTG), pulvinar, and superior frontal gyrus after correction for age and BMI, and in the STG/MTG, middle frontal gyrus, and cingulate after correction for age. A correlational group difference was detected for body dissatisfaction and GMV in the STG. Our findings suggest that decreased GMV in the STG is related to body dissatisfaction that could come from impaired visuospatial perception, together with GMV decreases in several regions, which may be involved in development of AN.

Risk factors for elevated liver enzymes during refeeding of severely malnourished patients with eating disorders: a retrospective cohort study.

BACKGROUND: There are few previous reports regarding the cause and evolution of liver injury in patients with anorexia nervosa (AN) during the refeeding process, and its management remains controversial. This study aimed to determine the risk factors for elevated liver enzymes during refeeding and their effect on the therapeutic process in severely malnourished patients with eating disorders. METHODS: In a retrospective cohort study of 167 female inpatients in a single hospital from January 2004 to March 2015, 67 who had normal alanine aminotransferase (ALT) levels on admission were divided into two groups according to the presence or absence of elevated ALT levels during refeeding, and then compared. RESULTS: The median age and body mass index (BMI) of the patients on admission were 22 [interquartile range (IQR), 16-33] years and 12.2 (IQR, 11.1-13.0) kg/m2, respectively. Compared with their cohorts, significantly more patients in the early onset age group (<15 years old) had elevated ALT levels during refeeding (67% vs. 33%, p = 0.033), as did patients with longer median time to nadir BMI (3.0 vs. 0 days, p = 0.03). In addition, onset age [odds ratio (OR): 0.274; 95% confidence interval (CI): 0.077-0.981; p = 0.047] and time to nadir BMI (OR: 1.271; 95% CI: 1.035-1.56; p = 0.022) were significantly associated with the odds of elevated ALT levels during refeeding. CONCLUSIONS: The results of this study suggest that early age at onset may be a potential risk factor for elevated ALT levels during refeeding in severely malnourished patients with eating disorders. Furthermore, elevated ALT levels during refeeding were significantly associated with delay in the start of weight gain. No significant relationship was found between the amount of initial prescribed calories and elevated ALT levels during refeeding. The median time to maximum ALT was 27 (IQR, 21-38) days after the refeeding process started.

Dysfunction of response inhibition in eating disorders.

INTRODUCTION: Response inhibition in eating disorders (ED) has been studied using methods such as Go/No-go tasks and cognitive conflict tasks, but the results have been inconsistent with regard to the presence or absence of impaired response inhibition in ED. This may be due to variation across the studies in the characteristics of the tasks and in the degree of underweight of ED participants. METHOD: We investigated the presence or absence of impaired response inhibition in an ED patient group, including many severe cases (body mass index <15 kg/m(2)), by comparing the interference effect of ED patients and healthy participants with an arrow-space interference task as the cognitive conflict task. RESULTS: There was a significant interference effect on response time in healthy participants and ED patients, with no significant intergroup difference in response times. However, the interference effect on error rate was significantly greater in ED patients than healthy participants. There was no significant difference in this trend across different ED subtypes (restricting type anorexia nervosa, binge-eating/purging type anorexia nervosa, and eating disorder not otherwise specified). CONCLUSIONS: Attentional control such as focused attention and sustained attention are preserved in ED patients, but there appears to be dysfunction of response inhibition. This might be the basis of poor impulse control in the eating behavior of ED patients.

Association of Beck Depression Inventory score and Temperament and Character Inventory-125 in patients with eating disorders and severe malnutrition.

The authors investigated the association between personality and physical/mental status in malnourished patients with eating disorders. A total of 45 patients with anorexia nervosa, avoidant/restrictive food intake disorder, and other specified feeding or eating disorders were included and compared with 39 healthy controls. Personality characteristics and severity of depression were assessed using the Temperament and Character Inventory-125 and Beck's Depression Inventory. Depression correlated with harm avoidance and self-directedness in both cases and controls. Body mass index did not correlate with personality in either group. These findings should be verified by longitudinal studies with higher weight/weight recovered patients.

The effects of acute treatment with ramelteon, triazolam, and placebo on driving performance, cognitive function, and equilibrium function in healthy volunteers.

RATIONALE: Hypnotics are widely used to treat insomnia but adverse effects of different hypnotics, especially benzodiazepine receptor agonists, are getting more attention lately. The effects of novel hypnotics have not been fully examined. OBJECTIVE: This study aims to assess the effects of two hypnotics, ramelteon and triazolam, on driving performance, cognitive function, and equilibrium function. METHODS: In this double-blinded, three-way crossover trial, 17 healthy males received acute doses of 8 mg ramelteon, 0.125 mg triazolam, and placebo. The subjects were administered three driving tasks-road-tracking, car-following, and harsh-braking-using a driving simulator and three cognitive tasks-Continuous Performance Test, N-back Test, and Trail-Making Test-at baseline and at 1 and 4 h post-dosing. The Stanford Sleepiness Scale scores and computerized posturography were also assessed. RESULTS: In the driving simulations, ramelteon and triazolam increased the number of subjects who slid off the road. Triazolam increased the standard deviation of lateral position compared to ramelteon and placebo at 1 h post-dosing. Ramelteon and triazolam significantly increased the time to complete of Trail-Making Test part A and the environmental area in posturography compared to placebo at 1 and 4 h post-dosing. Ramelteon and triazolam significantly increased subjective sleepiness compared to placebo at 1 h post-dosing. CONCLUSIONS: Ramelteon may affect road-tracking performance, visual attention and/or psychomotor speed measured by Trail-Making Test part A, and body balance in acute dosing. Lower dose of triazolam also impaired performance worse than ramelteon. Physicians should consider risks and benefits when prescribing both drugs, especially in the initial period of administration.

Social insecurity in relation to orbitofrontal activity in patients with eating disorders: a near-infrared spectroscopy study.

BACKGROUND: Functional neuroimaging techniques are widely used to elucidate changes in brain activity, and various questionnaires are used to investigate psychopathological features in patients with eating disorders (ED). It is well known that social skills and interpersonal difficulties are strongly associated with the psychopathology of patients with ED. However, few studies have examined the association between brain activity and social relationships in patients with ED, particularly in patients with extremely low body weight. METHODS: In this study, 22-channel near-infrared spectroscopy was used to quantify regional hemodynamic changes during a letter fluency task (LFT) in 20 female patients with ED with a mean body mass index of 14.0 kg/m(2) and 31 female controls (CTLs). Symptoms were assessed using the Eating Disorder Inventory-2 and Beck Depression Inventory. We hypothesized that frontal activity in patients with ED would be lower than in CTLs and would show different correlations with psychopathological features compared with CTLs. RESULTS: The LFT performance and score on the social insecurity subscale of the Eating Disorder Inventory-2 were significantly higher in the ED group than in the CTL group. The mean change in oxygenated hemoglobin (oxy-Hb) in bilateral frontal regions during the LFT was significantly smaller in the ED group than in the CTL group. Social insecurity score was positively correlated with the concentration of oxy-Hb in the bilateral orbitofrontal cortex in the ED group but not in the CTL group. CONCLUSIONS: These results suggest that activity of the orbitofrontal cortex is associated with social insecurity and disturbed in patients with ED. Therefore, disturbed orbitofrontal cortex activity may underlie the lack of insight and social isolation that is characteristic of patients with ED.

Effects of low-dose mirtazapine on driving performance in healthy volunteers.

OBJECTIVE: This study aimed to assess whether a lower initial dose of mirtazapine can lessen the harmful effect on driving performance or not in a double-blinded, placebo-controlled crossover trial. METHODS: Thirteen healthy men received 8 days of continuous nocturnal doses of mirtazapine at 7.5 mg or 15 mg, or placebo. At baseline and on days 2 and 9, subjects performed three driving tasks (road-tracking, car-following, and harsh-braking tasks) using a driving simulator and a Continuous Performance Test. Stanford Sleepiness Scale (SSS) scores were also assessed. In the mirtazapine 7.5 mg series, 15 mg of mirtazapine was additionally administered on day 9, followed by all the same assessments on day 10. RESULTS: Mirtazapine 7.5 mg had no significant effects on any tasks except for SSS compared with placebo. Mirtazapine 15 mg impaired road-tracking task and SSS. The increase in mirtazapine dose also had no significant effects on any tasks compared with those before dose increase. CONCLUSIONS: Mirtazapine 7.5 mg did not cause driving impairment compared with mirtazapine 15 mg, while both doses of mirtazapine produced subjective somnolence. The increase in mirtazapine had no detrimental effects on psychomotor performance. Initial low-dose mirtazapine may be safer for automobile driving than the normal starting dose.

Effects of repeated dosing with mirtazapine, trazodone, or placebo on driving performance and cognitive function in healthy volunteers.

OBJECTIVE: This study aimed to evaluate the effects of repeated treatments with the sedative antidepressants mirtazapine and trazodone on driving performance and cognitive function. METHODS: Nineteen healthy men received continuous nocturnal doses of 15-mg mirtazapine , 25-mg trazodone, or placebo for 8 days in a double-blinded, three-way crossover trial. Subjects were asked to perform three driving tasks (road tracking, car following, and harsh braking) using a driving simulator and cognitive tasks (the Wisconsin Card Sorting Test, Continuous Performance Test, and N-back Test) at baseline and on Days 2 and 9. Stanford Sleepiness Scale scores were also assessed. RESULTS: Mirtazapine significantly increased the standard deviation of lateral position in the road-tracking task as compared with trazodone on Day 2. Mirtazapine significantly increased Stanford Sleepiness Scale scores as compared with trazodone and placebo. For the remaining tasks, no significant effects of treatment were observed. CONCLUSIONS: Acute treatment of mirtazapine impaired road-tracking performance and increased sleepiness, but sedative effects disappeared under repeated administrations. Trazodone did not affect driving performance or cognitive function under acute or repeated administrations. Both initial sedative effects and pharmacological profiles should be taken into consideration when using sedative antidepressants.

Effects of sedative antidepressants on prefrontal cortex activity during verbal fluency task in healthy subjects: a near-infrared spectroscopy study.

RATIONALE: Japanese researchers have recently conducted studies using near-infrared spectroscopy (NIRS) to help diagnose psychiatric disorders based on changes in brain activity. However, the influence of psychotropic drugs on NIRS measurements has not been clarified. OBJECTIVE: To assess the effects of sedative antidepressants on prefrontal cortex activity in healthy subjects using NIRS in a double-blinded, placebo-controlled, crossover trial. METHODS: Nineteen healthy males received nocturnal doses of mirtazapine 15 mg, trazodone 25 mg, or placebo for eight consecutive days in rotation, with a washout period of more than 1 week between each rotation. Subjects performed a verbal fluency task during NIRS on a total of seven occasions during the study period: more than a week prior to receiving the first dose of the first medication; and on days 2 and 9 of each rotation. The number of words correctly generated during the task (behavioral performance) was also recorded. Stanford Sleepiness Scale (SSS) scores were determined each day. RESULTS: Mirtazapine 15 mg significantly increased oxyhemoglobin (oxy-Hb) concentration change in NIRS on day 9, compared to trazodone 25 mg and placebo. Mirtazapine 15 mg significantly increased SSS on day 2, compared to the other conditions. No significant differences in behavioral performance were observed. CONCLUSIONS: Administration of mirtazapine for eight consecutive days affected oxy-Hb changes on NIRS. This result indicates that researchers should consider how certain types of antidepressant could influence brain function when the brain activity of patients with psychiatric disorders is assessed.

Wisconsin Card Sorting Test scores and clinical and sociodemographic correlates in Schizophrenia: multiple logistic regression analysis.

OBJECTIVES: This study investigated what clinical and sociodemographic factors affected Wisconsin Card Sorting Test (WCST) factor scores of patients with schizophrenia to evaluate parameters or items of the WCST. DESIGN: Cross-sectional study. SETTING: Patients with schizophrenia from three hospitals participated. PARTICIPANTS: Participants were recruited from July 2009 to August 2011. 131 Japanese patients with schizophrenia (84 men and 47 women, 43.5±13.8 years (mean±SD)) entered and completed the study. Participants were recruited in the study if they (1) met DSM-IV criteria for schizophrenia; (2) were physically healthy and (3) had no mood disorders, substance abuse, neurodevelopmental disorders, epilepsy or mental retardation. We examined their basic clinical and sociodemographic factors (sex, age, education years, age of onset, duration of illness, chlorpromazine equivalent doses and the positive and negative syndrome scale (PANSS) scores). PRIMARY AND SECONDARY OUTCOME MEASURES: All patients carried out the WCST Keio version. Five indicators were calculated, including categories achieved (CA), perseverative errors in Milner (PEM) and Nelson (PEN), total errors (TE) and difficulties of maintaining set (DMS). From the principal component analysis, we identified two factors (1 and 2). We assessed the relationship between these factor scores and clinical and sociodemographic factors, using multiple logistic regression analysis. RESULTS: Factor 1 was mainly composed of CA, PEM, PEN and TE. Factor 2 was mainly composed of DMS. The factor 1 score was affected by age, education years and the PANSS negative scale score. The factor 2 score was affected by duration of illness. CONCLUSIONS: Age, education years, PANSS negative scale score and duration of illness affected WCST factor scores in patients with schizophrenia. Using WCST factor scores may reduce the possibility of type I errors due to multiple comparisons.

Evaluation of factors affecting continuous performance test identical pairs version score of schizophrenic patients in a Japanese clinical sample.

Aim. Cognitive impairment in schizophrenia strongly relates to social outcome and is a good candidate for endophenotypes. When we accurately measure drug efficacy or effects of genes or variants relevant to schizophrenia on cognitive impairment, clinical factors that can affect scores on cognitive tests, such as age and severity of symptoms, should be considered. To elucidate the effect of clinical factors, we conducted multiple regression analysis using scores of the Continuous Performance Test Identical Pairs Version (CPT-IP), which is often used to measure attention/vigilance in schizophrenia. Methods. We conducted the CPT-IP (4-4 digit) and examined clinical information (sex, age, education years, onset age, duration of illness, chlorpromazine-equivalent dose, and Positive and Negative Symptom Scale (PANSS) scores) in 126 schizophrenia patients in Japanese population. Multiple regression analysis was used to evaluate the effect of clinical factors. Results. Age, chlorpromazine-equivalent dose, and PANSS-negative symptom score were associated with mean d' score in patients. These three clinical factors explained about 28% of the variance in mean d' score. Conclusions. As conclusion, CPT-IP score in schizophrenia patients is influenced by age, chlorpromazine-equivalent dose and PANSS negative symptom score.

Common variants in MAGI2 gene are associated with increased risk for cognitive impairment in schizophrenic patients.

Schizophrenia is a complex psychiatric disorder characterized by positive symptoms, negative symptoms, and cognitive impairment. MAGI2, a relatively large gene (∼1.5 Mbps) that maps to chromosome 7q21, is involved in recruitment of neurotransmitter receptors such as AMPA- and NMDA-type glutamate receptors. A genetic association study designed to evaluate the association between MAGI2 and cognitive performance or schizophrenia has not been conducted. In this case-control study, we examined the relationship of single nucleotide polymorphism (SNP) variations in MAGI2 and risk for schizophrenia in a large Japanese sample and explored the potential relationships between variations in MAGI2 and aspects of human cognitive function related to glutamate activity. Based on the result of first schizophrenia genome-wide association study in a Japanese population (JGWAS), we selected four independent SNPs and performed an association study using a large independent Japanese sample set (cases 1624, controls 1621). Wisconsin Card Sorting Test (WCST) was used to evaluate executive function in 114 cases and 91 controls. We found suggestive evidence for genetic association of common SNPs within MAGI2 locus and schizophrenia in Japanese population. Furthermore in terms of association between MAGI2 and cognitive performance, we observed that genotype effect of rs2190665 on WCST score was significant (p = 0.034) and rs4729938 trended toward significance (p = 0.08). In conclusion, although we could not detect strong genetic evidence for association of common variants in MAGI2 and increased schizophrenia risk in a Japanese population, these SNPs may increase risk of cognitive impairment in schizophrenic patients.

A case control association study and cognitive function analysis of neuropilin and tolloid-like 1 gene and schizophrenia in the Japanese population.

BACKGROUND: Using a knock-out mouse model, it was shown that NETO1 is a critical component of the NMDAR complex, and that loss of Neto1 leads to impaired hippocampal long term potentiation and hippocampal-dependent learning and memory. Moreover, hemizygosity of NETO1 was shown to be associated with autistic-like behavior in humans. PURPOSE OF THE RESEARCH: We examined the association between schizophrenia and the neuropilin and tolloid-like 1 gene (NETO1). First, we selected eight single nucleotide polymorphisms (SNPs) within the NETO1 locus, based on the Japanese schizophrenia genome wide association study (JGWAS) results and previously conducted association studies. These SNPs were genotyped in the replication sample comprised of 963 schizophrenic patients and 919 healthy controls. We also examined the effect of associated SNPs on scores in the Continuous Performance Test and the Wisconsin Card Sorting Test Keio version (schizophrenic patients 107, healthy controls 104). RESULTS: There were no significant allele-wise and haplotype-wise associations in the replication analysis after Bonferroni correction. However, in meta-analysis (JGWAS and replication dataset) three association signals were observed (rs17795324: p = 0.028, rs8098760: p = 0.017, rs17086492: p = 0.003). These SNPs were followed up but we could not detect the allele-specific effect on cognitive performance measured by the Continuous performance test (CPT) and Wisconsin Card Sorting test (WCST). MAJOR CONCLUSIONS: We did not detect evidence for the association of NETO1 with schizophrenia in the Japanese population. Common variants within the NETO1 locus may not increase the genetic risk for schizophrenia in the Japanese population. Additionally, common variants investigated in the current study did not affect cognitive performance, as measured by the CPT and WCST.