Effect of blue-blocking glasses in major depressive disorder with sleep onset insomnia: A randomized, double-blind, placebo-controlled study.

Blue wavelengths form the portion of the visible electromagnetic spectrum that most potently regulates circadian rhythm. We hypothesized that wearing blue-blocking (BB) glasses in the evening may influence circadian rhythm disturbances in patients with major depressive disorder (MDD), resulting in improved sleep and mood. We used a randomized placebo-controlled double-blinded design. Patients with MDD with sleep onset insomnia were randomly assigned to wearing either BB glasses or clear glasses (placebo). Patients were instructed to wear the glasses from 20:00 hours until bedtime for 2 weeks. We assessed sleep state (sleep quality on a visual analog scale, the Morningness-Eveningness Questionnaire [MEQ], and a sleep diary) and depressive symptoms at baseline and after 2 weeks. Data were analyzed with a full analysis set. In total, 20 patients were randomly assigned to the BB and placebo groups (BB group, n = 10; placebo group, n = 10). There were three dropouts (BB group, n = 1; placebo group, n = 2). At baseline, sleep quality, sleep latency (assessed via a sleep diary), and antipsychotics use differed between the groups. To take account of these differences, the baseline sleep state or depressive symptoms and antipsychotics use were used as covariates in the later analysis. The change scores for sleep quality did not show a significant improvement in the BB group compared with the placebo group (mean [standard deviation, SD] scores for BB versus placebo: 36.1 [31.7] versus 16.2 [15.1], p = 0.43), although half of the BB group showed a clear improvement in sleep quality. The change in MEQ scores did not significantly differ between the groups (p = 0.14), although there was a trend of a shift to morning type in the BB group (3.10 [4.95] points) and to evening type in the placebo group (0.50 [3.89] points). There were no statistically significant changes in depressive symptoms in either group. Across both groups, 40% of the participants reported pain or discomfort from wearing the glasses, which were available in only one size. Thus, the failure to find significant differences may have resulted from the glasses used in this study. Glasses fitted to individual patients may improve efficacy and safety. Replication of the study with a larger sample size and size-adjustable glasses is needed.

Escitalopram versus paroxetine controlled release in major depressive disorder: a randomized trial.

OBJECTIVE: There are no direct comparisons between escitalopram and paroxetine controlled release in patients with major depressive disorder (MDD). METHODS: We conducted a 24-week, rater-masked, randomized trial of escitalopram (5-20 mg/day) versus paroxetine controlled release (12.5-50 mg/day) in patients with MDD (UMIN000011191). Patients with the diagnosis of moderate-to-severe MDD (a 17-item Hamilton Rating Scale for Depression [HAMD-17], with total score at baseline being ≥20) were recruited to participate in a parallel, randomized, controlled trial. The primary outcome for efficacy was an improvement in the 21-item HAMD (HAMD-21) total score at 24 weeks. The secondary outcomes were the response, remission, and discontinuation rates and the incidence of individual adverse events. RESULTS: A total of 88 patients with MDD (males, 61.4%; mean age, 40.8±13.4 years) were recruited. The discontinuation rate was 58.0% (escitalopram, 55.8%; paroxetine controlled release, 60.0%). Both escitalopram and paroxetine controlled-release treatment groups exhibited significant reduction in the HAMD-21 total score at 2, 4, 8, 12, and 24 weeks from the baseline. However, there were no significant differences in the HAMD-21 total score, response rate, remission rate, and discontinuation rate at any time point between the groups. In addition, there were no significant differences in the incidence of any individual adverse events (eg, nausea, vomiting, and somnolence) between the treatment groups. CONCLUSION: Our results suggest that escitalopram and paroxetine controlled release had similar efficacy and safety profiles in patients with MDD. One of the primary limitations of this study is the small sample size.

An autopsy case of dementia with Lewy bodies clinically diagnosed to have a behavioral variant of frontotemporal dementia.

We herein report the case of a 75-year-old male who had shown many psychiatric symptoms, but whose autopsy disclosed the presence of dementia with Lewy bodies (DLB). When he was 70 years old, the patient had presented with stereotyped behavior, dietary changes, and a decline in social interpersonal conduct in clinical settings, and it was thought that these symptoms were consistent with a behavioral variant of frontotemporal dementia (bvFTD), and he lacked the core features of DLB. Nevertheless, this case was pathologically defined as the limbic type of DLB after he died at the age of 75 years. Looking retrospectively at the clinical course, it was considered that the following features were suggestive or supportive of DLB: neuroleptic sensitivity, autonomic symptoms, and psychiatric symptoms. It can be presumed that the bvFTD-like behavioral disturbances were caused by the severe Lewy pathology of the locus ceruleus (LC) and left anterior temporal region. The clinical symptoms of DLB might be more multifarious than has conventionally been thought, because the symptoms can be modified by the pathological spread of DLB within the brain. It is important to be aware of these possible symptoms of DLB so as not to overlook the diagnosis in the clinical setting.
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A randomized trial of aripiprazole vs blonanserin for the treatment of acute schizophrenia and related disorders.

OBJECTIVE: There has been no direct comparison of aripiprazole and blonanserin for schizophrenia treatment. We conducted a 24-week, rater-masked, randomized trial of aripiprazole (6-30 mg/d) vs blonanserin (4-24 mg/d) in schizophrenia patients who were not taking any antipsychotic medication for more than 2 weeks before enrollment (UMIN000011194). METHODS: The primary outcome measure for efficacy was improvement of Positive and Negative Syndrome Scale (PANSS) total score at week 24. Secondary outcomes were PANSS subscale scores, 21-item Hamilton Rating Scale for Depression (HAMD-21) score, response rate, discontinuation rate, and individual adverse events. RESULTS: Forty-four patients were recruited. The discontinuation rate was 86.4% in the aripiprazole group and 68.2% in the blonanserin treatment group. There was no significant difference in mean time to discontinuation between the groups. Although both treatment groups showed significant reductions in the PANSS total score, PANSS subscale scores, and HAMD-21 scores at week 24, the magnitudes of the changes did not differ between the groups. There were no significant differences in the incidences of adverse events including somnolence, extrapyramidal symptoms, prolactin-related adverse events, and weight change between the groups. CONCLUSION: Our results suggest similar efficacy and safety profiles of aripiprazole and blonanserin in the patients with schizophrenia. Double-blind controlled studies are needed to further explore the efficacy and safety of aripiprazole and blonanserin in schizophrenia.

Efficacy and safety of noradrenalin reuptake inhibitor augmentation therapy for schizophrenia: a meta-analysis of double-blind randomized placebo-controlled trials.

BACKGROUND: We performed an updated meta-analysis of noradrenalin reuptake inhibitor (NRI) augmentation therapy in patients with schizophrenia treated with antipsychotics based on a previous meta-analysis (Singh et al.). METHODS: PubMed, Cochrane Library databases, and PsycINFO citations were searched from their inception to June 10, 2013 without language restrictions. We conducted a systematic review and meta-analysis of individual patient data from randomized controlled trials comparing NRI augmentation therapy with placebo. The outcome measure for efficacy was the psychopathology of schizophrenia and the measures for safety were discontinuation rate and several side effects. We used standardized mean differences (SMD) to estimate treatment effects for continuous variables, and risk ratios (RR) for dichotomous variables, with their 95% confidence intervals (CIs). A random-effects model was used. RESULTS: Nine studies (4 atomoxetine studies, 3 reboxetine studies, 1 reboxetine-betahistine combination study and 1 mazindol study, total n=298) were identified. No statistically significant effects of NRI augmentation therapy on overall (p=0.90), positive (p=0.81), and negative (p=0.89) symptoms were found. NRI augmentation therapy was marginally superior to placebo for efficacy of depressive symptoms (SMD=-1.08, p=0.05). Dropout due to all-cause (p=0.70), inefficacy (p=0.64), or adverse events (p=0.18) was similar in both groups. NRI augmentation therapy showed a significantly lower increase or larger reduction in body weight than placebo (SMD=-0.47, p=0.03). Reboxetine augmentation was associated with less weight gain that placebo in antipsychotic treated schizophrenia patients (SMD=-0.78, p=0.0001). CONCLUSION: NRIs may exert an effect on depressive symptoms, and seem to be well-tolerated treatments.

Comparative clinical profile of mirtazapine and duloxetine in practical clinical settings in Japan: a 4-week open-label, parallel-group study of major depressive disorder.

No studies have compared mirtazapine with duloxetine in patients with major depressive disorder (MDD). Fifty-six patients were nonrandomly assigned to a 4-week treatment with either 15 to 45 mg/day of mirtazapine (n = 22) or 20 to 60 mg/day of duloxetine (n = 34). The primary efficacy measurements were the Hamilton Rating Scale for Depression (HRSD) and the Montgomery-Åsberg Depression 6-point Rating Scale (MADRS) scores. The second efficacy measurements were the response and remission rates of treatment. Tolerability assessments were also performed. Fifty-six patients (43 male; age, 43.6 years) were recruited. There was no significant difference in the discontinuation rate between the mirtazapine and duloxetine treatment groups (P = 0.867). Both mirtazapine and duloxetine significantly improved the HRSD and MADRS scores from baseline (P < 0.0001-0.0004). While mirtazapine was superior to duloxetine in the reduction of HRSD scores (P = 0.0421), there was no significant change in MADRS scores in terms of between-group differences (P = 0.171). While more somnolence was observed with mirtazapine (P = 0.0399), more nausea was associated with duloxetine (P = 0.0089). No serious adverse events were observed for either antidepressant. Mirtazapine and duloxetine were safe and well-tolerated treatments for Japanese patients with MDD. Double-blind controlled studies are needed to further explore the efficacy and safety of mirtazapine and duloxetine in Japanese patients with MDD.

Efficacy and tolerability of clozapine in Japanese patients with treatment-resistant schizophrenia: results from a 12-week, flexible dose study using raters masked to antipsychotic choice.

Japan approved clozapine for treatment-resistant schizophrenia in June 2009. The aim of this study was to evaluate clozapine's efficacy and tolerability in Japanese patients. A twelve-week, single-arm clinical trial of clozapine in treatment-resistant schizophrenia inpatients, was conducted under real-world conditions using raters masked for type of antipsychotic. Thirty-eight patients were recruited, with 33 (86.8%) completing the trial. At week 12, clozapine was associated with significant improvement in the Positive and Negative Syndrome Scale (PANSS) total (p < 0.0001), PANSS positive (p < 0.0001), negative (p = 0.0055) and general subscale scores (p < 0.0001). Significant improvements occurred in all PANSS scores by week 4, the first post-baseline psychopathology rating. Altogether, 50.0% of patients showed ≥20% reduction in PANSS total score, 20.6% had ≥30% reduction and 14.7% had >40% reduction. Eighteen patients (47.4%) were discharged before week 12. However, all patients experienced ≥1 adverse event. Two of 38 patients (5.2%) dropped out due to moderate leucopenia and one of them developed agranulocytosis after stopping clozapine. However, both patients recovered. Eight adverse events (hypersalivation, fatigue, sedation, constipation, insomnia, nausea/vomiting, chest pain and leucopenia) were observed in 34-79% of patients. These findings suggest that clozapine is beneficial in Japanese treatment-resistant schizophrenia patients. However, attention should be paid to patients' adverse events.

Relationship between nicotine dependence and the endophenotype-related trait of cognitive function but not acoustic startle reponses in Japanese patients with schizophrenia.

OBJECTIVES: We investigated whether nicotine dependence affects these endophenotypes in Japanese schizophrenia patients and whether alpha4 and beta2 subunits of neuronal nicotinic acetylcholine receptor genes (alpha4 subunit of the nAChR gene (CHRNA4)/beta2 subunit of the nAChR gene (CHRNB2)) were associated with nicotine dependence in patients (n = 100) and healthy controls (n = 107). METHODS: First, in patients, we evaluated cognitive function, using the Brief Assessment of Cognition in Schizophrenia, and acoustic startle responses. Second, we evaluated the severity of nicotine dependence, using the Tobacco Dependence Screener, the Fagerström Test for Nicotine Dependence, and the Brinkman index in current smokers in both groups. Third, we evaluated the relationship between acoustic startle responses, cognitive function, and severity of nicotine dependence. Finally, using 12 tagging single-nucleotide polymorphisms in each the CHRNA4/CHRNB2, we used multiple linear regression analysis to examine the association between nicotine dependence measures and each selected single-nucleotide polymorphism. RESULTS: The presence and severity of nicotine dependence were associated with verbal memory and executive function in schizophrenia patients. However, nicotine dependence was not correlated with any acoustic startle response. In addition, rs755203 and rs1044397 in CHRNA4 were associated with nicotine dependence in healthy controls. CONCLUSIONS: Nicotine dependence might influence the level of verbal memory and executive function in schizophrenia patients. In addition, rs755203 and rs1044397 in CHRNA4 might play a role in the pathophysiology of nicotine dependence in healthy controls in the Japanese population.

The relationship between acoustic startle response measures and cognitive functions in Japanese patients with schizophrenia.

Recently, schizophrenia endophenotypes have been actively investigated to better understand the pathophysiology of schizophrenia. Past studies have shown that cognitive functions, including working memory and executive function, correlate with acoustic startle responses, such as prepulse inhibition (PPI), in patients with schizophrenia. The aim of this study was to investigate the relationship between cognitive functions and acoustic startle response in Japanese patients with schizophrenia. In 100 patients with schizophrenia, we evaluated cognitive function, using the Brief Assessment of Cognition in Schizophrenia, Japanese-language version (BACS-J), and acoustic startle responses, including acoustic startle reflex, habituation, and PPI (three different intensities: 82, 86, and 90 dB SPL, equivalent to signal-to-noise ratios of +12, +16, and +20 dB, respectively). Using multiple regression analysis, we examined the relationship between acoustic startle responses and BACS-J primary measures or composite score. Level of attention was associated with magnitude of habituation in schizophrenia (P = 0.0009, ß = -0.357). None of the other domains of cognitive function were significantly associated with any measure of acoustic startle response. This included attention regarding ASR (P = 0.513), PPI (P = 0.521-0.842), verbal memory (P = 0.423-0.981), working memory (P = 0.312-0.966), motor speed (P = 0.323-0.955), verbal fluency (P = 0.125-0.920), executive function (P = 0.118-0.470), and the BACS-J composite score (P = 0.230-0.912). In this first investigation of the relationship between cognitive functions and acoustic startle responses in Japanese patients with schizophrenia, attentional deficits correlated highly with the level of habituation. However, a replication study using other population samples is required to further investigate this relationship.

Effect of aripiprazole, risperidone, and olanzapine on the acoustic startle response in Japanese chronic schizophrenia.

BACKGROUND: Studies have also shown that differences in the kind of the antipsychotics influenced disruption of the sensorimotor gating system, including prepulse inhibition (PPI), acoustic startle reflex (ASR), and habituation (HAB). We investigated the influence on startle response in chronic schizophrenia in 20 patients with schizophrenia taking risperidone, 21 patients with schizophrenia taking olanzapine, and 20 patients with schizophrenia taking aripiprazole. METHOD: The patients who participated in this study were on maintenance therapy with only one antipsychotic drug for 4 months. We performed the test for the association between all PPI measures (ASR, HAB, and PPI at prepulse sound pressure intensities of 82, 86, and 90 dB) and each the risperidene, olanzapine, and aripiprazole groups, with analysis of covariance (ANCOVA; using age, duration of illness, and daily dose of the antipsychotic as covariates). Also, when significant difference was detected in ANCOVA, the differences of PPI measures between every pairs of two drug groups were tested as a post hoc analysis with the use of t test and Bonferroni's correction of multiple tests. RESULT: We found that PPI90 showed significant differences with ANCOVA among patients with schizophrenia taking each of the antipsychotics. When we performed a post hoc analysis for PPI90, the value was higher in the aripiprazole group than in the olanzapine group and higher in the risperidone group than in the olanzapine group. CONCLUSION: Aripiprazole and risperidone may improve PPI90. ASR, HAB, PPI82, and PPI86 were no different among the Japanese schizophrenic patient groups with different antipsychotics.

Investigation of clinical factors influencing cognitive function in Japanese schizophrenia.

Several investigators have reported cognitive dysfunction in chronic schizophrenia that was associated with insight and social skills. Such cognitive dysfunction seriously hinders an immediate return to normal life. Recently, Kaneda et al. reported that the Brief Assessment of Cognition in Schizophrenia, Japanese-language version (BACS-J) was superior in the evaluation of the cognitive function. We investigated which clinical factors (age, sex, duration of illness, level of education, smoking status, the Positive and Negative Syndrome Scale (PANSS) score and medication dosage) affected cognitive dysfunction in 115 Japanese schizophrenic patients, with the use of multiple regression analysis. We detected an association between composite score, verbal memory, working memory and executive function and PANSS total score. Moreover, most cognitive tasks were associated with a negative PANSS score but not a positive PANSS score or general score. We also showed an association between age and verbal fluency and attention in schizophrenia. In addition, anxiolytics/hypnotics (diazepam-equivalent) were associated with composite score, working memory and motor speed. In conclusion, cognitive function was associated with PANSS score, especially negative PANSS score. Because anxiolytics/hypnotics might have a detrimental influence on cognitive function, we strongly suggest that the use of anxiolytics/hypnotics be reduced in schizophrenics as much as possible.

Prepulse inhibition of the startle response with chronic schizophrenia: a replication study.

Prepulse inhibition (PPI) deficit, the acoustic startle reflex (ASR) and habituation (HAB) impairment are considered to be endophenotypes for schizophrenia. The recent two studies have reported that a PPI deficit was detected in Japanese schizophrenic patients. We replicated that study using larger samples (115 schizophrenic patients and 111 normal controls) than the original study and a method same as original study. A startle response monitoring system was used to deliver acoustic startle stimuli, and to record and score the electromyographic activity of the orbicularis oculi muscle. We evaluated the startle measures of mean magnitude of ASR, HAB, and PPI at prepulse sound pressure intensities of 82dB (PPI82), 86dB (PPI86), and 90dB (PPI90). ASR was significantly different between schizophrenic patients and controls. HAB and all PPI session data from schizophrenic patients were significantly lower than in controls. In addition, we detected significant differences for ASR, HAB and each PPI (82, 86 and 90dB) between schizophrenic patients and controls with the use of multiple regression analysis. The gender and smoking state were not correlated with ASR, HAB or any PPI in multiple regression analysis. In conclusion, we were able to replicate the finding of HAB impairment and PPI deficit in chronic Japanese schizophrenic patients.