岸 太郎

This meta-analysis of randomized controlled trials (RCTs) investigated the advantages of long-acting injectable antipsychotics (LAI-APs) over oral antipsychotics (OAPs) with regard to efficacy and safety for patients with recent-onset psychotic disorders. Effect sizes and 95% confidence intervals (95%CIs) were calculated. We identified five RCTs (1022 patients, mean study duration=18 +/- 7.59 months) that compared LAI-APs (paliperidone or risperidone) with OAPs. Pooled LAI-APs did not outperform OAPs in terms of the preventing of relapse (N=3, n=875). However, there was significant heterogeneity (I-2=76%), with one study showing no superiority of LAI-APs over OAPs [Malla 2013: risk ratio (RR)=1.83, 95%CI=0.70-4.77, n=77] and the other two studies showing LAI-APs to be superior [Schreiner 2015: [RR=0.71, 95%CI=0.51-0.97, number needed to treat (NNT)=-17, n=715, Subotnik 2015: RR=0.15, 95%CI=0.04-0.63, NNT=-4, n=83]. Pooling the studies, there were no significant differences between LAI-APs and OAPs in the improvement of Positive and Negative Syndrome Scale scores or in discontinuation due to all-cause, adverse events (AEs), and death, but LAI-APs outperformed OAPs in terms of discontinuation due to inefficacy (RR=0.34, NNT=-50) and nonadherence (RR=0.30, NNT=-33). However, the LAI-APs were associated with a higher incidence of at least one AE (RR=1.13) and tremor (RR=2.38) compared with OAPs.

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.

Long-acting injectable (LAI) antipsychotics (LAI-APs) have several advantages over oral medications, but deaths reported in Japan during the early post-marketing phase vigilance period have raised safety concerns. We conducted a series of meta-analyses to assess whether LAI-APs affect the mortality of patients with schizophrenia. Three categorical meta-analyses of randomized controlled trials (RCTs) were performed to compare all-cause death (primary outcome) and death due to suicide: individual and pooled LAI-APs vs placebo, individual and pooled LAI-APs vs oral antipsychotics (OAPs), and head-to-head comparisons of LAI-APs. The risk ratios (RRs) and 95% CIs were calculated. We identified 52 RCTs (53 comparisons; total participants = 17 416, LAI-APs = 11 360, OAP = 3910, and placebo = 2146; mean study duration [wk]: LAI-APs vs placebo = 28.9, LAI-APs vs OAPs = 64.5). Neither pooled nor individual LAI-APs (aripiprazole, fluphenazine, olanzapine, paliperidone, and risperidone) differed from the placebo regarding the incidences of all-cause death (pooled LAI-APs: RR = 0.64, P = .37) and death due to suicide (pooled LAI-APs: RR = 0.98, P = .98). However, in a subgroup meta-analysis of only short-duration RCTs (a parts per thousand currency sign13wk), pooled LAI-APs exhibited a trend toward lower incidence of all-cause death than placebo (RR = 0.29, P = .08). Pooled LAI-APs (aripiprazole, fluphenazine, haloperidol, olanzapine, paliperidone, risperidone, and zuclopenthixol) did not differ from pooled OAPs regarding all-cause death (pooled LAI-APs: RR = 0.71, P = .30) and death due to suicide (pooled LAI-APs: RR = 0.94, P = .91). Individual LAI-APs and OAPs were associated with similar risks of death. Data for head-to-head comparisons of individual LAI-APs were insufficient. In conclusion, there was no significant difference between LAI-APs and placebo or OAPs regarding all-cause death and death due to suicide.

This meta-analysis of randomized controlled trials aimed to examine the advantages of long-acting injectable antipsychotics over placebo or oral medications regarding efficacy and safety for patients with bipolar disorder. Two categorical meta-analyses of randomized controlled trials were performed to compare study-defined relapse rate (primary), discontinuation rates, and individual adverse events: (1) risperidone-long-acting injectable vs placebo, and (2) long-acting injectable antipsychotics vs oral medications. We identified 7 randomized controlled trials (n=1016; long-acting injectable antipsychotics [flupenthixol (1 randomized controlled trial) and risperidone (6 randomized controlled trials)=449]; oral medications [mood stabilizers, antidepressants, antipsychotic, or any combination of these agents=283]; and placebo=284). Risperidone-long-acting injectable antipsychotic was superior to placebo for study-defined relapse rate (risk ratio=0.63, P <.0001), relapse of manic symptoms (risk ratio=0.42, P <.00001), and all-cause discontinuation (risk ratio=0.75, P=.007). Risperidone-long-acting injectable was associated with higher incidence of prolactin-related adverse events (risk ratio=4.82, P=.001) and weight gain (risk ratio=3.80, P <.0001) than placebo. The pooled long-acting injectable antipsychotics did not outperform oral medications regarding primary outcome but with significant heterogeneity (I-2=74%). Sensitivity analysis, including only studies with rapid cycling or high frequency of relapse patients, revealed that long-acting injectable antipsychotics were superior compared to oral medications (I-2=0%, RR=0.58, P=.0004). However, the comparators in this sensitivity analysis did not include second-generation antipsychotic monotherapy. In sensitivity analysis, including only studies with second-generation antipsychotic monotherapy as the comparator, long-acting injectable antipsychotics did not outperform second-generation antipsychotic monotherapy. Risperidone-long-acting injectable was also associated with higher incidence of prolactin-related adverse events than oral medications (RR=2.66, P=.03). Long-acting injectable antipsychotics appear beneficial for relapse prevention in patients with rapid cycling. Furthermore, randomized controlled trials comparing long-acting injectable antipsychotics and oral second-generation antipsychotic using larger samples of rapid cycling patients are warranted.

The aim of this study was to perform a systematic review and an updated and comprehensive meta-analysis of oxytocin augmentation therapy in patients with schizophrenia who received antipsychotic agents. Data published up to 07/11/2015 were obtained from PubMed, PsycINFO, and Cochrane Library databases. We conducted a systematic review and meta-analysis of patients' data from randomized controlled trials (RCTs) comparing oxytocin with placebo. Relative risk (RR), standardized mean difference (SMD), and 95 % confidence intervals (95 % CI) based on the random-effects model were calculated. We included seven RCTs; the total sample size was 206 patients. Oxytocin was superior to placebo for decreasing the Positive and Negative Syndrome Scale (PANSS) general subscale scores (SMD = -0.44, 95 % CI -0.82 to -0.06, p = 0.02, I (2) = 0 %, N = 4, n = 112); however, it was not different from placebo for total symptoms (SMD = -0.46, 95 % CI -1.20 to 0.28, p = 0.22, I (2) = 80 %, N = 6, n = 162), positive symptoms (SMD = -0.18, 95 % CI -0.87 to 0.51, p = 0.60, I (2) = 81 %, N = 6, n = 192), and negative symptoms (SMD = -0.34, 95 % CI -0.76 to 0.08, p = 0.12, I (2) = 55 %, N = 7, n = 214). However, a sensitivity analysis including only oxytocin administration on consecutive days studies was superior to placebo in negative symptoms (SMD = -0.44, 95 % CI -0.87 to -0.01, p = 0.04, I (2) = 51 %, N = 6 n = 192). There were no significant differences for all-cause discontinuation (RR = 1.02) and individual side effects such as headache and dizziness between oxytocin and placebo. Oxytocin may improve PANSS general subscale scores in schizophrenia and seems to be well tolerated. However, because the number of studies in the current analysis was small, further study will be required using larger sample sizes.

Objectives We performed an updated meta-analysis of antipsychotic treatment in patients with delirium, based on a previous meta-analysis published in 2007. Methods Included in this study were randomised, placebo-controlled or usual care (UC) controlled trials of antipsychotics in adult patients with delirium. Our primary outcome measure was response rate at the study end point. The secondary outcome measures included improvement of severity of delirium, Clinical Global Impression-Severity Scale (CGI-S), time to response (TTR), discontinuation rate and individual adverse effects. The risk ratio (RR), the number-needed-to-treat/harm (NNT/NNH), 95% CIs and standardised mean difference (SMD), were calculated. Results We identified 15 studies (mean duration: 9.8 days) for the systematic review (total n=949, amisulpride=20, aripiprazole= 8, chlorpromazine=13, haloperidol=316, intramuscular olanzapine or haloperidol injection=62, olanzapine=144, placebo= 75, quetiapine= 125, risperidone= 124, UC= 30 and ziprasidone= 32), 4 of which were conference abstracts and unpublished. When pooled as a group, antipsychotics were superior to placebo/UC in terms of response rate (RR= 0.22, NNT= 2), delirium severity scales scores (SMD=-1.27), CGI-S scores (SMD=-1.57) and TTR (SMD=-1.22). The pooled antipsychotic group was associated with a higher incidence of dry mouth (RR= 13.0, NNH= 5) and sedation (RR= 4.59, NNH= 5) compared with placebo/UC. Pooled second-generation antipsychotics (SGAs) were associated with shorter TTR (SMD=-0.27) and a lower incidence of extrapyramidal symptoms (RR= 0.31, NNH= 7) compared with haloperidol. Conclusions Our results suggested that SGAs have a benefit for the treatment of delirium with regard to efficacy and safety compared with haloperidol. However, further study using larger samples is required.

Background Earlier studies implicated norepinephrine transporter (NET) gene (SLC6A2) polymorphisms in the etiology of major depressive disorder (MDD). Recently, two single nucleotide SLC6A2 polymorphisms, G1287A in exon 9 and T-182C in the promoter region, were found to be associated with MDD in different populations. We investigated the relationship between the brain volume and these two polymorphisms of the SLC6A2 in MDD patients. Methods We obtained 3D high-resolution T1-weighted images of 30 first-episode MDD patients and 48 age- and sex-matched healthy subjects (HS). All were divided into 4 groups based on polymorphism of either the G1287A or the T-182C genotype. VBM analysis examined the effects of diagnosis, genotype, and genotype-diagnosis interactions. Results Diagnosis effects on the brain morphology were found in the left superior temporal cortex. No significant genotype effects were found in the T-182C and the G1287A. A significant genotype (G1287A)-diagnosis interaction was found in the left dorsolateral prefrontal cortex. No significant genotype (T-182C)-diagnosis interaction effects were observed in any brain region. Conclusions In MDD patients there seems to be a relationship between the volume of the dorsolateral prefrontal cortex and polymorphism of the SLC6A2 G1287A gene.

Background: We performed a meta-analysis of cholinesterase inhibitors for patients with Lewy body disorders, such as Parkinson's disease, Parkinson's disease dementia, and dementia with Lewy bodies. Methods: The meta-analysis included only randomized controlled trials of cholinesterase inhibitors for Lewy body disorders. Results: Seventeen studies (n = 1798) were assessed. Cholinesterase inhibitors significantly improved cognitive function (standardized mean difference [SMD] = -0.53], behavioral disturbances (SMD = -0.28), activities of daily living (SMD = -0.28), and global function (SMD = -0.52) compared with control treatments. Changes in motor function were not significantly different from control treatments. Furthermore, the cholinesterase inhibitor group had a higher all-cause discontinuation (risk ratio [RR] = 1.48, number needed to harm [NNH] = 14), discontinuation due to adverse events (RR = 1.59, NNH = 20), at least one adverse event (RR = 1.13, NNH = 11), nausea (RR = 2.50, NNH = 13), and tremor (RR = 2.30, NNH = 20). Conclusions: Cholinesterase inhibitors appear beneficial for the treatment of Lewy body disorders without detrimental effects on motor function. However, a careful monitoring of treatment compliance and side effects is required.

This study aimed to perform a comprehensive meta-analysis of topiramate-augmentation therapy in patients with schizophrenia receiving antipsychotic agents. Data published up to June 20, 2016 were obtained from the PubMed, PsycINFO, and Cochrane Library databases. Twelve randomized controlled trials comparing topiramate to placebo or antipsychotic only were included (n=676 patients). The primary outcome was change in overall symptoms. Relative risk (RR) and standardized mean difference (SMD), along with 95% confidence intervals, were calculated using random effects model for each outcome. Topiramate-augmentation therapy was superior to the control for decreasing overall symptoms (SMD -0.55, 95% confidence interval -0.86 to -0.24; P= 0.001; I-2 = 55%, eight comparisons, n= 380), positive symptoms (SMD -0.4), negative symptoms (SMD -0.47), and Positive and Negative Syndrome Scale general subscale scores (SMD -0.67). Furthermore, topiramate-augmentation therapy decreased weight (SMD -0.69) and body mass index (SMD -0.95) compared with the control. Topiramate was similar to the control with respect to discontinuation due to all causes (RR 1.19), inefficacy (RR 1.71), and adverse events (RR 1.09). Topiramate was associated with higher incidence of paresthesia (RR 2.67) and attention difficulty (RR 8.97) compared with the control. Our results seemed to suggest that topiramate-augmentation therapy improves the psychopathology of schizophrenia with good tolerability and has the additional advantage of weight maintenance. However, because there were some limitations (numbers of studies and patients included in the meta-analysis were small, some studies used completer analysis, Chinese studies were included in the meta-analysis, and studies that had a risk of bias were included in the meta-analysis) in this study, we cannot apply the results of this study in daily clinical practice.

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.

Background: There is uncertainty about the efficacy and tolerability of serotonin 2A (5-HT2A) receptor negative modulators for Parkinson's disease psychosis (PDP). Objective: This is the first meta-analysis of randomized placebo-controlled trials (RCTs) testing negative modulators of the 5-HT2A receptor as a treatment for PDP. Methods: The primary outcome was the Scale for Assessment of Positive Symptoms (SAPS)-hallucinations (H) and-delusions (D) scores (SAPS-H+D). Other outcome measures were SAPS-H, SAPS-D, the Unified Parkinson's Disease Rating Scale Part II and III (UPDRS-II+III), discontinuation rates, and individual adverse events. Results: Four RCTs were identified that met inclusion criteria, all assessing the 5-HT2A inverse agonist pimavanserin (including 417 drug-treated and 263 placebo-treated PDP patients). Pimavanserin significantly decreased SAPS-H+D scores compared to placebo [weighted mean differences (WMD) =-2.26, 95% confidence interval (95% CI) =-3.86 to -0.67, p = 0.005, I-2 = 30%, N=4 studies, n = 502 patients]. Moreover, pimavanserin was superior to placebo for reducing SAPS-H (WMD=-2.15, 95% CI =-3.45 to -0.86, p = 0.001, I-2 = 0%, N=2, n = 237) and SAPS-D scores (WMD=-1.32, 95% CI =-2.32 to -0.32, p = 0.010, I-2 = 0%, N=2, n = 237). Pimavanserin was associated with less orthostatic hypotension than placebo (risk ratio = 0.33, 95% CI = 0.15-0.75, p = 0.008, I-2 = 0%, number needed to harm = 17, p = 0.01, N=3, n = 476). There were no significant differences in rates of all-cause discontinuation, adverse events, and death, UPDRS-II+ III scores, and incidences of individual adverse events (other than orthostatic hypotension) between pimavanserin and placebo groups. Conclusions: Pooled RCT results suggest that pimavanserin is beneficial for the treatment of PDP and is well tolerated. We did not identify other negative modulators of the 5-HT2A receptor for the treatment of PDP.

Background: Previous clinical studies found that yokukansan has a therapeutic effect on behavioral and psychological symptoms of dementia (BPSD) in dementia patients. Objective: To perform an updated meta-analysis of randomized controlled trials (RCTs) testing yokukansan for patients with BPSD. Methods: Primary efficacy and safety endpoints were BPSD total scores and all-cause discontinuation, respectively. Secondary outcomes were BPSD subscales, cognitive function scores [Mini-mental state examination (MMSE)], activities of daily living (ADL) scores, discontinuation due to adverse events (AEs), and incidences of AEs. Results: Five RCTs with 381 patients with BPSD were included. Compared with controls [placebo+ usual care (UC)], yokukansan significantly decreased BPSD total scores [standardized mean difference (SMD) = -0.32, 95% confidence interval (CI) = - 0.53 to -0.11, p = 0.003, I-2 = 0%, N= 5 studies, n = 361]. Yokukansan was more efficacious in reducing BPSD subscale scores (delusions: SMD=-0.51, 95% CI = -0.98 to -0.04, hallucinations: SMD= -0.54, 95% CI = -0.96 to -0.12, agitation/aggression: SMD=- 0.37, 95% CI = -0.60 to -0.15) than placebo+UC. However, yokukansan was not superior to placebo+UC for BPSD total as well as any subscales scores only in Alzheimer's disease patients. Compared with UC, yokukansan treatment improved ADL scores (SMD = -0.32, 95% CI = -0.62 to -0.01). MMSE scores did not differ between the yokukansan and placebo+UC treatment groups. No significant differences were found in all-cause discontinuation, discontinuation due to AEs, and incidences of AEs between yokukansan and placebo+UC treatments. Conclusions: Our results suggest that yokukansan is beneficial for the treatment of patients with BPSD and is well-tolerated; it was not beneficial for BPSD total and any subscale scores only in Alzheimer's disease patients.

Background: There has not been conclusive evidence for prevention of brain atrophy by anti-dementia drugs in mild cognitive impairment and Alzheimer's Disease. Methods: Relevant studies were identified through searches of PubMed, databases of the Cochrane Library, and PsycINFO citations up to 16 May, 2015. Only double-blind, randomized, placebo-controlled clinical trials of anti-dementia drugs in patients with mild cognitive impairment or Alzheimer's Disease were included. Primary outcomes were annualized percent change of total brain volume (% TBV/y), annualized percent change of hippocampal volume (% HV/y), and annualized percent change of ventricular volume (% VV/y) measured by magnetic resonance imaging. Standardized mean difference (SMD) and 95% confidence intervals (CI) were calculated for relevant outcomes. Results: Seven randomized, placebo-controlled clinical trials (n = 1708) were found to meet the inclusion criteria, including 4 mild cognitive impairment studies (n = 1327) and 3 Alzheimer's Disease studies (n = 381) [ 3 donepezil studies (2 mild cognitive impairment studies and 1 Alzheimer's Disease study), 1 galantaime study for mild cognitive impairment, 2 mementine studies for Alzheimer's Disease, and 1 rivastigmine study for mild cognitive impairment]. Pooled anti-dementia drugs showed superior protective outcomes compared with placebo regarding % TBV/y (SMD = -0.21, 95% CI = -0.37 to -0.04, P =.01, N = 4, n = 624) and % VV/y (SMD = -0.79, 95% CI = -1.40 to -0.19, P =.01, N = 3, n = 851). However, % HV/y failed to show difference between both groups. Among anti-dementia drugs, donepezil showed significantly greater protective effects than placebo regarding % TBV/y (SMD = -0.43, 95% CI = -0.74 to -0.12, P =.007, N = 1, n = 164) and % VV/y (SMD = -0.51, 95% CI = -0.73 to -0.29, P <.00001, N = 2, n = 338). Rivastigmine was also superior to placebo regarding % VV/y (SMD = -1.33, 95% CI = -1.52 to -1.14, P <.00001). Conclusions: The results favored the hypothesis that anti-dementia drugs may prevent brain atrophy in patients with mild cognitive impairment and Alzheimer's Disease.

Objective: We conducted a systematic review and meta-analysis of the efficacy of aripiprazole once monthly (AOM) for schizophrenia. Methods: Randomized controlled trials (RCTs) on AOM, published until June 25, 2015, were retrieved from PubMed, Cochrane, and PsycINFO databases. Relative risk (RR), standardized mean difference (SMD), 95% confidence intervals (95% CIs), and numbers needed to treat/harm (NNT/NNH) were calculated. Results: We identified four relevant RCTs (total n=1,860), two placebo-controlled trials, one noninferiority trial comparing AOM to oral aripiprazole (OA), and one including therapeutic doses of AOM and OA, as well as an AOM dose below therapeutic threshold (control arm). AOM was superior to placebo for decreasing Positive and Negative Syndrome Scale (PANSS) total scores (SMD =-0.65, 95% CI =-0.90 to -0.41, n=1,126). However, PANSS total scores did not differ significantly between pooled AOM and OA groups. The pooled AOM group showed significantly lower incidence of all-cause discontinuation (RR =0.54, 95% CI =0.41–0.71, n=1,139, NNH =4) and inefficacy (RR =0.28, 95% CI =0.21–0.38, n=1,139, NNH =5) than placebo, but was not superior to placebo regarding discontinuation due to adverse events (AEs) or death. The AOM group exhibited a lower incidence of all-cause discontinuation than OA (RR =0.78, 95% CI =0.64–0.95, n=986, NNH =14), but there were no intergroup differences in discontinuation due to inefficacy, AEs, or death. There were no significant differences in extrapyramidal symptoms scale scores between AOM and placebo or between AOM and OA. AOM resulted in higher weight gain than placebo (SMD =0.41, 95% CI =0.18–0.64, n=734) but lower than OA (SMD =-0.16, 95% CI =-0.29 to -0.02, n=847). Conclusion: AOM has antipsychotic efficacy and low risk of discontinuation due to AEs.

We performed an updated systematic review and meta-analysis of randomized controlled trials (RCTs) of intramuscular (IM)-olanzapine (OLA-IM) versus controls in agitated patients. The risk ratio, number-needed-to-treat/harm, and standardized mean difference based on a random effects model were calculated. We identified 13 RCTs (19 comparisons) as follows: 7 comparisons with 1059 patients for OLA-IM versus placebo; 5 comparisons with 613 patients for OLA-IM versus haloperidol (HAL)-IM; 2 comparisons with 108 patients for OLA-IM versus ziprasidone (ZIP)-IM; 2 comparisons with 110 patients for OLA-IM versus HAL-IM plus midazolam; and 3 comparisons with 412 patients for OLA-IM versus HAL-IM plus promethazine, 2 comparisons with 355 patients for OLA-IM versus lorazepam-IM (LOR-IM); and 1 comparison with 67 patients for OLA-IM versus HAL-IM plus LOR-IM. OLA-IM was superior to placebo in both Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) and Agitation Calmness Evaluation Scale (ACES) scores 2 h after first injection, and had a comparable side effect profile, including over sedation, extrapyramidal symptoms, akathisia, and anticholinergic use. While there was no significant difference in PANSS-EC scores after 2 h between OLA-IM and HAL-IM, OLA-IM outperformed HAL-IM in ACES after 2 h. Compared with HAL-IM, OLA-IM was associated with fewer side effects, including anticholinergic use, akathisia, extrapyramidal symptoms, and dystonia, and marginally less QT prolongation compared with HAL-IM. Based on our findings, OLA-IM is preferable to HAL-IM for the treatment of agitated patients. However, comparator data for ZIP-IM, LOR-IM and HAL-IM combination therapy were insufficient. (C) 2015 Elsevier Ltd. All rights reserved.

The brain-derived neurotrophic factor (BDNF) relates to basic neuronal functions, such as cell survival, axonal outgrowth, and dendritic growth. The Va166Met polymorphism of the BDNF gene may affect genetic susceptibility to major depressive disorder (MDD). We prospectively investigated the relationship between the Va166Met BDNF genotype and voxel-based morphometry (VB1V1) findings for first episode and drug-naive 1VIDD patients and healthy subjects (HS). Participants comprised 381VIDD patients and 42 age- and sex-matched HS were divided into groups based on their BDNF genotype. The effects of diagnosis and genotype, as well as the genotype-diagnosis interaction, in relation to brain morphology were evaluated using a voxel-by-voxel statistical analysis of high-resolution magnetic resonance imaging (MRI) findings. Among the Met-carriers, the volume of the left middle frontal gyms (composition of the prefrontal cortex [PFCI) was significantly smaller for MDD patients than for the HS, i.e., there was a significant genotype-diagnosis interaction effect on brain morphology noted in the left PFC. The BDNF polymorphism was associated with atrophy of the PFC in MDD patients, which suggests that the BDNF Va166Met polymorphism may play an important role in the pathogenesis of early stages of MDD. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

Objective We performed a systematic review and meta-analysis of double-blind, randomized, placebo-controlled trials evaluating suvorexant for primary insomnia. Methods Relevant studies were identified through searches of PubMed, databases of the Cochrane Library, and PsycINFO citations through June 27, 2015. We performed a systematic review and meta-analysis of suvorexant trial efficacy and safety outcomes. The primary efficacy outcomes were either subjective total sleep time (sTST) or subjective time-to-sleep onset (sTSO) at 1 month. The secondary outcomes were other efficacy outcomes, discontinuation rate, and individual adverse events. The risk ratio, number-needed-to-treat/harm, and weighted mean difference (WMD) and 95% confidence intervals (CI) based on a random effects model were calculated. Results The computerized literature database search initially yielded 48 results, from which 37 articles were excluded following a review of titles and abstracts and another eight review articles after full-text review. Thus, we identified 4 trials that included a total of 3,076 patients. Suvorexant was superior to placebo with regard to the two primary efficacy outcomes (sTST: WMD = -20.16, 95% CI = -25.01 to -15.30, 1889 patients, 3 trials, sTSO: WMD = -7.62, 95% CI = -11.03 to -4.21, 1889 patients, 3 trials) and was not different from placebo in trial discontinuations. Suvorexant caused a higher incidence than placebo of at least one side effects, abnormal dreams, somnolence, excessive daytime sleepiness/sedation, fatigue, dry mouth, and rebound insomnia. Conclusions Our analysis of published trial results suggests that suvorexant is effective in treating primary insomnia and is well-tolerated.

Objective: This study examined the utility of adenine for preventing clozapine induced neutropenia. Methods: This retrospective study examined the effect of adenine on clozapine induced neutropenia in patients with treatment resistant schizophrenia and was conducted at Okehazama Hospital in Japan from July 2010 to June 2013. Adenine was available for use from June 2011 onwards. Twenty one patients started receiving clozapine treatment from July 2010 to April 2011 (the pre adenine adoption group), and 47 patients started receiving it from May 2011 to June 2013 (the post adenine adoption group). The effects of adenine were assessed based on changes in the patients' leukocyte counts and the frequency of treatment discontinuation due to clozapine induced neutropenia. Results: Sixty eight patients were treated with clozapine from July 2010 to June 2013. Of the 21 patients in the pre adenine adoption group, 4 discontinued treatment due to clozapine induced neutropenia, whereas only 2 of the 47 patients in the post adenine adoption group discontinued treatment. The frequency of treatment discontinuation due to clozapine induced neutropenia was significantly lower in post adenine adoption group than in the pre adenine adoption group (p=0.047). Conclusion: Adenine decreased the frequency of treatment discontinuation due to clozapine induced neutropenia. Our data suggest that combined treatment with clozapine and adenine is a safe and effective strategy against treatment resistant schizophrenia.

We conducted a cross-sectional survey to assess the prevalence of physical pain in Japanese major depressive disorder (MDD) and schizophrenia (SZ) patients as well as in healthy controls (HCs). We also examined the association between their psychopathology and characteristics of pain according to a face-to-face survey by an experienced psychiatrist and psychologist. We analyzed 233 HCs, 94 MDD patients, and 75 SZ patients using the McGill Pain Questionnaire (MPQ) and SF-8 (all participants), the Hamilton Depression Rating Scale 21 items (MDD patients), and the Positive and Negative Symptom Scale (SZ patients). Although MDD patients experienced more pain than HCs, there was no difference in the prevalence of pain between SZ patients and HCs. Moreover, HCs with pain did not have higher SF-8 total scores than those without pain, whereas both MDD and SZ patients with pain had higher SF-8 total scores than those without pain. The severity of psychopathology in MDD and SZ patients was also positively associated with both the prevalence of pain and MPQ scores. MPQ scores were also associated with positive symptoms in SZ patients. Considering these results, physicians need to query MDD patients about physical pain during examination if they are to ensure a favorable and quick response to treatment. The severity of positive symptoms (i.e., clinical status) in SZ patients might also be associated with pain sensitivity, and warrants further investigation. (C) 2015 Elsevier Inc. All rights reserved.

Objective: To clarify whether memantine is more efficacious in several outcomes and safer than placebo in patients with Lewy body disorders, we performed a meta-analysis of memantine in patients with Lewy body disorders. Methods: The meta-analysis included randomized controlled trials of memantine for Lewy body disorders in all patients with Lewy body disorders. Motor function, activities of daily living, Neuropsychiatric Inventory, Mini-Mental State Exam, discontinuation rate, and individual side effects were evaluated. Results: No significant effects of memantine on motor function scores, Mini-Mental State Exam scores, Neuropsychiatric Inventory scores, and activity of daily living scores were found. However, memantine was superior to placebo in Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change scores (standardized mean difference: -0.26; 95% confidence interval: -0.51 to -0.02; z = 2.08; p = 0.04; two studies; N = 258). Dropout due to all causes, inefficacy, or adverse events were similar in both groups. Moreover, no significant differences in serious adverse events, somnolence/tiredness, stroke, dizziness/vertigo, and confusion were found between the groups. Conclusion: Our results suggest that memantine did not have a benefit for the treatment of Lewy body disorders in cognition and motor function. However, memantine may be superior to placebo for the overall impression of the disorders. Further, memantine is well tolerated.

Objective: To determine whether the extent of surgery is associated with survival in anorectal malignant melanoma (ARMM). Background: ARMM is a rare and highly malignant neoplasm with unfavorable prognosis. The optimal surgical management, abdominoperineal resection (APR) or local excision (LE), has been long debated, but conclusive evidence has not been obtained. Methods: A comprehensive electronic literature search was performed to identify studies evaluating survival between APR and LE for ARMM. The main outcome measures were overall survival, relapse-free survival, and local recurrence. A meta-analysis was performed using the random-effects models to calculate the odds ratios (ORs) and 95% confidence intervals (CIs). Results: Thirty-one studies, with a total of 1006 patients [544 (54.1%) APR and 462 (45.9%) LE], were included. Meta-analyses showed that overall survival (OR, 1.14; 95% CI, 0.74-1.76; P = 0.54) and relapse-free survival (OR, 0.95; 95% CI, 0.43-2.09; P = 0.89) did not differ significantly between the APR and LE groups. APR significantly reduced local recurrence compared with LE (OR, 0.18; 95% CI, 0.09-0.36; P < 0.00001). Conclusions: Although several limitations, such as inclusion of only retrospective studies with relatively small sample size and selection biases for surgical procedure, are involved, this meta-analysis suggested that APR has no survival benefit; however, APR confers better local control than LE. Given that local failures after LE could be managed by salvage surgery, minimizing morbidity and maximizing quality of life should be the focus in surgical treatment of ARMM.

We performed an updated meta-analysis of randomized double-blind placebo-controlled trials (RCTs) on the effects of varenicline adjuvant therapy for smoking cessation in people with schizophrenia, on the basis of a previous meta-analysis (Tsoi in Cochrane Database Syst Rev 2:CD007253, 2013). We searched PubMed, the Cochrane Library databases, and PsycINFO up to August 1, 2014. RCTs comparing varenicline adjuvant therapy with placebo in schizophrenia were included. The risk ratio (RR), number needed to harm (NNH), and standardized mean differences with its 95 % confidence interval (CI) were used. Seven studies (total n = 439), including 6 with only schizophrenia (total n = 352), 1 with both schizophrenia (n = 77) and bipolar disorder (n = 10), were included. Varenicline was not superior to placebo in smoking cessation (RR = 0.79, 95 % CI 0.58-1.08, p = 0.14, 5 RCTs, n = 322). Varenicline failed to show its superiority to placebo for overall, positive, negative, and depressive symptoms. Moreover, there was no significant difference in the discontinuation rate due to all causes, clinical deterioration, or side effects between varenicline and placebo. Although varenicline caused less abnormal dreams/nightmares than placebo (RR = 0.47, 95 % CI 0.22-0.99, p = 0.05, NNH = not significant, 4 RCTs, n = 288), it caused more nausea (RR = 1.79, 95 % CI 1.20-2.67, p = 0.004, NNH = 6, p = 0.004, 6 RCTs, n = 417). We detected no significant difference in suicidal ideation and depression between varenicline and placebo. Our results suggest that although varenicline adjuvant therapy is well tolerated, varenicline is not superior to placebo for smoking cessation in people with schizophrenia. Because of the limited sample sizes of the available studies, future studies will require larger samples to ensure that these findings are generalizable.

Background We performed an updated meta-analysis of randomized placebo-controlled trials testing memantine monotherapy for patients with Alzheimer's disease (AD). Methods The meta-analysis included randomized controlled trials of memantine monotherapy for AD, omitting those in which patients were also administered a cholinesterase inhibitor. Cognitive function, activities of daily living, behavioral disturbances, global function, stage of dementia, drug discontinuation rate, and individual side effects were compared between memantine monotherapy and placebo groups. The primary outcomes were cognitive function and behavioral disturbances; the others were secondary outcomes. Results Nine studies including 2433 patients that met the study's inclusion criteria were identified. Memantine monotherapy significantly improved cognitive function [standardized mean difference (SMD)=-0.27, 95% confidence interval (CI)=-0.39 to -0.14, p=0.0001], behavioral disturbances (SMD=-0.12, 95% CI=-0.22 to -0.01, p=0.03), activities of daily living (SMD=-0.09, 95% CI=-0.19 to -0.00, p=0.05), global function assessment (SMD=-0.18, 95% CI=-0.27 to -0.09, p=0.0001), and stage of dementia (SMD=-0.23, 95% CI=-0.33 to -0.12, p=0.0001) scores. Memantine was superior to placebo in terms of discontinuation because of inefficacy [risk ratio (RR)=0.36, 95% CI=0.17 to 0.74, p=0.006, number needed to harm (NNH)=non significant]. Moreover, memantine was associated with less agitation compared with placebo (RR=0.68, 95% CI=0.49 to 0.94, p=0.02, NNH=non significant). There were no significant differences in the rate of discontinuation because of all causes, all adverse events, and individual side effects other than agitation between the memantine monotherapy and placebo groups. Conclusions Memantine monotherapy improved cognition, behavior, activities of daily living, global function, and stage of dementia and was well-tolerated by AD patients. However, the effect size in terms of efficacy outcomes was small and thus there is limited evidence of clinical benefit.

Clozapine has been demonstrated to be useful for treating refractory schizophrenia. However, hypersalivation occurs in 31.0-97.4% of the patients treated with clozapine. Accordingly, some patients who are disturbed by their hypersalivation refuse to continue with clozapine treatment. This study investigated the efficacy of the anticholinergic agent scopolamine butylbromide against clozapine-induced hypersalivation. Five schizophrenia patients were coadministered scopolamine butylbromide (30-60 mg/day) for 4 weeks. At the baseline and after 4 weeks' treatment, we subjectively evaluated hypersalivation using a visual analog scale and objectively assessed it using the Drooling Severity Scale and Drooling Frequency Scale. As a result, improvements in the patients' Drooling Severity Scale and Drooling Frequency Scale scores, but no improvements in their visual analog scale scores, were observed after scopolamine butylbromide treatment. These results indicate that at least some schizophrenic patients with clozapine-induced hypersalivation would benefit from scopolamine butylbromide treatment. We conclude that clozapine-induced hypersalivation is one factor of stress to patients. Subjective hypersalivation was not improved, but objective hypersalivation was, by scopolamine butylbromide treatment. However, scopolamine butylbromide and clozapine possess anticholinergic effects so clinicians should closely monitor patients who take scopolamine butylbromide.

Background: We performed an updated meta-analysis of randomized controlled trials of combination therapy with cholinesterase inhibitors and memantine in patients with Alzheimer's disease. Methods: We reviewed cognitive function, activities of daily living, behavioral disturbance, global assessment, discontinuation rate, and individual side effects. Results: Seven studies (total n = 2182) were identified. Combination therapy significantly affected behavioral disturbance scores (standardized mean difference = -0.13), activity of daily living scores (standardized mean difference = -0.10), and global assessment scores (standardized mean difference = -0.15). In addition, cognitive function scores (standardized mean difference = -0.13, P=.06) exhibited favorable trends with combination therapy. The effects of combination therapy were more significant in the moderate-to-severe Alzheimer's disease subgroup in terms of all efficacy outcome scores. The discontinuation rate was similar in both groups, and there were no significant differences in individual side effects. Conclusions: Combination therapy was beneficial for the treatment of moderate-to-severe Alzheimer's disease in terms of cognition, behavioral disturbances, activities of daily living, and global assessment was well tolerated.

Background: We conducted a systematic review and meta-analysis of randomized controlled trials comparing aripiprazole with pooled antipsychotics in Japanese patients with schizophrenia. Methods: We performed a literature search of data published in PubMed®, the Cochrane Library database, the Japan Medical Abstracts Society, and PsycINFO® up to January 5, 2014. The odds ratio (OR), number-needed-to-harm (NNH), and standardized mean difference (SMD) based on a random effects model were calculated. Results: We identifed fve relevant studies (seven comparisons, n=684 one comparison each for haloperidol [n=243], mosapramine [n=238], olanzapine [n=39], quetiapine [n=42], perospirone [n=100], and two comparisons for risperidone [n=66]). There were no signifcant differences in the Positive and Negative Syndrome Scale (PANSS) total, negative, and general scores (SMD=0.10, SMD=-0.09, SMD=0.10, respectively) discontinuation rate associated with all causes (OR=1.35) or side effects (OR=1.03) between aripiprazole and the pooled antipsychotics. Aripiprazole was inferior to the pooled antipsychotics in PANSS positive subscale scores (SMD=0.17) and discontinuation because of ineffcacy (OR=2.21, NNH=11). However, aripiprazole had fewer side effects compared with the pooled antipsychotics (OR=0.21, NNH=20 for one or more side effects), including fatigue (OR=0.22, NNH=8), hyperpro-lactinemia (OR=0.00, NNH=1), extrapyramidal symptoms (OR=0.46, NNH=6), and weight gain (OR=0.36, NNH=7). Moreover, aripiprazole was associated with lower total cholesterol (SMD=-0.20) and triglyceride (SMD=-0.17) levels and body weight (SMD=-0.20) compared with the pooled antipsychotics. Conclusion: Although the discontinuation rate associated with ineffcacy was higher with aripiprazole than with the pooled antipsychotics, aripiprazole was associated with a lower risk of hyperprolactinemia and metabolic and extrapyramidal symptoms compared with the pooled antipsychotics.

The short-term safety and efficacy of insertion of a self-expandable metallic colonic stent followed by elective surgery, bridge to surgery (BTS), for malignant large-bowel obstruction (MLBO) have been well described. However, long-term oncological outcomes are still debated. Hence, this study is conducted to evaluate long-term outcomes of colonic stent insertion followed by surgery for MLBO. A comprehensive electronic literature search through May 2014 was performed to identify studies comparing long-term outcomes between BTS and emergency surgery for MLBO. The main outcome measures were overall survival (OS), disease-free survival (DFS), and recurrence. A meta-analysis was performed using random-effects models to calculate risk ratios (RRs) with 95 % confidence intervals (95 % CIs). There were 11 studies that matched the criteria for inclusion, yielding a total of 1136 patients, of whom 432 (38.0 %) underwent BTS and 704 (62.0 %) underwent emergency surgery. In OS analyses of all patients and patients who underwent curative resection, BTS was similar to emergency surgery [(RR = 0.95; 95 % CI 0.75-1.21; P = 0.66) (RR = 0.96; 95 % CI 0.67-1.37; P = 0.82), respectively]. DFS (RR = 1.06; 95 % CI 0.91-1.24; P = 0.43) and recurrence (RR = 1.13; 95 % CI 0.82-1.54; P = 0.46) did not differ significantly between the BTS and emergency surgery groups. Results of this meta-analysis on long-term as well as well-described short-term outcomes suggest that BTS could be a promising alternative strategy for MLBO patients.

Introduction: No comprehensive meta-analysis has been performed concerning the efficacy and tolerability of adjunctive therapy with histamine-2 receptor antagonists (H2R-ANTs) in schizophrenia patients who were treated with antipsychotics. Methods: Risk ratios, standardized mean differences (SMD), and 95% confidence intervals were calculated. Results: We included 8 double-blinded, randomized placebo-controlled trials (RCTs) (n=418) that met the inclusion criteria (famotidine: N=3, n=74; nizatidine: N=4, n=292; ranitidine: N=1, n=52). Pooled H2R-ANTs were not different from placebo with regard to reduction in overall symptoms and body weight. However, pooled H2R-ANTs resulted in lower body mass index (BMI) than placebo (SMD=-0.68). Moreover, nizatidine was associated with an increase in plasma leptin levels (SMD=-1.14). There were no significant differences in the discontinuation rates due to all-cause, side effects, and inefficacy between pooled H2R-ANTs and placebo. However, nizatidine produced more depression and dry mouth than placebo. Discussion: H2R-ANT adjunctive therapy did not improve overall symptoms. To clarify the opposite results between body weight and BMI, future research should investigate long-term efficacy and generate more safety data by using larger samples.

Background: There is no conclusive evidence supporting the efficacy of memantine in frontotemporal dementia (FTD). We conducted a comprehensive meta-analysis of memantine concerning the efficacy and tolerability of memantine in FTD. Methods: Studies were identified through searches of PubMed, databases of the Cochrane Library, and PsycINFO citations up to April 10, 2015. Outcomes were Clinical Global Impression (primary), Mini-Mental State Examination, Neuropsychiatric Inventory, and Zarit Burden Interview scores as well as all-cause discontinuation. Standardized mean difference and risk ratio with 95% confidence interval were calculated. Results: Two randomized controlled trials (RCTs) (total n=130) met the inclusion criteria. Memantine was marginally superior to placebo as assessed by the Clinical Global Impression scores (standardized mean difference =-0.34, 95% confidence interval =-0.68-0.01, P=0.06). However, there were no significant differences in Mini-Mental State Examination, Neuropsychiatric Inventory, and Zarit Burden Interview scores as well as all-cause discontinuation between memantine and placebo. Conclusion: Our results suggest that memantine may benefit FTD patients. However, because only two randomized controlled trials have addressed this issue, further studies using larger samples are needed.

Background: We conducted a systematic review and meta-analysis of randomized controlled trials comparing aripiprazole with pooled antipsychotics in Japanese patients with schizophrenia. Methods: We performed a literature search of data published in PubMed (R), the Cochrane Library database, the Japan Medical Abstracts Society, and PsycINFO (R) up to January 5, 2014. The odds ratio (OR), number-needed-to-harm (NNH), and standardized mean difference (SMD) based on a random effects model were calculated. Results: We identified five relevant studies (seven comparisons, n=684; one comparison each for haloperidol [n=243], mosapramine [n=238], olanzapine [n=39], quetiapine [n=42], perospirone [n=100], and two comparisons for risperidone [n=66]). There were no significant differences in the Positive and Negative Syndrome Scale (PANSS) total, negative, and general scores (SMD=0.10, SMD=-0.09, SMD=0.10, respectively); discontinuation rate associated with all causes (OR=1.35); or side effects (OR=1.03) between aripiprazole and the pooled antipsychotics. Aripiprazole was inferior to the pooled antipsychotics in PANSS positive subscale scores (SMD=0.17) and discontinuation because of inefficacy (OR=2.21, NNH=11). However, aripiprazole had fewer side effects compared with the pooled antipsychotics (OR=0.21, NNH=20 for one or more side effects), including fatigue (OR=0.22, NNH=8), hyperprolactinemia (OR=0.00, NNH=1), extrapyramidal symptoms (OR=0.46, NNH=6), and weight gain (OR=0.36, NNH=7). Moreover, aripiprazole was associated with lower total cholesterol (SMD=-0.20) and triglyceride (SMD=-0.17) levels and body weight (SMD=-0.20) compared with the pooled antipsychotics. Conclusion: Although the discontinuation rate associated with inefficacy was higher with aripiprazole than with the pooled antipsychotics, aripiprazole was associated with a lower risk of hyperprolactinemia and metabolic and extrapyramidal symptoms compared with the pooled antipsychotics.

Background: This is the first meta-analysis of randomized placebo-controlled trials testing lithium as a treatment for patients with Alzheimer's disease (AD) and individuals with mild cognitive impairment (MCI). Methods: The primary outcome measure was efficacy on cognitive performance as measured through the Alzheimer's Disease Assessment Scale cognitive subscale or the Mini-Mental State Examination. Other outcome measures were drug discontinuation rate, individual side effects, and biological markers (phosphorylated tau 181, total tau, and amyloid-beta(42)) in cerebrospinal fluid (CSF). Results: Three clinical trials including 232 participants that met the study's inclusion criteria were identified. Lithium significantly decreased cognitive decline as compared to placebo (standardized mean difference = -0.41, 95% confidence interval = -0.81 to -0.02, p = 0.04, I-2 = 47%, 3 studies, n = 199). There were no significant differences in the rate of attrition, discontinuation due to all causes or adverse events, or CSF biomarkers between treatment groups. Conclusions: The results indicate that lithium treatment may have beneficial effects on cognitive performance in subjects with MCI and AD dementia.

Background: No comprehensive meta-analysis has been performed concerning the efficacy and tolerability of histamine H3 receptor antagonists (H3R-ANTs) in Alzheimer's disease patients. Objective: We performed a systematic review and meta-analysis of double-blind randomized placebo-controlled trials (RCTs) of H3R-ANTs for Alzheimer's disease. Methods: Relevant studies were identified through searches of PubMed (R), databases of the Cochrane Library (c), and PsycINFO citations up to June 19, 2015. The primary outcome was a change in the Mini-Mental State Examination (MMSE) scores. Secondary outcomes were Neuropsychiatric Inventory (NPI) scores, discontinuation rate, and individual adverse events/side effects. Risk ratios, numbers-needed-to-treat/harm, and standardized mean differences were calculated based on a random effects model. Results: The computerized search initially yielded 33 studies after excluding duplicates. We excluded 29 of these articles following a review of titles and abstracts and one RCT including healthy subjects after full-text review. We identified three RCTs (two on GSK239512 and one on ABT-288) including 402 patients. Pooled H3R-ANTs were not superior to placebo for improvement in MMSE and NPI scores. Discontinuation rate and individual adverse events/side effects did not differ among the pooled groups. Conclusions: Our results suggest that H3R-ANTs are not effective in treating cognitive dysfunction in Alzheimer's disease. However, further studies with larger samples are required for definitive conclusions regarding responsive subpopulations.

Results: Thirty-seven patients were recruited (56.8% of them had first-episode schizophrenia), and 28 (75.7%) completed the trial. At week 8, blonanserin was associated with a significant improvement in the Positive and Negative Syndrome Scale (PANSS) total score (P&lt 0.0001) and in positive (P&lt 0.0001), negative (P&lt 0.0001), and general subscale scores (P&lt 0.0001). In terms of percentage improvement of PANSS total scores from baseline to week 8, 64.9% of patients showed a ≥20% reduction in the PANSS total score and 48.6% showed a ≥30% reduction. However, 8.1% of patients experienced at least one adverse event. Using the 20% reduction in the PANSS total score at week 4 as a definition of an early response, the negative predictive values for later responses (ie, reductions of ≥30 and ≥40 in the PANSS total scores) were 88.9% and 94.1%, respectively. The specificities were 80.0% and 51.6%, respectively. Conclusion: Our results suggest that the blonanserin response at week 4 could predict the later response at week 8. Background: Blonanserin is a second-generation antipsychotic used for the treatment of schizophrenia in Japan and Korea. The present study aimed to examine early prediction of blonanserin in patients with schizophrenia. Methods: An 8-week, prospective, single-arm, flexible-dose clinical trial of blonanserin in patients with schizophrenia was conducted under real-world conditions. The inclusion criteria were antipsychotic naïve, and first-episode schizophrenia patients or schizophrenia patients with no consumption of any antipsychotic medication for more than 4 weeks before enrollment in this study. The positive predictive value, negative predictive value, sensitivity, specificity, and predictive power were calculated for the response status at week 4 to predict the subsequent response at week 8.

ObjectiveThis study aimed to perform a comprehensive meta-analysis of minocycline augmentation therapy in patients with schizophrenia receiving antipsychotic agents. MethodsData published up to 2 June 2014 were obtained from the PubMed, PsycINFO, Google Scholar, and Cochrane Library databases. We conducted a systematic review and meta-analysis of patient data from randomized controlled trials (RCTs) comparing minocycline with placebo. Relative risk (RR), standardized mean difference (SMD), and 95% confidence intervals were calculated. ResultsWe included four RCTs. The total sample included 330 patients. Minocycline was superior to placebo for decreasing Positive and Negative Syndrome Scale (PANSS) total scores (SMD=-0.70), PANSS negative subscale scores (SMD=-0.86), and PANSS general subscale scores (SMD=-0.50) but was not different from placebo for PANSS positive subscale scores (SMD=-0.26) and depressive symptoms (SMD=-0.28). Minocycline was equivalent to placebo for all-cause discontinuation (RR=1.10), discontinuation due to inefficacy (RR=0.42), discontinuation due to adverse events (RR=1.56), and discontinuation due to death (RR=3.18). Minocycline was superior to placebo for extrapyramidal side-effect scores (SMD=-0.32). ConclusionsMinocycline may improve the psychopathology of schizophrenia, especially the negative symptoms, and seems to be well tolerated. Copyright (c) 2014 John Wiley & Sons, Ltd.

Electroencephalogram-recorded epileptiform activity is common in children with autism spectrum disorder (ASD), even without clinical seizures. A systematic literature search identified 7 randomized, placebo-controlled trials of antiepileptic drugs (AEDs) in ASD (total n = 171), including three of valproate, and one each of lamotrigine, levetiracetam, and topiramate. Meta-analysis revealed no significant difference between medication and placebo in four studies targeting irritability/agitation and three studies investigating global improvement, although limitations include lack of power and different medications with diverse actions. Across all seven studies, there was no significant difference in discontinuation rate between two groups. AEDs do not appear to have a large effect size to treat behavioral symptoms in ASD, but further research is needed, particularly in the subgroup of patients with epileptiform abnormalities.

Double-blinded, randomized, placebo-control trials of selective serotonin 3 receptor antagonists (5-HT3R-ANTs) for schizophrenia have differed in outcome. This meta-analysis tests the hypothesis that 5-HT3R-ANTs are effective for the treatment for schizophrenia. We searched PubMed, the Cochrane Library database, and PsycINFO up to June 15, 2013. We conducted a systematic review and meta-analysis of individual patient data from randomized controlled trials comparing 5-HT3R-ANTs add-on therapy with placebo. The risk ratio (RR), 95 % confidence intervals (CI), and standardized mean difference (SMD) were calculated. A random-effects model was used. Six studies (total n = 311) were identified. These included one granisetron plus risperidone study, one ondansetron plus risperidone study, one ondansetron plus haloperidol, and three tropisetron plus risperidone studies. The statistically significant effects of 5-HT3R-ANTs add-on therapy on Positive and Negative Syndrome Scale (PANSS) total scores were SMD = -1.03, CI = -1.70 to -0.36, p = 0.003 (I (2) = 82 %, 5 studies, n = 261); on negative scores were SMD = -1.10, CI = -1.82 to -0.39, p = 0.002 (I (2) = 84 %, 5 studies, n = 261); and on PANSS general scores were SMD = -0.70, CI = -1.23 to -0.17, p = 0.01 (I (2) = 73 %, 5 studies, n = 261). However, 5-HT3R-ANTs add-on therapy was not superior to placebo in PANSS positive scores (SMD = -0.12, p = 0.33). Dropout due to all cause (RR = 0.80, p = 0.50), inefficacy (RR = 0.76, p = 0.65), or adverse events (RR = 0.84, p = 0.75) was similar in both groups. Constipation occurred significantly more often with 5-HT3R-ANTs than placebo (RR = 2.05, CI = 1.07-3.91, p = 0.03, NNH = 11, p = 0.02). 5-HT3R-ANTs add-on therapy is more beneficial on the psychopathology (especially negative symptoms) than controls in patients with schizophrenia, and 5-HT3R-ANTs seem to be well-tolerated treatments.

We examined whether noradrenergic and specific serotonergic antidepressants (NaSSAs: mirtazapine and mianserin), as augmentation therapy, have therapeutic potential for schizophrenia treatment. A systematic review was conducted of PubMed, Cochrane Library and PsycINFO in December 2012 and meta-analyses of double-blind, randomized placebo-controlled trials were performed. Standardized mean difference (SMD), risk ratio (RR), number-needed-to-treat (NNT), number-needed-to-harm (NNH) and 95% confidence intervals (CI) were calculated. Results were across 12 studies and 362 patients were included (mirtazapine: seven trials and 221 patients; mianserin: five trials and 141 patients). NaSSA augmentation therapy was superior to placebo in overall symptoms (s.m.d.=-0.75, CI -1.24 to -0.26, p=0.003, N=11, n=301), negative symptoms (s.m.d.=-0.88, CI -1.41 to -0.34, p=0.001, N=9, n=240) and response rate (RR=0.71, CI 0.57-0.88, p=0.002, NNT=4, p<0.00001, N=6, n=163). There was no significant difference in positive symptoms, depressive symptoms or discontinuation rate between NaSSAs and placebo treatments. In addition, no patients who received NaSSAs developed worsening psychosis during the study. For individual NaSSAs, mirtazapine was superior to placebo in overall symptoms (s.m.d.=0.98, CI=-1.74 to -0.22, p=0.01, N=7, n=194), negative symptoms (s.m.d.=-1.25, CI -1.88 to -0.62, p=0.0001, N=6, n=172) and response rate (RR=0.70, p=0.04, NNT=4, p=0.0004, N=4, n=119). Moreover, NaSSAs were associated with reduced akathisia score (p<0.00001) and extrapyramidal symptom scales (p=0.01). However, NaSSAs caused drowsiness/sedation/somnolence compared with placebo (RR=3.52, p=0.002, NNT=6, p=0.01, N=8, n=209). Our results indicate that NaSSA (especially mirtazapine) augmentation therapy improved overall and negative symptoms in patients with schizophrenia. Because the included studies were small, the results should be treated with caution.

Background: The present study aimed to evaluate cardiometabolic risks [weight gain, blood lipid levels (total cholesterol and triglycerides), blood glucose levels, hemoglobin A(1c) (HbA(1c)) levels, and corrected QT interval (QTc) prolongation] associated with the use of blonanserin and perospirone versus other antipsychotics in the management of patients with schizophrenia. Method: We conducted a systematic review and meta-analysis of patient data from randomized controlled trials comparing blonanserin or perospirone with other antipsychotics. Results: In total, 4 blonanserin studies (n = 1080) were identified [vs. risperidone (2 studies, n = 508); vs. haloperidol (2 studies, n = 572)]. Blonanserin produced less weight gain compared with risperidone (weighted mean difference = -0.86, 95% confidence intervals = -1.36 to -0.36, p = 0.0008; 2 studies, 480 patients). However, no significant differences were observed in blood lipid, glucose, and HbA(1c) levels or QTc prolongation between blonanserin and risperidone or haloperidol. For perospirone studies, 5 studies [562 adult patients with schizophrenia randomized to perospirone (n = 256), olanzapine (n = 20), quetiapine (n = 28), risperidone (n = 53), aripiprazole (n = 49), haloperidol (n = 75), or mosapramine (n = 81)] were identified. Perospirone did not differ from other antipsychotics with regard to weight gain and total cholesterol levels. Conclusions: Our results suggest that blonanserin is associated with a lower of weight gain compared with other antipsychotics. Because the number of studies was small, additional controlled clinical trials with larger number of patients are indicated.

Background: We conducted a meta-analysis of the iminodibenzyl antipsychotics carpipramine, clocapramine, and mosapramine, which are classified as second-generation antipsychotics (SGAs) for schizophrenia treatment. Methods: We searched data that had been published in PubMed, the Cochrane Library databases, PsycINFO, CiNii, and the Japan Medical Abstracts Society up to August 29, 2014. Randomized controlled trials that compared iminodibenzyl antipsychotics with other antipsychotics in patients with schizophrenia were included. Odds ratios and standardized mean differences were evaluated. Results: We included four randomized controlled trials on carpipramine (number of patients [n]=290), six on clocapramine (n=1,048), and five on mosapramine (n=986) in the meta-analysis. There were no significant differences in the response rates or in the discontinuation rates either between carpipramine and the other pooled antipsychotics or between clocapramine and the other pooled antipsychotics. On the Positive and Negative Syndrome Scale, mosapramine's positive subscale scores were superior to those of the other pooled antipsychotics (standard mean of difference =-0.22); however, on that same scale, there were no significant differences in total scores, negative scores, general subscale scores, response rates, or the discontinuation rates between mosapramine and the other pooled antipsychotics. Furthermore, the incidences of extrapyramidal symptoms and of hyperprolactinemia were significantly greater with mosapramine than with the other pooled antipsychotics. Conclusion: The pharmacological profiles of carpipramine and clocapramine, which are classified as SGAs, were similar to those of first-generation antipsychotics because there were no significant differences in efficacy and safety outcomes. However, mosapramine was associated with a greater risk of extrapyramidal symptoms and hyperprolactinemia than the other SGAs were, although it may be beneficial for the improvement of positive symptoms.

We investigated the association between the Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene, the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene, and white matter changes in patients with major depressive disorder (MDD) and healthy subjects using diffusion tensor imaging (DTI). We studied 30 patients with MDD (17 males and 13 females, with mean age +/- standard deviation [SD] =44 +/- 12 years) and 30 sex-and age-matched healthy controls (17 males and 13 females, aged 44 +/- 13 years). Using DTI analysis with a tract-based spatial statistics (TBSS) approach, we investigated the differences in fractional anisotropy, radial diffusivity, and axial diffusivity distribution among the three groups (patients with the COMT gene Val158Met, those with the BDNF gene Val66Met, and the healthy subjects). In a voxel-wise-based group comparison, we found significant decreases in fractional anisotropy and axial diffusivity within the temporal lobe white matter in the Met-carriers with MDD compared with the controls (P<0.05). No correlations in fractional anisotropy, axial diffusivity, or radial diffusivity were observed between the MDD patients and the controls, either among those with the BDNF Val/Val genotype or among the BDNF Met-carriers. These results suggest an association between the COMT gene Val158Met and the white matter abnormalities found in the temporal lobe of patients with MDD.

Background: Blonanserin is a second-generation antipsychotic used for the treatment of schizophrenia in Japan and Korea. The present study aimed to examine early prediction of blonanserin in patients with schizophrenia. Methods: An 8-week, prospective, single-arm, flexible-dose clinical trial of blonanserin in patients with schizophrenia was conducted under real-world conditions. The inclusion criteria were antipsychotic naive, and first-episode schizophrenia patients or schizophrenia patients with no consumption of any antipsychotic medication for more than 4 weeks before enrollment in this study. The positive predictive value, negative predictive value, sensitivity, specificity, and predictive power were calculated for the response status at week 4 to predict the subsequent response at week 8. Results: Thirty-seven patients were recruited (56.8% of them had first-episode schizophrenia), and 28 (75.7%) completed the trial. At week 8, blonanserin was associated with a significant improvement in the Positive and Negative Syndrome Scale (PANSS) total score (P<0.0001) and in positive (P<0.0001), negative (P<0.0001), and general subscale scores (P<0.0001). In terms of percentage improvement of PANSS total scores from baseline to week 8, 64.9% of patients showed a >= 20% reduction in the PANSS total score and 48.6% showed a >= 30% reduction. However, 8.1% of patients experienced at least one adverse event. Using the 20% reduction in the PANSS total score at week 4 as a definition of an early response, the negative predictive values for later responses (ie, reductions of >30 and >40 in the PANSS total scores) were 88.9% and 94.1%, respectively. The specificities were 80.0% and 51.6%, respectively. Conclusion: Our results suggest that the blonanserin response at week 4 could predict the later response at week 8.