岸 太郎

ObjectiveThis study is a meta-analysis of inositol as a treatment for depression and anxiety disorders. MethodsPubMed, Cochrane Library database, and PsycINFO were searched up to 14 August 2013. A systematic review and meta-analysis of double-blind, randomized, placebo-controlled trials (RCTs) were conducted comparing inositol for depressed or anxiety disorder patients. ResultsSeven RCTs in depression (two bipolar depression studies, one bipolar depression and major depressive disorder (MDD) study, two MDD studies, and two premenstrual dysphoric disorder (PMDD) studies) (n=242) were identified. Four RCTs in anxiety disorders (two obsessive-compulsive disorder studies, one panic disorder study, and one posttraumatic stress disorder study) (n=70) were also identified. There were no statistically significant effects of inositol on depressive, anxiety, and obsessive-compulsive symptoms and discontinuation (all-cause, side effects, and worsening psychiatric symptoms). However, inositol had marginally more responders in depression than placebo (p=0.06), and inositol showed a trend towards superior efficacy for depressive symptoms in patients with PMDD (p=0.07). Inositol marginally caused gastrointestinal upset compared with placebo (p=0.06). ConclusionsOur results suggest that inositol may be beneficial for depressed patients, especially those with PMDD. The main limitation of this report is that a small number of studies were included in this meta-analysis. Copyright (c) 2013 John Wiley & Sons, Ltd.

Objective It is important to predict a response to an antidepressant in early time after starting the antidepressant. We previously reported that serum brain-derived neurotrophic factor (BDNF) levels in responders to treatment with antidepressants were increased, whereas, those in nonresponders were not. Therefore, we hypothesized that the changes in serum levels of BDNF from baseline (TO) to 4 weeks (T4) after treatment with selective serotonin reuptake inhibitors (SSRIs) predict the response to the treatment at 8 weeks (T8) in depressed patients. To confirm the hypothesis, we measured serum BDNF at TO, T4, and T8 during the treatment with SSRIs (paroxetine, sertraline, and fluvoxamine). Methods One hundred fifty patients (M/F; 51/99, age; 50.4 +/- 15.1 years) met major depressive disorder (MDD) using by DSM-IV-TR enrolled in the present study. We measured serum BDNF concentrations at TO, T4, and T8 in patients with MDD treated with SSRIs. Results The changes in serum BDNF, age, sex, dose of SSRIs, and HAMD-17 score did not predict the response to SSRIs at T8. Conclusion These results suggest that the changes in serum BDNF levels from TO to T4 could not predict the subsequent responses to SSRIs at T8.

We performed an updated meta-analysis of fluvoxamine add-on therapy in patients with schizophrenia treated with antipsychotics based on two previous meta-analyses (Sepehry et al., in J Clin Psychiatry 68:604-610, 2007 and Singh et al., in Br J Psychiatry J Mental Sci 197:174-179, 2010). We searched PubMed, the Cochrane Library database, and PsycINFO up to January 2013. We conducted a systematic review and meta-analysis of individual patient data from randomized controlled trials comparing fluvoxamine add-on therapy with placebo. The risk ratio (RR), 95 % confidence intervals (CI), and standardized mean difference (SMD) were calculated. Seven studies (total n = 272) were identified. These included two clozapine studies, one olanzapine study, one second-generation antipsychotic (SGA) monotherapy study, and three first-generation antipsychotics (FGAs) monotherapy studies. There were significant effect of fluvoxamine add-on therapy on overall (SMD = -0.46, CI = -0.75 to -0.16, p = 0.003, I (2) = 0 %, 5 studies, n = 180) and negative symptoms (SMD = -0.44, CI = -0.74 to -0.14, p = 0.004, I (2) = 0 %, 5 studies, n = 180). However, fluvoxamine add-on therapy showed no significant effects on positive symptoms, depressive symptoms, and discontinuations from any cause or adverse events. Fluvoxamine add-on therapy in patients primarily treated with SGAs improved overall (p = 0.02) but not negative symptoms (p = 0.31). On the other hand, fluvoxamine add-on therapy in patients primarily treated with FGAs improved both overall (p = 0.04) and negative symptoms (p = 0.004) compared with control groups. Our results suggest that fluvoxamine add-on therapy is more beneficial on the psychopathology (especially negative symptoms) than controls in patients with schizophrenia who are primarily treated with FGAs. Given that a small number of studies were included in this meta-analysis, the results should be treated with caution.

Hepatic pedicle clamping (HPC) has been demonstrated to be effective for short-term outcomes during hepatic resection. However, HPC-induced hepatic ischemia/reperfusion injury can accelerate the outgrowth of hepatic micrometastases in experimental studies. The conclusive evidence regarding effects of HPC on long-term patient outcomes after hepatic resection for colorectal liver metastasis (CRLM) has not been determined. A comprehensive electronic literature search was performed to identify studies evaluating the oncological effects of HPC after hepatic resection for CRLM. The main outcome measures were intrahepatic recurrence (IHR), disease-free survival (DFS), and overall survival (OS). A meta-analysis was performed using the random-effects models to compute odds ratio (OR) along with 95 % confidence intervals (CI). Four studies, with a total of 2,114 patients (73.7 % HPC, 26.3 % non-HPC), matched the inclusion criteria. Meta-analyses revealed that IHR (OR 0.88; 95 % CI 0.69-1.11; P = 0.27), DFS (OR 0.88; 95 % CI 0.70-1.10; P = 0.27) and OS (OR 0.99; 95 % CI 0.79-1.24; P = 0.90) did not differ significantly between the HPC and non-HPC groups. This meta-analysis provides persuasive evidence that HPC during hepatic resection for CRLM has no significant adverse oncological outcomes. HPC should be considered an option during parenchymal liver resection from current available evidence.

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. Crown Copyright (C) 2013 Published by Elsevier Ltd. All rights reserved.

Perospirone is a second-generation antipsychotic (SGA) used only in Japan, and acts as a serotonin (5-HT)(1A) receptor partial agonist, 5-HT2A receptor inverse agonist, and dopamine (D)(2), D-4, and alpha(1)-adrenergic receptor antagonist. To our knowledge, no meta-analysis addressing the efficacy and effectiveness of perospirone in schizophrenia has been published to date. The aim of the study was to identify the characteristics of perospirone by assessing the efficacy, discontinuation rate, and side effects of perospirone versus other antipsychotics in the treatment of patients with schizophrenia. Using information obtained from the PubMed, PsycINFO, Google Scholar and Cochrane Library databases without language restrictions published up to 10 June 2013, we conducted a systematic review and meta-analysis of patient data from randomized controlled trials comparing perospirone with other antipsychotic medications. Risk ratio (RR), standardized mean difference (SMD) and 95 % confidence intervals were calculated. All studies used the Positive and Negative Syndrome Scale (PANSS) for the evaluation of the schizophrenia psychopathology. The search in PubMed, Cochrane Library databases, Google Scholar and PsycINFO yielded 69 hits. We included three studies in the current meta-analysis and excluded 66 studies based on title, abstract, and full text review. Moreover, two additional studies were identified from a review article. Across the five studies (mean duration 9.6 weeks), 562 adult patients with schizophrenia were randomized to perospirone (n = 256), olanzapine (n = 20), quetiapine (n = 28), risperidone (n = 53), aripiprazole (n = 49), haloperidol (n = 75), or mosapramine (n = 81). Perospirone was not different from other pooled antipsychotics regarding reduction in PANSS negative (SMD = 0.38, p = 0.09) and general (SMD = 0.28, p = 0.06) subscale scores, and discontinuation due to any cause (RR = 1.03, p = 0.83), inefficacy (RR = 0.99, p = 0.98) and side effects (RR = 0.72, p = 0.25). However, perospirone was inferior to other pooled antipsychotics in the reduction of PANSS total scores (SMD = 0.36, p = 0.04) and positive subscale scores (SMD = 0.34, p = 0.03). Moreover, excluding the comparison of perospirone with the first-generation antipsychotic (haloperidol), perospirone was inferior to other pooled SGAs in the reduction of PANSS total scores (SMD = 0.46, p = 0.02), positive (SMD = 0.42, p = 0.03), negative (SMD = 0.52, p = 0.02) and general subscale scores (SMD = 0.37, p = 0.03). However, perospirone was superior to haloperidol in the reduction of PANSS negative subscale scores (SMD = -0.41, p = 0.01). Perospirone also had lower scores related to extrapyramidal symptoms than other pooled antipsychotics (SMD = -0.30, p = 0.01). Our results suggest that although perospirone seems to be a well tolerated treatment, perospirone does not reduce PANSS score as much as other SGAs.

Objective: Adenosine has been reported to interact with dopamine and glutamate of which are currently central pathophysiology of schizophrenia. Further, there have been emerging reports that patients with bipolar disorder (BD) have pathophysiological changes of the purinergic system. Thus, we performed a systematic review and meta-analysis of adenosine modulators in these disorders. Method: We searched PubMed, EMBASE, the Cochrane Library databases, CINAHL, and PsycINFO up to April 25, 2013. Randomized controlled trials comparing adenosine modulator adjuvant therapy with placebo in patients with schizophrenia and BD were included. Primary outcome measures were Positive and Negative Syndrome Scale (PANSS) and Young Mania Rating Scales (YMRS). The risk ratio, 95% confidence interval, and standardized mean differences (SMD) were used. Results: Nine studies, including six studies in schizophrenia (total n = 457) and three studies in BD (total n = 289) were included. Overall, adenosine modulators were superior to placebo in PANSS total scores (SMD = -1.07, p = 0.01) and positive and general but not negative symptom subscale scores in schizophrenia. Individually, allopurinol failed to show its superiority to placebo in all primary outcome measures in schizophrenia. In BD, data from pooled adenosine modulators indicated significant reduction of YMRS scores in comparison to placebo (SMD = -0.39, p = 0.004). Conclusions: Our results suggest that adenosine modulator adjuvant therapy is more beneficial in overall psychopathology (especially positive symptoms) in schizophrenia and in treating mania episodes of BD in comparison to placebo. The limited sample size of available studies suggests that more research should be done to evaluate both efficacy and tolerability of these medications. (C) 2013 Elsevier B.V. All rights reserved.

Background: The negative impact of postoperative complications (POCs) on long-term outcomes is well documented for several cancer surgeries, but conclusive evidence has yet to be provided on the influence of POCs on long-term oncological outcomes after hepatic resection for colorectal liver metastasis (CRLM). Methods: Studies published through February 2012 evaluating the oncological impact of POCs after hepatectomy for CRLM were identified by an electronic literature search. Finally, 4 studies were identified and included in the meta-analysis. The main outcome measures were 5-year disease-free survival (DFS) and overall survival (OS). A meta-analysis was performed using the DerSimonian-Laird random-effects models to compute odds ratio (OR) along with 95 % confidence intervals (95 % CI). Results: The outcomes of 2,280 patients were studied. Meta-analysis of 5-year DFS data extracted from three studies demonstrated a significant reduction in 5-year DFS after POCs, with an OR of 1.98 (95 % CI = 1.33-2.96 P =.0008). Meta-analysis of 5-year OS data extracted from four studies demonstrated a significant reduction in 5-year OS after POCs, with an OR of 1.68 (95 % CI = 1.25-2.27 P =.0006). No differences between study heterogeneity were observed in either the DFS or the OS analyses. Conclusions: This study provides persuasive evidence that POCs following hepatic resection for CRLM have significant adverse oncological outcomes. These findings emphasize the need for meticulous surgical technique and careful perioperative management to minimize POCs. © 2013 Society of Surgical Oncology.

The aim of the study was to evaluate the evidence that serotonin(1A) (5-HT1A) receptor partial agonists of the azapirone class, which are not antipsychotic, have benefits for adjunctive treatment of overall psychopathology, positive and negative symptoms for patients with schizophrenia. We carried out a systematic review of the literature available through PubMed, Cochrane Library, PsycINFO and Google Scholar during September 2012, followed by a meta-analysis of randomized placebo-controlled trials. Risk ratio (RR), 95% confidence intervals (CI) and standardized mean difference (S.M.D.) were calculated. Four studies, involving 163 patients with schizophrenia, met inclusion criteria: buspirone: three trials and 137 patients; tandospirone: one trial and 26 patients. As adjunctive therapy, 5-HT1A partial agonists were significantly superior to placebo for overall improvement in psychopathology (S.M.D. = -0.46, CI = -0.79 to -0.13, p = 0.006, N = 4, n = 149) and marginally more effective to improve positive symptoms (S.M.D. = -0.31, CI = -0.64 to 0.01, p = 0.06, N = 4, n = 149). However, 5-HT1A partial agonists were not more efficacious than placebo as adjunctive therapy for improving negative symptoms (S.M.D. = -0.09, CI = -0.60 to 0.42, p = 0.72, N = 4, n = 149). In addition, there was no significant difference in discontinuation rates between 5-HT1A partial agonists and placebo (all cause: RR = 0.98, CI = 0.49-1.98, p = 0.96, N 4, n = 153, side-effects: RR = 1.96, CI = 0.54-7.19, p = 0.31, N = 4, n = 153). 5-HT1A partial agonists as adjunctive therapy improved overall psychopathology with a trend to improve positive symptoms in patients with schizophrenia. Because the number of studies was small, additional controlled clinical trials with larger numbers of patients are indicated.

Objective: We sought to meta-analytically assess the utility of antipsychotics in patients with primary alcohol dependence. Data Sources: We searched PubMed, Cochrane Library, and PsycINFO without language restrictions from database inception until December 2012, using the following keywords: (randomized, random, OR randomly) AND (placebo) AND (alcohol dependence) AND (neuroleptic OR antipsychotic OR antidopaminergic OR the names of 34 individual antipsychotics). Study Selection: Included in this study were randomized, placebo controlled trials of antipsychotics lasting >= 2 weeks in patients with primary alcohol dependence and without schizophrenia or bipolar disorder. Data Extraction: Two independent evaluators extracted data. Standardized mean difference (SMD), risk ratio (RR), and numbers needed to harm (NNH) +/- 95% confidence intervals (CIs) were calculated. Results: Across 13 double-blind studies, 1,593 patients were randomly assigned to one of the following: amisulpride (1 study, n = 37), aripiprazole (2 studies, n = 163), flupenthixol decanoate (1 study, n = 142), olanzapine (2 studies, n = 62), quetiapine (4 studies, n = 174), tiapride (3 studies, n = 212), or placebo (13 studies, n = 803). Neither pooled nor individual antipsychotics outperformed placebo regarding relapse prevention (pooled RR = 1.05 [95% CI, 0.95 to 1.16], P = .38, 9 studies, n = 1,405). Antipsychotics were similar to placebo regarding heavy drinking days (P = .15), craving (P = .82), and first alcohol consumption time (P = .94). Placebo outperformed pooled antipsychotics regarding number or percentage of abstinent days/lack of drinking days (SMD = 0.17 [95% CI, 0.01 to 0.33], P = .04, 5 studies, n = 918), without significant group differences after removal of 1 outlying flupenthixol decanoate study (P = .24). Individually, flupenthixol decanoate (1 study, n = 281) was inferior to placebo regarding abstinence/drinking days (P = .004), whereas aripiprazole (1 study, n = 30) was superior regarding heavy drinking days (P < .00001). Antipsychotics caused greater all-cause discontinuation than placebo (RR = 1.24 [95% CI, 1.07 to 1.45], P = .005, NNH = 14), especially aripiprazole (P = .01) and flupenthixol decanoate (P = .001). Discontinuation due to intolerability was similar between antipsychotics and placebo (P = .12), but aripiprazole's risk was higher (P = .003). Drowsiness/sedation (P < .0001, NNH = 9), increased appetite (P = .02, NNH = 14), and dry mouth (P < .0001, NNH = 7) occurred more frequently with pooled antipsychotics. Conclusions: Except for 1 isolated outcome, the studied antipsychotics did not improve abstinence or reduce drinking or craving in patients with primary alcohol dependence. (C) Copyright 2013 Physicians Postgraduate Press, Inc.

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. © 2013 Nagao et al, publisher and licensee Dove Medical Press Ltd.

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&lt 0.0001), PANSS positive (p&lt 0.0001), negative (p=0.0055) and general subscale scores (p&lt 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 &gt 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. © 2012 Elsevier B.V.

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 Fagerstrom 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. Copyright (c) 2013 John Wiley & Sons, Ltd.

The serotonin 1A receptor gene (HTR1A) has been associated with mood disorders (MDs), including major depressive disorder (MDD) and bipolar disorder (BP). Therefore, we conducted a systematic review and meta-analysis between rs6295 (C-1019G) as well as rs878567 in HTR1A and MDs. Searching PubMed through May 2012, 15 studies, including our own, previously unpublished association study (135 MDD patients and 107 healthy controls), met inclusion criteria for the meta-analysis of rs6295 (4,297 MDs patients and 5,435 controls). Five association studies met criteria for the meta-analysis of rs878567 (2041MDs patients and 2,734 controls). rs6295 was associated with combined MDs (P (allele model) = 0.007 and P (recessive model) = 0.01). When divided by diagnostic subgroup (MDD = 3,119 patients and 4,380 controls or BP = 1,170 patients and 2,252 controls), rs6295 was associated with each MDs separately (MDD: P (allele model) = 0.006, P (recessive model) = 0.01; BP: P (dominant model) = 0.003). Likewise, rs878567 was associated with combined MDs (2,041 patients and 2,734 controls (P (allele model) = 0.0002, P (dominant model) = 0.0008, and P (recessive model) = 0.01). When divided by diagnostic subgroup (MDD = 1,013 patients and 1,728 controls or BP = 1,051 patients and 2,099 controls), rs878567 was associated with MDD (P (allele model) = 0.0007 and P (dominant model) = 0.01), while only one BP study had such data, precluding a meta-analysis. All of these significances survived correction for multiple comparisons. Results from this expanded meta-analysis, which included our own new study, suggest that rs6295 (C-1019G) and rs878567 in HTR1A are related to the pathophysiology of MDs, with overlap between MDD and BP. Findings provide additional clues to the underlying biology and treatment targets in MDs.

Implantation of exfoliated cancer cells has been suggested as a possible mechanism of local recurrence at the site of colorectal anastomosis. Intraoperative rectal washout has been suggested to eliminate free cancer cells; however, there is no conclusive evidence of a beneficial effect of intraoperative rectal washout on local recurrence after anterior resection of rectal cancer. Studies published through February 2012 evaluating the impact of intraoperative rectal washout for local recurrence or positive cytology from donuts wash were identified by an electronic literature search. A meta-analysis was performed using the DerSimonian-Laird random-effects models to compute risk ratio (RR) along with 95 % confidence intervals (CI). Nine studies met the inclusion criteria, yielding a total of 5,395 patients. Eight studies evaluated overall local recurrence, including anastomotic recurrence, and five of the eight studies evaluated anastomotic recurrence separately. Two studies evaluated positive cytology from donuts wash. Local recurrence rate was 5.79 % in the washout group and 10.05 % in the no washout group-a difference that was statistically significant (RR = 0.57; 95 % CI = 0.46-0.71; P < 0.00001). Rectal washout significantly reduced the risk of anastomotic recurrence (RR = 0.3; 95 % CI = 0.12-0.71; P = 0.007). No influence of rectal washout was observed on positive cytology from donuts wash. From the results of this meta-analysis, it may be justified to recommend intraoperative rectal washout to prevent local recurrence in rectal cancer surgery.

Background: There is uncertainty about the efficacy and tolerability of blonanserin in schizophrenia. Method: PubMed, the Cochrane Library databases, PsycINFO, and Google Scholar were searched up to September 2012. A systematic review and meta-analysis of individual patient data from randomized, controlled trials comparing blonanserin with other antipsychotics were conducted. The risk ratio (RR), 95% confidence intervals (CI), numbers-needed-to-harm (NNH), and weighted mean difference (WMD) were calculated. Results: Four studies (total n = 1080) were identified (vs. risperidone studies [n = 508], vs. haloperidol studies [n = 572]). Comparing blonanserin with other pooled antipsychotics, there were no significant differences in the Positive and Negative Syndrome Scale (PANSS) total score (p = 0.75), PANSS positive (p = 0.41), PANSS negative (p = 0.09), and PANSS general psychopathology subscale scores (p = 0.96), and response rate (p = 0.72). However, blonanserin showed greater efficacy in PANSS negative subscale scores compared with haloperidol (WMD = -1.29, CI = -2.29 to -030, p = 0.01, I-2 = 0%). No significant differences were found in discontinuation rates between blonanserin and other pooled antipsychotics (due to any cause: p = 0.29, inefficacy: p = 0.32, adverse events: p = 0.56). Blonanserin had a 0.31 lower risk of hyperprolactinemia than the other pooled antipsychotics (CI = 0.20-0.49, NNH = not significant). While dizziness (RR = 0.47, CI = 0.23-0.93, NNH = not significant) and akathisia (RR = 0.54, CI = 0.32-0.90, NNH = 7) occurred significantly less often with blonanserin than with haloperidol, blonanserin had a 1.62 higher risk of akathisia than risperidone (CI = 1.18-2.22, NNH = 3). Conclusion: Our results suggest that although blonanserin has a more beneficial effect on negative symptoms than haloperidol, there was a significant difference in the adverse events profile between blonanserin and other antipsychotics. (C) 2012 Elsevier Ltd. All rights reserved.

Objectives There is currently no meta-analysis of the efficacy and tolerability of Yokukansan in the treatment of behavioral and psychological symptoms of dementia. Method We used information obtained from the PubMed and Cochrane Library databases until October 2012. We conducted a systematic review and meta-analysis of individual patient data from randomized controlled trials comparing Yokukansan with usual care (UC, i.e., controls). Standardized mean difference and weighted mean difference were calculated. All studies used the Neuropsychiatric Inventory (NPI) for the evaluation of behavioral and psychological symptoms of dementia. Results Four relevant studies (total n?=?236) were identified. Yokukansan was superior to UC in the reduction of total NPI scores (p?=?0.0009, weighted mean difference?=-7.20, I2?=?0%). In addition, Yokukansan was more efficacious in reducing scores on the NPI subscale (delusions, hallucinations, and agitation/aggression) than UC (p?<?0.000010.0009). Yokukansan treatment also improved activities of daily living scores compared with UC (p?=?0.04, standardized mean difference?=?-0.32, I2?=?0%). Mini-mental state examination scores did not differ between the Yokukansan and UC treatment groups. Yokukansan was not different from UC regarding discontinuation due to any cause. Conclusion Our results suggest that Yokukansan has a beneficial effect on NPI and on ADL scores and that Yokukansan seems to be a well-tolerated treatment. Copyright (c) 2013 John Wiley & Sons, Ltd.

Background: We examined whether N-methyl d-aspartate (NMDA) receptor antagonists as adjunctive therapy have therapeutic potential for schizophrenia treatment. Method: Systematic review of PubMed, Cochrane Library, PsycINFO and Google Scholar up until October 2012 and meta-analysis of randomized placebo-controlled trials were performed. Risk ratio (RR), 95% confidence intervals (CI), numbers-needed-to-harm (NNH), and standardized mean difference (SMD) were calculated. Results: Results were across 8 studies and 406 patients (85.5% schizophrenia related disorder and 14.5% bipolar disorder) were included (amantadine: 5 trials and 220 patients, memantine: 3 trials and 186 patients). NMDA receptor antagonists (NMDAR-ANTs) as adjunctive therapy were not superior to placebo in overall (SMD=-0.25, CI=-0.72, 0.23, p=0.31, N=6, n=347), positive symptoms (SMD=-0.20, CI=-0.70, 0.31, p=0.44, N=4, n=205), and negative symptoms (SMD=-0.69, CI=-1.65, 0.27, p=0.16, N=4, n=205), and Clinical Global Impression Severity scale (SMD=-0.27, CI=-1.20, 0.65, p=0.56, N=3, n=177). There was also no significant difference in discontinuation rate between NMDAR-ANTs and placebo treatments (all cause: RR=1.23, CI=0.89-1.70, p=0.20, N=8, n=396, side effects: RR=1.86, CI=0.84-4.13, p=0.13, N=6, n=359, inefficacy/worsening psychosis: RR=0.70, CI=0.20-2.38, p=0.56, N=7, n=380). However, memantine was favorable compared with placebo in Mini-Mental State Examination in schizophrenia (SMD=-0.77, CI=-1.27,-0.28, p=0.002, N=3, n=71). While NMDAR-ANTs caused weight loss compared with placebo (SMD=-0.42, CI=-0.73,-0.11, p=0.008, N=3, n=165), amantadine caused more frequent insomnia than placebo (RR=3.83, CI=1.41-10.38, p=0.008, NNH=9, p=0.002, N=2, n=147). Conclusion: Our results indicate that NMDAR-ANTs as adjunctive therapy may improve cognitive function in patients with schizophrenia. Because the included studies were small, a replication study using larger samples is needed. © 2013 Elsevier Ltd.

A recent meta-analysis showed that long-acting injectable (LAI) antipsychotics were not superior to oral antipsychotics for preventing relapse in patients with -schizophrenia. We therefore designed a treatment strategy combining risperidone LAI and COMPASS -(COMprehensive Psycho-educational Approach and Scheme Set), an original psychoeducational program supporting treatment with risperidone LAI and evaluating subjective treatment satisfaction, transition of symptoms, and effectiveness in preventing symptomatic relapse. The aim of this study was to examine whether addition of COMPASS to risperidone LAI was more effective in preventing relapse in schizophrenia patients than risperidone LAI alone, with the latter group consisting of patients enrolled in a Phase III trial of risperidone LAI in Japan. Patients were followed up for 6 months, with COMPASS continuously implemented from the transition to the observation phase. The primary efficacy measurements were relapse rate (rates of rehospitalization and discontinuation due to inefficacy). Secondary efficacy measurements were the Brief Psychiatric Rating Scale (BPRS) and Global Assessment of Functioning (GAF) scores. Of the 96 patients originally enrolled, 19 (19.8%) were discontinued from all causes. During the 6-month study period, ten of the 96 patients (10.4%) relapsed, compared with a 12.2% relapse rate in patients enrolled in a Phase III trial of risperidone LAI in Japan. Patients showed significant improvements in BPRS total scores (P = 0.0031), BPRS positive (P = 0.0451), BRPS negative (P, 0.0001), and general subscale scores (P = 0.0031), and GAF (P, 0.0001) from baseline to 6 months. In conclusion, the lower relapse rate observed in patients treated with COMPASS plus risperidone LAI than in patients treated with risperidone LAI alone suggests that -COMPASS may have benefits in the treatment of schizophrenia, indicating a need for randomized, controlled trials in larger numbers of patients.

Objective: Although antipsychotics have been used empirically to prevent the development of postoperative delirium, there has been no confirming evidence to support their use. Thus, we conducted a systematic review and a meta-analysis to elucidate their efficacy and tolerability in surgical patients. Data Sources: MEDLINE, EMBASE, the Cochrane Library databases, CINAHL, and PsycINFO were searched up to February 2013 without language restrictions, using the following keywords: (antipsychotics OR [nonproprietary name of each antipsychotic medication, separated by OR]) AND delirium AND (randomized OR random OR randomly). Study Selection: Randomized controlled trials comparing prophylactic use of antipsychotics with placebo in surgical patients were included. Data Extraction: Two authors extracted and scrutinized the data. The risk ratio (RR), 95% confidence interval (CI), number needed to treat (NNT), and standardized mean difference were used. Results: Six studies (3 haloperidol, 1 olanzapine, and 2 risperidone) including 1,689 surgical patients were identified. The results showed significant efficacy in reducing the occurrence of delirium (RR = 0.50, 95% CI = 0.34 to 0.73, P = .0003; NNT = 7, P = .001, 6 studies). Sensitivity analysis showed that second-generation antipsychotics were superior to placebo (RR = 0.36, P < .00001; NNT = 4, P < .00001), whereas haloperidol failed to show superiority to placebo. There were no statistically significant differences between groups in severity of delirium, discontinuation rate, or rates of several adverse events. Conclusions: Our results suggest that second-generation antipsychotics are more beneficial than placebo for preventing the incidence of delirium. Among patients who do develop delirium, the severity of delirium is not reduced in those who received prophylactic antipsychotics. (C) Copyright 2013 Physicians Postgraduate Press, Inc.

Objective: Since cocaine and psychostimulant dependence are related to increased dopamine release, antipsychotics have been tried to reduce their reinforcing properties. A meta-analysis was undertaken to assess the efficacy and tolerability of antipsychotics in cocaine-or stimulant-dependent patients. Data Sources: We searched PubMed, Cochrane Library databases, and PsycINFO from database inception until June 24, 2013, using the following keywords: (randomized OR random OR randomly) AND (placebo) AND (methylphenidate OR cocaine OR methamphetamine OR amphetamine OR 3,4-methylenedioxymethamphetamine) AND (dependence OR abuse) AND (antipsychotic OR neuroleptic OR 34 specific antipsychotic names). Study Selection: Included were randomized, placebo-controlled trials of antipsychotics lasting at least 2 weeks in patients with primary cocaine or psychostimulant dependence. Of 363 hits, we removed 316 duplicates, 20 references based on abstract/title, and 13 ineligible full-text articles, retaining 14 trials for this meta-analysis. Data Extraction: Two authors independently extracted the data. Coprimary outcomes included degree of substance use and lack of abstinence. Risk ratio (RR), 95% CI, and standardized mean difference were calculated. Results: Ten studies in patients with primary cocaine dependence (risperidone = 5, olanzapine = 3, reserpine = 2; n = 562) and 4 in those with amphetamine/methamphetamine dependence (aripiprazole = 4; n = 179) were meta-analyzed (14 studies, total n = 741). When study results were pooled together, antipsychotics did not differ from placebo in regard to cocaine use days and lack of cocaine or amphetamine/methamphetamine abstinence, severity of addiction, cocaine or amphetamine/methamphetamine craving, Clinical Global Impressions-Severity of Illness (CGI-S) scores, depression, anxiety, compliance, all-cause discontinuation, and several side effects. However, antipsychotics caused more intolerability-related discontinuation than placebo (P = .0009). Individually, aripiprazole was superior to placebo in regard to CGI-S (P = .001), while olanzapine was inferior to placebo in regard to cocaine craving (P = .03) and risperidone was inferior to placebo in regard to depression (P = .002). Conclusions: Antipsychotics had no advantages over placebo in regard to cocaine use and cocaine or psychostimulant abstinence or craving, while causing more intolerability-related discontinuations. (C) Copyright 2013 Physicians Postgraduate Press, Inc.

Background: Tetrahydrobiopterin (BH4) plays an important role in the biosynthesis of serotonin, melatonin and catecholamines, all of which are implicated in the pathophysiology of mood disorders (MDs), including major depressive disorder (MDD) and bipolar disorder (BP). Production of BH4 is regulated by GTP cyclohydrolase transcription and activity. Thus, we considered the GTP cyclohydrolase gene (GCH1) to be a good candidate gene in the pathophysiology of MDs and of the serotonin selective reuptake inhibitors (SSRIs) response in MDD, and conducted a case-control study utilizing three SNPs (rs8007267, rs3783641 and rs841) and moderate sample sizes (405 MDD patients, including 262 patients treated by SSRIs, 1022 BP patients and 1805 controls). Method: A multiple logistic regression analysis was carried out to compare the frequencies of each SNP genotype for the target phenotype across patients and controls in several genetic models, while adjusting for possible confounding factors. A clinical response was defined as a decrease of more than 50% from the baseline score on the Structured Interview Guide for Hamilton Rating Scale for Depression (SIGH-D) within 8 weeks, and clinical remission as a SIGH-D score of less than 7 at 8 weeks. Result: No associations between three SNPs in GCH1 and MDD or BP were observed; however, GCH1 was associated with SSRI therapeutic response in MDD in all the marker's haplotype analysis (Global P value=0.0379). Conclusions: Results suggest that GCH1 may predict response to SSRI in MDD in the Japanese population. Nevertheless, a replication study using larger samples may be required for conclusive results, since our sample size was small. (C) 2012 Elsevier B.V. All rights reserved.

Objective: Only two-thirds of depressive patients respond to antidepressant treatment. In recent years, addition of an atypical antipsychotic drug to ongoing treatment with an antidepressant has been considered effective and well-tolerated. In the present study, we compared the efficacy between paroxetine and sertraline augmented with aripiprazole in patients with refractory major depression. Subjects and methods: Twenty-four patients who met the DSM-IV criteria for major depressive disorder who did not at least two different classes of antidepressants were enrolled in the study. Nine were male and thirteen were female, and their ages ranged from 28 to 66 (mean +/- SD = 39 +/- 12) years. Patients were prescribed paroxetine (n =11) or sertraline (n = 13) for 4 weeks. Then, those whose scores on the 17-item Hamilton Rating Scale for Depression (HAMD17) decreased below 50% received adjunctive therapy of aripiprazole for 4 weeks. Results: Although the use of either combination treatment decreased the HAMD17 scores compared to the respective monotherapy, there was no significant difference in HAMD17 scores between the paroxetine plus aripiprazole group and sertraline plus aripiprazole group. Conclusion: Aripiprazole augmentation therapy with paroxetine or sertraline was equally effective and tolerated in patients with refractory major depressive order. (C) 2012 Elsevier Inc. All rights reserved.

Disturbances of the circadian rhythm are involved in the pathophysiology of bipolar disorder (BD), schizophrenia (SCZ) and major depressive disorder (MDD). Specifically, because clock gene dysfunction is good candidate for enhancing the susceptibility to these psychiatric disorders, we selected two circadian rhythm-related genes (CSNK1D and CSNK1E) and investigated genetic associations of the genes with these three disorders. None of the SNPs showed a significant association with MDD, but a SNP (rs2075984) in CSNK1E and SNP (rs6502097) in CSNK1D were associated with SCZ (P=0.0091. uncorrected) and BD (P=0.030, uncorrected), respectively. To confirm these findings, we analyzed an independent dataset (maximum N=3815) but found a lack of association (P=0.63 for rs2075984 and P=0.61 for rs6502097). The final meta-analysis showed no association between these SNPs with SCZ (P=0.21) and BD (P=0.53). These results do not support that genetic variation in CSNK1D and CSNK1E is a susceptibility factor for major psychiatric disorders in the Japanese population. (C) 2012 Elsevier Ireland Ltd. All rights reserved.

Object. We investigated an association between the polymorphism of brain-derived neurotrophic factor (BDNF) gene Val66Met and the response to mirtazapine in Japanese patients with major depressive disorder (MDD). We also examined mirtazapine's effects on the serum BDNF and plasma levels of catecholamine metabolites in these patients. Methods. Eighty-four patients who met the DSM-IV-TR criteria for MDD were treated with only mirtazapine for 4 weeks. The BDNF Val66Met polymorphism was detected by direct sequencing in the region, and serum BDNF levels and plasma levels of catecholamine metabolites were measured by ELISA and HPLC-ECD, respectively. Results. Mirtazapine treatment for 4 weeks significantly increased serum BDNF levels in the responders, whereas nonresponders showed significant decreases. No association was found between either of the two genotypes (Val/Val vs. Met-carriers) and the response to mirtazapine at T4 or the serum BDNF levels at T0. Mirtazapine did not alter the plasma levels of homovanillic acid (HVA) or 3-methoxy-4-hydroxyphenylglycol (MHPG). Discussion. The dynamics of serum BDNF levels, but not plasma levels of HVA and MHPG, reflect the response to mirtazapine treatment; the BDNF Val66Met polymorphism in patients with depression is, however, associated with neither a particular response to mirtazapine treatment nor baseline serum BDNF levels. Conclusion. Serum BDNF levels, but not plasma levels of HVA or MHPG, and BDNF Val66Met polymorphism are related to the mirtazapine response in MDD. Received 31 January 2012; Accepted 27 April 2012

Background: A previous meta-analysis reported a positive association between an insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme gene (ACE) and the risk of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Here, we updated this meta-analysis and additionally assessed the association of this polymorphism with ALI/ARDS mortality. Methods: We searched electronic databases through October 2011 for the terms "angiotensin-converting enzyme gene", "acute lung injury", and "acute respiratory distress syndrome," and reviewed all studies that reported the relationship of the I/D polymorphism in ACE with ALI/ARDS in humans. Seven studies met the inclusion criteria, comprising 532 ALI/ARDS patients, 3032 healthy controls, and 1432 patients without ALI/ARDS. We used three genetic models: the allele, dominant, and recessive models. Results: The ACE I/D polymorphism was not associated with susceptibility to ALI/ARDS for any genetic model. However, the ACE I/D polymorphism was associated with the mortality risk of ALI/ARDS in Asian subjects (P-allele < 0.0001, P-dominant = 0.001, P-recessive = 0.002). This finding remained significant after correction for multiple comparisons. Conclusions: There is a possible association between the ACE I/D polymorphism genotype and the mortality risk of ALI/ARDS in Asians.

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 ( = 0.0009, beta = -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 ( = 0.513), PPI ( = 0.521-0.842), verbal memory ( = 0.423-0.981), working memory ( = 0.312-0.966), motor speed ( = 0.323-0.955), verbal fluency ( = 0.125-0.920), executive function ( = 0.118-0.470), and the BACS-J composite score ( = 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.

Objectives Several lines of evidence suggest that genetic alterations in serotonin 6 (5-HT6) receptors might be associated with the pathophysiology of schizophrenia. We sought to assess the relationship between genotype alterations in 5-HT6 receptors and schizophrenia both in a case-control study and a meta-analysis. Methods We conducted an association study of the 5-HT6 receptor gene (HTR6) in Japanese patients with schizophrenia (n = 836) and controls (n = 857). Five tagging single-nucleotide polymorphisms (SNPs), including rs1805054 (C267T) in HTR6, were selected. In addition, we carried out a meta-analysis between rs1805054, which has been examined in other studies, and schizophrenia, searching PubMed through August 2011. Results There were no significant associations between the tagging SNPs in HTR6 and schizophrenia in any of the genotype models in both the simple and the multiple logistic regression analyses correcting for potential confounds. Similarly, no significant association was found in the all-marker haplotype multiple logistic regression analysis (p = 0.491). Moreover, in the meta-analysis of rs1805054, drawing data from five studies, including our own (schizophrenia patients = 1366, controls = 1376), rs1805054 was also not associated with schizophrenia. Conclusions Our results indicate that tagging SNPs in HTR6 may not play a role in the pathophysiology of schizophrenia. Copyright (C) 2012 John Wiley & Sons, Ltd.

Objective: To assess the utility of antipsychotics for weight gain and improvement of illness-related psychopathology in patients with anorexia nervosa. Data Sources: PubMed, the Cochrane Library databases, and PsycINFO citations from the inception of the databases until March 27, 2012, were searched without language restrictions using the following keywords: randomized, random, randomly, and anorexia nervosa. In addition, we hand-searched for additional studies eligible for inclusion in this meta-analysis and contacted authors for unpublished data. Study Selection: Included in this study were randomized placebo-or usual care-controlled trials of antipsychotics in patients with anorexia nervosa. Data Extraction: Two independent evaluators extracted data. The primary outcome of interest was body weight, expressed as the standardized mean difference (SMD) between the 2 groups in baseline to endpoint change of body mass index (BMI), endpoint BMI, or daily weight change. SMD, risk ratio (RR), and number needed to harm (NNH) ± 95% confidence interval (CI) were calculated. Results: Across 8 studies (mean duration = 9.6 weeks range, 7-12 weeks), 221 patients (mean age = 22.5 years, 219 [99.1%] females) with anorexia nervosa were randomly assigned to olanzapine (n = 54), quetiapine (n = 15), risperidone (n = 18), pimozide (n = 8), sulpiride (n = 9), placebo (n = 99), or usual care (n = 18). Both individually (P = .11 to P = .47) and pooled together (SMD = 0.27, 95% CI, -0.01 to 0.56 P = .06, I&lt sup&gt 2&lt /sup&gt = 0% 7 studies, n = 195), weight/BMI effects were not significantly different between antipsychotics and placebo/usual care. Moreover, pooled antipsychotics and placebo/ usual care did not differ regarding scores on questionnaires related to anorexia nervosa (P = .32, 5 studies, n = 114), body shape (P = .91, 4 studies, n = 100), depressive symptoms (P = .08, 4 studies, n = 103), and anxiety (P = .53, 4 studies, n = 121). Individually, quetiapine (1 study, n = 33) outperformed usual care regarding eating disorder attitudes (P = .01) and anxiety (P = .02). While rates of dropout due to any reason (P = .83, I &lt sup&gt 2&lt /sup&gt = 0%) and due to adverse events (P = .54, I&lt sup&gt 2&lt /sup&gt = 5%) were similar in both groups, drowsiness/sedation occurred significantly more often with antipsychotics than placebo/usual care (RR = 3.69, 95% CI, 1.37-9.95 I&lt sup&gt 2&lt /sup&gt = 67%, P = .01 NNH = 2, P = .001 5 studies, n = 129), but most other adverse effects were only sparsely reported. Conclusions: Although limited by small samples, this meta-analysis failed to demonstrate antipsychotic efficacy for body weight and related outcomes in females with anorexia nervosa. © Copyright 2012 Physicians Postgraduate Press, Inc.

Objective: This study examined the association between the brain-derived neurotrophic factor (BDNF) (Val66Met) polymorphism and the response to the addition of an atypical antipsychotic drug to a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) in treatment-refractory depression. Methods: The study enrolled 64 patients meeting the Diagnostic and Statistical Manual of Mental Disorders-IV criteria for major depressive disorder who were treated with at least two courses of a single antidepressant, but who had Hamilton Depression Rating Scale (HAMD-17) scores ≥15 points that were reduced less than 50% over at least a 4-week treatment period. There were 24 males and 40 females (age range 27-68 years mean±SD, 48±13 years). The patients' clinical improvement was evaluated using the HAMD-17. Patients with at least a 50% decrease in the HAMD-17 score were defined as responders. Serum BDNF levels were assayed using enzyme-linked immunosorbent assays and the presence of the BDNF (Val66Met) polymorphism was determined using the TaqMan genotyping assay. Results: No correlation was found between the BDNF (Val66Met) polymorphism and a positive response to adding an atypical antipsychotic drug. No differences were observed in the changes in the serum BDNF levels and HAMD-17 scores between Val66Val and Met-carriers. In addition, in patients who experienced remission, the atypical antipsychotic drug was discontinued after at least 3 months of treatment and the patients were then followed for 1 year 14 of 27 patients (52%) relapsed within 1 year. Conclusion: These results suggest that the BDNF (Val66Met) polymorphism is not associated with the response to the augmentation of a SSRI or SNRI with an atypical antipsychotic drug, and that the combination of an atypical antipsychotic drug and a SSRI or SNRI should be continued for 3 months or more in refractory depressed patients in the Japanese population. Copyright©2012, Korean College of Neuropsychopharmacology.

Objectives We previously showed that the sirtuin 1 gene (SIRT1 gene), one of the clock genes, was associated with schizophrenia in a Japanese patient population. Because the symptoms of methamphetamine (METH)-induced psychosis are similar to those of paranoid type schizophrenia and because not every METH user develops psychosis, it is conceivable that METH-induced psychosis and schizophrenia have common susceptibility genes. Therefore, we conducted an analysis of the association of SIRT1 gene with METH-induced psychosis, hypothesizing a significant relationship. Methods This paper presents a case-control study of the SIRT1 gene in 515 Japanese individuals (197 with METH-induced psychosis and 318 age-matched and sex-matched controls) with four tagging single nucleotide polymorphisms (rs12778366, rs2273773, rs4746720, and rs10997875), selected a priori using the HapMap database. Results rs10997875 (located in the 3' flanking region) was associated with METH-induced psychosis (unadjusted p(genotype)=0.0203). However, these results became non-significant after Bonferroni correction (corrected p(genotype)=0.0812). In the all-marker haplotype analysis, the SIRT1 gene was not associated with METH-induced psychosis (p=0.146). Conclusion Our findings suggest that SIRT1 gene does not contribute to the development of METH-induced psychosis in the Japanese population. However, a replication study using larger samples should be conducted to obtain conclusive results. Copyright (C) 2011 John Wiley & Sons, Ltd.

Background Depression is a risk factor for coronary heart disease. Nitric oxide (NO) plays an important role in both coronary heart disease and depression. Methods Fifty-one inpatients and outpatients who met the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition criteria for major depressive disorder (MDD) in the university hospital of the University of Occupational and Environmental Health and 58 age-matched and sex-matched healthy controls enrolled in this study. We investigated the association between the three polymorphisms of the endothelial nitric oxide synthase (eNOS) gene (single-nucleotide polymorphism (SNP); rs2070744, rs1799983, variable number tandem repeat (VNTR) in intron 4) and scores on the Hamilton Rating Scale for Depression, plasma metabolites of NO (NOx) or ankle brachial index in patients with MDD and healthy controls. Results We did not find significant differences in the genotype distributions between patients with MDD and healthy volunteers. No associations were observed between any of the polymorphisms of the eNOS gene and the Hamilton Rating Scale for Depression or ankle brachial index in patients with MDD. However, plasma NOx level was significantly associated with a polymorphism of the eNOS gene (rs207044 and variable number tandem repeat in intron 4). Conclusion These results suggest that the direct association was not observed between the polymorphisms of the eNOS gene and the pathogenesis of depression. Copyright (C) 2011 John Wiley & Sons, Ltd.

Background: Several investigations have reported that abnormalities in circadian rhythms might be related to the pathophysiology of major depressive disorder (MDD) and the therapeutic response to selective serotonin reuptake inhibitors (SSRIs). Recently, ubiquitin-specific peptidase 46 (USP46), a new molecule related to the circadian clock system, has been described. We conducted a case control study between seven tagging SNPs (rs10517263, rs17675844, rs6554557, rs12646800, rs2244291, rs10034164, rs346005) in the USP46 gene, MDD, and the SSRI therapeutic response in MDD in the Japanese population. Method: We recruited 432 MOD patients (202 males and 230 females) and 792 healthy controls (319 males and 473 females). Two hundred sixty-one of 432 MOD patients were treated with SSRIs (fluvoxamine, sertraline or paroxetine). Result: We detected an association between the USP46 gene and MOD in a haplotype analysis (rs2244291-rs10034164-rs346005 and rs12646800-rs2244291-rs10034164-rs346005). However, we did not find any association between the USP46 gene and SSRI response or remission in MDD in the Japanese population. Limitations: A replication study using larger samples may be required for conclusive results, since our sample size was small. Conclusions: Our results suggest that the USP46 gene might play a role in the pathophysiology of MOD in the Japanese population. Crown Copyright (C) 2011 Published by Elsevier B.V. All rights reserved.

Objectives: Recently, we detected that the prokineticin 2 receptor gene was associated with not only major depressive disorder (MDD) but also methamphetamine dependence. Therefore, it is possible that mood disorders and drug addiction have shared susceptibility genes. The translin-associated factor X gene (TSNAX)/disrupted-in-schizophrenia-1 gene (DISC1) has been associated with psychiatric disorders, including schizophrenia, MDD and bipolar disorder. TSNAX is located immediately upstream of DISC1 and has been shown to undergo intergenic splicing with DISC1. Based on this evidence, we hypothesized that TSNAX might be a good candidate gene for methamphetamine dependence. Methods: We conducted a case-control study of Japanese individuals (215 with methamphetamine dependence and 318 age- and sex-matched controls) with three tagging SNPs (rs1630250, rs766288 and rs6662926) selected by HapMap database. Results: rs1630250 was associated in males with methamphetamine dependence in the allele analysis (P-value: 0.0253). However, these results did not remain significant after Bonferroni correction to adjust for multiple comparisons (corrected P-value: 0.152). Conclusion: Our findings suggest that TSNAX does not play a role in methamphetamine dependence in the Japanese population. A replication study using larger samples needs to be conducted to obtain conclusive results. (C) 2011 Elsevier Inc. All rights reserved.

Background: We investigated the relationship between a brain-derived neurotrophic factor (BDNF) polymorphism (Val66Met) and the clinical response of patients with major depressive disorder to selective serotonin reuptake inhibitors (SSRIs; here, paroxetine and sertraline). In addition, serum BDNF levels in these patients were considered together with the clinical response. Methods: A total of 132 patients who met the DSM-IV criteria for major depressive disorder were enrolled in the study. 54 of these patients were male and 78 were female (age range, 20-74 years; mean +/- S.D., 51 +/- 15). The patients' clinical improvement was evaluated using the 17-item Hamilton Rating Scale for Depression (HAMD-17) before (T0) and at 8 weeks after the administration of SSRI treatment (T8). Patients with at least a 50% decrease in the HAMD-17 score were classified as responders. Results: No correlation was observed between the BDNF Val66Met polymorphism and response to SSRIs or between the BDNF Val66Met polymorphism and serum BDNF levels at TO. An inverse correlation was found between serum BDNF levels and HAMD-17 scores at TO. Conclusions: These results suggest that the BDNF Val66Met polymorphism is independent of both the response to SSRI treatment and serum BDNF levels. The findings in the present study reconfirm that the serum BDNF level is a state biomarker for depression. (C) 2011 Elsevier Inc. All rights reserved.

Background Brain-derived neurotrophic factor (BDNF) plays an important role in the regulation of synaptic plasticity and neurotransmitter release across multiple neurotransmitter systems. Recent studies have suggested that BDNF plays a role in the pathogenesis of psychiatric symptoms in patients with systemic lupus erythematosus (SLE). Objectives We hypothesized that the polymorphism of BDNF Val66Met is associated with the emergence of psychiatric symptoms (PS) and serum BDNF levels in SLE patients. To examine the hypothesis, we compared the BDNF Val66Met polymorphism and serum BDNF levels in patients with SLE with or without PS. Methods Psychiatric symptoms were assessed in 54 patients with SLE. PS were evaluated using the Brief Psychiatric Rating Scale. Genotyping was carried out using a 54-nuclease assay. Serum BDNF levels were measured by using enzyme-linked immunosorbent assay. Results The presence of the Met allele was not significantly associated with the presence of PS or with serum BDNF levels in patients with SLE. Conclusion Our data do not support the common variant Val66Met of the BDNF gene as an etiologic factor in the various forms of PS and serum BDNF levels in SLE. Copyright (C) 2011 John Wiley & Sons, Ltd.

Synaptonemal complex protein 3 (SYCP3) plays a critical role in homologous chromosome pairing and recombination in meiosis, and mice deficient in this gene show infertility in males and subfertility in females. The aim of our current study was to determine whether genetic alterations in the SYCP3 gene are associated with female infertility in humans. We examined sequence variations of the SYCP3 gene in genomic DNA from 88 Japanese women with unexplained infertility and 165 samples obtained from a fertile control group. Case-control study using seven tagging single nucleotide polymorphisms revealed no significant association between common SYCP3 variants and unexplained infertility. However, only infertile women were homozygous for the minor allele of a novel rare variant in the coding region, c.666A&gt G (222Q&gt Q). The minor allele frequency was significantly higher in the infertile cohort (P &lt 0.05). This variant is predicted to create a cryptic splice site, although the expression of a mini-gene harboring the variant in HeLa cells or mouse testis did not demonstrate any effects on gene splicing. Our current findings therefore suggest that the c.666A&gt G variant in the SYCP3 gene might possibly contribute to female infertility in humans, although larger studies are needed to assess the possible effects of SYCP3 gene variation on human female infertility. © The Author 2010. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.

Several lines of evidence suggest that alterations in circadian rhythms might be associated with the pathophysiology of psychiatric disorders such as schizophrenia and bipolar disorder (BP). A recent study reported that SIRT1 is a molecule that plays an important role in the circadian clock system. Therefore, to evaluate the association among the SIRT1 gene, schizophrenia and BP, we conducted a case-control study of Japanese population samples (1158 schizophrenia patients, 1008 BP patients and 2127 controls) with four tagging SNPs (rs12778366, rs2273773, rs4746720 and rs10997875) in the SIRT1 gene. Marker-trait association analysis was used to evaluate the allele and the genotype association with the χ 2 test, and haplotype association analysis was evaluated with a likelihood ratio test. We showed an association between rs4746720 in the SIRT1 gene and schizophrenia in the allele and the genotype analysis. However, the significance of these associations did not survive after Bonferroni's correction for multiple testing. On the other hand, the SIRT1 gene was associated with Japanese schizophrenia in a haplotype-wise analysis (global P all markers = 4.89 × 10 -15). Also, four tagging SNPs in the SIRT1 gene were not associated with BP. In conclusion, the SIRT1 gene may play an important role in the pathophysiology of schizophrenia in the Japanese population. © 2011 The Authors. Genes, Brain and Behavior © 2011 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society.

Background: Genome-wide association studies have detected a small number of weak but strongly supported schizophrenia risk alleles. Moreover, a substantial polygenic component to the disorder consisting of a large number of such alleles has been reported by the International Schizophrenia Consortium. Method: We report a Japanese genome-wide association study of schizophrenia comprising 575 cases and 564 controls. We attempted to replicate 97 markers, representing a nonredundant panel of markers derived mainly from the top 150 findings, in up to three data sets totaling 1990 cases and 5389 controls. We then attempted to replicate the observation of a polygenic component to the disorder in the Japanese and to determine whether this overlaps that seen in UK populations. Results: Single-locus analysis did not reveal genome-wide support for any locus in the genome-wide association study sample (best p = 6.2 x 10(-6)) or in the complete data set in which the best supported locus was SULT6B1 (rs11895771: p = 3.7 x 10(-5) in the meta-analysis). Of loci previously supported by genome-wide association studies, we obtained in the Japanese support for NOTCH4 (rs2071287: p(meta) = 5.1 x 10(-5)). Using the approach reported by the International Schizophrenia Consortium, we replicated the observation of a polygenic component to schizophrenia within the Japanese population (p = .005). Our trans Japan-UK analysis of schizophrenia also revealed a significant correlation (best p = 7.0 x 10(-5)) in the polygenic component across populations. Conclusions: These results indicate a shared polygenic risk of schizophrenia between Japanese and Caucasian samples, although we did not detect unequivocal evidence for a novel susceptibility gene for schizophrenia.

Several investigations suggested abnormalities in circadian rhythms are related to the pathophysiology of psychiatric disorders, including drug addiction. Recently, orphan nuclear receptor rev-erb alpha and glycogen synthase kinase-3 beta (GSK-3 beta) were shown to be important circadian components. In addition, the orphan nuclear receptor rev-erb alpha is a key negative feedback regulator of the circadian clock. These evidences indicate that rev-erb alpha gene (NR1D1) is a good candidate gene for the pathogenesis of methamphetamine dependence. To evaluate the association between NR1D1 and methamphetamine dependence, we conducted a case-control study of Japanese samples (215 methamphetamine dependence and 232 controls) with three tagging SNPs selected by HapMap database. Written informed consent was obtained from each subject. This study was approved by the ethics committees at Fujita Health University, Nagoya University Graduate School of Medicine and each participating member of the Institute of the Japanese Genetics Initiative for Drug Abuse (JGIDA). We did not detect an association between NR1D1 and Japanese methamphetamine dependence patients in allele/genotype-wise analysis, or the haplotype analysis. Our findings suggest that NR1D1 does not play a major role in the pathophysiology of methamphetamine dependence in the Japanese population.

Disruption of circadian rhythms may be involved in the pathophysiology of psychiatric disorders, including drug addiction. Recently, we detected the significant association between prokineticin 2 receptor gene (PROKR2) and Japanese methamphetamine dependence patients. Also, prokineticin 2 (PK2) gene deficient mice showed reduced physiological and behavioral parameters, including circadian locomotor activity, circulating glucocorticoid, glucose levels and the expression of peripheral clock genes compared with WT mice. These evidences indicate that PK2 gene (PROK2) is a good candidate gene for the pathogenesis of methamphetamine dependence. To evaluate the association between PROK2 and methamphetamine dependence, we conducted a case-control study of Japanese samples (215 methamphetamine dependence and 232 controls) with four tagging SNPs selected by HapMap database. The age and sex of the control subjects did not differ from those of the methamphetamine dependence patients. Written informed consent was obtained from each subject. This study was approved by the ethics committees at Fujita Health University, Nagoya University Graduate School of Medicine and each participating member of the Institute of the Japanese Genetics Initiative for Drug Abuse (JGIDA). We did not detect an association between PROK2 and Japanese methamphetamine dependence patients in allele/genotype-wise analysis, or the haplotype analysis. Our findings suggest that PROK2 does not play a major role in the pathophysiology of methamphetamine dependence in the Japanese population.

The neuronal nitric oxide synthase gene (NOS1) is located at 12q24, a susceptibility region for schizophrenia, and produces nitric oxide (NO). NO has been reported to play important roles as a gaseous neurotransmitter in brain. NO is a second messenger for the N-methyl-D aspartate (NMDA) receptor and is related to the dopaminergic system. Because the symptomatology of methamphetamine (METH) use disorder patients with psychosis is similar to that of patients with schizophrenia, NOS1 is a good candidate gene for METH-induced psychosis. Therefore, we conducted a case-control association study between NOS1 and METH-induced psychosis with Japanese subjects (183 with METH-induced psychosis patients and 519 controls). We selected seven SNPs (rs41279104, rs3782221, rs3782219, rs561712, rs3782206, rs6490121, rs2682826) in NOS1 from previous reports. Written informed consent was obtained from each subject. This study was approved by the Ethics Committee at Fujita Health University School of Medicine and each participating institute of the Japanese Genetics Initiative for Drug Abuse (JGIDA). No significant association was found between NOS1 and METH-induced psychosis in the allele/genotype-wise or haplotype-wise analyses. In conclusion, we suggest that NOS1 might not contribute to the risk of METH-induced psychosis in the Japanese population.

Several investigations have suggested that abnormalities in glutamate neural transmission play a role in the pathophysiology of psychiatric disorders, including schizophrenia. The metabotropic glutamate 3 receptor (mGluR3) gene was reported to be associated with schizophrenia, and paranoid type schizophrenia has symptoms that are similar to those of methamphetamine-induced psychosis. This suggests that mGluR3 gene (GRM3) is a good candidate gene for the pathogenesis of methamphetamine-induced psychosis. To evaluate the association between GRM3 and methamphetamine-induced psychosis, we conducted a case-control study of Japanese samples (181 methamphetamine-induced psychosis and 232 controls). Methods: We selected one functional SNP (rs6465084), reported to be associated with prefrontal brain functioning, for an association analysis. Written informed consent was obtained from each subject. This study was approved by the ethics committees at Fujita Health University, Nagoya University Graduate School of Medicine and each participating member of the Institute of the Japanese Genetics Initiative for Drug Abuse (JGIDA). Results: We did not detect an association between rs6465084 in GRM3 and Japanese methamphetamine-induced psychosis. Conclusion: Our findings suggest that rs6465084 in GRM3 does not play a major role in the pathophysiology of methamphetamine-induced psychosis in the Japanese population. However, because we did not perform an association analysis based on linkage disequilibrium (LD) or a mutation scan of GRM3, a replication study using a larger sample and based on LD may be required for conclusive results.

Endothelial nitric oxide synthase (NOS3) is one of the enzymes influencing nitric oxide (NO) function in the human brain. NO is a gaseous neurotransmitter that is involved in a variety of mechanisms in the central nervous system, such as N-methyl-D-aspartate receptor activation and oxidative stress. The evidence from animal pharmacological studies and postmortem studies supports an association between NO and psychotic disorders. Methamphetamine (METH) use disorder is a known psychotic disorder, and we therefore conducted a gene-based case-control study between tagging single nucleotide polymorphisms (SNPs) (rs2070744, rs1799983) in NOS3 and METH-induced psychosis in Japanese subjects (183 with METH-induced psychosis and 267 controls). Written informed consent was obtained from each subject. No significant association was found between any tagging SNP in NOS3 and METH-induced psychosis in the allele/genotype-wise or haplotype-wise analyses. In conclusion, we suggest that NOS3 might not contribute to the risk of METH-induced psychosis in the Japanese population. ©2011 Bentham Science Publishers Ltd.

Several investigations have reported associations between serotonin 1A (5-HT1A) receptor and major psychiatric disorders, such as schizophrenia and bipolar disorder (BP), making the 5-HT1A receptor gene (HTR1A) a good candidate gene for the pathophysiology of schizophrenia and BP. To evaluate the association between HTR1A and schizophrenia and BP, we conducted a case-control study of Japanese population samples with two single- nucleotide polymorphisms (SNPs), including rs6295 (C-1019G) in HTR1A. In addition, we conducted a meta-analysis of rs6295, which has been examined in other studies. Using one functional single- nucleotide polymorphism (SNP; rs6295) and one tagging SNP (rs878567), we conducted a genetic association analysis of case-control samples (857 schizophrenic patients, 1028 BP patients and 1810 controls) in the Japanese population. Two association studies for schizophrenia and three association studies for BP, including this study, met our criteria for the meta-analysis of rs6295. We found an association between HTR1A and Japanese BP in a haplotype-wise analysis, the significance of which remained after Bonferroni correction. In addition, we detected an association between rs6295 and BP in the meta-analysis (fixed model: P(Z) = 0.000400). However, we did not detect an association between HTR1A and schizophrenia in the allele/genotype-wise, haplotype-wise or meta-analysis. HTR1A may play an important role in the pathophysiology of BP, but not schizophrenia in the Japanese population. In the meta-analysis, rs6295 in HTR1A was associated with BP patients. Crown Copyright (C) 2010 Published by Elsevier Ireland Ltd. All rights reserved.

Background: Altered serotonergic neural transmission is hypothesized to be a susceptibility factor for psychotic disorders such as schizophrenia. The serotonin 6 (5-HT6) receptor is therapeutically targeted by several second generation antipsychotics, such as clozapine and olanzapine, and D-amphetamine-induced hyperactivity in rats is corrected with the use of a selective 5-HT6 receptor antagonist. In addition, the disrupted prepulse inhibition induced by D-amphetamine or phencyclidine was restored by 5-HT6 receptor antagonist in an animal study using rats. These animal models were considered to reflect the positive symptoms of schizophrenia, and the above evidence suggests that altered 5-HT6 receptors are involved in the pathophysiology of psychotic disorders. The symptoms of methamphetamine (METH)-induced psychosis are similar to those of paranoid type schizophrenia. Therefore, we conducted an analysis of the association of the 5-HT6 gene (HTR6) with METH-induced psychosis. Method: Using five tagging SNPs (rs6693503, rs1805054, rs4912138, rs3790757 and rs9659997), we conducted a genetic association analysis of case-control samples (197 METH-induced psychosis patients and 337 controls) in the Japanese population. The age and sex of the control subjects did not differ from those of the methamphetamine dependence patients. Results: rs6693503 was associated with METH-induced psychosis patients in the allele/genotype-wise analysis. Moreover, this association remained significant after Bonferroni correction. In the haplotype-wise analysis, we detected an association between two markers (rs6693503 and rs1805054) and three markers (rs6693503, rs1805054 and rs4912138) in HTR6 and METH-induced psychosis patients, respectively. Conclusion: HTR6 may play an important role in the pathophysiology of METH-induced psychosis in the Japanese population. Crown Copyright (C) 2010 Published by Elsevier Ireland Ltd. All rights reserved.