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Background: Individual differences in serotonin 7 receptor (5-HT7R) may result in variable response to antipsychotics with 5-HT7R antagonism. This study investigated the relationship between single nucleotide polymorphisms (SNPs) in the 5-HT7R gene (HTR7) and the efficacy of second-generation antipsychotic drugs with a high affinity for this receptor in Japanese schizophrenia., Methods: Perospirone or aripiprazole was administered to 100 patients with schizophrenia in a randomized controlled study. All patients were genotyped for three candidate SNPs (rs12412496, rs7916403, and rs1935349). Patient improvement on the Positive and Negative Syndrome Scale (PANSS) total score at 12 weeks was assessed as the primary outcome. PANSS 5-factor scores were investigated as the secondary outcome., Results: Improvement on the PANSS total score and genetic polymorphisms showed no correlation. The rs12412496-rs7916403-rs1935349 A-T-A haplotype was correlated with worse improvement in the cognition score (haplotype frequency: 0.285, p = 0.046, permuted p = 0.043)., Conclusion: Our results show that HTR7 variants are not related to the overall improvement in schizophrenia symptoms., (© 2015 S. Karger AG, Basel.)

Objective: To compare postprandial efficacy in type 2 diabetic patients given mitiglinide and sitagliptin, both of which are known to improve postprandial hyperglycemia, by using continuous glucose monitoring (CGM)., Methods: Eleven patients with type 2 diabetes were given mitiglinide 10 mg three times a daily or sitagliptin 50 mg once a day for 1 month and were hospitalized for 4 days and evaluated by CGM. On discharge, they were crossed over to the other regimen for 1 month of treatment/4 days of evaluation. The CGM data were used to compare each parameter for glycemic variability., Results: The patients were 60 ± 10 (mean ± SD) years old, and had HbA1c value 7.3 ± 0.9%. The pre-meal glucose levels before lunch were significantly lower with mitiglinide than with sitagliptin (116 ± 26/131 ± 34 mg/dl, p = 0.022). The AUC measuring over 140 mg/dl 3 h after breakfast (mitiglinide 4812 ± 4219/sitagliptin 7807 ± 6391 mg/dl·min, p = 0.042) and lunch (mitiglinide 5658 ± 5856/sitagliptin 8492 ± 7161, p = 0.050) was significantly lower with mitiglinide than with sitagliptin., Conclusions: A CGM-based comparison showed that mitiglinide and sitagliptin were different in their glucose-lowering effects, where mitiglinide significantly improved hyperglycemia after breakfast and lunch, and significantly lowered pre-meal glucose levels before lunch, compared to sitagliptin.

Objective: Treatment of bipolar depression is complicated by variable response and risk of switch to mania. Guidance is informed by the strength of evidence rather than by comparative data., Method: We performed a multiple-treatments meta-analysis of randomised, double-blind, controlled comparisons of 4-16 weeks in adults in bipolar depression. The primary efficacy outcome was effect size. The primary acceptability outcome was 'switch to mania'. Secondary outcomes were likelihood of response and withdrawals from trials., Results: Twenty-nine studies were included (8331 participants). Olanzapine + fluoxetine and olanzapine performed best on primary outcome measure being ranked highest for effect size. Switch to mania was least likely with ziprasidone and then quetiapine. Olanzapine + fluoxetine was also ranked the highest for response with lurasidone second, but olanzapine + fluoxetine and olanzapine had the optimal effect on response and withdrawal from treatment when the two parameters were considered together. Several treatments [monoamine oxidase inhibitors (MAOIs), ziprasidone, aripiprazole and risperidone] have limited or no therapeutic activity in bipolar depression., Conclusion: Olanzapine + fluoxetine should be first-line treatment. Olanzapine, quetiapine, lurasidone, valproate and selective serotonin re-uptake inhibitors are also recommended. Tricyclic antidepressants and lithium are worthy of consideration but lamotrigine (high risk of switching, less robust efficacy) and MAOIs, ziprasidone, aripiprazole and risperidone (no evidence of efficacy) should not be used., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Depression is the predominant pole of illness disability in bipolar disorder and, compared with acute mania, has less systematic research guiding treatment development. The aim of this review is to present the therapeutic options currently available for managing bipolar depression and to highlight areas of unmet need and future research., Methods: Literature search of PubMed, PsycINFO, and Cochrane databases and bibliographies from 2000 to August 2013 for treatments that have regulatory approval for bipolar depression or early controlled preliminary data on efficacy., Results: Treatment options for bipolar depression have increased over the last decade, most notably with regulatory approval for olanzapine/fluoxetine combination, quetiapine, and lurasidone. Conventional mood stabilizers lamotrigine and divalproex have meta-analyses suggesting acute antidepressant response. Manual-based psychotherapies also appear to be effective in treating bipolar depression. The therapeutic utility of unimodal antidepressants, as a class, for the treatment of patients with bipolar depression, as a group, remains to be confirmed. There is a substantially unmet need to develop new interventions that are efficacious, effective, and have low side effect burden., Limitations: Additional compounds are currently being developed that may ultimately be applicable to the treatment of bipolar depression and early open-trial data encourage further studies, but both of these topics are beyond the scope of this review., Conclusion: Future registrational trials will need to establish initial efficacy, but increasing interest for personalized or individualized medicine will encourage further studies on individual predictors or biomarkers of response., (Copyright © 2014 Elsevier B.V. All rights reserved.)

A major challenge in the treatment of major depressive episodes associated with bipolar disorder is differentiating this illness from major depressive episodes associated with major depressive disorder. Mistaking the former for the latter will lead to incorrect treatment and poor outcomes. None of the classic antidepressants, serotonin specific reuptake inhibitors, or serotonin-norepinephrine reuptake inhibitors have ever received regulatory approval as monotherapies for the treatment of bipolar depression. At present, there are only 3 approved medication treatments for bipolar depression: olanzapine/fluoxetine combination, quetiapine (immediate or extended release), and lurasidone (monotherapy or adjunctive to lithium or valproate). All 3 have similar efficacy profiles, but they differ in terms of tolerability. Number needed to treat (NNT) and number needed to harm (NNH) can be used to quantify these similarities and differences. The NNTs for response and remission for each of these interventions vs placebo range from 4 to 7, and 5 to 7, respectively, with overlap in terms of their 95% confidence intervals. NNH values less than 10 (vs placebo) were observed for the spontaneously reported adverse events of weight gain and diarrhea for olanzapine/fluoxetine combination (7 and 9, respectively) and somnolence and dry mouth for quetiapine (3 and 4, respectively). There were no NNH values less than 10 (vs placebo) observed with lurasidone treatment. NNH values vs placebo for weight gain of at least 7% from baseline were 6, 16, 58, and 36, for olanzapine/fluoxetine combination, quetiapine, lurasidone monotherapy, and lurasidone combined with lithium or valproate, respectively. Individualizing treatment decisions will require consideration of the different potential adverse events that are more likely to occur with each medication. The metric of the likelihood to be helped or harmed (LHH) is the ratio of NNH to NNT and can illustrate the tradeoffs inherent in selecting medications. A more favorable LHH was noted for treatment with lurasidone. However, OFC and quetiapine monotherapy may still have utility in high urgency situations, particularly in persons who have demonstrated good outcomes with these interventions in the past, and where a pressing clinical need for efficacy mitigates their potential tolerability shortcomings. In terms of maintenance therapy, adjunctive quetiapine is the only agent where the NNT vs lithium or valproate alone is less than 10 for both the prevention of mania and the prevention of depression.

Lurasidone is a new second-generation antipsychotic approved in October 2010 by the Food and Drug Administration and in March 2014 by the European Medicines Agency for the treatment of schizophrenia. Like other second-generation antipsychotics, lurasidone is an antagonist of D2 dopamine and 5HT2A serotonin receptors, but differs from the other second-generation antipsychotics in its action profile for certain receptors. Lurasidone is the second-generation antipsychotic with the greatest affinity for 5HT7 receptors and has a low affinity for α1 and α2C-adrenergic and 5HT2C serotonin receptors, and no affinity for histaminergic H1 or muscarinic M1 receptors. Lurasidone has demonstrated its efficacy in several short-term studies in acute schizophrenia with significantly reducing total scores of Positive and Negative Syndrome Scale (PANSS) and Brief Psychiatric Rating Scale (BPRS) compared with placebo. Early improvement was observed by days 3-7 for the 80-160 mg/day doses. Two studies with several methodological limitations showed that lurasidone might be involved in the improvement of cognitive performance in schizophrenic patients. Post hoc analysis of four pooled short-term studies showed significantly better effects on improving depressive symptoms associated with schizophrenia in patients treated with lurasidone as compared to patients treated with placebo. Lurasidone differs from the other second-generation antipsychotics by a good tolerability profile, in particular in terms of metabolic and cardiovascular profiles. Although results of the preclinical studies suggested that lurasidone had a low potential for causing clinically significant extrapyramidal symptoms, these were observed with a higher frequency than expected. It seems to have a significant though moderate link with the occurrence of akathisia, extrapyramidal symptoms, and hyperprolactinemia during initiation of treatment. This new tolerance profile greatly broadens the scope of second-generation antipsychotics and supports the view of some authors that the term second-generation antipsychotic is now outdated. Other therapeutic perspectives of lurasidone have been assessed, in particular in bipolar depression., (Copyright © 2014 L’Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.)

Infants with autism have difficulties performing joint visual attention (JVA), defined as following another person's pointing gesture and gaze. Some non-human primates (NHPs) can also perform JVA. Most preclinical research on autism spectrum disorders (ASD) has used rodents as animal models of this social interaction disorder. However, models using rodents fail to capture the complexity of social interactions that are disrupted in ASD. Therefore, JVA impairment in NHPs might be a more useful model of ASD. The aim of this study was to develop an appropriate and convenient ASD model with common marmosets. We first tested whether marmosets were capable of performing JVA. Subsequently, we administered ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, to induce JVA impairment and investigated the effects of lurasidone, a newer antipsychotic agent, on the JVA impairments. An apparatus was constructed using 4 white boxes, which were attached to the corners of a frame. All boxes had a hinged door, and marmosets could easily obtain a reward by pushing the door. An experimenter pointed and gazed at the boxes to inform the marmosets which box contained the reward. Their behavior was scored according to the number of incorrect choices. The JVA score was significantly higher in the cued vs. uncued tasks. Ketamine significantly decreased the JVA score, but lurasidone significantly reversed this effect. These findings suggest that this experimental system could be a useful animal model of neuropsychiatric disorders characterized by NMDA-receptor signaling, including ASD, and that lurasidone might be effective for some aspects of ASD., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: The effects of the mitiglinide/voglibose fixed-dose combination on postprandial glycemic/metabolic responses in patients with type 2 diabetes mellitus (T2DM) treated with dipeptidyl peptidase-4 (DPP-4) inhibitors are unknown., Methods: Twelve T2DM patients treated with a DPP-4 inhibitor underwent identical meal tolerance tests (MTTs) at breakfast, lunch and dinner, before and 2 - 3 weeks after treatment with a fixed-dose combination of mitiglinide 10 mg and voglibose 0.2 mg (combination). Patients were randomized in a cross-over fashion to administer the combination either three-times-daily before each meal or twice-daily before breakfast and dinner. Glycemic/metabolic responses were evaluated at 0, 30, 60 and 120 min in each MTT., Results: Three-times-daily administration of the combination significantly suppressed postprandial hyperglycemia after each meal, particularly after lunch and dinner. Active glucagon-like peptide-1 levels increased significantly after each meal, as did early-phase insulin secretion without excessive insulin secretion. Postprandial hyperglycemia after lunch was significantly greater after twice-daily than three-times-daily administration, but there were no clinically relevant differences in other metabolic responses., Conclusion: This study revealed that adding the mitiglinide/voglibose combination to a DPP-4 inhibitor elicited additive improvements in postprandial glycemic/metabolic responses assessed using MTTs at breakfast, lunch and dinner with identical meal compositions.

Aim: To investigate the efficacy of tandospirone in patients with irritable bowel syndrome-diarrhea (IBS-D) and anxiety in a prospective, randomized, controlled study., Methods: Two hundred patients with IBS-D and moderate anxiety were randomized to receive pinaverium and tandospirone (arm A) or pinaverium and placebo (arm B). Tandospirone or placebo was given thrice daily at a fixed dose of 10 mg and pinaverium was given thrice daily at a fixed dose of 50 mg. The duration of treatment was 8 wk. Patients were assessed for abdominal pain and diarrhea. Anxiety was evaluated using the Hamilton Rating Scale for Anxiety (HAM-A). The primary study endpoints were response rates for abdominal pain and diarrhea. The secondary study endpoints were response rates for anxiety. Adverse events were also evaluated., Results: One hundred and seventy of 200 patients (82 patients in arm A and 88 patients in arm B) completed the study. Demographic and baseline characteristics of the 200 participants were comparable in the two arms. At week 8, the overall response rate for abdominal pain and diarrhea was 52.0% for arm A and 37.0% for arm B (P < 0.05). The HAM-A score showed that the response rate was 61.0% for arm A and 21.0% for arm B (P < 0.01). The treatments were well tolerated and no significant adverse events were reported., Conclusion: Tandospirone is effective and can be combined with pinaverium in IBS-D patients with anxiety.

Objective: Postprandial hyperglycemia and blood glucose fluctuations increase the risk of macroangiopathy in patients with type 2 diabetes mellitus (T2DM). However, few studies have examined the effects of oral hypoglycemic drugs on blood glucose fluctuations in daily life., Methods: Twenty-nine T2DM patients treated with acarbose were randomized to receive either sitagliptin (14 patients) or mitiglinide (15 patients) together with acarbose for 4 weeks. Patients were then switched to a combination of 10 mg mitiglinide and 0.2 mg voglibose for 4 weeks. All patients wore a continuous glucose monitoring (CGM) device for 5 - 7 days in week 3 of each treatment period., Results: The percentage of blood glucose levels in the hyperglycemic range, blood glucose indices derived from 24-h CGM profiles and the glycemic parameters (HbA1c, glycated albumin and fasting plasma glucose) were significantly improved by adding sitagliptin or mitiglinide to ongoing acarbose therapy. These parameters also tended to improve in the mitiglinide/voglibose combination period., Conclusion: Daily blood glucose fluctuations were significantly improved by adding sitagliptin or mitiglinide to acarbose, and improved after switching to the mitiglinide/voglibose combination. Larger controlled studies are needed to verify the effects of adding sitagliptin or mitiglinide to acarbose on glucose fluctuations.

The majority of patients with bipolar disorder spend a lot of time in depressive episodes that impose a great burden on patients, caregivers, and society and accounts for the largest part of the morbidity-mortality of the illness. Lurasidone is an atypical antipsychotic with a potent binding affinity as antagonist for D2, 5-HT2A, 5-HT7, and partial agonist at 5-HT1A receptors. Affinity for other receptors as H1 and muscarinic were negligible. Lurasidone was approved in 2010 for the treatment of schizophrenia and recently, 2013, for bipolar depression in monotherapy and an adjunct to lithium or valproate. Clinical trials have established that lurasidone adjuvant to lithium or valproate has more efficacy than the placebo and is associated with minimal weight gain and no clinically meaningful alterations in glucose, lipids, or the QT interval. Additional studies are desirable to know the clinical profile of lurasidone in long-term treatment, in patients with bipolar II disorders, and versus other antipsychotic agents.

Objective: The aim of this analysis was to compare the effects of 2 atypical antipsychotic agents, lurasidone (80 mg/d or 160 mg/d) and quetiapine XR (600 mg/d), on daytime alertness, and to evaluate the effects of daytime sleepiness on treatment outcomes in patients with an acute exacerbation of schizophrenia., Methods: Patients who met Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision (DSM-IV-TR) criteria for schizophrenia were randomized to 6 weeks of double-blind treatment with fixed doses of lurasidone 80 mg/d (n = 125), lurasidone 160 mg/d (n = 121), quetiapine XR 600 mg/d (n = 119), or placebo (n = 121), all dosed once daily in the evening, with food. Daytime sleepiness was assessed using the Epworth Sleepiness Scale (ESS)., Results: Daytime sleepiness improved in the lurasidone and placebo-treated groups but worsened in the quetiapine XR treatment group when compared to placebo (p = 0.001) and to either dose of lurasidone (both p < 0.01). Sedation associated with quetiapine XR treatment mediated an improvement in agitation [assessed by the Positive and Negative Syndrome Scale-Excitement (PANSS-EC) subscale] and a worsening in functional capacity [assessed by the University of California-San Diego (UCSD) Performance-Based Skills Assessment-Brief Version (UPSA-B) total score]; these mediating relationships were not observed for the lurasidone or placebo treatment groups., Conclusion: In this 6-week double-blind study, treatment with lurasidone 80 mg or 160 mg, administered once daily in the evening, was associated with a reduction in daytime sleepiness similar in magnitude to placebo, while quetiapine XR 600 mg/d was associated with a significant increase in daytime sleepiness, compared to both lurasidone dose groups and placebo. Daytime sleepiness was associated with improvement in agitation and worsening in functional capacity for quetiapine XR, but not lurasidone or placebo-treated patients.

Unlabelled: OBJECTIVE/INTRODUCTION: Lurasidone is an atypical antipsychotic medication approved for the treatment of schizophrenia over a dose range of 40-160 mg/day. This study examined D2 receptor occupancy and its association with clinical improvement and side effects in patients with schizophrenia or schizoaffective disorder following repeated doses of 80, 120, or 160 mg/day of lurasidone., Methods: Twenty-five patients with The Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) diagnoses of schizophrenia or schizoaffective disorder were washed out of their antipsychotic medications (5 half-lives) and randomly assigned to 80, 120, or 160 mg/day of lurasidone. Subjects were imaged with 18F-fallypride at baseline and at steady-state lurasidone treatment to determine D2 receptor occupancy., Results: Blood lurasidone concentration (plus major metabolite), but not dose, significantly correlated with D2 receptor occupancy. D2 receptor occupancy in several subcortical structures is associated with positive but not negative symptom improvement or the presence of movement symptoms., Discussion: Blood concentrations greater than 70 ng/mL may be required to achieve a 65% occupancy level in subcortical areas. Intersubject blood concentrations at fixed dose were highly variable and may account for the lack of dose correlations., Conclusions: Positron emission tomography (PET) occupancy data suggest that greater than 65% occupancy can be achieved across the dose range of 80-160 mg/day and that some patients require higher doses to achieve antipsychotic efficacy; this finding supports prior randomized clinical trial results.

Patients with bipolar disorder are symptomatic about half of the time, experiencing depression more often than mania/hypomania. Because patients usually seek treatment during a depressive episode (rather than a manic episode), bipolar depression is commonly misdiagnosed as unipolar depression. Providing an accurate and timely bipolar depression diagnosis is critical for the proper treatment of the patient. Some FDA-approved treatments are helpful during acute and maintenance phases of therapy, but there is a significant unmet need for effective bipolar depression treatments with favorable side-effect profiles. Newer agents offer the promise of improvements in tolerability, but additional research is needed to actualize this promise into better treatments for patients struggling with bipolar depression., (© Copyright 2014 Physicians Postgraduate Press, Inc.)

Purpose of Review: Heat shock protein 90 (Hsp90) protects cellular proteins from degradation by the ubiquitin-proteasome system in conditions of stress. Many cancers have increased expression of Hsp90 to ensure their malignant phenotype of increased proliferation, decreased apoptosis, and metastatic potential by conservation of proteins like epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2, anaplastic lymphoma kinase (ALK), v-Raf murine sarcoma viral oncogene homologue B1, AKT, B-cell lymphoma 2, and cell cycle proteins. This review discusses recent developments in the strategy of Hsp90 inhibition as a targeted therapy in non-small-cell lung cancer (NSCLC)., Recent Findings: Hsp90 inhibitors result in growth inhibition and tumor regression in NSCLC cell lines and tumor xenograft models, both as monotherapy and in combination with other drugs. Hsp90 inhibition has particular efficacy in molecular subtypes of NSCLC, such as EGFR-mutated and ALK-rearranged NSCLC. IPI-504 and ganetespib have activity in NSCLC both as monotherapy and in combination with docetaxel., Summary: Preclinical studies and early clinical trials have confirmed the efficacy of Hsp90 inhibition as a targeted therapy in NSCLC. Ongoing trials will further define the utility of Hsp90 inhibitors in NSCLC.

Background: Patients with schizophrenia frequently switch between antipsychotics, underscoring the need to achieve and maintain important treatment outcomes such as health-related quality of life (HRQoL) following the switch. This analysis evaluated HRQoL changes among patients with schizophrenia switched from their current antipsychotic to lurasidone., Methods: Stable but symptomatic outpatients with schizophrenia were switched from their current antipsychotic to lurasidone in a six-week, open-label trial. HRQoL was assessed using two validated patient-reported measures, the Personal Evaluation of Transitions in Treatment (PETiT) scale and the Short-Form 12 (SF-12). Total and domain scores (psychosocial function and adherence-related attitude) were assessed using the PETiT scale; patients' mental and physical component summary scores (MCS and PCS) were assessed using the SF-12. Changes in HRQoL from baseline to study endpoint were compared using ANCOVA, with baseline score, treatment, and pooled site as covariates. Changes were assessed among all patients and those switched from specific antipsychotics to lurasidone., Results: The analysis included 235 patients with data on the PETiT and SF-12 who had received ≥ 1 dose of lurasidone. Statistically significant improvements were observed from baseline to study endpoint on the PETiT total (mean change [SD]: 3.2 [8.5]) and psychosocial functioning (2.5 [6.9]) and adherence-related attitude (0.7 [2.6]) domain scores (all p ≤ 0.002). When examined by preswitch antipsychotic, significant improvements in PETiT total scores were observed in patients switched from quetiapine, risperidone, aripiprazole, and ziprasidone (all p < 0.03) but not olanzapine (p = 0.893). Improvements on the SF-12 MCS score were observed for all patients (mean change [SD]: 3.7 [11.5], p < 0.001) and for those switched from quetiapine or aripiprazole (both p < 0.03). The SF-12 PCS scores remained comparable to those at baseline in all patient groups., Conclusions: These findings indicate that patients switching from other antipsychotics to lurasidone experienced statistically significant improvement of HRQoL, based on PETiT scores, within six weeks of treatment. Patient health status remained stable with respect to the SF-12 physical component and showed improvement on the mental component. Changes in HRQoL varied based on the antipsychotic used before switching to lurasidone., Trial Registration: NCT01143077.

Background: The present study aimed to evaluate cardiometabolic risks [weight gain, blood lipid levels (total cholesterol and triglycerides), blood glucose levels, hemoglobin A1c (HbA1c) 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 HbA1c 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: Meal tolerance tests (MTTs) are usually conducted at breakfast after overnight fasting in type 2 diabetes mellitus (T2DM) patients, but differences in postprandial glycemic responses between meals have been reported., Objective: We conducted MTTs at breakfast, lunch, and dinner to examine the effects of a fixed combination of 10 mg mitiglinide/0.2 mg voglibose (the combination) on glycemic/metabolic responses to meals during the day in T2DM patients. MTTs with unified meals were conducted in 11 T2DM patients before and after 4 weeks of treatment with the combination administered thrice daily before meals. Glycemic/metabolic profiles measured before and at 30, 60, and 120 min after each meal were compared between each meal and between the baseline and treatment periods., Results and Conclusion: The combination significantly reduced postprandial hyperglycemia after each meal. Postprandial AUC0 - 120 min for insulin significantly decreased after lunch and dinner compared with after breakfast, while insulin levels significantly increased at only 30 min after breakfast and dinner. The combination also significantly increased postprandial C-peptide and active glucagon-like peptide-1 levels, and reduced free fatty acid and triglyceride levels, but did not significantly affect glucagon levels compared with baseline, confirming that treatment with the combination improves postprandial responses in Japanese T2DM patients.

Background: Prior to recent FDA approval of lurasidone for treatment of bipolar depression there were only two approved treatments for this condition (quetiapine and olanzapine-fluoxetine combination), and these were as likely to provide therapeutic benefit as adverse effects. We assessed the efficacy, safety, and tolerability of lurasidone for major depressive episodes associated with bipolar I disorder, using number needed to treat (NNT, for benefits), number needed to harm (NNH, for harms), and likelihood of being helped or harmed (LHH, ratio of NNH to NNT, for trade-offs between benefits vs. harms)., Methods: Data was collected from two 6-week multicenter, randomized, double-blind, placebo-controlled, flexibly-dosed acute bipolar I depression studies, one using lurasidone monotherapy at 20-60mg/d or 80-120mg/d, and the other using lurasidone 20-120mg/d adjunctive to lithium or valproate. The NNT or NNH was calculated for lurasidone vs. placebo for the following dichotomous outcomes: response (≥50% reduction from baseline on Montgomery Asberg Depression Rating Scale (MADRS) total score); remission (final MADRS total score ≤12); discontinuation due to an adverse event (AE); weight gain ≥7% from baseline; incidence of spontaneously reported AEs; and incidence of total cholesterol ≥240mg/dl, low-density lipoprotein cholesterol ≥160mg/dl, fasting triglycerides ≥200mg/dl and glucose ≥126mg/dl post-baseline., Results: NNT vs. placebo for response was 5 for lurasidone monotherapy (both dose ranges) and 7 for adjunctive therapy. NNT vs. placebo for remission for lurasidone monotherapy was 6 for 20-60mg/d and 7 for 80-120mg/d and 7 for adjunctive lurasidone. NNH vs. placebo for discontinuation due to an AE for lurasidone monotherapy was 642 for 20-60mg/d and -181 for 80-120mg/d, and for adjunctive lurasidone was -54 (negative NNH denotes an advantage for lurasidone). Lurasidone was not associated with any clinically meaningful mean weight or metabolic changes compared to placebo; NNH vs. placebo for weight gain ≥7% was 29 for 20-60mg/d and 5550 for 80-120mg/d and 42 for adjunctive lurasidone. The three most frequently occurring AEs with the largest difference in incidence for lurasidone vs. placebo were nausea, akathisia, and somnolence, with NNH values for lurasidone vs. placebo ranging from 11 (nausea with lurasidone monotherapy 80-120mg/d) to 130 (somnolence with lurasidone monotherapy 20-60mg/d). LHH was substantially and consistently >1 (indicating benefit being more likely than harm) when contrasting response or remission vs. AEs or weight gain., Limitations: Additional studies, including longer-term and open-label, "real world" data is needed to confirm the results reported here., Conclusions: NNT, NNH, and LHH help quantify relative benefits (efficacy) and harms (side effects), thus placing lurasidone findings in research studies into clinical perspective. Lurasidone, compared to other treatments approved for bipolar depression, yielded comparable benefits (all had single-digit NNT vs. placebo for response or remission), and less risk of harm (double-digit or greater NNHs with lurasidone compared to single-digit NNHs for sedation with quetiapine and for ≥7% weight gain with olanzapine-fluoxetine combination), and thus a substantially more favorable LHH (> or >>1) with lurasidone monotherapy and adjunctive therapy, compared to quetiapine and olanzapine-fluoxetine combination (LHH

Objective: The authors evaluated the efficacy and safety of lurasidone in the treatment of patients with major depressive episodes associated with bipolar I disorder., Method: Patients were randomly assigned to receive double-blind treatment with lurasidone (20-60 mg/day [N=166] or 80-120 mg/day [N=169]) or placebo (N=170) for 6 weeks. Primary and key secondary endpoints were change from baseline to week 6 on the Montgomery-Åsberg Depression Rating Scale (MADRS) and depression severity score on the Clinical Global Impressions scale for use in bipolar illness (CGI-BP), respectively., Results: Lurasidone treatment significantly reduced mean MADRS total scores at week 6 for both the 20-60 mg/day group (-15.4; effect size=0.51) and the 80-120 mg/day group (-15.4; effect size=0.51) compared with placebo (-10.7). Similarly, lurasidone treatment resulted in significantly greater endpoint reduction in CGI-BP depression severity scores for both the 20-60 mg/day group (-1.8; effect size=0.61) and the 80-120 mg/day group (-1.7; effect size=0.50) compared with placebo (-1.1). Both lurasidone groups also experienced significant improvements compared with placebo in anxiety symptoms and in patient-reported measures of quality of life and functional impairment. Discontinuation rates due to adverse events were similar in the 20-60 mg/day (6.6%), 80-120 mg/day (5.9%), and placebo (6.5%) groups. The most frequent adverse events associated with lurasidone were nausea, headache, akathisia, and somnolence. Minimal changes in weight, lipids, and measures of glycemic control were observed with lurasidone., Conclusion: Monotherapy with lurasidone in the dosage range of 20-120 mg/day significantly reduced depressive symptoms in patients with bipolar I depression. Lurasidone was well tolerated, with few changes in weight or metabolic parameters.

OBJECTIVE Few studies have been reported that support the efficacy of adjunctive therapy for patients with bipolar I depression who have had an insufficient response to monotherapy with mood-stabilizing agents. The authors investigated the efficacy of lurasidone, a novel antipsychotic agent, as adjunctive therapy with lithium or valproate for the treatment of bipolar I depression. METHOD Patients were randomly assigned to receive 6 weeks of double-blind adjunctive treatment with lurasidone (N=183) or placebo (N=165), added to therapeutic levels of either lithium or valproate. Primary and key secondary endpoints were change from baseline to week 6 on the Montgomery-Åsberg Depression Rating Scale (MADRS) and depression severity score on the Clinical Global Impressions scale for use in bipolar illness (CGI-BP), respectively. RESULTS Lurasidone treatment significantly reduced mean MADRS total score at week 6 compared with the placebo group (-17.1 versus -13.5; effect size=0.34). Similarly, lurasidone treatment resulted in significantly greater endpoint reduction in CGI-BP depression severity scores compared with placebo (-1.96 versus -1.51; effect size=0.36) as well as significantly greater improvement in anxiety symptoms and in patient-reported measures of quality of life and functional impairment. Discontinuation rates due to adverse events were 6.0% and 7.9% in the lurasidone and placebo groups, respectively. Adverse events most frequently reported for lurasidone were nausea, somnolence, tremor, akathisia, and insomnia. Minimal changes in weight, lipids, and measures of glycemic control were observed during treatment with lurasidone. CONCLUSIONS In patients with bipolar I depression, treatment with lurasidone adjunctive to lithium or valproate significantly improved depressive symptoms and was generally well tolerated.

Patients with psychiatric disorders, including schizophrenia, are reported to suffer from sleep disorders. In this study, we investigated the effects of lurasidone, an atypical antipsychotic, on sleep architecture in rats using sleep electroencephalography. The course of sleep in rats was classified into 3 stages: WAKE, non-rapid eye movement (NREM) sleep, and rapid eye movement (REM) sleep. Lurasidone shortened REM duration and prolonged the mean duration of one bout in WAKE and NREM. Quantitative frequency band analysis during NREM sleep revealed that lurasidone increases slow waves and decreases fast waves. These results suggest that lurasidone ameliorates sleep disorders associated with psychosis.

Objectives/introduction: Herein we review the evidence supporting Food and Drug Administration (FDA) approved and emerging treatments for bipolar depression., Methods: A PubMed search of all English-language articles published up to July 2013 was conducted. The search terms were quetiapine, olanzapine-fluoxetine, olanzapine, lurasidone, ketamine, modafinil/armodafinil, and lamotrigine. The search was augmented with a manual review of relevant article reference lists, as well as posters presented at national and international meetings. Articles selected for review were based on the adequacy of sample size, the use of standardized diagnostic instruments, validated assessment measures, and overall manuscript quality., Results: Olanzapine-fluoxetine combination (OFC), quetiapine, and lurasidone are FDA-approved for the acute treatment of bipolar depression. Lurasidone is the most recently approved agent for bipolar depression. Olanzapine-fluoxetine combination and quetiapine are approved as single modality therapies while lurasidone is approved as a monotherapy and as an adjunct to lithium or divalproex. The overall effect size of the 3 treatments in mitigating depressive symptoms is similar. Clinically significant weight gain and metabolic disruption as well as sedation are significant limitations of OFC and quetiapine. The minimal propensity for weight gain as well as the metabolic neutrality of lurasidone in the bipolar population is a clinically significant advantage. Evidence also supports lamotrigine with compelling evidence as an adjunct to lithium and in recurrence prevention paradigm; suggested evidence also exists for ketamine and modafinil/armodafinil; notwithstanding, these treatments remain investigational., Conclusion: Relatively few agents are FDA-approved for bipolar depression. The selection and sequencing of agents in bipolar depression should give primacy to those agents that are FDA-approved. Further refinement of the selection process will need to pay careful attention to the relative hazards of weight gain and metabolic disruption in this highly susceptible population. Other agents with differential mechanisms (eg, ketamine) offer a promising alternative in bipolar depression.

Naturally occurring smallpox has been eradicated but remains a considerable threat as a biowarfare/bioterrorist weapon (F. Fleck, Bull. World Health Organ. 81:917-918, 2003). While effective, the smallpox vaccine is currently not recommended for routine use in the general public due to safety concerns (http://www.bt.cdc.gov/agent/smallpox/vaccination). Safe and effective countermeasures, particularly those effective after exposure to smallpox, are needed. Currently, SIGA Technologies is developing the small-molecule oral drug, tecovirimat (previously known as ST-246), as a postexposure therapeutic treatment of orthopoxvirus disease, including smallpox. Tecovirimat has been shown to be efficacious in preventing lethal orthopoxviral disease in numerous animal models (G. Yang, D. C. Pevear, M. H. Davies, M. S. Collett, T. Bailey, et al., J. Virol. 79:13139-13149, 2005; D. C. Quenelle, R. M. Buller, S. Parker, K. A. Keith, D. E. Hruby, et al., Antimicrob. Agents Chemother., 51:689-695, 2007; E. Sbrana, R. Jordan, D. E. Hruby, R. I. Mateo, S. Y. Xiao, et al., Am. J. Trop. Med. Hyg. 76:768-773, 2007). Furthermore, in clinical trials thus far, the drug appears to be safe, with a good pharmacokinetic profile. In this study, the efficacy of tecovirimat was evaluated in both a prelesional and postlesional setting in nonhuman primates challenged intravenously with 1 × 10(8) PFU of Variola virus (VARV; the causative agent of smallpox), a model for smallpox disease in humans. Following challenge, 50% of placebo-treated controls succumbed to infection, while all tecovirimat-treated animals survived regardless of whether treatment was started at 2 or 4 days postinfection. In addition, tecovirimat treatment resulted in dramatic reductions in dermal lesion counts, oropharyngeal virus shedding, and viral DNA circulating in the blood. Although clinical disease was evident in tecovirimat-treated animals, it was generally very mild and appeared to resolve earlier than in placebo-treated controls that survived infection. Tecovirimat appears to be an effective smallpox therapeutic in nonhuman primates, suggesting that it is reasonably likely to provide therapeutic benefit in smallpox-infected humans.

Serotonin 1A receptor (5-HT1A-R) agonists have been demonstrated to elicit antidepressant and anxiolytic effects. Lactate has been considered to play a major role in energy metabolism in the brain. Specifically, extracellular lactate concentrations (eLAC) have been suggested to reflect neural activity. Mild physical (e.g., handling) and non-physical (e.g., psychological) stressors have been shown to increase eLAC in several brain regions, including the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA). Using in vivo microdialysis technique, we measured eLAC in the mPFC and BLA of rats under electric footshock stress to clarify the effect of repeated injection procedure (saline, once daily for 14 days) as a stressor on brain energy metabolism. Then, we examined the effect of chronic treatment with tandospirone, a 5-HT1A-R partial agonist, on eLAC during footshock stress in the mPFC. Footshock stress led to an increase in eLAC both in the mPFC and BLA in rats without injections. Repeated saline injection increased basal eLAC in the BLA, while footshock-induced lactate increment was reduced. In the mPFC, repeated saline injection did not affect basal eLAC and footshock-induced eLAC increments. Chronic treatment with tandospirone, at 0.2 and 1.0 mg/kg/day, but not 2.0 mg/kg/day, attenuated footshock stress-induced eLAC elevation in the mPFC. These observations suggest that eLAC in the BLA is sensitive to repeated exposure to physical stress. Data also indicate chronic treatment with tandospirone diminishes acute energy demands during neural activation in the mPFC. The implications of the present findings in relation to clinical efficacy of 5-HT1A agonists are discussed., (© 2013.)

Background: An elevated PI/I ratio is attributable to increased secretory demand on β-cells. However, the effect of postprandial targeting therapy on proinsulin level is unknown. We evaluated the metabolic effect of glinide and sulfonylurea (SU) using the meal tolerance test (MTT)., Methods: MTT was applied to previously untreated Type 2 Diabetes Mellitus (T2DM) subjects. Twenty-two participants were given a test meal (450 kcal). Plasma glucose and insulin were measured at 0 (fasting), 30, 60, 120, and 180 min. Serum proinsulin and C-peptide immunoreactivity (CPR) were measured at 0 and 120 min. Postprandial profile was assessed at baseline and following 3 months treatment with either mitiglinide or glimepiride., Results: Plasma glucose level at 30, 60, 120, and 180 min was significantly improved by mitiglinide. Whereas, glimepiride showed a significant improve plasma glucose at 0, 180 min. Peak IRI shifted from 120 to 30 min by mitiglinide treatment. The pattern of insulin secretion was not changed by glimepiride treatment. Whereas mitiglinide did not affect the PI/I ratio, glimepiride tended to increase the PI/I ratio. Moreover, although mitiglinide did not affect PI/I ratio as a whole, marked reduction was noted in some patients treated by mitiglinide. PI/I ratio was reduced significantly in the responder group. The responder subgroup exhibited less insulin resistance and higher insulinogenic index at baseline than non-responders. Moreover, the triglyceride level of responders was significantly lower than that of non-responders., Conclusions: Mitiglinide improved postprandial insulin secretion pattern and thereby suppressed postprandial glucose spike. In T2DM patients with low insulin resistance and low triglyceride, mitiglinide recovered impaired β-cell function from the viewpoint of the PI/I ratio., Trial Registration Umin-Ctr: UMIN000010467.

Schizophrenia is a serious, chronic, and devastating mental illness with a substantial impact on psychological, physical, social, and economical areas of an individual and society. To treat such critical mental illness, a number of first-generation (typical) and second-generation (atypical) antipsychotics are currently available in the market. Despite such treatment options, most of patients with schizophrenia have a poor treatment outcome and become treatment resistant, causing continual deterioration on positive, negative, and cognitive symptoms, resulting in impairment of socio-occupational functioning. Hence, additional novel antipsychotics with better efficacy, safety, and tolerability profiles are needed to enable clinicians to diversify treatment options to improve treatment of schizophrenia. Recently, the 3 antipsychotics, including iloperidone (2009), asenapine (2009), and lurasidone (2010), have been approved by the US Food and Drug Administration. Two other atypical antipsychotics, including sertindole and blonanserin, are approved and used outside the United States for treatment of schizophrenia. Sertindole, after it has been voluntarily suspended by the manufacturer in 1998 due to its potential risk in causing cardiovascular-related death, was relaunched to the European market in 2005. More recently, blonanserin was approved in Japan (2008) and in Korea (2009) for the management of schizophrenia. Individual antipsychotic may have differential pros and cons compared with other antipsychotic in terms of efficacy, safety, tolerability, restoration of functional capacity, and economic aspect reflecting relapse prevention. The purpose of this review was to provide distinctive clinical characteristics and up-to-date of clinical trial data of the 5 novel atypical antipsychotics for the management of schizophrenia, which may deliver clinicians better understanding in the use of such atypical antipsychotics for the treatment of schizophrenia in clinical practice.

Objective: Although selective serotonin reuptake inhibitors are now established as first-line pharmacotherapy for social anxiety disorder (SAD), other agents with different mechanisms have shown promise in treating SAD. The aim of this study was to examine the efficacy and safety of tandospirone in treating adolescents with SAD., Methods: Adolescent patients meeting the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for SAD were randomly assigned (1:1) to open-label treatment with either tandospirone or sertraline for 8 weeks. The primary outcome measures were changes from baseline in the Hamilton Anxiety (HAM-A) scale and response using the Clinical Global Impression of Improvement (CGI-I) scale., Results: The adjusted mean change in HAM-A scores from baseline was indicating a significant improvement over baseline in both treatment arms (p < 0.0001). The mean CGI-I scale score at week was with no significant difference between the two arms (p = 0.42). Rates of response were 48.6% for tandospirone and 55.6% for sertraline using the CGI-I. Response rates were 37.1% for tandospirone and 41.7% for sertraline using a HAM-A response criterion (≥50% reduction). The adjusted mean change in Social Phobia Inventory scores from baseline was indicating a significant improvement over baseline in both treatment arms (p < 0.0001)., Conclusions: Tandospirone is safe and effective and appears non-inferior to sertraline for SAD in youths., (Copyright © 2013 John Wiley & Sons, Ltd.)

This double-blind study evaluated change in cognitive performance and functional capacity in lurasidone and quetiapine XR-treated schizophrenia patients over a 6-week, placebo-controlled study, followed by a 6-month, double-blind extension. Cognitive performance and functional capacity were assessed with the CogState computerized cognitive battery and the UPSA-B. Analyses were conducted for all subjects, as well as the subsample whose test scores met prespecified validity criteria. No statistically significant differences were found for change in the composite neurocognitive score for lurasidone (80 mg/day and 160 mg/day) groups, quetiapine XR and placebo in the full sample at week 6. For the evaluable sample (N = 267), lurasidone 160 mg was superior to both placebo and quetiapine on the neurocognitive composite, while lurasidone 80 mg, quetiapine XR, and placebo did not differ. UPSA-B scores were superior to placebo at 6 weeks for all treatments. In the double-blind extension study, analysis of the full sample showed significantly better cognitive performance in the lurasidone (40-160 mg) group compared to the quetiapine XR (200-800 mg) group at both 3 and 6 months. Cognitive and UPSA-B total scores were significantly correlated at baseline and for change over time. This is the first study to date where the investigational treatment was superior to placebo on both cognitive assessments and a functional coprimary measure at 6 weeks, as well as demonstrated superiority to an active comparator on cognitive assessments at 6 weeks and at 6 months of extension study treatment. These findings require replication, but are not due to practice effects, because of the placebo and active controls., (© 2013 Elsevier B.V. and ECNP. All rights reserved.)

Introduction: Mitiglinide , a rapid-acting insulin secretion-stimulating agent, is approved in Japan for the treatment of type 2 diabetes (T2DM). Rapid-acting insulin secretion-stimulating agents, also known as meglitinides, are not recommended as monotherapy, however, may be added to metformin therapy for those patients with continued postprandial hyperglycemia. Currently, repaglinide (Prandin®) and nateglinide (Starlix®) are the only US Food and Drug Administration-approved agents in this class of drugs., Areas Covered: This review describes the pharmacology, pharmacokinetics, efficacy, safety, and potential role in therapy of mitiglinide therapy. Phase II and III clinical studies have demonstrated that A1C levels should be expected to decrease by 0.17 - 1.1% with mitiglinide therapy. The most common adverse effects in these studies were hypoglycemia related., Expert Opinion: Meglitinides are limited by their cost, frequency of administration, and minimal available data assessing clinical impact; however, mitiglinide shows selective action on the pancreatic β-cells, has greater affinity for β-cells, and limited metabolism when compared to other meglitinides. These properties may allow more utility in patients with chronic kidney disease or at high risk of hypoglycemia. The primary role in therapy for mitiglinide is the treatment of elevated postprandial glucose in patients with T2DM.

Introduction: Lurasidone is a novel antipsychotic drug approved for the treatment of schizophrenia in adults. It is formulated into tablets, administered orally once/day (dose range 40-160 mg/day) does not require titration, but needs to be given with food to maximize its plasma exposure., Areas Covered: This review focuses on the preclinical discovery of lurasidone. Furthermore, the article provides analysis on the pharmacological, behavioral and molecular mechanisms of lurasidone and their contribution to its therapeutic advantages. The article is based on the literature reported in published preclinical and clinical studies, product labels, poster presentations and press releases., Expert Opinion: Lurasidone demonstrated high affinity for serotonin 5-HT(1A), 5-HT(2A), 5-HT₇, dopamine D₂ and adrenergic α(2C) receptors followed by α₁ and α(2A) receptors. The drug was active in animal models predictive of antipsychotic and antidepressant activities. In addition, it demonstrated procognitive effects, as it was effective in several animal models that assessed memory, cognition and executive functions in rats and in primates. At a cellular level, lurasidone promotes neuronal plasticity, can modulate epigenetic mechanisms controlling gene transcription, and increases the expression of the neurotrophic factor BDNF in cortical and limbic brain regions. Lurasidone's mechanisms of action might contribute to its unique psychopharmacological properties in the improved treatment of schizophrenia, and perhaps other psychiatric disorders.

Objective: To report a case of risperidone-induced Pisa syndrome in a patient with multiple sclerosis (MS) that resolved with lurasidone, recurred with chlorpromazine, and was complicated by possible drug-drug interactions., Case Summary: A 31-year-old white male with MS developed Pisa syndrome after years of treatment with risperidone at varying doses for behavioral symptoms associated with pervasive developmental disorder. The patient experienced improvement in symptoms after treatment was switched to lurasidone; however, due to psychiatric decompensation, a switch to chlorpromazine was made and Pisa syndrome recurred. To maintain control of the patient's behavioral symptoms, chlorpromazine was not discontinued., Discussion: Pisa syndrome is a rare adverse drug reaction induced most often by neuroleptic medications. The reaction is characterized by dystonia affecting cervical and lumbar musculature, resulting in flexion of the head and body to one side with axial rotation of the trunk. The etiology is believed to involve a dopaminergic-cholinergic imbalance. Most practitioners are not familiar with this syndrome, and it has not been reported previously in a patient with MS. Definitive diagnostic criteria and treatment have not been established. We identified 15 case reports involving risperidone, paliperidone, chlorpromazine, clomipramine, or valproic acid. The time to development of Pisa syndrome, patient demographics, dosing and titration of causative medications, approach to treatment, and resolution of Pisa syndrome varied widely in these reports. Dystonia in MS often presents differently than Pisa syndrome. The Naranjo probability scale indicated a probable relationship between either risperidone or chlorpromazine in each instance of Pisa syndrome in our patient., Conclusions: Pisa syndrome is a rare adverse drug reaction associated with neuroleptic medications. Our report highlights the importance of identifying this uncommon type of dystonia in order to consider modification of the medication regimen when appropriate.

Background: 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, D₄, and α₁-adrenergic receptor antagonist. To our knowledge, no meta-analysis addressing the efficacy and effectiveness of perospirone in schizophrenia has been published to date., Objective: 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., Methods: 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., Results: 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)., Conclusions: Our results suggest that although perospirone seems to be a well tolerated treatment, perospirone does not reduce PANSS score as much as other SGAs.

Purpose: To model the economic impact of annual relapses/relapse-related hospitalizations among adults with schizophrenia treated with lurasidone or quetiapine extended-release (XR)., Methods: A probabilistic model estimating per-patient-per-year (PPPY) direct mental healthcare (MH) cost differences due to relapses/relapse-related hospitalizations was developed using relapse and relapse-related hospitalization rates from a 12-month, double-blind, parallel-group, global comparison study of lurasidone vs quetiapine XR (all patients previously treated with lurasidone or quetiapine XR for 6 weeks). Analyses were conducted for both all subjects and clinical responders. Direct costs associated with inpatient and outpatient mental healthcare-related services were obtained from a large, prospective, observational study of schizophrenia treatment in usual-care settings for relapsing and non-relapsing patients, including psychiatric hospitalizations, emergency services, medication management, and outpatient individual therapy. Model robustness was tested using univariate and probabilistic sensitivity analyses., Results: Model-estimated PPPY MH cost savings associated with relapse-related hospitalization rates in all subjects were $3276 for lurasidone vs quetiapine XR. Lurasidone resulted in PPPY MH cost savings of $2702 vs quetiapine XR in all subjects, using relapse rates. Sensitivity analyses indicated lurasidone had lower 1-year MH costs than quetiapine XR in 100% and 99.7% of simulations, using relapse-related hospitalization rates and relapse rates, respectively, in all subjects. Similar results were seen in clinical responders., Limitations: The model represents a simplification of treatment patterns and response to treatment. Cost of treatment with lurasidone and quetiapine XR was not included in the model. Estimates of cost savings are likely conservative, as the model did not assess the impact of long-term cardiometabolic consequences. Indirect costs associated with relapses and non-mental health-related costs were also excluded from the model., Conclusion: Adults treated for schizophrenia with lurasidone are predicted to have lower 12-month MH costs compared to those treated with quetiapine XR due to fewer relapses and relapse-related hospitalizations.

Background and Objective: The objective of this study was to clarify the effects of mitiglinide on daily glycemic variability and oxidative stress markers in outpatients with type 2 diabetes mellitus that is insufficiently controlled by diet and/or non-insulin secretagogues., Methods: We enrolled 24 patients with type 2 diabetes whose glycemic control had been suboptimal [i.e. glycosylated hemoglobin (HbA(1c)) ≥ 6.9 %]. The patients were treated with mitiglinide 10 mg three times daily for 16 weeks. If their glycemic control was not improved at week 8, the dose of mitiglinide was increased to 20 mg three times daily. Daily glycemic variability was assessed by 7-point self-monitoring of blood glucose for 2 days, and standard deviation (SD), M value, and mean of daily differences(MODD) were calculated. Oxidative stress was assessed by oxidized low-density lipoprotein, pentosidine,urinary 8-iso-prostaglandin F2 alpha, and urinary 8-hydroxydeoxy guanosine., Results: After 16 weeks of mitiglinide treatment, the HbA(1c) level was significantly decreased (mean ± SD,7.4 ± 0.7 to 6.8 ± 0.5 %, P < 0.0001). Postprandial glucose excursion and glycemic variability were also significantly improved after mitiglinide treatment (all P < 0.05). The reductions in SD, M value, and MODD were 17, 50,and 48 %, respectively. There was a significant positive correlation between the change in HbA(1c) and change in SD during the study (r = 0.454, P = 0.03). There were no significant changes in oxidative stress markers., Conclusions: The present study supports the notion that mitiglinide improves postprandial glucose excursion and HbA(1c) level in patients with type 2 diabetes. In addition,we demonstrated that mitiglinide also effectively improves daily glycemic variability. The effect of mitiglinide on oxidative stress needs further investigation.

Prochlorperazine is often used to prevent opioid-induced nausea; however, this drug causes extrapyramidal symptoms. It is important to determine the incidence of such symptoms and identify coping mechanisms because these symptoms induce intense and possibly life-threatening patient suffering. The purpose of this study was to determine the incidences of nausea and extrapyramidal symptoms associated with the use of prochlorperazine and perospirone as preventive antiemetics when initiating opioid treatment(a sustained-release tablet of oxycodone at a dose of 10 mg/day)and to compare the benefits of the 2 drugs. A total of 100 cancer patients who received medical care from a physician in the palliative care department of our center between May 2007 and September 2008 were consecutively enrolled for a retrospective review of the medical records. Of the patients, 50 had received prochlorperazine treatment(10 or 15 mg/day, orally)and 50 had received perospirone treatment(4 or 8 mg/day, orally)concomitantly with oxycodone treatment(10 mg/day)on an in-patient or outpatient basis. The incidence of nausea and vomiting within 1 week after starting treatment with opioids and the extrapyramidal symptoms during treatment were evaluated. The results showed that the incidence of nausea and vomiting was 8. 0% for the prochlorperazine group and 4. 0% for the perospirone group, and this difference was not statistically significant; however, the incidence of extrapyramidal symptoms was significantly higher for the prochlorperazine group(14%)than for the perospirone group(0%). Furthermore, the extrapyramidal symptom observed in the prochlorperazine group was akathisia, which occurred within a week. The results of this study suggest that careful attention should be paid so as not to overlook akathisia when using prochlorperazine as an antiemetic in cancer patients and that atypical antipsychotics, such as perospirone, could be used as alternatives.

Background: The management of schizophrenia has seen significant strides over the last few decades, due to the increasing availability of a number of antipsychotics. Yet, the diminished efficacy in relation to the negative and cognitive symptoms of schizophrenia, and the disturbing adverse reactions associated with the current antipsychotics, reflect the need for better molecules targeting unexplored pathways., Purpose: To review the salient features of the recently approved antipsychotics; namely, iloperidone, asenapine, lurasidone and blonanserin., Methods: We discuss the advantages, limitations and place in modern pharmacotherapy of each of these drugs. In addition, we briefly highlight the new targets that are being explored., Results: Promising strategies include modulation of the glutamatergic and GABAergic pathways, as well as cholinergic systems., Conclusions: Although regulatory bodies have approved only a handful of antipsychotics in recent years, the wide spectrum of targets that are being explored could eventually bring out antipsychotics with improved efficacy and acceptability, as well as the potential to revolutionize psychiatric practice.

Objective: Compare long-term costs and outcomes of lurasidone to aripiprazole among adults with schizophrenia in the US who previously failed ≥1 atypical antipsychotic (olanzapine, risperidone, quetiapine, or ziprasidone) based on an indirect comparison of outcomes data from clinical trials., Methods: A 5-year Markov cohort model was developed to compare long-term effectiveness of lurasidone to aripiprazole, including total discontinuations, relapse rates, and hospitalization rates. Cost inputs included pharmacy, mental health, and medical costs associated with cardiometabolic risks (diabetes and cardiovascular [CV] events). Effectiveness inputs were derived from an indirect comparison of aripiprazole and lurasidone using common comparators from CATIE. Cardiometabolic risks were derived from claims data analysis for diabetes, weight change and CV events, and Framingham body mass index (BMI) risk equation. Cost inputs were derived from published sources and Red Book. Costs and outcomes were discounted at 3% and tested with sensitivity analyses., Results: Over 5 years, total discounted costs for lurasidone and aripiprazole patients were $86,480 and $90,500, respectively. During this period, the number of relapses per patient, hospitalizations per patient, diabetes rates, and CV events per 1000 patients, respectively, were estimated to be lower for lurasidone (0.442, 0.245, 7.29%, and 37.3) than aripiprazole (0.478, 0.369, 7.36%, and 37.8). Results were sensitive to lurasidone and aripiprazole hospitalization rates. At a willingness-to-pay threshold of $50,000 per hospitalization avoided, lurasidone had a 100% probability of being more cost-effective than aripiprazole., Limitations: The model was based on results from various comparative clinical trials. Differences in patient population and study methods may change estimates from the model. The model does not account for patient heterogeneity., Conclusions: Based on this model, when switching from another atypical antipsychotic, lurasidone had fewer relapses and hospitalizations with a lower incidence of diabetes and CV events than aripiprazole. Additionally, lurasidone may be less costly than aripiprazole among adults with schizophrenia.

Major depression is a common psychiatric disorder associated with high symptomatic and functional burdens. Pharmacological treatment is often effective, but there remain substantial unmet needs in the form of non-responders, delayed onset of clinical effect, and side effects. Recent studies have positioned the serotonin 5-HT₇ receptor as a new target for the treatment of depression. Preclinical studies have shown that antagonists induce an antidepressant-like response, a phenotype that can also be observed in mice lacking the receptor. Lurasidone is a new atypical antipsychotic agent with very high affinity for the 5-HT₇ receptor. Patients in clinical trials have reported improved scores in depression ratings. We have tested lurasidone in both acute and chronic mouse models of depression. In the tail suspension and forced swim tests lurasidone decreased immobility, an antidepressant-like response. The effect required functional 5-HT₇ receptors as it was absent in mice lacking the receptor. In the repeated open-space swim test lurasidone was able to reverse the despair induced by repeated swims in a manner similar to the commonly used antidepressant citalopram. The results provide evidence that lurasidone can act as a 5-HT₇ receptor antagonist and provide a possible explanation for the antidepressant effect data currently emerging from lurasidone clinical trials. Additionally, the results give further support for targeting the 5-HT₇ receptor in the treatment of depression. It will be of interest to clinically evaluate lurasidone as an antidepressant either as monotherapy or as an adjunctive therapy to available drugs., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Aim: To evaluate the efficacy of miglitol and mitiglinide alone or in combination on the metabolic profile and incretin secretion in Japanese type 2 diabetes patients., Methods: Patients on diet and exercise with or without metformin, were randomized to receive either miglitol, mitiglinide, or a combination, three times daily for 12 weeks., Results: At 12 weeks, HbA1c decreased significantly (p<0.001) and 1,5-AG increased significantly (p<0.001) in all three groups, with the greatest change seen with combination therapy. Effective improvement of postprandial hyperglycemia was demonstrated by a meal-loading test in all three interventions but serum insulin concentration was not increased by miglitol. In a subset of patients without prior metformin administration, faster and better glycemic control was achieved with the initial combination. After meal loading, serum total GLP-1 significantly increased only with miglitol monotherapy (p<0.05) and serum total GIP significantly decreased (p<0.01) in the arms employing miglitol after 12 weeks., Conclusion: Miglitol/mitiglinide combination is more potent than monotherapy in improving glycemic control through the reduction of postprandial glucose excursion and the simultaneous sparing of additional insulin secretion. A marked difference in the effects of miglitol and mitiglinide on incretin secretion was also demonstrated., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Second-generation antipsychotics (SGA) are multi-target agents widely used for the treatment of schizophrenia and bipolar disorder that also hold potential for the treatment of impaired emotional control, thanks to their diverse receptor profiles as well as their potential in modulating neuroadaptive changes in key brain regions. The aim of this study was thus to establish the ability of lurasidone, a novel SGA characterized by a multi-receptor signature, to modulate behavioural and molecular defects associated with a genetic model of impaired emotional control, namely serotonin transporter knockout (SERT KO) rats. At behavioural level, we found that chronic lurasidone treatment significantly increased fear extinction in SERT KO rats, but not in wild-type control animals. Moreover, at molecular level, lurasidone was able to normalize the reduced expression of the neurotrophin brain-derived neurotrophic factor in the prefrontal cortex of SERT KO rats, an effect that occurred through the regulation of specific neurotrophin transcripts (primarily exon VI). Furthermore, chronic lurasidone treatment was also able to restore the reduced expression of different GABAergic markers that is present in these animals. Our results show that lurasidone can improve emotional control in SERT KO rats, with a primary impact on the prefrontal cortex. The adaptive changes set in motion by repeated treatment with lurasidone may in fact contribute to the amelioration of functional capacities, closely associated with neuronal plasticity, which are deteriorated in patients with schizophrenia, bipolar disease and major depression.

Aβ, the product of APP (amyloid precursor protein), has been implicated in the pathophysiology of Alzheimer's disease (AD). β-Site APP cleaving enzyme1 (BACE1) is the enzyme initiating the processing of the APP to Aβ peptides. Small molecule BACE1 inhibitors are expected to decrease Aβ-peptide generation and thereby reduce amyloid plaque formation in the brain, a neuropathological hallmark of AD. BACE1 inhibition thus addresses a key mechanism in AD and its potential as a therapeutic target is currently being addressed in clinical studies. Here, we report the discovery and the pharmacokinetic and pharmacodynamic properties of BACE1 inhibitor AZ-4217, a high potency compound (IC50 160 pM in human SH-SY5Y cells) with an excellent in vivo efficacy. Central efficacy of BACE1 inhibition was observed after a single dose in C57BL/6 mice, guinea pigs, and in an APP transgenic mouse model of cerebral amyloidosis (Tg2576). Furthermore, we demonstrate that in a 1 month treatment paradigm BACE1 inhibition of Aβ production does lower amyloid deposition in 12-month-old Tg2576 mice. These results strongly support BACE1 inhibition as concretely impacting amyloid deposition and therefore potentially an important approach for therapeutic intervention in AD.

Objective: To evaluate the relapse prevention efficacy of lurasidone compared with quetiapine XR (QXR) in adults patients with schizophrenia., Method: This double-blind study evaluated the relapse prevention efficacy of 12 months of flexible-dose treatment with lurasidone (40-160 mg/day) compared with QXR (200-800 mg/day), in outpatients with an acute exacerbation of chronic schizophrenia who had recently completed a 6-week placebo-controlled trial of treatment with either lurasidone or QXR. The primary endpoint, time-to-relapse, was analyzed using a Cox proportional hazards model in this noninferiority trial., Results: The Kaplan-Meier estimate of the probability of relapse over 12 months was 23.7% for subjects receiving lurasidone vs. 33.6% for QXR. The hazard ratio [95% CI] for probability of relapse was 0.728 [0.410, 1.295] (log-rank p=0.280). Since the upper limit of the hazard ratio (1.295) was smaller than the prespecified noninferiority margin (1.93), noninferiority of lurasidone compared with QXR was demonstrated in this study. The probability of hospitalization at 12 months was lower for the lurasidone group compared with the QXR group (9.8% vs. 23.1%; log-rank p=0.049). A significantly higher proportion of lurasidone subjects achieved remission at study endpoint compared with the QXR group (61.9% vs. 46.3%; p=0.043). Discontinuation rates due to AEs were similar for lurasidone and QXR (7% vs. 5%). Treatment with lurasidone was not associated with clinically significant changes in weight or metabolic parameters., Conclusions: Twelve months of treatment with lurasidone met noninferiority criteria, and was associated with higher rates of remission, and reduced risk of hospitalization compared with QXR. No clinically significant effects on weight or metabolic parameters were observed during maintenance treatment with lurasidone., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Despite the availability of established antipsychotic agents for the treatment of schizophrenia, continued unmet needs exist for effective medications with lower adverse-effect burden. The present study evaluated the efficacy, safety, and tolerability of treatment with the atypical antipsychotic lurasidone for patients with an acute exacerbation of schizophrenia. Patients were randomized to 6 weeks of double-blind treatment with lurasidone 40 mg/day, 80 mg/day, or 120 mg/day, or placebo. Changes in Positive and Negative Syndrome Scale (PANSS) scores were evaluated using mixed-model repeated-measures (MMRM) analysis. Vital signs, laboratory parameters, extrapyramidal symptoms, and electrocardiogram were assessed. Treatment with lurasidone 80 mg/day resulted in significantly greater improvement in PANSS total score compared with placebo (-23.4 versus -17.0; p < 0.05) at study endpoint (MMRM); lurasidone 40 mg/day and 120 mg/day achieved clinically meaningful overall PANSS score reductions from baseline (-19.2 and -20.5), but not significant separation from placebo. Differences between all lurasidone groups and placebo for changes in laboratory parameters and electrocardiographic measures were minimal. Weight gain ≥ 7% occurred in 8.2% of patients receiving lurasidone and 3.2% receiving placebo. Modest increases in prolactin (median increase, 0.7 ng/mL) and extrapyramidal symptoms were observed following treatment with lurasidone compared with placebo. Akathisia was the most commonly reported adverse event with lurasidone (17.6%, versus 3.1% with placebo). In this study, in which a large placebo response was observed, lurasidone 80 mg/day, but not 40 mg/day or 120 mg/day, was statistically superior to placebo in treating acute exacerbation of chronic schizophrenia. All lurasidone doses were generally well tolerated., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objective: This study was designed to evaluate the short-term efficacy and safety of once-daily lurasidone (80 mg/day and 160 mg/day) in the treatment of an acute exacerbation of schizophrenia., Methods: Participants, who were recently admitted inpatients with schizophrenia with an acute exacerbation of psychotic symptoms, were randomly assigned to 6 weeks of fixed-dose, double-blind treatment with lurasidone 80 mg (n=125), lurasidone 160 mg (n=121), quetiapine XR 600 mg (QXR-600 mg; n=119; active control included to test for assay sensitivity), or placebo (n=121), all dosed once daily in the evening. Efficacy was evaluated using a mixed-model repeated-measures analysis of the change from Baseline to Week 6 in Positive and Negative Syndrome Scale (PANSS) total score (the primary efficacy measure) and Clinical Global Impressions severity (CGI-S) score (the key secondary efficacy measure)., Results: Treatment with both doses of lurasidone or with QXR-600 mg was associated with significantly greater improvement at Week 6 on PANSS total score, PANSS positive and negative subscale scores, and CGI-S score compared with placebo. The endpoint responder rate (≥ 20% improvement in PANSS total score) was higher in subjects treated with lurasidone 80 mg (65%; p<0.001), lurasidone 160 mg (79%; p<0.001), and QXR-600 mg (79%; p<0.001) compared with placebo (41%). The proportion of patients experiencing ≥ 7% weight gain was 4% for each lurasidone group, 15% for the QXR-600 mg group, and 3% for the placebo group. Endpoint changes in levels of cholesterol, triglycerides, and low-density lipoprotein (LDL) cholesterol were comparable for both lurasidone groups and placebo, while the QXR-600 mg group showed a significant median increase compared with the placebo group in levels of cholesterol (p<0.001), LDL cholesterol (p<0.01), and triglycerides (p<0.05)., Conclusions: Lurasidone 80 mg and 160 mg doses administered once-daily in the evening, were safe and effective treatments for subjects with acute schizophrenia, with increased response rates observed at the higher dose. Dose-related adverse effects were limited, and both doses were generally well-tolerated., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Considerable effort has gone into making mathematical and computer models of smallpox spread and control measures, typically consisting of vaccination and quarantine. The orally available antiorthopoxvirus drug tecovirimat has recently completed Phase 2 clinical trials and shows promise as a smallpox control agent. We constructed 2 computer simulations to explore the use of tecovirimat in combination with vaccination and social cooperativity to control an outbreak. Two scenarios were considered: (1) a homogenously mixed, deterministic simulation of a single metropolitan area; and (2) a stochastic network of the 50 largest US metropolitan areas connected by commercial air traffic. Metropolitan-level mass vaccination coupled with drug treatment for all individuals who develop a fever considerably outperforms treating only those who develop smallpox's distinctive rash. Incorporating mass chemoprophylaxis represents another large improvement. More aggressive responses are more robust to low cooperation of the population with public health efforts and to faster disease spread. However, even with the most aggressive public health intervention, an attack that initially infects hundreds or thousands of individuals will need to be fought in multiple cities across the country.

Objective: We examined the effects of a fixed-dose combination of 10 mg mitiglinide and 0.2 mg voglibose on postprandial glycemic excursions in Japanese type 2 diabetes mellitus (T2DM) patients., Research Design and Methods: After a 2-week baseline period, 11 T2DM patients were treated with mitiglinide alone for 2 weeks and with the mitiglinide/voglibose combination for 6 weeks., Main Outcome Measures: Self-monitoring of blood glucose (SMBG) at home before and after unified meals, metabolic parameters during meal tolerance tests, and overall glycemic control parameters., Results: Postprandial glycemic excursions after all three meals, as assessed by SMBG, were significantly lower in the combination period than in the baseline period, and after lunch and dinner in the combination period than in the mitiglinide period. The meal tolerance test confirmed that the magnitude of postprandial hyperglycemia was significantly lower, with significantly greater early-phase serum insulin secretion and sustained GLP-1 production, in the combination period compared with the baseline period. Overall glycemic control parameters also improved significantly in the combination period compared with the baseline period. These profiles suggest the combination is superior to mitiglinide alone, and may spare insulin secretion., Conclusion: The mitiglinide/voglibose combination significantly reduced postprandial glycemic excursions in Japanese T2DM patients. This trial was registered with the University Hospital Medical Information Network clinical trials database (no. UMIN000007202).