Adjunctive brexpiprazole 1 mg and 2 mg daily for Japanese patients with major depressive disorder following inadequate response to antidepressants: a phase 2/3, randomized, double-blind (BLESS) study.

AIMS: Inadequate antidepressant response interrupts effective treatment of major depressive disorder (MDD). The BLESS study evaluates the dosage, efficacy, and safety of brexpiprazole adjunctive therapy in Japanese patients with inadequate antidepressant therapy (ADT) response. METHODS: This placebo-controlled, randomized, multicenter, parallel-group phase 2/3 study randomized Japanese MDD patients (Hamilton Rating Scale for Depression 17-item total score ≥ 14; historical inadequate response to 1-3 ADTs) with inadequate response to 8-week single-blind, prospective SSRI/SNRI treatment to 6-week adjunctive treatment with brexpiprazole 1 mg, 2 mg, or placebo. The primary endpoint was change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score from baseline. Secondary endpoints included MADRS response, remission rate, and Clinical Global Impression-Improvement score. Safety was comprehensively evaluated, especially regarding antipsychotic adverse events (AEs). RESULTS: Of 1194 screened patients, 740 were randomized and 736 (1 mg, n = 248; 2 mg, n = 245; placebo, n = 243) had ≥1 baseline/post-baseline MADRS total score. The LSM (SE) change from baseline in MADRS total score at Week 6 by MMRM analysis was -8.5 (0.47) with brexpiprazole 1 mg, -8.2 (0.47) with brexpiprazole 2 mg, and -6.7 (0.47) with placebo (placebo-adjusted LSM difference [95% CI]: 1 mg, -1.7 [-3.0, -0.4]; P = 0.0089; 2 mg, -1.4 [-2.7, -0.1]; P = 0.0312). Secondary efficacy results supported the primary endpoint. Brexpiprazole was generally well tolerated. CONCLUSION: Brexpiprazole 1 mg daily was an appropriate starting dose and both 1 mg and 2 mg daily were effective and well tolerated as adjunctive therapy for Japanese MDD patients not adequately responsive to ADT.

Lurasidone in the long-term treatment of Japanese patients with bipolar I disorder: a 52 week open label study.

BACKGROUND: The current study evaluated the long-term (52 week) safety and impact on symptom measures of lurasidone (with or without lithium or valproate) for the treatment of bipolar I disorder in Japanese patients. METHODS: Bipolar patients for this open-label flexibly dosed lurasidone (20-120 mg/day) study were recruited from those with a recent/current depressive episode who completed an initial 6 week, double-blind, placebo-controlled, lurasidone study (depressed group), and those with a recent/current manic, hypomanic, or mixed episode (non-depressed group) who agreed to enroll directly into the long-term study. Measures of adverse events and safety included treatment-emergent adverse events, vital signs, body weight, ECG, laboratory tests, and measures of suicidality and extrapyramidal symptoms. Symptom measures included Montgomery Åsberg Depression Rating Scale (MADRS) and Young Mania Rating Scale (YMRS). RESULTS: The most common adverse events associated with lurasidone were akathisia (30.7%), nasopharyngitis (26.6%), nausea (12.1%), and somnolence (12.1%). Minimal changes in lipids and measures of glycemic control occurred. Mean change in body weight was + 1.0 kg in the non-depressed group and - 0.8 kg in the depressed group. MADRS total scores declined by a mean (SD) of 2.0 (14.7) points from long-term baseline to endpoint in the depressed group who had received placebo in the prior 6 week trial. The depressed group that had received lurasidone during the prior 6 week study maintained their depressive symptom improvements. For the non-depressed group, YMRS total scores decreased over time. LIMITATIONS: No control group was included, treatment was open-label, and 49.7% of patients completed the 52 week study. CONCLUSIONS: Long-term treatment with lurasidone 20-120 mg/day for Japanese patients with bipolar disorder maintained improvements in depressive symptoms for depressed patients who were treated in a prior 6 week trial and led to improvements in manic symptoms among a newly recruited subgroup of patients with a recent/current manic, hypomanic, or mixed episode. Few changes in weight or metabolic parameters were evident. CLINICAL TRIAL REGISTRATION: JapicCTI-132319, clinicaltrials.gov-NCT01986114.

Safety and Effectiveness of Lurasidone in Patients with Schizophrenia: A 12-Week, Open-Label Extension Study.

PURPOSE: The goal of this study was to evaluate the safety and effectiveness of lurasidone among patients with schizophrenia in a 12-week open-label extension study. PATIENTS AND METHODS: Patients who completed a 6-week, double-blind, placebo-controlled study were enrolled in a 12-week open-label extension study with flexible dosing of lurasidone at 40 or 80 mg/day. Safety assessments included adverse events, vital signs, laboratory tests, and electrocardiogram (ECG) parameters. Effectiveness measures included the Positive and Negative Syndrome Scale (PANSS) total score, Clinical Global Impression-Severity Scale (CGI-S), Calgary Depression Scale for Schizophrenia (CDSS) and quality of life measure. RESULTS: A total of 289 patients were enrolled in the open-label extension study. Rates of treatment-emergent adverse events (TEAEs) were low; akathisia was the most common TEAE with an incidence of 6.6%. There were 54 patients (18.7%) who discontinued the extension study, with 17 (5.9%) discontinuing due to adverse events. Minimal or no effects of lurasidone on weight, body mass index, metabolic parameters, prolactin, and ECG parameters were evident. There was continued improvement to week 12 in PANSS and CGI-S scores beyond the initial gains made during the prior 6-week double-blind study. Non-responders to lurasidone 40 mg/day in the prior 6-week study showed a mean (standard deviation) improvement from open-label baseline of 10.7 (13.8) points on the PANSS total score after lurasidone dose was increased to a modal dose of 80 mg/day during the extension study. Changes from double-blind baseline in CDSS and quality of life were maintained in the extension study. CONCLUSION: Treatment with lurasidone 40 or 80 mg once daily (flexibly dosed) continued to be well tolerated with patients demonstrating further improvement in symptoms over the course of a 12-week open-label extension study in patients with schizophrenia.

Efficacy and safety of lurasidone in acutely psychotic patients with schizophrenia: A 6-week, randomized, double-blind, placebo-controlled study.

AIM: The aim of this study was to evaluate the efficacy of lurasidone in acute schizophrenia in Japan and other countries. METHODS: Subjects (aged 18-74 years) diagnosed with schizophrenia were randomized to lurasidone 40 mg/day or placebo. The primary efficacy endpoint was change from baseline on the Positive and Negative Syndrome Scale (PANSS) total score at Week 6. Secondary efficacy assessments included the Clinical Global Impression-Severity Scale (CGI-S). Safety endpoints included adverse events, and laboratory and electrocardiogram parameters. RESULTS: A total of 483 subjects were randomized to lurasidone or placebo; 107 subjects were from Japan. Mean changes from baseline at Week 6 endpoint in PANSS total scores were -19.3 in the lurasidone group and -12.7 in the placebo group (treatment difference: P < 0.001, effect size = 0.41). Changes from baseline for Week 6 CGI-S scores were -1.0 for lurasidone and -0.7 for placebo (treatment difference: P < 0.001, effect size = 0.41). All-cause discontinuation during the 6-week, double-blind period was 19.4% for lurasidone and 25.4% for placebo, and discontinuation rates due to adverse event were 5.7% for lurasidone and 6.4% for placebo. The following common treatment-emergent adverse events occurred in more than 2% on lurasidone and at a rate at least twice that of the placebo group: akathisia (4.0%), dizziness (2.8%), somnolence (2.8%), abdominal discomfort (2.0%) and asthenia (2.0%). No significant changes in bodyweight or metabolic parameters were observed. CONCLUSION: Lurasidone 40 mg once daily dosing demonstrated efficacy in a patient population with acute schizophrenia, including subjects from Japan, and was generally safe and well-tolerated.

Lurasidone in the Long-Term Treatment of Bipolar I Depression: A 28-week Open Label Extension Study.

BACKGROUND: Lurasidone has demonstrated efficacy for short-term treatment of bipolar depression in a diverse ethnic population including Japanese. This study evaluated the long-term safety and effectiveness of open-label lurasidone treatment in these patients. METHODS: Patients for this 28-week extension study were recruited from those who completed a 6-week double-blind study of lurasidone, 20-60 mg/day, lurasidone 80-120 mg/day, and placebo. In the extension study, lurasidone was flexibly dosed (20 to 120 mg/day). Safety was evaluated in terms of change from extension-phase baseline to endpoint including adverse events, vital signs, body weight, ECG, laboratory tests, and measures of suicidality and extrapyramidal symptoms. Effectiveness was determined by Montgomery Åsberg Depression Rating Scale (MADRS) and other measures. RESULTS: 303 of 413 (73.3%) subjects completed the extension study. Discontinuation due to a treatment-emergent adverse event occurred for 11.4% of those who received placebo, and 8.9% of those who received lurasidone, in the prior 6-week trial. The most common treatment-emergent adverse event was akathisia. Minimal changes were evident on body weight and metabolic parameters. Long-term treatment with lurasidone further reduced mean MADRS total scores from long-term baseline to week 28 (or endpoint) for both those who had received prior placebo (-11.3), and those who had receive prior lurasidone (-8.9), in the 6-week double-blind trial. LIMITATIONS: There was no placebo control and treatment was not double-blind. CONCLUSIONS: Long-term treatment with lurasidone (20-120 mg/day) was well-tolerated with no new safety concerns and associated with continued improvement in depressive symptoms in this international sample of patients with bipolar depression. CLINICAL TRIAL REGISTRATION: JapicCTI-132319, clinicaltrials.gov - NCT01986114.

Double-blind, placebo-controlled study of lurasidone monotherapy for the treatment of bipolar I depression.

AIM: Previous studies conducted primarily in the USA and Europe have demonstrated the efficacy and safety of lurasidone 20-120 mg/day for the treatment of bipolar I depression. The aim of the current study was to evaluate the efficacy and safety of lurasidone monotherapy for the treatment of bipolar I depression among patients from diverse ethnic backgrounds, including those from Japan. METHODS: Patients were randomly assigned to double-blind treatment for 6 weeks with lurasidone, 20-60 mg/day (n = 184) or 80-120 mg/day (n = 169), or placebo (n = 172). The primary end-point was change from baseline to Week 6 on the Montgomery-Åsberg Depression Rating Scale (MADRS). RESULTS: Lurasidone treatment significantly reduced mean MADRS total scores from baseline to Week 6 for the 20-60-mg/day group (-13.6; adjusted P = 0.007; effect size = 0.33), but not for the 80-120-mg/day group (-12.6; adjusted P = 0.057; effect size = 0.22) compared with placebo (-10.6). Treatment with lurasidone 20-60 mg/day also improved MADRS response rates, functional impairment, and anxiety symptoms. The most common adverse events associated with lurasidone were akathisia and nausea. Lurasidone treatments were associated with minimal changes in weight, lipids, and measures of glycemic control. CONCLUSION: Monotherapy with once daily doses of lurasidone 20-60 mg, but not 80-120 mg, significantly reduced depressive symptoms and improved functioning in patients with bipolar I depression. Results overall were consistent with previous studies, suggesting that lurasidone 20-60 mg/day is effective and safe in diverse ethnic populations, including Japanese.

Efficacy and safety of blonanserin transdermal patch in patients with schizophrenia: A 6-week randomized, double-blind, placebo-controlled, multicenter study.

BACKGROUND: Blonanserin is a second-generation antipsychotic used for the treatment of schizophrenia. This study determined the efficacy, safety and pharmacokinetics of a blonanserin transdermal patch in patients with acutely exacerbated schizophrenia. METHODS: This double-blind, multicenter, phase 3 study consisted of a 1-week observation period during which patients were treated with two patches of placebo, followed by a 6-week double-blind period where patients were randomized (1:1:1) to receive once-daily blonanserin 40 mg, blonanserin 80 mg, or placebo patches. The primary endpoint was the change from baseline in the total Positive and Negative Symptom Scale (PANSS) score. Safety assessments included treatment-emergent adverse events (TEAEs). RESULTS: Between December 2014 and October 2018, patients were recruited and randomly assigned to blonanserin 40 mg (n = 196), blonanserin 80 mg (n = 194), or placebo (n = 190); of these, 77.2% completed the study. Compared with placebo, blonanserin significantly improved PANSS total scores at 6 weeks (least square mean [LSM] difference vs placebo: -5.6 with blonanserin 40 mg; 95% confidence interval [CI] -9.6, -1.6; adjusted p = 0.007, and - 10.4 with blonanserin 80 mg; 95% CI -14.4, -6.4; adjusted p < 0.001). Blonanserin was well tolerated; the most common TEAEs reported were application-site erythema and pruritus, akathisia, tremor, and insomnia. CONCLUSIONS: Blonanserin transdermal patch improved the symptoms of acute schizophrenia with acceptable tolerability.

Long-Term Safety and Efficacy of Blonanserin Transdermal Patches in Japanese Patients with Schizophrenia: A 52-Week Open-Label, Multicenter Study.

BACKGROUND: Blonanserin transdermal patch therapy is now available in Japan for the treatment of schizophrenia and may provide several advantages over the tablet formulation. OBJECTIVE: The aim was to evaluate the long-term safety and efficacy of blonanserin transdermal patches in Japanese patients with schizophrenia. METHODS: An open-label study was conducted in adults with schizophrenia at 37 sites in Japan. Patients were enrolled in either cohort 1 or 2. Patients in cohort 1 received 8-16 mg/day blonanserin tablets for 6 weeks and then 40-80 mg/day blonanserin patches for 52 weeks. The dose of blonanserin patches was determined according to the dose of the tablets. In cohort 2, every patient started from 40 mg/day and then 40-80 mg/day blonanserin transdermal patches for 52 weeks. Both cohorts had 1-2 weeks of follow-up. Safety endpoints included the incidence of adverse events (AEs), treatment-related AEs, extrapyramidal AEs [also assessed using the change in Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS) score], the use of any concomitant antiparkinsonian drugs, and skin-related AEs, including skin irritation. Patients also underwent assessment of laboratory values including for serum prolactin concentration, vital signs, body weight, electrocardiographic (ECG) changes, and the corrected QT (QTc) interval. Suicidal ideation was assessed via the Columbia-Suicide Severity Rating Scale (C-SSRS) score. Efficacy was assessed via duration of blonanserin transdermal patch treatment, Positive and Negative Syndrome Scale (PANSS) total and subscale scores, and Clinical Global Impression-Severity (CGI-S) scores. Other endpoints included total Drug Attitude Inventory 10 (DAI-10) scores, EuroQol-5 Dimension (EQ-5D) effect values, and a patient questionnaire about the dosage form. RESULTS: A total of 223 patients with consents, 117 in cohort 1 and 106 in cohort 2 were included in the study. Of the 117 patients in cohort 1, 108 were treated with blonanserin tablets, and 97 received blonanserin patches and were included in the safety analysis set. In cohort 2, 103 of the 106 patients were treated with blonanserin transdermal patches and were included in the safety analysis set. In total, 91 patients were male (45.5%). The mean age was 43.8 years. Discontinuation occurred in 40 patients (41.2%) in cohort 1 and 44 patients (42.7%) in cohort 2. Discontinuation resulted from AEs in 18.6% (cohort 1) and 11.7% (cohort 2) and from withdrawal of consent in 13.4% (cohort 1) and 20.4% (cohort 2), and seven patients overall discontinued due to skin reactions. AEs were reported in 174 patients (87.0%), and 13 serious AEs occurred in 12 patients (6.0%), of which six patients were in cohort 1 and six patients were in cohort 2. Serious AEs were six schizophrenia (n = 6) and seven other AEs (n = 6), which included impulse-control disorder, fracture, epistaxis, asthma, pneumonia aspiration, pneumonia hemophilus, and pneumonia. The most common AEs were nasopharyngitis (n = 62, 31.0%), application site erythema (n = 45, 22.5%), application site pruritus (n = 23, 11.5%), and akathisia (n = 20, 10.0%). AE incidence was similar in cohort 1 (84.5%) and cohort 2 (89.3%). Extrapyramidal and skin-related AEs were reported in 51 patients (25.5%) and 83 patients (41.5%), respectively. None of these AEs were serious. The mean change from baseline in total DIEPSS score at Week 52 {last observation carried forward [LOCF] (standard deviation [SD])} was -0.1 (1.55), indicating no marked effect. In terms of concomitant medications used in cohort 1 and cohort 2, 33.0% (32/97) and 22.3% (23/103) used antiparkinsonian drugs, respectively. The majority of skin-related AEs occurred early in treatment and were appropriately managed with topical therapies. Of the patients who answered "No" to all C-SSRS categories at baseline (n = 129), 13 patients (10.1%) were evaluated as having emergence of suicidal ideation. Among patients who answered "No" to all C-SSRS suicidal behavior categories at baseline (n = 172), one (0.6%) was evaluated as having suicidal behavior during blonanserin transdermal patch treatment. There were no clinically significant changes in laboratory tests or examinations, including prolactin level, vital signs, body weight, ECG, metabolism-related parameters, and QTc interval. The mean (SD) change in body weight was - 0.04 (4.561) kg and - 0.67 (6.841) kg in cohort 1 and cohort 2, respectively. The mean changes from baseline in PANSS total score at Week 52 (LOCF [SD]) were - 0.1 [11.6] and - 3.4 [15.3] in cohort 1 and 2, respectively. PANSS scores did not change after switching from tablet to patch formulation in cohort 1 and decreased over the 52 weeks of treatment with the blonanserin patches. The mean change from baseline in CGI-S score at Week 52 (LOCF [SD]) was - 0.2 [1.03] in both cohorts combined. After 52 weeks of blonanserin patch treatment, the total DAI-10 score increased or remained unchanged compared with baseline in 82 of the 129 patients (63.6%) for whom these data were available. In the intention-to-treat population of the combined cohorts (n = 200), the mean (SD) change from baseline in EQ-5D score at the last assessment was - 0.0365 (0.17603). Patients' attitudes to the blonanserin transdermal patches were generally positive. CONCLUSIONS: Blonanserin transdermal patches are safe and effective in the long-term treatment of schizophrenia. CLINICALTRIALS. GOV REGISTRATION: NCT02335658.

Safety and effectiveness of lurasidone for the treatment of schizophrenia in Asian patients: Results of a 26-week open-label extension study.

INTRODUCTION: This study was designed to evaluate the long-term safety and effectiveness of lurasidone in the treatment of schizophrenia among Asian patients. METHODS: Patients (N = 281) with schizophrenia who had completed a randomized, double-blind (DB), 6-week comparison of lurasidone (40 and 80 mg/day) and placebo were enrolled in a 26-week extension study in which all patients received open-label (OL), flexible doses of lurasidone (40 or 80 mg/day). Effectiveness was measured using the Positive and Negative Syndrome Scale (PANSS) scale. RESULTS: Fifty-seven percent of patients completed the OL extension study; 16.7% discontinued early due to lack of effectiveness; and 10.3% due to adverse events. The most common adverse events were insomnia (11.3%), akathisia (11.0%), and nasopharyngitis (10.6%). Adverse events related to weight gain, metabolic parameters, prolactin, and ECG measures were uncommon. Mean change in the PANSS total score from the DB baseline to OL endpoint was -28.4, with mean improvement of -7.5 observed from baseline to OL endpoint, and with a PANSS responder rate of 73.7%. DISCUSSION: The results of the current 26-week extension study found lurasidone to be a generally safe, well-tolerated, and effective long-term treatment for schizophrenia in Asian patients.

Lurasidone in the treatment of schizophrenia: Results of a double-blind, placebo-controlled trial in Asian patients.

INTRODUCTION: To evaluate efficacy and safety of lurasidone for the treatment of Asian patients with schizophrenia. METHODS: Patients with schizophrenia from Japan, South Korea, Malaysia, and Taiwan were randomly assigned to 6 weeks of double-blind treatment with 40 or 80 mg/d of lurasidone or placebo. The primary efficacy measure was change from baseline to week 6 on the Positive and Negative Syndrome Scale (PANSS) total score. Efficacy was evaluated using a mixed-model repeated-measures (MMRM) analysis in the modified intention-to-treat (mITT) population. RESULTS: On the basis of the analysis for the mITT population, the estimated difference score for lurasidone 40 and 80 mg/d vs placebo was -4.8 (P = 0.050) and -4.2 (P = 0.080). For the full intention-to-treat (ITT) population, the difference score for lurasidone 40 and 80 mg/d vs placebo was -5.8 (P = 0.017) and -4.2 (P = 0.043). The most frequent adverse events in the lurasidone 40 and 80 mg/d and placebo groups, respectively, were akathisia (7.3%, 10.4%, 3.3%), somnolence (6.0%, 2.6%, 0.7%), and vomiting (6.0%, 5.8%, 2.0%). The proportion of patients experiencing clinically significant weight gain (≥7%) was 5.3% for lurasidone 40 mg/d, 1.3% for 80 mg/d, and 1.4% for placebo. End point changes in metabolic parameters and prolactin were comparable for both lurasidone groups and placebo. CONCLUSIONS: In the ITT (but not the mITT) population, treatment with lurasidone was associated with significant improvement in the PANSS total score in patients with schizophrenia. Lurasidone was generally well tolerated with minimal impact on weight and metabolic parameters.

Randomized, double-blind, placebo, and risperidone-controlled study of lurasidone in the treatment of schizophrenia: Results of an inconclusive 6-week trial.

OBJECTIVE: The efficacy and safety of lurasidone in schizophrenia has been demonstrated in multiple controlled trials, primarily in US and European populations. The aim of the current study was To evaluate lurasidone for the treatment of schizophrenia among patients in Japan, Korea, and Taiwan. METHODS: Hospitalized patients (N = 460) with schizophrenia were randomized to 6 weeks of fixed-dose lurasidone 40 mg/d, lurasidone 80 mg/d, risperidone 4 mg/d, or placebo. Efficacy was assessed using the Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression-Severity (CGI-S). RESULTS: No significant endpoint differences in PANSS total score were found for lurasidone or risperidone vs placebo. Lurasidone was safe and well tolerated, with minimal effects on weight and metabolic parameters. DISCUSSION: The current study was inconclusive regarding the efficacy of lurasidone in schizophrenia but further confirmed its safety and tolerability.

Integrated profiling of phenotype and blood transcriptome for stress vulnerability and depression.

Etiology of depression and its vulnerability remains elusive. Using a latent profile analysis on dimensional personality traits, we previously identified 3 different phenotypes in the general population, namely stress-resilient, -vulnerable, and -resistant groups. Here we performed microarray-based blood gene expression profiling of these 3 groups (n = 20 for each group) in order to identify genes involved in stress vulnerability as it relates to the risk of depression. Identified differentially expressed genes among the groups were most markedly enriched in ribosome-related pathways. These ribosomal genes, which included ribosomal protein L17 (RPL17) and ribosomal protein L34 (RPL34), were upregulated in relation to the stress vulnerability. Protein-protein interaction and correlational co-expression analyses of the differentially expressed genes/non-coding RNAs consistently showed that functional networks involving ribosomes were affected. The significant upregulation of RPL17 and RPL34 was also observed in depressed patients compared to healthy controls, as confirmed in 2 independent case-control datasets by using pooled microarray data and qPCR experiments (total number of subjects was 122 and 166, respectively). Moreover, the upregulation of RPL17 and RPL34 was most marked in DSM-IV major depressive disorder, followed by in bipolar disorder, and then in schizophrenia, suggesting some diagnostic specificity of these markers as well as their general roles in stress vulnerability. These results suggest that ribosomal genes, particularly RPL17 and RPL34, can play integral roles in stress vulnerability and depression across nonclinical and clinical conditions. This study presents an opportunity to understand how multiple psychological traits and underlying molecular mechanisms interact to render individuals vulnerable to depression.

13C-phenylalanine breath test and serum biopterin in schizophrenia, bipolar disorder and major depressive disorder.

Phenylalanine is required for the synthesis of the neurotransmitters dopamine, noradrenaline, and adrenaline. The rate-limiting step for phenylalanine metabolism is catalyzed by phenylalanine hydroxylase (PAH) and its cofactor tetrahydrobiopterin. We aimed to detect altered phenylalanine metabolism in major psychiatric disorders using the l-[1-13C]phenylalanine breath test (13C-PBT) and serum biopterin levels. We also investigated association of PAH mutations with schizophrenia and phenylalanine metabolism. 13C-phenylalanine (100 mg) was orally administered, and the breath 13CO2/12CO2 ratio was monitored for 120 min in four groups: 103 patients with schizophrenia (DSM-IV), 39 with bipolar disorder, 116 with major depressive disorder (MDD), and 241 healthy controls. Serum biopterin levels were measured by high performance liquid chromatography. Mutation screening of PAH exons was performed by direct sequencing in 46 schizophrenia patients. Association analysis was performed using six tag single nucleotide polymorphisms and the PAH Arg53His mutation by TaqMan assays in 616 schizophrenia patients and 1194 healthy controls. Analyses of covariance controlling for age, sex, and body weight showed that the index for the amount of exhaled 13CO2 was significantly lower in the schizophrenia group than in the other three groups (all p < 0.05). Biopterin levels in schizophrenia and MDD were significantly lower than those in controls. Biopterin levels correlated with 13C-PBT indices in controls. PAH polymorphisms were not associated with schizophrenia or 13C-PBT indices. 13C-PBT revealed reduced phenylalanine metabolism in schizophrenia, though we obtained no evidence of involvement of PAH polymorphism. Serum biopterin levels were lower in schizophrenia and MDD, warranting further investigation.

Plasma amino acid profile in major depressive disorder: Analyses in two independent case-control sample sets.

Some amino acids act as neurotransmitters themselves, or are precursors of neurotransmitters. Previous studies reported inconsistent results regarding their changes in blood in major depressive disorder (MDD), which prompted us to examine plasma levels of amino acids and related molecules in two independent case-control sample sets. In total, 511 subjects were recruited. Sample set A consisted of 164 patients with MDD (147 currently depressed [dMDD]; 17 in remission, DSM-IV) and 217 healthy controls. Sample set B consisted of 65 patients (51 dMDD; 14 in remission) and 65 controls. Plasma amino acid levels were measured using high-performance liquid chromatography for set A and liquid chromatography/mass spectrometry for set B. We further analyzed the relationships between plasma amino acid levels and clinical variables. In sample set A, plasma asparagine, histidine+1-methylhistidine, methionine, phenylalanine, tryptophan, and tyrosine levels were decreased, while plasma glutamate and phosphoethanolamine were elevated in dMDD compared to controls (all P < 0.0005), even after correcting for multiple testing. Plasma leucine levels were associated with "psychic anxiety." In sample set B, glutamate and methionine levels were also altered in the same direction to that in sample set A (both P < 0.05). In the integrative analysis, plasma glutamate and methionine levels were found to be significantly associated with the diagnosis of MDD with small to medium effect sizes (both P < 1.0E-6). In conclusion, several amino acids and related molecules were altered in patients with MDD. Decreased methionine and increased glutamate levels were found consistently in the two sample sets, suggesting their involvement in MDD. Further investigations are warranted on the possible role of amino acids in the pathophysiology of MDD.

A personality-based latent class typology of outpatients with major depressive disorder: association with symptomatology, prescription pattern and social function.

BACKGROUND: While major depressive disorder (MDD) is considered to be a heterogeneous disorder, the nature of the heterogeneity remains unclear. Studies have attempted to classify patients with MDD using latent variable techniques, yet the empirical approaches to symptom-based subtyping of MDD have not provided conclusive evidence. Here we aimed to identify homogeneous classes of MDD based on personality traits, using a latent profile analysis. METHODS: We studied 238 outpatients with DSM-IV MDD recruited from our specialized depression outpatient clinic and assessed their dimensional personality traits with the Temperament and Character Inventory. Latent profile analysis was conducted with 7 dimensions of the Temperament and Character Inventory as indicators. Relationships of the identified classes with symptomatology, prescription pattern, and social function were then examined. RESULTS: The latent profile analysis indicated that a 3-class solution best fit the data. Of the sample, 46.2% was classified into a "neurotic" group characterized by high harm avoidance and low self-directedness; 30.3% into an "adaptive" group characterized by high self-directedness and cooperativeness; and 23.5% into a "socially-detached" group characterized by low reward dependence and cooperativeness and high self-transcendence. The 2 maladaptive groups, namely neurotic and socially-detached groups, demonstrated unique patterns of symptom expression, different classes of psychotropic medication use, and lower social functioning. LIMITATIONS: Generalizability of the findings was limited since our patients were recruited from the specialized depression outpatient clinic. CONCLUSIONS: Our personality-based latent profile analysis identified clinically meaningful 3 MDD groups that were markedly different in their personality profiles associated with distinct symptomatology and functioning.

Efficacy and Safety of Bitopertin in Patients with Schizophrenia and Predominant Negative Symptoms: Subgroup Analysis of Japanese Patients from the Global Randomized Phase 2 Trial.

OBJECTIVE: The aim of the present study was to perform a subgroup analysis of data from a phase II global, multi-center, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of bitopertin, a glycine reuptake inhibitor that activates N-methyl-D-aspartate receptors by increasing the concentration of glycine in the synaptic cleft, in Japanese and non-Japanese patients with schizophrenia and predominant negative symptoms. METHODS: Patients with schizophrenia and predominant negative symptoms on one or two antipsychotic drugs, including atypical antipsychotic drugs (olanzapine, risperidone, quetiapine, aripiprazole, and paliperidone) as the primary treatment, received bitopertin (10, 30, or 60 mg/day) or placebo once daily for 8 weeks as an add-on treatment. Efficacy was assessed using the Positive and Negative Syndrome Scale (PANSS) negative symptom factor score (NSFS). RESULTS: The efficacy of bitopertin (10 mg and 30 mg) was similar between Japanese and non-Japanese patients. In the bitopertin 60-mg group, no difference from the placebo group was observed in Japanese or non-Japanese patients. The response to placebo was lower in Japanese patients, and there was a trend towards a greater difference in the change in PANSS NSFS between the placebo group and the 10-mg and 30-mg groups among Japanese patients. The safety profile of bitopertin was favorable in Japanese and non-Japanese patients. CONCLUSION: According to this subgroup analysis from a global phase II study of bitopertin, there was no difference in terms of efficacy and safety between Japanese and non-Japanese patients.

Transcranial Magnetic Stimulation Modulates Resting EEG Functional Connectivity Between the Left Dorsolateral Prefrontal Cortex and Limbic Regions in Medicated Patients With Treatment-Resistant Depression.

High-frequency left prefrontal repetitive transcranial magnetic stimulation (rTMS) has been shown to have efficacy in treatment-resistant depression. However, the effects of rTMS on functional connectivity are still not clear. To examine changes in functional connectivity before and after rTMS, resting EEG of 14 patients with treatment-resistant depression was recorded twice at baseline and at week 4, respectively. The EEG data were analyzed using the standardized low-resolution brain electromagnetic tomography (sLORETA). The results reveal that high-frequency left prefrontal rTMS modulates resting EEG functional connectivity between the left dorsolateral prefrontal cortex and limbic regions, including the subgenual cingulate cortex and parahippocampal gyrus.