Optimal dose for the efficacy of asenapine in patients with schizophrenia: Real-world data.

AIMS: A meta-analysis of short-term studies revealed no significant differences between the doses of asenapine, 10 and 20 mg/day, in the acute treatment of schizophrenia. However, it should be noted that many patients from clinical practice were excluded, and the dose-response to asenapine in a real-world setting is still unclear. Additionally, the dose-response in the maintenance phase is not clear. This study aimed to evaluate the differences in the efficacy of different asenapine doses in patients with maintenance phase of schizophrenia in a real-world setting. METHODS: This study conducted post-marketing surveillance of asenapine in clinical settings in Japan. It followed patients diagnosed with schizophrenia who received asenapine for the first time for a maximum of 52 weeks. These patients were divided into two categories based on their average daily asenapine dosage: ≤10 mg/day and >10 mg/day. Asenapine efficacy was assessed by adjusting for patient demographics using multivariate logistic regression analysis, employing the Clinical Global Impression-Global Improvement (CGI-I) scale, which has seven categories. RESULTS: A total of 2774 patients were included in the analysis. Of these, 1689 and 1085 patients were treated with asenapine ≤10 mg/day and >10 mg/day, respectively. The CGI-I improvement rate was significantly higher in the asenapine >10 group (p = 0.012) after adjusting for patient background factors. CONCLUSION: These results suggest that asenapine doses >10 mg/day may be more effective than 10 mg/day in the treatment of schizophrenia; however, further studies are needed to confirm these findings.

Characteristics of persistent depression in the long-term: Randomized controlled trial and two-year observational study.

Major depressive disorder is a chronic condition that can recur and relapse. It would be clinically useful to know the patient background to predict the chronicity of depressive symptoms, and the change in diagnosis of bipolar disorder. This study included 197 patients enrolled in a six-week randomized controlled trial with a two-year follow-up. We conducted multiple logistic regression analyses to identify the clinical and sociodemographic characteristics associated with persistent depressive disorder (PDD), relapse, and changes in bipolar disorder diagnosis. The significantly correlated factors were residual symptoms, including insight, work and activity, and general somatic symptoms at week six. We could not identify any factors that contributed to relapse or change in the diagnosis of bipolar disorder. We found that the specific residual symptoms of acute treatment affected long-term treatment outcomes for depression. Attention should be paid to the residual symptoms of depression in the early stages of treatment, and measures should be considered to improve them. There are several limitations to this study, including the fact that PDD may exist among patients who discontinued treatment, treatment was not standardized during the study period, and adherence was confirmed verbally.

Usefulness of mirtazapine and SSRIs in late-life depression: post hoc analysis of the GUNDAM study.

OBJECTIVE: Mirtazapine and SSRIs are widely prescribed as first-line agents for late-life depression. However, evidence for these drugs is mostly based on non-elderly patients. Therefore, we reanalyzed a randomized controlled trial of mirtazapine versus SSRIs for depression in a sub-population of late-life patients. METHODS: A randomized controlled trial was conducted with 141 patients, of whom 41 were elderly, and 100 were non-elderly. This study compared SSRIs and mirtazapine in late-life depression, examined late-onset and early adult-onset separately and compared elderly and non-elderly patients for each drug. Treatment effects and adverse events were assessed using the Hamilton Depression Rating Scale and the Udvalg for Kliniske Undersøgelser Side Effect Rating Scale, respectively. RESULTS: In late-life depression, mirtazapine showed faster HAM-D total score improvement (3.3 points difference, p = 0.021) and higher improvement in insomnia (1.7 points difference, p = 0.001) and appetite (1.2 points difference, p = 0.020). Similar findings were observed for late-onset depression with the HAM-D total score (4.3 points difference, p = 0.007) and appetite (0.9 points difference, p = 0.004), favoring mirtazapine. Depressive symptoms were generally less improved in late-life depression than in non-late-life depression. Regarding the effect of mirtazapine on appetite, late-life depression showed greater improvement (0.7 points difference, p = 0.008). Nausea and micturition disturbances were more common with SSRIs in late-life depression than in non-late-life depression. In contrast, somnolence was less common in late-life depression with mirtazapine. CONCLUSION: The potential usefulness of mirtazapine in elderly patients was demonstrated. The results also showed differences in the treatment response to SSRIs and mirtazapine between elderly and non-elderly patients.

Changes in Multiple microRNA Levels with Antidepressant Treatment Are Associated with Remission and Interact with Key Pathways: A Comprehensive microRNA Analysis.

Individual treatment outcomes to antidepressants varies widely, yet the determinants to this difference remain elusive. MicroRNA (miRNA) gene expression regulation in major depressive disorder (MDD) has attracted interest as a biomarker. This 4-week randomized controlled trial examined changes in the plasma miRNAs that correlated with the treatment outcomes of mirtazapine (MIR) and selective serotonin reuptake inhibitor (SSRI) monotherapy. Pre- and post- treatment, we comprehensively analyzed the miRNA levels in MDD patients, and identified the gene pathways linked to these miRNAs in 46 patients. Overall, 141 miRNA levels significantly demonstrated correlations with treatment remission after 4 weeks of MIR, with miR-1237-5p showing the most robust and significant correlation after Bonferroni correction. These 141 miRNAs displayed a negative correlation with remission, indicating a decreasing trend. These miRNAs were associated with 15 pathways, including TGF-ß and MAPK. Through database searches, the genes targeted by these miRNAs with the identified pathways were compared, and it was found that MAPK1, IGF1, IGF1R, and BRAF matched. Alterations in specific miRNAs levels before and after MIR treatment correlated with remission. The miRNAs mentioned in this study have not been previously reported. No other studies have investigated treatment with MIR. The identified miRNAs also correlated with depression-related genes and pathways.

Effectiveness and Changes in Brain Functions by an Occupational Therapy Program Incorporating Mindfulness in Outpatients with Anxiety and Depression: A Randomized Controlled Trial.

INTRODUCTION: This study examined the efficacy of an 8-week occupational therapy program incorporating mindfulness (MOT) as a form of psychiatric rehabilitation to ameliorate residual social and occupational impairment in patients with anxiety disorders and depression. The objective was to evaluate the effects of MOT on their personal well-being and to assess the impact of MOT on brain function using quantitative electroencephalography (qEEG). METHODS: This study was a randomized, wait-list control trial with assessments performed at baseline, post-intervention (9 weeks), and follow-up (18 weeks) in outpatients with anxiety disorders and depression. The MOT was conducted in small groups, comprising eight weekly 1.5-h sessions. The primary outcome was the mean score change between the pre- and post-interventions with Questionnaire about the Process of Recovery (QPR) scale. Other clinical assessments and qEEG served as secondary and biological outcomes, respectively. RESULTS: A total of 25 patients (mean age: 44.1) were included in the analysis. The MOT group demonstrated a significantly improved QPR compared to the control group after adjusting for baseline covariates (p < 0.01). This improvement was sustained for 9 weeks after the 8-week intervention. In the qEEG analysis, a significant increase in current source density in the ß2 band of the left dorsolateral prefrontal cortex was observed in the MOT group compared to the control group (p < 0.02). CONCLUSION: This study demonstrates that MOT improves subjective well-being and potentially, global function. This suggests that MOT may serve as a viable option for those whose symptoms have abated but who still struggle with social and occupational functioning.

Relationship between circulating mitochondrial DNA and microRNA in patients with major depression.

BACKGROUND: MicroRNAs (miRNAs) and circulating cell-free mitochondrial DNA (ccf-mtDNA) have attracted interest as biological markers of affective disorders. In response to stress, it is known that miRNAs in mitochondria diffuse out of the cytoplasm alongside mtDNA; however, this process has not yet been identified. We hypothesized that miRNAs derived from specific cell nuclei cause mitochondrial damage and mtDNA fragmentation under MDD-associated stress conditions. METHODS: A comprehensive analysis of the plasma miRNA levels and quantification of the plasma ccf-mtDNA copy number were performed in 69 patients with depression to determine correlations and identify genes and pathways interacting with miRNAs. The patients were randomly assigned to receive either selective serotonin reuptake inhibitors (SSRI) or mirtazapine. Their therapeutic efficacy over four weeks was evaluated in relation to miRNAs correlated with ccf-mtDNA copy number. RESULTS: The expression levels of the five miRNAs showed a significant positive correlation with the ccf-mtDNA copy number after correcting for multiple testing. These miRNAs are involved in gene expression related to thyroid hormone synthesis, the Hippo signaling pathway, vasopressin-regulated water reabsorption, and lysine degradation. Of these five miRNAs, miR-6068 and miR-4708-3p were significantly associated with the SSRI and mirtazapine treatment outcomes, respectively. LIMITATIONS: This study did not show comparison with a healthy group. CONCLUSIONS: The expression levels of specific miRNAs were associated with ccf-mtDNA copy number in untreated depressed patients; moreover, these miRNAs were linked to antidepressant treatment outcomes. These findings are expected to lead to the elucidation of new pathological mechanism of depression.

Development and acceptability testing of a decision aid for considering whether to reduce antipsychotics in individuals with stable schizophrenia.

AIM: Continued antipsychotic treatment is the key to preventing relapse. Maintenance antipsychotic monotherapy and optimal dose use are recommended for individuals with stable schizophrenia because of their undesirable effects. Decision aids (DAs) are clinical conversation tools that facilitate shared decision-making (SDM) between patients and health-care providers. This study aimed to describe the development process and results of acceptability testing of a DA for individuals with stable schizophrenia, considering (i) whether to continue high-dose antipsychotics or reduce to the standard dose and (ii) whether to continue two antipsychotics or shift to monotherapy. METHODS: A DA was developed according to the guidelines for the appropriate use of psychotropic medications and International Patient Decision Aid Standards (IPDAS). First, a DA prototype was developed based on a previous systematic review and meta-analysis conducted for identifying the effects of continuing or reducing antipsychotic treatment. Second, mixed-method survey was performed among individuals with schizophrenia and health-care providers to modify and finalize the DA. RESULTS: The DA consisted of an explanation of schizophrenia, options to continue high-dose antipsychotics or reduce to the standard dose, options to continue two antipsychotics or shift to monotherapy, pros and cons of each option, and a value-clarification worksheet for each option. The patients (n = 20) reported acceptable language use (75%), adequate information (75%), and well-balanced presentation (79%). Health-care providers (n = 20) also provided favorable overall feedback. The final DA covered six IPDAS qualifying criteria. CONCLUSION: A DA was successfully developed for schizophrenia, considering whether to reduce antipsychotics, which can be used in the SDM process.

Long-term safety and efficacy of sublingual asenapine for the treatment of schizophrenia: A phase III extension study with follow-up for 52 weeks (P06125)-Secondary publication.

After completion of a 6-week double-blind trial of asenapine sublingual tablets (10 or 20 mg/day) versus placebo in Asian patients with acute exacerbation of schizophrenia, including Japanese patients, this open-label study evaluated the safety and efficacy of a 52-week treatment with asenapine at flexible doses. In 201 subjects, including 44 who had received placebo (P/A group) and 157 who had received asenapine (A/A group) in the feeder trial, adverse events occurred at rates of 90.9% and 85.4% and serious adverse events at rates of 11.4% and 20.4%, respectively. One patient in the P/A group died. No clinically significant abnormal measurements of body weight, body mass index, or glycated hemoglobin, fasting plasma glucose, insulin, and prolactin levels were observed. The sustained efficacy rate, as evaluated by the Positive and Negative Syndrome Scale total score and other measures, remained at approximately 50% between 6 and 12 months of treatment. These results suggest that long-term treatment with asenapine is well tolerated and provides sustained efficacy.

Efficacy of Asenapine in Drug-resistant Psychotic Patients with Dopamine Supersensitivity Psychosis: Two Cases.

Dopamine supersensitivity psychosis (DSP) is an unstable clinical condition observed in individuals with schizophrenia who have been treated with an antipsychotic medication at a high dosage and/or for a long period. An up-regulation of dopamine D2 receptors (DRD2) is thought to be involved in the essential pathology of DSP. An antipsychotic agent with both tight binding to DRD2 and a long half-life is generally effective for treating DSP, but a patient who meets the criteria of treatment-resistant schizophrenia sometimes needs treatment with clozapine. We report the case details of two patients whose DSP was not controlled with several antipsychotics but was successfully controlled with asenapine. Asenapine binds to a broad range of dopamine receptors and serotonin receptors, and it is thus distinct from other atypical antipsychotics. The unique profile of asenapine may contribute to the control of severe DSP symptoms in individuals with schizophrenia.

Precise Discrimination for Multiple Etiologies of Dementia Cases Based on Deep Learning with Electroencephalography.

INTRODUCTION: It is critical to develop accurate and universally available biomarkers for dementia diseases to appropriately deal with the dementia problems under world-wide rapid increasing of patients with dementia. In this sense, electroencephalography (EEG) has been utilized as a promising examination to screen and assist in diagnosing dementia, with advantages of sensitiveness to neural functions, inexpensiveness, and high availability. Moreover, the algorithm-based deep learning can expand EEG applicability, yielding accurate and automatic classification easily applied even in general hospitals without any research specialist. METHODS: We utilized a novel deep neural network, with which high accuracy of discrimination was archived in neurological disorders in the previous study. Based on this network, we analyzed EEG data of healthy volunteers (HVs, N = 55), patients with Alzheimer's disease (AD, N = 101), dementia with Lewy bodies (DLB, N = 75), and idiopathic normal pressure hydrocephalus (iNPH, N = 60) to evaluate the discriminative accuracy of these diseases. RESULTS: High discriminative accuracies were archived between HV and patients with dementia, yielding 81.7% (vs. AD), 93.9% (vs. DLB), 93.1% (vs. iNPH), and 87.7% (vs. AD, DLB, and iNPH). CONCLUSION: This study revealed that the EEG data of patients with dementia were successfully discriminated from HVs based on a novel deep learning algorithm, which could be useful for automatic screening and assisting diagnosis of dementia diseases.

Association between the Rostral Anterior Cingulate Cortex and Anterior Insula in the Salience Network on Response to Antidepressants in Major Depressive Disorder as Revealed by Isolated Effective Coherence.

INTRODUCTION: Functional connectivity is attracting increasing attention for understanding the pathophysiology of depression and predicting the therapeutic efficacy of antidepressants. In this study, we evaluated effective connectivity using isolated effective coherence (iCoh), an effective functional connectivity analysis method developed from low-resolution brain electromagnetic tomography (LORETA) and estimated its practical usefulness for predicting the reaction to antidepressants in theta and alpha band iCoh values. METHODS: We enrolled 25 participants from a depression treatment randomized study (the GUNDAM study) in which electroencephalography was performed before treatment. We conducted iCoh between the rostral anterior cingulate cortex (rACC) and anterior insula (AI), which are associated with the salience network. The patients were divided into responder and nonresponder groups at 4 weeks after the start of treatment, and iCoh values were compared between the two groups. Additionally, the sensitivity and specificity of iCoh were calculated using the receiver-operating characteristic (ROC) curve. RESULTS: The Mann-Whitney U test showed significantly weaker connectivity flow from the rACC to the left AI in the alpha band in the responder group. The ROC curve for the connectivity flow from the rACC to the left AI in the alpha band showed 82% sensitivity and 86% specificity. DISCUSSION/CONCLUSION: These findings suggest the pathological importance of effective connectivity flow from the rACC to the left AI in the alpha and theta bands and suggest its usefulness as a biomarker to distinguish responders to antidepressants.

Personality as a basis for antidepressant selection for patients with depression: A two-point outcome study at 4 and 8 weeks.

BACKGROUND: The treatment course for depression is multifactorial, and the gold standard method for antidepressant selection remains unclear. Therefore, we focused on patients' personality as a possible indicator of the treatment response to mirtazapine and selective serotonin reuptake inhibitors (SSRIs) and whether it can contribute to antidepressant selection. METHODS: One hundred one patients with major depressive disorder were randomized at baseline to receive either mirtazapine or SSRI treatment. Their personality was measured using the NEO Five-Factor Inventory at baseline, and depressive symptoms were evaluated using the Hamilton Rating Scale for Depression at baseline and 4 and 8 weeks. Stepwise multivariable logistic regression and receiver operating characteristic analyses were performed to determine the association of personality traits with remission and better antidepressant selection. RESULTS: Neuroticism had the substantial influence on remission at 4 and 8 weeks among the entire sample. The cutoff T-score of neuroticism for predicting remission at 4 weeks was 62.5. The patients with moderate neuroticism (scores below the cutoff) were more likely to experience remission after 4-week mirtazapine treatment (remission rate: 73.7 %) than after SSRI treatment (40.0 %); those with high neuroticism (scores above the cutoff) were more likely to experience remission after 8-week SSRI treatment (74.1 %) than after mirtazapine treatment (35.7 %). LIMITATIONS: The small sample size increased the confidence intervals. CONCLUSIONS: The treatment response of the patients with depression differed according to the type of antidepressants and degree of neuroticism. Measuring personality traits at treatment initiation may help in selecting better antidepressants and predicting the time to remission.

Multiple Pre-Treatment miRNAs Levels in Untreated Major Depressive Disorder Patients Predict Early Response to Antidepressants and Interact with Key Pathways.

Major depressive disorder (MDD) is a life-impairing disorder, and early successful treatment is important for a favorable prognosis. However, early response to antidepressants differs widely among individuals, and is difficult to predict pre-treatment. As miRNAs have been reported to play important roles in depression, identification of miRNAs associated with antidepressant treatment responses and their interacting genes and pathways will be beneficial in understanding the predictors and molecular mechanisms of depression treatment. This randomized control trial examined miRNAs correlated with the early therapeutic effect of selective serotonin reuptake inhibitors (SSRIs; paroxetine or sertraline) and mirtazapine monotherapy. Before medication, we comprehensively analyzed the miRNA expression of 92 depressed participants and identified genes and pathways interacting with miRNAs. A total of 228 miRNAs were significantly correlated with depressive symptoms improvements after 2 weeks of SSRIs treatment, with miR-483.5p showing the most robust correlation. These miRNAs are involved in 21 pathways, including TGF-ß, glutamatergic synapse, long-term depression, and the mitogen-activated protein kinase (MAPK) signaling pathways. Using these miRNAs enabled us to predict SSRI response at week 2 with a 57% difference. This study shows that pre-treatment levels of miRNAs could be used to predict early responses to antidepressant administration, a knowledge of genes, and an identification of genes and pathways associated with the antidepressant response.

Pre-treatment plasma cytokine levels as potential predictors of short-term remission of depression.

OBJECTIVES: The response to antidepressants varies significantly among individuals and is difficult to predict before treatment. In this randomised control trial, we explored cytokines that correlate with the therapeutic effect of mirtazapine (MIR) and selective serotonin reuptake inhibitors (SSRIs) and whether they could be predictors of remission for each antidepressant. METHODS: Plasma cytokines, such as tumour necrosis factor-α (TNF-α), interleukin (IL)-1ß, IL-2, IL-4, IL-6, IL-8, and granulocyte-macrophage colony-stimulating factor (GM-CSF) were assayed in 95 participants before medication and assayed by the enzyme-linked immunosorbent assay. The Hamilton Rating Scale for Depression assessed depressive symptoms over 4 weeks. RESULTS: In the SSRI group, the baseline GM-CSF level was significantly higher in the remission group than in the non-remission group (p = .022). In the MIR group, the baseline level of TNF-α was significantly higher (p = .039) and IL-2 was lower (p = .032) in the remission group than in the non-remission group. In patients prescribed with MIR, the cut-off values of TNF-α (10.035 pg/mL) and IL-2 (1.170 pg/mL) calculated from the receiver operating characteristic curve suggested that the remission rate, which corresponds to a positive predictive value, could be increased from 31.3% to 60.0% and 50.0%, respectively. For those prescribed with SSRIs, the remission rate was 37.0% and using the cut-off value of GM-CSF (0.205 pg/mL), the remission rate could be almost doubled to 70%. CONCLUSIONS: Our study shows that pre-treatment plasma concentrations of TNF-α, IL-2, and GM-CSF may suggest the predictability of remission by SSRIs or MIR.

Divergence of dose-response with asenapine: a cluster analysis of randomized, double-blind, and placebo control study.

BACKGROUND: Differences in psychiatric background and dose-response to asenapine in patients with schizophrenia were examined based on efficacy and safety, using data obtained in a double-blind, placebo-controlled trial. METHODS: Patients with schizophrenia were classified into three clusters by a cluster analysis based on the Positive and Negative Symptom Scale (PANSS) subscores at baseline, using the data from a 6-week, double-blind, placebo-controlled trial. PANSS Marder factor scores were calculated for each cluster. The efficacy of 10 or 20 mg/day of asenapine on PANSS score was used as the primary endpoint, with the incidence of adverse events evaluated as the secondary endpoint. RESULTS: A total of 529 asenapine-treated patients were classified into 3 clusters: Cluster-P with the higher scores in positive symptoms, disorganized thoughts, and hostility/excitement, Cluster-N with higher scores in negative symptoms, and Cluster-L with overall lower scores. In Cluster-N and Cluster-L, both 10 and 20 mg/day groups showed significant improvement in PANSS scores, while only the 20 mg/day group showed a significant difference in Cluster-P. Cluster-N and Cluster-L had differences in the incidence of adverse events, but this was not seen in Cluster-P. CONCLUSIONS: The efficacy and safety of asenapine 10 and 20 mg/day differed between the 3 clusters of patients. This suggests that background information regarding baseline psychiatric symptoms may affect the therapeutic response in patients with schizophrenia.

Pharmacological treatment algorithms for the acute phase, agitation, and maintenance phase of first-episode schizophrenia: Japanese Society of Clinical Neuropsychopharmacology treatment algorithms.

OBJECTIVE: There are only a few treatment algorithms for first-episode schizophrenia. Moreover, all the algorithms apply to acute treatment, but not maintenance treatment. Therefore, we aimed to develop acute and maintenance treatment algorithms for first-episode schizophrenia. METHODS: The algorithm committee of the Japanese Society of Clinical Neuropsychopharmacology developed pharmacological treatment algorithms for the acute phase, agitation, and maintenance phase of first-episode schizophrenia. RESULTS: The acute treatment algorithm focuses on drug-naïve patients with first-episode schizophrenia who are not old or very agitated and recommends first-line treatment with aripiprazole, second- or third-line treatment with risperidone/paliperidone or olanzapine, and fourth-line treatment with clozapine. Long-acting injection of the current antipsychotic agent can be used for poor medication adherence or based on patient preference. The agitation treatment algorithm recommends first-line treatment with lorazepam and second- or third-line treatment with quetiapine or levomepromazine and clearly instructs that the medication used for agitation should be reduced and then discontinued after remission of agitation. The maintenance treatment algorithm recommends the gradual reduction of antipsychotics to the minimum effective dose after remission of positive symptoms. CONCLUSIONS: We hope that our unique algorithms will be used broadly and will contribute to minimizing patients' burden related to antipsychotic treatment.

Sevoflurane in electroconvulsive therapy: A systematic review and meta-analysis of randomised trials.

Sevoflurane is the most commonly used inhaled anaesthetic in electroconvulsive therapy (ECT). The objective of this study was to provide an up-to-date and comprehensive review on how the use of sevoflurane affects seizure adequacy (seizure duration and postictal suppression index [PSI]) and circulatory dynamics in ECT. We performed a meta-analysis of RCTs that investigated seizure adequacy and circulatory dynamics in patients treated with ECT using sevoflurane (sevoflurane group) and intravenous anaesthetics (non-sevoflurane group). A total of 12 RCTs (377 patients and 1339 ECT sessions) were included. Sevoflurane significantly decreased the electroencephalogram (EEG) seizure durations in comparison with intravenous anaesthetics, whereas no significant difference was observed in PSI (EEG: 9 studies, standardized mean difference (SMD) = 0.74, 95% confidence interval (CI) = -1.11 to -0.38, p = 0.0002; PSI: 4 studies, SMD = -0.06, CI -0.13 to 0.25, p = 0.59). The use of sevoflurane in ECT significantly increased heart rate (HR) compared with intravenous anaesthetics (9 studies, SMD = 0.31, CI 012-0.51, p = 0.004). In the pre-planned subgroup analysis, sevoflurane significantly reduced seizure duration compared with other types of anaesthetics, including propofol, barbiturates and ketamine. Furthermore, it was found that the risk of adverse events in ECT with sevoflurane were not significantly different from intravenous anaesthetics (6 studies, risk ratio = 1.33, CI 0.95-1.86, p = 0.09), with agitaion being the most common adverse effects. The results of our study suggest that using sevoflurane for ECT significantly reduces seizure duration, increases maximum HR and brings about no difference in the adverse event risk compared with those using intravenous anaesthetics for ECT. Therefore, there may not be compelling evidence favouring sevoflurane use for ECT, except in cases where intravenous access is difficult.

Rehospitalization Risk of Receptor-Affinity Profile in Antipsychotic Drug Treatment: A Propensity Score Matching Analysis Using a Japanese Employment-Based Health Insurance Database.

PURPOSE: The aim of this study was to examine whether there is a difference in the risk of rehospitalization when antipsychotics are classified into two groups treated using drugs with a higher or lower affinity to H1 or α1 receptors than to D2 receptors (histamine H1 receptors, adrenaline α1 receptors [HA] high- and HA low-affinity drug group, respectively) based on affinity to receptors related to sedation using a nationwide insurance claims database in Japan. PATIENTS AND METHODS: We identified eligible patients by the following two criteria: (i) hospitalization due to schizophrenia (International Classification of Disease [ICD]-10 code: F20 or F25) in psychiatric wards between January 1st, 2005 and August 31st, 2017, and (ii) administration of HA high- or HA low-affinity drugs in the next month after discharge from the earliest hospitalization due to schizophrenia (index month). The primary endpoint was rehospitalization due to schizophrenia. The secondary endpoints were (i) involuntary rehospitalization, (ii) concomitant use of anxiolytics/hypnotics, mood stabilizers, and antiparkinsonian drugs, (iii) all-cause death, and (iv) medication discontinuation. Propensity score (PS) matching analysis was applied, and the hazard ratio (HR) of the event rate in the HA high-affinity drug group relative to the HA low-affinity drug group was calculated using Cox's proportional hazards model. RESULTS: Two thousand nine hundred and forty patients were identified as eligible patients. Among PS-matched patients (819 in each group), the HR in the HA high-affinity drug group compared with the HA low-affinity drug group was 1.018 (0.822-1.260, P = 0.870). Other outcomes did not differ significantly between the two groups. CONCLUSION: No significant difference was observed in the rehospitalization risk due to schizophrenia associated with HA high-affinity antipsychotic drugs. Although this study was a retrospective PS-matched cohort study, the possibility of masking of the rehospitalization risk cannot be excluded because more than 80% of the patients were administered an anxiolytic/hypnotic at the time of admission.

Brain Volume-Related Polymorphisms of the Glycogen Synthase Kinase-3ß Gene and Their Effect on Antidepressant Treatment in Major Depressive Disorder.

BACKGROUND: Glycogen synthase kinase-3ß (GSK-3ß) polymorphisms are known to influence hippocampal brain tissue volume in individuals with major depressive disorder (MDD). However, the effects of the GSK-3ß gene single nucleotide polymorphisms (SNPs) in those receiving antidepressant therapy are unknown. OBJECTIVES: In the present study, we examined the relationship between brain volume-related SNPs of the GSK-3ß gene and antidepressant treatment effects in patients with MDD. METHODS: Paroxetine, fluvoxamine, or milnacipran was administered to 143 Japanese patients with MDD. Two SNPs of the GSK-3ß gene (rs6438552 and rs12630592) that influence brain volume in the hippocampus were genotyped. For the primary outcome, the relationship between genetic variations in the SNPs and the percent change in the Hamilton Rating Scale for Depression (HAM-D) score at week 6 was examined. In addition, rs334558, which has been reported repeatedly, was also genotyped. RESULTS: There was a significant correlation between the two SNPs and the percent change in the HAM-D scores at week 6 (rs6438552 A/A vs. A/G + G/G: p = 0.016; rs12630592 G/G vs. G/T + T/T: p = 0.016). There was high linkage disequilibrium between the rs6438552 and rs12630592 SNPs. The correlation between high therapeutic response over time and the two SNPs were also confirmed (rs6438552 A/A vs. others: p = 0.031; rs12630592 G/G vs. others: p = 0.031). CONCLUSIONS: Our results suggest that two GSK-3ß variants that influence brain volume were associated with changes in the HAM-D scores at week 6 in patients with MDD.

Switching to antipsychotic monotherapy vs. staying on antipsychotic polypharmacy in schizophrenia: A systematic review and meta-analysis.

BACKGROUND: While recent meta-analyses have reported the superiority of antipsychotic polypharmacy (APP) over antipsychotic monotherapy (APM) in schizophrenia, switching to APM can be beneficial in terms of side effects. To determine whether patients receiving APP should switch to APM or stay on APP, we conducted a systematic review and meta-analysis. METHODS: Randomized controlled trials (RCTs) examining a switch from APP to APM vs. staying on APP were systematically selected from a previous meta-analysis comparing APP with APM in patients with schizophrenia. In addition, we conducted an updated systematic literature search using MEDLINE, Embase, and Cochrane Central Register of Controlled Trials. Data on study discontinuation, relapse, psychopathology, neurocognition, extrapyramidal symptoms, and body weight/body mass index (BMI) were extracted and synthesized. RESULTS: A total of 6 RCTs involving 341 patients were included. All studies examined a switch from 2 antipsychotic agents to a single agent. Clozapine-treated patients were included in 3 studies. There was a significant difference in study discontinuation due to all causes in favor of staying on APP (N = 6, n = 341, RR = 2.28, 95% CI = 1.50-3.46, P < 0.001). There were no significant differences in relapse, any psychopathology, neurocognition, extrapyramidal symptoms, or body weight/BMI between the 2 groups. The quality of evidence was low to very low. CONCLUSIONS: The findings suggest that clinicians should closely monitor patient condition when switching to APM after receiving 2 antipsychotics. Given the low to very low overall quality of the evidence, the findings should be considered preliminary and inconclusive.