Targeting Method for rTMS for Treating Depression in Japanese Patients: A Comparison of the Standard, F3, and Neuronavigation Approaches.

INTRODUCTION: The left dorsolateral prefrontal cortex (lDLPFC) is a commonly targeted brain region for repetitive transcranial magnetic stimulation (rTMS) for depression. The lDLPFC has been identified using the "5-cm rule." However, identification of the lDLPFC may deviate from the ideal stimulation site localized by neuronavigation. Therefore, we aimed to compare this method with other methods and examine the relationship between deviation from the ideal stimulation site and treatment effects. While most existing studies have focused on participants of European descent, this study focused on Japanese participants. METHODS: The study participants were 16 patients who underwent rTMS and had the stimulus location identified using the 5-cm method. The lDLPFC was identified by the F3 electrode position and neuronavigation in addition to the 5-cm rule, and these locations were compared. We then performed a correlation analysis of the distance between the sites identified by the 5-cm method and by neuronavigation, as well as changes in scores on the 17-item Hamilton Depression Scale (HAMD-17). RESULTS: The lDLPFC identified by the F3 site and neuronavigation was approximately 3 cm more anterolateral than that identified by the 5-cm method. A significant correlation was found between the distance between the sites identified by the 5-cm method and neuronavigation and the rate of change in HAMD-17 scores. CONCLUSION: The ideal stimulation site may be approximately 3 cm anterior to the site identified by the 5-cm method, and stimulation of the F3 site may be a valid alternative to the 5-cm method.

Lithium-induced cognitive dysfunction assessed over 1-year hospitalisation: A case report.

Introduction: Lithium-induced neurotoxicity is almost always reversible but can cause irreversible neurological sequelae, namely the syndrome of irreversible lithium-effectuated neurotoxicity (SILENT). As there is no definitive treatment for SILENT, caution is required when administering lithium. Reports on the effect of lithium-effectuated neurotoxicity on cognitive function are limited. We report a case in which high cognitive function was lost after lithium overdose and hardly recovered, as evaluated using multiple neuropsychological tests during a 1-year hospitalisation period. Patient presentation: A 52-year-old man on lithium medication with bipolar disorder was admitted to the intensive care unit because of lithium overdose. The patient achieved lucid consciousness after continuous haemodiafiltration. However, he could not move his body as desired or produce appropriate verbal expressions; thus, he was moved to our psychiatric ward, where his treatment continued. Management and outcome: After several months, the patient was diagnosed with SILENT owing to persistent motor and cognitive dysfunctions. Multiple neuropsychological tests were performed, and cognitive function was evaluated. The Neurobehavioural Cognitive Status Examination showed a worsening trend, and the full intelligence quotient of the Wechsler Adult Intelligence Scale-Third Edition was in the mild intellectual disability range. Conclusion: This is a clear case of cognitive dysfunction due to SILENT and is difficult to treat. Thus, it is crucial to prevent the onset of SILENT. Contribution: This report is valuable because it is one of the few to track changes in cognitive function over time in a patient with SILENT using objective measures over 1 year of hospitalisation.

Relapse Following Electroconvulsive Therapy for Schizophrenia: A Systematic Review and Meta-analysis.

BACKGROUND: Evidence regarding schizophrenia relapse following acute electroconvulsive therapy (ECT) is sparse compared with that for depression, and we have no clear consensus on relapse proportions. We aimed to provide longitudinal information on schizophrenia relapse following acute ECT. STUDY DESIGN: This systematic review and meta-analysis included randomised controlled trials (RCTs) and observational studies on post-acute ECT relapse and rehospitalization for schizophrenia and related disorders. For the primary outcome, we calculated the post-acute ECT pooled relapse estimates at each timepoint (3, 6, 12, and 24 months post-acute ECT) using a random effects model. For subgroup analyses, we investigated post-acute ECT relapse proportions by the type of maintenance therapy. STUDY RESULTS: Among a total of 6413 records, 29 studies (3876 patients) met our inclusion criteria. The risk of bias was consistently low for all included RCTs (4 studies), although it ranged from low to high for observational studies (25 studies). Pooled estimates of relapse proportions among patients with schizophrenia responding to acute ECT were 24% (95% CI: 15-35), 37% (27-47), 41% (34-49), and 55% (40-69) at 3, 6, 12, and 24 months, respectively. When continuation/maintenance ECT was added to antipsychotics post-acute ECT, the 6-month relapse proportion was 20% (11-32). CONCLUSION: Relapse occurred mostly within 6 months post-acute ECT for schizophrenia, particularly within the first 3 months. Relapse proportions plateaued after 6 months, although more than half of all patients could be expected to relapse within 2 years. Further high-quality research is needed to optimise post-acute ECT treatment strategies in patients with schizophrenia.

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.

Clinical characteristics and prescriptions associated with a 2-year course of rapid cycling and euthymia in bipolar disorder: a multicenter treatment survey for bipolar disorder in psychiatric clinics.

Objective: In patients with bipolar disorder (BD), rapid cycling (RC) presents a risk for a more severe illness, while euthymia (EUT) has a better prognosis. This study focused on the progression of RC and EUT, which are contrasting phenomenology, and aimed to clarify the influence of patient backgrounds and prescription patterns on these different progressions, using a large sample from the first and second iterations of a multicenter treatment survey for BD in psychiatric clinics (MUSUBI). Methods: In the cross-sectional study (MUSUBI), a questionnaire based on a retrospective medical record survey of consecutive BD cases (N = 2,650) was distributed. The first survey was conducted in 2016, and the second one in 2017. The questionnaire collected information on patient backgrounds, current episodes, and clinical and prescribing characteristics. Results: In the first survey, 10.6% of the participants had RC and 3.6% had RC for two consecutive years, which correlated with BP I (Bipolar disorder type I), suicidal ideation, duration of illness, and the use of lithium carbonate and antipsychotic medications. Possible risk factors for switching to RC were comorbid developmental disorders and the prescription of anxiolytics and sleep medication. Moreover, 16.4% of the participants presented EUT in the first survey, and 11.0% presented EUT for two consecutive years. Possible factors for achieving EUT included older age; employment; fewer psychotic symptoms and comorbid personality disorders; fewer antidepressants, antipsychotics, and anxiolytics, and more lithium prescriptions. Conclusion: RC and EUT generally exhibit conflicting characteristics, and the conflicting social backgrounds and factors contributing to their outcomes were distinctive. Understanding these clinical characteristics may be helpful in clinical practice for management of patients with BD.

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.

Implementations of an evidence-based assertive case management intervention for suicide attempters: Post-ACTION-J Study (PACS).

Aim: An assertive case management intervention program, ACTION-J, proved effective for preventing suicide attempters from reattempting suicide within 6 months. The ACTION-J randomized trial was conducted as part of the "National Strategic Research Projects." The program has been covered by the national medical payment system of Japan since 2016. The aim of the Post-ACTION-J Study (PACS) was to examine the current implementation status of assertive case management in a real-world clinical setting. Methods: PACS was a prospective, multicenter registry cohort study. The participants were suicide attempters admitted to the emergency departments of 10 participating medical facilities from October 2016 to September 2018. The assertive case management intervention developed by the ACTION-J Study was offered to all patients, and the primary outcome was the duration and frequency of use of the intervention at 6 months. Results: A total of 1159 patients were admitted to emergency departments after a suicide attempt during the study period, 144 of whom were included in our analysis. The proportion of participants who received the intervention for 6 months was 72.2% (104/144), and 63.9% (92/144) of the patients completed ≥7 case management interviews within 6 months. Conclusion: The findings of this study indicate successful implementation of an assertive case management intervention program based on the ACTION-J Study in a real-world clinical setting, following its integration with the national medical payment scheme in Japan. The study provided the useful information that could improve the implementation of assertive case management interventions in future.

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.

Disentangling cognitive inflexibility in major depressive disorder: A transcranial direct current stimulation study.

BACKGROUND: Cognitive dysfunction is a persistent residual symptom in major depressive disorders (MDDs) that hinders social and occupational recovery. Cognitive inflexibility is a typical cognitive dysfunction in MDD and refers to difficulty in switching tasks, which requires two subcomponents: forgetting an old task and adapting to a new one. Here, we aimed to disentangle the subcomponents of cognitive inflexibility in MDD and investigate whether they can be improved by transcranial direct current stimulation (tDCS) on the prefrontal cortex. METHODS: The current study included 20 patients with MDD (seven females) and 22 age-matched healthy controls (HCs) (seven females). The participants received anodal tDCS on either the dorsomedial prefrontal cortex (DMPFC) or dorsolateral prefrontal cortex (DLPFC) in a crossover design. Before and after the application of tDCS, the participants performed a modified Wisconsin Card Sorting Test, in which the task-switching rules were explicitly described and proactive interference from a previous task rule was occasionally released. RESULTS: We found that the behavioral cost of a task switch was increased in patients with MDD, but that of proactive interference was comparable between patients with MDD and HCs. The response time for anodal DMPFC tDCS was decreased compared with that for anodal tDCS on the DLPFC in MDD. CONCLUSIONS: These findings suggest that cognitive inflexibility in MDD is primarily explained by the difficulty to adapt to a new task and environment, and that tDCS on the DMPFC improves behavioral performance during cognitively demanding tasks that require conflict resolution.

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.