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.

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.

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.

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.

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.

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.

Long-term oral blonanserin treatment for schizophrenia: a review of Japanese long-term studies.

In general, the course of schizophrenia is chronic accompanied not only by positive and negative symptoms but also by cognitive dysfunction associated with psychosocial disability, and thus treatment combining antipsychotics and psychological therapy is considered promising. This review focused on two prospective, open-label, multicenter, phase 3 long-term studies for approval of oral blonanserin for the treatment of schizophrenia. These two studies included both inpatients and outpatients with variable disease duration or symptom prominence according to the Positive and Negative Syndrome Scale (PANSS). The selected two studies consisted of almost the same study schedule and eligibility criteria but different protocols regarding prior medications and concomitant antipsychotics. The proportion of patients who had a baseline PANSS negative score higher than the positive score was 82.2 and 67.2% in the two studies. In both studies, patients with an illness duration of ≥ 10 years were the most common. Based on the clinical symptoms at baseline, the physician determined the treatment: blonanserin monotherapy, blonanserin in combination with the existing antipsychotic medication, or therapy simplified to haloperidol together with blonanserin. The 28-week completion rate for long-term blonanserin treatment was high in both studies (82.2 and 78.7%). The types of adverse events in both studies were similar to those in the preceding 8-week randomized, active-controlled studies in Japan, which were included in the application package for the approval of oral blonanserin for patients with schizophrenia. Long-term blonanserin use did not increase the risk of extrapyramidal symptoms but reduced the dose of antiparkinsonian drugs, minimally affecting functioning. In both studies, the PANSS total score, positive score, and negative score were improved at the last observation carried forward compared with those at baseline. In conclusion, blonanserin is useful for long-term treatment of chronic schizophrenic patients when the appropriate management of clinical symptoms and adverse drug reactions are applied. Blonanserin might represent a promising treatment option that partially or completely relieves patients with chronic schizophrenia of polypharmacy. Blonanserin may possibly fit both the current real-world clinical setting and the currently recommended approach to antipsychotic medication.

Two-day assertive-case-management educational program for medical personnel to prevent suicide attempts: A multicenter pre-post observational study.

AIM: Suicide attempters have a high risk of repeated suicide attempts and completed suicide. There is evidence that assertive case management can reduce the incidence of recurrent suicidal behavior among suicide attempters. This study evaluated the effect of an assertive-case-management training program. METHODS: This multicenter, before-and-after study was conducted at 10 centers in Japan. Participants were 274 medical personnel. We used Japanese versions of the Attitudes to Suicide Prevention Scale, the Gatekeeper Self-Efficacy Scale, the Suicide Intervention Response Inventory (SIRI), and the Attitudes Toward Suicide Questionnaire. We evaluated the effects with one-sample t-tests, and examined prognosis factors with multivariable analysis. RESULTS: There were significant improvements between pre-training and post-training in the Attitudes to Suicide Prevention Scale (mean: -3.07, 95% confidence interval [CI]: -3.57 to -2.57, P < 0.001), the Gatekeeper Self-Efficacy Scale (mean: 10.40, 95%CI: 9.48 to 11.32, P < 0.001), SIRI-1 (appropriate responses; mean: 1.15, 95%CI: 0.89 to 1.42, P < 0.001), and SIRI-2 (different to the expert responses; mean: -4.78, 95%CI: -6.18 to -3.38, P < 0.001). Significant improvements were found on all Attitudes Toward Suicide Questionnaire subscale scores, except Unjustified Behavior. The effect of training was influenced by experience of suicide-prevention training and experience of working with suicidal patients. CONCLUSION: The training program (which was developed to implement and disseminate evidence-based suicide-prevention measures) improved attitudes, self-efficacy, and skills for suicide prevention among medical personnel. Specialized suicide-prevention training and experience with suicidal patients are valuable for enhancing positive attitudes and self-efficacy; furthermore, age and clinical experience alone are insufficient for these purposes.

The association of obesity and coronary artery disease genes with response to SSRIs treatment in major depression.

Selective serotonin reuptake inhibitors (SSRIs) are first-line antidepressants for the treatment of major depressive disorder (MDD). However, treatment response during an initial therapeutic trial is often poor and is difficult to predict. Heterogeneity of response to SSRIs in depressed patients is partly driven by co-occurring somatic disorders such as coronary artery disease (CAD) and obesity. CAD and obesity may also be associated with metabolic side effects of SSRIs. In this study, we assessed the association of CAD and obesity with treatment response to SSRIs in patients with MDD using a polygenic score (PGS) approach. Additionally, we performed cross-trait meta-analyses to pinpoint genetic variants underpinnings the relationship of CAD and obesity with SSRIs treatment response. First, PGSs were calculated at different p value thresholds (PT) for obesity and CAD. Next, binary logistic regression was applied to evaluate the association of the PGSs to SSRIs treatment response in a discovery sample (ISPC, N = 865), and in a replication cohort (STAR*D, N = 1,878). Finally, a cross-trait GWAS meta-analysis was performed by combining summary statistics. We show that the PGSs for CAD and obesity were inversely associated with SSRIs treatment response. At the most significant thresholds, the PGS for CAD and body mass index accounted 1.3%, and 0.8% of the observed variability in treatment response to SSRIs, respectively. In the cross-trait meta-analyses, we identified (1) 14 genetic loci (including NEGR1, CADM2, PMAIP1, PARK2) that are associated with both obesity and SSRIs treatment response; (2) five genetic loci (LINC01412, PHACTR1, CDKN2B, ATXN2, KCNE2) with effects on CAD and SSRIs treatment response. Our findings implicate that the genetic variants of CAD and obesity are linked to SSRIs treatment response in MDD. A better SSRIs treatment response might be achieved through a stratified allocation of treatment for MDD patients with a genetic risk for obesity or CAD.

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.

Automated Source Estimation of Scalp EEG Epileptic Activity Using eLORETA Kurtosis Analysis.

OBJECTIVES: eLORETA (exact low-resolution brain electromagnetic tomography) is a technique created by Pascual-Marqui et al. [Int J Psychophysiol. 1994 Oct; 18(1): 49-65] for the 3-dimensional representation of current source density in the brain by electroencephalography (EEG) data. Kurtosis analysis allows for the identification of spiky activity in the brain. In this study, we focused on the evaluation of the reliability of eLORETA kurtosis analysis. For this purpose, the results of eLORETA kurtosis source localization of paroxysmal activity in EEG were compared with those of eLORETA current source density (CSD) analysis of EEG data in 3 epilepsy patients with partial seizures. METHODS: EEG was measured using a digital EEG system with 19 channels. We set the bandpass filter at traditional frequency band settings (1-4, 4-8, 8-15, 15-30, and 30-60 Hz) and 5-10 and 20-70 Hz and performed eLORETA kurtosis to compare the source localization of paroxysmal activity with that of visual interpretation of EEG data and CSD analysis of eLORETA in focal epilepsy patients. RESULTS: The eLORETA kurtosis analysis of EEG data preprocessed by bandpass filtering from 20 to 70 Hz and traditional frequency band settings did not show any discrete paroxysmal source activity compatible with the results of CSD analysis of eLORETA. In all 3 cases, eLORETA kurtosis analysis filtered at 5-10 Hz showed paroxysmal activities in the theta band, which were all consistent with the visual inspection results and the CSD analysis results. DISCUSSION: Our findings suggested that eLORETA kurtosis analysis of EEG data might be useful for the identification of spiky paroxysmal activity sources in epilepsy patients. Since EEG is widely used in the clinical practice of epilepsy, eLORETA kurtosis analysis is a promising method that can be applied to epileptic activity mapping.

Hyperactivation of the Frontal Control Network Revealed by Symptom Provocation in Obsessive-Compulsive Disorder Using EEG Microstate and sLORETA Analyses.

The aim of this study was to investigate the changes of brain electric field induced by symptom provocation in patients with obsessive-compulsive disorder (OCD) in comparison to healthy controls in the resting state. For this purpose, EEG recordings in conditions of initial rest, clean control, symptom provocation by imaginal exposure, and final rest were used for computing spatiotemporal activity characteristics based on microstate segmentation. Within-group comparisons were significant for the symptom provocation condition: OCD showed high global field power (GFP) and transition rates into a medial frontal microstate, whereas healthy controls showed high frequency of occurrence and high percent of dwelling time for a medial occipitoparietal microstate. Between-group comparisons demonstrated significantly lower GFP and dwelling time for the medial occipitoparietal microstate in OCD in several conditions including initial rest and symptom provocation. In addition, OCD compared to healthy controls showed significant instability of the medial occipitoparietal microstate, with high preference for transitions into the medial frontal microstate. In conclusion, during rest and symptom provocation, OCD patients make preferential use of a medial frontal brain network, with concomitant reduction of use of a medial occipitoparietal network, as shown by dwelling times, explained variance, and dynamic transition rates. These findings support the idea of a possible biological marker for OCD, which might correspond to pathological hyperactivation of the frontal control network.

Uterine rupture due to placenta percreta in the first trimester of a pregnancy subsequent to a transverse uterine fundal cesarean section: A case report.

Transverse uterine fundal cesarean section in cases of total placenta previa reduces blood loss, but its influence on subsequent pregnancies, including the uterine rupture risk, remains unclear. We report a case of uterine rupture due to placenta percreta in the first trimester in a 43-year-old woman who underwent transverse uterine fundal incision in a previous pregnancy (at 40 years old). The patient did not undergo assessment of the uterine scare after the previous operation. Oocyte donation and in vitro fertilization at another institution resulted in the current pregnancy. At 11 weeks 3 days, she was admitted to the emergency department because of sudden severe abdominal pain. Ultrasound showed massive accumulation of free fluid in the peritoneal cavity and the fetus was outside the uterine cavity; uterine rupture was diagnosed. During emergency laparotomy, the uterine rupture was detected at exactly the previous incision site; a total hysterectomy was performed. Pregnancy after a transverse uterine fundal cesarean section is at high risk. As uterine scar dehiscence might have caused the uterine rupture, wounds should be evaluated before allowing subsequent pregnancies.

Therapeutic Response to Paroxetine in Major Depressive Disorder Predicted by DNA Methylation.

BACKGROUND: Antidepressants have variable therapeutic effects, depending on genetic and environmental factors. Approximately 30% of major depressive disorder (MDD) patients do not respond significantly to antidepressants such as paroxetine, a selective serotonin reuptake inhibitor (SSRI). However, the biological mechanisms behind this phenomenon are mostly unknown. Here, we examined the role of patients' epigenetic background in SSRI efficacy. METHODS: Genome-wide DNA methylation analysis of the peripheral blood of Japanese MDD patients was performed by using the Infinium HumanMethylation450 BeadChip. RESULTS: We compared the results of the 10 patients who best responded to paroxetine (BR) with the 10 worst responders (WR), and found 623 CpG sites with a >10% difference in DNA methylation level. Among them, 218 sites were nominally significant between BR and WR (p < 0.05), and 2 sites (cg00594917 and cg07260927) were significantly different after false discovery rate (FDR) correction (q < 0.05). The methylation difference was greatest at cg00594917, located in the first exon of the PPFIA4 gene, which codes for liprin-α (p = 0.00012). Hierarchical cluster analysis of 23 CpG sites in the PPFIA4 gene distinguished BR and WR, except for 1 WR patient. The cg07260927 site was located in the 5'UTR of the heparin sulfate-glucosamine 3-sulfotransferase 1 (HS3ST1) gene (p = 0.00013). Hierarchical cluster analysis of 28 CpG sites in HS3ST1 distinguished BR and WR, except for 1 WR and 2 BR patients. CONCLUSION: Our results suggest that patients' DNA methylation profile at specific genes such as PPFIA4 and HS3ST1 is associated with individual variations in therapeutic responses to paroxetine.

Efficacy of hormonal and mental treatments with MMPI in FtM individuals: cross-sectional and longitudinal studies.

BACKGROUND: Cross-sex hormone treatment (CSHT) is an important option for gender dysphoria (GD) individuals to improve the quality of life. However, in Japan, sex reassignment surgery (SRS) and CSHT for GD had been discontinued until 1998 (over 30 years). After resumption, the number of GD individuals wishing treatment rapidly increased. On the other hand, the number of medical institutions available for evaluation was limited. For this reason, hormonal treatment has been administered to GD individuals requiring the prompt start of CSHT in the absence of mental health assessment by specialists. In this study, we examined the efficacy of CSHT and psychotherapy. METHODS: The participants were 155 female-to-male (FtM) individuals who consulted our gender identity clinic, and were definitively diagnosed. A cross-sectional study was conducted by dividing them into two groups: groups with and without CSHT on the initial consultation (Group CSHT: n = 53, Group no-CSHT: n = 102). In all participants, Minnesota Multiphasic Personality Inventory (MMPI) and blood hormone tests were performed on the initial consultation. In addition, CSHT was combined with psychotherapy for a specific period in Group no-CSHT, and FtM individuals in whom an additional MMPI test could be conducted (Group combined treatment (CT), n = 14) were enrolled in a longitudinal study. RESULTS: In the cross-sectional study, there was no significant difference on the MMPI test. In the longitudinal study, there were improvements in the clinical scales other than the Mf scale on the MMPI test. In Group CT, the D, Sc, and Si scale scores on the initial consultation were significantly higher than in Group CSHT. However, there was no clinical scale with a significantly higher value after the start of treatment. The Pd scale score was significantly lower. CONCLUSIONS: CSHT improved mental health. Psychotherapy-combined CSHT may further improve it. TRIAL REGISTRATION: The study was reviewed and approved by the Ethics Committee of Kansai Medical University (A comprehensive treatment for gender dysphoria: No. 0314 registered date 10th December 2003), and was approved at UMIN000028102 on 6th July 2017 as retrospectively registered.

Pyoderma gangrenosum in a pregnant patient: A case report and literature review.

Pyoderma gangrenosum (PG) is a rare ulcerative skin disease that usually starts as a pustular lesion and rapidly progresses to a painful ulcer with undermined violaceous borders. The occurrence of PG during pregnancy is uncommon. We describe a case of a pregnant patient with PG who was diagnosed as having ulcerative colitis after delivery. Obstetricians need to understand the pathogenesis of PG and its associated conditions because it is important to make a proper diagnosis and provide targeted therapy.

Pregnancy outcomes after assisted reproductive procedures with embryos that had been derived from affected and unaffected ovaries among women with small unilateral endometriomas.

Aim: To clarify the effects of small endometriomas on in vitro fertilization (IVF) outcomes. In the present study, the potential impact of small ovarian endometriomas on the quantitative and qualitative outcomes of IVF was evaluated in the same individual. Methods: A retrospective analysis was performed, in which 118 infertile women with unilateral endometriomas that were <40 mm in size and who underwent IVF or intracytoplasmic sperm injection were evaluated. Single frozen embryo transfer cycles were performed, with separate data collections for both the affected and the unaffected ovaries, which allowed for an evaluation of the implantation rate. Results: The mean antral follicular count and the number of follicular flushings, retrieved oocytes, and obtained embryos were significantly lower for the endometrioma-containing ovary than for the contralateral, intact ovary. No significant difference was observed regarding the blastocyst retrieval and good-quality blastocyst retrieval rates, pregnancy rate, and clinical pregnancy or live birth rate. Conclusion: Although the patients with a small endometrioma had a decreased ovarian reserve, they had lower pregnancy rates. The decision to transfer an embryo from an endometrioma-containing ovary or from a contralateral, intact ovary also might not influence the pregnancy rate.