木村 敦史

Abstract Patients with bipolar disorder (BD) and major depressive disorder (MDD) experience psychological distress associated with daily events that do not meet the threshold for traumatic experiences, referred to as event-related psychological distress (ERPD). Recently, we developed an assessment tool for ERPD, the ERPD-24. This tool considers four factors of ERPD: feelings of revenge, rumination, self-denial, and mental paralysis. We conducted a cross-sectional study between March 2021 and October 2022 to identify the differences and clinical features of ERPD among patients with MDD and BD and healthy subjects who did not experience traumatic events. Specifically, we assessed ERPD using the ERPD-24 and anxiety-related symptoms with the State-Trait Anxiety Inventory, Liebowitz Social Anxiety Scale, and anxious-depressive attack. Regarding the ERPD-24 scores among the groups, as the data did not rigorously follow the test of normality, the Kruskal–Wallis test was used to compare the differences among the groups, followed by the Dunn–Bonferroni adjusted post-hoc test. Non-remitted MDD patients and BD patients, regardless of remission/non-remission, presented more severe ERPD than healthy subjects. This study also demonstrated the relationships between all anxiety-related symptoms, including social phobia and anxious-depressive attack and ERPD, in both BD and MDD patients and in healthy subjects. In conclusion, patients with non-remitted MDD and with BD regardless of remission/non-remission experience severe ERPD related to anxiety-related symptoms.

STUDY OBJECTIVES: Although novel hypnotics have recently emerged, there are currently no data comparing the clinical potency of benzodiazepine receptor agonists (BZRAs) and novel hypnotics, or the effectiveness of different methods of switching between them. This study examined how novel hypnotics might help reduce BZRA use in real-world practice. METHODS: 289 patients with psychiatric disorders who took BZRAs for over 1 year before switching to either of two dual-orexin receptor antagonists (DORAs) (suvorexant (SUV) or lemborexant (LEM)) or a melatonin receptor agonist (ramelteon (RMT)) were enrolled. We collected data on BZRAs at baseline and 3 months after commencement of SUV/LEM/RMT. RESULTS: Significant reductions in BZRAs were observed for all three agents: -4.10, -2.80 and -1.65 mg in diazepam-equivalent dose in the SUV, LEM and RMT groups, respectively. Dose reduction was significantly greater in the DORA than the RMT group (F=15.053, P<0.001). Within the DORA group, dose reduction was significantly greater in patients taking SUV than those taking LEM (F=4.337, P=0.043). The switching success rate did not differ among the switching methods for any of the hypnotics. CONCLUSIONS: The reduction rate of BZRAs achieved by the switch fell into their equivalent-potency range estimated from clinical trials. The results suggest that DORAs can replace approximately one tablet of a BZRA. The difference in dose reduction between DORAs and RMT reflected the greater sleeping potency of the DORAs, whereas that between SUV and LEM might have reflected patient backgrounds: patients taking LEM may have been more strongly dependent on BZRAs.

Glial cell line-derived neurotrophic factor (GDNF) plays an important role in the pathophysiology of neuropsychiatric disorders. We examined serum GDNF levels in bipolar disorder (BD) patients and major depressive disorder (MDD) patients and their association with response to lithium therapy. We used a multicenter (six sites), exploratory, cross-sectional case-control design and recruited 448 subjects: 143 BD patients, 116 MDD patients, and 158 healthy controls (HCs). We evaluated the patients' clinical severity using the Clinical Global Impression (CGI), and responses to lithium therapy using the Alda scale. The serum GDNF levels were significantly decreased in the BD and MDD groups compared to the HCs, with no significant difference between the BD and MDD groups. After adjustment, the serum GDNF levels in the BD and MDD patients in remission or depressive states were decreased compared to the HC values. Lower serum GDNF levels in BD patients were associated with higher CGI and Alda scores (i.e., severe illness and good response to lithium therapy, respectively). Our findings suggest that the serum GDNF level may be a biomarker for both BD and MDD in remission or depressive states. The serum GDNF level may be associated with the lithium response of BD patients.

Treatment-resistant schizophrenia (TRS) has a quite complex pathophysiology that includes not only severe positive symptoms but also other symptom domains. Much attention has been devoted to the overlapping psychological and biological profiles of schizophrenia and autistic spectrum disorder (ASD). We compared TRS patients (n = 30) with schizophrenia patients in remission (RemSZ, n = 28) and ASD patients (n = 28), focusing on general cognitive and social cognitive impairment and oxytocin system dysfunction. Our analyses revealed that there was no difference in oxytocin concentration among the three groups. The TRS patients' oxytocin blood concentrations were positively correlated with their processing speed and theory-of-mind scores, whereas the RemSZ and ASD groups had no significant relation with any measures. Rs53576, a single nucleotide polymorphism on the oxytocin receptor gene, affected social cognition abilities in the schizophrenia group. Although the overall findings are preliminary, they indicate that oxytocin system dysfunction could be involved in the serious cognitive deficits in TRS patients. Further, these results suggest that patients with TRS might have early neurodevelopmental abnormalities based on their shared biological features with ASD patients.

Objectives: Although clozapine exhibited high efficacy for treating the symptoms of patients with treatment-resistant schizophrenia (TRS), its precise action mechanisms have not been fully understood. Recently, accumulating evidence has suggested the presence of abnormalities in the gamma-aminobutyric acid (GABA) systems in patients with schizophrenia, and the potential effects of clozapine on GABA receptors have gained a great deal of attention. Experimental Designs: In the present study, the cortical silent period (CSP), an electrophysiological parameter of GABA function via GABAB receptors, was measured using with the transcranial magnetic stimulation in patients with schizophrenia and healthy control subjects. Then the CSP of patients treated with clozapine (N = 12) was compared with that of patients treated with other antipsychotics (N = 25) and with that of healthy controls (N = 27). Principal Observations: The CSP of the patients treated with clozapine was significantly longer compared to those of the other two groups. The CSP of patients treated with other antipsychotics was similar to that of healthy subjects. There was a positive correlation between CSP and global assessment of function (GAF) in patients with TRS. Conclusions: The present study indicated that CSP was prolonged in patients receiving clozapine, and suggested that clozapine enhances the transmission signal via GABAB receptors.

Bipolar disorder (BD) is frequently misdiagnosed as major depressive disorder (MDD) due to overlapping depressive symptoms. This study investigated whether serum platelet-derived growth factor BB (PDGF-BB) is a differential diagnostic biomarker for BD and MDD. An initial SOMAscan proteomics assay of 1311 proteins in small samples from patients with BD and MDD and healthy controls (HCs) suggested that serum levels of PDGF-BB differed between BD and MDD. We then conducted a two-step, exploratory, cross-sectional, case-control study at our institute and five sites that included a total of 549 participants (157 with BD, 144 with MDD, and 248 HCs). Clinical symptoms were assessed using the Hamilton Depression Rating Scale and the Young Mania Rating Scale. In the initial analysis at our institute, serum PDGF-BB levels in the MDD group (n = 36) were significantly lower than those in the BD (n = 39) and HC groups (n = 36). In the multicenter study, serum PDGF-BB levels in the MDD group were again significantly lower than those in the BD and HC groups, with no significant difference between the BD and HC groups. Treatment with sodium valproate was associated with significantly lower serum PDGF-BB levels in patients with BD. After controlling for confounding factors (sex, age, body mass index, clinical severity, and valproate medication), serum PDGF-BB levels were lower in the MDD group than in the BD group regardless of mood state. Our findings suggest that serum PDGF-BB may be a potential biomarker to differentiate BD and MDD.

Stressful events in daily life that are non-traumatic (e.g., family-, school-, work-, interpersonal-, and health-related problems) frequently cause various mood disturbances. For some people, being exposed to non-traumatic but stressful events could trigger the onset and relapse of mood disorders. Furthermore, non-traumatic stressful events also cause event-related psychological distress (ERPD), similar to that of post-traumatic stress disorder (PTSD; i.e., intense intrusive imagery or memory recall, avoidance, and hyperarousal) in the general population and individuals with mood disorders. However, previous ERPD studies only showed that people with ERPD display PTSD-like symptoms after non-traumatic experiences; they failed to get to the crux of the matter by only utilizing trauma- or PTSD-related assessment tools. We thus aimed to identify the psychological phenomena and features of ERPD after individuals experienced non-traumatic stressful events, and to develop and validate an appropriate ERPD assessment tool. First, we conducted a qualitative study to obtain the psychological features through interviews with 22 individuals (mean age = 41.50 years old, SD = 12.24) with major depressive disorder or bipolar disorder. Second, in the quantitative component, we implemented a web-based survey with 747 participants of the general population (mean age = 41.96 years old, SD = 12.64) by using ERPD-related questionnaires created based on the qualitative study; then, we examined the reliability and validity of the ERPD assessment tool. Results yielded that the psychological features of ERPD comprised four factors: feelings of revenge, rumination, self-denial, and mental paralysis. These were utilized in the developed 24-item measure of ERPD-a novel self-report assessment tool. For various professionals involved in mental healthcare, this tool can be used to clarify and assess psychological phenomena in people with ERPD.

The complex pathophysiology of treatment-resistant schizophrenia (TRS) includes severe positive symptoms but also other symptom domains. The overlapping psychological profiles of schizophrenia and autistic spectrum disorder (ASD) are not established. We compared TRS patients (n = 30) with schizophrenia patients in remission (RemSZ, n = 28) and ASD patients (n = 28), focusing on both neurodevelopmental aspects and general and social cognitive impairments. The TRS group performed the worst on general neurocognition (measured by the MATRICS Consensus Cognitive Battery) and social cognition (measured by the theory of mind and emotional expression). The RemSZ group performed the best among the three groups. Regarding autistic traits, all measurements by the Autism-Spectrum Quotient/Autism Screening Questionnaire/Pervasive Developmental Disorder Assessment Rating Scale showed that (1) the ASD patients had the highest autistic traits (2) the TRS patients' scores were less severe than the ASD group's, but (3) the overall trends placed the TRS group between the ASD and the RemSZ group. These findings indicate that TRS patients and remitted patients could have distinctive neurodevelopmental and cognitive profiles. Further, the degrees of social cognitive dysfunction and autistic traits in TRS patients could be close to those of ASD patients, suggesting similarities between TRS and ASD.

Dopamine supersensitivity psychosis (DSP) is a key factor contributing to the development of antipsychotic treatment-resistant schizophrenia. We examined the efficacy and safety of blonanserin (BNS) and olanzapine (OLZ) as adjuncts to prior antipsychotic treatment in patients with schizophrenia and DSP in a 24-week, multicenter (17 sites), randomized, rater-blinded study with two parallel groups (BNS and OLZ add-on treatments) in patients with schizophrenia and DSP: the ROADS Study. The primary outcome was the change in the Positive and Negative Syndrome Scale (PANSS) total score from baseline to week 24. Secondary outcomes were changes in the PANSS subscale scores, Clinical Global Impressions, and Extrapyramidal Symptom Rating Scale (ESRS), and changes in antipsychotic doses. The 61 assessed patients were allocated into a BNS group (n = 26) and an OLZ group (n = 29). The PANSS total scores were reduced in both groups (mean ± SD: -14.8 ± 24.0, p = 0.0042; -10.5 ± 12.9, p = 0.0003; respectively) with no significant between-group difference (mean, -4.3, 95 %CI 15.1-6.4, p = 0.42). The BNS group showed significant reductions from week 4; the OLZ group showed significant reductions from week 8. The ESRS scores were reduced in the BNS group and the others were reduced in both groups. The antipsychotic monotherapy rates at the endpoint were 26.3 % (n = 6) for BNS and 23.8 % (n = 5) for OLZ. The concomitant antipsychotic doses were reduced in both groups with good tolerability. Our results suggest that augmentations with BNS and OLZ are antipsychotic treatment options for DSP patients, and BNS may be favorable for DSP based on the relatively quick responses to BNS observed herein.

Stressful life events, although less serious than traumatic experiences, affect the clinical course of patients with bipolar disorder. We previously found that bipolarity in patients with major depression is related to the severity of psychological distress symptoms associated with onset-related events. Here, we investigated whether, and to what extent, bipolar patients perceive stressful events as psychological distress symptoms, specifically, intrusion, avoidance, and hyperarousal. Further, we investigated the relationship between the clinical features and the severity of psychological distress symptoms associated with stressful life events, according to mood states. We recruited 79 bipolar patients (depression group, n = 32 mania, n = 22 euthymia, n = 25) in this cross-sectional study. We adopted the Impact of Event Scale-Revised (IES-R) to assess the severity of psychological distress symptoms associated with past stressful events. We also evaluated the Hamilton Depression Rating Scale (HDRS) and the Young Mania Rating Scale (YMRS). The mean (standard deviation) IES-R scores of bipolar patients with a depressive episode (38.06 [16.56], p = 0.0005) and of those with a manic/hypomanic episode (44.56 [24.14], p = 0.004) were significantly higher than of those with euthymia (19.81 [12.86]). The HDRS, but not the YMRS, scores showed significant correlations with the IES-R scores, regardless of mood episodes (depression group, r = 0.42 mania, r = 0.64 euthymia, r = 0.70). This study demonstrates that bipolar patients with a manic/hypomanic or depressive episode perceive stressful life events as more severe psychological distress symptoms than do euthymic patients. Moreover, in patients with bipolar disorder, the severity of depressive symptoms, but not of manic symptoms, is positively correlated with that of the psychological distress symptoms, regardless of their mood episodes or euthymic state. Therefore, depressive symptoms may be closely related to the psychological distress symptoms associated with stressful past events in patients with bipolar disorder.

Objective 'Treatment-resistant depression' is depression that does not respond to an adequate regimen of evidence-based treatment. Treatment-resistant depression frequently becomes chronic. Children with treatment-resistant depression might also develop bipolar disorder (BD). The objective of this study was to determine whether serum levels of oxytocin (OXT) in treatment-resistant depression in adolescents (TRDIA) differ from non-treatment-resistant depression in adolescents (non-TRDIA) or controls. We also investigated the relationships between serum OXT levels and the clinical symptoms, severity, and familial histories of adolescent depressive patients. Methods We measured serum OXT levels: TRDIA (n = 10), non-TRDIA (n = 27), and age-and sex-matched, neurotypical controls (n = 25). Patients were evaluated using the Children's Depression Rating Scale-Revised (CDRS-R) and the Depression Self-Rating Scale for Children-Japanese Version (DSRS-C-J). The patients were also assessed retrospectively using the following variables: familial history of major depressive disorder and BD (1st degree or 2nd degree), history of disruptive mood dysregulation disorder, recurrent depressive disorder (RDD), history of antidepressant activation. Results Serum levels of OXT among the TRDIA and non-TRDIA patients and controls differed significantly. Interestingly, the rates of a family history of BD (1st or 2nd degree), RDD and a history of antidepressant activation in our TRDIA group were significantly higher than those of the non-TRDIA group. Conclusions Serum levels of OXT may play a role in the pathophysiology of TRDIA.

Objective: Glutamatergic neurotransmission via the N-methyl-D-aspartate (NMDA) receptor is integral to the pathophysiology of depression. This study was performed to examine whether amino acids related to NMDA receptor neurotransmission are altered in the serum of patients with depression. Method: We measured the serum levels of D-serine, L-serine, glycine, glutamate and glutamine in patients with depression (n = 70), and age-matched healthy subjects (n = 78). Results: Serum levels of D-serine and L-serine in patients with depression were significantly higher than those of healthy controls (p &lt; 0.001). In contrast, serum levels of glycine, glutamate and glutamine did not differ between the two groups. Interestingly, the ratio of L-serine to glycine in patients was significantly higher than that of healthy controls (p &lt; 0.001). Conclusion: This study suggests that serine enantiomers may be peripheral biomarkers for depression, and that abnormality in the D-serine-L-serine-glycine cycle plays a role in the pathophysiology of depression.

Objective Glutamatergic neurotransmission via the N-methyl-d-aspartate (NMDA) receptor is integral to the pathophysiology of depression. This study was performed to examine whether amino acids related to NMDA receptor neurotransmission are altered in the serum of patients with depression. Method We measured the serum levels of d-serine, l-serine, glycine, glutamate and glutamine in patients with depression (n=70), and age-matched healthy subjects (n=78). Results Serum levels of d-serine and l-serine in patients with depression were significantly higher than those of healthy controls (p&lt 0.001). In contrast, serum levels of glycine, glutamate and glutamine did not differ between the two groups. Interestingly, the ratio of l-serine to glycine in patients was significantly higher than that of healthy controls (p&lt 0.001). Conclusion This study suggests that serine enantiomers may be peripheral biomarkers for depression, and that abnormality in the d-serine-l-serine-glycine cycle plays a role in the pathophysiology of depression.

Background: Previous studies have reported that various non-life-threatening life events could cause psychological distress symptoms like posttraumatic stress disorder in adults and adolescents. We examined whether patients with treatment-refractory depression (TRD) perceive their experiences of life events, of which they think as triggering the onset of depression, as more serious psychological distress symptoms than remitted or mildly symptomatic patients with major depressive disorder (MOD). Methods: This study employed a cross-sectional design. We recruited 78 outpatients consisting 0131 TRD patients, 31 remitted MOD patients, and 16 mildly symptomatic MOD patients. We adopted the Impact of Event Scale-Revised (IES-R) to assess the severity of psychological distress symptoms associated with the events that patients thought as triggering the onset of depression. We also evaluated clinical features and variables including the Hamilton Depression Rating Scale (HORS). Results: The mean [+/- SD] score of the IES-R in patients with TRD (46.7 [15.11) was significantly higher than in remitted (10.3 19.91, p &lt; 0.001) or mildly symptomatic (31.3 [17.7], p &lt; 0.001) patients with MOD. The HORS scores showed significant correlations with those of the IES-R among all patients (r=0.811). Limitations: This study was not able to exclude the possibility that the severity of psychological distress symptoms associated with onset-related events could influence the difficult therapeutic course in patients with TRD clue to the cross-sectional design. Conclusions: This study demonstrated that patients with TRD perceive their onset-related life events as serious psychological distress symptoms. This result contributes to understanding the pathophysiology of TRD. (C) 2015 Elsevier B.V. All rights reserved.

Background: Meta-analyses have identified serum levels of brain-derived neurotrophic factor (BDNF) as a potential biomarker for major depressive disorder (MDD). However, at the time, commercially available human ELISA kits are unable to distinguish between proBDNF (precursor of BDNF) and mature BDNF because of limited BDNF antibody specificity. In this study, we examined whether serum levels of proBDNF, mature BDNF, and matrix metalloproteinase-9 (MMP-9), which converts proBDNF to mature BDNF, are altered in patients with MDD. Methodology/Principal Findings: Sixty-nine patients with MDD and 78 age-and gender-matched healthy subjects were enrolled. Patients were evaluated using 17 items on the Structured Interview Guide for the Hamilton Depression Rating Scale. Cognitive impairment was evaluated using the CogState battery. Serum levels of proBDNF, mature BDNF, and MMP-9 were measured using ELISA kits. Serum levels of mature BDNF in patients with MDD were significantly lower than those of normal controls. In contrast, there was no difference in the serum levels of proBDNF and MMP-9 between patients and normal controls. While neither proBDNF nor mature BDNF serum levels was associated with clinical variables, there were significant correlations between MMP-9 serum levels and the severity of depression, quality of life scores, and social function scores in patients. Conclusions/Significance: These findings suggest that mature BDNF may serve as a biomarker for MDD, and that MMP-9 may play a role in the pathophysiology of MDD. Further studies using larger sample sizes will be needed to investigate these results.