Fronto-striato network function is reduced in major depressive disorder.

Introduction: Major depressive disorder (MDD) is a major cause of poor quality of life and disability and is highly prevalent worldwide. Various pathological mechanisms are implicated in MDD, including the reward system. The human brain is equipped with a reward system that is involved in aspects such as motivation, pleasure, and learning. Several studies including a meta-analysis have been reported on the reward system network and MDD. However, to our knowledge, no studies have examined the relationship between the reward system network of drug-naïve, first-episode MDD patients and the detailed symptoms of MDD or age. The fronto-striato network (FSN) is closely related to the reward system network. The present study primarily aimed to elucidate this point. Methods: A total of 89 drug-naïve first-episode MDD patients and 82 healthy controls (HCs) patients were enrolled in the study. The correlation between the FSN and age and the interaction between age and illness in the FSN were investigated in 75 patients in the MDD group and 79 patients in the HC group with available information on the FSN and age. In addition, the association between the FSN and the total scores on the 17-item Hamilton Rating Scale for Depression (HAMD-17) and scores in each symptom item was analyzed in 76 MDD subjects with information on the FSN and HAMD-17. The significance of each result was evaluated according to a p-value of <0.05. Results: Age was inversely correlated with the FSN (p=2.14e-11) in the HC group but not in the MDD group (p=0.79). FSN varied with the presence of MDD and with age, particularly showing an interaction with MDD and age (p=1.04e-08). Specifically, age and the presence or absence of MDD each affected FSN, but the effect of age on FSN changed in the presence of depression. FSN did not correlate with total HAMD-17 scores or scores in each item. Discussion: The reward system may be dysfunctional in patients with MDD. In addition, the effect could be greater in younger patients. Meanwhile, there is no correlation between the function of the reward system and the severity of MDD or the severity of each symptom. Thus, the reward system network may be an important biological marker of MDD, although careful consideration should be given to age and its association with the severity of the disorder. Conclusion: The reward system function is decreased in MDD patients, and this decrease may be more pronounced in younger patients, although further research is still needed.

Volume enlargement of the choroid plexus and brain ventricles in drug-naïve, first-episode major depressive disorder.

BACKGROUND: We investigated volumetric alterations in the bilateral choroid plexus (ChP) and brain ventricles of patients during their first episode of major depressive disorder (MDD) prior to antidepressant treatment. METHODS: Seventy-one first-episode drug-naïve patients with MDD and seventy-four healthy control (HC) subjects were recruited. MRI data were obtained, and bilateral ChP and brain ventricle volumes were evaluated using segmentation, based on the adaptive multiscale and expectation maximization method. One-way multivariate analysis of covariance was used to calculate volumetric differences in the bilateral ChP and brain ventricles between the groups, and partial Pearson correlation analyses were used to investigate the relationship between the volumes of the bilateral ChP and brain ventricles. RESULTS: First-episode drug-naïve patients with MDD showed enlarged volumes of the bilateral ChP, bilateral lateral ventricle (LV), and third ventricle compared with HCs. The ChP volume positively correlated with the LV and third ventricle, but not with the fourth ventricle in patients with MDD, whereas it correlated with all four brain ventricles in HCs. We did not observe significant correlations between bilateral ChP volume and brain ventricles, HAMD scores, or symptom severity. LIMITATIONS: Our study populations differed in age and sex and we did not extensively measure the amount of neuroinflammation in the brain or blood, include a functional assessment, nor evaluate other neural comorbidities or neuropsychiatric conditions. CONCLUSIONS: Our study extends the existing research to suggest that illness-related alterations in ChP volume enlargement in first-episode antidepressant-naïve patients with MDD may serve as a trait measure.

Oromandibular Dystonia After Low-Dose Olanzapine Treatment in a Patient With Marchiafava-Bignami Disease With Demyelinating Lesions in the Corpus Callosum: A Case Report.

Marchiafava-Bignami disease is a rare disorder characterized by demyelination and necrosis of the central nervous system. Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions. Herein, we present the case of a patient with Marchiafava-Bignami disease who developed acute oromandibular dystonia after receiving a very low dose of olanzapine. He was a 60-year-old Japanese man who was diagnosed with demyelinating lesions in the corpus callosum associated with Marchiafava-Bignami disease. At one point, he became agitated at night and was administered olanzapine 2.5 mg, resulting in the onset of oromandibular dystonia; however, the symptoms disappeared upon discontinuation of the drug. Primary dystonia is believed to arise solely from abnormal basal ganglia function in the absence of apparent morphological changes, according to the traditional view. However, recent studies suggest the involvement of lesions beyond the basal ganglia and organic factors, including ultrastructural changes. Rare side effects that develop following small doses of olanzapine indicate that demyelinating lesions of the corpus callosum may be partially responsible for oromandibular dystonia. This case report supports previous reports that the corpus callosum is involved in dystonia and provides insights into the pathophysiology underlying oromandibular dystonia.

Effect modification of tumor necrosis factor-α on the kynurenine and serotonin pathways in major depressive disorder on type 2 diabetes mellitus.

Major depressive disorder (MDD) is strongly associated with type 2 diabetes mellitus (T2DM). The kynurenine and serotonin pathways, as well as chronic low-grade inflammation, are being considered potential links between them. MDD associated with T2DM is less responsive to treatment than that without T2DM; however, the underlying mechanism remains unknown. We aimed to investigate the effects of inflammatory cytokines on the kynurenine and serotonin pathways in patients with comorbid MDD and T2DM and those with only MDD. We recruited 13 patients with comorbid MDD and T2DM and 27 patients with only MDD. We measured interleukin-6 and tumor necrosis factor-α (TNF-α) levels as inflammatory cytokines and metabolites of the kynurenine pathway and examined the relationship between the two. TNF-α levels were significantly higher in patients with comorbid MDD and T2DM than in those with only MDD in univariate (p = 0.044) and multivariate (adjusted p = 0.036) analyses. TNF-α showed a statistically significant effect modification (interaction) with quinolinic acid/tryptophan and serotonin in patients from both groups (ß = 1.029, adjusted p < 0.001; ß = - 1.444, adjusted p = 0.047, respectively). Limitations attributed to the study design and number of samples may be present. All patients were Japanese with mild to moderate MDD; therefore, the generalizability of our findings may be limited. MDD with T2DM has more inflammatory depression components and activations of the kynurenine pathway by inflammatory cytokines than MDD without T2DM. Hence, administering antidepressants and anti-inflammatory drugs in combination may be more effective in patients with comorbid MDD and T2DM.

Association between salivary mature brain-derived neurotrophic factor and psychological distress in healthcare workers.

INTRODUCTION: Previous studies have suggested association between brain-derived neurotrophic factor (BDNF) and the stress level of workers. However, no studies have investigated the potential of salivary mature BDNF (mBDNF) level as a noninvasive biomarker for psychological distress. This study aimed to explore the reliability of salivary mBDNF as a biomarker for psychological distress in healthcare workers. Furthermore, we examined the relationship between salivary and plasma mBDNF levels and their correlation with age, sex, body mass index (BMI), and exercise habits. METHODS: Fifty-one healthy healthcare workers (26 men) from the University of Occupational and Environmental Health, Japan, participated in this study. In this cross-sectional study, participants provided demographic information. Psychological distress was assessed using the Kessler 6 (K6). Saliva and blood samples were collected, and mBDNF was measured by ELISA. Spearman's rank correlation coefficient was performed to analyze the relationship between mBDNF (saliva and plasma) and K6. Statistical analyses were conducted using Stata 17.0, and a significance level of p < .05 was applied. RESULTS: The median K6 score was 1 (interquartile range [IQR]: 0-3). The median (IQR) salivary mBDNF was 1.36 (1.12-1.96) pg/mL, whereas the mean (standard deviation) plasma mBDNF was 1261.11 (242.98) pg/mL. No correlation was observed between salivary and plasma mBDNF concentrations or with the K6 score. Additionally, there were no associations between salivary or plasma mBDNF concentrations and age, sex, or exercise habits. Finally, an association between plasma mBDNF concentration and BMI was found only in univariate analysis. CONCLUSION: Our findings indicate that salivary mBDNF can be accurately measured noninvasively in healthcare workers. Within our study sample, salivary mBDNF did not demonstrate any correlation with K6 and plasma mBDNF. Future studies with a larger study sample and a diverse study population consisting of healthy participants and patients with psychiatric disorders are warranted.

Serum Extracellular Vesicle-Derived hsa-miR-2277-3p and hsa-miR-6813-3p Are Potential Biomarkers for Major Depression: A Preliminary Study.

The aim of the present study was to examine the association between miRNA levels in extracellular vesicles (EVs) from serum and the severity of Major Depression (MD). Patient sera from 16 MD cases were collected at our university hospital. The miRNAs contained in EVs were extracted using a nanofiltration method, and their expression levels were analyzed using miRNA microarrays. Intergroup comparisons were performed to validate the diagnostic performance of miRNAs in EVs. Furthermore, candidate miRNAs in EVs were added to neural progenitor cells, astrocytes, and microglial cells in vitro, and the predicted target genes of the candidate miRNAs were extracted. The predicted target genes underwent enrichment analysis. The expression levels of hsa-miR-6813-3p and hsa-miR-2277-3p were significantly downregulated with increasing depression severity of MD. The pathway enrichment analysis suggests that hsa-miR-6813-3p may be involved in glucocorticoid receptor and gamma-aminobutyric acid receptor signaling. Additionally, hsa-miR-2277-3p was found to be involved in the dopaminergic neural pathway. The analysis of serum miRNAs in EVs suggests that hsa-miR-6813-3p and hsa-miR-2277-3p could serve as novel biomarkers for MD, reflecting its severity. Moreover, these miRNAs in EVs could help understand MD pathophysiology.

Triple network connectivity changes in patients with major depressive disorder versus healthy controls via structural network imaging after electroconvulsive therapy treatment.

OBJECTIVE: To investigate the effect of electroconvulsive treatment (ECT) on dynamic structural network connectivity in major depressive disorder (MDD), based on the triple-network model. METHODS: Twenty-one first-episode, drug-naïve patients with MDD and 21 age- and sex-matched healthy subjects were recruited. Bilateral electrical stimulation was performed thrice a week for a total of 4-5 weeks in the MDD group. MRI data were obtained, and triple-network structural connectivity was evaluated using source-based morphometry (SBM) analysis. A paired t-test was used to analyze structural connectivity differences between pre- and post-ECT MDD groups, one-way analysis was used to calculate three intrinsic network differences between HCs, pre- and post-ECT groups, and partial least squares structural equation modelling was used to investigate dynamic structural network connectivity (dSNC) across groups. RESULTS: Pre-ECT patients with MDD exhibited significantly lower salience network (SN) structural connectivity (p = 0.010) than the healthy control (HC) group and after ECT therapy SN structural connectivity was significantly elevated (p = 0.002) in post-ECT group compared with pre-ECT. PLS-SEM analysis conducted on inter-network connectivity in the triple-network model indicated a significant difference between SN and central executive network (CEN) in all three groups. The HC and post-ECT MDD groups showed notable direct connectivity between the SN and default mode network (DMN), while the pre-ECT MDD group showed consequential pathological connectivity between the CEN and DMN. A mediation analysis revealed a significant indirect effect of the SN on the DMN through the CEN (ß = 0.363, p = 0.008) only in the pre-ECT MDD group. CONCLUSIONS: ECT may be an effective and minimally invasive treatment for addressing structural changes in the SN and direct communication abnormalities between the three core brain networks in patients with MDD, with possible beneficial correction of indirect connections.

Effect of the personality traits of healthy Japanese workers on depressive symptoms and social adaptation, and on the achievement rate of exercise therapy to prevent major depression.

Background: This study determined the effects of personality traits on depressive symptoms and social adaptation in healthy workers, and the effects of depressive symptoms or social adaptation before and after exercise therapy, and personality traits before exercise therapy on the achievement rates of exercise therapy aimed at preventing major depression. Methods: Two hundred fifty healthy Japanese workers were given an eight-week walking program as exercise therapy. After excluding 35 participants who had dropped or provided incomplete information, 215 were included in the analysis. The Japanese version of the NEO five-factor inventory was used to assess participants' personality traits before the exercise therapy. Depressive symptoms were evaluated using the Japanese version of the Zung self-rating depression scale (SDS-J) and social adaptation was evaluated using the Japanese version of the social adaptation self-evaluation scale (SASS-J) before and after the exercise therapy. Results: The SDS-J scores correlated with neuroticism and negatively correlated with extraversion, agreeableness, and conscientiousness before the exercise therapy. The SDS-J was also negatively correlated with openness in women, but not in men, while the SASS-J was associated with extraversion, openness, agreeableness, and conscientiousness, and negatively correlated with neuroticism. There was no significant change in levels of depression before and after exercise therapy; however, social adaptation increased significantly in men. No association was found between SDS-J and SASS-J scores before the exercise therapy and the achievement rate. The achievement rates of exercise therapy were negatively correlated with SDS-J or SASS-J after exercise therapy in women. The SDS-J after exercise therapy was correlated with neuroticism in men and negatively correlated with extraversion in women. The SASS-J after exercise therapy was negatively correlated with neuroticism and correlated with extraversion and openness in men. In contrast, the SASS-J after exercise therapy correlated with openness and agreeableness in women. Conscientiousness was correlated with the achievement rate of exercise therapy in men, but not with the various personality traits in women. Conclusion: Depressive symptoms and social adaptation were differently associated with personality traits and achievement rates before and after exercise therapy. Conscientiousness before exercise therapy predicted a higher achievement rate for exercise therapy in men.

Acute pancreatitis during valproic acid administration in a patient with vascular dementia, epileptic seizures, and psychiatric symptoms: a case report.

BACKGROUND: Valproic acid (VPA) is a relatively safe drug widely used for the treatment of epileptic seizures and mania in bipolar disorder, as well as the prevention of migraine headaches. Here, we present a case of VPA-induced pancreatitis in a patient with vascular dementia, epileptic seizures, and psychiatric symptoms. He had no distinctive abdominal symptoms. CASE PRESENTATION: A 66-year-old Japanese man was treated with VPA for agitation and violent behavior due to vascular dementia, epileptic seizures, and psychiatric symptoms. During admission, he experienced a sudden decrease in consciousness and blood pressure. Abdominal findings were unremarkable; however, blood tests showed an inflammatory response and elevated amylase levels. Contrast-enhanced abdominal computed tomography showed diffuse pancreatic enlargement and inflammation extending to the subrenal pole. VPA-induced acute pancreatitis was diagnosed, VPA was discontinued, and high-dose infusions were administered. Acute pancreatitis resolved after treatment initiation. CONCLUSIONS: Clinicians should be aware of this relatively rare side effect of VPA. Diagnosis may be challenging in elderly people and patients with dementia as they may present with non-specific symptoms. Clinicians should consider the risk of acute pancreatitis when using VPA in patients who cannot report spontaneous symptoms. Blood amylase and other parameters should be measured accordingly.

Volumetric assessment of individual thalamic nuclei in patients with drug-naïve, first-episode major depressive disorder.

Introduction: Despite the previous inconsistent findings of structural and functional abnormalities of the thalamus in patients with major depressive disorder (MDD), the disruption of the thalamic nuclei in the pathophysiology of this disorder has not yet been adequately studied. Therefore, we investigated the volumetric changes of thalamic subregions and their nuclei in drug-naïve, first-episode MDD patients. We also investigated the association between HAM-D scores, a clinical scale frequently used to evaluate the severity of depression and thalamic nuclei volumes in MDD patients. Methods: This study included 76 drug-naïve MDD patients and an equal number of healthy subjects. Magnetic resonance imaging (MRI) data were obtained using a 3T MR system and thalamic nuclei volumes were evaluated using FreeSurfer ver.7.11. The volumetric differences were compared by one-way analysis of covariance (ANCOVA) and to ensure that effects were not accounted for by other factors, age, sex, and ETICV variables were included as covariates. Results: We observed significant volume reductions of the left whole thalamus (p < 0.003) and several thalamic nuclei mostly on the left side in the MDD group compared with healthy controls (HCs). Furthermore, we have revealed weak negative correlations between several thalamic nuclei volumes and HAM-D total and subscale scores. Discussion: This is the first research study to investigate alterations of the various thalamic nuclei volumes in MDD patients compared with HCs. Moreover, we first analyzed the association between individual thalamic nuclei volumes and HAM-D subscale scores. Though our study may be restricted at certain levels, especially by the demographic difference between the two groups, they possibly contribute at a preliminary level to understanding the thalamic structural changes at its subregions in patients with drug-naïve, first-episode MDD.

Risk Factors in Japanese Drug Overdose Patients: Identifying Their Associations With Suicide Risk.

Several suicide attempts presented at the emergency department are due to drug overdose associated with psychiatric disorders. We examined and identified the major risk factors among Japanese drug overdose patients and several close associations of suicide risk. We enrolled 101 patients who attempted suicide by drug overdose between January 2015 and April 2018, assessed their background using the SAD PERSONS scale, and performed association rule analysis to characterize the major risk factors and their associations. We identified three main nodes-depressive state, social support lacking, and no spouse-as considerable risk factors. Furthermore, we identified several close associations of suicide risk and their intensity; in cases with previous suicide attempts and ethanol abuse or substance use, a simultaneous social support lacking is likely. These findings align with previous studies that used conventional statistical analysis on suicide and suicide attempt risk and highlight its importance.

Prolonged delirium caused by lithium poisoning in an endometrial cancer patient at advanced stage: A case report.

A patient with schizoaffective disorder and receiving long-term treatment with lithium developed prolonged delirium. She had recently been diagnosed with stage IVB endometrial cancer and presented a deteriorating general condition. Toxic levels of lithium were measured in serum. After hemodialysis, lithium levels gradually decreased and the symptoms disappeared completely.

Comparison of Serum Metabolomics Pathways and Patterns between Patients with Major Depressive Disorder with and without Type 2 Diabetes Mellitus: An Exploratory Study.

BACKGROUND: A close relationship exists between major depressive disorder (MDD) and diabetes mellitus. The metabolomic difference and similarity between patients with and without diabetes mellitus have not been well studied in the context of MDD. We aimed to examine these differences and common serum metabolomics patterns, pathways and biomarkers that can comprehensively reflect the pathogenetic difference and similarity between these MDD groups. METHODS: We performed a metabolomics analysis of serum samples of healthy controls (n = 6), patients with MDD and type 2 diabetes mellitus (n = 13), and patients with MDD without type 2 diabetes mellitus (n = 27). Metabolomics analysis was conducted using capillary electrophoresis Fourier transform mass spectrometry and a candidate compound was assigned to the 496 (290 cation, 206 anion) peaks. Moreover, we evaluated the sensitivity and specificity of the candidate biomarkers for distinguishing between MDD patients with or without type 2 diabetes mellitus. RESULTS: Principal component analysis revealed no clear distinction among the three groups, while naive partial least squares discriminant analysis yielded three relatively good and distinct populations based on the first principal component. Energy conversion by the tricarboxylic acid cycle represented the highest percentage among the top 30 positive factors of the first principal component, and glutamate metabolism and urea cycle represented the highest percentage among the top 30 negative factors of the first principal component. Synthesis and degradation of ketone bodies had high impact in MDD with type 2 diabetes mellitus group and taurine and hypotaurine metabolism had high impact in MDD without type 2 diabetes mellitus group for the pathway. CONCLUSIONS: Patterns of serum metabolites may be different among MDD with type 2 diabetes mellitus, MDD without type 2 diabetes mellitus, and healthy controls groups. Specifically, comorbid type 2 diabetes mellitus could affect metabolomics pathway and alter the distribution of serum metabolites in patients with MDD. These findings may shed light on the influence of the type 2 diabetes on the pathophysiology of MDD.

The Serum Brain-Derived Neurotrophic Factor Increases in Serotonin Reuptake Inhibitor Responders Patients with First-Episode, Drug-Naïve Major Depression.

Brain-derived neurotrophic factor (BDNF) is a growth factor synthesized in the cell bodies of neurons and glia, which affects neuronal maturation, the survival of nervous system, and synaptic plasticity. BDNF play an important role in the pathophysiology of major depression (MD). The serum BDNF levels changed over time, or with the improvement in depressive symptoms. However, the change of serum BDNF during pharmacotherapy remains obscure in MDD. In particular, the changes in serum BDNF associated with pharmacotherapy have not yet been fully elucidated. The present study aimed to compare the changes in serum BDNF concentrations in first-episode, drug-naive patients with MD treated with antidepressants between treatment-response and treatment-nonresponse groups. The study included 35 inpatients and outpatients composed of 15 males and 20 females aged 36.7 ± 6.8 years at the Department of Psychiatry of our University Hospital. All patients met the DSM-5 diagnostic criteria for MD. The antidepressants administered included paroxetine, duloxetine, and escitalopram. Severity of depressive state was assessed using the 17-item HAMD before and 8 weeks after drug administration. Responders were defined as those whose total HAMD scores at 8 weeks had decreased by 50% or more compared to those before drug administration, while non-responders were those whose total HAMD scores had decreased by less than 50%. Here we showed that serum BDNF levels were not significantly different at any point between the two groups. The responder group, but not the non-responder group, showed statistically significant changes in serum BDNF 0 and serum BDNF 8. The results suggest that the changes of serum BDNF might differ between the two groups. The measurement of serum BDNF has the potential to be a useful predictor of pharmacotherapy in patients with first-episode, drug-naïve MD.

Reduced homovanillic acid, SDF-1α and SCGF-ß levels in cerebrospinal fluid are related to depressive states in systemic lupus erythematosus.

OBJECTIVE: This study aimed to seek a new method of evaluation and surrogate markers for diffuse neuropsychiatric SLE (NPSLE). METHODS: We enrolled 44 patients with SLE between 2017 and 2020 who fulfilled at least one of three specific inclusion criteria: high disease activity, abnormal findings (cerebrospinal fluid [CSF] examination, brain MRI, or electroencephalography), or history of neuropsychiatric illness. Psychiatric symptom rating scales (PSYRATS) were evaluated retrospectively. The primary end point was the PSYRATS positivity rate in SLE patients who had not been diagnosed with diffuse NPSLE. RESULTS: Based on the 1999 ACR classifications, 7 out of the 44 patients evaluated using PSYRATS had been diagnosed with diffuse NPSLE. PSYRATS positivity was seen in 13 out of 37 SLE patients (35.1%) who had not been diagnosed with diffuse NPSLE, and all these patients were positive for Montgomery-Åsberg Depression Rating Scale (MADRS), an indicator of depression state in PSYRATS. Additionally, in the 20 SLE patients exhibiting depression symptoms who were MADRS-positive, CSF concentrations of the neuroinflammatory markers homovanillic acid (HVA; P = 0.0400), stromal cell-derived factor-1α (SDF-1α; P = 0.0431) and stem cell growth factor-ß (SCGF-1ß; P = 0.0061) were significantly reduced compared with the 24 MADRS-negative SLE patients, and the levels of HVA, SDF-1α and SCGF-1ß correlated with one another (P < 0.05). CONCLUSION: Many patients with active SLE have subclinical depression, and MADRS evaluation of neuropsychiatric symptoms is useful for detecting them. Additionally, the decrease in CSF levels of HVA, SDF-1 α and SCGF-1ß reflects the same pathology, and these may serve as surrogate markers.

The effects of telecommuting and family cohabiting situation on psychological distress in Japanese workers during the COVID-19 pandemic: A cross-sectional study.

OBJECTIVE: This study aimed to determine whether telecommuting's impact on psychological distress differed depending on the status of workers' cohabiting family members during the COVID-19 pandemic. METHODS: We collected data from 33 302 workers in Japan through an Internet survey, and included 27 036 valid responses in the analysis. The survey included items on family cohabitation and telecommuting status during the COVID-19 pandemic. We assessed workers' psychological distress using the Kessler 6. RESULTS: The psychological distress odds ratios (ORs) were higher for participants who lived with family members requiring care (OR = 1.38, P < .001), and lower for participants living with preschool children (OR = 0.77, P < .001) or a spouse (OR = 0.80, P < .001). Furthermore, odds ratios were higher for participants who worked from home and lived with family members requiring care or preschool children (OR = 1.52, P = .002; OR = 1.28, P = .028). Stratified by the presence or absence of family members living with them, psychological distress was higher for telecommuters with family members requiring care, preschool children, or elementary school children. CONCLUSION: The association between telecommuting and psychological distress varies, depending on workers' living situation with family members.