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.

Choosing Appropriate Nutritional Therapy for Patients With Anorexia Nervosa Exhibiting Liver Dysfunction: A Case Report.

Anorexia nervosa (AN) presents with a variety of physical complications such as hypoglycemia, electrolyte abnormalities, and dehydration associated with starvation, requiring rapid weight gain through nutritional therapy. However, despite nutritional therapy, patients are at risk of many serious medical complications, including hypoglycemia, hypophosphatemia, edema, and liver damage. Starvation has been found to cause hepatocyte injury with mild-to-severe increases in liver enzyme levels, and distinguishing between autophagy and refeeding syndrome is important for treatment strategies. Herein, we report a rare case of sudden liver injury after the initiation of nutritional therapy in a patient with AN. A 35-year-old woman was admitted to our hospital for the treatment of weight loss due to AN. Nutritional therapy was initiated at 600 kcal/day and increased to 1500 kcal/day on the 21st day of admission. On the 22nd day after admission, rapid liver injury was observed, with an aspartate aminotransferase level of 141 U/L and an alanine aminotransferase level of 221 U/L. After the exclusion of refeeding syndrome, since there was no evidence of hypokalemia, hypophosphatemia, or fatty liver disease based on blood tests and abdominal echography, we diagnosed starvation-induced hepatocyte autophagy, and she was treated with the same calories. Her liver dysfunction gradually improved thereafter. This case report highlights the clinical utility of identifying the etiology of hepatic dysfunction in patients with AN. Clinicians must make appropriate decisions regarding continuing or reducing nutritional therapy based on relevant tests when patients with AN develop liver dysfunction after the initiation of nutritional therapy.

A Cross-sectional Study on the Impact of Unfair Treatment Associated With COVID-19 Infection and Psychological Distress in Japanese Workers.

OBJECTIVE: Psychological distress is commonly reported sequela in COVID-19-infected people. We investigated the association between experiencing COVID-19 infection and psychological distress in Japan. METHOD: A total of 14,901 persons who participated in a follow-up survey in December 2022 were included in the analysis. Odds ratios and regression coefficients were estimated by statistical analysis, with history of COVID-19 infection as the independent variable and presence of psychological distress as the dependent variable. RESULT: Experiencing COVID-19 infection was associated with psychological distress. In a model adjusted for "feeling treated unfairly," the association between infection experience and a high K6 score was significantly attenuated. CONCLUSIONS: The results showed that the experience of COVID-19 infection is associated with psychological distress. Moreover, most cases of psychological distress among those who experienced COVID-19 infection can be at least partly explained by a perception of unfair treatment.

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.

Agoraphobia and panic attacks complicated by primary aldosteronism improved by treatment with eplerenone: a case report.

BACKGROUND: Primary aldosteronism (PA) is an adrenal gland disease, that induces increased secretion of the mineralocorticoid, aldosterone, resulting in symptoms such as hypertension. This study reports a patient with agoraphobia and panic attacks, associated with PA. This patient's psychiatric symptoms improved after treatment with eplerenone, a mineralocorticoid receptor antagonist. CASE PRESENTATION: The patient was a 40-year-old female with agoraphobia, which refers to the irrational fear of situations that may cause anxiety, and panic attacks characterized by profuse sweating, palpitations, and generalized weakness. She was diagnosed with hypertension from PA. Subsequently, she received treatment with eplerenone, which improved her agoraphobia and panic attacks. CONCLUSIONS: There have been no previous reports on PA associated with agoraphobia and panic attacks that improved with pharmacotherapy. Patients with agoraphobia and panic attacks should be evaluated for PA. In patients with PA, pharmacotherapy with eplerenone should be considered.

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.

Disturbed hippocampal intra-network in first-episode of drug-naïve major depressive disorder.

Complex networks inside the hippocampus could provide new insights into hippocampal abnormalities in various psychiatric disorders and dementia. However, evaluating intra-networks in the hippocampus using MRI is challenging. Here, we employed a high spatial resolution of conventional structural imaging and independent component analysis to investigate intra-networks structural covariance in the hippocampus. We extracted the intra-networks based on the intrinsic connectivity of each 0.9 mm isotropic voxel to every other voxel using a data-driven approach. With a total volume of 3 cc, the hippocampus contains 4115 voxels for a 0.9 mm isotropic voxel size or 375 voxels for a 2 mm isotropic voxel of high-resolution functional or diffusion tensor imaging. Therefore, the novel method presented in the current study could evaluate the hippocampal intra-networks in detail. Furthermore, we investigated the abnormality of the intra-networks in major depressive disorders. A total of 77 patients with first-episode drug-naïve major depressive disorder and 79 healthy subjects were recruited. The independent component analysis extracted seven intra-networks from hippocampal structural images, which were divided into four bilateral networks and three networks along the longitudinal axis. A significant difference was observed in the bilateral hippocampal tail network between patients with major depressive disorder and healthy subjects. In the logistic regression analysis, two bilateral networks were significant predictors of major depressive disorder, with an accuracy of 78.1%. In conclusion, we present a novel method for evaluating intra-networks in the hippocampus. One advantage of this method is that a detailed network can be estimated using conventional structural imaging. In addition, we found novel bilateral networks in the hippocampus that were disturbed in patients with major depressive disorders, and these bilateral networks could predict major depressive disorders.

Increased Stimulation Intensity Helped to Cope with Prolonged Seizures During the Next Round of Modified Electroconvulsive Therapy: A Case Report.

Background: Numerous protocols exist to counteract prolonged seizures during modified electroconvulsive therapy (mECT), such as anaesthetic adjustments and ventilation. Evidence on methods for deciding whether to continue with the next round of mECT after a prolonged seizure and to prevent recurrent seizures is currently not well established. Case Presentation: The patient was a 76-year-old woman with major depressive disorder. She suffered from depressive symptoms such as decreased appetite, anxiety, and agitation. She was admitted to our hospital for mECT for the fifth time. The mECT was bilateral and started at 35% stimulus intensity, and effective convulsions were obtained for the first time. During the 8th mECT at the same intensity (35% stimulus intensity), an unexpected prolonged seizure of 966 s (over 16 minutes) occurred. The seizure was abruptly stopped with diazepam 10 mg and midazolam 2 mg. During the ninth mECT session, the stimulation intensity was increased to 50%, which resulted in effective seizures and no prolonged seizures. Subsequently, appropriate convulsions were obtained with the same stimulation intensity, and she completed 12 sessions. Her depressive symptoms improved, and she was discharged on the 45th day of hospitalization. Conclusion: Prolonged seizures in mECT can be prevented by raising the stimulation intensity during the following cycle.

Hippocampal Volume and Plasma Brain-Derived Neurotrophic Factor Levels in Patients With Depression and Healthy Controls.

The aim of the present study was to investigate associations between hippocampal subfield volumes and plasma levels of brain-derived neurotrophic factor (BDNF) in patients experiencing a first episode of major depression (MD) (n = 30) as compared to healthy controls (HC) (n = 49). Covariate-adjusted linear regression was performed to compare the MD and healthy groups, adjusting for age, sex, and total estimated intracranial volume. We demonstrated that there were no differences in total hippocampal volume between the MD and HC groups. However, the volumes of the hippocampus-amygdala-transition-area (HATA) on the left side of the brain as well as the parasubiculum, presubiculum, and fimbria on the right side were statistically significantly smaller in the MD group than in the HC group. Furthermore, the volume of the hippocampal fissure on the right side was statistically significantly smaller in the HC group than in the MD group. In the MD group, we found a positive linear correlation between hippocampal volume and plasma BDNF concentrations in the CA4 area on the left side (p = 0.043). In contrast, in the HC group, we found a negative linear correlation between parasubiculum volume on the right side and plasma BDNF concentrations (p = 0.04). These results suggest that some hippocampal subfields may already be atrophic at the start of MD. In addition, our findings suggest that the sensitivity of the right parasubiculum region to BDNF may differ between MD and HC groups. These findings guide future research directions and, if confirmed, may ultimately inform medical guidelines.

Volume of Amygdala Subregions and Plasma Levels of Brain-Derived Neurotrophic Factor and Cortisol in Patients with s/s Genotype of Serotonin Transporter Gene Polymorphism of First-Episode and Drug-Naive Major Depressive Disorder: An Exploratory Study.

The amygdala is a prominent region of the brain that plays a critical role in the pathophysiology of major depressive disorder (MDD). The amygdala is formed from a collection of interconnected substructures (nuclei) that relay signals from multiple brain areas, which suggests that the amygdala has different functions depending on its subregion. There are two main alleles of serotonin transporter gene polymorphism (5-HTTLPR): a 44-bp insertion (l-allele) or deletion (s-allele). The transcriptional activity of the l-allele of the gene is twice that of the s-allele. The present study aimed to investigate the association between the volume of the whole amygdala and subregions of the amygdala in 25 first-episode and drug-naive patients with MDD and 46 healthy controls (HCs) with the s/s genotype of 5-HTTLPR and plasma levels of brain-derived neurotrophic factor (BDNF) or cortisol. No significant difference was observed in the amygdala total and subregion volumes between the HC and MDD groups. No significant difference was found in the plasma levels of BDNF and cortisol between the two groups. In addition, no correlations were found between the total and subregion amygdala volume and plasma levels of cortisol or BDNF.

Association Between Loneliness and Sleep-Related Problems Among Japanese Workers During the COVID-19 Pandemic.

Background: The coronavirus disease 2019 (COVID-19) pandemic has been linked to a rise in loneliness. Loneliness is associated with sleep-related problems, which in turn can be a risk factor for various psychiatric disorders. However, it is unclear whether loneliness is linked to sleep-related problems during the pandemic. Here, we studied the association between loneliness and sleep-related problems during the COVID-19 pandemic in Japan. Methods: A total of 33,302 individuals who indicated they were employed were surveyed online. The survey responses of 27,036 participants were analyzed. Odds ratios (ORs) were estimated using univariate and multiple logistic regression analyses. Results: Of those analyzed, 2,750 (10.2%) experienced feelings of loneliness. Further, sleep-related problems were significantly more common among those who felt lonely both in the short term (more than 3 days) and the long term (more than 3 months). The ORs were much weaker after adjusting for factors related to interpersonal connections, such as family and friendships, than after adjusting for factors related to socioeconomic status. Conclusion: Loneliness may be a risk factor for sleep-related problems in the COVID-19 pandemic. Having connections with family and friends may have a moderating effect on the occurrence of sleep-related problems.

Gyrification patterns in first-episode, drug-naïve major depression: Associations with plasma levels of brain-derived neurotrophic factor and psychiatric symptoms.

Background and objectives: Cortical structural changes in major depressive disorder (MDD) are usually studied using a voxel-based morphometry approach to delineate the cortical gray matter volume. Among cortical structures, gyrification patterns are considered a relatively stable indicator. In this study, we investigated differences in gyrification patterns between MDD patients and healthy controls (HCs) and explored the association of gyrification patterns with plasma brain-derived neurotrophic factor (BDNF) levels and depressive symptoms in MDD patients. Methods: We evaluated 79 MDD patients and 94 HCs and assessed depression severity in the patients using the 17-item Hamilton Depression Rating Scale (HAM-D). Blood samples of both groups were collected to measure plasma BDNF levels. Magnetic resonance imaging (MRI) data were obtained using three-dimensional fast-spoiled gradient-recalled acquisition. Differences in plasma BDNF levels between groups were examined using the Mann-Whitney U test. Principal component analysis and orthogonal partial least squares discriminant analysis (OPLS-DA) were conducted to investigate the gyrification patterns which were significantly different between the groups, i.e., those with variable importance in projection (VIP) scores of >1.5 and p-value < 0.05 in multiple regression analyses adjusted for age and sex. Finally, multiple regression analysis was performed on the selected gyrification patterns to examine their association with BDNF levels in the two groups and HAM-D in the patients. Results: There were no significant differences in plasma BDNF levels between the groups. We found that 108 (71.0%) of 152 total local gyrification indices were MDD < HC. We identified 10 disease-differentiating factors based on critical gyrification features (VIP > 1.5 and p-value adjusted for age and sex < 0.05). However, we found no significant correlations between the 10 gyrification patterns and plasma BDNF levels and no interaction with group. Moreover, no significant correlations were observed between the local gyrification indices and HAM-D total scores. Conclusion: These results suggest that abnormal early cortical neurodevelopment may mediate vulnerability to MDD, independent of plasma BDNF levels and depressive symptoms.

Associations Between the Kynurenine Pathway, Proinflammatory Cytokines, and Brain-Derived Neurotrophic Factor in Hospitalized Patients With Chronic Schizophrenia: A Preliminary Study.

Purpose: The kynurenine (Kyn) pathway may play a role in the pathophysiology of schizophrenia. This pathway shows crosstalk with proinflammatory cytokines, including interleukin-1ß (IL-1ß), IL-6, and tumor necrosis factor-α (TNF-α), and/or brain-derived neurotrophic factor (BDNF). Moreover, Kyn metabolites affect neurotransmission and cause neurotoxicity. To date, the influence of the Kyn pathway on proinflammatory cytokines and BDNF remains to be fully elucidated. The aim of this study was to investigate the relationships of the Kyn pathway with proinflammatory cytokines, BDNF, and psychiatric symptoms in patients with schizophrenia. Methods: Thirty patients with schizophrenia and ten healthy control participants were recruited for this study. All patients were diagnosed with schizophrenia using the Diagnostic and Statistical Manual for Mental Disorders, Fifth Edition (DSM-5). The healthy controls were those who did not fulfill any of the diagnostic criteria in the DSM-5. The serum levels of Kyn and its metabolites, proinflammatory cytokines, and BDNF were measured in patients with schizophrenia and healthy controls. Patients with schizophrenia were also assessed for psychiatric symptoms using the Positive and Negative Syndrome Scale (PANSS). Results: Patients with schizophrenia and healthy controls showed no significant differences in the levels of Kyn and its metabolites, proinflammatory cytokines, and BDNF. A significant positive correlation was found between the serum levels of TNF-α and Kyn (r = 0.53, p = 0.0026) and the Kyn/tryptophan (Trp) value (r = 0.67, p = 0.000046) in the schizophrenia group, but not in the healthy control group. Conclusion: TNF-α affects the Kyn pathway in patients with chronic schizophrenia, but not in the healthy individuals, although serum TNF-α levels showed no difference between the two groups. Associations between the Kyn pathway and the levels of proinflammatory cytokines and BDNF or psychotic symptoms might be complicated in hospitalized patients with chronic schizophrenia.

A Low Clozapine Dose Improved Refractory Tardive Dystonia without Exacerbating Psychiatric Symptoms: A Case Report.

Clozapine is recommended for patients with schizophrenia and tardive dystonia (TD); however, the appropriate dose remains unclear. In this case, a low dose (150 mg/day) of clozapine improved refractory TD and further ameliorated psychiatric symptoms. Herein, we report on a 41-year-old female with schizophrenia and TD who was treated with a low clozapine dose. After eight weeks of continuous clozapine at 150 mg/day (16 weeks after clozapine initiation), her TD dramatically improved, and her psychiatric symptoms were relieved. Low clozapine doses could ameliorate refractory TD. However, this effect might require up to several weeks. Clinicians should be patient unless they consider it better to increase the clozapine dose.

Volume of Amygdala Subregions and Clinical Manifestations in Patients With First-Episode, Drug-Naïve Major Depression.

We examined amygdala subregion volumes in patients with a first episode of major depression (MD) and in healthy subjects. Covariate-adjusted linear regression was performed to compare the MD and healthy groups, and adjustments for age, gender, and total estimated intracranial volume showed no differences in amygdala subregion volumes between the healthy and MD groups. Within the MD group, we examined the association between amygdala subregion volume and the 17-item Hamilton Rating Scale for Depression (HAMD) score and the HAMD subscale score, and found no association in the left amygdala. In the right amygdala, however, there was an inverse linear association between the HAMD total and the HAMD core and lateral nucleus and anterior-amygdaloid-regions. Furthermore, an inverse linear association was seen between the HAMD psychic and the lateral nucleus, anterior-amygdaloid-regions, transition, and whole amygdala. The findings of this study suggest that the severity of MD and some symptoms of MD are associated with right amygdala volume. There have been few reports on the relationship between MD and amygdala subregional volume, and further research is needed to accumulate more data for further validation.

Attention-deficit/hyperactivity disorder symptoms and suicidal behavior in adult psychiatric outpatients.

AIM: We aimed to examine the association between attention-deficit/hyperactivity disorder (ADHD) symptoms and suicidal behavior in psychiatric outpatients and whether this association differs among patients with different psychiatric disorders. METHODS: Cross-sectional data came from the Japan Prevalence Study of Adult ADHD at Psychiatric Outpatient Care, which included psychiatric outpatients aged 18-65 years recruited from one university hospital and three general psychiatric outpatient clinics in Kitakyushu City, Fukuoka, Japan from April 2014 to January 2015 (N = 864). The Adult ADHD Self-Report Scale (ASRS) Screener was used to collect information on ADHD symptoms. Reports of current and lifetime suicidal behavior were also obtained. A multivariable Poisson regression analysis was used to examine the association between ADHD symptoms and suicidal behavior. RESULTS: After adjusting for covariates there was a strong association between possible ADHD (ASRS ≥14) and suicidal behavior with prevalence ratios ranging from 1.17 (lifetime suicidal ideation) to 1.59 (lifetime suicide attempt) and 2.36 (current suicidal ideation). When ASRS strata were used, there was a dose-response association between increasing ADHD symptoms and suicidal ideation and suicide attempts. Analyses of individual ICD-10 psychiatric disorders showed that associations varied across disorders and that for anxiety disorder, ADHD symptoms were significantly linked to all forms of suicidal behavior. CONCLUSION: ADHD symptom severity is associated with an increased risk for suicidal behavior in general psychiatric outpatients. As ADHD symptoms are common among adult psychiatric outpatients, detecting and treating ADHD in this population may be important for preventing suicidal behavior.