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.

Corrigendum: Estimation of subjective quality of life in schizophrenic patients using speech features.

[This corrects the article DOI: 10.3389/fresc.2023.1121034.].

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.

Estimation of subjective quality of life in schizophrenic patients using speech features.

Introduction: Patients with schizophrenia experience the most prolonged hospital stay in Japan. Also, the high re-hospitalization rate affects their quality of life (QoL). Despite being an effective predictor of treatment, QoL has not been widely utilized due to time constraints and lack of interest. As such, this study aimed to estimate the schizophrenic patients' subjective quality of life using speech features. Specifically, this study uses speech from patients with schizophrenia to estimate the subscale scores, which measure the subjective QoL of the patients. The objectives were to (1) estimate the subscale scores from different patients or cross-sectional measurements, and 2) estimate the subscale scores from the same patient in different periods or longitudinal measurements. Methods: A conversational agent was built to record the responses of 18 schizophrenic patients on the Japanese Schizophrenia Quality of Life Scale (JSQLS) with three subscales: "Psychosocial," "Motivation and Energy," and "Symptoms and Side-effects." These three subscales were used as objective variables. On the other hand, the speech features during measurement (Chromagram, Mel spectrogram, Mel-Frequency Cepstrum Coefficient) were used as explanatory variables. For the first objective, a trained model estimated the subscale scores for the 18 subjects using the Nested Cross-validation (CV) method. For the second objective, six of the 18 subjects were measured twice. Then, another trained model estimated the subscale scores for the second time using the 18 subjects' data as training data. Ten different machine learning algorithms were used in this study, and the errors of the learned models were compared. Results and Discussion: The results showed that the mean RMSE of the cross-sectional measurement was 13.433, with k-Nearest Neighbors as the best model. Meanwhile, the mean RMSE of the longitudinal measurement was 13.301, using Random Forest as the best. RMSE of less than 10 suggests that the estimated subscale scores using speech features were close to the actual JSQLS subscale scores. Ten out of 18 subjects were estimated with an RMSE of less than 10 for cross-sectional measurement. Meanwhile, five out of six had the same observation for longitudinal measurement. Future studies using a larger number of subjects and the development of more personalized models based on longitudinal measurements are needed to apply the results to telemedicine for continuous monitoring of QoL.

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.

The Molecular Mechanism of Exercise for Treatment of Patients with Major Depression: A Preliminary Report on the Dynamics of Metabolites of Nitric Oxide and Catecholamines.

BACKGROUND: There has been increasing evidence that exercise therapy is effective in the treatment and prevention of major depression (MD). However, the basic molecular mechanisms underlying the effects of exercise on MD remain unclear. We conducted a preliminary study to clarify the effect of exercise therapy on MD, focusing on the dynamics of nitric oxide (NO) and catecholamine metabolites, which have been found to be associated with MD. METHODS: Eleven outpatients with mild to moderate MD and 37 healthy controls (HC) were included in the study. The participants' clinical records and questionnaires were screened for their past medical history. For their exercise therapy, the participants were instructed to walk the equivalent of 17.5 kcal/kg/week for 8 weeks. Blood samples were collected from all participants at baseline, 4 weeks, and 8 weeks after the start of exercise therapy, and plasma metabolites of NO (NOx), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) were analyzed. We also assessed the 17-item Hamilton Rating Scale for Depression (HRSD-17) in patients with MD. A mixed-effects regression model was used to compare the mean values by time (baseline, 4, and 8 weeks) for the three corresponding groups (NOx, MHPG, and HVA). RESULTS: HRSD-17 scores decreased significantly in the MD group after 8 weeks of exercise therapy. NOx and MHPG increased, but there was no significant change in HVA in the MD group after the exercise therapy. NOx decreased after exercise, and HVA increased significantly from baseline after 4 weeks of exercise but decreased after 8 weeks of exercise in the HC group. CONCLUSIONS: The effects of exercise on NOx, MHPG, and HVA may differ between MD and HC. The potential mechanisms for the benefits of walking exercise in MD patients will be the subject for future research.

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.

Associations of Serum Cytokines, Growth Factors, and High-Sensitivity C-Reactive Protein Levels in Patients with Major Depression with and without Type 2 Diabetes Mellitus: An Explanatory Investigation.

PURPOSE: We investigated the serum levels of cytokines, including interleukin 1ß (IL-ß), IL-6, IL-8, IL-10, tumor necrosis factor-alpha (TNF-α), and growth factors, including brain-derived neurotrophic factor, vascular endothelial growth factor, and insulin-like growth factor 1, and their association with major depression in patients with and without type 2 diabetes mellitus. We also investigated the response to antidepressant treatment in both groups. PATIENTS AND METHODS: Forty-one patients with major depression were recruited at the University Hospital of Occupational and Environmental Health. All patients were diagnosed with major depression using the Diagnostic and Statistical Manual for Mental Disorders, Fifth Edition. Type 2 diabetes mellitus was diagnosed according to the criteria of the Japan Diabetes Society. Six healthy controls with no history of psychiatric or physical diseases were also enrolled. Serum levels of several cytokines, growth factors, and high-sensitivity C-reactive protein (hs-CRP) were measured. The clinical symptoms of patients with major depression were assessed using the Montgomery-Asberg Depression Rating Scale. RESULTS: Significant differences in cytokines, growth factors, and hs-CRP were observed between the major depression and healthy control groups. Serum TNF-α levels were significantly higher in patients with major depression and type 2 diabetes mellitus than in those without type 2 diabetes mellitus. In the major depression group, serum IL-6 and hs-CRP levels tended to be higher in patients with type 2 diabetes mellitus than in those without. Several correlations among cytokines, growth factors, and hs-CRP were observed in patients with major depression with and without type 2 diabetes mellitus. Responses to pharmacological interventions for major depression did not differ between patients with and without type 2 diabetes mellitus. CONCLUSION: Serum levels of TNF-α, hs-CRP, and IL-6 were different between patients with major depression with and without type 2 diabetes mellitus. Also, correlations were found between serum levels of cytokines, growth factors, and hs-CRP in patients with major depression. Inflammatory factors, which may be associated with growth factors, may be involved in the pathophysiology of major depression, particularly among patients with comorbid type 2 diabetes mellitus.

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.