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.

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.

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.

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.

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.

A Young Japanese Patient with Spinocerebellar Ataxia Type 3 Presenting Depressive State with Cenesthopathy and Delusion: a Case Report.

Depressive state is a common complication of spinocerebellar ataxia type 3 (SCA3). To the best of our knowledge, cases of SCA3 presenting with cenesthopathy have not been described. Here, we present a case of a severe depressive state with cenesthopathy and delusion in a young Japanese man with SCA3. A 43-year-old Japanese man with SCA3 developed a severe depressive state with associated cenesthopathy and delusion. He was treated with escitalopram (10 mg/day) and olanzapine (2.5 mg/day). Computed tomography showed atrophy of the cerebellum, bilateral superior cerebellar peduncle, and tegmentum of the pons. Single-photon emission computed tomography demonstrated reduced blood flow in the cerebellum, vermis, and brainstem. After 8 weeks, his depressive state and delusion improved; however, his cenesthopathy persisted. We encountered a case of a severe depressive state with cenesthopathy and delusion in a young Japanese man with SCA3. This case supports previous studies that the cerebellum could have a role beyond motor functions.

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.

Major depression with musical obsession treated with vortioxetine: a case report.

BACKGROUND: Musical obsession has been reported as the "stuck song syndrome" and can be accompanied by obsessive compulsive disorder (OCD). Musical obsession is the phenomenon where a particular set of known musical notes are perceived repeatedly. We present a case of major depression with musical obsession. In this case, vortioxetine improved both depressive symptoms and musical obsession. CASE PRESENTATION: A female, 34-year-old, high school teacher presented with a depressed mood, anergia, difficulty in concentration, poor motivation, restlessness, anxiety, insomnia, and loss of appetite. She was diagnosed with major depression by her family physician and prescribed escitalopram (20 mg/day). Her depressive state partially responded to escitalopram. When she had been depressed, she also experienced musical obsessions as repetitive commercial tunes or instrumental notes inside her head that were not under conscious voluntary control and lasting several hours, causing a high level of distress in her daily life. After switching from escitalopram to vortioxetine (20 mg/day), her depressive symptoms and musical obsession symptoms were ameliorated. CONCLUSIONS: This case report endorses the utility of vortioxetine for major depression with musical obsession, and further studies should be conducted to establish the optimal treatment.

Structural Changes in Hippocampal Subfields in Patients with Continuous Remission of Drug-Naive Major Depressive Disorder.

OBJECTIVE: Hippocampal volume is reduced in patients with major depressive disorder (MDD) compared with healthy controls. The hippocampus is a limbic structure that has a critical role in MDD. The aim of the present study was to investigate the changes in the volume of the hippocampus and its subfields in MDD patients who responded to antidepressants and subsequently were in continuous remission. SUBJECTS AND METHODS: Eighteen patients who met the following criteria were enrolled in the present study: the DSM-IV-TR criteria for MDD, drug-naïve at least 8 weeks or more, scores on the 17-items of Hamilton Rating Scale for Depression (HAMD) of 14 points or more, and antidepressant treatment response within 8 weeks and continuous remission for at least 6 months. All participants underwent T1-weighted structural MRI and were treated with antidepressants for more than 8 weeks. We compared the volumes of the hippocampus, including its subfields, in responders at baseline to the volumes at 6 months. The volumes of the whole hippocampus and the hippocampal subfields were measured using FreeSurfer v6.0. RESULTS: The volumes of the left cornu Ammonis (CA) 3 (p = 0.016) and the granule cell layer of the dentate gyrus (GC-DG) region (p = 0.021) were significantly increased after 6 months of treatment compared with those at baseline. CONCLUSIONS: Increases in volume was observed in MDD patients who were in remission for at least 6 months.

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.

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.