Recent Progress in Mass Spectrometry-Based Metabolomics in Major Depressive Disorder Research.

Major depressive disorder (MDD) is a serious mental illness with a heavy social burden, but its underlying molecular mechanisms remain unclear. Mass spectrometry (MS)-based metabolomics is providing new insights into the heterogeneous pathophysiology, diagnosis, treatment, and prognosis of MDD by revealing multi-parametric biomarker signatures at the metabolite level. In this comprehensive review, recent developments of MS-based metabolomics in MDD research are summarized from the perspective of analytical platforms (liquid chromatography-MS, gas chromatography-MS, supercritical fluid chromatography-MS, etc.), strategies (untargeted, targeted, and pseudotargeted metabolomics), key metabolite changes (monoamine neurotransmitters, amino acids, lipids, etc.), and antidepressant treatments (both western and traditional Chinese medicines). Depression sub-phenotypes, comorbid depression, and multi-omics approaches are also highlighted to stimulate further advances in MS-based metabolomics in the field of MDD research.

[Screening of small molecule inhibitors of IL-15Rα using molecular docking and surface plasmon resonance technology].

The study aims to explore the active molecules of traditional Chinese medicine that specifically bind to interleukin-15 receptor α (IL-15Rα) using molecular docking and surface plasmon resonance (SPR) technology. AutoDock molecular docking software was used to perform simulated docking of more than 3 000 compounds from 48 traditional Chinese medicines at IL-15Rα and screen the specific binding compounds. Then Biocore T200 biomolecular interaction analysis system of SPR was used to confirm the binding specificity of the selected target compounds. Finally, the biological effects of the target compounds on IL-15Rα were verified by cell biological experiments. The results showed that neoprzewaquinone A (Neo) possessed the highest specific binding affinity among the active molecules from traditional Chinese medicine, and the dissociation constant (KD) value was (0.62 ± 0.20) µmol/L. The results of cell experiment showed that Neo significantly inhibited the proliferation of Mo7e cells induced by IL-15, and the IC50 was 1.075 µmol/L, approximately 1/120 of the IC50 of Cefazolin (IL-15 specific antagonist). These results suggest that Neo is a specific inhibitor of IL-15Rα and may be a potential active drug for the treatment of diseases related to the dysfunction of the IL-15Rα signaling.

Microglia in depression: an overview of microglia in the pathogenesis and treatment of depression.

Major depressive disorder is a highly debilitating psychiatric disorder involving the dysfunction of different cell types in the brain. Microglia are the predominant resident immune cells in the brain and exhibit a critical role in depression. Recent studies have suggested that depression can be regarded as a microglial disease. Microglia regulate inflammation, synaptic plasticity, and the formation of neural networks, all of which affect depression. In this review, we highlighted the role of microglia in the pathology of depression. First, we described microglial activation in animal models and clinically depressed patients. Second, we emphasized the possible mechanisms by which microglia recognize depression-associated stress and regulate conditions. Third, we described how antidepressants (clinical medicines and natural products) affect microglial activation. Thus, this review aimed to objectively analyze the role of microglia in depression and focus on potential antidepressants. These data suggested that regulation of microglial actions might be a novel therapeutic strategy to counteract the adverse effects of devastating mental disorders.

Protective Effects of Shi-Zhen-An-Shen Decoction on the Cognitive Impairment in MK801-Induced Schizophrenia Model.

BACKGROUND: Cognitive dysfunction is a core feature of schizophrenia that strongly correlates to the patients' difficulties in independent living and occupational functioning. Synaptic dysfunction may result in cognitive and behavioral changes similar to what have been identified in schizophrenia. Shi-Zhen-An-Shen Decoction (SZASD) is the empirical formula of traditional Chinese medicine adopted in treating psychiatric symptoms, especially the cognitive impairment in schizophrenia patients, with proven efficacy in the long term of clinical practice in Beijing Anding Hospital, Capital Medical University. However, the mechanisms of SZASD on the cognitive improvement in schizophrenia is still unclear. Here, we aim to investigate the underlying mechanisms of the impact of SZASD on the cognitive impairment in MK801-induced schizophrenia-like rats. METHODS: Six rat groups (n = 12 per group) were subjected to different treatments for 14 days. All the six groups were injected intraperitoneally with a given volume of 0.9% saline and MK801 (0.2 mg/kg) for consecutive 14 days for modelling. And the rats in the SZASD-treated groups and the clozapine-treated group were given SZASD (low, middle, and high doses) or clozapine, respectively, by intragastric administration. Then, we performed behavioral tests after the treatments, and the rats were sacrificed on the 19th day for biological analysis. RESULTS: Behavioral tests indicated that SZASD mitigated the aberrant motor activity and improved schizophrenia-like rats' spatial reference memory and sensory gating ability. Furthermore, SZASD significantly increased the expressions of PSD95, BDNF, and synapsin I in the hippocampus of MK801-induced schizophrenia-like rats. CONCLUSIONS: Our findings suggest that SZASD may ameliorate cognitive impairment by restoring the levels of synaptic proteins in the hippocampus.

Shi-Zhen-An-Shen Decoction, a Herbal Medicine That Reverses Cuprizone-Induced Demyelination and Behavioral Deficits in Mice Independent of the Neuregulin-1 Pathway.

Shi-Zhen-An-Shen decoction (SZASD), a Chinese herbal medicine that is a liquor extracted from plants by boiling, has been reported to be effective in treating schizophrenia. However, the mechanism is unclear. Abnormal demyelination has been implicated in schizophrenia. The aim of this study was to investigate the effect of SZASD on myelin in demyelinated mice exhibiting schizophrenia-like behaviors. Sixty male C57BL/6 mice were randomly divided into six groups (n = 10 per group): (1) control group, (2) cuprizone (CPZ, a copper chelator that induced demyelination, 0.2% w/w)+saline, (3) CPZ+low-dose SZASD (8.65 g·kg-1·d-1), (4) CPZ+medium-dose SZASD (17.29 g·kg-1·d-1), (5) CPZ+high-dose SZASD (25.94 g·kg-1·d-1), and (6) CPZ+quetiapine (QTP, an atypical antipsychotic that served as a positive treatment control, 10 mg·kg-1·d-1). Mice in groups 2-6 were treated with CPZ added to rodent chow for six weeks to induce demyelination. During the last two weeks, these mice were given an oral gavage of sterile saline, SZASD, or quetiapine. Behavioral tests and brain analyses were conducted after the last treatment. The brain expression of myelin basic protein (MBP) and neuregulin-1 (NRG-1) was assessed using immunohistochemistry and Western blots. CPZ induced significant schizophrenia-like behaviors in the mice, including reduced nest-building activity and sensory gating deficits. Hyperlocomotor activity was accompanied by significant reductions in MBP expression in the corpus callosum, hippocampus, and cerebral cortex. However, both QTP and SZASD significantly reversed the schizophrenia-like behaviors and demyelination in CPZ-fed mice. The QTP and medium-dose SZASD resulted in better therapeutic effects compared to the low and high SZASD doses. Reduced NRG-1 expression was observed in CPZ-fed mice compared with controls, but neither QTP nor SZASD showed significant influence on NRG-1 expression in the hippocampus. Together, SZASD showed a therapeutic effect on demyelinated mice, and the improvement of demyelination might not be through the NRG-1 pathway.

Serum amyloid P component: Structure, biological activity, and application in diagnosis and treatment of immune-associated diseases.

Serum amyloid P component (SAP) is a member the innate immune humoral arm and participated in various processes, including the innate immune responses, tissue remodeling, and the pathogenesis of inflammatory diseases. Remarkably, SAP is a highly versatile immunomodulatory factor that can serve as a drug target for treating amyloid diseases and reduce inflammation, fibrosis degree, and respiratory disease. In this review, we focus on the biological activities of SAP and its application in different systemic immune-associated diseases. First, we reviewed the regulatory effects of SAP on innate immune cells and possible mechanisms. Second, we emphasized SAP as a diagnostic marker and therapeutic target for immune-associated diseases, including the neuropsychiatric disorders. Third, we presented several recommendations for regulating SAP in immune cell function and potential areas for future research. Some authorities consider SAP to be a pattern recognition molecule that plays multiple roles in the innate immune system and inflammation. Developing therapeutics that target SAP or its associated signaling pathways may be a promising strategy for treating immune-associated diseases.

Sleep Disturbance in Rodent Models and Its Sex-Specific Implications.

Sleep disturbances, encompassing altered sleep physiology or disorders like insomnia and sleep apnea, profoundly impact physiological functions and elevate disease risk. Despite extensive research, the underlying mechanisms and sex-specific differences in sleep disorders remain elusive. While polysomnography serves as a cornerstone for human sleep studies, animal models provide invaluable insights into sleep mechanisms. However, the availability of animal models of sleep disorders is limited, with each model often representing a specific sleep issue or mechanism. Therefore, selecting appropriate animal models for sleep research is critical. Given the significant sex differences in sleep patterns and disorders, incorporating both male and female subjects in studies is essential for uncovering sex-specific mechanisms with clinical relevance. This review provides a comprehensive overview of various rodent models of sleep disturbance, including sleep deprivation, sleep fragmentation, and circadian rhythm dysfunction. We evaluate the advantages and disadvantages of each model and discuss sex differences in sleep and sleep disorders, along with potential mechanisms. We aim to advance our understanding of sleep disorders and facilitate sex-specific interventions.

A genome-wide association study of escitalopram treatment outcomes in patients with major depressive disorder.

Major depressive disorder (MDD) is a common psychological condition, the consequences of which, such as suicide, can be severe. Escitalopram, a selective serotonin reuptake inhibitor, is a commonly used antidepressant in clinics. However, more than one-third of patients with MDD do not respond to this drug. Gene polymorphism may affect the efficacy of escitalopram, but the genetic architecture of the antidepressant response in patients with MDD remains unclear. We perform a genome-wide association study (GWAS) of the genetic effect on the outcome of escitalopram in patients with MDD. A total of 203 patients with MDD and 176 healthy control (HC) adults were recruited from Beijing Anding Hospital. Patients received 12 weeks of antidepressant treatment with escitalopram. The Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR) or Hamilton depression scale (HAMD) were used to evaluate the severity of depression symptoms at the baseline and the end of 2 and 12 weeks of treatment. A total of 140 variants in MDD patients were identified by GWAS to have genome-wide significance (p < 5e - 8) compared with HCs. Similarly, 189 and 18 variants were identified to be associated with QIDS-SR and HAMD score changes in patients after antidepressant treatment (p < 1e - 5), including rs12602361, rs72799048, rs16842235, and rs2518256. In the two weeks QIDS-SR score study, the gene-level association for these variants and gene set enrichment analyses implicate the enrichment of genes involved in the synaptic plasticity process and nervous system development. Our results implicate the predictive capacity of the effect of escitalopram treatment, supporting a link between genetic basis and remission of depression.

Integrated Single-Cell RNA-seq and ATAC-seq Reveals Heterogeneous Differentiation of CD4+ Naive T Cell Subsets is Associated with Response to Antidepressant Treatment in Major Depressive Disorder.

The mechanism involved in major depressive disorder (MDD) is well-studied but the mechanistic origin of the heterogeneous antidepressant effect remains largely unknown. Single-cell RNA-sequencing (scRNA-seq) and assay for transposase-accessible chromatin using sequencing (ATAC-seq) on peripheral blood mononuclear cells from 8 healthy individuals and 8 MDD patients before or after 12 weeks of antidepressant treatment is performed. scRNA-seq analysis reveals a lower proportion of naive T cells, particularly CD4+ naive T cells, in MDD patients compared to controls, and in nonresponders versus responders at the baseline. Flow cytometry data analysis of an independent cohort of 35 patients and 40 healthy individuals confirms the findings. Enrichment analysis of differentially expressed genes indicated obvious immune activation in responders. A specific activated CD4+ naive T population in responders characterized by enhanced mitogen-activated protein kinases (MAPK) pathway is identified. E-twenty six (ETS) is proposed as an upstream regulator of the MAPK pathway and heterogeneous differentiation in activated CD4+ naive T population is associated with the response to antidepressant treatment in MDD patients. A distinct immune feature manifested by CD4+ naive T cells during antidepressant treatment in MDD is identified. Collectively, this proposes the molecular mechanism that underlies the heterogeneous antidepressant outcomes for MDD.

Gut microbial CAZymes markers for depression.

Major depressive disorder (MDD) is a serious mental illness, characterized by disturbances of gut microbiome, it is required to further explore how the carbohydrate-active enzymes (CAZymes) were changed in MDD. Here, using the metagenomic data from patients with MDD (n = 118) and heath controls (HC, n = 118), we found that the whole CAZymes signatures of MDD were significantly discriminated from that in HC. α-diversity indexes of the two groups were also significantly different. The patients with MDD were characterized by enriched Glycoside Hydrolases (GHs) and Polysaccharide Lyases (PLs) relative to HC. A panel of makers composed of 9 CAZymes mainly belonging to GHs enabled to discriminate the patients with MDD and HC with AUC of 0.824. In addition, this marker panel could classify blinded test samples from the two groups with an AUC of 0.736. Moreover, we found that baseline 4 CAZymes levels also could predict the antidepressant efficacy after adjusted confounding factors and times of depressive episode. Our findings showed that MDD was associated with disturbances of gut CAZymes, which may help to develop diagnostic and predictive tools for depression.

Therapeutic drug monitoring of psychotropic drugs in China: a nationwide survey.

OBJECTIVE: To understand the status of therapeutic drug monitoring (TDM) of psychotropic drugs in psychiatric facilities in mainland China and to lay the foundation for improvement of TDM in psychiatry. METHODS: A cross-sectional survey was conducted with a locally developed questionnaire among psychiatric facilities in which TDM of psychotropic drugs was available. The questionnaire included laboratory situations, implementation of TDM, equipment and analytical methods, internal quality control (IQC), and external quality assessment (EQA). RESULTS: Forty-seven of the 58 delivered questionnaires were collected from the psychiatric facilities involving 26 provinces in mainland China. The response rate was 81.0%. Among all facilities surveyed, lithium was the most common psychotropic drug (68.1% of the laboratories) monitored by TDM, followed by clozapine (44.7%), carbamazepine (25.5%), chlorpromazine (21.3%), norclozapine (19.1%), risperidone (19.1%), paliperidone (17.0%), valproic acid (14.9%), and quetiapine (10.6%). Only 10.2% of the laboratories had recommendations for dose adjustments based on their TDM reports. Others only provided drug concentration results with no clinical recommendations. The analytical methods used included high-performance liquid chromatography, liquid chromatography with tandem mass spectrometric detection, and immunoassay. For lithium, most hospitals used ion-selective electrode methods. IQC and EQA were still in their infancy. CONCLUSIONS: This first nationwide survey showed that TDM has been available in a considerable number of psychiatric hospitals across China. Though current equipment and analytical methods meet the TDM need, much improvement is needed, particularly in new analytical method development, interpretation of results, consultation services, and quality control, including IQC and EQA. Guidance or consensus guideline for TDM of psychotropic drugs in the Chinese language is also urgently required.

The use of biochemical indexes in hair for clinical studies of psychiatric diseases: What can we learn about mental disease from hair?

Analysis of hair samples provides unique advantages, including non-invasive sampling, sample stability, and the possibility of additional optimization of high sensitivity detection methods. Hair sample analysis is often used in psychiatric disease research to evaluate previous periods of stress encountered by patients. Glucocorticoid analysis is the most frequently tested indicator of stress. Furthermore, the hypothalamus-pituitary-gonad axis and endocannabinoid system also are involved in the occurrence and development of mental disorders. The endocannabinoid and sex hormone levels in patients experiencing mental illness are considerably different from levels observed in healthy individuals. Nevertheless, due to the different methods used to assess the degree of disease and the range of analytical methods involved in clinical research, the trends in changes for these biomarkers are not uniform. The correlations between changes in biomarker concentrations and illness severity also are not clear. The observed alterations suggest these biochemical substances in hair have potential as biomarkers for diagnosis or predictive treatment. However, the variable results obtained thus far could hamper further development of hair samples for clinical assessment in psychiatric disorders. This article summarizes the published reports documenting the changes in the content of relevant substances in hair in individuals experiencing mental illness and the degree of correlation. In the discussion section, we proposed several issues that should be considered in future studies of hair samples obtained from patients with mental disorders to promote the use of hair sample assessment as an aid in diagnosis or predictive treatment.

Chiral Amino Acid Profiling in Serum Reveals Potential Biomarkers for Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) is a complex neurodegenerative disease, and increasing evidence has linked dysregulation of amino acids to AD pathogenesis. However, the existing studies often ignore the chirality of amino acids, and some results are inconsistent and controversial. The changes of amino acid profiles in AD from the perspective of enantiomers remain elusive. OBJECTIVE: The purpose of this study is to investigate whether the levels of amino acids, especially D-amino acids, are deregulated in the peripheral serum of AD patients, with the ultimate goal of discovering novel biomarkers for AD. METHODS: The chiral amino acid profiles were determined by HPLC-MS/MS with a pre-column derivatization method. Experimental data obtained from 37 AD patients and 34 healthy controls (HC) were statistically analyzed. RESULTS: Among the 35 amino acids detected, D-proline, D/total-proline ratio, D-aspartate, and D/total-aspartate ratio were decreased, while D-phenylalanine was elevated in AD compared to HC. Significant age-dependent increases in D-proline, D/total-proline ratio, and D-phenylalanine were observed in HC, but not in AD. Receiver operator characteristic analyses of the combination of D-proline, D-aspartate, D-phenylalanine, and age for discriminating AD from HC provided satisfactory area under the curve (0.87), specificity (97.0%), and sensitivity (83.8%). Furthermore, the D-aspartate level was significantly decreased with the progression of AD, as assessed by the Clinical Dementia Rating Scale and Mini-Mental State Examination. CONCLUSION: The panels of D-proline, D-phenylalanine, and D-aspartate in peripheral serum may serve as novel biomarker candidates for AD. The latter parameter is further associated with the severity of AD.

Simultaneous measurement of amino acid enantiomers in the serum of late-life depression patients using convenient LC-MS/MS method with Nα-(5-fluoro-2,4-dinitrophenyl)-l-leucinamide Derivatization.

D-amino acids may be indicators of late-life depression but separation and quantification of enantiomers which differ only by optical rotation sign remain challenging due to their identical physical and chemical properties. A convenient LC-MS/MS method was developed for the simultaneous measurement of l- and d-amino acids based on the chiral derivatization reagent, Nα-(5-fluoro-2,4-dinitrophenyl)-L-leucinamide, and conventional octadecylsilane reversed-phase column. Methanol was used as the extraction solvent and a single-step derivatization reaction using volatile triethylamine eliminated the requirement for desalination prior to LC-MS/MS. Simultaneous separation and identification of 21 amino acids and the enantiomeric compositions of the 18 chiral proteogenic entities were achieved. Low limits of detection (0.03-4.0 nM), wide linear range (0.01-20 µM), good precision (RSDs < 10 %) and negligible matrix effects indicated the suitability of the method. Application of the method to the quantification of serum chiral amino acids in late-life depression patients (n = 40) and controls (n = 35) found a total of 17 L-amino acids, 14 D-amino acids, DL-asparagine, glycine and γ-aminobutyric acid. The statistical evaluation showed significant differences of glycine, L-threonine and D-methionine between late-life depression patients and controls, indicating that these are potential biomarkers of late-life depression.

Multi-omics reveal microbial determinants impacting the treatment outcome of antidepressants in major depressive disorder.

BACKGROUND: There is a growing body of evidence suggesting that disturbance of the gut-brain axis may be one of the potential causes of major depressive disorder (MDD). However, the effects of antidepressants on the gut microbiota, and the role of gut microbiota in influencing antidepressant efficacy are still not fully understood. RESULTS: To address this knowledge gap, a multi-omics study was undertaken involving 110 MDD patients treated with escitalopram (ESC) for a period of 12 weeks. This study was conducted within a cohort and compared to a reference group of 166 healthy individuals. It was found that ESC ameliorated abnormal blood metabolism by upregulating MDD-depleted amino acids and downregulating MDD-enriched fatty acids. On the other hand, the use of ESC showed a relatively weak inhibitory effect on the gut microbiota, leading to a reduction in microbial richness and functions. Machine learning-based multi-omics integrative analysis revealed that gut microbiota contributed to the changes in plasma metabolites and was associated with several amino acids such as tryptophan and its gut microbiota-derived metabolite, indole-3-propionic acid (I3PA). Notably, a significant correlation was observed between the baseline microbial richness and clinical remission at week 12. Compared to non-remitters, individuals who achieved remission had a higher baseline microbial richness, a lower dysbiosis score, and a more complex and well-organized community structure and bacterial networks within their microbiota. These findings indicate a more resilient microbiota community in remitters. Furthermore, we also demonstrated that it was not the composition of the gut microbiota itself, but rather the presence of sporulation genes at baseline that could predict the likelihood of clinical remission following ESC treatment. The predictive model based on these genes revealed an area under the curve (AUC) performance metric of 0.71. CONCLUSION: This study provides valuable insights into the role of the gut microbiota in the mechanism of ESC treatment efficacy for patients with MDD. The findings represent a significant advancement in understanding the intricate relationship among antidepressants, gut microbiota, and the blood metabolome. Additionally, this study offers a microbiota-centered perspective that can potentially improve antidepressant efficacy in clinical practice. By shedding light on the interplay between these factors, this research contributes to our broader understanding of the complex mechanisms underlying the treatment of MDD and opens new avenues for optimizing therapeutic approaches. Video Abstract.

Tissue-Specific Oxysterols as Predictors of Antidepressant (Escitalopram) Treatment Response in Patients With Major Depressive Disorder.

Background: There is growing evidence that disturbances in cholesterol metabolism may be involved in major depressive disorder (MDD). However, it is not known if cholesterol metabolites present in the brain and periphery can be used to diagnose and predict an MDD patient's response to antidepressant treatment. Methods: A total of 176 subjects (85 patients with MDD and 91 healthy control subjects) were included in this study. The expression of peripheral and brain-specific oxysterols and related gene polymorphisms were investigated in all subjects. The severity of depression was measured using the 17-item Hamilton Depression Rating Scale, 16-item Quick Inventory of Depressive Symptoms-Self-Report, and Patient Health Questionnaire-9 for all patients with MDD before and after 12 weeks of antidepressant treatment. Results: Patients with MDD expressed higher plasma levels of 24(S)-hydroxycholesterol (24OHC) (mainly secreted from the brain) compared with healthy control subjects, and the higher levels of 24OHC were associated with 24OHC synthetase (CYP46A1) gene polymorphisms. In patients with MDD, an improved response to the 12-week antidepressant treatment was associated with a reduction of both 24OHC and 27OHC (mainly secreted from the peripheral system) levels relative to baseline levels. Nonresponders exhibited increased levels of oxysterols at the end of treatment compared with baseline. The superior reduction in oxysterol levels correlated with better outcomes from the antidepressant treatment. Conclusions: These data suggest a potential role for oxysterols as diagnostic and treatment response-related indicators for MDD.

Changes of gut microbiota reflect the severity of major depressive disorder: a cross sectional study.

Disturbed gut microbiota is a potential factor in the pathogenesis of major depressive disorder (MDD), yet whether gut microbiota dysbiosis is associated with the severity of MDD remains unclear. Here, we performed shotgun metagenomic profiling of cross-sectional stool samples from MDD (n = 138) and healthy controls (n = 155). The patients with MDD were divided into three groups according to Hamilton Depression Rating Scale 17 (HAMD-17), including mild (n = 24), moderate (n = 72) and severe (n = 42) individuals, respectively. We found that microbial diversity was closely related to the severity of MDD. Compared to HCs, the abundance of Bacteroides was significantly increased in both moderate and severe MDD, while Ruminococcus and Eubacterium depleted mainly in severe group. In addition, we identified 99 bacteria species specific to severity of depression. Furthermore, a panel of microbiota marker comprising of 37 bacteria species enabled to effectively distinguish MDD patients with different severity. Together, we identified different perturbation patterns of gut microbiota in mild-to-severe depression, and identified potential diagnostic and therapeutic targets.

Serum amyloid P component (SAP) modulates antidepressant effects through promoting membrane insertion of the serotonin transporter.

Serum amyloid P component (SAP) is a universal constituent of human amyloid deposits including those in Alzheimer's disease. SAP has been observed to be elevated in patients with depression, and higher SAP levels are associated with better response to the antidepressant escitalopram. The mechanisms underlying these clinical observations remain unclear. We examined the effect of SAP on serotonin transporter (SERT) expression and localization using Western blot, confocal microscopy, and positron emission tomography with the radioligand [11C]DASB. We also investigated the effect of SAP on treatment response to escitalopram in mice with the forced swim test (FST), a classical behaviour paradigm to assess antidepressant effects. SAP reduced [11C]DASB binding as an index of SERT levels, consistent with Western blots showing decreased total SAP protein because of increased protein degradation. In conjunction with the global decrease in SERT levels, SAP also promotes VAMP-2 mediated SERT membrane insertion. SAP levels are correlated with behavioural despair and SSRI treatment response in mice with FST. In MDD patients, the SAP and membrane SERT levels are correlated with response to SSRI treatment. SAP has complex effects on SERT levels and localization, thereby modulating the effect of SSRIs, which could partially explain clinical variability in antidepressant treatment response. These results add to our understanding of the mechanism for antidepressant drug action, and with further work could be of clinical utility.

The association of C-reactive protein with responses to escitalopram antidepressant treatment in patients with major depressive disorder.

BACKGROUND: The effects of escitalopram vary markedly among MDD patients, and approximately one-third of patients fail to respond. A poor antidepressant response might be associated with excessively high C-reactive protein (CRP) levels, but the impact is not clear. We hypothesized that in adults with major depressive disorder, the peripheral biomarker, CRP, was associated with the response to escitalopram (SSRI). METHODS: This was a prospective follow-up study. All 71 patients were treated with escitalopram for 12 weeks. Blood samples were collected at baseline and week 12. Remission was defined as a score of 7 or less on the HAMD-17 scale at week 12. Spearman correlations and multiple linear regressions were used to explore the relationship between continuous CRP levels and the HAMD-17 scores. Logistic regression was used to determine the predictors for remission. The restricted maximum likelihood (REML)-based mixed-effect model for repeated measures (MMRM) was used to examine the change of the HAMD-17 total scores between high and low CRP groups. RESULTS: Compared with the high CRP group (≥0.8 mg/l), the low baseline CRP group had a higher remission rate (22.73% vs. 48.89%, χ2 = 4.2, p = 0.0403). Logistic regression revealed that patients with lower CRPs were 3.920 times (95% CI: 1.142, 13.460) more likely to experience remission (p = 0.0300). The multiple linear regression model showed that the HAMD-17 total score reduction (baseline to week 12) was negatively correlated with the baseline CRP level (t = -2.00, p = 0.0494). CONCLUSIONS: We observed a predictive role of CRP for remission and symptomatic improvement after escitalopram treatment of MDD patients based on continuous or categorical CRP levels.

Deep brain stimulation improved depressive-like behaviors and hippocampal synapse deficits by activating the BDNF/mTOR signaling pathway.

Our previous study demonstrated that acute deep brain stimulation (DBS) in the ventromedial prefrontal cortex (vmPFC) remarkably improved the depressive-like behaviors in a rat model of chronic unpredictable mild stress (CUS rats). However, the mechanisms by which chronic DBS altered depressive-like behaviors and reversed cognitive impairment have not been clarified. Recent work has shown that deficits in brain-derived neurotrophic factor (BDNF) and its downstream proteins, including mammalian target of rapamycin (mTOR), might be involved in the pathogenesis of depression. Therefore, we hypothesized that the antidepressant-like and cognitive improvement effects of DBS were achieved by activating the BDNF/mTOR pathway. CUS rats received vmPFC DBS at 20 Hz for 1 h once a day for 28 days. After four weeks of stimulation, the rats were assessed for the presence of depressive-like behaviors and euthanized to detect BDNF/mTOR signaling using immunoblots. DBS at the vmPFC significantly ameliorated depressive-like behaviors and spatial learning and memory deficits in the CUS rats. Furthermore, DBS restored the reduced synaptic density in the hippocampus induced by CUS and increased the expression or activity of BDNF, Akt, and mTOR in the hippocampus. Thus, the antidepressant-like effects and cognitive improvement produced by vmPFC DBS might be mediated through increased activity of the BDNF/mTOR signaling pathway.