Treatment Of Major Depressive Disorder In Patients Research Articles

Association between TNF-α & IL-6 level changes and remission from depression with duloxetine treatment

Purpose/Aim of the study The pathophysiology of major depressive disorder (MDD) involves multiple factors, including inflammatory processes. This study investigated the relationship between changes in the levels of cytokines and remission in patients with MDD following duloxetine treatment. Materials and methods MDD patients were administered duloxetine for 16 weeks. Clinical evaluation and immunological monitoring were performed every 4 weeks. Results Our results indicated that changes in serum levels of TNF-α and IL-6 were associated with remission following duloxetine treatment in MDD patients. There was a slight increase in TNF-α levels in the first four weeks following duloxetine treatment, which correlated significantly with patients who were in remission. Furthermore, patients in remission exhibited an initial increase in IL-6 levels in the first four weeks, followed by a decrease at 16 weeks. Conclusions These results suggest an important relationship between changes in cytokine levels and remission in patients with major depression after duloxetine treatment.

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.

Bupropion Associated Immunomodulatory Effects on Peripheral Cytokines in Male with Major Depressive Disorder

Background: Experimental and clinical studies have reported increased levels of pro-inflammatory cytokines in patients with major depressive disorder (MDD), suggesting that immune system dysregulation may contribute to MDD pathophysiology. Aim: Due to the lack of knowledge about the immune potential of antidepressants, this study investigated the immunomodulatory effects of bupropion, a norepinephrine–dopamine reuptake inhibitor. Methods: This study involved 18 patients with MDD treated with bupropion (150 mg/d) for 4 weeks and 23 healthy volunteers. All participants underwent multiplex bead-based cytokine assessment before and after bupropion treatment to quantify the following cytokines: interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, interferon-γ, tumor necrosis factor-α, granulocyte colony-stimulating factor, granulocyte-macrophage CSF, monocyte chemotactic protein-1, and macrophage inflammatory protein-1β. Results: Four-week treatment with bupropion significantly increased the levels of IL-1β (P = 0.011), IL-4 (P = 0.019), IL-5 (P = 0.019), IL-7 (P = 0.021), and IL-8 (P = 0.023) compared to the control group. Furthermore, the percentage change in most cytokines, including anti-inflammatory cytokines such as IL-4, IL-5, IL-10, and IL-13, was significantly increased after bupropion treatment. Conclusion: The promoted synthesis of anti-inflammatory cytokines to surpass the pro-inflammatory cytokines may be a crucial step in the treatment of MDD patients with bupropion.

A multimodal prediction model for suicidal attempter in major depressive disorder.

Suicidal attempts in patients with major depressive disorder (MDD) have become an important challenge in global mental health affairs. To correctly distinguish MDD patients with and without suicidal attempts, a multimodal prediction model was developed in this study using multimodality data, including demographic, depressive symptoms, and brain structural imaging data. This model will be very helpful in the early intervention of MDD patients with suicidal attempts. Two feature selection methods, support vector machine-recursive feature elimination (SVM-RFE) and random forest (RF) algorithms, were merged for feature selection in 208 MDD patients. SVM was then used as a classification model to distinguish MDD patients with suicidal attempts or not. The multimodal predictive model was found to correctly distinguish MDD patients with and without suicidal attempts using integrated features derived from SVM-RFE and RF, with a balanced accuracy of 77.78%, sensitivity of 83.33%, specificity of 70.37%, positive predictive value of 78.95%, and negative predictive value of 76.00%. The strategy of merging the features from two selection methods outperformed traditional methods in the prediction of suicidal attempts in MDD patients, with hippocampal volume, cerebellar vermis volume, and supracalcarine volume being the top three features in the prediction model. This study not only developed a new multimodal prediction model but also found three important brain structural phenotypes for the prediction of suicidal attempters in MDD patients. This prediction model is a powerful tool for early intervention in MDD patients, which offers neuroimaging biomarker targets for treatment in MDD patients with suicidal attempts.

Enhanced rich club connectivity in mild or moderate depression after nonpharmacological treatment: A preliminary study.

It has been suggested that the rich club organization in major depressive disorder (MDD) was altered. However, it remained unclear whether the rich club organization could be served as a biomarker that predicted the improvement of clinical symptoms in MDD. The current study included 29 mild or moderate patients with MDD, who were grouped into a treatment group (receiving cognitive behavioral therapy or real-time fMRI feedback treatment) and a no-treatment group. Resting-state MRI scans were obtained for all participants. Graph theory was employed to investigate the treatment-related changes in network properties and rich club organization. We found that patients in the treatment group had decreased depressive symptom scores and enhanced rich club connectivity following the nonpharmacological treatment. Moreover, the changes in rich club connectivity were significantly correlated with the changes in depressive symptom scores. In addition, the nonpharmacological treatment on patients with MDD increased functional connectivity mainly among the salience network, default mode network, frontoparietal network, and subcortical network. Patients in the no-treatment group did not show significant changes in depressive symptom scores and rich club organization. Those results suggested that the remission of depressive symptoms after nonpharmacological treatment in MDD patients was associated with the increased efficiency of global information processing.

Transcutaneous electrical cranial-auricular acupoint stimulation versus escitalopram for modulating the brain activity in mild to moderate major depressive disorder: An fMRI study

Transcutaneous electrical cranial-auricular acupoint stimulation (TECAS) is an innovative, non-invasive therapy for major depressive disorder (MDD). However, its effectiveness and underlying neural mechanisms remain not fully understood. This study aimed to investigate the treatment response and neurological effects of TECAS compared to escitalopram, a commonly used depression medication, using resting-state functional magnetic resonance imaging (rs-fMRI). Fifty-one patients with mild-to-moderate MDD (34 in the TECAS group and 17 in the Escitalopram group) and 51 healthy controls (HCs) participated in the study. We employed the low-frequency fluctuations (ALFF) and regional homogeneity (ReHo) methods to explore brain abnormalities in MDD patients and HCs. Additionally, seed-based functional connectivity (FC) analysis was conducted to examine altered brain networks before and after treatment.Compared to the HCs group, the MDD group exhibited lower ReHo and ALFF values in the right medial superior frontal gyrus (mSFG_R), indicating altered neural activity in this region. Furthermore, mSFG-based FC analysis revealed abnormal FC values in the right inferior occipital gyrus (IOG_R) and middle temporal gyrus (MTG) between after and before treatment in MDD patients. Interestingly, TECAS treatment was found to normalize these abnormal FC brain regions, suggesting its potential role in restoring neural connectivity in MDD patients. Notably, both TECAS and escitalopram demonstrated equivalent antidepressant efficacy, with both treatments showing modulatory effects on connectivity within the default mode network (DMN). The observed normalization of abnormal FC regions, including mSFG_R, IOG_R, and MTG, all belong to the DMN. In conclusion, this study sheds light on the neurological effects and treatment response of TECAS in MDD, highlighting its potential as a non-invasive therapeutic option for depressed patients.

No evidence for clinical efficacy of adjunctive celecoxib with vortioxetine in the treatment of depression: A 6-week double-blind placebo controlled randomized trial

Given the role of low-grade inflammation in the pathophysiology of major depressive disorder (MDD), anti-inflammatory strategies may improve treatment outcomes in some patients. However, it is controversial whether they can be used as adjunctive treatments and whether pre-treatment levels of inflammation can predict treatment outcomes. This study was conducted to measure the efficacy of anti-inflammatory augmentation of antidepressant treatment in MDD patients; and to investigate whether treatment response was dependent on baseline inflammation levels. This parallel-group randomised, double-blind, placebo-controlled trial was conducted at the University of Adelaide (Australia). Participants with MDD were randomised to receive vortioxetine with celecoxib or vortioxetine with placebo for six weeks, and baseline blood high sensitivity C reactive protein levels were measured. Primary outcome was change in depressive symptoms (Montgomery–Åsberg Depression Rating Scale) and secondary outcomes included change in cognition (THINC-integrated tool – Codebreaker task) and functioning (Functioning Assessment Short Test) over 6 weeks. There was no evidence of superior efficacy of celecoxib augmentation over placebo on depressive symptom severity, response and remission rates, cognition and psychosocial functioning. There was also no evidence that pre-treatment inflammation levels modified the effect of celecoxib augmentation versus placebo. This observed lack of efficacy of celecoxib add-on does not support the use of celecoxib augmentation of antidepressants in the treatment of MDD in a cohort that mostly comprises treatment-resistant individuals. Additionally, C-reactive protein may not be suitable to predict treatment selection and response in MDD.The study was registered on the Australian New Zealand Clinical Trials Registry: ACTRN12617000527369 (www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12617000527369p).

Incidence Trends and Risk Prediction Nomogram for Suicidal Attempts in Patients With Major Depressive Disorder

Background: Major depressive disorder (MDD) is often associated with suicidal attempt (SA). Therefore, predicting the risk factors of SA would improve clinical interventions, research, and treatment for MDD patients. This study aimed to create a nomogram model which predicted correlates of SA in patients with MDD within the Chinese population.Method: A cross-sectional survey among 474 patients was analyzed. All subjects met the diagnostic criteria of MDD according to the International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10). Multi-factor logistic regression analysis was used to explore demographic information and clinical characteristics associated with SA. A nomogram was further used to predict the risk of SA. Bootstrap re-sampling was used to internally validate the final model. Integrated Discrimination Improvement (IDI) and Akaike Information Criteria (AIC) were used to evaluate the capability of discrimination and calibration, respectively. Decision Curve Analysis (DCA) and the Receiver Operating Characteristic (ROC) curve was also used to evaluate the accuracy of the prediction model.Result: Multivariable logistic regression analysis showed that being married (OR = 0.473, 95% CI: 0.240 and 0.930) and a higher level of education (OR = 0.603, 95% CI: 0.464 and 0.784) decreased the risk of the SA. The higher number of episodes of depression (OR = 1.854, 95% CI: 1.040 and 3.303) increased the risk of SA in the model. The C-index of the nomogram was 0.715, with the internal (bootstrap) validation sets was 0.703. The Hosmer–Lemeshow test yielded a P-value of 0.33, suggesting a good fit of the prediction nomogram in the validation set.Conclusion: Our findings indicate that the demographic information and clinical characteristics of SA can be used in a nomogram to predict the risk of SA in Chinese MDD patients.

No Association Between SLC6A4 Gene Polymorphisms With Treatment Remission to Venlafaxine in Han Chinese Depressive Patients.

Major depressive disorder (MDD) is a heterogeneous psychiatric disorder and considered to be one of the most common mental diseases worldwide. The antidepressant venlafaxine, as a serotonin noradrenaline reuptake inhibitor, is applied to MDD relief. Solute carrier family 6 member 4 (SLC6A4) has been reported to promote the reuptake of serotonin and to be closely correlated to depression. The present study examined whether rs6354 and rs1487971 in SLC6A4 are associated with remission after venlafaxine treatment in MDD patients. This study consisted of 195 Han Chinese patients with MDD, who accepted a 6-week treatment with venlafaxine. Two SLC6A4 single-nucleotide polymorphisms (SNPs) were selected from database of SNP and genotyped by matrix-assisted laser desorption/ionization time of flight mass spectrometer in MassARRAY Analyzer 4 platforms. The 17-item Hamilton Depression Scale was used to access the severity of major depression. Allele and genotype frequencies between patients in remission and nonremission were calculated with online software SHEsis. No significant differences in allele or genotype frequencies were observed in rs6354 and rs1487971. There were no significant associations between 2 SNPs and venlafaxine treatment outcome. It suggested that rs6354 or rs1487971 within SLC6A4 appears not to be involved in the venlafaxine treatment outcome in Han Chinese patients with MDD.

Selective serotonin reuptake inhibitor attenuates the hyperresponsiveness of TLR2+ and TLR4+ Th17/Tc17-like cells in multiple sclerosis patients with major depression.

Elevated frequency of Th17-like cells expressing Toll-like receptors (TLRs) has been recently associated with relapsing-remitting multiple sclerosis (MS) pathogenesis, a chronic inflammatory demyelinating autoimmune disease of the central nervous system. We aimed to investigate the impact of current major depressive disorder (MDD) on the behaviour of these cells following in vitro stimulation with TLR2, TLR4, TLR5 and TLR9 agonists. Here, the level of both cell proliferation and cytokine production related to Th17/Tc17 phenotypes in response to TLR2 (Pam3C) and TLR4 (LPS) ligands was significantly higher in CD4+ and CD8+ T-cell cultures from MS/MDD patients when compared to non-depressed patients. These cytokine levels were positively associated with neurological disabilities in patients. No difference for responsiveness to TLR5 (flagellin) and TLR9 (ODN) agonists was observed. LPS, but not Pam3C, induced significant IL-10 release, mainly in patients without MDD. Interestingly, more intense expression of TLR2 and TLR4 on these cells was observed in MDD patients. Finally, in vitro addition of serotonin and treatment of MDD patients with selective serotonin reuptake inhibitors (SSRIs) reduced the production of Th17/Tc17-related cytokines by CD4+ and CD8+ T cells in response to Pam3C and LPS. However, only SSRI therapy diminished the frequency and intensity of TLR2 and TLR4 expression on circulating CD4+ and CD8+ T cells. In summary, although preliminary, our findings suggest that adverse events that elevate circulating levels of TLR2 and TLR4 ligands can affect MS pathogenesis, particularly among depressed patients.

Volumetric changes in subcortical structures following repeated ketamine treatment in patients with major depressive disorder: a longitudinal analysis

Abnormal subcortical structures have been associated with major depressive disorder (MDD) and could be reversed by antidepressant treatment. To date no study has examined the relationship between subcortical volumes and repeated ketamine treatment. The current study investigated volume changes in specific subcortical structures and hippocampal subfields after six ketamine infusions. Forty-four patients with MDD received six subanesthetic dose infusions of ketamine. Depressive symptoms were assessed and magnetic resonance imaging scans were performed before and after six ketamine infusions. FreeSurfer software was used to process the T1 images and analyze the volumes of the subcortical regions and hippocampal subfields. After six ketamine infusions, increases were observed in the volumes of the left amygdala; the right hippocampus; the cornu ammonis 4 body, granule cell and molecular layer of the dentate gyrus body in the left hippocampus; and the cornu ammonis 4 head and molecular layer head in the right hippocampus. Positive correlations were found between symptom improvement and the pretreatment volumes of the right thalamus (r = 0.501; P = 0.001) and left subiculum head of the hippocampus (r = 0.471; P = 0.002), and changes in the volumes of the left amygdala (r = −0.452; P = 0.003) and the left cornu ammonis 4 body (r = −0.537; P < 0.001). Our findings provided evidence for critical roles of the amygdala and specific hippocampal subfields in the antidepressant effect of repeated ketamine treatment. Relatively larger volumes in right thalamus and left subiculum head in the hippocampus can predict a superior clinical outcome of ketamine treatment in MDD patients.

Machine Learning Analysis of Blood microRNA Data in Major Depression: A Case-Control Study for Biomarker Discovery.

BackgroundThere is a lack of reliable biomarkers for major depressive disorder (MDD) in clinical practice. However, several studies have shown an association between alterations in microRNA levels and MDD, albeit none of them has taken advantage of machine learning (ML).MethodSupervised and unsupervised ML were applied to blood microRNA expression profiles from a MDD case-control dataset (n = 168) to distinguish between (1) case vs control status, (2) MDD severity levels defined based on the Montgomery-Asberg Depression Rating Scale, and (3) antidepressant responders vs nonresponders.ResultsMDD cases were distinguishable from healthy controls with an area-under-the receiver-operating characteristic curve (AUC) of 0.97 on testing data. High- vs low-severity cases were distinguishable with an AUC of 0.63. Unsupervised clustering of patients, before supervised ML analysis of each cluster for MDD severity, improved the performance of the classifiers (AUC of 0.70 for cluster 1 and 0.76 for cluster 2). Antidepressant responders could not be successfully separated from nonresponders, even after patient stratification by unsupervised clustering. However, permutation testing of the top microRNA, identified by the ML model trained to distinguish responders vs nonresponders in each of the 2 clusters, showed an association with antidepressant response. Each of these microRNA markers was only significant when comparing responders vs nonresponders of the corresponding cluster, but not using the heterogeneous unclustered patient set.ConclusionsSupervised and unsupervised ML analysis of microRNA may lead to robust biomarkers for monitoring clinical evolution and for more timely assessment of treatment in MDD patients.

No association between CYP2C19 genetic polymorphism with treatment remission to antidepressant venlafaxine in Han Chinese population.

Major depressive disorder (MDD) is a global mental health problem. As a serotonin-noradrenaline reuptake inhibitor (SNRI), the antidepressant venlafaxine is used to alleviate MDD clinically. Recent research has shown that Cytochrome P450 (CYP) enzymes affect venlafaxine efficacy by mediating its metabolism. The present study investigates genetic polymorphisms of cytochrome P450 family 2 subfamily C member 19 (CYP2C19) are associated with remission after venlafaxine treatment for MDD. A total of 175 Han Chinese patients with depression were recruited to accept a 6-week treatment with venlafaxine. Three single-nucleotide polymorphisms of CYP2C19 were selected from dbSNP and previous literature to compare the allele and genotype frequencies between patients in remission and nonremission. Seventeen items Hamilton Depression Scale (17-HAMD) was used to access the outcomes of patients' depressive symptoms through the study. Our results denied the role of CYP2C19 polymorphisms for remission after venlafaxine treatment in MDD patients. CYP2C19 genetic polymorphism may not have association with SNRI venlafaxine treatment remission in the Han Chinese population.

The Phosphodiesterase Inhibitor Pentoxifylline as a Novel Adjunct to Antidepressants in Major Depressive Disorder Patients: A Proof-of-Concept, Randomized, Double-Blind, Placebo-Controlled Trial

Background: There is evidence for an association between major depressive disorder (MDD) and both inflammatory and phosphodiesterase (PDE) pathways. This study aimed to evaluate the adjunct role of the PDE inhibitor pentoxifylline (PTX), a compound with anti-inflammatory properties, in the treatment of adult patients with MDD. Methods: This was a prospective, 12-week, double-blind study of parallel groups. Eighty adult outpatients who met the DSM-IV criteria for MDD participated in the trial. Patients were required to have a baseline Hamilton Rating Scale for Depression (HAM-D) score of at least 18. Patients were allocated randomly: 40 received escitalopram 20 mg/day plus placebo while the other 40 received escitalopram 20 mg/day plus PTX (400 mg b.i.d.). Patients were assessed by a psychiatrist at baseline, and 4, 8, and 12 weeks after the medication had been started. The serum levels of TNF-α, IL-6, IL-10, BDNF, 8-OHdG, and serotonin were measured at baseline and after therapy. Results: After 8 and 12 weeks, the PTX group showed a statistically significantly greater improvement in HAM-D score compared to the control group (least squares mean difference [LSMD] –3.29, p = 0.000 and LSMD –3.49, p = 0.000, respectively). Moreover, the PTX group showed a statistically significantly greater reduction in the serum levels of TNF-α, IL-6, IL-10, and 8-OHdG along with a statistically significant increase in the levels of BDNF and serotonin in comparison with the control group after the treatment. Conclusion: The findings of this study suggest that PTX could be a promising adjunct to antidepressants in the treatment of MDD patients.

Depression Severity Classification from Speech Emotion.

Major Depressive Disorder (MDD) is a common psychiatric illness. Automatically classifying depression severity using audio analysis can help clinical management decisions during Deep Brain Stimulation (DBS) treatment of MDD patients. Leveraging the link between short-term emotions and long-term depressed mood states, we build our predictive model on the top of emotion-based features. Because acquiring emotion labels of MDD patients is a challenging task, we propose to use an auxiliary emotion dataset to train a Deep Neural Network (DNN) model. The DNN is then applied to audio recordings of MDD patients to find their low dimensional representation to be used in the classification algorithm. Our preliminary results indicate that the proposed approach, in comparison to the alternatives, effectively classifies depressed and improved phases of DBS treatment with an AUC of 0.80.

Prefrontal transcranial direct current stimulation (tDCS) as treatment for major depression: study design and methodology of a multicenter triple blind randomized placebo controlled trial (DepressionDC).

ClinicalTrials.gov Identifier NCT0253016.

Polygenic Score for Cardiometabolic and Psychiatric Phenotypes Predict Response to Treatment with Selective Serotonin Reuptake Inhibitors in Major Depressive Disorder

Selective serotonin reuptake inhibitors (SSRIs) are the first line antidepressants to treat major depressive disorder (MDD). Among other factors, the co-morbidity of depression with other psychiatric and cardiometabolic disorders may negatively influence antidepressants treatment response. Moreover, response to antidepressants is considered as a complex trait with substantial contribution from a large number of common genetic variants of small effect. Hence, polygenic scores (PGSs) could be a useful tool to estimate the overall effect of genetically driven factors on the treatment outcome.Here, we evaluated whether PGSs derived from 25 recognized comorbid cardiometabolic and psychiatric disorders, personality traits and educational parameters predict treatment response to SSRIs in MDD. In order to create the PGSs, we used genome-wide genotype data obtained from 865 MDD patients who received SSRIs treatment and GWAS summary statistics for the 25 disorders and phenotypes. The PGSs were calculated within a P-value threshold (PT) as the sum of the single nucleotide polymorphisms effect allele multiplied by its corresponding GWAS effect size (β- coefficient or log (OR)) weighted by the sum of the GWAS effect sizes.Clinical, demographic and SSRIs treatment response data were collected from 865 MDD patients by the ISPC. Baseline and follow-up SSRIs treatment response were measured using the 17-item Hamilton Rating Scale for Depression (HRSD-17). After 4 weeks of treatment, patients with at least 50% reduction in HRSD-17 from the baseline score were classified as responders and patients with a score of less than or equal to seven were considered as remitters. Once the PGSs were calculated, binary logistic regression analyses were performed between the dependent variables (response or remission to SSRIs) and the PGSs in each of the 25 disorders and phenotypes adjusted for the covariates (age, sex and study sites). Finally, we reported the best-predictive PGS for each disorder and phenotype that predicts the treatment outcome with the smallest p-value. A statistically significant association was determined at P < 0.05.We found that the PGSs for MDD, depressive symptoms, type 2 diabetes, body mass index, plasma levels of fasting proinsulin or fasting glucose, openness personality trait, subjective wellbeing and educational attainment significantly (P < 0.05) predicted both response and remission to SSRIs treatment in MDD patients. Additionally, the PGS for coronary artery disease, plasma level of total cholesterol, agreeableness and conscientiousness personality traits showed a significant association with remission, but not with response. Our findings suggest that the influence of cardiometabolic and psychiatric co-morbidities on antidepressants treatment response could be at least partly determined at a genetic level.

Hsa_circRNA_103636: potential novel diagnostic and therapeutic biomarker in Major depressive disorder.

This study aimed to determine whether circular RNA (circRNA) molecules in peripheral blood mononuclear cells (PBMCs) could be used as novel non-invasive biomarkers for major depressive disorder (MDD). Differentially expressed circRNAs were screened using an Arraystar Human CircRNA Array (which includes 13,617 human circRNAs) and qRT-PCR. Thirty MDD patients were randomly selected to retest the circRNA levels after 4-week and 8-week antidepressant regimens. Four differentially expressed circRNAs were identified between MDD patients and controls, and only down-regulated hsa_circRNA_103636 was significantly altered after the 8-week treatment in MDD patients. These results suggest that altered expression of hsa_circRNA_103636 in PBMCs is a potential novel biomarker for the diagnosis and treatment of MDD.

Correlation of clinical response with homocysteine reduction during therapy with reduced B vitamins in patients with MDD who are positive for MTHFR C677T or A1298C polymorphism: a randomized, double-blind, placebo-controlled study.

This study was designed to evaluate the efficacy and safety of reduced B vitamins as monotherapy in adults with major depressive disorder (MDD) who were also positive for at least 1 methylenetetrahydrofolate reductase (MTHFR) polymorphism associated with depression and further test the hypothesis that reduced (metabolized) B vitamins will lower homocysteine in a majority of clinically responding patients. 330 adult patients with MDD (DSM-5) and positive for either MTHFR C677T or A1298C polymorphism were enrolled in a trial conducted between August 1, 2014, and April 3, 2015. 160 patients received placebo, while 170 received a capsule containing a combination of reduced B vitamins. Plasma homocysteine levels were measured at baseline and week 8. The Montgomery-Asberg Depression Rating Scale (MADRS) was used to evaluate efficacy for MDD. 159 of 170 vitamin-treated patients and 123 of 160 placebo-treated patients were completers. Of the active treatment group, 131 (82.4%) showed a reduction in homocysteine (for a mean in this subgroup of 25%, P < .001), while 28 (17.6%) showed no significant change. Placebo patients demonstrated a small elevation in homocysteine. Active-treatment patients demonstrated, on average, a 12-point reduction on the MADRS by week 8, and 42% achieved full remission (P < .001). No side effect was significantly different between groups. No patients experienced mania. A combination of reduced B vitamins and micronutrients, when used in the treatment of MDD in patients with MTHFR polymorphism, resulted in a separation from placebo by week 2, and 42% of the treatment arm achieved remission by week 8. Further, clinical improvement correlated with a significant reduction in homocysteine levels in a majority of responders. These results support the homocysteine theory of depression and the safety and therapeutic benefit of reduced B vitamins as monotherapy for MDD, particularly in patients with MTHFR polymorphism. ClinicalTrials.gov identifier: NCT02709668.

Randomized controlled study of early medication change for non-improvers to antidepressant therapy in major depression – The EMC trial

Patients with Major Depressive Disorder (MDD) and no improvement after two weeks of antidepressant pharmacotherapy have a high risk of treatment failure. The aim of the study was to determine whether an early medication change (EMC) strategy is superior to a guideline-based treatment in MDD patients without improvement after two weeks of antidepressant pharmacotherapy. Eight-hundred-and-eighty-nine patients with MDD were enrolled, 879 patients received the SSRI escitalopram. Of those, 192 patients had no improvement, defined as a reduction of <20% on the Hamilton Depression Rating Scale (HAMD-17) after 14 days of treatment, and were randomly assigned to open treatment with the EMC strategy (n=97; venlafaxine XR for study days 15–56; in case of sustained non-improvement on day 28, lithium augmentation for days 29–56) or TAU (n=95; escitalopram continuation; non-responders on day 28 were switched to venlafaxine XR for four weeks, i.e. days 29–56). The primary outcome was remission (HAMD-17≤7) after 8 weeks of treatment as assessed by blinded raters. Remission rates were 24% for EMC and 16% for TAU, which was not significantly different (p=0.2056). Sensitivity analyses for the primary and secondary effectiveness endpoints consistently showed favorable results for patients randomized to EMC. The results confirm data from post-hoc analyses of clinical trials showing that early non-improvement identifies patients who likely need alternate interventions. However, the herein used two-step switch/augmentation strategy for this risk group was not more effective than the control intervention. Alternate strategies and other design aspects are discussed in order to support researchers addressing the same research question.