Treatment Of Major Depressive Disorder Research Articles

Comorbidity between major depressive disorder and physical diseases: a comprehensive review of epidemiology, mechanisms and management.

Populations with common physical diseases - such as cardiovascular diseases, cancer and neurodegenerative disorders - experience substantially higher rates of major depressive disorder (MDD) than the general population. On the other hand, people living with MDD have a greater risk for many physical diseases. This high level of comorbidity is associated with worse outcomes, reduced adherence to treatment, increased mortality, and greater health care utilization and costs. Comorbidity can also result in a range of clinical challenges, such as a more complicated therapeutic alliance, issues pertaining to adaptive health behaviors, drug-drug interactions and adverse events induced by medications used for physical and mental disorders. Potential explanations for the high prevalence of the above comorbidity involve shared genetic and biological pathways. These latter include inflammation, the gut microbiome, mitochondrial function and energy metabolism, hypothalamic-pituitary-adrenal axis dysregulation, and brain structure and function. Furthermore, MDD and physical diseases have in common several antecedents related to social factors (e.g., socioeconomic status), lifestyle variables (e.g., physical activity, diet, sleep), and stressful live events (e.g., childhood trauma). Pharmacotherapies and psychotherapies are effective treatments for comorbid MDD, and the introduction of lifestyle interventions as well as collaborative care models and digital technologies provide promising strategies for improving management. This paper aims to provide a detailed overview of the epidemiology of the comorbidity of MDD and specific physical diseases, including prevalence and bidirectional risk; of shared biological pathways potentially implicated in the pathogenesis of MDD and common physical diseases; of socio-environmental factors that serve as both shared risk and protective factors; and of management of MDD and physical diseases, including prevention and treatment. We conclude with future directions and emerging research related to optimal care of people with comorbid MDD and physical diseases.

The Effects of CYP2C19 Genotype on Proxies of SSRI Antidepressant Response in the UK Biobank.

Selective serotonin reuptake inhibitors (SSRIs) are the most commonly used psychopharmaceutical treatment for major depressive disorder (MDD), but individual responses to SSRIs vary greatly. CYP2C19 is a key enzyme involved in the metabolism of several drugs, including SSRIs. Variations in the CYP2C19 gene are associated with differential metabolic activity, and thus differential SSRI exposure; accordingly, the CYP2C19 genotype may affect the therapeutic response and clinical outcomes, though existing evidence of this link is not entirely consistent. Therefore, we analysed data from the UK Biobank, a large, deeply phenotyped prospective study, to investigate the effects of CYP2C19 metaboliser phenotypes on several clinical outcomes derived from primary care records, including multiple measures of antidepressant switching, discontinuation, duration, and side effects. In this dataset, 24,729 individuals were prescribed citalopram, 3012 individuals were prescribed escitalopram, and 12,544 individuals were prescribed sertraline. Consistent with pharmacological expectations, CYP2C19 poor metabolisers on escitalopram were more likely to switch antidepressants, have side effects following first prescription, and be on escitalopram for a shorter duration compared to normal metabolisers. CYP2C19 poor and intermediate metabolisers on citalopram also exhibited increased odds of discontinuation and shorter durations relative to normal metabolisers. Generally, no associations were found between metabolic phenotypes and proxies of response to sertraline. Sensitivity analyses in a depression subgroup and metabolic activity scores corroborated results from the primary analysis. In summary, our findings suggest that CYP2C19 genotypes, and thus metabolic phenotypes, may have utility in determining clinical responses to SSRIs, particularly escitalopram and citalopram, though further investigation of such a relationship is warranted.

Upregulation of HDAC9 in hippocampal neurons mediates depression-like behaviours by inhibiting ANXA2 degradation

Major depressive disorder (MDD) is a pervasive and devastating mental disease. Broad spectrum histone deacetylase (HDAC) inhibitors are considered to have potential for the treatment of depressive phenotype in mice. However, due to its non-specific inhibition, it has extensive side effects and can not be used in clinical treatment of MDD. Therefore, finding specific HDAC subtypes that play a major role in the etiology of MDD is the key to develop corresponding specific inhibitors as antidepressants in the future. Copy number variation in HDAC9 gene is thought to be associated with the etiology of some psychiatric disorders. Herein, we found that HDAC9 was highly expressed in the hippocampus of chronic restraint stress (CRS) mouse model of depression. Upregulation of HDAC9 expression in hippocampal neurons of mice induced depression-like phenotypes, including anhedonia, helplessness, decreased dendritic spine density, and neuronal hypoexcitability. Moreover, knockdown or knockout of HDAC9 in hippocampal neurons alleviated depression-like phenotypes caused by chronic restraint stress (CRS) in WT mice. Importantly, using immunoprecipitation–mass spectrometry (IP–MS), we further found that Annexin A2 (ANXA2) was coupled to and deacetylated by HDAC9. This coupling resulted in the inhibition of ubiquitinated ANXA2 degradation and then mediates depression-like behavior. Overall, we discovered a previously unrecognized role for HDAC9 in hippocampal neurons in the pathogenesis of depression, indicating that inhibition of HDAC9 might be a promising clinical strategy for the treatment of depressive disorders.

Rumination symptoms in treatment-resistant major depressive disorder, and outcomes of repetitive Transcranial Magnetic Stimulation (rTMS) treatment

Rumination is a maladaptive style of regulating thoughts and emotions. It is a common symptom of Major Depressive Disorder (MDD), and more severe rumination is associated with poorer medication and psychotherapy treatment outcomes, particularly among women. It is unclear to what extent rumination may influence the outcomes of, or be responsive to, repetitive Transcranial Magnetic Stimulation (rTMS) treatment of MDD. We retrospectively examined data collected during rTMS treatment of 155 patients (age 42.52 ± 14.22, 79 female) with moderately severe treatment-resistant MDD. The severity of rumination and depression was assessed before and during a course of 30 sessions of measurement-based rTMS treatment using the Ruminative Responses Scale (RSS) and the Patient Health Questionnaire (PHQ-9), respectively. Relationships among baseline levels of rumination, depression, and treatment outcome were assessed using a series of repeated measures linear mixed effects models. Both depression and rumination symptoms significantly improved after treatment, but improvement in depression was not a significant mediator of rumination improvement. Higher baseline rumination (but not depression severity) was associated with poorer depression outcomes independently of depression severity. Female gender was a significant predictor of worse outcomes for all RRS subscales. Both depressive and ruminative symptoms in MDD improved following rTMS treatment. These improvements were correlated, but improvement in rumination was not fully explained by reduction in depressive symptoms. These findings suggest that while improvement in rumination and depression severity during rTMS treatment are correlated, they are partly independent processes. Future studies should examine whether rumination symptoms should be specifically targeted with different rTMS treatment parameters.

Transcranial alternating current stimulation for the treatment of major depressive disorder: from basic mechanisms toward clinical applications.

Non-pharmacological treatment is essential for patients with major depressive disorder (MDD) that is medication resistant or who are unable to take medications. Transcranial alternating current stimulation (tACS) is a non-invasive brain stimulation method that manipulates neural oscillations. In recent years, tACS has attracted substantial attention for its potential as an MDD treatment. This review summarizes the latest advances in tACS treatment for MDD and outlines future directions for promoting its clinical application. We first introduce the neurophysiological mechanism of tACS and its novel developments. In particular, two well-validated tACS techniques have high application potential: high-definition tACS targeting local brain oscillations and bifocal tACS modulating interarea functional connectivity. Accordingly, we summarize the underlying mechanisms of tACS modulation for MDD. We sort out the local oscillation abnormalities within the reward network and the interarea oscillatory synchronizations among multiple MDD-related networks in MDD patients, which provide potential modulation targets of tACS interventions. Furthermore, we review the latest clinical studies on tACS treatment for MDD, which were based on different modulation mechanisms and reported alleviations in MDD symptoms. Finally, we discuss the main challenges of current tACS treatments for MDD and outline future directions to improve intervention target selection, tACS implementation, and clinical validations.

Single-Dose Psilocybin Treatment for Major Depressive Disorder

Psilocybin shows promise as a treatment for major depressive disorder (MDD). To evaluate the magnitude, timing, and durability of antidepressant effects and safety of a single dose of psilocybin in patients with MDD. In this phase 2 trial conducted between December 2019 and June 2022 at 11 research sites in the US, participants were randomized in a 1:1 ratio to receive a single dose of psilocybin vs niacin placebo administered with psychological support. Participants were adults aged 21 to 65 years with a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition diagnosis of MDD of at least 60 days' duration and moderate or greater symptom severity. Exclusion criteria included history of psychosis or mania, active substance use disorder, and active suicidal ideation with intent. Participants taking psychotropic agents who otherwise met inclusion/exclusion criteria were eligible following medication taper. Primary and secondary outcomes and adverse events (AEs) were assessed at baseline (conducted within 7 days before dosing) and at 2, 8, 15, 29, and 43 days after dosing. Interventions were a 25-mg dose of synthetic psilocybin or a 100-mg dose of niacin in identical-appearing capsules, each administered with psychological support. The primary outcome was change in central rater-assessed Montgomery-Asberg Depression Rating Scale (MADRS) score (range, 0-60; higher scores indicate more severe depression) from baseline to day 43. The key secondary outcome measure was change in MADRS score from baseline to day 8. Other secondary outcomes were change in Sheehan Disability Scale score from baseline to day 43 and MADRS-defined sustained response and remission. Participants, study site personnel, study sponsor, outcome assessors (raters), and statisticians were blinded to treatment assignment. A total of 104 participants (mean [SD] age, 41.1 [11.3] years; 52 [50%] women) were randomized (51 to the psilocybin group and 53 to the niacin group). Psilocybin treatment was associated with significantly reduced MADRS scores compared with niacin from baseline to day 43 (mean difference,-12.3 [95% CI, -17.5 to -7.2]; P <.001) and from baseline to day 8 (mean difference, -12.0 [95% CI, -16.6 to -7.4]; P < .001). Psilocybin treatment was also associated with significantly reduced Sheehan Disability Scale scores compared with niacin (mean difference, -2.31 [95% CI, 3.50-1.11]; P < .001) from baseline to day 43. More participants receiving psilocybin had sustained response (but not remission) than those receiving niacin. There were no serious treatment-emergent AEs; however, psilocybin treatment was associated with a higher rate of overall AEs and a higher rate of severe AEs. Psilocybin treatment was associated with a clinically significant sustained reduction in depressive symptoms and functional disability, without serious adverse events. These findings add to increasing evidence that psilocybin-when administered with psychological support-may hold promise as a novel intervention for MDD. ClinicalTrials.gov Identifier: NCT03866174.

Efficacy of Transcranial Photobiomodulation on Depressive Symptoms: A Meta-Analysis.

Background: Transcranial photobiomodulation (tPBM) is a novel, noninvasive, device-based intervention, which has been tested as a possible treatment for various neurological and psychiatric conditions. Recently, it has been investigated as an innovative treatment for major depressive disorder (MDD). There have been several animal and clinical studies that evaluated the underlying mechanism and the efficacy of its antidepressant effects, but results have been conflicting. Objective: Thus, we conducted the first meta-analysis on effects of tPBM on depressive symptoms. Materials and methods: Thirty original articles on tPBM were retrieved, eight of them met criteria for inclusion to a random effects meta-analysis. Results: tPBM appeared effective in decreasing depressive symptom severity regardless of diagnosis (Hedges' g = 1.415, p < 0.001, k = 8), but a significant heterogeneity has been found. The meta-analysis of single-arm studies (baseline to endpoint changes) limited to participants with MDD has supported the significant effect of tPBM in reducing the depression severity, without a significant heterogeneity (Hedges' g = 1.142, 95% confidence interval = 0.780-1.504, z = 6.19, p < 0.001, k = 5). However, the meta-analysis of the few double-blind, sham-controlled studies in MDD has not supported the statistically significant superiority of tPBM over sham (Hedges' g = 0.499, p = 0.211, k = 3), although a sample size bias is likely present. Conclusions: Overall, this meta-analysis provides weak support for the promising role of tPBM in the treatment of depressive symptoms. Dose finding studies to determine optimal tPBM parameters followed by larger, randomized, sham-controlled studies will be needed to fully demonstrate the antidepressant efficacy of tPBM.

Discovery and In Vitro Characterization of SPL028: Deuterated N,N-Dimethyltryptamine.

The psychedelic N,N- dimethyltryptamine (DMT) is in clinical development for the treatment of major depressive disorder. However, when administered via intravenous infusion, its effects are short-lived due to rapid clearance. Here we describe the synthesis of deuterated analogues of DMT with the aim of prolonging the half-life and decreasing the clearance rate while maintaining similar pharmacological effects. The molecule with the greatest degree of deuteration at the α-carbon (N,N-D2-dimethyltryptamine, D2-DMT) demonstrated the longest half-life and intrinsic clearance in hepatocyte mitochondrial fractions when compared with DMT. The in vitro receptor binding profile of D2-DMT was comparable to that of DMT, with the highest affinity at the 5-HT1A, 5-HT2A, and 5-HT2C receptors. D2-DMT was therefore the preferred candidate to consider for further evaluation.

Additional Clinical Benefit of Agomelatine Treatment for Major Depressive Disorder in Naturalistic Treatment Setting.

This study tried to observe additional benefit of agomelatine (AGO) treatment for major depressive disorder (MDD) in routine practice. Retrospective chart review (n = 63) was conducted for additional benefit of combination with or switching to AGO in MDD patients without full remission. The primary endpoint was the mean change of Clinical Global Impression-Clinical Benefit (CGI-CB) total scores from baseline to the endpoint. Additional secondary endpoints were also collected. The changes of CGI-CB (Z = -3.073, p = 0.002) and Montgomery-Åsberg Depression Rating Scale (Z = -3.483, p < 0.001) total scores were significantly decreased from baseline to the endpoint, respectively. At the endpoint, the remission rate was 22.6% (n = 18) and 28.6% of patient had improvement in CGI-CB total scores at the endpoint. No significant adverse events were observed. This study has shown additional benefit of AGO treatment as combination or switching agent for MDD patients without full remission in routine practice. However, adequately-powered and well-controlled studies are necessary for generalization of the present findings.

A review on a selected Ayurvedic herbal formula in the management of Kaphaja Unmada (Major depressive disorder): A critical analysis

The widespread psychiatric disease known as major depressive disorder (MDD) is associated with a high rate of morbidity and mortality with correlation to Kaphaja Unmāda. According to family, twin and adoption studies, genetic variables are crucial in the emergence of MDD and may provide crucial details regarding the disease's pathophysiology. Bacopa monniera (Brāhmi) and Evolvulus alsinoides (Vishnukrānthi) were the ingredients of a decoction from a traditional formula and this review's objective was to investigate how well the herbal formula of decoction effective to treat MDD. Information about MDD and Kaphaja Unmāda was acquired from Ayurvedic scriptures, contemporary texts and earlier research studies (from primary and secondary sources). A survey of the literature was done on those two herbs in the selected decoction and then examined for their Pancha Padārtha (5 elements of herb) and pharmacological qualities regarding in the management of MDD. Ayurvedic Pancha Padārtha study has revealed that selected herbal formula has anti-depressant qualities because of their compatibility with Mēdhya (nootropic action) Prabhāva (special action). The majority of studies have demonstrated the anti-depressant effects of herbal formula, but reviewed articles have also highlighted additional qualities that aid in lowering the symptoms of MDD. According to the literature review and Pancha Padārtha analysis, selected herbal formula is useful in the treatment of MDD.

Effects of Exercise on Functional Recovery in Patients with Bipolar Depression: A Study Protocol for a Randomized Controlled Trial.

Treatment of bipolar disorder is prone to prolongation despite various treatments, including medication. The efficacy of exercise treatment (i.e., interventions involving physical exercise and sports intervention) for major depressive disorders has been reported for depressive symptoms, cognitive function, and sleep disturbances. However, its efficacy for bipolar disorder has yet to be established. We designed a randomized, controlled, double-blind clinical trial that includes 100 patients with bipolar disorder aged 20-65 years. This will be a cluster-randomized, two-group trial that will be conducted in ten psychiatric hospitals. The hospitals will be randomly assigned to an exercise intervention + treatment as usual (exercise) group or a placebo exercise intervention (stretching) + treatment as usual (control) group. Patients will be assessed using an extensive battery of clinical tests, physical parameters, sleep status, biological parameters (cytokines, neurotrophic factors), and genetic parameters (DNA and RNA) at baseline after a 6-week intervention period, at 10-week follow-up, and at 6-month follow-up. This innovative study may provide important evidence for the effectiveness of exercise in the treatment of bipolar depression based on clinical, biological, genetic, and physiological markers.

Cell type-specific NRBF2 orchestrates autophagic flux and adult hippocampal neurogenesis in chronic stress-induced depression

Dysfunctional autophagy and impairment of adult hippocampal neurogenesis (AHN) each contribute to the pathogenesis of major depressive disorder (MDD). However, whether dysfunctional autophagy is linked to aberrant AHN underlying MDD remains unclear. Here we demonstrate that the expression of nuclear receptor binding factor 2 (NRBF2), a component of autophagy-associated PIK3C3/VPS34-containing phosphatidylinositol 3-kinase complex, is attenuated in the dentate gyrus (DG) under chronic stress. NRBF2 deficiency inhibits the activity of the VPS34 complex and impairs autophagic flux in adult neural stem cells (aNSCs). Moreover, loss of NRBF2 disrupts the neurogenesis-related protein network and causes exhaustion of aNSC pool, leading to the depression-like phenotype. Strikingly, overexpressing NRBF2 in aNSCs of the DG is sufficient to rescue impaired AHN and depression-like phenotype of mice. Our findings reveal a significant role of NRBF2-dependent autophagy in preventing chronic stress-induced AHN impairment and suggest the therapeutic potential of targeting NRBF2 in MDD treatment.

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

BackgroundThere 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.ResultsTo 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.ConclusionThis 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.86QpdFZ1CFqqddzdYP5qf7Video

The core inflammatory factors in patients with major depressive disorder: a network analysis.

The symptoms of major depressive disorder (MDD) vary widely. Psycho-neuro-inflammation has shown that MDD's inflammatory factors can accelerate or slow disease progression. This network analysis study examined the complex interactions between depressed symptoms and inflammatory factors in MDD prevention and treatment. We gathered participants' inflammatory factor levels, used the Hamilton Depression Scale (HAMD-17), and network analysis was used to analyzed the data. Network analysis revealed the core inflammatory (nodes) and their interactions (edges). Stability and accuracy tests assessed these centrality measures' network robustness. Cluster analysis was used to group persons with similar dimension depressive symptoms and examine their networks. Interleukin-1β (IL-1β) is the core inflammatory factor in the overall sample, and IL-1β-interleukin-4 (IL-4) is the strongest correlation. Network precision and stability passed. Network analysis showed significant differences between Cluster 1 (with more severe anxiety/somatization and sleep disruption) and Cluster 3 (with more severe retardation and cognitive disorders), as well as between Cluster 2 (with more severe anxiety/somatization, sleep disruption and body weight) and Cluster 3. IL-1β is the core inflammatory factor in Cluster 1 and Cluster 2, while tumor necrosis factor alpha (TNF-α) in Cluster 3. IL-1β is the central inflammatory factor in the network, and there is heterogeneity in the core inflammatory factor of MDD with specific depressive dimension symptoms as the main manifestation. In conclusion, inflammatory factors and their links should be prioritized in future theoretical models of MDD and may provide new research targets for MDD intervention and treatment.

Study protocol: effects of treatment expectation toward repetitive transcranial magnetic stimulation (rTMS) in major depressive disorder—a randomized controlled clinical trial

BackgroundPatients’ expectations toward any given treatment are highly important for the effectiveness of such treatment, as has been demonstrated for several disorders. In particular, in major depressive disorder (MDD), one of the most frequent and most serious mental disorders with severe consequences for the affected, the augmentation of available treatment options could mean a ground-breaking success. Repetitive transcranial magnetic stimulation (rTMS), a new, non-invasive, and well-tolerated intervention with proven effects in the treatment of MDD, appears particularly suitable in this context as it is assumed to exert its effect via structures implicated in networks relevant for both expectation and depression.MethodsAll patients will receive rTMS according to its approval. Half of the patients will be randomized to a psychological intervention, which is a comprehensive medical consultation aiming to improve positive treatment expectations; the control group will receive a conventional informed consent discussion (in the sense of a treatment-as-usual condition). As outcome parameters, instruments for both self-assessment and external assessment of depression symptoms will be applied. Furthermore, psycho-immunological parameters such as inflammation markers and the cortisol awakening response in saliva will be investigated. Resting-state functional magnetic resonance imaging (rs fMRI) will be performed to analyze functional connectivity, including the cerebellum, and to identify neuronal predictors of expectation effects. In addition, possible cerebellar involvement will be assessed based on a cerebellar-dependent motor learning paradigm (i.e., eyeblink conditioning).DiscussionIn this study, the effects of treatment expectations towards rTMS are investigated in patients with MDD. The aim of this study is to identify the mechanisms underlying the expectation effects and, beyond that, to expand the potential of non-invasive and well-tolerated treatments of MDD.Trial registrationGerman Registry of Clinical Studies (DRKS DRKS00028017. Registered on 2022/03/07. URL: https://www.drks.de/drks_web/.

Effects of a video game intervention on symptoms, training motivation, and visuo-spatial memory in depression.

People with Major Depressive Disorder (MDD) often experience reduced affect, mood, and cognitive impairments such as memory problems. Although there are various treatments for MDD, many of them do not address the cognitive deficits associated with the disorder. Playing 3D video games has been found to improve cognitive functioning in healthy people, but it is not clear how they may affect depressed mood and motivation in people with MDD. The aim of this study was to investigate whether a six-week video game intervention leads to improvements in depressed mood, training motivation, and visuo-spatial (working) memory functions in patients with MDD. A total of 46 clinically depressed individuals were randomly assigned to one of three groups: an experimental "3D video gaming" group (n = 14) which played a video game, an active control group (n = 16) which trained with a computer program "CogPack," and a treatment-as-usual group (n = 16) which received a standard clinical treatment including psychotherapy and/or pharmacotherapy. Participants performed a neuropsychological assessment, including self-report questionnaires asking for depressive symptoms, training motivation, and visuo-spatial (working) memory functions before and after the training intervention. Regarding depressive symptoms, a significant decrease in the proportion of participants who showed clinical levels of depressive symptoms as measured by the Beck Depression Inventory was only found in the 3D video gaming group. Additionally, mean motivational levels of performing the training were significantly higher in the 3D video gaming group when compared with the active control group. Moreover, whereas the 3D Video Gaming group only significantly improved on one visuo-spatial memory test, the active control group improved in all visuo-spatial memory functions. The 3D video gaming group did not perform significantly better than the CogPack group, and the TAU group. Besides a standalone cognitive training, the current findings suggest that cognitive trainings using a video game have potential to increase subjective well-being, show higher levels of training motivation, and lead to improvements in visuo-spatial (working) memory functions in MDD. However, given the mixed and unblinded nature of this study, the results should be interpreted with caution. Further research with larger samples and follow-up measurements is needed.

Neuroendocrine Biomarkers of Herbal Medicine for Major Depressive Disorder: A Systematic Review and Meta-Analysis.

Major depressive disorder (MDD) is a medical condition involving persistent sadness and loss of interest; however, conventional treatments with antidepressants and cognitive behavioral therapy have limitations. Based on the pathogenesis of MDD, treatments using herbal medicines (HM) have been identified in animal studies. We conducted a systematic review of clinical studies to identify neurobiological outcomes and evaluate the effectiveness of HM in treating MDD. A meta-analysis was performed by searching nine databases from their inception until 12 September 2022, including 31 randomized controlled trials with 3133 participants, to examine the effects of HM on MDD using neurobiological biomarkers and a depression questionnaire scale. Quality assessment was performed using a risk of bias tool. Compared to antidepressants alone, HM combined with an antidepressant significantly increased concentrations of serotonin (SMD = 1.96, 95% CI: 1.24-2.68, p < 0.00001, I2 = 97%), brain-derived neurotrophic factor (SMD = 1.38, 95% CI: 0.92-1.83, p < 0.00001, I2 = 91%), and nerve growth factors (SMD = 2.38, 95% CI: 0.67-4.10, p = 0.006, I2 = 96%), and decreased cortisol concentrations (SMD = -3.78, 95% CI: -4.71 to -2.86, p < 0.00001, I2 = 87%). Although HM or HM with an antidepressant benefits MDD treatment through improving neuroendocrine factors, these findings should be interpreted with caution because of the low methodological quality and clinical heterogeneity of the included studies.

Functional and structural alterations in different durations of untreated illness in the frontal and parietal lobe in major depressive disorder

Major depressive disorder (MDD) is one of the most disabling illnesses that profoundly restricts psychosocial functions and impairs quality of life. However, the treatment rate of MDD is surprisingly low because the availability and acceptability of appropriate treatments are limited. Therefore, identifying whether and how treatment delay affects the brain and the initial time point of the alterations is imperative, but these changes have not been thoroughly explored. We investigated the functional and structural alterations of MDD for different durations of untreated illness (DUI) using regional homogeneity (ReHo) and voxel-based morphometry (VBM) with a sample of 125 treatment-naïve MDD patients and 100 healthy controls (HCs). The MDD patients were subgrouped based on the DUI, namely, DUI ≤ 1 M, 1 < DUI ≤ 6 M, 6 < DUI ≤ 12 M, and 12 < DUI ≤ 48 M. Subgroup comparison (MDD with different DUIs) was applied to compare ReHo and grey matter volume (GMV) extracted from clusters of regions with significant differences (the pooled MDD patients relative to HCs). Correlations and mediation effects were analysed to estimate the relationships between the functional and structural neuroimaging changes and clinical characteristics. MDD patients exhibited decreased ReHo in the left postcentral gyrus and precentral gyrus and reduced GMV in the left middle frontal gyrus and superior frontal gyrus relative to HCs. The initial functional abnormalities were detected after being untreated for 1 month, whereas this duration was 3 months for GMV reduction. Nevertheless, a transient increase in ReHo was observed after being untreated for 3 months. No significant differences were discovered between HCs and MDD patients with a DUI less than 1 month or among MDD patients with different DUIs in either ReHo or GMV. Longer DUI was related to reduced ReHo with GMV as mediator in MDD patients. We identified disassociated functional and anatomical alterations in treatment-naïve MDD patients at different time points in distinct brain regions at the early stage of the disease. Additionally, we also discovered that GMV mediated the relationship between a longer DUI and diminished ReHo in MDD patients, disclosing the latent deleterious and neuro-progressive implications of DUI on both the structure and function of the brain and indicating the necessity of early treatment of MDD.

Neutrophil to lymphocyte ratio and antidepressant treatment response in patients with major depressive disorder: Effect of sex and hippocampal volume

Several factors may affect response to treatment in Major Depressive Disorder (MDD) including immune/inflammatory alterations and regional brain volumes, particularly in hippocampal regions which have shown to be influenced by inflammatory status. Neutrophil-to-lymphocyte ratio (NLR) is an inflammatory marker found to be elevated in depressed women in large population studies. Here we investigate the effect of NLR on treatment response in MDD patients, and the role of sex and hippocampal volume on influencing this relationship. A sample of 124 MDD depressed inpatients (F = 80) underwent MRI acquisition, admission NLR was calculated by dividing absolute neutrophil by absolute lymphocyte counts and depression severity was assessed at admission and discharge via the Hamilton Depression Rating Scale (HDRS). As a measure of treatment response, delta HDRS was calculated. We found a significant moderation effect of sex on the relationship between NLR and Delta HDRS: a negative relation was found in females and a positive one in males. NLR was found to negatively affect hippocampal volumes in females. Both left and right hippocampal volume positively associated with Delta HDRS. Finally, left hippocampal volume mediated the effect of NLR on Delta HDRS in females. Sex moderated the relation between inflammation and treatment response in line with previous reports linking inflammation to hampered antidepressant effect in females. Further, this effect is partially mediated by hippocampal volume, suggesting that antidepressant response may be hampered by the detrimental effect of inflammation on the brain.

Modifiable risk factors of major depressive disorder: A Mendelian randomization study.

Identifying modifiable risk factors early on is essential to prevent major depressive disorder (MDD). This study systematically investigated the causal relationship between 19 modifiable risk factors and MDD. Single-nucleotide polymorphisms (SNPs) associated with 19 potentially modifiable risk factors were screened via the genome-wide association study (GWAS) enrolling individuals of European descent. Summary-level data for MDD (59,851 cases and 113,154 controls) were extracted from the UK Biobank. The inverse-variance-weighted (IVW) method was utilized as the primary analysis. Sensitivity analyses were performed using the MR-Egger method, the Maximum likelihood method, the MR-pleiotropy residual sum outlier (MR-PRESSO) method, and MR-robust adjusted profile score (MR-RAPS) method. MR-Egger regression, heterogeneity tests, pleiotropy tests, and leave-one-out tests were also performed to analyze sensitivity. The MR Steiger test was used to verify the directionality of the exposure to the outcome. Genetically predicted smoking initiation increased the risk of MDD (P = 6.00E-09), while smoking status: never and past tobacco smoking decreased the risk of MDD (all P < 0.01). In addition, education level was inversely associated with MDD risk (all P < 0.01). Genetically instrumented sleeplessness/insomnia, daytime naps, and nap during the day were positively related to the risk of MDD (all P < 0.01). Personal feelings, including guilt, hurt, tension, and worry too long after an embarrassing experience, had a suggestive increased risk for MDD (all P < 0.000). The remaining five modifiable risk factors were all causally associated with the risk of MDD, including neuroticism, neuroticism scores, body mass index (BMI), average total household income before tax, and types of physical activity in the last 4 weeks (all P < 0.01). All 19 potentially modifiable risk factors were causally associated with the risk of MDD. The main hypothesis of this MR study was that identifying and intervening in these 19 potentially modifiable risk factors could be beneficial to the prevention and treatment of MDD and further reduce mortality and economic burden.