Efficacy and influencing factors of acupuncture in major depressive disorder: a systematic review and exploratory network meta-analysis.

BackgroundLeptin is a multifunctional hormone secreted from adipose tissue, which plays a core role in regulating energy intake and expenditure. Evidence has demonstrated that leptin receptors are located in brain areas involved in emotional processing, and major depressive disorder (MDD) is characterized by dysfunction of emotional processing. Taken together, these features suggest that leptin may play a potential role in the pathophysiology of MDD. However, the precise roles of leptin in modulating depressive symptoms in MDD remain unclear.MethodsParticipants [18 drug-naïve MDD patients, 15 unaffected first-degree relatives of MDD patients (FDR-MDD), and 40 healthy controls] completed clinical assessments and provided blood samples for measurement of leptin levels. We evaluated the effect of leptin on clinical status (MDD or FDR-MDD) and symptomatic dimensionalities of MDD using mediation analysis.ResultsWe found that leptin was increased in MDD patients and this only predicted “somatic anxiety” symptoms. Furthermore, leptin was a significant and indirect mediator of the association between clinical status (MDD or FDR-MDD) and “somatic anxiety” symptoms.ConclusionOur finding that leptin was a significant and indirect mediator of clinical status (MDD or FDR-MDD) and “somatic anxiety” symptoms suggests that leptin may indirectly affect somatic depressive symptoms in MDD. Our findings may provide a theoretical basis for novel clinical interventions in MDD.

Omega-3 polyunsaturated fatty acid (PUFA) supplementation has been proposed as (adjuvant) treatment for major depressive disorder (MDD). In the present meta-analysis, we pooled randomized placebo-controlled trials assessing the effects of omega-3 PUFA supplementation on depressive symptoms in MDD. Moreover, we performed meta-regression to test whether supplementation effects depended on eicosapentaenoic acid (EPA) or docosahexaenoic acid dose, their ratio, study duration, participants' age, percentage antidepressant users, baseline MDD symptom severity, publication year and study quality. To limit heterogeneity, we only included studies in adult patients with MDD assessed using standardized clinical interviews, and excluded studies that specifically studied perinatal/perimenopausal or comorbid MDD. Our PubMED/EMBASE search resulted in 1955 articles, from which we included 13 studies providing 1233 participants. After taking potential publication bias into account, meta-analysis showed an overall beneficial effect of omega-3 PUFAs on depressive symptoms in MDD (standardized mean difference=0.398 (0.114–0.682), P=0.006, random-effects model). As an explanation for significant heterogeneity (I2=73.36, P<0.001), meta-regression showed that higher EPA dose (β=0.00037 (0.00009–0.00065), P=0.009), higher percentage antidepressant users (β=0.0058 (0.00017–0.01144), P=0.044) and earlier publication year (β=−0.0735 (−0.143 to 0.004), P=0.04) were significantly associated with better outcome for PUFA supplementation. Additional sensitivity analyses were performed. In conclusion, present meta-analysis suggested a beneficial overall effect of omega-3 PUFA supplementation in MDD patients, especially for higher doses of EPA and in participants taking antidepressants. Future precision medicine trials should establish whether possible interactions between EPA and antidepressants could provide targets to improve antidepressant response and its prediction. Furthermore, potential long-term biochemical side effects of high-dosed add-on EPA supplementation should be carefully monitored.

Background and Objectives: Depressive symptoms are prominent in both major depressive disorder (MDD) and bipolar disorder (BD). However, comparative research on the network structure of depressive symptoms in these two diagnostic groups has been limited. This study aims to compare the network structure of depressive symptoms in MDD and BD, providing a deeper understanding of the depressive symptomatology of each disorder. Materials and Methods: The Zung Self-Rating Depressive Scale, a 20-item questionnaire, was administered to assess the depressive symptoms in individuals with MDD (n = 322) and BD (n = 516). A network analysis was conducted using exploratory graph analysis (EGA), and the network structure was analyzed using regularized partial correlation models. To validate the dimensionality of the Zung SDS, principal component analysis (PCA) was adopted. Centrality measures of the depressive symptoms within each group were assessed, followed by a network comparison test between the two groups. Results: In both diagnostic groups, the network analysis revealed four distinct categories, aligning closely with the PCA results. "Depressed affect" emerged as the most central symptom in both MDD and BD. Furthermore, non-core symptoms, "Personal devaluation" in MDD and "Confusion" in BD, displayed strong centrality. The network comparison test did not reveal significant differences in the network structure between MDD and BD. Conclusions: The absence of significant differences in the network structures between MDD and BD suggests that the underlying mechanisms of depressive symptoms may be similar across these disorders. The identified central symptoms, including "Depressed affect", in both disorders and the distinct non-core symptoms in each highlight the complexity of the depressive symptomatology. Future research should focus on validating these symptoms as therapeutic targets and incorporate various methodologies, including non-metric dimension reduction techniques or canonical analysis.

Men's Depression, Externalizing, and DSM-5-TR: Primary Signs and Symptoms or Co-occurring Symptoms?

Network meta-analysis of antidepressants

Adjunctive memantine for major mental disorders: A systematic review and meta-analysis of randomized double-blind controlled trials

Orexin receptor antagonists are a group of medications primarily developed to treat insomnia. Preliminary studies support their efficacy in treatment of depression. In this systematic review, we aim to evaluate the efficacy of orexin receptor antagonists for the treatment of major depressive disorder (MDD). Electronic databases were searched from inception to February 2024 to find relevant studies. Original studies in English that evaluated efficacy of orexin receptor antagonists were included. A total of 5 randomized clinical trials involving 498 participants were included. Seltorexant (20 mg) significantly decreased depression scores when compared to placebo, as measured by the Hamilton Depression Rating Scale (HDRS). In patients with inadequate responses to antidepressants, seltorexant (20 mg) also showed improvement in Montgomery-Ǻsberg Depression Rating Scale (MADRS) total scores compared to placebo. However, filorexant did not exhibit a significant difference in MADRS total scores compared to placebo. A separate study on seltorexant (40 mg) for MDD patients resulted in a non-significant decrease in depressive symptoms compared to placebo, as measured by the Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR). Taken together, the potential of orexin receptor antagonists, particularly seltorexant, as a novel avenue for managing depressive symptoms in MDD. Further research is warranted to better understand their role in depression treatment and safety profile.

Major depressive disorder (MDD) often co-occur with fibromyalgia (FM), and both conditions have been associated with impaired resting state functional connectivity (rs-FC). The present systematic review aims to summarize the evidence on rs-FC in individuals with MDD and FM compared with healthy controls and explore overlapping connectivity patterns and their relationships with clinical symptoms. A systematic search of the EMBASE, PubMed, Scopus and ScienceDirect databases was conducted according to PRISMA guidelines. Studies were included that addressed rs-FC using seed-based analysis in MDD and FM patients compared to HC. Methodological quality and risk of bias were assessed using a 13-point checklist adapted from previous neuroimaging meta-analyzes. A total of 33 articles were included in the analysis (17 with MDD and 16 with FM). The sample comprised 1,877 individuals, including 947 patients and 930 controls, with a mean age of 39.83 years. The seeds were categorized into six neural networks. Shared disruptions across MDD and FM studies have been identified in key circuits, including decreased connectivity between the insula and anterior cingulate cortex (ACC), middle frontal gyrus (MFG), superior frontal gyrus (SFG), and putamen. Increased FC was observed between the dorsolateral prefrontal cortex (DLPFC) and ACC, as well as between the thalamus and precuneus. Decreased insula-ACC connectivity correlated with greater pain intensity and catastrophizing in FM and with more severe depressive symptoms in MDD. Unique patterns of rs-FC were also observed: FM-specific changes involved the periaqueductal gray, hypothalamus, and thalamus, indicating impaired pain modulation and emotional processing. In contrast, MDD-specific changes were primarily observed in the reward, salience, and default mode networks, reflecting impaired emotional regulation. The studies showed considerable heterogeneity in the selection of seeds and study designs, which limits the feasibility of meta-analyses and underlines the need for standardized methods. This study provides information about overlapping and distinct neural mechanisms in FM and MDD, suggesting potentially the presence of a potential neurosignature that reflects shared disruptions in pain and emotion regulation networks while highlighting unique pathways underlying their respective pathophysiology.

Adolescent major depressive disorder (MDD) prevalence has nearly doubled in the past decade. The US Preventive Services Task Force endorses universal adolescent MDD screening in primary care; however, most adolescents lack preventive health care, resulting in worsening disparities in MDD screening and treatment. To evaluate the effectiveness of universal adolescent MDD screening in the school setting in an effort to reduce disparities and improve MDD identification and treatment initiation. This randomized clinical trial, conducted from November 6, 2018, to November 20, 2020, compared the usual school practice of targeted or selected screening based on observable behaviors of concern with universal MDD screening. Students within an identified school were randomized by grade to 1 of the 2 study groups. Study groups were compared using mixed-effects logistic regression. Participants included students in grades 9 through 12 enrolled at 1 of the 14 participating Pennsylvania public high schools. In targeted screening, students with behaviors prompting concern for MDD were referred to the Student Assistance Program (SAP), mandated in all Pennsylvania schools. The SAP determined follow-up recommendations. In universal screening, all students completed the Patient Health Questionnaire-9 (PHQ-9); students with positive scores proceeded to SAP. The universal screening group could also have targeted referral to SAP for concerning behavior independent of the PHQ-9. The primary outcome was initiation of MDD treatment or services based on data collected by school SAP teams during the academic year. A total of 12 909 students were included (median age, 16 years [range, 13-21 years]; 6963 male [53.9%]), of whom 2687 (20.8%) were Hispanic, 2891 (22.4%) were non-Hispanic Black, 5842 (45.3%) were non-Hispanic White, and 1489 (11.5%) were multiracial or of other race or ethnicity. A total of 6473 students (50.1%) were randomized to universal screening, and 6436 (49.9%) were randomized to targeted screening. Adolescents in the universal screening group had 5.92 times higher odds (95% CI, 5.07-6.93) of being identified with MDD symptoms, 3.30 times higher odds (95% CI, 2.49-4.38) of SAP confirming follow-up needs, and 2.07 times higher odds (95% CI, 1.39-3.10) of initiating MDD treatment. No differences were identified in initiation for planned subgroup analyses by sex or race and ethnicity. In this randomized clinical trial, universal school-based MDD screening successfully increased identification of MDD symptoms and treatment initiation among adolescents, confirming the value of this approach to address this rising public health concern. ClinicalTrials.gov identifier: NCT03716869.

Differences in Quantification of the Metabotropic Glutamate Receptor 5 Across Bipolar Disorder and Major Depressive Disorder

The authors investigated the theoretical and clinical role of depression among cocaine abusers in treatment. Eighty-nine cocaine-abusing patients underwent 2 weeks of substance abuse treatment. Posttreatment major depressive disorder, depressive symptoms before and after substance abuse treatment, and alcohol diagnoses were assessed and their relation to pretreatment substance use, cravings in high-risk situations, and 3-month follow-up status was examined. High rates of major depressive disorder were found but were unrelated to pretreatment substance use. The decrease in depressive symptoms during treatment was independent of major depressive disorder or alcohol diagnoses and predicted treatment attrition. Higher levels of depressive symptoms during treatment were associated with greater urge to use cocaine, alcohol, and other drugs in high-risk situations. Concurrent major depressive disorder and depressive symptoms did not predict cocaine use at follow-up. However, patients who had an alcohol relapse episode experienced more depressive symptoms during treatment than did those who abstained. The results highlight the relationship of depression to alcohol use among cocaine abusers and suggest a need for further studies of the association between depression and substance use disorders.

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.

Given the increasing acceptability and legalization of cannabis in some jurisdictions, clinicians need to improve their understanding of the effect of cannabis use on mood disorders. The purpose of this task force report is to examine the association between cannabis use and incidence, presentation, course and treatment of bipolar disorder and major depressive disorder, and the treatment of comorbid cannabis use disorder. We conducted a systematic literature review using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, searching PubMed, Embase, PsycINFO, CINAHL and Cochrane Central Register of Controlled Trials from inception to October 2020 focusing on cannabis use and bipolar disorder or major depressive disorder, and treatment of comorbid cannabis use disorder. The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach was used to evaluate the quality of evidence and clinical considerations were integrated to generate Canadian Network for Mood and Anxiety Treatments recommendations. Of 12,691 publications, 56 met the criteria: 23 on bipolar disorder, 21 on major depressive disorder, 11 on both diagnoses and 1 on treatment of comorbid cannabis use disorder and major depressive disorder. Of 2,479,640 participants, 12,502 were comparison participants, 73,891 had bipolar disorder and 408,223 major depressive disorder without cannabis use. Of those with cannabis use, 2,761 had bipolar disorder and 5,044 major depressive disorder. The lifetime prevalence of cannabis use was 52%-71% and 6%-50% in bipolar disorder and major depressive disorder, respectively. Cannabis use was associated with worsening course and symptoms of both mood disorders, with more consistent associations in bipolar disorder than major depressive disorder: increased severity of depressive, manic and psychotic symptoms in bipolar disorder and depressive symptoms in major depressive disorder. Cannabis use was associated with increased suicidality and decreased functioning in both bipolar disorder and major depressive disorder. Treatment of comorbid cannabis use disorder and major depressive disorder did not show significant results. The data indicate that cannabis use is associated with worsened course and functioning of bipolar disorder and major depressive disorder. Future studies should include more accurate determinations of type, amount and frequency of cannabis use and select comparison groups which allow to control for underlying common factors.

Bright light therapy is increasingly recommended (alone or in combination with antidepressant medication) to treat symptoms of nonseasonal major depressive disorder (MDD). However, little is known about its impacts on quality of life (QoL), a holistic, patient-valued outcome. This study utilizes secondary outcome data from an 8-week randomized, controlled, double blind trial comparing light monotherapy (n = 32), fluoxetine monotherapy (n = 30), and the combination of these (n = 27) to placebo (n = 30). QoL was assessed using the Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF). Treatment-related differences in QoL improvements were assessed using a repeated measures analysis of variance. The influence of potential predictors of QoL (demographic variables and change in depressive symptoms) were investigated via hierarchical linear regression. Q-LES-Q-SF scores significantly improved across all treatment conditions; however, no significant differences were observed between treatment arms. QoL remained poor relative to community norms by the end of the trial period: Across conditions, 70.6% of participants had significantly impaired QoL at the 8-week assessment. Reduction in depressive scores was a significant predictor of improved QoL, with the final model accounting for 54% of variance in QoL change scores. The findings of this study emphasize that improvement in QoL and reduction in depressive symptoms in MDD, while related, cannot be taken to be synonymous. Adjunctive therapies may be required to address unmet QoL needs in patients with MDD receiving antidepressant or light therapies. Further research is required to explore additional predictors of QoL in order to better refine treatments for MDD.

Older adults with major depressive disorder (MDD) or early cognitive decline during the subjective cognitive decline (SCD) stage may exhibit neuropsychiatric symptoms such as anxiety, depression, and subtle cognitive impairment. The clinicopathological features and biological mechanisms of MDD differ from those of SCD among older adults; these conditions thus require different treatment strategies. This study enrolled 82 participants above 50 years old with normal cognitive levels from the communities to examine biomarker–behavior correlations between MDD (n = 23) and SCD (n = 23) relative to a normal control (NC) group (n = 36). Multidomain assessments were performed for all participants, including immunomagnetic reduction tests to detect plasma beta-amyloid (Aβ), total tau (Tau), phosphorylated tau-181 (p-Tau181), neurofilament light chain, and glial fibrillary acidic protein (GFAP). This study observed that depressive symptoms in MDD were associated with amyloid pathology (plasma Aβ40 vs. HADS-D: R = 0.45, p = 0.031; Aβ42/Aβ40 vs. HADS-D: R = −0.47, p = 0.024), which was not observed in the NC (group difference p < 0.05). Moreover, cognitive decline in MDD was distinguished by a mixed neurodegenerative process involving amyloid (plasma Aβ42 vs. facial memory test: R = 0.48, p = 0.025), tau (Tau/Aβ42 vs. digit symbol substitution test (DSST): R = −0.53, p = 0.01), and astrocytic injury (plasma GFAP vs. Montreal cognitive assessment score: R = −0.44, p = 0.038; plasma GFAP vs. DSST: R = −0.52, p = 0.014), findings that did not apply to the NC (group difference p < 0.05). Moreover, this study revealed different biomarker–behavior correlations between individuals with SCD and the NC. Compared with the NC, cognitive decline in the SCD group might be unrelated to amyloid pathology and instead might be early manifestations of tau pathology. This study underscores the difference in clinicopathological features between MDD and SCD among older adults, which differ from those of the NC. These findings enhance our understanding of the mechanisms underlying MDD and SCD in older individuals.