Major Depressive Disorder Research Articles

Depression and metabolic connectivity: insights into the locus coeruleus, HF-rTMS, and anxiety

The use of repetitive Transcranial Magnetic Stimulation (rTMS) in treating major depressive disorder (MDD) is increasingly being explored in precision medicine. However, there’s a notable lack of understanding of the underlying neurobiological effects, which limits our ability to correlate specific imaging features with treatment efficacy. As one possible neurobiological mechanism, clinical research has already shown that in MDD, lower norepinephrine release in the locus coeruleus (LC) triggers depressive symptoms, and pharmacological approaches that block norepinephrine reuptake boost its levels, easing depression. Surprisingly, the LC has not received a more pronounced focus in contemporary rTMS research. This study investigates the role of the LC in MDD and its response to high-frequency (HF)-rTMS using 18FDG-PET imaging. We compared LC metabolic connectivity between MDD patients (n = 43) and healthy controls (n = 32). Additionally, we evaluated the predictive value of LC connectivity for HF-rTMS treatment outcomes and examined post-treatment changes in LC metabolic connectivity. Our findings revealed significant differences in LC metabolic connectivity between MDD patients and controls. Baseline LC metabolic connectivity did not predict HF-rTMS treatment outcomes. However, post-treatment analyses showed a significant correlation between improved clinical outcomes and attenuation of LC metabolic connectivity in regions associated with cognitive control and the default mode network. Notably, a reduction in state anxiety moderated this relationship, highlighting the role of anxiety in HF-rTMS efficacy for MDD treatment. Our findings suggest that LC metabolic connectivity, influenced by state anxiety levels, may be crucial in HF-rTMS efficacy, offering further insights for personalized MDD treatment strategies.

A transdiagnostic approach of negative symptoms in psychiatric disorders: replication of a two-factor structure in major depressive disorder and bipolar disorder.

Recent empirical findings suggest that negative symptoms are not limited to schizophrenia (SCZ) but also present in major depressive disorder (MDD) and bipolar disorder (BD) patients. Although SCZ patients generally showed a latent structure comprising the motivation and pleasure (MAP) and expression (EXP) factors, it remains unclear whether the same latent structure exists in MDD and BD patients. We administered the Clinical Assessment Interview for Negative Symptoms (CAINS) and the Brief Negative Symptom Scale (BNSS) to 179 MDD patients and 152 BD patients. Confirmatory Factor Analysis (CFA) was conducted to examine the one-factor model, the two-factor model of the MAP and the EXP domain, the five-factor model of anhedonia, avolition, asociality, alogia, and blunted affect, and the hierarchical model comprising the first-order five-factor, and the second-order two-factor (MAP and EXP factors). We further examined the correlations between demographics and the negative symptom dimensions found in the best factor model. The CFA showed that, when the CAINS and the BNSS were combined together, the two-factor model of MAP and EXP provided the best model fit than other competing models, in the MDD alone sample, BD alone sample, and the combined clinical sample. The two-factor model of the MAP and EXP appears to be a stable, transdiagnostic latent structure of negative symptoms across BD and MDD. Clarifying negative symptoms in MDD and BD can facilitate future research on the underlying neural mechanisms of the MAP and EXP dimensions.

Brain single-cell transcriptomics highlights comorbidity-related cell type-specific changes of Parkinson’s disease with major depressive disorder after paraquat exposure

Paraquat (PQ), a commonly used herbicide, is a potent environmental neurotoxin associated with Parkinson’s disease (PD) and major depressive disorder (MDD). While the involvement of various brain cell types in the etiology of each disorder is well recognized, the specific cell subtypes implicated in the comorbidity of PD and MDD, especially under PQ neurotoxicity, remain poorly understood. In this study, we used single-cell RNA sequencing (scRNA-seq) to analyze brain tissues from mice with PQ-induced PD with MDD. By integrating genomic data with scRNA-seq profiles, we identified differences in cellular heterogeneity related to the pathogenesis of PD and MDD under PQ exposure. Our analysis of risk enrichment in genes with cell type-specific expression patterns revealed that astrocytes are predominantly linked to the comorbidity of PQ-induced PD and MDD. Furthermore, we identified a specific astrocyte subtype that plays a major role in the comorbidity-related changes observed in PQ-induced PD and MDD. This subtype appears to interact with and potentially transform into MDD-specific and PD-specific subtypes. Additionally, pathways related to chemical synaptic function and neuro-projection development were involved in all key stages of PD and MDD co-occurrence. We also identified RNF7 and MTCH2 as shared diagnostic hub genes for PD and MDD, which changed significantly in astrocytes following PQ exposure. These genes may serve as potential markers for astrocyte-specific prognostic diagnosis of PQ-induced PD with MDD. In summary, this study provides the first scRNA-seq profile of comorbidity in a PQ-exposed model. It highlights the heterogeneity of astrocytes in comorbidity and elucidates potential mechanisms underlying the co-occurrence of PD and MDD. These findings emphasize the need for further research into the pathogenesis of PD comorbid with MDD and offer novel insights into PQ neurotoxicity.

Associations between white matter microstructure and cognitive decline in major depressive disorder versus controls in Germany: a prospective case-control cohort study

Cognitive deficits are a key source of disability in individuals with major depressive disorder (MDD) and worsen with disease progression. Despite their clinical relevance, the underlying mechanisms of cognitive deficits remain poorly elucidated, hampering effective treatment strategies. Emerging evidence suggests that alterations in white matter microstructure might contribute to cognitive dysfunction in MDD. We aimed to investigate the complex association between changes in white matter integrity, cognitive decline, and disease course in MDD in a comprehensive longitudinal dataset. In the naturalistic, observational, prospective, case-control Marburg-Münster Affective Disorders Cohort Study, individuals aged 18-65 years and of Caucasian ancestry were recruited from local psychiatric hospitals in Münster and Marburg, Germany, and newspaper advertisements. Individuals diagnosed with MDD and individuals without any history of psychiatric disorder (ie, healthy controls) were included in this subsample analysis. Participants had diffusion-weighted imaging, a battery of neuropsychological tests, and detailed clinical data collected at baseline and at 2 years of follow-up. We used linear mixed-effect models to compare changes in cognitive performance and white matter integrity between participants with MDD and healthy controls. Diffusion-weighted imaging analyses were conducted using tract-based spatial statistics. To correct for multiple comparisons, threshold free cluster enhancement (TFCE) was used to correct α-values at the family-wise error rate (FWE; ptfce-FWE). Effect sizes were estimated by conditional, partial R2 values (sr2) following the Nakagawa and Schielzeth method to quantify explained variance. The association between changes in cognitive performance and changes in white matter integrity was analysed. Finally, we examined whether the depressive disease course between assessments predicted cognitive performance at follow-up and whether white matter integrity mediated this association. People with lived experience were not involved in the research and writing process. 881 participants were selected for our study, of whom 418 (47%) had MDD (mean age 36·8 years [SD 13·4], 274 [66%] were female, and 144 [34%] were male) and 463 (53%) were healthy controls (mean age 35·6 years [13·5], 295 [64%] were female, and 168 [36%] were male). Baseline assessments were done between Sept 11, 2014, and June 3, 2019, and after a mean follow-up of 2·20 years (SD 0·19), follow-up assessments were done between Oct 6, 2016, and May 31, 2021. Participants with MDD had lower cognitive performance than did healthy controls (p<0·0001, sr2=0·056), regardless of timepoint. Analyses of diffusion-weighted imaging indicated a significant diagnosis × time interaction with a steeper decline in white matter integrity of the superior longitudinal fasciculus over time in participants with MDD than in healthy controls (ptfce-FWE=0·026, sr2=0·002). Furthermore, cognitive decline was robustly associated with the decline in white matter integrity over time across both groups (ptfce-FWE<0·0001, sr2=0·004). In participants with MDD, changes in white matter integrity (p=0·0040, β=0·071) and adverse depressive disease course (p=0·0022, β=-0·073) independently predicted lower cognitive performance at follow-up. Alterations of white matter integrity occurred over time to a greater extent in participants with MDD than in healthy controls, and decline in white matter integrity was associated with a decline in cognitive performance across groups. Our findings emphasise the crucial role of white matter microstructure and disease progression in depression-related cognitive dysfunction, making both priority targets for future treatment development. German Research Foundation (DFG).

Intrusive thoughts and memories in adolescents with major depressive disorder or post-traumatic stress disorder.

Research in adults suggests that intrusive memories and intrusive thoughts (often referred to as intrusive cognitions) are common in members of the general population and are often seen in clinical disorders. However, little is known about the experience of intrusive cognitions in adolescents, particularly in adolescents with major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). The present study sought to gather fundamental data on these phenomena (i.e., frequency, characteristics and appraisals of intrusive cognitions) in adolescents with MDD and PTSD. Adolescents aged 11-18 with MDD (n = 11), PTSD (n = 13) and a non-clinical control group (n = 25) completed structured interviews concerning their intrusive memories and thoughts. Intrusive thoughts were common in all three groups but were particularly frequently experienced in the MDD group. Intrusive memories were expectedly very common in the PTSD group but also experienced by over half of the adolescents with MDD. Both clinical groups reported more negative emotions in response to their intrusive thoughts or memories and appraised these cognitions more negatively than the non-clinical group. Intrusive memories and thoughts are common experiences in adolescents with MDD and PTSD. Emotions and appraisals relating to these cognitions may be targets for psychological intervention in this age group. However, small sample sizes limit the conclusions that can be drawn. Replication is needed with larger numbers of clinical participants.

Risk of subsequent Parkinson's disease among patients with bipolar disorder or major depression: A nationwide longitudinal study in Taiwan.

Bipolar disorder (BD) and major depression have been associated with an increased risk of developing Parkinson's disease (PD); however, few studies have directly compared the risk of PD development between patients with BD and major depression while considering relevant risk factors and psychotropic medications. Using the Taiwan National Health Insurance Research Database, 21,186 patients with BD, 21,188 patients with major depression, and 42,374 controls were enrolled between 2001 and 2009, and followed until the end of 2011. Individuals who developed PD during the follow-up period were identified. Cox regression models were used to analyze the hazard ratio (HR) of developing PD, adjusting for demographic factors, comorbidities, and psychotropic medication usage. Both patients with BD [HR 8.63, 95% confidence interval (CI) 6.35-11.72] and those with major depression (HR 5.68, 95% CI 4.15-7.78) had an elevated risk of subsequent PD compared to the controls. Patients with BD were associated with a 51% increased risk of subsequent PD compared with patients with major depression. Long-term treatment with antiepileptic mood stabilizers was associated with increased PD risk among patients with late-onset BD and high Charlson comorbidity index scores. Lithium was not associated with an increased PD risk. The study highlights an elevated PD risk in patients with BD and major depression compared to the controls, with BD patients at highest risk. Further research is needed to elucidate the complex interplay between psychotropic medications and neurodegenerative processes in BD, aiming to optimize therapeutic strategies and improve patient outcomes.

Evaluating the Efficacy of Telehealth-Based Treatments for Depression in Adults: A Rapid Review and Meta-Analysis.

Major depressive disorder (MDD) is one of the leading causes of work-related disability, and accessing telehealth therapies can be a promising modality for workers with MDD. Barriers to accessing in-person mental healthcare, such as limited availability and accessibility in rural and remote communities, financial constraints, and stigma, have highlighted the need for alternative approaches like telehealth. This study investigated the efficacy of telehealth interventions including CBT for adults over 18 diagnosed with MDD. This rapid review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to ensure a transparent methodology. Out of the 2549 studies screened, 19 were incorporated into the rapid review, and of those, 10 were included in the subsequent meta-analyses. Articles were screened independently by two reviewers, with the disagreements reconciled through discussion. A reviewer extracted data from eligible articles. Descriptive statistics and narrative syntheses were used to describe outcomes. Two meta-analyses were conducted to investigate the efficacy of cognitive behavioral therapy (CBT) delivered by telehealth (tCBT). The first compared tCBT to in-person CBT (pCBT). The second meta-analysis compared tCBT to a control group that did not receive CBT or another telehealth-based treatment. Non-CBT interventions investigated within the non-CBT group included somatic rhythm therapy, problem-solving therapy, psychiatry, behavioral activation, and interpersonal psychotherapy. Overall, individuals with MDD who received tCBT showed significant improvement in depression symptoms. However, the efficacy of tCBT compared to non-telehealth control groups varied across studies. The first meta-analysis indicated the magnitudes of effect were similar for both interventions in reducing depression symptoms 0.023 (95% CI -0.120 to 0.166); p = 1.00. In the second meta-analysis, the ratio of means comparing tCBT (0.51 ± 0.14 SD) to the control group (0.68 ± 0.12 SD) exhibited a statistically significant 25% reduction with regard to depression scores (one-sided p = 0.002), favouring tCBT to non-telehealth, non-CBT study groups. Telehealth-based CBT demonstrated positive effects on depression symptoms; it was generally superior when compared to control groups not receiving CBT and was on par with pCBT. The growing mental health burden in the community underscores the need for accessible telehealth services like tCBT. Effective policy formulation and implementation in national health agendas are essential to meet the increasing demand for mental health support.

Disruptions in segregation mechanisms in fMRI-based brain functional network predict the major depressive disorder condition

This study investigates the functional brain network in major depressive disorder using network theory and a consensus network approach. At the macroscopic level, we found significant differences in connectivity measures such as node strength and clustering coefficient, with healthy controls exhibiting higher values. This is consistent with disruptions in functional brain network segregation in patients with major depressive disorder. Consensus network analysis revealed that the central executive and salience networks were predominant in healthy controls, whereas depressed patients showed greater overlap with the default mode network. No differences were found in network efficiency measures, indicating comparable brain network integration between healthy controls and major depressive disorder groups. Importantly, the clustering coefficient emerged as an effective diagnostic biomarker for depression, achieving high sensitivity (90%), specificity (92%), and overall precision (90%). Further analysis at the mesoscale level uncovered unique functional connections distinguishing healthy controls and major depressive disorder groups. Our findings underscore the utility of analyzing functional networks from the macroscale to the mesoscale, and provide insight into overcoming the challenges associated with intersubject variability and the multiple comparisons problem in network analysis.

Glutamatergic Modulators for Major Depression from Theory to Clinical Use.

Major depressive disorder (MDD) is a chronic, burdensome, highly prevalent disease that is characterized by depressed mood and anhedonia. MDD is especially burdensome as approved monoamine antidepressant treatments have weeks-long delays before clinical benefit and low remission rates. In the past 2decades, a promising target emerged to improve patient outcomes in depression treatment: glutamatergic signaling. This narrative review provides a high-level overview of glutamate signaling in synaptogenesis and neural plasticity and the implications of glutamate dysregulation in depression. Based on this preclinical evidence implicating glutamate in depression and the rapid improvement of depression with ketamine treatment in a proof-of-concept trial, a range of N-methyl-D-aspartate (NMDA)-targeted therapies have been investigated. While an array of treatments has been investigated in registered phase 2 or 3 clinical trials, the development of most of these agents has been discontinued. Multiple glutamate-targeted antidepressants are actively in development, and two are approved. Nasal administration of esketamine (Spravato®) was approved by the US Food and Drug Administration (FDA) in 2019 to treat adults with treatment-resistant depression and in 2020 for adults with MDD with acute suicidal ideation or behavior. Oral combination dextromethorphan-bupropion (AXS-05, Auvelity® extended-release tablet) was FDA approved in 2022 for the treatment of MDD in adults. These approvals bolster the importance of glutamate in depression and represent an exciting breakthrough in contemporary psychiatry, providing new avenues of treatment for patients as first-line therapy or with either poor response or unacceptable side effects to monoaminergic antidepressants.

Brain structural associations of syntactic complexity and diversity across schizophrenia spectrum and major depressive disorders, and healthy controls

Deviations in syntax production have been well documented in schizophrenia spectrum disorders (SSD). Recently, we have shown evidence for transdiagnostic subtypes of syntactic complexity and diversity. However, there is a lack of studies exploring brain structural correlates of syntax across diagnoses. We assessed syntactic complexity and diversity of oral language production using four Thematic Apperception Test pictures in a sample of N = 87 subjects (n = 24 major depressive disorder (MDD), n = 30 SSD patients both diagnosed according to DSM-IV-TR, and n = 33 healthy controls (HC)). General linear models were used to investigate the association of syntax with gray matter volume (GMV), fractional anisotropy (FA), axial (AD), radial (RD), and mean diffusivity (MD). Age, sex, total intracranial volume, group, interaction of group and syntax were covariates of no interest. Syntactic diversity was positively correlated with the GMV of the right medial pre- and postcentral gyri and with the FA of the left superior-longitudinal fasciculus (temporal part). Conversely, the AD of the left cingulum bundle and the forceps minor were negatively correlated with syntactic diversity. The AD of the right inferior-longitudinal fasciculus was positively correlated with syntactic complexity. Negative associations were observed between syntactic complexity and the FA of the left cingulum bundle, the right superior-longitudinal fasciculus, and the AD of the forceps minor and the left uncinate fasciculus. Our study showed brain structural correlates of syntactic complexity and diversity across diagnoses and HC. This contributes to a comprehensive understanding of the interplay between linguistic and neural substrates in syntax production in psychiatric disorders and HC.

Depressive symptoms and quality of life in patients with benign essential blepharospasm under long-term therapy with botulinum toxin.

Regular and long-term injections of botulinum toxin (BoNT) are considered the first line therapy for essential blepharospasm (BEB), but no data exists on the long-term effect of this therapy on depressive symptoms and quality of life. This study aims to prospectively evaluate the long-term effects of BoNT therapy on depressive symptoms as well as on daily activities, emotional well-being and quality of life using validated questionnaires (BEB-scale, Beck`s Depression Inventory (BDI)). 86 patients diagnosed with BEB were followed up for a median of 4 years. Clinical symptoms improved significantly after BoNT-injections. Everyday activities and subjective assessment of the overall situation improved gradually under long-term BoNT therapy. Significant correlations (p < 0.0001; r-values between 0.498 and 0.706) were found between the BDI and items of the BEB-scale. No significant antidepressive effect of long-term BoNT therapy was found with a low median BDI total score (5/max. 63), but up to 31.3% of BEB patients had a BDI score ≥ 11, indicating clinically relevant depressive symptoms. Of these, 65.4% had no known history of depression. Although, several studies reported an antidepressant effect of botulinum toxin injections in patients with major depression, this effect does not seem to be present in patients with BEB despite clinical improvement of symptoms. A high prevalence of previously undetected depressive symptoms was found in BEB patients. As this may influence BoNT therapy success, identifying potential depressive symptoms at the time of BEB diagnosis and initiating appropriate treatment seems important.

Multilevel hybrid handcrafted feature extraction based depression recognition method using speech

Background and purposeDiagnosis of depression is based on tests performed by psychiatrists and information provided by patients or their relatives. In the field of machine learning (ML), numerous models have been devised to detect depression automatically through the analysis of speech audio signals. While deep learning approaches often achieve superior classification accuracy, they are notably resource-intensive. This research introduces an innovative, multilevel hybrid feature extraction-based classification model, specifically designed for depression detection, which exhibits reduced time complexity. Materials and methodsMODMA dataset consisting of 29 healthy and 23 Major depressive disorder audio signals was used. The constructed model architecture integrates multilevel hybrid feature extraction, iterative feature selection, and classification processes. During the Hybrid Handcrafted Feature (HHF) generation stage, a combination of textural and statistical methods was employed to extract low-level features from speech audio signals. To enhance this process for high-level feature creation, a Multilevel Discrete Wavelet Transform (MDWT) was applied. This technique produced wavelet subbands, which were then input into the hybrid feature extractor, enabling the extraction of both high and low-level features. For the selection of the most pertinent features from these extracted vectors, Iterative Neighborhood Component Analysis (INCA) was utilized. Finally, in the classification phase, a one-dimensional nearest neighbor classifier, augmented with ten-fold cross-validation, was implemented to achieve detailed, results. ResultsThe HHF-based speech audio signal classification model attained excellent performance, with the 94.63 % classification accuracy. ConclusionsThe findings validate the remarkable proficiency of the introduced HHF-based model in depression classification, underscoring its computational efficiency.

Effectiveness of 8-week TReatment with vortioxetine on depressive symptoms in major depressive disorder patients with comorbid generalized anxiety disorder in UAE (TRUE)

BackgroundMajor Depressive Disorder (MDD) is a leading cause of disability and results in excessive utilization of healthcare resources worldwide. The Middle East and North Africa (MENA) region shows a high prevalence of depressive disorders. Generalized Anxiety Disorder (GAD) and MDD have the highest rate of comorbidity of all mood and anxiety disorders, ranging from 40 to 98% in drug studies. Comorbid GAD results in more significant impairment in MDD and increases the severity of symptoms. Although several clinical trials supported the safety and effectiveness of vortioxetine, no data regarding these aspects has been revealed in the MENA region. This study aimed to assess the safety and efficacy of vortioxetine in patients with comorbid GAD in the United Arab Emirates (UAE).MethodIn a multicenter observational study, 118 patients with confirmed anxiety and depressive disorders were evaluated over four visits (baseline visit, two weeks, four weeks, and eight weeks) using MADRS and HAM-A scales to assess depression and anxiety severity, respectively by calculating mean change and the percent using Kendall’s W test.ResultsA significant mean difference in MADRS score was observed, with a gradual decrease of mean MADRS total scores over the assessment weeks (p < 0.001) as well as in HAM-A scores, from severe to moderate-severe anxiety through the four visits (p < 0.001). Furthermore, only one case was reported as a serious side effect. Nausea and insomnia were the most predominant side effects reported among the studied population.ConclusionVortioxetine was found effective and safe among patients with MDD and comorbid GAD.

Glucocorticoids induce HMGB1 release in primary cultured rat cortical microglia

Stress, a risk factor for major depressive disorder and Alzheimer disease, leads to the release of high-mobility group box-1 (HMGB1) protein, which in turn causes neuroinflammation. The mechanism underlying stress-induced HMGB1 release is unknown, but stress-associated glucocorticoids could be involved. Primary cultured rat cortical microglia and neurons were treated with corticosterone, a stress-associated glucocorticoid, and HMGB1 release was measured by ELISA and western blotting to test this hypothesis. With corticosterone treatment, significant HMGB1 was released in microglia but not in neuronal cell cultures. HMGB1 mRNA expression and HMGB1 protein expression in microglia were not affected by corticosterone treatment. Thus, the source of extracellular HMGB1 released into the medium is likely to be existing nuclear HMGB1 rather than newly synthesized HMGB1. Corticosterone-induced HMGB1 release in microglia culture was significantly attenuated by blocking glucocorticoid receptors but not mineralocorticoid receptors. Dexamethasone, a selective glucocorticoid receptor agonist, and dexamethasone-bovine serum albumin (BSA), a membrane-impermeable glucocorticoid receptor agonist used to confirm the membrane receptor-mediated effects of glucocorticoids, increased the release of HMGB1. Immunocytochemistry showed that HMGB1 translocated from the nucleus to the cytoplasm following dexamethasone or dexamethasone-BSA treatment through glucocorticoid receptors. The present findings suggest that glucocorticoids stimulate microglial membrane glucocorticoid receptors and trigger cytoplasmic translocation and extracellular release of nuclear HMGB1. Thus, under stress conditions, glucocorticoids induce microglial HMGB1 release, leading to a neuroinflammatory state that could mediate neurological disorders.

Suicidality Is Most Centrally Situated Within Network of Depression Symptom Criteria in Unipolar Depression Patients With Mood Stabilizer in Asia

Lithium and mood stabilizers are considered effective augmentation agents of antidepressants for treatment-resistant depression. Thus, this study aimed to estimate the network structure of depression symptom criteria among unipolar depression patients with mood stabilizers, using data from the Research on Asian Psychotropic Prescription Patterns for mood stabilizers (REAP-MS). We estimated a network of the 9 depression symptom criteria among 411 unipolar depression patients in Asia. Each of the depression symptom criteria was considered to be a dichotomous categorical variable. Suicidality (suicidal ideation or attempt) was the most centrally situated within the network of depression symptoms, followed by depressed mood, loss of energy, anhedonia and weight loss or gain. Contrastingly, concentration problem was the least interconnected. The depression symptom criteria were organized into 4 clusters by the community detection method. The findings suggest that suicidality may be one of the significant therapeutic target symptoms in unipolar depression patients with mood stabilizers.

A self-help mobile messaging intervention to improve subthreshold depressive symptoms among older adults in a socioeconomically deprived region of Brazil (PRODIGITAL): a pragmatic, two-arm randomised controlled trial

Subthreshold depression is a risk factor for major depression and is associated with increased morbidity and mortality, especially in older adults. There is emerging evidence that digital interventions, including self-help interventions, may reduce depressive symptoms. We aimed to evaluate the effectiveness of a mobile messaging intervention at reducing subthreshold depressive symptoms among older adults in Brazil. PRODIGITAL was a single blind, two-arm, individually randomised controlled trial conducted in 46 primary care clinics in the city of Guarulhos, Brazil. Individuals aged 60+ years were contacted by phone following a randomly ordered list for a screening assessment. Those who presented with anhedonia and/or depressed mood (Patient Health Questionnaire (PHQ)-2≥1), and who subsequently scored between 5 and 9 on the PHQ-9 were invited to participate. The intervention arm received the 'Viva Vida' digital self-help intervention consisting of automated multi-media messages sent via WhatsApp. Forty-eight audio and visual messages based on psychoeducation and behavioural activation were automatically delivered over six weeks. The control arm received a single message containing information about depression. The primary outcome was the difference in mean PHQ-9 scores between treatment arms at the three-month follow-up. All primary analyses were performed according to allocated arm with imputed data. The trial is registered with ReBEC, RBR-6c7ghfd. Participants were recruited between 8 September 2021 and 19 August 2022. Of the 454 participants enrolled, 223 were randomised to the intervention arm, 231 to the control arm. Participants' mean age was 65.3 years (SD 5.0) and 64.0% (n=292) were female. A total of 385 (84.8%) completed the three-month follow-up assessment; no difference in mean PHQ-9 scores between the treatment arms was observed (adjusted difference:-0.61; 95% CI:-1.75, 0.53; p=0.29). These results demonstrate that the Viva Vida digital self-help intervention did not help to improve subthreshold depressive symptoms amongst older adults. Further research is needed to understand why this self-help intervention was not effective in this population, and to explore how it might be adapted to achieve this goal. São Paulo Research Foundation and UK Joint Global Health Trials.

Voice-Based Screening May Predict Risk of Major Depression

Voice-Based Screening May Predict Risk of Major Depression

Predictive Value of Inflammatory Biomarkers in Assessing Major Depression in Adults

Background: There are studies that have investigated the association of pro-inflammatory cytokines with depressive disorders, but they often present certain limitations. In this study, two substantial groups of patients were analyzed: 92 patients with major depressive disorder and 76 without depressive disorders. The strict inclusion and exclusion criteria for the analyzed groups significantly increased the value of the obtained results. The research question of this study was whether levels of inflammation, measured by the inflammatory markers IL-6, IL-1α, and TNF-α, could predict the severity of depressive symptoms. This could provide additional evidence supporting the hypothesis that inflammation plays a notable role in the pathogenesis of depression. The data analysis supports the hypothesis that the biological mechanisms of inflammation contribute to the clinical manifestations of depression. Elevated levels of inflammatory markers, especially interleukins (IL-6, IL-1α) and tumor necrosis factor-alpha (TNF α), have been identified in patients with major depressive disorder compared to the findings in healthy controls. Materials and Methods: Inflammatory markers (IL-6, IL-1α, and TNF-α) were measured in a sample of 92 patients hospitalized at the Socola Institute of Psychiatry in Iasi, Romania, and compared to a control group with no depression or inflammatory conditions (n = 76). Severity of depressive symptoms was assessed using HAM-D scores. Results: The study results indicated that values of plasma inflammatory markers were significantly higher in patients with major depressive disorder (MDD) compared to the control group (IL-1α: 1.16 ± 0.44 pg/mL vs. 0.89 ± 0.25 pg/mL, p = 0.0004; IL-6: 9.21 ± 4.82 pg/mL vs. 7.16 ± 4.32 pg/mL, p = 0.0149; and TNF-α: 2.02 ± 0.96 pg/mL vs. 1.67 ± 0.8 pg/mL, p = 0.0286). The differences remained significant after applying logarithmic transformation, which was necessary to adjust for outlier values. An analysis of demographic characteristics showed that the frequency of women (67.4% vs. 36.84%, p &lt; 0.001), cohabiting individuals (28.26% vs. 10.53%, p = 0.0001), and alcohol consumers (67.39% vs. 47.37%, p = 0.0087) was significantly higher in patients with MDD. The level of education was significantly lower in patients with MDD (median (IQR): 12 (2.5) years vs. 14 (8) years, p = 0.0016). The evaluation of confounding variables, including patients’ gender, marital status, education level, and alcohol consumption, was performed using multiple linear regression models. The results indicated that these demographic variables did not significantly influence the correlation between the HAM-D score and the values of IL-6, IL-1α, and TNF-α. A significant correlation between the HAM-D score and the logarithmic values of inflammatory markers was observed for log IL-1α in men (r = 0.355, p = 0.0014), log IL-6 in women (r = 0.0313, p = 0.0027), and log TNF-α in women (r = 0.3922, p = 0.0001). The results of the multiple linear regression and predictive analysis indicated that IL-1α (AUC = 0.677, p = 0.0004), IL-6 (AUC = 0.724, p &lt; 0.001), and TNF-α (AUC = 0.861, p &lt; 0.001) demonstrate high accuracy in discriminating patients with MDD. Conclusions: The results highlighted that IL-6 (AUC = 0.724; 95% CI: 0.648–0.801) and TNF-α (AUC = 0.861; 95% CI: 0.797–0.925) are significant predictors for major depressive disorder. The study highlights the potential of cytokines (IL-1α, IL-6 and TNF-α) as diagnostic markers. These findings support the hypothesis that inflammation may play an important role in the development or exacerbation of depressive symptoms.

CYP2C19 Genetic Variants and Major Depressive Disorder: A Systematic Review

Major depressive disorder (MDD) affects over 300 million people globally and has a multifactorial etiology. The CYP2C19 enzyme, involved in metabolizing certain antidepressants, can influence treatment response. Following the PRISMA protocol and PECOS strategy, this systematic review assessed the variation in common CYP2C19 gene variants’ frequencies across populations with MDD, evaluating their impact on clinical characteristics and treatment response. We comprehensively searched five databases, identifying 240 articles, of which only nine within the last decade met our inclusion criteria. Except for one study that achieved 74.28% of STROPS items, the rest met at least 75% of GRIPS and STROPS guidelines for quality and bias risk assessment. The CYP2C19’s *1 allele, the *1/*1 genotype, and the NM phenotype, considered as references, were generally more frequent. Other CYP2C19 polymorphism frequencies exhibit significant variability across different populations. Some studies associated variants with MDD development, a more extended history of depression, prolonged depressive episodes, and symptom severity, while others reported no such association. Some studies confirmed variants’ effects on escitalopram and citalopram metabolism but not that of other drugs, such as sertraline, venlafaxine, and bupropion. Treatment tolerability and symptom improvement also varied between studies. Despite some common findings, inconsistencies highlight the need for further research to clarify the role of these polymorphisms in MDD and optimize treatment strategies.

Molecular signature underlying (R)-ketamine rapid antidepressant response on anhedonic-like behavior induced by sustained exposure to stress.

Anhedonia induced by sustained stress exposure is a hallmark symptom of major depressive disorder (MDD) and in rodents, it can be accessed through the sucrose preference test (SPT). (R)-ketamine is a fast-acting antidepressant with less detrimental side effects and abuse liability compared to racemic ketamine. The present study combined high-throughput proteomics and network analysis to identify molecular mechanisms involved in chronic variable stress (CVS)-induced anhedonia and promising targets underlying (R)-ketamine rapid antidepressant response. Male Wistar rats were subjected to CVS for five weeks. Based on the SPT, animals were clustered into resilient or anhedonic-like (ANH) groups. ANH rats received a single dose of saline or (R)-ketamine (20 mg/kg, i.p.), which was proceeded by treatment response evaluation. After prefrontal cortex collection, proteomic analysis was performed to uncover the differentially expressed proteins (DEPs) related to both anhedonic-like behavior and pharmacological response. The behavioral assessment showed that the ANH animals had a significant decrease in SPT, and that (R)-ketamine responders showed a reversal of anhedonic-like behavior. On a molecular level, anhedonia-like behavior was associated with the downregulation of Neuronal Pentraxin Receptor (Nptxr) and Galectin-1 (Gal-1). These data reinforce a disruption in the inflammatory response, neurotransmitter receptor activity, and glutamatergic synapses in chronic stress-induced anhedonia. (R)-ketamine response-associated DEPs included novel potential targets involved in the modulation of oxidative stress, energetic metabolism, synaptogenesis, dendritic arborization, neuroinflammation, gene expression, and telomere length, converging to biological themes extensively documented in MDD physiopathology. Our data provide valuable insights into the molecular mechanisms underlying the response to (R)-ketamine and highlight these pathways as potential therapeutic targets for anhedonia. By addressing proteins involved in oxidative stress, energy metabolism, synaptogenesis, dendritic arborization, neuroinflammation, gene expression, and telomere length, we can target multiple key factors involved in the pathophysiology of MDD. Modulating these proteins could open avenues for novel therapeutic strategies and deepen our understanding of anhedonia, offering hope for improved outcomes in individuals facing this challenging condition. However, additional studies will be essential to validate these findings and further explore their therapeutic implications.