Depressive Disorder Research Articles

Machine learning-optimized non-invasive brain stimulation and treatment response classification for major depression

Background/ObjectivesTranscranial direct current stimulation (tDCS) is a non-invasive brain stimulation intervention that shows promise as a potential treatment for depression. However, the clinical efficacy of tDCS varies, possibly due to individual differences in head anatomy affecting tDCS dosage. While functional changes in brain activity are more commonly reported in major depressive disorder (MDD), some studies suggest that subtle macroscopic structural differences, such as cortical thickness or brain volume reductions, may occur in MDD and could influence tDCS electric field (E-field) distributions. Therefore, accounting for individual anatomical differences may provide a pathway to optimize functional gains in MDD by formulating personalized tDCS dosage.MethodsTo address the dosing variability of tDCS, we examined a subsample of sixteen active-tDCS participants’ data from the larger ELECT clinical trial (NCT01894815). With this dataset, individualized neuroimaging-derived computational models of tDCS current were generated for (1) classifying treatment response, (2) elucidating essential stimulation features associated with treatment response, and (3) computing a personalized dose of tDCS to maximize the likelihood of treatment response in MDD.ResultsIn the ELECT trial, tDCS was superior to placebo (3.2 points [95% CI, 0.7 to 5.5; P = 0.01]). Our algorithm achieved over 90% overall accuracy in classifying treatment responders from the active-tDCS group (AUC = 0.90, F1 = 0.92, MCC = 0.79). Computed precision doses also achieved an average response likelihood of 99.981% and decreased dosing variability by 91.9%.ConclusionThese findings support our previously developed precision-dosing method for a new application in psychiatry by optimizing the statistical likelihood of tDCS treatment response in MDD.

Sexual Trauma, Polygenic Scores, and Mental Health Diagnoses and Outcomes

Leveraging real-world clinical biobanks to investigate the associations between genetic and environmental risk factors for mental illness may help direct clinical screening efforts and evaluate the portability of polygenic scores across environmental contexts. To examine the associations between sexual trauma, polygenic liability to mental health outcomes, and clinical diagnoses of schizophrenia, bipolar disorder, and major depressive disorder in a clinical biobank setting. This genetic association study was conducted using clinical and genotyping data from 96 002 participants across hospital-linked biobanks located at Vanderbilt University Medical Center (VUMC), Nashville, Tennessee (including 58 262 individuals with high genetic similarity to the 1000 Genomes Project [1KG] Northern European from Utah reference population [1KG-EU-clustered] and 11 047 with high genetic similarity to the 1KG African-ancestry reference population of Yoruba in Ibadan, Nigeria [1KG-YRI-clustered]), and Mass General Brigham (MGB), Boston, Massachusetts (26 693 individuals with high genetic similarity to the combined European-ancestry superpopulation [1KG-EU-clustered]). Clinical data analyzed included diagnostic billing codes and clinical notes spanning from 1976 to 2023. Data analysis was performed from 2022 to 2024. Clinically documented sexual trauma disclosures and polygenic scores for schizophrenia, bipolar disorder, and major depressive disorder. Diagnoses of schizophrenia, bipolar disorder, and major depressive disorder, determined by aggregating related diagnostic billing codes, were the dependent variables in logistic regression models including sexual trauma disclosure status, polygenic scores, and their interactions as the independent variables. Across the VUMC and MGB biobanks, 96 002 individuals were included in analyses (VUMC 1KG-EU-clustered: 33 011 [56.7%] female; median [range] age, 56.8 [10.0 to >89] years; MGB 1KG-EU-clustered: 14 647 [54.9%] female; median [range] age, 58.0 [10.0 to >89] years; VUMC 1KG-YRI-clustered: 6961 [63.0%] female; median [range] age, 44.6 [10.1 to >89] years). Sexual trauma history was associated with all mental health conditions across institutions (ORs ranged from 8.83 [95% CI, 5.50-14.18] for schizophrenia in the VUMC 1KG-YRI-clustered cohort to 17.65 [95% CI, 12.77-24.40] for schizophrenia in the VUMC 1KG-EU-clustered cohort). Sexual trauma history and polygenic scores jointly explained 3.8% to 8.8% of mental health phenotypic variance. Schizophrenia and bipolar disorder polygenic scores had greater associations with mental health outcomes in individuals with no documented disclosures of sexual trauma (schizophrenia interaction: OR, 0.70 [95% CI, 0.56-0.88]; bipolar disorder interaction: OR, 0.83 [95% CI, 0.74-0.94]). Sexual trauma and mental health polygenic scores, while correlated with one another, were independent and joint risk factors for severe mental illness in a large, diverse hospital biobank population. Furthermore, associations of schizophrenia and bipolar disorder polygenic scores with respective diagnoses were greater in those without disclosures, suggesting that genetic predisposition to mental illness as measured by polygenic scores may be less impactful in the presence of this severe environmental risk factor.

Challenges and Opportunities in Managing Geriatric Depression: The Role of Personalized Medicine and Age-Appropriate Therapeutic Approaches

The global aging population has experienced rapid growth in recent decades, leading to an increased prevalence of psychiatric disorders, particularly depression, among older adults. Depression in the geriatric population is often compounded by chronic physical conditions and various psychosocial factors, significantly impacting their quality of life. The main question raised in this review is as follows: how can personalized medicine and age-appropriate therapeutic approaches improve the management of geriatric depression? This paper explores the epidemiology of geriatric depression, highlighting the influence of gender, race, and socioeconomic status on its prevalence. The classification and diagnosis of geriatric depressive disorders, based on ICD-11 and DSM-5 criteria, reveal the complexity of managing these conditions in older adults. Personalized medicine (PM) emerges as a promising approach, focusing on tailoring treatments to the individual’s genetic, clinical, and environmental characteristics. However, the application of PM in this demographic faces challenges, particularly in the context of pharmaceutical forms. The need for age-appropriate drug delivery systems is critical, given the prevalence of polypharmacy and issues such as dysphagia among the older patients. This study emphasizes the importance of developing patient-centric formulations to enhance the effectiveness of personalized therapy in geriatric patients.

Psychiatric symptom profiles of inpatient refugees in Egypt: insights from a single center study

BackgroundThe global surge in refugee populations has sparked considerable apprehension regarding their mental health. This study explores the symptom profile and associated factors among refugee patients admitted to Okasha Institute of Psychiatry, Ain Shams University, hospitals between 2018 and 2021.MethodsA retrospective analysis was conducted utilizing the medical records of refugee patients admitted to Okasha Institute of Psychiatry between 2018 and 2021. Data collection encompassed socio-demographic characteristics, diagnoses, reported stressors, and specific symptom profiles.ResultsThe study involved 36 refugee patients, averaging 26.7 years, predominantly female (61.1%), and predominantly of Sudanese origin (45.9%). Prevalent diagnoses included bipolar disorder (36.8%), schizophrenia (26.3%), and major depressive disorder (13.2%). A diverse array of stressors emerged, with immigration-related issues ranking highest (21.2%). Other noteworthy stressors comprised marital conflicts (15.2%) and house-related difficulties (15.2%).ConclusionThis study highlighted the prevalence of severe mental illnesses, varied stressors, and distinct symptom profiles in refugees with psychiatric admissions and underscored the imperative for culturally sensitive and trauma-informed mental health services. Further research is imperative to devise effective interventions and enhance the mental health outcomes of refugee populations.

Plasma Brain-Derived Neurotrophic Factor (BDNF) Levels and BDNF Promoters’ DNA Methylation in Workers Exposed to Occupational Stress and Suffering from Psychiatric Disorders

Introduction: Decreased plasma BDNF (pBDNF) levels have been proposed as a biomarker in the illness phases of mood disorders. This cross-sectional study aimed to evaluate the pBDNF and BDNF promoters’ DNA methylation levels in workers exposed to occupational stress and suffering from work-related stress disorders. Methods: the pBDNF and BDNF exon I and IV promoters’ methylation levels were measured by specific immunoassays and methylation-sensitive high-resolution melting (MS-HRM) in 62 patients with adjustment disorders (AD), 79 patients with major depressive disorder (MDD) and 44 healthy controls. Occupational stress was evaluated in the patients and controls using the Job Content Questionnaire (JCQ). Results: the pBDNF levels were significantly higher in the MDD (p < 0.001) and AD (p < 0.0001) patients than in the controls. The MDD patients showed significantly lower pBDNF levels than the AD ones (p = 0.01). The BDNF exon I and IV promoters’ methylation levels were significantly higher in the MDD patients than in the AD ones (exon I promoter: p = 0.0001, exon IV promoter: p < 0.0001) and controls (exon I promoter: p = 0.0001, exon IV promoter: p < 0.0001). In the patients, but not in the controls, the BDNF promoters’ methylation levels showed significant negative correlations with occupational stress. Conclusions: BDNF could play a key role in the pathophysiology of stress-related disorders and the peripheral elevation of it observed in patients exposed to occupational stress could suggest a protective mechanism for neurons from stress-mediated damage. The elevation of the pBDNF levels, even in MDD, may characterize a “reactive” subtype of depressive episode, while the significant elevation of the BDNF promoters’ methylation levels in depressed patients could indicate a predisposition to more severe illness under stress. Further research is needed, focusing on biomarkers for stress-related disorders as a potential tool for the diagnosis and prevention of occupational diseases.

Prevalence of central nervous system-active polypharmacy in a cohort of older adults in Argentina.

Central nervous system (CNS)-active polypharmacy is frequent and potentially harmful in older patients. Data on its burden outside the USA and European countries remain limited. To estimate the period prevalence of and factors associated with out-of-hospital CNS-active polypharmacy in older adults. We used data from a cohort of out-patients aged ≥60 years affiliated to the Hospital Italiano de Buenos Aires' health maintenance organisation on 1 January 2021. A CNS-active polypharmacy event was defined as the concurrent exposure to ≥3 CNS-active medications (i.e. antidepressants, anti-epileptics, antipsychotics, benzodiazepines, Z-drugs and opioids) through filled out-of-hospital prescriptions. We calculated the period prevalence of CNS-active polypharmacy for 2021. We identified factors associated with CNS-active polypharmacy using a multivariable logistic regression model to estimate odds ratios and 95% confidence intervals (CI). We included 63 857 patients. Pre-existing mental health diagnoses included anxiety (21%), depressive (14%) and sleep (11%) disorders. CNS-active polypharmacy occurred in 4535 patients, for a period prevalence of 7.1% (95% CI: 6.9-7.3%). The combination of an antidepressant, an antipsychotic and a benzodiazepine accounted for 21% of the CNS-active polypharmacy events. Frontotemporal dementia (odds ratio: 14.67; 95% CI: 4.47-48.20), schizophrenia (odds ratio: 7.93; 95% CI: 4.64-13.56), bipolar disorder (odds ratio: 7.20; 95% CI: 5.45-9.50) and depressive disorder (odds ratio: 3.50; 95% CI: 3.26-3.75) were associated with CNS-active polypharmacy. One in 14 adults aged 60 years and older presented out-of-hospital CNS-active polypharmacy. Future studies should evaluate measures to reduce CNS-active medication use in this population.

Gendered socio-economic and mental health effects of the COVID-19 pandemic among adults living in selected informal settlements in Kenya: an intersectional analysis

BackgroundCOVID-19 pandemic had devastating socio-economic and health effects, including mental health. This study examines the intersectionality between gender and mental health outcomes among Kenyan adults in informal settlements of Nairobi, Kisumu, and Kilifi Counties during the COVID-19 crisis. This is necessary to inform mental health response in case of another pandemic.MethodsWe analyzed data collected in a longitudinal survey between July 2020 (fourth round) and February 2021 (fifth round). The data covered COVID-19-related effects on job loss, food insecurity, access to health services, and mental health. Participants were randomly sampled from existing cohorts at the Population Council. The outcomes of interest were depressive and anxiety disorders, combined into a binary composite outcome variable. Descriptive statistics included means for continuous variables and frequencies and proportions for categorical variables. Chi-square tests were used to examine the differences between groups. The relationship between the gendered COVID-19 socio-economic effects and participants’ mental health was examined using modified Poisson regression.ResultsA total of 4,050 participants were interviewed, 66% female and median age 38 [interquartile range (IQR): 29–46]. Complete income loss was strongly associated with negative mental health outcomes in multiple intersections with varied magnitudes. The association was larger among older females (≥50 years) (PR = 1.33, 95% CI = 1.17–1.51, p < 0.001) than older males (PR = 1.22, 95% CI = 1.17–1.27, p < 0.001). Partial loss of income was protective against negative mental health outcomes among young males (18–29 years) (PR = 0.81, 95% CI = 0.76–0.87, p < 0.001) but linked to negative outcomes among middle-aged males (30–49 years old) (PR = 1.14, 95% CI = 1.12–1.16, p < 0.001). Skipping meals was associated with negative mental health outcomes for both genders particularly the married (married male: PR = 1.49, 95% CI = 1.22–1.83, p < 0.001; married female: PR = 1.42, 95% CI = 1.26–1.60, p < 0.001).ConclusionWe observed significant gender differences in the prevalence of depressive symptoms and anxiety disorders during the COVID-19 pandemic, underscoring the importance of socio-economic factors and health services access in shaping mental health outcomes. Interventions targeting pandemic-related mental health issues should be gender-sensitive and address economic vulnerabilities such as job losses and food insecurity. Policies to mitigate these effects, especially for at-risk groups are crucial for reducing mental health burden in future crises.

Omega-3 Fatty Acids and Neuroinflammation in Depression: Targeting Damage-Associated Molecular Patterns and Neural Biomarkers

Major Depressive Disorder (MDD) is a prevalent mental health condition with a complex pathophysiology involving neuroinflammation, neurodegeneration, and disruptions in neuronal and glial cell function. Microglia, the innate immune cells of the central nervous system, release inflammatory cytokines in response to pathological changes associated with MDD. Damage-associated molecular patterns (DAMPs) act as alarms, triggering microglial activation and subsequent inflammatory cytokine release. This review examines the cellular mechanisms underlying MDD pathophysiology, focusing on the lipid-mediated modulation of neuroinflammation. We explore the intricate roles of microglia and astrocytes in propagating inflammatory cascades and discuss how these processes affect neuronal integrity at the cellular level. Central to our analysis are three key molecules: High Mobility Group Box 1 (HMGB1) and S100 Calcium Binding Protein β (S100β) as alarmins, and Neuron-Specific Enolase (NSE) as an indicator of neuronal stress. We present evidence from in vitro and ex vivo studies demonstrating how these molecules reflect and contribute to the neuroinflammatory milieu characteristic of MDD. The review then explores the potential of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) as neuroinflammation modulators, examining their effects on microglial activation, cytokine production, and neuronal resilience in cellular models of depression. We critically analyze experimental data on how ω-3 PUFA supplementation influences the expression and release of HMGB1, S100β, and NSE in neuronal and glial cultures. By integrating findings from lipidomic and cellular neurobiology, this review aims to elucidate the mechanisms by which ω-3 PUFAs may exert their antidepressant effects through modulation of neuroinflammatory markers. These insights contribute to our understanding of lipid-mediated neuroprotection in MDD and may inform the development of targeted, lipid-based therapies for both depression and neurodegenerative disorders.

Feasibility of a multifaceted nutrition-risk screening tool for mental health settings: the NutriMental screener.

People living with mental illness report a broad spectrum of nutrition risks, beyond malnutrition, but appropriate and adequately validated nutrition risk screening tools for mental health settings are lacking. This study aimed to develop a nutrition-risk screening tool, the NutriMental Screener, and to perform preliminary feasibility and validity testing. In an international, stakeholder engaging approach, a multifaceted nutrition-risk screening tool for mental health services was developed by means of workshops with international stakeholders and two online surveys. Feasibility of the NutriMental screener was tested as part of a research study in Switzerland with 196 participants, evenly distributed across the three study groups (sixty-seven outpatients and sixty-five inpatients with psychotic or depressive disorders as well as sixty-four controls without mental illness). The NutriMental screener consists of ten items covering different nutritional issues that indicate the need for referral to a dietitian or clinical nutritionist. Almost all patients (94·7 %) reported at least one nutrition risk by means of the NutriMental screener. Prevalence for nutrition risks via NutriMental screener was higher in patients than in controls. Almost every second patient expressed a desire for nutritional support (44·7 %). After further validity testing is completed, there is the potential for the NutriMental Screener to replace malnutrition screening tools as routine screening in various mental health settings aiming to organise nutritional therapy prescriptions in a more targeted and efficient manner.

EFFECTIVENESS OF AN ALTERNATIVE PROTOCOL TO FACE SUBSTANCE USE DISORDER AND SYMPTOMS OF COMORBID DEPRESSION

Introduction: There is scarcity of studies in the national and international literature on alternative protocols to pharmacological and psychotherapeutic intervention for the treatment of Substance Use Disorder (SUD) and symptoms of comorbid depression. This study aimed to develop a protocol based on alternative therapies through mindfulness meditation, reiki, acupuncture and auriculotherapy to improve substance use problems and symptoms of comorbid depression. Method: This is a randomized single-blind controlled study. The final sample consisted of 18 participants randomized divided into two groups of nine participants: experimental and control. Participants were evaluated by four validated instruments during the screening process and after the intervention. The instruments were: Beck Depression Scale (BDI), Depression, Anxiety and Stress Scale (DASS-21), Alcohol Use Disorders Identification Test (AUDIT), Drug Abuse Screening Test (DAST-10) and Brazilian Economic Classification Criteria (CCEB). Results: the results of the analysis indicate a significant reduction in the pattern of alcohol consumption (p <0.001); other drugs related problems (p<0.001); symptoms of depression (p<0.001); anxiety (p<0.001) and stress (p<0.001) between the two distinct groups (experimental and control) after the intervention. Conclusion: The protocol proposed in this study was effective in reducing the pattern of problems related to alcohol and other drugs, in addition to being effective in reducing symptoms of depression, stress and anxiety.

Adult mental health outcomes of adolescent depression and co-occurring alcohol use disorder: a longitudinal cohort study

AbstractDepression and alcohol use disorder (AUD) are frequently co-occurring in adolescence, which often goes undetected in routine care. While this may potentially compromise treatment effectiveness and lead to a less favourable long-term prognosis, few longitudinal studies have followed this group into adulthood. The aim of this study was to explore the risk for adult depression, anxiety disorders, suicidality, and AUD in adolescents with concurrent depression and AUD. The study was based on the Uppsala Longitudinal Adolescent Depression Study (ULADS), a Swedish prospective cohort study. Diagnostic interviews were conducted in adolescence (age 16-17) and adulthood (around age 30). Adolescents with concurrent depression and AUD (n = 38) were compared with peers having only depression (n = 189) or neither of the conditions (n = 144). Logistic regression was used to calculate adjusted odds ratios (aORs) with 95% confidence intervals (CIs). Adolescents with concurrent depression and AUD were more likely than their non-affected peers to experience adult depressive episodes (aOR, 5.33; 95% CI, 2.22–12.83), anxiety disorders (4.05; 1.77–9.27), suicidality (5.37; 2.28–12.66), and AUD (7.68; 2.59–22.81). Notably, 34% of adolescents with both depression and AUD subsequently experienced both these conditions as adults, compared to 7% of adolescents with only depression. Adolescents suffering only from depression were less likely than those with both conditions to experience suicidality (0.44; 0.21–0.95) and AUD in adulthood (0.18; 0.07–0.44). These findings underscore the clinical imperative to identify adolescents with this comorbidity. Recognition of the poor long-term prognosis can inform targeted interventions for this vulnerable group, ultimately improving health and well-being throughout the life course.

Patient Experiences With Group Teletherapy for the Treatment of Mental Illness: A Qualitative Study.

The authors sought to understand patient experiences with group teletherapy to inform improvements in service delivery. From December 2022 to October 2023, semistructured interviews were conducted with 20 adults with depression or bipolar disorder who had received outpatient group teletherapy in the past 2 years. A rapid thematic analysis was conducted by using a matrix to identify patterns and synthesize data. A logic model from the patients' perspective was developed by extracting common themes related to elements of effective group teletherapy. Telehealth allowed for more empowered engagement in group teletherapy and enabled better access and longitudinal attendance for many patients, compared with in-person group therapy. However, many patients reported a reduced sense of emotional intimacy and connectedness with telehealth, and some reported that technology challenges and distractions contributed to feelings of disconnection. Patients were divided in their modality preferences, but many expressed an interest in receiving at least some of their group therapy sessions by telehealth. Although group teletherapy has the potential to meet patients' needs and preferences, more work is needed to improve the quality of the experience for patients.

Deprescribing Antidepressants in Children and Adolescents: A Systematic Review of Discontinuation Approaches, Cross-Titration, and Withdrawal Symptoms.

Background: Antidepressant medications, including selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), are commonly used to treat depressive, anxiety, and obsessive-compulsive disorders in youth. Yet, data on discontinuing these medications, withdrawal symptoms, and strategies to switch between them are limited. Methods: We searched PubMed and ClinicalTrials.gov through June 1, 2024, to identify randomized controlled trials assessing antidepressant discontinuation in youth. We summarized pediatric pharmacokinetic data to inform tapering and cross-titration strategies for antidepressants and synthesized these data with reports of antidepressant withdrawal. Results: Our search identified 528 published articles, of which 28 were included. In addition, 19 records were obtained through other methods, with 14 included. The corpus of records included 13 randomized, double-blind, placebo-controlled trials (3026 patients), including SSRIs (K = 10), SNRIs (K = 4), andTCAs (K = 1), ranging from 4 to 35 weeks. Deprescribing antidepressants requires considering clinical status, treatment response, and, in cross-titration cases, the pharmacokinetics and pharmacodynamics of both medications. Antidepressant withdrawal symptoms are related to the pharmacokinetics of the medication, which vary across antidepressants and may include irritability, palpitations, anxiety, nausea, sweating, headaches, insomnia, paresthesia, and dizziness. These symptoms putatively involve changes in serotonin transporter expression and receptor sensitivity, impacting the serotonin, dopamine, and norepinephrine pathways. Conclusions: Although approaches to deprescribing antidepressants in pediatric patients are frequently empirically guided, accumulating data related to the course of relapse and withdrawal symptoms, as well as the pharmacokinetic and pharmacodynamic properties of medications, should inform these approaches. Recommendations within this review support data-informed discussions of deprescribing-including when and how-that are critically important in the clinician-family-patient relationship.

Review of Guidelines on Bupropion for Depression

What Is the Issue? Bupropion is a drug used in the treatment of depression. Bupropion is 1 of many treatment options available for depression and is associated with several side effects as well as the potential for misuse. Some patients continue to experience symptoms of depression despite trying multiple medications (known as treatment-resistant depression). Therefore, it is important to determine the place in therapy of bupropion for the treatment of depression. What Did We Do? To help determine the potential place in therapy for bupropion for the treatment of major depressive disorder (MDD) and treatment-resistant depression in adults, we sought to identify and summarize recommendations in evidence-based guidelines. We searched key resources, including journal citation databases, and conducted a focused internet search for relevant evidence published since 2019. One reviewer screened articles for inclusion based on predefined criteria, critically appraised the included publications, and narratively summarized the findings. What Did We Find? We identified 4 evidence-based guidelines that included recommendations on the use of bupropion for MDD. We identified 1 evidence-based guideline that included a recommendation on the use of bupropion for difficult-to-treat depression (defined as persistent depression despite several standard treatments). All 4 included guidelines recommend bupropion for the treatment of adults with MDD. Two of the guidelines recommend bupropion as a first-line treatment option. One guideline suggests bupropion as an option for initial pharmacologic treatment or for patients who have previously responded well to pharmacotherapy. One guideline suggests bupropion as an option for adjunctive treatment for patients in the acute phase of moderate to severe MDD who did not respond to treatment with a second-generation antidepressant. One guideline suggests bupropion as a second-line adjunctive option for adults with difficult-to-treat depression. What Does It Mean? The included evidence-based guidelines consistently recommend bupropion as an option for the treatment of adults with MDD. Additional factors such as the availability of other options, costs, and patient preferences may also be important to decision-making around the use of bupropion for MDD. Only 1 of the included guidelines included a recommendation on the use of bupropion for patients with difficult-to-treat depression. Future evidence-based guidelines that include recommendations on the use of bupropion for treatment-resistant depression would help fill the gaps identified in this report.

Exploring mitochondrial blood-based and genetic markers in older adults with mild cognitive impairment and remitted major depressive disorder

Mild cognitive impairment (MCI) is a prodromal stage in aging to possible progression to Alzheimer’s disease and related dementia (ADRD), where co-occurrence of major depressive disorder (MDD) accelerates the progression. Metabolic and mitochondrial abnormalities in ADRD and other neurodegenerative disorders have been widely suggested, while possible mitochondrial dysfunction has been associated with etiopathology of both MCI and MDD. Hence, investigation of mitochondrial markers in MCI, MDD, and presence of both conditions is warranted. In total, 332 older adult participants were included: 168 with MCI, 108 with MCI plus remitted MDD (rMDD), and 56 with rMDD but without MCI. We measured plasma circulating mitochondrial DNA (ccf-mtDNA), lactate, and extracted nuclear mitochondrial encoded (NMt) single-nucleotide variants (SNVs) (n = 312). Non-parametric statistical tests on ccf-mtDNA and lactate levels were performed on the diagnosis, clinical and cardiometabolic variables. Binary sequence kernel association test (SKAT-O) and burden test were performed on NMt-SNV, adjusted for age, race, gender, type II diabetes, and APOE genotype. Lower level of lactate was observed in MCI (KW χ2 = 14.8, P = 0.0024), more specifically, significant differences of lower plasma lactate between MCI only and rMDD, but not between MCI+rMDD and MCI were found, suggesting potential roles in MCI driving lactate lower levels. While higher levels of ccf-mtDNA were observed in APOE-ε4 carrier (χ2 = 5.04, P = 0.05). This relationship was present only in MCI (P = 0.043) and MCI+rMDD groups (P = 0.023). No significant nuclear-encoded mitochondrial gene associations were observed with MCI or MDD. The results suggest decreased level of plasma lactate in individuals with MCI and MCI+rMDD, with inverse correlation with ccf-mtDNA, in addition to effect of APOE-ε4 in further increasing ccf-mtDNA specifically in participants with cognitive impairment. These findings contribute to a deeper understanding of the mitochondrial markers in MCI and MDD, warranting further research to explore the precise roles of mitochondrial abnormalities in the development and progression of MCI.

Characteristic activation pattern and network connectivity of prefrontal cortex in patients with type 2 diabetes mellitus and major depressive disorder during a verbal fluency task: A functional near-infrared spectroscopy study based on network-based statistic prediction.

Type 2 diabetes (T2DM) and major depressive disorder (MDD) together occur frequently among the elderly population. However, the inconsistency in assessments and limited medical resources in the community make it challenging to identify depression in patients with T2DM. This cross-sectional study aimed to investigate the activation pattern and network connectivity of prefrontal cortex (PFC) during a verbal fluency task (VFT) in patients with T2DM and MDD using functional near-infrared spectroscopy (fNIRS). Three parallel groups (T2DM with MDD group, T2DM group, and healthy group) with 100 participants in each group were included in the study. Recruitment took place from August 1, 2020, to December 31, 2023. Due to the close association between the PFC and depressive emotions, fNIRS was used to monitor brain activation and network connectivity of PFC in all participants during a task of Chinese-language phonological VFT. Network-based statistic prediction (NBS-predict) was adopted as data analysis method. Patients in the T2DM with MDD group showed characteristic activation pattern and network connectivity in contrast with patients with T2MD and healthy controls, including decreased activation in PFC, and decreased network connectivity of right dorsolateral prefrontal cortex (DLPFC). Furthermore, the network connectivity of the right DLPFC in patients with T2DM and MDD was negatively correlated with scores of Hamilton Depression Scale-24 (HAMD-24). There was a distinctive activation pattern and network connectivity of the prefrontal cortex in patients with T2DM and MDD. The right DLPFC could serve as a potential target for the diagnosis and intervention of MDD in patients with T2DM.

Mood disorders and 5-HTR2A genetic variants – the moderator effect of inflammation on expression of affective polarity phenotype

BackgroundAlthough repeatedly confirmed, the molecular nature of gene-environment (GxE) interactions has rarely been investigated in the clinical context of mood disorders. This study assesses the relationship between HTR2A genetic variants and the modulatory effect of inflammation in a collective cohort of patients with major depressive disorder (MDD) and bipolar disorder (BD), as a unified group with two distinct phenotypes.MethodsThe study included 138 patients with acute mood episodes (BD = 83; MDD = 55). HTR2A rs6313 and rs6314 genotyping was performed while measuring platelet-derived indicators of inflammation (platelet count (PLT), mean platelet volume (MPV), plateletcrit, and platelet distribution width) and the MPV/PLT ratio.ResultsThe HTR2A rs6313 variant is a significant predictor of the polarity phenotype in mood disorders, with the MPV/PLT ratio moderating this relationship, but only under low-inflammatory conditions. In more pronounced inflammatory states, genetic influences lose their predictive role.ConclusionsTo our knowledge, this is the first study to investigate the complex interplay between platelet-derived indicators of inflammation and HTR2A variants in the context of mood disorders. Without pro-inflammatory conditions, mood disorders seem to be more genetically determined. Under pro-inflammatory conditions, phenotypic presentation is less dependent on genetic factors. GxE interactions in mood disorders are multifaceted, context-dependent and relevant for assessing their clinical presentation and course.

Corticosterone-Mediated BDNF Changes and Their Effects on Adult Neurogenesis in Depression

Adult neurogenesis, the process of generating functional neurons from neural precursor cells in the adult brain, is essential for cognitive function and emotional regulation. Major Depressive Disorder (MDD), characterized by persistent sadness and decreased psychosocial function, is associated with impaired adult hippocampal neurogenesis (AHN). Elevated levels of corticosterone (CORT), a glucocorticoid released in response to stress, have been shown to downregulate brain-derived neurotrophic factor (BDNF), a crucial regulator of neurogenesis, thereby inhibiting AHN. Despite significant advances in understanding the impact of CORT and BDNF on neurogenesis, the precise molecular and cellular pathways involved remain unclear. This review highlights key gaps in the research, particularly the need for a deeper understanding of how glucocorticoid and mineralocorticoid receptors regulate BDNF transcription, the role of autophagic pathways in BDNF degradation, and the influence of glutamatergic signaling on these processes. Future research should focus on elucidating these mechanisms to develop targeted therapeutic strategies, including pharmacological interventions that modulate BDNF and CORT levels and lifestyle modifications like exercise and adequate sleep to enhance neurogenesis. Understanding these complex interactions will be crucial for advancing treatments for depression and improving mental health outcomes.

Procognitive Effects of Adjunctive D-Cycloserine to Intermittent Theta-Burst Stimulation in Major Depressive Disorder: Effets procognitifs de la D-cyclosérine en traitement complémentaire par la stimulation thêta-burst intermittente dans le trouble dépressif caractérisé.

Major depressive disorder (MDD) is associated with cognitive impairments that persist despite successful treatment. Transcranial magnetic stimulation is a noninvasive treatment for MDD that is associated with small procognitive effects on working memory and executive function. We hypothesized that pairing stimulation with N-methyl-D-aspartate (NMDA) receptor agonism would enhance the effects of stimulation and its procognitive effects. The effect of NMDA receptor agonism (D-cycloserine, 100 mg) on cognitive performance was tested in two randomized double-blind placebo-controlled trials: (1) acute effects of in the absence of stimulation (n = 20 healthy participants) and (2) a treatment study of individuals with MDD (n = 50) randomized to daily intermittent theta-burst stimulation (iTBS) with placebo or D-cycloserine for 2 weeks. Cognitive function was measured using the THINC-it battery, comprised of the Perceived Deficits Questionnaire, the Choice Reaction Time, the Trail Making Test, the Digit Symbol Substitution Test, and the 1-Back tests. D-cycloserine had no acute effect on cognition compared to placebo. iTBS + D-cycloserine was associated with significant improvements in subjective cognitive function and correct responses on the 1-Back when compared to iTBS + placebo. Improvements in subjective cognition paralleled depressive symptoms improvement, however 1-Back improvements were not attributable to improvement in depression. An intersectional strategy pairing iTBS with NMDA receptor agonism may restore cognitive function in MDD.

A personalised nutrition intervention for adolescent depression: a mixed-methods feasibility pilot study.

Randomised controlled trials have demonstrated the benefit of diet modification to improve diet quality in the treatment of adult major depressive disorder (MDD). However, research examining nutritional interventions for adolescents with MDD is sparse. This pilot study examined the feasibility of a personalised nutrition intervention for adolescents with MDD. Ten adolescents with MDD and their parents recruited from a tertiary care setting participated in an 8-week, single-arm mixed-methods study. Feasibility was assessed using five criteria (demand, acceptability, implementation, adaptation and limited efficacy testing) alongside qualitative interviews. The intervention involved four bi-weekly virtual nutrition counselling sessions with a stepped approach to dietary change, menu planning, grocery delivery and educational eHealth messages. Study participants sought positive changes in diet, health and lifestyle for adolescents and family-wide benefits. Recruitment challenges included concerns about managing mood fluctuations, anticipated dietary restrictions and the potential time and effort required for diet adherence. Feedback based on interviews emphasised moderate to high acceptability, satisfaction with menu planning and counselling and recognition of the benefits of trying new foods and sustaining positive dietary changes beyond the study. Improvements in depression symptoms (Cohen's d = 0·36, 95 % CI (-0·24, 3·36)), parent food modeling (Cohen's d = 0·24, 95 % CI (-0·43, 1·16) and the family food environment (Cohen's d = 0·61, 95 % CI (-0·04, 2·61)) were observed. This nutrition intervention was feasible for adolescents with MDD and was acceptable to both parents and depressed adolescents. These preliminary data suggest that further examination of the intervention and its potential benefits on depression symptoms and family food dynamics are warranted.