Omega-3 Polyunsaturated Fatty Acids and Blood-Brain Barrier Integrity in Major Depressive Disorder: Restoring Balance for Neuroinflammation and Neuroprotection.

Major depressive disorder (MDD), affecting over 264 million individuals globally, is associated with immune system dysregulation and chronic neuroinflammation, potentially linked to neurodegenerative processes. This review examines blood-brain barrier (BBB) dysfunction in MDD, focusing on key regulators like matrix metalloproteinase 9 (MMP9), aquaporin-4 (AQP4), and ATP-binding cassette subfamily B member 1 (ABCB1). We explore potential mechanisms by which compromised BBB integrity in MDD may contribute to neuroinflammation and discuss the therapeutic potential of omega-3 polyunsaturated fatty acids (n-3 PUFAs). n-3 PUFAs have demonstrated anti-inflammatory and neuroprotective effects, and potential ability to modulate MMP9, AQP4, and ABCB1, thereby restoring BBB integrity in MDD. This review aims to elucidate these potential mechanisms and evaluate the evidence for n-3 PUFAs as a strategy to mitigate BBB dysfunction and neuroinflammation in MDD.

A randomized controlled trial of a self-guided mobile app targeting repetitive negative thought to prevent depression in university students: study protocol of the Nurture-U Reducing Worry prevention trial.

BACKGROUND: Tackling poor mental health in university students has been identified as a priority in higher education. However, there are few evidence-based prevention initiatives designed for students. Repetitive Negative Thought (RNT, e.g. worry, rumination) is elevated in university students and is a well-established vulnerability factor for anxiety and depression. Furthermore, there are now evidence-based cognitive-behavioural interventions to tackle RNT. A mobile self-help cognitive-behavioural app targeting RNT, adapted for students may therefore be an effective, scalable, and acceptable way to improve prevention in students. METHODS: An online single blind, two-arm parallel-group Randomised Controlled Trial (RCT) to examine the incidence of major depression and symptoms of anxiety and depression across 12 months in university students aged over 16 who screen into the study with self-reported high levels of worry and/or rumination and no current diagnosis of major depression. Eligible participants will be randomised to the active intervention arm (usual practice plus using a self-guided mobile app targeting RNT) or to the control arm (usual practice). In total, 648 participants aged over 16, with no current major depression, bipolar disorder or psychosis will be recruited from UK universities. Assessments will take place at baseline (pre-randomisation), 3 months and 12 months post- randomisation. Primary endpoint and outcome is incidence of major depression as determined by self-reported diagnostic criteria at 12-month follow-up. Depressive symptoms, anxiety, well-being, health-related quality of life, functioning and academic outcomes are secondary outcomes. Compliance, adverse events, and potentially mediating variables will be carefully monitored. DISCUSSION: The trial aims to provide a better understanding of the causal role of tackling RNT (worry, rumination) using a self-help mobile app with respect to preventing depression in university students. This knowledge will be used to develop and disseminate innovative evidence-based, feasible, and effective mobile-health public health strategies for preventing common mental health problems. TRIAL REGISTRATION: https://www.isrctn.com/ISRCTN86795807 Date of registration: 27 October 2022.

Evaluating the effectiveness of a multi-component lifestyle therapy program versus psychological therapy for managing mood disorders (HARMON-E): protocol of a randomised non-inferiority trial.

BACKGROUND: Mood disorders, including unipolar and bipolar depression, contribute significantly to the global burden of disease. Psychological therapy is considered a gold standard non-pharmacological treatment for managing these conditions; however, a growing body of evidence also supports the use of lifestyle therapies for these conditions. Despite some clinical guidelines endorsing the application of lifestyle therapies as a first-line treatment for individuals with mood disorders, there is limited evidence that this recommendation has been widely adopted into routine practice. A key obstacle is the insufficient evidence on whether lifestyle therapies match the clinical and cost effectiveness of psychological therapy, particularly for treating those with moderate to severe symptoms. The HARMON-E Trial seeks to address this gap by conducting a non-inferiority trial evaluating whether a multi-component lifestyle therapy program is non-inferior to psychological therapy on clinical and cost-effectiveness outcomes over 8-weeks for adults with major depressive disorder and bipolar affective disorder. METHODS: This trial uses an individually randomised group treatment design with computer generated block randomisation (1:1). Three hundred and seventy-eight adults with clinical depression or bipolar affective disorder, a recent major depressive episode, and moderate-to-severe depressive symptoms are randomised to receive either lifestyle therapy or psychological therapy (adjunctive to any existing treatments, including pharmacotherapies). Both therapy programs are delivered remotely, via a secure online video conferencing platform. The programs comprise an individual session and six subsequent group-based sessions over 8-weeks. All program aspects (e.g. session duration, time of day, and communications between participants and facilitators) are matched except for the content and program facilitators. Lifestyle therapy is provided by a dietitian and exercise physiologist focusing on four pillars of lifestyle (diet, physical activity, sleep, and substance use), and the psychological therapy program is provided by two psychologists using a cognitive behavioural therapy approach. Data collection occurs at baseline, 8-weeks, 16-weeks, and 6 months with research assistants blinded to allocation. The primary outcome is depressive symptoms at 8 weeks, measured using the Montgomery-Åsberg Depression Rating Scale (MADRS) (minimal clinically important difference = 1.6). A pre-specified within-trial economic evaluation will also be conducted. DISCUSSION: Should lifestyle therapy be found to be as clinically and cost effective as psychological therapy for managing mood disorders, this approach has potential to be considered as an adjunctive treatment for those with moderate to severe depressive symptoms. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12622001026718, registered 22nd July 2022. PROTOCOL VERSION:  4.14, 26/06/2024.

Effects of cognitive training under hypoxia on cognitive proficiency and neuroplasticity in remitted patients with mood disorders and healthy individuals: ALTIBRAIN study protocol for a randomized controlled trial.

BACKGROUND: Cognitive impairment is prevalent across neuropsychiatric disorders but there is a lack of treatment strategies with robust, enduring effects. Emerging evidence indicates that altitude-like hypoxia cognition training may induce long-lasting neuroplasticity and improve cognition. We will investigate whether repeated cognition training under normobaric hypoxia can improve cognitive functions in healthy individuals and patients with affective disorders and the neurobiological underpinnings of such effects. METHODS: In sub-study 1, 120 healthy participants are randomized to one of four treatment arms in a double-blind manner, allowing for examination of separate and combined effects of three-week repeated moderate hypoxia and cognitive training, respectively. In sub-study 2, 60 remitted patients with major depressive disorder or bipolar disorder are randomized to hypoxia with cognition training or treatment as usual. Assessments of cognition, psychosocial functioning, and quality of life are performed at baseline, end-of-treatment, and at 1-month follow-up. Functional magnetic resonance imaging (fMRI) scans are conducted at baseline and 1-month follow-up, and [11C]UCB-J positron emission tomography (PET) scans are performed at end-of-treatment to quantify the synaptic vesicle glycoprotein 2A (SV2A). The primary outcome is a cognitive composite score of attention, verbal memory, and executive functions. Statistical power of ≥ 80% is reached to detect a clinically relevant between-group difference with minimum n = 26 per treatment arm. Behavioral data are analyzed with an intention-to-treat approach using mixed models. fMRI data is analyzed with the FMRIB Software Library, while PET data is quantified using the simplified reference tissue model (SRTM) with centrum semiovale as reference region. DISCUSSION: The results will provide novel insights into whether repeated hypoxia cognition training increases cognition and brain plasticity, which can aid future treatment development strategies. TRIAL REGISTRATION: ClinicalTrials.gov, NCT06121206 . Registered on 31 October 2023.

Differential effects of lifetime stressors on major depressive disorder severity: a longitudinal community-based cohort study.

BACKGROUND: Stressors across the lifespan are associated with the onset of major depressive disorder (MDD) and increased severity of depressive symptoms. However, it is unclear how lifetime stressors are related to specific MDD subtypes. The present study aims to examine the relationships between MDD subtypes and stressors experienced across the lifespan while considering potential confounders. METHODS: Data analyzed were from the Zone d'Épidémiologie Psychiatrique du Sud-Ouest de Montréal (N = 1351). Lifetime stressors included childhood maltreatment, child-parent bonding, and stressful life events. Person-centered analyses were used to identify the clusters/profiles of the studied variables and multinomial logistic regression analyses were performed to examine the relationships between stressors and identified MDD subtypes. Intersectional analysis was applied to further examine how distal stressors interact with proximal stressors to impact the development of MDD subtypes. RESULTS: There was a significant association between proximal stressors and melancholic depression, whereas severe atypical depression and moderate depression were only associated with some domains of stressful life events. Additionally, those with severe atypical depression and melancholic depression were more likely to be exposed to distal stressors such as childhood maltreatment. The combinations of distal and proximal stressors predicted a greater risk of all MDD subtypes except for moderate atypical depression. CONCLUSIONS: MDD was characterized into four subtypes based on depressive symptoms and severity. Different stressor profiles were linked with various MDD subtypes. More specific interventions and clinical management are called to provide precision treatment for MDD patients with unique stressor profiles and MDD subtypes.

Temporal and spatial convergence: the major depressive disorder burden attributed to intimate partner violence against women.

Background: There is a strong causal relationship between intimate partner violence and major depressive disorder, which partly endangers women's safety across the life course and potentially affects the development of future generations. The international community has placed a high priority on addressing the intimate partner violence and the resulting burden of mental illness. Data collection needs to be captured across the temporal trend and spatial distribution for major depressive disorder attributed to intimate partner violence, to reflect the priorities and expectations of survivors.Method: This research obtained raw disability-adjusted life years (DALYs) information for major depressive disorder attributed to intimate partner violence from the Global Burden of Disease 2019. Using estimated annual percentage change and two-way fixed effects models, a secondary spatio-temporal analysis of the age-standardized DALYs rate from 1990 to 2019 was performed.Results: In 2019, DALYs lost among women experiencing major depressive disorder (3.16 million) accounted for 37.18% of the DALYs lost worldwide due to intimate partner violence. The age-standardized DALYs rate of major depressive disorder attributed to intimate partner violence was 108.57 per 100,000. The highest was concentrated in the menopausal transition (45-55), with 133.61 per 100,000, and particularly distributed in Uganda (429.31 per 100,000). The early reproductive period (15-19) showed the increasing age-standardized DALYs rate from 1990 to 2019, which was mainly driven by Malaysia (3.73% per year). Furthermore, countries with higher initial levels of the age-standardized DALYs rate were growing faster than those with lower levels.Conclusions: The burden of major depressive disorder attributed to intimate partner violence showed biological and spatial inequality, prioritized intervention should be targeted at vulnerable stage women in their early reproductive period and menopausal transition. Combined political, socio-cultural as well as medical measures to prevent violence and treat major depressive disorder should be implemented and developed.

Vulnerability to different biological stages of the burden of experiencing intimate partner violence leading to major depressive disorder in women. Women in their reproductive years and during the menopausal transition were more vulnerable.Intimate partner violence-induced depressive disorder is trending younger, with an increasing burden on girls aged 15­19 over the past 30 years.The burden of major depressive disorder attributed to intimate partner violence varies increasingly across countries.

Quantitative proteomics combined independent PRM analysis reveals the mitochondrial and synaptic mechanism underlying norisoboldine's antidepressant effects.

Major depressive disorder (MDD) is a common disease affecting 300 million people worldwide. The existing drugs are ineffective for approximately 30% of patients, so it is urgent to develop new antidepressant drugs with novel mechanisms. Here, we found that norisoboldine (NOR) showed an antidepressant efficacy in the chronic social defeat stress (CSDS) depression model in the tail suspension, forced swimming, and sucrose consumption tests. We then utilized the drug-treated CSDS mice paradigm to segregate and gain differential protein groups of CSDS versus CON (CSDSCON), imipramine (IMI)-treated versus CSDS (IMICSDS), and NOR-treated versus CSDS (NORCSDS) from the prefrontal cortex. These protein expression alterations were first analyzed by ANOVA with p < 0.05. The protein cluster 1 and cluster 3, in which the pattern of protein levels similar to the mood pattern, showed enrichment in functions and localizations related to mitochondrion, ribosome and synapses. Further GO analysis of the common proteins for NORCSDS groups and NORIMI groups supported the findings from ANOVA analysis. We employed Protein-Protein interaction (PPI) analysis to examine the proteins of NORCSDS and NORIMI, revealing an enrichment of the proteins associated with the mitochondrial ribosomal and synaptic functions. Further independent analysis using parallel reaction monitoring (PRM) revealed that Cox7c, Mrp142, Naa30, Ighm, Apoa4, Ssu72, Mrps30, Apoh, Acbd5, and Cdv3, exhibited regulation in the NOR-treated group to support the homeostasis of mitochondrial functions. Additionally, Dcx, Arid1b, Rnf112, and Fam3c, were also observed to undergo modulation in the NOR-treated groups to support the synaptic formation and functions. These findings suggest that the proteins involved in depression treatment exert effects in strengthen the mitochondrial and synaptic functions in the mice PFC. Western blot analysis supported the data that the levels of Mrpl42, Cox7c, Naa30, Rnf112, Dcx Apoa4, Apoh and Fam3c were altered in the CSDS mice, and rescued by NOR treatment, supporting the PRM data. NOR treatment also rescued the NLRP3 inflammasome activation in CSDS mice. In summary, the current proteomic research conducted on the prefrontal cortex has provided valuable insights into the specific and shared molecular mechanisms underlying pathophysiology and treatment to CSDS-induced depression, shedding light on the therapeutic effects of Norisoboldine.

Associations between antagonistic SNPs for neuropsychiatric disorders and human brain structure.

A previously published genome-wide association study (GWAS) meta-analysis across eight neuropsychiatric disorders identified antagonistic single-nucleotide polymorphisms (SNPs) at eleven genomic loci where the same allele was protective against one neuropsychiatric disorder and increased the risk for another. Until now, these antagonistic SNPs have not been further investigated regarding their link to brain structural phenotypes. Here, we explored their associations with cortical surface area and cortical thickness (in 34 brain regions and one global measure each) as well as the volumes of eight subcortical structures using summary statistics of large-scale GWAS of brain structural phenotypes. We assessed if significantly associated brain structural phenotypes were previously reported to be associated with major neuropsychiatric disorders in large-scale case-control imaging studies by the ENIGMA consortium. We further characterized the effects of the antagonistic SNPs on gene expression in brain tissue and their association with additional cognitive and behavioral phenotypes, and performed an exploratory voxel-based whole-brain analysis in the FOR2107 study (n = 754 patients with major depressive disorder and n = 847 controls). We found that eight antagonistic SNPs were significantly associated with brain structural phenotypes in regions such as anterior parts of the cingulate cortex, the insula, and the superior temporal gyrus. Case-control differences in implicated brain structural phenotypes have previously been reported for bipolar disorder, major depressive disorder, and schizophrenia. In addition, antagonistic SNPs were associated with gene expression changes in brain tissue and linked to several cognitive-behavioral traits. In our exploratory whole-brain analysis, we observed significant associations of gray matter volume in the left superior temporal pole and left superior parietal region with the variants rs301805 and rs1933802, respectively. Our results suggest that multiple antagonistic SNPs for neuropsychiatric disorders are linked to brain structural phenotypes. However, to further elucidate these findings, future case-control genomic imaging studies are required.

The role of emotion regulation in perinatal depression and anxiety: a systematic review.

BACKGROUND: Major depressive disorder and anxiety disorders are highly prevalent and comorbid during the perinatal period. Although research and clinicians agree that emotion regulation (ER) is an important transdiagnostic factor underlying both disorders in the general population, ER during the perinatal period has received less research attention. The aim of this systematic review was to assess the literature regarding the role of ten commonly studied ER strategies in the onset and maintenance of perinatal depression and anxiety in pregnant women and young mothers, using the Process Model of Gross (1998) as a theoretical framework. METHODS: We searched four electronic databases with variations of the following key words: women; emotion regulation (i.e., behavioral approach, behavioral avoidance, problem solving, support seeking, distraction, rumination, reappraisal, acceptance, expressive suppression, and expressive engagement); perinatal period; and psychopathology. The aim was to identify peer-reviewed, and quantitative studies published between January 1999 and January 2023. Six articles were selected for analysis. RESULTS: Similar ER strategies emerged as risk and protective factors in perinatal depression and anxiety. Overall, behavioral avoidance, distraction, rumination, and expressive engagement appeared as risk factors, while problem solving, emotional and instrumental support seeking, cognitive reappraisal, and acceptance, emerged as protective factors in the onset and maintenance of perinatal depression and anxiety. These findings align with previous research in perinatal community samples, as well as in non-perinatal clinical samples. CONCLUSIONS: Our results support the role of ER as a transdiagnostic factor underlying both perinatal depression and anxiety. Clinicians are encouraged to implement ER strategies into the screening, prevention, and treatment of perinatal depression and anxiety. Further research is needed to strengthen these findings and to examine the role of emotion regulation during antenatal depression and anxiety more closely.

Contribution of resting-state functional connectivity of the subgenual anterior cingulate to prediction of antidepressant efficacy in patients with major depressive disorder.

This study investigated how resting-state functional connectivity (rsFC) of the subgenual anterior cingulate cortex (sgACC) predicts antidepressant response in patients with major depressive disorder (MDD). Eighty-seven medication-free MDD patients underwent baseline resting-state functional MRI scans. After 12 weeks of escitalopram treatment, patients were classified into remission depression (RD, n = 42) and nonremission depression (NRD, n = 45) groups. We conducted two analyses: a voxel-wise rsFC analysis using sgACC as a seed to identify group differences, and a prediction model based on the sgACC rsFC map to predict treatment efficacy. Haufe transformation was used to interpret the predictive rsFC features. The RD group showed significantly higher rsFC between the sgACC and regions in the fronto-parietal network (FPN), including the bilateral dorsolateral prefrontal cortex (DLPFC) and bilateral inferior parietal lobule (IPL), compared to the NRD group. These sgACC rsFC measures correlated positively with symptom improvement. Baseline sgACC rsFC also significantly predicted treatment response after 12 weeks, with a mean accuracy of 72.64% (p < 0.001), mean area under the curve of 0.74 (p < 0.001), mean specificity of 0.82, and mean sensitivity of 0.70 in 10-fold cross-validation. The predictive voxels were mainly within the FPN. The rsFC between the sgACC and FPN is a valuable predictor of antidepressant response in MDD patients. These findings enhance our understanding of the neurobiological mechanisms underlying treatment response and could help inform personalized treatment strategies for MDD.

Strategies to overcome mental health stigma: Insights and recommendations from young people with major depressive disorder (MDD).

BACKGROUND: Young people with depression are met with stigma related to their mental health, which exacerbates loneliness, social isolation, and depression symptoms. While disclosing depression could improve one's mental health, stigma can also make social interactions more challenging and reduce the likelihood of receiving treatment. This research explored young people's experiences with stigma and recommendations for addressing it. METHODS: Semi-structured interviews conducted with N = 35 young people aged 18-25 years (Mage = 20.09) were analyzed with thematic analysis. Participants met the criteria for clinical depression using the Mood and Feelings Questionnaire (score >27) or had recently obtained a medical diagnosis (N = 18) of depression by a medical professional. RESULTS: Participants faced stigma when deciding to disclose their depression, which fed into a vicious cycle influencing feelings of loneliness, social isolation, and withdrawal. Their recommendations for others to avoid this cycle can be summarized under three main themes: (1) Social affirmation: identify allies and build meaningful connections; (2) Self-affirmation: build a constructive relationship with the self; and (3) Societal affirmation: structural changes are needed. CONCLUSIONS: The current research indicates that social, self-, and societal affirmation are considered important for reducing the detrimental impacts of stigma. Policies and programs are needed that provide mental health support to young people, and public awareness campaigns that guide young people to appropriate resources (i.e., support and intervention) via governmental public health bodies.

Is lack of goal-conflict-specific rhythmicity a biomarker for treatment resistance in generalised anxiety but not social anxiety or major depression?

BACKGROUND: Anxiety and depression cause major detriment to the patient, family, and society - particularly in treatment-resistant (TR) cases, which are highly prevalent. TR prevalence may be due to current diagnoses being based not on biological measures but on symptom lists that suffer from clinical subjectivity, variation in symptom presentation, and comorbidity. AIMS: Goal-conflict-specific rhythmicity (GCSR) measured using the Stop-Signal Task (SST) may provide the first neural biomarker for an anxiety process and disorder. This GCSR has been validated with selective drugs for anxiety. So, we proposed that GCSR could differ between TR and non-TR individuals and do so differently between those diagnoses normally sensitive to selective anxiolytics and those not. METHODS: We recorded electroencephalograms (EEG) from 20 TR participants (4 GAD, 5 SAD and 11 MDD) and 24 non-TR participants (4 GAD, 5 SAD and 15 Comorbid GAD/MDD (GMD)) while they performed the SST. RESULTS: There was significant positive GCSR in all groups except the GAD-TR group. GAD-TR lacked GCSR in the low-frequency range. However, TR had little effect in SAD or MDD/GMD populations with apparent increases not decreases. CONCLUSIONS: Overall, these results suggest that GAD may occur in two forms: one resulting from excessive GCSR and so being drug sensitive, and the other resulting from some other mechanism and so being TR. In SAD and MDD groups, heightened GCSR could be a consequence rather than the cause, driven by mechanisms that are normally more sensitive to non-selective panicolytic antidepressants.

Comparing Email Versus Text Messaging as Delivery Platforms for Supporting Patients With Major Depressive Disorder: Noninferiority Randomized Controlled Trial.

BACKGROUND: The prevalence of major depressive disorder (MDD) poses significant global health challenges, with available treatments often insufficient in achieving remission for many patients. Digital health technologies, such as SMS text messaging-based cognitive behavioral therapy, offer accessible alternatives but may not reach all individuals. Email communication presents a secure avenue for health communication, yet its effectiveness compared to SMS text messaging in providing mental health support for patients with MDD remains uncertain. OBJECTIVE: This study aims to compare the efficacy of email versus SMS text messaging as delivery platforms for supporting patients with MDD, addressing a critical gap in understanding optimal digital interventions for mental health care. METHODS: A randomized noninferiority pilot trial was conducted, comparing outcomes for patients receiving 6-week daily supportive messages via email with those receiving messages via SMS text message. This duration corresponds to a minimum of 180 days of message delivery. The supportive messages maintained consistent length and structure across both delivery methods. Participants (N=66) were recruited from the Access 24/7 clinic in Edmonton, Alberta, among those who were diagnosed with MDD. The outcomes were measured at baseline and 6 months after enrollment using the Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7), and the World Health Organization Well-Being Index (WHO-5). RESULTS: Most of the participants were females (n=43, 65%), aged between 26 and 40 years (n=34, 55%), had high school education (n=35, 58%), employed (n=33, 50%), and single (n=24, 36%). Again, most participants had had no history of any major physical illness (n=56, 85%) and (n=61, 92%) responded "No" to having a history of admission for treatment of mood disorders. There was no statistically significant difference in the mean changes in PHQ-9, GAD-7, and WHO-5 scores between the email and SMS text messaging groups (mean difference, 95% CI: -1.90, 95% CI -6.53 to 2.74; 5.78, 95% CI -1.94 to 13.50; and 11.85, 95% CI -3.81 to 27.51), respectively. Both supportive modalities showed potential in reducing depressive symptoms and improving quality of life. CONCLUSIONS: The study's findings suggest that both email and SMS text messaging interventions have equivalent effectiveness in reducing depression symptoms among individuals with MDD. As digital technology continues to evolve, harnessing the power of multiple digital platforms for mental health interventions can significantly contribute to bridging the existing treatment gaps and improving the overall well-being of individuals with depressive conditions. Further research is needed with a larger sample size to confirm and expand upon these findings. TRIAL REGISTRATION: ClinicalTrials.gov NCT04638231; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8552095/.

The effect of repetitive transcranial magnetic stimulation on the Hamilton Depression Rating Scale-17 criterion in patients with major depressive disorder without psychotic features: a systematic review and meta-analysis of intervention studies.

AIM: In line with the publication of clinical information related to the therapeutic process of repetitive transcranial magnetic stimulation (rTMS) and the updating of relevant treatment guidelines, the present meta-analysis study was designed and conducted to determine the effect of repetitive transcranial magnetic stimulation (rTMS) on the Hamilton Depression Rating Scale-17 (HDRS-17) criterion in patients with major depressive disorder (MDD) without psychotic features. METHODS: In this study, a systematic search was conducted in electronic databases such as PubMed [Medline], Scopus, Web of Science, Embase, Ovid, Cochrane Library, and ClinicalTrials. gov using relevant keywords. The search period in this study was from January 2000 to January 2022, which was updated until May 2023. Randomized controlled trials (RCTs) that determined the effect of repetitive transcranial magnetic stimulation (rTMS) on the Hamilton Depression Rating Scale-17 (HDRS-17) criterion in patients with major depressive disorder (MDD) without psychotic features were included in the analysis. The quality of the included RCTs was assessed using the Cochrane Risk of Bias checklist. Statistical analyses were performed using STATA (Version 16) and RevMan (Version 5). RESULTS: Following the combination of results from 16 clinical trial studies in the present meta-analysis, it was found that the mean Hamilton Depression Rating Scale-17 (HDRS-17) in patients with major depressive disorder (MDD) decreases by an average of 1.46 units (SMD: -1.46; % 95 CI: -1.65, -1.27, I square: 45.74%; P heterogeneity: 0.56). Subgroup analysis results indicated that the standardized mean difference of Hamilton Depression Rating Scale-17 (HDRS-17) varied based on the number of treatment sessions: patients receiving 10 or fewer repetitive transcranial magnetic stimulation (rTMS) sessions showed a mean Hamilton Depression Rating Scale-17 (HDRS-17) reduction of 2.60 units (SMD: -2.60; % 95 CI: -2.86, -2.33, I square: 55.12%; P heterogeneity: 0.55), while those receiving 11 to 20 sessions showed a mean Hamilton Depression Rating Scale-17 (HDRS-17) reduction of 0.28 units (SMD: -0.28; % 95 CI: -0.65, -0.09, I square: 39.91%; P heterogeneity: 0.89). CONCLUSION: In conclusion, our meta-analysis demonstrates the efficacy of repetitive transcranial magnetic stimulation (rTMS) in reducing depressive symptoms in major depressive disorder (MDD) patients. The complex results of subgroup analysis revealed insight on the possible benefits of a more focused strategy with fewer sessions, as well as the impact of treatment session frequency. These findings add to our understanding of repetitive transcranial magnetic stimulation (rTMS) as a therapeutic intervention for the treatment of major depressive illnesses.

Clinical characteristics of 217 Chinese cases with depersonalization/derealization disorder.

Depersonalization/derealization disorder (DPD) is a prevalent yet inadequately understood clinical condition characterized by a recurrent or persistent sense of unreality. This study aims to provide insight into DPD through descriptive and comparative analyses involving a large group of Chinese participants. The socio-demographic details (age, gender proportion, education, occupational status, marital status), depersonalized and dissociative symptom characteristics (symptomatic factors or subscales of the Cambridge Depersonalization Scale and the Dissociative Experiences Scale), development trajectory (age of onset, potential precipitating factors, course characteristics), treatment history (duration of delayed healthcare attendance, duration of delayed diagnosis, previous diagnoses), and adverse childhood experiences of the DPD patients are presented. Comparisons of anxiety and depressive symptoms, alongside psychosocial functioning, between DPD participants and those diagnosed with generalized anxiety disorder, bipolar disorders, and major depressive disorder were conducted. The analysis highlights a higher male preponderance and early onset of DPD, symptomatology marked by derealization, notable impairment in psychosocial functioning, and prolonged periods of delayed healthcare attendance and diagnosis associated with symptom severity. Furthermore, noteworthy relationships between adverse childhood experiences and symptom levels were identified. The findings substantiate the view that DPD is a serious but neglected mental disorder, urging initiatives to improve the current condition of DPD patients.

Distinct connectivity patterns in bipolar and unipolar depression: a functional connectivity multivariate pattern analysis study.

BACKGROUND: Patients with bipolar disorder (BD) and major depressive disorder (MDD) exhibit depressive episodes with similar symptoms despite having different and poorly understood underlying neurobiology, often leading to misdiagnosis and improper treatment. This exploratory study examined whole-brain functional connectivity (FC) using FC multivariate pattern analysis (fc-MVPA) to identify the FC patterns with the greatest ability to distinguish between currently depressed patients with BD type I (BD I) and those with MDD. METHODOLOGY: In a cross-sectional design, 41 BD I, 40 MDD patients and 63 control participants completed resting state functional magnetic resonance imaging scans. Data-driven fc-MVPA, as implemented in the CONN toolbox, was used to identify clusters with differential FC patterns between BD patients and MDD patients. The identified cluster was used as a seed in a post hoc seed-based analysis (SBA) to reveal associated connectivity patterns, followed by a secondary ROI-to-ROI analysis to characterize differences in connectivity between these patterns among BD I patients, MDD patients and controls. RESULTS: FC-MVPA identified one cluster located in the right frontal pole (RFP). The subsequent SBA revealed greater FC between the RFP and posterior cingulate cortex (PCC) and between the RFP and the left inferior/middle temporal gyrus (LI/MTG) and lower FC between the RFP and the left precentral gyrus (LPCG), left lingual gyrus/occipital cortex (LLG/OCC) and right occipital cortex (ROCC) in MDD patients than in BD patients. Compared with the controls, ROI-to-ROI analysis revealed lower FC between the RFP and the PCC and greater FC between the RFP and the LPCG, LLG/OCC and ROCC in BD patients; in MDD patients, the analysis revealed lower FC between the RFP and the LLG/OCC and ROCC and greater FC between the RFP and the LI/MTG. CONCLUSIONS: Differences in the RFP FC patterns between currently depressed patients with BD and those with MDD suggest potential neuroimaging markers that should be further examined. Specifically, BD patients exhibit increased FC between the RFP and the motor and visual networks, which is associated with psychomotor symptoms and heightened compensatory frontoparietal FC to counter distractibility. In contrast, MDD patients exhibit increased FC between the RFP and the default mode network, corresponding to sustained self-focus and rumination.

Convergence of endothelial dysfunction, inflammation and glucocorticoid resistance in depression-related cardiovascular diseases.

Major Depressive Disorder, or depression, has been extensively linked to dysregulated HPA axis function, chronic inflammation and cardiovascular diseases. While the former two have been studied in depth, the mechanistic connection between depression and cardiovascular disease is unclear. As major mediators of vascular homeostasis, vascular pathology and immune activity, endothelial cells represent an important player connecting the diseases. Exaggerated inflammation and glucocorticoid function are important topics to explore in the endothelial response to MDD. Glucocorticoid resistance in several cell types strongly promotes inflammatory signaling and results in worsened severity in many diseases. However, endothelial health and inflammation in chronic stress and depression are rarely considered from the perspective of glucocorticoid signaling and resistance. In this review, we aim to discuss (1) endothelial dysfunction in depression, (2) inflammation in depression, (3) general glucocorticoid resistance in depression and (4) endothelial glucocorticoid resistance in depression co-morbid inflammatory diseases. We will first describe vascular pathology, inflammation and glucocorticoid resistance separately in depression and then describe their potential interactions with one another in depression-relevant diseases. Lastly, we will hypothesize potential mechanisms by which glucocorticoid resistance in endothelial cells may contribute to vascular disease states in depressed people. Overall, endothelial-glucocorticoid signaling may play an important role in connecting depression and vascular pathology and warrants further study.

Investigating the bacterial profiles of Lactobacillus, Bifidobacterium, Actinobacteria, Fusobacterium, Firmicutes, and Bacteroides in stool samples from patients with severe depression and healthy individuals.

Depression is a multifaceted mental health disorder with complex etiology and significant global burden. Recent research indicates that the gut microbiota plays a role in the pathophysiology of depression, highlighting the potential role of specific bacterial species in influencing mood and cognitive function. In this study, we aimed to investigate the presence, copy numbers, and Ct values of selected bacterial species in stool samples from depressed patients (n=50) compared to control subjects (n=50). Our findings revealed significant differences in the abundance of Fusobacterium spp., Bifidobacterium spp., Lactobacillus spp., Bacteroidetes phylum, Firmicutes phylum, and Actinobacteria spp. between the two groups. Dysregulation of the gut microbiota, characterized by decreased presence of beneficial bacteria (e.g., Bifidobacterium spp., Lactobacillus spp.) and altered abundance of potentially pathogenic bacteria (e.g., Fusobacterium spp.), may contribute to the development or exacerbation of depression. These findings support the emerging concept of the gut-brain axis and its role in mental health. However, further research is needed to better understand the underlying mechanisms and explore the therapeutic potential of microbiota-targeted interventions for depression. Understanding the intricate interplay between the gut microbiota and depression could pave the way for novel treatment strategies and personalized approaches in mental health care.

PRKCB methylation: a potential biomarker of MDD with childhood chronic stress, a cross-sectional study in drug-naive, first-episode adolescent MDD.

The purpose of this study was to investigate the relationship between childhood chronic stress(CCS), Protein kinase C beta (PRKCB) methylation and adolescent major depressive disorder (MDD). After recruiting 100 adolescents with MDD and 50 healthy controls (HCs), we evaluated the severity of CCS. PRKCB methylation was assessed by pyrosequencing using whole blood-derived DNA. To explore the relationship between CCS, PRKCB and adolescent MDD, we conducted correlation analysis and regression analysis, and constructed multiplicative interaction models and generalized linear models. PRKCB methylation and CCS were both found to be associated with MDD, and CCS was associated with PRKCB methylation. No significant CCS-PRKCB methylation interactions were observed. However, we found the interaction of CCS and MDD on PRKCB methylation. Our results found that PRKCB methylation was influenced by CCS and the disease itself, and PRKCB methylation was significantly positively associated with MDD severity, suggesting that PRKCB methylation may be a potential biomarker for adolescent MDD. This study is a cross-sectional observational study, which cannot draw the conclusion of causality. Prospective cohort studies are needed to further examine the relationship between CCS, adolescent MDD, and PRKCB methylation.

Defective regulation of the eIF2-eIF2B translational axis underlies depressive-like behavior in mice and correlates with major depressive disorder in humans.

Major depressive disorder (MDD) is a significant cause of disability in adults worldwide. However, the underlying causes and mechanisms of MDD are not fully understood, and many patients are refractory to available therapeutic options. Impaired control of brain mRNA translation underlies several neurodevelopmental and neurodegenerative conditions, including autism spectrum disorders and Alzheimer's disease (AD). Nonetheless, a potential role for mechanisms associated with impaired translational control in depressive-like behavior remains elusive. A key pathway controlling translation initiation relies on the phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2α-P) which, in turn, blocks the guanine exchange factor activity of eIF2B, thereby reducing global translation rates. Here we report that the expression of EIF2B5 (which codes for eIF2Bε, the catalytic subunit of eIF2B) is reduced in postmortem MDD prefrontal cortex from two distinct human cohorts and in the frontal cortex of social isolation-induced depressive-like behavior model mice. Further, pharmacological treatment with anisomycin or with salubrinal, an inhibitor of the eIF2α phosphatase GADD34, induces depressive-like behavior in adult C57BL/6J mice. Salubrinal-induced depressive-like behavior is blocked by ISRIB, a compound that directly activates eIF2B regardless of the phosphorylation status of eIF2α, suggesting that increased eIF2α-P promotes depressive-like states. Taken together, our results suggest that impaired eIF2-associated translational control may participate in the pathophysiology of MDD, and underscore eIF2-eIF2B translational axis as a potential target for the development of novel approaches for MDD and related mood disorders.