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Depression and related mood disorders constitute an enormous burden on health, quality of life, and the global economy, and women have roughly twice the lifetime risk of men for experiencing depression. Here, we review sex differences in human brain physiology that may be connected to the increased susceptibility of women to major depressive disorder (MDD). Moreover, we summarize decades of preclinical research using animal models for the study of mood dysfunction that uncover some of the potential molecular, cellular, and circuit-level mechanisms that may underlie sex differences and disease etiology. We place particular emphasis on a series of recent studies demonstrating the central contribution of the circuit projecting from ventral hippocampus to nucleus accumbens and how inherent sex differences in the excitability of this circuit may predict and drive depression-related behaviors. The findings covered in this review underscore the continued need for studies using preclinical models and circuit-specific strategies for uncovering molecular and physiological mechanisms that could lead to potential sex-specific diagnosis, prognosis, prevention, and/or treatments for MDD and other mood disorders.

Background & Objective: We have previously identified aberrant connectivity of the left precuneus, ventrolateral prefrontal cortex, anterior cingulate cortex, and anterior insula in patients with either a paranoid (schizophrenia), or a depressive syndrome (both unipolar and bipolar). In the current study, we attempted to replicate and expand these findings by including a healthy control sample and separating the patients in a depressive episode into two groups: unipolar and bipolar depression. We hypothesized that the connections between those major nodes of the resting state networks would demonstrate different patterns in the three patient groups compared to the healthy subjects. Method: Resting-state functional MRI was performed on a sample of 101 participants, of which 26 patients with schizophrenia (current psychotic episodes), 24 subjects with Bipolar Disorder (BD), 33 with Major Depressive Disorder (MDD) (both BD and MDD patients were in a current depressive episode), and 21 healthy controls. Spectral Dynamic Causal Modeling was used to calculate the coupling values between eight regions of interest, including the anterior precuneus (PRC), anterior hippocampus, anterior insula, angular gyrus, lateral Orbitofrontal Cortex (OFC), middle frontal gyrus, planum temporale, and anterior thalamus. Results & Conclusion: We identified disturbed effective connectivity from the left lateral orbitofrontal cortex to the left anterior precuneus that differed significantly between unipolar depression, where the influence was inhibitory, and bipolar depression, where the effect was excitatory. A logistic regression analysis correctly classified 75% of patients with unipolar and bipolar depression based solely on the coupling values of this connection. In addition, patients with schizophrenia demonstrated negative effective connectivity from the anterior PRC to the lateral OFC, which distinguished them from healthy controls and patients with major depression. Future studies with unmedicated patients will be needed to establish the replicability of our findings.

BackgroundWhile walking in nature has been shown to improve affect in adults from the community to a greater extent than walking in urban settings, it is unknown whether such findings can be generalized to individuals suffering from depression. Using a parallel group design, this randomized controlled trial examined the effects of a single walk in nature versus urban settings on negative and positive affect in adult psychiatric outpatients diagnosed with major depressive disorder (MDD).MethodParticipants recruited from a psychiatric outpatient clinic for adults with MDD were randomly assigned to a nature or urban walk condition. Thirty-seven adults (mean age=49 years) completed a single 60-minute walk. Negative and positive affect were assessed using The Positive and Negative Affect Schedule or PANAS at 6 time points: before the walk, halfway during the walk, immediately post-walk, at home before bedtime, 24 hours post-walk, and 48 hours post-walk.ResultsControlling for baseline levels of affect before the walk, individuals who walked in nature experienced overall lower levels of negative affect, F(1, 35.039)=4.239, p=.047, compared to those who walked in urban settings. Positive affect did not differ across walk conditions.LimitationsThe generalizability of results are limited by the small sample size and the presence of more female than male participants.ConclusionsWalking in nature might be a useful strategy to improve the affect of adults with MDD. Future research should investigate different ways to integrate the beneficial effects of nature exposure into existing treatment plans for psychiatric outpatients with MDD.

The thalamic connectivity system, with the thalamus as the central node, enables transmission of the brain’s neural computations via extensive connections to cortical, subcortical and cerebellar regions. Emerging reports suggest deficits in this system across multiple psychiatric disorders, making it a unique network of high translational and transdiagnostic utility in mapping neural alterations that potentially contribute to symptoms and disturbances in psychiatric patients. However, despite considerable research effort, it is still debated how this system contributes to psychiatric disorders. This review characterizes current knowledge regarding thalamic connectivity system deficits in psychiatric disorders, including schizophrenia, bipolar disorder, major depressive disorder and autism spectrum disorder, across multiple levels of the system. We identify the presence of common and distinct patterns of deficits in the thalamic connectivity system in major psychiatric disorders and assess their nature and characteristics. Specifically, this review assembles evidence for the hypotheses of 1) thalamic microstructure, particularly in the mediodorsal nucleus, as a state marker of psychosis; 2) thalamo-prefrontal connectivity as a trait marker of psychosis; and 3) thalamo-somatosensory/parietal connectivity as a possible marker of general psychiatric illness. Furthermore, possible mechanisms contributing to thalamocortical dysconnectivity are explored. We discuss current views on the contributions of cerebellar-thalamic connectivity to the thalamic connectivity system and propose future studies to examine its effects at multiple levels, from the molecular (e.g., glutamatergic) to the behavioral (e.g., cognition), to gain a deeper understanding of the mechanisms that underlie the disturbances observed in psychiatric disorders.

Anhedonia is a core symptom of major depressive disorder (MDD) resulting from maladaptive reward processing. Electroconvulsive therapy (ECT) is an effective treatment for patients with MDD. No previous neuroimaging studies have taken a dimensional approach to assess whether ECT-induced volume changes are specifically related to improvements in anhedonia and positive valence emotional constructs. We aimed to assess the relationship between ECT-induced brain volumetric changes and improvement in anhedonia and reward processing in patients with MDD.We evaluated 15 patients with MDD before and after ECT. We used magnetic resonance imaging, clinical scales (i.e., Quick Inventory of Depressive Symptomatology for syndromal depression severity and Snaith-Hamilton Pleasure Scale for anhedonia) and the Temporal Experience of Pleasure Scale for anticipatory and consummatory experiences of pleasure. We identified 5 regions of interest within the reward circuit and a 6th control region relevant for MDD but not core to the reward system (Brodmann Area 25).Anhedonia, anticipatory and consummatory reward processing improved after ECT. Volume increases within the right reward system separated anhedonia responders and non-responders. Improvement in anticipatory (but not consummatory) reward correlated with increases in volume in hippocampus, amygdala, ventral tegmental area and nucleus accumbens.We evaluated a modest sample size of patients with concurrent pharmacological treatment using a subjective psychometric assessment.We highlight the importance of a dimensional and circuit-based approach to understanding target engagement and the mechanism of action of ECT, with the goal to define symptom- and circuit-specific response biomarkers for device neuromodulation therapies.

Acute-phase cognitive therapy (CT) is an efficacious treatment for major depressive disorder (MDD), but how CT helps patients is incompletely understood. As a potential means to clarify CT mechanisms, we defined “symptom linkage density” (SLD) as a patient’s mean time-lagged correlation among nine depressive symptoms across 13 weekly assessments. We hypothesized that patients with higher SLD during CT have better outcomes (treatment response, and fewer symptoms after response), and we explored whether SLD correlated with other possible CT processes (growth in social adjustment and CT skills). Data were drawn from two clinical trials of CT for adult outpatients with recurrent MDD (primary sample n = 475, replication sample n = 146). In both samples, patients and clinicians completed measures of depressive symptoms and social adjustment repeatedly during CT. In the primary sample, patients and cognitive therapists rated patients’ CT skills. After CT, responders were assessed for 32 (primary sample) or 24 (replication sample) additional months to measure long-term depression outcomes. Higher SLD predicted increases in social adjustment (both samples) and CT skills (primary sample) during CT, CT response (both samples), and lower MDD severity for at least 2 years after CT response (both samples). Analyses controlled patient-level symptom means and variability to estimate SLD’s incremental predictive validity. These novel findings from two independent samples with longitudinal follow-up require further replication and extension. SLD may reflect or facilitate generalization of CT skills, improvement in social functioning, or other processes responsible for CT’s shorter and longer term benefits.

Many individuals seeking mental health services for depression often suffer from a comorbid medical condition. The goal of the present study was to assess the presence of medical comorbidity in a community mental health center setting that primarily serves a Medicare and Medicaid population, characterize the types of comorbid medical conditions experienced in this setting, and explore the association between medical conditions on the alliance, attrition from services, and outcome. Medical diagnoses were collected from patient charts and structured clinical interviews from 353 participants who had a baseline assessment as part of a comparative effectiveness study of cognitive and dynamic therapies for major depressive disorder. We calculated the Charlson Comorbidity Index and the number of total medical diagnoses for each patient. Results from this study revealed that a high percentage of patients in this setting experienced a comorbid medical condition. No significant associations were found between the number of medical conditions or the Charlson Comorbidity Index and the alliance. No significant relationship was found between the number of medical conditions or the Charlson Comorbidity Index and early attrition from treatment or treatment outcome. However, exploratory analyses found that presence of a nervous system disorder was associated with relatively poorer treatment outcomes after initial engagement. Implications of these findings are discussed. Treatments for major depressive disorder may benefit from addressing the impact of medical disorders on physical functioning. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Background Major depressive disorder (MDD) is a common and highly heterogeneous psychiatric disorder but little is known about the genetic characterisation of this heterogeneity. Understanding the genetic etiology of MDD can be challenging as large sample sizes are needed for gene discovery – often achieved with a trade-off in the depth phenotyping. Methods The Australian Genetics of Depression Study is the largest stand-alone depression cohort with both genetic data and in-depth phenotyping and comprises a total of 15,792 participants of European ancestry, 92% of whom, met diagnostic criteria for MDD. We leveraged the unique nature of this cohort to conduct a meta-analysis with the largest depression GWAS to date and subsequently used polygenic scores (PGS) to investigate genetic heterogeneity across various clinical subtypes of MDD. Results We increased the number of known genome-wide significant variants associated with depression from 103 to 126 and found evidence of association of novel genes implicated in neuronal development. We show that a PGS for depression explains 5.7% of variance in MDD liability in our sample. Lastly, we find strong support for genetic heterogeneity in depression with differential associations of multiple psychiatric and comorbid traits with age of onset, longitudinal course and various subtypes of MDD. Conclusions Until now, this degree of detailed phenotyping in such a large sample of MDD cases has not been possible. Along with discovery of novel loci, we provide support for differential pathways to illness models that recognize both the overlap with other common psychiatric disorders, as well as pathophysiological differences.

Background: Both major depressive disorder (MDD) and schizophrenia (SCH) are characterized by neurodevelopmental abnormalities; however, transdiagnostic and diagnosis-specific patterns of such abno...

Marital problems are one of the leading causes of depression in low income countries. In collectivistic cultures, inability to bear child makes individual more vulnerable towards depression. An increasing body of literature suggests the efficacy of solution-focused brief therapy for depressive disorders. People with eagerness to see change and not showing response for cognitive behaviour therapy respond to solution-focused brief therapy. This case study describes the course of major depressive disorder in a 39-year-old female and treatment strategy of solution-focused brief therapy. The client in this case responded to the therapy and also showed optimistic change in her attitude. Treatment implications of solution-focused brief therapy with its effectiveness on females with major depressive disorder have been discussed in the article.

Objective Sexual minority female (SMF) veterans experience unique stressors apart from their service in the military. In this study, we compared SMF and heterosexual female (HF) veterans' rates of deployment-related stressors (i.e., military sexual assault, combat exposure, and harassment), posttraumatic stress disorder (PTSD), and major depressive disorder (MDD) and their association with one another. Method Participants were 699 female veterans who provided self-report data on exposure to deployment-related stressors and were assessed for MDD and PTSD by trained diagnosticians. Results SMF and HF veterans had similar rates of PTSD, MDD, and deployment-related stressors. However, deployment-related stressors were less likely to be associated with diagnosis or symptoms of either PTSD or MDD among SMF veterans. Conclusion SMF veterans may have unique stressors driving their development of MDD and PTSD. Understanding how different military stressors may confer risk for SMF veterans versus HF veterans is necessary to provide informed and sensitive clinical care to SMF veterans. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Background Cannabis remains one of the most widely abused drugs during pregnancy. In utero exposure to its principal psychoactive component, Δ9-tetrahydrocannabinol (THC), can result in long-term neuropsychiatric risk for the progeny. The current study investigated epigenetic signatures underlying these enduring consequences. Methods Rat dams were exposed daily to THC (0.15mg/kg) during pregnancy and adult male offspring were examined for reward and depressive-like behavioral endophenotypes. Using unbiased sequencing approaches, we explored transcriptional and epigenetic profiles in the nucleus accumbens (NAc), a brain area central to reward and emotional processing. An in vitro CRISPRa model coupled with RNA-sequencing was also applied to study specific consequences of epigenetic dysregulation and altered molecular signatures were compared to human major depressive disorder (MDD) transcriptome datasets. Results Prenatal THC-exposure induced increased motivation for food, heightened learned helplessness and anhedonia, and altered stress sensitivity. We identified a robust increase specific to males in the expression of Histone-Lysine N-Methyltransferase 2A (Kmt2a) that targets lysine 4 on histone H3 (H3K4me) in cellular chromatin. Normalizing Kmt2a in the NAc restored the motivational phenotype of prenatally THC-exposed animals. Comparison of RNA and H3K4me3 sequencing datasets from the NAc of rat offspring with the in vitro model of Kmt2a upregulation revealed overlapping, significant disturbances in pathways that mediate synaptic plasticity. Similar epigenetic alterations were detected in human MDD. Conclusions These studies provide direct evidence for the persistent effects of prenatal cannabis exposure on transcriptional and epigenetic deviations in the NAc via Kmt2a dysregulation and associated psychiatric vulnerability.

This study aimed to develop and assess the effectiveness of an encounter decision aid for Malaysian patients with MDD to support treatment decision-making during the consultation.The decision aid prototype was developed following a literature review and six focus groups. Alpha testing assessed its comprehensibility, acceptability, usability and desirability through user-centered cognitive interviews. Beta-testing evaluated preliminary evidence on its efficacy using the SDM Scale and PDMS. Feasibility was assessed by timing the consultation.The alpha testing demonstrated that the decision aid was patient-oriented, comprehensible, comprehensive, concise and objective with an appealing design. Beta-testing indicated that PtDA significantly increased patients satisfaction with SDM from patients' [83.32 (13.92) vs 85.76 (13.80); p 0.05] and physicians' [81.07 (10.09) vs 86.36 (10.10); p 0.05] perspectives and prepared the patients for decision making from the patients' [PDMS patients: 84.10 (12.69)] and physicians' [PDMS physicians: 83.78 (16.62)] perspectives as well. There was no change in the consultation time between the control and the intervention groups.We developed an antidepressant PtDA for Malaysian patients with MDD that increases patients' involvement in shared decision making and enhances their preparedness for decision making.Using the PtDA can support collaborative decision-making in routine clinical practice without extending the consultation time.

Major depressive disorder (MDD) is a disease associated with many factors; specifically, environmental, genetic, psychological, and biological factors play critical roles. Recent studies have demonstrated that histone modification may occur in the human brain in response to severely stressful events, resulting in transcriptional changes and the development of MDD. In this review, we discuss five different histone modifications, histone methylation, histone acetylation, histone phosphorylation, histone crotonylation and histone β-hydroxybutyrylation, and their relationships with MDD. The utility of histone deacetylase (HDAC) inhibitors (HDACis) for MDD treatment is also discussed. As a large number of MDD patients in China have been treated with traditional Chineses medicine (TCM), we also discuss some TCM therapies, such as Xiaoyaosan (XYS), and their effects on histone modification. In summary, targeting histone modification may be a new strategy for elucidating the mechanism of MDD and a new direction for MDD treatment.

Repetitive transcranial magnetic stimulation (rTMS) is a tool that can be used to administer treatment for neuropsychiatric disorders such as major depressive disorder, although the clinical efficacy is still rather modest. Overly general stimulation protocols that consider neither patient-specific depression symptomology nor individualized brain characteristics, such as anatomy or structural and functional connections, may be the cause of the high inter- and intraindividual variability in rTMS clinical responses. Multimodal neuroimaging can provide the necessary insights into individual brain characteristics and can therefore be used to personalize rTMS parameters. Optimal coil positioning should include a three-step process: 1) identify the optimal (indirect) target area based on the exact symptom pattern of the patient; 2) derive the cortical (direct) target location based on functional and/or structural connectomes derived from functional and diffusion magnetic resonance imaging data; and 3) determine the ideal coil position by computational modeling, such that the electric field distribution overlaps with the cortical target. These TMS-induced electric field simulations, derived from anatomical and diffusion magnetic resonance imaging data, can be further applied to compute optimal stimulation intensities. In addition to magnetic resonance imaging, electroencephalography can provide complementary information regarding the ongoing brain oscillations. This information can be used to determine the optimal timing and frequency of the stimuli. The heightened benefits of these personalized stimulation approaches are logically reasoned, but speculative. Randomized clinical trials will be required to compare clinical responses from standard rTMS protocols to personalized protocols. Ultimately, an optimized clinical response may result from precision protocols derived from combinations of personalized stimulation parameters.

Background: Identification of a peripheral biological marker might aid in identifying patients at high risk of attempting suicide and might help in effective early intervention. Objective: In the present study, we extend the findings of our previous multidimensional proteomics study by examining the levels of plasma Apolipoprotein-AIV in patients diagnosed with major depression with and without suicidal ideation compared to age and gender-matched controls. Methods: Using the mass spectrometry platform, we quantified the levels of plasma Apolipoprotein- AIV in patients with major depressive disorder with and without suicidal ideation compared to matched controls with isotope-labelled peptides-based quantitative proteomics approach. Results: The targeted quantitative proteomics approach with isotope-labelled peptides showed that plasma Apolipoprotein-AIV was significantly downregulated in depressed patients having suicidal ideation 1.45 (CI:1.11-1.90) compared to those without suicidal ideation 0.88 (CI:0.77-1.003). Conclusion: These findings extend our earlier observation of downregulation of plasma Apolipoprotein- AIV in patients with suicidal attempts to depressed patients with suicidal ideation. The consistent downregulation of plasma Apolipoprotein-AIV observed in both the proteomics studies suggests Apolipoprotein-AIV might be a plasma-based biomarker for suicidal behaviour.

Objectives Vagus nerve stimulation (VNS) is reemerging as an exciting form of brain stimulation, due in part to the development of its noninvasive counterpart transcutaneous auricular VNS. As the field grows, it is important to understand where VNS emerged from, including its history and the studies that were conducted over the past four decades. Here, we offer a comprehensive review of the history of VNS in the treatment of major depression. Materials and methods Using PubMed, we reviewed the history of VNS and aggregated the literature into a narrative review of four key VNS epochs: 1) early invention and development of VNS, 2) path to Food and Drug Administration (FDA) approval for depression, 3) refinement of VNS treatment parameters, and 4) neuroimaging of VNS. Results VNS was described in the literature in the early 1900s; however, gained traction in the 1980s as Zabara and colleagues developed an implantable neurocybernetic prosthesis to treat epilepsy. As epilepsy trials proceed in the 1990s, promising mood effects emerged and were studied, ultimately leading to the approval of VNS for depression in 2005. Since then, there have been advances in understanding the mechanism of action. Imaging techniques like functional magnetic resonance imaging and positron emission tomography further aid in understanding direct brain effects of VNS. Conclusions The mood effects of VNS were discovered from clinical trials investigating the use of VNS for reducing seizures in epileptic patients. Since then, VNS has gone on to be FDA approved for depression. The field of VNS is growing, and as noninvasive VNS quickly advances, it is important to consider a historical perspective to develop future brain stimulation therapies.

INTRODUCTION Few studies have examined the changes in the prevalence of comorbidity of mental and physical disorders in recent years. The present study sought to examine whether the prevalence of comorbidity of mental and physical disorders in Singapore showed any changes between 2010 and 2016. METHODS We extracted data from two repeated nationally representative cross-sectional surveys conducted among resident adults aged ≥ 18 years in Singapore. Significant changes were tested using pooled multinomial logistic regression analyses. RESULTS The prevalence of comorbid mental and physical disorders increased significantly from 5.8% in 2010 to 6.7% in 2016. Among those with physical disorders, there were significant increases over time in the prevalence of comorbid generalised anxiety disorder (GAD) (0.1% vs. 0.4%) and obsessive-compulsive disorder (OCD) (1.4% vs. 3.9%) in diabetes mellitus, and alcohol dependence in cardiovascular disorders (0.1% vs. 1.3%). Among those with mental disorders, there were significant increases over time in the prevalence of comorbid diabetes mellitus in OCD (4.1% vs. 10.9%), cancer in major depressive disorder (0.4% vs. 2.4%), and cardiovascular disorders in GAD (0.4% vs. 6.7%) and alcohol dependence (0.9% vs. 11.8%). Significant changes in the overall prevalence of comorbid mental and physical disorders were also observed across age group, education and employment status. CONCLUSION The prevalence of comorbid mental and physical disorders increased significantly over time. This finding supports the need for more appropriate clinical management with better integration between mental health and general medical care professionals across all aspects of the healthcare system to treat this comorbidity in Singapore.

OBJECTIVE: Adolescent depression is prevalent and is associated with significant morbidity and mortality. Although intravenous ketamine has shown efficacy in adult treatment-resistant depression, its efficacy in pediatric populations is unknown. The authors conducted an active-placebo-controlled study of ketamine’s safety and efficacy in adolescents. METHODS: In this proof-of-concept randomized, double-blind, single-dose crossover clinical trial, 17 adolescents (ages 13–17) with a diagnosis of major depressive disorder received a single intravenous infusion of either ketamine (0.5 mg/kg over 40 minutes) or midazolam (0.045 mg/kg over 40 minutes), and the alternate compound 2 weeks later. All participants had previously tried at least one antidepressant medication and met the severity criterion of a score >40 on the Children’s Depression Rating Scale–Revised. The primary outcome measure was score on the Montgomery-Åsberg Depression Rating Scale (MADRS) 24 hours after treatment. RESULTS: A single ketamine infusion significantly reduced depressive symptoms 24 hours after infusion compared with midazolam (MADRS score: midazolam, mean=24.13, SD=12.08, 95% CI=18.21, 30.04; ketamine, mean=15.44, SD=10.07, 95% CI=10.51, 20.37; mean difference=−8.69, SD=15.08, 95% CI=−16.72, −0.65, df=15; effect size=0.78). In secondary analyses, the treatment gains associated with ketamine appeared to remain 14 days after treatment, the latest time point assessed, as measured by the MADRS (but not as measured by the Children’s Depression Rating Scale–Revised). A significantly greater proportion of participants experienced a response to ketamine during the first 3 days following infusion as compared with midazolam (76% and 35%, respectively). Ketamine was associated with transient, self-limited dissociative symptoms that affected participant blinding, but there were no serious adverse events. CONCLUSIONS: In this first randomized placebo-controlled clinical trial of intravenous ketamine in adolescents with depression, the findings suggest that it is well tolerated acutely and has significant short-term (2-week) efficacy in reducing depressive symptoms compared with an active placebo. Reprinted from Am J Psychiatry 2021; 178:352–362 with permission from American Psychiatric Association Publishing.

BACKGROUND: Left frontal alpha oscillations are associated with decreased approach motivation and have been proposed as a target for non-invasive brain stimulation for the treatment of depression and anhedonia. Indeed, transcranial alternating current stimulation (tACS) at the alpha frequency reduced left frontal alpha power and was associated with a higher response rate than placebo stimulation in patients with major depressive disorder (MDD) in a recent double-blind placebo controlled clinical trial. METHODS: In this current study, we aimed to replicate successful target engagement by delineating the effects of a single session of bifrontal tACS at the individualized alpha frequency (IAF-tACS) on alpha oscillations in patients with MDD. 84 participants were randomized to receive verum or sham IAF-tACS. Electrical brain activity was recorded during rest and while viewing emotionally-salient images before and after stimulation to investigate if the modulation of alpha oscillation by tACS exhibited specificity with regards to valence. RESULTS: In agreement with the previous study of tACS in MDD, we found that a single session of bifrontal IAF-tACS reduced left frontal alpha power during the resting state when compared to placebo. Furthermore, the reduction of left frontal alpha oscillation by tACS was specific for stimuli with positive valence. In contrast, these effects on left frontal alpha power were not found in healthy control participants. CONCLUSION: Together these results support an important role of tACS in reducing left frontal alpha oscillations as a future treatment for MDD. NATIONAL CLINICAL TRIAL: NCT03449979, “Single Session of tACS in a Depressive Episode (SSDE)” https://www.clinicaltrials.gov/ct2/show/NCT03449979

Individuals with intellectual and developmental disabilities (IDD) are at high risk of co-occurring mental health conditions, including major depressive disorder, bipolar disorder, anxiety disorders, psychotic illnesses, impulse control disorders, and others. Because of symptoms associated with these illnesses and with the disabilities themselves, these individuals are often served in a mental health service system framework. However, treatment for them in these settings has typically not been sufficiently nimble, knowledgeable, or adept. Most mental health professionals receive little training about the needs of this population, and system structures typically bifurcate care, when, in reality, conditions can be complex and overlapping. In this first of two articles on care for persons with IDD in the mental health system, the authors provide a clinical overview of these neurodevelopmental disorders and of mental health and other conditions that co-occur with IDD. Considerations and challenges for treating this population in the mental health system include early recognition of mental health conditions, which often requires caregiver and family input, as well as information from a variety of additional collateral sources; the importance of trauma-informed and person-centered care; the promotion of self-determination through use of decision supports; use of approaches such as applied behavior analysis to develop a frame to address challenging behaviors; and the need to properly assess and provide thoughtful pharmacologic intervention when appropriate. The ability of individuals with IDD to thrive in a wide range of community integration opportunities depends on many factors, and clinicians must understand and use the available approaches for treating them.

Background Brain functional alterations during emotion processing in patients with major depressive disorder (MDD) compared with healthy control subjects (HCs) are frequently reported. However, evidence for functional correlates of emotion processing with regard to MDD trajectories is scarce. This study investigates the role of lifetime disease course for limbic brain activation during negative emotional face processing in patients with MDD. Methods In a large sample of patients with MDD (n = 333; 58.55% female) and HCs (n = 333; 60.06% female), brain activation was investigated during a negative emotional face-processing task within a cross-sectional design. Differences between HC and MDD groups were analyzed. Previous disease course, characterized by 2 components, namely hospitalization and duration of illness, was regressed on brain activation of the amygdala, (para-)hippocampus, and insula in patients with MDD. Results Patients with MDD showed increased activation in the amygdala, insula, and hippocampus compared with HCs (all p values corrected for familywise error [pFWE] .057). Conclusions This study investigated negative emotion processing in a large sample of patients with MDD and HCs. Our results confirm limbic hyperactivation in patients with MDD during negative emotion processing; however, this hyperactivation may resolve with a more severe lifetime disease course in the insula and (para-)hippocampus—brain regions involved in emotion processing and regulation. These findings need further replication in longitudinal studies.

The loss of a spouse is a common and natural life event for older adults. Nearly one of four older bereaved spouses experience prolonged grief, impaired function or chronic depression. Mechanisms underlying these and other long-term health risks are not well understood. We conducted a scoping literature review to examine the interventions and outcomes that have been studied for late-life spousal bereavement to date. We identified 22 studies of group and individual-level interventions with most studies concerning grief processes within the first year. Nearly all studies evaluated emotional and psychological symptoms of loss and a small number evaluated the restoration of adaptive functioning. Four interventions addressed the treatment of complicated grief or grief with major depressive disorder. Qualitative studies explored themes of spirituality and mindfulness. There were 17 controlled studies, including 13 randomized controlled trials. Findings were eclectic, with evidence supporting mindfulness techniques in a group format for emotional and life satisfaction outcomes; an individual, function-based therapy addressing sleep to improve emotion and function; an individual, writing-based emotional expression therapy for short-term improvement in emotion and function; nortriptyline for the treatment of bereavement-related major depressive disorder; a group-based, complicated grief therapy for this condition; an internet-based CBT intervention for prolonged grief; and pharmacotherapy for cardiovascular changes during bereavement. These findings highlight the small literature of methodologically strong intervention studies addressing spousal bereavement in older adults and the need for greater exploration of relevant biological, social, cognitive and behavioral factors to improve short and long term health outcomes.

Electrical neuromodulation is an approved therapy for a number of neurologic disease states, including Parkinson's disease (PD), Obsessive Compulsive Disorder, Essential Tremor, epilepsy and neuropathic pain. Neuromodulatory strategies are also being piloted for an increasing number of additional indications, including Major Depressive Disorder, Dystonia, and addiction. The development of implantable devices capable of both neural sensing and adaptive stimulation may prove essential for both improving therapeutic outcomes and expanding the neuromodulation indication space. Nevertheless, an increasingly fragmented device ecosystem forces researchers and therapy developers to customize and reinvent data visualization, clinician engagement, and device control software to support individual clinical studies. Each hardware platform provides a unique software interface to the implanted neurostimulator, making pre-existing code from prior studies difficult to leverage for future work ‐‐ a hindrance that will expand as device technology diversifies. Here, we envision, detail, and demonstrate the use of a novel software architecture, OMNI, that accelerates neuromodulation research by providing a flexible, platform- and device-agnostic interface for clinical research and therapy development.

BackgroundSeveral social determinants of health (SDoH) have been associated with the onset of major depressive disorder (MDD). However, prior studies largely focused on individual SDoH and thus less is known about the relative importance (RI) of SDoH variables, especially in older adults. Given that risk factors for MDD may differ across the lifespan, we aimed to identify the SDoH that was most strongly related to newly diagnosed MDD in a cohort of older adults.MethodsWe used self-reported health-related survey data from 41 174 older adults (50–89 years, median age = 67 years) who participated in the Mayo Clinic Biobank, and linked ICD codes for MDD in the participants' electronic health records. Participants with a history of clinically documented or self-reported MDD prior to survey completion were excluded from analysis (N = 10 938, 27%). We used Cox proportional hazards models with a gradient boosting machine approach to quantify the RI of 30 pre-selected SDoH variables on the risk of future MDD diagnosis.ResultsFollowing biobank enrollment, 2073 older participants were diagnosed with MDD during the follow-up period (median duration = 6.7 years). The most influential SDoH was perceived level of social activity (RI = 0.17). Lower level of social activity was associated with a higher risk of MDD [hazard ratio = 2.27 (95% CI 2.00–2.50) for highest v. lowest level].ConclusionAcross a range of SDoH variables, perceived level of social activity is most strongly related to MDD in older adults. Monitoring changes in the level of social activity may help identify older adults at an increased risk of MDD.

Background H protons magnetic resonance spectroscopy (1H-MRS) has been used to detect abnormal biochemical changes and the mechanism of executive dysfunction in major depressive disorder (MDD). While, finding information associated with non-suicidal self-injury (NSSI) among adolescents with MDD is challenging. The present study aimed to examine the executive function and biochemical metabolism alterations as well as to elucidate their associations in depressed adolescents with NSSI. Methods A total of 86 adolescents with MDD (40 with NSSI, and 46 without NSSI) and 28 healthy controls were recruited in the current study. The executive function was assessed by Digital symbol test (DST), Wisconsin Card Sorting Test (WCST), Trail Making Test, part B (TMT-B), and Verbal fluency (VF). Bilateral metabolite levels of the prefrontal cortex (PFC), anterior cingulated cortex (ACC), lenticular nucleus (LN) of basal ganglia and thalamus were obtained by 1H-MRS at 3.0 T, and then the ratios of N-acetyl aspartate (NAA) and choline-containing compounds (Cho) to creatine (Cr) were determined, respectively. Finally, association analysis was conducted to investigate their relationships. Results The depressed adolescents with NSSI showed significantly lower VF scores than those without NSSI and healthy controls. We also found significantly higher NAA/Cr ratios in the right thalamus, while significantly lower Cho/Cr ratios in the right thalamusof NSSI group than the MDD without NSSI group and healthy controls. And NSSI group also showed lower NAA/Cr ratio in the right LNthan the MDD without NSSI group. For MDD with NSSI, the NAA/Cr ratios of the left thalamus was positively correlated with the time of TMTB and the Cho/Cr ratios of the left ACC was positively correlated with the VF scores. Conclusions Depressed adolescents with NSSI may have executive dysfunction and an abnormal NAA and Cho metabolism in thalamus. Andthe NAA/Cr ratios of the right LN could distinguish NSSI from depressed adolescents. Further, the executive dysfunction may associated with the abnormal NAA metabolism in the right thalamus and ACC.

Depression is the leading cause of disability worldwide, and half of patients with depression have treatment-resistant depression. Intermittent theta-burst stimulation (iTBS) is approved by the U.S. Food and Drug Administration for the treatment of treatment-resistant depression but is limited by suboptimal efficacy and a 6-week duration. The authors addressed these limitations by developing a neuroscience-informed accelerated iTBS protocol, Stanford neuromodulation therapy (SNT; previously referred to as Stanford accelerated intelligent neuromodulation therapy, or SAINT). This protocol was associated with a remission rate of ∼90% after 5 days of open-label treatment. Here, the authors report the results of a sham-controlled double-blind trial of SNT for treatment-resistant depression.Participants with treatment-resistant depression currently experiencing moderate to severe depressive episodes were randomly assigned to receive active or sham SNT. Resting-state functional MRI was used to individually target the region of the left dorsolateral prefrontal cortex most functionally anticorrelated with the subgenual anterior cingulate cortex. The primary outcome was score on the Montgomery-Åsberg Depression Rating Scale (MADRS) 4 weeks after treatment.At the planned interim analysis, 32 participants with treatment-resistant depression had been enrolled, and 29 participants who continued to meet inclusion criteria received either active (N=14) or sham (N=15) SNT. The mean percent reduction from baseline in MADRS score 4 weeks after treatment was 52.5% in the active treatment group and 11.1% in the sham treatment group.SNT, a high-dose iTBS protocol with functional-connectivity-guided targeting, was more effective than sham stimulation for treatment-resistant depression. Further trials are needed to determine SNT's durability and to compare it with other treatments.

OBJECTIVES: Arabs in Israel have been found to experience higher levels of mental distress compared to Jews due to COVID-19. However, the social mechanisms underlying mental health vulnerability in the context of mass crisis have been understudied. Based on the Conservation of Resources (COR) theory, the aim of the current study was to examine experiences of resource loss, social exclusion, ethnic discrimination, and social support and their association with depression and anxiety symptoms during the COVID-19 outbreak among Arabs in Israel. METHOD: The sample included 665 adult Arabs in Israel who completed an online self-report questionnaire regarding background variables, resource loss due to COVID-19, social exclusion, ethnic discrimination, social support, and depression and anxiety symptoms. RESULTS: Participants reported on average mild depression and anxiety severity scores, and 15.2% met criteria for major depressive disorder. Many (43.1%) reported experiencing more than 1 loss due to COVID-19 in health, finances or occupation, and interpersonal relationships. Path analyses show that cumulative losses due to COVID-19 and social exclusion were directly associated with depression and anxiety symptom levels. Discrimination moderated the association between losses and both depression and anxiety symptom levels. CONCLUSION: Mental health is embedded in dynamic sociopolitical contexts. Arabs as a national minority in Israel have a perceived sense of social exclusion and discrimination and social and material resource deprivation, which relates to their vulnerability, especially in the face of crisis. It is our obligation as researchers and practitioners to illuminate the centrality of these oppressive mechanisms in shaping mental health vulnerability. Clinical Impact Statement: The present study suggests that social exclusion and cumulative resource losses due to COVID-19 in areas of health, occupation, finances, and social connections predict depression and anxiety among Arabs in Israel. In addition, ethnic discrimination moderates the relationship between cumulative losses and mental health outcomes. These results highlight the importance of developing and implementing context-informed health and social care policies and practices, especially in this time of crisis. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

PURPOSE: Although many studies have shown that transgender women (TW) tend to have more depressive symptoms compared with the general population, the exact prevalence of major depressive disorder and contributing risk factors have not yet been studied, especially in those who have undergone gender-affirming genital surgery (GAS). METHODS: Every TW aged 20–60 years attending transgender clinics in the Thai Red Cross Society for postoperative checkup were invited to complete a self-report questionnaire, including (1) demographic data, (2) the Thai Patient Health Questionnaire 9 (PHQ-9), (3) satisfaction with psychosocial factors (relationship in family, friends, and society), sexual experiences and outcomes of gender-affirming treatments before and after GAS, and (4) contributing factors to depressive symptoms. Correlations between demographic data and depressive scores were tested. Paired t-test was used to compare pre- and post-GAS data. RESULTS: A total of 97 TW were analyzed, with 22.7% considered to have “major depression” (PHQ-9≥9) after GAS. Postoperative improvement in satisfaction with psychosocial factors and gender-affirming treatment outcomes were observed, especially in sexual experience. Depression severity was found to be negatively correlated with age and sexual satisfaction. Notably, presence of male characteristics before surgery, poor social support and understanding, and postoperative surgical complications were greatly considered as factors contributing to depressive symptoms. CONCLUSION: Compared with non-GAS TW, depression among those who underwent GAS in Thailand was lower but still significant and was linked to younger age and poor postoperative sexual experiences. These findings were supported by the number of qualitative assessments in the psychosexual domain and postoperative treatment outcomes. Clinical Trial Registration Number - TCTR20190904003.

Background Despite the importance of Beck's theoretical cognitive model of psychopathology, the neural mechanisms underlying future thinking in cognitive behavioral therapy (CBT) remain elusive. Recent neuroimaging studies have shown that the function of the frontopolar cortex (Brodmann area 10 [BA10]) is associated with future thinking. We hypothesized that, compared with unstructured psychotherapy (talking control: TC), CBT may involve different neural responses in BA10 associated with future thinking. Methods This randomized clinical trial included 38 adult patients with moderate-to-severe major depressive disorder who underwent up to 16 weeks of CBT or TC with a 6-month follow-up period. We evaluated changes in BA10 activation during distant future thinking using functional magnetic resonance imaging during a future-thinking task. We assessed frontal neurocognitive function and clinical symptoms at baseline and post-treatment. Depression severity and automatic thoughts were assessed at the 6-month follow-up. Results We found decreased activation in the frontopolar cortex during distant future thinking after CBT (t=3.00, df=15, p=0.009) and no changes after TC. Further, the reduction in BA10 activity significantly correlated with changes in frontal cognitive function after the treatment (r=0.48, p=0.007), and in positive automatic thought after 6 months of treatments (r=0.39; p=0.03). Limitations Relatively small sample size and homogenous clinical profile could limit the generalizability. Patients received pharmacotherapy including antidepressant. Conclusions CBT appears to improve frontopolar cortex function during future thinking in a manner distinct from TC. Larger clinical trials are necessary to provide firm evidence whether BA10 activity may serve as a neuro-marker for monitoring successful depression treatment with CBT.

Psychiatric disorders in first-degree relatives (FDRs) often differ from the index patient's diagnosis, suggesting that there is genetic contribution to psychiatric disorders in which related cases do not all map to the same diagnosis as the index case. Our aim is to look for psychiatric comorbidities across major mental illnesses using three approaches, genetics, clinical diagnosis, and brain imaging to address common associations and pathology among mental illnesses. Genome-wide association studies from the Psychiatric Genomics Consortium showed single gene polymorphisms are common across 5 major psychiatric disorders, including schizophrenia (SZ), bipolar disorder (BD), major depressive disorder (MDD), autism spectrum disorder (ASD), and attention deficit hyperactivity disorder (ADHD). Clinically, results of Taiwan's nationwide population studies showed that other major psychiatric disorders were more likely to coaggregate in families with an index case of an individual with a psychiatric disorder, compared to control families. Finally, resting functional connectivity (FC) magnetic resonance imaging (MRI) and whole-brain connectomic analysis of SZ, BD I, BD II, MDD, and healthy controls revealed that the four groups of patients shared similar patterns of abnormal neural substrate in the brain that differed from controls. In conclusion, using big data from genetics, administrative health claims, and brain imaging, we identified concordance, indicating dimensional coherence of genetic heritability, clinical mutual associations, and common neurobiological substrates across major psychiatric disorders. These results will challenge the current diagnostic classification system and possibly move psychiatry beyond descriptive syndromes towards a nosology informed by disease cause.

BACKGROUND: Treatment studies of children and adolescents with internalizing disorders suggest that the combination of a selective serotonin reuptake inhibitor (SSRI) and cognitive behavioral therapy (CBT) consistently produces greater improvement than either treatment alone. We sought to determine how response to combined treatment varies across disorders (anxiety versus depression), and by specific patient characteristics. METHODS: Three large National Institutes of Health-funded trials of children and adolescents with major depression (n=2) and anxiety disorders (n=1) were evaluated, each comparing CBT + SSRI to SSRI only, Bayesian Hierarchical Models (BHMs) were used, for endpoint response, time course of response and predictors of response in participants who received SSRI or SSRI+CBT. RESULTS: SSRI+CBT significantly decreased symptoms by week 4 (p

Rapid antidepressant effects associated with ketamine have shifted the landscape for the development of therapeutics to treat major depressive disorder (MDD) from a monoaminergic to glutamatergic model. Treatment with ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, may be effective, but has many non-glutamatergic targets, and clinical and logistical problems are potential challenges. These factors underscore the importance of manipulations of binding mechanics to produce antidepressant effects without concomitant clinical side effects. This will require identification of efficient biomarkers to monitor target engagement. The mismatch negativity (MMN) is a widely used electrophysiological signature linked to the activity of NMDA receptors (NMDAR) in humans and animals and validated in pre-clinical and clinical studies of ketamine. In this review, we explore the flexibility of the MMN and its capabilities for reliable use in drug development for NMDAR antagonists in MDD. We supplement this with findings from our own research with three distinct NMDAR antagonists. The research described illustrates that there are important distinctions between the mechanisms of NMDAR antagonism, which are further crystallized when considering the paradigm used to study the MMN. We conclude that the lack of standardized methodology currently prevents MMN from being ready for common use in drug discovery. Clinical trial registration: This manuscript describes data collected from the following National Institutes of Health (NIH) and Veterans Affairs (VA) studies: AV-101, NCT03583554; lanicemine, NCT03166501; ketamine, NCT02556606.

Introduction Social anxiety disorder (SAD) and major depressive disorder (MDD) often co-occur; however, there is limited research evaluating how cognitive-affective and behavioral factors maintain SAD and MDD for specific individuals. Evidence suggests that individuals exhibit symptom-level heterogeneity, necessitating a person-specific approach to assessment and intervention. We compared group and person-specific models of SAD-MDD comorbidity and hypothesized that individuals would demonstrate person-specific patterns of comorbidity factors that differed from the group. Methods Cisgender women (N = 35) with SAD and a current or past major depressive episode were recruited. Ages ranged from 18 to 37 years old and a majority of women were White (n = 18; 51.43%). Brief ecological momentary assessment surveys related to SAD-MDD comorbidity were administered five times a day for a month (T = 4,357). Results Multilevel and person-specific network analyses were used to examine between-, within-, and person-specific patterns. Intra-daily depressed mood demonstrated the strongest connections to other variables and exhibited additional, unexpected temporal effects. All models demonstrated person-specific patterns relevant to SAD-MDD comorbidity. Limitations These results are descriptive in nature from women with a similar psychiatric profile. Future research integrating intensive EMA and personalized modeling within the context of experimental design is needed to determine the extent to which individuals truly differ from the group. Conclusions Patterns of SAD-MDD comorbidity varied substantially across women, underscoring the potential for results from person-specific (idiographic) networks to inform the development and implementation of personalized directives for clinical assessment and intervention.

Background The amygdala is vital in processing psychological stress and predicting vulnerability or resilience to stress-related disorders. This study aimed to build the link between functional magnetic resonance imaging data obtained before the stress event and the subsequent stress-related depressive symptoms. Methods Neuroimaging data obtained before the coronavirus disease 2019 pandemic from 39 patients with major depressive disorder (MDD) and 61 health controls (HCs) were used in this study. The participants were divided retrospectively into four groups in accordance with the severity of depressive symptoms during the pandemic: remitted patients, non-remitted patients, depressed HCs (HCd) and non-depressed HCs (HCnd). Seed-based resting-state functional connectivity (rsFC) analyses of the amygdala and its subregions, including the centromedial (CM), the basolateral and the superficial (SF), were performed. Results Vulnerability to depression was suggested by decreased rsFC between the left CM amygdala and the bilateral lingual gyrus in the HCd group compared with the HCnd group, and decreased rsFC of the left CM or right SF amygdala with the precuneus and the postcentral gyrus in the HCd group compared with patients with MDD. No evidence supported the rsFC of the amygdala or its subregions as a biomarker for the resilience of patients with MDD to stress under antidepressant treatment. Limitations Smaller sample size and no longitudinal neuroimaging data. Conclusions Our findings suggested that the rsFC of amygdala subregions may represent a neurobiological marker of vulnerability to depression following stress.

Background Studies show that disturbances of the fronto-striato-thalamic-cerebellar circuit could be correlated to facial emotion processing (FEP) biases in major depressive disorder (MDD). Nevertheless, the underlying mechanism of natural metabolism-emotion relationships in adolescent MDD remains unclear. Methods Thirty-seven adolescent patients with MDD and 30 healthy controls completed FEP tasks using the Chinese Facial Affective Picture System (CAFPS). Proton magnetic resonance spectroscopy (1H-MRS) was also used to obtain ratios of N-acetylaspartate (NAA) /creatine (Cr) and choline (Cho) /Cr ratios in the prefrontal cortex (PFC), anterior cingulate cortex (ACC), putamen, thalamus and cerebellum. Correlations between abnormal neurometabolic ratios and FEP were also computed. Results Compared with the control group, the MDD group had significantly lower accuracy and perception intensity of happiness, and significantly higher accuracy of disgust and perception intensity of sad and fearful faces in FEP tasks. Compared to healthy controls, adolescent patients with MDD showed significantly lower NAA/Cr ratios in the left PFC, higher NAA/Cr ratios in the right thalamus, and higher Cho/Cr ratios in the right putamen, although there were no significant differences in metabolites in the ACC and cerebellum between two groups. In the MDD group, NAA/Cr ratios of the right thalamus were negatively correlated with happy reaction time and positively correlated with sad, anger, and fear intensity; Cho/Cr ratios in the right putamen were positively correlated with fear reaction time. Conclusions Our findings suggest that FEP bias may exist in adolescents with MDD, while the impairment of FEP may be associated with abnormal metabolites in the fronto-striato-thalamic circuit.

Big Data neuroimaging collaborations including Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) integrated worldwide data to identify regional brain deficits in major depressive disorder (MDD). We evaluated the sensitivity of a novel approach to translate ENIGMA-defined MDD deficit patterns to the individual level. We treated ENIGMA MDD regional deficit patterns as a vector to gauge the similarity between an individual and MDD pattern by calculating ENIGMA dot product (EDP). We analyzed the sensitivity and specificity of EDP in separating subjects with (1) subclinical depressive symptoms but without a diagnosis of MDD, (2) single episode MDD, (3) recurrent MDD, and (4) controls free of neuropsychiatric disorders. We compared EDP to the Quantile Regression Index (QRI; a linear alternative to the widely used ‘brain age’ metric) and the global gray matter thickness and subcortical volumes and fractional anisotropy (FA) of water diffusion. We performed this analysis in a large epidemiological sample of UK Biobank (UKBB) participants (N=17,053/19,265 M/F, age=64.8±7.4 years). Group-average increases in depressive symptoms from controls to recurrent MDD was mirrored by EDP (r2=0.85), followed by FA (r2=0.81) and QRI (r2=0.56). Subjects with MDD showed worse performance on cognitive tests than controls with significant deficits observed for 3 out of 9 cognitive tests administered by the UKBB. We calculated correlations of EDP and other brain indices with measures of cognitive performance in controls. The correlation pattern between EDP and cognition in controls was similar (r2=0.75) to the pattern of cognitive differences in MDD. This suggests that the elevation in EDP, even in controls, is associated with cognitive performance - specifically in the MDD-affected domains. That specificity was missing for QRI, FA or other brain imaging indices. In summary, translating anatomically informed meta-analytic indices of similarity using a linear vector approach led to similar or better sensitivity to depressive symptoms and cognitive patterns than whole-brain imaging measurements or an index of accelerated aging.

Background The anterior cingulate cortex (ACC) is a crucial region in the pathophysiology of major depressive disorder (MDD). However, the relationship between functional alterations of the ACC subregions, anhedonia and sleep quality remains unclear in MDD patients. Methods The resting-state functional connectivity (rsFC) of ACC subregions was measured in 41 first-episode medication-naive MDD patients and 63 healthy controls who underwent functional magnetic resonance imaging. Between-group differences were examined using two-sample t-test. Furthermore, correlation and mediation analyses were carried out to investigate the relationships between the aberrant rsFC of ACC subregions, anhedonia and sleep quality in the patients and controls. Results Compared to healthy controls, the MDD patients exhibited increased rsFC of ACC subregions to areas of the anterior default mode network (DMN) and showed decreased rsFC of the right subgenual ACC to left precuneus (PCUN), which belongs to the posterior DMN. In MDD group, the sleep quality and consummatory anhedonia are correlated with some rsFC, which involves the angular gyrus (ANG) and superior frontal gyrus (SFG). More importantly, the rsFC between the right perigenual ACC and left SPG mediates the association between anhedonia and sleep quality in MDD. Limitations The cross-sectional design and the subjective questionaries for assessment. Conclusion These findings confirm the functional alterations of the ACC subregions and reveal the mediating role of ACC subregions in sleep and reward dysfunction in MDD.

Background Childhood anxiety and depression lead to great distress and impairment. Preventing them simultaneously in early life is critically important. We evaluated the long-term efficacy of an emotion regulation-based (ER) and a behavioural activation-based (BA) program. Both aimed to build resilience to prevent worry, a transdiagnostic feature across anxiety and depression. Methods Participants were 316 students (52.2% female; 8–13 years) from six South Australian primary schools. Schools were randomised to the ER, BA or a control condition. Measures of resilience, worry, anxiety, and depression were taken at pre- and post- program, and at 6- and 12-month follow-up. In addition, levels of emotion regulation, behavioural activation and resilience were measured as potential mediators of changes in anxiety and depression. Results No significant condition × time interactions were observed. However, the percentage of children who met the clinical cut-offs for generalised anxiety disorder and major depressive disorder decreased significantly in the BA condition at 12-month follow-up, as well as the percentage of children who met the clinical cut-off for obsessive compulsive disorder in the ER condition. Furthermore, emotion regulation mediated the relationship between condition and worry at post-program in the ER condition. Limitations The sample size is relatively small. Reliance on child self-report may have resulted in inaccurate responses. Conclusion The ER and BA transdiagnostic prevention programs for childhood anxiety and depression showed promising results for certain anxiety disorders not otherwise observed in universal school-based studies. Future research should consider evaluating the programs with a larger sample using alternative outcome measures.

Reproducibility is one of the most important issues for generalizing the results of clinical research; however, low reproducibility in neuroimaging studies is well known. To overcome this problem, the Enhancing Neuroimaging Genetics through Meta‐Analysis (ENIGMA) consortium, an international neuroimaging consortium, established standard protocols for imaging analysis and employs either meta‐ and mega‐analyses of psychiatric disorders with large sample sizes. The Cognitive Genetics Collaborative Research Organization (COCORO) in Japan promotes neurobiological studies in psychiatry and has successfully replicated and extended works of ENIGMA especially for neuroimaging studies. For example, (a) the ENIGMA consortium showed subcortical regional volume alterations in patients with schizophrenia (n = 2,028) compared to controls (n = 2,540) across 15 cohorts using meta‐analysis. COCORO replicated the volumetric changes in patients with schizophrenia (n = 884) compared to controls (n = 1,680) using the ENIGMA imaging analysis protocol and mega‐analysis. Furthermore, a schizophrenia‐specific leftward asymmetry for the pallidum volume was demonstrated; and (b) the ENIGMA consortium identified white matter microstructural alterations in patients with schizophrenia (n = 1,963) compared to controls (n = 2,359) across 29 cohorts. Using the ENIGMA protocol, a study from COCORO showed similar results in patients with schizophrenia (n = 696) compared to controls (n = 1,506) from 12 sites using mega‐analysis. Moreover, the COCORO study found that schizophrenia, bipolar disorder (n = 211) and autism spectrum disorder (n = 126), but not major depressive disorder (n = 398), share similar white matter microstructural alterations, compared to controls. Further replication and harmonization of the ENIGMA consortium and COCORO will contribute to the generalization of their research findings., The Cognitive Genetics Collaborative Research Organization (COCORO), which is a Japanese consortium established to elucidate psychiatric disorders and brain functions, replicated the results of the ENIGMA consortium, such as subcortical volume abnormalities and white matter microstructural abnormalities in schizophrenia, using the mega‐analysis method. These replication studies strengthened the reliability and generalization of the results of the ENIGMA consortium based on common and different methods in both consortiums. Further replication and harmonization of large consortia will contribute to the generalization of their research findings.

Background Major depressive disorder is characterized by a depressed mood or feeling of sadness, loss of interest or pleasure in everyday activities. Depressed individuals have a cognitive impairment, low self-esteem, difficulty making decisions, feeling helpless and hopeless. The factors that have been associated with depression include the lack of social support, living in rural areas, suffering from chronic diseases, smoking, and alcohol abuse. This study aimed to investigate the global prevalence of major depressive disorder in the elderly. Method The electronic database such as Web of Science (WoS), Scopus, SID, PubMed, Google Scholar, Mag Iran, and IranDoc were systematically searched for studies reporting the prevalence of major depressive disorderin the elderly published up to March 2021. Meta-analysis was performed using Comprehensive Meta-Analysis (CMA) software. Heterogeneity between the studies was evaluated using the I2 index. Begg and Mazumdar rank correlation test was used to assess publication bias. Result A total of 20 studies involving 18953 participants were included in this study. The global prevalence of major depression in the elderly was 13.3 % (95 % CI: 8.4–20.3 %). In the subgroup analysis, the prevalence of major depression in elderly women was 11.9 % (95 % CI: 7.6−18.6) and men 9.7 % (95 % CI: 5.2-17.3). No comparison was made between the two sexes, but based on the confidence intervals and large overlap, the two groups are not statistically different. Among continents, Australia had the highest prevalence of major depression in the elderly at 20.1 % (CI: 14.5-27.2 %). This was followed by Europe at 12.9 % (95 % CI: 5.1-28.9 %). Conclusion Major depressive disorder has a growing trend in the elderly population of the world. The prevalence of major depression in the elderly depends on various clinical and demographic factors such as age and gender. Therefore, mental health and the quality of life (QoL) of the elderly are important. The present study emphasizes the importance of social support in mental health that can reduce depression in the elderly.

The prevalence, correlates, and management of tobacco use disorder (TUD) or nicotine dependence (ND) among people with severe mental illness (SMI), namely schizophrenia, bipolar disorder (BD), and major depressive disorder (MDD), remain unclear. Therefore, a systematic review and meta-analysis was conducted. Electronic databases were systematically searched from inception to July 12, 2020, for observational studies documenting the prevalence, odds, and correlates of TUD/ND among people with SMI; randomized controlled trials (RCTs) informing the management of TUD/ND in people with SMI were also included. Random-effects meta-analyses were conducted. Sources of heterogeneity were explored. Nineteen observational studies, including 7527 participants with SMI met inclusion criteria. TUD/ND co-occurred in 33.4-65% of people with SMI. Rates were higher among males. While bupropion and varenicline represent promising treatment opportunities for schizophrenia with TUD/ND, non-pharmacological interventions require further research, mainly for people with primary mood disorders. TUD/ND represent prevalent co-occurring conditions among people with SMI. Further well-designed RCTs are warranted to inform their management.

BACKGROUND: Repetitive transcranial magnetic stimulation (TMS) is an evidence-based treatment for pharmacoresistant major depressive disorder (MDD), however, the evidence in veterans has been mixed. To this end, VA implemented a nationwide TMS program that included evaluating clinical outcomes within a naturalistic design. TMS was hypothesized to be safe and provide clinically meaningful reductions in MDD and posttraumatic stress disorder (PTSD) symptoms. METHODS: Inclusion criteria were MDD diagnosis and standard clinical TMS eligibility. Of the 770 patients enrolled between October 2017 and March 2020, 68.4% (n=521) met threshold-level PTSD symptom criteria. Treatments generally used standard parameters (e.g., left dorsolateral prefrontal cortex, 120% motor threshold, 10Hz, 3000 pulses/treatment). Adequate dose was operationally defined as 30 sessions. MDD and PTSD symptoms were measured using the 9-item patient health questionnaire (PHQ-9) and PTSD checklist for DSM-5 (PCL-5), respectively. RESULTS: Of the 770 who received at least one session, TMS was associated with clinically meaningful (Cohen’s d>1.0) and statistically significant (all p

Background : The number of digital game users is increasing, and so is attention to digital gaming's effects on mental health. We aimed to reveal if risky (game addiction) and usual game use (non-risky) are associated with mental health in early adulthood. Methods : Using data from the nationwide cross-sectional Korean Epidemic Catchment Area study for psychiatric disorders, 415 participants aged 18–30 years were divided into “non-game,” “usual game,” and “risky game” user groups based on the previous month's game use and cut-off value of game overuse screening questionnaire. Multiple linear and logistic regressions revealed the association between game use groups, perceived mental health, and lifetime prevalence of clinical mental disorders including suicidal ideation. Results : Among the 415 participants, 167 were non-game users, 175, usual game users, and 73, risky game users. Risky game users self-reported decreased satisfaction and happiness, and a significantly higher lifetime prevalence of major depressive disorder, alcohol dependence, and suicidal ideation. Usual game users were significantly associated with higher lifetime prevalence of alcohol dependence and suicidal ideation. Self-reported happiness partially mediated between game use and lifetime suicidal ideation in risky, but not usual game users. Limitations : This study is a cross-sectional observational study which was not possible to define the temporal relationship. Conclusions : Both risky and usual game use are associated with mental health problems in early adulthood, indicating the need for careful mental health screening on not only risky game users but also usual game users.

Background The symptoms that patients with major depressive disorder (MDD) experience are the dominant contributing factors to its heavy disease burden. This study sought to identify key symptoms leading to disability in patients with MDD. Methods Subjects consisted of patients who had a 12-month MDD diagnosis based on the China Mental Health Survey (CMHS). World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) was used to assess the degree of disability. The associations between depressive symptoms and disability were analyzed using a linear regression and logistic regression with a complex sampling design. Results Of the 32,552 community residents, 655 patients were diagnosed with 12-month MDD. The disability rate due to MDD was 1.06% (95% CI: 0.85%–1.28%) among adults in Chinese community and 50.7% (95% CI: 44.3%–57.1%) among MDD patients. Depression was associated with all functional losses measured by the WHODAS. Feelings of worthlessness in life or inappropriate guilt, and psychomotor agitation or retardation were the key symptoms related to disability. Economic status, co-morbidity of physical diseases or anxiety disorders were correlates of disability scores. Limitations The disability rate might be underestimated due to the exclusion of MDD patients living in hospitals. The effect of treatments on disability was excluded. Conclusions Psychological symptoms, not somatic symptoms, contribute to disability in MDD patients. Disability worsens when physical diseases or anxiety disorders are present. More attention could be paid to psychological symptoms, physical diseases, and anxiety disorders in MDD patients with disabilities.

Introduction Stress in pregnancy is associated with adverse outcomes in offspring, and developmental programming is a potential mechanism. We have previously shown that depression in pregnancy is a valid and clearly defined stress paradigm, and both maternal antenatal and offspring stress-related biology is affected. This study aims to clarify whether maternal biology in pregnancy and offspring outcomes can also be influenced by a history of a prior depression, in the absence of depression in pregnancy. Our primary hypothesis is that, similarly to women with depression in pregnancy, women with a history of depression but who are not depressed in pregnancy will have increased cortisol secretion and markers of immune system function, and that their offspring will have poorer neuro-developmental competencies and increased cortisol stress response. Methods A prospective longitudinal design was used in 59 healthy controls and 25 women with a past history of depression who were not depressed in pregnancy, named as ‘history-only’, and their offspring. Maternal antenatal stress-related biology (cortisol and markers of immune system function) and offspring outcomes (gestational age at birth, neonatal neurobehaviour (Neonatal Behavioural Assessment Scale, NBAS), cortisol stress response and basal cortisol at 2 and 12 months) and cognitive, language and motor development (Bayley Scales of Infant and Toddler Development (BSID)) were measured. Results Compared with healthy pregnant women, those with a history of depression who remain free of depression in pregnancy exhibit increased markers of immune system function in pregnancy: IL-8 (d = 0.63, p = 0.030), VEGF (d = 0.40, p = 0.008) and MCP-1 (d = 0.61, p = 0.002) and have neonates with lower neurobehavioural scores in most areas, reaching statistical significance in the social-interactive (d = 1.26, p = 0.015) cluster. However, there were no differences in maternal or offspring HPA axis function or in infant development at 12 months. Conclusion Our study indicates that pregnant women with a history of depression have increased markers of immune system function, and their offspring show behavioural alterations that may be the effects of in utero programming, epigenetic factors or genetic predisposition.

Background and Objectives Concerns exist around the generalizability of randomised controlled trials (RCTs) for adolescents with major depressive disorder (MDD). This review assesses whether adolescents with MDD treated in RCTs are representative of clinical samples. Methods A systematic narrative review of selection criteria used in RCTs for adolescent MDD (PROSPERO CRD42018096298). Included were studies assessing psychological, pharmacological or combination treatments. Results 52 studies were included. Overall, the reporting of selection criteria (defined as both inclusion and exclusion criteria), in the 23 psychotherapy trials was low (52% did not report on comorbid emotional disorders and 48% did not report on suicidal ideation). In contrast, the majority of selection criteria were reported in the 22 medication trials and the 7 combination trials. Where selection criteria were reported, most adolescents with comorbidities were excluded from psychotherapy and medication trials. The 7 combination trials included more adolescents with comorbidities. Of note, only 10 of the 52 studies reported on self-harm as a selection criteria. Conclusion Reporting of the characteristics of depressed adolescents was poor in psychotherapy trials. Both psychotherapy and medication trials excluded many adolescents with co-morbid conditions, however combination trials tended to be more inclusive. There is concern that many RCTs for adolescent MDD may not be generalizable to clinical populations, particularly with regards to comorbidity, self-harm and suicidal ideation. The findings suggest that clinicians need to view the evidence base and guidelines developed from RCTs with discernment. Pragmatic trials are needed with representative clinical populations and comprehensive reporting of the selection criteria.

Background Aside from the concept of seasonal affective disorder, the evidence for a seasonal pattern (SP) of major depressive disorder (MDD) is controversial. Furthermore, the effect of sex and age is still unclear. Methods This is a nationwide, registry-based study assessing all inpatient admissions in mental health hospitals due to MDD episodes according to ICD-10 (moderate (F32/33.1), severe (F32/33.2) and severe with psychotic features (F32/33.3)) in Austria across 14 years. Calculations were based on deviations from expected monthly admissions. Results The sample comprised 231,824 hospitalisations (36.8% men) for MDD. A significant SP (p=0.001) in moderate and severe depressive episodes in both women and men with decreased admission rates in the summer months and December was detected. In psychotic depression a significant SP was only evidenced in women (p = 0.002, men: p = 0.291). Patients older than 55 years had a reduced SP compared to those being younger. Limitations Only anonymised admission data of inpatient treatments were available. Hospitalization rates cannot fully be equated to the occurrence of MDD. Conclusions The current study indicates a seasonal variation in MDD symptoms that may go beyond seasonal affective disorder. Knowledge about the predictability of depressive symptoms in patients should encourage preventive strategies.

More instability (MSSD) and variability (SD) of negative affect (NA) have been related to current and future depressive symptoms. We investigated whether NA instability and variability were predictive of the rate of symptom improvement during treatment and of reaching remission status. Forty-six individuals with major depressive disorder completed six days of ecological momentary assessments (10 beeps/day) before starting a combination of pharmacotherapy and supportive therapy. During and after treatment, the Hamilton Depression Rating Scale (HDRS) diagnostic interview was performed monthly for 18 months. The rate of change in HDRS scores over five months (during treatment) and remission status (HDRS ≤ 7) over eighteen months were predicted by the SD, MSSD and Mean of NA, and relevant baseline predictors. Higher Mean NA and baseline symptom severity, but not NA variability or instability, predicted stronger depressive symptom reduction during treatment. Higher odds of remitting were only associated with lower Mean NA. Higher mean NA may indicate more room for improvement and thus for a steeper rate of symptom change, while lower mean NA levels may imply that remission status is more readily reached. To resolve the inconclusive findings for instability and variability as predictors of symptom improvement replication in larger samples is required.

Background Resting-state functional magnetic resonance imaging has been widely used for the assessment of brain functional network, yet with inconsistent results. The present study aimed to investigate intranetwork and internetwork connectivity differences between patients with major depressive disorder (MDD) and healthy controls at the integrity, network and edge levels of 8 well-defined resting state networks. Methods Thirty patients with MDD and sixty-three healthy control subjects were recruited in this study. Results Compared with healthy controls, patients with MDD showed increased node degree in the right amygdala and putamen, increased connectivity strength in the deep gray matter network (DGN) and increased functional connectivity in intranetwork and internetwork. Meanwhile, MDD showed decreased connectivity strength in visual network-DGN pair. Limitations The sample size was small, and all patients in this study were of Asian ethnicity, especially Han individuals. Conclusions These findings demonstrate that MDD cases and healthy controls may have divergent intranetwork and internetwork connectivity at an early stage without confounding influence of medication. These differences may underlie cognitive and behavioral alterations in patients with MDD. And these differences may help with the discrimination of patients and healthy people at an early stage of MDD. More studies in the future are warranted to assist in the diagnosis of this burdensome disease.