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OBJECTIVES: We conducted an implementation science mental health treatment study in western Kenya, testing strategies for scale up of evidence-based mental health services for common adult disorders using a non-specialist workforce, integrated with existing primary care (Sequential Multiple, Assignment Randomized Trial of non-specialist-delivered psychotherapy (Interpersonal Psychotherapy) and/or medication (fluoxetine) for major depression and post-traumatic stress disorder (PTSD) (SMART DAPPER)). Because study launch coincided with the COVID-19 pandemic, participants were allowed to attend treatment visits via mHealth (audio-only mobile phone) or in-person. We conducted a secondary data analysis of the parent study to evaluate preference for mHealth or in-person treatment among our study participants, including rationale for choosing in-person or mHealth treatment modality, and comparison of baseline demographic and clinical characteristics. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: Participants were public sector primary care patients at Kisumu County Hospital in western Kenya with major depression and/or PTSD and were individually randomised to non-specialist delivery of evidence-based psychotherapy or medication (n=2162). OUTCOMES: Treatment modality preference and rationale were ascertained before randomised assignment to treatment arm (psychotherapy or medication). The parent SMART DAPPER study baseline assessment included core demographic (age, gender, relationship status, income, clinic transport time and cost) and clinical data (eg, depression and PTSD symptoms, trauma exposures, medical comorbidities and history of mental healthcare). Given that this evaluation of mHealth treatment preference sought to identify the demographic and clinical characteristics of participants who chose in-person or mHealth treatment modality, we included most SMART DAPPER core measurement domains (not all subcategories). RESULTS: 649 (30.3%) SMART DAPPER participants preferred treatment via mHealth, rather than in person. The most cited rationales for choosing mHealth were affordability (18.5%) (eg, no transportation cost) and convenience (12.9%). On multivariate analysis, compared with those who preferred in-person treatment, participants who chose mHealth were younger and had higher constraints on receiving in-person treatment, including transport time 1.004 (1.00, 1.007) and finances 0.757 (0.612, 0.936). Higher PTSD symptoms 0.527 (0.395, 0.702) and higher disability 0.741 (0.559, 0.982) were associated with preference for in-person treatment. CONCLUSIONS: To our knowledge, this is the first study of public sector mental healthcare delivered by non-specialists via mHealth for major depression and/or PTSD in Sub-Saharan Africa. Our finding that mHealth treatment is preferred by approximately one-third of participants, particularly younger individuals with barriers to in-person care, may inform future mHealth research to (1) address knowledge gaps in mental health service implementation and (2) improve mental healthcare access to evidence-based treatment. TRIAL REGISTRATION NUMBER: NCT03466346.

OBJECTIVE: This study evaluates regularization variants in logistic regression (L1, L2, ElasticNet, Adaptive L1, Adaptive ElasticNet, Broken adaptive ridge [BAR], and Iterative hard thresholding [IHT]) for discrimination and calibration performance, focusing on both internal and external validation. MATERIALS AND METHODS: We use data from 5 US claims and electronic health record databases and develop models for various outcomes in a major depressive disorder patient population. We externally validate all models in the other databases. We use a train-test split of 75%/25% and evaluate performance with discrimination and calibration. Statistical analysis for difference in performance uses Friedmans test and critical difference diagrams. RESULTS: Of the 840 models we develop, L1 and ElasticNet emerge as superior in both internal and external discrimination, with a notable AUC difference. BAR and IHT show the best internal calibration, without a clear external calibration leader. ElasticNet typically has larger model sizes than L1. Methods like IHT and BAR, while slightly less discriminative, significantly reduce model complexity. CONCLUSION: L1 and ElasticNet offer the best discriminative performance in logistic regression for healthcare predictions, maintaining robustness across validations. For simpler, more interpretable models, L0-based methods (IHT and BAR) are advantageous, providing greater parsimony and calibration with fewer features. This study aids in selecting suitable regularization techniques for healthcare prediction models, balancing performance, complexity, and interpretability.

Single administration of low-dose ketamine has both acute and sustained anti-depressant effects. Sustained effect is associated with restoration of glutamatergic synapses in medial prefrontal cortic (mFPC) neurons. Ketamine induced profound changes in a number of molecular pathways in a mouse model for chronic stress. Cell-cell communication analyses predicted that planar-cell-polarity (PCP) signaling was decreased after chronic administration of corticosterone but increased following ketamine administration in most of the excitatory neurons. Similar decrease of PCP signaling in excitatory neurons was predicted in dorsolateral prefrontal cortical (dl-PFC) neurons of patients with major depressive disorder (MDD). We showed that the basolateral amygdala (BLA)-projecting infralimbic prefrontal cortex (IL PFC) neurons regulate immobility time in the tail suspension test and food consumption. Conditionally knocking out Celsr2 and Celsr3 or Prickle2 in the BLA-projecting IL PFC neurons abolished ketamine-induced synapse restoration and behavioral remission. Therefore, PCP proteins in IL PFC-BLA neurons mediate synapse restoration induced by of low-dose ketamine.

BACKGROUND: The prevalence of alcohol use among pregnant women aged 18-44 years old increased in recent years. The influence of mental health issues on an individuals likelihood to use alcohol during pregnancy has not been thoroughly investigated. This study will examine the association between experiencing a major depressive episode (MDE) in the past year and past-month alcohol use among pregnant women using the 2011-2020 National Survey on Drug Use and Health (NSDUH). METHODS: Pregnant women between the ages of 18 and 44 years old were included in the study for analysis. Multivariable logistic regression analysis was used to examine the association between past-year MDE and past-month alcohol use adjusting for age, race/ethnicity, marital status, and employment status. Additional logistic regression analysis was performed to investigate whether this relationship differed by trimester of pregnancy. RESULTS: A total of 6745 participants were included in the analytic sample. The prevalence of past-year MDE and past-month alcohol use was 7.67% and 9.15% respectively. Logistic regression analysis showed past-year MDE was significantly associated with past-month alcohol use in pregnant women adjusting for age, race/ethnicity, marital status, and employment status (aOR = 1.96; 95% CI, 1.34-2.87). This relationship became stronger in second and third trimesters of pregnancy. CONCLUSIONS: This study showed a positive association between MDE and past-month alcohol use among pregnant women, with strongest effect estimates in the third trimester. These findings may inform approaches for improved screening guidelines and health education for individuals who may be at higher risk of prenatal alcohol use.

BackgroundAnhedonia, an impairment in the motivation for or experience of pleasure, is a well-established transdiagnostic harbinger and core symptom of mental illness. Given increasing recognition of early life origins of mental illness, we posit that anhedonia should, and could, be recognized earlier if appropriate tools were available. However, reliable diagnostic instruments prior to childhood do not currently exist.MethodsWe developed an assessment instrument for anhedonia/reward processing in infancy, the Infant Hedonic/Anhedonic Processing Index (HAPI-Infant). Exploratory factor and psychometric analyses were conducted using data from 6- and 12-month-old infants from two cohorts (N = 188, N = 212). Then, associations were assessed between infant anhedonia and adolescent self-report of depressive symptoms.ResultsThe HAPI-Infant (47-items), exhibited excellent psychometric properties. Higher anhedonia scores at 6 (r = 0.23, p

BACKGROUND: There is growing evidence for the therapeutic effects of the psychedelic drug psilocybin for major depression. However, due to the lack of safety data on combining psilocybin with selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) and concerns that there may be a negative interaction on efficacy, participants enrolling in psychedelic trials are usually required to discontinue SNRI/SNRIs prior to enrolling. AIMS: Using data from a recent clinical trial examining the comparative efficacy the psychedelic drug psilocybin (P) combined with approximately 20 h of psychological support to a 6-week (daily) course of the SSRI escitalopram plus matched psychological support for major depressive disorder, we explored the effects of discontinuing SSRI/SNRIs prior to study enrolment on study outcomes. METHODS: Exploratory post hoc analyses using linear mixed effects model were performed to investigate the discontinuation effect on various validated depression symptom severity scales and well-being. The impact of SSRI/SNRIs discontinuation on the acute psychedelic experience was also explored. RESULTS/OUTCOMES: In the psilocybin group, there was a reduced treatment effect on all outcome measures for SSRI/SNRIs discontinuers compared with unmedicated patients at trial entry. However, no effects of discontinuation on measures of the acute psychedelic experience were found. CONCLUSION: Discontinuation of SSRI/SNRIs before psilocybin might diminish response to treatment; however, as we did not test SSRI/SNRI continuation in our trial, we cannot infer such causation. Moreover, the exploratory nature of the analyses makes them hypothesis generating, and not confirmatory. A controlled trial of SSRI/SNRI discontinuation versus continuation prior to psilocybin is urgently required.

BACKGROUND: Research suggests that effort-cost decision-making (ECDM), the estimation of work required to obtain reward, may be a relevant framework for understanding motivational impairment in psychotic and mood pathology. Specifically, research has suggested that people with psychotic and mood pathology experience effort as more costly than controls, and thus pursue effortful goals less frequently. This study examined ECDM across psychotic and mood pathology. HYPOTHESIS: We hypothesized that patient groups would show reduced willingness to expend effort compared to controls. STUDY DESIGN: People with schizophrenia (N = 33), schizoaffective disorder (N = 28), bipolar disorder (N = 39), major depressive disorder (N = 40), and controls (N = 70) completed a physical ECDM task. Participants decided between completing a low-effort or high-effort option for small or larger rewards, respectively. Reward magnitude, reward probability, and effort magnitude varied trial-by-trial. Data were analyzed using standard and hierarchical logistic regression analyses to assess the subject-specific contribution of various factors to choice. Negative symptoms were measured with a clinician-rated interview. STUDY RESULTS: There was a significant effect of group, driven by reduced choice of high-effort options in schizophrenia. Hierarchical logistic regression revealed that reduced choice of high-effort options in schizophrenia was driven by weaker contributions of probability information. Use of reward information was inversely associated with motivational impairment in schizophrenia. Surprisingly, individuals with major depressive disorder and bipolar disorder did not differ from controls. CONCLUSIONS: Our results provide support for ECDM deficits in schizophrenia. Additionally, differences between groups in ECDM suggest a seemingly similar behavioral phenotype, reduced motivation, could arise from disparate mechanisms.

Childhood maltreatment has been repeatedly linked to a higher incidence of health conditions with an underlying proinflammatory component, such as asthma, chronic obstructive pulmonary disease, stroke, and cardiovascular disease. Childhood maltreatment has also been linked to elevated systemic inflammation prior to the onset of disease. However, childhood maltreatment is highly comorbid with other risk factors which have also been linked to inflammation, namely major depression. The present analysis addresses this issue by assessing the association of maltreatment with genome-wide transcriptional profiling of immune cells collected from four orthogonal groups of adolescents (aged 13-17): maltreated and not maltreated in childhood, with and without major depressive disorder. Maltreatment and psychiatric history were determined using semi-structured clinical interviews and cross-validated using self-report questionnaires. Dried whole blood spots were collected from each participant (n = 133) and assayed to determine the extent to which maltreatment in childhood was associated with a higher prevalence of transcriptional activity among differentially expressed genes, specific immune cell subtypes, and up- or down-regulation of genes involved in immune function after accounting for current major depression. Maltreatment was associated with increased interferon regulatory factor (IRF) transcriptional activity (p = 0.03), as well as nuclear factor erythroid-2 related factor 1 (NRF1; p = 0.002) and MAF (p = 0.01) among up-regulated genes, and increased activity of nuclear factor kappa beta (NF-κB) among down-regulated genes (p = 0.01). Non-classical CD16+ monocytes were implicated in both the up- and down-regulated genes among maltreated adolescents. These data provide convergent evidence supporting the role of maltreatment in altering intracellular and molecular markers of immune function, as well as implicate monocyte/macrophage functions as mechanisms through which childhood maltreatment may shape lifelong immune development and function.

Correlations between altered body temperature and depression have been reported in small samples; greater confidence in these associations would provide a rationale for further examining potential mechanisms of depression related to body temperature regulation. We sought to test the hypotheses that greater depression symptom severity is associated with (1) higher body temperature, (2) smaller differences between body temperature when awake versus asleep, and (3) lower diurnal body temperature amplitude. Data collected included both self-reported body temperature (using standard thermometers), wearable sensor-assessed distal body temperature (using an off-the-shelf wearable sensor that collected minute-level physiological data), and self-reported depressive symptoms from > 20,000 participants over the course of ~ 7 months as part of the TemPredict Study. Higher self-reported and wearable sensor-assessed body temperatures when awake were associated with greater depression symptom severity. Lower diurnal body temperature amplitude, computed using wearable sensor-assessed distal body temperature data, tended to be associated with greater depression symptom severity, though this association did not achieve statistical significance. These findings, drawn from a large sample, replicate and expand upon prior data pointing to body temperature alterations as potentially relevant factors in depression etiology and may hold implications for development of novel approaches to the treatment of major depressive disorder.

Most genome-wide association studies (GWAS) of major depression (MD) have been conducted in samples of European ancestry. Here we report a multi-ancestry GWAS of MD, adding data from 21 cohorts with 88,316 MD cases and 902,757 controls to previously reported data. This analysis used a range of measures to define MD and included samples of African (36% of effective sample size), East Asian (26%) and South Asian (6%) ancestry and Hispanic/Latin American participants (32%). The multi-ancestry GWAS identified 53 significantly associated novel loci. For loci from GWAS in European ancestry samples, fewer than expected were transferable to other ancestry groups. Fine mapping benefited from additional sample diversity. A transcriptome-wide association study identified 205 significantly associated novel genes. These findings suggest that, for MD, increasing ancestral and global diversity in genetic studies may be particularly important to ensure discovery of core genes and inform about transferability of findings.

BACKGROUND: Depression is a major global health challenge, affecting over 300 million people worldwide. Current pharmacological and psychotherapeutic interventions have limited efficacy, underscoring the need for novel approaches. Emerging evidence suggests that peak emotional experiences characterized by awe, transcendence, and meaning hold promise for rapidly shifting maladaptive cognitive patterns in depression. Aesthetic chills, a peak positive emotion characterized by physical sensations such as shivers and goosebumps, may influence reward-related neural pathways and hold promise for modifying core maladaptive beliefs rooted in early adverse experiences. METHODS: We enrolled 96 patients diagnosed with major depressive disorder. A validated database of multimedia known to elicit chills responses (ChillsDB) was used for stimulus presentation. Participants emotional responses were assessed using the Emotional Breakthrough Inventory (EBI), while shifts in self-schema were measured via the Young Positive Schema Questionnaire (YSPQ). RESULTS: The study found that chill-inducing stimuli have the potential to positively influence the core schema of individuals with depression, impacting areas of self-related beliefs. The associated phenomenology triggered by chills appears to share similarities with the altered states of consciousness induced by psychedelic substances like psilocybin. CONCLUSIONS: These preliminary results suggest that the biological processes involved in aesthetic chills could be harnessed as a non-pharmacological intervention for depression. However, further investigation is necessary to comprehensively understand the neurophysiological responses to chills and to evaluate the practicality, effectiveness, and safety of utilizing aesthetic chills as a preventive measure in mental health care.

The biological mechanisms underlying the onset of major depressive disorder (MDD) have predominantly been studied in adult populations from high-income countries, despite the onset of depression typically occurring in adolescence and the majority of the world's adolescents living in low- and middle-income countries (LMIC). Taking advantage of a unique adolescent sample in an LMIC (Brazil), this study aimed to identify biological pathways characterizing the presence and increased risk of depression in adolescence, and sex-specific differences in such biological signatures. We collected blood samples from a risk-stratified cohort of 150 Brazilian adolescents (aged 14-16 years old) comprising 50 adolescents with MDD, 50 adolescents at high risk of developing MDD but without current MDD, and 50 adolescents at low risk of developing MDD and without MDD (25 females and 25 males in each group). We conducted RNA-Seq and pathway analysis on whole blood. Inflammatory-related biological pathways, such as role of hypercytokinemia/hyperchemokinemia in the pathogenesis of influenza (z-score = 3.464, p

BackgroundAlthough social rejection is among the strongest proximal precipitants of major depressive disorder (MDD), little is known about the underlying neurobiological mechanisms and whether neural sensitivity to social rejection may help explain differences in MDD risk. To address this issue, we tested whether neural responses to social threat differed in female adolescents at high vs. low maternal risk for MDD.MethodFemale adolescents with (high-risk; n = 22, Mage = 14.68) and without (low-risk; n = 30, Mage = 15.07) a maternal history of depression were experimentally exposed to negative and neutral social evaluation while undergoing an fMRI scan. Neural responses were assessed by event-related activity and functional connectivity, as well as multivoxel pattern analysis. Activity and functional connectivity analyses focused on a priori-selected regions of interest implicated in self-referential processing and emotion regulation.ResultsCompared to low-risk female adolescents, high-risk female adolescents exhibited greater increases in self-reported depression and social disconnection following social evaluation. Moreover, compared to low-risk female adolescents, high-risk female adolescents exhibited greater amygdala responses to negative social evaluation and a differential pattern of functional connectivity in brain regions related to emotion regulation, self-referential processing, and negative affect. Additionally, these markers of neural threat reactivity were related to depressive symptoms.LimitationsA cross-sectional study design and relatively small, Western sample.ConclusionsThese results suggest that exaggerated neural reactivity to social threat-and an atypical pattern of related functional connectivity-is evident in individuals with a preclinical risk factor for depression. Targeting such responding may thus be a fruitful strategy for preventing depression in at-risk youth.

BACKGROUND: Psilocybin Therapy (PT) is being increasingly studied as a psychiatric intervention. Personality relates to mental health and can be used to probe the nature of PTs therapeutic action. METHODS: In a phase 2, double-blind, randomized, active comparator controlled trial involving patients with moderate-to-severe major depressive disorder, we compared psilocybin with escitalopram, over a core 6-week trial period. Five-Factor model personality domains, Big Five Aspect Scale Openness aspects, Absorption, and Impulsivity were measured at Baseline, Week 6, and Month 6 follow-up. RESULTS: PT was associated with decreases in neuroticism (B = -0.63), introversion (B = -0.38), disagreeableness (B = -0.47), impulsivity (B = -0.40), and increases in absorption (B = 0.32), conscientiousness (B = 0.30), and openness (B = 0.23) at week 6, with neuroticism (B = -0.47) and disagreeableness (B = -0.41) remaining decreased at month 6. Escitalopram Treatment (ET) was associated with decreases in neuroticism (B = -0.38), disagreeableness (B = -0.26), impulsivity (B = -0.35), and increases in openness (B = 0.28) at week 6, with neuroticism (B = -0.46) remaining decreased at month 6. No significant between-condition differences were observed. CONCLUSIONS: Personality changes across both conditions were in a direction consistent with improved mental health. With the possible exception of trait absorption, there were no compelling between-condition differences warranting conclusions regarding a selective action of PT (v. ET) on personality; however, post-ET changes in personality were significantly moderated by pre-trial positive expectancy for escitalopram, whereas expectancy did not moderate response to PT.

Background: Major Depressive Disorder (MDD) during the perinatal period is a significant global health concern, ranking as the fourth-leading contributor to the global burden of disease and the second-leading cause of disability in individuals aged 15–44. This study investigates the association between perinatal MDD, poor nutrition, low prenatal care adherence, substance use and increased suicide risk. Methodology: A comprehensive review of existing research studies examined the prevalence and consequences of perinatal MDD. Studies focusing on symptoms, risk factors, and associated outcomes in mothers and infants were analyzed to provide a comprehensive overview of the multifaceted impact of MDD during the perinatal period. Conclusion: Approximately 10–15% of women experience postpartum depression, with over 60% reporting symptoms within the first 6 weeks postpartum. perinatal MDD increases the likelihood of preterm birth, small-for-gestational-age newborns and developmental delay. These findings underscore the critical need for comprehensive screening, identification and intervention approaches to mitigate the short and long term consequences of perinatal MDD. [ABSTRACT FROM AUTHOR]

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

Background: Non‐operative management of splenic injuries has significantly increased in the last decade with an increased emphasis on splenic preservation. This shift was assisted by increased availability of angioembolization, however, potential geographical variability in access exists in Aotearoa New Zealand (AoNZ). The aim of this study was to assess the management of splenic injury across AoNZ. Method: Five‐year retrospective study of all patients admitted to AoNZ hospitals with blunt major trauma and a splenic injury. Patients were identified using the National Trauma Registry and cross‐referenced with the National Minimum Data Set to determine their management. The primary outcome was the non‐operative rate. Results: Seven hundred seventy‐three patients were included. Four hundred sixty‐nine presented to a tertiary major trauma hospital and 304 to a secondary major trauma hospital. A difference was found in the rate of non‐operative management between tertiary and secondary hospitals (P = 0.019). The rate of non‐operative management was similar in mild (P = 0.814) and moderate (P = 0.825) injuries, however, significantly higher in severe injuries in tertiary hospitals (P = 0.009). No difference in mortality rate was found. Conclusion: This study found a difference in the management of splenic injuries between tertiary and secondary major trauma hospitals; predominantly due to a higher rate of operative management in patients with severe injuries at secondary hospitals. Despite this, no difference in mortality rate was found between tertiary and secondary hospitals. [ABSTRACT FROM AUTHOR]

This study investigated the impact of students’ background variables (gender, grade level, and major) on their self-regulated learning in a flipped classroom setting. This study implemented the flipped classroom method in a general education course, “Data Science with Excel.” The “self-regulated learning skill scale” questionnaire was used to examine the impact of students’ self-regulated learning skills (goal setting, learning environment setting, learning strategy, time management, and help-seeking) in a flipped classroom for 66 valid participants. The results indicated that, in terms of the gender factor, females reported more help-seeking behaviors than males. It was also found that major had a significant influence on self-regulated learning. Students from the College of Humanities and Applied Science were more likely to manage their time and set goals to learn the course content in comparison with students from other colleges. However, the results did not show a significant difference between grade levels. [ABSTRACT FROM AUTHOR]

Objective: Major depressive disorder (MDD) stands as one of the serious psychiatric conditions that detrimentally affect patients' quality of life and leads to a significant part of disability worldwide. Due to the limited understanding of the basic molecular mechanisms of depression and antidepressant medications, a clear understanding of the onset and development of MDD is unavailable. This study aims to figure out the pivotal genes and pathways implicated in the MDD development and identify medications that can potentially improve MDD treatment based on their relation with the key genes. Method: Symbols of human coding genes were retrieved from the HUGO Gene Nomenclature Committee database. These symbols were then queried for MDD-related associations using a Python script in PubMed. Subsequently, genes with two or more related articles to MDD were selected. A union of our search data and MDD-related genes in the DisGeNET database was found. The gene interaction network was generated and analyzed utilizing the STRING and Cytoscape, respectively. Finally, a drug-gene network was constructed and medications that can affect multiple genes were selected. Results: The union of our search data and DisGeNET data contained 1734 genes. Based on network analysis, TNF, IL1B, IL6, STAT1, and STAT3 were identified as the key genes in the MDD pathogenesis. Eleven drugs that affect more than one gene were detected through a drug-gene network. These medications include Acitretin, Adalimumab, Alteplase, Cisplatin, Digoxin, Etanercept, Infliximab, Insulin, Omeprazole, Pentoxifylline, and Rabeprazole. Conclusion: In summary, our findings identified five genes as key genes in MDD development, as well as medications related to key genes. This study provides a new vision of the pathogenesis and treatment of MDD. However, further experimental and clinical studies are necessary. [ABSTRACT FROM AUTHOR]

The Diagnostic Statistical Manual of Mental Disorders (DSM-5) recommends diagnosing neurocognitive disorders (i.e., cognitive impairment) when a patient scores beyond – 1 SD below neurotypical norms on two tests. I review how this approach will fail due to cognitive tests' power limitations, validity issues, imperfect reliabilities, and biases, before summarizing their resulting negative consequences. As a proof of concept, I use developmental prosopagnosia, a condition characterized by difficulties recognizing faces, to show the DSM-5 only diagnoses 62–70% (n1 = 61, n2 = 165) versus 100% (n1 = 61) through symptoms alone. Pooling the DSM-5 missed cases confirmed the presence of group-level impairments on objective tests, which were further evidenced through meta-analyses, thus validating their highly atypical symptoms. These findings support a paradigm shift towards bespoke diagnostic approaches for distinct cognitive impairments, including a symptom-based method when validated effective. I reject dogmatic adherence to the DSM-5 approach to neurocognitive disorders, and underscore the importance of a data driven, transdiagnostic approach to understanding patients' subjective cognitive impairments. This will ultimately benefit patients, their families, clinicians, and scientific progress. [ABSTRACT FROM AUTHOR]

Background: Varieties of tumors can arise from major salivary glands primarily or secondarily. Over 30 histological subtypes have been documented by the World Health Organization, serving as a guide in diagnosis and management. Objectives: To evaluate the clinical and histological pattern of presentation of major salivary gland tumors. Materials and Methods: This is a clinical retrospective study, done at the University of Nigeria Teaching Hospital, Ituku-Ozalla, Enugu, Nigeria, assessing records of patients with major salivary gland tumors seen between January 2018 and December 2022. Data obtained were analyzed using Statistical Package for Social Sciences version 26. The results were presented in tables and charts and comparisons were made using the Chi-squared test. Results: Out of the 57 patients with major salivary gland tumors studied, 30 (52.6%) were benign tumors, and 27 (47.4%) were malignant tumors. About 63.2% of patients were predominantly females, whereas 36.8% were males with a male-to-female ratio of 1:1.7. The most common presenting symptom was swelling. The average duration of symptoms before presentation was 24 and 12 months for benign and malignant tumors, respectively. The parotid gland (61.4% total) was the most common site of tumor presentation for both benign and malignant tumors followed by the submandibular and sublingual the least. The most common histological variant was pleomorphic adenoma (40.4%) for benign and mucoepidermoid carcinoma (28.1%) for malignant. Surgery was the first line of treatment given. Conclusion: The observed pattern of clinical and histological presentation of major salivary gland tumors will guide clinicians on the approach for the management.

Study objectivesAn evening circadian preference is common among adolescents. It is characterized by a behavioral predilection for later sleep and wake timing and is associated with higher rates of Major Depressive Disorder (MDD). The present study aims to (a) test the effectiveness of a cognitive behavioral sleep intervention (Transdiagnostic Sleep and Circadian Intervention; TranS-C) in a sample of adolescents with an evening circadian preference and clinically significant depressive symptoms and (b) evaluate improved alignment between circadian biology and sleep-wake behavior as a potential mechanism in the relationship between sleep and depression symptom improvement.MethodsAdolescents with an evening circadian preference and clinically significant depressive symptoms were randomized to receive TranS-C (n = 24) or a psychoeducation condition (PE; n = 18). Alignment between circadian biology and sleep-wake behavior was measured using objective biological measurement. Measures of sleep and circadian rhythm were taken at pre- and posttreatment, and depression symptoms were measured at pre- and posttreatment and 6- and 12-month follow-up.ResultsMixed effects modeling revealed that compared with an active control condition, TranS-C resulted in a significant reduction in MDD severity at 12-month follow-up. A MacArthur mediation analysis conducted to explore alignment between circadian biology and sleep-wake behavior as a mediator of depression severity reduction through 12-month follow-up revealed a significant interaction between change in alignment between circadian biology and sleep-wake behavior and treatment arm, indicating that improved alignment between circadian biology and sleep-wake behavior at posttreatment was associated with improvements in depression outcomes at 12-month follow-up under the treatment condition.ConclusionsThese results provide novel evidence for improved alignment between circadian biology and sleep-wake behavior as a specific mechanism of depression improvement, provide key clues into the complex relationship between sleep and depression, and have significant clinical implications for adolescents with depression.

Differential diagnosis is sometimes difficult in practical psychiatric settings, in terms of using the current diagnostic system based on presenting symptoms and signs. The creation of a novel diagnostic system using objective biomarkers is expected to take place. Neuroimaging studies and others reported that subcortical brain structures are the hubs for various psycho-behavioral functions, while there are so far no neuroimaging data-driven clinical criteria overcoming limitations of the current diagnostic system, which would reflect cognitive/social functioning. Prior to the main analysis, we conducted a large-scale multisite study of subcortical volumetric and lateralization alterations in schizophrenia, bipolar disorder, major depressive disorder, and autism spectrum disorder using T1-weighted images of 5604 subjects (3078 controls and 2526 patients). We demonstrated larger lateral ventricles volume in schizophrenia, bipolar disorder, and major depressive disorder, smaller hippocampus volume in schizophrenia and bipolar disorder, and schizophrenia-specific smaller amygdala, thalamus, and accumbens volumes and larger caudate, putamen, and pallidum volumes. In addition, we observed a leftward alteration of lateralization for pallidum volume specifically in schizophrenia. Moreover, as our main objective, we clustered the 5,604 subjects based on subcortical volumes, and explored whether data-driven clustering results can explain cognitive/social functioning in the subcohorts. We showed a four-biotype classification, namely extremely (Brain Biotype [BB] 1) and moderately smaller limbic regions (BB2), larger basal ganglia (BB3), and normal volumes (BB4), being associated with cognitive/social functioning. Specifically, BB1 and BB2-3 were associated with severe and mild cognitive/social impairment, respectively, while BB4 was characterized by normal cognitive/social functioning. Our results may lead to the future creation of novel biological data-driven psychiatric diagnostic criteria, which may be expected to be useful for prediction or therapeutic selection.

Biobanks often contain several phenotypes relevant to diseases such as major depressive disorder (MDD), with partly distinct genetic architectures. Researchers face complex tradeoffs between shallow (large sample size, low specificity/sensitivity) and deep (small sample size, high specificity/sensitivity) phenotypes, and the optimal choices are often unclear. Here we propose to integrate these phenotypes to combine the benefits of each. We use phenotype imputation to integrate information across hundreds of MDD-relevant phenotypes, which significantly increases genome-wide association study (GWAS) power and polygenic risk score (PRS) prediction accuracy of the deepest available MDD phenotype in UK Biobank, LifetimeMDD. We demonstrate that imputation preserves specificity in its genetic architecture using a novel PRS-based pleiotropy metric. We further find that integration via summary statistics also enhances GWAS power and PRS predictions, but can introduce nonspecific genetic effects depending on input. Our work provides a simple and scalable approach to improve genetic studies in large biobanks by integrating shallow and deep phenotypes.

Major depressive disorder (MDD) is a leading cause of disability worldwide. One of the most efficacious treatments for treatment-resistant MDD is electroconvulsive therapy (ECT). Recently, magnetic seizure therapy (MST) was developed as an alternative to ECT due to its more favorable side effect profile. While these approaches have been very successful clinically, the neural mechanisms underlying their therapeutic effects are unknown. For example, clinical slowing of the electroencephalogram beginning in the postictal state and extending days to weeks post-treatment has been observed in both treatment modalities. However, a recent longitudinal study of a small cohort of ECT patients revealed that, rather than delta oscillations, clinical slowing was better explained by increases in aperiodic activity, an emerging EEG signal linked to neural inhibition. Here we investigate the role of aperiodic activity in a cohort of patients who received ECT and a cohort of patients who received MST treatment. We find that aperiodic neural activity increases significantly in patients receiving either ECT or MST. Although not directly related to clinical efficacy in this dataset, increased aperiodic activity is linked to greater amounts of neural inhibition, which is suggestive of a potential shared neural mechanism of action across ECT and MST.

OBJECTIVE: Patient memory for treatment is emerging as an important transdiagnostic mechanism of treatment outcomes. However, patient memory for treatment is limited. The Memory Support Intervention was developed to improve patient memory for treatment and thereby strengthen treatment outcomes. In this secondary analysis, the primary, preregistered aim was to test the 12-month follow-up outcomes of the Memory Support Intervention when used with cognitive therapy (CT + MS) for major depressive disorder, relative to CT-as-usual. The secondary, exploratory aim was to investigate opportunities to improve efficacy of the Memory Support Intervention. METHOD: Adults (N = 178) with major depressive disorder were randomized to CT-as-usual or CT + MS. Therapist use of memory support and patient memory for treatment, depression symptoms, and overall functioning were measured in blind assessments. RESULTS: Findings did not support differences between treatment conditions at 12-month follow-up. Therapists used memory support strategies with a narrow subset of treatment contents, and similarly, patients recalled a narrow subset of treatment contents. CONCLUSIONS: The findings highlight ways to strengthen the efficacy of the Memory Support Intervention, such as applying memory support strategies across a wider variety of treatment contents, which in turn, may boost patient recall and outcomes.

Major depression (MD) is a serious psychiatric illness afflicting nearly 5% of the worlds population. A large correlational literature suggests that loneliness is a prospective risk factor for MD; correlational assocations of this nature may be confounded for a variety of reasons. This report uses Mendelian Randomization (MR) to examine potentially causal associations between loneliness and MD. We report on analyses using summary statistics from three large genome wide association studies (GWAS). MR analyses were conducted using three independent sources of GWAS summary statistics. In the first set of analyses, we used available summary statistics from an extant GWAS of loneliness to predict MD risk. We used two sources of outcome data: the Psychiatric Genomics Consortium (PGC) meta-analysis of MD (PGC-MD; N = 142,646) and the Million Veteran Program (MVP-MD; N = 250,215). Finally, we reversed analyses using data from the MVP and PGC samples to identify risk variants for MD and used loneliness outcome data from UK Biobank. We find robust evidence for a bidirectional causal relationship between loneliness and MD, including between loneliness, depression cases status, and a continuous measure of depressive symptoms. The estimates remained significant across several sensitivity analyses, including models that account for horizontal pleiotropy. This paper provides the first genetically-informed evidence that reducing loneliness may play a causal role in decreasing risk for depressive illness, and these findings support efforts to reduce loneliness in order to prevent or ameliorate MD. Discussion focuses on the public health significance of these findings, especially in light of the SARS-CoV-2 pandemic.

According to the operational diagnostic criteria, psychiatric disorders such as schizophrenia (SZ), bipolar disorder (BD), major depressive disorder (MDD), and autism spectrum disorder (ASD) are classified based on symptoms. While its cluster of symptoms defines each of these psychiatric disorders, there is also an overlap in symptoms between the disorders. We hypothesized that there are also similarities and differences in cortical structural neuroimaging features among these psychiatric disorders. T1-weighted magnetic resonance imaging scans were performed for 5,549 subjects recruited from 14 sites. Effect sizes were determined using a linear regression model within each protocol, and these effect sizes were meta-analyzed. The similarity of the differences in cortical thickness and surface area of each disorder group was calculated using cosine similarity, which was calculated from the effect sizes of each cortical regions. The thinnest cortex was found in SZ, followed by BD and MDD. The cosine similarity values between disorders were 0.943 for SZ and BD, 0.959 for SZ and MDD, and 0.943 for BD and MDD, which indicated that a common pattern of cortical thickness alterations was found among SZ, BD, and MDD. Additionally, a generally smaller cortical surface area was found in SZ and MDD than in BD, and the effect was larger in SZ. The cosine similarity values between disorders were 0.945 for SZ and MDD, 0.867 for SZ and ASD, and 0.811 for MDD and ASD, which indicated a common pattern of cortical surface area alterations among SZ, MDD, and ASD. Patterns of alterations in cortical thickness and surface area were revealed in the four major psychiatric disorders. To our knowledge, this is the first report of a cross-disorder analysis conducted on four major psychiatric disorders. Cross-disorder brain imaging research can help to advance our understanding of the pathogenesis of psychiatric disorders and common symptoms.

OBJECTIVE: Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures. METHODS: This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses. RESULTS: Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values

Based on the Entropy Model of Uncertainty, this study aimed to investigate the predictive effect of tolerance for ambiguity on happiness among Chinese college students, the mediating role of students' creativity in this relationship, and the differences in the predictive and mediating effects between art and science students. Using one-wave cross-sectional survey research design and convenience sampling method, participants were voluntarily and anonymously recruited online. The final sample included 378 college students aged from 16.93 to 26.76 years, with 92 males and 286 females. The self-reported data were accumulated via the Chinese versions of the Multiple Stimulus Types Tolerance for Ambiguity Scale-II, the self-rated creativity scale, and the short-form version of the Oxford Happiness Questionnaire. The structural equation modeling results revealed that tolerance for ambiguity positively predicted happiness, and creativity fully mediated this relationship among the total sample and art students, rather than science students. Specifically, for the total sample and art students, tolerance for ambiguity positively predicted creativity, which, in turn, positively predicted happiness. However, for science students, the positive predictive effects of tolerance for ambiguity on happiness and creativity were not significant. When controlling for tolerance for ambiguity, creativity positively predicted happiness. Furthermore, the multiple-group invariance test results revealed that the predictive paths from tolerance for ambiguity to happiness and creativity, and from tolerance for ambiguity and creativity to happiness, were invariant across majors. Meanwhile, the major differences in the estimates of the direct and indirect effects were not significant. Therefore, the predictive patterns were equivalent across majors. [ABSTRACT FROM AUTHOR]

Thalassemia is a genetics syndrome which lead to abnormal hemoglobin protein and this produce hemolysis, inefficient erythropoiesis, and moderate to severe anemia. Very few studies focus on the frequency of this disease. Therefore, the aims of current study is to determine features, and frequency of thalassemia patients at the thalassemia center in the Misan Governorate. In 2024, we performed a descriptive file-based study on 499 patients with thalassemia at the Thalassemia Center in Misan City. We reviewed the patient files and gathered the necessary data. After filling out a unique form with information about the patient's features from their medical records and from the patients or caregivers, data analysis was completed using Microsoft Excel and SPSS. The results showed that the majority of cases (78%), which were of the major type of B-thalassemia, were followed by intermediate cases (16%) and alpha-thalassemia (6%). Of these, 54% were female, and 48% were in the age range of 5-19 years. There were fewer cases in the age range of 0-4 years and older than 40 years. The study's findings also showed that 52% of patients lived in rural areas and 48% in urban areas. O had the highest blood group among the patients, followed by B, A, and AB. According to the study's findings, 64 patients had passed away, with both new and old cases accounting for 12% of all deaths. The kind of thalassemia, age group, and case outcome were statistically significantly correlated (p values were 0.006 and 0.0001, respectively). In conclusion, our research consider as the first a descriptive study at Misan province that sheds the light on B-thalassemia major. However, genetic study required next to stablish the database in Misan province. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic has forced higher education institutions to rapidly transition to online learning, significantly changing traditional teaching methods and campus organization. Despite these challenges, universities must prioritize students' learning experiences, changes, and development, as these are key factors in verifying their effectiveness and improving teaching and learning. This study analyzed data from the National Assessment of Student Engagement in Learning (NASEL) in Korea to investigate the effect of personal background and learning experiences on the cognitive outcomes of 2,086 university students in the online learning environment. Results of the study showed significant mean differences by major for the variables of university students' learning experience and performance. It also showed that major, grade, learning attitude, challenging learning experiences, interaction with professors, and interaction with campus community members had significant effects on knowledge acquisition, while major, gender, active class participation, learning attitude, thinking activities, challenging learning, interaction with students from different backgrounds, and interaction with campus community members had significant effects on cognitive capacity. These results highlight the need for universities to identify effective teaching and learning methods in the online learning environment and implement appropriate improvement plans. [ABSTRACT FROM AUTHOR]

The scope of the research was two-fold: (1) to determine climate change hope of preservice teachers enrolled in three majors; (2) to investigate the effect of major and gender on their hope about climate change. The data of the study, which followed the survey method, were gathered utilizing the "Climate Change Hope Scale - CCHS". First, the data from 336 pre-service teachers were used to assess whether the Turkish version of the CCHS was valid and reliable. The results indicated that it could be used as a valid instrument to measure pre-service teachers' hope about climate change. The reliability coefficient was found to be .82. The CCHS was then administered to 859 pre-service teachers enrolled at different universities in Turkey. The data were analyzed using twoway ANOVA, one-way ANOVA, and contrast command. A statistically significant difference in climate change hope between female and male pre-service teachers enrolled in science education was found, in favor of females. However, simple effects in the other majors were not significant, indicating that for pre-service teachers enrolled in both primary school education and pre-school education, females and males had similar climate change hope scores. [ABSTRACT FROM AUTHOR]

Major burn injury, despite advancements in care and prevention, can have a profound impact on long-term morbidity, affecting quality of life and socioeconomic standing. We aim to explore factors predicting recovery of independence, the expected rate and time in majorly burned patients, and the measures of progress used. A systematic search of four databases (MEDLINE, EMBASE, COCHRANE, CINAHL) was conducted for studies reporting outcomes pertaining to physical ability indicative of independent function in adult (>15 y) cohorts who had suffered a major burn (>20% TBSA) up to 30 years after treatment in a developed specialised burn service. Data extracted included factors affecting rate of and time to achievement of function in five independence domains, as well as the outcome measures used. 21 eligible studies were included comprising 1298 major burns survivors with a combined mean age of 39.6 y and a mean TBSA of 25.8%. The most significant recurring factors impacting recovery of independent function were older age, female gender, burn severity, prolonged ICU and hospital admission, preceding mental health conditions, and post-acute psychological issues. Exercise-based rehabilitation conferred benefits on major burn patients even over 2 years following injury. Discharge to independent living from hospital occurred in 27% to 97% of patients, while reported return to work rates varied from 52% to 80%. Burns Specific Health Scale-Brief, Functional Independence Measure, and Physical Composite Score (SF-36) were the most widely used outcome scoring systems. Major burn survivors have protracted recovery with potential for persistent chronic impairments, remaining consistently below baseline levels of function. Non-modifiable factors such as age and gender, and disease characteristics such as burn size with associated physical, physiological and psychosocial sequelae are contributory. Further research is required to explore achievement of specific milestones of major burn and polytrauma critical care patients, while early targeted rehabilitation addressing physical, psychological, and vocational needs has promising potential benefit. • Survivors of severe burns persistently remain below baseline levels of function. • Many do not return to independent living or work, exacting a socioeconomic burden. • Older, female, and mental health patients may be less likely to regain independence. • Higher burn size/depth and prolonged admission are also significant risk factors. • Early physical & vocational rehabilitation with psychological support aids recovery. [ABSTRACT FROM AUTHOR]

Wildfires significantly influence the environmental distribution of various elements through their fire-induced input and mobilization, yet little is known about their effects on the forest floor in Siberian forests. The present study evaluated the effects of spring wildfires of various severities on the levels of major and minor (Ca, Al, Fe, S, Mg, K, Na, Mn, P, Ti, Ba, and Sr) trace and ultra-trace (B, Co, Cr, Cu, Ni, Se, V, Zn, Pb, As, La, Sn, Sc, Sb, Be, Bi, Hg, Li, Mo, and Cd) elements in the forest floors of Siberian forests. The forest floor (Oi layer) samples were collected immediately following wildfires in Scots pine (Pinus sylvestris L.), larch (Larix sibirica Ledeb.), spruce (Picea obovata Ledeb.), and birch (Betula pendula Roth) forests. Total concentrations of elements were determined using inductively coupled plasma–optical emission spectroscopy. All fires resulted in a decrease in organic matter content and an increase in mineral material content and pH values in the forest floor. The concentrations of most elements studied in a burned layer of forest floor were statistically significantly higher than in unburned precursors. Sb and Sn showed no statistically significant changes. The forest floor in the birch forest showed a higher increase in mineral material content after the fire and higher levels of most elements studied than the burned coniferous forest floors. Ca was a predominant element in both unburned and burned samples in all forests studied. Our study highlighted the role of wildfires in Siberia in enhancing the levels of geochemical elements in forest floor and the effect of forest type and fire severity on ash characteristics. The increased concentrations of elements represent a potential source of surface water contamination with toxic and eutrophying elements if wildfire ash is transported with overland flow. [ABSTRACT FROM AUTHOR]

Background: This study aimed to investigate the characteristics of psychiatric consultations in a general hospital. Methods: All the patients hospitalized in Rasoul Akram Hospital from April 2011 to March 2019 who were asked for a psychiatric consultation were studied. Patients' information was obtained from the patients' records. The records of the year 2008 were also used to compare the characteristics between the years 2008 and 2017. Results: Over an eight-year period, 0.61% of the patients received psychiatric consultations. 54% of the consulted patients were male and 46% were female. The mean age of the patients was 44.7±18.72 years. The highest requested consultations (28.4%) were from the internal department followed by the surgery department (11.8%). The highest frequency of the reasons for requesting consultation was presence of psychiatric symptoms (27.5%). The most common psychiatric diagnosis was adjustment disorder (18.4%) followed by major depressive disorder (14.2%). Comparing consultations in the year 2008 with 2017 demonstrated that 1.57% ofthe patients admitted in 2008 and 1.17% of the patients in 2017 received psychiatric consultations, and in both years, the number of male patients was higher than females, the highest demand for consultation was from the internal department, and the most common reason for seeking consultation was the presence of psychiatric symptoms and then depressive symptoms. In 2008, the most common diagnosis was major depressive disorder and in 2017 was substance use disorder. Conclusion: The consultation rate was alarmingly low in this study compared to the other studies. [ABSTRACT FROM AUTHOR]

Rumination is a maladaptive style of regulating thoughts and emotions. It is a common symptom of Major Depressive Disorder (MDD), and more severe rumination is associated with poorer medication and psychotherapy treatment outcomes, particularly among women. It is unclear to what extent rumination may influence the outcomes of, or be responsive to, repetitive Transcranial Magnetic Stimulation (rTMS) treatment of MDD. We retrospectively examined data collected during rTMS treatment of 155 patients (age 42.52 ± 14.22, 79 female) with moderately severe treatment-resistant MDD. The severity of rumination and depression was assessed before and during a course of 30 sessions of measurement-based rTMS treatment using the Ruminative Responses Scale (RSS) and the Patient Health Questionnaire (PHQ-9), respectively. Relationships among baseline levels of rumination, depression, and treatment outcome were assessed using a series of repeated measures linear mixed effects models. Both depression and rumination symptoms significantly improved after treatment, but improvement in depression was not a significant mediator of rumination improvement. Higher baseline rumination (but not depression severity) was associated with poorer depression outcomes independently of depression severity. Female gender was a significant predictor of worse outcomes for all RRS subscales. Both depressive and ruminative symptoms in MDD improved following rTMS treatment. These improvements were correlated, but improvement in rumination was not fully explained by reduction in depressive symptoms. These findings suggest that while improvement in rumination and depression severity during rTMS treatment are correlated, they are partly independent processes. Future studies should examine whether rumination symptoms should be specifically targeted with different rTMS treatment parameters.

BACKGROUND: Treatment-resistant depression (TRD) refers to patients with major depressive disorder who do not remit after 2 or more antidepressant trials. TRD is common and highly debilitating, but its neurobiological basis remains poorly understood. Recent neuroimaging studies have revealed cortical connectivity gradients that dissociate primary sensorimotor areas from higher-order associative cortices. This fundamental topography determines cortical information flow and is affected by psychiatric disorders. We examined how TRD impacts gradient-based hierarchical cortical organization. METHODS: In this secondary study, we analyzed resting-state functional magnetic resonance imaging data from a mindfulness-based intervention enrolling 56 patients with TRD and 28 healthy control subjects. Using gradient extraction tools, baseline measures of cortical gradient dispersion within and between functional brain networks were derived, compared across groups, and associated with graph theoretical measures of network topology. In patients, correlation analyses were used to associate measures of cortical gradient dispersion with clinical measures of anxiety, depression, and mindfulness at baseline and following the intervention. RESULTS: Cortical gradient dispersion was reduced within major intrinsic brain networks in patients with TRD. Reduced cortical gradient dispersion correlated with increased network degree assessed through graph theory-based measures of network topology. Lower dispersion among default mode, control, and limbic network nodes related to baseline levels of trait anxiety, depression, and mindfulness. Patients baseline limbic network dispersion predicted trait anxiety scores 24 weeks after the intervention. CONCLUSIONS: Our findings provide preliminary support for widespread alterations in cortical gradient architecture in TRD, implicating a significant role for transmodal and limbic networks in mediating depression, anxiety, and lower mindfulness in patients with TRD.

BACKGROUND: For infants born in the contemporary era of neonatal care, little is known about adult mental health outcomes of extremely preterm birth (EP; 2499 g) controls, and to compare change in prevalence of mental health symptoms and disorders from 18 to 25 years. METHODS: Participants were a prospective geographical cohort of 297 consecutive survivors born EP/ELBW during 1991-1992 and 260 NBW controls. At age 25 years, 174 EP/ELBW and 139 NBW participants completed the Adult ADHD Rating Scale, Structured Clinical Interview for DSM-IV Disorders, Beck Anxiety Inventory, and Center for Epidemiologic Studies Depression Scale-Revised. Data from follow-up at 18 years were also utilized. Multiple imputation was used to account for attrition. RESULTS: Mental health outcomes at 25 years were similar between groups: prevalence rates were ADHD 7% v. 5%; anxiety 32% v. 27%; mood 38% v. 35%; substance use 12% v. 14% in the EP/ELBW and NBW groups, respectively. In both groups, ADHD declined between 18 and 25 years [odds ratio (OR) per year = 0.87, 95% confidence interval (CI) 0.79-0.95], and generalized anxiety disorder and major depressive episode became more common (OR 1.22, 95% CI 1.10-1.35 per year; OR 1.20, 95% CI 1.10-1.30 respectively). CONCLUSIONS: This contemporary EP/ELBW cohort has comparable young adult mental health outcomes to controls, and similar patterns of change in mental health from late adolescence.

BACKGROUND: In a recent clinical trial examining the comparative efficacy of psilocybin therapy (PT) versus escitalopram treatment (ET) for major depressive disorder, 14 of 16 major efficacy outcome measures yielded results that favored PT, but the Quick Inventory of Depressive Symptomatology, Self-Report, 16 items (QIDS-SR16) did not. AIMS: The present study aims to (1) rationally and psychometrically account for discrepant results between outcome measures and (2) to overcome psychometric problems particular to individual measures by re-examining between-condition differences in depressive response using all outcome measures at item-, facet-, and factor-levels of analysis. METHOD: Four depression measures were compared on the basis of their validity for examining differences in depressive response between PT and ET conditions. RESULTS/OUTCOMES: Possible reasons for discrepant findings on the QIDS-SR16 include its higher variance, imprecision due to compound items and whole-scale and unidimensional sum-scoring, vagueness in the phrasing of scoring options for items, and its lack of focus on a core depression factor. Reanalyzing the trial data at item-, facet-, and factor-levels yielded results suggestive of PTs superior efficacy in reducing depressed mood, anhedonia, and a core depression factor, along with specific symptoms such as sexual dysfunction. CONCLUSION/INTERPRETATION: Our results raise concerns about the adequacy of the QIDS-SR16 for measuring depression, as well as the practice of relying on individual scales that tend not to capture the multidimensional structure or core of depression. Using an alternative approach that captures depression more granularly and comprehensively yielded specific insight into areas where PT therapy may be particularly useful to patients and clinicians.

Limited research has examined the mental health of individuals experiencing homelessness in Hawai'i, which bears the nation's second highest homelessness rate. Mental health, substance use, treatment need, and health data were collected from 162 unhoused individuals in Hawai'i County by visiting community locations where they congregate (e.g., beaches, vacant buildings). 77% of participants were Native Hawaiian/Pacific Islander (NH/PI) with participants demonstrating severe rates of mental and substance use disorders including 57% experiencing major depressive disorder (MDD), 56% experiencing generalized anxiety disorder (GAD), and 64%, 74%, and 12% experiencing alcohol, methamphetamine, and opioid use disorders, respectively-heightening overdose risk. Treatment need was high (62%) but health was poor (85% reporting fair/poor health), with MDD and GAD predicting reduced general health (p

STUDY OBJECTIVES: Several studies have shown that patients with short sleep duration show a poor response to cognitive behavioral therapy for insomnia (CBT-I), but such studies have not included patients with comorbid conditions. The current study was conducted to determine whether pretreatment sleep duration moderates the response of patients with major depression and insomnia disorders to a combined CBT-I and antidepressant medication treatment. METHODS: This study comprised a secondary analysis of a larger randomized trial that tested combined CBT-I/antidepressant medication treatment of patients with major depression and insomnia. Participants (n = 99; 70 women; Mage = 47.712.4 years) completed pretreatment polysomnography and then were randomly assigned to a 12-week treatment with antidepressant medication combined with CBT-I or a sham therapy. Short and longer sleepers were defined using total sleep time cutoffs of < 5, < 6, and < 7 hours for short sleep. Insomnia and depression remission ascertained respectively from the Insomnia Severity Index and Hamilton Rating Scale for Depression were used to compare treatment responses of short and longer sleepers defined by the cutoffs mentioned. RESULTS: Logistic regression analyses showed that statistically significant results were obtained only when the cutoff of < 5 hours of sleep was used to define short sleep. Both the CBT-I recipients with < 5 hours of sleep (odds ratio = 0.053; 95% confidence interval = 0.006-0.499) and the sham-therapy group with ≥ 5 hours of sleep (odds ratio = 0.149; 95% confidence interval = 0.045-0.493) were significantly less likely to achieve insomnia remission than were CBT-I recipients with ≥ 5 hours of sleep. The shorter sleeping CBT-I group (odds ratio = 0.118; 95% confidence interval = 0.020-0.714) and longer sleeping sham-therapy group (odds ratio = 0.321; 95% confidence interval = 0.105-0.983) were also less likely to achieve insomnia and/or depression remission than was the longer sleeping CBT-I group with ≥ 5 hours of sleep. CONCLUSIONS: Sleeping < 5 hours may dispose comorbid major depression/insomnia patients to a poor response to combined CBT-I/medication treatments for their insomnia and depression. Future studies to replicate these findings and explore mechanisms of treatment response seem warranted. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: Treatment of Insomnia and Depression (TRIAD); URL: https://clinicaltrials.gov/ct2/show/results/NCT00767624; Identifier: NCT00767624. CITATION: Edinger JD, Smith ED, Buysse DJ, et al. Objective sleep duration and response to combined pharmacotherapy and cognitive behavioral insomnia therapy among patients with comorbid depression and insomnia: a report from the TRIAD study. J Clin Sleep Med. 2023;19(6):1111-1120.

The genetic dissection of major depressive disorder (MDD) ranks as one of the success stories of psychiatric genetics, with genome-wide association studies (GWAS) identifying 178 genetic risk loci and proposing more than 200 candidate genes. However, the GWAS results derive from the analysis of cohorts in which most cases are diagnosed by minimal phenotyping, a method that has low specificity. I review data indicating that there is a large genetic component unique to MDD that remains inaccessible to minimal phenotyping strategies and that the majority of genetic risk loci identified with minimal phenotyping approaches are unlikely to be MDD risk loci. I show that inventive uses of biobank data, novel imputation methods, combined with more interviewer diagnosed cases, can identify loci that contribute to the episodic severe shifts of mood, and neurovegetative and cognitive changes that are central to MDD. Furthermore, new theories about the nature and causes of MDD, drawing upon advances in neuroscience and psychology, can provide handles on how best to interpret and exploit genetic mapping results.

Background and objectivesPatient adherence to treatment is an important barrier to the implementation of evidence-based psychological treatments (EBPTs). There is a need for simple and deployable measures of patient adherence to treatment for use across EBPTs. The Treatment Adherence Rating Scale (TARS) was developed and validated in two samples.MethodsThis study includes two samples: adults with Major Depressive Disorder who received Cognitive Therapy for depression (Sample 1; N = 48, mean age = 44.27 years), and at-risk adolescents who received either the Transdiagnostic Sleep and Circadian Intervention or Psychoeducation (Sample 2; N = 176, mean age = 14.77 years). Factor structure of the TARS scores was examined via Exploratory Factor Analyses (EFA) in Sample 1 and Confirmatory Factor Analyses (CFA) in Sample 2. Internal consistency, predictive validity, and construct validity of the TARS scores were examined.ResultsResults from EFA in Sample 1 supported a one-factor model. Results from CFA in Sample 2 suggested that a two-factor model (i.e., agreement and compliance) fit better than a one-factor model. TARS scores from both samples demonstrated adequate predictive validity with primary clinical outcomes and construct validity with treatment expectations.LimitationsThe sample was small with two specific populations. Future research should focus on other patient populations, a larger population, and other EBPTs. Future research examining patient ratings of these items are needed for further validation of the TARS.ConclusionsPreliminary findings support the use of a two-factor model and highlight the potential utility of a simple measure of patient adherence to treatment across age and diagnostic groups.

BACKGROUND: Little is known about specific obsessive-compulsive clinical features associated with lifetime history of suicide attempt in individuals with obsessive-compulsive disorder (OCD) and major depression. METHODS: The study sample included 515 adults with OCD and a history of major depression. In exploratory analyses, we compared the distributions of demographic characteristics and clinical features in those with and without a history of attempted suicide and used logistic regression to evaluate the association between specific obsessive-compulsive clinical features and lifetime suicide attempt. RESULTS: Sixty-four (12%) of the participants reported a lifetime history of suicide attempt. Those who had attempted suicide were more likely to report having experienced violent or horrific images (52% vs. 30%; p

Background Major depressive disorder (MDD) and schizophrenia are linked to accelerated aging leading to reduced lifespan, health span and cognitive decline. Cellular senescence, in which cells lose proliferative capacity and develop a senescence-associated secretory phenotype (SASP), plays a role in this process. Emerging research suggests that the senolytic regimen of dasatinib+quercetin (D+Q) reduces senescent cells, potentially mitigating age-related health and cognitive decline. This pilot study aims to assess the feasibility and safety of D+Q in older adults with schizophrenia, schizoaffective disorder, and treatment-resistant depression (TRD). Methods This single-center study will recruit 30 participants total aged 50 years or older with schizophrenia/schizoaffective disorder or 60 years or older with TRD; the difference in age limits is because individuals with schizophrenia are biologically about 10 years older than general population owing to metabolic burden. Each participant will receive two consecutive days of 100 mg oral dasatinib plus 1250 mg oral quercetin at baseline and weeks one through three, (i.e., two days on, five days off) along with lifestyle risk management education. Questionnaires and assessments will measure health and cognitive function as well as psychiatric function at baseline, week 10, and one year. Magnetic Resonance Imaging (MRI) will measure structural and functional brain health at baseline and 10 weeks. Blood sampling for SASP testing will occur at seven time points: baseline, weeks one through four, week 10, and one year. Conclusion This pilot aims to evaluate the safety and feasibility of the senolytic regimen and D+Q’s potential to counteract accelerated aging in adults with schizophrenia/schizoaffective disorder and TRD. Trial registration Dasatinib Plus Quercetin for Accelerated Aging in Mental Disorders is registered on ClinicalTrials.gov: NCT05838560; posted May 1, 2023.

Selective serotonin reuptake inhibitors (SSRIs) are the most prescribed treatment for individuals experiencing major depressive disorder. The therapeutic mechanisms that take place before, during, or after SSRIs bind the serotonin transporter (SERT) are poorly understood, partially because no studies exist on the cellular and subcellular pharmacokinetic properties of SSRIs in living cells. We studied escitalopram and fluoxetine using new intensity-based, drug-sensing fluorescent reporters targeted to the plasma membrane, cytoplasm, or endoplasmic reticulum (ER) of cultured neurons and mammalian cell lines. We also used chemical detection of drug within cells and phospholipid membranes. The drugs attain equilibrium in neuronal cytoplasm and ER at approximately the same concentration as the externally applied solution, with time constants of a few s (escitalopram) or 200-300 s (fluoxetine). Simultaneously, the drugs accumulate within lipid membranes by ≥18-fold (escitalopram) or 180-fold (fluoxetine), and possibly by much larger factors. Both drugs leave cytoplasm, lumen, and membranes just as quickly during washout. We synthesized membrane-impermeant quaternary amine derivatives of the two SSRIs. The quaternary derivatives are substantially excluded from membrane, cytoplasm, and ER for >2.4 h. They inhibit SERT transport-associated currents sixfold or 11-fold less potently than the SSRIs (escitalopram or fluoxetine derivative, respectively), providing useful probes for distinguishing compartmentalized SSRI effects. Although our measurements are orders of magnitude faster than the therapeutic lag of SSRIs, these data suggest that SSRI-SERT interactions within organelles or membranes may play roles during either the therapeutic effects or the antidepressant discontinuation syndrome.SIGNIFICANCE STATEMENT Selective serotonin reuptake inhibitors stabilize mood in several disorders. In general, these drugs bind to SERT, which clears serotonin from CNS and peripheral tissues. SERT ligands are effective and relatively safe; primary care practitioners often prescribe them. However, they have several side effects and require 2-6 weeks of continuous administration until they act effectively. How they work remains perplexing, contrasting with earlier assumptions that the therapeutic mechanism involves SERT inhibition followed by increased extracellular serotonin levels. This study establishes that two SERT ligands, fluoxetine and escitalopram, enter neurons within minutes, while simultaneously accumulating in many membranes. Such knowledge will motivate future research, hopefully revealing where and how SERT ligands engage their therapeutic target(s).

BACKGROUND AND OBJECTIVES: Mood, anxiety disorders, and suicidality are more frequent in people with epilepsy than in the general population. Yet, their prevalence and the types of mood and anxiety disorders associated with suicidality at the time of the epilepsy diagnosis are not established. We sought to answer these questions in patients with newly diagnosed focal epilepsy and to assess their association with suicidal ideation and attempts. METHODS: The data were derived from the Human Epilepsy Project study. A total of 347 consecutive adults aged 18-60 years with newly diagnosed focal epilepsy were enrolled within 4 months of starting treatment. The types of mood and anxiety disorders were identified with the Mini International Neuropsychiatric Interview, whereas suicidal ideation (lifetime, current, active, and passive) and suicidal attempts (lifetime and current) were established with the Columbia Suicidality Severity Rating Scale (CSSRS). Statistical analyses included the t test, χ2 statistics, and logistic regression analyses. RESULTS: A total of 151 (43.5%) patients had a psychiatric diagnosis; 134 (38.6%) met the criteria for a mood and/or anxiety disorder, and 75 (21.6%) reported suicidal ideation with or without attempts. Mood (23.6%) and anxiety (27.4%) disorders had comparable prevalence rates, whereas both disorders occurred together in 43 patients (12.4%). Major depressive disorders (MDDs) had a slightly higher prevalence than bipolar disorders (BPDs) (9.5% vs 6.9%, respectively). Explanatory variables of suicidality included MDD, BPD, panic disorders, and agoraphobia, with BPD and panic disorders being the strongest variables, particularly for active suicidal ideation and suicidal attempts. DISCUSSION: In patients with newly diagnosed focal epilepsy, the prevalence of mood, anxiety disorders, and suicidality is higher than in the general population and comparable to those of patients with established epilepsy. Their recognition at the time of the initial epilepsy evaluation is of the essence.

The opioid G-protein coupled receptors (GPCRs) strongly modulate many of the central nervous system structures that contribute to neurological and psychiatric disorders including pain, major depressive disorder, and substance use disorders. To better treat these and related diseases, it is essential to understand the signaling of their endogenous ligands. In this review, we focus on what is known and unknown about the regulation of the over two dozen endogenous peptides with high affinity for one or more of the opioid receptors. We briefly describe which peptides are produced, with a particular focus on the recently proposed possible synthesis pathways for the endomorphins. Next, we describe examples of endogenous opioid peptide expression organization in several neural circuits and how they appear to be released from specific neural compartments that vary across brain regions. We discuss current knowledge regarding the strength of neural activity required to drive endogenous opioid peptide release, clues about how far peptides diffuse from release sites, and their extracellular lifetime after release. Finally, as a translational example, we discuss the mechanisms of action of naltrexone (NTX), which is used clinically to treat alcohol use disorder. NTX is a synthetic morphine analog that non-specifically antagonizes the action of most endogenous opioid peptides developed in the 1960s and FDA approved in the 1980s. We review recent studies clarifying the precise endogenous activity that NTX prevents. Together, the works described here highlight the challenges and opportunities the complex opioid system presents as a therapeutic target.

BackgroundThe Research Domain Criteria (RDoC) approach proposes a novel psychiatric nosology using transdiagnostic dimensional mechanistic constructs. One candidate RDoC indicator is delay discounting (DD), a behavioral economic measure of impulsivity, based predominantly on studies examining DD and individual conditions. The current study sought to evaluate the transdiagnostic significance of DD in relation to several psychiatric conditions concurrently.MethodsParticipants were 1388 community adults (18-65) who completed an in-person assessment, including measures of DD, substance use, depression, anxiety, posttraumatic stress disorder, and attention-deficit hyperactivity disorder (ADHD). Relations between DD and psychopathology were examined with three strategies: first, examining differences by individual condition using clinical cut-offs; second, examining DD in relation to latent psychopathology variables via principal components analysis (PCA); and third, examining DD and all psychopathology simultaneously via structural equation modeling (SEM).ResultsIndividual analyses revealed elevations in DD were present in participants screening positive for multiple substance use disorders (tobacco, cannabis, and drug use disorder), ADHD, major depressive disorder (MDD), and an anxiety disorder (ps < 0.05-0.001). The PCA produced two latent components (substance involvement v. the other mental health indicators) and DD was significantly associated with both (ps < 0.001). In the SEM, unique significant positive associations were observed between the DD latent variable and tobacco, cannabis, and MDD (ps < 0.05-0.001).ConclusionsThese results provide some support for DD as a transdiagnostic indicator, but also suggest that studies of individual syndromes may include confounding via comorbidities. Further systematic investigation of DD as an RDoC indicator is warranted.