Journal of Psychiatric Research

Introduction: Pesticide exposure has been associated with poorer mental health, yet little is known about whether seasonal fluctuations in agricultural pesticide use are associated with cyclical changes in mood among people living in agricultural communities. We evaluated associations between 10 peak and off-peak pesticide spray seasons and ecological momentary assessment (EMA)-derived mood in a floricultural region in Ecuador. Methods: 496 participants completed repeated EMA surveys across 10 assessment administrations over 2.5 years (2022-2024), including one single-assessment administration and nine 10-day bursts (Nobservations=14,332). Mood outcomes included negative affect (sadness, anxiety, stress, anger, tiredness, difficulty concentrating; overall mean=2.79, Standard Deviation [SD]=1.32), positive affect (happiness, motivation; overall mean=4.21, SD=1.60), and behavioral dysregulation (aggression and impulsivity, overall mean=1.86, SD=1.29). Generalized linear mixed models estimated pooled, between-person and within-person associations between peak pesticide spray seasons and mood, adjusting for demographic and longitudinal factors Effect modification by sex, floricultural occupation, and cohabitation with a floricultural worker was assessed. Results: Peak spray seasons were associated with higher negative affect ({beta}=0.11 [0.06, 0.16]) and behavioral dysregulation ({beta}=0.10 [0.05, 0.15]) but not positive affect ({beta}=0.01 [-0.05, 0.07]). Associations were driven by within-person changes. Sex modified associations with negative affect, which were stronger in males than females. Floricultural occupation modified associations, with poorer mood, greater behavioral dysregulation and lower positive affect among floricultural workers than non-workers. Discussion: Peak pesticide spray seasons were associated with worsening of negative affect and behavioral dysregulation. EMA may provide a sensitive approach for detecting short-term neurobehavioral changes associated with seasonal pesticide exposure.

Accelerated 5x5 repetitive Transcranial Magnetic Stimulation (rTMS; five stimulation sessions per day for five days) is an effective treatment for Major Depressive Disorder (MDD), and has efficacy comparable to conventional once-daily rTMS. Considering the heterogeneity of symptoms in patients with MDD, it is critical to determine how accelerated 5x5 and conventional rTMS affect depression symptom domains. We compared symptom change over time in patients treated with either accelerated 5x5 rTMS (25 total sessions, n = 40) or conventional once-daily rTMS administered over six weeks (30 total sessions, n = 135). Accelerated 5x5 patients received either prolonged intermittent theta burst stimulation (piTBS) or personalized "resonant frequency" (RF) stimulation. Mixed-effects linear models were built to compare the two protocols, with the primary outcome variables being the Inventory of Depression Symptomology Self-Report (IDS), the Ruminative Response Scale (RRS), and the Profile of Mood States - Brief (POMS), yielding measures of 14 unique depression symptom domains. Both protocols led to similar improvements in all 14 depression symptom domains (all interaction term p-values > .05). Subsequent exploratory analyses demonstrated that accelerated 5x5 and conventional rTMS may differ in the time courses of their effects on anxiety, rumination, mood, depression, and vigor (p-values < .05, uncorrected). These results suggested that accelerated 5x5 rTMS has a similar efficacy in alleviating 14 depression symptom domains compared to conventional once-daily rTMS, and that either protocol may be appropriate for MDD patients with a variety of symptom profiles.

Major depressive disorder (MDD) and post-traumatic stress disorder (PTSD) are prevalent, chronic, and disabling mental health conditions which are difficult to treat. Ketamine has demonstrated effect for improving depression and PTSD symptoms independently but reports often overlook focused comorbid improvement of these symptoms within individuals. To address this, we assessed blood-based biomarker and psychological changes following low-dose oral ketamine treatment for adults with MDD alone (n=14) and comorbid MDD+PTSD (n=21). Before treatment, the MDD clinical group presented with more severe depression, lower serotonin levels and higher kynurenine levels than the MDD+PTSD group. Post-treatment there were no detectable differences in the biological response between clinical groups, with combined analysis revealing common decreases in circulating brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF-A). Additionally, post-treatment, both clinical groups showed improvements in anxiety, stress, social functioning, suicidal ideation, and general well-being measures, as well as individual improvements in depression scores and PTSD symptoms in the MDD- and PTSD-containing groups, respectively. Collectively, this study presents additional evidence that low-dose oral ketamine treatment can be effective for MDD and MDD+PTSD, individually and comorbidly, and that both MDD and PTSD clinical groups responded in the same biological manner.

Brief assessments reduce clinician and patient burden and increase utilization. Recently, five core depression symptoms (low mood, poor concentration, low self-worth, loss of interest, low energy) have been shown to be particularly sensitive to treatment effects in adults. How these core depressive symptom domains perform for screening or diagnostic purposes in youth is unknown. To address this question, we extracted five analogous symptom items from four widely used symptom assessment tools for children and adolescents (Child Behavior Checklist [CBCL], Youth Self Report [YSR], Parent General Behavior Inventory [P-GBI], and Adolescent General Behavior Inventory [A-GBI]) to create 5-item short forms. We evaluated their psychometric properties and diagnostic utility in a large (N=1185), racially diverse sample (48% Black youth) across community and academic outpatient mental health settings, with diagnoses established through LEAD consensus. All short forms correlated highly with full-length measures (r=.74-.92) and demonstrated comparable inter-item correlations (r =.19-.46). The short forms did not differ meaningfully from the full measures in correlations with psychiatric diagnoses, demographics, or diagnostic interviews. Area under the curve (AUC) values for identifying depression and any mood disorder diagnosis (determined by semi-structured diagnostic interviews) were fair to good (AUC=0.60-0.79), which were not worse than full measures, except for the P-GBI. The CBCL-5, YSR-5, P-GBI-5, and A-GBI-5 may be useful brief depression assessments in youth. How these five symptom domains perform as outcome measures in treatment deserves study.

Suicidal behavior results from complex behavioral and biological changes. Previous cross-sectional studies indicate that proinflammatory immunobiological factors are often increased in close temporal proximity to a suicide attempt. Suicidal individuals may also exhibit a biological trait vulnerability to stress and inflammation, due to persistent epigenetic modifications. We enrolled 130 individuals with major depressive disorder (MDD), 83 with suicidal behavior at intake, and followed them for 12 months with up to eight clinical assessments. Quantification of plasma inflammatory markers and metabolites was performed by high-sensitivity electrochemiluminescence and Ultra High-Performance-Liquid-Mass Spectrometry (UPLC-MS), respectively. Epigenetic changes were identified using Illumina EPIC arrays. We identified 15 genes with altered DNA-methylation associated with suicidal behavior and attempts at baseline. Childhood trauma predicted lifetime suicide attempts and was associated with altered methylation of seven genes. Increased neutrophils and lower plasma serotonin at baseline predicted future suicide attempts over the following year (neutrophil estimate = 0.42, P = 0.016; serotonin OR = 0.58, 95% CI: 0.39-1.13). Utilizing biomarkers from baseline and epigenetic data from the genes with highest predictive values (STBD1 ,PRDM8, and TRIM15), we achieved an area under the curve (AUC) of 0.84 for suicide attempts over the year. Suicidal behavior in MDD was associated with specific epigenetic signatures. Several of the identified genes, such as MAD1L1, have been implicated in psychiatric disease, suicidal behavior and the immune response. These findings support the usefulness of epigenetic and immunometabolic blood markers for identifying suicidal individuals in clinical settings, potentially enhancing preventative efforts.

Objective: Brief measures of depressive symptoms and family psychiatry history may support the identification of youth who warrant further assessment, but their interpretation requires population-based measurement evidence. This study evaluated the Very Quick Inventory of Depressive Symptomatology (VQIDS) and Family Index of Risk for Mood (FIRM) in the BENCHMARK 2025 national survey. Method: The sample consisted of 2,252 parent reports for children aged 6-18 years and 1,008 linked adolescent self-reports aged 12-18 years. Analyses examined VQIDS dimensionality, reliability, item functioning, age- and sex-based norms, and informant agreement, alongside FIRM score distributions, alternative scoring approaches, and associations with depressive symptoms. Results: VQIDS findings supported a single dimension and good internal consistency, with greatest IRT precision at elevated symptom levels and no practically meaningful differential item functioning across age or sex. Two-week stability was moderate, and parent-adolescent agreement was lower within more symptomatic subsets. FIRM totals showed stronger cross-informant agreement and retest stability. Family history scores were associated with higher VQIDS percentiles and discriminated scores at or above the 90th percentile across informants (AUROC = .670-.698). FIRMs associations were strongest with internalizing symptoms, although evidence was mixed for mood specificity. Conclusions: These findings provide a measurement and normative foundation for brief depressive symptom assessment and support family history as a complementary correlate of symptom elevation. Diagnostic and prospective prediction utility require further evaluation.

Non-suicidal self-injury (NSSI) is highly prevalent and exhibits substantial fluctuations among adolescents with mood disorders, yet the heterogeneity and differential treatment responses accompanied by such fluctuations remain unclear. The current study employed ecological momentary assessment (EMA) and latent profile analysis to identify latent subtypes of NSSI ideation via temporal features, and constructed machine-learning models to validate the predictive value of dynamic features for post-treatment self-injury risk. Thirty-five Chinese female adolescents with mood disorders and co-occurring NSSI (Mage = 14.4 years) receiving inpatient psychiatric treatment completed baseline assessments and 5 daily surveys of NSSI ideation throughout the course of treatment. Two subtypes were identified: the high-mean paroxysmal subtype (54.3%) and the low-mean sporadic subtype (45.7%). The high-mean paroxysmal subtype exhibited significantly more severe clinical symptoms, more emotional abuse experiences, lower self-esteem, higher impulsivity and greater difficulties in emotion regulation. The temporal-feature-based model outperformed the baseline-feature-based model in predicting self-injury risk. These findings underscore the dynamic nature and heterogeneity of NSSI ideation among adolescents with mood disorders, and offering implications for tailoring interventions to distinct youth subgroups.

Background: In the age of TikTok, YouTube, and Netflix, video streaming (VS) is highly popular among adolescents. Yet, risky to addiction-like viewing patterns (i.e., problematic (P)VS) may adversely affect well-being. Prevalence estimates based on established criteria and etiological understanding of this phenomenon remain scarce. It is associated with de-pression, a major issue within the youth mental health crisis. However, causality remains unclear. This study investigated prevalence trends of adolescent PVS and its temporal rela-tionship with depression. Methods: Population-based data were drawn from four annual waves (2022-2025) of a rep-resentative online survey among 3,477 German adolescents (aged 10-17 years). Weighted annual PVS prevalence estimates were calculated based on standardized measures applying ICD-11 criteria of behavioural addictions distinguishing pathological from hazardous behav-ioural patterns. A cross-lagged panel analysis examined the reciprocal relationship between PVS and depression over four years. Results: Prevalence of pathological VS ranged between 2 to 4% across waves. Hazardous VS prevalence was 13-14% from 2022 to 2024, before increasing to 25% in 2025. Up to 81% of adolescents with pathological VS (21% with hazardous VS) showed clinically relevant symptoms of depression, versus 8-9% of non-affected adolescents. Depression significantly predicted PVS in two of three lags ({beta}W1-W2=0.233, {beta}W2-W3=0.155), but not vice versa. Conclusions: Prevalence rates and their divergent associations with depression support dis-tinguishing hazardous from pathological VS and underline the clinical relevance of PVS. Depression preceded PVS, pointing to the role of maladaptive coping. This has direct impli-cations for effective intervention measures. Future research should clarify the mechanisms underlying this relationship.

Background: Major depressive disorder (MDD) is a severe mental illness associated with severe clinical consequences and substantial societal burden. It's characterized by immune-inflammatory dysregulation and immune sensitization. Objective: To determine whether in vitro ketamine attenuates phytohemagglutinin (PHA)/lipopolysaccharide (LPS)-induced immune sensitization in patients with MDD and healthy controls (HCs). Methods: Whole blood from 18 patients with MDD and 18 HCs was stimulated with PHA/LPS and exposed to ketamine (0.3 M, 0.6 M, and 6 M) for 72 hours. Cytokines, chemokines, growth factors, and composite immune profiles, including M1/M2 macrophages, T helper (Th)1/2/17, the immune-inflammatory response system (IRS), and compensatory immunoregulatory system (CIRS), were synthesized and determined. Results: Under PHA and LPS stimulation in vitro, the MDD group exhibited markedly elevated immune profiles, including M1, M2, Th1, Th2, Th17, IRS, CIRS, chemokines, and growth factors, consistent with immune sensitization. Significant group-by-treatment interactions were observed for Th1-Th2, M2, growth factors, IL-12(p70), M1, and chemokines. Ketamine produced minimal changes in HCs but broader suppression in MDD, particularly at the highest concentration, without normalizing the sensitized immune phenotype. Among the immune markers with no notable group-by-treatment interactions, ketamine exerted diagnosis-independent effects, decreasing MIP-1{beta}, IL-1&{beta}, Th1, TNF-{beta} IRS, IFN-{gamma}, and IL-2 compared to the control condition. Conclusions: Ketamine exhibited two distinct immunoregulatory patterns: selective, disease-dependent attenuation of sensitized immune pathways and broader, diagnosis-independent suppression of the stimulated immune response, predominantly at higher concentrations. However, these effects were insufficient to normalize the immune-sensitized phenotype of MDD.

Cognitive deficits in depression often persist despite pharmacological and psychotherapeutic treatment. Existing cognitive retraining programs are typically time- and resource-intensive, and place limited emphasis on addressing subjectively perceived cognitive difficulties or generalization of gains. This proof-of-concept study aimed to adapt the Integrated Cognitive Control Training (ICCT) into a brief format for patients with depression and to generate preliminary evidence of feasibility and effectiveness. The intervention was adapted into a manualized five-session program through a literature review, expert surveys involving clinicians and individuals with lived experience of depression, and a trial run. The study followed a single-group, open-label pre-post design (N = 16). Significant improvements were observed in cognitive flexibility (Color Trails Test-2: t = 3.52, p = 0.003, d = 0.88), depression severity (Montgomery-[A]sberg Depression Rating Scale: t = 6.66, p < 0.001, d = 1.67), and subjective cognition (Perceived Deficits Questionnaire: t = 5.06, p < 0.001, d = 1.3). The intervention demonstrated high acceptability and demand. These findings suggest that the Brief ICCT is a feasible and potentially effective approach for addressing cognitive deficits, with improvements extending to depressive symptom severity and socio-occupational functioning. These proof-of-concept findings justify further evaluation of Brief ICCT in adequately powered randomized controlled trials.

Background: Interview-based suicide assessments are insufficient for near-term risk detection, but there are no evidence-based, high-performing alternatives. The Death Implicit Association Test (DIAT) has been proposed as a suicide risk assessment tool. However, traditional DIAT scoring methods exhibit limited association with suicidality. Methods: We tested whether temporal structure in reaction times (RTs) from the Brief Death Implicit Association Test (BDIAT) tracks active suicidal ideation (SI), which was ascertained by ecological momentary assessment (EMA). Seventy-seven participants who either did or did not endorse active SI during EMA (SI+ n=22; SI- n=55) completed 18 alternating blocks of the BDIAT (9 Life + Me, 9 Death + Me). We computed the conventional D-score, an aggregate index of self-life versus self-death associations, and separately treated RTs as time-varying signals, examining entrainment to block alternation and habituation during conflict-related trials. We then developed a bilinear logistic regression classifier to extract these temporal RT features and trained it to predict SI status, with performance validated using leave-one-out cross-validation. Results: The conventional D-score did not reliably classify SI+/SI- individuals. In contrast, temporal RT dynamics reveal group differences in block-level entrainment and trial-level habituation. A bilinear logistic regression classifier leveraging these dynamics predicts SI status with 77% balanced accuracy and AUC 0.799. Conclusions: Results demonstrate that temporal dynamics of RT during the BDIAT track active ideation and can be used to distinguish SI status at the individual level, implicating RT temporal dynamics evoked during BDIAT as a candidate behavioral marker of near-term suicide risk.

Objective: To identify speech features distinguishing adults with depression from healthy controls, evaluate whether these features track with depression severity during naturalistic treatment, and assess whether baseline speech features predict treatment response. Design: Cross-sectional group comparison (Objective A) followed by longitudinal evaluation in an independent sample (Objectives B and C). Candidate features surviving false discovery rate (FDR) correction in the cross-sectional analysis were carried forward to longitudinal and predictive analyses. Setting: A community mental health center in New York. Participants: Dataset I (cross-sectional): 82 adults with chart-diagnosed depressive disorders and 80 healthy controls (N=162), recruited via convenience sampling. Dataset II (longitudinal): 85 adults with depressive disorders followed for up to four timepoints over a mean of 10.4 weeks during naturalistic treatment; 63 with baseline PHQ-9 >=10 and at least one follow-up were included in prediction analyses. Recruitment occurred under protocols approved between 2020 and 2021. Interventions: None; participants received naturalistic clinical care. Outcome Measures: Cross-sectional: diagnostic group membership (depressive disorder vs. healthy control). Longitudinal: Patient Health Questionnaire-9 (PHQ-9) total score. Predictive: treatment response, defined as >=50% PHQ-9 reduction from baseline to last follow-up. Results: Across three speech tasks (journaling, picture description, phonemic fluency), 11 voice quality features, six shimmer variants and five harmonics-to-noise ratio (HNR) variants, survived FDR correction (all q<.05) in all tasks, with higher shimmer and lower HNR in the depressed group (largest adjusted effect beta=1.89, q<.001). In longitudinal analysis, one phonemic fluency voice quality feature was associated with PHQ-9 at FDR<.05 (maximum HNR beta=-1.43, SE=0.41, FDR=.006), with the remaining ten consistent in direction at FDR<.10; no speech x time interactions were significant. Sex moderated voice quality-depression associations in picture description and phonemic fluency. For treatment response prediction, phonemic fluency voice quality features achieved cross-validated AUC=0.727 [95% CI: 0.662, 0.792], comparable to clinical features alone (AUC=0.700-0.715); the combined model across all tasks and clinical features achieved AUC=0.730 [0.639, 0.820]. No pairwise AUC comparisons between predictor configurations reached significance after correction (all corrected p>.54). Conclusions: Voice quality features, particularly shimmer and HNR, were the most consistent speech correlates of depression across cross-sectional, longitudinal, and predictive analyses and across multiple speech tasks. These features are computationally simple to extract from brief recordings and showed preliminary predictive utility comparable to standard clinical variables. However, the modest sample sizes, chart-based diagnoses and heterogeneous treatment exposures preclude clinical application at this stage. Larger, prospectively designed studies with standardized recording protocols, structured diagnostic assessment, and recruitment at treatment initiation are needed before voice quality features can be recommended as clinical biomarkers.

Circadian biology has long been implicated in mood and depressive disorders. While longer, infradian rhythms are increasingly recognised across diverse physiological processes, their relevance to mood remains poorly understood. Using long-term wearable heart rate data, this study mapped depressive symptom severity onto person-specific multiday physiological phase. Individual-specific cycles were estimated from 413 young adult participants (Notre Dame NetHealth project) alongside up to four repeated Beck Depression Inventory (BDI) assessments (955 observations). Individual's dominant infradian rhythm (2-60 days) was estimated from heart rate using wavelet analysis, and BDI scores were indexed according to whether surveys occurred during the cycle peak or trough. Mixed-effects linear modelling examined the relationship of cycle phase with mood symptoms, and whether this relationship differed by exercise level. In those with significant cycles (360 participants, 864 observations), depressive symptom severity varied across multiday physiological phase as a function of exercise level: Cycle Phase X Exercise Group interaction, F(1,712.21)=5.13, p=0.024. BDI scores were higher at the peak than trough in the Low-exercise group, {Delta} = 1.69, 95% CI [0.11, 3.28], p=0.037, with no peak-trough difference in the Higher-exercise group. Higher daily heart rate, lower exercise, female sex, and winter season were associated with higher BDI scores. Notably, this study introduces a "when" dimension to depressive symptom variation and provides the groundwork for clinical studies testing whether wearable-derived cycles can characterise temporal patterns of symptom vulnerability and support personalised tracking of mood dynamics.

Background: Major depressive disorder (MDD) is a heterogeneous condition characterized by neuro-immune-metabolic-oxidative stress (NIMETOX) pathways. A systems-biology approach may help elucidate how these interconnected NIMETOX disturbances relate to early-life adversity and multidimensional clinical phenomes in adolescent MDD. Objectives: This study aimed to define the peripheral metabolic, vascular, and acute-phase, oxidative, and lipid biomarker profiles of adolescent MDD and to investigate associations with ACEs and clinical phenotypes. Methods: This cross-sectional study recruited 80 adolescents with MDD and 53 matched healthy controls and assessed C-peptide and insulin, vascular tone markers, the acute-phase inflammatory axis, oxidative stress, and lipid profiles. Results: MDD adolescents exhibited significant reductions in C-peptide, NO, ApoE, ApoA1, HDL-C, albumin, and transferrin, together with increased ApoB/ApoA1 ratio. These biomarkers correlated significantly with family dysfunction, childhood trauma, bullying exposure, and maladaptive parenting. These biomarkers and stressors accounted for 46.2% to 61.2% of the variance in psychological resilience, and major affective, physiosomatic, self-injurious, suicidal, and self-regulation phenomes. ACEs and bullying exposure, together with relevant socio-demographic data, explained 10.5% to 28.4% of the variance in selected metabolic, vascular, and acute-phase biomarkers. Multivariable classification models showed adequate discrimination between MDD and healthy controls, achieving up to 88.5% classification accuracy and an AUC of 0.948. Conclusion: Adolescent MDD is characterized by coordinated reductions in negative acute-phase proteins, metabolic and lipoprotein protective factors, and endothelial NO, without overt CRP-defined inflammation or conventional dyslipidemia. These findings support a systems-biology model of impaired peripheral homeostatic protection associated with developmental adversity and multidimensional depressive phenomes.

Negative emotional bias, including reduced processing of positive information and negative interpretation of ambiguous stimuli, is a core feature of depression. Esketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist with rapid antidepressant effects in treatment-resistant depression (TRD), reduces depressive symptoms, but its effects on distinct components of emotional processing remain unclear. Fifty-three patients with TRD and 53 healthy controls performed an Emotional Facial Expression Morphing task. Patients were assessed at baseline, 24 hours after the first esketamine administration, and after 4 weeks of treatment. Statistical models examined detection thresholds for happy and sad faces, negative categorisation of neutral faces, and signal detection indices separating emotion-neutral discrimination sensitivity (d') from response criterion (c), indexing the evidence required to report the presence of an emotion. At baseline, patients required greater happy-face intensity for emotion detection and were more likely to categorise detected neutral faces as negative. They also showed a more conservative response criterion without group difference in discrimination sensitivity. Responders showed an early increase in d'; and, by week 4, less negative categorisation of neutral faces than non-responders. A lower baseline response criterion was associated with responder status and, in secondary continuous analyses, with greater subsequent MADRS improvement. These findings indicate that TRD involves abnormalities across detection-related, valence-related, and decisional aspects of facial-emotion processing that are differently associated with esketamine response: baseline response criterion emerged as a candidate prognostic marker, whereas negative categorisation of neutral faces tracked clinical response. Assessing these domains may inform clinical evaluation, pending independent replication.

Background: Metabolomic studies of depression have yielded heterogeneous findings, potentially because metabolic correlates differ across symptoms and metabolic states. We examined symptom-specific metabolomic associations and whether body mass index (BMI) modifies these relationships. Methods: We analyzed 83,717 Estonian Biobank participants (70.6% female) with 249 Nightingale metabolite measures and 14 lifetime depressive symptoms. Logistic regression models progressively adjusted for sociodemographic, lifestyle, medication, and BMI factors. BMI-related attenuation and metabolite x BMI interactions were evaluated, followed by self-organizing map analyses of broader metabolic context. Results: Before BMI adjustment, 660 metabolite-symptom associations were Bonferroni-significant; 136 were significant after BMI adjustment, including 105 retained associations. Weight-related associations showed the strongest BMI dependence: none of 199 weight-gain associations and 2 of 115 weight-loss associations were retained. Among 691 preselected metabolite-symptom pairs, 211 (30.5%) showed significant metabolite x BMI interactions after false discovery rate correction. Six systemic metabolic profiles were identified, but only 3 of 211 BMI-sensitive pairs showed additional profile-dependent heterogeneity. Conclusions: Circulating metabolic correlates of depressive symptoms are heterogeneous and strongly dependent on symptom phenotype and BMI-related metabolic context. These findings suggest that metabolic biomarkers in depression should be interpreted in relation to both symptom presentation and metabolic state rather than as uniform correlates of the disorder.

Individuals with major depressive disorder (MDD) show an attentional bias toward negatively valenced stimuli and thoughts. In this study, we applied a closed-loop neurofeedback procedure designed to reduce this bias. Participants were shown composite negative faces and neutral scenes with variable opacity and were instructed to attend to the neutral scene while ignoring the negative face. Internal attentional states were decoded in real time from functional magnetic resonance imaging (fMRI) data. When a participant's decoded attentional state indicated a failure to ignore the negative faces, the faces became more visible (higher opacity), thus externalizing the brain's attentional lapse in that moment. Forty-eight individuals with MDD were randomly assigned to a real neurofeedback training group (N = 24) or a sham control group (N = 24); the control group received feedback yoked to a participant in the real group. All participants completed three fMRI neurofeedback sessions. The main outcome quantified the extent to which participants got ``stuck'' in the most negative attentional state of focusing strongly on the negative faces. We hypothesized that the real neurofeedback group would learn to escape that state by the end of training, relative to the sham control group. Consistent with our hypothesis, neurofeedback training reduced the probability of getting stuck in the most negative attentional state. In offline analyses, training reduced fMRI activity in the precuneus/posterior cingulate and the medial prefrontal cortex when participants successfully attended to scenes and ignored faces. These results demonstrate the efficacy of remediating the negative attentional bias in depression with closed-loop neurofeedback from real-time fMRI.

Objective: To evaluate the psychometric properties, factor structure, validity, and age- and sex-specific norms of the 21- and 10-item parent-report Child Mania Rating Scale (CMRS-P) in a nationally representative U.S. sample of youth aged 6-18 years. Method: Parents of 2,229 youth aged 6-18 years [weighted M(SD)=12.0(3.3) years; 45.9% female] completed the CMRS-P and related measures between July 2025 and March 2026. Data were weighted to represent U.S. demographics. A clinical comparison sample included parents of 522 youth seeking outpatient mental health services. Complete-case analyses evaluated reliability, factor structure, item response theory, measurement equivalence, retest stability, and convergent and discriminant validity. GAMLSS estimated age- and sex-specific norms. Results: Weighted mean scores were 8.5(SD=9.0) for CMRS-P-21 and 4.0(4.3) for CMRS-P-10. Internal consistency was high ({omega}=.97/.93), and forms correlated .95. A general severity factor explained most reliable variance ({omega}H=.94). Three items differed in response thresholds across samples, with an average impact below one point on expected total scores. Both forms correlated strongly with attention problems, suicidality, depression, externalizing symptoms, and emotion dysregulation (r=.51-.63 for CMRS-P-21) and negligibly with pubertal status. Reliable-change thresholds were 14.5 (CMRS-P-21) and 6.8 (CMRS-P-10) points. Weighted GAMLSS CMRS-P-21 95th percentiles declined with age in males (30-23) and increased in females (22-30), with wide bootstrap intervals at age extremes; the female trend was not replicated without weights. Conclusions: Findings support both CMRS-P forms for assessing youth manic symptoms. The first nationally representative U.S. norms provide age- and sex-adjusted benchmarks for interpreting scores and informing further clinical assessment.

Home-based 2 mA transcranial direct current stimulation (tDCS) was recently approved by the US Food and Drug Administration for depression, but tDCS amplitude has been limited largely by skin tolerance, and higher-intensity, accelerated dosing may be more efficacious or faster-acting. Using a novel high-capacity tDCS (HC-tDCS) stimulator and hydrogel electrodes, we evaluated the safety, tolerability and feasibility of accelerated HC-tDCS (20-minute bifrontal 6 mA sessions, twice daily for five days) in 20 patients with major depressive disorder. A Safety Review Committee reviewed data from the first three participants, who completed a within-day escalation to 6 mA, before the remaining 17 were enrolled. Retention and adherence were 100% (203 of 203 sessions), and 19/20 tolerated the full 6 mA amplitude without dose reduction. There were no serious adverse events. The most common symptoms were fatigue (49% of sessions), burning (46%) and tingling (43%) at the electrode, and difficulty concentrating (40%). Electrode-site erythema occurred in all participants, with no severe reaction or skin breakdown. At 1 week, 7 of 20 reported a residual skin change, mostly peeling or redness, none painful; at 1 month, hyperpigmentation at the electrode site persisted in 2 participants, both Black. At the end of the five-day course, PHQ-9 scores decreased from 15.8 to 7.2 (Hedges g = 1.62); 50% of participants responded, 45% remitted, and improvement was maintained at 1-month follow-up. Accelerated HC-tDCS was feasible, well tolerated, and warrants a sham-controlled trial.

Background: Substance use is common among individuals with depression. Transcranial magnetic stimulation (TMS) is an effective treatment for depression, but current clinical guidelines have discouraged TMS treatment for individuals with depression and co-occurring substance use given concerns for limited efficacy. However, limited data exists on whether substance use affects response to TMS. Methods: Using electronic health record data from patients who received a standard course of TMS for major depressive disorder at an academic medical center, we investigated associations between substance use frequency and response to TMS, defined as change in Patient Health Questionnaire-9 (PHQ-9) scores. Substance use frequency was extracted for alcohol, cannabis, nicotine, stimulants, benzodiazepines, opioids, inhalants, psychedelics, and other drugs. We performed ANCOVA and multiple regression analyses to predict change in PHQ-9 score based on substance use frequency, controlling for pre-TMS PHQ-9 score, age, sex, and number of TMS sessions received. Results: We extracted data from 219 TMS courses. Alcohol was the substance used most commonly (34.2%), followed by prescription benzodiazepines (28.3%), and prescription stimulants (21.0%). Across all substance categories, substance use was not associated with change in PHQ-9 score (all p > 0.05, Cohens d=0.00 to 0.30). In multiple regression models to compare individual levels of substance use frequency (e.g., daily use vs. no use), level of substance use was not associated with change in PHQ-9 score (all p > 0.05). The range of plausible effects of substance use frequency on PHQ-9 change was generally below the minimal clinically important difference for PHQ-9, suggesting substance use was unlikely to have a meaningful clinical effect on antidepressant response to TMS. Conclusions: Low to moderate substance use does not have a clinically significant effect on antidepressant response to TMS. Low-level substance use should not exclude individuals with depression from receiving TMS.