Importance:Default mode network (DMN) activity has been implicated in mechanisms of antidepressant treatment response, particularly expectancy processes that contribute to placebo effects. However, causal evidence is limited. Objective:To test whether modulating DMN function via theta burst stimulation (TBS) over the dorsomedial prefrontal cortex (PFC) alters placebo-related neural activity and expectancy-driven mood responses. Design, Setting, and Participants:This randomized clinical trial was conducted from October 2020 to March 2025 and represented a within-person, counterbalanced design. Adults with depressive symptoms aged 18 to 53 years not taking psychotropic medication were included in the analysis. Participants were recruited from the University of Pittsburgh Medical Center. Trial × trial expectancy and mood ratings were recorded. Data analysis was performed on a rolling basis from October 2021 to March 2025. Interventions:Three TBS sessions over the dorsomedial PFC (electroencephalogram coordinate F2; 80% resting motor threshold, 1 week apart): intermittent (iTBS), continuous (cTBS), and sham (sTBS). One hour later, they completed the antidepressant placebo functional magnetic resonance imaging (MRI) task, which manipulated anticipatory beliefs using expectancy cues and sham neurofeedback. Main Outcomes and Measures:Outcomes included expectancy and mood ratings during the antidepressant placebo functional MRI task and placebo-related neural activation in the DMN. Results:A total of 103 individuals were enrolled in the study. Of those enrolled, 67 completed at least 1 session, and 50 (mean [SD] age, 28.3 [9.5] years; 26 male [52.0%]) composed the final analytic sample. Voxelwise analyses showed that iTBS increased dorsomedial PFC activity relative to cTBS in the DMN (threshold-free cluster enhancement corrected P = .98). Cluster-based analyses confirmed a main effect of stimulation, with a significant monotonic pattern (iTBS > sTBS > cTBS, F2,144 = 4.55; P = .01; η2 = 0.06). In models predicting mood, greater DMN activation predicted stronger expectancy-related mood responses under iTBS compared with sTBS (β = 0.30; 95% credible interval [CrI], 0.07-0.52). In contrast, in models predicting expectancies, greater DMN activation predicted higher expectancy ratings in response to the treatment cue (β = 0.38; 95% CrI, 0.22-0.55), but this coupling was strongest under cTBS (β = -0.22; 95% CrI, -0.44 to 0), likely reflecting engagement of upstream regions. Behaviorally, cTBS increased expectancy ratings relative to the other conditions. Conclusions and Relevance:Results of this randomized clinical trial show that a single session of iTBS targeting the dorsomedial PFC enhanced expectancy-related modulation of the DMN and amplified placebo-induced mood improvement. These findings implicate DMN plasticity in the rapid shaping of antidepressant expectancy effects and highlight a potential circuit-based mechanism for augmenting treatment response in depression. Trial Registration:ClinicalTrials.gov Identifier: NCT04276259.

In the past decade, interest in studying psychedelic compounds as potential therapeutic agents has resurged. These studies carefully exclude individuals at risk for developing psychotic symptoms in response to psychedelic use. Given the potential for psychedelics to be established as treatments in psychiatry, it is important to more robustly understand their link with psychosis and schizophrenia spectrum disorders (SSDs). In this narrative review, we examine the historical and theoretical relationship between psychedelic drugs and SSDs, including the origins of the psychotomimetic hypothesis. For key psychedelic compounds, we review their phenomenological manifestations in relation to the experiential alterations characteristic of SSDs, revealing both areas of overlap and important qualitative differences that challenge the uniform psychotomimetic classification. We also review putative neural mechanisms underlying altered experiential states associated with psychedelic use and SSDs, with attention to serotonergic, dopaminergic, and glutamatergic contributions. Clinical evidence demonstrates that psychedelics can exacerbate pre-existing psychotic illness and may trigger psychosis in vulnerable individuals, though the magnitude of these risks remains inadequately quantified. However, phenomenological and mechanistic distinctions suggest that potential therapeutic applications may exist for carefully selected symptoms (negative symptoms, depression) in stable patients using low-dose, controlled approaches. Based on published work, we provide recommendations regarding psychosis-related risk and potential avenues for the treatment of SSDs as psychedelics gain traction as therapeutics.

Anhedonia emerges in adolescence, has putative substrates in neural reward and dopamine systems, and is a hallmark of poor course in depression. Psychoneuroimmunology models suggest altered immune and reward systems may jointly underlie its development. When dopamine availability (rather than function) is considered, immune activation may be understood as a moderator amplifying how lower dopamine levels translate into motivational deficits. This cross-sectional study analyzed data from 55 youth with current depression (Mage=21.4 years; Female=75%). Plasma was assayed for relative quantification of 92 immune proteins, followed by dimensionality reduction via principal component (PC) analysis, forming five PC scores. Dopamine availability was indexed by basal ganglia tissue iron, quantified by MRI R2', a measure detectable in youth. Anhedonia was assessed using the Snaith-Hamilton Pleasure Scale (SHAPS), thought to capture overall anhedonia, and Positive Valence Systems Scale (PVSS), which provides overall, anticipatory, and consummatory anhedonia scores. PC1 scores-whose loadings indicated broadly distributed immune protein elevations consistent with general immune activation-moderated the relationship between basal ganglia dopamine availability and anhedonia: At higher PC1 levels, lower dopamine availability was linked to greater overall anhedonia (as measured by SHAPS) and anticipatory anhedonia, but not to consummatory anhedonia. Lower PC2 scores were associated with greater PVSS overall and consummatory anhedonia. Analyses examining individual basal ganglia regions suggest potential differences in dopaminergic-immune interactions across these regions, with effects most consistently observed in the putamen. Findings highlight nuanced neuroimmune pathways underlying anhedonia components in youth and support inflammation-based models of depression emphasizing dopaminergic-immune interplay.

Abstract Elucidating the neurobiological basis of neurodevelopmental and psychiatric conditions (NDPCs) remains challenging because brain alterations vary within diagnoses and overlap across them. Whether diverse alterations follow a systematic organization that may reflect shared vulnerabilities remains unknown. Here, we assembled 10,135 individuals with schizophrenia, autism, bipolar, obsessive-compulsive, generalized anxiety, and major depressive disorders, and 11,998 reference participants across six continents through the ENIGMA consortium. Using normative modeling, we quantified individual deviations in cortical thickness, surface area, and subcortical volumes relative to lifespan reference trajectories (5 to 80 years). We show that structural deviations converged along cortical axes reflecting connectome organization, maturation, and cytoarchitectonic diversity. These axes mirrored typical population variation, but their expression differed across diagnoses and partly scaled with symptom severity. Even rare and highly individualized extreme deviations followed this organization, concentrating in densely connected regions. Finally, brain structural deviations overlapped substantially across diagnoses, while differences between them increased toward the association cortex. Together, we provide large-scale evidence that structural deviations across NDPCs are systematically constrained by the brain’s intrinsic architecture. This shared organization provides a framework for reconciling individual variability with transdiagnostic similarities and motivates an integrative, systems-level understanding of mental health.

BACKGROUND:Psychosocial health is an important predictor of surgical outcomes. Resilience, defined as the ability to "bounce back" from adversity, has been associated with various outcomes, but no consensus exists on measuring resilience in surgical populations. The Connor-Davidson Resilience Scale (CD-RISC), a widely used instrument, has not been explored in relation to other psychometric scales. This study compared CD-RISC with measures of psychological symptom burden to inform future evaluations of whether interventions that improve resilience also improve postoperative outcomes. METHODS:This cross-sectional study analyzed secondary data from the baseline assessment within a larger randomized controlled trial, comprising 265 adults scheduled for major abdominal or pelvic surgery who completed preoperative research surveys, including the CD-RISC-10; Patient-Reported Outcomes Measurement Information System (PROMIS) Anxiety, Depression, Sleep Disturbance short forms; and Pain Catastrophizing Scale (PCS). Patients were stratified into low, normal, and high resilience groups using ±1 standard deviation thresholds. Group differences were tested using multivariable analysis of variance (MANOVA) with follow-up analysis of variance (ANOVAs). Spearman's correlations quantified associations between resilience and symptom burden. Receiver operating characteristic (ROC) analyses evaluated whether CD-RISC scores predicted elevated symptom burden. RESULTS:Multivariable analysis showed significant differences between CD-RISC strata across all measures (Pillai's trace = 0.29, F(8, 520) = 11.0, P < .001, = 0.15). Follow-up analyses revealed the strongest effects for anxiety (F(2, 262) = 38.8, P < .001, = 0.23) and depression (F(2, 262) = 39.4, P < .001, = 0.23), and modest effects for sleep disturbance (F(2, 262) = 10.9, P < .001, = 0.08) and pain catastrophizing (F(2, 262) = 10.9, P < .001, = 0.08). Spearman's correlations demonstrated moderate negative associations between resilience versus anxiety (ρ = -0.48 [-0.57 to -0.38], P < .001) and depression (ρ = -0.50 [-0.59 to -0.40], P < .001); and modest negative associations versus sleep disturbance (ρ = -0.30 [-0.42 to -0.18], P < .001) and pain catastrophization (ρ = -0.31 [-0.42 to -0.19], P < .001). CD-RISC showed fair discrimination for ruling out elevated symptom burden using a composite of PROMIS and PCS scores (area under the curve [AUC] = 0.71 [0.63-0.78], specificity = 0.86 [0.81-0.90], cutoff ≤28). CONCLUSIONS:Preoperative resilience measured with CD-RISC demonstrates moderate negative associations with measures of anxiety and depression in preoperative patients. CD-RISC could be used as a brief preoperative screening tool to rule out elevated psychological symptom burden. Future studies should assess whether perioperative interventions to increase resilience can positively influence recovery outcomes such as risk of persistent postoperative opioid use.

Higher predicted brain age difference has been associated with several psychiatric disorders. Generalized anxiety disorder (GAD) is associated with markers of accelerated aging. In this study, we determined brain predicted age difference (PAD) in individuals with GAD and healthy controls (HC) as well as group differences in PAD variability using voxel-wise structural MRI. The training dataset included 3,511 controls, and the testing dataset included 1,595 individuals with GAD and 4,552 HC from the ENIGMA-Anxiety GAD Working Group. A convolutional neural network model using four input modalities per subject and a model ensemble approach was used to predict brain age. The PAD was then calculated by subtracting chronological age. Model performance was consistent with other image-based brain age prediction models with similar accuracy across the training set (mean absolute error (MAE) = 2.95 years) and HC in the testing set (MAE = 2.94). We found no evidence of accelerated brain aging in individuals with GAD, though we did find evidence for greater variation in PAD for individuals with GAD (Levene's test: W = 442.98, p < .001) and evidence for greater variability in PAD of those with GAD over 25 years of age. No relationships between PAD and clinical or demographic measures were found. To conclude, using large training and testing samples, the study found no significant association between GAD and PAD, although individuals with GAD had greater heterogeneity in brain-predicted age.

Cognitive impairments have been observed in patients with depression. These include deficits in inhibition, shifting, and updating; cognitive processes that are critical for goal-directed control over behavior (‘model-based planning’). Nevertheless, results of model-based planning in depression have been mixed. We aimed to address this by taking a within-person approach, examining model-based planning before and after a range of effective treatments for depression. Across two parallel studies, participants completed a two-step reinforcement learning paradigm before and after antidepressant medication, internet-based cognitive behavioral therapy (iCBT) or intravenous (IV) ketamine infusion. In experiment 1, 93 patients with treatment-resistant depression were randomized to a single dose of IV ketamine (0.5 mg/kg) or IV saline (50 mL 0.9% NaCl). In Experiment 2, 781 participants were followed for four weeks of antidepressant (N = 83), or iCBT (N = 611) treatment. N = 87 participants without any psychiatric diagnosis were followed as a control group. In both experiments, depressive symptoms significantly improved in treatment groups compared to their corresponding control groups, but we did not find evidence of changes in model-based planning. Moreover, we failed to find associations between individual differences in model-based planning and differential response to ketamine, iCBT or antidepressant treatments. Individual differences in model-based planning at baseline were associated with compulsivity, but not with depression symptoms. These findings suggest that model-based planning is not necessarily compromised in depression and does not improve following treatments. This result provides evidence for the trait-like nature of model-based planning and underscores the specificity of its relation to disorders of compulsivity.

BACKGROUND: Ketamine is known for its rapid antidepressant effect, but its impact on affective information processing (including attentional bias [AB], a putative cognitive mechanism of depression) remains largely unexplored. We leveraged a novel measurement of AB and sought to 1) establish adequate test-retest reliability and validity among participants with depression prior to ketamine treatment and 2) harness a single dose of ketamine to assess mechanistic shifts in AB and their relationship to antidepressant efficacy. METHODS: A novel dual probe video task was used to index AB toward sad film clips. In study 1, treatment-seeking adults with moderate-to-severe depression (N = 40) completed the task at baseline, 1-week retest, and 1-month retest; a subset of participants (n = 15) also performed the task at 24 hours postketamine infusion (0.5 mg/kg over 40 minutes). In study 2, participants (N = 43) completed the task pre- and 24 hours postketamine. RESULTS: Indices from the novel AB task were stable prior to ketamine, demonstrating good 1-week and 1-month test-retest reliability. Participants in both studies exhibited a robust reduction in AB from pre- to 24 hours postketamine infusion. In study 1, cross-sectional correlations were observed between AB and clinician-rated depressive symptoms at each pretreatment assessment. In study 2, changes in AB were correlated with improved symptoms from pre- to postinfusion. CONCLUSIONS: Results provide evidence for the validity of a novel, psychometrically robust measure of AB among individuals with depression. Findings indicate that ketamine reliably and rapidly reduces AB, offering insight into a replicable, potential cognitive mechanism involved in its antidepressant action.

Understanding how the brain distinguishes emotional from neutral scenes is crucial for advancing brain-computer interfaces, enabling real-time emotion detection for faster, more effective responses, and improving treatments for emotional disorders like depression and anxiety. However, inconsistent research findings have arisen from differences in study settings, such as variations in the time windows, brain regions, and emotion categories examined across studies. This review sought to compile the existing literature on the timing at which the adult brain differentiates basic affective from neutral scenes in less than one second, as previous studies have consistently shown that the brain can begin recognizing emotions within just a few milliseconds. The review includes studies that used electroencephalography (EEG) or magnetoencephalography (MEG) in healthy adults to examine brain responses to emotional versus neutral images within one second. Articles of interest were limited to the English language but not to any publication year. Excluded studies involved only patients (of any diagnosis), participants under age 18 (since emotional processing can differ between adults and younger individuals), non-passive tasks, low temporal resolution techniques, time intervals over one second, and animals. Of the 3,045 screened articles, 19 met these criteria. Despite the variations between studies, the earliest onset for heightened brain responses to basic affective scenes compared to neutral ones was most commonly observed within the 250-300 ms time window. To the best of our knowledge, this review is the first to synthesize data on the timing of brain differentiation between emotional and neutral scenes in healthy adults.

Adolescent depression is associated with significant morbidity and psychosocial impairment across the lifespan. Robust associations between peripheral inflammatory markers (PIMs) and depression have been found in clinically depressed adults. Studies suggest associations between PIMs and a range of biopsychosocial factors (e.g., stress, sleep) in community samples of adults. No prior studies have examined links between PIMs and a wide array of biological/psychosocial factors (including parent-reported factors, such as parent report of child’s depression severity) in a clinically depressed cohort of adolescents, which might independently inform depression risk and also guide development of interventions to reduce risk and severity of depression. We conducted a cross-sectional study of both depressed adolescents (n = 52) and healthy adolescents (n = 20) and explored associations between 31 biopsychosocial factors and PIMs, specifically tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6). We also conducted moderation analyses. We also utilized multiverse analyses, examining robustness of results to analytic decisions. Given the described gaps in the field, our overarching scientific objective was to identify biopsychosocial factors that might contribute to variance in associations between PIMs and biopsychosocial measures in depressed adolescents. We found that TNFα was reproducibly associated with parent-reported depression severity amongst all adolescents and depressed adolescents. Less reproducible associations between IL-6 and diastolic blood pressure were also found. In moderation analyses, only links between TNFα and parent-reported depression severity were stronger in depressed adolescents. We found that specifically in depressed adolescents, TNFα may reflect parent-reported depression severity (which may serve as a more proximal measure of a child’s observable behaviors related to depression). However, few other biopsychosocial variables were linked to PIMs, with small or negligible effect size associations for most examined relationships, suggesting small sample sizes (e.g., n’s < 75) may be insufficient to detect links between PIMs and biopsychosocial variables. Given the use of our multiverse analyses, our analyses can help future researchers focus on understanding potential mechanisms linking PIMs to parent-reported depression severity.

BACKGROUND:Ketamine is a rapid-acting treatment for treatment-resistant depression (TRD), though mechanisms related to ketamine's effects remain unclear. Blood-based neurotrophic and inflammatory factors (NIFs; e.g., brain-derived neurotrophic factor, interleukin-6) have emerged as markers potentially linked to ketamine and ketamine treatment response. METHODS:In this secondary analysis of a randomized controlled trial (RCT), 133 adults with TRD received a single-dose infusion of ketamine (n = 89; 0.5 mg/kg) or saline (n = 44) and provided measures of peripheral blood NIF levels and depression severity across a five-day post-infusion period. Differences between ketamine and saline groups were examined for (1) NIF levels, (2) associations between NIF trajectories and depression score trajectories, and (3) associations between baseline NIF levels and depression score trajectories. Subgroup sensitivity analyses examined identical relationships within many (n = 28) discrete subgroups of individuals. RESULTS:No differences were found between ketamine and saline cohorts for NIF trajectories, associations of NIF and depression trajectories, or associations of baseline NIF levels and depression trajectories. On subgroup analyses, in participants with lower BMI (BMI < 25; n = 66), increasing interleukin-1 receptor antagonist (IL-1RA) trajectories post-ketamine were associated with less improvement in depression in the first day post-infusion. DISCUSSION:Associations between ketamine treatment and peripheral neurotrophic/inflammatory factors were not detected in our RCT of 133 adults with TRD. The sole exception across exhaustive sensitivity analyses was that, in individuals with low BMI, increases in IL-1RA levels may be linked to worse immediate treatment response. Future research investigating CNS-specific NIF activity is needed to more definitively test the posited role of NIFs in ketamine's antidepressant mechanisms.

Although ample research links social factors and suicidality, there remains a gap in understanding how distinct processes within social communication relate to suicidality. We demonstrate how reciprocity of eye-gaze and facial expressions of happiness differ during parent-adolescent conflict based on adolescents' future suicidal ideation (SI). Facial affect analyses were based on 103 girls (ages 11-13; M = 12.28; 75% White) and their parents. Eye-gaze analyses were conducted in subset of these dyads (N = 70). Participants completed a conflict discussion during which gaze to their partners' eyes was assessed using mobile eye-tracking glasses and facial affect was coded using FaceReader Observer XT. Adolescents' SI was assessed 12-months later. Actor-partner interdependence models tested whether participants' gaze and affect predicted their own and their partners' gaze and affect one second later and if these intra and interpersonal dynamics differed based on adolescents' future levels of SI. Girls from dyads with less parental reciprocity of eye-gaze and happiness reported higher levels of SI 12-months later. During early adolescence, girls whose parents reciprocate their eye-contact or positive affect less during conflict may be at heightened risk for SI. If replicated, social communication could provide a promising intervention target to reduce suicidality prospectively.

IntroductionThis is the first randomized controlled trial to use both qualitative and quantitative methods to evaluate the effects of a combined sensory intervention that included mindfulness, music, and a light-occluding eye mask during antidepressant-dose ketamine treatment for depression.MethodsForty-three participants with unipolar depressive disorder enrolled in the study; 22 individuals were randomly assigned to receive mindfulness, music, and eye mask during ketamine infusion, and 21 individuals in the control group received only ketamine without additional interventions. Quantitative analyses assessed the impact of combined sensory intervention on ketamine’s antidepressant effects, and qualitative analyses explored the participants’ experiences.ResultsDepression scores improved significantly and similarly across both groups. However, adding combined sensory interventions to ketamine infusion enriched subjective experience. More participants in the combined sensory intervention group reported deeper engagement, a stronger sense of connection to reality, increased focus on the experience rather than the strangeness of it, moments of relief from sadness, and feelings of awe and spiritual insight compared to the control group. Four individuals in the combined sensory intervention group also reported discomfort.DiscussionKetamine’s antidepressant effects remained consistent with or without combined sensory intervention; however, mindfulness, music, and eye mask made the experience more meaningful and emotionally rich for many, though it also introduced discomfort for a few—this outcome might be avoided by making these interventions optional. Given the limited research on combining ketamine with sensory interventions, these results contribute valuable insights and underscore the need for further studies to explore this combined therapeutic approach.Clinical trial registrationhttps://clinicaltrials.gov/study/NCT05168735, identifier NCT05168735.

Peripheral inflammatory markers (PIMs), such as C-reactive protein (CRP) or white blood cell count (WBC), have been associated with depression severity in meta-analyses and large cohort studies. However, in typically-sized psychoimmunology studies (N < 200) that explore associations between PIMs and neurobiological/psychosocial constructs related to depression and studies that examine less-studied PIMs (e.g., interferon gamma), significant concerns about reproducibility of results exist. For the well-characterized association between PIMs (CRP/WBC) and depression severity, we examined statistical errors as a function of sample size in a large community cohort (n = 24,550). We further assessed how statistical errors varied as related to analytic decisions (e.g., number of covariates) and characteristics related to study design (e.g., relationships within subgroups of patients). Only large samples (e.g., n = 1000 to n = 10,000) were sufficiently powered to detect PIM-depression associations and minimized overestimation of effect sizes (e.g., effect size inflation), and greater sample sizes were required as more covariates were included in analytic models. Moderately sized samples (n > 500) generally ensured the correct directionality of effect sizes (e.g., low rates of sign reversal). Sample sizes required for 80% power also varied widely depending on study design characteristics (e.g., N = 350 to N = 10,000+). Typically-sized psychoimmunology studies examining PIM-depression associations (N < 200) are likely underpowered and at high risk of overestimation of effect sizes. Study design characteristics also notably influence power and statistical error rates. Use of large sample sizes (e.g., N > 7000) and consideration of analytic decisions (e.g., number/choice of covariates) will maximize reproducibility of psychoimmunology studies related to depression to enhance development of treatments for depression or to help understand pathophysiological mechanisms of depression.

Importance:Suicide is a public health crisis, and despite renewed efforts to confront this problem, suicide rates continue to rise in the US. While suicide prevention encompasses a broad array of strategies, treatment development is lagging. Within this realm, clinical trials are the criterion standard for evaluating safety and efficacy of new treatments. Observations:Most clinical trials conducted among patients with mental illness have excluded patients at risk of suicide. Historical reasons for this include regulatory challenges, liability concerns, ethical questions, discomfort working directly with high-risk patients, and the belief that research is too risky for individuals at elevated risk for suicide. Conclusions and Relevance:Several considerations are provided for investigators in the design of trials targeting at-risk populations, including thoughtful selection of study outcome, use of time-to-event design and analysis (which may simultaneously satisfy ethical concerns and scientific aims), enrolling an enriched sample (eg, among patients recently discharged from the hospital), and provision of usual care in the comparator group. Caution should be exercised to avoid excessive or unreasonable safety requirements, which may lead participants to minimize self-report of suicidal ideation or to drop out of trials. Where possible, regulatory bodies (institutional review boards [IRBs] and data and safety monitoring boards) should consult with or include as members those with direct clinical experience with this high-risk population. An important ethical principle for IRB members and other regulators to consider is that suicide-related events are expected in this clinical population.

Background Obsessive-Compulsive Personality Disorder (OCPD) is characterized by a lifelong pattern of excessive attention to detail, rigidity and perfectionism. Although OCPD was historically linked to Obsessive-Compulsive and Related Disorders (OCRDs), this connection lacks consistent evidence. Compulsive behaviors, core to OCRDs, are repetitive actions aimed at reducing distress. To elucidate mechanistic links between OCPD and compulsive behaviors, this study examined relationships between OCPD traits, OCRD symptom domains, and cognitive functioning. Methods In a transdiagnostic sample of 229 adults with reported compulsive behaviors (CBs) enrolled in a larger clinical trial, we assessed maladaptive OCPD traits using the Pathological Obsessive Compulsive Personality Scale (POPS) and examined their associations with a range of OCRD self-report scales, including measures of hair pulling and skin picking. We evaluated cognitive performance using two NIH toolbox tests and a “two-step” reinforcement learning task. Results OCPD symptom scores correlated positively with OCD symptom severity on the OCI-R (r = 0.42, p < .001) and YBOCS (r = 0.38, p < .001). Higher OCPD scores were also associated with having a larger number of discrete OCRD symptom domains (r = 0.39, p < .001), and with higher scores across the majority of OCRD scales examined. OCPD scores, unlike OCD scores, showed no significant association with Flanker test or two-step task performance. Discussion Severity of pathological OCPD traits was related to overall higher severity of OCD symptoms, and linked to several individual domains of OCRDs. Neurocognitive indices showed modest relationships with OCRD symptom severity but not with OCPD. These findings contribute to our understanding of how these phenotypes may co-occur, and help guide future research.

Background Understanding the effects of ketamine on depressive symptoms could help identify which patients might benefit and clarify its mechanism of action in both the early (≤1 day post-infusion) and late (e.g. 2–30 days post-infusion) post-infusion periods. Symptom network analyses could provide complementary information regarding relationships between symptoms. Aims To identify the effects of ketamine on symptom-level changes in depression across both the early and late post-infusion periods and on depressive symptom network changes. Methods In this secondary analysis of 152 adults with treatment-resistant depression (with 38.8% reporting suicidal ideation at baseline), we compared symptom changes in the early and late post-infusion periods between individuals randomised to a single 40 min infusion of intravenous ketamine 0.5 mg/kg ( n = 103) or saline ( n = 49) and identified changes in symptom networks between pre- and post-ketamine treatment using network analyses. Results In the early post-infusion period, the greatest improvement (comparing ketamine with saline) was in depressive symptoms related to sadness. In network analyses, symptom network connectivity increased following ketamine infusion. Symptoms of sadness and lassitude showed persistent improvement in the first week post-infusion, whereas improvements in suicidal thoughts first emerged 3–4 weeks post-infusion. Conclusion Ketamine improved all symptoms but showed the greatest effect on symptoms of sadness, both immediately and in the initial week after treatment. Ketamine also rapidly altered the topology of symptom networks, strengthening interrelationships between residual symptoms. The efficacy of ketamine (compared with saline) regarding suicidal symptoms emerged later. Our findings suggest potentially divergent efficacy, time courses and mechanisms for different symptoms of depression.

Risk for depression rises during adolescence, particularly among children of depressed mothers. Altered neurophysiological reward processing, measured using event-related potentials (ERPs), is related to depression vulnerability. However, it is unclear whether disruptions in youth reward responsiveness are driven by parental reward dysfunction (e.g., anhedonia) versus parent-child relationship factors (e.g., closeness). This work examined concurrent and prospective associations between youth neurophysiological reward responsiveness and parental anhedonia, parent-adolescent discord, and parent-adolescent closeness. Participants included 93 youth assigned female at birth (ages 13-15) and their mothers (n = 62 with a depression history). Youth reward responsiveness was assessed at baseline and one-year follow-up using the reward positivity (RewP) ERP component. Parental anhedonia, parent-adolescent discord, and parent-adolescent closeness were measured at each timepoint using questionnaires. Regression analyses demonstrated positive concurrent associations between parent-adolescent closeness and youth RewP at both timepoints. RewP was not significantly related to parental anhedonia or parent-adolescent discord, and no prospective cross-lagged effects were observed. Among adolescents at varying depression risk, youth with greater closeness with their mothers consistently demonstrated enhanced reward responsiveness, even after accounting for adolescent depressive symptoms and maternal depression history. Findings suggest that positive, but not negative, aspects of parent-child relationships are related to adolescent responsiveness to reward.