Improved implicit self-esteem is associated with extended antidepressant effects following a novel synergistic intervention.

INTRODUCTION: In a previously published randomized controlled trial, automated self-association training (ASAT), a novel digital intervention, was found to extend the rapid antidepressant effect of a single infusion of ketamine for at least 30 days. In this secondary analysis, we aimed to understand the potential role of implicit self-esteem in the combined antidepressant effect of ketamine and ASAT training, by investigating the novel synergistic treatment's effects on implicit self-associations and their relation to symptom improvement. METHODS: A total of 154 adults (ages 18-60) with treatment-resistant unipolar depression and lower-than-normative explicit self-esteem were randomized in a double-blind, parallel-arm design to receive one of three treatment allocations: an active/active treatment combination consisting of one infusion of ketamine (0.5 mg/kg) followed by four days of ASAT ( ~ 30-40 min/day), or one of two control arms that lacked either the active drug or the active behavioral component. The Implicit Association Test (IAT) was used to behaviorally assess the strength of association between self-related stimuli and negative concepts. Linear regression models were used to test the relationship between group assignment, IAT scores acquired immediately post-treatment, and both acute and extended clinical outcomes (% change in Montgomery-Asberg Depression Rating Scale scores, relative to pre-treatment baseline) in the trial. RESULTS: The group assigned to ketamine + ASAT intervention, compared to the other groups, had a pattern of IAT scores indicating more positive self-associations immediately after treatment relative to the control arms (F(1, 131) = 3.979; p = 0.048). In regression models, IAT scores tracked with concurrent (acute post-treatment) % change in MADRS scores across all treatment arms (p = 0.001), and mediated more extended (Day 30) depression improvements specifically for the ketamine+ASAT arm (group * IAT interaction term: ß = -0.201; p = 0.049). DISCUSSION: Our findings suggest that changing implicit self-worth during a post-ketamine 'plasticity window' is one key mechanism whereby the novel ketamine+ASAT treatment combination exerts its antidepressant benefit, confirming the intended treatment target at the level of implicit cognition. Future studies should seek to further enhance the reliability of the biobehavioral intervention's impact on implicit cognition, as this mechanism appears linked to the intervention's enduring clinical benefits.

International pooled patient-level meta-analysis of ketamine infusion for depression: In search of clinical moderators.

Depression is disabling and highly prevalent. Intravenous (IV) ketamine displays rapid-onset antidepressant properties, but little is known regarding which patients are most likely to benefit, limiting personalized prescriptions. We identified randomized controlled trials of IV ketamine that recruited individuals with a relevant psychiatric diagnosis (e.g., unipolar or bipolar depression; post-traumatic stress disorder), included one or more control arms, did not provide any other study-administered treatment in conjunction with ketamine (although clinically prescribed concurrent treatments were allowable), and assessed outcome using either the Montgomery-Åsberg Depression Rating Scale or the Hamilton Rating Scale for Depression (HRSD-17). Individual patient-level data for at least one outcome was obtained from 17 of 25 eligible trials [pooled n = 809]. Rates of participant-level data availability across 33 moderators that were solicited from these 17 studies ranged from 10.8% to 100% (median = 55.6%). After data harmonization, moderators available in at least 40% of the dataset were tested sequentially, as well as with a data-driven, combined moderator approach. Robust main effects of ketamine on acute [~24-hours; ß*(95% CI) = 0.58 (0.44, 0.72); p < 0.0001] and post-acute [~7 days; ß*(95% CI) = 0.38 (0.23, 0.54); p < 0.0001] depression severity were observed. Two study-level moderators emerged as significant: ketamine effects (relative to placebo) were larger in studies that required a higher degree of previous treatment resistance to federal regulatory agency-approved antidepressant medications (≥2 failed trials) for study entry; and in studies that used a crossover design. A comprehensive data-driven search for combined moderators identified statistically significant, but modest and clinically uninformative, effects (effect size r ≤ 0.29, a small-medium effect). Ketamine robustly reduces depressive symptoms in a heterogeneous range of patients, with benefit relative to placebo even greater in patients more resistant to prior medications. In this largest effort to date to apply precision medicine approaches to ketamine treatment, no clinical or demographic patient-level features were detected that could be used to guide ketamine treatment decisions.Review Registration: PROSPERO Identifier: CRD42021235630.

The association of physical illness and low-grade inflammatory markers with depressive symptoms in a large NHANES community sample: Dissecting mediating and moderating effects.

BACKGROUND: Both low-grade elevation in peripheral inflammatory markers (e.g., white blood count (WBC) and C-reactive protein (CRP)) and physical illness (both chronic and acute) have been associated with depressive symptomology. However, it is unclear if low-grade elevation in inflammatory markers mediates relationships between physical illness and depression or if physical illness positively moderates relationships between inflammatory markers and depression. METHODS: In a well-powered, racially diverse cohort (n = 21,525) from NHANES datasets, we examined if inflammatory markers (CRP and WBC) and physical illnesses (acute and chronic) were independently associated with depression severity. We also examined if associations between physical illness and depression severity were mediated by inflammatory markers and if physical illness moderated associations between inflammatory markers and depression. RESULTS: We found that both inflammatory markers and physical illness were associated with depression severity, even after considering a wide range of potential confounders (e.g., age, gender, body mass index). Inflammatory markers mediated a marginal portion (<5%; p < 0.001) of potential effects of physical illness on depression severity. In moderation analyses, associations between inflammatory markers and depression severity were significantly stronger in participants with chronic physical illness than those without. This moderating effect was not present for acute physical illness. CONCLUSIONS: Inflammatory markers and physical illness appear independently linked to depression severity and, in individuals with chronic physical illness, inflammatory markers are more tightly connected to depressive symptomology. Such findings could help guide future individualized treatment research for depression based on both inflammatory marker level and physical illness burden.

Longitudinal relationships of cytokines, depression and anhedonia in depressed adolescents.

BACKGROUND: Depression has been associated with low-grade elevation of plasma cytokines (e.g. interleukin-6, IL-6; tumor necrosis factor alpha, TNFα) in both cross-sectional and longitudinal studies in adults. Preclinical and clinical studies also suggest that IL-6 and TNFα elevation are associated with anhedonia. However, few studies have examined longitudinal relationships between cytokines and depression/anhedonia in clinically depressed samples, particularly adolescents. METHODS: Thirty-six adolescents with a depressive disorder receiving standard-of-care community treatment were assessed at a baseline and a follow-up timepoint. Self-report and clinical measures of depression and anhedonia, along with plasma IL-6 and TNFα levels, were obtained at both timepoints. Baseline cytokine measures were examined in association with baseline and follow-up clinical measures. On an exploratory basis, change in clinical measures over time was examined in relation to change in cytokine levels over time. RESULTS: Higher baseline TNFα levels predicted higher follow-up depression severity after approximately four months (controlling for baseline depression). Higher baseline TNFα levels also associated positively with baseline anhedonia and predicted higher anhedonia at follow-up (controlling for baseline anhedonia). No association was found between change in clinical measures and change in cytokine levels over time. CONCLUSIONS: Among adolescents receiving standard-of-care community treatment for depression, higher levels of TNFα predicted greater depressive symptoms at 4-month follow-up, suggesting this cytokine may be used to help identify patients in need of more intensive treatment. Elevated TNFα levels were also associated with concurrent and future anhedonia symptoms, suggesting a specific mechanism in which TNFα affects depression trajectories. Future studies should examine the relationships between cytokine levels and depression/anhedonia symptoms at multiple timepoints in larger cohorts of depressed adolescents.

Neuroplasticity in cognitive and psychological mechanisms of depression: an integrative model.

Chronic stress and depressive-like behaviors in basic neuroscience research have been associated with impairments of neuroplasticity, such as neuronal atrophy and synaptic loss in the medial prefrontal cortex (mPFC) and hippocampus. The current review presents a novel integrative model of neuroplasticity as a multi-domain neurobiological, cognitive, and psychological construct relevant in depression and other related disorders of negative affect (e.g., anxiety). We delineate a working conceptual model in which synaptic plasticity deficits described in animal models are integrated and conceptually linked with human patient findings from cognitive science and clinical psychology. We review relevant reports including neuroimaging findings (e.g., decreased functional connectivity in prefrontal-limbic circuits), cognitive deficits (e.g., executive function and memory impairments), affective information processing patterns (e.g., rigid, negative biases in attention, memory, interpretations, and self-associations), and patient-reported symptoms (perseverative, inflexible thought patterns; inflexible and maladaptive behaviors). Finally, we incorporate discussion of integrative research methods capable of building additional direct empirical support, including using rapid-acting treatments (e.g., ketamine) as a means to test this integrative model by attempting to simultaneously reverse these deficits across levels of analysis.

Adolescent girls' physiological reactivity to real-world peer feedback: A pilot study to validate a Peer Expressed Emotion task.

Peer feedback becomes highly salient during adolescence, especially for girls. The way in which adolescents react to social feedback is associated with psychosocial adjustment and mental health. Consequently, researchers are increasingly interested in understanding the physiological and neural underpinnings of adolescent response to feedback by simulating the experience of rejection and acceptance using computer-based paradigms. However, these paradigms typically use nonfamiliar peers and the facade of internet chatrooms or games to present artificial peer feedback. The current study piloted the use of a novel and potentially more ecologically valid peer expressed emotion paradigm in which participants listen to prerecorded clips of ostensible personalized feedback made by their close friend. Physiological data measuring autonomic nervous system response were collected as an index of emotional reactivity/arousal and cognitive-affective processing. Results show promising preliminary evidence validating the task for future use. Participants (N = 18 girls, aged 11-17 years) reported feeling more positive following praise, relative to critical and neutral feedback, and reported feeling more upset following criticism, relative to praise and neutral feedback. Girls exhibited greater pupillary dilation, skin conductance levels (N = 17), and/or heart rate (N = 17) while listening to affectively charged, peer feedback compared with neutral yet personally relevant statements. Girls also exhibited variable physiological response when listening to praising versus critical feedback. Findings from this pilot study validate the use of this novel Peer Expressed Emotion task for the investigation of adolescents' emotional and physiological reactivity in response to real-world peer evaluation. However, it is important to recognize that this study provides only preliminary findings and that future research is needed to replicate the results in larger samples.

Using mobile eye-tracking technology to examine adolescent daughters' attention to maternal affect during a conflict discussion.

Attention to socio-emotional stimuli (i.e., affect-biased attention) is an integral component of emotion regulation and human communication. Given the strong link between maternal affect and adolescent behavior, maternal affect may be a critical influence on adolescent affect-biased attention during mother-child interaction. However, prior methodological constraints have precluded fine-grained examinations of factors such as maternal affect on adolescent attention during real-world social interaction. Therefore, this pilot study capitalized on previously validated technological advances by using mobile eye-tracking and facial affect coding software to quantify the influence of maternal affect on adolescents' attention to the mother during a conflict discussion. Results from 7,500 to 9,000 time points sampled for each mother-daughter dyad (n = 28) indicated that both negative and positive maternal affect, relative to neutral, elicited more adolescent attentional avoidance of the mother (ORs = 2.68-9.20), suggesting that typically developing adolescents may seek to avoid focusing on maternal affect of either valence during a conflict discussion. By examining the moment-to-moment association between in vivo displays of maternal affect and subsequent adolescent attention toward the mother's face, these results provide preliminary evidence that maternal affect moderates adolescent attention. Our findings are consistent with cross-species approach-avoidance models suggesting that offspring respond to affectively charged conversations with greater behavioral avoidance or deference.

Looking for the negative: Depressive symptoms in adolescent girls are associated with sustained attention to a potentially critical judge during in vivo social evaluation.

Attention biases toward negative stimuli are implicated in the development and maintenance of depression. However, research is needed to understand how depression affects attention biases as they unfold in a dynamic social environment, particularly during adolescence when depression rates significantly increase due to enhanced reactivity to social stress. To examine attention biases in a live, socially evaluative environment, 26 adolescent girls from the community gave a speech in front of a potentially critical judge and a positive judge while wearing mobile eye tracking glasses. Girls' depressive symptoms were measured using the Moods and Feelings Questionnaire. Across the sample, girls looked at the positive judge more frequently and for longer periods of time compared with the potentially critical judge. In contrast, higher depressive symptoms were associated with looking at the potentially critical judge for longer periods of time. When directly comparing attention to the potentially critical judge relative to the positive judge, dysphoric girls looked at the potentially critical judge more frequently and for longer periods of time compared with the positive judge. Findings suggest that adolescent depressive symptoms are related to sustained attention toward potentially critical evaluation at the exclusion of positive evaluation. This novel approach allowed for an in vivo examination of attention biases as they unfold during social evaluation, which begins to illuminate the interpersonal significance of attention biases. If replicated and extended longitudinally, this research could be used to identify adolescents at high risk for future depression and potentially be leveraged clinically in attention bias modification treatment.

Adolescent Gaze-Directed Attention During Parent-Child conflict: The Effects of Depressive Symptoms and Parent-Child Relationship Quality.

Although dysfunctions in attention have been implicated in the development and maintenance of depression in adults, findings from studies of depressed adolescents have been inconsistent. While some research has shown that youth with depressive symptoms exhibit increased attention to negative stimuli, other findings demonstrated attentional avoidance. Additionally, given the increase in parent-child conflict during adolescence, parent-child relationship quality may be an important moderating factor in the association between depressive symptoms and attention. To examine how depressive symptoms and parent-child relationship quality during adolescence influence attention, 25 mother-daughter pairs (girls ages 11-16) completed a conflict discussion task while wearing mobile eye-tracking glasses. Results suggest that girls with low positive parent-child relationship quality and greater depressive symptoms may have difficulty disengaging from their mother during negative interactions, which may exacerbate depressive symptoms. Therefore, the parent-child relationship should be further considered in treatments that target maladaptive attention patterns in youth with depressive symptoms.

Attention to Peer Feedback Through the Eyes of Adolescents with a History of Anxiety and Healthy Adolescents.

During adolescence, youth may experience heightened attention bias to socially relevant stimuli; however, it is unclear if attention bias toward social threat may be exacerbated for adolescents with a history of anxiety. This study evaluated attentional bias during the Chatroom-Interact task with 25 adolescents with a history of anxiety (18F, Mage = 13.6) and 22 healthy adolescents (13F, Mage = 13.8). In this task, participants received feedback from fictional, virtual peers who either chose them (acceptance) or rejected them (rejection). Overall, participants were faster to orient toward and spent longer time dwelling on their own picture after both rejection and acceptance compared to non-feedback cues. Social feedback was associated with greater pupillary reactivity, an index of cognitive and emotional neural processing, compared to non-feedback cues. During acceptance feedback (but not during rejection feedback), anxious youth displayed greater pupil response compared to healthy youth, suggesting that positive feedback from peers may differentially influence youth with a history of an anxiety disorder.

Vigilant attention to threat, sleep patterns, and anxiety in peripubertal youth.

BACKGROUND: Vigilant attention to threat is commonly observed in anxiety, undergoes developmental changes in early adolescence, and has been proposed to interfere with sleep initiation and maintenance. We present one of the first studies to use objective measures to examine associations between vigilant attention to threat and difficulties initiating and maintaining sleep in an early adolescent anxious sample. We also explore the moderating role of development (age, puberty) and sex. METHODS: Participants were 66 peripubertal youth (ages 9-14) with a primary anxiety disorder and 24 healthy control subjects. A dot-probe task was used to assess attentional bias to fearful relative to neutral face stimuli. Eye-tracking indexed selective attentional bias to threat, and reaction time bias indexed action readiness to threat. Sleep was assessed via actigraphy (e.g. sleep onset delay, wake after sleep onset, etc.), parent report (Children's Sleep Habits Questionnaire), and child report (Sleep Self-Report). The Pediatric Anxiety Rating Scale assessed anxiety severity. RESULTS: Eye-tracking initial threat fixation bias (ß = .33, p = .001) and threat dwell time bias (ß = .22, p = .041) were positively associated with sleep onset latency. Reaction time bias was positively associated with wake after sleep onset (ß = .24, p = .026) and parent-reported sleep disturbance (ß = .25, p = .019). Anxiety (severity, diagnosis) was not associated with these outcomes. Sex (ß = -.32, p = .036) moderated the relation between initial threat fixation bias and sleep onset latency, with a positive association for males (p = .005), but not for females (p = .289). Age and pubertal status did not moderate effects. CONCLUSIONS: Vigilant attention to threat is related to longer sleep onset and reduced sleep maintenance. These associations are not stronger in early adolescents with anxiety. Implications for early intervention or prevention that targets vigilant attention to threat to impact sleep disturbance, and vice versa, are discussed.

Less is more: Patient-level meta-analysis reveals paradoxical dose-response effects of a computer-based social anxiety intervention targeting attentional bias.

BACKGROUND: The past decade of research has seen considerable interest in computer-based approaches designed to directly target cognitive mechanisms of anxiety, such as attention bias modification (ABM). METHODS: By pooling patient-level datasets from randomized controlled trials of ABM that utilized a dot-probe training procedure, we assessed the impact of training "dose" on relevant outcomes among a pooled sample of 693 socially anxious adults. RESULTS: A paradoxical effect of the number of training trials administered was observed for both posttraining social anxiety symptoms and behavioral attentional bias (AB) toward threat (the target mechanism of ABM). Studies administering a large (>1,280) number of training trials showed no benefit of ABM over control conditions, while those administering fewer training trials showed significant benefit for ABM in reducing social anxiety (P = .02). These moderating effects of dose were not better explained by other examined variables and previously identified moderators, including patient age, training setting (laboratory vs. home), or type of anxiety assessment (clinician vs. self-report). CONCLUSIONS: Findings inform the optimal dosing for future dot-probe style ABM applications in both research and clinical settings, and suggest several novel avenues for further research.

Prefrontal-limbic connectivity during worry in older adults with generalized anxiety disorder.

OBJECTIVES: Although generalized anxiety disorder (GAD) is one of the most prevalent anxiety disorders in older adults, very little is known about the neurobiology of worry, the hallmark symptom of GAD in adults over the age of 60. This study investigated the neurobiology and neural circuitry of worry in older GAD patients and controls. METHOD: Twenty older GAD patients and 16 age-matched controls (mean age = 67.88) were compared on clinical measures and neural activity during worry using functional magnetic resonance imaging. RESULTS: As expected, worry elicited activation in frontal regions, amygdala, and insula within the GAD group, with a similar but less prominent frontal pattern was observed in controls. Effective connectivity analyses revealed a positive directional circuit in the GAD group extending from ventromedial through dorsolateral prefrontal cortices, converging on the amygdala. A less complex circuit was observed in controls with only dorsolateral prefrontal regions converging on the amygdala; however, a separate circuit passing through the orbitofrontal cortex converged on the insula. CONCLUSION: Results elucidate a different neurobiology of pathological versus normal worry in later life. A limited resource model is implicated wherein worry in GAD competes for the same neural resources (e.g. prefrontal cortical areas) that are involved in the adaptive regulation of emotion through cognitive and behavioral strategies.

C'mon get happy: reduced magnitude and duration of response during a positive-affect induction in depression.

BACKGROUND: Depression involves decreased positive affect. Whether this is due to a failure to achieve or maintain positive emotion in response to discrete stimuli is unclear. Understanding the nature of decreased positive affect could help to address how to intervene in the phenomenon, for example, how to structure interventions using positive and rewarding stimuli in depression. Thus, we examined the time course of affect following exposure to positive stimuli in depressed and healthy individuals. METHODS: Seventy-one adults with major depressive disorder and thirty-four never-depressed controls read a self-generated highly positive script and continuously rated their affect for 7 min. RESULTS: Both groups quickly achieved increased positive affect, however, compared to controls, depressed participants did not achieve the same level of positive affect, did not maintain their positive affect, spent less time rating their affect as happy, and demonstrated larger drops in mood. CONCLUSIONS: These data indicate that depressed and nondepressed individuals can generate positive reactions to happy scripts, but depressed individuals cannot achieve or sustain equivalent levels of positive affect. Interventions for depression might fruitfully focus on increasing depressed individuals' ability to maintain initial engagement with positive stimuli over a sustained period of time.

Looking under the hood of the dot-probe task: an fMRI study in anxious youth.

BACKGROUND: Anxious youth have shown altered behavioral performance on the dot-probe task, but neural activation patterns provoked by the task remain poorly understood. In particular, neural mechanisms of threat disengagement, a clinically relevant construct, have been inadequately explored. METHOD: During fMRI acquisition, 121 youth (ages 9-13; 90 with Generalized Anxiety Disorder, Separation Anxiety Disorder, and/or Social Phobia; 31 nonanxious controls) completed a dot-probe task, which required participants to identify the location of a dot replacing either a neutral or fearful face in a pair containing both faces. We assessed neural substrates of threat disengagement by comparing congruent trials (in which the dot replaces the fearful face) to incongruent trials (in which the dot replaces the neutral face). RESULTS: Across subjects, decreased rostrodorsal anterior cingulate cortex (rdACC) activity was observed specifically during incongruent trials. Nonanxious youth showed a convergent pattern in bilateral parahippocampal and hippocampal regions, whereas anxious youth showed an opposing pattern in these limbic areas, suggesting less integration of response across cortical and limbic areas relevant to threat appraisal. Reduced functional connectivity between rdACC and left parahippocampus/hippocampus was associated with greater anxiety. CONCLUSIONS: In the largest dot-probe fMRI sample to date, both anxious and nonanxious youth showed a neural pattern consistent with successful disengagement of threat reactivity in the rdACC. However, anxious youth showed evidence of abnormal disengagement in bilateral parahippocampal/hippocampal clusters when attention was directed away from threat. Early interventions targeting neural mechanisms of threat disengagement may be beneficial, for example, by increasing integration across rdACC and limbic regions.

Effects of ketamine on explicit and implicit suicidal cognition: a randomized controlled trial in treatment-resistant depression.

BACKGROUND: Preliminary evidence suggests intravenous ketamine has rapid effects on suicidal cognition, making it an attractive candidate for depressed patients at imminent risk of suicide. In the first randomized controlled trial of ketamine using an anesthetic control condition, we tested ketamine's acute effects on explicit suicidal cognition and a performance-based index of implicit suicidal cognition (Implicit Association Test; IAT) previously linked to suicidal behavior. METHOD: Symptomatic patients with treatment-resistant unipolar major depression (inadequate response to ≥3 antidepressants) were assessed using a composite index of explicit suicidal ideation (Beck Scale for Suicidal Ideation, Montgomery-Asberg Rating Scale suicide item, Quick Inventory of Depressive Symptoms suicide item) and the IAT to assess suicidality implicitly. Measures were taken at baseline and 24 hr following a single subanesthetic dose of ketamine (n = 36) or midazolam (n = 21), a psychoactive placebo agent selected for its similar, rapid anesthetic effects. Twenty four hours postinfusion, explicit suicidal cognition was significantly reduced in the ketamine but not the midazolam group. RESULTS: Fifty three percent of ketamine-treated patients scored zero on all three explicit suicide measures at 24 hr, compared with 24% of the midazolam group (χ(2) = 4.6; P = .03). Implicit associations between self- and escape-related words were reduced following ketamine (P = .01; d = .58) but not midazolam (P = .68; d = .09). Ketamine-specific decreases in explicit suicidal cognition were largest in patients with elevated suicidal cognition at baseline, and were mediated by decreases in nonsuicide-related depressive symptoms. CONCLUSIONS: Intravenous ketamine produces rapid reductions in suicidal cognition over and above active placebo. Further study is warranted to test ketamine's antisuicidal effects in higher-risk samples.

Experiences of Awe Mediate Ketamine's Antidepressant Effects: Findings From a Randomized Controlled Trial in Treatment-Resistant Depression.

Background: Ketamine, an NMDA receptor antagonist, provides rapid antidepressant effects. Although much research has focused on neural and molecular mechanisms of action, it is critical to also consider psychological mechanisms that may contribute to its therapeutic efficacy. The construct of an awe-inducing experience, which is a well-validated psychological phenomenon tied to emotional well-being, had not been applied previously in ketamine research. Methods: One hundred sixteen participants with depression, 77 of whom received a ketamine infusion (0.5 mg/kg over 40 minutes) and 39 patients who received saline placebo, completed a validated measure of awe (the Awe Experience Scale [AWE-S]) at 40 minutes postinfusion. AWE-S scores were examined as potential mediators of depression outcomes (% improvement in Montgomery-Åsberg Depression Rating Scale score) at 5 postinfusion time points (24 hours and 5, 12, 21, and 30 days). Dissociative effects, measured by Clinician-Administered Dissociative States Scale scores, were tested in parallel mediation models for comparison. Results: We found that the psychological experience of awe was strongly reported by participants during ketamine infusion, but not saline infusion, and there were significant associations between total AWE-S scores and Montgomery-Åsberg Depression Rating Scale score improvement (% change) in the ketamine arm at all 5 time points. Furthermore, at all 5 time points, total AWE-S scores statistically mediated the relationship between ketamine and Montgomery-Åsberg Depression Rating Scale scores. By contrast, Clinician-Administered Dissociative States Scale scores did not mediate outcomes at any time point. Conclusions: Ketamine infusion strongly induced heightened feelings of awe, and these experiences consistently mediated depression outcomes over a 1- to 30-day period, unlike general dissociative side effects. The specific awe-inspiring properties of ketamine may contribute to its antidepressant effects.

Rapidly acting pharmacological agents, such as subanesthetic ketamine, have offered the promise of a breakthrough in the way that depression is managed. However, to build on this potential, we still have much to learn about ketamine's mechanisms of action, particularly possible psychological mechanisms of action. Here, Aepfelbacher et al. conducted secondary analyses from a randomized controlled trial in depression. The authors found that a ketamine infusion strongly induced heightened feelings of awe, and these experiences consistently mediated depression improvements over a 1- to 30-day period, unlike general dissociative side effects. The specific awe-inspiring properties of ketamine may contribute to its antidepressant effects.

Exploring the impact of music on response to ketamine/esketamine: A scoping review.

Music and ketamine are both known to affect therapeutic outcomes, but few studies have investigated their co-administration. This scoping review describes the existing literature on the joint use of music and ketamine-or esketamine (the S(+) enantiomer of ketamine)-in humans. The review considers that extant studies have explored the intersection of ketamine/esketamine and music in healthy volunteers and in patients of various age groups, at different dosages, through different treatment processes, and have varied the sequence of playing music relative to ketamine/esketamine administration. Studies investigating the use of music during ketamine anesthesia are also included in the review because anesthesia and sedation were the early drivers of ketamine use. Studies pertaining to recreational ketamine use were omitted. The review was limited to articles published in the English language but not restricted by publication year. To the best of our knowledge, this scoping review is the first comprehensive exploration of the interplay between music and ketamine/esketamine and offers valuable insights to researchers interested in designing future studies.

Sustained neural alterations in anxious youth performing an attentional bias task: a pupilometry study.

BACKGROUND: Biased attention patterns have been observed at early (16-500 ms poststimulus onset) and intermediate (1,500-4,000 ms post-onset) time points in anxious youth, but it is unclear whether a more sustained form of neural attentional bias, persisting well beyond the time frame of stimulus presentation and behavioral response, is also apparent. We investigated early, intermediate, and sustained forms of bias using behavioral measures and pupillary reactivity, an index of cognitive and affective load, to gain insight into potential neurocognitive targets for early intervention. METHOD: Twenty nonanxious youth and 74 youth with generalized anxiety disorder (GAD), separation anxiety disorder (SAD), and/or social phobia (SP) completed a dot-probe task, which requires participants to respond to a dot replacing either a neutral or fearful face. Emotional faces were presented for short/early (200 ms) or intermediate (2 s) intervals and followed by a sustained (up to 10.5 s) poststimulus interval. Pupil dilation, gaze direction, and reaction times (RTs) were measured during task completion. RESULTS: Early and intermediate vigilance patterns in RTs and an avoidant pattern in gaze direction were observed in all participants irrespective of anxiety. Sustained pupil dilation in anxious youth was observed on trials in which the dot replaced fearful faces, along with an inflexible pattern of pupillary responding in comparison to controls. CONCLUSION: Sustained cognitive-affective load following emotional face viewing is altered and inflexible in anxious youth. These prolonged alterations extend well beyond the time frame of behavioral attentional bias and may indicate inflexible and insufficient sustained cognitive control. Early interventions targeting these alterations could improve long-term mental health trajectories.

Rapid neuroplasticity changes and response to intravenous ketamine: a randomized controlled trial in treatment-resistant depression.

Intravenous ketamine is posited to rapidly reverse depression by rapidly enhancing neuroplasticity. In human patients, we quantified gray matter microstructural changes on a rapid (24-h) timescale within key regions where neuroplasticity enhancements post-ketamine have been implicated in animal models. In this study, 98 unipolar depressed adults who failed at least one antidepressant medication were randomized 2:1 to a single infusion of intravenous ketamine (0.5 mg/kg) or vehicle (saline) and completed diffusion tensor imaging (DTI) assessments at pre-infusion baseline and 24-h post-infusion. DTI mean diffusivity (DTI-MD), a putative marker of microstructural neuroplasticity in gray matter, was calculated for 7 regions of interest (left and right BA10, amygdala, and hippocampus; and ventral Anterior Cingulate Cortex) and compared to clinical response measured with the Montgomery-Asberg Depression Rating Scale (MADRS) and the Quick Inventory of Depressive Symptoms-Self-Report (QIDS-SR). Individual differences in DTI-MD change (greater decrease from baseline to 24-h post-infusion, indicative of more neuroplasticity enhancement) were associated with larger improvements in depression scores across several regions. In the left BA10 and left amygdala, these relationships were driven primarily by the ketamine group (group * DTI-MD interaction effects: p = 0.016-0.082). In the right BA10, these associations generalized to both infusion arms (p = 0.007). In the left and right hippocampus, on the MADRS only, interaction effects were observed in the opposite direction, such that DTI-MD change was inversely associated with depression change in the ketamine arm specifically (group * DTI-MD interaction effects: p = 0.032-0.06). The acute effects of ketamine on depression may be mediated, in part, by acute changes in neuroplasticity quantifiable with DTI.