John Krystal

Posttraumatic stress disorder (PTSD) is associated with lower cortical thickness (CT) in prefrontal, cingulate, and insular cortices in diverse trauma-affected samples. However, some studies have failed to detect differences between PTSD patients and healthy controls or reported that PTSD is associated with greater CT. Using data-driven dimensionality reduction, we sought to conduct a well-powered study to identify vulnerable networks without regard to neuroanatomic boundaries. Moreover, this approach enabled us to avoid the excessive burden of multiple comparison correction that plagues vertex-wise methods. We derived structural covariance networks (SCNs) by applying non-negative matrix factorization (NMF) to CT data from 961 PTSD patients and 1124 trauma-exposed controls without PTSD. We used regression analyses to investigate associations between CT within SCNs and PTSD diagnosis (with …

Correction: Psychosocial moderators of polygenic risk scores of inflammatory biomarkers in relation to GrimAge - PMC Back to Top Skip to main content NIH NLM Logo Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation Search PMC Full-Text Archive Search in PMC Advanced Search User Guide Journal List Neuropsychopharmacology v.49(4); 2024 Mar PMC10876612 Other Formats PDF (405K) Actions Cite Collections Share Permalink Copy RESOURCES Similar articles Cited by other articles Links to NCBI Databases Journal List Neuropsychopharmacology v.49(4); 2024 Mar PMC10876612 As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsement of, or agreement with, the contents by NLM or the National Institutes of Health. Learn more: PMC Disclaimer | PMC Copyright Notice Logo of nppharm Neuropsychopharmacology. …

BackgroundOpioid misuse is highly comorbid with PTSD and individuals with this comorbidity exhibit a higher severity of PTSD symptomatology and poorer treatment efficacy. However, the underlying biological mechanisms are unknown.MethodsHere, we present a study utilizing multiple bioinformatics approaches to comprehensively characterize the transcriptional landscape of opioid misuse, PTSD, and its comorbidity in 212 postmortem brain samples from four human prefrontal cortex (PFC) regions.ResultsOur findings indicate that individuals with comorbid opioid misuse and PTSD exhibit a higher number of differentially expressed genes at a false discovery rate of< 0.05 in the PFC compared to those with PTSD, or opioid misuse only. Particularly, we identified a set of genes with distinct expression profiles, specifically in the orbitofrontal cortex and subgenual prefrontal cortex. These genes were enriched in …

GrimAge acceleration has previously predicted age-related morbidities and mortality. In the current study, we sought to examine how GrimAge is associated with genetic predisposition for systemic inflammation and whether psychosocial factors moderate this association. Military veterans from the National Health and Resilience in Veterans study, which surveyed a nationally representative sample of European American male veterans, provided saliva samples for genotyping (N = 1135). We derived polygenic risk scores (PRS) from the UK Biobank as markers of genetic predisposition to inflammation. Results revealed that PRS for three inflammatory PRS markers—HDL (lower), apolipoprotein B (lower), and gamma-glutamyl transferase (higher)—were associated with accelerated GrimAge. Additionally, these PRS interacted with a range of potentially modifiable psychosocial variables, such as exercise and …

It is widely hoped that statistical models can improve decision-making related to medical treatments. Because of the cost and scarcity of medical outcomes data, this hope is typically based on investigators observing a model’s success in one or two datasets or clinical contexts. We scrutinized this optimism by examining how well a machine learning model performed across several independent clinical trials of antipsychotic medication for schizophrenia. Models predicted patient outcomes with high accuracy within the trial in which the model was developed but performed no better than chance when applied out-of-sample. Pooling data across trials to predict outcomes in the trial left out did not improve predictions. These results suggest that models predicting treatment outcomes in schizophrenia are highly context-dependent and may have limited generalizability.

BackgroundPosttraumatic stress disorder (PTSD) is a complex mental illness that can be developed in individuals exposed to trauma. While recent epigenome-wide association analysis (EWAS) studies have revealed differential methylation associated with PTSD, this work has mostly examined peripheral tissue. In this study, we map CpG and non-CpG methylome (5mC) and hydroxymethylome (5hmC) in cortical neurons of individuals with PTSD and healthy controls.MethodsReduced-representation oxidative bisulfite sequencing was conducted on 38 postmortem brain samples (25 PTSD, 13 controls) from the National PTSD Brain Bank.ResultsBy using methylKit R package, we identified hundreds of differential 5mC and 5hmC sites significantly associated with PTSD after multiple test correction (FDR< 0.5). Discernible variations between CpG and non-CpG sites in terms of gene feature annotation and directional …

Recent advances in our understanding of how to treat TRD have largely expanded our knowledge of best practices in, and efficacy of, interventional psychiatric approaches. Recent research has used a variety of TRD definitions for study inclusion criteria; research on TRD should adhere to inclusion criteria based on internationally defined guidelines for more meaningfully generalizable results.

Although the cerebellum contributes to higher-order cognitive and emotional functions relevant to posttraumatic stress disorder (PTSD), prior research on cerebellar volume in PTSD is scant, particularly when considering subregions that differentially map on to motor, cognitive, and affective functions. In a sample of 4215 adults (PTSD n = 1642; Control n = 2573) across 40 sites from the ENIGMA-PGC PTSD working group, we employed a new state-of-the-art deep-learning based approach for automatic cerebellar parcellation to obtain volumetric estimates for the total cerebellum and 28 subregions. Linear mixed effects models controlling for age, gender, intracranial volume, and site were used to compare cerebellum volumes in PTSD compared to healthy controls (88% trauma-exposed). PTSD was associated with significant grey and white matter reductions of the cerebellum. Compared to controls, people with …

Background:Ketamine has emerged as one of the most promising therapies for treatment-resistant depression. However, inter-individual variability in response to ketamine is still not well understood and it is unclear how ketamine’s molecular mechanisms connect to its neural and behavioral effects.Methods:We conducted a single-blind placebo-controlled study, with participants blinded to their treatment condition. 40 healthy participants received acute ketamine (initial bolus 0.23 mg/kg, continuous infusion 0.58 mg/kg/hr). We quantified resting-state functional connectivity via data-driven global brain connectivity and related it to individual ketamine-induced symptom variation and cortical gene expression targets.Results:We found that:(i) both the neural and behavioral effects of acute ketamine are multi-dimensional, reflecting robust inter-individual variability;(ii) ketamine’s data-driven principal neural gradient effect matched somatostatin (SST) and parvalbumin (PVALB) cortical gene expression patterns in humans, while the mean effect did not; and (iii) behavioral data-driven individual symptom variation mapped onto distinct neural gradients of ketamine, which were resolvable at the single-subject level.Conclusions:These results highlight the importance of considering individual behavioral and neural variation in response to ketamine. They also have implications for the development of individually precise pharmacological biomarkers for treatment selection in psychiatry.

Slow waves are a distinguishing feature of non-rapid-eye-movement (NREM) sleep, an evolutionarily conserved process critical for brain function. Non-human studies posit that the claustrum, a small subcortical nucleus, coordinates slow waves. We recorded claustrum neurons in humans during sleep. In contrast to neurons from other brain regions, claustrum neurons increased their activity and tracked slow waves during NREM sleep suggesting that the claustrum plays a role in human sleep architecture.

BackgroundTo adapt to threats in the environment, animals must predict them and engage in defensive behavior. While the representation of a prediction error signal for reward has been linked to dopamine, a neuromodulatory prediction error for aversive learning has not been identified.MethodsHere, we measured and manipulated norepinephrine release during threat learning using optogenetics and a novel fluorescent norepinephrine sensor.ResultsWe found that norepinephrine response to conditioned stimuli reflects aversive memory strength. When delays between auditory stimuli and footshock are introduced, norepinephrine acts as a prediction error signal. However, temporal difference prediction errors do not fully explain norepinephrine dynamics. To explain noradrenergic signaling, we used an updated reinforcement learning model with uncertainty about time and found that it explained norepinephrine …

Background: Alcohol use disorder (AUD) is a complex condition associated with adverse health consequences that affect millions of individuals worldwide. Epigenetic modifications, including DNA methylation (5 mC), have been associated with AUD and other alcohol-related traits. Epigenome-wide association studies (EWAS) have identified differentially methylated genes associated with AUD in human peripheral and brain tissue. More recently, epigenetic studies of AUD have also evaluated DNA hydroxymethylation (5 hmC) in the human brain. However, most of the epigenetic work in postmortem brain tissue has examined bulk tissue. In this study, we investigated neuronal-specific 5 mC and 5 hmC alterations at CpG sites associated with AUD in the human orbitofrontal cortex (OFC). Methods: Neuronal nuclei from the OFC were evaluated in 34 human postmortem brain samples (10 AUD, 24 non-AUD). Reduced representation oxidative bisulfite sequencing was used to assess 5 mC and 5 hmC at the genome-wide level. Differential 5 mC and 5 hmC were evaluated using the methylKit R package and significance was set at false discovery rate < 0.05 and differential methylation > 2. Functional enrichment analyses were performed, and gene-level convergence was evaluated in an independent dataset that assessed 5 mC and 5 hmC of AUD in bulk cortical tissue. Results: We identified 417 5 mC and 363 5hmC significant differential CpG sites associated with AUD, with 59% in gene promoters. Some of the identified genes have been previously implicated in alcohol consumption, including SYK, DNMT3A for 5 mC, GAD1, DLX1, DLX2, for 5 …

It is a peculiar sensation, this double consciousness, this sense of always looking at one’s self through the eyes of others.. One ever feels his twoness–an American, a Negro;. two warring ideals in one dark body, whose dogged strength alone keeps it from being torn asunder.

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The present invention relates to the use of mavoglurant in the treatment of gambling disorder. The present invention also relates to the use of mavoglurant in the treatment of gaming disorder.

Ketamine is an open channel blocker of ionotropic glutamatergic N-Methyl-D-Aspartate (NMDA) receptors. The discovery of its rapid antidepressant effects in patients with depression and treatment-resistant depression fostered novel effective treatments for mood disorders. This discovery not only provided new insight into the neurobiology of mood disorders but also uncovered fundamental synaptic plasticity mechanisms that underlie its treatment. In this review, we discuss key clinical aspects of ketamine’s effect as a rapidly acting antidepressant, synaptic and circuit mechanisms underlying its action, as well as how these novel perspectives in clinical practice and synapse biology form a road map for future studies aimed at more effective treatments for neuropsychiatric disorders.

Esketamine is the first US Food and Drug Administration approved rapid-acting drug for treatmentresistant depression (TRD) and the first novel-mechanism antidepressant in more than 60 years. 1 Approved on March 5, 2019, esketamine rapidly ameliorates symptoms in the estimated 5% to 6% of individuals with pharmaceutically treated depression who meet criteria for TRD. 2, 3 Geographic and clinician-level patterns of esketamine prescription remain unclear. Ensuring equitable access to new drugs like esketamine is of interest given well-documented rural-urban disparities in access to mental health care and differences in the prevalence of major depressive disorder and other mood disorders between rural and urban populations. Further intersectional disparities may exist, as psychiatric clinicians who only accept self-pay or private insurances may adopt therapies at different rates than those who accept lower …

Traumatic events can lead to lifelong, inflexible adaptations in threat perception and behavior, which characterize posttraumatic stress disorder (PTSD). This process involves associations between sensory cues and internal states of threat and then generalization of the threat responses to previously neutral cues. However, most formulations neglect adaptations to threat that are not specific to those associations. To incorporate nonassociative responses to threat, we propose a computational theory of PTSD based on adaptation to the frequency of traumatic events by using a reinforcement learning momentum model. Recent threat prediction errors generate momentum that influences subsequent threat perception in novel contexts. This model fits primary data acquired from a mouse model of PTSD, in which unpredictable footshocks in one context accelerate threat learning in a novel context. The theory is consistent …

BackgroundEpigenetic mechanisms have been implicated in the etiology of post-traumatic stress disorder (PTSD). Considering the cell-and tissue-specific nature of epigenetic alterations, studies evaluating cell-type specificity and human postmortem brain tissue are warranted. Here, we examine DNA methylation (5mC) and hydroxymethylation (5hmC) at both CpGs and non-CpGs in human postmortem orbitofrontal neurons in PTSD.MethodsReduced-representation oxidative bisulfite sequencing was conducted on 38 postmortem brain samples (25 PTSD, 13 controls) from the National PTSD Brain Bank. Differential 5mC/5hmC of CpG and non-CpG sites were analyzed using methylKit R package. Significance set at FDR< 0.05. WGCNA R package was utilized for co-5mC/5hmC network analyses. Enrichment analyses were conducted on Metascape. Multiomics integrative analysis was evaluated for gene-level …

ObjectiveMultidisciplinary studies of posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) implicate the dorsolateral prefrontal cortex (DLPFC) in disease risk and pathophysiology. Postmortem brain studies have relied on bulk-tissue RNA sequencing (RNA-seq), but single-cell RNA-seq is needed to dissect cell-type-specific mechanisms. The authors conducted the first single-nucleus RNA-seq postmortem brain study in PTSD to elucidate disease transcriptomic pathology with cell-type-specific resolution.MethodProfiling of 32 DLPFC samples from 11 individuals with PTSD, 10 with MDD, and 11 control subjects was conducted (∼415K nuclei; >13K cells per sample). A replication sample included 15 DLPFC samples (∼160K nuclei; >11K cells per sample).ResultsDifferential gene expression analyses identified significant single-nucleus RNA-seq differentially expressed genes (snDEGs) in …

Methods of treating mental disorders, including anxiety disorders such as obsessive-compulsive disorder, are provided. The methods comprise administering an effective amount of a glutamate modulator to an individual in need thereof. Also provided are methods of enhancing the activity of a serotonin reuptake inhibitor (SRI) comprising coadministering a glutamate modulator and a serotonin reuptake inhibitor. Pharmaceutical composition comprising a serotonin reuptake inhibitor and a glutamate modulator are also provided.

Psychedelic drugs may produce therapeutic effects purely by engaging forms of neuroplasticity that compensate for detrimental effects of stress and depression upon the brain. In animals and, increasingly, in humans, psychedelic drugs without prominent hallucinatory effects show evidence of producing similar neuroplastic changes as hallucinatory psychedelic drugs and antidepressant-like behavioral effects (1). These findings would seem to make the subjective effects of psychedelic drugs irrelevant to their therapeutic effects. This may indeed be the case. However, many people report that the experience of taking a psychedelic drug is among the most important experiences of their lives [cited in (2)]. Yet in talking to people who describe this effect, it is often difficult to determine the qualities or insights gleaned that made the experience so important. This brief commentary will raise the question of whether the …

Although people experienced difficulties related to traumatic events long before the late 20th century, the diagnosis of Post-Traumatic Stress Disorder (PTSD) did not appear in the Diagnostic and Statistical Manual of Mental Disorders (DSM-III, American Psychiatric Association [APA], 1980) until relatively recently. Since that time, the definition has been revised twice, based on a wealth of clinical and empirical study.The contemporary definition of PTSD (APA, 1994) includes specifications of the traumatic events, the symptoms, and the duration of symptoms. Criterion A requires that the person must experience or be confronted with a traumatic event that involves the threat of death, serious injury, or loss of physical integrity, to which the person responds with fear, helplessness, or horror. By definition, the event must have occurred prior to the manifestation of symptoms. Criteria B, C, and D refer to symptomatic requirements of the diagnosis. First, the person must have at least one symptom of persistently reexperiencing the traumatic event, such as intrusive images or thoughts, dreams about the event, a sense that the event is reoccurring, intense distress when confronted with reminders of the event, or physiological reactivity when in the presence of event-related cues. Next, the person must have at least three symptoms of avoidance and numbing, such as avoiding thoughts, feelings, or conversations about the event; avoiding activity, places, or people that are reminders of the event; inability to remember part of the event; decreased participation in important activities; a sense of detachment from others; inability to experience a full range of emotion; or …

Problematic alcohol use (PAU), a trait that combines alcohol use disorder and alcohol-related problems assessed with a questionnaire, is a leading cause of death and morbidity worldwide. Here we conducted a large cross-ancestry meta-analysis of PAU in 1,079,947 individuals (European, N = 903,147; African, N = 122,571; Latin American, N = 38,962; East Asian, N = 13,551; and South Asian, N = 1,716 ancestries). We observed a high degree of cross-ancestral similarity in the genetic architecture of PAU and identified 110 independent risk variants in within- and cross-ancestry analyses. Cross-ancestry fine mapping improved the identification of likely causal variants. Prioritizing genes through gene expression and chromatin interaction in brain tissues identified multiple genes associated with PAU. We identified existing medications for potential pharmacological studies by a computational drug …

ObjectiveVeterans are at high risk for health morbidities linked to premature mortality. Recently developed “epigenetic clock” algorithms, which compute intra-individual differences between biological and chronological aging, can help inform prediction of accelerated biological aging and mortality risk. To date, however, scarce research has examined potentially modifiable correlates of GrimAge, a novel epigenetic clock comprised of DNA methylation surrogates of plasma proteins and smoking pack-years associated with various morbidities and time-to-death. The objective of the study was to examine psychosocial correlates of this novel epigenetic clock.DesignCross-sectional study.SettingU.S. veteran population.ParticipantsParticipants were male, European American (EA), and derived from a nationally representative sample of U.S. veterans (N = 1,135, mean age = 63.3, standard deviation [SD] = 13.0 …

Objective:To perform a secondary analysis quantifying neural-to-symptom relationships in MDD as a function of antidepressant treatment.Design:Double blind randomized controlled trial.Setting:Multicenter.Participants:Patients with early onset recurrent depression from the public Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study.Interventions:Either sertraline or placebo during 8 weeks (stage 1), and according to response a second line of treatment for 8 additional weeks (stage 2).Main Outcomes and Measures:To identify a data-driven pattern of symptom variations during these two stages, we performed a Principal Component Analysis (PCA) on the variations of individual items of four clinical scales measuring depression, anxiety, suicidal ideas and manic-like symptoms, resulting in a univariate measure of clinical improvement. We then investigated how …

MethodsCONNEX consists of three replicate randomized, double-blind, placebo-controlled parallel-group trials in patients with schizophrenia (NCT04846868, NCT04846881, NCT04860830) currently stable on antipsychotic treatment. Each trial aims to recruit~ 586 patients, 18–50 years old, treated with 1–2 antipsychotic medications (≥ 12 weeks on current drug;≥ 35 days on current dose prior to treatment), who have functional impairment in day-to-day activities, and interact≥ 1 hour per week with a designated study partner. Patients with cognitive impairment due to developmental, neurological, or other disorders, or receiving cognitive remediation therapy within 12 weeks prior to screening, will be excluded. Patients will be recruited from multiple centers across 32 countries in Asia, North and South America, and Europe, and randomized 1: 1 to receive either oral iclepertin 10 mg (n= 293), or placebo (n= 293 …

High-throughput experimental methods in neuroscience have led to an explosion of techniques for measuring complex interactions and multi-dimensional patterns. However, whether sophisticated measures of emergent phenomena can be traced back to simpler, low-dimensional statistics is largely unknown. To explore this question, we examined resting-state functional magnetic resonance imaging (rs-fMRI) data using complex topology measures from network neuroscience. Here we show that spatial and temporal autocorrelation are reliable statistics that explain numerous measures of network topology. Surrogate time series with subject-matched spatial and temporal autocorrelation capture nearly all reliable individual and regional variation in these topology measures. Network topology changes during aging are driven by spatial autocorrelation, and multiple serotonergic drugs causally induce the same …

BackgroundPost-traumatic stress disorder is a multigenic disorder occurring in the aftermath of severe trauma exposure. Recent studies have begun to detail the molecular biology of the postmortem PTSD brain using bulk-tissue transcriptomic analyses. However, given the array of PTSD-perturbed molecular pathways identified it is unlikely that a single cell type is responsible. It is therefore necessary to uncover the individual cell types contributing to the molecular pathology of PTSD.MethodsWe isolated 1.2 M nuclei from human postmortem dorsolateral prefrontal cortex from cases and controls for single nucleus RNA and ATAC sequencing across three diagnostic cohorts: PTSD, MDD and normal controls to identify cell type-specific gene expression and chromatin changes. We also test whether genome-wide significant SNPs identified from the MVP GWAS of PTSD are associated with gene expression within …

NMDA receptor antagonists have a vital role in extinction, learning, and reconsolidation processes. During the reconsolidation window, memories are activated into a labile state and can be reconsolidated in an altered form. This concept might have significant clinical implications in treating PTSD. In this pilot study we tested the potential of a single infusion of ketamine, followed by brief exposure therapy, to enhance post-retrieval extinction of PTSD trauma memories. 27 individuals diagnosed with PTSD were randomly assigned to receive either ketamine (0.5 mg/kg 40 min; N = 14) or midazolam (0.045 mg/kg; N = 13) after retrieval of the traumatic memory. 24 h following infusion, participants received a four-day trauma-focused psychotherapy. Symptoms and brain activity were assessed before treatment, at the end of treatment, and at 30-day follow-up. Amygdala activation to trauma scripts (a major …

The mechanisms underlying the molecular encoding of stress in modifying complex genetic risk for brain disorders have not been well elucidated. Towards explaining why individuals exposed to identical stressors may present with divergent clinical outcomes, we explore genotype by environment (G x E) interactions, asking whether common genetic risk factors determine individual differences in molecular encoding of stress response on a genome-wide scale. Analysis of post-mortem brain tissue revealed non-coding stress-interactive expression quantitative trait loci (eQTLs) that regulate transcriptomic responses to stress in a genotype-dependent manner. In total, we find 8557 eQTLs where interactions with prior traumatic exposures impact expression of 915 eGenes in the post-mortem brain (n=304). These effects are cell type- and brain region- specific, persisting for up to 45 years post-trauma. These dynamic variants tend to lie in stress-related transcription factor binding sites. Up to 50% of stress-interactive eGenes validate in hiPSC-derived glutamatergic and GABAergic neurons treated with glucocorticoids (n=39 donors), unexpectedly demonstrating that response to stress (whether trauma in vivo or glucocorticoid treatment in vitro) is highly robust across experimental paradigms. Stress-interactive eGenes show cell type-specificity, and, in the post-mortem brain, implicate glial and endothelial mechanisms. The neural response to stress broadly dysregulates long-term expression of neuropsychiatric disorder and neurodegenerative disease risk genes in a genotype-dependent manner; in fact, stress-aware transcriptomic imputation uncovered …

Investigators from minoritized backgrounds are underrepresented in psychiatric research. That underrepresentation contributes to disparities in outcomes of access to mental health care. Drawing on lived experience, scholarly qualitative reports, and empirical data, the authors review how the underrepresentation of minoritized researchers arises from interlocking, self-reinforcing effects of structural biases in our research training and funding institutions. Minoritized researchers experience diminished early access to advanced training and opportunities, stereotype threats and microaggressions, isolation due to lack of peers and senior mentors, decreased access to early funding, and unique community and personal financial pressures. These represent structural racism—a system of institutional assumptions and practices that perpetuates race-based disparities, in spite of those institutions’ efforts to increase diversity …

The field of psychiatry is hampered by a lack of robust, reliable and valid biomarkers that can aid in objectively diagnosing patients and providing individualized treatment recommendations. Here we review and critically evaluate the evidence for the most promising biomarkers in the psychiatric neuroscience literature for autism spectrum disorder, schizophrenia, anxiety disorders and post‐traumatic stress disorder, major depression and bipolar disorder, and substance use disorders. Candidate biomarkers reviewed include various neuroimaging, genetic, molecular and peripheral assays, for the purposes of determining susceptibility or presence of illness, and predicting treatment response or safety. This review highlights a critical gap in the biomarker validation process. An enormous societal investment over the past 50 years has identified numerous candidate biomarkers. However, to date, the overwhelming …

For people with post-traumatic stress disorder (PTSD), recall of traumatic memories often displays as intrusions that differ profoundly from processing of ‘regular’ negative memories. These mnemonic features fueled theories speculating a unique cognitive state linked with traumatic memories. Yet, to date, little empirical evidence supports this view. Here we examined neural activity of patients with PTSD who were listening to narratives depicting their own memories. An intersubject representational similarity analysis of cross-subject semantic content and neural patterns revealed a differentiation in hippocampal representation by narrative type: semantically similar, sad autobiographical memories elicited similar neural representations across participants. By contrast, within the same individuals, semantically similar trauma memories were not represented similarly. Furthermore, we were able to decode memory type …

BackgroundThe presentation, etiology, and relative risk of psychiatric disorders are strongly influenced by biological sex. Neuroticism is a transdiagnostic feature of psychiatric disorders displaying prominent sex differences. We performed genome-wide association studies of neuroticism separately in males and females to identify sex-specific genetic and transcriptomic profiles.MethodsNeuroticism scores were derived from the Eysenck Personality Inventory Neuroticism scale. Genome-wide association studies were performed in 145,669 females and 129,229 males from the UK Biobank considering autosomal and X chromosomal variation. Two-sided z tests were used to test for sex-specific effects of discovered loci, genetic correlates (n = 673 traits), tissue and gene transcriptomic profiles, and polygenic associations across health outcomes in the Vanderbilt University Biobank (39,692 females and 31,268 males …

Ketamine has emerged as a transformative and mechanistically novel pharmacotherapy for depression. Its rapid onset of action, efficacy for treatment-resistant symptoms, and protection against relapse distinguish it from prior antidepressants. Its discovery emerged from a reconceptualization of the neurobiology of depression and, in turn, insights from the elaboration of its mechanisms of action inform studies of the pathophysiology of depression and related disorders. It has been 25 y since we first presented our ketamine findings in depression. Thus, it is timely for this review to consider what we have learned from studies of ketamine and to suggest future directions for the optimization of rapid-acting antidepressant treatment.

Posttraumatic stress disorder (PTSD) is associated with changes in fear learning and decision-making, suggesting involvement of the brain’s valuation system. Here we investigate the neural mechanisms of subjective valuation of rewards and punishments in combat veterans. In a functional MRI study, male combat veterans with a wide range of posttrauma symptoms (N = 48, Clinician Administered PTSD Scale, CAPS-IV) made a series of choices between sure and uncertain monetary gains and losses. Activity in the ventromedial prefrontal cortex (vmPFC) during valuation of uncertain options was associated with PTSD symptoms, an effect which was consistent for gains and losses, and specifically driven by numbing symptoms. In an exploratory analysis, computational modeling of choice behavior was used to estimate the subjective value of each option. The neural encoding of subjective value varied as a …

BackgroundGlutamatergic neurotransmission mediated by N-methyl-D-aspartate receptors (NMDAR) is critical for cortical computations underlying cognition; associated disruptions are hypothesized to underlie psychosis spectrum disorders (PSD). Cortical microcircuit models hypothesize that NMDAR disinhibition facilitates impaired cognition in PSD by weakening neural tuning. However, the mechanisms explaining the relationship between altered microcircuit tuning and system-level neural dynamics, specifically in humans, have yet to be studied.MethodsUsing pharmacological neuroimaging, we examined how the NMDAR antagonist ketamine affects neural tuning during working memory (WM) in healthy adults (n= 40). fMRI data was obtained while subjects saw, memorized, and reported the location of visual stimuli once under the administration of ketamine, and once under saline placebo. We used a …

BackgroundAlcohol use disorder is a public health problem, especially among US veterans. This study examined the nature and predictors of 10-year trajectories of alcohol consumption in US veterans.MethodsData were analyzed from the 2011–2021 National Health and Resilience in Veterans Study, a nationally representative, longitudinal study of 2309 US veterans.ResultsLatent growth mixture modeling analyses revealed four trajectories of alcohol consumption (Alcohol Use Disorders Identification Test–Consumption [AUDIT-C]) over a 10-year period: excessive (4.1%; mean [standard deviation] AUDIT-C baseline=8.6 [2.0], slope= −0.33 [0.07]); at-risk (22.1%; baseline=4.1 [1.6], slope=0.02 [0.07]); rare (71.7%; baseline=1.2 [1.3], slope= −0.01 [0.03]); and recovering alcohol consumption (2.1%; baseline=8.4 [1.9], slope= −0.70 [0.14]). The strongest predictors of excessive vs. rare alcohol consumption group …

We assessed the interrater reliability, convergent validity, and discriminant validity of the Self-Injurious Thoughts and Behaviors Interview-Short Form (SITBI-SF) in a sample of 1,944 active duty service members and veterans seeking services for posttraumatic stress disorder (PTSD) and related conditions. The SITBI-SF demonstrated high interrater reliability and good convergent and discriminant validity. The measurement properties of the SITBI-SF were comparable across service members and veterans. Approximately 8% of participants who denied a history of suicidal ideation on the SITBI-SF reported suicidal ideation on a separate self-report questionnaire (i.e., discordant responders). Discordant responders reported significantly higher levels of PTSD symptoms than those who denied suicidal ideation on both response formats. Findings suggest that the SITBI-SF is a reliable and valid interview-based measure …

Post-traumatic stress disorder (PTSD) is a common and disabling psychiatric disorder. Here we present findings from the first proteome-wide study of the postmortem PTSD brain. We performed tandem mass spectrometry on large cohort of donors (N = 66) in two prefrontal cortical areas and found differentially expressed proteins and co-expression modules disturbed in PTSD. Integrative analysis pointed to hsa-mir-589 as a regulatory miRNA responsible for disruptions in neuronal protein networks for PTSD, including the GABA vesicular transporter, SLC32A1. In addition, we identified significant enrichment of risk genes for Alzheimers Disease (N= 94,403), major depression (N = 807,553), and schizophrenia (N = 35,802) within PTSD co-expression protein modules, suggesting shared molecular pathology. Our findings highlight the altered proteomic landscape of postmortem PTSD brain and provide a novel framework for future studies integrating proteomic profiling with transcriptomics in postmortem human brain tissue.

Opioid use disorder (OUD) is influenced by genetic and environmental factors. While recent research suggests epigenetic disturbances in OUD, this is mostly limited to DNA methylation (5mC). DNA hydroxymethylation (5hmC) has been widely understudied. We conducted a multi-omics profiling of OUD in a male cohort, integrating neuronal-specific 5mC and 5hmC as well as gene expression profiles from human postmortem orbitofrontal cortex (OUD = 12; non-OUD = 26). Single locus methylomic analysis and co-methylation analysis showed a higher number of OUD-associated genes and gene networks for 5hmC compared to 5mC; these were enriched for GPCR, Wnt, neurogenesis, and opioid signaling. 5hmC marks also showed a higher correlation with gene expression patterns and enriched for GWAS of psychiatric traits. Drug interaction analysis revealed interactions with opioid-related drugs, some used …

N-methyl-d-aspartate glutamate receptor (NMDAR) hypofunction is implicated in the impaired neuroplasticity and cognitive impairments associated with schizophrenia (CIAS). We hypothesized that enhancing NMDAR function by inhibiting the glycine transporter-1 (GLYT1) would improve neuroplasticity and thereby augment benefits of non-pharmacological cognitive training (CT) strategies. This study examined whether co-administration of a GLYT1 inhibitor and computerized CT would have synergistic effects on CIAS. Stable outpatients with schizophrenia participated in this double-blind, placebo-controlled, within-subject, crossover augmentation study. Participants received placebo or GLYT1 inhibitor (PF-03463275) for two 5-week periods separated by 2 weeks of washout. PF-03463275 doses (40 or 60 mg twice daily) were selected to produce high GLYT1 occupancy. To limit pharmacodynamic variability, only …

Background The coronavirus disease-2019 (COVID-19) pandemic has caused myriad health, social, and economic stressors. To date, however, no known study has examined changes in mental health during the pandemic in the U.S. military veteran population. Methods Data were analyzed from the 2019–2020 National Health and Resilience in Veterans Study, a nationally representative, prospective cohort survey of 3078 veterans. Pre-to-peri-pandemic changes in psychiatric symptoms were evaluated, as well as pre-pandemic risk and protective factors and pandemic-related correlates of increased psychiatric distress. Results The prevalence of generalized anxiety disorder (GAD) positive screens increased from pre- to peri-pandemic (7.1% to 9.4%; p < 0.001) and was driven by an increase among veterans aged 45–64 years (8.2% to 13.5%; p < 0.001), but the prevalence of major depressive disorder and …

Ketamine has emerged as a transformative and mechanistically novel pharmacotherapy for depression. Its rapid onset of action, efficacy for treatment-resistant symptoms, and protection against relapse distinguish it from prior antidepressants. Its discovery emerged from a reconceptualization of the neurobiology of depression and, in turn, insights from the elaboration of its mechanisms of action inform studies of the pathophysiology of depression and related disorders. It has been 25 y since we first presented our ketamine findings in depression. Thus, it is timely for this review to consider what we have learned from studies of ketamine and to suggest future directions for the optimization of rapid-acting antidepressant treatment.

Mental health issues are a growing concern in the workplace, linked to negative outcomes including reduced productivity, increased absenteeism, and increased turnover. Employer-sponsored mental health benefits that are accessible and proactive may help address these concerns. The aim of this retrospective cohort study was to evaluate the impact of a digital mental health benefit (Spring Health) on frontline healthcare service workers’ clinical and workplace outcomes. The benefit was sponsored by a national health services company from 2021–2022 and included mental health screening, care navigation, psychotherapy and/or medication management. We hypothesized program use would be associated with improvements in depression and anxiety symptoms, and increased productivity and retention. Participants were employees enrolled in the benefit program, had at least moderate anxiety or depression, at least 1 treatment appointment, and at least 2 outcome assessments. Clinical improvement measures were PHQ-9 scale (range, 0–27) for depression and GAD-7 scale (range, 0–21) for anxiety; workplace measures were employee retention and the Sheehan Disability Scale (SDS) for functional impairment. A total of 686 participants were included. Participants using the mental health benefit had a 5.60 point (95% CI, 4.40–6.79, d = 1.28) reduction in depression and a 5.48 point (95% CI, 3.88–7.08, d = 1.64) reduction in anxiety across 6 months. 69.9% (95% CI, 61.8%–78.1%) of participants reliably improved (≥5 point change) and 84.1% (95% CI, 78.2%–90.1%) achieved reliable improvement or recovery (<10 points). Participants …

Post-traumatic stress disorder is a mental disorder that may occur in the aftermath of severe psychological trauma. We examined 1,065,750 DNA methylation (DNAm) sites from 171 donors including neurotypicals, PTSD, and major depressive disorder cases across six areas implicated in the fear circuitry of the brain. We found significant differential methylation for PTSD near 195 genes and utilizing cross-region modeling, identified 6,641 candidate genes. Approximately 26% of differentially methylated CpGs were present near risk loci for PTSD. To identify potential therapeutic intersections for PTSD, we found significant methylation changes in the MAD1L1, ELFN1, and WNT5A genes in ketamine responders. Finally, to better understand the unique biology of PTSD, we analyzed matching methylation data for a cohort of MDD donors with no known history of trauma or PTSD. Our results implicate DNAm as an epigenetic mechanism underlying the molecular changes associated with the subcortical fear circuitry of the PTSD brain.

BackgroundStudying patients under drugs that produce rapid changes in mood and consciousness, such as ketamine and psychedelics, promises to yield critical findings about the neurobiology of consciousness and mood-transforming psychiatric therapeutics. However, such drugs can disrupt neurovascular-coupling, hampering correct interpretation of fMRI experimental results. Measuring the cerebral metabolic rate of oxygen (CMRO2) via calibrated fMRI is a possible solution. Here, we report initial results supporting this measure’s sensitivity to ketamine’s effects in healthy humans.MethodsWe measured CMRO2 in 23 healthy subjects on two counterbalanced experimental days, one with saline and the other with a subanesthetic dose of ketamine infused. Ketamine or saline was infused in the MRI scanner, first with a bolus of 0.23 mg/kg/min for 5 minutes, then with a steady state infusion of 0.58 mg/kg/hour, with …

Smoking is a serious public health issue linked to more than 8 million deaths per year worldwide and may lead to nicotine dependence (ND). Although the epigenomic literature on smoking is well established, studies evaluating the role of epigenetics in ND are limited. In this study, we examined the epigenomic signatures of ND and how these differ from smoking exposure to identify biomarkers specific to ND. We investigated the peripheral epigenetic profile of smoking status (SS) and ND in a US male veteran cohort. DNA from saliva was collected from 1135 European American (EA) male US military veterans. DNAm was assessed using the Illumina Infinium Human MethylationEPIC BeadChip array. SS was evaluated as current smokers (n = 137; 12.1%) and non‐current smokers (never and former; n = 998; 87.9%). NDFTND was assessed as a continuous variable using the Fagerström Test for ND (FTND; n …

BackgroundLittle is known about environmental factors that may influence associations between genetic liability to suicidality and suicidal behavior.MethodsThis study examined whether a suicidality polygenic risk score (PRS) derived from a large genome-wide association study (N = 122,935) was associated with suicide attempts in a population-based sample of European-American US military veterans (N = 1664; 92.5% male), and whether cumulative lifetime trauma exposure moderated this association.ResultsEighty-five veterans (weighted 6.3%) reported a history of suicide attempt. After adjusting for sociodemographic and psychiatric characteristics, suicidality PRS was associated with lifetime suicide attempt (odds ratio 2.65; 95% CI 1.37–5.11). A significant suicidality PRS-by-trauma exposure interaction emerged, such that veterans with higher levels of suicidality PRS and greater trauma burden had the …

ImportanceConcerns have been raised since the onset of the COVID-19 pandemic that vulnerable populations, such as military veterans, may be at increased risk of suicidal thoughts and behaviors (STBs).ObjectiveTo examine longitudinal trends in STBs in US military veterans during the first 3 years of the COVID-19 pandemic.Design, Setting, and ParticipantsThis cohort study is a population-based longitudinal study including US military veterans that used 3 surveys from the National Health and Resilience in Veterans Study. Median dates of data collection were November 21, 2019 (prepandemic); November 14, 2020; and August 18, 2022.Main Outcomes and MeasuresLifetime and past-year suicidal ideation, suicide planning, and suicide attempt.ResultsIn this longitudinal study including 2441 veterans (mean [SD] age, 63.2 years [14.0]; 2182 [92.1%] male), past-year suicidal ideation decreased from 9.3 …

Introduction DNA methylation (DNAm), an epigenetic mechanism, has been associated with opioid use disorder (OUD) in preclinical and human studies. However, most of the studies have focused on DNAm at CpG sites. DNAm at non-CpG sites (mCpHs, where H indicates A, T, or C) has been recently shown to have a role in gene regulation and to be highly abundant in neurons. However, its role in OUD is unknown. This work aims to evaluate mCpHs in the human postmortem orbital frontal cortex (OFC) in the context of OUD. Methods A total of 38 Postmortem OFC samples were obtained from the VA Brain Bank (OUD = 12; Control = 26). mCpHs were assessed using reduced representation oxidative bisulfite sequencing in neuronal nuclei. Differential analysis was performed using the “methylkit” R package. Age, ancestry, postmortem interval, PTSD, and smoking status were included as covariates. Significant mCpHs were set at q-value < 0.05. Gene Ontology (GO) and KEGG enrichment analyses were performed for the annotated genes of all differential mCpH loci using String, ShinyGO, and amiGO software. Further, all annotated genes were analyzed using the Drug gene interaction database (DGIdb). Results A total of 2,352 differentially methylated genome-wide significant mCpHs were identified in OUD, mapping to 2,081 genes. GO analysis of genes with differential mCpH loci showed enrichment for nervous system development (p-value = 2.32E-19). KEGG enrichment analysis identified axon guidance and glutamatergic synapse (FDR 9E-4–2.1E-2). Drug interaction analysis found 3,420 interactions between the annotated genes and …

Objective In posttraumatic stress disorder (PTSD), the assumption of the equipotentiality of traumas ignores potentially unique contexts and consequences of different traumas. Accordingly, Stein et al.(2012) developed a reliable typing scheme in which assessors categorized descriptions of traumatic events into six “types”: life threat to self (LTS), life threat to other, aftermath of violence (AV), traumatic loss, moral injury by self (MIS), and moral injury by other (MIO). We extended this research by validating the typing scheme using participant endorsements of type, rather than assesor-based types. We examined the concordance of participant and assesor types, frequency, and validity of participant-based trauma types by examining associations with baseline mental and behavioral health problems. Method Interviewers enrolled military personnel and veterans (N= 1,443) in clinical trials of PTSD and helped them select …

BackgroundRecent advances in data-driven computational approaches have been helpful in devising tools to objectively diagnose psychiatric disorders. However, current machine learning studies limited to small homogeneous samples, different methodologies, and different imaging collection protocols, limit the ability to directly compare and generalize their results. Here we aimed to classify individuals with PTSD versus controls and assess the generalizability using a large heterogeneous brain datasets from the ENIGMA-PGC PTSD Working group.MethodsWe analyzed brain MRI data from 3,477 structural-MRI; 2,495 resting state-fMRI; and 1,952 diffusion-MRI. First, we identified the brain features that best distinguish individuals with PTSD from controls using traditional machine learning methods. Second, we assessed the utility of the denoising variational autoencoder (DVAE) and evaluated its classification …

Working memory (WM) is a crucial resource for temporary memory storage and the guiding of ongoing behavior. N-methyl-D-aspartate glutamate receptors (NMDARs) are thought to support the neural underpinnings of WM. Ketamine is an NMDAR antagonist that has cognitive and behavioral effects at subanesthetic doses. To shed light on subanesthetic ketamine effects on brain function, we employed a multimodal imaging design, combining gas-free calibrated functional magnetic resonance imaging (fMRI) measurement of oxidative metabolism (CMRO2), resting-state cortical functional connectivity assessed with fMRI, and WM-related fMRI. Healthy subjects participated in two scan sessions in a randomized, double-blind, placebo-controlled design. Ketamine increased CMRO2 and cerebral blood flow (CBF) in prefrontal cortex (PFC) and other cortical regions. However, resting-state cortical functional connectivity was not affected. Ketamine did not alter CBF-CMRO2 coupling brain-wide. Higher levels of basal CMRO2 were associated with lower task-related PFC activation and WM accuracy impairment under both saline and ketamine conditions. These observations suggest that CMRO2 and resting-state functional connectivity index distinct dimensions of neural activity. Ketamine’s impairment of WM-related neural activity and performance appears to be related to its ability to produce cortical metabolic activation. This work illustrates the utility of direct measurement of CMRO2 via calibrated fMRI in studies of drugs that potentially affect neurovascular and neurometabolic coupling.

Aging is a complex process with interindividual variability, which can be measured by aging biological clocks. Aging clocks are machine-learning algorithms guided by biological information and associated with mortality risk and a wide range of health outcomes. One of these aging clocks are transcriptomic clocks, which uses gene expression data to predict biological age; however, their functional role is unknown. Here, we profiled two transcriptomic clocks (RNAAgeCalc and knowledge-based deep neural network clock) in a large dataset of human postmortem prefrontal cortex (PFC) samples. We identified that deep-learning transcriptomic clock outperforms RNAAgeCalc to predict transcriptomic age in the human PFC. We identified associations of transcriptomic clocks with psychiatric-related traits. Further, we applied system biology algorithms to identify common gene networks among both clocks and performed …

BackgroundPatients with schizophrenia (SCZ) and patients with OCD share symptomatology, including motivational and cognitive impairments, suggesting common and distinct associated mechanisms. We analyzed data from SCZ, OCD and typical adults (TA) who performed an incentivized spatial working memory (sWM) task.MethodsThree groups (SCZ (N= 27, M= 21/F= 6), OCD (N= 39, M= 18/F= 21), TA (N= 34, M= 21/F= 13)) completed an incentivized sWM task during 3T-scanning. Participants kept spatial locations in mind, and also won/lost money depending on sWM performance. Incentives were cued at each trial or presented in a non-cued, contextual manner. Behavioral data examined angular accuracy. Preliminary neuroimaging analyses are presented.ResultsPatients with SCZ had worse baseline sWM performance than patients with OCD and TA (interaction, p< 0.001; pairwise, p< 0.005), with no …

This study is the first randomized controlled trial to test the effects of ketamine in Borderline Personality Disorder (BPD). BPD remains undertreated in the community and no medication has FDA approval for this indication. People with BPD experience chronic mood disturbances with depressed mood, suicidal ideation, and severe social difficulties. In this double-blind, randomized controlled pilot study, we tested the effects of one infusion of ketamine (0.5 mg/kg, n = 10) or the psychoactive comparator drug midazolam (0.04 mg/kg, n = 12) in adults with BPD. Infusions were well tolerated in both groups. Dissociative symptoms during infusion were more intense with ketamine than midazolam (t(12.3) = 3.61, p = 0.01), but they resolved by 40 min after infusion in both groups. Post-infusion adverse events were at the expected low levels in both groups. For our primary outcome measure of suicidal ideation and …

Neural activity and behavior manifest state and trait dynamics, as well as variation within and between individuals. However, the mapping of state-trait neural variation to behavior is not well understood. To address this gap, we quantify moment-to-moment changes in brain-wide co-activation patterns derived from resting-state functional magnetic resonance imaging. In healthy young adults, we identify reproducible spatio-temporal features of co-activation patterns at the single subject level. We demonstrate that a joint analysis of state-trait neural variations and feature reduction reveal general motifs of individual differences, encompassing state-specific and general neural features that exhibit day-to-day variability. The principal neural variations co-vary with the principal variations of behavioral phenotypes, highlighting cognitive function, emotion regulation, alcohol and substance use. Person-specific probability of …

Introduction Posttraumatic stress disorder (PTSD) is a complex multifactorial disorder influenced by the interaction of genetic and environmental factors. Analyses of epigenomic and transcriptomic modifications may help to dissect the biological factors underlying the gene-environment interplay in PTSD. To date, most human PTSD epigenetics studies have used peripheral tissue, and these findings have complex and poorly understood relationships to brain alterations. Studies examining brain tissue may help characterize the brain-specific transcriptomic and epigenomic profiles of PTSD. In this review, we compiled and integrated brain-specific molecular findings of PTSD from humans and animals. Methods A systematic literature search according to the PRISMA criteria was performed to identify transcriptomic and epigenomic studies of PTSD, focusing on brain tissue from human postmortem samples or animal …

BackgroundUnderstanding the interplay between psychosocial factors and polygenic risk scores (PRS) may help elucidate the biopsychosocial etiology of high alcohol consumption (HAC). This study examined the psychosocial moderators of HAC, determined by polygenic risk in a 10-year longitudinal study of US military veterans. We hypothesized that positive psychosocial traits (e.g. social support, personality traits, optimism, gratitude) may buffer risk of HAC in veterans with greater polygenic liability for alcohol consumption (AC).MethodsData were analyzed from 1323 European-American US veterans who participated in the National Health and Resilience in Veterans Study, a 10-year, nationally representative longitudinal study of US military veterans. PRS reflecting genome-wide risk for AC (AUDIT-C) was derived from a Million Veteran Program genome-wide association study (N = 200 680).ResultsAmong the …

ObjectiveProblem opioid use (POU) is a serious public health crisis in the United States. However, little research has examined the prevalence, correlates, and psychiatric characteristics of POU in vulnerable segments of the population, such as US military veterans.MethodsData were analyzed from the National Health and Resilience in Veterans Study, which surveyed a nationally representative sample of 2441 US veterans. Multivariable logistic regression models were conducted to identify correlates and psychiatric correlates of POU (defined as a positive screen on the Tobacco, Alcohol, Prescription Medication, and Other Substance Use Tool).ResultsA total 3.0%(95% confidence interval, 2.0%–4.5%) of US veterans screened positive for POU. Black, non-Hispanic race/ethnicity (odds ratio [OR], 3.83), lifetime alcohol use disorder (OR, 3.38), major depressive disorder (MDD; OR, 2.52), greater number of medical …

The phenotype of schizophrenia, regardless of etiology, represents the most studied psychotic disorder with respect to neurobiology and distinct phases of illness. The early phase of illness represents a unique opportunity to provide effective and individualized interventions that can alter illness trajectories. Developmental age and illness stage, including temporal variation in neurobiology, can be targeted to develop phase-specific clinical assessment, biomarkers, and interventions. We review an earlier model whereby an initial glutamate signaling deficit progresses through different phases of allostatic adaptation, moving from potentially reversible functional abnormalities associated with early psychosis and working memory dysfunction, and ending with difficult-to-reverse structural changes after chronic illness. We integrate this model with evidence of dopaminergic abnormalities, including cortical D1 dysfunction …

A considerable minority of US adults (approximately 13%) 1, 2 experienced significant increases in distress2 during the height of the COVID-19 pandemic. It is not clear whether these increases portend exacerbated or persistent courses of distress, and what risk or protective factors are associated with these courses.In this study, we build upon our previous study of US military veterans, 2 which characterized the prevalence of distress (ie, positive screens for major depressive disorder [MDD], generalized anxiety disorder [GAD], or posttraumatic stress disorder [PTSD]) before and 1 year into the COVID-19 pandemic by analyzing 2 additional years of longitudinal data, and identifying factors associated with exacerbated and persistent courses of distress.

BackgroundPTSD is a complex psychiatric disorder developed after exposure to a traumatic event and influenced by the interplay between genetic and environmental factors. DNA methylation (5mC), an epigenetic mechanism that underlies this interplay, has been implicated in PTSD; hydroxymethylation (5hmC) has not been yet explored. Epigenetic alterations can be cell-type specific and studies using postmortem brain are limited, particularly in PTSD. Here, we examine differential 5mC/5hmC in human postmortem orbitofrontal neurons in PTSDMethodsReduced-representation-bisulfite-sequencing was conducted on cortical-neurons of 38 postmortem-brain samples (25 PTSD, 13 controls from the-National-PTSD-Brain-Bank). Based on methylation proportion between cases and controls, logistic-regression was used by methylKit R-package to model the log-odds-ratio. Significant genome-wide differential 5mC …

ObjectiveThe COVID-19 pandemic is a traumatic stressor resulting in anxiety, depression, post-traumatic stress, and burnout among healthcare workers. We describe an intervention to support the health workforce and summarize results from its 40-week implementation in a large, tri-state health system during the COVID-19 pandemic.MethodWe conducted 121 virtual and interactive Stress and Resilience Town Halls attended by 3555 healthcare workers. Town hall participants generated 1627 stressors and resilience strategies that we coded and analyzed using rigorous qualitative methods (Kappa = 0.85).ResultsWe identify six types of stressors and eight types of resilience strategies reported by healthcare workers, how these changed over time, and how town halls were responsive to emerging health workforce needs. We show that town halls dedicated to groups working together yielded 84% higher mean …

Background: DNA methylation and hydroxymethylation at CpG dinucleotides (5mC and 5hmC) are stable epigenetic marks with a critical role in fine-tuning transcriptional activation and/or repression. While previous studies have implicated 5mC and 5hmC in the etiology of post-traumatic stress disorder (PTSD), all this work has been performed using peripheral tissue. Considering the cell-and tissue-specific nature of epigenetic alterations, more targeted studies are warranted. In addition, although 5mC and 5hmC have been mainly evaluated at CpG sites, there is growing evidence that non-CpG modifications also play an important role in epigenetic regulation, particularly in neurons. Here, we examine differential 5mC and 5hmC at both CpG and non-CpG sites on human postmortem orbitofrontal neurons in PTSD.Methods: Reduced-representation oxidative bisulfite sequencing was conducted on 38 postmortem …

BackgroundCurrent clinical assessments of Posttraumatic stress disorder (PTSD) rely solely on subjective symptoms and experiences reported by the patient, rather than objective biomarkers of the illness. Recent advances in data-driven computational approaches have been helpful in devising tools to objectively diagnose psychiatric disorders. Here we aimed to classify individuals with PTSD versus controls using heterogeneous brain datasets from the ENIGMA-PGC PTSD Working group.MethodsWe analyzed brain MRI data from 3,527 structural-MRI; 2,502 resting state-fMRI; and 1,953 diffusion-MRI. First, we identified the brain features that best distinguish individuals with PTSD from controls (TEHC and HC) using traditional machine learning methods. Second, we assessed the utility of the denoising variational autoencoder (DVAE) and evaluated its classification performance. Third, we assessed the generalizability and reproducibility of both models using leave-one-site-out cross-validation procedure for each modality.ResultsWe found lower performance in classifying PTSD vs. controls with data from over 20 sites (60% test AUC for s-MRI, 59% for rs-fMRI and 56% for d-MRI), as compared to other studies run on single-site data. The performance increased when classifying PTSD from HC without trauma history across all three modalities (75% AUC). The classification performance remained intact when applying the DVAE framework, which reduced the number of features. Finally, we found that the DVAE framework achieved better generalization to unseen datasets compared with the traditional machine learning frameworks, albeit …

ObjectiveTo determine to what extent did health care workers experience the pandemic as a severe stress event.MethodsThis cross-sectional evaluation of 8299 health care workers, representing a 22% response rate, utilized machine learning to predict high levels of escalating stress based on demographics and known predictors for adverse psychological outcomes after trauma.ResultsA third of health care workers experienced the pandemic as a potentially traumatic stress event; a greater proportion of health care workers experienced high levels of escalating stress. Predictive factors included sense of control, ability to manage work-life demands, guilt or shame, age, and level of education. Gender was no longer predictive after controlling for other factors. Escalating stress was especially high among nonclinical academics and clinical private practitioners.ConclusionFindings suggest adverse effects on total …

Integrating motivational signals with cognition is critical for goal-directed activities. The mechanisms that link neural changes with motivated working memory continue to be understood. Here, we tested how externally cued and non-cued (internally represented) reward and loss impact spatial working memory precision and neural circuits in human subjects using fMRI. We translated the classic delayed-response spatial working memory paradigm from non-human primate studies to take advantage of a continuous numeric measure of working memory precision, and the wealth of translational neuroscience yielded by these studies. Our results demonstrated that both cued and non-cued reward and loss improved spatial working memory precision. Visual association regions of the posterior prefrontal and parietal cortices, specifically the precentral sulcus (PCS) and intraparietal sulcus (IPS), had increased BOLD signal …

Post-traumatic stress disorder is a prevalent disorder within the USA and worldwide with a yearly diagnosis rate of 2–4% and affecting women more than men. One of the primary methods for study of this stress disorder relies on animal models as there are few noninvasive methods and few replicated peripheral biomarkers for use in humans. One area of active research in psychiatric neuroscience is the field of epigenetics–how the chemical modifications of the genetic code regulate behavior. The dynamic changes in histone acetylation and deacetylation in the brain are not fully reflected by the study of peripheral biomarker. In this review, we aim to examine the role of histone acetylation and deacetylation in memory formation and fear memory learning. The studies discussed here focus largely on the role of histone deacetylases (HDACs) in animal models of trauma and fear response. Many studies used HDAC …

Results of neuroimaging datasets aggregated from multiple sites may be biased by site-specific profiles in participants’ demographic and clinical characteristics, as well as MRI acquisition protocols and scanning platforms. We compared the impact of four different harmonization methods on results obtained from analyses of cortical thickness data: (1) linear mixed-effects model (LME) that models site-specific random intercepts (LMEINT), (2) LME that models both site-specific random intercepts and age-related random slopes (LMEINT+SLP), (3) ComBat, and (4) ComBat with a generalized additive model (ComBat-GAM). Our test case for comparing harmonization methods was cortical thickness data aggregated from 29 sites, which included 1,340 cases with posttraumatic stress disorder (PTSD) (6.2–81.8 years old) and 2,057 trauma-exposed controls without PTSD (6.3–85.2 years old). We found that, compared to …

ImportanceWhether ketamine is as effective as electroconvulsive therapy (ECT) among patients with major depressive episode remains unknown.ObjectiveTo systematically review and meta-analyze data about clinical efficacy and safety for ketamine and ECT in patients with major depressive episode.Data SourcesPubMed, MEDLINE, Cochrane Library, and Embase were systematically searched using Medical Subject Headings (MeSH) terms and text keywords from database inception through April 19, 2022, with no language limits. Two authors also manually and independently searched all relevant studies in US and European clinical trial registries and Google Scholar.Study SelectionIncluded were studies that involved (1) a diagnosis of depression using standardized diagnostic criteria, (2) intervention/comparator groups consisting of ECT and ketamine, and (3) depressive symptoms as an efficacy outcome …

IntroductionKetamine can produce rapid-acting antidepressant effects. Esketamine (Spravato), the S-enantiomer of racemic ketamine, was approved by the FDA for treatment-resistant depression in 2019. Here we review what is known about the long-term safety of both racemic ketamine and esketamine as therapies for psychiatric disorders.Areas CoveredIn this article, we conducted a safety review of ketamine and esketamine. In looking at ketamine and esketamine long-term safety effects, we considered data available from experimental studies and several phase-three clinical trials.Expert OpinionBased on available data, the most common side effects of ketamine/esketamine are generally transient, mild, and self-limited. These include dissociation, nausea, headache, elevated heart rate, and blood pressure. Treatment with esketamine may lead to an increased risk of lower urinary tract symptoms, such as dysuria …

BackgroundPosttraumatic stress disorder (PTSD) is accompanied by disrupted cortical neuroanatomy. We investigated alteration in covariance of structural networks associated with PTSD in regions that demonstrate the case-control differences in cortical thickness (CT) and surface area (SA).MethodsNeuroimaging and clinical data were aggregated from 29 research sites in >1300 PTSD cases and >2000 trauma-exposed control subjects (ages 6.2–85.2 years) by the ENIGMA-PGC (Enhancing Neuro Imaging Genetics through Meta Analysis–Psychiatric Genomics Consortium) PTSD working group. Cortical regions in the network were rank ordered by the effect size of PTSD-related cortical differences in CT and SA. The top-n (n = 2–148) regions with the largest effect size for PTSD > non-PTSD formed hypertrophic networks, the largest effect size for PTSD < non-PTSD formed atrophic networks, and the smallest …

A number of studies of posttraumatic stress disorder (PTSD) report thinner cerebral cortical gyri using gyrus-based analysis or thinner foci within the gyri using vertex-based analysis. However, the locations of these findings are inconsistent across studies, and the spatial transformations required during vertex-based analysis may affect the focal findings. A mega-analysis using a large number of subjects from multiple PTSD studies could potentially identify more reproducible cortical thickness abnormalities. Investigating both the vertex and gyral thicknesses simultaneously may verify the vertex-based focal findings using gyral data without imposing any spatial transformation. Here we aggregated data from 24 international laboratories using ENIGMA standardized procedures for 949 adult PTSD patients and 1493 controls without PTSD (age 18 to 65 years). We examined whether gyral and vertex cortical thickness are (a) different between subjects with PTSD and controls and (b) associated with PTSD symptom severity in trauma-exposed subjects. Regions with overlapping thinner cortical gyri and thinner vertex clusters were located in frontal, temporal, parietal, and occipital cortices. Thinner right lateral orbitofrontal and right lingual gyri and concomitantly thinner vertex clusters in the anterior portions of both gyri were associated with PTSD symptom severity. Convergent findings in these locations suggest focally thinner cortex in these gyri, which may be involved in altered processing and regulation of emotion and sensory inputs underlying posttraumatic stress symptoms.

Technology is ubiquitous in society and is now being extensively used in mental health applications. Both assessment and treatment strategies are being developed and deployed at a rapid pace. The authors review the current domains of technology utilization, describe standards for quality evaluation, and forecast future developments. This review examines technology-based assessments of cognition, emotion, functional capacity and everyday functioning, virtual reality approaches to assessment and treatment, ecological momentary assessment, passive measurement strategies including geolocation, movement, and physiological parameters, and technology-based cognitive and functional skills training. There are many technology-based approaches that are evidence based and are supported through the results of systematic reviews and meta-analyses. Other strategies are less well supported by high-quality …

Importance Investment in workplace wellness programs is increasing despite concerns about lack of clinical benefit and return on investment (ROI). In contrast, outcomes from workplace mental health programs, which treat mental health difficulties more directly, remain mostly unknown. Objective To determine whether participation in an employer-sponsored mental health benefit was associated with improvements in depression and anxiety, workplace productivity, and ROI as well as to examine factors associated with clinical improvement. Design, Setting, and Participants This cohort study included participants in a US workplace mental health program implemented by 66 employers across 40 states from January 1, 2018, to January 1, 2021. Participants were employees who enrolled in the mental health benefit program and had at least moderate anxiety or depression, at least 1 appointment, and at least 2 outcome …

MethodsA nationally representative sample of US veterans participated in the National Health and Resilience in Veterans Study; 4,069 veterans completed a baseline survey from November 18, 2019, to March 8, 2020, and 3,078 veterans (75.6%) completed a 1-year follow-up from November 9, 2020, to December 19, 2020.

Psychiatry faces a number of challenges, among them are the reconceptualization of symptoms and diagnoses, disease prevention, treatment development and monitoring of its effects, and the provision of individualized, precision medicine. Achieving these goals will require an increase in the biological, quantitative, and theoretical grounding of psychiatry. To address these challenges, psychiatry must confront the complexity and heterogeneity intrinsic to the nature of brain disorders. This chapter seeks to identify the sources of complexity and heterogeneity as a means of confronting the challenges facing the field. These sources include the interplay between genetic and epigenetic factors with the environment and their impact on neural circuits. Moreover, these interactions are expressed dynamically over the course of development and continue to play out during the disease process and treatment.We propose that computational approaches provide a framework for addressing the complexity and heterogeneity that underlie the challenges facing psychiatry. Central to our argument is the idea that these characteristics are not noise to be eliminated from diagnosis and treatment of disorders. Instead, such complexity and heterogeneity arises from intrinsic features of brain function and, therefore, represent opportunities for com-

Reductions in default mode (DMN) connectivity strength have been reported in posttraumatic stress disorder (PTSD). However, the specificity of DMN connectivity deficits in PTSD compared to major depressive disorder (MDD), and the sensitivity of these alterations to acute stressors are not yet known. 52 participants with primary diagnosis of PTSD (n= 28) or MDD (n= 24) completed resting state functional magnetic resonance imaging immediately before and after a mild affective stressor. A 2x2 design was conducted to determine the effects of group, stress, and group* stress on DMN connectivity strength. Exploratory analyses were completed to identify the brain region (s) underlying the DMN alterations. We found 13% reduction in DMN strength in PTSD compared to MDD (p= 0.04). There was significant group* stress interaction (p= 0.03), reflecting stress-induced reduction in DMN strength in PTSD (p= 0.02), but not MDD (p= 0.50). Nodal exploration of connectivity strength in the DMN identified regions of the ventromedial prefrontal cortex and the precuneus contributing to DMN connectivity deficits. The findings indicate distinct, disease-specific, patterns of connectivity strength reduction in the DMN in PTSD, especially following an experimental stressor. The identified stress-induced dynamic shift in functional connectivity underscores the potential utility of the DMN connectivity and raises the question whether these disruptions are inversely affected by antidepressants known to treat both MDD and PTSD psychopathology.

BackgroundThe underlying neurochemical factors of posttraumatic stress disorder (PTSD) are largely unknown. α7 nicotinic acetylcholine receptors (nAChRs) exert dual roles as modulators of neuronal plasticity and neuroimmune mediators, with both mechanisms relevant to PTSD. This study aimed to characterize relationships of brain α7 nAChRs, measured with positron emission tomography (PET) brain imaging, with peripheral cytokine levels in people with PTSD and controls.MethodsPET scans with the α7 nAChR specific radioligand [18F] ASEM were acquired in 11 individuals with PTSD (PCL-5 Scores= 60±11) and 9 age-matched controls. Imaging data were acquired for 120 min after a 323±81 MBq bolus injection. α7 nAChR availability was indexed by [18F] ASEM distribution volume (VT), estimated using multilinear analysis. Cytokine panels were run on peripheral blood samples from the PTSD group on …

RESULTSA total of 18.3%(95% confidence interval [CI]= 16.0%–20.8%) of the sample had accelerated GrimAge. Relative to veterans without accelerated GrimAge, those with accelerated GrimAge were less likely to be married/partnered and to have an annual household income> $60,000/year and more likely to be combat veterans, obese, and current smokers and to screen positive for current alcohol use disorder and PTSD; they also reported more cumulative traumas and medical conditions (Table 1).

Clinical heterogeneity presents important challenges to optimizing psychiatric diagnoses and treatments. Patients clustered within current diagnostic schema vary widely on many features of their illness, including their responses to treatments. As outlined by the American Psychiatric Association Diagnostic and Statistical Manual (DSM), psychiatric diagnoses have been refined since DSM was introduced in 1952. These diagnoses serve as the targets for current treatments and supported the emergence of psychiatric genomics. However, the Research Domain Criteria highlight DSM's shortcomings, including its limited ability to encompass dimensional features linking patients across diagnoses. This chapter considers elements of the dimensional and categorical features of psychiatric diagnoses, with a particular focus on schizophrenia. It highlights ways that computational neuroscience approaches have shed light on both dimensional and categorical features of the biology of schizophrenia. It also considers opportunities and challenges associated with attempts to reduce clinical heterogeneity through categorical and dimensional approaches to clustering patients. Finally, discussion will consider ways that one might work with both approaches in parallel or sequentially, as well as diagnostic schema that might integrate both perspectives.

Objective: Determine if sublingual dexmedetomidine, a selective α 2 adrenergic receptor agonist, reduces symptoms of acute agitation associated with schizophrenia or schizoaffective disorder.Methods: This phase 3, randomized, double-blind, placebo-controlled study was conducted in adults diagnosed with schizophrenia or schizoaffective disorder per the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria. The study was conducted at 15 US sites between January 23, 2020, and May 8, 2020. Participants were randomized to sublingual dexmedetomidine 180 μg, 120 μg, or matching placebo. The primary efficacy endpoint was mean change from baseline in the Positive and Negative Syndrome Scale-Excited Component (PEC) total score at 2 hours postdose.Results: Altogether, 380 participants (mean age 45.6 years, 63.4% identifying as male, 77.9% identifying as Black or African …

BackgroundEmraclidine is a novel, brain-penetrant, highly selective M4 receptor positive allosteric modulator in development for the treatment of schizophrenia. We aimed to evaluate the safety and tolerability of multiple ascending doses of emraclidine in patients with schizophrenia.MethodsWe conducted a two-part, randomised, phase 1b trial in the USA. Eligible participants were aged 18–50 years (part A) or 18–55 years (part B) with a primary diagnosis of schizophrenia per the Diagnostic and Statistical Manual of Mental Disorders 5th edition, as confirmed by the Mini International Neuropsychiatric Interview, and extrapyramidal symptom assessments indicating normal to mild symptoms at screening. Part A evaluated the safety and tolerability of emraclidine in five cohorts of participants with stable schizophrenia who received ascending oral doses of emraclidine 5–40 mg (40 mg was administered as 20 mg twice …