A New Rapid-Acting Antidepressant.

The discovery of the strikingly rapid and robust antidepressant effects of r/s-ketamine for the treatment of antidepressant-resistant symptoms of depression has led to new insights into the biology of antidepressants and the FDA approval of its s-isomer, Esketamine (Spravato), the first mechanistically new treatment for depression in over 60 years. To view this Bench to Bedside, open or download the PDF.

Psychiatric disorders: diagnosis to therapy.

Recent findings in a range of scientific disciplines are challenging the conventional wisdom regarding the etiology, classification, and treatment of psychiatric disorders. This Review focuses on the current state of the psychiatric diagnostic nosology and recent progress in three areas: genomics, neuroimaging, and therapeutics development. The accelerating pace of novel and unexpected findings is transforming the understanding of mental illness and represents a hopeful sign that the approaches and models that have sustained the field for the past 40 years are yielding to a flood of new data and presaging the emergence of a new and more powerful scientific paradigm.

Microglia-mediated neuroimmune suppression in PTSD is associated with anhedonia.

Dynamic brain immune function in individuals with posttraumatic stress disorder is rarely studied, despite evidence of peripheral immune dysfunction. Positron emission tomography brain imaging using the radiotracer [11C]PBR28 was used to measure the 18-kDa translocator protein (TSPO), a microglial marker, at baseline and 3 h after administration of lipopolysaccharide (LPS), a potent immune activator. Data were acquired in 15 individuals with PTSD and 15 age-matched controls. The PTSD group exhibited a significantly lower magnitude LPS-induced increase in TSPO availability in an a priori prefrontal-limbic circuit compared to controls. Greater anhedonic symptoms in the PTSD group were associated with a more suppressed neuroimmune response. In addition, while a reduced granulocyte-macrophage colony-stimulating factor response to LPS was observed in the PTSD group, other measured cytokine responses and self-reported sickness symptoms did not differ between groups; these findings highlight group differences in central-peripheral immune system relationships. The results of this study provide evidence of a suppressed microglia-mediated neuroimmune response to a direct immune system insult in individuals with PTSD that is associated with the severity of symptoms. They also provide further support to an emerging literature challenging traditional concepts of microglial and immune function in psychiatric disease.

Ketamine and the neurobiology of depression: Toward next-generation rapid-acting antidepressant treatments.

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.

Medial prefrontal cortex neurotransmitter abnormalities in posttraumatic stress disorder with and without comorbidity to major depression.

Posttraumatic stress disorder (PTSD) is a chronic psychiatric condition that follows exposure to a traumatic stressor. Though previous in vivo proton (1H) MRS) research conducted at 4 T or lower has identified alterations in glutamate metabolism associated with PTSD predisposition and/or progression, no prior investigations have been conducted at higher field strength. In addition, earlier studies have not extensively addressed the impact of psychiatric comorbidities such as major depressive disorder (MDD) on PTSD-associated 1H-MRS-visible brain metabolite abnormalities. Here we employ 7 T 1H MRS to examine concentrations of glutamate, glutamine, GABA, and glutathione in the medial prefrontal cortex (mPFC) of PTSD patients with MDD (PTSD+MDD+; N = 6) or without MDD (PTSD+MDD-; N = 5), as well as trauma-unmatched controls without PTSD but with MDD (PTSD-MDD+; N = 9) or without MDD (PTSD-MDD-; N = 18). Participants with PTSD demonstrated decreased ratios of GABA to glutamine relative to healthy PTSD-MDD- controls but no single-metabolite abnormalities. When comorbid MDD was considered, however, MDD but not PTSD diagnosis was significantly associated with increased mPFC glutamine concentration and decreased glutamate:glutamine ratio. In addition, all participants with PTSD and/or MDD collectively demonstrated decreased glutathione relative to healthy PTSD-MDD- controls. Despite limited findings in single metabolites, patterns of abnormality in prefrontal metabolite concentrations among individuals with PTSD and/or MDD enabled supervised classification to separate them from healthy controls with 80+% sensitivity and specificity, with glutathione, glutamine, and myoinositol consistently among the most informative metabolites for this classification. Our findings indicate that MDD can be an important factor in mPFC glutamate metabolism abnormalities observed using 1H MRS in cohorts with PTSD.

Cerebellar Contributions to Traumatic Autobiographical Memory in People with Post-Traumatic Stress Disorder.

Post-traumatic stress disorder (PTSD) is a debilitating mental health condition characterized by recurrent re-experiencing of traumatic events. Despite increasing evidence suggesting that the cerebellum is involved in PTSD pathophysiology, it remains unclear whether this involvement is related to symptoms directly resulting from previous trauma exposure, such as involuntary re-experiencing of the traumatic events, or reflects a broader cerebellar engagement in negative affective states. In this study, we investigated the specific role of the cerebellum in PTSD by employing a script reactivation paradigm with personalized traumatic and sad autobiographical memories in 28 individuals diagnosed with chronic PTSD. Functional magnetic resonance imaging (fMRI) data were collected while participants listened to their own autobiographical narratives recounted by a third person. Activation in the right cerebellar lobule VI was uniquely associated with traumatic autobiographical recall and was parametrically modulated by the severity of re-experiencing symptoms. In contrast, cerebellar Crus II showed increased activation during both traumatic and sad autobiographical recall, suggesting a broader involvement in processing negative emotions. Our findings highlight the unique contribution of the right cerebellar lobule VI in the processing of traumatic autobiographical memories, potentially through its engagement in low-level representation of sensory and emotional aspects of traumatic events.

Recent Advances in the Treatment of Treatment-Resistant Depression: A Narrative Review of Literature Published from 2018 to 2023.

PURPOSE OF REVIEW: We review recent advances in the treatment of treatment-resistant depression (TRD), a disorder with very limited treatment options until recently. We examine advances in psychotherapeutic, psychopharmacologic, and interventional psychiatry approaches to treatment of TRD. We also highlight various definitions of TRD in recent scientific literature. RECENT FINDINGS: Recent evidence suggests some forms of psychotherapy can be effective as adjunctive treatments for TRD, but not as monotherapies alone. Little recent evidence supports the use of adjunctive non-antidepressant pharmacotherapies such as buprenorphine and antipsychotics for the treatment of TRD; side effects and increased medication discontinuation rates may outweigh the benefits of these adjunctive pharmacotherapies. Finally, a wealth of recent evidence supports the use of interventional approaches such as electroconvulsive therapy, ketamine/esketamine, and transcranial magnetic stimulation for TRD. 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.

Dexmedetomidine HCL (BXCL501) as a potential treatment for alcohol use disorder and comorbid PTSD: A phase 1b, placebo-controlled crossover laboratory study.

BACKGROUND AND OBJECTIVES: Noradrenergic dysregulation is important in the pathophysiology of posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD); pharmacotherapies targeting adrenergic function have potential as treatment for comorbidity. Dexmedetomidine (sublingual film formulation-BXCL501; IGALMI) is a highly potent, selective ⍺2-adrenergic receptor agonist and may be superior to other pharmacotherapeutic approaches. A within subjects, phase 1b safety laboratory study was conducted to evaluate adverse effects of BXCL501 when combined with alcohol; BXCL501's potential efficacy was also explored. METHODS: Heavy drinker participants with a diagnosis of or who were at risk for PTSD participated in three separate test days which included pretreatment with BXCL501 (40 µg, 80 µg or placebo) administered in a randomized, double-blind fashion, followed by three testing conditions: alcohol cue reactivity, trauma-induced reactivity, and IV ethanol administration. Safety outcomes included blood pressure (BP) and sedation. Exploratory outcomes included alcohol craving, trauma-induced anxiety and craving and subjective effects of alcohol. RESULTS: Ten of twelve randomized participants competed the entire study. BXCL501 (80 µg) was associated with expected mild changes in BP and sedation; administration with alcohol did not affect those parameters. There were no clinically significant adverse effects. BXCL501 attenuated trauma-induced anxiety and attenuated subjective effects of alcohol. DISCUSSIONS AND CONCLUSIONS: BXCL501 is safe for use in humans who may drink alcohol while undergoing treatment. BXCL501 may be explored as a potential treatment for PTSD and AUD. SCIENTIFIC SIGNIFICANCE: This is the first study to provide scientific support for BXCL501's potential to treat PTSD and comorbid AUD.

Effects of Altered Excitation-Inhibition Balance on Decision Making in a Cortical Circuit Model.

The synaptic balance between excitation and inhibition (E/I balance) is a fundamental principle of cortical circuits, and disruptions in E/I balance are commonly linked to cognitive deficits such as impaired decision-making. Explanatory gaps remain in a mechanistic understanding of how E/I balance contributes to cognitive computations, and how E/I disruptions at the synaptic level can propagate to induce behavioral deficits. Here, we studied how E/I perturbations may impair perceptual decision-making in a biophysically-based association cortical circuit model. We found that both elevating and lowering E/I ratio, via NMDA receptor (NMDAR) hypofunction at inhibitory interneurons and excitatory pyramidal neurons, respectively, can similarly impair psychometric performance, following an inverted-U dependence. Nonetheless, these E/I perturbations differentially alter the process of evidence accumulation across time. Under elevated E/I ratio, decision-making is impulsive, overweighting early evidence and underweighting late evidence. Under lowered E/I ratio, decision-making is indecisive, with both evidence integration and winner-take-all competition weakened. The distinct time courses of evidence accumulation at the circuit level can be measured at the behavioral level, using multiple psychophysical task paradigms which provide dissociable predictions. These results are well captured by a generalized drift-diffusion model (DDM) with self-coupling, implementing leaky or unstable integration, which thereby links biophysical circuit modeling to algorithmic process modeling and facilitates model fitting to behavioral choice data. In general, our findings characterize critical roles of cortical E/I balance in cognitive function, bridging from biophysical to behavioral levels of analysis.SIGNIFICANCE STATEMENT Cognitive deficits in multiple neuropsychiatric disorders, including schizophrenia, have been associated with alterations in the balance of synaptic excitation and inhibition (E/I) in cerebral cortical circuits. However, the circuit mechanisms by which E/I imbalance leads to cognitive deficits in decision-making have remained unclear. We used a computational model of decision-making in cortical circuits to study the neural and behavioral effects of E/I imbalance. We found that elevating and lowering E/I ratio produce distinct modes of dysfunction in decision-making processes, which can be dissociated in behavior through psychophysical task paradigms. The biophysical circuit model can be mapped onto a psychological model of decision-making which can facilitate experimental tests of model predictions.

Emraclidine, a novel positive allosteric modulator of cholinergic M4 receptors, for the treatment of schizophrenia: a two-part, randomised, double-blind, placebo-controlled, phase 1b trial.

BACKGROUND: Emraclidine 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. METHODS: We 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 daily) or placebo at a single US site. Part B was a double-blind, randomised, placebo-controlled study that enrolled adults with acute schizophrenia across five US sites; participants were randomly assigned (1:1:1) to receive emraclidine 30 mg once daily, emraclidine 20 mg twice daily, or placebo for 6 weeks (doses established in part A). The primary endpoint was safety and tolerability, assessed in the safety population (participants who received at least one dose of emraclidine or placebo). This trial is now complete and is registered with ClinicalTrials.gov, NCT04136873. FINDINGS: Between Sept 23, 2019, and Sept 17, 2020, 118 patients were assessed for eligibility and 49 were randomly assigned across five cohorts in part A. 44 participants completed the study, with 36 participants receiving emraclidine and eight receiving placebo. The two highest doses tested were selected for part B. Between Oct 12, 2020, and May 7, 2021, 148 patients were assessed for eligibility and 81 were randomly assigned to emraclidine 30 mg once daily (n=27), emraclidine 20 mg twice daily (n=27), or placebo (n=27) in part B. Incidence of adverse events (14 [52%] of 27 participants in the emraclidine 30 mg once daily group, 15 [56%] of 27 in the emraclidine 20 mg twice daily group, and 14 [52%] of 27 in the placebo group), clinical assessments, and weight changes were similar across groups. The most common adverse event was headache (15 [28%] of 54 participants in the emraclidine groups, seven [26%] of 27 in the placebo group). Modest, transient increases in blood pressure and heart rate in emraclidine groups observed at treatment initiation diminished over time and were not considered clinically meaningful by week 6. INTERPRETATION: These data support further investigation of emraclidine as a once-daily treatment for schizophrenia without need for titration and with a potentially favourable side-effect profile. FUNDING: Cerevel Therapeutics.

A Non-D2-Receptor-Binding Drug for the Treatment of Schizophrenia.

BACKGROUND: An oral compound, SEP-363856, that does not act on dopamine D2 receptors but has agonist activity at trace amine-associated receptor 1 (TAAR1) and 5-hydroxytryptamine type 1A (5-HT1A) receptors, may represent a new class of psychotropic agent for the treatment of psychosis in schizophrenia. METHODS: We performed a randomized, controlled trial to evaluate the efficacy and safety of SEP-363856 in adults with an acute exacerbation of schizophrenia. The patients were randomly assigned in a 1:1 ratio to receive once-daily treatment with SEP-363856 (50 mg or 75 mg) or placebo for 4 weeks. The primary end point was the change from baseline in the total score on the Positive and Negative Symptom Scale (PANSS; range, 30 to 210; higher scores indicate more severe psychotic symptoms) at week 4. There were eight secondary end points, including the changes from baseline in the scores on the Clinical Global Impressions Severity (CGI-S) scale and the Brief Negative Symptom Scale (BNSS). RESULTS: A total of 120 patients were assigned to the SEP-363856 group and 125 to the placebo group. The mean total score on the PANSS at baseline was 101.4 in the SEP-363856 group and 99.7 in the placebo group, and the mean change at week 4 was -17.2 points and -9.7 points, respectively (least-squares mean difference, -7.5 points; 95% confidence interval, -11.9 to -3.0; P = 0.001). The reductions in the CGI-S and BNSS scores at week 4 were generally in the same direction as those for the primary outcome, but the results were not adjusted for multiple comparisons. Adverse events with SEP-363856 included somnolence and gastrointestinal symptoms; one sudden cardiac death occurred in the SEP-363856 group. The incidence of extrapyramidal symptoms and changes in the levels of lipids, glycated hemoglobin, and prolactin were similar in the trial groups. CONCLUSIONS: In this 4-week trial involving patients with an acute exacerbation of schizophrenia, SEP-363856, a non-D2-receptor-binding antipsychotic drug, resulted in a greater reduction from baseline in the PANSS total score than placebo. Longer and larger trials are necessary to confirm the effects and side effects of SEP-363856, as well as its efficacy relative to existing drug treatments for patients with schizophrenia. (Funded by Sunovion Pharmaceuticals; ClinicalTrials.gov number, NCT02969382.).

A computational model for learning from repeated traumatic experiences under uncertainty.

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 with epidemiological data that show that PTSD incidence increases with the number of traumatic events, as well as the disproportionate impact of early life trauma. Because the theory proposes that PTSD relates to the average of recent threat prediction errors rather than the strength of a specific association, it makes novel predictions for the treatment of PTSD.

Mental health impact of the COVID-19 pandemic in U.S. military veterans: a population-based, prospective cohort study.

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 posttraumatic stress disorder positive screens remained stable. Using a continuous measure of psychiatric distress, an estimated 13.2% of veterans reported a clinically meaningful pre-to-peri-pandemic increase in distress (mean = 1.1 standard deviation). Veterans with a larger pre-pandemic social network size and secure attachment style were less likely to experience increased distress, whereas veterans reporting more pre-pandemic loneliness were more likely to experience increased distress. Concerns about pandemic-related social losses, mental health COVID-19 effects, and housing stability during the pandemic were associated with increased distress, over-and-above pre-pandemic factors. CONCLUSIONS: Although most U.S. veterans showed resilience to mental health problems nearly 1 year into the pandemic, the prevalence of GAD positive screens increased, particularly among middle-aged veterans, and one of seven veterans experienced increased distress. Clinical implications of these findings are discussed.

Positive personality traits moderate persistent high alcohol consumption, determined by polygenic risk in U.S. military veterans: results from a 10-year, population-based, observational cohort study.

BACKGROUND: Understanding 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). METHODS: Data 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). RESULTS: Among the total sample, 328 (weighted 24.8%) had persistent HAC, 131 (weighted 9.9%) had new-onset HAC, 44 (weighted 3.3%) had remitted HAC, and 820 (weighted 62.0%) had no/low AC over the 10-year study period. AUDIT-C PRS was positively associated with persistent HAC relative to no/low AC [relative risk ratio (RRR) = 1.43, 95% confidence interval (CI) = 1.23-1.67] and remitted HAC (RRR = 1.63, 95% CI = 1.07-2.50). Among veterans with higher AUDIT-C PRS, greater baseline levels of agreeableness and greater dispositional gratitude were inversely associated with persistent HAC. CONCLUSIONS: AUDIT-C PRS was prospectively associated with persistent HAC over a 10-year period, and agreeableness and dispositional gratitude moderated this association. Clinical interventions designed to target these modifiable psychological traits may help mitigate risk of persistent HAC in veterans with greater polygenic liability for persistent HAC.

Genetic liability to suicidal thoughts and behaviors and risk of suicide attempt in US military veterans: moderating effects of cumulative trauma burden.

BACKGROUND: Little is known about environmental factors that may influence associations between genetic liability to suicidality and suicidal behavior. METHODS: This 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. RESULTS: Eighty-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 highest probability of lifetime suicide attempt (16.6%), whereas the probability of attempts was substantially lower among those with high suicidality PRS and low trauma exposure (1.4%). The PRS-by-trauma interaction effect was enriched for genes implicated in cellular and developmental processes, and nervous system development, with variants annotated to the DAB2 and SPNS2 genes, which are implicated in inflammatory processes. Drug repurposing analyses revealed upregulation of suicide gene-sets in the context of medrysone, a drug targeting chronic inflammation, and clofibrate, a triacylglyceride level lowering agent. CONCLUSION: Results suggest that genetic liability to suicidality is associated with increased risk of suicide attempt among veterans, particularly in the presence of high levels of cumulative trauma exposure. Additional research is warranted to investigate whether incorporation of genomic information may improve suicide prediction models.

Psychosocial moderators of polygenic risk for suicidal ideation: Results from a 7-year population-based, prospective cohort study of U.S. veterans.

Polygenic risk scores (PRS) may help inform the etiology of suicidal thoughts and behaviors. In this study, we evaluated whether a suicidality PRS derived from a large genome-wide association study (GWAS) of suicidality from the UK Biobank (N = 122,935) predicted suicidal ideation (SI) in a 7-year population-based, prospective cohort of European-American US veterans (N = 1326). Results revealed that 8.8% (n = 115) of veterans developed new-onset SI, 4.0% (n = 52) had chronic SI, 3.4% (n = 31) had remitted SI, and 83.8% (n = 1128) denied SI over the study period. Suicidality PRSstandardized was positively associated with chronic SI (relative risk ratio [RRR] = 4.54, 95% confidence interval [CI] = 1.01-20.48) and new-onset SI (RRR = 2.97, 95%CI = 1.22-7.23), and negatively associated with remitted SI (RRR = 0.12, 95% CI = 0.02-0.60). Among veterans with higher suicidality PRS, those with higher baseline dispositional optimism had a lower likelihood of chronic SI (RRR = 0.67, 95% CI = 0.49-0.91) and higher likelihood of remitted SI (RRR = 1.98, 95% CI = 1.18-3.31). Among veterans with higher suicidality PRS, those with higher baseline levels of social support were less likely to develop new-onset SI (RRR = 0.95, 95% CI = 0.92-0.99). These interaction effects were enriched for genes implicated in neuron recognition and development, while the PRS main effect was enriched for genes involved in mannosylation. Collectively, results of this study suggest that suicidality PRS is linked prospectively to symptomatic courses of SI, and that dispositional optimism and social support moderate these associations. Interventions targeting these modifiable psychosocial factors may help mitigate risk of SI in veterans with high polygenic risk for suicidality.

Validation of ketamine as a pharmacological model of thalamic dysconnectivity across the illness course of schizophrenia.

N-methyl-D-aspartate receptor (NMDAR) hypofunction is a leading pathophysiological model of schizophrenia. Resting-state functional magnetic resonance imaging (rsfMRI) studies demonstrate a thalamic dysconnectivity pattern in schizophrenia involving excessive connectivity with sensory regions and deficient connectivity with frontal, cerebellar, and thalamic regions. The NMDAR antagonist ketamine, when administered at sub-anesthetic doses to healthy volunteers, induces transient schizophrenia-like symptoms and alters rsfMRI thalamic connectivity. However, the extent to which ketamine-induced thalamic dysconnectivity resembles schizophrenia thalamic dysconnectivity has not been directly tested. The current double-blind, placebo-controlled study derived an NMDAR hypofunction model of thalamic dysconnectivity from healthy volunteers undergoing ketamine infusions during rsfMRI. To assess whether ketamine-induced thalamic dysconnectivity was mediated by excess glutamate release, we tested whether pre-treatment with lamotrigine, a glutamate release inhibitor, attenuated ketamine's effects. Ketamine produced robust thalamo-cortical hyper-connectivity with sensory and motor regions that was not reduced by lamotrigine pre-treatment. To test whether the ketamine thalamic dysconnectivity pattern resembled the schizophrenia pattern, a whole-brain template representing ketamine's thalamic dysconnectivity effect was correlated with individual participant rsfMRI thalamic dysconnectivity maps, generating "ketamine similarity coefficients" for people with chronic (SZ) and early illness (ESZ) schizophrenia, individuals at clinical high-risk for psychosis (CHR-P), and healthy controls (HC). Similarity coefficients were higher in SZ and ESZ than in HC, with CHR-P showing an intermediate trend. Higher ketamine similarity coefficients correlated with greater hallucination severity in SZ. Thus, NMDAR hypofunction, modeled with ketamine, reproduces the thalamic hyper-connectivity observed in schizophrenia across its illness course, including the CHR-P period preceding psychosis onset, and may contribute to hallucination severity.

Imaging the effect of ketamine on synaptic density (SV2A) in the living brain.

The discovery of ketamine as a rapid and robust antidepressant marks the beginning of a new era in the treatment of psychiatric disorders. Ketamine is thought to produce rapid and sustained antidepressant effects through restoration of lost synaptic connections. We investigated this hypothesis in humans for the first time using positron emission tomography (PET) and [11C]UCB-J-a radioligand that binds to the synaptic vesicle protein 2A (SV2A) and provides an index of axon terminal density. Overall, we did not find evidence of a measurable effect on SV2A density 24 h after a single administration of ketamine in non-human primates, healthy controls (HCs), or individuals with major depressive disorder (MDD) and/or posttraumatic stress disorder (PTSD), despite a robust reduction in symptoms. A post-hoc, exploratory analysis suggests that patients with lower SV2A density at baseline may exhibit increased SV2A density 24 h after ketamine. This increase in SV2A was associated with a reduction in depression severity, as well as an increase in dissociative symptoms. These initial findings suggest that a restoration of synaptic connections in patients with lower SV2A at baseline may underlie ketamine's therapeutic effects, however, this needs replication in a larger sample. Further work is needed to build on these initial findings and further establish the nuanced pre- and post-synaptic mechanisms underpinning ketamine's therapeutic effects.

Genetically regulated multi-omics study for symptom clusters of posttraumatic stress disorder highlights pleiotropy with hematologic and cardio-metabolic traits.

Posttraumatic stress disorder (PTSD) is a psychiatric disorder that may arise in response to severe traumatic event and is diagnosed based on three main symptom clusters (reexperiencing, avoidance, and hyperarousal) per the Diagnostic Manual of Mental Disorders (version DSM-IV-TR). In this study, we characterized the biological heterogeneity of PTSD symptom clusters by performing a multi-omics investigation integrating genetically regulated gene, splicing, and protein expression in dorsolateral prefrontal cortex tissue within a sample of US veterans enrolled in the Million Veteran Program (N total = 186,689). We identified 30 genes in 19 regions across the three PTSD symptom clusters. We found nine genes to have cell-type specific expression, and over-representation of miRNA-families - miR-148, 30, and 8. Gene-drug target prioritization approach highlighted cyclooxygenase and acetylcholine compounds. Next, we tested molecular-profile based phenome-wide impact of identified genes with respect to 1678 phenotypes derived from the Electronic Health Records of the Vanderbilt University biorepository (N = 70,439). Lastly, we tested for local genetic correlation across PTSD symptom clusters which highlighted metabolic (e.g., obesity, diabetes, vascular health) and laboratory traits (e.g., neutrophil, eosinophil, tau protein, creatinine kinase). Overall, this study finds comprehensive genomic evidence including clinical and regulatory profiles between PTSD, hematologic and cardiometabolic traits, that support comorbidities observed in epidemiologic studies of PTSD.

Psychosocial Factors Associated With Accelerated GrimAge in Male U.S. Military Veterans.

OBJECTIVE: Veterans 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. DESIGN: Cross-sectional study. SETTING: U.S. veteran population. PARTICIPANTS: Participants 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). MEASUREMENTS: We examined the prevalence of accelerated GrimAge and its association with a broad range of health, lifestyle, and psychosocial variables. RESULTS: A total 18.3% of veterans had accelerated GrimAge (≥5 years greater GrimAge than chronological age; mean = 8.4 years acceleration, SD = 2.2). Fewer days of weekly physical exercise (relative variance explained [RVE] = 27%), history of lifetime substance use disorder (RVE = 21%), greater number of lifetime traumas (RVE = 19%), lower gratitude (RVE = 13%), reduced sleep quality (RVE = 7%), lower openness to experience (RVE = 7%), and unmarried/partnered status (RVE = 6%) were independently associated with increased odds of accelerated GrimAge. Increasing numbers of these risk factors were associated with greater odds of accelerated GrimAge, with greatest likelihood of acceleration for veterans with ≥3 risk factors (weighted 21.5%). CONCLUSIONS: These results suggest that nearly 1-of-5 EA male U.S. veterans have accelerated GrimAge, and highlight a broad range of health, lifestyle, and psychosocial variables associated with accelerated GrimAge. Given that many of these factors are modifiable, these findings provide promising leads for risk stratification models of accelerated biological aging and precision medicine-based targets for interventions to mitigate risk for premature mortality in this population.