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Background: Racemic ketamine is a mixture of (R)-ketamine (arketamine) and (S)-ketamine (esketamine), with the latter regarded as the main isomer for antidepressant effects. However, preclinical data and one open-label human trial suggest arketamine might exert a more potent and longer-lasting antidepressant effect with fewer side effects. We aimed to explore the feasibility of a randomized controlled trial of arketamine for treatment-resistant depression (TRD) and to assess its efficacy and safety compared to placebo., Methods: This is a, randomized, double-blind, crossover, pilot trial (n = 10). All participants received saline and arketamine (0.5 mg/kg) with a one-week interval. Treatment effects were analyzed with a linear mixed effects (LME) model., Results: Our analysis suggested the presence of a carryover effect, so the main efficacy analysis was limited to the first week, which demonstrated a main effect of time (p = 0.038) but not for treatment (p = 0.40) or their interaction (p = 0.95). This indicates that depression improved over time, but without significant difference between arketamine and placebo. Analyzing the two weeks together, findings were the same. Dissociation and other adverse events were minimal., Limitations: This was a pilot study with a small sample and underpowered., Conclusions: Arketamine was not superior to placebo for TRD but demonstrated to be extremely safe. Our findings reinforce the importance of continuing studies with this drug, with better powered clinical trials, perhaps considering a parallel design with higher or flexible doses and repeated administrations., Competing Interests: Conflict of interest Dr. Lacerda reports grants and personal fees from Janssen Pharmaceutical, Daiichi Sankyo, Cristalia Produtos Químicos e Farmacêuticos, Libbs, Pfizer, Myralis Farma, Aché Laboratórios, Hypera Pharma, Sanofi-Aventis, Eli Lilly, H. Lundbeck A/S, Servier Laboratories, Hoffman-La Roche, and Forum Pharmaceuticals. Dr. Sanacora, in the last 12 months, has provided consulting services to Ancora, Aptinyx, Axsome Therapeutics, Biohaven Pharmaceuticals, Bristol-Myers Squibb, Clexio Biosciences, Denovo Biopharma, EMA Wellness, Engrail, Gilgamesh, Freedom Biosciences, Intra-Cellular Therapies, Janssen, miCure Therapeutics, Merck, Navitor Pharmaceuticals, Neurocrine, Novartis, Noven Pharmaceuticals, Perception Neuroscience, Praxis, Sage Pharmaceuticals, Seelos Pharmaceuticals, and XW Labs. He has received funds for contracted research from Janssen Pharmaceuticals, Merck, and Usona Institute. He holds equity in Biohaven Pharmaceuticals and has received royalties paid from patent licenses with Biohaven Pharmaceuticals. His employer, Yale University, has a financial relationship with Janssen Pharmaceuticals and may receive financial benefits from this relationship. Other authors have no conflicts of interest to report., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Older, compared with younger, patients with treatment-resistant depression (TRD) typically have lower response and remission rates with poorer tolerability to antidepressant treatment. This post-hoc analysis compared outcomes following treatment with esketamine nasal spray (ESK) between younger (18-64 years) and older (≥65 years) patients with TRD., Methods: SUSTAIN-2, an up to 1-year open-label safety and efficacy study of ESK plus an oral antidepressant, included patients with TRD either directly enrolled (≥18-year) or transferred from a phase 3 double-blind study, TRANSFORM-3 (≥65-year). Patients were treated in two phases: 4-week induction and 48-week optimization/maintenance., Results: Younger (n = 624) and older (n = 178) patients had similar baseline characteristics except for hypertension history (21.5% versus 48.3%, respectively). Patients (younger versus older) had similar mean baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total scores and mean (SD) reductions in MADRS total scores for induction (-18.0 [7.19] versus -18.1 [9.37]; p = 0.492 [t = 0.69, df = 701]) and optimization/maintenance (week 12) (-19.9 [7.03] versus -22.2 [9.50]; p = 0.265 [t = -1.12, df = 3470]) phases. Treatment-emergent adverse events (TEAEs) reported in younger versus older patients, respectively, were: induction, 86.1% versus 74.8%; optimization/maintenance, 86.8% versus 81.0%; serious TEAEs: induction, 2.2% versus 1.9%; optimization/maintenance, 6.7% versus 4.8%; TEAEs of increased blood pressure: induction, 6.9% versus 6.5%; optimization/maintenance, 7.1% versus 9.5%; and falls: induction, 0.3% versus 0.6%; optimization/maintenance, 0.2% versus 0.8%. Cognitive tests did not show clinically meaningful differences between the age groups., Conclusions: Although limited by the open-label design of SUSTAIN-2, this post-hoc analysis showed generally comparable improvement in depression between ESK-treated younger and older adult patients with TRD, with consistent safety outcomes., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Absence seizures (AS), presenting as short losses of consciousness with staring spells, are a common manifestation of childhood epilepsy that is associated with behavioral, emotional, and social impairments. It has also been suggested that patients with AS are more likely to suffer from mood disorders such as depression and anxiety. This systematic review and meta-analysis synthesizes human and animal models that investigated mood disorders and AS. Of the 1019 scientific publications identified, 35 articles met the inclusion criteria for this review. We found that patients with AS had greater odds of developing depression and anxiety when compared to controls (odds ratio = 4.93, 95% confidence interval = 2.91-8.35, p < .01). The included studies further suggest a strong correlation between AS and depression and anxiety in the form of a bidirectional relationship. The current literature emphasizes that these conditions likely share underlying mechanisms, such as genetic predisposition, neurophysiology, and anatomical pathways. Further research will clarify this relationship and ensure more effective treatment for AS and mood disorders., (© 2021 International League Against Epilepsy.)

Synaptic loss and deficits in functional connectivity are hypothesized to contribute to symptoms associated with major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). The synaptic vesicle glycoprotein 2A (SV2A) can be used to index the number of nerve terminals, an indirect estimate of synaptic density. Here, we used positron emission tomography (PET) with the SV2A radioligand [ 11 C]UCB-J to examine synaptic density in n = 26 unmedicated individuals with MDD, PTSD, or comorbid MDD/PTSD. The severity of depressive symptoms was inversely correlated with SV2A density, and individuals with high levels of depression showing lower SV2A density compared to healthy controls (n = 21). SV2A density was also associated with aberrant network function, as measured by magnetic resonance imaging (MRI) functional connectivity. This is the first in vivo evidence linking lower synaptic density to network alterations and symptoms of depression. Our findings provide further incentive to evaluate interventions that restore synaptic connections to treat depression.

The discovery of the antidepressant effects of ketamine has opened a breakthrough opportunity to develop a truly novel class of safe, effective, and rapid-acting antidepressants (RAADs). In addition, the rapid and robust biological and behavioral effects of ketamine offered a unique opportunity to utilize the drug as a tool to thoroughly investigate the neurobiology of stress and depression in animals, and to develop sensitive and reproducible biomarkers in humans. The ketamine literature over the past two decades has considerably enriched our understanding of the mechanisms underlying chronic stress, depression, and RAADs. However, considering the complexity of the pharmacokinetics and in vivo pharmacodynamics of ketamine, several questions remain unanswered and, at times, even answered questions continue to be considered controversial or at least not fully understood. The current perspective paper summarizes our understanding of the neurobiology of depression, and the mechanisms of action of ketamine and other RAADs. The review focuses on the role of glutamate neurotransmission - reviewing the history of the "glutamate inhibition" and "glutamate activation" hypotheses, proposing a synaptic connectivity model of chronic stress pathology, and describing the mechanism of action of ketamine. It will also summarize the clinical efficacy findings of putative RAADs, present relevant human biomarker findings, and discuss current challenges and future directions., (Published by Elsevier Inc.)

Objective: Suicide is a public health crisis with limited treatment options. The authors conducted a systematic review and individual participant data meta-analysis examining the effects of a single dose of ketamine on suicidal ideation., Method: Individual participant data were obtained from 10 of 11 identified comparison intervention studies that used either saline or midazolam as a control treatment. The analysis included only participants who had suicidal ideation at baseline (N=167). A one-stage, individual participant data, meta-analytic procedure was employed using a mixed-effects, multilevel, general linear model. The primary outcome measures were the suicide items from clinician-administered (the Montgomery-Åsberg Depression Rating Scale [MADRS] or the Hamilton Depression Rating Scale [HAM-D]) and self-report scales (the Quick Inventory of Depressive Symptomatology-Self Report [QIDS-SR] or the Beck Depression Inventory [BDI]), obtained for up to 1 week after ketamine administration., Results: Ketamine rapidly (within 1 day) reduced suicidal ideation significantly on both the clinician-administered and self-report outcome measures. Effect sizes were moderate to large (Cohen's d=0.48-0.85) at all time points after dosing. A sensitivity analysis demonstrated that compared with control treatments, ketamine had significant benefits on the individual suicide items of the MADRS, the HAM-D, and the QIDS-SR but not the BDI. Ketamine's effect on suicidal ideation remained significant after adjusting for concurrent changes in severity of depressive symptoms., Conclusions: Ketamine rapidly reduced suicidal thoughts, within 1 day and for up to 1 week in depressed patients with suicidal ideation. Ketamine's effects on suicidal ideation were partially independent of its effects on mood, although subsequent trials in transdiagnostic samples are required to confirm that ketamine exerts a specific effect on suicidal ideation. Additional research on ketamine's long-term safety and its efficacy in reducing suicide risk is needed before clinical implementation.

Traditional antidepressants require many weeks to reveal their therapeutic effects. However, the widely replicated observation that a single subanesthetic dose of the N-methyl-D-aspartate glutamate receptor antagonist ketamine produced meaningful clinical improvement within hours, suggested that rapid-acting antidepressants might be possible. The ketamine studies stimulated a new generation of basic antidepressant research that identified new neural signaling mechanisms in antidepressant response and provided a conceptual framework linking a group of novel antidepressant mechanisms. This article presents the path that led to the testing of ketamine, considers its promise as an antidepressant, and reviews novel treatment mechanisms that are emerging from this line of research., (Published by Elsevier Inc.)

Objectives: Studies now provide strong evidence that the N-methyl-D-aspartate receptor antagonist ketamine possesses rapidly acting antidepressant properties. This study aimed to determine if a low dose of ketamine could be used to expedite and augment the antidepressant effects of electroconvulsive therapy (ECT) treatments in patients experiencing a severe depressive episode., Materials and Methods: Subjects with major depressive disorder or bipolar disorder referred for ECT treatment of a major depressive episode were randomized to receive thiopental alone or thiopental plus ketamine (0.5 mg/kg) for anesthesia before each ECT session. The Hamilton Depression Rating Scale (HDRS) was administered at baseline and at 24 to 72 hours after the first and sixth ECT sessions., Results: Electroconvulsive therapy exerted a significant antidepressant effect in both groups (F2,24 = 14.35, P < 0.001). However, there was no significant group effect or group-by-time interaction on HDRS scores. In addition, post hoc analyses of the time effect on HDRS showed no significant HDRS reduction after the first ECT session for either group., Conclusions: The results of this pilot study suggest that ketamine, at a dose of 0.5 mg/kg, given just before ECT, did not enhance the antidepressant effect of ECT. Interestingly, the results further suggest that the coadministration of ketamine with a barbiturate anesthetic and ECT may attenuate the immediate antidepressant effects of the N-methyl-D-aspartate antagonist.

We describe a new term: glutamate-based depression (GBD). GBD is defined as a chronic depressive illness associated with environmental stress and diseases associated with altered glutamate neurotransmission. We hypothesize that glutamate-induced over-activation of extrasynaptic NMDA receptors in the subgenual cingulate area called Brodmann's 25 plays an important role in the etiology of depression and may be responsible for the high incidence of co-morbid depression associated in diseases with glutamate etiology. While depression is a syndrome with multiple possible etiologies, we propose that a disruption in glutamatergic neurotransmission may underline a substantial proportion of clinically observed depression. The high rates of depressive symptoms associated with various disorders in which altered glutamatergic functions have been identified, may suggest a common pathophysiological mechanism is underlying the diverse clinical presentations., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Rationale: The neuroprotective agent riluzole has antidepressant-like properties in humans, but its mechanisms of action are unclear. Despite the increasing utility of transgenic and knockout mice in addressing such issues, previous studies aimed at characterizing biochemical mechanisms have been conducted in rats., Objectives: We sought to optimize an oral riluzole administration protocol with antidepressant-like consequences in C57BL/6 mice, a common background strain in genetically modified mice., Methods: Riluzole (6-60 μg/ml) was dissolved in tap water and replaced regular drinking water for up to 3 weeks; sensitivity to tail suspension, forced swimming, and the locomotor response to extinction training in a model of "incentive disengagement" were tested. Peripheral and central effects of long-term 60-μg/ml treatment were also evaluated., Results: Riluzole had dose-dependent antidepressant-like effects in the forced swim test, and like chronic fluoxetine, exerted antidepressant-like actions in an adaptation of the "incentive disengagement" model at the highest concentration tested. This 60-μg/ml concentration also restored hippocampal brain-derived neuroptrophic factor (BDNF) expression after chronic corticosteroid exposure and increased glutamate glial transporter 1 (GLT-1, or EAAT2) expression without significantly affecting baseline locomotor activity, thymus and adrenal gland weights, or blood serum corticosterone. The lowest 6-μg/ml concentration increased locomotor activity, potentially consistent with an anxiolytic-like effect., Conclusions: Riluzole's therapeutic potential for treating mood disorders may involve GLT-1 and BDNF, and we suggest this protocol could be used to further characterize its precise long-term biochemical mechanisms of action in animal models of depression.

Accumulating evidence indicates that dysfunction in amino acid neurotransmission contributes to the pathophysiology of depression. Consequently, the modulation of amino acid neurotransmission represents a new strategy for antidepressant development. While glutamate receptor ligands are known to have antidepressant effects, mechanisms regulating glutamate cycling and metabolism may be viable drug targets as well. In particular, excitatory amino acid transporters (EAATs) that are embedded in glial processes constitute the primary means of clearing extrasynaptic glutamate. Therefore, the decreased glial number observed in preclinical stress models, and in postmortem tissue from depressed patients provides intriguing, yet indirect evidence for a role of disrupted glutamate homeostasis in the pathophysiology of depression. More direct evidence for this hypothesis comes from studies using magnetic resonance spectroscopy (MRS), a technique that non-invasively measures in vivo concentrations of glutamate and other amino acids under different experimental conditions. Furthermore, when combined with the infusion of (13)C-labeled metabolic precursors, MRS can measure flux through discrete metabolic pathways. This approach has recently shown that glial amino acid metabolism is reduced by chronic stress, an effect that provides a link between environmental stress and the decreased EAAT activity observed under conditions of increased oxidative stress in the brain. Furthermore, administration of riluzole, a drug that enhances glutamate uptake through EAATs, reversed this stress-induced change in glial metabolism. Because riluzole has antidepressant effects in both animal models and human subjects, it may represent the prototype for a novel class of antidepressants with the modulation of glial physiology as a primary mechanism of action.

Anhedonia remains a major clinical issue for which there is few effective interventions. Untreated or poorly controlled anhedonia has been linked to worse disease course and increased suicidal behavior across disorders. Taking a proof-of-mechanism approach under the auspices of the National Institute of Mental Health FAST-FAIL initiative, we were the first to show that, in a transdiagnostic sample screened for elevated self-reported anhedonia, 8 weeks of treatment with a kappa-opioid receptor (KOR) antagonist resulted in significantly higher reward-related activation in one of the core hubs of the brain reward system (the ventral striatum), better reward learning in the Probabilistic Reward Task (PRT), and lower anhedonic symptoms, relative to 8 weeks of placebo. Here, we performed secondary analyses of the PRT data to investigate the putative effects of KOR antagonism on anhedonic behavior with more precision by using trial-level model-based Bayesian computational modeling and probability analyses. We found that, relative to placebo, KOR antagonism resulted in significantly higher learning rate (i.e., ability to learn from reward feedback) and a more sustained preference toward the more frequently rewarded stimulus, but unaltered reward sensitivity (i.e., the hedonic response to reward feedback). Collectively, these findings provide novel evidence that in a transdiagnostic sample characterized by elevated anhedonia, KOR antagonism improved the ability to modulate behavior as a function of prior rewards. Together with confirmation of target engagement in the primary report (Krystal et al., Nat Med, 2020), the current findings suggest that further transdiagnostic investigation of KOR antagonism for anhedonia is warranted.

The National Institute of Mental Health (NIMH) 'fast-fail' approach seeks to improve too-often-misleading early-phase drug development methods by incorporating biomarker-based proof-of-mechanism (POM) testing in phase 2a. This first comprehensive application of the fast-fail approach evaluated the potential of κ-opioid receptor (KOR) antagonism for treating anhedonia with a POM study determining whether robust target engagement favorably impacts the brain circuitry hypothesized to mediate clinical effects. Here we report the results from a multicenter, 8-week, double-blind, placebo-controlled, randomized trial in patients with anhedonia and a mood or anxiety disorder (selective KOR antagonist (JNJ-67953964, 10 mg; n = 45) and placebo (n = 44)). JNJ-67953964 significantly increased functional magnetic resonance imaging (fMRI) ventral striatum activation during reward anticipation (primary outcome) as compared to placebo (baseline-adjusted mean: JNJ-67953964, 0.72 (s.d. = 0.67); placebo, 0.33 (s.d. = 0.68); F(1,86) = 5.58, P

Background: Trauma and chronic stress are believed to induce and exacerbate psychopathology by disrupting glutamate synaptic strength. However, in vivo in human methods to estimate synaptic strength are limited. In this study, we established a novel putative biomarker of glutamatergic synaptic strength, termed energy-per-cycle (EPC). Then, we used EPC to investigate the role of prefrontal neurotransmission in trauma-related psychopathology. Methods: Healthy controls (n = 18) and patients with posttraumatic stress (PTSD; n = 16) completed 13C-acetate magnetic resonance spectroscopy (MRS) scans to estimate prefrontal EPC, which is the ratio of neuronal energetic needs per glutamate neurotransmission cycle (VTCA/VCycle). Results: Patients with PTSD were found to have 28% reduction in prefrontal EPC (t = 3.0; df = 32, P =.005). There was no effect of sex on EPC, but age was negatively associated with prefrontal EPC across groups (r = –0.46, n = 34, P =.006). Controlling for age did not affect the study results. Conclusion: The feasibility and utility of estimating prefrontal EPC using 13C-acetate MRS were established. Patients with PTSD were found to have reduced prefrontal glutamatergic synaptic strength. These findings suggest that reduced glutamatergic synaptic strength may contribute to the pathophysiology of PTSD and could be targeted by new treatments. [ABSTRACT FROM AUTHOR]

Introduction: Ketamine has emerged as a rapid-acting antidepressant. While ongoing treatment can prevent relapse, concerns exist regarding long-term exposure.Objective: We conducted a randomized trial to examine the feasibility and efficacy of cognitive behavioral therapy (CBT) following intravenous ketamine in treatment-resistant depression (TRD).Methods: Subjects with TRD were recruited and treated with 6 intravenous infusions of ketamine over 3 weeks. Subjects who experienced a clinical response (≥50% improvement in depression severity) were then randomized to receiving CBT or treatment as usual (TAU) for an additional 14 weeks, using a sequential treatment model.Results: Of the 42 patients who signed consent, 28 patients achieved a response and were randomized to CBT or TAU. When measured using the Montgomery-Asberg Depression Rating Scale (primary outcome measure), the effect size at the end of the study was moderate (Cohen d = 0.65; 95% CI -0.55 to 1.82), though the group-by-time interaction effect was not significant. There was a significant group-by-time interaction as measured by the Quick Inventory of Depressive Symptomatology (F = 4.58; p = 0.033), favoring a greater sustained improvement in the CBT group. This corresponded to a moderate-to-large effect size of the Cohen d = 0.71 (95% CI -0.30 to 1.70) at the end of the study (14 weeks following the last ketamine infusion). In a subset of patients (N = 20) who underwent cognitive testing using the emotional N-back assessments before and after ketamine, ketamine responders showed improvement in the accuracy of emotional N-back (t[8] = 2.33; p < 0.05) whereas nonresponders did not (t[10] <1; p ns).Conclusions: This proof-of-concept study provides preliminary data indicating that CBT may sustain the antidepressant effects of ketamine in TRD. Further study and optimization of this treatment approach in well-powered clinical trials is recommended. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is a stress-related disorder associated with many cytoarchitectural and neurochemical changes. However, the majority of these changes cannot be reliably detected in the living brain. The examination of animal stress models and postmortem human brain tissue has significantly contributed to our understanding of the pathophysiology of MDD. Ronald Duman's work in humans and in rodent models was critical to the investigation of the contribution of synaptic deficits to MDD and chronic stress pathology, their role in the development and expression of depressive-like behavior, and reversal by novel drugs. Here, we review evidence from magnetic resonance imaging in humans and animals that suggests that corticolimbic alterations are associated with depression symptomatology. We also discuss evidence of cytoarchitectural alterations affecting neurons, astroglia, and synapses in MDD and highlight how similar changes are described in rodent chronic stress models and are linked to the emotion-related behavioral deficits. Finally, we report on the latest approaches developed to measure the synaptic and astroglial alterations in vivo, using positron emission tomography, and how it can inform on the contribution of MDD-associated cytoarchitectural alterations to the symptomatology and the treatment of stress-related disorders. [ABSTRACT FROM AUTHOR]

Ketamine has attracted widespread attention as a potential rapid-acting antidepressant. There is also considerable interest in its use for the rapid treatment of patients deemed at risk for suicide. Here, we review the available evidence (open-label and randomized controlled trials) that examine the effects of ketamine on suicidal ideation (SI). Overall, data suggest that ketamine has a rapid albeit transient effect in reducing SI, though some studies had mixed results at different time points or using different assessments. Weaknesses to the existing literature include the small sample sizes of the studies, the exclusion of patients with significant SI at baseline from many of the studies, and the potential functional unblinding when participants are randomized to saline as placebo. The evidence supporting the clinical use of ketamine for SI is very preliminary. Although ketamine appears to a promising therapeutic option in a context where there is a great unmet need (i.e., patients at imminent risk of suicide), further controlled trials are needed to allow for meaningful clinical recommendations. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is a common and debilitating psychiatric disorder. Traditional antidepressants are of limited efficacy and take weeks to months to yield full therapeutic effects. Thus, there is a clear need for effective rapid-acting antidepressant medications. The N-methyl-d-aspartate receptor (NMDA-R) antagonist, ketamine, has received a great deal of attention over the last 20 years due to the discovery that a single subanesthetic dose leads to a rapid antidepressant effect in individuals with treatment-resistant depression. Animal and human research suggest that ketamine's antidepressant effects are mediated by a glutamate surge that leads to a cascade of events that result in synaptogenesis and reversal of the negative effects of chronic stress and depression, particularly within the prefrontal cortex (PFC). Preclinical and clinical data have provided compelling insights into the mechanisms underlying the rapid-acting antidepressant effects of ketamine. This review discusses stress-related neurobiology of depression and the safety, tolerability, and efficacy of ketamine for MDD, along with a review of ketamine's mechanism of action and prospective predictors of treatment response. Research limitations and future clinical prospects are also discussed. [ABSTRACT FROM AUTHOR]

Ketamine is the prototype for a new generation of glutamate-based antidepressants that rapidly alleviate depression within hours of treatment. Over the past decade, there has been replicated evidence demonstrating the rapid and potent antidepressant effects of ketamine in treatment-resistant depression. Moreover, preclinical and biomarker studies have begun to elucidate the mechanism underlying the rapid antidepressant effects of ketamine, offering a new window into the biology of depression and identifying a plethora of potential treatment targets. This article discusses the efficacy, safety, and tolerability of ketamine, summarizes the neurobiology of depression, reviews the mechanisms underlying the rapid antidepressant effects of ketamine, and discusses the prospects for next-generation rapid-acting antidepressants. [ABSTRACT FROM AUTHOR]

Objectives. Preclinical and clinical research in neuropsychiatric disorders, particularly mood and substance use disorders, have historically focused on neurons; however, glial cells-astrocytes, microglia, and oligodendrocytes - also play key roles in these disorders. Methods. Peer-reviewed PubMed/Medline articles published through December 2012 were identified using the following keyword combinations: glia, astrocytes, oligodendrocytes/glia, microglia, substance use, substance abuse, substance dependence, alcohol, opiate, opioid, cocaine, psychostimulants, stimulants, and glutamate. Results. Depressive and substance use disorders are highly comorbid, suggesting a common or overlapping aetiology and pathophysiology. Reduced astrocyte cell number occurs in both disorders. Altered glutamate neurotransmission and metabolism - specifically changes in the levels/activity of transporters, receptors, and synaptic proteins potentially related to synaptic physiology - appear to be salient features of both disorders. Glial cell pathology may also underlie the pathophysiology of both disorders via impaired astrocytic production of neurotrophic factors. Microglial/neuroinflammatory pathology is also evident in both depressive and substance use disorders. Finally, oligodendrocyte impairment decreases myelination and impairs expression of myelin-related genes in both substance use and depressive disorders. Conclusions. Glial-mediated glutamatergic dysfunction is a common neuropathological pathway in both substance use and depression. Therefore, glutamatergic neuromodulation is a rational drug target in this comorbidity. [ABSTRACT FROM AUTHOR]

Several structural and cellular changes, including marked glial anomalies, have been observed in association with major depressive disorder. Here we review these cellular alterations and highlight the importance of glial cell pathology, especially astroglial dysfunction, in the pathophysiology of neuropsychiatric disorders with a particular interest in major depressive disorder. The functional role of astrocytes in glutamate uptake and glutamate/glutamine cycling is discussed, as is the deleterious effects of chronic stress on glial cell function. Lastly, we discuss the effect of antidepressants on glial cell function and the possibility of targeting glial cells in the quest to develop novel therapeutics. [ABSTRACT FROM AUTHOR]

Background: Reduced γ-aminobutyric acid (GABA) concentrations have been reported in plasma, cerebrospinal fluid, and cortex of depressed subjects. Treatment with both electroconvulsive therapy (ECT) and selective serotonin reuptake inhibitors (SSRI) increased occipital cortex GABA concentrations in prior studies. The purpose of this study was to determine whether treatment of major depression with cognitive behavioral therapy (CBT) produces similar changes in cortical GABA concentrations. Methods: Occipital cortex GABA concentrations were measured in eight subjects with Major Depressive Disorder prior to and after a course of CBT using proton magnetic resonance spectroscopy. Results: The effect of CBT on occipital cortex GABA content was different than that seen for ECT and SSRI medication treatment of depressed patients. Conclusions: This preliminary finding suggests CBT has a less robust effect on cortical GABA content than ECT and SSRI treatments and might indicate a difference between the mechanisms of antidepressant action. [Copyright &y& Elsevier]

• Psychedelics are emerging as therapeutics for a variety of psychiatric conditions. • Psilocybin has shown promise for the treatment of mood disorders. • MDMA has demonstrated phase 3 efficacy in the treatment of PTSD. • Various new psychedelic compounds are currently under investigation. • Psychedelics present novel challenges to bringing psychiatric drug to market. Psychiatric disorders represent the largest cause of disability worldwide. Global interests in psychedelic substances as potentially therapeutic agents for psychiatric disorders has recently re-emerged. Here, we review progress in the development of psychedelic compounds that have potential therapeutic effects as well as the safety concerns. We include psilocybin, N , N –dimethyltryptamine (DMT), lysergic acid diethylamide (LSD), and the entactogen 3,4-methyl-enedioxy-methamphetamine (MDMA). We also review the potential interactive effects these compounds can have with psychotherapeutic approaches. We provide a cutting-edge review of active and recently completed clinical trials based on the published literature (from MEDLINE), published abstracts at citable conferences, clinical trials from the US Clinical Trials registry (clinicaltrials.gov) and media press releases. [ABSTRACT FROM AUTHOR]

Understanding the neurobiology underlying bipolar disorder (BD) versus major depressive disorder (MDD) is crucial for accurate diagnosis and for driving the discovery of novel treatments. A promising target is the metabotropic glutamate receptor 5 (mGluR5), a modulator of glutamate transmission associated with synaptic plasticity. We measured mGluR5 availability in individuals with MDD and BD for the first time using positron emission tomography. Individuals with BD (n = 17 depressed; n = 10 euthymic) or MDD (n = 17) and healthy control (HC) individuals (n = 18) underwent imaging with [18F]FPEB positron emission tomography to quantify mGluR5 availability in regions of the prefrontal cortex, which was compared across groups and assessed in relation to depressive symptoms and cognitive function. Prefrontal cortex mGluR5 availability was significantly different across groups (F 6,116 = 2.18, p =.050). Specifically, mGluR5 was lower in BD versus MDD and HC groups, with no difference between MDD and HC groups. Furthermore, after dividing the BD group, mGluR5 was lower in both BD-depression and BD-euthymia groups versus both MDD and HC groups across regions of interest. Interestingly, lower dorsolateral prefrontal cortex mGluR5 was associated with worse depression in MDD (r = −0.67, p =.005) but not in BD. Significant negative correlations were observed between mGluR5 and working memory in MDD and BD-depression groups. This work suggests that mGluR5 could be helpful in distinguishing BD and MDD as a possible treatment target for depressive symptoms in MDD and for cognitive alterations in both disorders. Further work is needed to confirm differentiating roles for mGluR5 in BD and MDD and to probe modulation of mGluR5 as a preventive/treatment strategy. [ABSTRACT FROM AUTHOR]

• Esketamine is approved for the treatment of major depressive disorder in individuals with acute suicidal ideation or behavior. • The protocols this approval is based on did not provide longer-term maintenance therapy with esketamine; hence the optimal long-term approach remains unclear. • Cognitive behavioral therapy (CBT) is highly effective in relapse prevention and has been shown to prevent suicide attempts in high-risk populations. • The current protocol examines the combination of CBT with esketamine in individuals with major depressive disorder and suicidal ideation. In 2020, esketamine received a supplemental indication as a therapy for major depression with suicidal ideation (MDSI), based on protocols enrolling hospitalized patients. Given the high risk of suicide following hospital discharge and the high relapse rates following discontinuation of esketamine, the optimal long-term treatment approach remains unclear. Cognitive behavioral therapy (CBT) is highly effective in relapse prevention and has been shown to prevent suicide attempts in high-risk populations. Here we describe the study protocol for the CBT-ENDURE trial: C ognitive B ehavioral T herapy Following E sketami n e for Major D epression and S U icidal Ideation for RE lapse Prevention. Patients with depression (N = 100) who are admitted to hospital or are outpatients with clinically significant suicidal ideation will be enrolled in the study. All patients will receive esketamine (twice weekly for four weeks) and will be randomly assigned (1:1 ratio) to receive a 16-week course of CBT plus treatment as usual (CBT group) or treatment as usual only (TAU only group). Patients are followed for a total of 6 months. Supported under a funding announcement from NIMH to conduct safety and feasibility trials for patients at high risk for suicide, the primary outcome of the CBT-ENDURE study is feasibility (as measured by recruitment and retention), with a key secondary outcome being relapse among those who experience substantial benefit following two weeks of esketamine. [ABSTRACT FROM AUTHOR]

Abstract Background While ketamine has been increasingly studied for treatment resistant depression (TRD), the impact of sex differences on treatment outcomes has not been well studied. The objective was to ascertain whether there were differences in response to a single administration of ketamine for TRD between men and women, and between pre- and post-menopausal women. Methods A randomized, double-blind, placebo-controlled trial (N = 99; N = 50 male; N = 49 female) was conducted to investigate the efficacy of intravenous ketamine versus active placebo as augmentation of antidepressant therapy for TRD. Patients were assigned to one of five arms; one-time administration of ketamine of varying doses (i.e., 0.1, 0.2, 0.5, and 1.0 mg/kg), and one group receiving active placebo (intravenous midazolam). A priori -planned analyses were conducted to compare responses between women and men, as well pre-vs. postmenopausal women. Results Analyses demonstrated no significant differences between women and men in terms of treatment response (F(1,80) = 0.06, p = 0.80). There were no significant differences in the frequency of adverse effects (AEs) reported by those assigned to ketamine treatment groups (p > 0.21 for all AEs reported more than once), although women reported more headaches (12% vs. 6%, p = 0.30) and nausea (10% vs. 6%, p = 0.47). In comparing pre-vs. postmenopausal women, no differences in efficacy were observed (F(1,76) = 0.36, p = 0.55). Conclusions Results do not support differential efficacy or tolerability of ketamine for the treatment of TRD between women and men, nor based on menopause status among women. However, larger trials with these a priori aims are needed to confirm these results. [ABSTRACT FROM AUTHOR]

Background: Clinical studies report that scopolamine, an acetylcholine muscarinic receptor antagonist, produces rapid antidepressant effects in depressed patients, but the mechanisms underlying the therapeutic response have not been determined. The present study examines the role of the mammalian target of rapamycin complex 1 (mTORC1) and synaptogenesis, which have been implicated in the rapid actions of N-methyl-D-aspartate receptor antagonists. Methods: The influence of scopolamine on mTORC1 signaling was determined by analysis of the phosphorylated and activated forms of mTORC1 signaling proteins in the prefrontal cortex (PFC). The numbers and function of spine synapses were analyzed by whole cell patch clamp recording and two-photon image analysis of PFC neurons. The actions of scopolamine were examined in the forced swim test in the absence or presence of selective mTORC1 and glutamate receptor inhibitors. Results: The results demonstrate that a single, low dose of scopolamine rapidly increases mTORC1 signaling and the number and function of spine synapses in layer V pyramidal neurons in the PFC. Scopolamine administration also produces an antidepressant response in the forced swim test that is blocked by pretreatment with the mTORC1 inhibitor or by a glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor antagonist. Conclusions: Taken together, the results demonstrate that the antidepressant actions of scopolamine require mTORC1 signaling and are associated with increased glutamate transmission, and synaptogenesis, similar to N-methyl-D-aspartate receptor antagonists. These findings provide novel targets for safer and more efficacious rapid-acting antidepressant agents. [Copyright &y& Elsevier]

Abstract: Hyperpolarization activated cyclic nucleotide-gated (HCN) potassium channels are implicated in the control of neuronal excitability and are expressed widely in the brain. HCN4 is expressed in brain regions relevant to mood and anxiety disorders including specific thalamic nuclei, the basolateral amygdala, and the midbrain dopamine system. We therefore examined the association of HCN4 with a group of mood and anxiety disorders. We genotyped nine tag SNPs in the HCN4 gene using Sequenom iPLEX Gold technology in 285 Caucasian patients with DSM-IV mood disorders and/or obsessive compulsive disorder and 384 Caucasian controls. HCN4 polymorphisms were analyzed using single marker and haplotype-based association methods. Three SNPs showed nominal association in our population (rs12905211, rs3859014, rs498005). SNP rs12905211 maintained significance after Bonferroni correction, with allele T and haplotype CTC overrepresented in cases. These findings suggest HCN4 as a genetic susceptibility factor for mood and anxiety disorders; however, these results will require replication using a larger sample. [Copyright &y& Elsevier]