Disrupted excitation-inhibition (E/I) balance involving GABA and glutamate (Glu) is implicated in the pathophysiology of depression. Ketamine, an NMDA receptor antagonist with rapid antidepressant properties, may modulate this balance, yet proton magnetic resonance spectroscopy (¹H-MRS) studies report inconsistent findings regarding the direction, magnitude, and timing of neurochemical effects....
Background: Suicide is a public health crisis in the US, with limited evidence demonstrating efficacy of treatments for high-risk patients due in part to their exclusion from most clinical trials. This clinical trial evaluates the feasibility and efficacy of adjunctive cognitive behavioral therapy (CBT) with esketamine in patients with major depression and suicidal ideation (MDSI). Methods:...
Patients with treatment-resistant depression (TRD) have higher rates of relapse and pronounced decreases in daily functioning and health-related quality of life compared to patients with major depressive disorder who are not treatment-resistant, underscoring the need for treatment choices with sustained efficacy and long-term tolerability. Adults with TRD who participated in ≥1 of 6 phase 3...
Ketamine is a powerful and rapid-acting antidepressant but has no regulatory authorization for any psychiatric illness. The S-enantiomer of ketamine, esketamine, was approved by the FDA in 2019 as adjunctive therapy for treatment-resistant depression. Substantial controversy exists as to whether there is a significant clinical difference between intravenous (IV) ketamine racemate and intranasal...
The development of novel, rapid-acting treatments and the resurgence of interest in the therapeutic potential of psychedelic-like compounds has stimulated excitement and enthusiasm within the pharmaceutical industry, and provided new hope for millions of individuals suffering with mental illness such as major depressive disorder and post-traumatic stress disorder. This review summarizes the...
OBJECTIVE The objective of this study was to comprehensively examine the real-world safety of esketamine using 58 months of postapproval data in the United States. METHODS U.S. safety data from patient monitoring forms submitted to the esketamine Risk Evaluation and Mitigation Strategy (REMS) program and reports submitted to the Janssen U.S. Global Medical Safety (US-GMS) database were...
This review examines ketamine's neurotoxic potential across preclinical and clinical studies. The authors synthesized data from preclinical models, then integrated findings from human clinical trials of esketamine and observational studies in recreational users. Animal studies have found that repeated or high-dose subanesthetic ketamine administration results in consistent excitotoxic neuronal...
Electroconvulsive therapy (ECT) has potent antidepressant effects yet can lead to neurocognitive side effects. Ketamine is a rapid-acting antidepressant, which may be an alternative to ECT. Few have directly compared the cognitive effects of ECT and ketamine treatment. We compared cognitive effects of intravenous ketamine and ECT in patients with treatment-resistant depression (TRD), collected...
Selective N‐methyl‐D‐aspartate receptor subunit 2b negative allosteric modulators (NR2B NAMs) are being explored as potential new treatment options for major depressive disorder (MDD). This Phase Ib, randomized, double‐blind, placebo‐controlled, parallel‐group trial was conducted in adults (N = 59) with moderate‐to‐severe MDD and insufficient response to ongoing antidepressant monotherapy....
Treatment-resistant mood disorders are often managed with intensive interventions that include electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), ketamine, and esketamine, but the role of genetics in clinical response to those interventions is yet to be clearly determined. Here, we review the current literature on the genetics of response to these treatment modalities. To...
The rates of relapse and suicide risk are higher in treatment-resistant depression (TRD) vs non-treatment-resistant major depressive disorder. Even among patients with TRD who initially respond, the majority (70%) relapse within 6 months. To evaluate the long-term safety and efficacy of esketamine nasal spray, combined with an oral antidepressant, in patients with TRD. Phase 3, open-label,...
Previous studies have shown patient preference can have large effects on treatment adherence and patient satisfaction. However, the direct effects of matching treatment with patient preference on efficacy and safety outcomes remain unclear. We aimed to evaluate the effects of patient preference and preference-matching on efficacy, adverse events, and adherence to electroconvulsive therapy (ECT)...
This Viewpoint explores potential justifications underlying the US Food and Drug Administration (FDA)’s rejection of methylenedioxymethamphetamine (MDMA) as a treatment for posttraumatic stress disorder, including lack of blinding and issues around the integrity of relevant clinical trials.
The effective treatment of major depressive disorder remains one of the biggest public health challenges globally. For moderate to severe cases, pharmacotherapy often falls short, leading to treatment-resistant depression. Electroconvulsive therapy (ECT) has generally been considered the gold standard for severe cases of treatment-resistant depression. However, emerging evidence suggests that...
Esketamine nasal spray (ESK) is approved, in conjunction with an oral antidepressant, for the treatment of treatment-resistant depression in adults and for the treatment of depressive symptoms in adults with major depressive disorder with acute suicidal ideation or behavior. No adverse events (AEs) of respiratory depression were reported in ESK phase 3 clinical trials; however, postmarketing...
While esketamine is effective in treatment-resistant depression (TRD), detailed information about the effect of esketamine on cognition is relatively scarce. This analysis assessed the effect of short-term (3 double-blind [DB] studies: DB1, DB2, and DB4) or long-term maintenance treatment (DB3) with esketamine nasal spray (ESK) compared with a placebo (PBO) combined with active-comparator, on...
The ELEKT-D: Electroconvulsive Therapy (ECT) vs Ketamine in Patients With Treatment Resistant Depression (TRD) (ELEKT-D) trial demonstrated noninferiority of intravenous ketamine vs ECT for nonpsychotic TRD. Clinical features that can guide selection of ketamine vs ECT may inform shared decision-making for patients with TRD. To evaluate whether selected clinical features were associated with...
This Viewpoint discusses changes in the use of ketamine as a medical therapeutic and a recreational substance, the potential risks of use, and the need for increased research and surveillance.
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),...
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...
Importance Psilocybin shows promise as a treatment for major depressive disorder (MDD). Objective To evaluate the magnitude, timing, and durability of antidepressant effects and safety of a single dose of psilocybin in patients with MDD. Design, Setting, and Participants In this phase 2 trial conducted between December 2019 and June 2022 at 11 research sites in the US, participants were...
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...
BACKGROUND Electroconvulsive therapy (ECT) and subanesthetic intravenous ketamine are both currently used for treatment-resistant major depression, but the comparative effectiveness of the two treatments remains uncertain. METHODS We conducted an open-label, randomized, noninferiority trial involving patients referred to ECT clinics for treatment-resistant major depression. Patients with...