Ketamine is a rapid-acting antidepressant with demonstrated efficacy in major depressive disorder and treatment-resistant depression, yet the mechanisms by which its molecular actions translate into sustained clinical improvement remain incompletely understood. Prevailing models have emphasized N-methyl-D-aspartate receptor antagonism and downstream glutamatergic signaling; however, convergent...
Short-acting tryptamine psychedelics are emerging as candidate psychiatric therapeutics with pharmacological profiles that may offer practical advantages over longer-acting psychedelics. N,N-dimethyltryptamine (N,N-DMT) and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) differ in pharmacokinetic, receptor, and phenomenological properties, while zalsupindole is a putatively non-hallucinogenic...
Cognitive impairment is a core feature of major depressive disorder (MDD) and bipolar disorder (BD). Most conventional antidepressants do not have direct and clinically relevant procognitive effects. Ketamine and esketamine are effective in treating treatment-resistant depression (TRD). Herein, this systematic review aims to evaluate the effects of both pharmacotherapeutics on cognitive...
Extant literature indicates mitochondrial dysfunction may contribute to the pathophysiology of depressive disorders. Preclinical data indicate that anesthetic doses of ketamine are associated with deficits in mitochondrial viability and function. Ketamine and esketamine have demonstrated rapid antidepressant effects in persons with difficult-to-treat depressive disorders. Herein, we aim to...
Ketamine has emerged as a promising rapid-acting treatment for mood disorders and suicidality. Notwithstanding its replicated antidepressant efficacy, ketamine-associated risk for abuse, dependence, and misuse remain. We conducted a systematic review of clinical and preclinical studies from database inception to August 2025, including randomized and observational trials, open-label extensions,...
This systematic review aims to assess the efficacy and tolerability of ketamine in the treatment of obsessive-compulsive disorder. Obsessive-compulsive disorder is a chronic and severe disorder characterized by intrusive thoughts and repetitive behaviours that can cause significant distress. Notwithstanding current treatments and interventions for obsessive-compulsive disorder, some individuals...
Approximately 80% of individuals diagnosed with major depressive disorder (MDD) report symptoms of insomnia. Glutamatergic modulators, such as ketamine, are reported to be effective for the treatment of depressive symptomatology in adults with MDD. Disrupted glutamate homeostasis is linked to poor sleep quality and sleep disorders. Herein, we sought to systematically determine the effect of...
Major depressive disorder (MDD) and treatment-resistant depression (TRD) remain leading causes of disability, providing the impetus for receptor-level treatment strategies beyond monoamine reuptake. The serotonin 5-HT2B receptor (5-HT2BR) is uniquely positioned at the interface of central-antidepressant mechanisms and peripheral cardiac risks. Herein, we reviewed preclinical, translational and...
Importance: Psychedelic drugs possess acute psychoactive effects that can compromise blinding integrity in randomized clinical trials (RCTs). Functional unblinding, when participants or raters correctly identify treatment allocation based on subjective effects, may bias outcomes through expectancy effects, challenging the validity of efficacy estimates and regulatory acceptance. Objective: To...
Ketamine and esketamine exhibit rapid antidepressant effects in persons with treatment-resistant depression (TRD) and bipolar depression (TRBD). However, the synaptic mechanisms governing dose, frequency, and durability of response remain unclear. This review aims to evaluate the dosing parameters, including minimum dose and optimal dosing intervals, that reliably induce or maintain long-term...
Extant literature suggests that anhedonia, defined as a loss of the ability to feel pleasure or interest, is subserved by dysregulation of reward processing in the central nervous system. Dextromethorphan (DXM), an uncompetitive N-Methyl-d-Aspartate (NMDA) receptor antagonist and sigma-1 (σ1) receptor agonist, is a glutamatergic modulator with antidepressant properties. The effect of DXM on...
Background: Anhedonia and reward-processing deficits are core features of major depressive disorder (MDD) that respond poorly to traditional antidepressants.Ketamine has rapid antidepressant effects, yet its neurofunctional actions within reward circuits remain unclear.We synthesized human neuroimaging evidence on ketamine-related modulation of reward circuitry and implications for...
Ketamine, esketamine, rTMS and ECT are associated with reductions in SI in persons with MDD, with the strongest evidence from randomized controlled trials supporting rapid, short-term effects, particularly for ketamine and esketamine. Further characterization and differentiation of the durability of antisuicidal effects of the aforementioned interventions requires investigation in large-scale,...
Serotonergic psychedelics, such as lysergic acid diethylamide, and psilocybin, and the entactogen 3,4-methylenedioxymethamphetamine exhibit agonist activity at the 5-hydroxytryptamine 2B receptor, a signalling pathway known to mechanistically mediate drug-induced valvular heart disease. This systematic review evaluates whether chronic or repeated use of psychedelics and...
Convergent evidence suggests that disrupted reward processing may be associated with observed alterations in frontostriatal activity in persons with major depressive disorder (MDD). Replicated evidence suggests that glutamatergic modulators may benefit persons experiencing disrupted reward function compared to healthy controls (HC). Herein, we systematically reviewed functional magnetic...
Up to 50% of adults with major depressive disorder (MDD) fail to achieve remission after two or more monoaminergic antidepressants and meet criteria for treatment-resistant depression (TRD). Low-dose intravenous ketamine, intranasal esketamine, and oral dextromethorphan represent the first glutamatergic treatments to exhibit rapid and robust efficacy in persons with TRD, yet their precise...
The reported mixed findings suggest that the opioid system may exert a partial mediating effect of ketamine in TRD. However, given the inconsistent attenuation of ketamine's antidepressant effects by opioid receptor antagonists, the opioid system likely functions as a context-dependent modulator rather than a primary mediator, particularly at standard antidepressant doses.
Ketamine is a dissociative anesthetic with potential for treating mood, anxiety, and related disorders; however, concerns have emerged regarding hepatotoxicity in the context of chronic treatment. Systematic searches of PubMed, Scopus, and Ovid databases were conducted from inception to August 2025. Eligible studies included randomized controlled trials (RCTs), observational studies, and case...
Dextromethorphan/Buproprion (DXM/BUP) has received breakthrough FDA approval in August 2022 as a rapid-acting antidepressant. DXM/BUP is a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist and sigma-1 receptor agonist, with bupropion (BUP), a norepinephrine/dopamine reuptake inhibitor and cytochrome P450 2D6 (CYP2D6) inhibitor. As DXM/BUP moves closer to widespread clinical use for...
ABSTRACT Introduction Posttraumatic stress disorder (PTSD) is a mental disorder resulting from exposure to traumatic events. Evidence suggests that ketamine may be efficacious in treating PTSD, however, ketamine's mechanisms in treating PTSD remain unclear. Herein, this review aims to evaluate the clinical outcomes of ketamine treatment in persons with PTSD and investigate the possible...
INTRODUCTION: Functional impairment is commonly reported amongst individuals with major depressive disorder (MDD) or treatment-resistant depression (TRD). Extant evidence suggests that ketamine and esketamine, N-methyl-D-aspartate (NMDA) receptor antagonists and glutamatergic modulators, have shown efficacy in treating MDD/TRD. While symptom reduction remains central to treatment, many...
Our results suggest that NMDAR antagonism improves alpha and beta cell function and viability, which may have translational relevance to comorbid metabolic dysfunction in depression. These mechanisms may subserve the antidepressant effects of select NMDA antagonists (e.g., ketamine/esketamine, dextromethorphan). Further research should aim to investigate the effects of subanesthetic doses of...
Although these findings suggest psilocybin is associated with dynamic and temporally distinct neuroplastic changes linked to clinical improvement, several limitations must be acknowledged. Many studies reused overlapping datasets with high exploratory flexibility and risk of bias. The generalizability of results is therefore constrained. Future research should emphasize independent datasets,...
G protein-coupled receptors (GPCRs) are involved in many physiological and pathophysiological processes. Conventional pharmacological models categorize the typology of pharmacologic ligands as agonists or antagonists. Biased agonism is a relatively newer pharmacodynamic characteristic that has potential to optimize therapeutic efficacy while minimizing adverse effects in psychiatric and...
Background: Ketamine and esketamine have been reported to rapidly alleviate various parameters of suicidality, with antisuicidal effects that may be independent of their rapid-acting antidepressant effects. However, it remains unclear whether ketamine and/or esketamine are associated with the emergence or worsening of suicidality. Methods: In this global observational pharmacovigilance cohort...