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...
Background Anhedonia is a debilitating core feature of mood disorders, and is associated with significant functional impairment and poor quality of life. Psilocybin has recently emerged as a novel antidepressant treatment in MDD, however, its effects on anhedonia specifically have yet to be systematically reviewed. This review evaluates available clinical and pre-clinical research, exploring...
Cluster B personality disorders (PDs) are highly comorbid with depression and are associated with attenuated antidepressant response. No clinical trials to date have reported on psilocybin-assisted psychotherapy (PAP) in comorbid treatment-resistant depression (TRD) and PDs. This is the first clinical trial to describe a subgroup of ten participants with a comorbid PD ( n = 9 cluster B; n = 1...
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...
Importance Antidepressant efficacy of intravenous (IV) ketamine has been demonstrated in major depressive disorder; however, the efficacy and safety of ketamine for bipolar depression remain largely unknown, with limited data available in this specific population. Objective To evaluate the efficacy, safety, and tolerability of adjunctive IV ketamine compared with midazolam for...
1.0 According to the 2023 iteration of the Global Burden of Diseases, Injuries and Risk Factor studies (GBD) assessing 375 injuries and diseases and 12 mental disorders, mental disorders are now th...
August 17, 2026Tychique T. Wasolua, Morgan S. Hardy, Tanner J. Bommersbach et al.
INTRODUCTION: Approximately 30-40% of patients with major depressive disorder fail to respond to conventional antidepressants. Ketamine and esketamine are increasingly used, yet synthesized data on cumulative safety remain limited. This systematic review evaluated long-term safety of both agents. METHODS: MEDLINE, PsycINFO, Embase, and Cochrane Library were searched from inception through...
Depression and existential distress are highly prevalent among patients with advanced cancer, and there is growing evidence for ketamine as a rapidly acting antidepressant in the population, but few studies have examined existential distress outcomes with ketamine treatment. The INKeD-PC trial demonstrated efficacy of intranasal racemic ketamine for depression in patients with cancer receiving...
This scoping review maps literature for use of ketamine or esketamine with psychotherapy for depression or depressive symptoms. Forty-seven studies were identified including 4/47 (9%) randomized controlled trials, 4/47 (9%) open label trials, 27/47 (57%) observational or retrospective studies, and 12/47 (26%) individual case reports. Studies were categorized as Ketamine/Esketamine Combined with...
JAMA PsychiatryJuly 1, 2026Sung Ryul Shim, Hye Su Jeong, Tanner J. Bommersbach et al.1 citation
While intravenous ketamine is not approved by the US Food and Drug Administration, it is increasingly used with off-label indications as a novel treatment for suicidal and depressive symptoms. To systematically review and metasynthesize the efficacy and safety data for intravenous ketamine in treating major depressive episodes (MDEs). PubMed, PsycInfo, Cochrane Library, and Embase were...
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...
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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...
Abstract Ketamine and esketamine are increasingly used as rapid-acting antidepressants, yet concerns remain regarding potential structural neurotoxicity, particularly with chronic or high-dose exposure. Despite expanding clinical use, no comprehensive systematic review has integrated neurotoxicity evidence across preclinical and human studies while formally evaluating methodological quality....
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...
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...
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,...
1. Esketamine as monotherapy or adjunct to conventional antidepressants is proven efficacious in clinical trials in adults with treatment-resistant depression (TRD) and depression with high risk of...
Anhedonia, a core symptom of depression, is often resistant to conventional treatments and significantly impacts quality of life. This secondary analysis aimed to evaluate the effects of psilocybin-assisted psychotherapy (PAP) on anhedonia severity in individuals with treatment-resistant depression (TRD). Participants (n = 30) with TRD and a primary diagnosis of Major Depressive Disorder or...