Nature
April 24, 2016
P. Zanos, R. Moaddel, Patrick J. Morris et al.
1,602 citations
A metabolite of ketamine, (2R,6R)-hydroxynorketamine (HNK), produces rapid and sustained antidepressant-like effects in mice without the side effects associated with ketamine itself. These effects do not rely on blocking NMDA receptors but instead involve early and ongoing activation of AMPA receptors. This finding points to a new mechanism for developing faster-acting antidepressants with fewer unwanted effects.
Pharmacological Reviews
June 26, 2018
P. Zanos, R. Moaddel, Patrick J. Morris et al.
1,272 citations
Ketamine, in clinical use since 1970, is best known as a dissociative anesthetic but also has analgesic, anti-inflammatory, and antidepressant effects. This review covers its therapeutic uses by dose, route, and time course, along with side effects from short-term or prolonged exposure and recreational use. Ketamine is rapidly metabolized into norketamine, dehydronorketamine, hydroxyketamine, and hydroxynorketamine (HNK). While anesthetic and analgesic actions stem from inhibition of N-methyl-D-aspartate receptors, other targets include GABA, dopamine, serotonin, sigma, opioid, and cholinergic receptors, plus ion channels. HNK metabolites show antidepressant efficacy in preclinical studies, suggesting broader clinical relevance. Understanding these targets may help develop new drugs with ketamine's benefits but fewer side effects.
American Journal of Psychiatry
March 17, 2021
R. Mcintyre, J. Rosenblat, C. Nemeroff et al.
694 citations
Ketamine and esketamine are the first non-monoamine-based antidepressants with rapid-onset efficacy for adults with treatment-resistant depression, offering hope to those who do not recover fully with standard antidepressants. However, concerns remain about their safety, tolerability, and appropriate placement in treatment algorithms. An international group of mood disorder experts synthesizes evidence on efficacy, safety, and tolerability, and provides guidance for clinical implementation, including practice parameters at point of care. Areas of consensus and future research directions are discussed.
American Journal of Psychiatry
October 3, 2017
S. Wilkinson, Elizabeth D. Ballard, M. Bloch et al.
680 citations
A single dose of ketamine rapidly reduces suicidal thoughts within one day and for up to one week in depressed patients with suicidal ideation. The effect is moderate to large and partially independent of changes in depressive symptoms. The analysis combined data from 167 participants across 10 studies comparing ketamine to a placebo (saline or midazolam). Ketamine significantly improved clinician-rated and self-reported suicidal ideation, though not on one self-report measure (the Beck Depression Inventory). The authors call for further research on long-term safety and suicide risk reduction before clinical use.
Journal of Affective Disorders
September 23, 2020
A. Bahji, G. Vázquez, C. Zarate
404 citations
A systematic review and meta-analysis of 24 randomized controlled trials with 1,877 participants compared racemic ketamine and esketamine for unipolar and bipolar major depression. Racemic ketamine showed greater treatment response (rate ratio 3.01 versus 1.38) and remission rates (rate ratio 3.70 versus 1.47) than esketamine, and had lower dropout rates (rate ratio 0.76 versus 1.37). Intravenous ketamine appears more efficacious than intranasal esketamine for depression.
Psychological Medicine
February 12, 2016
Taishiro Kishimoto, J. M. Chawla, K. Hagi et al.
363 citations
A single intravenous infusion of ketamine reduces depression significantly more than placebo in people with major depressive disorder or bipolar depression, with effects beginning within 40 minutes, peaking at one day, and lasting up to one week. Non-ketamine NMDAR antagonists were superior to placebo only on days 5–8. Ketamine also led to greater response and remission rates at multiple time points. Adverse effects were transient and clinically insignificant, and discontinuation rates did not differ from placebo. The review analyzed 14 randomized controlled trials involving 588 participants.
Journal of Affective Disorders
February 18, 2014
D. Luckenbaugh, M. Niciu, D. Ionescu et al.
282 citations
In treatment-resistant inpatients with major depressive or bipolar disorder, the dissociative side effects of a single ketamine infusion predicted a more robust and sustained antidepressant response. Greater dissociation measured 40 minutes after infusion correlated with greater improvement in depression scores at 230 minutes and 7 days later. In contrast, psychotomimetic symptoms, manic symptoms, and changes in blood pressure or pulse were not significantly linked to antidepressant efficacy. The findings suggest that dissociation, rather than other side effects, may be a marker or mediator of ketamine's antidepressant action, though further prospective research is needed.
Molecular Psychiatry
April 15, 2021
J. Bonaventura, Sherry Lam, Meghan L. Carlton et al.
266 citations
Ketamine, a mixture of two mirror-image molecules called (S)-ketamine and (R)-ketamine, is used as an anesthetic and, more recently, as an antidepressant, but it carries a risk of abuse. The (S)-form is FDA-approved for treatment-resistant depression, while the (R)-form shows promise in animal models but has not been tested in people. In rats and mice, (S)-ketamine, but not (R)-ketamine, produced behaviors linked to abuse potential, such as self-administration, increased movement, and preference for places where the drug was given. (S)-ketamine also boosted activity and dopamine levels in a brain region called the medial prefrontal cortex, partly by activating opioid receptors. These findings indicate that the abuse liability of racemic ketamine stems mainly from its (S)-enantiomer.
Molecular Psychiatry
February 27, 2018
A. Nugent, Elizabeth D. Ballard, T. Gould et al.
254 citations
In a double-blind, placebo-controlled, randomized cross-over trial with 35 unmedicated people with major depressive disorder (MDD) and 25 healthy controls, ketamine (0.5 mg/kg) improved depressive symptoms in MDD subjects but caused modest, temporary increases in depressive symptoms in healthy controls. Both groups showed increased resting gamma power measured by magnetoencephalography. Among MDD subjects, gamma power did not directly predict the size of the antidepressant effect. However, baseline gamma power moderated the link between post-ketamine gamma and response: higher post-ketamine gamma was tied to better response in those with low baseline gamma, but the opposite pattern appeared in those with high baseline gamma. This suggests biological subtypes based on homeostatic dysregulation and cautions against inferring ketamine's mechanism solely from studies of healthy controls.
Proceedings of the National Academy of Sciences of the United States of America
February 22, 2019
E. Lumsden, Timothy A. Troppoli, S. J. Myers et al.
159 citations
A single low dose of the ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) produces rapid antidepressant-like effects in mice without blocking NMDA glutamate receptors (NMDARs), unlike ketamine itself. At a dose of 10 mg/kg, which triggers antidepressant-related behavioral and cellular responses, (2R,6R)-HNK reaches hippocampal concentrations of about 8 µM—far below the levels needed to inhibit NMDARs in vitro. The dose required to prevent NMDA-induced lethality was 228 mg/kg for (2R,6R)-HNK versus 6.4 mg/kg for ketamine, indicating weak NMDAR inhibition. These findings suggest that (2R,6R)-HNK's antidepressant effects occur through alternative molecular targets, potentially avoiding ketamine's adverse effects such as dissociation and abuse potential.
Journal of Affective Disorders
February 17, 2018
M. Niciu, Bridget J. Shovestul, Brittany A. Jaso et al.
134 citations
Depersonalization—a feeling of detachment from one's own body or thoughts—was the dissociative symptom most strongly linked to ketamine's antidepressant effect in patients with treatment-resistant depression. Analyzing data from 126 patients with major depressive or bipolar disorder who received a single ketamine infusion, researchers found that higher scores on the depersonalization subscale of the Clinician-Administered Dissociative States Scale consistently predicted greater improvement in depression ratings across multiple time points. Derealization (feeling the world is unreal) showed a weaker and less consistent association, while amnesia was unrelated to antidepressant response. The finding suggests that depersonalization and antidepressant response may share neurobiological mechanisms, though off-target effects cannot be ruled out.
Molecular Psychiatry
September 14, 2020
A. Mkrtchian, Jennifer W. Evans, C. Kraus et al.
110 citations
Ketamine increased fronto-striatal functional connectivity in people with treatment-resistant major depression toward levels seen in healthy volunteers, while shifting connectivity in healthy volunteers toward a state similar to depressed participants under placebo. These effects occurred largely without changes in inflammatory markers (C-reactive protein) and were associated with both acute and sustained symptom improvements in the depressed group. Ketamine thus normalized reward-related brain circuitry in depression but disrupted it in healthy individuals, highlighting the potential importance of this circuitry in ketamine's mechanism of action for motivational symptoms.
Pharmacology and Therapeutics
May 1, 2023
J. Johnston, I. Henter, C. Zarate
106 citations
Ketamine shows rapid antidepressant effects in treatment-resistant depression, but side effects and misuse risk limit its use. Its two enantiomers, (S)- and (R)-ketamine, work through different mechanisms: (S)-ketamine affects mTORC1 signaling, while (R)-ketamine affects ERK signaling. Preclinical studies suggest divergent pathways, and clinical research indicates (R)-ketamine has a milder side effect profile and reduces depression scores. However, recent randomized controlled trials found (R)-ketamine had no significant antidepressant efficacy compared to placebo, so caution is needed when interpreting its therapeutic potential. Further research is required to optimize dosing, route, and administration for each enantiomer.
Drug Discovery Today
February 1, 2023
J. Johnston, Maximillian Greenwald, I. Henter et al.
64 citations
Stress triggers inflammation in the brain, a pattern also seen in the blood of people with depression. This stress-induced inflammation may contribute to treatment-resistant depression. The rapid-acting antidepressant ketamine works partly by reducing inflammation through effects on the HPA axis, the kynurenine pathway, or by suppressing cytokines. Understanding the link between ketamine, inflammation, and stress could reveal how ketamine works and lead to new rapid-acting antidepressants that target inflammation.
International Journal of Neuropsychopharmacology
April 30, 2021
A. Bahji, C. Zarate, G. Vázquez
62 citations
Ketamine appears to help treat bipolar depression, though evidence is preliminary. A systematic review of six studies involving 135 adults (53% female, average age 44.7 years) found that 61% of those receiving intravenous racemic ketamine (0.5 mg/kg, added to a mood stabilizer) achieved at least a 50% reduction in depression severity, compared to 5% receiving placebo. Response rates across studies ranged from 52% to 80%. Ketamine was reasonably well tolerated, but two participants developed manic symptoms (one on ketamine, one on placebo), and some experienced significant dissociative symptoms 40 minutes after infusion in two trials. Longer-term outcomes and alternative formulations need further study.
Current topics in behavioral neurosciences
March 22, 2022
Marina Kojić, J. Saelens, B. Kadriu et al.
11 citations
Ketamine, approved for treatment-resistant depression, and serotonergic psychedelics both show rapid antidepressant effects. Although they act on different primary targets, both may restore synaptic deficits and reconfigure brain networks. A glutamate surge activates AMPA receptor throughput and increases BDNF levels. Understanding these shared mechanisms could guide development of new rapid-acting antidepressants with fewer side effects.