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.
Discover Mental Health
April 15, 2022
Mani Yavi, Holim Lee, Ioline D. Henter et al.
150 citations
Ketamine and its enantiomer esketamine offer rapid antidepressant effects, often within one day, for treatment-resistant depression, with symptom improvement lasting three to seven days. Esketamine received FDA approval in 2019 as an adjunctive treatment for adults with treatment-resistant depression, administered under medical supervision due to a risk evaluation and mitigation strategy. Side effects such as dissociative symptoms, hypertension, and confusion or agitation are generally tolerable and limited to the time of treatment, though longer-term risks including abuse or dependence remain poorly understood. The drug has also been studied for suicidality, obsessive-compulsive disorder, post-traumatic stress disorder, substance abuse, and social anxiety disorder. Research on ketamine may also deepen understanding of mood disorder mechanisms and guide development of new treatments.
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.
The International Journal of Neuropsychopharmacology
November 16, 2020
Bashkim Kadriu, Maximillian Greenwald, Ioline D. Henter et al.
98 citations
Both the anesthetic ketamine and classic serotonergic psychedelics such as psilocybin may produce rapid and sustained antidepressant effects after a transient psychoactive period. Evidence suggests a potentially shared mechanism wherein both types of drugs engender rapid neuroplastic effects in a glutamatergic activity-dependent manner. They appear to produce acute alterations in cortical network activity that may initially cause psychoactive effects and later produce milder, sustained changes in network efficiency associated with therapeutic response. However, the connection between psychoactive impact and antidepressant efficacy remains unclear and requires more rigorous research. Rapid-acting antidepressants currently under investigation may share downstream pharmacological effects, suggesting related mechanisms of action.
The Journal of Clinical Psychiatry
December 6, 2016
Jennifer L. Vande Voort, Elizabeth D. Ballard, David A. Luckenbaugh et al.
67 citations
People with depression who had a reduction in suicidal thoughts after a single ketamine infusion also showed less nighttime wakefulness, measured by EEG, the night after the infusion compared to those whose suicidal thoughts did not improve. The level of wakefulness in responders was similar to that of healthy controls. This suggests that ketamine's effect on suicidal ideation may involve changes in sleep-wake regulation.
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.
Translational Psychiatry
May 2, 2022
Ruin Moaddel, Panos Zanos, Cristan A Farmer et al.
32 citations
Subanesthetic-dose ketamine produces rapid antidepressant effects, but its mechanism remains unclear. A targeted metabolomic analysis of plasma and cerebrospinal fluid from nine healthy volunteers receiving a 40-minute ketamine infusion (0.5 mg/kg), along with parallel analysis in mice given ketamine, (2R,6R)-hydroxynorketamine (HNK), or saline, found that both ketamine and HNK affect multiple inflammatory pathways. Some changes were unique to humans or mice, suggesting species differences. Consistently implicated mechanisms across both species and sample types include LAT1, IDO1, NAD+, nitric oxide signaling, and the sphingolipid rheostat.
Acta Psychiatrica Scandinavica
July 17, 2020
Lawrence T. Park, David A. Luckenbaugh, Steven Pennybaker et al.
23 citations
A single intravenous dose of ketamine improved both typical/melancholic and atypical depressive symptoms in people with treatment-resistant major depressive disorder or bipolar depression. At one day after infusion, the effect was larger for typical/melancholic symptoms (Cohen's d = 0.61) than for atypical symptoms (Cohen's d = 0.41), and improvements persisted at day three. The findings suggest ketamine may have early preferential effects on typical/melancholic symptoms, though it benefits both symptom dimensions.
Journal of Psychopharmacology
October 17, 2017
Mark J. Niciu, Nicolas D. Iadarola, Dipavo Banerjee et al.
23 citations
In a sample of 55 unmedicated individuals with treatment-resistant major depressive disorder, baseline volumes of the hippocampus, amygdala, and thalamus measured with 3-Tesla MRI did not correlate with the antidepressant effect of a single 0.5 mg/kg ketamine infusion at any time point (230 minutes, 1 day, or 1 week). A secondary analysis by BDNF rs6265 genotype suggested that in val/val homozygotes, larger thalamic volume was positively associated with response at 230 minutes, while in met carriers, larger thalamic volume was negatively associated, though these correlations did not reach statistical significance. The authors conclude that baseline thalamic volume combined with BDNF genotype may serve as a rapid antidepressant response biomarker.
Neuropsychiatric Disease and Treatment
October 1, 2018
Wallace C. Duncan, Elizabeth E. Slonena, Nadia S. Hejazi et al.
17 citations
Patients with major depressive disorder who had a brief antidepressant response to ketamine (lasting 24-48 hours) showed blunted 24-hour wrist activity amplitude from baseline through three days post-infusion and a phase advance of activity on day one that returned to baseline by day three. Those with a continued response (over 72 hours) had phase-advanced activity at baseline and day one, plus increased amplitude on days one and three. Nonresponders did not show these patterns. The time course of antidepressant response to ketamine appears linked to underlying biological differences in motor activity timekeeping, which may involve circadian system mechanisms.
CNS Drugs
May 1, 2021
Ioline D. Henter, Lawrence T. Park, Carlos A. Zarate
Many patients with mood disorders such as major depressive disorder and bipolar depression do not respond well to standard antidepressants, creating a need for new treatments. Dysfunction in the brain's glutamate system is thought to play a role in these disorders. Subanesthetic doses of racemic (R,S)-ketamine, a glutamatergic modulator, have been observed to produce rapid reductions in depressive symptoms. This has led to investigation of other glutamate-modulating agents, including broad modulators, glycine site modulators, NMDA receptor antagonists, metabotropic glutamate receptor modulators, and mTORC1 activators. Most are in early development and have shown modest effects compared to (R,S)-ketamine and esketamine, though some have more favorable characteristics. The most promising agents appear to be those targeting ionotropic glutamate receptors.
October 23, 2018
B. Kadriu, Subha Subramanian, Z. Deng et al.
preprint
Major depressive disorder (MDD) is common, debilitating, and linked to suicide risk. Standard antidepressants can take weeks to work and have low remission rates, with about a third of patients not fully responding. Newer therapies targeting the glutamatergic system, such as ketamine, offer rapid antidepressant effects and high remission rates. This chapter reviews evidence for several novel therapeutics—ketamine, esketamine, nitrous oxide, scopolamine, GLYX-13, and buprenorphine—as well as interventional techniques like sleep deprivation. Ketamine and esketamine also rapidly reduce suicidal thoughts, making them useful in emergencies. Pivotal drug trials using rodents, neuroimaging, and electrophysiological studies are also reviewed to understand the neurocircuitry underlying MDD.