The International Journal of Neuropsychopharmacology
September 12, 2011
Oz Malkesman, Daniel Austin, Tyson Tragon et al.
91 citations
D-serine, a co-agonist at NMDA receptors, produces antidepressant-like effects in rodents. A single acute dose of D-serine reduced immobility in the forced swim test without affecting motor function, reversed sexual reward-seeking deficits caused by serotonin depletion, and reversed learned helplessness behavior. Mice lacking NMDA receptor NR1 subunits in forebrain excitatory neurons showed a depression-like phenotype and did not respond to D-serine. These findings suggest D-serine has antidepressant-like effects and support the idea of complex glutamatergic dysfunction in depression, though it remains unclear whether D-serine shares a convergent mechanism with NMDA antagonists like ketamine.
Bipolar Disorders
September 18, 2013
Allison C. Nugent, Nancy Diazgranados, Paul J. Carlson et al.
86 citations
In people with bipolar disorder who are depressed, a single ketamine infusion alters brain glucose metabolism in regions linked to mood disorders. Those who improved most showed the largest metabolic increase in the right ventral striatum. Ketamine also lowered metabolism in the left hippocampus compared with placebo. Higher baseline activity in the subgenual anterior cingulate cortex predicted a stronger antidepressant response to ketamine. These metabolic changes may help explain how ketamine works.
Molecular Psychiatry
September 7, 2022
Rebecca B Price, Nicholas Kissel, Andrew Baumeister et al.
80 citations
Ketamine given intravenously rapidly reduces depressive symptoms, with effects lasting at least a week. In an analysis of 17 randomized controlled trials with 809 participants, the benefit over placebo was larger for patients who had already failed two or more prior antidepressant trials. However, no patient-level clinical or demographic characteristics—such as age, sex, or diagnosis—could predict who would respond best, limiting the ability to personalize ketamine prescriptions. The findings confirm ketamine's broad effectiveness for depression but show that precision medicine approaches cannot yet guide treatment decisions.
The International Journal of Neuropsychopharmacology
October 31, 2014
Elizabeth D. Ballard, Níall Lally, Allison C. Nugent et al.
74 citations
Suicidal ideation in treatment-resistant major depression is linked to activity in the infralimbic cortex (Brodmann area 25). In 19 medication-free patients, higher baseline metabolism in this brain region correlated with more severe suicidal thoughts, but not with overall mood. A single ketamine infusion (0.5 mg/kg) reduced both suicidal ideation and metabolism in the infralimbic cortex, and the degree of metabolic decrease matched the degree of symptom improvement. Other brain areas examined—the amygdala and subgenual anterior cingulate cortex—showed no significant association with suicidal ideation or depression. The infralimbic cortex may be a specific neural substrate for suicidal thinking, distinct from general mood.
Expert Opinion on Drug Safety
March 9, 2022
Anees Bahji, Carlos A. Zarate, Gustavo Vazquez
71 citations
Ketamine and esketamine are effective, safe, and acceptable treatments for depression. A meta-analysis of 36 randomized controlled trials (2,903 participants, 57% female, average age 45 years) found that treatment with either form of ketamine improved response (2.14 times more likely), remission (1.64 times more likely), and depression severity compared to placebo. There was no difference in treatment retention, dropouts due to adverse events, or overall number of adverse events between ketamine and placebo.
Bipolar Disorders
September 14, 2012
David A. Luckenbaugh, Lobna Ibrahim, Nancy E. Brutsché et al.
69 citations
In people with bipolar depression, those who have a first-degree relative with alcohol dependence show a greater and more sustained antidepressant response to a single low dose of ketamine than those without such a family history. The study also found that individuals with a positive family history experienced fewer psychosis-like and dissociative side effects after ketamine infusion. These findings suggest that family history of alcohol dependence may help predict who benefits most from ketamine treatment and should be considered when developing new glutamatergic therapies for depression.
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.
Neuropharmacology
January 13, 2023
Jenessa N Johnston, Bashkim Kadriu, Josh Allen et al.
64 citations
Ketamine and serotonergic psychedelics both show promise as rapid-acting antidepressants, though through different primary mechanisms: ketamine modulates glutamate, while serotonergic psychedelics increase serotonin signaling. However, downstream effects like mTORC1 signaling and GABAA receptor activity appear similar, which may explain their shared antidepressant properties. Research on serotonergic psychedelics remains less advanced than on ketamine, and both face regulatory and methodological challenges, including difficulties with placebo controls in trials and the need for long-term observation.
World Psychiatry
September 25, 2015
Carlos A. Zarate, Mark J. Niciu
63 citations
Ketamine, an NMDA receptor antagonist, produces rapid and robust antidepressant effects in patients with treatment-resistant major depressive disorder and bipolar depression. Sub-anesthetic dose infusions (0.5 mg/kg for 40 minutes) show efficacy within 24 hours, with relapse often within one week. Ketamine also rapidly reduces suicidal thinking. The drug's mechanism involves blocking NMDA receptors on inhibitory interneurons, leading to increased glutamate release and activation of AMPA receptors, which triggers intracellular signaling cascades that stimulate synaptic plasticity. Challenges include lack of FDA approval, need for standardized dosing and administration, and risks of abuse and long-term side effects with repeated use. Future research requires better control conditions, identification of enriched subgroups, and development of glutamate biomarkers.
The International Journal of Neuropsychopharmacology
April 10, 2018
Jessica R. Gilbert, Julia S. Yarrington, Kathleen E. Wills et al.
58 citations
Ketamine, a drug that modulates glutamate signaling, produces rapid antidepressant effects. In a double-blind, crossover, placebo-controlled study, 18 people with major depressive disorder and 18 healthy controls each received a single intravenous infusion of ketamine (0.5 mg/kg) and a saline placebo. Magnetoencephalography measured brain activity during tactile stimulation 6 to 9 hours after each infusion. Dynamic causal modeling revealed that ketamine altered NMDA receptor-mediated connectivity differently in the two groups: backward connections were enhanced in depressed subjects, while forward connections were enhanced in controls. Among depressed subjects, improved mood correlated with reduced NMDA and AMPA connectivity in the somatosensory network. The findings indicate that AMPA- and NMDA-mediated glutamatergic signaling is central to ketamine's antidepressant action.
The International Journal of Neuropsychopharmacology
December 19, 2014
Mark J. Niciu, David A. Luckenbaugh, Dawn F. Ionescu et al.
55 citations
A single low-dose infusion of the anesthetic ketamine produces rapid antidepressant effects in people with treatment-resistant major depressive disorder. In this trial, depressed individuals with a family history of alcohol use disorder showed a longer-lasting antidepressant response to ketamine compared to those without such a family history. Adding the drug riluzole did not extend or enhance ketamine's antidepressant durability. The findings suggest that family history of alcohol use disorder may predict a more durable ketamine response, which should be accounted for in future ketamine depression studies.
The American journal of psychiatry
March 1, 2025
Marjorie R Levinstein, Reece C Budinich, Jordi Bonaventura et al.
49 citations
Ketamine, a racemic compound used as an anesthetic, analgesic, and recreational drug, is being investigated for treating refractory depression and comorbid conditions like anxiety, obsessive-compulsive disorder, and opioid use disorder. Although ketamine is traditionally classified as an NMDA receptor antagonist, this review argues its pharmacology should be redefined to include opioid receptors and the endogenous opioid system. The authors propose that ketamine's antidepressant effects may arise from bifunctional, synergistic interactions involving both NMDA and opioid receptors.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
May 1, 2025
Johan Saelens, Anna Gramser, Victoria Watzal et al.
47 citations
A systematic review and network meta-analysis of 69 randomized controlled trials with 10,285 adults who had not responded to at least two antidepressant trials compared 25 treatments for treatment-resistant depression. Six treatments showed higher response rates than placebo or sham: electroconvulsive therapy (ECT) had the strongest effect, followed by minocycline, theta-burst stimulation, repetitive transcranial magnetic stimulation, ketamine, and aripiprazole. Odds ratios ranged from 1.9 for aripiprazole to 12.86 for ECT. Moderate heterogeneity was observed. These findings may help guide evidence-based treatment choices for treatment-resistant depression.
The lancet. Psychiatry
October 1, 2023
Gustavo C Medeiros, Malcolm Matheson, Isabella Demo et al.
38 citations
A systematic review of 69 neuroimaging studies (1751 participants) found no well-replicated biomarker for ketamine's antidepressant response, but identified several promising candidates. Response to ketamine was associated with post-treatment increases in gamma power in frontoparietal regions, increased functional connectivity within the prefrontal cortex, and increased functional activation of the striatum. The review highlights substantial methodological heterogeneity across studies and calls for further investigation of these biomarkers.
Advances in pharmacology (San Diego, Calif.)
January 1, 2020
Bashkim Kadriu, Elizabeth D. Ballard, Ioline D. Henter et al.
35 citations
Psychiatry is moving toward early identification and intervention to reduce the burden and duration of severe mental illnesses. The rapid-acting antidepressant ketamine has transformed understanding of antidepressant response and expanded treatment options for treatment-resistant depression. Efforts to characterize biomarkers of ketamine response aim to identify biologically enriched subgroups more likely to benefit. This chapter reviews translational biomarkers from imaging, electrophysiology, sleep, circadian rhythms, HPA axis function, metabolism, immune, (epi)genetic, and neurotrophic systems. Ketamine's properties may model new rapid-acting treatments. However, most studies focus on acute effects, and no biomarkers are ready for clinical use.
Clinical pharmacology and therapeutics
November 1, 2024
Shruti M Raja, Jeffrey T Guptill, Michelle Mack et al.
34 citations
A metabolite of ketamine, (2R,6R)-hydroxynorketamine (RR-HNK), was tested in a Phase 1 study in healthy volunteers for safety and tolerability. RR-HNK lacks anesthetic and dissociative effects but retains antidepressant and analgesic activity in preclinical models. In single doses from 0.1 to 4 mg/kg and multiple doses of 1 and 2 mg/kg given intravenously over 40 minutes, RR-HNK showed minimal adverse events and no serious adverse events. It did not cause dissociation or sedation. Drug levels in the body increased proportionally with dose, and cerebrospinal fluid analysis confirmed it reached the central nervous system. Some participants showed increases in gamma brain wave activity at lower to mid doses. These results support moving to Phase 2 trials.
Translational Psychiatry
November 29, 2024
Gustavo C Medeiros, Isabella Demo, Fernando S Goes et al.
32 citations
Treatment-resistant depression accounts for a large share of the burden of major depressive disorder. Intravenous ketamine and intranasal esketamine are rapid-acting antidepressants that can effectively treat this condition, but response varies. Reliable predictors of response are urgently needed. Clinical predictors of a robust response to ketamine include a family history of alcohol use disorder and a history of childhood trauma. A promising brain-based biomarker is an increase in gamma power in frontoparietal regions measured by EEG. Blood-based biomarkers have shown limited usefulness, with small-effect increases in BDNF being the most consistent indicator. Dissociative symptoms during treatment are not typically associated with response. Most predictors have modest effect sizes, so multivariate models will be needed.
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.
Neural Plasticity
January 1, 2015
Annie J. Xu, Mark J. Niciu, Nancy B. Lundin et al.
27 citations
Ketamine and lithium both inhibit an enzyme called glycogen synthase kinase 3, and in rodents they show synergistic antidepressant-like effects at low doses. In a randomized, double-blind, placebo-controlled crossover trial, 36 patients with treatment-resistant bipolar depression maintained on either lithium or valproate received a single 0.5 mg/kg ketamine infusion. Both groups showed significant improvement in depressive symptoms on the Montgomery-Åsberg Depression Rating Scale, but there was no statistically significant difference between the mood stabilizer groups. Serum levels of lithium or valproate did not correlate with ketamine's antidepressant effects. The results suggest that lithium may not enhance ketamine's antidepressant efficacy in this population.
Translational Psychiatry
December 3, 2023
Laith Alexander, Peter C. T. Hawkins, Jennifer W. Evans et al.
26 citations
Ketamine's antidepressant effects involve changes in brain connectivity that depend on which part of the anterior cingulate cortex (ACC) is examined. In a double-blind, placebo-controlled crossover trial, patients with treatment-resistant depression and healthy volunteers received intravenous ketamine or placebo. Two days later, resting-state functional connectivity between ACC subregions and other brain areas differed between groups. Changes in perigenual ACC connectivity to the insula correlated with improved depression scores. Subgenual ACC connectivity was most altered by ketamine compared to placebo, and changes in its connectivity to other ACC subregions and the ventral striatum correlated with reduced anhedonia. Accurate ACC segmentation is needed to understand ketamine's effects.
Frontiers in Neuroimaging
June 27, 2023
Vasileia Kotoula, Jennifer W. Evans, Claire Punturieri et al.
26 citations
Functional magnetic resonance imaging (fMRI) can identify brain areas linked to depression symptoms and potential treatment targets. A review of fMRI studies on selective serotonin reuptake inhibitors (SSRIs) and ketamine found that both conventional and fast-acting antidepressants normalize amygdala hyperactivity in response to negative emotional stimuli, suggesting a common pathway for antidepressant action. Ketamine's rapid effects on brain activity and connectivity also trend toward normalizing depression-related abnormalities. While fMRI shows promise for identifying treatment targets, improved methodology and study design are needed before its findings can be used as primary clinical trial outcomes.
Neuron
May 7, 2025
Federica Lucantonio, Jacob Roeglin, Shuwen Li et al.
24 citations
Ketamine rapidly and sustainably alleviates anhedonia, a core symptom of depression, by restoring weakened excitatory synapses onto D1-medium spiny neurons in the nucleus accumbens of chronically stressed mice. Artificially strengthening these synapses reproduces ketamine's behavioral benefits, while blocking the synaptic restoration prevents the therapeutic effect. The relevant synaptic inputs originate from the medial prefrontal cortex and ventral hippocampus.
Journal of Affective Disorders
March 15, 2025
Polymnia Georgiou, Cristan A Farmer, Gustavo C Medeiros et al.
24 citations
Baseline levels of stress-related hormones (CRF, ACTH, and cortisol) did not significantly influence how well ketamine worked as an antidepressant in people with treatment-resistant depression. However, higher levels of ACTH and CRF were associated with longer overall duration of depressive episodes, suggesting these hormones might serve as biomarkers for chronic depression. Additionally, people who developed depression at a younger age tended to have more severe depressive symptoms, indicating that earlier onset may lead to greater cumulative stress on the brain and body. The study involved 42 participants in a randomized, placebo-controlled, crossover trial.
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.