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 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.
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.
Anesthesiology
August 1, 2024
Connor T A Brenna, Benjamin I Goldstein, Carlos A Zarate et al.
19 citations
Anesthetic drugs such as ketamine, nitrous oxide, propofol, and isoflurane show rapid and sustained antidepressant properties, positioning anesthesiologists at a new frontier in treating neuropsychiatric disorders. This article reviews these drugs as novel antidepressants and identifies future candidates for depression treatment. The authors call for collaboration between anesthesiologists and psychiatrists to repurpose anesthetic drugs as antidepressants and address mood disorders in surgical patients.
European archives of psychiatry and clinical neuroscience
July 13, 2024
Jenessa N Johnston, Carlos A Zarate, Mark D Kvarta
18 citations
Esketamine, the (S)-enantiomer of racemic ketamine, is an FDA-approved rapid-acting antidepressant for treatment-resistant depression (TRD) that outperforms traditional oral antidepressants. Research on biomarkers predicting response to esketamine remains limited and mostly extrapolated from racemic ketamine studies. Genetic, proteomic, and metabolomic profiles suggest inflammation and mitochondrial function may contribute to its effects, but these findings require verification. Neuroimaging consistently implicates the prefrontal cortex, striatum, and anterior cingulate cortex. In perioperative settings, esketamine reduces depression and anxiety, correlating with increased brain-derived neurotrophic factor and serotonin. Better-designed biomarker-focused clinical trials are needed to clarify mechanisms and identify patients most likely to benefit.
Molecular psychiatry
September 1, 2024
Brandi Quintanilla, Carlos A Zarate, Anilkumar Pillai
17 citations
Over 300 million people worldwide have major depressive disorder (MDD), but only 30-40% achieve remission with standard antidepressants. Ketamine offers rapid relief within hours, unlike weeks for conventional drugs. While many studies focus on ketamine's effects on glutamate, this review highlights its anti-inflammatory actions, especially through the complement system—a part of innate immunity involved in synaptic plasticity. The complement system is linked to depression, with increased complement component 3 (C3) expression found in the prefrontal cortex of suicidal individuals with depression. Given ketamine's anti-inflammatory properties and the complement system's role in glutamate modulation, the review suggests a common link between the complement system and ketamine's mechanism of action.
Progress in brain research
January 1, 2023
Vasileia Kotoula, Jennifer W Evans, Claire Punturieri et al.
17 citations
Imaging studies of treatment-resistant depression (TRD) have examined brain activity, structure, and metabolite concentrations to identify critical areas of investigation and potential treatment targets. This chapter reviews findings from structural MRI, functional MRI, and magnetic resonance spectroscopy. Decreased connectivity and metabolite concentrations in frontal brain areas appear to characterize TRD, though results are not consistent across studies. Treatments including rapid-acting antidepressants and transcranial magnetic stimulation have shown some efficacy in reversing these changes while alleviating depressive symptoms. However, few TRD imaging studies exist, often with small sample sizes or varied methods, making firm conclusions difficult. Larger studies with unified hypotheses and data sharing could improve characterization of the illness and identify new treatment targets.
Translational psychiatry
June 4, 2024
Elizabeth D Ballard, Deanna Greenstein, Philip T Reiss et al.
16 citations
Ketamine, a drug that modulates the glutamate system, is linked to changes in sleep, depression, and suicidal thoughts. In a randomized, double-blind, crossover trial, 36 people with treatment-resistant major depression and 25 healthy volunteers underwent polysomnography before and after receiving ketamine or placebo. At baseline, those with depression had less total sleep time and shorter REM latency. Ketamine increased slow-wave (delta) brain activity early in the night and both alpha and delta activity later, compared to placebo. However, ketamine did not significantly alter sleep arousal metrics or mediate its antidepressant or anti-suicidal effects through sleep changes. The findings suggest sleep-related variables are part of broader neurobiological shifts after ketamine.
Biological psychiatry
March 15, 2025
Anna Onisiforou, Andria Michael, Markos Apostolakis et al.
14 citations
Opioid use disorder (OUD) has reached epidemic levels, and current medications, while lifesaving, fail to address negative affect and cognitive impairment, leading to high relapse rates even years after drug cessation. Ketamine, an anesthetic and rapid-acting antidepressant, shows promise for treating OUD, including managing acute withdrawal symptoms, negative affect during protracted abstinence, and preventing return to opioid use. This review examines preclinical and clinical research on ketamine and its metabolites as novel therapeutic strategies. Evidence demonstrates that ketamine and its metabolites can modulate pathophysiological processes in OUD, suggesting a promising role in treatment and relapse prevention.
Neuroscience and biobehavioral reviews
July 1, 2024
Mina Kheirkhah, Allison C Nugent, Alicia A Livinski et al.
13 citations
Music and ketamine each influence therapeutic outcomes, yet their combined use is rarely studied. This scoping review maps existing research on administering music alongside ketamine or esketamine in humans. Studies include healthy volunteers and patients of various ages, using different doses and treatment processes, with music played at varying times relative to drug administration. Research on music during ketamine anesthesia is included, as anesthesia drove early ketamine use. Recreational ketamine studies are excluded. The review is limited to English-language articles with no year restriction. It is the first comprehensive overview of music and ketamine/esketamine interplay, offering guidance for future study design.
The Journal of clinical psychiatry
April 24, 2024
Gregory H Jones, Courtney M Vecera, Ana C Ruiz et al.
13 citations
A single dose of intranasal ketamine (50 mg) produced rapid antidepressant effects compared to placebo in unmedicated inpatients with major depression and current suicidal ideation, but did not significantly reduce suicidal thoughts. Patients with comorbid alcohol use disorder showed a statistical trend toward greater improvement in suicidality, though the primary outcome was not met. The treatment was well tolerated. The antidepressant benefit was largely unaffected by the presence of alcohol use disorder or the type of mood disorder (unipolar or bipolar). Among those receiving ketamine, improvement in depression correlated with reduced suicidal ideation only in patients without alcohol use disorder.
The American journal of psychiatry
September 1, 2024
Evan M Hess, Dede K Greenstein, Olivia L Hutchinson et al.
12 citations
Ketamine increases pleasure from social situations in people with treatment-resistant depression and promotes helping behavior in rats. In a randomized, double-blind, placebo-controlled study, participants who received a single intravenous dose of ketamine (0.5 mg/kg) reported greater pleasure from being with family or close friends, seeing smiling faces, helping others, and receiving praise for up to one week after treatment, compared to those given placebo. In a rodent experiment, ketamine-treated rats were more willing to forgo obtaining sucrose to protect a cage mate from electric shock, maintaining lower response rates for six days and delivering fewer shocks overall. These findings indicate that ketamine has prosocial, entactogen effects.
Scientific reports
February 24, 2024
Jennifer W Evans, Morgan C Graves, Allison C Nugent et al.
9 citations
The hippocampus and amygdala are brain regions involved in major depressive disorder (MDD) and its treatment. Preclinical work suggests antidepressants, including ketamine, can reverse stress-related changes in these areas. Clinical studies show reduced volumes in MDD, worsened by early life stress and repeated episodes. This analysis of structural MRI data from a prior double-blind, placebo-controlled, crossover trial examined changes in hippocampal and amygdalar subfield volumes after ketamine treatment. Participants included healthy volunteers and unmedicated individuals with treatment-resistant depression scanned at baseline and twice after a single ketamine or saline infusion. At 10 days post-infusion, a slight increase in whole left amygdalar volume was observed in the ketamine group among those with depression. No other differences were found between groups at either 3T or 7T field strength.
Journal of affective disorders
July 15, 2024
Kelly T Hurst, Abigail Vogeley, Deanna K Greenstein et al.
8 citations
People who received ketamine for depression in early clinical trials at the National Institute of Mental Health (NIMH) were more likely to obtain ketamine or esketamine after leaving the research setting. Among 203 former participants followed up an average of nine years later, 25.6% had originally received ketamine at the NIMH. Those who had received ketamine were significantly more likely to have used ketamine or esketamine afterward. However, receiving ketamine at the NIMH was not linked to higher rates of suicide attempts, psychiatric hospitalizations, dissociation, hallucinations, or attempts to obtain non-prescribed ketamine. Participants who used ketamine or esketamine after discharge reported more depressive symptoms. No symptoms indicating abuse were reported. The findings highlight the need for long-term monitoring of patients receiving rapid-acting antidepressants.
Brain, behavior, and immunity
July 1, 2025
Brandi Quintanilla, Dede Greenstein, Ashutosh Tripathi et al.
7 citations
Ketamine, a rapid-acting antidepressant, may also regulate immune function. The complement system, part of the innate immune response involved in synaptic plasticity, has been linked to depression. This analysis of data from 39 people with major depressive disorder and 25 healthy volunteers, originally part of a randomized, double-blind trial comparing intravenous ketamine (0.5 mg/kg) to placebo, measured plasma levels of complement proteins C3a and C4a at baseline, 230 minutes, Day 1, and Day 3. A significant interaction between diagnosis and sex was found for C3a but not C4a levels. Ketamine's effects on C3a and C4a did not change over time. The findings suggest that targeting the complement pathway could lead to advances in treating major depressive disorder.
CNS spectrums
June 30, 2025
Jose Manuel Quintero, Rosa Helena Bustos, Sharon Lechtig-Wassermann et al.
6 citations
Ketamine, first made in 1962, has become important for its fast-acting and lasting antidepressant effects in people with treatment-resistant depression. Unlike older antidepressants, it works through multiple brain chemical systems, including blocking NMDA receptors and boosting AMPA receptors. It also remains a useful anesthetic and painkiller for acute and chronic pain, and shows anti-inflammatory, neuroprotective, and possible antitumor properties. However, its dissociative and hallucinogenic effects lead to recreational misuse, which can cause bladder and liver problems. Its rediscovery as an antidepressant in the early 2000s transformed psychiatric care, and research now explores its use in bipolar depression, PTSD, OCD, and substance use disorders. The review covers ketamine's many uses and the need to balance benefits with risks.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
May 1, 2025
Mina Kheirkhah, Wallace C Duncan, Qiaoping Yuan et al.
6 citations
People with treatment-resistant depression show higher REM density in the first REM period and shorter REM latency than healthy volunteers, while total night REM density does not differ. Ketamine treatment reduces REM density in the first REM period but does not change total night REM density or REM latency. Baseline REM density in the first REM period moderately predicts whether a person will respond to ketamine, with higher levels indicating greater likelihood of response. This marker could help identify individuals most likely to benefit from ketamine therapy.
Journal of affective disorders
March 1, 2025
Elizabeth D Ballard, Lucinda Neely, Laura Waldman et al.
4 citations
Suicidal ideation, depression, hopelessness, psychological pain, and traumatic stress are all elevated during a suicide crisis and respond to a single ketamine infusion. In a study of 118 adults spanning the suicide risk continuum, 14 high-risk individuals who had recently attempted or seriously considered suicide were compared with those whose crisis had resolved. A subset of 10 high-risk participants received open-label ketamine (0.5 mg/kg). Results were mixed depending on the assessment used, but all five clinical characteristics were elevated near the time of crisis and decreased after ketamine. The small sample and use of only one intervention limit the findings.
Translational psychiatry
November 18, 2025
Jenessa N Johnston, Peixiong Yuan, Bashkim Kadriu et al.
2 citations
In neurons derived from induced pluripotent stem cells of five women with treatment-resistant depression (average age 40.2 years), both the glycoprotein reelin and the ketamine metabolite (2R,6R)-hydroxynorketamine increased expression of several synaptic proteins (GluA1, PSD-95, Dab1, Synapsin I, and p-ERK) within one hour, with effects declining by 24 hours. Gene expression changes were similar for both compounds, though only reelin upregulated mTORC1 signaling. The findings suggest that iPSC-derived neurons may serve as a useful in vitro model for studying treatment-resistant depression and testing potential therapeutics.