Recommended readings 4
Ketamine

 

This list was made by Jagoda Mackowiak in cooperation, and co-published, with Blossom.

Ketamine, historically an anesthetic, has been shown to be a promising molecule for bringing about therapeutic changes. Ketamine is part of the WHO Model List of Essential Medicines.1 Ketamine is a dissociative but has been included in most of the broader definitions of psychedelics (as atypical psychedelic). Dissociative drugs are substances causing the perception of detachment from one’s body and environment. Like many other psychoactive substances, ketamine is also used recreationally and its effects are highly dependent on the dose.

The duration and follow-up effects of ketamine are typically shorter than those of ‘classic,’ serotonergic psychedelics (psilocybin, LSD). A sub-anesthetic or therapeutic dose is typically administrated via sublingual lozenges, intramuscularly, or intravenously. All routes of administration lead to perceptional effects, such as dissociation and visual distortion. There is, however, much variation in its bioavailability – a lozenge’s bioavailability will be around 15-25% as efficient as intravenous delivery.2 Intravenous doses in the framework of ketamine-assisted psychotherapy (KAP) usually are set around the standard dose of 0,5 mg/kg body weight.

The ketamine molecule comes in two variations3 (enantiomers, mirror images, just like a left and a right hand), R- and S-ketamine (arketamine and esketamine). If not specified otherwise, studies are usually done with racemic ketamine containing 50% of each. Esketamine was developed by Johnson & Johnson as a nasal spray under the brand name Spravato4 for treatment-resistant depression (TRD). Their choice of enantiomer was based on the evidence that esketamine is a stronger inhibitor of action on the NMDA receptor.5 Further studies have now suggested that this pathway is probably not the key mechanism behind the antidepressant effects and arketamine may still prove to be a more effective therapeutic agent.6

This selection of research on ketamine for mental health will explore its promise in treating not only depression but also the positive effects on suicidal ideation, addiction, and further symptoms of mental health disorders.

1. https://www.who.int/medicines/events/fs/en/
2. Wieber, J., Gugler, R., Hengstmann, J. H., & Dengler, H. J. (1975). Pharmacokinetics of ketamine in man. Der Anaesthesist, 24(6):260-263.
3. Hashimoto, K. (2019). Rapid‐acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective. Psychiatry and clinical neurosciences, 73(10):613-627.
4. https://www.jnj.com/janssen-announces-u-s-fda-approval-of-spravato-esketamine-ciii-nasal-spray-to-treat-depressive-symptoms-in-adults-with-major-depressive-disorder-with-acute-suicidal-ideation-or-behavior
5. Temme, L., Schepmann, D., Schreiber, J. A., Frehland, B., & Wünsch, B. (2018). Comparative pharmacological study of common NMDA receptor open channel blockers regarding their affinity and functional activity toward GluN2A and GluN2B NMDA receptors. ChemMedChem, 13(5):446-452.
6. Zhang, J. C., Li, S. X., & Hashimoto, K. (2014). R (−)-ketamine shows greater potency and longer lasting antidepressant effects than S (+)-ketamine. Pharmacology Biochemistry and Behavior, 116:137-141.

Historical Perspective

The “psychedelic effects” of ketamine – in the sense of creating more or less meaningful altered states of consciousness – have already been identified in the previous century. In 1998, Bowdle and colleagues investigated subanesthetic doses of ketamine in healthy volunteers and established that these effects are dose-dependent and linearly related to the steady-state venous plasma ketamine concentrations.
The effectiveness of ketamine for the treatment of depression was something that Krystal and colleagues (2019) did not anticipate when they first studied it over 20 years ago (Krystal et al., 1999 and Berman et al., 2000). Since then, the introduction of ketamine has led to a rejection of the ‘monoamine hypothesis of depression’ – instead of a lack of monoamines (a neurotransmitter), other mechanisms could also contribute to the development of depression. The paradigm shift that has been found by studying ketamine’s effect on the brain lies in the understanding that cortico-limbic mechanisms play a role in depression. As discussed in the following sections, the glutamatergic and GABAergic signaling pathways play an important role in depression development.

Krystal, J. H., Abdallah, C. G., Sanacora, G., Charney, D. S., & Duman, R. S. (2019). Ketamine: a paradigm shift for depression research and treatment. Neuron, 101(5):774-778

Ketamine is the first exemplar of a rapid-acting antidepressant with efficacy for treatment-resistant symptoms of mood disorders. Its discovery emerged from a reconceptualization of the biology of depression. Neurobiological insights into ketamine efficacy shed new light on the mechanisms underlying antidepressant efficacy.

Bowdle, A.T., Radant, A.D., Cowley, D.S., Kharasch, E.D., Strassman, R.J., and Roy-Byrne, P.P. (1998) Psychedelic Effects of Ketamine in Healthy Volunteers: Relationship to Steady-state Plasma Concentrations. Anesthesiology, 88:82–88

Background: Ketamine has been associated with a unique spectrum of subjective "psychedelic" effects in patients emerging from anesthesia. This study quantified these effects of ketamine and related them to steady-state plasma concentrations.
Methods: Ketamine or saline was administered in a single-blinded crossover protocol to 10 psychiatrically healthy volunteers using computer-assisted continuous infusion. A stepwise series of target plasma concentrations, 0, 50, 100, 150, and 200 ng/ml were maintained for 30 min each. After 20 min at each step, the volunteers completed a visual analog (VAS) rating of 13 symptom scales. Peripheral venous plasma ketamine concentrations were determined after 28 min at each step. One hour after discontinuation of the infusion, a psychological inventory, the hallucinogen rating scale, was completed.
Results: The relation of mean ketamine plasma concentrations to the target concentrations was highly linear, with a correlation coefficient of R = 0.997 (P = 0.0027). Ketamine produced dose-related psychedelic effects. The relation between steady-state ketamine plasma concentration and VAS scores was highly linear for all VAS items, with linear regression coefficients ranging from R = 0.93 to 0.99 (P < 0.024 to P < 0.0005). Hallucinogen rating scale scores were similar to those found in a previous study with psychedelic doses of N,N-dimethyltryptamine, an illicit LSD-25-like drug. Conclusions: Subanesthetic doses of ketamine produce psychedelic effects in healthy volunteers. The relation between steady-state venous plasma ketamine concentrations and effects is highly linear between 50 and 200 ng/ml.

Molecular Properties

To understand the function of ketamine on a molecular level, researchers often investigate its target neuronal receptors. Eldufani and colleagues (2018) reviewed the pharmacology of ketamine, which is an inhibitor of, among others, NMDA receptors, which activate signaling pathways leading to dissociative anesthesia.
Another review by Jelen, Young, and Stone (2021) dives deeper into the biochemical and physiological effects (pharmacodynamics) of ketamine. The study investigated the different mechanisms and showed that arketamine, though less thoroughly studied, can potentially offer more effectiveness with fewer acute side effects. The AMPA receptor activation has a role in the antidepressant effects of ketamine, but the specific pathways need to be further investigated. Downstream from these effects, ketamine also influences BDNF-TrkB, mTORC1, and ERK signaling. Ketamine and its metabolites also interact with serotonin receptors, inhibit dopamine uptake, and interact with the gut-brain axis.

Jelen, L. A., Young, A. H., and Stone, J. M. (2021). Ketamine: a tale of two enantiomers. Journal of Psychopharmacology, 35(2):109-123

The discovery of the rapid antidepressant effects of the dissociative anaesthetic ketamine, an uncompetitive N-Methyl-D-Aspartate receptor antagonist, is arguably the most important breakthrough in depression research in the last 50 years. Ketamine remains an off-label treatment for treatment-resistant depression with factors that limit widespread use including its dissociative effects and abuse potential. Ketamine is a racemic mixture, composed of equal amounts of (S)-ketamine and (R)-ketamine. An (S)-ketamine nasal spray has been developed and approved for use in treatment-resistant depression in the United States and Europe; however, some concerns regarding efficacy and side effects remain. Although (R)-ketamine is a less potent N-Methyl-D-Aspartate receptor antagonist than (S)-ketamine, increasing preclinical evidence suggests (R)-ketamine may have more potent and longer lasting antidepressant effects than (S)-ketamine, alongside fewer side effects. Furthermore, a recent pilot trial of (R)-ketamine has demonstrated rapid-acting and sustained antidepressant effects in individuals with treatment-resistant depression. Research is ongoing to determine the specific cellular and molecular mechanisms underlying the antidepressant actions of ketamine and its component enantiomers in an effort to develop future rapid-acting antidepressants that lack undesirable effects. Here, we briefly review findings regarding the antidepressant effects of ketamine and its enantiomers before considering underlying mechanisms including N-Methyl-D-Aspartate receptor antagonism, γ-aminobutyric acid-ergic interneuron inhibition, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptor activation, brain-derived neurotrophic factor and tropomyosin kinase B signalling, mammalian target of rapamycin complex 1 and extracellular signal-regulated kinase signalling, inhibition of glycogen synthase kinase-3 and inhibition of lateral habenula bursting, alongside potential roles of the monoaminergic and opioid receptor systems..

Eldufani, J., Nekoui, A., and Blaise, G. (2018) Nonanesthetic Effects of Ketamine: A Review Article. The American Journal of Medicine, 131(12):1418-1424

Ketamine is considered a dissociative anesthetic medication, and it is commonly administered by a parenteral route. It works mainly by blocking the N-methyl-D-aspartate receptor. It inhibits the voltage-gated Na and K channels and serotonin and dopamine reuptake; also, it affects specific receptors, such as α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, kainate, and aminobutyric acid A receptors. Ketamine appears to have particular mechanisms that are potentially involved during analgesic induction, including enhancing of descending inhibition and antiinflammatory effects. More recently, it has been shown that ketamine has potential in clinical practice for the management of chronic pain, cognitive function, depression, acute brain injury, and disorders of the immune system.

 

Ketamine in depression

The number of studies investigating ketamine as a possible novel treatment of depression has been steadily growing in the past ten years. Even more rapidly, since in 2017, Sanacora et al. published a comprehensive guide to safe and effective use of ketamine in the treatment of mood disorders.
In 2018, Ionescu and colleagues published a comprehensive review of 47 neuroimaging studies investigating the effects of ketamine in the brain and discussed several emerging patterns which might be responsible for these effects. The researchers identified the reduction in the blood flow in the subgenual anterior cingulate cortex and the orbitofrontal cortex as a possible mechanism behind the dissociation effect. Although not consistently reported by all the reviewed studies, this particular action of ketamine leading to dissociation might play an important role in the antidepressant effect. Inhibition of the Default Mode Network (DMN) and self-monitoring behaviors may significantly contribute to mood improvements and increased emotional control. Other studies proposed further candidate mechanisms. Zanos and Gould (2018) discussed GABAergic synaptic inhibition, BNDF signaling, and NMDA receptor inhibition-independent mechanisms. In another publication by Zanos, Gould, and colleagues (2018), a convergent mechanism of ketamine antidepressant action in the brain was proposed. Nugent et al. (2019) investigated the gamma wave oscillations in antidepressant response to ketamine, while Siegel and colleagues (2021) focused on connectivity in the limbic system and the frontal lobe.

Sanacora, G., Frye, M.A., McDonald, W., … & Nemeroff, C.B. (2017) A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders. JAMA Psychiatry, 74(4):399–405

Importance: Several studies now provide evidence of ketamine hydrochloride’s ability to produce rapid and robust antidepressant effects in patients with mood and anxiety disorders that were previously resistant to treatment. Despite the relatively small sample sizes, lack of longer-term data on efficacy, and limited data on safety provided by these studies, they have led to increased use of ketamine as an off-label treatment for mood and other psychiatric disorders.
Observations: This review and consensus statement provides a general overview of the data on the use of ketamine for the treatment of mood disorders and highlights the limitations of the existing knowledge. While ketamine may be beneficial to some patients with mood disorders, it is important to consider the limitations of the available data and the potential risk associated with the drug when considering the treatment option.
Conclusions and Relevance: The suggestions provided are intended to facilitate clinical decision making and encourage an evidence-based approach to using ketamine in the treatment of psychiatric disorders considering the limited information that is currently available. This article provides information on potentially important issues related to the off-label treatment approach that should be considered to help ensure patient safety.

Ionescu, D. F., Felicione, J. M., Gosai, A., Cusin, C., Shin, P., Shapero, B. G., and Deckersbach, T. (2018). Ketamine-Associated Brain Changes: A Review of the Neuroimaging Literature. Harvard Review of Psychiatry, 26(6):320–339

Major depressive disorder (MDD) is one of the most prevalent conditions in psychiatry. Patients who do not respond to traditional monoaminergic antidepressant treatments have an especially difficult-to-treat type of MDD termed treatment-resistant depression. Interestingly, subanesthetic doses of ketamine—a glutamatergic modulator—have shown great promise for rapidly treating patients with the most severe forms of depression. As such, ketamine represents a promising probe for understanding the pathophysiology of depression and treatment response. Through neuroimaging, ketamine’s mechanism may be elucidated in humans. Here, we review 47 articles of ketamine’s effects as outlined by neuroimaging studies. Taken together, some important brain areas emerge, especially the subgenual anterior cingulate cortex. Furthermore, ketamine may decrease the ability to self-monitor, increase emotional blunting, and increase activity in reward processing. However, further studies are necessary to elucidate ketamine’s mechanism of antidepressant action.

Zanos, P. and Gould, T. D. (2018). Mechanisms of ketamine action as an antidepressant. Molecular psychiatry, 23(4):801–811

Clinical studies have demonstrated that a single sub-anesthetic dose of the dissociative anesthetic ketamine induces rapid and sustained antidepressant actions in treatment-resistant patients. Although this finding has been met with enthusiasm, ketamine’s widespread use is limited by its abuse potential and dissociative properties. Recent preclinical research has focused on unraveling the molecular mechanisms underlying the unique antidepressant actions of ketamine in an effort to develop novel pharmacotherapies, which will mimic ketamine’s antidepressant actions but lack its undesirable effects. Here, we review hypotheses for the mechanism of action of ketamine as an antidepressant, including direct synaptic or extra-synaptic (GluN2B-selective) NMDAR inhibition, selective inhibition of NMDARs localized on GABAergic interneurons, and the role of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) activation. We also discuss links between ketamine’s antidepressant actions and downstream mechanisms regulating synaptic plasticity, including brain-derived neurotrophic factor (BDNF), eukaryotic elongation factor 2 (eEF2), mechanistic target of rapamycin (mTOR), and glycogen synthase kinase-3 (GSK-3). Mechanisms that do not involve direct inhibition of the NMDAR, including a role for ketamine’s (R)-ketamine enantiomer and hydroxynorketamine (HNK) metabolites, specifically (2R,6R)-HNK, are also discussed. Proposed mechanisms of ketamine’s action are not mutually exclusive and may act in a complementary fashion to exert the acute changes in synaptic plasticity, leading to sustained strengthening of excitatory synapses, which are necessary for antidepressant behavioral actions. Understanding the molecular mechanisms underpinning ketamine’s antidepressant actions will be invaluable for the identification of targets, which will drive the development of novel, effective, next-generation pharmacotherapies for the treatment of depression.

Zanos, P., Thompson, S. M., Duman, R. S., Zarate, C. A., Jr, & Gould, T. D. (2018). Convergent Mechanisms Underlying Rapid Antidepressant Action. CNS drugs, 32(3):197–227

Traditional pharmacological treatments for depression have a delayed therapeutic onset, ranging from several weeks to months, and there is a high percentage of individuals who never respond to treatment. In contrast, ketamine produces rapid-onset antidepressant, anti-suicidal, and anti-anhedonic actions following a single administration to patients with depression. Proposed mechanisms of the antidepressant action of ketamine include N-methyl-d-aspartate receptor (NMDAR) modulation, gamma aminobutyric acid (GABA)-ergic interneuron disinhibition, and direct actions of its hydroxynorketamine (HNK) metabolites. Downstream actions include activation of the mechanistic target of rapamycin (mTOR), deactivation of glycogen synthase kinase-3 and eukaryotic elongation factor 2 (eEF2), enhanced brain-derived neurotrophic factor (BDNF) signaling, and activation of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors (AMPARs). These putative mechanisms of ketamine action are not mutually exclusive and may complement each other to induce potentiation of excitatory synapses in affective-regulating brain circuits, which results in amelioration of depression symptoms. We review these proposed mechanisms of ketamine action in the context of how such mechanisms are informing the development of novel putative rapid-acting antidepressant drugs. Such drugs that have undergone pre-clinical, and in some cases clinical, testing include the muscarinic acetylcholine receptor antagonist scopolamine, GluN2B-NMDAR antagonists (i.e., CP-101,606, MK-0657), (2R,6R)-HNK, NMDAR glycine site modulators (i.e., 4-chlorokynurenine, pro-drug of the glycineB NMDAR antagonist 7-chlorokynurenic acid), NMDAR agonists [i.e., GLYX-13 (rapastinel)], metabotropic glutamate receptor 2/3 (mGluR2/3) antagonists, GABAA receptor modulators, and drugs acting on various serotonin receptor subtypes. These ongoing studies suggest that the future acute treatment of depression will typically occur within hours, rather than months, of treatment initiation.

Nugent, A.C., Ballard, E.D., Gould, T.D. et al. (2019) Ketamine has distinct electrophysiological and behavioral effects in depressed and healthy subjects. Mol Psychiatry, 24:1040–1052

Ketamine’s mechanism of action was assessed using gamma power from magnetoencephalography (MEG) as a proxy measure for homeostatic balance in 35 unmedicated subjects with major depressive disorder (MDD) and 25 healthy controls enrolled in a double-blind, placebo-controlled, randomized cross-over trial of 0.5 mg/kg ketamine. MDD subjects showed significant improvements in depressive symptoms, and healthy control subjects exhibited modest but significant increases in depressive symptoms for up to 1 day after ketamine administration. Both groups showed increased resting gamma power following ketamine. In MDD subjects, gamma power was not associated with the magnitude of the antidepressant effect. However, baseline gamma power was found to moderate the relationship between post-ketamine gamma power and antidepressant response; specifically, higher post-ketamine gamma power was associated with better response in MDD subjects with lower baseline gamma, with an inverted relationship in MDD subjects with higher baseline gamma. This relationship was observed in multiple regions involved in networks hypothesized to be involved in the pathophysiology of MDD. This finding suggests biological subtypes based on the direction of homeostatic dysregulation and has important implications for inferring ketamine’s mechanism of action from studies of healthy controls alone.

Siegel, J. S., Palanca, B., Ances, B. M., Kharasch, E. D., Schweiger, J. A., Yingling, M. D., Snyder, A. Z., Nicol, G. E., Lenze, E. J., & Farber, N. B. (2021). Prolonged ketamine infusion modulates limbic connectivity and induces sustained remission of treatment-resistant depression. Psychopharmacology

Ketamine produces a rapid antidepressant response in over 50% of adults with treatment-resistant depression. A long infusion of ketamine may provide durable remission of depressive symptoms, but the safety, efficacy, and neurobiological correlates are unknown. In this open-label, proof-of-principle study, adults with treatment-resistant depression (N = 23) underwent a 96-h infusion of intravenous ketamine (0.15 mg/kg/h titrated toward 0.6 mg/kg/h). Clonidine was co-administered to reduce psychotomimetic effects. We measured clinical response for 8 weeks post-infusion. Resting-state functional magnetic resonance imaging was used to assess functional connectivity in patients pre- and 2 weeks post-infusion and in matched non-depressed controls (N = 27). We hypothesized that responders to therapy would demonstrate response-dependent connectivity changes while all subjects would show treatment-dependent connectivity changes. Most participants completed infusion (21/23; mean final dose 0.54 mg/kg/h, SD 0.13). The infusion was well tolerated with minimal cognitive and psychotomimetic side effects. Depressive symptoms were markedly reduced (MADRS 29 ± 4 at baseline to 9 ± 8 one day post-infusion), which was sustained at 2 weeks (13 ± 8) and 8 weeks (15 ± 8). Imaging demonstrated a response-dependent decrease in hyperconnectivity of the subgenual anterior cingulate cortex to the default mode network, and a treatment-dependent decrease in hyperconnectivity within the limbic system (hippocampus, amygdala, medial thalamus, nucleus accumbens). In exploratory analyses, connectivity was increased between the limbic system and frontal areas, and smaller right hippocampus volume at baseline predicted larger MADRS change. A single prolonged infusion of ketamine provides a tolerated, rapid, and sustained response in treatment-resistant depression and normalizes depression-related hyperconnectivity in the limbic system and frontal lobe.

Role of Glutamate

The psychosis-like effects of ketamine administration, most likely arising from NMDA receptor inhibition, have been investigated by numerous studies. Interestingly, Deakin and colleagues (2008) observed that the enhancement of glutamate (Glu) release might be a key mediator of the subjective effects of ketamine.
The complexity of the glutamate system was further explored by Murrough and colleagues (2017); the inhibitory action of ketamine may contribute to the restoration of healthy Glu signaling via a decrease in the activity of inhibitory GABA receptors. Although ketamine leads to both the promotion and the inhibition of Glu signaling, the antidepressant effect might also result from NMDA receptor-independent mechanisms.
The “glutamate inhibition” and “glutamate activation” hypotheses were also discussed in a review published by researchers led by Abdallah (together with John Krystal mentioned in #1), who proposed a synaptic connectivity model which accounts for extrasynaptic Glu levels and the levels of NMDA receptor expression. Overall, it seems that modulation of glutamate release, both inhibition and release, contribute to the effects of ketamine.

Deakin, J.F.W., Lees, J., McKie, S., Hallak, J.E.C., Williams, S.R., and Dursun, S.M. (2008) Glutamate and the Neural Basis of the Subjective Effects of Ketamine: A Pharmaco–Magnetic Resonance Imaging Study. Arch Gen Psychiatry. 65(2):154–164

Context: Ketamine evokes psychosislike symptoms, and its primary action is to impair N-methyl-D-aspartate glutamate receptor neurotransmission, but it also induces secondary increases in glutamate release.
Objectives: To identify the sites of action of ketamine in inducing symptoms and to determine the role of increased glutamate release using the glutamate release inhibitor lamotrigine.
Design: Two experiments with different participants were performed using a double-blind, placebo-controlled, randomized, crossover, counterbalanced-order design. In the first experiment, the effect of intravenous ketamine hydrochloride on regional blood oxygenation level–dependent (BOLD) signal and correlated symptoms was compared with intravenous saline placebo. In the second experiment, pretreatment with lamotrigine was compared with placebo to identify which effects of ketamine are mediated by increased glutamate release.
Setting: Wellcome Trust Clinical Research Facility, Manchester, England.
Participants: Thirty-three healthy, right-handed men were recruited by advertisements.
Interventions: In experiment 1, participants were given intravenous ketamine (1-minute bolus of 0.26 mg/kg, followed by a maintenance infusion of 0.25 mg/kg/h for the remainder of the session) or placebo (0.9% saline solution). In experiment 2, participants were pretreated with 300 mg of lamotrigine or placebo and then were given the same doses of ketamine as in experiment 1.
Main Outcome Measures: Regional BOLD signal changes during ketamine or placebo infusion and Brief Psychiatric Rating Scale and Clinician-Administered Dissociative States Scale scores.
Results: Ketamine induced a rapid, focal, and unexpected decrease in ventromedial frontal cortex, including orbitofrontal cortex and subgenual cingulate, which strongly predicted its dissociative effects and increased activity in mid-posterior cingulate, thalamus, and temporal cortical regions (r = 0.90). Activations correlated with Brief Psychiatric Rating Scale psychosis scores. Lamotrigine pretreatment prevented many of the BOLD signal changes and the symptoms.
Conclusions: These 2 changes may underpin 2 fundamental processes of psychosis: abnormal perceptual experiences and impaired cognitive-emotional evaluation of their significance. The results are compatible with the theory that the neural and subjective effects of ketamine involve increased glutamate release.

Murrough, J., Abdallah, C. and Mathew, S. (2017) Targeting glutamate signalling in depression: progress and prospects. Nat Rev Drug Discov, 16:472–486

Major depressive disorder (MDD) is severely disabling, and current treatments have limited efficacy. The glutamate N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine was recently repurposed as a rapidly acting antidepressant, catalysing the vigorous investigation of glutamate-signalling modulators as novel therapeutic agents for depressive disorders. In this Review, we discuss the progress made in the development of such modulators for the treatment of depression, and examine recent preclinical and translational studies that have investigated the mechanisms of action of glutamate-targeting antidepressants. Fundamental questions remain regarding the future prospects of this line of drug development, including questions concerning safety and tolerability, efficacy, dose–response relationships and therapeutic mechanisms.

Abdallah, C.G., Sanacora, G., Duman, R.S., Krystal, J.H. (2018) The neurobiology of depression, ketamine and rapid-acting antidepressants: Is it glutamate inhibition or activation? Pharmacology & Therapeutics, 190:148-158

The discovery of the antidepressant effects of ketamine has opened a breakthrough opportunity to develop a truly novel class of safe, effective, and rapid-acting antidepressants (RAADs). In addition, the rapid and robust biological and behavioral effects of ketamine offered a unique opportunity to utilize the drug as a tool to thoroughly investigate the neurobiology of stress and depression in animals, and to develop sensitive and reproducible biomarkers in humans. The ketamine literature over the past two decades has considerably enriched our understanding of the mechanisms underlying chronic stress, depression, and RAADs. However, considering the complexity of the pharmacokinetics and in vivo pharmacodynamics of ketamine, several questions remain unanswered and, at times, even answered questions continue to be considered controversial or at least not fully understood. The current perspective paper will summarize our understanding of the neurobiology of depression, and the mechanisms of action of ketamine and other RAADs. The review will focus on the role of glutamate neurotransmission – reviewing the history of the “glutamate inhibition” and “glutamate activation” hypotheses, proposing a synaptic connectivity model of chronic stress pathology, and describing the mechanism of action of ketamine. It will also summarize the clinical efficacy findings of putative RAADs, present relevant human biomarker findings, and discuss current challenges and future directions.

Suicidal Ideation            

Suicidal ideation (SI) is a phenomenon characterized by thinking about, considering, or actively planning suicide. For those suffering from mental health disorders, an above-average percentage also suffers from SI. Currently, there are no effective treatments available, but ketamine is showing promise to rapidly lower scores of SI measures.
A randomized controlled trial (RCT) with 80 participants who suffered from depression showed that a single treatment with ketamine (versus midazolam, an active placebo) led to significant reductions in suicidal ideation. Grunebaum and colleagues (2018) found that within 24h, 55% of subjects (versus 30% in the placebo group) had a 50% or greater reduction in SI scores. Part of this effect was mediated by the general mood improvement. With continued treatment, the reduction in SI was maintained for the whole six weeks of the study course.
A meta-analysis on 167 patients suffering from a mental health disorder and suicidal ideation by Wilkinson and colleagues (2018) found that ketamine led to moderate- to large improvements of SI. This meta-analysis assessed the immediate relief that ketamine provides and posited that the effect on SI is partly independent of changes in mental health scores.
A recent study by Can and colleagues (2021) provided further evidence of the positive effects of ketamine on SI. The study with 32 participants suffering from chronic SI was done with an open-label design – every subject received ketamine. The group used six repeated oral dosages over six weeks. The data showed that even four weeks after the study, 50% of the participants reported significant improvement, showing that with repeated dosages, the positive effects may continue for several weeks and offering a possible treatment for acute SI cases.

Grunebaum, M. F., Galfalvy, H. C., Choo, T. H., Keilp, J. G., Moitra, V. K., Parris, M. S., ... & Mann, J. J. (2018). Ketamine for rapid reduction of suicidal thoughts in major depression: a midazolam-controlled randomized clinical trial. American Journal of Psychiatry, 175(4):327-335

Objective: Pharmacotherapy to rapidly relieve suicidal ideation in depression may reduce suicide risk. Rapid reduction in suicidal thoughts after ketamine treatment has mostly been studied in patients with low levels of suicidal ideation.
Method: This randomized clinical trial tested the effect of adjunctive sub-anesthetic intravenous ketamine on clinically significant suicidal ideation in major depressive disorder (MDD). Adults (N=80) with current MDD and score ≥4 on the Scale for Suicidal Ideation (SSI), of whom 54% (N=43) were taking antidepressant medication, were randomized to ketamine or midazolam infusion. The primary outcome was Day 1 SSI score (24 hours post-infusion). Other outcomes included global depression and adverse effects.
Results: Reduction of SSI score was 4.96 points greater after ketamine compared with midazolam at Day 1 (95% confidence interval (CI)=2.33 to 7.59; p=0.0003; Cohen’s d=0.75). Proportion of responders (≥50% reduction in SSI) at Day 1 was 55% after ketamine and 30% after midazolam (OR=2.85 (95% CI=1.14 to 7.15); p=0.0237; NNT=4.00). Improvement in the Profile of Mood States (POMS) depression subscale was greater at Day 1 compared with midazolam treatment (Estimate=7.65 (95% CI=1.36 to 13.94), df=75, t=2.42, p=0.0178), and this effect mediated 33.6% of ketamine’s effect on SSI score. Side effects were short-lived. Benefit was sustained for up to six weeks with clinical pharmacotherapy.
Conclusions: Adjunctive ketamine demonstrated greater reduction of clinically significant suicidal ideation in depressed patients within 24 hours compared to midazolam, partially independent of antidepressant effect. Research is needed to understand ketamine’s mechanism of action and to develop safe, longer-term treatment.

Wilkinson, S. T., Ballard, E. D., Bloch, M. H., Mathew, S. J., Murrough, J. W., Feder, A., ... & Sanacora, G. (2018). The effect of a single dose of intravenous ketamine on suicidal ideation: a systematic review and individual participant data meta-analysis. American Journal of Psychiatry, 175(2):150-158

Objective: Suicide is a public health crisis with limited treatment options. The authors conducted a systematic review and individual participant data meta-analysis examining the effects of a single dose of ketamine on suicidal ideation.
Method: Individual participant data were obtained from 10 of 11 identified comparison intervention studies that used either saline or midazolam as a control treatment. The analysis included only participants who had suicidal ideation at baseline (N=167). A one-stage, individual participant data, meta-analytic procedure was employed using a mixed-effects, multilevel, general linear model. The primary outcome measures were the suicide items from clinician-administered (the Montgomery-Åsberg Depression Rating Scale [MADRS] or the Hamilton Depression Rating Scale [HAM-D]) and self-report scales (the Quick Inventory of Depressive Symptomatology–Self Report [QIDS-SR] or the Beck Depression Inventory [BDI]), obtained for up to 1 week after ketamine administration.
Results: Ketamine rapidly (within 1 day) reduced suicidal ideation significantly on both the clinician-administered and self-report outcome measures. Effect sizes were moderate to large (Cohen’s d=0.48–0.85) at all time points after dosing. A sensitivity analysis demonstrated that compared with control treatments, ketamine had significant benefits on the individual suicide items of the MADRS, the HAM-D, and the QIDS-SR but not the BDI. Ketamine’s effect on suicidal ideation remained significant after adjusting for concurrent changes in severity of depressive symptoms.
Conclusions: Ketamine rapidly reduced suicidal thoughts, within 1 day and for up to 1 week in depressed patients with suicidal ideation. Ketamine’s effects on suicidal ideation were partially independent of its effects on mood, although subsequent trials in transdiagnostic samples are required to confirm that ketamine exerts a specific effect on suicidal ideation. Additional research on ketamine’s long-term safety and its efficacy in reducing suicide risk is needed before clinical implementation.

Can, A. T., Hermens, D. F., Dutton, M., Gallay, C. C., Jensen, E., Jones, M., ... & Lagopoulos, J. (2021). Low dose oral ketamine treatment in chronic suicidality: An open-label pilot study. Translational Psychiatry, 11(1):1-9

Recently, low-dose ketamine has been proposed as a rapid-acting treatment option for suicidality. The majority of studies to date have utilised intravenous (IV) ketamine, however, this route of administration has limitations. On the other hand, oral ketamine can be administered in a range of settings, which is important in treating suicidality, although studies as to safety and feasibility are lacking. n = 32 adults (aged 22–72 years; 53% female) with chronic suicidal thoughts participated in the Oral Ketamine Trial on Suicidality (OKTOS), an open-label trial of sub-anaesthetic doses of oral ketamine over 6 weeks. Participants commenced with 0.5 mg/kg of ketamine, which was titrated to a maximum 3.0 mg/kg. Follow-up assessments occurred at 4 weeks after the final dose. The primary outcome measure was the Beck Scale for Suicide Ideation (BSS) and secondary measures included scales for suicidality and depressive symptoms, and measures of functioning and well-being. Mean BSS scores significantly reduced from a high level of suicidal ideation at the pre-ketamine (week 0) timepoint to below the clinical threshold at the post-ketamine (week 6) timepoint. The proportion of participants that achieved clinical improvement within the first 6 weeks was 69%, whereas 50% achieved a significant improvement by the follow-up (week 10) timepoint. Six weeks of oral ketamine treatment in participants with chronic suicidality led to significant reduction in suicidal ideation. The response observed in this study is consistent with IV ketamine trials, suggesting that oral administration is a feasible and tolerable alternative treatment for chronic suicidality.

Electroconvulsive Therapy

Electroconvulsive therapy (ECT) uses small electric currents to induce seizures in the brain. Via several mechanisms, this treatment can lead to positive outcomes for those suffering from depression, mania, and schizophrenia. Although the treatment is effective, it can lead to transient memory loss and other adverse effects. Currently, ECT is a standard practice in treating severe depression.
Basso and colleagues (2020) compared repeated dosages of ketamine to ECT in 50 patients. They found that both led to similar improvements in depression scores. Ketamine also led to improvements in brain functions, whereas ECT led to small decreases.
A broader outlook was explored in a recent review by Veraart and colleagues (2020). The researchers reviewed studies that combined ECT and ketamine treatments and did not find conclusive evidence for ketamine being more effective. Although the antidepressant effects are quicker, they are also more transient.
When combining both treatments in the same patients, for a population that did not benefit from ECT alone, positive effects were found and sustained for seven days. A study by Jianjing Zang and colleagues (2020) found that the combination also led to decreased connectivity in the Default Mode Network (DMN).
Overall, it is not clear yet if ketamine could entirely replace ECT in MDD treatment.

Basso, L., Bönke, L., Aust, S., Gärtner, M., Heuser-Collier, I., Otte, C., ... & Grimm, S. (2020). Antidepressant and neurocognitive effects of serial ketamine administration versus ECT in depressed patients. Journal of Psychiatric Research, 123:1-8

Background: While electroconvulsive therapy (ECT) is considered the gold standard for acute treatment of patients with otherwise treatment-resistant depression, ketamine has recently emerged as a fast-acting treatment alternative for these patients. Efficacy and onset of action are currently among the main factors that influence clinical decision making, however, the effect of these treatments on cognitive functions should also be a crucial point, given that cognitive impairment in depression is strongly related to disease burden and functional recovery. ECT is known to induce transient cognitive impairment, while little is known about ketamine's impact on cognition. This study therefore aims to compare ECT and serial ketamine administration not only with regard to their antidepressant efficacy but also to acute neurocognitive effects.
Methods: Fifty patients suffering from depression were treated with either serial ketamine infusions or ECT. Depression severity and cognitive functions were assessed before, during, and after treatment.
Results: ECT and ketamine administration were equally effective, however, the antidepressant effects of ketamine occurred faster. Ketamine improved neurocognitive functioning, especially attention and executive functions, whereas ECT was related to a small overall decrease in cognitive performance.
Conclusions: Due to its pro-cognitive effects and faster antidepressant effect, serial ketamine administration might be a more favorable short-term treatment option than ECT.
Limitations: As this research employed a naturalistic study design, patients were not systematically randomized, there was no control group and patients received concurrent and partially changing medications during treatment.

Zhang, J., Tian, H., Li, J., Ji, S., Chen, S., Zhu, J., ... & Zhuo, C. (2020). Ketamine plus propofol-electroconvulsive therapy (ECT) transiently improves the antidepressant effects and the associated brain functional alterations in patients with propofol-ECT-resistant depression. Psychiatry Research, 287:112907

New methods for using ketamine in patients with propofol-electroconvulsive therapy-resistant depression (ECT-RD) are needed in the clinic. This study aimed to investigate the therapeutic efficacy of ketamine plus ECT in ECT-RD patients, along with the treatment-induced brain alterations. A total of 28 ECT-RD patients were intravenously injected with ketamine six times and treated with propofol-ECT six times alternately within two weeks. The Hamilton Depression Scale was used to assess the treatment effect. Global functional connectivity density (gFCD) and functional connectivity strength (FCS) were used to evaluate functional brain alterations. As compared with the propofol-ECT treatment group, the addition of ketamine could improve the therapeutic outcomes in patients with ECT-RD. The treatment increased gFCD in the left temporal and subgenual anterior cingulated cortex. Simultaneously, the treatment decreased FCS within the default mode network. Although increased functional connectivity could be sustained for 10 days, the clinical effect was only sustained 7 days, indicating that the clinical effect and functional brain alterations were disjointed. Ketamine plus propofol-ECT can obviously improve the effects of propofol-ECT in ECT-RD patients. However, the effect is limited in 7 days, suggesting the benefit is short-term.

Veraart, J. K., Smith-Apeldoorn, S. Y., Spaans, H. P., Kamphuis, J., & Schoevers, R. A. (2020). Is ketamine an appropriate alternative to ECT for patients with treatment-resistant depression? A systematic review. Journal of Affective Disorders

Objective: Ketamine has repeatedly shown to have rapid and robust antidepressant effects in patients with treatment resistant depression (TRD). An important question is whether ketamine is as effective and safe as the current gold standard electroconvulsive therapy (ECT).
Methods: The literature was searched for trials comparing ketamine treatment with ECT for depression in the Pubmed/MEDLINE database and Cochrane Trials Library.
Results: A total of 137 manuscripts were identified, 6 articles were included in this review. Overall quality of the included studies was diverse with relevant risk of bias for some of the studies. Results suggest that ketamine treatment might give faster but perhaps less durable antidepressant effects. Side effects differed from ECT, in particular less cognitive impairment was apparent in ketamine treatment.
Limitations: The included studies have limited sample sizes, use different treatment protocols and in most trials, longer term follow up is lacking. Furthermore, allocation bias appears likely in the non-randomized trials.
Conclusions: Current available literature does not yet provide convincing evidence to consider ketamine as an equally effective treatment alternative to ECT in patients with TRD. There are indications for a more favourable short term cognitive side effect profile after ketamine treatment. Methodologically well-designed studies with larger sample sizes and longer follow up duration are warranted.

Esketamine

As already mentioned in the introduction, ketamine can be administered in two different enantiomers or a (race)mix of both. A systematic review and meta-analysis of over 1800 administrations investigated the effect differences between esketamine and the racemic mixture in depression. Bahji and colleagues (2020) found that the racemic ketamine led to greater overall response and lower dropout rates in the 24 trials they studied. Further studies are necessary to establish the exact differences in effects induced by r-ketamine, s-ketamine, and the racemic mixture.

Bahji, A., Vazquez, G. H., & Zarate Jr, C. A. (2020). Comparative efficacy of racemic ketamine and esketamine for depression: A systematic review and meta-analysis. Journal of Affective Disorders, 278: 542-555

Background: Ketamine appears to have a therapeutic role in certain mental disorders, most notably depression. However, the comparative performance of different formulations of ketamine is less clear.
Objectives: This study aimed to assess the comparative efficacy and tolerability of racemic and esketamine for the treatment of unipolar and bipolar major depression.
Design: Systematic review and meta-analysis.
Data sources: We searched PubMed, MEDLINE, Embase, PsycINFO, the Cochrane Central Register of Controlled Clinical Trials, and the Cochrane Database of Systematic Reviews for relevant studies published since database inception and December 17, 2019.
Study eligibility criteria: We considered randomized controlled trials examining racemic or esketamine for the treatment of unipolar or bipolar major depression.
Outcomes: Primary outcomes were response and remission from depression, change in depression severity, suicidality, retention in treatment, drop-outs, and drop-outs due to adverse events.
Analysis: Evidence from randomized controlled trials was synthesized as rate ratios (RRs) for treatment response, disorder remission, adverse events, and withdrawals and as standardized mean differences (SMDs) for change in symptoms, via random-effects meta-analyses.
Findings: 24 trials representing 1877 participants were pooled. Racemic ketamine relative to esketamine demonstrated greater overall response (RR = 3.01 vs. RR = 1.38) and remission rates (RR = 3.70 vs. RR = 1.47), as well as lower dropouts (RR = 0.76 vs. RR = 1.37).
Conclusions: Intravenous ketamine appears to be more efficacious than intranasal esketamine for the treatment of depression.

PTSD

Patients suffering from chronic post-traumatic stress disorder (PTSD) have shown significant improvements after treatment with ketamine. A double-blind study with the active placebo control midazolam by Feder and colleagues (2021) found that two weeks after six infusions of ketamine, 67% of the group (versus 20% in the control group) positively responded to the treatment. The mean CAPS-5 score (a measure of PTSD symptoms) was 12 points lower than in the control group. The effects were maintained on average for one month, after which half of the responders (from the initial 67% of participants) were back at a high score on the PTSD scale. This study shows that extended treatment duration may promise to lengthen the treatment effects of ketamine on mental health disorders.
An earlier review of the literature by Felix Liriano and colleagues (2019) showed effects only lasting up to two weeks and only one earlier double-blind study was reported on. The review also concluded that there were no safety issues and that up to 49mg/70kg, no adverse events were reported.

Feder, A., Costi, S., Rutter, S. B., Collins, A. B., Govindarajulu, U., Jha, M. K., ... & Charney, D. S. (2021). A Randomized Controlled Trial of Repeated Ketamine Administration for Chronic Posttraumatic Stress Disorder. American Journal of Psychiatry, 178(2):193-202

Objective: Posttraumatic stress disorder (PTSD) is a chronic and disabling disorder, for which available pharmacotherapies have limited efficacy. The authors’ previous proof-of-concept randomized controlled trial of single-dose intravenous ketamine infusion in individuals with PTSD showed significant and rapid PTSD symptom reduction 24 hours postinfusion. The present study is the first randomized controlled trial to test the efficacy and safety of repeated intravenous ketamine infusions for the treatment of chronic PTSD.
Methods: Individuals with chronic PTSD (N=30) were randomly assigned (1:1) to receive six infusions of ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg) (psychoactive placebo control) over 2 consecutive weeks. Clinician-rated and self-report assessments were administered 24 hours after the first infusion and at weekly visits. The primary outcome measure was change in PTSD symptom severity, as assessed with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), from baseline to 2 weeks (after completion of all infusions). Secondary outcome measures included the Impact of Event Scale–Revised, the Montgomery-Åsberg Depression Rating Scale (MADRS), and side effect measures.
Results: The ketamine group showed a significantly greater improvement in CAPS-5 and MADRS total scores than the midazolam group from baseline to week 2. At week 2, the mean CAPS-5 total score was 11.88 points (SE=3.96) lower in the ketamine group than in the midazolam group (d=1.13, 95% CI=0.36, 1.91). Sixty-seven percent of participants in the ketamine group were treatment responders, compared with 20% in the midazolam group. Among ketamine responders, the median time to loss of response was 27.5 days following the 2-week course of infusions. Ketamine infusions were well tolerated overall, without serious adverse events.
Conclusions: This randomized controlled trial provides the first evidence of efficacy of repeated ketamine infusions in reducing symptom severity in individuals with chronic PTSD. Further studies are warranted to understand ketamine’s full potential as a treatment for chronic PTSD.

Liriano, F., Hatten, C., & Schwartz, T. L. (2019). Ketamine as treatment for post-traumatic stress disorder: a review. Drugs in Context, 8:212305

Post-traumatic stress disorder (PTSD) continues to make headlines given multiple military engagements across the world and civilian traumas, and resultant PTSD development continues at an even pace. Currently, antidepressant and cognitive-behavioral therapy have the greatest evidence base but still do not yield a remission of PTSD symptoms in many patients. Off-label and novel treatments continue to be considered for more refractory and disabling cases of PTSD. Ketamine is one such treatment that has been discussed and utilized more often for treatment-resistant major depressive disorder (MDD). Its mechanism is controversial regarding its potential to create anxiety, but the perceived benefit of a rapid reduction of symptoms makes it worthy for study in animal models of, and possibly human studies in, PTSD. The current literature and theoretical mechanism of action is discussed in this manuscript.

Substance Use Disorder

Another important aspect of ketamine efficacy is its effect in the treatment of patients suffering from substance use disorders (SUDs). Ketamine treatment, after detoxification, has been shown to prolong abstinence from alcohol and heroin.

Already an early study by Kruptsky and Grinenko (1997) showed that one year post-treatment 66% of the ketamine treated group, versus 24% of the conventionally treated group, were abstinent from alcohol. The study with over 200 participants did, however, lack randomization and blinding. Participation in the ketamine group was based on motivation, and participants knew who received ketamine or not.
Ezquerra-Romano and colleagues (2018) reviewed the recent literature and found that ketamine reduced cravings for cocaine in recreational users. The neuroplasticity effects and blocking reconsolidation of drug-related memories are the likely candidate mechanisms playing an important role in this observation.

Krupitsky, E. M., & Grinenko, A. Y. (1997). Ketamine psychedelic therapy (KPT): a review of the results of ten years of research. Journal of Psychoactive Drugs, 29(2):165–183

Ketamine is a prescription drug used for general anesthesia. In subanesthetic doses, it induces profound psychedelic experiences and hallucinations. The subanesthetic effect of ketamine was the hypothesized therapeutic mechanism in the authors' use of ketamine-assisted psychotherapy for alcoholism. The results of a controlled clinical trial demonstrated a considerable increase in efficacy of the authors' standard alcoholism treatment when supplemented by ketamine psychedelic therapy (KPT). Total abstinence for more than one year was observed in 73 out of Ill (65.8%) alcoholic patients in the KPT group, compared to 24% (24 out of 100 patients) of the conventional treatment control group (p<0.01). The authors' studies of the underlying psychological mechanisms of KPT have indicated that ketamine-assisted psychedelic therapy of alcoholic patients induces a harmonization of the Minnesota Multiphasic Personality Inventory (MMPI) personality profile, positive transformation of nonverbalized (mostly unconscious) self-concept and emotional attitudes to various aspects of self and other people, positive changes in life values and purposes. important insights into the meaning of life and anincrease in the level of spiritual development. Most importantly, these psychological changes were shown to favor a sober lifestyle. The data from biochemical investigations showed that the phannacological action of KPT affects both monoaminergic and opioidergic neurotransmitter metabolism, i.e., those neurochemical systems which are involved in the pathogenesis of alcohol dependence. The data from EEG computer-assisted analysis demonstrated that ketamine increases theta activity in cerebrocortical regions of alcoholic patients. This is evidence of the reinforcement of limbic cortex interaction during the KPT session.

Ezquerra-Romano, I. I., Lawn, W., Krupitsky, E., & Morgan, C. J. A. (2018). Ketamine for the treatment of addiction: Evidence and potential mechanisms. Neuropharmacology, 142:72-82

Ketamine is a dissociative anaesthetic drug which acts on the central nervous system chiefly through antagonism of the n-methyl-d-aspartate (NMDA) receptor. Recently, ketamine has attracted attention as a rapid-acting anti-depressant but other studies have also reported its efficacy in reducing problematic alcohol and drug use. This review explores the preclinical and clinical research into ketamine's ability to treat addiction. Despite methodological limitations and the relative infancy of the field, results thus far are promising. Ketamine has been shown to effectively prolong abstinence from alcohol and heroin in detoxified alcoholics and heroin dependent individuals, respectively. Moreover, ketamine reduced craving for and self-administration of cocaine in non-treatment seeking cocaine users. However, further randomised controlled trials are urgently needed to confirm ketamine's efficacy. Possible mechanisms by which ketamine may work within addiction include: enhancement of neuroplasticity and neurogenesis, disruption of relevant functional neural networks, treating depressive symptoms, blocking reconsolidation of drug-related memories, provoking mystical experiences and enhancing psychological therapy efficacy. Identifying the mechanisms by which ketamine exerts its therapeutic effects in addiction, from the many possible candidates, is crucial for advancing this treatment and may have broader implications understanding other psychedelic therapies. In conclusion, ketamine shows great promise as a treatment for various addictions, but well-controlled research is urgently needed.

Ketamine and ‘Classic’ Psychedelics

Ketamine and classical psychedelics (LSD, psilocybin) share the acute effect, which rapidly produces therapeutic outcomes (usually within 24h). Both types of substances lead to acute alterations in the brain network activity and, as discussed above, more subtle long-term changes. Although differences are present, some overlapping mechanisms are set in motion.
Savalia and colleagues (2020) established a framework that proposes that both ketamine and classical psychedelics induce excitability effects on the dendrites (information receivers) of brain cells. This model overlaps with the findings of Jelen et al. (2021), mentioned in the ‘molecular properties’ section. The neuronal calcium influx and accumulation leads to the upregulation of neurotrophins crucial in synapse formation, such as BDNF, mTOR, and TrkB. Ketamine and psychedelics both share this effect leading to an increase in neural plasticity.
The glutamatergic system plays a role in the effects of both types of substances, according to Kadriu and colleagues (2020). A glutamate surge, specifically in the layer V pyramidal neurons with serotonin receptors, has been found in studies with classical psychedelics. Still, many of the overlaps and different actions of both types of substances remain to be explored.
Interestingly, ketamine experiences may resemble psychedelic experiences because of the perceptual changes and the ‘afterglow’ effect. Sumner et al. (2021) suggested that, although the questionnaires used to measure the psychedelic experience might be inadequate for the psychedelic effects of ketamine, these effects are likely to contribute to the long-term antidepressant action of ketamine.

Kadriu, B., Greenwald, M., Henter, I. D., Gilbert, J. R., Kraus, C., Park, L. T., & Zarate Jr, C. A. (2021). Ketamine and serotonergic psychedelics: common mechanisms underlying the effects of rapid-acting antidepressants. International Journal of Neuropsychopharmacology, 24(1):8-21

Background: The glutamatergic modulator ketamine has created a blueprint for studying novel pharmaceuticals in the field. Recent studies suggest that “classic” serotonergic psychedelics (SPs) may also have antidepressant efficacy. Both ketamine and SPs appear to produce rapid, sustained antidepressant effects after a transient psychoactive period.
Methods: This review summarizes areas of overlap between SP and ketamine research and considers the possibility of a common, downstream mechanism of action. The therapeutic relevance of the psychoactive state, overlapping cellular and molecular effects, and overlapping electrophysiological and neuroimaging observations are all reviewed.
Results: Taken together, the evidence suggests a potentially shared mechanism wherein both ketamine and SPs may engender rapid neuroplastic effects in a glutamatergic activity-dependent manner. It is postulated that, though distinct, both ketamine and SPs appear to produce acute alterations in cortical network activity that may initially produce psychoactive effects and later produce milder, sustained changes in network efficiency associated with therapeutic response. However, despite some commonalities between the psychoactive component of these pharmacologically distinct therapies—such as engagement of the downstream glutamatergic pathway—the connection between psychoactive impact and antidepressant efficacy remains unclear and requires more rigorous research.
Conclusions: Rapid-acting antidepressants currently under investigation may share some downstream pharmacological effects, suggesting that their antidepressant effects may come about via related mechanisms. Given the prototypic nature of ketamine research and recent progress in this area, this platform could be used to investigate entirely new classes of antidepressants with rapid and robust actions

Savalia, N. K., Shao, L. X., & Kwan, A. C. (2020). A Dendrite-Focused Framework for Understanding the Actions of Ketamine and Psychedelics. Trends in Neurosciences, 44(4):260-275

Pilot studies have hinted that serotonergic psychedelics such as psilocybin may relieve depression, and could possibly do so by promoting neural plasticity. Intriguingly, another psychotomimetic compound, ketamine, is a fast-acting antidepressant and induces synapse formation. The similarities in behavioral and neural effects have been puzzling because the compounds target distinct molecular receptors in the brain. In this opinion article, we develop a conceptual framework that suggests the actions of ketamine and serotonergic psychedelics may converge at the dendrites, to both enhance and suppress membrane excitability. We speculate that mismatches in the opposing actions on dendritic excitability may relate to these compounds’ cell-type and region selectivity, their moderate range of effects and toxicity, and their plasticity-promoting capacities.

Sumner, R. L., Chacko, E., McMillan, R., Spriggs, M. J., Anderson, C., Chen, J., French, A., Jung, S., Rajan, A., Malpas, G., Hay, J., Ponton, R., Muthukumaraswamy, S. D., & Sundram, F. (2021). A qualitative and quantitative account of patient's experiences of ketamine and its antidepressant properties. Journal of Psychopharmacology

Background: Ketamine is central to one of the most rapidly growing areas of neuroscientific research into novel treatments for depression. Limited research has indicated that the psychedelic properties of ketamine may play a role in its antidepressant effects.
Aim: The aim of the current study was to explore the psychedelic experiences and sustained impact of ketamine in major depressive disorder.
Methods: In the current study, ketamine (0.44 mg/kg) was administered to 32 volunteers with major depressive disorder in a crossover design with the active-placebo remifentanil, in a magnetic resonance imaging (MRI) environment. The 11-dimension altered states of consciousness questionnaire and individual qualitative interviews were used to capture the acute psychedelic experience. The Montgomery-Asberg Depression Rating Scale and further interviewing explored lasting effects. The second qualitative interview took place ⩾3 weeks post-ketamine.
Results: Greater antidepressant response (reduction in Montgomery-Asberg Depression Rating Scale at 24 h) correlated with the 11-dimension altered states of consciousness dimensions: spirituality, experience of unity, and insight. The first qualitative interview revealed that all participants experienced perceptual changes. Additional themes emerged including loss of control and emotional and mood changes. The final interview showed evidence of a psychedelic afterglow, and changes to perspective on life, people, and problems, as well as changes to how participants felt about their depression and treatments.
Conclusions: The current study provides preliminary evidence for a role of the psychedelic experience and afterglow in ketamine’s antidepressant properties. Reflexive thematic analysis provided a wealth of information on participants’ experience of the study and demonstrated the psychedelic properties of ketamine are not fully captured by commonly used questionnaires.

Neuroplasticity

Alterations in dendritic spine morphology and spine density are possible markers of chronic stress and depression. The study of Sumner and colleagues (2020) investigated the effects of ketamine on neuroplasticity through the assessment of changes in predictive coding in patients suffering from treatment-resistant depression, based on the assumption that insensitivity to prediction error is one of the characteristics of depression. The results of this double-blind, active placebo-controlled study suggested that ketamine may have a positive effect on short-term plasticity through the restoration of sensitivity deficits of prediction error. This effect could improve the sensory context sensitivity, which is reduced by rumination and fatigue in MDD patients. Although there were several limitations to the study, such as the lack of a healthy control group and the fact that some patients were being treated with antidepressants during the course of the study, the data points out the potential of ketamine in improving short-term plasticity and sensitivity to prediction errors.

Sumner, R. L., McMillan, R., Spriggs, M. J., Campbell, D., Malpas, G., Maxwell, E., … & Muthukumaraswamy, S. D. (2020). Ketamine improves short-term plasticity in depression by enhancing sensitivity to prediction errors. European Neuropsychopharmacology, 38:73-85

Major depressive disorder negatively impacts the sensitivity and adaptability of the brain's predictive coding framework. The current electroencephalography study into the antidepressant properties of ketamine investigated the downstream effects of ketamine on predictive coding and short-term plasticity in thirty patients with depression using the auditory roving mismatch negativity (rMMN). The rMMN paradigm was run 3–4 h after a single 0.44 mg/kg intravenous dose of ketamine or active placebo (remifentanil infused to a target plasma concentration of 1.7 ng/mL) in order to measure the neural effects of ketamine in the period when an improvement in depressive symptoms emerges. Depression symptomatology was measured using the Montgomery-Asberg Depression Rating Scale (MADRS); 70% of patients demonstrated at least a 50% reduction their MADRS global score. Ketamine significantly increased the MMN and P3a event related potentials, directly contrasting literature demonstrating ketamine's acute attenuation of the MMN. This effect was only reliable when all repetitions of the post-deviant tone were used. Dynamic causal modelling showed greater modulation of forward connectivity in response to a deviant tone between right primary auditory cortex and right inferior temporal cortex, which significantly correlated with antidepressant response to ketamine at 24 h. This is consistent with the hypothesis that ketamine increases sensitivity to unexpected sensory input and restores deficits in sensitivity to prediction error that are hypothesised to underlie depression. However, the lack of repetition suppression evident in the MMN evoked data compared to studies of healthy adults suggests that, at least within the short term, ketamine does not improve deficits in adaptive internal model calibration.

Palliative Care and Pain Management

Lastly, ketamine has also been studied in the context of palliative care. Since classic psychedelics have previously shown positive effects on anxiety and depressive symptoms in cancer patients (Griffiths & Johnson, 2016), it seems worthwhile to investigate the effects shared with ketamine in terminal patients. Goldman and colleagues (2019) reviewed the literature and found that ketamine improved depression scores in a palliative care population.
Another study on ketamine found mixed results on the analgesic (pain-relieving) effect on the palliative care population. The recent investigation by Falk and colleagues (2020) found that esketamine lowered anxiety but not depression and pain scores. Nevertheless, the effects of ketamine administration in end-of-life stages may induce relief of psychological distress and increase life quality in terminal patients.

Goldman, N., Frankenthaler, M., & Klepacz, L. (2019). The efficacy of ketamine in the palliative care setting: a comprehensive review of the literature. Journal of Palliative Medicine, 22(9):1154-1161

Background: Previous literature suggests that ketamine may be an effective drug in the palliative care population as this drug has been shown to treat multiple conditions that are common in these patients.
Objective: This review examines the efficacy of ketamine for the treatment of depression and physical pain in palliative care patients. Methods: Eleven studies were included on the topic of ketamine as an antidepressant in the palliative care population. Additionally, 5 RCT studies were included on the topic of physical pain in this population.
Results: All 11 studies, including one RCT, found antidepressant effects of ketamine in this patient population. Ketamine's effect on treating physical pain was mixed with the largest and most recent RCTs suggesting no significant analgesic effect.
Discussion: This review suggests that starting qualified patients on intravenous (IV) ketamine and switching to oral or intranasal administration may be the most effective and convenient for treating depression, especially for patients who wish to receive treatment at home. Significant analgesia was found in patients who received epidural or intrathecal ketamine as well as in one study using intravenous administration. More research is necessary to determine which palliative care patients may benefit from ketamine treatment.

Falk, E., Schlieper, D., van Caster, P., Lutterbeck, M. J., Schwartz, J., Cordes, J., ... & Neukirchen, M. (2020). A rapid positive influence of S-ketamine on the anxiety of patients in palliative care: a retrospective pilot study. BMC palliative care, 19(1):1-15

Background: Patients in palliative care need rapid-acting pharmacological options for psychological distress. N-methyl-D-aspartate antagonist ketamine is known to have a fast onset of anti-depressant and anxiolytic action. Its S-enantiomer S-ketamine (or esketamine) is an analgesic used as a routine treatment for refractory pain as an intravenous infusion (0.25 mg/kg over 45 min). This study investigates whether S-ketamine pain therapy has a positive impact on psychological distress caused by anxiety and depression in palliative care.
Methods: Patient routine data from a palliative care unit of a tertiary care hospital were used in a retrospective analysis after positive ethics approval. Eight patients, who received analgesic S-ketamine treatment, were compared to a control group matched by gender and age. The main analysis was conducted using three-way mixed MANOVA followed by two-way mixed ANOVA. Target variables were the values for anxiety and depression in the state-trait anxiety-depression inventory STADI. The predictor variables were the time of measurement before (T1) and after (T2) S-ketamine application and group membership.
Results: Comparison of the S-ketamine group (n = 8; 4 male, 4 female; average age 52 years) with the control group (n = 8; 3 male, 5 female; average age 55 years) revealed a significant multivariate effect on anxiety and depression F(1, 14) = 4.78; p = 0.046; r = 0.50. The univariate comparisons showed a significant reduction of the anxiety scores from T1 to T2 in the S-ketamine group compared to the control group F(1, 14) = 10.14; p = 0.007; r = 0.65. With regard to depression, there was no significant reduction from T1 to T2 in the group comparison F(1, 14) = 1.60; p = 0.23; r = 0.32. No long-lasting effects on pain were found.
Conclusions: Our findings show that psychological distress of patients in palliative care may improve after a single administration of S-ketamine, which mainly alleviates anxiety in those patients. Limitations of this study arise from non-randomization, retrospective analysis and low sample size. Therefore, further prospective and ideally randomized studies are necessary.