Review of Ketamine as a Rapid Antidepressant for Treatment- Resistant Depression

Sankung X. Darboe1*‡, Peter J. Koszuta1*‡, Paul W. Lee1*‡, and Mannaa I. Mannaa1*‡

¹Geisinger Commonwealth School of Medicine, Scranton, PA 18509 *Master of Biomedical Sciences Program ‡Authors contributed equally Correspondence: mmannaa@som.geisinger.edu

Abstract

The anesthetic agent ketamine has been under investigation as a potential antidepressant for two decades. Animal studies and subsequent randomized control trials for patients have provided extensive evidence of ketamine’s rapid antidepressant outcomes both structurally at the receptor level as well as behaviorally. A review of current literature hones in on the putative rapid mechanisms of action of ketamine, which place the drug ahead of nearly all current antidepressants for treatment-resistant depression (TRD) patients. Clinical investigations, safety, and ethical implications are highlighted along with the need for reduced treatment cost. Finally, to more fully understand the effects of long-term use, efficacy in other types of psychiatric disorders, and interactions with comorbidities, more extensive trials are warranted.

Introduction

Major depressive disorder (MDD) is a major psychiatric problem worldwide, reportedly affecting 12% of males and 20% of females in the United States alone (1, 2). The etiology of MDD is not well known since there are various neurobiological causes, such as glutamatergic transmission defects in the central nervous system, as well as social and environmental factors that may lead to the stress levels of patients suffering from MDD (3, 4). In patients suffering from MDD, glutamatergic transmission is believed to be homeostatically downregulated by rapid-acting antidepressants (3). While several pharmacological treatments have proven successful in treating MDD, many patients with serious cases experience TRD with existing treatment approaches, with long-term effectiveness lagging after several trials, and 30% of patients continue to experience depression after a short duration of effective treatment (1, 4, 5). Usually, these patients are diagnosed with TRD after not successfully responding to at least two different antidepressant treatments (6). Most of the antidepressants used for MDDs have been shown to function in monoaminergic pathways, but it normally takes weeks to months before any meaningful therapeutic effect is generated (4, 7). Due to its rapid biological effects and effectiveness, ketamine has attracted attention in neuropharmacology over the past few decades. Ketamine was originally FDA-approved as a rapid-acting anesthetic in 1970 and evidence of its antidepressant action also began to emerge in the 1970s as preclinical studies with sub-anesthetic doses of the drug showed similar mechanisms of action to antidepressants at much rapid response rates (8). Ketamine is not approved by the FDA for depression, but its enantiomer, S-ketamine (esketamine), was FDA-approved in 2019 as it was found to be a more potent N-methyl-D-aspartate (NMDA) receptor antagonist with favorable adverse effects compared to (R)-ketamine and showed lower variability in pharmacokinetics and pharmacodynamics in various patients (8, 9, 10). Esketamine was a more potent mu-opioid receptor agonist and a less potent sigma-opioid receptor agonist (10). In addition to its rapid effects, ketamine has also been reported to rapidly reverse anhedonic behavior and synaptic defects in animal models studies with chronic unpredictable stress (CUS) (11). Although the effects of ketamine on anhedonia in humans remains to be determined, these findings highlight the efficacy advantages of ketamine compared to current antidepressants that are relied upon for treatment (11, 12). Moreover, this review is based on the hypotheses on the mechanism of action of ketamine and how sub-anesthetic doses of ketamine can modulate homeostatic plasticity in the treatment of MDD. Homeostatic plasticity modulates strong neuronal connectivity as a composite of global plasticity and synaptic scaling. In patients with MDD, achieving and maintaining homeostatic plasticity becomes paramount (13). MDD patients are identified as having downregulation of synapses of the prefrontal cortex (PFC) and hippocampal gray matter due to neuronal excitotoxicity resulting from prolonged stress (13). Inflammatory cytokines and neurotrophins are among factors that mediate this downregulation (14, 15). Prolonged stress-associated neuronal atrophy and synaptic depression have been linked to disruption of the glutamatergic system and downstream excess of extracellular glutamate (13, 16). Neuronal atrophy and synaptic depression are encompassed by dysfunctional synaptic strength, reduced dendritic spine density, retraction of spines and reduced dendritic branching of the prefrontal cortex (PFC) (17).

Methods

The literature review was conducted by accessing multiple databases, including primarily but not limited to PubMed, PubPsych, and Google Scholar. Most data, results, and perspectives were obtained from recent publications of research journals, some a mix of primary and secondary data. Some data were obtained from clinicaltrials.gov, and some clinical perspectives were obtained by blogs of medical schools and physician-writers. The time frame was principally comprised of the ten years since 2011, but older sources were relevant and reliable, and therefore included. The search was conducted between January and March 2021. Search terms include “ketamine,” “esketamine,” “depression,” “major depression,” “suicidal ideation,” “pharmacology,” “pharmacodynamics,” “clinical trial,” “randomized controlled trial,” and others. Inclusion criteria included articles or reports published in reputable

sources, emphasizing the last decade of research, clinical use, any attitudes toward ketamine, and the effects of ketamine. Exclusion criteria included unverified authors, discernable bias, unsubstantial discussion of results, incompletely available articles, and data never achieving statistical significance.

Discussion

Pharmacodynamics It has been hypothesized that the mechanism of action of sub-anesthetic dosing of ketamine lies in three primary actions followed by important downstream actions. It is believed that rapid improvement in homeostatic plasticity is accomplished by inhibition of NMDARs on GABAergic interneurons, extrasynaptic NMDAR inhibition, activation of post-synaptic a-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors (AMPARs), and blockage of spontaneous (NMDAR) activation (18). Vital downstream actions include increased BDNF and protein translation by mechanistic target of rapamycin complex 1 (mTORC1) (19-21). The pharmacodynamics of ketamine show both its enantiomers (R)-ketamine and (S)-ketamine to influence antidepressant actions. (S)-ketamine is a more potent NMDA antagonist; however, (R)-ketamine shows more potent antidepressant effects in rodents and longer lasting action in neonatal dexamethasone-treated pediatric depression animal model, chronic social defeat stress animal model, and learned helplessness animal model of depression (22–25). (R)-ketamine also shows greatly reduced psychotomimetic and dissociative side effects (26, 27). Among ketamine’s primary actions, it is hypothesized that it preferentially inhibits NMDARs on GABAergic interneurons, a mechanism unique to ketamine (28). It also has a high affinity for forebrain inhibitory interneurons expressing GluN2D-NMDAR subunits (29–32). The resulting overall decrease of inhibition is proposed to lead to the disinhibition of pyramidal cells facilitating bursts of excitatory glutamatergic neurotransmission in the medial prefrontal cortex (mPFC) (33, 34). Two-photon imaging of prelabeled layer V medial PFC pyramidal neurons post-ketamine administration demonstrated that ketamine increases synapse and spine formation. They confirmed rapid increase in spine number and morphology in distal and proximal apical tufts at 24 hours post ketamine administration (35). The bursts of neurotransmission further evoke the release of glutamate facilitating synaptic glutamatergic neurotransmission. Activation of post-synaptic α-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid receptors (AMPARs) via this evoked release is vital for synaptic potentiation and plasticity (36). AMPARs are transmembrane glutamatergic receptors working ionotropically for transduction of fast synaptic neurotransmission in the brain (37). Ketamine has been shown to enhance AMPAR synaptic transmission in the mPFC and hippocampus through upregulation of receptors and increased phosphorylation of at least the GluA2 subunit (38). Increased levels of the GluA1 unit of the AMPA receptor were noted two hours post ketamine administration (39). As AMPARs conduct Na+ and CA²+ into the cell, the resulting local increase of intracellular Ca²+ signals increases vesicular delivery of BDNF into the synaptic space. The downstream effect is activation of mTOR up-regulation of protein synthesis and synaptic plasticity (40). The result was significant enhancement of synaptogenesis and connectivity in the hippocampus and PFC (41). Extra-synaptic GluN2B-NMDARs are believed to be specifically inhibited by ketamine which prevents extracellular ambient glutamate activation of the NMDAR receptors. Inhibition of extra-synaptic NMDARS shuts down the NMDAR-regulation of mTORC1 which results in de-suppression of protein synthesis important for synaptic homeostasis (42–45). This specific mTOR pathway activation is associated with increased synaptic spine density within the mPFC (46). Ketamine has been shown to block NMDAR-mediated miniature excitatory postsynaptic currents (mEPSCs) where spontaneous glutamate neurotransmission at rest regulates synaptic strength and suppresses protein synthesis (23). mEPSCs promote phosphorylation and inactivation of eukaryotic elongation factor 2 (eEF2). Ketamine blocks this transmission facilitating active eEF2 promotion of synaptic plasticity as well as potentiation in the CA1 region of the hippocampus resulting in behavioral antidepressant actions (23, 47, 48). In addition to the most prominent target, NMDA receptors, other low-affinity targets include γ-amynobutyric acid (GABA), dopamine, serotonin, sigma, opioid, and cholinergic receptors and others (49).

Pharmacokinetics

Ketamine can be administered via several routes. This is due to its water and lipid solubility. The most common routes are oral, inhalation, intramuscular, subcutaneous, intravenous, epidural, or intrathecal (50, 51). Bioavailability is up to 24% oral, approximately 93% intramuscular, approximately 30% rectal, approximately 45% intranasal, and 77% epidural (50). Due to its lipid solubility and low protein binding, distribution is 160–550 L/70 kg (50). Steady-state plasma concentration for anesthetic purposes is 2,200 ng/ml, awakening concentration range is 640 to 1,100 ng/ml (52). Ketamine is distributed to highly perfused tissues including the brain with 10% plasma protein binding, which facilitates distribution across the blood-brain barrier (50, 53). Plasma concentrations of both enantiomers are equal after one minute post IV administration (54). Cytochrome P450 enzymes play a major role in the metabolism of ketamine via N-demethylation to metabolite norketamine (R,S)-norKET (55). The main ketamine metabolizer, CYP2B6, demethylates both enantiomers equally. CYP3A4 demethylates (S)-ketamine at a higher rate than (R)-ketamine (55). (R,S)norKET hydroxylation is enacted by several enzymes including CYP2A6 or CYP2B6 to produce, among others, (2R,6R;2S,6S)hydroxynorketamine (HNK) and (R,S)-dehydroxonorketamine (DHNK). CYP2A6 is responsible for direct hydroxylation of ketamine to (2R, 6R;2S,6S)-HK (56). Peak concentrations in the plasma of (R)- and (S)-ketamine and norketamine, and (2R,6R;2S,6S)-HNK, were found to be 1.33 hours, and 3.83 hours respectively (57). High polymorphism of the main ketamine metabolizer, CYP2B6, has clinical significance (58). This is due to the diminished metabolic ketamine N-demethylation activity with CYP2B6 polymorphism. The order of effective metabolism based on genotype is wild-type CYP2B6.1, then CYP2B6.4, then CYP2B6.26, CYP2B6.19, CYP2B6.17, and CYP2B6.6. The variant CYP2B6.9 is up to 35% that of the wild type, and

CYP2B6.16 and CYP2B6.18 are inactive (58). Consequences for ketamine pharmacokinetics, therapeutic effects, and elimination must be assessed in those with variants other than wildtype (58).

Administered antidepressant dose of ketamine shows no detectable plasma levels within 1 day. This is due to ketamine’s short elimination half-life for both (R)- and (S)-ketamine demonstrated at 155 minutes (49). Far shorter times have been noted for children with elimination half-lives 50% that of adults (53). However, (2R,6R;2S,6S)-HNK have been shown to remain in circulation up to 3 days post-dosing (57). Ketamine elimination is primarily (~80%) via urine and bile as glucuronic acid-labile conjugates of HK and HNK (59). The remainder is eliminated via urine as ketamine and norketamine both at 4%, and DHNK at 16% (53, 59-62).

Clinical investigations The leading cause of disability worldwide is major depressive disorder (63, 64). Between 1999 and 2016, suicide rates rose over 30% in 25 U.S. states (64), and of patients with major depressive disorder (MDD), approximately a third do not respond to existing antidepressants despite enduring the weeks of medicating needed to see an effect (63, 65). A clear unmet need exists for efficacious treatment for depression, including suicidal ideation (SI) (63, 66, 67). Few therapies act within a week, but emergent SI and MDD demand quick and superior treatments (63, 68). Ketamine administered by IV is typically a racemic mixture of both enantiomers, and isolated esketamine (S-ketamine) is used as a nasal spray, both FDA approved as an anesthetic (64, 69). Multiple systematic reviews support the efficacy of ketamine against MDD, bipolar depression (BD), post-traumatic stress disorder (PTSD), acute suicidal ideation and treatmentresistant depression (TRD) (63, 7, 67, 70). Ketamine is primarily for use in MDD and TRD (63, 71, 72). Use as a rapid-acting antidepressant has been investigated for over a decade (73) and currently constitutes off-label use (68). TRD is characterized by lax symptom relief by traditional antidepressants such as SSRIs (63). Ketamine given by single IV dose (0.5mg/kg) results in 50%-70% response in TRD (63). Systematic reviews report significant relief in as little as 15 minutes (74,75) to 2 hours (63, 68, 69, 76) lasting up to 2 weeks from a single dose, 11% reporting relief on day 14 (63, 7, 66, 74). A randomized control trial confirmed significant effects of ketamine at 4, 24, 48, and 72 hours post administration, and was superior to midazolam at reducing SI at every interval (74). IV treatment lasts 2 hours (77). Notably, 75–80% of patients experiencing regular depression improve on ketamine, compared to 35–40% on traditional medications (77). SI on the hopelessness scale reduced 90.7% at 3 days post infusion (75). Use is documented for opioid-induced hyperanalgesia by reducing pain threshold (78). Ketamine works for an apparent shorter duration in BD (63, 71) but predicts efficacy in patients with high BMI, family history of alcohol use, and anxious depression (76). Intramuscular and sublingual administration is documented with lesser improvement of MDD (71). Importantly, it is not necessary to wash out other antidepressants (79). Proof of concept has been verified (79) and observed over a 3-year period (80). Emergency medicine warrants the need for rapid and severe reduction in acute SI (70). In repeated administration, the magnitude of response after 6 infusions was predicted by response 4 hours after first infusion (80). Most patients responded prior to third infusion (68). Effects are durable over treatment (70), yet it is unclear how often ketamine should be administered (66) and how effects diminish following cessation of treatment (81). Ketamine is carried at hospitals and increasing numbers of outpatient clinics (66). The most effective alternative for TRD is electroconvulsive therapy (81). SSRIs are commonly associated with weight gain, but this is not a side effect of ketamine (77). Midazolam improved 30% of patients compared to over 55% of patients on ketamine in one single-blind study (74). Psychotherapy is less reliably effective and requires some patient cooperation, complicated by instances of suicidal ideation (67).

Safety Not all patients respond to ketamine (68, 71). Off-label use for depression is due to piecemeal data with unverified accuracy (68). The main drawbacks are side effects (82). Patients primarily report disturbances, dissociations, or abnormal sensations (83). Other adverse effects include increased heart rate and blood pressure up to four hours following administration, dizziness, headache, nausea, dry mouth, and restlessness (82). Long-term use is associated with mild cognitive disturbances and urinary cystitis, yet may be confined to daily users (68). Transient effects typically subside within an hour (7). Anesthetic doses, which are higher than those for depression, can cause hepatotoxicity (84). Systematic reviews do not report mania but include mild talkativeness after ketamine (83). Ketamine may augment other antidepressants without increasing observed adverse reactions (66). Adverse reactions are twice as likely with intranasal esketamine versus placebo (66). Patients with cardiovascular illness should be carefully monitored (63). This drug should be avoided in patients with status epilepticus due to sympathomimetic activity (76). Rapid onset requires readiness of supportive measures if needed (72).

Ethics

Any new therapy encourages discussions of ethics surrounding efficacy and potentially uncertain risk and benefit analyses. Because ketamine is not officially approved for all disorders it may effectively treat, proper professional use is vital to maintain availability of ketamine for these cases, and not prohibited (81). Because physicians may want to appear progressive, and because patients may not be of sound mind when presented with the option to receive ketamine, physicians need to respectfully balance their autonomy and patient risks and benefits (68). Potential patients likely present with an inhibited decision capacity due to their condition, thereby relying on decisions of medical staff, which could lead to conflict with the recovered patient (68). Responsible ethical decision-making is essential. Despite being called a breakthrough, cost is still high, and a burden to some patients, particularly unwanted if ketamine was administered when patients were in altered mental states (85).

Limitations

Many clinical investigations into ketamine for depression are small in scale and target specific clinical endpoints. Systematic reviews compile data into significant reports with reproducible conclusions, but robust experimental data is sparse, conferring uncertainty about specific anti-suicidal properties of ketamine (70), long-term effects (83), usage beyond 12 doses and habituation (86), addiction potential (66), if ketamine should be avoided in patients with psychoses (73) or head injury (76), effects in special populations (7), timing of adverse effects (81), and mechanism in humans (82). Ketamine is a generic drug, so investment in expensive trials is unlikely and unprofitable, though required for approval (68). Recreational use complicates dosing (80, 86). Professional use may suit military, cancer patients, Alzheimer’s patients (65), and end-of-life care, especially in patients with MDD and pain (87). Ketamine is not covered by insurance; each treatment costs $300 to $450, with estimates reaching thousands per session, though coverage may soon expand (85, 77). Patients and physicians should understand knowledge of ketamine is subpar, though great hope exists in the anti-suicidal properties of ketamine (68).

Conclusion

The need for a more rapid response to TRD exists and is compounded by the imminent dangers associated with suicidal ideation, major depressive disorder, and bipolar depression, as well as the tendency for these conditions to recur (8890). Non-ketamine treatments can take up to 8 weeks to become fully effective, while ketamine treatments can reach full effectiveness within 24 hours (88, 89). Due to its rapid biological effects and effectiveness, ketamine has attracted attention in neuropharmacology over the past few decades to become the future of rapid pharmacotherapy for TRD patients (4, 7). However, despite the apparent advantages of ketamine treatments, there are still noteworthy concerns. Different studies have indicated different success rates for ketamine treatment against TRD, with two examples being 71% and 65% (91, 92). While these success rates could be considered strong, they still leave the need for other treatments for the remaining 29% and 35% of patients respectively (91, 92). Those taking ketamine also face a variety of safety concerns, commonly including dizziness, vertigo, nausea, vomiting, anxiety, numbness, and high blood pressure (90). The cost of treatment could also be an issue for many patients; the first month of esketamine under the brand Spravato costs $4,800–6,800 with $1,200–3,600 per month after as of mid-2020 (90). Furthermore, the mechanism of action for these treatments is uncertain. Several possibilities exist, mostly based on antagonism of NMDA receptors and/or enhancement of AMPA receptors (28, 38). With AMPA receptor enhancement, a signal cascade begins and results in the release of BDNF, leading to amplified synaptogenesis and connectivity in brain areas often lacking BDNF in depressed patients (38, 40, 41, 90). Those who suffer from depression are known to have lower amounts of BDNF in certain areas of the brain like the prefrontal cortex and hippocampus (90). On the other hand, NMDA receptor antagonism on GABAergic interneurons and inhibitory interneurons results in glutamatergic activity, ultimately leading to synaptic potentiation and plasticity (28–34, 36). Inhibition of NMDA receptors can also prevent NMDA receptor-mediated inactivation of protein synthesis in multiple ways. First, NMDA receptors can block homeostatic protein synthesis through mTORC1 and inhibition of the NMDA receptors can prevent this (42–45). Second, eEF2 inactivation can be dependent on NMDA receptors, and by blocking those receptors, the inactivation can be blocked as well, allowing eEF2 to function in protein synthesis to promote plasticity and potentiation (23, 47, 48). Perhaps multiple mechanisms of action work in tandem but determining the precise mechanisms of action in the treatment of depression is a topic for future studies. Some of these mechanisms also had similar end effects, so another possibly beneficial area of future study would be discerning which effects are simply biological and which are therapeutic. Efforts should be made to determine whether other NMDA blockers are as, or more, effective than ketamine. Safety based on dosage should also be investigated since extant data suggests ketamine is tolerated well in low doses in depressed patients, but the same data does not exist for higher repeated doses (88). General safety over longer periods of time could also be a cause for concern due to an apparent lack of data regarding long-term toxicity (90). Different studies utilizing different routes of administration at different dosages have resulted in different efficacies, so discernment of the most feasible and effective administrations would be valuable (88). Finally, more and larger studies could provide more data to determine the intensity of interstudy variations and interactions with comorbidities like anxiety and trauma.

Acknowledgments

Guidance on appropriate referencing and expanding content in addition to editing and final review was graciously provided by Brian Piper, PhD. Dr. Piper is an assistant professor of neuroscience at Geisinger Commonwealth School of Medicine.

References

1. Ionescu DF, Bentley KH, Eikermann M, Taylor N, Akeju

O, Swee MB, et al. Repeat-dose ketamine augmentation for treatment-resistant depression with chronic suicidal ideation: A randomized, double blind, placebo-controlled trial. J Affect Disord. 2019;243:516-24. DOI: https://doi. org/10.1016/j.jad.2018.09.037 2. Feifel D, Malcolm B, Boggie D, Lee K. Low-dose ketamine for treatment resistant depression in an academic clinical practice setting. J Affect Disord. 2017;221:283-8. DOI: https://doi.org/10.1016/j.jad.2017.06.043 3. Ren Z, Pribiag H, Jefferson SJ, Shorey M, Fuchs T,

Stellwagen D, et al. Bidirectional homeostatic regulation of a depression-related brain state by gamma-aminobutyric acidergic deficits and ketamine treatment. Biol Psychiatry. 2016;80(6):457-68. DOI: https://doi.org/10.1016/j. biopsych.2016.02.009 4. Marcantoni WS, Akoumba BS, Wassef M, Mayrand J, Lai H,

Richard-Devantoy S, et al. A systematic review and metaanalysis of the efficacy of intravenous ketamine infusion for treatment resistant depression: January 2009–January 2019. J Affect Disord. 2020. DOI: https://doi.org/10.1016/j. jad.2020.09.007

5. Chen MH, Li CT, Lin WC, Hong CJ, Tu PC, Bai YM, et al. Rapid inflammation modulation and antidepressant efficacy of a low-dose ketamine infusion in treatmentresistant depression: A randomized, double-blind control study. Psychiatry Res. 2018;269:207-11. DOI: https://doi. org/10.1016/j.psychres.2018.08.078 6. Correia-Melo FS, Leal GC, Vieira F, Jesus-Nunes AP, Mello RP, Magnavita G, et al. Efficacy and safety of adjunctive therapy using esketamine or racemic ketamine for adult treatment-resistant depression: A randomized, doubleblind, non-inferiority study. J Affect Disord. 2020;264:52734. DOI: https://doi.org/10.1016/j.jad.2019.11.086 7. Mandal S, Sinha VK, Goyal N. Efficacy of ketamine therapy in the treatment of depression. Indian J

Psychiatry. 2019;61(5):480-85. DOI: 10.4103/psychiatry.

IndianJPsychiatry_484_18. 8. Zanos P, Moaddel R, Morris PJ, Riggs LM, Highland JN,

Georgiou P, et al. Ketamine and ketamine metabolite pharmacology: Insights Insights into therapeutic mechanisms. Pharmacol. Rev. 2018;70(3):621-60. DOI: https://doi.org/10.1124/pr.117.015198 9. Włodarczyk A, Cubała WJ, Szarmach J, Małyszko A,

Wiglusz MS. Short-term ketamine administration in treatment-resistant depression patients: Focus on adverse effects on the central nervous system. Psychiatr Danub. 2019;31(Suppl 3):530-3. 10. Andrade C. Ketamine for depression, 3: Does chirality matter? J. Clin. Psychiatry. 2017;78(6):674-7. DOI: 10.4088/JCP.17f11681 11. Zhuo C, Tian H, Li G, Chen M, Jiang D, Lin X, et al.

Effects of ketamine on circadian rhythm and synaptic homeostasis in patients with treatment-resistant depression: A protocol for mechanistic studies of its rapid and sustained antidepressant actions in humans. Brain

Behav. 2019;9(11):e01423. DOI: https://doi.org/10.1002/ brb3.1423 12. Caffino L, Piva A, Giannotti G, Di Chio M, Mottarlini F,

Venniro M, et al. Ketamine self-administration reduces the homeostasis of the glutamate synapse in the rat brain.

Mol Neurobiol. 2017;54(9):7186-93. DOI: https://doi. org/10.1007/s12035-016-0231-6 13. Zanos P, Gould TD. Mechanisms of ketamine action as an antidepressant. Mol Psychiatry. 2018;23(4):801-11. 14. Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, Cheng

PF, et al. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature. 2011;475(7354):91-5. DOI: 10.1038/nature10130 15. Garcia LS, Comim CM, Valvassori SS, Réus GZ, Barbosa

LM, Andreazza AC, et al. Acute administration of ketamine induces antidepressant-like effects in the forced swimming test and increases BDNF levels in the rat hippocampus. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32(1):140-4. DOI 10.1016/j.pnpbp.2007.07.027 16. Yoshii A, Constantine-Paton M. Postsynaptic BDNF-TrkB signaling in synapse maturation, plasticity, and disease. Dev.

Neurobiol. 2010;70(5):304-22. DOI: 10.1002/dneu.20765 17. Yang C, Yang J, Luo A, Hashimoto K. Molecular and cellular mechanisms underlying the antidepressant effects of ketamine enantiomers and its metabolites. Transl Psychiatry. 2019;9(280). DOI: 10.1038/s41398-019-0624-1 18. Zanos P, Gould TD. Mechanisms of ketamine action as an antidepressant. Mol Psychiatry. 2018;23(4):801-1. DOI: 10.1038/mp.2017.255 19. Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, Cheng

PF, et al. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature. 2011;475(7354):91-5. DOI: 10.1038/nature10130 20. Garcia LS, Comim CM, Valvassori SS, Reus GZ, Barbosa

LM, Andreazza AC, et al. Acute administration of ketamine induces antidepressant-like effects in the forced swimming test and increases BDNF levels in the rat hippocampus. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32(1):140-4. DOI 10.1016/j.pnpbp.2007.07.027 21. Yoshii A, Constantine-Paton M. Post-synaptic BDNF-TrkB signaling in synapse maturation, plasticity and disease. Dev

Neurobiol. 2010;70(5):304–22. DOI: 10.1002/dneu.20765 22. Yang C, Yang J, Luo A, Hashimoto K. Molecular and cellular mechanisms underlying the antidepressant effects of ketamine enantiomers and its metabolites. Transl Psychiatry. 2019;9(280). DOI 10.1038/s41398-019-0624-1 23. Zhang JC, Li SX, Hashimoto K. R(-)-ketamine shows greater potency and longer lasting antidepressant effects than

S(+)-ketamine. Pharm Biochem Behav. 2014;116:137-41.

DOI 10.1016/j.pbb.2013.11.033 24. Yang C, Shirayama Y, Zhang JC, Ren Q, Yao W, Ma M, et al. Correction: R-ketamine: a A rapid-onset and sustained antidepressant without psychotomimetic side effects.

Transl Psychiatry. 2020;10(1):295. [Erratum in: Transl

Psychiatry 2015; 5:e632] 25. Zanos, P, Moaddel R, Morris PJ, Georgiou P, Fischell

J, Elmer IE, et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature. 2016;533(7604):481-6. DOI: 10.1038/nature17998 26. Fukumoto K, Toki H, Iijima M, Hashihayata T, Yamaguchi

J, Hashimoto K, et al. Antidepressant potential of (R)ketamine in rodent Models: Comparison with (S)-ketamine.

J Pharmacol Exp Ther. 2017; 361(1):9-16. [Erratum in: J

Pharmacol Exp Ther. 2017;362(1):1] 27. Hashimoto K, Kakiuchi T, Ohba H, Nishiyama S, Tsukada

H. Reduction of dopamine D2/3 receptor binding in the striatum after a single administration of esketamine, but not R-ketamine: A PET study in conscious monkeys. Eur

Arch Psychiatry Clin Neurosci. 2017;267(2):173-176. DOI: 10.1007/s00406-016-0692-7 28. Matveychuk D, Thomas RK, Swainson J, Khullar A, MacKay

MA, Baker GB, et al. Ketamine as an antidepressant: overview of its mechanisms of action and potential predictive biomarkers. Ther Adv Psychopharmacol. 2020;10:1-21. DOI 10.1177/2045125320916657

29. Moghaddam B, Adams B, Verma A, Daly D. Activation of glutamatergic neurotransmission by ketamine: A novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J Neurosci. 1997;17(8):2921–7 DOI: 10.1523/JNEUROSCI.17-08-02921.1997 30. Homayoun H, Moghaddam B. NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons. J

Neurosci. 2007;27(43):11496–500. DOI: 10.1523/

JNEUROSCI.2213-07.2007 31. Kotermanski SE, Johnson JW. Mg2+ imparts NMDA receptor subtype selectivity to the Alzheimer’s drug memantine. J Neurosci. 2009;29(9):2774-9. DOI: 10.1523/

JNEUROSCI.3703-08.2009 32. Khlestova E, Johnson JW, Krystal JH, Lisman J. The role of GluN2C-containing NMDA receptors in ketamine’s psychotogenic action and in schizophrenia models.

J Neurosci. 2016;36(44):11151-7. DOI: 10.1523/

JNEUROSCI.1203-16.2016 33. Henley JM, Wilkinson KA. Synaptic AMPA receptor composition in development, plasticity and disease. Nat Rev

Neurosci. 2016;17(6):337-50. DOI: 10.1038/nrn.2016.37 34. Derkach VA, Oh MC, Guire ES, Soderling TR. Regulatory mechanisms of AMPA receptors in synaptic plasticity. Nat

Rev Neurosci. 2007; 8(2):101–13. DOI: 10.1038/nrn2055 35. Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010;329(5994):959-64. DOI: 10.1126/science.1190287 36. Zanos, P, Moaddel R, Morris PJ, Georgiou P, Fischell

J, Elmer IE, et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature. 2016; 533(7604):481-6. DOI: 10.1038/nature17998 37. Aleksandrova LR, Phillips AG, Wang YT. Antidepressant effects of ketamine and the roles of AMPA glutamate receptors and other mechanisms beyond NMDA receptor antagonism. J Psychiatry Neurosci. 2017;42(4):222-9. DOI: 10.1503/jpn.160175 38. Duman RS, Aghajanian GK, Sanacora G, Krystal JH.

Synaptic plasticity and depression: New insights from stress and rapid-acting antidepressants. Nat Med. 2016;22(3):238-49. DOI: 10.1038/nm.4050 39. Duman RS. Ketamine and rapid-acting antidepressants:

A new era in the battle against depression and suicide. F1000Res. 2018;7:F1000. DOI: 10.12688/ f1000research.14344.1 40. Miller OH, Yang L, Wang CC, Hargroder EA, Zhang Y,

Delpire E, et al. GluN2B-containing NMDA receptors regulate depression-like behavior and are critical for the rapid antidepressant actions of ketamine. Elife. 2014;3:e03581. DOI:10.7554/eLife.03581 41. Wang CC, Held RG, Chang SC, Yang L, Delpire E,

Ghosh A, et al. A critical role for GluN2B-containing

NMDA receptors in cortical development and function.

Neuron. 2011;72(5):789–805. DOI: 10.1016/j. neuron.2011.09.023 42. Wang CC, Held RG, Hall BJ. SynGAP regulates protein synthesis and homeostatic synaptic plasticity in developing cortical networks. PloS One. 2013;8(12):e83941. DOI: 10.1371/journal.pone.0083941 43. Gray JA, Shi Y, Usui H, During MJ, Sakimura K, Nicoll

RA. Distinct modes of AMPA receptor suppression at developing synapses by GluN2A and GluN2B: single-cell NMDA receptor subunit deletion in vivo.

Neuron. 2011;71(6):1085-101. DOI: 10.1016/j. neuron.2011.08.007 44. Sutton MA, Taylor AM, Ito HT, Pham A, Schuman

EM. Postsynaptic decoding of neural activity: eEF2 as a biochemical sensor coupling miniature synaptic transmission to local protein synthesis. Neuron. 2007;55(4):648-61. DOI: 10.1016/j.neuron.2007.07.030 45. Nosyreva E, Szabla K, Autry AE, Ryazanov AG, Monteggia

LM, Kavalali ET. Acute suppression of spontaneous neurotransmission drives synaptic potentiation. J

Neurosci. 2013;33(16):6990-7002. DOI: 10.1523/

JNEUROSCI.4998-12.2013 46. Park SW, Lee JG, Seo MK, Lee CH, Cho HY, Lee BJ, et al. Differential effects of antidepressant drugs on mTOR signalling in rat hippocampal neurons. Int J

Neuropsychopharmacol. 2014;17(11):1831-46. DOI: 10.1017/S1461145714000534 47. Chotiner JK, Khorasani H, Nairn AC, O’dell TJ, Watson

JB. Adenylyl cyclase-dependent form of chemical longterm potentiation triggers translational regulation at the elongation step. Neuroscience. 2003;116(3):743-52. DOI: 10.1016/S0306-4522(02)00797-2 48. Park S, Park JM, Kim S, Kim JA, Shepherd JD, Smith-

Hicks CL, et al. Elongation factor 2 and fragile X mental retardation protein control the dynamic translation of Arc/

Arg3.1 essential for mGluR-LTD. Neuron. 2008;59(1):7083. DOI: 10.1016/j.neuron.2008.05.023 49. Zanos P, Moaddel R, Morris PJ, Riggs LM, Highland

JN, Georgiou P, et al. Ketamine and ketamine metabolite pharmacology: insights into therapeutic mechanisms. Pharmacol Rev. 2018;70(3):621-660. DOI: 10.1124/pr.117.015198. [Erratum in: Pharmacol Rev 2018;70(4):879] 50. Peltoniemi MA, Hagelberg NM, Olkkola KT, Saari TI.

Ketamine: A review of clinical pharmacokinetics and pharmacodynamics in anesthesia and pain therapy. Clin

Pharmacokinet. 2016;55(9):1059-77. DOI: 10.1007/ s40262-016-0383-6 51. Johnson BA. Addiction medicine: Science and Practice.

London: Springer; 2011. 604 p.

52. Idvall J, Ahlgren I, Aronsen K, Stenberg P. Ketamine infusions: Pharmacokinetics and clinical effects. Br J

Anaesth. 1980;24(6):378. DOI: 10.1093/bja/51.12.1167 53. Haas DA, Harper DG. Ketamine: A review of its pharmacologic properties and use in ambulatory anesthesia. Anesth Prog. 1992;39(3):61-8. 54. Geisslinger G, Hering W, Thomann P, Knoll R, Kamp HD,

Brune K. Pharmacokinetics and pharmacodynamics of ketamine enantiomers in surgical patients using a stereoselective analytical method. Br J Anaesth. 1993;70(6):666-71. DOI: 10.1093/bja/70.6.666 55. Portmann S, Kwan HY, Theurillat R, Schmitz A, Mevissen

M, Thormann W. Enantioselective capillary electrophoresis for identification and characterization of human cytochrome P450 enzymes which metabolize ketamine and norketamine in vitro. J Chromatogr A. 2010;1217:7942–7948. DOI: 10.1016/j.chroma.2010.06.028 56. Adams JD Jr, Baillie TA, Trevor AJ, Castagnoli N Jr. Studies on the biotransformation of ketamine. 1-Identification of metabolites produced in vitro from rat liver microsomal preparations. Biomed Mass Spectrom. 1981;8(11):527-38.

DOI: 10.1002/bms.1200081103 57. Zhao X, Venkata SL, Moaddel R, Luckenbaugh DA,

Brutsche NE, Ibrahim L, et al. Simultaneous population pharmacokinetic modelling of ketamine and three major metabolites in patients with treatment-resistant bipolar depression. Br J Clin Pharmacol. 2012;74(2):304-14. DOI: 10.1111/j.1365-2125.2012.04198.x 58. Wang PF, Neiner A, Kharasch ED. Stereoselective ketamine metabolism by genetic variants of cytochrome p450 cyp2b6 and cytochrome p450 oxidoreductase.

Anesthesiology. 2018;129(4):756-768. doi: 10.1097/

ALN.0000000000002371 59. Dinis-Oliveira RJ. Metabolism and metabolomics of ketamine: A toxicological approach. Forensic Sci Res. 2017;2(1):2-10. DOI: 10.1080/20961790.2017.1285219 60. Lin HR, Lua AC. Detection of acid-labile conjugates of ketamine and its metabolites in urine samples collected from pub participants. J Anal Toxicol. 2004;28(3):181-6.

DOI: 10.1093/jat/28.3.181 61. Adamowicz P, Kala M. Urinary excretion rates of ketamine and norketamine following therapeutic ketamine administration: method and detection window considerations. J Anal Toxicol. 2005;29(5):376-82. DOI: 10.1093/jat/29.5.376 62. Karch SB, Drummer OH. Karch’s Pathology of Drug Abuse. 5th edition. Boca Raton, FL: CRC Press; 2001. 697–754 p. 63. Schwartz J, Murrough JW, Iosifescu DV. Ketamine for treatment-resistant depression: Recent developments and clinical applications. Evid.-Based Ment. Health. 2016;19:358. 64. Meisner RC. Ketamine for major depression: new tool, new questions. Harv Health. 2019. 65. Pribish A, Wood N, Kalava A. A review of nonanesthetic uses of ketamine. Anesthesiol Res Pract. 2020;5798285. 66. Thase M, Connolly KR. Ketamine and esketamine for treating unipolar depression in adults: administration, efficacy, and adverse effects [Internet]. Up To Date; 2020

Aug [cited 2021 Feb 6]. Available from: https://www. uptodate.com/contents/ketamine-and-esketamine-fortreating-unipolar-depression-in-adults-administrationefficacy-and-adverse-effects

67. Naval Medical Center Camp Lejeune. Initiating ketamine in acutely suicidal patients in the emergency department [Internet]. National Library of Medicine; 2020 Feb [cited 2021 Feb 6]. Available from: https://clinicaltrials.gov/ct2/ show/NCT04260607 68. Singh I, Morgan C, Curran V, Nutt D, Schlag A, McShane

R. Ketamine treatment for depression: opportunities for clinical innovation and ethical foresight. Lancet Psychiatry. 2017;4(5):419-26. 69. Hashimoto K. Rapid-acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective. Psychiatry Clin Neurosci. 2019

Oct;73(10):613-27. 70. Wilkinson ST, Ballard ED, Bloch MH, Mathew SJ, Murrough

JW, Feder A, et al. The effect of a single dose of intravenous ketamine on suicidal ideation: a systematic review and individual participant data meta-analysis. Am. J. Psychiatry. 2018;175(2):150-8. 71. Phillips JL, Norris S, Talbot J, Hatchard T, Ortiz A,

Birmingham M, et al. Single and repeated ketamine infusions for reduction of suicidal ideation in treatmentresistant depression. Neuropsychopharmacology. 2020;45(4):606-12. 72. Reinstatler L, Youssef NA. Ketamine as a potential treatment for suicidal ideation: A systematic review of the literature. Drug Dev. 2015;15(1):37-43. 73. Schwartz N. Ketamine for suicidal patients: a chance for meaningful psychiatric care in the ED [Internet].

Emergency Physicians Monthly; 2018 [cited 2021 Feb 6].

Available from: https://epmonthly.com/article/ketaminefor-suicidal-patients-a-chance-for-meaningful-psychiatriccare-in-the-ed/ 74. Murrough JW, Soleimani L, DeWilde KE, Collins KA,

Lapidus KA, Iacoviello BM, et al. Ketamine for rapid reduction of suicidal ideation: a randomized controlled trial.

Psychol Med. 2015;45(16):3571-80. 75. Haapanen LH. Ketamine safe for acutely suicidal patients in the emergency department setting [Internet]. Psychiatry

Advisor; 2019 [cited 2021 Feb 6]. Available from: https:// www.psychiatryadvisor.com/home/depression-advisor/ ketamine-safe-for-acutely-suicidal-patients-in-theemergency-department-setting/ 76. Jansen KL. A review of the nonmedical use of ketamine: use, users and consequences. J Psychoactive Drugs. 2000;32(4):419-33. 77. Chen J. Treating depression: an expert discusses risks, benefits of ketamine [Internet]. Yale Medicine; 2017 [cited 2021 Feb 18]. Available from https://www.yalemedicine. org/news/ketamine-the-new-miracle-drug

78. Willeford A, Atayee RS, Winters KD, Mesarwi P. The enigma of low-dose ketamine for treatment of opioid-induced hyperalgesia in the setting of psychosocial suffering and cancer-associated pain. J Pain Palliat Care Pharmacother. 2018;32(4):248-55. 79. Domany Y, Shelton RC, McCullumsmith CB. Ketamine for acute suicidal ideation. An emergency department intervention: a randomized, double-blind, placebocontrolled, proof-of-concept trial. Depress Anxiety. 2020;37(3):224-33. 80. Murrough J. Ketamine for suicidal ideation [Internet].

National Library of Medicine; 2017 [cited 2021 Feb 17]. Available from: https://clinicaltrials.gov/ct2/show/

NCT01507181 81. Phillips JL, Jaworska N, Kamler E, Bhat V, Blier J, Foster

JA, et al. A randomized, crossover comparison of ketamine and electroconvulsive therapy for treatment of major depressive episodes: a Canadian biomarker integration network in depression (CAN-BIND) study protocol. BMC

Psychiatry. 2020;20(1):268. 82. Makin S. Behind the buzz: how ketamine changes the depressed patient’s brain [Internet]. Scientific American; 2019 [cited 2021 Feb 6]. Available from: https://www. scientificamerican.com/article/behind-the-buzz-howketamine-changes-the-depressed-patients-brain/ 83. Serafini G, Howland RH, Rovedi F, Girardi P, Amore M.

The role of ketamine in treatment-resistant depression: A systematic review. Curr Neuropharmacol. 2014;12(5):44461. 84. Kelly T, Rosonke S. Ketamine's therapeutic value in suicidal patients [Internet]. Emergency Medicine Resident; 2019 [cited 2021 Feb 6]. Available from: http://www.emra.org/ emresident/article/ketamine/ 85. Otto AM. Ketamine tied to remission from suicidal ideation [Internet]. MDedge Psychiatry; 2019 [cited 2021 Feb 6]. Available from: https://www.mdedge.com/psychiatry/ article/202023/depression/ketamine-tied-remissionsuicidal-ideation 86. Dadiomov D, Lee K. The effects of ketamine on suicidality across various formulations and study settings. Ment Health

Clin. 2019;9(1):48-60. 87. Jansen KL. A review of the nonmedical use of ketamine: use, users and consequences. J Psychoactive Drugs. 2000;32(4):419-33. 88. Corriger A, Pickering G. Ketamine and depression: A narrative review. Drug Des Devel Ther. 2019;13:3051–67. 89. Al-harbi KS. Treatment-resistant depression: Therapeutic trends, challenges, and future directions. Patient Prefer

Adherence. 2012;6:369-88. 90. Salahudeen MS, Wright CM, Peterson GM. Esketamine:

New hope for the treatment of treatment-resistant depression? A narrative review. Ther Adv Drug Saf. 2020;11:204209862093789. 91. Zarate CA, Singh JB, Carlson PJ, Brutche NE, Ameli R,

Luckenbaugh DA, et al. A randomized trial of an N-methyl-

D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63(8):864-5. 92. Mather SJ, Shah A, Lapidus K, Clark C, Jarun N,

Ostermeyer B, et al. Ketamine for treatment-resistant unipolar depression. CNS Drugs. 2012;26(3):189-204.