A Survey of the Clinical, Off-Label Use of Ketamine as a Treatment for Psychiatric Disorders

Wilkinson, Samuel T.; Toprak, Mesut; Turner, Mason S.; Levine, Steven P.; Katz, Rachel; Sanacora, Gerard

doi:10.1176/appi.ajp.2017.17020239

Cited by 101 publications

(75 citation statements)

References 5 publications

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“…Although ketamine is increasingly being used as a treatment [357], there is not a single rapid-acting antidepressant medication that is approved for the treatment of major depression to date. ( S )-ketamine and GLYX-13 are currently in phase III clinical trials for the treatment of depression.…”

Section: Discussionmentioning

confidence: 99%

Convergent Mechanisms Underlying Rapid Antidepressant Action

et al. 2018

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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 depressed patients. Proposed mechanisms of ketamine’s antidepressant action include N-methyl-D-aspartate receptor (NMDAR) modulation, GABAergic interneuron disinhibition, and direct actions of its hydroxynorketamine (HNK) metabolites. Downstream actions include activation of 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 undergoing 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.

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Section: Discussionmentioning

confidence: 99%

Convergent Mechanisms Underlying Rapid Antidepressant Action

et al. 2018

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“…Although the psychotomimetic effects and dissociative symptoms in humans after ketamine infusion are well known, off‐label ketamine treatment for depression has become popular in the USA . In 2018, an estimated 300 clinics were providing off‐label ketamine treatment to patients with depression, although the US FDA had not approved ketamine for depression .…”

Section: Enantiomers Of Ketamine and Its Metabolitesmentioning

confidence: 99%

“…Ketamine‐induced side‐effects are suggested to be associated with NMDAR inhibition . ( S )‐ketamine is metabolized to ( S )‐norketamine (Ki = 1.70 μM or Ki = 2.25 μM for NMDAR) by the CYP enzymes (Table and Fig.…”

Section: Enantiomers Of Ketamine and Its Metabolitesmentioning

confidence: 99%

Rapid‐acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective

Hashimoto

2019

Psychiatry Clin Neurosci

272

193

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Major depressive disorder (MDD) is one of the most disabling psychiatric disorders. Approximately one‐third of the patients with MDD are treatment resistant to the current antidepressants. There is also a significant therapeutic time lag of weeks to months. Furthermore, depression in patients with bipolar disorder (BD) is typically poorly responsive to antidepressants. Therefore, there exists an unmet medical need for rapidly acting antidepressants with beneficial effects in treatment‐resistant patients with MDD or BD. Accumulating evidence suggests that the N‐methyl‐D‐aspartate receptor (NMDAR) antagonist ketamine produces rapid and sustained antidepressant effects in treatment‐resistant patients with MDD or BD. Ketamine is a racemic mixture comprising equal parts of (R)‐ketamine (or arketamine) and (S)‐ketamine (or esketamine). Because (S)‐ketamine has higher affinity for NMDAR than (R)‐ketamine, esketamine was developed as an antidepressant. On 5 March 2019, esketamine nasal spray was approved by the US Food and Drug Administration. However, preclinical data suggest that (R)‐ketamine exerts greater potency and longer‐lasting antidepressant effects than (S)‐ketamine in animal models of depression and that (R)‐ketamine has less detrimental side‐effects than (R,S)‐ketamine or (S)‐ketamine. In this article, the author reviews the historical overview of the antidepressant actions of enantiomers of ketamine and its major metabolites norketamine and hydroxynorketamine. Furthermore, the author discusses the other potential rapid‐acting antidepressant candidates (i.e., NMDAR antagonists and modulators, low‐voltage‐sensitive T‐type calcium channel inhibitor, potassium channel Kir4.1 inhibitor, negative modulators of γ‐aminobutyric acid, and type A [GABAA] receptors) to compare them with ketamine. Moreover, the molecular and cellular mechanisms of ketamine’s antidepressant effects are discussed.

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“…5 While some clinicians have reported more frequent dosing strategies, 2 there is currently no published evidence to support the benefits of this practice over lower-frequency treatments.…”

Section: Course Of Treatment Planningmentioning

confidence: 99%

“…1 Patients in these trials have been diagnosed with major depressive disorder and bipolar disorder, and the sample sizes have ranged from 8 to 99. While there is broad agreement that ketamine-like drugs hold considerable promise as novel antidepressant agents, the increasing number of clinicians from a variety of medical specialties offering ketamine as an off-label treatment for psychiatric disorders 2 has raised concern.…”

mentioning

confidence: 99%

A Survey of the Clinical, Off-Label Use of Ketamine as a Treatment for Psychiatric Disorders

Cited by 101 publications

References 5 publications

Convergent Mechanisms Underlying Rapid Antidepressant Action

Convergent Mechanisms Underlying Rapid Antidepressant Action

Rapid‐acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective

Considerations on the Off-label Use of Ketamine as a Treatment for Mood Disorders

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