New Expert Guidance on Ketamine for Resistant Depression

Megan Brooks

March 25, 2021

An international panel of mood disorder experts has published guidance on how to safely and effectively use ketamine and esketamine to treat adults with treatment-resistant depression (TRD).

"Ketamine and esketamine are the first rapid-onset treatments for adults with TRD, and there was an international need for best-practice guidance on the deft and safe implementation of ketamine and esketamine at the point of care, as none previously existed," first author Roger McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, Toronto, Canada, told Medscape Medical News.

"This need has only been amplified by the significant increase in the number of clinics and centers providing this treatment," added McIntyre, head of the Mood Disorders Psychopharmacology Unit.

Their article was published online March 17 in the American Journal of Psychiatry.

Insufficient Evidence of Long-term Efficacy

As reported by Medscape Medical News, the US Food and Drug Administration (FDA) approved esketamine nasal spray (Spravato) for TRD in March 2019.

In August 2020, the FDA updated the approval to include adults with major depression and suicidal thoughts or actions.

To provide clinical guidance, McIntyre and colleagues synthesized the available literature on the efficacy, safety, and tolerability of ketamine and esketamine for TRD.

The evidence, they note, supports the rapid-onset (within 1–2 days) efficacy of esketamine and ketamine in TRD.

The strongest evidence of efficacy is for intranasal esketamine and intravenous ketamine. There is insufficient evidence for oral, subcutaneous, or intramuscular ketamine for TRD, they report.

Intranasal esketamine demonstrates efficacy, safety, and tolerability for up to 1 year in adults with TRD. Evidence for long-term efficacy, safety, and tolerability of intravenous ketamine for patients with TRD is insufficient, the group notes.

They also note that esketamine is approved in the United State for major depression in association with suicidal ideation or behavior and that it has been proven to reduce suicide completion.

Safety concerns with ketamine and esketamine identified in the literature include, but are not limited to, psychiatric, neurologic/cognitive, genitourinary, and hemodynamic effects.

Implementation Checklist

The group has developed an "implementation checklist" for use of ketamine/esketamine in clinical practice.

Starting with patient selection, they note that appropriate patients are those with a confirmed diagnosis of TRD for whom psychosis and other conditions that would significantly affect the risk-benefit ratio have been ruled out.

They suggest that a physical examination and monitoring of vital signs be undertaken during treatment and during posttreatment surveillance. A urine drug screen should be considered if appropriate.

The group advises that esketamine and ketamine be administered only in settings with multidisciplinary personnel, including, but not limited to, those with expertise in the assessment of mood disorders.

Clinics should be equipped with appropriate cardiorespiratory monitoring and be capable of psychiatric assessment of dissociation and psychotomimetic effects.

Depressive symptoms should be measured, and the authors suggest assessing for anxiety, cognitive function, well-being, and psychosocial function.

Patients should be monitored immediately after treatment to ensure cardiorespiratory stability, clear sensorium, and attenuation of dissociative and psychotomimetic effects.

The United States and some other countries require a risk evaluation and mitigation strategy (REMS) when administering esketamine. Regarding the REMS, it is advised that all patients be monitored for a minimum of 2 hours before discharge.

Patients should arrange for reliable transportation for each appointment, and they should be advised not to operate motor vehicles or hazardous machinery without at least one night of sleep.

"The rate of treatment-resistant depression as well as suicide is extraordinary and rising in many parts of the world, only worsened by COVID-19," said McIntyre.

"Clinicians of different professional backgrounds have been interested in ketamine/esketamine, and we are extraordinarily pleased to see our international guidelines published," he added.

"Extremely Useful"

Reached for comment, Alan Schatzberg, MD, professor of psychiatry and behavioral sciences at Stanford Medicine, Stanford, California, said this document "puts a lot of information in one place as far as what we know and what we don't know right now, and that's helpful. I think it's an attempt to have a kind of a somewhat objective review of the literature, and it's in a good journal."

The article, Schatzberg added, "could be extremely useful for someone who is considering whether ketamine is useful for a patient or what they can tell a patient about ketamine, that is, about how long they might need, is it going to work, will it continue to work, and the level of data we have either on benefits or side effects."

The research had no specific funding. The original article contains a complete list of author disclosures. Schatzberg has received grant support from Janssen; has served as a consultant for Alkermes, Avanir, Brain Resource, Bracket, Compass, Delpor, Epiodyne, GLG, Jazz, Janssen Pharmaceuticals, Lundbeck/Takeda, McKinsey and Company, Merck, Myriad Genetics, Neuronetics, Owl Analytics, Pfizer, Sage, Sunovion, and Xhale; holds equity in Corcept (co-founder), Delpor, Dermira, Epiodyne, Gilead, Incyte Genetics, Intersect ENT, Madrigal, Merck, Owl Analytics, Seattle Genetics, Titan, and Xhale; and is listed as an inventor on patents for pharmacogenetics and antiglucocorticoid use in the prediction of antidepressant response.

Am J Psychiatry. Published online March 17, 2021. Abstract

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