Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation

This study (2021), written by a large group of international experts, reviews the state of knowledge around ketamine and esketamine as potential treatments for treatment-resistant depression (TRD). Special attention is given to the risk of suicide after discontinuing (es)ketamine treatment.

Abstract

“Replicated international studies have underscored the human and societal costs associated with major depressive disorder. Despite the proven efficacy of monoamine-based antidepressants in major depression, the majority of treated individuals fail to achieve full syndromal and functional recovery with the index and subsequent pharmacological treatments. Ketamine and esketamine represent pharmacologically novel treatment avenues for adults with treatment-resistant depression. In addition to providing hope to affected persons, these agents represent the first non-monoaminergic agents with proven rapid-onset efficacy in major depressive disorder. Nevertheless, concerns remain about the safety and tolerability of ketamine and esketamine in mood disorders. Moreover, there is uncertainty about the appropriate position of these agents in treatment algorithms, their comparative effectiveness, and the appropriate setting, infrastructure, and personnel required for their competent and safe implementation. In this article, an international group of mood disorder experts provides a synthesis of the literature with respect to the efficacy, safety, and tolerability of ketamine and esketamine in adults with treatment-resistant depression. The authors also provide guidance for the implementation of these agents in clinical practice, with particular attention to practice parameters at point of care. Areas of consensus and future research vistas are discussed.”

Authors: Roger S. McIntyre, Joshua D. Rosenblat, Charles B. Nemeroff, Gerard Sanacora, James W. Murrough, Michael Berk, Elisa Brietzke, Seetal Dodd, Philip Gorwood, Roger Ho, Dan V. Iosifescu, Carlos Lopez Jaramillo, Siegfried Kasper, Kevin Kratiuk, Jung Goo Lee, Yena Lee, Leanna M. W. Lui, Rodrigo B. Mansur, George I. Papakostas, Mehala Subramaniapillai, Michael Thase, Eduard Vieta, Allan H. Young, Carlos A. Zarate, Jr. & Stephen Stahl

Summary

Major depressive disorder patients who are treated with monoamine-based antidepressants fail to achieve full symptomatic and functional recovery. Manual-based psychotherapy may be effective in treatment-resistant depression.

Intranasal esketamine was approved by the U.S. Food and Drug Administration (FDA) for adults with TRD in March 2019, and the European Medicines Agency granted regulatory approval in December 2019.

Although increasing access to ketamine and esketamine for persons with TRD is welcome, legitimate concerns have been raised with respect to long-term efficacy, safety, tolerability, patient selection, and risk for precipitating substance use disorder.

This review is meant to provide practitioners with a synthesis of the current knowledge as it relates to ketamine’s pharmacology, efficacy, tolerability, and safety.

Pharmacodynamics

Ketamine facilitates synaptogenesis and synaptic potentiation by binding to the phencyclidine site of the N-methyl-D-aspartate receptor (NMDAR). This leads to an increase in brain-derived neurotrophic factor (BDNF)-TrkB-ERK activity as well as PI3-AKT-mammalian target of rapamycin (mTOR) activation.

Recent studies suggest that ketamine’s mechanism of action may involve effects on the subgenual anterior cingulate cortex (sgACC), which may be associated with response to conventional antidepressant treatments.

Ketamine may also act on opioid receptors, which co-localize with NMDARs in the CNS. Ketamine has antidepressant effects in rodents, but not humans, and naltrexone may be a relevant target in humans with TRD.

The findings of this elegant study need to be considered along with results of a separate small open-label pilot study. Although naltrexone pretreatment was used, significant antidepressant effects were reported as well as reductions in craving for alcohol consumption.

Pharmacokinetics

Ketamine is available in multiple formulations, of which the intravenous and intranasal routes have the most compelling evidence of efficacy in TRD. Ketamine has a gradient of bioavailability, with intravenous ketamine having a bioavailability of 100%.

Ketamine is metabolized primarily through CYP3A4 and CYP2B6, and its ratio of S-to-R ketamine is 0.84 in individuals with treatment-resistant bipolar depression.

Rodent studies indicate that ketamine has mild and likely clinically insignificant effects on CYP3A4. Concomitant administration of other drugs that are substrates of CYP3A4 may have effects on ketamine and norketamine levels.

KETAMINE AND ESKETAMINE EFFICACY IN TRD

Ketamine has been shown to be effective in treating TRD in both intranasal and intravenous formulations. However, non-specific effects such as functional unblinding and expectancy may inadvertently inflate the efficacy of ketamine.

Intravenous racemic ketamine is effective in treating TRD, but higher doses are associated with more treatment-related adverse events. The upper dosing limit for intravenous racemic ketamine in TRD is not established, but evidence from single-dose studies indicates efficacy at doses of 0.5 mg/kg as well as 1.0 mg/kg.

Intranasal racemic ketamine has not been definitively established as safe and effective in adults with TRD. However, a pilot study demonstrated the antidepressant efficacy and tolerability of intranasal esketamine given as a single administration (50 mg).

A meta-analysis of intranasal esketamine augmentation in TRD reported significant improvement, and the number needed to treat was 6 for response and 7 for remission. However, a secondary subgroup analysis indicated that placebo-subtracted differences in some subgroups were not significant.

Esketamine combined with a conventional antidepressant decreased the risk of relapse by 51% among persons who had achieved stable remission and 70% among persons who achieved a stable response with acute therapy.

The efficacy of intranasal esketamine in adults $65 years old is not yet established. However, preliminary evidence suggests that ketamine may be safe and effective in older populations with TRD.

The relative efficacies of intranasal esketamine and intravenous racemic ketamine are not known, but a single study suggested that intravenous racemic ketamine may be superior to intranasal esketamine co-initiated with an antidepressant.

Ketamine’s efficacy in TRD has been preliminarily reported using oral, intramuscular, and subcutaneous formulations. However, the efficacy of these formulations has not been established with adequately powered, replicated randomized double-blind placebo-controlled studies.

KETAMINE AND SUICIDALITY

Ketamine has been reported to reduce suicidal ideation in people with depression. The effect of ketamine on suicidal ideation may be independent of its effect on depressive symptoms.

Although two phase 3 studies and one phase 2 study of esketamine in adults with major depression at imminent risk for suicide showed rapid improvement in depressive symptoms, the studies did not find significant reductions in suicidal ideation compared with placebo.

KETAMINE TOLERABILITY AND SAFETY

Treatment-emergent adverse events with ketamine and esketamine in major depression may be categorized as psychiatric, neurologic/ cognitive, hemodynamic, genitourinary, and abuse liability. The frequency and severity of adverse events are affected by the formulation, route of delivery, patient population, and methodological aspects of study designs.

Psychiatric Adverse Events

Dissociation is the most common psychotomimetic effect reported with ketamine in TRD, but it is neither necessary nor sufficient for antidepressant response. A validated tool for measuring dissociation in adults with TRD receiving ketamine is not available at this time.

Ketamine can induce psychosis, especially in individuals with a pre-existing vulnerability. However, it remains possible that selected individuals with a primary psychotic disorder may safely and effectively benefit from ketamine administration.

Neurologic/Cognitive

Adults with TRD who were treated with racemic ketamine showed no replicated and persistent deficits in cognitive functions.

Ketamine may cause neurologic side effects, including dizziness, drowsiness, and light-headedness. It is not known whether long-term exposure to ketamine results in cellular or molecular evidence of neurotoxicity.

Hemodynamic

Ketamine exhibits cardiac-stimulating effects via central mechanisms, and may cause blood pressure elevations in 10% – 50% of patients. These elevations usually resolve within 2 – 4 hours, and 20% – 30% of patients may require pharmacological treatment for intravenous ketamine-induced hypertension.

Genitourinary

Lower urinary tract symptoms in persons receiving ketamine include nocturia, painful hematuria, dysuria, urinary urgency, and incontinence. Bladder cystoscopy reveals bladder wall inflammation, ureter thickening, stenosis, vesico-ureteral reflux, and hydroonephrosis.

Ketamine exposure is associated with the probability of experiencing lower urinary tract symptoms, but no evidence of genitourinary toxicity has been reported with repeated-dose esketamine in TRD.

Abuse Liability

Ketamine is an abusable substance that may cause sensitization of drug reward substrates, increasing the possibility of gateway activity.

There is no evidence that racemic ketamine or esketamine administered as single or repeated doses has increased the risk for substance use disorders, however, the status of the study subjects after completion is not known.

KETAMINE IMPLEMENTATION AT POINT OF CARE

All clinicians should consult country-specific regulatory requirements before administering esketamine to adults with TRD.

Patient Selection

The evidence for the efficacy, safety, and tolerability of ketamine and esketamine in adults with treatment-resistant major depressive disorder is best established in adults with treatment-resistant bipolar disorder, obsessive-compulsive disorder, and posttraumatic stress disorder.

The high rate of TRD in persons with bipolar disorder and preliminary evidence supporting the safety and efficacy of ketamine warrant consideration of ketamine as an investigational treatment in bipolar disorder, obsessive-compulsive disorder, and posttraumatic stress disorder.

Studies in adults with TRD have shown that ketamine is effective, but the efficacy may be attenuated in individuals with greater degrees of treatment resistance. It is not known whether failure to respond to ECT or repetitive transcranial magnetic stimulation (rTMS) affects subsequent response to ketamine.

Adults with TRD are heterogeneous, and no biomarker or biosignature has proven to reliably predict outcome with ketamine administration.

Ketamine and esketamine may be an appropriate strategy in some cases of major depression and psychotic features, and some individuals with comorbid substance use disorders may safely benefit from ketamine.

Patients with dementia experiencing TRD should be excluded from receiving ketamine treatment, as should those with uncontrolled hypertension, central aneurysmal disease, significant valvular disease, a recent cardiovascular event, or New York Heart Association class III heart failure.

Most patients with TRD will receive ketamine or esketamine in combination with their existing psychiatric medication. It is not known whether any particular combination of conventional antidepressant with intravenous racemic ketamine is uniquely effective.

Ketamine may interact with other drugs, including nonselective monoamine oxidase (MAO) inhibitors and reversible inhibitors of monoamine oxidase-A. Ketamine may also interact with psychostimulants and other agents with vasopressor activity, but no clinically significant drug interactions have been reported.

Ketamine may be attenuated or delayed by benzodiazepines and lamotrigine. It is also unknown whether lamotrigine affects ketamine’s efficacy in major depression.

Ketamine Dosing and Frequency

It is recommended to start intravenous ketamine at 0.5 mg/kg and to infuse over 40 minutes. Persons who are overweight or obese should dose ketamine based on ideal body weight.

There is not enough evidence to guide dose optimization with intravenous ketamine, but it is recommended that individuals with TRD start at 56 mg on day 1, and increase to 84 mg twice weekly for weeks 1 – 4, and then 56 – 84 mg once weekly for the following 4 weeks.

The frequency of intravenous ketamine administration for prevention of relapse or recurrence should be determined on an individual basis.

There is insufficient evidence guiding dosing, frequency, and long-term safety and tolerability of intravenous ketamine as a maintenance treatment for TRD. Intranasal esketamine administered approximately weekly to biweekly is a better alternative to intravenous ketamine.

It is unknown whether intravenous ketamine or intranasal esketamine is more effective, safer, better tolerated, and/ or more cost-effective for adults with TRD.

Some adults with TRD may begin treatment with intravenous ketamine, followed by transition to intranasal esketamine as a maintenance treatment strategy for those who responded acutely. However, the relative cost-effectiveness of esketamine and intravenous ketamine should be considered.

Strategies to Prolong Ketamine’sEfficacy

Various strategies have been attempted to prolong the efficacy of ketamine in TRD, but none have proven effective in replicated randomized controlled studies. However, repeated dosing appears to sustain benefits longer than single dosing.

Setting, Personnel, and Monitoring

Ketamine should be administered in a setting with personnel with expertise in the assessment, diagnosis, management, and follow-up of persons with mood disorders. Advanced cardiac life support training is required for intravenous ketamine administration, and a comfortable environment is recommended during administration.

Before receiving ketamine treatment, patients should have a psychiatric assessment, including evaluation of depression symptom severity, anxiety, psychosocial function, self-rated cognitive function, and well-being. A mandatory toxicology screening may be considered in cases where concerns about substance misuse are present.

A survey of treatment-emergent adverse events is encouraged. The CADSS cannot be considered a standardized safety metric at this time.

Esketamine patients should be monitored for 2 hours before discharge from the clinic. Adults with TRD receiving intravenous ketamine should be monitored for up to 2 hours.

For patients receiving maintenance ketamine treatment for major depression, safety should focus on evidence of drug or alcohol misuse, subjective cognitive complaints, genitourinary pathology, and change in concomitant medication.

Ketamine’s Positioning in the Algorithmic Treatment of TRD

Adults with TRD may benefit from second-generation antipsychotics, combined antidepressants, combination with other agents (e.g., lithium), and neurostimulation. Ketamine has been demonstrated to be efficacious in adults with TRD after two prior conventional antidepressants, but not all individuals considered for esketamine will meet criteria for TRD.

It has not been empirically established which somatic treatment is preferred in adults with TRD. The efficacy of ECT and ketamine in adults with TRD are being studied, but the combination of olanzapine with fluoxetine has been proven efficacious, but is limited by weight gain and metabolic liability.

CONCLUSIONS

Intravenous ketamine and intranasal esketamine offer hope in the treatment of TRD, but there are significant unanswered questions with respect to safety. Postdiscontinuation surveillance of patients who have received ketamine or esketamine would provide a fuller characterization of unintended safety events.

Future research will provide information on whether biomarkers (e.g., pharmacogenomics) or other clinical aspects can be used to predict outcome with ketamine. Moreover, ketamine combined with manual-based psychotherapies is a promising avenue.