Comparative efficacy of racemic ketamine and esketamine for depression: A systematic review and meta-analysis

This systemic review and meta-analysis (2020) of 24 clinical trials (n=1877) assessed the comparative efficacy and tolerability of racemic and esketamine for the treatment of unipolar and bipolar major depression. The authors found that intravenous ketamine appeared to be more efficacious than intranasal esketamine for the treatment of depression.

Abstract

“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.”

Authors: Anees Bahji, Gustavo H. Vazquez & Carlos A. Zarat Jr

Notes

This paper is included in our ‘Top 12 Articles on on Ketamine for Mental Health‘

Authors: Anees Bahji, Gustavo H. Vazquez & Carlos A. Zarat

Summary

We reviewed 24 randomized controlled trials on racemic ketamine and esketamine for the treatment of depression. Racemic ketamine demonstrated greater overall response and remission rates, as well as lower dropouts.

This systematic review and meta-analysis compared the efficacy and tolerability of racemic and esketamine for the treatment of unipolar and bipolar major depression.

A meta-analysis of 24 randomized controlled trials found that intravenous ketamine was more effective than intranasal esketamine for the treatment of depression.

Introduction

Depression is the leading cause of disability in the world, affecting nearly 300 million individuals globally. Treatment-resistant depression (TRD) is an ongoing search for effective treatments.

Racemic ketamine was first introduced into clinical practice in the 1960s as an invaluable anesthetic, but its use in the management of TRD is much more recent. Repeat doses of intravenous racemic ketamine have been shown to help sustain the short-term antidepressant effects.

Racemic ketamine has been shown to reduce suicidal thoughts in depressed patients within one day and for up to one week, partially independent of its effects on mood. This property may be particularly helpful in the emergent management of patients in acute crisis.

Ketamine appears to ameliorate the symptoms of depression at subanesthetic doses among individuals with major depressive disorder as well as bipolar depression, but its dissociative effects and abuse potential persist. Several alternative formulations and delivery systems have been explored across the literature. With the isolation of the enantiomeric S-ketamine (esketamine), lower doses of ketamine were possible and the dose-dependent dissociative properties of ketamine were reduced. Esketamine was also available through an intranasal delivery system.

Despite its potential for benefit, esketamine nasal spray for TRD has several concerns, including dissociative symptoms comparable to racemic intravenous ketamine. Ketamine’s antidepressant effects may be due to its activation of the NMDAR and AMPAR systems, as well as the gut microbiome. It also may have effects on the mammalian target of rapamycin (mTOR), low-voltage-sensitive T-type calcium channels, and endogenous options.

Objective

Racemic ketamine and esketamine have not been robustly compared in clinical contexts, and no extant or ongoing studies have yet investigated the comparative efficacy of racemic ketamine versus esketamine on remission from and symptoms of depression.

Methods

Eligibility criteria

We included randomized controlled trials examining the use of ketamine in adults with primary unipolar or bipolar depression. We excluded observational designs, reviews of mechanisms of ketamine, commentary articles, and clinical overviews that did not assess and synthesize individual studies.

Information sources and search

We searched MEDLINE, Embase, PsycINFO, the Cochrane Central Register of Controlled Clinical Trials (CENTRAL), and the Cochrane Database of Systematic Reviews via Ovid for studies on ketamine and depression.

Study selection

Two reviewers independently examined titles and abstracts of relevant articles, and assessed for inclusion independently by the two reviewers. Data were extracted via a pre-piloted, standardized data extraction tool in Microsoft Excel 2016, and risk of bias plots were generated using Review Manager.

Outcomes

We used seven outcome measures to assess the effectiveness of the treatment for depressed participants: improvement in depression score, response to treatment, remission from depression, improvement in suicidality, completion of treatment, and drop-outs due to adverse events.

We assessed between-study heterogeneity using the I2 statistic, and risk of bias within individual trials using the Cochrane risk of bias tool. We pooled continuous and dichotomous outcomes using random-effects, generic inverse variance meta-analyses. We conducted a random effects meta-analytic strategy, rather than using a fixed-effects model, and applied a Mantel-Haenszel approach and a DerSimonian-Laird estimator for heterogeneity using the meta package within R studio version 3.5.3.

Risk of bias across studies was assessed by assessing the inverse of the total sample size with the variance of the average event rate as weights. The study was not funded and all authors had full access to all data.

Results

Table 1 provides an overview of study characteristics, including type of study, country, number of participants, and mean age. Of the 1877 participants, 1836 were diagnosed with unipolar major depression, and 41 were diagnosed with bipolar spectrum depression. In 13 trials, ketamine was tested as a monotherapy or as an adjunctive treatment for depression. Most participants had an inadequate response to one, two, or three previous antidepressant trials.

Most studies excluded participants with other significant medical or psychiatric conditions, acute medical complications, and severe substance use disorders. Pregnant and breastfeeding women were also excluded.

Ketamine demonstrated a significant improvement in response and remission rates, alongside a significant reduction in depression severity and suicidality scores, relative to control conditions.

Ketamine was well tolerated in studies, with 147 participants dropping out compared to 141/980 participants who were to receive control interventions. Only 11 studies reported adverse events resulting in study discontinuation, with 37 in experimental arms and 15 in control arms.

Ketamine and esketamine were effective in treating depression and improving depression rating scores; however, their effect on suicidality decreased over time.

Table 4 provides an overview of the results of the moderator analyses for racemic ketamine vs. esketamine, TRD vs. non-TRD, unipolar vs. bipolar depression, crossover vs. parallel trial, monotherapy vs. adjunctive ketamine, and placebo vs. active control.

The results of publication bias assessments are illustrated in Figure 5. The effect sizes for response rates, remission rates, and depression rating scores were reduced significantly following correction for publication bias.

Discussion

This systematic review and meta-analysis found that intravenous racemic ketamine demonstrated more significant overall response and remission rates, as well as lower drop-outs due to adverse events, compared to intranasal esketamine.

Several reviews have demonstrated the merits of intravenous racemic ketamine for the treatment of depression, either as a standalone treatment or in combination with electroconvulsive therapy. The present data suggest that intravenous racemic ketamine is superior to intranasal esketamine for treatment-resistant major depressive disorders.

Ketamine and esketamine are effective treatments for patients who have failed to respond to conventional antidepressants, second-generation antipsychotics or mood-stabilizing medications. However, it remains unclear how ketamine may perform in individuals with non-TRD depression.

Ketamine blockade of glutamatergic neurotransmission promotes AMPA receptor activation, which triggers second messenger pathways required for several neuroplastic changes, ultimately conferring the rapid and sustained antidepressant effects of ketamine.

Ketamine’s antidepressant properties appear to be mediated by the antagonism of the NMDA pathway, but some studies have implied a role for opioid neurotransmission. However, the role of the opioid system in mediating ketamine’s antidepressant effects remains unclear.

Ketamine is an adjuvant to opioid-based pharmacotherapy of pain and may have a wider-reaching effect on opioid neurotransmitter systems outside of only depression. It may also be useful in the emergent management of patients in acute crisis.

Limitations

Although this review has several strengths, it has a few fundamental limitations. For example, the results are limited to four to eight weeks of follow-up and there is minimal information regarding longer-term follow-up.

The trials were unrepresentative of the real-world population with depression, and thus the results may not represent the real-world efficacy of ketamine.

The paper only reported dropout rates and general adverse event rates and could not report on specific side effects.

In our review, intravenous racemic ketamine had greater efficacy ratings in terms of response and remission, but this superiority dropped after the fourth week.

The high heterogeneity within the selected studies could have impacted our results. We accounted for this heterogeneity using subgroup analyses and meta-regression, however, there is likely to be unmeasurable, residual heterogeneity.

Conclusions

This review finds that intravenous ketamine demonstrated more significant overall response and remission rates, as well as lower drop-outs due to adverse events, compared to intranasal esketamine. However, racemic ketamine remains an off-label intervention, and more randomized controlled trials are needed to explore its long-term benefits.

Author Statement

All authors contributed to the development of the manuscript, and Dr. Vazquez and Dr. Zarate undertook supervisory roles. Dr. Bahji supported all phases of the manuscript’s development.

Ketamine has been shown to have antidepressant effects in depression and bipolar depression, and these effects may be due to AMPA glutamate receptors and other mechanisms beyond NMDA receptor antagonism. Ketamine may be used to treat depression in patients with treatment-resistant unipolar and bipolar major depression. A double-blind, randomized, placebo-controlled study was conducted in a military emergency department setting to assess the efficacy of ketamine in the treatment of acute depression and suicidality. Ketamine and other glutamate receptor modulators for depression in adults: a systematic review and meta-analysis of randomized controlled trials. Acute antidepressant effects of intramuscular versus intravenous ketamine have been studied in Indian patients. The Cochrane Collaboration, the American Academy of Pain Medicine, and the American Society of Anesthesiologists have all published consensus guidelines on the use of intravenous ketamine infusions for chronic pain. The FDA has approved a new nasal spray medication for treatment-resistant depression. Ketamine is used to treat depression. A randomized, double-blind, non-inferiority study examined the efficacy and safety of using esketamine or racemic ketamine as adjunctive therapy for adult treatment-resistant depression.

Domany, Y., Bleich-Cohen, M., Tarrasch, R., Meidan, R., Litvak-Lazar, O., Stoppleman, N., Schreiber, S., Bloch, M., Hendler, T., Sharon, H., 2018. Ketamine improves default mode connectivity in major depressive disorder up to 10 days after administration. Ketamine administration in depressive disorders: a systematic review and meta-analysis. Anesthesiology 56, 291 – 297. Ketamine is used in the treatment of bipolar depression. It has been proven effective in a pilot study and is currently being used in a randomized controlled trial.

Ketamine has been used to treat depression in older patients with treatment-resistant depression, and a randomized, double-blind, placebo-controlled study has been conducted to assess the efficacy and toxicity of subcutaneous ketamine in the management of cancer pain. Ketamine, its metabolites, and other candidates for antidepressant treatment: a historical overview and future perspective. Hashimoto, K., Yang, C., Herrman, H., Kieling, C., McGorry, P., Horton, R., Sargent, J., Patel, V., 2019, and Hu, Y.-D., 2016.

Ketamine augmentation for treatment-resistant depression with chronic suicidal ideation: a randomized, double-blind, placebo-controlled trial. Ketamine improves depression scores in patients with anxious bipolar depression and reduces current suicidal ideation following repeated doses. Esketamine for treatment-resistant depression is the first FDA-approved antidepressant in a new class. It is used to counter opioid-induced respiratory depression, and is used in a number of clinical trials.

Ketamine is a novel treatment for major depressive disorder and bipolar depression, and has been shown to improve the postoperative state of depressed patients. Ketamine has been used to treat depression for 50 years. A randomized controlled study was done to determine the effects of low-dose ketamine on the prefrontal cortex and amygdala in treatment-resistant depression. Ketamine is used to treat depression, but it can also be used to treat bipolar depression and suicidal behaviour. A pilot study has shown that riluzole can be used to treat relapse prevention following ketamine therapy in treatment-resistant depression.

Ketamine and other glutamate receptor modulators for depression in bipolar disorder in adults have been reviewed in the Cochrane Database Syst Rev. McGirr, A., Berlim, M.T., Bond, D.J., Neufeld, N.H., Chan, P.Y., Yatham, L.N., Lam, R.W., 2015a. Ketamine is an effective treatment for major depression. Ketamine and other NMDA antagonists have been used in the treatment of depression. A case of sustained remission following an acute course of ketamine in treatment-resistant depression has been reported. A meta-analysis of randomized controlled trials of esketamine nasal spray in elderly patients with treatment-resistant depression was conducted. The study found that esketamine nasal spray was effective and safe.

Sos, P., Klirova, M., Novak, T., Kohutova, B., Horacek, J., Palenicek, T., 2013. Relationship of ketamine’s antidepressant and psychotomimetic effects in unipolar depression. Ketamine’s rapid-onset antidepressant effect may be due to a number of mechanisms. Adjunctive ketamine for treatment-resistant depression in Taiwanese patients: a systematic review and meta-analysis. Esketamine for treatment-resistant depression was reviewed by the Nordic Cochrane Centre and Veritas Health Innovation. Ketamine has antidepressant and antisuicidal effects in adults with psychiatric disorders, but its effects are attenuated by opioid receptor antagonism. A systematic review and individual participant data meta-analysis has been performed.