The use of esketamine in the treatment of patients with oral antidepressant-resistant depression: systematic review and meta-analysis

Abstract

The Guidelines Project, an initiative of the Brazilian Medical Association, aims to combine information from the medical field to standardize how to conduct, and to assist in the reasoning and decision-making of doctors. The information provided by this project must be critically evaluated by the physician responsible for the conduct that will be adopted, depending on the conditions and the clinical condition of each patient.

Guideline conclusion: April 2023.

Societies: Brazilian Medical Association.

INTRODUCTION

Depression is a very common disabling mental illness and can be assessed through the application of several questionnaires, one of the most commonly used being the Montgomery-Asberg rating scale¹, scoring from 0 to 60, where 7–9 ranks mild depression, 20–24 ranks moderate depression, and greater than 34 ranks severe depression. Approximately one-third of patients with major depression do not experience remission when treated with up to two or more oral antidepressants (OAD), being considered treatment-resistant².

In post-mortem analysis, in vivo gene expression studies and brain imaging data suggest abnormalities in glutaminergic signaling in the pathophysiology of depression³,⁴, allowing the use of new antidepressants with a mechanism of action outside the monoaminergic system.

Esketamine, which is the S-enantiomer of racemic ketamine, is an antidepressive drug with a novel mechanism of action. This active drug is a non-selective, non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist; being an ionotropic glutamate receptor, it promotes increased stimulation of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) and neurotrophic signaling that restore brain synaptic function. However, the mechanism by which esketamine exerts its antidepressive effect is unknown. Unlike other antidepressive treatments, the primary antidepressive action of esketamine does not directly involve monoamine, GABA, or opioid receptors⁵.

The aim of this systematic review was to evaluate the use of esketamine in comparison with placebo in patients with resistant depression.

Clinical doubt

What is the efficacy and safety of using esketamine in the treatment of patients with resistant depression?

METHODOLOGY

Eligibility Criteria:

1. Patients with resistant depression;

2. Compared to placebo plus standard care;

3. Outcomes – improvement in the state of depression, evaluated with appropriate scores;

4. Included randomized controlled trials (RCTs);

5. No restrictions on the date of publication, age of participants, and language;

6. Full text available for access;

7. Follow-up time: minimum of 28 days.

The search for evidence will be carried out in the virtual scientific information database Medline/Pubmed, CENTRAL COCHRANE, and ClinicalTrials.gov, using the search strategy: (Depressive Disorder OR Depressive Disorder, Major OR Depressive Disorder, Treatment-Resistant) AND Esketamine AND Random*. The search in these databases was carried out until December 2022. This systematic review will be prepared according to the recommendations contained in Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)⁶, and the protocol of this study has been registered in PROSPERO (CRD42023403453).

The risk of bias for randomized clinical trials will be assessed using the items in version 2 of the Cochrane risk of bias tool for randomized clinical trials RoB 2⁷ plus other fundamental elements and expressed as low risk, some concerns, and high risk of bias. The risk of bias assessment will be conducted by two independent reviewers (AS and IF), and in case of disagreements, a third reviewer (WB) may deliberate on the assessment. The certainty of the evidence will be extrapolated from the risk of bias obtained from the study(ies) (if there is no meta-analysis) using the terminology GRADE⁸ in very low, low, moderate, and high and through the GRADEpro software⁹ (if meta-analysis) into very low, low, moderate, and high.

The measures used to express benefit or harm varied according to the outcomes, being expressed through continuous variables (mean and standard deviation (SD)) or categorical variables (absolute number of events). For continuous measurements, the result will be the difference in means (DM) and its SD. For categorical measures, it will be the risk difference (RD) and number needed to treat (NNT) or harm (NNH). The confidence level used is 95%.

When there are common outcomes among the included studies, patients and results will be added together, with different doses (esketamine 28–84 mg/week) for comparison with placebo. For calculation in absolute numbers or averages that can be paired, the results will be meta-analyzed using the RevMan 5.4 software¹⁰, with the global RD with 95% confidence intervals (CI) being the final measure used to support the synthesis of the evidence, which will answer the clinical doubts. The estimation of the size of the combined effects will be carried out by a fixed or random effect model after the evaluation of the heterogeneity results. Heterogeneity was calculated using the I² value.

RESULTS

In the search for evidence, 90 studies were retrieved, 27 being selected by title and abstract, of which 3¹¹–¹³ were selected to support this evaluation, whose characteristics are described in Table 1 (ANNEXES). The list of those excluded and the reasons are available in the references and Figure 1 and Table 2.

Table 1
Characteristics of clinical studies evaluating the use of esketamine compared to placebo.

Studies	Population	Intervention	Comparison	Outcome	Follow-up
Fedgchin (TRANSFORM-1) 2019	The study was randomized, double-blind and multicenter, with 346 participants aged between 18 and 64 years old with recurrent major depression or a single episode of depression for more than 2 years, without psychotic characteristics according to DSM-IV-TR criteria and confirmed by Mini International. Neuropsychiatric Interview(MINI). Participants scored ≥28 on the Montgomery-Åsberg Depression Rating Scale (MADRS) and scored ≥34 on the Inventory of Depressive Symptomatolgy. Several psychiatric comorbidities were exclusionary: suicidal ideation, current diagnosis of bipolar disorder, moderate to severe substance use disorder, and substance use.	Esketamine 56 and 84 mg, nasal spray twice a week for 4 weeks, combined with antidepressants	Placebo and antidepressants	Primary: mean reduction in MADRS scale score. Secondary: remission of depression (MADRS≤12), response≤50% in MADRS score reduction, and adverse events	4 weeks
Popova (TRANSFORM-2) 2019	Phase 3, double-blind multicenter study, conducted between June 2017 and December 2018, N=227 adult participants (18–64 years old) diagnosed with major depressive illness (DMD) according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), without psychotic features confirmed by application of the Mini International Neuropsychiatric Interview (MINI); having a score ≥34 on the “Inventory of Depressive Symptomatolgy (IDS-C)” scale. Exclusion criteria: suicidal ideation, psychotic disorders, and drug use.	Esketamine 56–84 mg nasal spray twice a week for 4 weeks plus antidepressants	Placebo and antidepressants	Primary: mean reduction in MADRS scale score. Secondary: remission of depression (MADRS≤12), response≤50% in MADRS score reduction, and adverse events	4 weeks
Ochs-Ross (TRANSFORM-3) 2019	Randomized, phase 3, double-blind, actively controlled, multicenter study conducted in 13 countries between August 2015 and August 2017. 138 participants were selected (N=72 esketamine/antidepressants and N=66 placebos/antidepressants. Eligible patients were aged ≥65 years old, diagnosed with major depressive illness (DMD) according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), treated with ≥2 oral antidepressants, without psychotic features confirmed by applying the Mini International questionnaire Neuropsychiatric Interview (MINI) Exclusion criteria were suicidal ideation, psychotic disorders, and drug use.	Esketamine 28–84 mg nasal spray twice a week for 4 weeks plus antidepressants	Placebo and antidepressants	Primary: mean reduction in MADRS scale score. Secondary: remission of depression (MADRS≤12), response ≤50% in MADRS score reduction, and adverse events	4 weeks

Figure 1
Diagram in recovery and selection of evidence. From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA statement. PLoS Med. 2009;6(7):e1000097. https://doi.org/10.1371/journal.pmed1000097

Table 2
Studies with exclusion reasons.

Studies	Reason for exclusion
Agboola 2020	Cost-effectiveness analysis
Anees Bahji 2020	Systematic review
Nickname 2019	Protocol
Correia-Melo 2020	Does not meet eligibility criteria
Daly 2017	Purpose of the study was to evaluate the relapse of depression in stable patients who do not meet the PICO
Diekamp 2021	Post hoc analysis of two ASPIRE I and ASPIRE II studies
Fedghin 2019	Depression resistant to conventional antidepressants
Jason Ng 2021	Systematic review
Jones 2022	Post hoc analysis, secondary outcome
Katz 2020	Post hoc analysis of three studies
Nijs 2020	Post hoc analysis
Papakostas 2020	Review article
SD Targum 2019	Pilot study
Singh 2016	Does not meet eligibility criteria
Takahashi 2021	Depression resistant to conventional antidepressants
Turkoz 2021	Post hoc analysis of the Transform study.
Vazquez 2021	Does not meet eligibility criteria
Wajs 2020	Depression resistant to conventional antidepressants

The population included was 703 patients, aged over 18 years, diagnosed with recurrent depression or a depressive episode for a period ≥2 years, diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria (DMS-5 criteria) and without associated psychotic disorders, confirmed by the Mini International Neuropysichiatric Interview (MINI) (Table 1 – ANNEXES). Participants had episodes of moderate to severe depression, with a score≥28 when assessed using the Montgomery-Asberg Depression Rating Scale (MADRS) or a score≥34 when assessed using the Inventory of Depressive Symptomatology.

Exclusion criteria were bipolar psychiatric disorder, drug addiction, intellectual disability, antisocial personality disorder, borderline personality, and psychotic disorder.

A total of 415 participants received esketamine for 4 weeks (28–84 mg, nasal route, 3 puffs in total, alternating nostrils, 5 min apart, twice a week) associated to treatment with oral antidepressants, individualized for each patient (standard of care), and 288 received placebo plus standard of care.

The primary outcome considered was the reduction in depressive symptoms assessed by the MADRS and the secondary ones were remission of depression (MADRS score ≤12) and response ≤50% in the reduction in the MADRS score initial and adverse events.

Regarding the risk of bias (Figure 2), two studies did not present analysis by intention to treat¹⁰,¹¹, and the overall risk of bias can be considered moderate. The evaluation was through the ROB 2 tool.

Figure 2
Risk of bias (red=presence; green=absence; and yellow=risk of unclear bias).

Results of comparing esketamine versus placebo in patients with resistant depression at 28-day follow-up

The evaluation of MADRS score reduction included three studies¹¹–¹³ with a total of 681 patients. The meta-analysis for this outcome showed a mean reduction of 4.09 points in favor of using esketamine compared to placebo (MD=-4.09, 95%CI −5.73 to −2.45, I²=0%, p=0.00001, Figure 3; moderate evidence certainty, Table 3 – ANNEXES).

Figure 3
Meta-analysis of the mean reduction in Montgomery-Asberg Depression Rating Scale.

Table 3
Quality of evidence (GRADE).

Summary of findings:
Evaluate the efficacy and safety of using esketamine and AD in elderly participants with treatment-resistant depression compared to placebo for treatment-resistant depression.
Patient or population: Patients with treatment-resistant depression Setting: Intervention: Evaluate the efficacy and safety of using esketamine and AD in participants with treatment-resistant depression. Comparison: Placebo
Outcomes	Anticipated absolute effects * (95%CI)		Relative effect (95%CI)	No. of participants (studies)	Certainty of the evidence (GRADE)
	Risk with placebo	Risk with esketamine
Mean change from baseline in MADRS total score up to endpoint	The mean change from baseline in MADRS total score up to endpoint was 0	MD 4.09 lower (5.73 lower to 2.45 lower)	–	681 (3 RCTs)	⊕⊕⊕O Moderatea
Participants in remission (MADRS£12)	243 per 1,000	340 per 1,000 (267–430)	RR 1.40 (1.10–1.77)	703 (3 RCTs)	⊕⊕⊕O Moderatea,b
Participants who achieved ³50% reduction from baseline in MADRS total score	215 per 1,000	336 per 1,000 (265–428)	RR 1.56 (1.23–1.99)	703 (3 RCTs)	⊕⊕⊕⊕ Moderateb
Adverse events serious	17 per 1,000	27 per 1,000 (10–79)	RR 1.58 (0.55–4.55)	703 (3 RCTs)	⊕OOO Very lowc

• ^*
  The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95%CI). CI: confidence interval; MD: mean difference; RR: risk ratio. GRADE Working Group grades of evidence: High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: the true effect may be slightly different from the estimate of the effect. Very low certainty: We have very less confidence in the effect estimate: the true effect is likely to be slightly different from the estimate of effect.
• ^a
  Does not apply analysis by the intent of treatment.
• ^b
  Wide confidence interval.
• ^c
  Confidence interval crosses the nullity line.

The meta-analysis for the outcome rate of patients in “remission” (MADRS≤12 points) included three studies¹¹–¹³ with a total of 703 participants. Compared with placebo, esketamine increased the number of patients with “remission” by 10% (RD=0.10, 95%CI 0.03–0.17; I²=8%, p=0.004), requiring treatment (NNT) of 10 patients for one get “remission” (Figure 4; moderate evidence certainty, Table 3 – ANNEXES).

Figure 4
Meta-analysis of the “remission” rate (reduction to ≤12 points on the Montgomery-Asberg Depression Rating Scale), fixed effect.

Three studies¹¹–¹³, including a total of 703 patients, were included to meta-analyze the outcome “≥50% reduction in baseline MADRS score.” Compared to placebo, esketamine increased the number of patients with “≥50% reduction in baseline score” by 11% (RD=0.11%, 95%CI 0.05–0.16, I²=8%, p=0.0001; NNT=9), (Figure 5; moderate evidence certainty, Table 3 – ANNEXES).

Figure 5
Meta-analysis of the rate of patients with a ≥50% reduction in Montgomery-Asberg Depression Rating Scale, fixed effect.

Serious adverse events were evaluated in three studies¹¹–¹³, with a total of 703 participants, in a 28-day follow-up and showed no difference when comparing esketamine versus placebo (RD=1%, 95%CI −0.01 to 0.03, I²=8%, p=0.36; NNH=NS) (Figure 6; very low certainty of evidence).

Figure 6
Meta-analysis of serious events, fixed effect.

Evidence summary

The use of esketamine over a period of 4 weeks (28–84 mg, nasal route, 3 puffs in total, alternating nostrils, with an interval of 5 min, twice a week) associated with treatment with oral antidepressants, in patients with drug-resistant depression treatment with oral antidepressants compared to placebo:

• It reduces depression rating scale scores (MADRS), standardized mean of 4.09 points on the MADRS. Moderate evidence certainty.

• It increases the “remission” rate by 10% (MADRS≤12 points); NNT=10. Certainty of moderate evidence.

• It increases the number of patients with reduction by 11%≥50% points on the MADRS initial; NNT=9. Certainty of moderate evidence.

• There is no difference in the number of serious adverse events. Very low certainty of evidence.

DISCUSSION

In this systematic review with meta-analysis, only randomized clinical trials were included, which evaluated the use of esketamine in comparison with placebo, in patients with depression resistant to treatment with two or more oral antidepressants (OAD).

The use of esketamine plus individualized antidepressants compared to placebo showed a reduction standardized mean of 4.09 points on the Montgomery-Asberg scale for depression. It should be noted that all patients included had scores≥28 points on the MADRS. In secondary endpoints, the remission rate (MADRS score≤12) and the ≥50% reduction in the baseline MADRS showed a benefit of 10% (NNT=10) and 11% (NNT=9), respectively, at the 28-day follow-up.

Esketamine has a rapid mechanism of action and an often transient response. With a short follow-up time (28 days), evaluated in this review, it is not possible to extrapolate, in the long term, the result obtained from the treatment of severe depressive illness with resistance to ADO, which is often chronic, demanding treatment for long and indeterminate periods.

As limitations of this study, first, we can mention the number of the tested population, which is relatively small and may lead to publication bias. According to the evaluation through the questionnaire (MARDS), with results in mean and SD, it may not reflect a categorical improvement in absolute and individual terms of these patients.

CONCLUSION

The use of esketamine and standard of care compared to placebo and standard of care, in patients with resistant depression, reduces baseline MADRS and increases the number of patients with ≥50% reduction MADRS initial as well as remission (MADRS score≤12), in a period of up to 28 days, in patients with ADO-resistant depression. Esketamine is shown to be safe, without increasing serious adverse events.

Therefore, it is concluded that patients with ADO-resistant depression benefit from the use of esketamine 28–84 mg, nasal spray, twice a week, for 4 weeks, associated with oral antidepressants.

• Funding: none.

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EXCLUDED STUDIES (reasons): REFERENCES

• ¹
  Agboola F, Atlas SJ, Touchette DR, Fazioli K, Pearson SD. The effectiveness and value of esketamine for the management of treatment-resistant depression. J Manag Care Spec Pharm. 2020;26:16-20. https://doi.org/10.18553/jmcp.2020.26.1.16 PMID: 31880219. (Cost-effectiveness analysis).
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• ²
  Bahji A, Vazquez GH, Zarate CA Jr. Comparative efficacy of racemic ketamine and esketamine for depression: a systematic review and meta-analysis. J Affect Disord. 2021;278:542-55. https://doi.org/10.1016/j.jad.2020.09.071 PMID: 33022440. (Systematic review).
  » https://doi.org/10.1016/j.jad.2020.09.071
• ³
  Smith-Apeldoorn SY, Veraart JKE, Kamphuis J, Asselt ADI, Touw DJ, Aan Het Rot M, et al. Oral esketamine for treatment-resistant depression: rationale and design of a randomized controlled trial. BMC Psychiatry. 2019;19:375. https://doi.org/10.1186/s12888-019-2359-1 PMID: 31783823. (Protocol).
  » https://doi.org/10.1186/s12888-019-2359-1
• ⁴
  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, double-blind, non-inferiority study. J Affect Disord. 2020;;264:527-34. https://doi.org/10.1016/j.jad.2019.11.086 PMID: 31786030. (Does not meet eligibility criteria).
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• ⁵
  Daly EJ, Trivedi MH, Janik A, Li H, Zhang Y, Li X, et al. Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry. 2019;76:893-903. https://doi.org/10.1001/jamapsychiatry.2019.1189 PMID: 31166571. (Study carried out with the objective of evaluating the use of esketamine and ADO in patients with resistant depression in remission).
  » https://doi.org/10.1001/jamapsychiatry.2019.1189
• ⁶
  Daly EJ, Singh JB, Fedgchin M, Cooper K, Lim P, Shelton RC, et al. Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry. 2018;75:139-48. https://doi.org/10.1001/jamapsychiatry.2017.3739 PMID: 29282469. (Aim of the study was to evaluate relapse of depression in stable patients).
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• ⁷
  Diekamp B, Borentain S, Fu DJ, Murray R, Heerlein K, Zhang Q, et al. Effect of concomitant benzodiazepine use on efficacy and safety of esketamine nasal spray in patients with major depressive disorder and acute suicidal ideation or behavior: pooled randomized, controlled trials. Neuropsychiatr Dis Treat. 2021;17:2347-57. https://doi.org/10.2147/NDT.S314874 PMID: 34290505. (Post hoc Analysis).
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  Ng J, Rosenblat JD, Lui LMW, Teopiz KM, Lee Y, Lipsitz O, Mansur RB, et al. Efficacy of ketamine and esketamine on functional outcomes in treatment-resistant depression: a systematic review. J Affect Disorder. 2021;293:285-94. https://doi.org/10.1016/j.jad.2021.06.032 PMID: 34225208. (Systematic review).
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  Nijs M, Wajs E, Aluisio L, Turkoz I, Daly E, Janik A, et al. Managing esketamine treatment frequency toward successful outcomes: analysis of phase 3 data. Int J Neuropsychopharmacol. 2020;23:426-33. https://doi.org/10.1093/ijnp/pyaa027 PMID: 32270176. (Post hoc Analysis).
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• ¹²
  Papakostas GI, Salloum NC, Hock RS, Jha MK, Murrough JW, Mathew SJ, et al. Efficacy of esketamine augmentation in major depressive disorder: a meta-analysis. J Clin Psychiatry. 2020;81:19r12889. https://doi.org/10.4088/JCP.19r12889 PMID: 32459407. (Review Article).
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• ¹³
  Singh JB, Fedgchin M, Daly E, Xi L, Melman C, Bruecker G, et al. Intravenous esketamine in adult treatment-resistant depression: a double- blind, double-randomization, placebo-controlled study. Biol Psychiatry. 2016;80(6):424-31. https://doi.org/10.1016/j.biopsych.2015.10.018 PMID: 26707087. (Esketamine intravenous).
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• ¹⁴
  Targum SD, Daly E, Fedgchin M, Cooper K, Singh JB. Comparability of blinded remote and site-based assessments of response to adjunctive esketamine or placebo nasal spray in patients with treatment resistant depression. J Psychiatr Res. 2019;111:68-73. https://doi.org/10.1016/j.jpsychires.2019.01.017 PMID: 30685564. (Pilot study).
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• ¹⁵
  Takahashi N, Yamada A, Shiraishi A, Shimizu H, Goto R, Tominaga Y. Efficacy and safety of fixed doses of intranasal Esketamine as an add-on therapy to oral antidepressants in Japanese patients with treatment-resistant depression: a phase 2b randomized clinical study. BMC Psychiatry. 2021;21:526. https://doi.org/10.1186/s12888-021-03538-y PMID: 34696742. (Phase 2 study, does not meet eligibility criteria).
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• ¹⁶
  Turkoz I, Daly E, Singh J, Lin X, Tymofyeyev Y, Williamson D, et al. Treatment response with esketamine nasal spray plus an oral antidepressant in patients with treatment-resistant depression without evidence of early response: a pooled post hoc analysis of the TRANSFORM studies. J Clin Psychiatry. 2021;82:20m13800. https://doi.org/10.4088/JCP.20m13800 PMID: 34288609. (Post hoc Analysis).
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• ¹⁷
  Vazquez GH, Bahji A, Undurraga J, Tondo L, Baldessarini RJ. Efficacy and tolerability of combination treatments for major depression: antidepressants plus second-generation antipsychotics vs. esketamine vs. lithium. J Psychopharmacol. 2021;35:890-900. https://doi.org/10.1177/02698811211013579 PMID: 34238049. (Does not meet eligibility criteria).
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• ¹⁸
  Wajs E, Aluisio L, Holder R, Daly EJ, Lane R, Lim P, et al. Esketamine nasal spray plus oral antidepressant in patients with treatment-resistant depression: assessment of long-term safety in a phase 3, open-label study (SUSTAIN-2). J Clin Psychiatry. 2020;81:19m12891. https://doi.org/10.4088/JCP.19m12891 PMID: 32316080. (COHORT study conducted to assess safety in long-term use of esketamine and secondarily efficacy (Before and After).
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Publication Dates

• Publication in this collection
  26 June 2023
• Date of issue
  2023

History

• Received
  06 Apr 2023
• Accepted
  19 Apr 2023