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

Floriano, Idevaldo; Silvinato, Antônio; Bernardo, Wanderley Marques

doi:10.1590/1806-9282.2023D696

Idevaldo Floriano ^**Corresponding author: idfloriano@hotmail.com

Conceptualization

Data curation

Formal Analysis

Funding acquisition

Investigation

Methodology

Project administration

Resources

Software

Supervision

Validation

Visualization

Writing – original draft

Writing – review & editing

Cooperativa Baixa Mogiana, Evidence-Based Medicine – Mogi-Guaçu (SP), Brazil.

https://orcid.org/0000-0002-3753-2866

Antônio Silvinato

Conceptualization

Data curation

Formal Analysis

Funding acquisition

Investigation

Methodology

Project administration

Resources

Software

Supervision

Validation

Visualization

Writing – original draft

Writing – review & editing

Brazilian Medical Association, Evidence-Based Medicine – São Paulo (SP), Brazil.

https://orcid.org/0000-0003-3718-1442

Wanderley Marques Bernardo

Conceptualization

Data curation

Formal Analysis

Funding acquisition

Investigation

Methodology

Project administration

Resources

Software

Supervision

Validation

Visualization

Writing – original draft

Writing – review & editing

University of São Paulo, School of Medicine – São Paulo (SP), Brazil.

https://orcid.org/0000-0002-8597-5207

*Corresponding author: idfloriano@hotmail.com

Conflicts of interest: the authors declare there is no conflicts of interest.

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

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

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 ^* * 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. (95%CI)		Relative effect (95%CI)	No. of participants (studies)	Certainty of the evidence (GRADE)
Outcomes	Risk with placebo	Risk with esketamine	Relative effect (95%CI)	No. of participants (studies)	Certainty of the evidence (GRADE)
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 Moderate^a a Does not apply analysis by the intent of treatment.
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 Moderate^a a Does not apply analysis by the intent of treatment. ,^b b Wide confidence interval.
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)	⊕⊕⊕⊕ Moderate^b b Wide confidence interval.
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 low^c c Confidence interval crosses the nullity line.

[1] *Corresponding author: idfloriano@hotmail.com

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