Table 3. Summary of post hoc studies, case/non-case study, and review.

NNT: number needed to treat; NNH: number needed to harm; LHH: likelihood of being helped or harmed; ESK: esketamine; OAD: oral antidepressant; FDA: Food and Drug Administration; FAERS: FDA Adverse Event Reporting System; AE: adverse effects; MADRS: Montgomery-Asberg Depression Rating Scale

Author/year of publication	Study type	Study characteristics	Results
			Efficacy		Safety
Citrome et al. (2020) [22]	Post hoc study	Four phase-three, double-blind studies were used to collect data (TRANSFORM 1, TRANSFORM 2, TRANSFORM 3, SUSTAIN 1); NNT and NNH were calculated for efficacy outcomes and tolerability outcomes, respectively for ESK plus OAD vs placebo plus OAD in each study. LHH calculated; pooled results calculated for acute studies	NNT for efficacy outcomes for ESK plus OAD vs placebo plus OAD were less than 10	AEs with NNH value of less than 10 were dissociation, nausea, dizziness, vertigo, and dysgeusia. Use of ESK plus OAD was three times more likely to result in acute remission as opposed to discontinuation due to side effects
Ochs-Ross et al. (2021) [23]	Post hoc study	This was a post hoc descriptive analysis used to compare the safety and tolerability of ESK in two treatment groups: TRD patients aged 18-64 vs TRD patients aged ≥ 65 in SUSTAIN-2 study	Treatment outcomes of ESK in both the age groups were comparable in terms of change in MADRS scores as well as response/remission rates	Treatment-emergent acute hypertension (TEAH) was observed more frequently in the elderly (age ≥ 65) patients. Except for this, the remaining findings on safety/tolerability of ESK were found to be comparable in both groups
Gastaldon et al. (2019) [24]	Post hoc study	Four phase-three clinical trials were reviewed (TRANSFORM-1, TRANSFORM-2, TRANSFORM-3, SUSTAIN-1). Efficacy re-analysis, as well as re-analysis of the incidence of dissociation, was done on three short-term phase-three clinical trials (TRANSFORM-1, TRANSFORM-2, TRANSFORM-3)	Efficacy re-analysis showed a reduction of MADRS by 4 points. However, the clinical meaningfulness of this result remains unknown	Re-analysis showed that the occurrence of dissociation was seven times higher in the ESK group compared to placebo. 25% of patients receiving ESK experienced severe dissociation during treatment
Gastaldon et al. (2021) [13]	Case/non-case study	FAERS database (March 2019-March 2020) containing 2274 esketamine-related side effects in 962 patients was used to evaluate safety signals of esketamine. In this case/non-case study design, cases included the AE reports where ESK was recorded, whereas non-cases included the AE reports of all the other drugs recorded in FAERS. Disproportionality was then tested to see if the AE were more commonly present in cases vs non-cases	Signals were detected for several side effects including dissociation, feeling drunk, sedation, depression, euphoric mood, suicidal ideation, and completed suicide. The study detected some rare AE which include self-harm ideation, increased loquacity, panic attacks, ataxia, mania, akathisia, and autoscopy.
Horowitz and and Moncrieff (2020) [25]	Narrative review	The study reviewed the efficacy and safety of ESK based on the results of trials submitted to regulators including the FDA	In addition to uncertainties on long-term safety, the evidence regarding efficacy of ESK also remains scarce