Table 2. Summary of phase-three clinical trials of esketamine.

ESK: esketamine; OAD: oral antidepressant; MADRS: Montgomery-Asberg Depression Rating Scale; CSSRS: Columbia-Suicide Severity Rating Scale; CADSS: Clinician-Administered Dissociative States Scale; BPRS+: Brief Psychiatric Rating Scale (4-item Positive Symptom Scale); MOAA/S: Modified Observer’s Assessment of Alertness/Sedation Scale; PWC-20: Physician Withdrawal Checklist; TRD: treatment-resistant depression; BPIC-SS: Bladder Pain/Interstitial Cystitis Symptom Score; TEAEs: treatment-emergent adverse events

*MADRS total score ranges from 0 to 60. A higher score indicates increased severity of depression, whereas a negative change in score is indicative of improvement. **TRD: Nonresponse (≤ 25% improvement in MADRS) to at least two OAD given at an adequate dose in the current depressive episode for at least six weeks duration. ***Stable remission: MADRS total score ≤12 for at least three weeks in the last four weeks. ****Stable response without remission: MADRS score reduction by ≥50% from the baseline seen in the last two weeks of optimization phase but without acquiring remission.

Author/Year of publication/Name of study	Study details	Study population and duration	Dosing	Results
				Efficacy	Safety
Fedgchin et al. (2019) [17] TRANSFORM-1	Randomized, multi-center, double-blind, and active-controlled; fixed dosing; arms = ESK (56 mg or 84 mg) plus OAD vs placebo plus OAD; N = 346 (56 mg ESK plus OAD = 117; 84mg ESK plus OAD = 116; placebo plus OAD = 113)	Adults with TRD**; age group = 18 to 64; treatment phase of four weeks, follow up for 24 weeks or entry into SUSTAIN-1	ESK 56 mg or 84 mg given intranasally two times per week	MADRS was used to assess efficacy, primary efficacy endpoint being a change in MADRS total score* from baseline (day one) to day 28. No statistically significant difference was seen between treatment with ESK plus OAD group compared to placebo plus OAD group	Safety assessment performed via physical examination, nasal examination, cognitive testing, CSSRS, CADSS, BPRS+, MOAA/S, PWC-20, Global Assessment of Discharge Readiness. Most common side effects included nausea, dizziness, dissociation, headache, and vertigo
Popova et al. (2019) [18] TRANSFORM-2	Randomized, multi-center, double-blind, and active-controlled; flexible dosing; arms = ESK (56 mg or 84 mg) plus OAD vs placebo plus OAD; N = 223 (ESK plus OAD = 114; placebo plus OAD = 109)	Adults with TRD; age group = 18 to 64; treatment phase of four weeks, follow up for 24 weeks or entry into SUSTAIN-1	ESK 56 mg or 84 mg given intranasally two times per week	MADRS used to assess efficacy, primary efficacy endpoint being a change in MADRS total score from baseline (day one) to day 28. Treatment with ESK plus OAD was associated with a significantly greater change in MADRS score compared to placebo plus OAD	Safety assessment performed via physical examination, nasal examination, cognitive testing, CSSRS, CADSS, BPRS+, MOAA/S, PWC-20, Global Assessment of Discharge Readiness. Most common side effects were dissociation, dizziness, vertigo, dysgeusia, and they were more frequently observed in ESK plus OAD group
Ochs-Ross et al. (2020) [19] TRANSFORM-3	Randomized, multi-center, double-blind, and active-controlled; flexible dosing; arms = ESK (28 mg or 56 mg or 84 mg) plus OAD vs placebo plus OAD; N = 138 (ESK plus OAD = 72; placebo plus OAD = 66)	Adults with TRD; age group ≥ 65 years; treatment phase of four weeks, follow up for 24 weeks or entry into SUSTAIN-2	ESK 28 mg or 56 mg or 84 mg given intranasally two times per week	MADRS was used to assess efficacy, primary efficacy endpoint being a change in MADRS total score from baseline (day one) to day 28. No statistically significant difference was seen between treatment with ESK plus OAD group compared to placebo plus OAD group	Safety assessment performed via physical examination, nasal examination, cognitive testing, CSSRS, CADSS, BPRS+, MOAA/S, PWC-20, Global Assessment of Discharge Readiness. Dizziness, nausea, transient elevation in BP, fatigue, headache, dissociation were the common TEAEs. Safety profile was comparable to other similar studies done in younger adults
Daly et al. (2019) [20] SUSTAIN-1	Randomized withdrawal design, double-blind, multi-center, active-controlled; arms = fixed or flexible dose ESK (56 mg or 84 mg) plus OAD vs placebo plus OAD; N = 705 (direct entry = 437; transferred entry = 268); patients with stable remission during maintenance phase: N = 176 (ESK plus OAD = 90; placebo plus OAD = 86); patients with stable response without remission during maintenance phase: N = 121 (ESK plus OAD = 62; placebo plus OAD = 59)	Adults with TRD; age group = 18 to 64; direct-entry patients: four weeks of induction phase with flexible dosing (56 mg or 84 mg intranasally twice a week), followed by 12 weeks of optimization phase (in those achieving treatment response) with dosing same as the induction phase given once per week for four weeks and then once every two weeks or weekly. Transferred-entry responders (from TRANSFORM-1 and TRANSFORM-2): 12 weeks of optimization with the frequency of dosing, same as that mentioned for direct-entry patients. Maintenance phase: patients showing stable remission*** and patients showing stable response without remission**** randomized (1:1) to either continue ESK plus OAD or switch to placebo plus OAD		MADRS used, and the relapse time was assessed between the two treatment arms. Significantly delayed relapse of depressive symptoms observed in ESK plus OAD group	Safety assessment performed via physical examination, nasal examination, cognitive testing, CSSRS, CADSS, BPRS+, PWC-20. Side effects such as dissociation, vertigo, dizziness, dysgeusia. and somnolence were reported more frequently in ESK plus OAD group
Wajs et al. (2020) [21] SUSTAIN-2	Long-term (one year) study, multi-center, uncontrolled; flexible dosing; N=802 (direct entry = 691; transferred entry from TRANSFORM-3 = 111)	Adults with TRD; age group ≥18 years; direct entry patients: ESK 28 mg (for ≥ 65 years), 56 mg or 84 mg given intranasally twice weekly during the four-week induction phase (given along with OAD), and the responders continued with treatment once weekly or every other week for a 48-week optimization/maintenance phase, followed by a four-week follow-up. Transferred-entry responders: ESK 28mg or 56 mg or 84 mg (along with OAD) once weekly or every other week for 48-week optimization/maintenance phase followed by a four-week follow-up		MADRS scale used for efficacy evaluation. Improvement in depressive symptoms was found to be sustained in patients with TRD	Safety assessment performed via physical examination, nasal examination, cognitive testing, CSSRS, CADSS, BPRS+, PWC-20, BPIC-SS. Most TEAEs were of mild to moderate severity and included dizziness, dissociation, nausea, and headache