Benefit-Risk Assessment of Esketamine Nasal Spray vs. Placebo in Treatment-Resistant Depression

Abstract

This post hoc analysis assessed the benefit-risk profile of esketamine nasal spray + oral antidepressant (AD) induction and maintenance treatment in patients with treatment-resistant depression (TRD). The Benefit-Risk Action Team framework was utilized to assess the benefit-risk profile using data from three induction studies and one maintenance study. Benefits were proportion of remitters or responders in induction studies and proportion of stable remitters or stable responders who remained relapse-free in the maintenance study. Risks were death, suicidal ideation, most common adverse events (AEs), and potential long-term risks. Per 100 patients on esketamine + AD vs. AD + placebo in induction therapy, 5-21 additional patients would remit and 14-17 additional patients would respond. In maintenance therapy, 19-32 fewer relapses would occur with esketamine. In both cases, there was little difference in serious or severe common AEs (primarily dissociation, vertigo, and dizziness). These findings support a positive benefit-risk balance for esketamine + AD as induction and maintenance treatment in patients with TRD.

Trial registration: ClinicalTrials.gov NCT02417064 NCT02418585 NCT02422186 NCT02493868.

Figure 1

Esketamine phase III studies overview. (a) Short‐term induction studies (b) Maintenance study. Short‐term induction studies had same design but differed in dose and patients’ age: (i) TRANSFORM‐1: esketamine 56 or 84 mg fixed dose; age 18–64 years; (ii) TRANSFORM‐2: flexible dose; age: 18–64 years; (iii) TRANSFORM‐3: flexible dose; age: ≥ 65 years; *Duloxetine, escitalopram, sertraline, or venlafaxine extended‐release; †Responders defined as ≥ 50% reduction in the MADRS total score from baseline (Day 1 prerandomization) at the end of the 4‐week double‐blind induction phase of the acute 3001 and 3002 studies; ‡Responders who entered the optimization phase remained on the same intranasal study drug as taken in the induction phase; §Frequency of intranasal medication sessions was reduced to once weekly for 4 weeks, then individualized to weekly or every other week based on severity of depressive symptoms (lowest dosing frequency adequate to maintain remission (MADRS ≤ 12)). AD, antidepressant; MADRS, Montgomery‐Åsberg Depression Rating Scale; OL, open label; PBO, placebo; R, randomization; TRD, treatment‐resistant depression. [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 2

Benefit–risk assessment for short‐term treatment, risk differences (per 100 patients) in adults 18–64 years: TRANSFORM‐1 and 2 efficacy and pooled safety. No CI (confidence interval) provided if the number of events is 0 or 1 in either group. AD, antidepressants; ADR, adverse drug reaction; D/C, discontinuation; MADRS, Montgomery‐Åsberg Depression Rating Scale. [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 3

Benefit–risk assessment for short‐term treatment, risk differences (per 100 patients) in adults ≥ 65 years: TRANSFORM‐3. No CI (confidence interval) provided if the number of events is 0 or 1 in either group. AD, antidepressants; ADR, adverse drug reaction; D/C, discontinuation; MADRS, Montgomery‐Åsberg Depression Rating Scale. [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 4

Benefit–risk assessment for maintenance treatment risk differences (per 100 patients): SUSTAIN‐1. No CI (confidence interval) provided if the number of events is 0 or 1 in either group. AD, antidepressants; ADR, adverse drug reaction; D/C, discontinuation. [Colour figure can be viewed at wileyonlinelibrary.com]