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

This pooled analysis of two phase III studies (n=518, TRANSFORM) finds that for those who didn’t respond, continued treatment may still be beneficial. This was both true for the esketamine group and the group that received a placebo.

Abstract

“Objective: To evaluate response to esketamine nasal spray plus an oral antidepressant (ESK + AD) at day 28 in patients with major depressive disorder (DSM-5) and treatment-resistant depression (TRD) who did not meet response criteria within the first week of treatment.

Methods: The current study is a pooled post hoc analysis of two phase 3, double-blind, active-controlled studies, conducted between August 2015 and February 2018, comparing ESK + AD with an oral antidepressant plus placebo (AD + PBO). Early treatment response was defined as a ≥ 50% decrease in Montgomery-Åsberg Depression Rating Scale total score at day 2 or days 2 and 8. Response rates at day 28 were determined among those not meeting early response criteria.

Results: 518 patients in the analysis had day 28 observations (ESK + AD, n = 310; AD + PBO, n = 208). A greater percentage of patients treated with ESK + AD versus AD + PBO met response criteria beginning at day 2 (17.3% [55/318] vs 9.4% [19/203]) and at all subsequent timepoints, including day 28 (58.7% [182/310] vs 45.2% [94/208]). In day 2 nonresponders, 54.9% vs 44.3% (ESK + AD vs AD + PBO, respectively) achieved response at day 28 (P < .01). Similarly, among day 2 and 8 nonresponders, 52.1% vs 42.4% achieved response by day 28 (P = .01). In nonresponders at day 2 and at days 2 and 8, the odds ratio for a response at day 28 was 1.61 (95% CI, 1.09-2.40) with ESK + AD versus 1.56 (95% CI, 1.04-2.35) with AD + PBO.

Conclusions: Patients with TRD without a demonstrated response within the first week of treatment may still derive benefit from a full 4-week induction course of esketamine nasal spray.”

Authors: Ibrahim Turkoz, Ella J. Daly, Jaskaran Singh, Xiwu Lin, Yevgen Tymofyeyev, David Williamson, Giacomo Salvadore, Abigail I. Nash, Matthew Macaluso, Samuel T. Wilkinson & J. Craig Nelson

Summary

Patients with major depressive disorder and treatment-resistant depression received esketamine nasal spray plus an oral antidepressant.

A pooled post hoc analysis of two phase 3, double-blind, active-controlled studies comparing ESK + AD with an oral antidepressant plus placebo was conducted.

Results: A greater percentage of patients treated with ESK + AD versus AD + PBO met response criteria beginning at day 2 (17.3% [55/318] vs 9.4% [19/203]) and at all subsequent timepoints, including day 28 (58.7% [182/310] vs 45.2% [94/208]).

Patients with TRD may benefit from a full 4-week induction course.

Trial registration numbers: NCT02417064 and NCT02418585.

Major depressive disorder (MDD) is associated with high rates of morbidity, disability, and excess mortality. Several oral antidepressants are often tried before an adequate option is found, but one-third of patients with MDD do not achieve an adequate response to multiple antidepressants.

Newer augmentation strategies and rapid-acting antidepressant treatments have increased expectations for visible results within the first week of treatment. However, the time to onset of improvement can be variable for individual patients.

Esketamine nasal spray, a rapid-acting NMDA receptor antagonist, is indicated for use in conjunction with an oral antidepressant for the treatment of adults with TRD. However, treatment for the full 4 weeks may still provide additional benefit in patients who do not respond within the first 2 doses.

Study Design

This was a post hoc analysis of pooled data from two phase 3, double-blind, active-controlled, multicenter studies of esketamine plus a newly initiated oral antidepressant compared to a newly initiated oral antidepressant plus placebo.

Computer-generated randomization schedules were used to assign patients to receive esketamine or placebo intranasal spray devices. Patients, investigators, site personnel, and those assessing outcomes and analyzing data were blinded to treatment assignment.

Study Drugs and Administration

Patients were randomly assigned to receive twice weekly esketamine or placebo and a newly initiated, open-label, oral antidepressant. Esketamine was self-administered for 4 weeks at the study site under direct supervision.

Study Population

At study entry, patients were aged 18-64 with recurrent MDD or single-episode MDD, without psychotic features, confirmed by the Mini-International Neuropsychiatric Interview.

Patients were required to have had nonresponse to 1 but 5 oral antidepressants at screening and confirm nonresponse to the current ongoing oral antidepressant during the 4-week screening/prospective observation phase.

Key exclusion criteria were suicidal ideation, suicidal behavior, diagnosis of psychotic disorder, moderate or severe substance use disorder, and positive urine drug test result. All patients provided written informed consent prior to participation.

MADRS was administered by telephone by independent raters blinded to the protocol details.

Statistical Analyses

In this analysis, we sought to determine treatment-related differences in overall response rates and treatment-related differences in the probability of response at day 28 given nonresponse at day 2 or days 2 and 8.

Overall response rates were determined for patients without an early response based on study criteria, and treatment group differences were compared using various methods. Multiple logistic regression models were performed with key demographic and baseline disease characteristics, and multivariate adaptive regression splines (MARS) was used to estimate day 28 response rates. Odds ratios and 95% confidence intervals were computed for both treatments, and patient-specific conditional probabilities were also computed using repeated-measures generalized linear mixed models.

Patients

The analysis set included 518 patients with MADRS scores at day 28. There were no major differences in baseline demographics or psychiatric history between treatment groups.

Response Rates

At the 2-week and 8-week visits, a significantly higher proportion of patients treated with ESK + AD met the criteria for response compared with patients treated with AD + PBO.

Among day 2 and day 2 and 8 nonresponders, ESK + AD was associated with a higher proportion of patients with response at day 28 than AD + PBO.

Multiple Logistic Regression Models

Patients who were day 2 nonresponders or day 2 and 8 nonresponders and received esketamine plus a placebo had a 61% or 56% increased odds of meeting response criteria at day 28 compared with those who received a placebo plus adrenocorticotropic drug.

MARS models identified several factors associated with achieving response at day 28. After adjusting for these factors in day 2 and 8 nonresponders, the OR of response versus nonresponse at day 28 was 1.66 (95% CI, 1.08 – 2.56), favoring ESK + AD.

Mixed Models

The repeated measures generalized linear mixed models suggest that ESK + AD has a higher likelihood of achieving response compared to AD + PBO in day 2 nonresponders and day 2 and 8 nonresponders, respectively.

Safety

Treatment-emergent adverse events and serious adverse events were consistent with primary analyses, and no new or unexpected safety concerns were noted.

Response to Esketamine After Initial Nonresponse

Patients with TRD receiving esketamine, or now, esketamine, experienced a higher rate of response at day 28 than those receiving AD + PBO at day 2 and day 8. This has important implications for clinical practice, patient choice, and institutional policies.

The phase 3 esketamine trials in patients with TRD differed from most adjunctive treatment trials conducted in patients with MDD in that a new oral antidepressant was initiated at the same time as esketamine or placebo, and the frequency of clinical contact far exceeded that typically observed in trials of oral antidepressants.

Finding the optimal antidepressant choice for an individual patient often involves several treatment trials. Electroconvulsive therapy is an important treatment for TRD, but carries a risk of cognitive side effects that some patients find unacceptable.

Early response to ketamine infusion is often cited as a predictor for future response, but little evidence is available regarding predictors of nonresponse. The present analysis contributes to a growing body of evidence that patients who do not show an early response may eventually show improvement with continued treatment.

Multiple analytic approaches provided similar conditional probability of response estimates at day 28 for patients with TRD who did not achieve an early full response to treatment. Esketamine + AD may lead to greater odds of response compared with AD + PBO.

This study was based on findings from 2 randomized clinical trials with strict inclusion criteria, and therefore the patient population studied may not fully reflect the diversity of patients with TRD encountered in real-world clinical practice.

Patients with TRD who do not respond to treatment with esketamine nasal spray may benefit from a full 4-week induction treatment course of esketamine nasal spray plus an oral antidepressant.