Commentary on Cochrane review: "Ketamine and other glutamate receptor modulators for depression in adults with unipolar major depressive disorder"

Abstract

Background: Cochrane recently published a review of esketamine and other glutamate receptor modulators in depression.

Aim: To address the limitations of the review, analyses of esketamine data were conducted to provide additional perspective to the reviewers' interpretation of their findings.

Methods: Response rate, remission rate, and change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total score were determined using data from all esketamine phase 2/3 registration studies of treatment-resistant depression (TRD) and, separately, all esketamine phase 2/3 registration studies of major depressive disorder (MDD) and active suicidal ideation with intent. Outcomes were assessed at all timepoints (i.e., 24 h, 72 h (MDD with active suicidal intent only), and 1, 2, and 4 weeks). Enrollment criteria of the TRD studies were different than those of the studies of MDD and active suicidal ideation with intent, resulting in differences in patients' clinical characteristics and depression severity between the cohorts. Thus, we did not compare results between these cohorts (as was done in the Cochrane review).

Results/outcomes: In the combined TRD studies, a statistically significant between-group difference favored esketamine plus antidepressant over antidepressant plus placebo at 24 h (based on response, remission, and change in MADRS score), 1 week (change in MADRS score), 2 weeks (response and change in MADRS score), and 4 weeks (response, remission, and change in MADRS score). In the combined studies of MDD and active suicidal ideation with intent, the between-group difference was statistically different, favoring esketamine plus standard-of-care over placebo plus standard-of-care, at 24 h (response, remission, and change in MADRS score), 72 h and 1 week (change in MADRS score), 2 weeks (response), and 4 weeks (response, remission, and change in MADRS score). For both study types, the between-group difference in outcomes was not statistically significant at the other timepoints.

Conclusions/interpretation: Esketamine improves response, remission, and depressive symptoms as early as 24 h post-first dose among patients with TRD and among patients with MDD and active suicidal ideation with intent.

Keywords: Esketamine; suicidal ideation; suicide risk; treatment-resistant depression.

Figure 1.

Response rate in esketamine registration studies of patients with TRD (observed cases at each visit). Esketamine nasal spray combined with newly initiated oral antidepressant versus newly initiated oral antidepressant combined with placebo nasal spray. Response defined as reduction ⩾50% from baseline on MADRS total score. Patients who missed assessments or withdrew prematurely were considered as non-responders. Daly et al. (2018): Panel A period 1 was reported. CI: confidence interval; MADRS: Montgomery-Åsberg Depression Rating Scale; OR: odds ratio; TRD: treatment-resistant depression.

Figure 2.

Response rate in esketamine registration studies of patients with MDD with active suicidal ideation with intent (observed cases at each visit). Esketamine or placebo nasal spray, each with comprehensive SOC treatment (initial psychiatric hospitalization and newly initiated or optimized oral antidepressant[s] therapy). Response defined as reduction ⩾50% from baseline on MADRS total score. Patients who missed assessments or withdrew prematurely were considered as non-responders. For data at week 4, the pre-dose value was used. CI: confidence interval; MADRS: Montgomery-Åsberg Depression Rating Scale; MDD: major depressive disorder; OR: odds ratio; SOC: standard-of-care.

Figure 3.

Remission rate in esketamine registration studies of patients with TRD (observed cases at each visit). Esketamine nasal spray combined with newly initiated oral antidepressant versus newly initiated oral antidepressant combined with placebo nasal spray. Remission defined as MADRS total score <11. Patients who missed assessments or withdrew prematurely were considered as non-responders. Daly et al., 2018: Panel A period 1 was reported. CI: confidence interval; MADRS: Montgomery-Åsberg Depression Rating Scale; OR = odds ratio; TRD: treatment-resistant depression.

Figure 4.

Remission rate in esketamine registration studies of patients with MDD with active suicidal ideation with intent (observed cases at each visit). Esketamine or placebo nasal spray, each with comprehensive SOC treatment (initial psychiatric hospitalization and newly initiated or optimized oral antidepressant[s] therapy). Remission defined as MADRS total score <11. Patients who missed assessments or withdrew prematurely were considered as non-responders. For data at week 4, the pre-dose value was used. CI: confidence interval; MADRS: Montgomery-Åsberg Depression Rating Scale; MDD: major depressive disorder; OR: odds ratio; SOC: standard-of-care.

Figure 5.

Change in MADRS from baseline in esketamine registration studies of patients with TRD (last observation carried forward). Esketamine nasal spray combined with newly initiated oral antidepressant versus newly initiated oral antidepressant combined with placebo nasal spray. Difference between the esketamine group and comparator group based on SMD. Daly et al. (2018): Panel A period 1 was reported. CI: confidence interval; MADRS: Montgomery-Åsberg Depression Rating Scale; SD: standard deviation; SMD: standardized mean difference; TRD: treatment-resistant depression.

Figure 6.

Change in MADRS from baseline in esketamine registration studies of patients with MDD with active suicidal ideation with intent (last observation carried forward). Esketamine or placebo nasal spray, each with comprehensive SOC treatment (initial psychiatric hospitalization and newly initiated or optimized oral antidepressant[s] therapy). Difference between the esketamine group and comparator group based on SMD. For data at week 4, the pre-dose value was used. CI: confidence interval; MADRS: Montgomery-Åsberg Depression Rating Scale; MDD: major depressive disorder; SD: standard deviation; SMD: standardized mean difference; SOC: standard-of-care.