Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study
Vanina Popova, M.D., Ella J. Daly, M.D., Madhukar Trivedi, M.D., Kimberly Cooper, M.S., Rosanne Lane, M.A.S., Pilar Lim, Ph.D., Christine Mazzucco, M.Sc., David Hough, M.D., Michael E. Thase, M.D., Richard C. Shelton, M.D., Patricio Molero, M.D., Ph.D., Eduard Vieta, M.D., Ph.D., Malek Bajbouj, M.D., Husseini Manji, M.D., Wayne C. Drevets, M.D., Jaskaran B. Singh, M.D.
American Journal of Psychiatry in Advance, 2019
Objective : About one-third of patients with depression fail to achieve remission despite treatment with multiple antidepressants. This study compared the efficacy and safety of switching patients with treatment-resistant depression from an ineffective antidepressant to flexibly dosed esketamine nasal spray plus a newly initiated antidepressant or to a newly initiated antidepressant (active comparator) plus placebo nasal spray.
Methods : Thiswas a phase 3, double-blind, active-controlled, multicenter study conducted at 39 outpatient referral centers. The study enrolled adults with moderate to severe nonpsychotic depression and a history of nonresponse to at least two antidepressants in the current episode, with one antidepressant assessed prospectively. Confirmed nonresponders were randomly assigned to treatment with esketamine nasal spray (56 or 84 mg twice weekly) and an antidepressant or antidepressant and placebo nasal spray. The primary efficacy endpoint, change from baseline to day 28 in Montgomery Åsberg Depression Rating Scale (MADRS) score, was assessed by a mixed-effects model using repeated measures.
Results : Of 435 patients screened, 227 underwent randomization and 197 completed the 28-day double-blind treatment phase. Change in MADRS score with esketamine plus antidepressant was significantly greater than with antidepressant plus placebo at day 28 (difference of least square means=24.0, SE=1.69, 95% CI=27.31, 20.64); likewise, clinically meaningful improvement was observed in the esketamine plus antidepressant arm at earlier time points. The five most common adverse events (dissociation, nausea, vertigo, dysgeusia, and dizziness) all were observed more frequently in the esketamine plus antidepressant arm than in the antidepressant plus placebo arm; 7% and 0.9% of patients in the respective treatment groups discontinued study drug because of an adverse event. Adverse events in the esketamine plus antidepressant arm generally appeared shortly after dosing and resolved by 1.5 hours after dosing.
Conclusions : Current treatment options for treatmentresistant depression have considerable limitations in terms of efficacy and patient acceptability. Esketamine is expected to address an unmet medical need in this population through its novel mechanism of action and rapid onset of antidepressant efficacy. The study supports the efficacy and safety of esketamine nasal spray as a rapidly acting antidepressant for patients with treatment-resistant depression.
Major depressive disorder is the leading cause of disability worldwide in terms of total years lost due to disability and is associated with excess mortality (1). About 30% of patients with major depression fail to achieve remission despite treatment with multiple antidepressants and are considered to have treatment-resistant depression (2). In patients who respond to antidepressants, the time to onset of effect is typically several weeks, during which time patients remain symptomatic and at risk of suicidal behavior and self-harm (3). There is a need to develop novel treatments that provide rapid relief of depressive symptoms, especially in patients with treatment-resistant depression.
Research on mood disorder pathophysiology has implicated abnormalities in glutamatergic transmission, along with disrupted function and structure in neural circuits involved in mood regulation (4), findings that led to further See related features: Commentary by Dr. Schatzberg (p. 422) and CME course (p. 491) investigation of glutamatergic N-methyl-D-aspartate (NMDA) receptor modulators in treating depression (5, 6).Ketamine (an NMDA receptor antagonist) affects fast excitatory glutamate transmission, increases release of brain-derived neurotrophic factor, and stimulates synaptogenesis (7). Early clinical evidence suggested a potential role of ketamine in the treatment of depression, with mood-elevating effects observed in challenge studies (8). Intravenous ketamine administered at subanesthetic doses was found to exhibit robust and rapid onset of efficacy in patients with treatment-resistant depression (9).
Esketamine, the S-enantiomer of ketamine racemate, with a higher affinity for the NMDA receptor than the R-enantiomer, was recently approved by the U.S. Food and Drug Administration for treatment-resistant depression in adults. In phase 2 studies, esketamine nasal spray demonstrated rapid onset and persistent efficacy in patientswith treatment-resistant depression as well as in depressed patients at imminent risk for suicide (10–12). Here we report findings from a phase 3 study comparing the efficacy and safety of switching adult patients with treatmentresistant depression from a prior antidepressant to which they had not responded, to flexibly dosed esketamine nasal spray and a newly initiated oral antidepressant or to a newly initiated oral antidepressant plus placebo nasal spray.