Intranasal Esketamine for MDD: Exploring Alternative Options for Treatment-Resistant Depression

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One-third of patients with major depressive disorder do not respond to currently available antidepressants.
One-third of patients with major depressive disorder do not respond to currently available antidepressants.

Intranasal esketamine hydrochloride may be an effective treatment for patients with major depressive disorder (MDD) whose depression does not respond to available antidepressants, according to research published in JAMA Psychiatry.

Researchers conducted a phase 2 study (A Study to Evaluate the Safety and Efficacy of Intranasal Esketamine in Treatment-resistant Depression [SYNAPSE]; identifier NCT01998959) to examine the safety, efficacy, and dose response of intranasal esketamine therapy in treatment-resistant MDD. Primary efficacy end points included participants' change in Montgomery-Åsberg Depression Rating Scale score from baseline to day 8 of each treatment period.

During the first study period, participants (N=67; 38 women) were randomly assigned 3:1:1:1 to receive either twice-weekly placebo or esketamine 28, 56, or 84 mg (n=34, 11, 11, and 12, respectively). During the second study period, researchers randomly re-assigned participants 1:1:1:1 to 1 of 4 treatment arms.

Study results indicated that change in overall Montgomery-Åsberg Depression Rating Scale score during both study periods was superior in all 3 esketamine groups vs placebo (least squares mean difference for 28, 56, and 84 mg: -4.2, -6.3, and -9.0); a “significant ascending dose-response relationship” was noted. During the open-label phase, participants continued a trend of improved depressive symptoms, despite a decrease in dosing frequency (from twice weekly to weekly to every 2 weeks).

Generalizability of these results is limited by the small sample size included in the study, as well as by enrollment criteria that excluded participants with histories of psychotic symptoms, substance or alcohol use disorders, or significant comorbidities.

Researchers noted that the evaluated esketamine doses appeared to be safe, noting “no new or unexpected safety concerns.” They concluded, “Intranasal esketamine…appeared to be safe and efficacious in treating [treatment-resistant depression]. Results support further investigation of intranasal efficacy of esketamine…in larger trials. A phase 3 study evaluating the necessary frequency of dosing and duration of effect [SUSTAIN-1; NCT02493868] is underway.”

Disclosures: Drs Daly, Singh, Fedgchin, Cooper, Lim, Van Nueten, Manji, and Drevets are employees of Janssen Research & Development, LLC, and hold company stock and stock options.


Daly EJ, Singh JB, Fedgchin M, et al. Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: a randomized clinical trial [published online December 27, 2017]. JAMA Psychiatry. doi:10.1001/jamapsychiatry.2017.3739

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