Effect of Esketamine Nasal Spray on Olfactory Function and Nasal Tolerability in Patients with Treatment-Resistant Depression: Results from Four Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase III Studies

Abstract

Background Intranasal drug delivery offers a non-invasive and convenient dosing option for patients and physicians, especially for conditions requiring chronic/repeated-treatment administration. However, in some cases such delivery may be harmful to nasal and olfactory epithelia. Objective The aim of this study was to assess the potential impact of long-term intermittent treatment with esketamine nasal spray, taken in conjunction with an oral antidepressant (AD), on olfactory function and nasal tolerability in patients with treatment-resistant depression (TRD). Methods A total of 1142 patients with TRD participated from four multicenter, randomized, double-blind, phase III studies: three short-term studies (two in patients aged 18-64 years, one in patients ≥65 years), and one long-term maintenance study of esketamine nasal spray + AD versus placebo nasal spray + AD. Across the four studies, assessments were performed at 208 sites in 21 countries. Olfactory function was measured using the 40-item University of Pennsylvania Smell Identification Test (UPSIT ® ) and the single-staircase Snap & Sniff ® Odor Detection Threshold Test (S&S-T). Nasal tolerability, including nasal examinations and a quantitative, self-administered nasal symptom questionnaire (NSQ), was also assessed. Data were analyzed using analyses of covariance. Results Of 1142 participants, 734 were women (64.3%). The mean age of all participants ranged from 45.7 to 70.0 years across the studies. Overall, 855 patients received esketamine nasal spray + AD and 432 received placebo nasal spray + AD. Objective evaluation of nasal function showed no evidence of an adverse impact following esketamine administration. Based on the UPSIT ® and S&S-T results, intranasal administration of esketamine had no effect on the odor identification or threshold test scores compared with placebo nasal spray + oral AD. Similarly, repeated administration with esketamine nasal spray had no meaningful impact on assessments of nasal function. No dose-response relationship was observed between esketamine doses and the olfactory test scores. Esketamine nasal spray was well tolerated, as indicated by responses on the NSQ and negative nasal examination findings. Conclusion Findings from this analysis indicate that there was no evidence of adverse effect on either olfactory or nasal health measures with repeated intermittent administration of esketamine nasal spray at any dose over the course of short-term (4 weeks) or long-term (16-100 weeks) studies.

Research advances in the clinical application of esketamine

“…For adults who inhale esketamine (dose range of 28–84 mg) through nasal spray once or twice a week to treat depression (treatment duration is 4–52 weeks), the drug will bring a short‐term increase in blood pressure. Blood pressure generally reaches the highest value 40 min after administration and drops to the pre‐administration level about 1.5 h. When used in combination with oral antidepressants, there is no short‐term or long‐term effect on olfactory function 35 . The use of this dose (<84 mg) will not damage the patient's cognitive function 36,37 .…”

Using the Intranasal Route to Administer Drugs to Treat Neurological and Psychiatric Illnesses: Rationale, Successes, and Future Needs

“…Changes to or a loss of the sense of smell as a result of IN delivery can also be problematic since olfactory function contributes significantly to the flavour of food and is essential for detecting external hazards such as gas or fire [ 70 , 71 ]. Indeed, a zinc-containing nasal decongestant spray known as Zicam was withdrawn from the US market in 2009 after it was shown to cause anosmia in some users [ 72 ].…”

Olfactory loss is a predisposing factor for depression, while olfactory enrichment is an effective treatment for depression

“…), and also has antidepressant action when used in lower doses and acts rapidly compared to other antidepressants ( Covvey et al, 2012 ). Esketamine (S-ketamine) alone, administered as a nasal spray, has also been shown to reduce depression symptoms, also with a rapid onset of action ( Dean et al, 2021 ; Doty et al, 2021 ). However, for both drugs, there is very low−certainty evidence provided for their efficacious use ( Dean et al, 2021 ; Doty et al, 2021 ).…”

“…Esketamine (S-ketamine) alone, administered as a nasal spray, has also been shown to reduce depression symptoms, also with a rapid onset of action ( Dean et al, 2021 ; Doty et al, 2021 ). However, for both drugs, there is very low−certainty evidence provided for their efficacious use ( Dean et al, 2021 ; Doty et al, 2021 ). Both versions of ketamine seem to have their mechanism of action as an antagonist on the NMDA glutamate receptor.…”