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Intranasal ketamine study stopped early due to poor tolerability
Contrary to previous research, a study published in Journal of Psychopharmacology found that intranasal ketamine was not useful for treatment-resistant depression, and that absorption and tolerability of intranasal ketamine varied between individual patients.
“It remains unclear whether ketamine nasal sprays can be safely relied upon as a treatment for patients with severe depression,” Colleen K. Loo, MD, PhD, of the School of Psychiatry, University of New South Wales, Australia, and the Black Dog Institute, said in a press release. "Our prior research has shown that altering the dose on an individual patient basis was important. However, we wanted to see if a simpler approach using a set dose of ketamine for all people and administered by nasal spray could work just as well in this latest pilot.”
In this randomized, double-blind, placebo-controlled pilot study, researchers examined the feasibility, safety, cognitive outcomes and efficacy of repeated intranasal ketamine treatments for patients with severe depression. After 10 participants with severe depression received extensive training in proper self-administration techniques, they were randomly allocated to receive either a course of eight 100-mg ketamine treatments or an active control (4.5 mg of midazolam) over a 4-week period.
Three participants who received ketamine and two who received midazolam completed the study. The study was stopped early because of poor tolerability after the inclusion of five patients with treatment-resistant depression. Specifically, participants who received ketamine experienced high blood pressure, psychotic-like adverse effects and motor incoordination, according to the press release. Due to incoordination, patients were unable to self-administer the ketamine nasal spray. Treatment time had to be extended sometimes to over 45 minutes because of the adverse effects. In addition, Loo and colleagues observed a twofold variation in plasma concentrations between participants who took ketamine nasal spray. After 4 weeks, one participant in each group had remitted.
"It's clear that the intranasal method of ketamine delivery is not as simple as it first seemed. Absorption will vary between people and can fluctuate on any given day within an individual based on such things as mucous levels in the nose and the specific application technique used,” Loo said in the release. “More research is needed to identify the optimal level of ketamine dosage for each specific application method before nasal sprays can be considered a feasible treatment option.” – by Savannah Demko
Disclosures: The authors report no relevant financial disclosures.
Perspective
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Given the apparent rapid efficacy of IV ketamine in treatment-resistant depression, and its novel glutamatergic mechanism, it makes sense to determine whether it is tolerable and efficacious when administered by other routes. IV administration has obvious limitations for use in clinical practice, particularly since ketamine has well-established abuse potential, and few psychiatrists have expertise in IV psychotropic administration. The intranasal route has potential benefits, as it bypasses first-pass hepatic metabolism and can therefore achieve, as the authors note, increased bioavailability and rapid absorption into the brain. The authors also are testing a fixed-dose formulation, which could also be useful for clinical practice. The intranasal route of administration poses potential challenges, as it is unfamiliar to psychiatrists and requires the patient’s active participation in self-administration. Also, this formulation does not eliminate abuse potential.
The results of this small study, which was discontinued prematurely, illustrate some of the challenges of finding a way to make this drug more accessible to clinical practitioners, and to achieve broader clinical impact. Ideally, clinicians would want a formulation of the drug that could be provided to a wide variety of patients, with simple dosing and administration, and which would obtain predictable and therapeutically efficacious blood levels, with generally tolerable side effects.
Their results suggest that other approaches need to be investigated, which could include different drug formulations, dosage strategies, or delivery devices. The novel mechanism and rapid onset of efficacy of this class of medications suggest it is an important problem needing to be solved.