Summary: A new study reports intranasal delivery of ketamine may cause problematic side effects for some people with depression.
Source: University of New South Wales.
Nasal spray devices have been touted as a promising way to deliver ketamine to patients with treatment-resistant depression, with this application easier to use and less invasive than other clinical delivery methods such as injections.
Yet contrary to previous trials, this latest study reveals the unpredictable nature of intranasal ketamine tolerance from one person to the next. The results are published today in Journal of Psychopharmacology.
“It’s clear that the intranasal method of ketamine delivery is not as simple as it first seemed,” said lead author UNSW Professor Colleen Loo, who is based at Black Dog Institute.
“Many factors are at play when it comes to nasal spray ketamine treatments. 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.”
The pilot trial aimed to test the feasibility of repeated doses of ketamine through an intranasal device amongst 10 participants with severe depression, ahead of a larger randomised controlled trial.
Participants were first given extensive training in proper self-administration techniques before receiving either a course of eight ketamine treatments or an active control over a period of four weeks, under supervision at the study centre.
Following initial reactions to the nasal spray, the dosage was adjusted amongst study patients to include longer time intervals between sprays.
However, the pilot study was eventually suspended after testing with five participants due to unexpected problems with tolerability. Side effects included high blood pressure, psychotic-like effects and motor incoordination which left some participants unable to continue to self-administer the spray.
“Intranasal ketamine delivery is very potent as it bypasses metabolic pathways, and ketamine is rapidly absorbed into the bloodstream,” said Professor Loo.
“But as our findings show, this can lead to problems with high peak levels of ketamine in some people causing problematic side effects.
“Other recent studies have questioned whether changes to ketamine’s composition after being metabolised into derivative compounds may actually deliver useful therapeutic effects.
“It remains unclear whether ketamine nasal sprays can be safely relied upon as a treatment for patients with severe depression.”
An earlier world-first study led by Professor Loo last year showed the effectiveness of ketamine’s antidepressant effects in elderly patients when delivered in repeated doses, which were adjusted on an individual basis and given by the subcutaneous method (injections under the skin).
“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,” said Professor Loo.
“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.”
Her team are now recruiting participants for the world’s largest independent trial of ketamine to treat depression, to determine the safety and effects of repeated dosing using subcutaneous injections.
Source: Emily Cook – University of New South Wales
Publisher: Organized by NeuroscienceNews.com.
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Original Research: Abstract in Journal of Psychopharmacology.
Repeated intranasal ketamine for treatment-resistant depression – the way to go? Results from a pilot randomised controlled trial
Ketamine research in depression has mostly used intravenous, weight-based approaches, which are difficult to translate clinically. Intranasal (IN) ketamine is a promising alternative but no controlled data has been published on the feasibility, safety and potential efficacy of repeated IN ketamine treatments.
This randomised, double-blind, placebo-controlled pilot study compared a 4-week course of eight treatments of 100 mg ketamine or 4.5 mg midazolam. Each treatment was given as 10 separate IN sprays, self-administered 5 min apart. The study was stopped early due to poor tolerability after five treatment-resistant depressed participants were included. Feasibility, safety (acute and cumulative), cognitive and efficacy outcomes were assessed. Plasma ketamine and norketamine concentrations were assayed after the first treatment.
Significant acute cardiovascular, psychotomimetic and neurological side effects occurred at doses < 100 mg ketamine. No participants were able to self-administer all 10 ketamine sprays due to incoordination; treatment time occasionally had to be extended (>45 min) due to acute side effects. No hepatic, cognitive or urinary changes were observed after the treatment course in either group. There was an approximately two-fold variation in ketamine and norketamine plasma concentrations between ketamine participants. At course end, one participant had remitted in each of the ketamine and midazolam groups.
IN ketamine, with the drug formulation and delivery device used, was not a useful treatment approach in this study. Absorption was variable between individuals and acute tolerability was poor, requiring prolonged treatment administration time in some individuals. The drug formulation, the delivery device, the insufflation technique and individual patient factors play an important role in tolerability and efficacy when using IN ketamine for TRD.