OPEN Foundation

C. Loo

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.
Gálvez, V., Li, A., Huggins, C., Glue, P., Martin, D., Somogyi, A. A., … & Loo, C. K. (2018). Repeated intranasal ketamine for treatment-resistant depression–the way to go? Results from a pilot randomised controlled trial. Journal of Psychopharmacology32(4), 397-407. 10.1177/0269881118760660
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Can we confidently use ketamine as a clinical treatment for depression?


Findings from several proof-of-concept, double-blinded, placebo-controlled studies have shown rapid and large antidepressant effects in patients with major depression after a single dose of ketamine.1 These data are remarkable in the rapidity of therapeutic effects, with remission within 24 h (though relapse often occurs within days), the high degree of antidepressant potency in cohorts with moderate-to-high treatment resistance, and the consistency of findings between studies. Given that ketamine is readily available in many countries as an approved anaesthetic drug, it is not surprising that there has been enthusiasm for the use of ketamine to treat depression.
Loo, C. (2018). Can we confidently use ketamine as a clinical treatment for depression?. The Lancet Psychiatry5(1), 11-12. 10.1016/S2215-0366(17)30480-7
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Side-effects associated with ketamine use in depression: a systematic review


This is the first systematic review of the safety of ketamine in the treatment of depression after single and repeated doses. We searched MEDLINE, PubMed, PsycINFO, and Cochrane Databases and identified 288 articles, 60 of which met the inclusion criteria. After acute dosing, psychiatric, psychotomimetic, cardiovascular, neurological, and other side-effects were more frequently reported after ketamine treatment than after placebo in patients with depression. Our findings suggest a selective reporting bias with limited assessment of long-term use and safety and after repeated dosing, despite these being reported in other patient groups exposed to ketamine (eg, those with chronic pain) and in recreational users. We recommend large-scale clinical trials that include multiple doses of ketamine and long-term follow up to assess the safety of long-term regular use.
Short, B., Fong, J., Galvez, V., Shelker, W., & Loo, C. K. (2017). Side-effects associated with ketamine use in depression: a systematic review. The Lancet Psychiatry. 10.1016/S2215-0366(17)30272-9
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