Pilot dose–response trial of i.v. ketamine in treatment-resistant depression

Abstract

Objectives. Research studies have reported impressive antidepressant effects with ketamine but significant knowledge gaps remain over the best method of administering ketamine, and the relationships between dose, antidepressant response and adverse effects. Methods. In this pilot dose-finding study, the efficacy and tolerability of ketamine given by rapid intravenous (i.v.) infusion were assessed in a double-blind, placebo-controlled, crossover design, in four subjects with treatment- resistant depression. Each subject received up to four i.v. doses of ketamine (0.1, 0.2, 0.3, 0.4 mg/kg), given over 2–5 min, 1 week apart, and one randomly inserted placebo treatment. Results. Three of four subjects achieved antidepressant response (≥ 50% decrease in Montgomery–Asberg Depression Rating Scale scores), two at the minimum 0.1 mg/kg dose, though all relapsed within a week. For two subjects, the greatest improvement occurred at the highest dose received. Rapid infusion over 2 min led to significant adverse psychotomimetic effects which also increased proportionately with ketamine dosage. Conclusions. This is the first trial to present dose–response data of ketamine efficacy and psychomimetic effects in depressed subjects. Antidepressant efficacy may be dose-related. Psychotomimetic effects were dose-related. Rapid infusion over 2 min may not be a feasible clinical approach to treatment, given poor tolerability.

Key words::

• ketamine
• depression
• dose–response relationship
• drug-related side effects and adverse reactions
• intravenous administration

Acknowledgements

Funding for this trial was supported by a Research Fellowship Grant to Dr Lai from the NSW Institute of Psychiatry. The authors would like to thank Dr Brett Simpson, Dr Jenny McGoldrick, Dr Harry Wark, Amanda Delory, Paula Earls and nursing staff of the Wesley Hospital, Kogarah, for their support for this study.

Statement of Interest

Rosalyn Lai was supported by a Research Fellowship Grant from NSW Institute of Psychiatry. Paul Glue has attended advisory board meetings for Janssen-Cilag, Forrest Pharmaceuticals and Demerx Pharmaceuticals. Colleen Loo, Natalie Katalinic, Andrew Somogyi, Philip Mitchell, John Leyden and Simon Harper report no conflicts of interest.