Ninety-six hour ketamine infusion with co-administered clonidine for treatment-resistant depression: A pilot randomised controlled trial

ABSTRACT

Objectives We examined the feasibility of a high-dose, 96-h infusion of ketamine in treatment-resistant depression. Methods Ten participants were randomised to receive a 96-h ketamine infusion, titrated as tolerated to a target rate of 0.6 mg/kg/h, while 10 received a 40-min ketamine infusion (0.5 mg/kg). Both groups received clonidine, titrated to a maximum of 0.6 mg orally daily, during the infusion to mitigate side effects of ketamine. Participants were followed for 8 weeks to examine potential antidepressant effects. Results All 20 participants completed the infusion. Most participants tolerated the infusion well, with minimal psychotomimetic symptoms or blood pressure elevation despite achieving high ketamine concentrations (mean 424 ng/ml for 96-h arm, 156 ng/ml for 40-min arm). There was no rebound hypertension upon discontinuing clonidine. Rapid and sustained improvement in depressive symptoms was observed in both study groups. Higher ketamine concentration was associated with sustained antidepressant response, and was not with greater psychotomimetic side effects, in the 96-h arm. Conclusions This study provides evidence for the feasibility of prolonged ketamine infusions in treatment-resistant depression. Co-administration of clonidine appeared to mitigate ketamine’s psychotomimetic effects. Further study is required to investigate the extent to which prolonged ketamine infusions could provide both rapid and sustained improvements in treatment-resistant depression.

Clinicaltrials.gov identifier NCT01179009

KEYWORDS:

• Affective disorders
• antidepressants
• major depressive disorder
• psychopharmacology

Acknowledgements

This study was supported primarily by the Sidney R. Baer Foundation, Taylor Family Institute for Innovative Psychiatric Research, and the Washington University Institute of Clinical and Translational Sciences grant UL1 TR000448 from the National Centre for Advancing Translational Sciences (NCATS). Additional funding came from the Washington University Department of Psychiatry, R01 MH083648, P30 DK56341, R01 DA14211 and R01 DA025931. The study sponsors had no role in the study design or conduct, data analysis, interpretation of results, or preparation of the manuscript. The investigators thank Karen Flavin, R.N., Celeste Herleth, M.D., Christina Friedel, and the nursing staff of the Washington University Clinical Research Unit, for their help in the study.

Statement of interest

Dr. Lenze receives research support from the NIH, McKnight Brain Research Foundation, Taylor Family Institute for Innovative Psychiatric Research, Takeda, and Barnes-Jewish Foundation (current), and Sidney R Baer Foundation, Roche, and Lundbeck (past). Dr. Farber receives research support from the Taylor Family Institute for Innovative Psychiatric Research, and Barnes-Jewish Foundation (current). Drs. Farber and Olney hold patents pertaining to improved use of NMDA antagonists as therapeutic agents. Dr. Newcomer has received research support from NIH, Foundation2Recovery, and Otsuka American Pharmaceutical, Inc., has consulted for Reviva Pharmaceuticals, Inc. and serves on a Data Safety Monitoring Board for Amgen. The other authors report no conflicts. Please also note that Dr. Olney is recently deceased.