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

Eric J Lenze,Nuri B Farber,Evan Kharasch,Julie Schweiger,Michael Yingling,John Olney,John W Newcomer

doi:10.3109/15622975.2016.1142607

Abstract

ABSTRACTObjectives 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

Highlights

15-30% of individuals with depression have a severe form that is resistant to standard antidepressant treatments (Trevino et al, 2014), leading to extended suffering, excess health care costs, and elevated risk of suicide (Mrazek et al, 2014; Petersen et al, 2004)
Higher ketamine concentration was associated with sustained antidepressant response, and was not with greater psychotomimetic side effects, in the 96-hour arm
Research groups have tested the antidepressant effects of a brief infusion of ketamine in both unipolar (Berman et al, 2000; Murrough et al, 2013; Zarate et al, 2006) and bipolar depression (Diazgranados et al, 2010), finding a significant reduction in depressive symptoms lasting approximately one week using 0.5mg/kg ketamine infused over 40- minutes

Summary

Introduction

15-30% of individuals with depression have a severe form that is resistant to standard antidepressant treatments (Trevino et al, 2014), leading to extended suffering, excess health care costs, and elevated risk of suicide (Mrazek et al, 2014; Petersen et al, 2004). Research groups have tested the antidepressant effects of a brief infusion of ketamine in both unipolar (Berman et al, 2000; Murrough et al, 2013; Zarate et al, 2006) and bipolar depression (Diazgranados et al, 2010), finding a significant reduction in depressive symptoms lasting approximately one week using 0.5mg/kg ketamine infused over 40- minutes. This focus on brief, low-dose infusions (Lai et al, 2014) stems from ketamine's propensity to have significant neuropsychiatric side effects, including dissociation, confusion, and even overt psychosis (Morgan et al, 2004). To provide a more sustained antidepressant effect while mitigating these safety concerns, serial brief infusions have been proposed (Liebrenz et al, 2009; Rasmussen et al, 2013)

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