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-hour infusion of ketamine in treatment-resistant depression. Methods Ten participants were randomized to receive a 96-hour ketamine infusion, titrated as tolerated to a target rate of 0.6mg/kg/hour, while 10 received a 40-minute ketamine infusion (0.5mg/kg). Both groups received clonidine, titrated to a maximum of 0.6mg orally daily, during the infusion to mitigate side effects of ketamine. Participants were followed for eight 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 424ng/ml for 96-hour arm, 156ng/ml for 40-minute 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-hour 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

Factors Influencing the Cardiovascular Response to Subanesthetic Ketamine: A Randomized, Placebo-Controlled Trial

“…The average onset age of depression is in a similar range, but older individuals may react differently with a possibly less stable response. Secondly, they may already be receiving antihypertensive drugs ( Tisdale, 2004 ; Lenze, 2016 ). Previous administration of antidepressant medication can also have an impact on the NET, potentially resulting in a different reaction to ketamine.…”

“…One such factor is already known. The alpha-2 adre nergic receptor agonist clonidine partially inhibited the blood pressure increase ( Lenze et al, 2016 ). We postulated that other mediators of autonomous nervous system tone such as gender and genetic effects could also influence the side effects.…”

A review of ketamine’s role in ECT and non-ECT settings

“…Safety concerns in the setting of ECT include higher rates of hypertension, QTc interval prolongation, transient arrhythmias, confusion, or fear, with hallucinations upon awakening from anesthesia. 7 – 9 , 12 , 16 , 23 , 25 The rates of these effects appear to have a positive correlation with an increasing dose of ketamine, notably in the 0.8–2.0 mg/kg dosing range. 8 , 9 , 12 , 16 , 23 , 25 Ketamine use in patients with cardiovascular disease should be considered with caution, especially when used in an ECT setting.…”

“…Lenze et al 23 attempted to demonstrate the efficacy and safety of prolonged ketamine infusion (0.6 mg/kg/h over 96 h) vs a single dose (0.5 mg/kg for 40 min), both with co-administration of clonidine (0.3 mg twice daily) in patients with TRD. Although there was no difference in Montgomery-Asberg Depression Rating Scale (MADRS) scores between prolonged infusion and a single dose of ketamine, a more sustained antidepressant response (spearman correlation coefficient between S-ketamine concentration and MADRS change from baseline: 0.75 for 96-hour arm and 0.17 for 40-minute arm; p <0.05) was observed at 8 weeks following prolonged infusion.…”

Ketamine in Major Depressive Disorder: Mechanisms and Future Perspectives

“…Based on the fact that patients with chronic pain sometimes receive prolonged ketamine infusion, 72 Lenze et al 73 applied a similar protocol in their study of depression. Twenty participants were randomly assigned to two groups that received a continuous infusion of 0.6 mg/kg/h ketamine for 96 hours and a standard ketamine infusion (0.5 mg/kg over 40 minutes).…”