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

Abstract

BackgroundThe increasing use of ketamine as a potential rapid-onset antidepressant necessitates a better understanding of its effects on blood pressure and heart rate, well-known side effects at higher doses. For the subanesthetic dose used for depression, potential predictors of these cardiovascular effects are important factors influencing clinical decisions. Since ketamine influences the sympathetic nervous system, we investigated the impact of autonomic nervous system-related factors on the cardiovascular response: a genetic polymorphism in the norepinephrine transporter and gender effects.MethodsBlood pressure and heart rate were monitored during and following administration of a subanesthetic dose of ketamine or placebo in 68 healthy participants (mean age 26.04 ±5.562 years) in a double-blind, randomized, controlled, parallel-design trial. The influences of baseline blood pressure/heart rate, gender, and of a polymorphism in the norepinephrine transporter gene (NET SLC6A2, rs28386840 [A-3081T]) on blood pressure and heart rate changes were investigated. To quantify changes in blood pressure and heart rate, we calculated the maximum change from baseline (ΔMAX) and the time until maximum change (TΔMAX).ResultsSystolic and diastolic blood pressure as well as heart rate increased significantly upon ketamine administration, but without reaching hypertensive levels. During administration, the systolic blood pressure at baseline (TP0Sys) correlated negatively with the time to achieve maximal systolic blood pressure (TΔMAXSys, P<.001). Furthermore, women showed higher maximal diastolic blood pressure change (ΔMAXDia, P<.001) and reached this peak earlier than men (TΔMAXDia, P=.017) at administration. NET rs28386840 [T] carriers reached their maximal systolic blood pressure during ketamine administration significantly earlier than [A] homozygous (TΔMAXSys, P=.030). In a combined regression model, both genetic polymorphism and TP0Sys were significant predictors of TΔMAXSys (P<.0005).ConclusionsSubanesthetic ketamine increased both blood pressure and heart rate without causing hypertensive events. Furthermore, we identified gender and NET rs28386840 genotype as factors that predict increased cardiovascular sequelae of ketamine administration in our young, healthy study population providing a potential basis for establishing monitoring guidelines.

Ketamine influences the locus coeruleus norepinephrine network, with a dependency on norepinephrine transporter genotype – a placebo controlled fMRI study

“…Genotyping of blood samples with regard to the NET gene rs28386840 was performed following a protocol published previously ( Liebe et al, 2017 ). To test the influence of genotype on rs-fc change, we extracted the change of the mean rs-fc beta-weights for the significant result in the ketamine group (baseline, directly after ketamine administration) and compared the groups ([AA] n = 15, [T]-carrier n = 13, no genetic data for one participant) using the non-parametric U Test for two independent samples.…”

“…Importantly, those effects are observed at plasma concentrations achievable with administration of subanaesthetic doses ( Miletich et al, 1973 ; Niesters et al, 2012 ). We have described this relationship in more detail previously ( Liebe et al, 2017 ). The NET is responsible for the recirculation of norepinephrine (NE) from the synaptic cleft into the presynaptic terminal ( Schroeder and Jordan, 2012 ).…”

“…The study of different NET genotypes provides an approach to exploring the role of NET in the antidepressant effects of ketamine. Indeed, one common NET polymorphism (rs28386840) has been associated with the severity of the ketamine-related initial blood pressure increase, indicating an acute influence of ketamine on the peripheral norepinephrine system ( Liebe et al, 2017 ).…”

Temporal dynamics of the pharmacological MRI response to subanaesthetic ketamine in healthy volunteers: A simultaneous EEG/fMRI study

“…Electrophysiological techniques have a distinct advantage over techniques using the BOLD response in that they are a direct measure of neural activity. Ketamine stimulates the sympathetic nervous system, resulting in significant increases in heart rate and blood pressure (Liebe et al, 2017). Due to its indirect nature, the BOLD signal may be more susceptible to contamination by these physiological effects, as vascular changes modulate the neurovascular coupling characteristics responsible for generating the signal.…”

Clinical Efficacy and Target Engagement of Glutamatergic Drugs: Placebo-Controlled RCTs of Pomaglumetad and TS-134 for Reversal of Ketamine-Induced Psychotic Symptoms and PharmacoBOLD in Healthy Volunteers

“…Toward this end, a methodologic refinement that will improve future studies is the measurement of cardiovascular activity and respiration and controlling for their effects. In doing so, the remaining BOLD activity can more reliably be assumed to derive from brain and reflect drug effects on glutamatergic, neural activity [44][45][46].…”