Evaluation of the pharmacokinetics of ketamine for the treatment of major depressive disorder.
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Date
2018
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Abstract
Recent reports have demonstrated ketamine’s potential use in the treatment of major depressive
disorder (MDD), as it elicits potent antidepressant effects via a different mechanism compared
to conventional antidepressants. Ketamine’s hypothesized antidepressant effect is elicited by a
neurochemical cascade involving the antagonization of the N-methyl-D-aspartate (NMDA)
receptors and the subsequent activation of the α-amino-3-hydroxy-5-methyl-4-isoxazole
propionic acid (AMPA) receptors; resulting in the disinhibition of glutamate signalling due to
the suppression of tonic glutamate input into the GABAergic interneurons, providing rapid
symptomatic relief as opposed to the two-week delay with conventional treatments. There is a
large escalation in the number of individuals being diagnosed with treatment resistant
depression (TRD) even after numerous trials on conventional antidepressant therapy. Health
care professionals are now resorting to unconventional treatments, such as ketamine’s off-label
use, to achieve therapeutic outcomes and provide symptomatic relief. MDD’s increasing
prevalence has been associated with significant public health costs and morbidity rates and
therefore alternative, effective treatments are now essential. Many reports have been published
on the intranasal (IN) efficacy of ketamine in the treatment of major depressive disorder,
however there have been no studies investigating the effects on the route of administration in
drug delivery to the brain.
The purpose of this study was to investigate pharmacokinetics of ketamine following oral,
intraperitoneal and intranasal administration. A dose of 15mg/kg (body weight) was
administered to healthy male Sprague-Dawley rats, and ketamine concentrations were
quantified in both plasma and brain tissue homogenates at time intervals of 5, 15, 30, 60, 120,
240 minutes post-treatment.
The results showed that with intraperitoneal administration, concentrations of 524,58 ng/mL
and 352,06 ng/mL, were achieved in plasma and brain tissue, respectively. Surprisingly, IN
administration which is believed to favour drug delivery to the brain only exhibited moderate
levels post administration; whereas, oral administration produced significantly lower levels due
to extensive first-pass metabolism of ketamine in the liver and intestines.
These results show that parenteral administration should be used for the administration of
ketamine in the treatment of MDD. The findings of the study provide a platform for future
investigations assessing alternative routes of administration of ketamine; and its use in clinical
practice for the treatment of MDD. This paves the way forward to optimize treatment and
provide symptomatic relief were conventional antidepressants have failed those suffering with
MDD.
Description
Master of Pharmacy in Pharmaceutical Chemistry. University of KwaZulu-Natal, Durban.