The pharmacokinetics and pharmacodynamics of ketamine Pharmacokinetics Owing to the water and lipid solubility of ketamine, it can be administered by a variety of routes, including intravenous (IV), intramuscular (IM), intranasal (IN) and oral. The bioavailability of ketamine is approximately 90% when given IV or IM, compared with 16% orally, ATR inhibitor although peak effects

occur rapidly with all methods [Craven, 2007]. Whilst oral administration is inevitably more convenient for both patients and staff, to date, the majority of research on the antidepressant effects of ketamine has used IV administration. IN and IM administration of ketamine have been far less explored in the treatment Inhibitors,research,lifescience,medical of depression. IN is reasonably easily administered, Inhibitors,research,lifescience,medical and has been shown to provide benefit in a trial of analgesic-refractory chronic pain patients [Carr et al. 2004]: there are currently two trials underway with IN administration, but as yet no data to support IN use in depression [aan het Rot, 2012]. To date, two case studies have investigated the efficacy of IM administration with promising results, but with a total number of three participants it is hard to infer efficacy at this time [Goforth and Holsinger, 2007; Glue et al. 2011]. Psychotomimetic effects The prefrontal cortex (PFC) homeostatically limits its own input via a cortico–striatal–thalamic–cortical

Inhibitors,research,lifescience,medical loop: glutamatergic neurons feedback to GABAergic interneurons that provide a tonic inhibition to ascending thalamic pyramidal neurons. Inhibitors,research,lifescience,medical Mesolimbic dopaminergic activity between the ventral tegmental area (VTA) and the striatal nucleus accumbens (NAcc) disinhibits the GABAergic interneurons, increasing stimuli that reach the PFC (Figure 1). Amongst the Inhibitors,research,lifescience,medical accepted neuropathological changes that occur in schizophrenia there is evidence for reduction in the PFC feedback and mesolimbic hyperdopaminergia leading to increased input to the PFC and cortical dysconnectivity. Figure 1. Schematic illustration

of the effects of ketamine. (A) Normal and pathological physiology: the prefrontal cortex (PFC) homeostatically limits input via a feedback loop to GABAergic interneurons. The mesolimbic pathway can increase such input through dopaminergic … Ketamine appears to produce its either psychotomimetic effects through a parallel disinhibitory process, acting as a noncompetitive and nonselective high-affinity NMDA antagonist [Krystal et al. 1994] on the GABAergic interneurons, increasing PFC input. Ketamine-induced psychosis has thus been shown to be independent of stimulation of mesolimbic dopaminergic D2 receptors. This model is incomplete insofar as it would predict that benzodiazepines, through facilitation of GABAergic activity, should ameliorate both the effects of ketamine and psychosis more generally [Moghaddam and Krystal, 2012].