Ready for a “breakthrough” with ketamine? A look at recent pharmacological insights!

Abstract

Purpose of reviewTo update pharmacological insights on ketamine integrating information from different disciplines for developing steps to ''breakthrough'' approaches in clinical challenges. Recent findingsPharmacokinetic/pharmacodynamic (PK/PD) models have incorporated recirculation, ketamine metabolites, drug-drug interaction, and covariates such as age. Ketamine-induced relief from treatment-resistant depression has been explained by ''disinhibition'' of gamma-aminobutyric acid-ergic interneurons and synaptogenic mechanisms requiring neurotrophic signals. Neuroimaging/electroencephalographic investigations have shown an increase in gamma spectral power in healthy volunteers and patients with depression, but also opposite changes in functional network connectivity after subanesthetic ketamine. Volunteer data may not be transferable to clinical conditions. Altered states of consciousness induced by subanesthetic ketamine have been described by disruption of resisting-state functional networks and frontoparietal connectivity with preservation of multisensory and sensor-motor networks. This has been interpreted as a ''disconnected consciousness''. SummaryMore precise PK/PD models may improve the ketamine use regimen. The findings from research on depression are an important discovery because ketamine's impact on neuronal plasticity and synaptogenesis in human brain disease has directly been documented. Psychic adverse effects with subanesthetic ketamine are related to a ''disconnected consciousness''. Overall, progress has been made, but the ''breakthrough'' still has to come.

Esketamine: Less Drowsiness, More Analgesia

“…54,56 We found an agonist/ partial agonist interaction of subanesthetic dose ketamine isomers in the racemate. 24 As expected, clinical studies that focused on arousal after anesthesia/ sedation reported shorter time frames after es- versus racemic ketamine 19,25,28,30,57 (Table 2). Table 4 summarizes pharmacological effects of esketamine compared to the racemate.…”

“…There was no measurement of drug plasma concentration although esketamine undergoes extensive metabolism. 24,49 Some of the multiple active metabolites even exert own analgesic action without psychedelic effects. 5…”

“…For treatment success in the vulnerable, injured brain, it is decisive to find this balance in ever-changing postlesional conditions. 24 So far, there is a lack of trials investigating long-term outcomes after ketamine in patients with brain injury.…”

“…There was no measurement of drug plasma concentration although esketamine undergoes extensive metabolism. 24,49 Some of the multiple active metabolites even exert own analgesic action without psychedelic effects. 5 To put it into a nutshell it has to be stated that the most effective administration and amount of esketamine necessary to reduce postsurgical pain is still unclear.…”

“…Apart from genetic disposition, 111 temporal pain summation and a dynamic engagement of the descending antinociceptive pathway predicted ketamine treatment efficacy. 24 Repeated, relatively high subanesthetic dose esketamine over several days is often necessary to affect the "imprinted" symptoms of chronic pain. However, in addition to the associated psychedelic action, prolonged, not recommendable continuous IV esketamine infusion is hepatotoxic.…”