Monday, May 28, 2018
Good things about a party drug (Ketamine).
Ketamine, used extensively as an anesthetic during the Vietnam war and also as a party drug, has a rapidly acting antidepressant effect. A recent clinical trial has shown the antidepressant efficacy of esketamine, the nasal-spray form of the club drug ketamine, suggesting that it might be useful for the rapid treatment of suicidal depression. Conventional antidepressants require 4-6 weeks to be effective. Several labs are studying ketamine's mechanism of action. Yang et al. have found that neuronal burst firing in the lateral habenula, which drives robust depressive-like behaviors, is rapidly blocked by local ketamine infusion. Instead of acting on GABAergic neurons as previously suggested, ketamine blocked glutamatergic neurons in the “anti-reward center” lateral habenula to disinhibit downstream dopaminergic and serotonergic neurons. Widman et al. report that ketamine enhances excitability of pyramidal cells indirectly by reducing synaptic GABAergic inhibition, thus causing disinhibition. They show that only those antagonists with antidepressant efficacy in humans disinhibit pyramidal cells at a clinically relevant concentration, supporting the concept that disinhibition is likely involved in the antidepressant effect of these antagonists.