Scopolamine and Ketamine: Evidence of Convergence?

Abstract

Recent findings have demonstrated that the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine and the muscarinic acetylcholine receptor antagonist scopolamine have rapid antidepressant effects in depressed individuals (1–3). Patients resistant to other treatments reported alleviation of core major depression symptoms following infusion of low-dose ketamine or scopolamine, with effects lingering for longer than 2 weeks in some patients. The rapid efficacy of these compounds is in striking contrast to traditional antidepressants, which target the monoamine system and exert mood-elevating effects only after repeated administration (typically several weeks to months). Because there is an urgent need for antidepressants that exert therapeutic effects within hours or days after administration, preclinical studies have started to elucidate the mechanism of how ketamine can trigger a fast-acting antidepressant response (4,5). Despite initial progress, it remains unclear whether ketamine can exert long-term effects (beyond 1–2 weeks) and, if so, how such an effect can be maintained. It is also unknown how scopolamine triggers a rapid antidepressant effect and whether this effect has any commonalities with the effect of ketamine. In the current issue of Biological Psychiatry, two articles begin to address these questions. Acute ketamine treatment in patients gives rise to the rapid relief of depressive-like symptoms lasting for a short duration of 1 to 2 days to longer than 2 weeks (6). For routine use of fast-acting antidepressants, it is extremely desirable to be able to elicit longer-lasting effects; however, the consequences of repeated ketamine administration is unknown. The study by Parise et al. (7) shows that repeated ketamine treatment (20 mg/kg, twice/day for 15 consecutive days) in adolescent male rats can elicit longlasting antidepressant and anxiolytic-like effects up to 2 months that are not due to drug-seeking behavior. As expected, the authors show that an acute dose of ketamine does not elicit these long-term sustained effects. This study is of interest because it provides a proof of principle that it is possible to prolong ketamine’s beneficial response using repeated administration. However, the repeated twice-daily injections of ketamine and the relatively high dose used raise concerns regarding the potential undesirable side effects that may affect the patient population. Nevertheless, this study provides important evidence that repeated ketamine exposure may have long-term beneficial effects. One intriguing aspect of the study is that ketamine has a relatively short half-life of approximately 2 to 3 hours, suggesting the long-term effects at 2 months are not due to persistent blockade of NMDA receptors but rather to synaptic plasticity processes. Future studies will need to delineate the impact of