Antidepressant Effects of the Muscarinic Receptor Antagonist Scopolamine: Clinical and Preclinical Review

The nonselective muscarinic antagonist scopolamine is a rapid-acting antidepressant in limited clinical studies and shares common downstream signaling partners to ketamine, which is much more thoroughly studied both in the clinic and in preclinical models. In psychiatry, a clinically validated pathway is a rare phenomenon that holds particular importance for guiding neuroscientists toward neurobiological targets with the potential of affording more effective medicines for patients: either through reverse translation in search of targets that retain the clinical efficacy but increase the therapeutic window or through formulations that can be tailored to dosing schedules amenable to patients’ ease of use. Scopolamine’s rapid antidepressant profile provides an opportunity to deliver optimized medicines to patients, much like the recent clinical success of S-ketamine that ensued from robust follow-up investigation of ketamine’s clinical profile. This chapter is an attempt to review the clinical and preclinical antidepressant data of scopolamine with a view on illuminating the critical muscarinic receptor subtype(s) that could prove fruitful as a next-generation antimuscarinic drug target for depression.