Involvement of muscarinic receptor mechanisms in antidepressant drug action.

Conventional antidepressants typically require weeks of daily dosing to achieve full antidepressant response in antidepressant responders. A newly evolving group of compounds can engender more rapid response times in depressed patients. These drugs include the newly approved antidepressant (S)-ketamine (esketamine, Spravato). A seminal study by Furey and Drevets in 2006 showed antidepressant response in patients after only a few doses with the antimuscarinic drug scopolamine. Several clinical reports have generally confirmed scopolamine as a rapid-acting antidepressant. The data with scopolamine are consistent with the adrenergic/cholinergic hypothesis of mania/depression derived from clinical reports originating in the 1970s from Janowsky and colleagues. Additional support for a role for muscarinic receptors in mood disorders comes from the greater efficacy of conventional antidepressants that have relatively high levels of muscarinic receptor blocking actions (e.g., the tricyclic antidepressant amitriptyline vs the selective serotonin reuptake inhibitor fluoxetine). There appears to be appreciable overlap in the mechanisms of action of scopolamine and other rapid-acting antidepressants (ketamine) or putative rapid-acting agents (mGlu2/3 receptor antagonists) although gaps exist in the experimental literature. Current hypotheses regarding the mechanisms underlying the rapid antidepressant response to scopolamine posit an M1 receptor subtype-initiated cascade of biological events that involve the amplification of AMPA receptors. Consequent impact on brain-derived neurotrophic factor and mTor signaling pathways result in the induction of dendritic spines that enable augmented functional connectivity in brain areas regulating mood. Two major goals for research in this area focus on finding ways in which scopolamine might best be utilized for depressed patients and the discovery of alternative compounds that improve upon the efficacy and safety of scopolamine.