The muscarinic-cholinergic system as a target in the treatment of depressive or manic episodes in bipolar disorder: A systematic review and meta-analysis

Background: Increasing evidence has implicated the cholinergic system as a modulator of mood episodes, with possible involvement of nicotinic and/or muscarinic receptors. A number of randomized controlled trials (RCTs) have demonstrated a putative rapid antidepressant effect of the muscarinic antagonist scopolamine. Here, we review the clinical evidence regarding the three principal muscarinic-modulating agents administered in studies involving mood disorders: scopolamine, biperiden and physostigmine. We conduct a meta-analysis on RCTs where these agents were administered to participants experiencing a depressive episode. Methods: A systematic bibliographic search of Medline, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL) for studies utilizing the above agents was conducted between January 1970 and December 2020. A meta-analysis was subsequently performed on 9 studies which satisfied inclusion criteria, including 322 participants. Results: Administration of scopolamine significantly reduced depressive symptoms compared to placebo, as measured by objective mood rating scales with SMD of -0.95 (95% CI -1.49, -0.42, p = 0.0005). This effect increased to -1.13 (95% CI -1.61, -0.66, p < 0.00001) when scopolamine was administered intravenously. Biperiden displayed no significant antidepressant effect. A systematic review noted anergia and an exacerbation of depressive symptomatology following physostigmine administration, but no obvious anti-manic effect. Limitations: There were a relatively small number of RCTs suitable for meta-analysis. 2 studies included patients enrolled in previous trials. Heterogeneity in study design examining physostigmine prevented meta-analysis for this agent. Conclusions: This study suggests that scopolamine may be a potential rapid-acting and efficacious antidepressant agent. Further adequately statistically powered RCTs should be conducted in participants experiencing depressive episodes in the context of major depressive and bipolar disorder to further elucidate any potential treatment and side effects.