Investigating the Psychopharmacology of Scopolamine in Major Depressive Disorder

Abstract

Introduction. Major depressive disorder (MDD) is the leading cause of disability and affects ~280 million people worldwide. With current traditional treatments, four courses of pharmacotherapies or psychotherapies improve two-thirds of patients’ symptoms but may take weeks before this improvement manifests. Furthermore, side effects of these therapies may persist for weeks and one-third of patients with MDD show no improvement. As such, new treatments are under constant development to afford better tolerability, efficacy, and speed of symptom improvement – one new potential treatment is scopolamine which has been investigated for its use as a treatment for MDD. Methods. Forty participants with MDD were enrolled into a randomised controlled parallel groups clinical trial. 24 participants received scopolamine hydrobromide and 16 received glycopyrronium bromide. Glycopyrronium was selected as an active placebo due to its similar antimuscarinic properties but inability to cross the blood-brain barrier. A further 12 healthy control participants all similarly received scopolamine as a 15-minute infusion. The MDD cohorts’ depressive symptoms were measured at 1-, 3-, 7-, 14-, 24-, and 42-days post-infusion with the Montgomery-Åsberg Depression Rating Scale (MADRS). All participants’ electrocardiography (ECG), electroencephalography (EEG), psychotropic experiences, and scopolamine plasma samples were recorded up to four hours post-infusion. Results. Scopolamine did not exhibit a significant antidepressant effect compared to the active placebo. However, both MDD cohorts exhibited large mood improvements within three days of infusion (11–12 point MADRS improvement). ECG heart rate variability (HRV) analysis characterised scopolamine’s acute decrease in HRV before recovering to above baseline levels. EEG analysis characterised scopolamine’s effect in increasing delta power, increasing aperiodic slope and offset, lack of decrease in alpha power, and a decrease in microstate D mean duration. Discussion. Scopolamine does not appear to be an antidepressant despite the large mood improvements. Nonetheless, the acute physiological effects of scopolamine indicate changes to both central and peripheral nervous systems which are implicated in MDD aetiology. Future research may consider using an alternative active placebo to better quantify scopolamine’s potential antidepressant effect. The rich characterisation of scopolamine’s physiological effects also provide a better understanding of the muscarinic receptor physiology.