Antidepressant efficacy of the antimuscarinic drug scopolamine: a randomized, placebo-controlled clinical trial

Abstract

Context: The need for improved therapeutic agents that more quickly and effectively treat depression is critical. In a pilot study we evaluated the role of the cholinergic system in cognitive symptoms of depression and unexpectedly observed rapid reductions in depression severity following the administration of the antimuscarinic drug scopolamine hydrobromide (4 microg/kg intravenously) compared with placebo (P = .002). Subsequently a clinical trial was designed to assess more specifically the antidepressant efficacy of scopolamine.

Objective: To evaluate scopolamine as a potential antidepressant agent.

Design: Two studies were conducted: a double-blind, placebo-controlled, dose-finding study followed by a double-blind, placebo-controlled, crossover clinical trial.

Setting: The National Institute of Mental Health. Patients Currently depressed outpatients aged 18 to 50 years meeting DSM-IV criteria for recurrent major depressive disorder or bipolar disorder. Of 39 eligible patients, 19 were randomized and 18 completed the trial.

Interventions: Multiple sessions including intravenous infusions of placebo or scopolamine hydrobromide (4 microg/kg). Individuals were randomized to a placebo/scopolamine or scopolamine/placebo sequence (series of 3 placebo sessions and series of 3 scopolamine sessions). Sessions occurred 3 to 5 days apart.

Main outcome measures: Psychiatric evaluations using the Montgomery-Asberg Depression Rating Scale and the Hamilton Anxiety Rating Scale were performed to assess antidepressant and antianxiety responses to scopolamine.

Results: The placebo/scopolamine group showed no significant change during placebo infusion vs baseline; reductions in depression and anxiety rating scale scores (P<.001 for both) were observed after the administration of scopolamine compared with placebo. The scopolamine/placebo group also showed reductions in depression and anxiety rating scale scores (P<.001 for both) after the administration of scopolamine, relative to baseline, and these effects persisted as they received placebo. In both groups, improvement was significant at the first evaluation after scopolamine administration (P< or =.002).

Conclusion: Rapid, robust antidepressant responses to the antimuscarinic scopolamine occurred in currently depressed patients who predominantly had poor prognoses.

Figures

Figure 1

Mean Montgomery-Asberg Depression Rating Scale (MADRS) scores from study 1 as assessed immediately before and in the first evaluation after infusions of placebo and each of 3 doses of scopolamine hydrobromide. Error bars represent SE. *Significantly different from baseline (P=.002) and from preadministration of 4.0 μg/kg of scopolamine (P=.02).

Figure 2

The study 2 blocked experimental design reflecting infusion series and assessment sessions for the 2 randomized patient groups. P/S indicates placebo followed by scopolamine hydrobromide; S/P, scopolamine followed by placebo.

Figure 3

Mean Montgomery-Asberg Depression Rating Scale (MADRS) (A), Hamilton Anxiety Rating Scale (HARS) (B), and Clinical Global Impressions–Improvement (CGI-I) scale (C) scores for the placebo/scopolamine hydrobromide (P/S) group and the scopolamine/ placebo (S/P) group across 8 assessments. Two baseline, 3 block 1, and 3 block 2 assessments are identified in each panel. Because the CGI-I scale reflects change from the first evaluation, no score is associated with assessment 1 (ie, baseline). Error bars represent SE. For each scale, there are significant group × assessment interactions (P<.001 for all).