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

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 mu g/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 mu g/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 <= .002). Conclusion: Rapid, robust antidepressant responses to the scopolamine occurred in currently depressed patients who predominantly had poor prognoses.