Scopolamine is a Rapid-Acting Antidepressant

Editor, Primary Psychiatry and Psychiatry Weekly, Professor of Psychiatry, New York University School of Medicine

Introduction

While pharmacologists search for new compounds to treat patients unresponsive to existing interventions, researchers continue to find previously unrecognized benefits among existing medications. Many of these old drugs were not even considered as having potential psychiatric applications.

In a just published paper, investigators from the Mood and Anxiety Disorders Program at the NIMH report that a study demonstrates “rapid, robust antidepressant responses” to another old drug, the antimuscarinic scopolamine. (Furey ML, Drevets WC. Antidepressant efficacy of the antimuscarinic drug scopolamine: a randomized, placebo-controlled clinical trial. Arch Gen Psychiatry. 2006;63:1121-1129) Scopolamine is used to prevent nausea, vomiting, and motion sickness. What makes this finding most intriguing from a clinical perspective is that it worked well in depressed patients who predominantly had poor prognoses, and also how rapidly depressive symptoms responded.

Recent Research

The current study grew out of a pilot trial examining the role of the cholinergic system in cognitive symptoms of depression. Unexpectedly, the researchers observed rapid improvement in mood following the intravenous administration of the scopolamine compared with placebo. The finding was highly significant in statistical terms (P=.002) and led to this trial, designed specifically to assess the antidepressant activity. Subjects met diagnostic criteria for recurrent major depressive disorder or bipolar disorder. Subjects showed no significant change during an initial placebo phase. The group given scopolamine demonstrated reductions in depression and anxiety compared with placebo. These effects persisted even after they were switched to placebo.

Although this study is the first to demonstrate such a strong and rapid antidepressant response to an antimuscarinic drug, there is a large body of research that implicates the cholinergic system in the pathophysiology of mood disorders. As the authors point out, there are studies demonstrating neuroendocrine changes, pupillary response, and sleep architecture changes among depressed patients challenged with muscarinic receptor agonists. Along with data from animal studies, these findings are suggestive of heightened cholinergic tone as an abnormality in some mood disorders.

Future Research

If further research replicates the finding that scopolamine infusion is a rapid and safe form of intervention for TRD, it could become an alternative to ECT, or to the various medication cocktails currently used in these situations. Vagus nerve stimulation directly affects muscarinic activity, and is approved as a treatment for resistant depression; however, it typically takes months to produce significant benefit.

An interesting implication of this trial is the possibility that some depressed patients might in fact derive more benefit from treatment with the tricyclic antidepressants, such as amitriptyline or doxepin, which have pronounced anticholinergic activity. Ironically, those agents were largely abandoned after the SSRIs were introduced because most patients found their anticholinergic side effects—such as drowsiness, dry mouth, blurred vision, lightheadedness, and dizziness—to be intolerable. These were the most common side effects observed in this study.

Disclosure: Dr. Sussman reports no affiliation with or financial interests in any organization that may pose a conflict of interest.