Antidepressant effects of the muscarinic cholinergic receptor antagonist scopolamine: a review

Abstract

The muscarinic cholinergic receptor system has been implicated in the pathophysiology of depression, with physiological evidence indicating this system is overactive or hyperresponsive in depression and with genetic evidence showing that variation in genes coding for receptors within this system are associated with higher risk for depression. In studies aimed at assessing whether a reduction in muscarinic cholinergic receptor function would improve depressive symptoms, the muscarinic receptor antagonist scopolamine manifested antidepressant effects that were robust and rapid relative to conventional pharmacotherapies. Here, we review the data from a series of randomized, double-blind, placebo-controlled studies involving subjects with unipolar or bipolar depression treated with parenteral doses of scopolamine. The onset and duration of the antidepressant response are considered in light of scopolamine's pharmacokinetic properties and an emerging literature that characterizes scopolamine's effects on neurobiological systems beyond the cholinergic system that appear relevant to the neurobiology of mood disorders. Scopolamine infused at 4.0 μg/kg intravenously produced robust antidepressant effects versus placebo, which were evident within 3 days after the initial infusion. Placebo-adjusted remission rates were 56% and 45% for the initial and subsequent replication studies, respectively. While effective in male and female subjects, the change in depression ratings was greater in female subjects. Clinical improvement persisted more than 2 weeks following the final infusion. The timing and persistence of the antidepressant response to scopolamine suggest a mechanism beyond that of direct muscarinic cholinergic antagonism. These temporal relationships suggest that scopolamine-induced changes in gene expression and synaptic plasticity may confer the therapeutic mechanism.

Figure 1

Mean change in Montgomery-Åsberg Depression Rating Scale (MADRS) over sessions relative to the first baseline session is shown for the group who received placebo (P) in block 1 and scopolamine (S) in block 2 (P/S; red bars) and the group receiving scopolamine in block 1 and placebo in block 2 (S/P; blue bars). The 52 participants whose data are represented in this graph were pooled from the randomized controlled trials described in the text (31,43,44). Errors bars reflect standard error.

Figure 2

In the dose range studied, scopolamine administration reduced heart rate and blood pressure, putatively reflecting enhancement of the central parasympathetic autonomic outflow (–52). (A) Mean heart rate (± SE) is shown for the placebo (blue) and the scopolamine (red) sessions averaged over all subjects. Bars reflect baseline, as well as heart rate, at each time point indicated, relative to infusion start time. (B) Mean systolic blood pressure (± SE) is shown for the placebo (blue) and the scopolamine (red) sessions averaged over all subjects. Bars reflect baseline, as well as systolic pressure, at each time point indicated, relative to infusion start time. (C) Diastolic blood pressure (± SE) is shown for the placebo (blue) and the scopolamine (red) sessions averaged over all subjects. Bars reflect baseline, as well as diastolic pressure, at each time point indicated, relative to infusion start time.