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.
Key Words
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Article info
Publication history
Published online: November 30, 2012
Accepted:
September 29,
2012
Received in revised form:
September 10,
2012
Received:
May 8,
2012
Identification
Copyright
Published by Elsevier Inc.
