Scopolamine for Depression

This is
another one of those pilot studies that may or may not go
anywhere.  Even if it doesn't it might contribute to our
theoretical understanding of major depression.



One nice thing about it is that href="http://en.wikipedia.org/wiki/Scopolamine" rel="tag">scopolamine
is old; presumably, it is not very expensive.  That attraction
is offset, though, by the fact that the pilot study used intravenous
scopolamine.  







One
interesting aspect of this study is that scopolamine is an
ingredient in nightshade, jimson weed, mandrake, and henbane.
 It blocks a family of cholinergic receptors: the muscarinic
receptors.  It is a belladonna alkaloid.  The term belladonna
translates to beautiful woman.  The
association comes about because one of its effects is dilation of the
pupils.  I suppose this is attractive, to some people.



Anticholinergic medications have been used for decades, for a variety
of purposes.  It seems likely that if anticholinergic drugs,
in general, had antidepressant properties, this would have been noticed
long ago.  So it is intriguing to see a study of this sort
sponsored by the National
Institute of Mental Health.  



Why did they do it?  It may turn out to have been a case of href="http://www.medterms.com/script/main/art.asp?articlekey=39321">medical
serendipity.



The study was publishing the the Archives of General
Psychiatry:  href="http://archpsyc.ama-assn.org/cgi/content/abstract/63/10/1121">Antidepressant
Efficacy of the Antimuscarinic Drug Scopolamine (Arch
Gen Psychiatry. 2006;63:1121-1129)

In a pilot study designed to evaluate the role of
the cholinergic neurotransmitter system in the cognitive symptoms
associated with depression, we unexpectedly observed an antidepressant
response to scopolamine in depressed patients. We then designed a
second study to more specifically establish the antidepressant effects
of scopolamine, and we confirmed the findings of the first experiment
by demonstrating antidepressant responses to scopolamine.

There were two parts to the study.  There were eight patients
in the first part, and eighteen in the second.  There were a
lot of exclusion criteria, so the patients they studied probably are
not at all typical of routine practice.  



So what, exactly, did they do to the people in the study?  In
the second part:

During each of 7 sessions, patients received a
15-minute intravenous infusion of either a placebo saline solution or
scopolamine hydrobromide, 4.0 µg/kg. A single-blind lead-in
session was used in which all the patients received a placebo infusion.
Because psychiatric assessments were obtained before session infusions,
the lead-in placebo in session 1 allowed for a second baseline
assessment to be obtained in session 2, before the session 2 infusion.
Subsequently, individuals were randomized to receive either placebo (3
sessions) followed by scopolamine (3 sessions) or scopolamine (3
sessions) followed by placebo (3 sessions) in a double-blind,
placebo-controlled, crossover design.

And the 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).

What about adverse effects.  Pretty much, they saw the usual,
predictable things: dry mouth, lightheadedness, dizziness, hypotension.
 They also saw some cognitive impairment, but they seemed to
think is was not very significant.



As to how it works, it is unlikely that it is a direct action on the
cholinergic receptors.  Rather, the authors hypothesize that
it may involve gene transcription:

 Although the specific mechanism through
which antimuscarinic effects may impact the pathogenesis of depression
is unknown, an effect that scopolamine shares with other somatic
antidepressant drug treatments involves modulation of
N-methyl-D-aspartate receptor (NMDAR) function. The delay before the
onset of the antidepressant response after scopolamine administration
seems consistent with an effect on "late-response" gene transcription
rather than a direct action on muscarinic receptors. The NMDAR gene
expression is regulated by muscarinic receptor stimulation in some
brain regions, and scopolamine reduces messenger RNA concentrations for
NMDAR types 1A and 2A in the rat brain. Elevated glutamatergic
transmission has been implicated in the pathogenesis of depression, and
long-term administration of antidepressant drugs and repeated
electroconvulsive shock reduce cortical NMDAR function. In addition, of
treatments with relatively rapid onset, ketamine hydrochloride exerts
direct NMDAR antagonist effects, and sleep deprivation induces
internalization of NMDAR, reducing NMDAR function in hippocampal
neurons.

I pointed out earlier that nobody is claiming this is ready for routine
clinical practice.  In fact, it may never be useful in that
way.  But it could help us understand another layer of
complexity in the pathophysiology of depression.  By helping
us get a better picture of what is going on, we may be able to focus
the effort to develop new lines of treatment.  The serotonin-reuptake-inhibitor
mother lode has been pretty well mined by now; it is time for something
new.