Question:
Scopolamine May Help Reduce Symptoms of Major Depression?
Answer:
Scopolamine therapy is effective in reducing
depressive symptoms in patients with major depression, according to the
results of a randomized controlled trial reported in the October issue
of the Archives of General Psychiatry.
"The need for improved therapeutic agents that more quickly and
effectively treat depression is critical," write Maura L. Furey, PhD,
and Wayne C. Drevets, MD, from the National Institute of Mental Health
in Bethesda, Maryland. "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
µg/kg intravenously) compared with placebo (P = .002). Subsequently a
clinical trial was designed to assess more specifically the
antidepressant efficacy of scopolamine."
The investigators conducted 2 studies at the National Institute of
Mental Health: a double-blind, placebo-controlled, dose-finding study,
followed by a double-blind, placebo-controlled, crossover clinical
trial.
Of 39 eligible patients, currently depressed outpatients aged 18 to 45
years meeting the Diagnostic and Statistical Manual of Mental
Disorders, Fourth Edition (DSM-IV) criteria for recurrent major
depressive disorder or bipolar disorder, 19 were randomized and 18
completed the study. Subjects underwent multiple sessions 3 to 5 days
apart, including intravenous infusions of placebo or 4 µg/kg of
scopolamine, and they were randomized to a placebo/scopolamine or
scopolamine/placebo sequence (series of 3 placebo sessions and series
of 3 scopolamine sessions). The primary endpoints were psychiatric
evaluations using the Montgomery-Asberg Depression Rating Scale and the
Hamilton Anxiety Rating Scale.
Compared with baseline, the placebo/scopolamine group had no
significant change during placebo infusion, but there were reductions
in depression and anxiety rating scale scores (P < .001 for both) after
the administration of scopolamine compared with placebo. The
scopolamine/placebo group also had reduced depression and anxiety
rating scale scores (P < .001 for both) relative to baseline after
receiving scopolamine, and these effects persisted as they received
placebo. Both groups showed improvement at the first evaluation after
scopolamine administration (P = .002).
"Rapid, robust antidepressant responses to the antimuscarinic
scopolamine occurred in currently depressed patients who predominantly
had poor prognoses," the authors write. "Determination of the optimal
schedule of administration and the potential long-term use of
scopolamine as an antidepressant agent requires further study,
particularly because potential adverse effects include confusion and
delirium. Future studies also may examine the antidepressant efficacy
of scopolamine when using routes of administration that are more
clinically practical in outpatient settings."
The National Institute of Mental Health, National Institutes of Health,
supported this study. A use-patent application for the use of
scopolamine as an antidepressant agent has been filed.
Arch Gen Psychiatry. 2006;63:1121-1129.
Learning Objectives for This Educational Activity
Upon completion of this activity, participants will be able to:
* Describe the relationship between depression and cholinergic
activity.
* Identify the effects of scopolamine in patients with depression.
Clinical Context
Several lines of evidence suggest that acetylcholine has a role in the
etiology of depression. The administration of physostigmine, an
inhibitor of cholinesterase, can exacerbate depression, and patients
with depression experience exaggerated polysomnographic findings and
pupillary responses following administration of cholinergic
medications. These findings suggest that anticholinergic medications
may improve depression, but a controlled study of the anticholinergic
medication biperiden failed to demonstrate a significant benefit of
therapy.
In the current study, the authors report on the efficacy of scopolamine
in the management of depression and bipolar disorder. The study began
as an investigation of the effect of anticholinergic treatment on
cognition in depression, but the authors designed a randomized,
crossover trial after noting an improvement of depression scores
associated with scopolamine.
Study Highlights
* Adults between the ages of 18 and 45 years who met DSM-IV
criteria for major depressive disorder or bipolar disorder were
eligible for study participation. Patients treated with psychotropic or
anticholinergic medications within 3 weeks of the study were excluded
from study participation, and subjects were generally healthy.
* In the first part of the study, 15 subjects were randomized to
receive scopolamine at doses of 2, 3, and 4 µg/kg or matching placebo.
Infusions were performed every 3 days during four 15-minute sessions.
* The Montgomery-Asberg Depression Rating Scale was measured at
baseline and after each infusion with scopolamine.
* Depression scores improved with time in all subjects. Only
scopolamine 4 µg/kg improved depression scores significantly more than
placebo.
* In the follow-up study, 19 participants were randomized to a
crossover trial of scopolamine 4 µg/kg and placebo. These subjects met
the same eligibility criteria as listed above. Treatment consisted of 1
placebo session for all subjects, and then 3 treatments each with
scopolamine and placebo.
* Researchers followed multiple measures of mood as well as a test
of the ability to concentrate.
* The mean age of subjects was 33 years, and 77.8% of participants
were women. Most subjects had duration of disease greater than 2 years.
Depression scores were similar between randomization groups at
baseline.
* Scopolamine was effective in reducing measures of depression
compared with placebo, and this difference was evident after only one
active treatment. Continued treatment with scopolamine further reduced
depression scores.
* Participants who received scopolamine in the first 3 sessions
continued to experience lower depression scores compared with baseline
through the remainder of the 7-week study, implying a lasting
beneficial effect of treatment with scopolamine.
* 11 subjects achieved at least a 50% reduction in depression
scores by the end of the study period, and 10 experienced a remission
of depression.
* Scopolamine was similarly effective in reducing anxiety scores.
Scores were significantly reduced compared with placebo after the first
active treatment, and further treatment contributed to even lower
anxiety scores. Scopolamine's beneficial effects on anxiety also
extended into the placebo treatment period.
* Participants with both major depression and bipolar disorder
benefited from scopolamine. Scopolamine was more effective for patients
with less severe disease.
* Scopolamine did not affect ratings of mania symptoms among
patients with bipolar disorder.
* Scopolamine did not reduce reaction times, although subjects
receiving scopolamine had a slight reduction in accuracy compared with
placebo during attention testing.
* No serious adverse events were associated with study treatment,
but scopolamine increased the rates of blurry vision and
lightheadedness compared with placebo.
Pearls for Practice
* Depression may be worsened by the cholinesterase inhibitor
physostigmine, and patients with depression experience exaggerated
polysomnography and pupillary responses following cholinergic
stimulation. However, a previous trial of an anticholinergic medication
in patients with depression failed to demonstrate a significant benefit
of treatment.
* The current study in a small patient cohort with either
depression or bipolar disorder demonstrates that scopolamine infusions
can quickly and effectively reduce depression and anxiety symptoms.
