The Antidepressant Efficacy of the Anticholinergic Scopolamine

Despite the availability of a wide range of antidepressant drugs, clinical trials indicate
that 30% to 40% of patients with major depression fail to respond to first-line
antidepressant treatment, despite adequate dosage, duration, and compliance. Moreover, in
those patients who do experience symptomatic relief following conventional anti-depressant
treatment, clinical improvement is not evident for 3-4 weeks. Thus, there is a clear need to
develop novel and improved therapeutics for unipolar and bipolar depression.

The cholinergic system is one of the neurotransmitter systems implicated in the
pathophysiology of mood disorders. Evidence suggests that during major depressive episodes,
the cholinergic system is hypersensitive to acetylcholine. Agents that enhance muscarinic
cholinergic receptor function increase depressive symptoms in depressed subjects, and can
produce symptoms of depression in healthy individuals. The preclinical literature more
specifically implicates the muscarinic receptors and indicates that the use of muscarinic
antagonists, in the context of animal models of depression, results in improvement in the
behavioral analogs of depression.

Preliminary results obtained under protocol 3-M-0108 provide strong evidence for the
potential effectiveness of the anticholinergic scopolamine in rapidly producing clinically
significant antidepressant effects. We observed large reductions in Montgomery-Asberg
Depression Rating Scale (MADRS) scores that occurred over hours/days following i.v. infusion
of scopolamine, which stood in marked contrast to the 3-4 week period generally required for
conventional therapies. Moreover, these improvements were observed in subjects who had been
nonresponsive or incompletely responsive to conventional antidepressant therapies,
highlighting the potential for this treatment to benefit a larger percentage of individuals
with depression. The goal of this research project is to perform a clinical trial to
evaluate the efficacy of the muscarinic cholinergic receptor antagonist scopolamine
administered via transdermal patch on clinical symptoms of depression.

- INCLUSION CRITERIA:

Two groups of subjects will be recruited for studies under this protocol: unipolar
depressives and bipolar depressives. Subjects with unipolar or bipolar depression appear
to exhibit abnormal cholinergic function during the depressed phase, and no differences
are hypothesized to exist between MDD and BD depressives herein. However, while BD
subjects are more difficult to recruit, the evidence for cholinergic abnormalities has
been particularly compelling for BD. Moreover, observations from our pilot study suggest
that scopolamine will improve symptoms in both MDD and BD, a particularly persuasive
observation given BD notoriously has been difficult to treat. Thus, the magnitude of this
serious clinical problem justifies the inclusion of BD subjects. Therefore both groups
will be recruited. However, BD Type I subjects will be included only if they are
currently stable on lithium or valproate to reduce the risks associated with possible
precipitation of mania.

The presence of inclusion and exclusion criteria will be established using both an
unstructured clinical interview with a psychiatrist and the Structured Clinical Interview
for DSM-IV (SCID). Family history of mental illness will be obtained from the subject
using the Family Interview of Genetic Studies. We will recruit 24 subjects per group.

DEPRESSED SAMPLES: Subjects (ages 18-55) currently suffering from a major depressive
episode falling into one of the following subgroups:

1. . MAJOR DEPRESSIVE DISORDER (MDD): Subjects will be selected with primary MDD and
are currently depressed as defined by DSM-IV criteria for recurrent MDD and current
MADRS score in the moderately-to-severely depressed range (greater than or equal to
20). The duration of the index episode is greater than or equal to four weeks.

2. . BIPOLAR DISORDER TYPE II (BD): Subjects will be selected who meet DSM-IV criteria
for bipolar disorder Type I or II and are currently depressed, with MADRS score in
the moderately-to-severely depressed range (greater than or equal to 20). The
duration of the index episode is greater than or equal to four weeks.

EXCLUSION CRITERIA:

Subjects will be recruited who are drug-naive or who have not received psychotropic drugs
for at least 3 weeks (8 weeks for fluoxetine) prior to screening. Subjects also will be
excluded if they have: a) serious suicidal ideation or behavior, or current delusions or
hallucinations, b) inability to provide informed consent, c) serious, unstable illnesses
including hepatic, renal, gastroenterologic, respiratory, cardiovascular (including
ischemic heart disease, endocrinologic, neurologic, immunologic, or hematologic disease,
d) a history of drug or alcohol abuse within 6 months or alcohol or drug dependence in the
last five years (DSM IV criteria), e) not using a medically accepted means of
contraception and are a woman of childbearing potential, f) current pregnancy (documented
by pregnancy testing prior to each brain scan to avoid exposing a fetus to radiation or to
a research MRI scan that is not medically necessary), g) current breast feeding, h)
history of ulcerative colitis or toxic megacolon, i) vision and/or hearing problems severe
enough to interfere with testing, j) electrocardiographic evidence of ischemia,
arrhythmia, conduction defect, or myocardial infarction, k) current blood pressure of
greater than 160 mm Hg or less than 90 mm Hg systolic, or greater than 90 mm Hg diastolic,
l) clinically significant cerebrovascular or cardiovascular disease, hypertension,
congestive heart disease, angina pectoris, clinic evidence of cerebrovascular disease,
gross neurological impairment, hyperthyroidism, known hypersensitivity or idiosyncracy to
anticholinergic agents (e.g. skin rashes), glaucoma, renal or hepatic impairment, m)
current nicotine use or nicotine dependence within last six months (due to the effects of
nicotine on the cholinergic system) n) narrow angle glaucoma (due to the possibility of
exacerbation of this condition by scopolamine) o) age greater than 55 years (to reduce the
biological heterogeneity encompassed by the MDD and BD criteria, since subjects with a
late age-at onset for depression have a far greater likelihood of having MRI correlates of
cerebrovascular disease than age-matched, healthy controls or age-matched, early-onset
depressives), p) exposure within two weeks to medications likely to affect mood or
cognition or likely to interact with scopolamine (e.g. narcotics or anti-cholinergic
agents)- as verified by history and urine drug screen, q) HIV positive status, r) history
of gastric or intestinal obstructions, s) history of urinary retention or bladder
obstruction. During the course of this study, participants will be unable to take some
medications, including antidepressant or antianxiety agents, sleep aids, diphenhydramine
(e.g. Benedryl) or cough/cold preparations that contain diphenhydramine or antihistamines.
A detailed list of allowed and not allowed medications is provided in Appendix B in the
protocol.

We are not excluding comorbid anxiety disorders. Exclusion of patients with comorbid
anxiety disorders would affect the generalizability of our findings since a substantial
percentage of patients with major depression have these comorbid diagnoses. Instead, we
will exclude patients with this comorbid diagnosis only if it is believed to be of
clinical significance. Allowing participation by patients with histories of comorbid
anxiety disorders broadens the inclusion criteria to more closely approximate patients
seen in real world settings.