A Study of the Use of IV Scopolamine to Augment the Efficacy of Electroconvulsive Therapy (ECT)

Electroconvulsive therapy (ECT) is a highly effective treatment for severe major depression.
It has been estimated that approximately 10 percent of all patients admitted to the hospital
for treatment of major depressive disorder receive ECT.

However, not all patients who receive ECT respond, and of those who do, not all achieve
remission. Furthermore, while there is a wide range in the number of ECT treatments done
among all people with depression, the average is approximately eight treatments. Because
treatments are usually done three times per week (Monday, Wednesday, and Friday), the
minimal length of stay for the average person receiving inpatient ECT is typically greater
than two weeks.

Finally, ECT is not without risk, and every round of ECT incurs additional risk of not just
the treatment itself, but also the risks of general anesthesia. Thus, although ECT is a
robust mode of treatment for Major Depressive Disorder (MDD), there remains a need for
improved treatment efficacy and speed of onset. Improving the efficacy of ECT would not only
benefit individuals with MDD, but also have far-reaching effects for the health care system
as it could impact the cost and resources utilized.

Ideally, an agent could be added to augment the effect of ECT, both in terms of efficacy as
well as speed of onset. In 2006, Furrey et al, reported the rapid antidepressant effect of
the antimuscarinic drug, scopolamine, delivered parenterally. Significant antidepressant
effect was found after the first scopolamine administration. The improvement was reported
immediately following the first IV administration, increased across all treatments, and was
sustained into the placebo crossover period.

Scopolamine is an anticholinergic muscarinic agent, with activity in the CNS and pilot data
to suggest a significant impact on rapidly improving depressive symptoms in patient with
MDD, when administered IV. Thus, it serves as a reasonable choice to augment the effects of
ECT in the treatment of patients with MDD.

Primary Aim 1) Assess the ability of scopolamine to augment the antidepressant effects of
ECT.

Hypothesis 1a: Patients receiving ECT plus scopolamine will have significantly greater mean
improvement on total HAM-D score between baseline and endpoint than those receiving ECT plus
placebo.

Hypothesis 1b: Patients receiving scopolamine in addition to ECT will require fewer mean ECT
treatments to obtain response/remission compared to the group receiving ECT plus placebo.

Primary Aim 2) Evaluate the hypothesis that scopolamine will shorten the time to response
and remission for patients receiving ECT.

Hypothesis 2: Time to response and to remission in the Scopolamine group will be
significantly shorter compared to ECT alone.

Secondary Aim: Provide evidence for the tolerability of intravenous scopolamine administered
during ECT.

Hypothesis 3a: There will be no between group difference (between ECT plus scopolamine vs
ECT plus placebo) in mean number of ECT sessions withheld due to cognitive impairment (as
determined by attending psychiatrist).

Hypothesis 3b: There will be no between group differences (between ECT plus scopolamine vs
ECT plus placebo) with regards to the mean number of moderate to severe side effects.

Hypothesis 3c: There will be no significant difference between the scopolamine plus ECT
group and the placebo plus ECT group on mean levels of physiological measures of ECT
including: heart rate, blood pressure, seizure length, duration of muscle paralysis,
duration of asystole, and energy need to induce seizure.

Exploratory Analyses: we will assess whether the scopolamine plus ECT group will have a
shorter average length of stay on the inpatient psychiatric unit compared to those receiving
ECT plus placebo.

We will also assess whether the scopolamine plus ECT group will have significant differences
in the cognitive measures at endpoint compared to those receiving ECT plus placebo.

Inclusion Criteria:

- Males and females between the ages of 18-50 (inclusive)

- DSM-IV diagnosis of Major Depressive Disorder (MDD), without psychotic features, and
a HAM-D-17 score of 18 or higher

- Female subjects must be postmenopausal, surgically sterile, or, if of child-bearing
age, using double-barrier contraceptive method or prescription oral contraceptives
(e.g. estrogen-progestin combinations), contraceptive implants (e.g. NorplantTM,
DepoProveraTM, or transdermally delivered contraceptives (Ortho EvraTM) before entry
and throughout the study; and have a negative urine b-HCG pregnancy test at
screening.

Exclusion Criteria:

1. Substance use disorder active use within the last 6 months (per assessment using
SCID)

2. Organic mental disorders

3. Seizure disorders

4. Unstable physical disorder or physical disorder judged to significantly affect the
central nervous system function

5. Heart block

6. Pre-existing sick-sinus

7. Chronic treatment with beta blockers

8. Any cardiac arrhythmia

9. Hypotension

10. Coronary artery disease

11. Liver and renal function impairment

12. Urge incontinence or prostatic hypertrophy

13. Colitis

14. Crohn's disease

15. GI motility disorders

16. Asthma

17. COPD

18. Treatment with anti-cholinergic and cholinomimetic medications

19. Contraindications to scopolamine including hypersensitivity to scopolamine, other
belladonna alkaloids, and/or any component of the formulation

20. Wide and narrow angle glaucoma

21. Acute hemorrhage

22. Paralytic ileus

23. Myasthenia gravis

24. Patients on belladonna, belladonna alkaloids, cisapride, or potassium chloride