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

Study Overview
=================
Brief Summary
-----------------
The primary purpose of this study is to assess the ability of scopolamine to improve the antidepressant effects of ECT and to determine whether scopolamine will shorten the time to response and remission for patients receiving ECT. The hypothesis are: Patients receiving ECT plus scopolamine will have greater improvement in depression symptoms than those receiving ECT plus placebo. Patients receiving scopolamine in addition to ECT will require fewer ECT treatments to obtain response/remission compared to the group receiving ECT plus placebo. Time to response and to remission in the scopolamine group will be significantly shorter compared to ECT alone.

Detailed Description
-----------------
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.

Official Title
-----------------
A Pilot Study of the Use of IV Scopolamine to Augment the Efficacy of Electroconvulsive Therapy (ECT)

Conditions
-----------------
Depression

Intervention / Treatment
-----------------
* Drug: Scopolamine


Participation Criteria
=================
Eligibility Criteria
-----------------
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: Substance use disorder active use within the last 6 months (per assessment using SCID) Organic mental disorders Seizure disorders Unstable physical disorder or physical disorder judged to significantly affect the central nervous system function Heart block Pre-existing sick-sinus Chronic treatment with beta blockers Any cardiac arrhythmia Hypotension Coronary artery disease Liver and renal function impairment Urge incontinence or prostatic hypertrophy Colitis Crohn's disease GI motility disorders Asthma COPD Treatment with anti-cholinergic and cholinomimetic medications Contraindications to scopolamine including hypersensitivity to scopolamine, other belladonna alkaloids, and/or any component of the formulation Wide and narrow angle glaucoma Acute hemorrhage Paralytic ileus Myasthenia gravis Patients on belladonna, belladonna alkaloids, cisapride, or potassium chloride

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Scopolamine<br>Patients receiving IV scopolamine at ECT treatment | Drug: Scopolamine<br>* Those receiving active drug will receive scopolamine 4mcg/kg IV with each treatment, until completion of ECT<br>|
| Placebo Comparator: Placebo<br>Patients receiving IV placebo at ECT treatment | Drug: Scopolamine<br>* Those receiving active drug will receive scopolamine 4mcg/kg IV with each treatment, until completion of ECT<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Ham D 17 Scores | Change in Ham D 17 scores measured by the difference between baseline HAM D score and HAM D score at last ECT administration. The HAM D 17 measures severity of depression with 52 being most severe and 0 being no depression. A negative change score refers to a decrease in HAM D score, while a positive change score would refer to an increase in HAM D score. | At the time of ECT completion (about 2 weeks) | 
| Time to Response for Patients Receiving ECT | The number of days between baseline HAM D score and HAM D score showing response (defined as a HAM D score less than half of baseline). If patients HAM D score rose above this marker at any point in the study, they were not considered as responding.The HAM D 17 measures severity of depression with 52 being most severe and 0 being no depression. . | Duration of ECT treatment (usually 2 weeks) | 
| Number of ECT Treatments Received to Achieve Response/Remission | The number of ECT treatments needed to achieve response (defined as a HAM D score less than half of baseline) and remission (defined as a HAM D score of less than 8). If patients HAM D score rose above these markers at any point in the study, they were not considered as responding or remitting.The HAM D 17 measures severity of depression with 52 being most severe and 0 being no depression. | Duration of ECTtreatment (usually 2 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of ECT Treatments Withheld Due to Cognitive Impairment | The number of ECT treatments withheld during the course of the study due to cognitive impairment. In these cases, the participant would still be enrolled in the study but have a reduced # of ECTs. This outcome measure does not include patients who withdrew from the study. | Duration of ECT treatment (usually 2 weeks) | 
| The Mean Number of Moderate to Severe Side Effects | The mean number of adverse events classified as moderate to severe. | Duration of ECT treatment (usually 2 weeks) | 
| The Mean Levels of Physiological Measures of ECT (Blood Pressure) | Blood pressure was taken immediately post ECT administration at each ECT visit. We averaged Blood pressure for each participant at each ECT administration. The reported mean refers to the average among all participants in each group. | Duration of ECT treatment (usually 2 weeks) | 
| The Mean Levels of Physiological Measures of ECT (Heart Rate) | Heart rate was taken immediately post ECT administration at each ECT visit. We averaged heart rate for each participant at each ECT administration. The reported mean refers to the average among all participants in each group. | Duration of ECT treatment (usually 2 weeks) | 
| The Mean Levels of Physiological Measures of ECT (Seizure Duration) | Mean duration in seconds of the seizure induced by ECT for each participant at each ECT administration they received.The reported mean refers to the average among all participants in each group. | Duration of ECT treatment (usually 2 weeks) | 
| The Mean Levels of Physiological Measures of ECT (Energy Needed) | Mean energy needed to induce the seizure for each participant at each ECT administration they received. The reported mean refers to the average among all participants in each group. | Duration of ECT treatment (usually 2 weeks) |