The Antidepressant Efficacy of the Anticholinergic Scopolamine

This study has been terminated.
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Mental Health (NIMH) )
ClinicalTrials.gov Identifier:
NCT00369915
First received: August 29, 2006
Last updated: August 20, 2013
Last verified: January 2013
  Purpose

A previous study showed that the intravenous administration of scopoalmine produces antidepressant effects. This study is designed to determine if other routes of administration of scopoalmine produce antidepressant effects.


Condition Intervention Phase
Unipolar Depression
Bipolar Depression
Drug: Scopolamine
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double-Blind
Primary Purpose: Treatment
Official Title: The Antidepressant Efficacy of the Anticholinergic Scopolamine

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Change in Depression Severity [ Time Frame: Days to Weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Persistence of change in depression severity [ Time Frame: Weeks to months ] [ Designated as safety issue: No ]

Enrollment: 17
Study Start Date: August 2006
Study Completion Date: January 2013
Primary Completion Date: January 2013 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: Scopolamine
    N/A
Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   18 Years to 55 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • 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.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00369915

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
Investigators
Principal Investigator: Maura L Furey, Ph.D. National Institute of Mental Health (NIMH)
  More Information

Publications:
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Institute of Mental Health (NIMH) )
ClinicalTrials.gov Identifier: NCT00369915     History of Changes
Other Study ID Numbers: 060234, 06-M-0234
Study First Received: August 29, 2006
Last Updated: August 20, 2013
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Cholinergic
Unipolar
Bipolar
Depression
Muscarinic
Scopolamine
Major Depressive Disorder
MDD
Bipolar Disorder
BP

Additional relevant MeSH terms:
Depression
Depressive Disorder
Behavioral Symptoms
Mood Disorders
Mental Disorders
Antidepressive Agents
Butylscopolammonium Bromide
Scopolamine Hydrobromide
Cholinergic Antagonists
Psychotropic Drugs
Central Nervous System Agents
Therapeutic Uses
Pharmacologic Actions
Parasympatholytics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Muscarinic Antagonists
Cholinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Adjuvants, Anesthesia
Mydriatics

ClinicalTrials.gov processed this record on September 18, 2014