Cholinergic Modulation of Condition and Emotion in Mood Disorders: Functional Neuroimaging Studies
Information source: National Institutes of Health Clinical Center (CC)
Information obtained from ClinicalTrials.gov on February 07, 2013
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Mood Disorders; Healthy; Unipolar Depression; Bipolar Depression
Intervention: Transderm Scopolamine (Drug)
Sponsored by: National Institute of Mental Health (NIMH)
Official(s) and/or principal investigator(s):
Maura L Furey, Ph.D., Principal Investigator, Affiliation: National Institute of Mental Health (NIMH)
Maura L Furey, Ph.D., Phone: (301) 594-7773, Email: firstname.lastname@example.org
This study looks at the role of a specific brain chemical system in the mood and attention
symptoms seen in major depression and bipolar disorders using functional brain imaging.
Official title: Cholinergic Modulation of Cognition and Emotion in Mood Disorders: Functional Neuroimaging Studies
Study design: Primary Purpose: Treatment
Primary outcome: Evaluation of the antidepressant effects of the antimuscarinic agent scopolamine
The goal of this research project is to evaluate the role of the cholinergic system in
behavioral and cognitive symptoms observed in mood disorders in humans, using functional
brain neuroimaging techniques. Specific aspects of behavior and cognition are impaired in
mood disorders, including selective attention, set-shifting and memory; and there is also
evidence that depressed subjects exhibit a mood congruent processing bias whereby they more
readily process negatively toned information as compared to positively toned information.
This cognitive pattern lends itself to evaluation with functional brain imaging, both in
terms of identifying the anatomical correlates of the specific behavioral and cognitive
deficits as well as characterizing the effects of pharmacological manipulation.
Attention and memory functions are closely tied to the cholinergic neurotransmitter system.
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 subjects. 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.
The proposed project investigates the role of cholinergic neurotransmission in the
behavioral and cognitive symptoms observed in the depressed phase of both major depressive
disorder (MDD) and bipolar disorder (BD). The studies proposed here will identify
anatomical correlates of the mood congruent processing bias, working memory, attention and
set-shifting deficits observed in depressed subjects. Further, these studies will evaluate
the effects of the cholinergic antagonist, scopolamine, both on the performance deficits and
on neural activity in brain regions recruited as subjects perform these tasks.
This approach is expected to reveal how neuromodulators influence processing in brain
structures recruited to perform these tasks, both in healthy subjects and in major
depressive disorders. The combined use of functional brain imaging and pharmacological
manipulation to evaluate the role of neurotransmitter dysfunction in depression may direct
us to potential therapeutic approaches.
Minimum age: 18 Years.
Maximum age: 55 Years.
- INCLUSION CRITERIA:
Three groups of right-handed subjects will be recruited for studies under this protocol:
unipolar depressives, bipolar depressives and age matched healthy controls. Subjects with
both unipolar and bipolar depression appear to exhibit abnormal cholinergic function
during the depressed phase (see above), 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. Therefore both groups will be recruited.
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 15 subjects per group per
study, including the dose finding study for a total of 90 subjects per group.
Subjects (ages 18-45) 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
currently depressed as defined by DSM-IV criteria for recurrent MDD and current IDS
score in the moderately-to-severely depressed range.
2. . Bipolar Disorder (BD); Subjects will be selected who meet DSM-IV criteria for
bipolar disorder and are currently depressed, with IDS score in the
moderately-to-severely depressed range.
Healthy Control Sample:
Subjects (ages 18-45) who have not met criteria for any major psychiatric disorder and
have no known first-degree relatives with MDD or BD will be selected. Control subjects
will be matched to depressed subject for age, gender and education.
Subjects will also be excluded if they have: a) serious suicidal ideation or behavior, or
current delusions or hallucinations, b) inability to provide informed consent, c) medical
or neurological illnesses likely to affect physiology or anatomy, d) a history of drug or
alcohol abuse within 1 year or a lifetime history of alcohol or drug dependence (DSM IV
criteria), e) current or past history of other axis I disorders that preceded the onset of
MDD or BD, f) current pregnancy (documented by pregnancy testing prior to scanning), g)
current breast feeding, h) general MRI exclusion criteria (including the presence of
pacemakers, cochlear implants, surgical clips or metal fragments in their eyes or body
parts), 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 > 140 mm Hg or < 90 mm Hg systolic, or > 90 mm
Hg diastolic (due to the potential cardiovascular effects of scopolamine and
physostigmine), l) clinically significant cerebrovascular or cardiovascular disease,
hypertension, congestive heart disease, angina pectoris, advanced arteriosclerosis, gross
neurological impairment, hyperthyroidism, known hypersensitivity or idiosyncracy to
anticholinergic agents, glaucoma, renal or hepatic impairment, m) current nicotine use
(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
45 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 effect cerebral blood flow and metabolism or likely to interact with anti-cholinergic
medications (e. g. narcotics or anti-cholinergic agents)- as verified by history and urine
drug screen, q) HIV positive status. q) HIV positive status.
Locations and Contacts
Maura L Furey, Ph.D., Phone: (301) 594-7773, Email: email@example.com
National Institutes of Health Clinical Center, 9000 Rockville Pike, Bethesda, Maryland 20892, United States; Recruiting
For more information at the NIH Clinical Center contact Patient Recruitment and Public Liaison Office (PRPL), Phone: 800-411-1222, Ext: TTY8664111010, Email: firstname.lastname@example.org
NIH Clinical Center Detailed Web Page
Elliott R, Rubinsztein JS, Sahakian BJ, Dolan RJ. Selective attention to emotional stimuli in a verbal go/no-go task: an fMRI study. Neuroreport. 2000 Jun 5;11(8):1739-44.
Murphy FC, Sahakian BJ, Rubinsztein JS, Michael A, Rogers RD, Robbins TW, Paykel ES. Emotional bias and inhibitory control processes in mania and depression. Psychol Med. 1999 Nov;29(6):1307-21.
Murray LA, Whitehouse WG, Alloy LB. Mood congruence and depressive deficits in memory: a forced-recall analysis. Memory. 1999 Mar;7(2):175-96.
Starting date: February 2003
Last updated: December 8, 2012