Cholinergic Modulation of Condition and Emotion in Mood Disorders: Functional Neuroimaging Studies

• 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.

Depressed Samples:

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.

EXCLUSION CRITERIA:

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.