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.

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.

• Mood Disorders
• Healthy
• Unipolar Depression
• Bipolar Depression

• 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.

• 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 be recruited who are drug-naive or who have not received psychotropic drugs for at least 3 weeks (8 weeks for fluoxetine).

Subjects will also be excluded if they have:

1. serious suicidal ideation or behavior, or current delusions or hallucinations,
2. inability to provide informed consent,
3. medical or neurological illnesses likely to affect physiology or anatomy,
4. a history of drug or alcohol abuse within 1 year or a lifetime history of alcohol or drug dependence (DSM IV criteria),
5. current or past history of other axis I disorders that preceded the onset of MDD or BD,
6. current pregnancy (documented by pregnancy testing prior to scanning),
7. current breast feeding,
8. general MRI exclusion criteria (including the presence of pacemakers, cochlear implants, surgical clips or metal fragments in their eyes or body parts),
9. vision and/or hearing problems severe enough to interfere with testing,
10. electrocardiographic evidence of ischemia, arrhythmia, conduction defect, or myocardial infarction,
11. current blood pressure of greater than 140 mm Hg or less than 90 mm Hg systolic, or greater than 90 mm Hg diastolic (due to the potential cardiovascular effects of scopolamine and physostigmine),
12. 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,
13. current nicotine use (due to the effects of nicotine on the cholinergic system),
14. narrow angle glaucoma (due to the possibility of exacerbation of this condition by scopolamine),
15. 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),
16. 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,
17. HIV positive status.