Efficacy and Safety of Galantamine for Improving Dysfunction in People With Bipolar Disorder

Approximately 2.6% of Americans age 18 and older, or 5.7 million people, suffer from bipolar
disorder. The manic and depressive episodes associated with bipolar disorder prevent normal
functioning in individuals with the disorder, but functional impairment can occur even when
bipolar disorder is in remission. Previous research indicates that this impairment in stable
individuals with bipolar disorder is linked to neurocognitive deficits, such as problems
with memory and attention. The drug extended release galantamine increases the level of
acetylcholine, a neurotransmitter important for memory, available in the brain. This drug
has already been approved by the FDA to treat neurocognitive impairment in Alzheimer's
disease patients. This study will examine whether administering the drug to individuals with
bipolar disorder who are in remission can also reduce their neurocognitive deficits and
improve the quality of their life. The study will also examine the safety of the drug for
use in the obsessive-compulsive disorder population.

Participation in this study will last about 18 weeks and will involve six study visits. Each
of the first two visits will include 2 hours of clinical, physical, and self-report tests,
the first for screening and the second to establish physical and mental health baseline
measurements. Participants will then be randomly assigned to receive either galantamine or
placebo daily for 16 weeks, and they will be provided with enough of the assigned pill to
last until the next visit. Half hour visits on Weeks 4, 8, and 12 will consist of
psychological self-report tests and interviews, clinical assessment of side effects from the
drug, and the determination by the examining doctor and participant whether to increase,
decrease, or maintain the same level of the drug. Participants will also be given enough of
the drug to last until the next visit. The final visit, on Week 16, will last 2 hours and
will consist of the same tests administered at the baseline visit in addition to the
neuropsychological tests administered at the screening visit. The full range of tests will
measure physical health, verbal memory, mental flexibility, attention, life impairment, and
life satisfaction.

Inclusion Criteria:

- DSM-IV diagnosis of Bipolar I disorder or Bipolar II disorder

- A baseline Hamilton-D 17 score of less than 10 at screening visit

- A baseline Young Mania Rating Scale (YMRS) score of less than 10 at screening visit

- No acute episodes of depression or mania for the previous 12 weeks

- Score of 17 or higher on the Massachusetts General Hospital (MGH) Cognitive and
Physical Functioning Questionnaire

- Treated with psychiatric medications, alone or in combination, having only minimal,
mild or moderate cognitive burden [as determined by a score of less than 3.5 on the
MGH Cognitive Impact of Psychotropic Medications Scale (CIPMS).

- Able to understand English

Exclusion Criteria:

- DSM-IV diagnosis of Bipolar NOS, Cyclothymia, or Schizoaffective Bipolar type.

- Meets DSM-IV criteria for acute manic, depressive, or mixed bipolar episode or had
met full criteria for 2 consecutive weeks within the past 12 weeks prior to
assessment

- Treated with psychiatric medications with large effects on cognition (as determined
by a MGH Cognitive Impact of Psychotropic Medications Scale score of 4.0 or above)

- Pregnant women or women of child bearing potential who are not using a medically
accepted means of contraception (defined as oral contraceptive pill or implant,
condom, diaphragm, spermicide, IUD, s/p tubal ligation, partner with vasectomy)

- Serious suicide or homicide risk

- Unstable medical illness including cardiovascular, hepatic, renal, respiratory,
endocrine, neurological, or hematological disease.

- History of seizure disorder, brain injury, or any known neurological disease
(multiple sclerosis, degenerative disease such as ALS, Parkinson disease and any
movement disorders, etc)

- The following DSM-IV diagnoses: 1) organic mental disorders; 2) any diagnosis of
dementia; 3) substance use disorders, including alcohol, active within the last year;
4) schizophrenia; 5) delusional disorder; 6) psychotic disorders not elsewhere
classified; 7) schizoaffective disorder; 8) major depressive disorder; 9) acute
bereavement; 10) severe borderline or antisocial personality disorder

- Presence of mood congruent or mood incongruent psychotic features

- Clinical or laboratory evidence of hypothyroidism

- History of multiple adverse drug reactions, allergy to galantamine or other AChEIs

- Current use, or use within the last week, of excluded drugs (psychotropic medications
and other central nervous system (CNS)-active drugs)

- Taken an investigational psychotropic drug within the last year

- Had electroconvulsive therapy (ECT) within the 6 months preceding enrollment