Prediction of Clinical Response to SSRI Treatment in Bipolar Disorder Using Serotonin 1A Receptor PET Imaging

Bipolar disorder is associated with alterations of chemicals in the brain, including one
named serotonin. Treatment of depression in bipolar disorder can be accomplished by
increasing serotonin function by medications named selective serotonin reuptake inhibitors
(SSRI's). Serotonin signals in the brain occur through receptors in a way that is similar to
a lock and key, where serotonin is a key and the receptor is a lock. One important receptor
is the serotonin 1A (5-HT1A) receptor. This receptor has been found to be abnormal in bipolar
disorder during periods of depression, as measured by a type of brain imaging called positron
emission tomography (PET). The amount of brain 5-HT1A receptor measured by imaging has also
been associated with how well depressed patients with major depressive disorder respond to an
SSRI medication. This project will measure the 5-HT1A receptors in bipolar depressed
individuals using PET with the radiotracer [11C]-CUMI-101 and will evaluate the ability of
this brain imaging signal to predict how patients respond to SSRI treatment when added to a
mood stabilizer.

Inclusion Criteria:

- Ability to provide informed consent

- Diagnosis of bipolar I disorder or bipolar II disorder and currently meet criteria for
a major depressive episode

- Patients who were on psychiatric medication at presentation will have failed that
regimen, as defined as not achieving at least partial remission after an adequate dose
of medication for at least six weeks.

- Depression of sufficient severity to score at least 16 on the first 17 items of the
Hamilton Depression Rating Scale

- Age range 18-60 years

- Females of child-bearing potential must be willing to use an acceptable method of
birth control throughout the study.

- Subject agrees to discontinue all psychotropic other than those in the PSF and other
types of drugs likely to interact with the 5-HT1A receptors.

- Subject is likely to tolerate medication cross-taper to monotherapy with a mood
stabilizer (valproate, lamotrigine or lithium).

Exclusion Criteria:

- Diagnosis of any other major psychiatric disorders such as lifetime schizophrenia,
schizoaffective disorder, current psychotic depression or current drug or alcohol
abuse (within two months before the study) or recent drug or alcohol dependence
(within six months before the study); anorexia nervosa or bulimia nervosa within the
last year; IV drug use of ecstasy use more than three times. Meet criteria for a manic
episode at the time of screening.

- Previous failed trial of fluoxetine and citalopram by themselves or in combination
with an anti-manic agent, defined as at least six weeks of treatment at the dose of 20
mg per day or more. Failure of two trials of any SSRI or SNRI antidepressant
medications.

- If the patients are discontinuing medications as part of the washout period or are
starting valproate, previous failed trial of mood stabilizer that they will take
alone.

- Experienced intolerable side effects of both citalopram and fluoxetine in the past. If
the subject is not on medications, intolerable side effects of valproate in the past.

- History of clinical deterioration when any of the medications that the patient is
taking at presentation have been discontinued in the past with the exception of any
medications that will be continued during the research protocol.

- A first-degree family history of schizophrenia if the subject is less than 33 years
old

- Significant active physical illness, including blood dyscrasias, lymphomas,
hypersplenism, endocrinopathies, renal failure, chronic obstructive lung disease,
autonomic neuropathies, peripheral vascular disease, malignancy

- Actively suicidal, as defined by expressing ideation with a plan for suicide or
develops suicidal ideation that requires immediate medication or treatment
intervention.

- Pregnancy, abortion or miscarriage in the two months prior to enrollment or plans to
conceive during the course of study participation

- Lactating women

- ECT within the past 6 months

- Subjects who endorse a history of prior head trauma and score 1.5 standard deviations
below the mean on Trail-making A & B will be excluded from study participation.

- Metal implants, pacemaker, metal prostheses, metal orthodontic appliances or shrapnel
in the body

- Current, past or anticipated exposure to radiation, including:

- Having been badged for radiation exposure in the workplace

- Participation in nuclear medicine protocols in the last year. Subjects will be
eligible, however, if the injected dose and dosimetry of the radiotracer are
known and the cumulative annual exposure of the previous study and this study is
lower than the annual limit for research subjects defined by the FDA (21 CFR
361.1)

- History of claustrophobia that would prevent the participation in imaging scans

- Current anticoagulant or anti-platelet treatment other than aspirin

- Obesity with weight >350 lbs or inability to fit into the MRI scanner