Lamotrigine Monotherapy in Pediatric Bipolar Disorder

Procedure Study 1 This study is planned to be conducted over 18 months, with an average
recruitment of 2 subjects per month. Each subject is involved in the study for 18 to 26
weeks. While the study medication is dosed over 8 weeks and treated with full dose over 6
weeks, withdrawal of medications that are on board prior to the study drug administration
and drug free period post washout required additional time line that is up to 12 weeks over
and above the 14 weeks of administering the study drug. Conversely, the range of time is
necessary to account for factors such as the child's age, sex, weight, reactions to the
medications and side effects. Based on these factors, the time it takes to titrate the
medication dose to the optimal amount will vary. Maintaining this flexibility in the
protocol is part of good clinical practice where medication is involved. Only children whose
medication is not currently improving their symptoms will be recruited. Therefore no
children who have been stabilized on a drug will be taken off of it. The initial 2 week
screening period includes a diagnostic interview and collection of demographic information.
Previous medication will be tapered slowly over 2-12-week period and is based on
tolerability and need to keep subjects in drug free state prior to start of study
medication. It is an open trial where subjects are aware of the type of medication and the
strength (For example, one pill=25 mg strength) of the pill. Research assessment of mood
symptoms and side effects will be carried out 5 times over the course of the active trial
period. Blood will be collected 3 times: once the subject is washed-out (baseline), once
optimal medication dose has been reached, and finally at the end of the 6-week period on
full dose.

The dose of lamotrigine will be 12.5 mg per day beginning the first day. It is increased in
12.5 mg increments every week until it reaches 50 mg and 25 mg per week of increment
thereafter until maximum dose of 150 mg in those below 50 kg and 200-400 mg depending on
clinical response in those above 50 kg. Increasing the medication to final dose will take 8
weeks and the response on full and tolerable dose is further monitored for response over 6
weeks. Therefore, this is a 18-26 week trial (2 to 12 weeks=screening and wash out; 8
weeks=dosing; 6 weeks=acute trial period on full dose).

Study 2 involves adolescent subjects (>10years of age) recruited from the Study 1 sample.
This part of the study is a fMRI treatment study to examine how the brain functions before
and after receiving lamotrigine medication for bipolar disorder. The goal of study 2 is to
understand how and where lamotrigine works in the brain. In order to do this, we will view
brain images in a fMRI scanner pre- and post-treatment. This will be done once before
subjects begin taking lamotrigine (subjects who require a "wash-out" period, described in
study 1, this will occur after the "wash-out.") The second scan will take place after the
medication trial (after the 6-week active treatment period). While in the scanner, subjects
will complete tasks related to thinking and emotion. Subjects will be shown pictures of
faces with varying expressions including happy, neutral and angry and will be asked to
identify the emotions of the faces, remember and identify previously seen faces, and
determine the age group of various faces (i.e., above or below 30 years). Subjects will also
complete tasks that involve processing words that express different emotions (e.g., happy,
angry), and respond to different "go" and "no-go" images that flash on a screen. Brain
activity will be recorded during these tasks. Each task will take around 5 minutes. Before
the actual fMRI scan, subjects practice lying in a simulator, a machine that looks and
sounds like a scanner.

Inclusion Criteria:

- Ages 10-20

- Must be able to swallow tablets

- Must be diagnosed with bipolar disorder

Exclusion Criteria:

- Children with general medical condition such as head injury, epilepsy, endocrine
disorders

- Those who are on mood altering medications such as steroids, and those diagnosed with
mental retardation are excluded to avoid confounding and contributing factors to mood
swings.

- If we discover during the interview that the parent and/or child does not understand
the consent/assent procedures, we will exclude them.

- Girls who are pregnant or plan to become pregnant during the study period will also
be excluded from the research. There have been no concerns raised in the literature
about the need for birth control practices in males treated with lamotrigine. As
such, there are no provisions to exclude males from the research who do not practice
birth control.

We expect only a small number of children to be excluded from the study due to
exclusionary criteria. Selection of the subjects is not based on sex, race, or ethnic
group.

For the fMRI study:

- Given the limited size of the magnet bore, individuals with a body weight over
two-hundred and fifty pounds will be unable to be tested within the MRI scanner.

- Women in the latter stages of pregnancy may be excluded due to large body size and
potential discomfort while in the MRI apparatus. Please note that girls who are
taking part in the drug portion of the study (this includes all female subjects
except the 5 healthy adult, control women) will be given 3 pregnancy during the drug
study. This is to rule out pregnancy since pregnant girls should not be taking the
study medications for safety reasons.

- Standard contraindications for fMRI studies include: cardiac pacemaker, aneurysm
clip, cochlear implants, shrapnel, history of metal fragments in eyes, claustrophobia

- Participants with an IQ of less than 70 (assessed by WRAT) are likely to be excluded
due to difficulties comprehending tasks and procedures