Safety and Efficacy Study of Lithium for the Treatment of Pediatric Mania.

The following are the objectives of this study:

1. To determine if lithium is more efficacious in reducing symptoms of mania than placebo.

2. To describe the short-term safety of lithium in the pediatric population relative to
placebo treatment.

3. To examine the effectiveness and efficacy of lithium as a maintenance treatment for
children and adolescents with bipolar I disorder.

4. To examine the long-term and short-term safety and tolerability of lithium in pediatric
bipolar I disorder.

5. To examine the effects of lithium treatment over time on specific aspects of cognitive
functioning that have been reported to be adversely affected by lithium in the adult
population.

6. More specifically, to determine the integrity of fine-motor, attention, verbal memory,
and selected executive function domains prior to treatment at baseline, at the end of
week 8/early termination of the Efficacy Phase, and at the end of week 24/early
termination from the Long- Term Effectiveness Phase (after 24/32 weeks of lithium
treatment).

7. To examine the relationship between systemic exposure to lithium and effectiveness and
toxicity.

8. To examine the long-term safety and tolerability of combination therapy, lithium plus
other psychotropic agents, in pediatric bipolar I disorder.

9. To critically assess the efficacy of lithium for prophylaxis against recurrence of mood
symptoms in children and adolescents.

10. In those participants who discontinue treatment with lithium and experience a mood
relapse, to determine the duration of lithium treatment necessary before
re-stabilization is achieved.

11. To evaluate the influence of intrinsic factors [e.g. age, gender, race, renal function,
height, (measured by stadiometer) and weight] on lithium exposure.

The Study population for this study: Children and adolescents 7- 17 years of age who meet
DSM-IV diagnostic criteria for Bipolar I (mania, mixed mania) without psychotic symptoms as
determined by a child and adolescent psychiatrist will be eligible for this study.

Inclusion Criteria:

1. Participants aged 7 years to 17 years, 11 months old at time of first dose

2. Participants must meet DSM-IV diagnostic criteria, as assessed by a semi-structured
assessment (KSADS-PL) and a separate clinical interview with a child/adolescent
psychiatrist for manic or mixed episodes in bipolar I disorder

3. Score of > 20 on the YMRS at screening and baseline

4. The participant and legal guardian must understand the nature of the study and be
able to comply with protocol requirements. The legal guardian must give written
informed consent and the youth, written assent

5. Participants with comorbid conditions [attention deficit hyperactivity disorder
(ADHD), conduct disorder], except those listed in Exclusion Criterion 2, may
participate

6. If female: is premenarchal, or is incapable of pregnancy because of a hysterectomy,
tubal ligation, or spousal/partner sterility. If sexually active and capable of
pregnancy, has been using an acceptable method of contraception (hormonal
contraceptives, intrauterine device, spermicide and barrier) for at least one month
prior to study entry and agrees to continue to use one of these for the duration of
the study. If sexually abstinent and capable of pregnancy, agrees to continued
abstinence or to use of an acceptable method of birth control should sexual activity
commence

7. Has a negative quantitative serum ß-human chorionic gonadotrophin hormone pregnancy
test at screening and a negative qualitative urine pregnancy test at baseline, if
female

8. Participants with a history of substance abuse may participate if they agree to
continue to abstain from drugs during the trial and have a negative drug screen at
screening or prior to baseline. Those with an initial positive drug screen during
screening may have another screen done 1-3 weeks later while in screening, and a
negative result will allow the participant to participate

9. The participant is willing and clinically able to wash out of exclusion medications
during the screening period. Prior to the administration of lithium, participants
will have not used any of the following medications: antipsychotics, monoamine
oxidase inhibitors, antidepressants within the preceding 2 weeks; stimulants within
the preceding week; or fluoxetine or depot antipsychotics in the past month (no
stable participants will be asked to discontinue medications)

10. ECG and bloodwork including CBC, electrolytes, etc. (as per Safety assessment
procedures listed in Table 6) showing no clinically significant abnormalities

Exclusion Criteria:

1. Participant who is clinically stable on current medication regimen for bipolar
disorder

2. A current or lifetime diagnosis of Schizophrenia or Schizoaffective Disorder, a
Pervasive Developmental Disorder (ASQ score > 15), Anorexia Nervosa, Bulimia Nervosa,
or Obsessive-Compulsive Disorder

3. Current DSM-IV diagnosis of Substance Dependence

4. Positive drug screen at screening and on retest 1-3 weeks later

5. Participants with symptoms of mania that may be attributable to a general medical
condition, or secondary to use of medications (e.g., corticosteroids)

6. Evidence of any serious, unstable neurological illness for which treatment under the
auspices of this study would be contraindicated

7. Any serious, unstable medical illness or clinically significant abnormal laboratory
assessments that would adversely impact the scientific interpretability or unduly
increase the risks of the protocol

8. Current general medical condition including neurological disease, diabetes mellitus,
thyroid dysfunction, or renal dysfunction that might be affected adversely by
lithium, could influence the efficacy or safety of lithium, or would complicate
interpretation of study results

9. Evidence of current serious homicidal/suicidal ideation such that in the treating
physician's opinion it would not be appropriately safe for the participant to
participate in this study

10. Evidence of current active hallucinations and delusions such that in the treating
physician's opinion it would not be appropriately safe for the participant to
participate in this study

11. Concomitant prescription of over-the-counter medication or nutritional supplements
(e.g., ibuprofen, naproxen, St John's wort) that would interact with lithium or
affect the participant's physical or mental status

12. Concomitant psychotherapy treatments provided outside the study initiated within 4
weeks prior to screening

13. Previous adequate trial with Li+ (at least 4 weeks with Li+ serum levels between
0.8-1.2 mEq/L)

14. History of allergy to lithium or lithium intolerance

15. Psychiatric hospitalization within 1 month of screening for psychosis or serious
homicidal/serious suicidal ideation

16. Clinician's judgment that participant is not likely to be able to complete the study
as an outpatient due to psychiatric reasons

17. Females who are currently pregnant or lactating

18. Sexually active females who, in the investigators' opinion, are not using an adequate
form of birth control.

19. Participants who are unable to swallow the study medication

20. Participants for whom a baseline YMRS score of < 20 is anticipated

21. Participants with an IQ less than 70 (determined using the Wechsler Abbreviated
Scales of Intelligence {WASI} Vocabulary and Matrix Reasoning Subscales)