The purpose of the study is to see if the investigational medication uridine reduces depression symptoms in adolescents with bipolar disorder. Uridine is a naturally occurring chemical that is made by the human liver. Uridine is part of a family of compounds called pyrimidines, and is normally involved in many of the body's processes such as the use of energy by cells. Uridine is considered experimental, because it has not been approved by the U.S. Food and Drug Administration (FDA) to treat bipolar depression in adolescents. The study will use standard methods of assessing adolescent's mood, such as rating scales and questionnaires. In addition, the study will use Magnetic Resonance Imaging Spectroscopy (MRI/MRS) brain scans to see if levels of certain chemicals in the brain change when adolescents are treated with uridine. These scans use a magnet to create images of the brain, and do not expose patients to radiation.

This is an open-label study of the investigational drug uridine in the treatment of adolescents with depression with bipolar disorder. Uridine has shown positive results in a Phase II study of bipolar disorder in adults (http://clinicaltrials.gov/ct2/show/NCT00322764). This study will enroll 30 depressed adolescent participants who meet DSM-IV-TR criteria for bipolar disorder type I, type II or bipolar disorder not otherwise specified. Participants who are currently taking psychotropic medication(s) will continue on their current regimen, with uridine added as adjunctive therapy. Participants who are untreated will be informed of the alternatives to study participation. This will include informing the parent(s) or guardian(s) that Lithium, Risperdal and Abilify are FDA-approved treatments for adolescent bipolar disorder that would be available to their child in community care.

The study has three objectives: 1) To use Magnetic Resonance Spectroscopy (MRS) brain imaging to measure levels of beta-nucleoside triphosphate (b-NTP) in the anterior cingulate cortex of 30 adolescents with bipolar disorder, before-and-after 6 weeks of treatment with the investigational drug uridine; 2) To measure the antidepressant response to uridine in the 30 participants with the Children's Depression Rating Scale (CDRS); and 3) To acquire structural Magnetic Resonance Imaging (MRI) data in the 30 participants with bipolar disorder and the 30 healthy controls, to establish regionally-specific structure/neurochemical relationships.

Adolescent participants with bipolar disorder will be treated with uridine 500mg twice daily for six weeks. The primary clinical outcome measure is the Children's Depression Rating Scale (CDRS), with response defined as a 30% reduction in CDRS score. In addition to this standardized clinical assessment, participants will undergo magnetic resonance imaging and magnetic resonance spectroscopy (MRI/MRS) brain scans at baseline, and after six weeks of treatment with uridine. This novel approach is designed to explore objectively measurable biomarkers of illness and treatment response in pediatric bipolar disorder. The investigators hypothesize that participants whose depression responds to uridine will demonstrate an increased concentration of beta-nucleoside triphosphate (b-NTP) in the anterior cingulate cortex. This would support the hypothesis that depressive states are associated with abnormalities in brain energy metabolism.

As a neuroimaging comparison group for the participants with bipolar disorder, 30 healthy adolescent controls with no history of psychiatric illness will be recruited for MRI/MRS scanning only. The investigators hypothesize that controls will have higher levels of b-NTP in the anterior cingulate cortex than participants with depression associated with bipolar disorder, further supporting a connection between brain bioenergetics and depression.

Selection of Participants with Bipolar Disorder:

Inclusion Criteria:

• Participants must meet DSM-IV-TR (American Psychiatric Association, 2000) criteria for Bipolar Disorder Type I, Type II, or Not Otherwise Specified (NOS) with current mood state depressed for > 2 weeks
• Participants must be between the age of 13 and 18 years
• Participants who enter the study on psychotropic medications must be on a regimen that has been stable for > 2 weeks at the time of study entry
• Participants must be able to give informed consent or assent, and parent(s)/guardian(s) must be able to give informed permission for study participation

Exclusion Criteria:

• Adolescents with an unstable co-morbid medical, neurological, or psychiatric disorder
• Pregnant females, nursing mothers, or females of childbearing potential who are unable or unwilling to practice contraception during the study
• Participants with high risk of suicidal behaviors, homicidal behaviors, or self-harm
• Participants who in the opinion of the investigator are unlikely to be able to comply with the study protocol
• Participants who meet DSM-IV-TR criteria for current substance abuse or substance dependence, with the exception of nicotine abuse or dependence
• Participants for whom the MRI/MRS scans are contraindicated, such as children with ferromagnetic implants or claustrophobia
• Participants whose mood state is manic
• Documented or suspected history of mental retardation (IQ<70)
• Positive urine drug screen for cocaine or amphetamines
• Known hypersensitivity to uridine

Selection of Healthy Volunteers:

Inclusion Criteria:

• Participants must be between the ages of 13 and 18 years
• Participants must not meet DSM-IV-TR diagnostic criteria for a mental disorder or substance abuse
• Participants must be able to give informed consent or assent and parents/guardians must be able to give informed permission for participation

Exclusion Criteria:

• Clinically significant medical, neurological, psychiatric or substance abuse disorder
• Pregnant subjects, due to the unknown effects of MRI/MRS scans on a fetus. In addition, women of childbearing potential who are unable or unwilling to practice contraception during the study will be excluded. Female participants who are of child-bearing potential must have a negative urine pregnancy test before each MRI/MRS scan.
• Participants with a contraindication to MRI/MRS scanning, such as a metallic implant
• Patients unable to comply with the protocol

Adverse events were collected from participants at every visit, starting after the treatment intervention was dispensed at baseline. Adverse events were assessed up to 6 weeks.

Healthy comparison participants were only seen for scans at baseline and week 6. Healthy comparison participants were not exposed to any treatment intervention, therefore, adverse events were not collected.

Limited sample size and small percentage of underrepresented racial/ethnic minority participants.