This is a randomized, double-blind, placebo-controlled study of the investigational drug uridine as a treatment for depressed adolescents with bipolar disorder (i.e. "bipolar depression"). Participants initially randomized to placebo who complete the 6-week protocol will be offered 6 months of open-label uridine treatment and follow-up. Participants initially randomized to uridine will be offered the open-label treatment as well.

This is a randomized, double-blind, placebo-controlled study of the investigational drug uridine as a treatment for depressed adolescents with bipolar disorder (i.e. "bipolar depression").

In addition to treatment with the investigational drug versus placebo, the study includes a translational neuroimaging component: magnetic resonance spectroscopy (1H-MRS) brain scans are performed at baseline, and then repeated following 6 weeks of treatment with uridine or placebo. The scans do not use radiation, and are performed on a 3 Tesla MRI system that is approved for clinical use. The scans allow researchers to measure the concentrations of several chemicals in the brain that are believed to be involved in bipolar disorder and depression.

The primary hypothesis is that uridine treatment will be associated with a significant decrease in GLX (i.e. glutamate + glutamine) levels, compared to placebo, in a part of the brain known as the anterior cingulate cortex.

The secondary hypothesis is that decreased depressive symptoms measured with the Children Depression Rating Scale-Revised (CDRS-R) and Montgomery-Asberg Depression Rating Scale (MADRS) will be correlated with reductions in GLX.

All participants who complete the initial 6-week protocol, including two brain scans, will be offered 6 months of open-label treatment with uridine.

Inclusion Criteria For Bipolar Disorder Participants:

• Participants under 18 years of age must be able to provide assent, and have the permission of a parent or guardian. Participants 18 years of age or older must be able to provide informed consent.
• Participants must be between the ages of 13 and 21 years.
• Participants must meet DSM criteria for Bipolar Disorder (Type I, II, or NOS), with current mood state depressed for at least 2 weeks.
• Participants must have a current Children's Depression Rating Scale-Revised (CDRS-R) score of 45 or greater, and/or a Montgomery/Asberg Depression Rating Scale (MADRS) score of 25 or greater.

Inclusion Criteria For Healthy Comparison Participants:

• Participants under 18 years of age must be able to provide assent, and have the permission of a parent or guardian. Participants 18 years of age or older must be able to provide informed consent.
• Participants must be between the ages of 13 and 21 years.
• Participants must not meet any DSM-IV criteria for a psychiatric illness or substance use disorder

Exclusion Criteria:

• Participants must not meet DSM criteria for a primary psychotic disorder, a developmental disorder or substance use disorder.
• Participants must not be at high risk for suicidal or homicidal actions.
• Participants must not be pregnant or breastfeeding.
• Participants must not have a contraindication to magnetic resonance imaging (e.g. ferromagnetic implant, or claustrophobic anxiety).
• Incarcerated persons are excluded, because this study is not approved for Research Involving Prisoners.

Informed Consent to publicly share individual participant data, e.g. MRI and MRS brain scans, was not obtained.

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 at baseline, and 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.