Uridine Adolescent Bipolar Depression Randomized Controlled Trial

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Placebo-Controlled Study of Uridine for Adolescent Bipolar Depression: a Magnetic Resonance Spectroscopy Study

Conditions
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Bipolar Disorder, Bipolar Depression, Manic Depression

Intervention / Treatment
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* Drug: Uridine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 13 Years
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Uridine<br>Subjects randomized to this study arm will receive uridine 500 mg twice daily by mouth for 6 weeks. | Drug: Uridine<br>* Uridine is the active treatment in this clinical trial.<br>|
| Placebo Comparator: Placebo<br>Subjects randomized to this arm of the study will receive placebo 500 mg twice daily by mouth for 6 weeks. | Drug: Placebo<br>* Pill placebo is the inactive treatment comparator in this clinical trial.<br>* Other names: Pill Placebo;|
| No Intervention: Healthy Comparison<br>Subjects are not randomized, and do not receive any treatment intervention. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in GLX (Glutamate + Glutamine) to Creatine (Cr) Ratio in the Anterior Cingulate Cortex of the Brain, as Measured With Proton-1 Magnetic Resonance Spectroscopy (1H-MRS). | Magnetic Resonance Spectroscopy is a safe, non-invasive method for measuring brain chemicals thought to be involved in mood disorders, such as GLX (glutamate + glutamine). Previous research indicates that adolescents with bipolar depression have elevated Glx concentrations, compared with controls. The measurement of Glx with 1H-MRS has the potential to identify translational biomarkers of juvenile BD pathophysiology and treatment response. | Baseline and 6 weeks | 
| Change in Children's Depression Rating Scale-Revised (CDRS-R) Score. | The CDRS-R is a brief rating scale based on a semi-structured interview with the participant (and/or their parent or guardian). The scale can be administered and scored in under 30 minutes. The CDRS-R gives you a single summary score -- with an interpretation of, and clinical recommendations for, six different score ranges. Total possible scores range from 17 to 113, with higher scores indicating more depressive symptoms reported by the participant (and/or their parent or guardian). | 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Columbia-Suicide Severity Rating Scale (C-SSRS) | The Columbia-Suicide Severity Rating Scale (C-SSRS) is used to measure suicidal thoughts and behaviors in Investigational New Drug (IND) studies. The C-SSRS rates an individual's degree of suicidal ideation (SI) on a scale, ranging from wish to be dead to active suicidal ideation with specific plan and intent. The scale identifies SI severity and intensity, which may be indicative of an individual's intent to commit suicide. C-SSRS SI severity subscale ranges from 0 (no SI) to 5 (active SI with plan and intent). | 6 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Adolescent, Bipolar Disorder, Bipolar Depression, Manic Depression, Neuroimaging, Magnetic Resonance Spectroscopy, Uridine, Pyrimidines