Uridine Adolescent Bipolar Depression Randomized Controlled Trial

• Sponsor: University of Utah (Other)
• Overall Status: Completed
• CT.gov ID: NCT01805440
• Collaborator: The Depressive and Bipolar Disorder Alternative Treatment Foundation (Other)
• Enrollment: 62
• Location: 1
• Arms: 3
• Duration (Months): 28
• Patients Per Site Per Month: 2.2

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Bipolar Disorder; Bipolar Depression; Manic Depression	Drug: Uridine; Drug: Placebo	N/A

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 62 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Other
• Official Title: Placebo-Controlled Study of Uridine for Adolescent Bipolar Depression: a Magnetic Resonance Spectroscopy Study
• Study Start Date: Aug 1, 2013
• Actual Primary Completion Date: Dec 1, 2015
• Actual Study Completion Date: Dec 1, 2015

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. 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). [Baseline and 6 weeks]

   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.

2. Change in Children's Depression Rating Scale-Revised (CDRS-R) Score. [6 weeks]

   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).

Secondary Outcome Measures

1. Columbia-Suicide Severity Rating Scale (C-SSRS) [6 weeks]

   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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 13 Years to 21 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Utah	Salt Lake City	Utah	United States	84108

Sponsors and Collaborators

• University of Utah
• The Depressive and Bipolar Disorder Alternative Treatment Foundation

Investigators

• Principal Investigator: Douglas Kondo, MD, University of Utah

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Free downloadable full-text article

Publications

• Kondo DG, Sung YH, Hellem TL, Delmastro KK, Jeong EK, Kim N, Shi X, Renshaw PF. Open-label uridine for treatment of depressed adolescents with bipolar disorder. J Child Adolesc Psychopharmacol. 2011 Apr;21(2):171-5. doi: 10.1089/cap.2010.0054. Epub 2011 Apr 12.

• Responsible Party: Douglas Kondo, MD, M.D., University of Utah
• ClinicalTrials.gov Identifier: NCT01805440
• Other Study ID Numbers: University of Utah
• First Posted: Mar 6, 2013
• Last Update Posted: Mar 12, 2018
• Last Verified: Mar 1, 2018

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Douglas Kondo, MD, M.D., University of Utah: Adolescent; Bipolar Disorder; Bipolar Depression; Manic Depression; Neuroimaging; Magnetic Resonance Spectroscopy; Uridine; Pyrimidines
• Additional relevant MeSH terms: Depression; Depressive Disorder; Bipolar Disorder

Study Results

Participant Flow

Arm/Group Title	Uridine	Placebo	Healthy Comparison
Arm/Group Description	Subjects randomized to this study arm will receive uridine 500 mg twice daily by mouth for 6 weeks. Uridine: Uridine is the active treatment in this clinical trial.	Subjects randomized to this arm of the study will receive placebo 500 mg twice daily by mouth for 6 weeks. Placebo: Pill placebo is the inactive treatment comparator in this clinical trial.	Subjects seen for screening and baseline scan. No randomization or treatment intervention for subjects enrolled as a Healthy Comparison.
Period Title: Overall Study
STARTED	19	17	26
COMPLETED	18	17	26
NOT COMPLETED	1	0	0

Baseline Characteristics

Arm/Group Title	Uridine	Placebo	Healthy Comparison	Total
Arm/Group Description	Subjects randomized to this study arm will receive uridine 500 mg twice daily by mouth for 6 weeks. Uridine: Uridine is the active treatment in this clinical trial.	Subjects randomized to this arm of the study will receive placebo 500 mg twice daily by mouth for 6 weeks. Placebo: Pill placebo is the inactive treatment comparator in this clinical trial.	Subjects seen for screening and baseline scan. No randomization or treatment intervention for subjects enrolled as a Healthy Comparison.	Total of all reporting groups
Overall Participants	19	17	26	62
Age (Count of Participants)
<=18 years	10 52.6%	6 35.3%	6 23.1%	22 35.5%
Between 18 and 65 years	9 47.4%	11 64.7%	20 76.9%	40 64.5%
>=65 years	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	16.74 (2.28)	18.29 (2.62)	18.54 (2.37)	17.47 (2.54)
Sex: Female, Male (Count of Participants)
Female	14 73.7%	10 58.8%	16 61.5%	40 64.5%
Male	5 26.3%	7 41.2%	10 38.5%	22 35.5%
Region of Enrollment (participants) [Number]
United States	19 100%	17 100%	26 100%	62 100%

Outcome Measures

1. Primary Outcome

Title	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).
Description	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.
Time Frame	Baseline and 6 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Uridine	Placebo	Healthy Comparison
Arm/Group Description	Subjects randomized to this study arm will receive uridine 500 mg twice daily by mouth for 6 weeks. Uridine: Uridine is the active treatment in this clinical trial.	Subjects randomized to this arm of the study will receive placebo 500 mg twice daily by mouth for 6 weeks. Placebo: Pill placebo is the inactive treatment comparator in this clinical trial.	Subjects did not receive study medication. Subjects were only seen for baseline visit.
Measure Participants	18	17	26
Before treatment	1.5731 (.1082)	1.6557 (.1105)	1.6051 (.1195)
After 6 weeks treatment	1.6738 (.1147)	1.6121 (.0977)	NA (NA)

2. Primary Outcome

Title	Change in Children's Depression Rating Scale-Revised (CDRS-R) Score.
Description	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).
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Uridine	Placebo	Healthy Comparison
Arm/Group Description	Subjects randomized to this study arm will receive uridine 500 mg twice daily by mouth for 6 weeks. Uridine: Uridine is the active treatment in this clinical trial.	Subjects randomized to this arm of the study will receive placebo 500 mg twice daily by mouth for 6 weeks. Placebo: Pill placebo is the inactive treatment comparator in this clinical trial.	Subjects did not receive study medication. Subjects were only seen for baseline visit.
Measure Participants	18	17	26
Total Score before treatment	59.05	58.18	21.31
Total Score after 6 weeks treatment	45.67	36.76	NA

3. Secondary Outcome

Title	Columbia-Suicide Severity Rating Scale (C-SSRS)
Description	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).
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Uridine	Placebo	Healthy Comparison
Arm/Group Description	Subjects randomized to this study arm will receive uridine 500 mg twice daily by mouth for 6 weeks. Uridine: Uridine is the active treatment in this clinical trial.	Subjects randomized to this arm of the study will receive placebo 500 mg twice daily by mouth for 6 weeks. Placebo: Pill placebo is the inactive treatment comparator in this clinical trial.	Subjects did not receive study medication. Subjects were only seen for baseline visit.
Measure Participants	18	17	26
Participants SI Severity at Baseline	0.6875 (0.7932)	0.5882 (1.0690)	0 (0)
Participants SI Severity after 6 Weeks Treatment	0.5 (0.6183)	0.4706 (1.0676)	NA (NA)

Adverse Events

Time Frame	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.
Adverse Event Reporting Description	Healthy comparison participants were only seen at baseline, and were not exposed to any treatment intervention, therefore, adverse events were not collected.
Arm/Group Title	Uridine		Placebo
Arm/Group Description	Subjects randomized to this study arm will receive uridine 500 mg twice daily by mouth for 6 weeks. Uridine: Uridine is the active treatment in this clinical trial.		Subjects randomized to this arm of the study will receive placebo 500 mg twice daily by mouth for 6 weeks. Placebo: Pill placebo is the inactive treatment comparator in this clinical trial.
All Cause Mortality
	Uridine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/19 (0%)		0/17 (0%)
Serious Adverse Events
	Uridine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/19 (5.3%)		0/17 (0%)
Psychiatric disorders
Other Serious (Important Medical Event)	1/19 (5.3%)	1	0/17 (0%)	0
Other (Not Including Serious) Adverse Events
	Uridine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/19 (63.2%)		5/17 (29.4%)
Gastrointestinal disorders
Stomach Discomfort	8/19 (42.1%)		3/17 (17.6%)
Nausea	5/19 (26.3%)		3/17 (17.6%)

Limitations/Caveats

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

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.