Oral Uridine for Treatment of Bipolar Depression in Adolescents

• Sponsor: University of Utah (Other)
• Overall Status: Completed
• CT.gov ID: NCT00841269
• Collaborator: National Institute of Mental Health (NIMH) (NIH)
• Enrollment: 42
• Location: 1
• Arms: 2
• Duration (Months): 49
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Bipolar Disorder	Drug: Uridine	Phase 2

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 42 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Oral Administration of Uridine for Treatment of Bipolar Depression in Adolescents: A Magnetic Resonance Spectroscopy Study
• Study Start Date: May 1, 2009
• Actual Primary Completion Date: Jun 1, 2013
• Actual Study Completion Date: Jun 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Uridine Uridine 500 mg by mouth twice daily for 6 weeks	Drug: Uridine; Uridine 500 mg by mouth twice per day for 6 weeks
No Intervention: Healthy Comparison Healthy comparison participants were seen for baseline and week 6 MRI scans. No treatment was administered to participants enrolled as healthy comparisons.

Outcome Measures

Primary Outcome Measures

1. Mean Scores in Children's Depression Rating Scale (CDRS-R), Assessed Before and After 6 Week Uridine Treatment [6 weeks]

   The CDRS-R is a 17-item scale, with items rated for severity on a 5 point scale for 3 items and on a 7 point scale for 14 items (possible total score from 17 to 113). Ratings are completed by a clinician via interviews with the child or parent. Scores ≥40 are indicative of depression, whereas scores ≤28 is often used to define remission.

2. The Primary Neuroimaging Outcome Will be Changes in Beta-NTP to TP (Total Phosphorus) Ratio in the Anterior Cingulate. [6 weeks]

Secondary Outcome Measures

1. A Secondary Outcome Measure Includes a Change in Young Mania Rating Scale (YMRS) Score [6 weeks]

   The Young Mania Rating Scale (YMRS) is an 11-item rating scale that evaluates manic symptoms. Total scores range from 0-60, with higher scores indicating more manic symptoms endorsed by research participants.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 13 Years to 18 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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

Contacts and Locations

Locations

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

Sponsors and Collaborators

• University of Utah
• National Institute of Mental Health (NIMH)

Investigators

• Principal Investigator: Douglas G Kondo, M.D., University of Utah

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• UtahBrain.org

Publications

None provided.

• Responsible Party: Douglas Kondo, MD, MD, University of Utah
• ClinicalTrials.gov Identifier: NCT00841269
• Other Study ID Numbers: 28455; 5R01MH058681-06
• First Posted: Feb 11, 2009
• Last Update Posted: Mar 26, 2018
• Last Verified: Feb 1, 2018

• Keywords provided by Douglas Kondo, MD, MD, University of Utah: Bipolar Manic Depression
• Additional relevant MeSH terms: Depression; Bipolar Disorder

Study Results

Participant Flow

Recruitment Details	Participants were recruited via clinician referrals and IRB-approved recruitment materials and advertising.

Arm/Group Title	Open Label Uridine Treatment	Healthy Comparison
Arm/Group Description	Participants received fixed-dose uridine 500 mg twice daily for 6 weeks. At each treatment visit, the following rating scales were administered: The CDRS-R, YMRS, and the Columbia-Suicide Severity Rating Scale (C-SSRS)	Participants assigned to this group were seen for two scan visits (baseline and week 6). Healthy comparison participants received no intervention.
Period Title: Overall Study
STARTED	20	22
COMPLETED	12	13
NOT COMPLETED	8	9

Baseline Characteristics

Arm/Group Title	Open Label Uridine Treatment	Healthy Comparison	Total
Arm/Group Description	All participants were Caucasian. There were 5 female participants and 2 male participants.	Participants assigned to this group were seen only at baseline and received no intervention.	Total of all reporting groups
Overall Participants	20	22	42
Age (Count of Participants)
<=18 years	20 100%	18 81.8%	38 90.5%
Between 18 and 65 years	0 0%	4 18.2%	4 9.5%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	16.05 (1.50)	15.67 (1.84)	15.83 (1.68)
Sex: Female, Male (Count of Participants)
Female	9 45%	9 40.9%	18 42.9%
Male	11 55%	13 59.1%	24 57.1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	2 9.1%	2 4.8%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	20 100%	20 90.9%	40 95.2%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	20 100%	22 100%	42 100%

Outcome Measures

1. Primary Outcome

Title	Mean Scores in Children's Depression Rating Scale (CDRS-R), Assessed Before and After 6 Week Uridine Treatment
Description	The CDRS-R is a 17-item scale, with items rated for severity on a 5 point scale for 3 items and on a 7 point scale for 14 items (possible total score from 17 to 113). Ratings are completed by a clinician via interviews with the child or parent. Scores ≥40 are indicative of depression, whereas scores ≤28 is often used to define remission.
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Open Label Uridine Treatment	Healthy Comparison
Arm/Group Description	Participants received fixed-dose uridine 500 mg twice daily for 6 weeks.	Participants assigned to this group were seen for two scan visits (baseline and week 6). Healthy comparison participants received no intervention/treatment.
Measure Participants	12	13
before treatment	60.00	21.29
after 6 week Uridine treatment	33.83	20

2. Primary Outcome

Title	The Primary Neuroimaging Outcome Will be Changes in Beta-NTP to TP (Total Phosphorus) Ratio in the Anterior Cingulate.
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Open Label Uridine Treatment	Healthy Comparison
Arm/Group Description	Participants received fixed-dose uridine 500 mg twice daily for 6 weeks.	Participants assigned to this group were seen for two scan visits (baseline and week 6). Healthy comparison participants received no intervention/treatment.
Measure Participants	12	13
Before treatment	0.1168 (0.0157)	0.1232 (0.0127)
After 6 weeks treatment	0.1193 (0.0142)	0.1297 (0.0140)

3. Secondary Outcome

Title	A Secondary Outcome Measure Includes a Change in Young Mania Rating Scale (YMRS) Score
Description	The Young Mania Rating Scale (YMRS) is an 11-item rating scale that evaluates manic symptoms. Total scores range from 0-60, with higher scores indicating more manic symptoms endorsed by research participants.
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Open Label Uridine Treatment	Healthy Comparison
Arm/Group Description	Participants received fixed-dose uridine 500 mg twice daily for 6 weeks.	Participants assigned to this group were seen for two scan visits (baseline and week 6). Healthy comparison participants received no intervention/treatment.
Measure Participants	12	13
Before treatment	5.42	0.7083
After 6 weeks treatment	3.08	2.1818

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 for scans at baseline and week 6. Healthy comparison participants were not exposed to any treatment intervention, therefore, adverse events were not collected.
Arm/Group Title	Uridine 500 mg by Mouth Twice Daily for 6 Weeks
Arm/Group Description	Because this was an open-label study, all participants received the investigational drug uridine.
All Cause Mortality
	Uridine 500 mg by Mouth Twice Daily for 6 Weeks
	Affected / at Risk (%)	# Events
Total	0/20 (0%)
Serious Adverse Events
	Uridine 500 mg by Mouth Twice Daily for 6 Weeks
	Affected / at Risk (%)	# Events
Total	1/20 (5%)
Psychiatric disorders
Suicidal ideation	1/20 (5%)	1
Other (Not Including Serious) Adverse Events
	Uridine 500 mg by Mouth Twice Daily for 6 Weeks
	Affected / at Risk (%)	# Events
Total	6/20 (30%)
Eye disorders
Hordeolum	1/20 (5%)	1
Gastrointestinal disorders
Abdominal cramp, Nausea, Indigestion	6/20 (30%)	10
General disorders
Flu-like symptoms (fatigue, bronchitis, sinusitis)	6/20 (30%)	7
Back pain	1/20 (5%)	1
Psychiatric disorders
suicidal ideation	1/20 (5%)	1
Insomnia	4/20 (20%)	4
Vivid Dreams	1/20 (5%)	1

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.