Bipolar Depression, Bipolar Disorder, Manic Depression
Conditions
Keywords
Adolescent, Bipolar Disorder, Bipolar Depression, Manic Depression, Neuroimaging, Magnetic Resonance Spectroscopy, Uridine, Pyrimidines
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.
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.
Interventions
DRUGUridine
Uridine is the active treatment in this clinical trial.
DRUGPlacebo
Pill placebo is the inactive treatment comparator in this clinical trial.
Sponsors
The Depressive and Bipolar Disorder Alternative Treatment Foundation
University of Utah
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
13 Years to 21 Years
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Uridine 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. | 19 |
| Placebo 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. | 17 |
| Healthy Comparison Subjects seen for screening and baseline scan. No randomization or treatment intervention for subjects enrolled as a Healthy Comparison. | 26 |
| Total | 62 |
Baseline characteristics
| Characteristic | Placebo | Healthy Comparison | Uridine | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 6 Participants | 6 Participants | 10 Participants | 22 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants | 20 Participants | 9 Participants | 40 Participants |
| Age, Continuous | 18.29 years STANDARD_DEVIATION 2.62 | 18.54 years STANDARD_DEVIATION 2.37 | 16.74 years STANDARD_DEVIATION 2.28 | 17.47 years STANDARD_DEVIATION 2.54 |
| Region of Enrollment United States | 17 participants | 26 participants | 19 participants | 62 participants |
| Sex: Female, Male Female | 10 Participants | 16 Participants | 14 Participants | 40 Participants |
| Sex: Female, Male Male | 7 Participants | 10 Participants | 5 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 19 | 0 / 17 |
| other Total, other adverse events | 12 / 19 | 5 / 17 |
| serious Total, serious adverse events | 1 / 19 | 0 / 17 |
Outcome results
Primary
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).
Time frame: 6 weeks
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Uridine | Change in Children's Depression Rating Scale-Revised (CDRS-R) Score. | Total Score before treatment | 59.05 Units on a scale |
| Uridine | Change in Children's Depression Rating Scale-Revised (CDRS-R) Score. | Total Score after 6 weeks treatment | 45.67 Units on a scale |
| Placebo | Change in Children's Depression Rating Scale-Revised (CDRS-R) Score. | Total Score before treatment | 58.18 Units on a scale |
| Placebo | Change in Children's Depression Rating Scale-Revised (CDRS-R) Score. | Total Score after 6 weeks treatment | 36.76 Units on a scale |
| Healthy Comparison | Change in Children's Depression Rating Scale-Revised (CDRS-R) Score. | Total Score before treatment | 21.31 Units on a scale |
| Healthy Comparison | Change in Children's Depression Rating Scale-Revised (CDRS-R) Score. | Total Score after 6 weeks treatment | NA Units on a scale |
Primary
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.
Time frame: Baseline and 6 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Uridine | 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). | Before treatment | 1.5731 Brain GLX/Cr | Standard Deviation 0.1082 |
| Uridine | 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). | After 6 weeks treatment | 1.6738 Brain GLX/Cr | Standard Deviation 0.1147 |
| Placebo | 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). | Before treatment | 1.6557 Brain GLX/Cr | Standard Deviation 0.1105 |
| Placebo | 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). | After 6 weeks treatment | 1.6121 Brain GLX/Cr | Standard Deviation 0.0977 |
| Healthy Comparison | 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). | Before treatment | 1.6051 Brain GLX/Cr | Standard Deviation 0.1195 |
| Healthy Comparison | 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). | After 6 weeks treatment | NA Brain GLX/Cr | — |
Secondary
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).
Time frame: 6 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Uridine | Columbia-Suicide Severity Rating Scale (C-SSRS) | Participants SI Severity at Baseline | 0.6875 Scores on a Scale | Standard Deviation 0.7932 |
| Uridine | Columbia-Suicide Severity Rating Scale (C-SSRS) | Participants SI Severity after 6 Weeks Treatment | 0.5 Scores on a Scale | Standard Deviation 0.6183 |
| Placebo | Columbia-Suicide Severity Rating Scale (C-SSRS) | Participants SI Severity at Baseline | 0.5882 Scores on a Scale | Standard Deviation 1.069 |
| Placebo | Columbia-Suicide Severity Rating Scale (C-SSRS) | Participants SI Severity after 6 Weeks Treatment | 0.4706 Scores on a Scale | Standard Deviation 1.0676 |
| Healthy Comparison | Columbia-Suicide Severity Rating Scale (C-SSRS) | Participants SI Severity at Baseline | 0 Scores on a Scale | Standard Deviation 0 |
| Healthy Comparison | Columbia-Suicide Severity Rating Scale (C-SSRS) | Participants SI Severity after 6 Weeks Treatment | NA Scores on a Scale | — |