Multimodal Neuroimaging of Treatment Effects in Adolescent Mania
Primary Purpose
Mania, Bipolar Disorder
Status
Completed
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Quetiapine & Placebo
Lithium and Placebo
Healthy Controls
Sponsored by
About this trial
This is an interventional diagnostic trial for Mania focused on measuring mania, adolescent, bipolar
Eligibility Criteria
Inclusion/Exclusion Criteria
Inclusion - Bipolar Disorder Subjects:
- DSM-IV-TR12 criteria for bipolar disorder, type I, manic or mixed episode, diagnosed by the Washington University in St. Louis Kiddie Schedule for Affective Disorders and Schizophrenia (WASH-U-KSADS)166,101,102-103,104-105,108
- Baseline YMRS112-114 score > 20;
- Ages 12-17 years 11 months old;
- Fluent in English;
- Provision of written informed consent by a legal guardian and written assent by the subject;
- Tanner scale stages III-V167, in order to include only post-pubescent subjects and minimize brain changes associated with the onset of puberty;168-169
- Less than 2 years from onset of bipolar disorder, defined by age at onset of first DSM-IV-TR affective episode (mania, hypomania, depression or mixed), to establish that our sample is early in their illness course;
- No prior psychiatric hospitalizations, <3 months of lifetime psychotropic medication exposure (with the exception of psychostimulants, since excluding patients with psychostimulant exposure would significantly limit the generalizability of our findings), and no active psychotropic medication during the week (72 hours for psychostimulants and benzodiazepines) prior to the index assessment (no treatment with fluoxetine during the prior month). Please note that patients will NOT be taken off medications for the purpose of this study; instead, this criterion is to exclude subjects receiving treatment at the time of index assessment;
- Does not have a history of intolerance or non-response to lithium or quetiapine;
- Manic or depressive symptoms do not result entirely from acute medical illness or acute intoxication or withdrawal from drugs or alcohol as determined by medical evaluation and rapid symptom resolution;
- No lifetime DSM-IV-TR diagnosis of post-traumatic stress disorder (PTSD), since PTSD has been associated with abnormalities in prefrontal NAA and function170-171,172. Furthermore, bipolar patients with co-occurring PTSD are less likely to respond to lithium monotherapy, and often need a serotonin specific reuptake inhibitor (SSRI) as adjunctive treatment to a mood stabilizer.173,174 ;
- If female and of child bearing potential, agrees to use one of the following method of birth control: complete abstinence from sexual intercourse, barrier (diaphragm or condom), or oral/injectable contraceptive.
Inclusion - Healthy Controls:
- Ages of 12-17 years and 11 month;
- No history of any DSM-IV-TR Axis I disorder (nicotine dependence is permitted);
- No first- or second-degree relatives with an affective or psychotic disorder;
- No medications with central nervous system effects within 5 half-lives;
- Fluent in English;
- Tanner stage III-V;
- Provision of informed consent and assent.
Exclusion - Bipolar Subjects & Healthy Controls:
- Contraindication to an MRI scan (e.g., braces or claustrophobia);
- An unstable medical or neurological illness that could influence fMRI or MRS results;
- IQ < 70, as determined by The Wechsler Abbreviated Scale of Intelligence (WASI) ;
- A positive pregnancy test;
- A history of major medical or neurological illness or a significant episode (> 10 minutes) of loss of consciousness;
- Any lifetime DSM-IV-TR substance use disorder (nicotine dependence is permitted);
- A lifetime DSM-IV-TR diagnosis of any pervasive developmental disorder;
- The patient lives >100 miles from the University of Cincinnati or is not able to attend follow-up visits.
Sites / Locations
- University of Cincinnati
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Active Comparator
Active Comparator
Placebo Comparator
Arm Label
1--Quetiapine & Placebo
2-- Lithium & Placebo
Placebo
Arm Description
Quetiapine & Placebo in the place of Lithium
Lithium & Placebo in the place of Quetiapine
Sugar Pill (Placebo) given to mimic drug
Outcomes
Primary Outcome Measures
The purpose of this study is to use magnetic resonance imaging (MRI) to examine brain structure, function and chemistry in people with Bipolar I disorder (manic or mixed episodes) who are being treated with either quetiapine or lithium.
Secondary Outcome Measures
Full Information
NCT ID
NCT00893581
First Posted
May 4, 2009
Last Updated
May 18, 2016
Sponsor
University of Cincinnati
Collaborators
Children's Hospital Medical Center, Cincinnati
1. Study Identification
Unique Protocol Identification Number
NCT00893581
Brief Title
Multimodal Neuroimaging of Treatment Effects in Adolescent Mania
Official Title
Multimodal Neuroimaging of Treatment Effects in Adolescent Mania
Study Type
Interventional
2. Study Status
Record Verification Date
May 2015
Overall Recruitment Status
Completed
Study Start Date
March 2009 (undefined)
Primary Completion Date
February 2016 (Actual)
Study Completion Date
March 2016 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Cincinnati
Collaborators
Children's Hospital Medical Center, Cincinnati
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
Specific Aim 1: To determine the effects of treatment with quetiapine or lithium on brain activation in adolescents. The investigators will use functional magnetic resonance imaging (fMRI) to examine brain activation during an attentional task.
Specific Aim 2: To determine the effects of treatment with quetiapine or lithium on neurometabolite measures, early in their illness course. The investigators will use 1H-MRS to identify myo-inositol (mI), N-acetyl aspartate (NAA), and glutamate (Glu) levels in prefrontal ALN regions.
Specific Aim 3: To determine the relationships among the changes in brain activation and neurometabolite measures, as well as symptomatic improvement in manic adolescents.
Detailed Description
Hypotheses 1 & 2 predict that following 6 weeks of treatment with lithium or quetiapine, manic adolescents who demonstrate symptomatic improvement will exhibit normalized (decreased) VLPFC and ACC activation and increased activation of compensatory posterior attentional brain areas as well as normalization of VLPFC and ACC neurometabolite measures (increased NAA and decreased Glu levels) compared with those who do not experience symptomatic improvement and healthy adolescents.
Hypothesis 3 predicts significant associations between fMRI activation changes (i.e. decreased activation in VLPFC and ACC ROIs and increased activation in the posterior attention ROI) and MRS changes (increases in NAA and decreases in Glu levels in the VLPFC and ACC) for patients who exhibit symptomatic improvement with either treatment.
Hypothesis 4 predicts that decreases in mI levels at 1 week will be associated with lithium, but not quetiapine, response at endpoint.
In contrast, Hypothesis 5 predicts higher baseline Cho levels will be associated with quetiapine, but not lithium, response at endpoint.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Mania, Bipolar Disorder
Keywords
mania, adolescent, bipolar
7. Study Design
Primary Purpose
Diagnostic
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
169 (Actual)
8. Arms, Groups, and Interventions
Arm Title
1--Quetiapine & Placebo
Arm Type
Active Comparator
Arm Description
Quetiapine & Placebo in the place of Lithium
Arm Title
2-- Lithium & Placebo
Arm Type
Active Comparator
Arm Description
Lithium & Placebo in the place of Quetiapine
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Sugar Pill (Placebo) given to mimic drug
Intervention Type
Drug
Intervention Name(s)
Quetiapine & Placebo
Intervention Description
Bipolar adolescents will be initiated on 100 mg per day of quetiapine (or placebo) and 30 mg/kg (maximum starting dose of 600 mg twice daily) of lithium carbonate (or placebo), depending on randomization assignment. Patients will be given placebo for the medication to which they were not assigned. Quetiapine will be adjusted based on tolerability and response to a target dose of 400-600 mg and lithium will be adjusted to a target dose based on achieving a serum level of 1.0-1.2 mEq/L.
Intervention Type
Drug
Intervention Name(s)
Lithium and Placebo
Intervention Description
Bipolar adolescents will be initiated on 100 mg per day of quetiapine (or placebo) and 30 mg/kg (maximum starting dose of 600 mg twice daily) of lithium carbonate (or placebo), depending on randomization assignment. Patients will be given placebo for the medication to which they were not assigned. Quetiapine will be adjusted based on tolerability and response to a target dose of 400-600 mg and lithium will be adjusted to a target dose based on achieving a serum level of 1.0-1.2 mEq/L.
Intervention Type
Other
Intervention Name(s)
Healthy Controls
Intervention Description
Healthy control (patients given placebo -- sugar pill intended to mimic drug)
Primary Outcome Measure Information:
Title
The purpose of this study is to use magnetic resonance imaging (MRI) to examine brain structure, function and chemistry in people with Bipolar I disorder (manic or mixed episodes) who are being treated with either quetiapine or lithium.
Time Frame
6 weeks
10. Eligibility
Sex
All
Minimum Age & Unit of Time
12 Years
Maximum Age & Unit of Time
17 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion/Exclusion Criteria
Inclusion - Bipolar Disorder Subjects:
DSM-IV-TR12 criteria for bipolar disorder, type I, manic or mixed episode, diagnosed by the Washington University in St. Louis Kiddie Schedule for Affective Disorders and Schizophrenia (WASH-U-KSADS)166,101,102-103,104-105,108
Baseline YMRS112-114 score > 20;
Ages 12-17 years 11 months old;
Fluent in English;
Provision of written informed consent by a legal guardian and written assent by the subject;
Tanner scale stages III-V167, in order to include only post-pubescent subjects and minimize brain changes associated with the onset of puberty;168-169
Less than 2 years from onset of bipolar disorder, defined by age at onset of first DSM-IV-TR affective episode (mania, hypomania, depression or mixed), to establish that our sample is early in their illness course;
No prior psychiatric hospitalizations, <3 months of lifetime psychotropic medication exposure (with the exception of psychostimulants, since excluding patients with psychostimulant exposure would significantly limit the generalizability of our findings), and no active psychotropic medication during the week (72 hours for psychostimulants and benzodiazepines) prior to the index assessment (no treatment with fluoxetine during the prior month). Please note that patients will NOT be taken off medications for the purpose of this study; instead, this criterion is to exclude subjects receiving treatment at the time of index assessment;
Does not have a history of intolerance or non-response to lithium or quetiapine;
Manic or depressive symptoms do not result entirely from acute medical illness or acute intoxication or withdrawal from drugs or alcohol as determined by medical evaluation and rapid symptom resolution;
No lifetime DSM-IV-TR diagnosis of post-traumatic stress disorder (PTSD), since PTSD has been associated with abnormalities in prefrontal NAA and function170-171,172. Furthermore, bipolar patients with co-occurring PTSD are less likely to respond to lithium monotherapy, and often need a serotonin specific reuptake inhibitor (SSRI) as adjunctive treatment to a mood stabilizer.173,174 ;
If female and of child bearing potential, agrees to use one of the following method of birth control: complete abstinence from sexual intercourse, barrier (diaphragm or condom), or oral/injectable contraceptive.
Inclusion - Healthy Controls:
Ages of 12-17 years and 11 month;
No history of any DSM-IV-TR Axis I disorder (nicotine dependence is permitted);
No first- or second-degree relatives with an affective or psychotic disorder;
No medications with central nervous system effects within 5 half-lives;
Fluent in English;
Tanner stage III-V;
Provision of informed consent and assent.
Exclusion - Bipolar Subjects & Healthy Controls:
Contraindication to an MRI scan (e.g., braces or claustrophobia);
An unstable medical or neurological illness that could influence fMRI or MRS results;
IQ < 70, as determined by The Wechsler Abbreviated Scale of Intelligence (WASI) ;
A positive pregnancy test;
A history of major medical or neurological illness or a significant episode (> 10 minutes) of loss of consciousness;
Any lifetime DSM-IV-TR substance use disorder (nicotine dependence is permitted);
A lifetime DSM-IV-TR diagnosis of any pervasive developmental disorder;
The patient lives >100 miles from the University of Cincinnati or is not able to attend follow-up visits.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Melissa DelBello, MD
Organizational Affiliation
University of Cincinnati
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Cincinnati
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45219
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
36229596
Citation
Lei D, Li W, Qin K, Ai Y, Tallman MJ, Patino LR, Welge JA, Blom TJ, Klein CC, Fleck DE, Gong Q, Adler CM, Strawn JR, Sweeney JA, DelBello MP. Effects of short-term quetiapine and lithium therapy for acute manic or mixed episodes on the limbic system and emotion regulation circuitry in youth with bipolar disorder. Neuropsychopharmacology. 2023 Mar;48(4):615-622. doi: 10.1038/s41386-022-01463-6. Epub 2022 Oct 13.
Results Reference
derived
PubMed Identifier
35091050
Citation
Li W, Lei D, Tallman MJ, Ai Y, Welge JA, Blom TJ, Fleck DE, Klein CC, Patino LR, Strawn JR, Gong Q, Strakowski SM, Sweeney JA, Adler CM, DelBello MP. Pretreatment Alterations and Acute Medication Treatment Effects on Brain Task-Related Functional Connectivity in Youth With Bipolar Disorder: A Neuroimaging Randomized Clinical Trial. J Am Acad Child Adolesc Psychiatry. 2022 Aug;61(8):1023-1033. doi: 10.1016/j.jaac.2021.12.015. Epub 2022 Jan 25.
Results Reference
derived
PubMed Identifier
34520250
Citation
Patino LR, Klein CC, Strawn JR, Blom TJ, Tallman MJ, Adler CM, Welge JA, DelBello MP. A Randomized, Double-Blind, Controlled Trial of Lithium Versus Quetiapine for the Treatment of Acute Mania in Youth with Early Course Bipolar Disorder. J Child Adolesc Psychopharmacol. 2021 Sep;31(7):485-493. doi: 10.1089/cap.2021.0039. Epub 2021 Sep 14.
Results Reference
derived
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Multimodal Neuroimaging of Treatment Effects in Adolescent Mania
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