Lithium Magnetic Resonance Spectroscopy Of Children And Adolescents With Bipolar
Constance M Moore
Mc Lean Hospital (belmont, Ma)
Project start date: 2008-10-22
Project end date: 2010-03-31
7R21MH082335-02 (2008): $105248
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Grants awarded to Constance M Moore
LITHIUM MAGNETIC RESONANCE SPECTROSCOPY OF CHILDREN AND ADOLESCENTS WITH BIPOLAR
Constance M Moore, Assistant Professor Of Psychiatry
Mc Lean Hospital (belmont, Ma), 115 Mill St, Belmont, Ma 02478
Grant 5R21MH082335-03 from National Institute Of Mental Health
Abstract: This research project proposes to use lithium (7Li) Magnetic Resonance Spectroscopy (MRS) to measure brain lithium levels in children and adolescents with Bipolar I Disorder (BPD) who are being treated with the medication. Lithium is considered to be a first-line mood stabilizer for acute mania, hypomania, depression, and prevention of relapse in youth. However, lithium has not been adequately studied in pediatric BPD samples; this shortcoming is currently being addressed through a multi-site contract with NIH [Collaborative Lithium Trials (COLT)]. We plan to measure brain lithium levels in a subgroup of patients participating in the COLT study. This study will be the first to evaluate the clinical significance of brain lithium levels in youths. Subjects enrolled in a COLT protocol (8-week double-blind placebo-controlled trial of lithium) at the Harvard site (expected N=25, ages 7 to 17 years old, with DSM-IV-TR diagnosis of Bipolar I Disorder, manic or mixed phase) will be invited to participate in this neuroimaging study. In order to ensure that participants remain blind to their drug status, all subjects will undergo 7Li MRS at weeks 2 and 8 of the efficacy trial. In addition, we will acquire proton (1H) MRS from the anterior cingulate cortex (ACC) at baseline and at 2 and 8 weeks to obtain measurements of myo-Inositol (Ino). All MRS examinations will be performed on 4.0 Tesla Varian/Inova. scanner. Serum lithium levels, YMRS, and Clinical Global Impression (CGI) will be obtained prior to the scan. Side effects will be measured using the Side Effects Form for Children and Adolescents and the UKU Side Effect Rating Scale. The goals of this project are to 1) Use 7Li MRS to obtain the brain-to-serum lithium ratio in children and adolescents to further define the serum lithium therapeutic range necessary to achieve lithium treatment response in an age dependent manner. 2) Use 7Li MRS to obtain the brain-to-serum lithium ratio in children and adolescents to further examine the serum lithium therapeutic range to minimize treatment emergent side effects in an age-dependent manner. 3) Use 1H MRS to examine the myo-Inositol depletion hypothesis of lithium efficacy in pediatric BPD. Our underlying hypothesis is that the brain-to-serum lithium ratio will increase with age. In addition, we hypothesize that higher Ino levels will be associated with mania, and positive responses to lithium treatment will be accompanied by decreased Ino levels. . Lithium is considered to be a first-line mood stabilizer for acute mania, hypomania, depression, and prevention of relapse in youth. However, it has not been adequately studied in pediatric samples; this shortcoming is currently being addressed through a multi-site trial under contract with NIH. We propose to use MRI-based methods to measure brain lithium levels in children and adolescents with bipolar disorder who are participating in that trial, making this the first study to evaluate the clinical significance of brain lithium levels in youths with BPD
Keywords: 0-11 years old; 17 year old; 21+ years old; Acute; Address; Adolescent; Adolescent Youth; Adult; Adverse effects; Affective Psychosis, Bipolar; Age; Analysis, Data; Anterior; Appointment; Bipolar Disorder; Blinded; Blood Serum; Body Tissues; Brain; Brain imaging; Child; Child Youth; Childhood; Children (0-21); Chiro-Inositol; Clinical; Clinical Trials, Phase I; Computer Programs; Computer software; Contracting Opportunities; Contracts; Data; Data Analyses; Development; Diagnosis; Disease; Disorder; Disorder, Manic; Doctor of Medicine; Doctor of Philosophy; Drugs; Early-Stage Clinical Trials; Encephalon; Encephalons; Enrollment; Ensure; Family; Funding; Goals; Grant; H+ element; HOSP; Health Alliance; Hospitals; Human, Adult; Human, Child; Hydrogen Ions; Image; Incidence; Inositol; Investigators; Li+ element; Lithium; M.D.; MR Spectroscopy; MRS; MRSI; Magnetic Resonance Spectroscopy; Manias; Manic; Manic Bipolar Affective Disorder; Manic Disorder; Manic State; Measurement; Measures; Medication; Medicine; Mesoinositol; Methods; Mood stabilizers; NIH; National Institutes of Health; National Institutes of Health (U.S.); Nervous System, Brain; PBO; Participant; Patients; Ph.D.; PhD; Pharmaceutic Preparations; Pharmaceutical Preparations; Phase; Phase 1 Clinical Trials; Phase I Clinical Trials; Phase I Study; Placebos; Prevention of relapse; Principal Investigator; Protocol; Protocols documentation; Protons; Psychosis, Manic-Depressive; Publications; R01 Mechanism; R01 Program; RPG; Recruitment Activity; Relative; Relative (related person); Research Grants; Research Personnel; Research Project Grants; Research Projects; Research Projects, R-Series; Researchers; SCHED; SUBGP; Safety; Sampling; Scanning; Schedule; Science of Medicine; Scientific Publication; Serum; Severities; Sham Treatment; Site; Software; Subgroup; Therapeutic; Time; Tissues; Toxic effect; Toxicities; Treatment Side Effects; United States National Institutes of Health; Youth; Youth 10-21; adult human (21+); age dependent; age related; base; bipolar affective disorder; bipolar depression manic phase; bipolar disorder manic phase; blind; brain visualization; children; cingulate cortex; clinical significance; clinically significant; collaborative trial; computer program/software; depression; disease/disorder; disorder later incidence prevention; double-blind placebo controlled trial; double-masked controlled study; double-masked controlled trial; drug/agent; efficacy trial; enroll; hypomania; imaging; impression; in vivo; juvenile; juvenile human; manic depressive disorder; manic depressive illness; multi-site trial; neuroimaging; neuron toxicity; neuronal toxicity; neurotoxicity; pediatric; phase 1 study; phase 1 trial; phase I trial; prevention of disease recurrence; prevention of disorder recurrence; prevention of later incidences of a disorder; prevention of recurrence; protocol, phase I; recruit; response; seventeen year old; sham therapy; side effect; therapy adverse effect; treatment adverse effect; treatment response; trial comparing; youngster
Project start date: 2008-10-22
Project end date: 2010-03-31
Budget start date: 1-APR-2009
Budget end date: 31-MAR-2010
PFA/PA: PA-06-181
5R21MH082335-03 (2009): $118276
Magnetic Resonance Spectroscopy In Affective Illness
Constance M Moore
Mc Lean Hospital (belmont, Ma) 115 Mill St Belmont, Ma 02478
Grant 5K01MH001978-05 from National Institute Of Mental Health IRG: ZRG1
Abstract: The specific aim of this application is to afford , a physicist, the opportunity to become an independent researcher applying magnetic resonance spectroscopy (MRS) in affective disorders. Two components are proposed to accomplish this formal academic training in psychology and neuroscience; and two research projects. There is an established literature that suggests the pathophysiology of affective illness may lie in irregularities in second messenger and signal transduction pathways; in particular the phosphatidylcholine (PtdCho) and phosphatidylinositol (PtdIno) cycles. Elements of the PthCho and PtdIno cycles are detectable using proton (1 H) and phosphorous (31 P) MRS, in particular choline containing compounds (Cho), myo-Inositol containing compounds (Ino), phosphomonoesters (PME), phosphodiesters (PDE) and the nucleotide triphosphates (NTPs). Over the five year course of the study 35 subjects with Major Depressive Disorder (MD), 35 subjects with Bipolar I Disorder (BD) and 20 comparison subjects (NC) will be recruited. A priori regions of interest are the anterior cingulate gyrus and the caudate nuclei since functional neuroimaging studies have noted mood state dependent alterations in metabolic activity in these regions and preliminary MRS data from these brain regions have demonstrated mood-state, medication, and diagnosis- dependent alterations in Cho, Ino, beta-NTP and PME. In the first two years of funding subjects will be examined using proton echo planar spectroscopic imaging (PEPSI) at 1.5 T. For the final three years of funding subjects will be examined using 1H decoupled 31P MRSI at 4.0 T. The use of PEPSI at 1.5 T and 1H decoupled 31P MRSI at 4.0 T will allow for the acquisition of spectra from smaller regions of interest, such as the anterior cingulate and the caudate, than is possible with older techniques. In addition, PEPSI affords a time advantage which allows for the absolute quantification of the metabolites detected. All subjects will be examined on two occasions six weeks apart and the following hypotheses will be tested Increased right cingulate cortex Cho will be associated with depression. A decrease in the left cingulate cortex Cho will occur as a result of antidepressant treatment. Decreased right cingulate cortex Ino will be associated with depression. Decreased caudate nucleus beta-NTP will be associated with depression. An increase in caudate nucleus PME will occur as a result of lithium treatment.
Keywords: antidepressant, bipolar depression, human therapy evaluation, major depression, mental disorder chemotherapy, mood disorder, neuroimaging, nuclear magnetic resonance spectroscopy, caudate nucleus, cingulate gyrus, ethanolamine, lithium, longitudinal human study, neuropsychology, nucleoside triphosphate, phosphatidylcholine, phosphoric ester, prognosis, behavioral /social science research tag, bioimaging /biomedical imaging, clinical research, human subject
Project start date: 2001-09-01
Project end date: 2006-07-31
5K01MH001978-05 (2005): $142655
5K01MH001978-04 (2004): $140067
5K01MH001978-03 (2003): $137554
1K01MH001978-01A1 (2001): $132226
GLUTAMINE AND GLUTAMATE IN CHILDREN AND ADOLESCENTS WITH BIPOLAR DISORDER
Constance M Moore
Univ Of Massachusetts Med Sch Worcester, Worcester, Ma 01655
Grant 7R01MH073998-03 from National Institute Of Mental Health
Abstract: Bipolar Disorder (BPD) may be as common among youths as it is among adults. The lifetime prevalence for Bipolar Disorder in adults ranges from 0.6% to 1.1%. Determining biological markers for mania in children with BPD is important in order to further our understanding of the underlying pathology of BPD in children. Significant glutamatergic dysfunction is associated with BPD, and many medications that are effective in the treatment of BPD may do so through engagement at various points in the glutamate neurotransmitter system. In addition, persuasive post-mortem evidence exists of frontal cortex glial and neuronal abnormalities in BPD. These abnormalities may be present in children with BPD. The aims of this study are to 1 establish an association between anterior cingulate cortex (ACC) glutamine and glutamate levels, and mania in children and adolescents with BPD; 2 investigate how the atypical antipsychotic risperidone interacts with ACC glutamine and glutamate in children and adolescents with BPD. We propose to study 60 unmedicated manic children and adolescents with BPD (Bipolar 1 Disorder, the narrow phenotype ; Young Mania Rating Scale (YMRS) > 15) before and after treatment with risperidone. In addition, 60 age and sex matched healthy comparison children (HCS) will participate. Glutamate and glutamine levels will be measured in the ACC and occipital cortex (OC) using Proton Magnetic Resonance Spectroscopy (1H MRS) at 4.0 T. A baseline MRS scan will be acquired from the unmedicated subjects with BPD prior to commencing risperidone treatment. Following 6 weeks of risperidone treatment the subjects with BPD will have a follow up 4.0 T MRS scan. The healthy comparison children will also have two MRS scans 6 weeks apart. Manic symptoms will be assessed prior to each MRS examination using the YMRS. We hypothesize that (a) the mania associated with pediatric BPD is a consequence of glutamatergic abnormalities manifested by reduced ACC glutamine and glutamate and; (b) risperidone will raise ACC glutamine and glutamate levels in children with BPD who are risperidone responders (a 30 % decrease in YMRS). Looking directly at the glutamine and glutamate resonances will allow the assessment of mania biochemically. This project will lay groundwork for further studies to test novel interventions that may be anti-manic agents and suitable for use in a pediatric population. We are proposing to use technology based on MRI to determine if brain frontal cortex levels of the amino acid glutamate, and its precursor glutamine, may be used as potential markers for pediatric mania. In addition, we will look at the effects of the atypical antipsychotic risperidone on glutamate, glutamine and mania in children with bipolar disorder. We believe this work will lay groundwork for further studies to test novel interventions that may be anti-manic agents and suitable for use in a pediatric population
Keywords: 0-11 years old; 16 year old; 21+ years old; 4H-Pyrido(1, 2-a)pyrimidin-4-one, 3-(2-(4-(6-fluoro-1, 2-benzisoxazol-3-yl)-1-piperidinyl)ethyl)-6 , 7, 8, 9-tetrahydro-2-methyl-; ANOVA; Active Follow-up; Adolescent; Adolescent Youth; Adult; Affective; Affective Psychosis, Bipolar; After Care; After-Treatment; Aftercare; Age; Amino Acids; Analysis of Variance; Anterior; Antidepressant Agent; Antidepressant Drugs; Antidepressants; Antidepressive Agents; Antipsychotic Agents; Antipsychotic Drugs; Antipsychotics; Biologic Marker; Biological Markers; Bipolar Disorder; Body Tissues; Brain; Child; Child Youth; Childhood; Children (0-21); Computer Programs; Computer software; Data; Development; Diagnosis; Disease; Disorder; Dose; Drug Delivery; Drug Delivery Systems; Drug Targeting; Drug Targetings; Drugs; Dysfunction; Encephalon; Encephalons; Evaluation; Functional disorder; Funding; Gln; Glutamates; Glutamine; H+ element; Human, Adult; Human, Child; Hydrogen Ions; Intervention; Intervention Strategies; Investigators; L-Glutamate; L-Glutamine; Linear Regressions; MR Imaging; MR Spectroscopy; MR Tomography; MRI; MRS; MRSI; Magnetic Resonance Imaging; Magnetic Resonance Imaging Scan; Magnetic Resonance Spectroscopy; Major Tranquilizers; Manias; Manic; Manic State; Measurement; Measures; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; Medication; Molecular Marker; Mood stabilizers; NMR Imaging; NMR Tomography; Nerve Cells; Nerve Transmitter Substances; Nerve Unit; Nervous System, Brain; Neural Cell; Neurocyte; Neuroleptic Agents; Neuroleptic Drugs; Neuroleptics; Neurons; Neurotransmitters; Nuclear Magnetic Resonance Imaging; Occipital lobe; Pathology; Pharmaceutic Preparations; Pharmaceutical Preparations; Phenotype; Physiologic pulse; Physiopathology; Population; Prevalence; Protons; Psychosis, Manic-Depressive; Pulse; Q. Levoglutamide; R01 Mechanism; R01 Program; RPG; Recruitment Activity; Regression Analyses; Regression Analysis; Regression Diagnostics; Research Grants; Research Personnel; Research Project Grants; Research Projects; Research Projects, R-Series; Researchers; Risperidone; Scanning; Signature Molecule; Software; Staging; Statistical Regression; Symptoms; System; System, LOINC Axis 4; Technology; Testing; Tissues; Tranquilizing Agents, Major; Variance Analyses; Work; Youth; Youth 10-21; Zeugmatography; adult human (21+); aminoacid; atypical antipsychotic; base; biomarker; bipolar affective disorder; childhood bipolar disorder; children; cingulate cortex; computer program/software; disease/disorder; drug/agent; follow-up; frontal cortex; frontal lobe; interventional strategy; juvenile; juvenile human; manic depressive disorder; manic depressive illness; meetings; neuronal; novel; occipital cortex; open label; pathophysiology; pediatric; recruit; resperidone; response; sex; sixteen year old; treatment response; youngster
Project start date: 2008-06-11
Project end date: 2013-03-31
Budget start date: 1-APR-2010
Budget end date: 31-MAR-2011
PFA/PA: PA-07-070
7R01MH073998-03 (2010): $346696
5R01MH073998-02 (2009): $284088
Constance M Moore
Univ Of Massachusetts Med Sch Worcester
Project start date: 2008-06-11
Project end date: 2013-03-31