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.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Developmental Brain Disorders Study Section (DBD)
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Grabb, Margaret C
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University of Massachusetts Medical School Worcester
Schools of Medicine
United States
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Atag√ľn, M I; ??ko?lu, E M; Can, S S et al. (2015) Investigation of Heschl's gyrus and planum temporale in patients with schizophrenia and bipolar disorder: a proton magnetic resonance spectroscopy study. Schizophr Res 161:202-9
Liso Navarro, Ana A; Sikoglu, Elif M; Heinze, Cailin R et al. (2014) Effect of diet on brain metabolites and behavior in spontaneously hypertensive rats. Behav Brain Res 270:240-7
Czerniak, Suzanne M; Sikoglu, Elif M; King, Jean A et al. (2013) Areas of the brain modulated by single-dose methylphenidate treatment in youth with ADHD during task-based fMRI: a systematic review. Harv Rev Psychiatry 21:151-62
Deligiannidis, Kristina M; Sikoglu, Elif M; Shaffer, Scott A et al. (2013) GABAergic neuroactive steroids and resting-state functional connectivity in postpartum depression: a preliminary study. J Psychiatr Res 47:816-28
Gonenc, Atilla; Frazier, Jean A; Crowley, David J et al. (2010) Combined diffusion tensor imaging and transverse relaxometry in early-onset bipolar disorder. J Am Acad Child Adolesc Psychiatry 49:1260-8