Adolescent offspring of parents with bipolar disorder, particularly those with prominent depressive symptoms, have an elevated risk of developing mania, and by definition bipolar I disorder, compared with the general population. However, medications that are commonly used to treat depressive symptoms may accelerate the onset of mania or hypomania. Therefore, studies evaluating the efficacy, safety, and tolerability of potential treatments for depressive symptoms in adolescents with a bipolar parent are necessary, and may lead to early intervention, and ultimately prevention, strategies for incipient manic and hypomanic episodes. Preclinical and clinical evidence suggests that omega-3 fatty acid deficiency may represent a preventable risk factor for developing bipolar disorder. Indeed, findings from preliminary placebo-controlled trials indicate that omega-3 fatty acid supplementation reduces mood symptom severity in youth and adults with mood disorders. Additionally, postmortem studies reveal significant omega-3 fatty acid deficits in the prefrontal cortex of young bipolar patients. Recent neuroimaging studies indicate that symptoms of bipolar disorder may arise from dysfunction within the anterior limbic network, which includes the ventrolateral prefrontal and anterior cingulate cortices. Specifically, proton magnetic resonance spectroscopy (1H MRS) studies reveal that adolescents with and at high risk for developing bipolar disorder exhibit excessive glutamate and myo-inositol and decreased N- acetyl aspartate levels, suggesting that hypermetabolism may underlie the disruption in anterior limbic brain regions. These neurochemical changes may be useful biomarkers of treatment effects. With these considerations in mind, the goals of this study are: 1) To collect pilot data regarding the efficacy, safety, and tolerability of omega-3 fatty acid supplementation for the treatment of adolescents with active depressive symptoms and a high risk for developing mania (i.e. they have a bipolar parent and meet DSM-IV-TR criteria for major depressive disorder), and 2) To use 1H MRS (i.e. prefrontal neurochemistry) and red blood cell (RBC) omega-3 fatty acid levels to examine potential mediators of treatment response to omega-3 fatty acids in adolescents with a high risk for mania. To accomplish these aims, a total of 60 adolescents (ages 12-21 years) with active depressive symptoms and significant risk factors for developing mania will be randomized to treatment with omega-3 fatty acids or placebo for 12 weeks.
The aims of this application are consistent with those of the NIMH R34 grant mechanism;""""""""pilot testing of new or adapted interventions"""""""" and """"""""development of novel interventions to target specific risk factors for psychopathology or etiologic factors identified through neuroscience research"""""""". Additionally, the proposed study will capitalize on the infrastructure of the NIMH supported Center for Interventions Development and Applied Research (CIDAR) grant;the University of Cincinnati Bipolar Disorder Imaging and Treatment Research Center (BITREC, P50MH077138). Public Health Relevance: Evidence-based treatments are urgently needed for mood disorders in youth at high risk for developing bipolar disorder. This proposal will combine novel neuroimaging techniques with a placebo-controlled double-bind treatment trial in order to examine the neurophysiologic and therapeutic effects of chronic omega-3 fatty acid supplementation in adolescents at high risk for developing bipolar disorder, as an initial step to establish early intervention and prevention strategies.

Public Health Relevance

Evidence-based treatments are urgently needed for mood disorders in youth at high risk for developing bipolar disorder. This proposal will combine novel neuroimaging techniques with a placebo-controlled double-bind treatment trial in order to examine the neurophysiologic and therapeutic effects of chronic omega-3 fatty acid supplementation in adolescents at high risk for developing bipolar disorder, as an initial step to establish early intervention and prevention strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Planning Grant (R34)
Project #
5R34MH083924-03
Application #
8054292
Study Section
Interventions Committee for Disorders Involving Children and Their Families (ITVC)
Program Officer
Sarampote, Christopher S
Project Start
2009-06-15
Project End
2013-12-31
Budget Start
2011-04-01
Budget End
2013-12-31
Support Year
3
Fiscal Year
2011
Total Cost
$233,145
Indirect Cost
Name
University of Cincinnati
Department
Psychiatry
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Welge, Jeffrey A; Saliba, Lawrence J; Strawn, Jeffrey R et al. (2016) Neurofunctional Differences Among Youth With and at Varying Risk for Developing Mania. J Am Acad Child Adolesc Psychiatry 55:980-989
McNamara, Robert K; Jandacek, Ronald; Tso, Patrick et al. (2016) Adolescents with or at ultra-high risk for bipolar disorder exhibit erythrocyte docosahexaenoic acid and eicosapentaenoic acid deficits: a candidate prodromal risk biomarker. Early Interv Psychiatry 10:203-11
McNamara, Robert K; Moser, Ann B; Jones, Richard I et al. (2016) Familial risk for bipolar disorder is not associated with impaired peroxisomal function: Dissociation from docosahexaenoic acid deficits. Psychiatry Res 246:803-807
McNamara, Robert K; Jandacek, Ronald; Rider, Therese et al. (2016) Effects of fish oil supplementation on prefrontal metabolite concentrations in adolescents with major depressive disorder: a preliminary 1H MRS study. Nutr Neurosci 19:145-55
McNamara, Robert K; Jandacek, Ronald; Tso, Patrick et al. (2015) First-episode bipolar disorder is associated with erythrocyte membrane docosahexaenoic acid deficits: Dissociation from clinical response to lithium or quetiapine. Psychiatry Res 230:447-53
Strawn, Jeffrey R; Adler, Caleb M; McNamara, Robert K et al. (2014) Antidepressant tolerability in anxious and depressed youth at high risk for bipolar disorder: a prospective naturalistic treatment study. Bipolar Disord 16:523-30
Barzman, Drew; Eliassen, Jim; McNamara, Robert et al. (2014) Correlations of inflammatory gene pathways, corticolimbic functional activities, and aggression in pediatric bipolar disorder: a preliminary study. Psychiatry Res 224:107-11
McNamara, Robert K; Jandacek, Ronald; Tso, Patrick et al. (2013) Lower docosahexaenoic acid concentrations in the postmortem prefrontal cortex of adult depressed suicide victims compared with controls without cardiovascular disease. J Psychiatr Res 47:1187-91
Lotrich, Francis E; Sears, Barry; McNamara, Robert K (2013) Elevated ratio of arachidonic acid to long-chain omega-3 fatty acids predicts depression development following interferon-alpha treatment: relationship with interleukin-6. Brain Behav Immun 31:48-53
Lotrich, Francis E; Sears, Barry; McNamara, Robert K (2013) Anger induced by interferon-alpha is moderated by ratio of arachidonic acid to omega-3 fatty acids. J Psychosom Res 75:475-83

Showing the most recent 10 out of 25 publications