The initial onset of mania, and by definition bipolar I disorder, most frequently occurs during childhood and adolescence. Bipolar disorder is associated with significant psychosocial morbidity as well as increased rates of obesity, metabolic syndrome, and associated cardiovascular risk factors, and outcomes data indicate excess premature mortality attributable in part to cardiometabolic-related disorders. Although second generation antipsychotic (SGA) medications are efficacious for the treatment of acute mania in bipolar youth, they frequently lead to excessive weight gain and obesity and precipitate and/or exacerbate cardiometabolic risk factors including elevated triglyceride levels. This is a significant concern because SGA-induced cardiometabolic symptoms and weight gain increase risk of treatment discontinuation and relapse, more frequent suicide attempts, and poses substantial long-term health risks in adulthood. There is therefore an urgent and unmet public health need to identify modifiable risk and protective factors for SGA-induced cardiometabolic symptoms and weight gain in pediatric and adolescent bipolar patients to guide ameliorative and preventative strategies. Emerging translational evidence suggests that long-chain omega-3 (LCn-3) fatty acid deficiency exhibited by first-episode adolescent manic patients may represent a modifiable risk factor for SGA-induced cardiometabolic symptoms and weight gain. Recent evidence also suggests that stearoyl-CoA desaturase, a lipogenic enzyme implicated in hypertriglyceridemia, insulin resistance, and obesity, may mediate the detrimental effects of SGA medications as well as the beneficial effects of LCn-3 fatty acids. We believe that extant evidence and our preliminary data supports the hypothesis that low LCn-3 fatty acid status is a modifiable risk factor for SGA-induced weight gain and cardiometabolic risk in pediatric and adolescent bipolar patients. Moreover, we hypothesize that SGA-induced weight gain and cardiometabolic risk are mediated through elevations in stearoyl-CoA desaturase activity, and that increasing LCn-3 fatty acids status through dietary supplementation will attenuate the progression of cardiometabolic symptoms and weight gain by reducing stearoyl-CoA desaturase activity. To evaluate these hypotheses, we propose a two-phase study design to first prospectively evaluate LCn-3 fatty acid status as a risk factor for the emergence of SGA-induced weight gain and cardiometabolic symptoms in first-episode bipolar youth (Phase I), and a 24-week randomized placebo-controlled double-blind LCn-3 fatty acid intervention trial to determine whether increasing LCn-3 fatty acid status can attenuate the progression of cardiometabolic symptoms and weight gain in SGA-treated patients (Phase II). It is anticipated that the data generated by this study will provide novel prospective evidence that low LCn-3 fatty acid status is a modifiable risk factor for SGA-induced adverse cardiometabolic effects and weight gain in adolescent bipolar patients in support of future large-scale primary prevention studies.

Public Health Relevance

Although second generation antipsychotic (SGA) medications are efficacious for the treatment of acute mania in children and adolescents, they frequently precipitate and/or exacerbate adverse cardiometabolic symptoms and lead to weight gain and obesity. Convergent translational evidence suggests that long-chain omega-3 fatty acid deficiency exhibited by first-episode adolescent manic patients may represent a modifiable risk factor for SGA-induced metabolic dysregulation through opposing effects on stearoyl-CoA desaturase. Here we propose to prospectively evaluate whether low long-chain omega-3 fatty acid status increases risk for SGA-induced adverse cardiometabolic symptoms and weight gain in first-episode bipolar adolescents (Phase I), and determine whether increasing long-chain omega-3 fatty acid status has protective effects in a controlled intervention trial (Phase II).

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK097599-02
Application #
8677887
Study Section
Clinical and Integrative Diabetes and Obesity Study Section (CIDO)
Program Officer
Malozowski, Saul N
Project Start
2013-07-01
Project End
2018-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Cincinnati
Department
Psychiatry
Type
Schools of Medicine
DUNS #
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
McNamara, Robert K; Asch, Ruth H; Schurdak, Jennifer D et al. (2017) Glutamate homeostasis in the adult rat prefrontal cortex is altered by cortical docosahexaenoic acid accrual during adolescence: An in vivo1H MRS study. Psychiatry Res 270:39-45
Messamore, Erik; Almeida, Daniel M; Jandacek, Ronald J et al. (2017) Polyunsaturated fatty acids and recurrent mood disorders: Phenomenology, mechanisms, and clinical application. Prog Lipid Res 66:1-13
McNamara, Robert K; Szeszko, Philip R; Smesny, Stefan et al. (2017) Polyunsaturated fatty acid biostatus, phospholipase A2 activity and brain white matter microstructure across adolescence. Neuroscience 343:423-433
Lindquist, Diana M; Asch, Ruth H; Schurdak, Jennifer D et al. (2017) Effects of dietary-induced alterations in rat brain docosahexaenoic acid accrual on phospholipid metabolism and mitochondrial bioenergetics: An in vivo31P MRS study. J Psychiatr Res 95:143-146
McNamara, Robert K; Asch, Ruth H; Lindquist, Diana M et al. (2017) Role of polyunsaturated fatty acids in human brain structure and function across the lifespan: An update on neuroimaging findings. Prostaglandins Leukot Essent Fatty Acids :
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
Messamore, Erik; McNamara, Robert K (2016) Detection and treatment of omega-3 fatty acid deficiency in psychiatric practice: Rationale and implementation. Lipids Health Dis 15:25
McNamara, Robert K; Welge, Jeffrey A (2016) Meta-analysis of erythrocyte polyunsaturated fatty acid biostatus in bipolar disorder. Bipolar Disord 18:300-6
Lotrich, Francis E; Sears, Barry; McNamara, Robert K (2016) Polyunsaturated fatty acids moderate the effect of poor sleep on depression risk. Prostaglandins Leukot Essent Fatty Acids 106:19-25
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

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