Mood disorders, including major depressive disorder, bipolar disorder and anxiety disorders are among the most common psychiatric disorders and are a major cause of disability globally.1 These disorders are associated with psychosocial impairment and excess premature mortality attributable to suicide and cardiovascular-related disorders.2,3,4 Once established, these disorders are typically treated with medications that often have undesirable side-effects and limited long-term efficacy.5,6,7 Medication discontinuation frequently leads to symptomatic relapse suggesting that a secondary prevention approach is sub-optimal and does not correct underlying pathophysiology mechanisms. Therefore, developing a clearer understanding of modifiable risk factors associated with the initial development of mood/anxiety dysregulation may offer new opportunities to intervene prior to illness onset, i.e., primary prevention.
Consistent with a neurodevelopmental etiology, mood and anxiety disorders frequently initially emerge in childhood and adolescence. Importantly, this development period is associated with robust changes in the functional and structural maturation of corticolimbic circuitry known to play a key role in regulating mood and anxiety.8,9 Indeed, compelling neuroimaging evidence indicates that mood and anxiety disorders are associated with abnormal corticolimbic circuit connectivity.10,11,12 Therefore, identifying safe and effective interventions to optimize corticolimbic circuit maturation may represent a plausible strategy to mitigate emotional dysregulation in youth.
A growing body of evidence has identified a deficiency in omega-3 polyunsaturated fatty acids (PUFAs), including docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), as a candidate for a modifiable neurodevelopmental risk for mood and anxiety disorders. This is supported in part by cross-sectional evidence that patients with mood and anxiety disorders exhibit significantly lower blood omega-3 PUFA levels compared with healthy subjects.13,14,15 Importantly, lower blood omega-3 PUFA levels are also observed in first-episode adolescent patients indicating that omega-3 PUFA insufficiency coincides with, and likely precedes, the initial onset of illness.16 Although controversial, controlled intervention trials further suggest that increasing omega-3 PUFA biostatus reduce mood and anxiety symptoms after the disorder has become established.17,18 These and other findings support a potential role of omega-3 PUFA insufficiency in the etiology of mood and anxiety disorders. However, the role of omega-3 PUFAs in corticolimbic circuit maturation is currently poorly understood.
Evidence from animal studies demonstrate that brain DHA levels progressively increase over the course of perinatal development and accumulate in synaptic membranes.19,20 Recent evidence suggests that deficits in perinatal DHA accrual impairs synaptogenesis and synaptic plasticity, as well as synaptic pruning, indicating a potential role in circuit maturation.21,22,23 Like humans, rodent corticolimbic circuitry undergoes substantial maturational changes during adolescent development,24 and deficits in perinatal DHA accrual are associated with elevated behavioral indices of anxiety and depression.25,26 A non-human primate study found that developmental omega-3 PUFA insufficiency reduced resting-state functional connectivity in corticolimbic networks in adulthood.27 Human preterm birth, which reduces fetal DHA accrual, is associated with enduring functional connectivity abnormalities in corticolimbic networks as well as increased risk for mood and anxiety disorders in childhood and adolescence.28,29 While these associations support a potential link between developmental omega-3 PUFA insufficiency, corticolimbic circuit maturation abnormalities, and mood and anxiety disorders, additional research is needed to formally evaluate this mechanism.
Ongoing translational research using different neuroimaging techniques is investigating the relationship between omega-3 PUFA biostatus and corticolimbic circuit connectivity in youth with or at high-risk for mood and anxiety disorders and in rat developmental models. It is anticipated that this research will clarify the role of omega-3 PUFAs in the structural and functional maturation of corticolimbic circuitry, and thereby provide an empirical foundation in support of omega-3 PUFA intervention as a primary prevention strategy to mitigate emotional dysregulation in youth.
Robert K. McNamara, Ph.D., is a professor of psychiatry and neuroscience at the University of Cincinnati College of Medicine.
- Whiteford H et al. “Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010.” Lancet. 2013;382:1575-1586.
- Osby U et al. “Excess mortality in bipolar and unipolar disorder in Sweden.” Arch Gen Psychiatry. 2001;58:844-850.
- Roest A et al. “Anxiety and risk of incident coronary heart disease: a meta-analysis.” J Am Coll Cardiol. 2010;56:38-46.
- Too L et al. “The association between mental disorders and suicide: A systematic review and meta-analysis of record linkage studies.” J Affect Disord. 2019;259:302-313.
- Correll C et al. “Cardiometabolic risk of second-generation antipsychotic medications during first-time use in children and adolescents.” JAMA. 2009;302:1765-1773.
- Hammad T, Laughren T, Racoosin J. “Suicidality in pediatric patients treated with antidepressant drugs. Arch Gen Psychiatry. 2006;63:332-339.
- Martin A et al. “Age effects on antidepressant-induced manic conversion.” Arch Pediatr Adolesc Med. 2004;158:773-780.
- Gee D et al. “A developmental shift from positive to negative connectivity in human amygdala-prefrontal circuitry.” J Neurosci. 2013;33:4584-4593.
- Wu M et al. “Age-related changes in amygdala-frontal connectivity during emotional face processing from childhood into young adulthood.” Hum Brain Mapp. 2016;37:1684-1695.
- Kaiser R et al. “Large-scale network dysfunction in major depressive disorder: A meta-analysis of resting-state functional connectivity.” JAMA Psychiatry. 2015;72:603-611.
- Roy A et al. “Intrinsic functional connectivity of amygdala-based networks in adolescent generalized anxiety disorder.” J Am Acad Child Adolesc Psychiatry. 2013;52:290-299.
- Wang F et al. “Functional and structural connectivity between the perigenual anterior cingulate and amygdala in bipolar disorder.” Biol Psychiatry. 2009;66:516-521.
- Green P et al. “Red cell membrane omega-3 fatty acids are decreased in nondepressed patients with social anxiety disorder.” Eur Neuropsychopharmacol. 2006;16:107-1
- Lin PY, Huang SY, Su KP. A meta-analytic review of polyunsaturated fatty acid compositions in patients with depression. Biol Psychiatry. 2010;68:140-147.
- McNamara R, Welge J. “Meta-analysis of erythrocyte polyunsaturated fatty acid biostatus in bipolar disorder.” Bipolar Disord. 2016;18:300-306.
- McNamara R et al. “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. 2016;10:203-211.
- Grosso G et al. “Role of omega-3 fatty acids in the treatment of depressive disorders: a comprehensive meta-analysis of randomized clinical trials.” PLoS One. 2014;9(5):e96905.
- Su K et al. “Association of use of omega-3 polyunsaturated fatty acids with changes in severity of anxiety symptoms: A systematic review and meta-analysis.” JAMA Netw Open. 2018;1(5):e182327.
- Green P, Yavin E. “Fatty acid composition of late embryonic and early postnatal rat brain.” Lipids. 1996;31:859-865.
- Suzuki H et al. “Rapid incorporation of docosahexaenoic acid from dietary sources into brain microsomal, synaptosomal and mitochondrial membranes in adult mice.” Int J Vitam Nutr Res. 1997;67:272-278.
- Cao D et al. “Docosahexaenoic acid promotes hippocampal neuronal development and synaptic function.” J Neurochem. 2009;111:510-5
- de Velasco P et al. “Nutritional restriction of omega-3 fatty acids alters topographical fine tuning and leads to a delay in the critical period in the rodent visual system.” Exp Neurol. 2012;234:220-229.
- Carbone B et al. “Synaptic connectivity and cortical maturation are promoted by the ω-3 fatty acid docosahexaenoic acid.” Cereb Cortex. 2019.
- Cressman V et al. “Prefrontal cortical inputs to the basal amygdala undergo pruning during late adolescence in the rat.” J Comp Neurol. 2010;518:2693-2709.
- Weiser M et al. “Dietary DHA during development affects depression-like behaviors and biomarkers that emerge after puberty in adolescent rats.” J Lipid Res. 2015;56:151-166.
- Chen H, Su H. “Exposure to a maternal n-3 fatty acid-deficient diet during brain development provokes excessive hypothalamic-pituitary-adrenal axis responses to stress and behavioral indices of depression and anxiety in male rat offspring later in life.” J Nutr Biochem. 2013;24:70-80.
- Grayson D et al. “Dietary omega-3 fatty acids modulate large-scale systems organization in the rhesus macaque brain.” J Neurosci. 2014;34:2065-2074.
- Rogers C et al. “Aberrant structural and functional connectivity and neurodevelopmental impairment in preterm children.” J Neurodev Disord. 2018;10:38.
- Burnett A et al. “Prevalence of psychiatric diagnoses in preterm and full-term children, adolescents and young adults: a meta-analysis.” Psychol Med. 2011;41:2463-2474.