Omega-3 Polyunsaturated Fatty Acid Deficiency and Progressive Neuropathology in Psychiatric Disorders: A Review of Translational Evidence and Candidate Mechanisms

Abstract

Meta-analytic evidence indicates that mood and psychotic disorders are associated with both omega-3 polyunsaturated fatty acid (omega-3 PUFA) deficits and progressive regional gray and white matter pathology. Although the association between omega-3 PUFA insufficiency and progressive neuropathological processes remains speculative, evidence from translational research suggests that omega-3 PUFA insufficiency may represent a plausible and modifiable risk factor for not only enduring neurodevelopmental abnormalities in brain structure and function, but also for increased vulnerability to neurodegenerative processes. Recent evidence from human neuroimaging studies suggests that lower omega-3 PUFA intake/status is associated with accelerated gray matter atrophy in healthy middle-aged and elderly adults, particularly in brain regions consistently implicated in mood and psychotic disorders including the prefrontal cortex, hippocampus, amygdala, anterior cingulate, and temporal cortex. Human neuroimaging evidence also suggests that both low omega-3 PUFA intake/status and psychiatric disorders are associated with reductions in white matter microstructural integrity and increased rates of white matter hyperintensities. Preliminary evidence suggests that increasing omega-3 PUFA status is protective against gray matter atrophy and deficits in white matter microstructural integrity in patients with mood and psychotic disorders. Plausible mechanisms mediating this relationship include elevated pro-inflammatory signaling, increased synaptic regression, and reductions in cerebral perfusion. Together these associations encourage additional neuroimaging research to directly investigate whether increasing omega-3 PUFA status can mitigate neuropathological processes in patients with or at high-risk for psychiatric disorders.

INTRODUCTION

Neuropsychiatric disorders, including major depressive disorder (MDD), bipolar disorder, and schizophrenia, are associated with significant psychosocial and cognitive impairment, and excess premature mortality attributable to increased rates of suicide and cardiovascular disease.^1–5 The onset of mood and psychotic disorders frequently initially occurs during adolescence and young adulthood,^6–9 a period associated with cortical circuit maturation involving increases in synaptic pruning and myelination.^10–15 However, the initial onset can also occur in late-adulthood and the prevalence of psychiatric symptoms including psychosis increase in elderly patients with dementia and Alzheimer’s disease.^16,17 Over the past three decades, magnetic resonance imaging (MRI) has been used extensively to investigate central pathological processes associated with mood and psychotic disorders, and recent meta-analyses provide strong evidence that these disorders are associated with progressive gray and white matter pathology.

Meta-analyses of cross-sectional structural MRI studies indicate that MDD is associated with reduced total gray and white matter volumes, and reduced gray matter volumes in the hippocampus, amygdala, and anterior cingulate.^18–20 Meta-analyses indicate that bipolar I disorder is associated with reduced anterior cingulate and inferior frontal gyrus gray matter volumes,²¹ and that children and adolescents, but not adults, with bipolar I disorder exhibit smaller amygdala volumes.²² Prospective and longitudinal and cross-sectional structural imaging studies further suggest that bipolar I disorder is associated with an accelerated loss in frontal gray matter volume compared with healthy subjects.^23,24 Moreover, meta-analyses indicate that schizophrenia is characterized by progressive gray matter atrophy particularly in the superior temporal gyrus,^25–28 and reductions in hippocampus and whole brain volumes are observed in first-episode patients.^29,30 Additionally, white matter volume reductions are observed in first-episode patients with schizophrenia and bipolar disorder,³¹ as are increased rates of deep white matter hyperintensities (WMH).^32,33 Meta-analyses of cross-sectional diffusion tensor imaging studies indicate widespread reductions in cortical white matter microstructural integrity in patients with first-episode schizophrenia,³⁴ bipolar disorder,³⁵ and MDD.³⁶ Extant meta-analytic evidence therefore suggests that psychiatric disorders are associated with overlapping as well as unique structural and microstructural neuropathological features which are apparent early in the illness course and prior to long-term exposure to psychotropic medications.

Despite this body of evidence, however, etiopathogenic mechanisms contributing to progressive structural pathology remain poorly understood. A growing and converging body of translational evidence suggests that omega-3 polyunsaturated fatty acids (PUFA) play a central role in normal brain development and resilience to insult, and that mood and psychotic disorders are associated with omega-3 PUFA deficits. Until recently, the majority of evidence for a role of omega-3 PUFA in brain development, resilience, and degeneration has come from animal studies. However, several neuroimaging studies have emerged recently which offer new insight into the role of omega-3 PUFA intake or biostatus in human brain structure and function. This review will provide a brief overview of omega-3 PUFAs and evidence for an association between omega-3 PUFA insufficiency and neuropsychiatric disorders, will then review evidence from human neuroimaging and animal studies implicating omega-3 PUFA in neurodevelopmental and neurodegenerative processes, and will then discuss candidate mediating mechanisms and clinical implications.

METHODS

Relevant peer-reviewed articles published up to November 2017 were identified using PubMed and the following search terms: “omega-3”, “DHA”, “PUFA”, “MRI”, “DTI”, “PET”, “SPECT”, “NIRS”, “structural,” “rat”, “non-human primate”, “brain”, and/or “psychiatry.” Additional relevant articles were selected from the bibliographies of identified papers. Articles were excluded if they were not peer-reviewed, were written in a language other than English, and/or did not specifically investigate relationships between PUFA measures and relevant brain outcomes. A total of 260 relevant articles were identified that met inclusion criteria. When available meta-analyses were used in order to provide a systematic synthesis of different studies.

PUFA BACKGROUND

The PUFA family includes omega-3 and omega-6 fatty acids. Flaxseed, linseed, canola, soy, and perilla oils are primary dietary sources of the short-chain omega-3 PUFA α-linolenic acid, and safflower, soy, and corn oils are primary sources of the short-chain omega-6 fatty acid linoleic acid. Because mammals cannot endogenously synthesize these short-chain PUFAs, they are considered ‘essential’ and necessitate procurement through the diet. Long-chain omega-3 PUFAs, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and long-chain omega-6 PUFAs, including arachidonic acid (AA), are biosynthesized from short-chain precursors by common microsomal desaturation and elongation reactions,³⁷ and peroxisomal enzymes catalyze the biosynthesis of DHA.³⁸ While nucleotide sequence polymorphisms^39,40 and epigenetic (i.e., DNA methylation) modifications⁴¹ have been observed in desaturase and peroxisomal genes, it is estimated that only one quarter of the variability in EPA and DHA levels can be attributed to heritable factors.⁴² Moreover, in healthy human subjects the biosynthesis of long-chain omega-3 and omega-6 PUFA from short-chain fatty acid precursors is limited.^43–46 Accordingly, dietary intake of preformed omega-3 PUFA, e.g., from fatty cold water fish, and omega-6 PUFA, e.g., from animal-based foods including beef, chicken, and eggs, is significantly more effective for increasing peripheral and central tissue DHA and AA levels.^44,47–51 Therefore, fish and seafood, as well as dietary fish oil supplements, are the primary dietary source of preformed EPA+DHA (hence forth: omega-3 PUFA) in humans. Because omega-3 and omega-6 PUFAs compete for incorporation onto tissue phospholipids, a reduction in dietary omega-3 PUFA intake is associated with systemic increases in the omega-6/omega-3 ratio (e.g., AA/EPA+DHA ratio).

OMEGA-3 PUFA AND PSYCHIATRIC DISORDERS

Cross-national epidemiological studies have observed a significant inverse relationship between lifetime prevalence rates of MDD^52,53 and bipolar spectrum disorders⁵⁴ and per capita fish or seafood consumption. A recent meta-analysis of cross-sectional and prospective observational studies indicate that higher fish or omega-3 PUFA intake is associated with reduced risk of depression in the general population.⁵⁵ The lifetime prevalence rates of schizophrenia are not associated with per capita fish or seafood consumption,⁵⁴ and there is conflicting evidence regarding whether higher fish or seafood consumption is associated better functional outcomes.^53,56 Although these findings provide general support for an inverse association between fish or omega-3 PUFA intake and mood disorders, cultural, socioeconomic, and/or genetic variables may also contribute to this association. It is also relevant that the omega-3 PUFA content in different types of fish and seafood varies widely, and fish and seafood also contain other potentially therapeutically-relevant substances including vitamin D and selenium.

A more objective and targeted approach is to investigate omega-3 PUFA levels in blood and tissues as an index of ‘biostatus’. For example, habitual dietary fish intake frequency^57,58 and fish oil supplementation dose⁵⁹ are positively and linearly correlated with erythrocyte (red blood cell) phospholipid membrane omega-3 PUFA (EPA+DHA) levels. Meta-analytic evidence from fourteen cross-sectional studies indicates that patients with MDD exhibit significant blood (plasma, erythrocyte) deficits in EPA and DHA, but not AA or total omega-6 fatty acids.⁶⁰ Similarly, cross-sectional studies indicate that patients with bipolar I disorder exhibit significant erythrocyte deficits in DHA, and to a lesser extent EPA, and no differences in the omega-6 PUFAs linoleic acid or AA.⁶¹ Meta-analyses also indicate that schizophrenia is associated with lower blood DHA and/or EPA levels as well as deficits in the omega-6 PUFA AA.⁶² Robust erythrocyte DHA deficits have also been observed in first-episode schizophrenia⁶² and bipolar disorder⁶³ patients, as well as adolescents at ultra-high risk for developing bipolar I disorder⁶⁵ i.e., they have MDD and a biological parent with bipolar I disorder.^64,66 These findings suggest that low omega-3 PUFA biostatus coincides with the initial onset of mood and psychotic symptoms and may be associated with symptom progression in high-risk youth.

A recent prospective longitudinal study further suggests that low omega-3 PUFA biostatus increases risk for the initial onset of mood symptoms. A 7-year prospective study found that lower erythrocyte omega-3 PUFA levels and a higher omega-6/omega-3 ratio at baseline were significant predictors for developing a mood disorder at follow-up in youth at high-risk for psychosis.⁶⁷ Prospective studies have similarly found that lower baseline DHA levels, or a higher AA/EPA+DHA ratio, predict the emergence of MDD in initially non-depressed hepatitis C patients during treatment with pro-inflammatory interferon-α (IFN-α).^68,69 Additionally, the emergence of anger and irritability, core symptoms of bipolar I disorder, are also predicted by a higher baseline AA/EPA+DHA ratio in hepatitis C patients during IFN-α treatment.⁷⁰ These prospective findings therefore suggest that low omega-3 PUFA biostatus increases vulnerability to inflammation-induced as well as endogenous mood dysregulation.

While the omega-3 PUFA deficits observed in patients with mood and psychotic disorders may be due to different factors, extant evidence indicates that supplementing the diet with omega-3 PUFAs is sufficient to increase blood and presumably brain omega-3 PUFA levels.^71–73 Additionally, some meta-analyses of controlled trials,^74–76 but not all, ⁷⁷ have found that omega-3 PUFA supplementation is superior to placebo for reducing depressive symptoms in patients with MDD, and may additionally have antidepressant efficacy in patients with bipolar disorder.^75,78 Preliminary trials have also reported significant reductions in depression and manic symptom severity in pediatric and adolescent patients following omega-3 PUFA supplementation.^71–73 Omega-3 PUFA supplementation was also found to be protective against the initial onset of depressive symptoms in hepatitis C patients being treated with the pro-inflammatory cytokine IFN-α,⁷⁹ and greater antidepressant efficacy is observed following omega-3 PUFA supplementation in MDD patients with higher pro-inflammatory biomarkers.⁸⁰ Additional evidence suggests that omega-3 PUFA supplementation reduces positive and negative symptom severity in early stage schizophrenic patients.⁸¹ In general, these findings suggest that increasing omega-3 PUFA intake reduces mood and psychotic symptoms and that early intervention may additionally reduce vulnerability to the initial onset of symptoms.

In mammalian brain gray matter, DHA is the most abundant omega-3 PUFA whereas other omega-3 PUFA comprise a small fraction of total brain fatty acid composition.⁸² Under steady-state dietary conditions, mammalian erythrocyte and cortical gray matter DHA levels are positively correlated,⁸³ and DHA levels increase gradually in both erythrocyte and cortical gray matter following dietary omega-3 PUFA supplementation.⁴⁸ However, cross-sectional postmortem studies investigating the fatty acid composition of regional gray matter from patients with mood and psychotic disorders have yielded inconsistent results, with some studies^84–89 but not others^90–96 finding lower omega-3 PUFA levels in patients. It is important to note, however, that the postmortem approach has several limitations including a lack of information regarding habitual dietary omega-3 PUFA intake, omega-3 PUFA deficits in non-psychiatric ‘controls’ dying from cardiovascular disease,⁸⁸ and translational evidence that psychotropic medications impact brain fatty acid turnover⁹⁷ and composition.^86,87,98 These and other limitations have prompted the use of alternative methods including neuroimaging to delineate associations between omega-3 PUFA and neuropathological processes in human brain.

HUMAN NEUROIMAGING FINDINGS

Recently several neuroimaging studies have investigated the role of omega-3 PUFA dietary intake or biostatus in human brain structure and function. Because low omega-3 PUFA intake/status has also been implicated in the pathophysiology of age-related cognitive decline and dementia,^99–101 the majority of these studies were conducted in healthy middle-aged or elderly adults without psychiatric illness. Findings from these studies provide important insight into progressive age-related brain changes that are not confounded by psychotropic medications which may contribute to or ameliorate brain structural abnormalities in psychiatric patients.^102–107 The results of these studies have been reviewed in detail previously¹⁰⁸ and key findings are summarized below.

Different cross-sectional and prospective longitudinal MRI studies of healthy elderly subjects have found that greater dietary fish intake frequency and/or biostatus are associated with slower gray matter atrophy over time and greater global gray matter volumes and larger anterior cingulate, hippocampus, and amygdala gray matter volumes.^109–117 However, a placebo-controlled trial found that 72-week supplementation with algal DHA did not significantly alter total brain or hippocampal volume atrophy rates in participants with mild to moderate Alzheimer disease.¹¹⁸ While the majority of cross-sectional and prospective studies did not observe an association between omega-3 PUFA intake and/or biostatus and global white matter volume, some cross-sectional and prospective longitudinal MRI studies found that greater omega-3 PUFA intake and/or biostatus were associated with reduced rates of white matter hyperintensity (WMH) in healthy elderly subjects.^{109,119–123} Moreover, a 26-week controlled fish oil supplementation trial observed significant increases in white matter microstructural integrity in several white matter tracts of healthy older adults.¹²⁵ A subset of studies also observed a positive association among blood DHA and/or EPA levels, gray matter volumes, and performance on cognitive tests of executive function.^109,117,125

These neuroimaging findings highlight several notable parallels with neuroimaging findings in psychiatric patients. Specifically, reduced hippocampus, amygdala, and anterior cingulate gray matter volumes are among the most consistent structural abnormalities observed in patients with MDD,^18–20 and lower omega-3 PUFA intake and/or biostatus are associated with smaller hippocampal, amygdala, and anterior cingulate volumes in healthy middle-aged and elderly adults.^112–114 Moreover, a prospective study found that lower baseline plasma EPA levels were associated with faster right hippocampus and amygdala gray matter atrophy in healthy elderly adults,¹¹⁵ and a controlled trial found that 26-week fish oil supplementation attenuated decreases in gray matter volume in the left hippocampus of healthy older adults.¹²⁵ It is also notable that schizophrenia is associated with accelerated deficits in the superior temporal gyrus gray matter volume,^27,28 and a 3.6-year prospective study found that lower whole blood DHA levels were associated with greater baseline-endpoint cortical thinning in the superior temporal gyrus of healthy elderly subjects.¹¹⁶ Additionally, a controlled trial found that 26-week supplementation with fish oil attenuated decreases in superior temporal gyrus gray matter volume in healthy older adults.¹²⁵ As discussed, reductions in cortical white matter microstructural integrity are observed in several white matter tracts of patients with schizophrenia,³⁴ bipolar disorder,³⁵ and MDD,³⁶ and a controlled trial found that 26-week fish oil supplementation significantly increased white matter microstructural integrity in the same white matter tracts of healthy older adults.¹²⁵

While these findings suggest that the omega-3 PUFA deficits and progressive neuropathological processes observed in patients with mood and psychotic disorders may be linked, there have been comparably fewer neuroimaging studies that have directly evaluated this relationship in patients with psychiatric disorders. A recent placebo-controlled trial found that 26-week adjunctive fish oil supplementation significantly attenuated reductions in cortical thickness in the parieto-occipital regions of first-episode antipsychotic-treated schizophrenia patients.¹²⁶ An open-label 6-week fish oil supplementation study using diffusion tensor imaging found that the resulting increase in plasma phospholipid DHA levels were associated with increased white matter integrity in the corpus callosum, cingulum, and bilateral anterior corona radiate of MDD patients.¹²⁷ Importantly, fish oil supplementation also reduced depression symptom severity which was associated with increases in white matter integrity in left corticospinal tract and superior longitudinal fasciculus. While limited, these preliminary findings corroborate prior findings indicating an association between omega-3 PUFA intake and/or biostatus and gray matter atrophy and white matter microstructural integrity in elderly adults and may therefore be mediated by common mechanisms.

ANIMAL STUDIES

There now exists an extensive body of evidence from rodent and non-human primate studies regarding the effects of omega-3 PUFA insufficiency and enrichment on brain maturation, resilience, degeneration. In rodents, omega-3 PUFA insufficiency during development causes delays in neurogenesis and neuroblast migration,^128–131 and reduces nerve growth factor and brain-derived neurotrophic factor (BDNF) expression,^132,133 synaptogenesis and plasticity,¹³⁴ forebrain white matter microstructural integrity,¹³⁵ and astrocyte-mediated glucose uptake and metabolism.^136–138 Although developmental omega-3 PUFA insufficiency is not associated with enduring gross neuronal lamination abnormalities or neuronal loss in the adult rat cortex,¹³⁹ enduring reductions in neuronal size have been observed in the rat hippocampus.¹⁴⁰ Moreover, omega-3 PUFA insufficiency is associated with an enduring dysregulation in serotonin,^141,142 acetylcholine,¹⁴³ glutamate,^134,144,145 and mesolimbic and mesocortical dopamine neurotransmission.^146–148 Omega-3 PUFA insufficiency is associated with elevated behavioral indices of depression and aggression,¹⁴⁹ abnormalities in dopamine-mediated behavior,^150,151 and impaired learning across are variety of different tasks.^152–158 Evidence from rodent studies therefore suggests that omega-3 PUFA insufficiency during development leads to enduring abnormalities in brain chemistry and function.

In contrast, omega-3 PUFA enrichment increases dendritic spine density,^159–161 increases frontal cortex dopamine levels,¹⁶² and is protective against age-related neurodegenerative processes¹⁶³ and associated reductions in hippocampus and prefrontal cortex volumes.¹⁶⁴ Omega-3 PUFA enrichment also increases neuronal and white matter resilience to degeneration resulting from inflammation,^165–167 lipid peroxidation,^168,169 glutamate excitotoxicity,^170–172 and cerebral ischemia.^173,174 Similar to antidepressant medications, dietary fish oil supplementation significantly reduces depression-like behavior in the forced swimming test,^175–177 and combining fish oil with fluoxetine reduces depression-like behavior to a greater extent that fluoxetine alone.^177,178 These finding suggest that omega-3 PUFA enrichment increases neuronal and white matter resilience, mitigates age-related neurodegenerative processes, and produces robust antidepressant-like effects in rodents.

In non-human primates maintained on standardized laboratory diets, developmental omega-3 PUFA insufficiency is associated with deficits in visual attention¹⁷⁹ and increased home cage activity and agitation.¹⁸⁰ A neuroimaging study found that developmental omega-3 PUFA insufficiency impaired resting-state functional connectivity among prefrontal cortical networks in adult monkeys compared with omega-3 PUFA enrichment.¹⁸¹ Omega-3 PUFA enrichment was also found to correct age-related deficits in cerebral blood flow in somatosensory cortex in response to tactile stimulation,¹⁸² and resting state cerebral glucose uptake and metabolism.¹⁸³ These findings provide additional evidence that omega-3 PUFA insufficiency is associated with a range of neurodevelopmental abnormalities as well as reduced resilience in the non-human primate brain.

CANDIDATE MEDIATING MECHANISMS

Although evidence from human neuroimaging and animal studies suggest that omega-3 PUFA insufficiency is associated with accelerated gray matter atrophy and reductions in white matter microstructural integrity, it is not currently known whether this is a direct effect or if there are mediating mechanisms. Below we briefly review translational evidence for plausible mechanisms that could mediate the association between omega-3 PUFA insufficiency and neuropathological processes in psychiatric disorders, including elevated inflammation, synaptic regression, and deficits in cerebral perfusion and glucose utilization (Figure 1).

Figure 1.

Diagram illustrating candidate mediators of the association between omega-3 PUFA deficiency and central pathological features observed in patients with mood and psychotic disorders.

Inflammation

Meta-analytic evidence indicates that patients with MDD,¹⁸⁴ bipolar disorder,¹⁸⁵ and schizophrenia¹⁸⁶ exhibit elevated pro-inflammatory cytokine levels. Neuroimaging evidence suggests that higher pro-inflammatory cytokine or C-reactive protein levels are associated with white matter microstructural integrity deficits,^187,188 smaller hippocampus and temporal lobe gray matter volumes,^189–194 elevated prefrontal and anterior cingulate activity,^195,196 and decreased functional connectivity.^195,197 It is relevant, therefore, that metabolites of omega-6 PUFAs including AA (i.e., prostaglandins and thromboxanes) and omega-3 PUFAs including EPA and DHA (i.e., D- and E-series resolvins) serve as precursors for immune-inflammatory modulators and in general have opposing effects on pro-inflammatory signaling processes.^198–202 Accordingly, omega-3 PUFA insufficiency increases constitutive peripheral and central pro-inflammatory processes,^203–206 and augment lipopolysaccharide-induced pro-inflammatory cytokine production.²⁰⁷ Conversely, omega-3 PUFA enrichment attenuates inflammation-induced elevations in brain pro-inflammatory cytokines, oxidative stress, and apoptosis,^208–210 and is protective against inflammation-induced white matter,^165,167 dendritic spine regression,²¹¹ and hippocampal neuronal degeneration.¹⁶⁶ Therefore, neuropathological processes associated with omega-3 PUFA insufficiency may be mediated in part by increases in, or impaired resolution of, pro-inflammatory signaling activity.

Synaptic regression

Postmortem studies have observed reduced dendritic spine density and synaptic markers in the prefrontal cortex of patients with mood or psychotic disorders.^212–220 In the absence of evidence for gross neuronal cell loss, this reduction in neuropil likely contributes to reductions in prefrontal cortex gray matter volume observed in patients with psychiatric disorders.²²¹ It is relevant, therefore, that omega-3 and omega-6 PUFAs have opposing effects on second messenger signaling pathways that regulate synaptic plasticity and stability.²²² Specifically, DHA inhibits, and arachidonic activates, protein kinase C (PKC) activity.^223–226 Importantly, PKC hyperactivity has been implicated in dendritic spine loss in the prefrontal cortex in response to chronic stress,²²⁷ and is associated with age-related prefrontal cortex dendritic atrophy and working memory impairment.²²⁸ PKC-mediated phosphorylation of substrate proteins, including myristoylated alanine-rich C kinase substrate (MARCKS) which cross-links actin filaments in a phosphorylation-reversible manner,²²⁹ markedly decreases dendritic spine formation and stability.²³⁰ Consistent with an inhibitory effect of DHA on PKC-induced dendritic instability, higher brain DHA levels are associated with elevated dendritic spine density^159–161 and is protective against inflammation-induced dendritic spine regression,²¹¹ whereas perinatal deficits in DHA accrual are associated with synaptic regression or agenesis.¹³⁴ Together, these findings suggest that the association between omega-3 PUFA insufficiency and gray matter volume deficits, and potentially functional connectivity deficits,¹⁸¹ may be mediated in part by elevations in PKC-mediated synaptic regression.

It is also noteworthy that PKC activity is elevated in postmortem frontal cortex of patients with bipolar disorder,²³¹ and that chronic lithium treatment decreases PKC activity²³² and increases in prefrontal cortex gray matter volume in patients with bipolar disorder.¹⁰⁷ Lithium is also protective against stress-induced dendritic remodeling²³³ and NMDA-induced dendritic spine collapse.²³⁴ Moreover, chronic antidepressant treatment mitigates stress-induced spine synapse loss,²³⁵ and ketamine, an NMDA receptor antagonist and rapid-acting antidepressant, increases spine synapse number in the prefrontal cortex of rodents and reverses the effects of chronic stress.²³⁶ These findings suggest that the antidepressant effects associated with omega-3 PUFA supplementation may also be mediated in part by preventing synaptic regression.

Cerebral perfusion and glucose utilization

Evidence from PET and SPECT studies indicate regional reductions in cerebral blood flow and glucose metabolism in the anterior cingulate and subregions of the prefrontal cortex of patients with MDD^237–242 and schizophrenia,²⁴³ and emerging translational evidence suggests that omega-3 PUFA regulates both cerebral blood flow and cerebral glucose uptake and metabolism. A cross-sectional PET study found that regional cerebral blood flow was positively correlated with DHA incorporation in a small group of healthy adult subjects.²⁴⁴ Several near-infrared spectroscopy studies have observed a positive association between omega-3 PUFA intake/status and cerebral blood flow in human subjects.^245–249 A SPECT study found that higher erythrocyte EPA+DHA levels were associated with greater cerebral perfusion in the right parahippocampal gyrus, right precuneus, and vermis in a cohort of middle-aged subjects with mixed diagnoses of depression, anxiety disorders, and ADHD.²⁵⁰ Plausible mechanisms by which omega-3 PUFA may promote cerebral blood flow include decreasing blood viscosity by reducing blood platelet aggregation²⁵¹ and blood triglyceride levels.²⁵² This is supported in part by findings that patients with MDD exhibit increased blood viscosity²⁴² and neuroimaging studies finding an inverse association between triglyceride levels and cerebral blood flow.^253,254 Additionally or alternatively, omega-3 PUFA may promote cerebral blood flow by attenuating platelet thromboxane A2 production which has vasoconstriction effects.^255–257

Regarding glucose uptake and metabolism, developmental omega-3 PUFA insufficiency impairs astrocyte-mediated glucose uptake and metabolism in rat brain.^136–138 A non-human primate study found that omega-3 PUFA enrichment increases resting state cerebral glucose uptake and metabolism.¹⁸³ In a cohort of healthy middle-aged adults, a nutrient pattern associated with higher omega-3 PUFA intake from fish was associated with greater glucose metabolism in the bilateral prefrontal cortex.²⁵⁸ However, a preliminary 3-week fish oil supplementation study did not observe alterations in glucose metabolism in the anterior cingulate, prefrontal cortex, or hippocampus of healthy young or elderly adults.²⁵⁹ In adult medication-free MDD patients, plasma DHA levels were negatively correlated with resting glucose metabolism in the anterior cingulate and prefrontal cortex, and positively correlated in the temporoparietal cortex.²⁶⁰ Alterations in astrocyte-mediated neurovascular coupling represents one plausible mechanism by which omega-3 PUFA could modulate cortical glucose uptake and metabolism.^{136–138,182}

CLINICAL IMPLICATIONS

The reviewed evidence suggests that omega-3 PUFA deficiency may contribute to progressive pathological processes in brain regions repeatedly implicated in psychopathology. Therefore, correcting omega-3 PUFA deficiency in patients with or at high-risk for developing psychiatric disorders may represent a plausible strategy to increase neuronal and white matter resilience. While it is not currently clear whether correcting omega-3 PUFA deficiency can ‘reverse’ regional brain pathology, existing evidence suggests that it can optimize neurodevelopmental processes as well as mitigate progressive neurodegenerative processes. Therefore, intervention prior to the onset of symptoms in high-risk youth or early in the course of illness (e.g., first-episode) may offer the greatest benefit. Importantly, omega-3 PUFA supplementation is safe and well-tolerated making it ideally suited for early intervention. Moreover, the Food and Drug Administration has approved and regulates several prescription fish oil formulations for the treatment of hypertriglyceridemia, and considers omega-3 PUFA doses up to 3 g/d to be ‘generally regarded as safe’. The American Psychiatric Association has adopted the consensus recommendations of the American Heart Association for an EPA+DHA dose of 1 g/d in patients with MDD.²⁶¹ It is also notable that standardized blood screening protocols now exist for determining omega-3 PUFA biostatus, and pilot studies have demonstrated the feasibility of routine blood omega-3 PUFA screening in psychiatric patients in clinic settings.^262,263 Therefore, early detection and treatment of omega-3 PUFA deficiency is currently feasible and may represent an urgently needed approach to mitigate progressive pathological brain changes in patients with or at high-risk for psychiatric disorders.

CONCLUSIONS

There is now strong evidence derived from meta-analyses that mood and psychotic disorders are associated with both omega-3 PUFA insufficiency and progressive regional gray and white matter pathology. Although the association between omega-3 PUFA insufficiency and progressive neuropathological processes in mood and psychotic disorders remains speculative, evidence from translational research suggests that omega-3 PUFA insufficiency may represent a plausible and modifiable risk factor for not only enduring neurodevelopmental abnormalities, but also for increased vulnerability to neurodegenerative processes in brain regions consistently implicated in mood and psychotic disorders. Moreover, low omega-3 PUFA intake/status is associated with reductions in white matter pathology, and early evidence suggests that increasing omega-3 PUFA status is protective against gray matter atrophy and white matter pathology in patients with mood and psychotic disorders. Animal studies additionally suggest that omega-3 PUFA insufficiency during developmental leads to enduring abnormalities in brain chemistry and function, and that omega-3 PUFA enrichment increases neuronal and white matter resilience and is protective against age-related neurodegenerative processes. Plausible mechanisms that could mediate the association between omega-3 PUFA insufficiency and neurodegenerative processes include elevated pro-inflammatory signaling, synaptic regression or agenesis, and reductions in cerebral perfusion and glucose uptake. Together these associations encourage additional neuroimaging research to directly investigate whether increasing omega-3 PUFA status can prevent or reverse central pathological processes in patients with or at high-risk for psychiatric disorders.