A look into the promising benefits of omega-3 in the treatment of Bipolar Disorder…
Omega-3s and BDNF
Omega-3s are polyunsaturated fatty acids that serve many vital functions to the human body- improving cardiac function, decreasing inflammation, and mental health benefits- improving mild depressive symptoms, increasing cognitive function, and reducing the risk of dementia. There are three types of omega-3s: ALA, EPA, and DHA. DHA has the greatest effects on cell membranes, neuronal firing and survival, and nerve impulse transmission. Humans accumulate the most amount of DHA inutero, but the greatest period of synthesizing ALA to DHA is during the young developing years (Balanza-Martinez et al., 2011). Diet is the best source to maintain omega-3 levels throughout adulthood, specifically foods like salmon, sardines, fish oils, walnuts, flaxseeds, and soybeans. Unbalanced intake of omega-3s can exacerbate inflammatory states, chronic diseases, and mental health problems.
Omega-3s play various important roles at the molecular level in the brain. They increase the supply of oxygen and glucose to the brain, protect against oxidative stress, improve neurotransmitter-receptor binding, normalize dopamine levels in the frontal cortex, prevent excessive neuronal apoptosis, and promote BDNF expression. Additionally, adequate intake of omega-3s assists in proper function of the BDNF/tyrosine kinase receptor B (Balanza-Martinez et al., 2011). This receptor is vital in the signaling pathway and expression of BDNF in the brain. Omega-3s have been found to normalize levels of BDNF in the hippocampus (Wu, Ying, & Gomez-Pinilla, 2004). One study demonstrated a correlation between low DHA and reduced BDNF expression in the hippocampus and the PFC (Levant et al., 2008). Likewise, data shows that higher levels of serum omega-3s are associated with greater BDNF expression.
BDNF and Bipolar Disorder
Brain-derived neurotrophic factor (BDNF) is a neuroprotective growth factor protein that plays many vital roles in the human brain. BDNF, which is synthesized from the transcription factor CREB, is involved in neuronal survival, neuron differentiation, dendritic branching, and synaptic plasticity (Balanza-Martinez et al., 2011). Increased BDNF expression is found in the cerebral cortex and hippocampus- areas involved with functions like memory and emotions. BDNF has plays a key role in long term potentiation, which is the process of strengthening the connections between neurons. The expression of adequate BDNF in the brain is a vital component to healthy neurocognitive processes.
There is a vast amount of data implicating BDNF, through various mechanisms, in the pathophysiology of bipolar disorder (BD). Various studies have found an association between low levels of BDNF and BD diagnoses. Levels tend to be lowest in BD patients during acute depressive episodes or acute manic episodes (Tramontina et al., 2009). During remission of symptoms, BDNF levels are higher than they were during the acute episodes of symptoms. Serum levels of BDNF are negatively correlated with length of illness (Kauer-Sant’Anna et al., 2009), such that the lower the levels of BDNF in BD patients, the longer the course of their illness. Those patients with a higher frequency of manic episodes present with lower levels of BDNF over time. One study found a genetic abnormality that occurs at the codon 66 in the BDNF gene (McIntosh et al., 2007). This allele can be found in healthy adults, but in BD patients they display a smaller temporal lobe- important for sensory information processing.
Many of the pharmacological treatments for BD, such as mood stabilizers and antidepressants, increase BDNF levels by increasing the activity of CREB- the transcription factor for BDNF. Interestingly enough, omega-3s play a similar role to that of mood stabilizers and antidepressants, such that omega-3s also increase the activity of CREB (Basselin et al., 2010).
Omega-3s and Bipolar Disorder
Omega-3s offer a wide array of psychiatric benefits: improving stress response, decreasing isolation, reducing aggression, and improving dopamine function. Across studies, patients with depressive symptoms, whether MDD or BD depression, present with lower serum levels of omega-3s, and omega-3s are actually inversely correlated with severity of the mood dysregulation symptoms (Balanza-Martinez et al., 2011). Recent research in the field of BD has been looking at correlations between the illness and omega-3s in order to advance, not only the knowledge of BD pathophysiology, but also to advance the health maintenance and treatment possibilities for these patients. The data is minimal, but it is promising.
Postmortem studies of patients with BD have shown decreased serum levels of omega-3s and decreased DHA levels in various brain tissues, specifically the OFC (McNamara et al., 2008). These postmortem brains, with decreased DHA levels, presented with cell membrane abnormalities in the gray and white matter, and we know that omega-3s assist with fatty acid composition of cell membranes.
Various ecological studies have been conducted to zone in on diet and consumption of omega-3s related to BD prevalence. A study conducted across ten countries found that lower per capita fish consumption was correlated with higher rates of BD (Hibbeln, 2002). An inverse relationship was found between high fish intake and rates of MDD and postpartum depression. Additionally, those who consumed fish at least twice per week were less likely to report depressive symptoms.
Knowing the inverse relationship between omega-3s and BD prevalence, a pioneer prophylaxis trial was completed, where over the course of four months some patients received adjunctive therapy with high dose fish oil and others received a placebo (Stoll et al., 1999). The fish oil group had longer remissions and vastly greater improvements in their BD symptoms and overall functioning. Positive effects were largely found for their bipolar depressive symptoms, with no positive effect for their manic symptoms. In another trial, researchers looked at the effects of giving different concentrations of omega-3s (1g/day vs 2g/day) to patients with BD (Frangou, Lewis, & McCrone, 2006). Both doses improved global bipolar symptoms and depressive symptoms, but no decrease in manic symptoms. Also, a dose effect was not observed. In a small study with female BD patients, omega-3s were given as an adjunct, and these patients showed increased neuronal density and integrity, which protected them against excitatory apoptosis (implicated in the pathophysiology of BD) (Frangou, Lewis, Wollard, & Simmons, 2007). Lastly, a study was conducted in youth with BD and they were given omega-3s as adjunctive therapy. Results suggest that omega-3s in youth may in fact reduce bipolar depressive symptoms, bipolar irritability, and bipolar manic symptoms (Clayton et al., 2009). Even more interesting, some youth in this trial were given DHA as a monotherapy, and they too showed modest improvements over eight weeks.
Prescription for Omega-3s?
The role of omega-3s in BD is a growing field of research, and the area does call for larger studies. We know that deficient intake of omega-3s is implicated in BD, even though the exact reason is not clear- whether it is due to its relationship to BDNF expression or not. Omega-3s have been more successful in treating bipolar depressive symptoms in adults, rather than mania symptoms, but some benefits in youth mania have been identified. Of great interest, is the fact that omega-3s share similar mechanisms of actions to drugs used to treat BD.
We mustn’t ignore the valuable information in front of us. Low levels of omega-3s have been associated with a higher prevalence of BD. Diets high in omega-3s and high serum omega-3 levels are associated with decreases in BD symptoms. Omega-3s are proven to increase BDNF expression in the brain, and patients with BD have decreased levels of BDNF. Prophylactic and adjunctive use of omega-3s in patients with BD has shown positive results in symptomology. With this in mind, we as providers working with patients with BD, should counsel our patients on the potential benefits of taking a fish oil supplement or adopting a high Omega-3 diet.
Balanza-Martinez, V., Fries, G.R., Colpo, G.D., Silveira, P.P., Portella, A.K. Tabares- Seisdedos, R., et al. (2011). Therapeutic use of omega-3 fatty acids in bipolar disorder. Expert Review of Neurotherapy, 11(7), 1029-1047. doi: 10.1586/ern.11.42.
Basselin, M., Kim, H.W., Chen, M., et al. (2010). Lithium modifies brain arachidonic and docosahexaenoic metabolism in rat lipopolysaccharide model of neuroinflammation. J Lipid=Research, 51(5), 1049–1056. doi: 10.1194/jlr.M002469
Clayton, E.H., Hanstock, T.L., Hirneth, S.J., Kable, C.J., Garg, M.L., & Hazell, P.L. (2009). Reduced mania and depression in juvenile bipolar disorder associated with long-chain omega-3 polyunsaturated fatty acid supplementation. European Journal of Clinical Nutrition, 63(8), 1037-1040. doi: 10.1038/ejcn.2008.81.
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Kauer-Sant’Anna, M., Kapczinski, F., Andreazza, A.C., et al. (2009). Brain-derived neurotrophic factor and inflammatory markers in patients with early-vs. late-stage bipolar disorder. International Journal of Neuropsychopharmacology, 12(4), 447–458. doi: 10.1017/S1461145708009310.
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McIntosh, A.M., Moorhead, T.W., McKirdy, J., et al. (2007).Temporal grey matter reductions in bipolar disorder are associated with the BDNF Val66Met polymorphism. Molecular Psychiatry,12(10), 902–903. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/17895927
McNamara, R.K., Jandacek, R., Rider, T., et al. (2008). Deficits in docosahexaenoic acid and associated elevations in the metabolism of arachidonic acid and saturated fatty acids in the postmortem orbitofrontal cortex of patients with bipolar disorder. Psychiatry Research, 160(3), 285–299. doi: 10.1016/j.psychres.2007.08.021
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Tramontina, J.F., Andreazza, A.C., Kauer-Sant’Anna, M., et al. (2009). Brain-derived neurotrophic factor serum levels before and after treatment for acute mania. Neuroscience Letters, 452(2), 111–113. doi: 10.1016/j.neulet.2009.01.028
Wu, A., Ying, Z., & Gomez-Pinilla, F. (2004). Dietary omega-3 fatty acids normalize BDNF levels, reduce oxidative damage, and counteract learning disability after traumatic brain injury in rats. Journal of Neurotrauma, 21, 1457–1467. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/15672635