Major Depressive Disorder Treatment Looks to Role of Lipids

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Up to 30% of patients with major depressive disorder (MDD) do not respond to antidepressant medication, and other patients show only a partial response.
Up to 30% of patients with major depressive disorder (MDD) do not respond to antidepressant medication, and other patients show only a partial response.

Up to 30% of patients with major depressive disorder (MDD) do not respond to antidepressant medication, while other patients show only a partial response, underscoring the need for effective treatment alternatives for MDD.1 Rather than looking toward novel pharmacologic therapies, however, increasing evidence suggests that dietary lipids may be a worthy focus. A growing body of research highlights the role of lipids in mental health in general and MDD specifically.

“We know that a large portion of the brain is composed of lipids, and that the ratio of these different lipids can have a significant impact on brain function,” said Robert K. McNamara, PhD, a professor of psychiatry and neuroscience and director of the Lipidomics Research Program at the University of Cincinnati College of Medicine, who has investigated the topic extensively. “This is particularly important during early development when the brain is undergoing rapid growth and tightly synchronized changes in neural connections,” he told Psychiatry Advisor.

The Evidence

Findings from a wide range of studies especially support a link between MDD and omega-3 polyunsaturated fatty acids (PUFAs) in particular. Rodent studies have found that maternal deficiency in docosahexaenoic acid (DHA) leads to DHA deficiency in the fetal brain.2 DHA is the most abundant omega-3 fatty acid in the brain, and unresolved deficiencies may result in long-term impairment in serotonergic and dopaminergic neurotransmission.3

“It is also known that young women with MDD and of childbearing potential exhibit very low blood levels of DHA — lower than women without MDD,” said Dr McNamara. This suggests that DHA deficiency would also be observed in the infants of these women, and that it may contribute to the familial transmission of MDD and other psychiatric disorders.

In addition, it is known that DHA “has neuroprotective actions —meaning that lower brain levels increase risk for neurodegeneration in response to stressor or toxins —  well as neurotrophic actions, which promote neuron development and connectivity,” Dr McNamara explained. “Additionally, we now know that DHA has anti-inflammatory effects, and brain inflammation is thought to contribute, at least in part, to the pathophysiology of MDD.”

Findings from both animal and clinical research have linked reduced inflammation with DHA supplementation. In a rodent study, for instance, supplementation was associated with a reduction in hippocampal inflammation.4 In a randomized controlled trial (RCT) published in 2015, DHA supplementation decreased systemic inflammation in obese pregnant women.5

Results of other studies show protective effects of omega-3 fatty acids in various inflammatory conditions such as rheumatoid arthritis, coronary heart disease, and Crohn disease.6,7 Their anti-inflammatory actions “are based on their ability to decrease the production of pro-inflammatory cytokines and eicosanoids by several tissues and cells,” according to the investigators in the 2015 RCT. “Diets that are rich in [omega-6] fatty acids produce eicosanoids, whereas a diet with a more balanced intake of [omega-6] and [omega-3] fatty acids makes less inflammatory and less immunosuppressive eicosanoids.”

In fact, it has been proposed that the steady increase in MDD rates in the United States could be at least partially due to the dietary shift away from omega-3 consumption in favor of greater omega-6 consumption. This change has been driven primarily by the >1000-fold increase in the estimated per capita consumption of soybean oil in the United States during the 20th century.8 It has been estimated that the ratio of omega-3 fatty acids to omega-6 fatty acids in Western diets is approximately 25:1, although 3:1 is the recommended ratio.

It has further been demonstrated that countries with populations with a high intake of dietary DHA have a lower prevalence of MDD. One such country is Japan, where the estimated lifetime prevalence of MDD ranges from 3% to 7% vs 16% in the United States.9,10

Clinical Implications

With evidence pointing to their role in depressive disorders, it seems logical that testing levels of omega-3 fatty acids such as DHA and eicosapentaenoic acid (EPA) could provide insight into a patient's MDD risk and potential treatment strategies. A recent review advocates for the use of peripheral biomarkers — including omega-3 and omega-6 fatty acids, cholesterol, and possibly others — to guide diagnosis and treatment of MDD.1

“Analogous to routine cholesterol testing in the field of cardiology, which is intended to alert the physician and patient of a ‘risk factor' for coronary heart disease, the balance of evidence now suggests that measuring a patient's blood EPA [eicosapentaenoic acid] and DHA [docosahexaenoic acid] levels is indicated not only in the field of psychiatry but also other areas of medicine,” according to Dr McNamara. EPA and DHA deficiencies can be easily corrected with fish oil supplementation, and the American Psychiatric Association now recommends EPA+DHA supplementation of 1 g/d for patients with MDD.11

“The recent emergence of laboratory facilities that perform standardized blood EPA and DHA testing, and the availability [of] over-the-counter and prescription omega-3 fatty acid formulations, provide the necessary infrastructure to implement routine EPA+DHA screening and corrective supplementation in psychiatric practice,” he noted.12 However, it is still unclear whether increasing DHA intake can reverse or reduce related brain abnormalities or long-established depressive symptoms.

Future Directions

Research in this area is ongoing, including neuroimaging research in Dr McNamara's program regarding the influence of DHA intake on brain health across the lifespan in animals and humans. Another research focus is the potential for early intervention with omega-3 fatty acids to delay or prevent the onset of psychiatric symptoms in youth with an elevated risk of psychiatric illness — for example, due to family history.

Although omega-3 fatty acids are safe and well-tolerated, the “real future challenge, from my perspective, is integrating diet and nutrition into psychiatric practice, which has become largely dominated by a secondary prevention, pharmacological treatment approach,” said Dr McNamara.

References

  1. Parekh A, Smeeth D, Milner Y, Thuret S. The role of lipid biomarkers in major depression. Healthcare (Basel). 2017;5(1):5. doi:10.3390/healthcare5010005
  2. Mulder KA, King DJ, Innis SM. Omega-3 fatty acid deficiency in infants before birth identified using a randomized trial of maternal dha supplementation in pregnancy. PLoS ONE. 2014;9(1):e83764. doi:10.1371/journal.pone.0083764
  3. Sinclair AJ, Begg D, Mathai M, Weisinger RS. Omega 3 fatty acids and the brain: review of studies in depression. Asia Pac J Clin Nutr. 2007;16(1):391-397.
  4. Thomas J, Garg ML, Smith DW. Dietary supplementation with resveratrol and/or docosahexaenoic acid alters hippocampal gene expression in adult C57Bl/6 mice. J Nutr Biochem. 2013;24(10:1735-1740. doi:10.1016/j.jnutbio.2013.03.002
  5. Haghiac M, Yang X-h, Presley L, et al. Dietary omega-3 fatty acid supplementation reduces inflammation in obese pregnant women: a randomized double-blind controlled clinical trial. PLoS ONE. 2015;10(9): e0137309. doi:10.1371/journal.pone.0137309
  6. Calder PC. n-3 polyunsaturated fatty acids, inflammation, and inflammatory diseases. Am J Clin Nutr. 2006; 83(6):1505S-1519S.
  7. Kromhout D. Omega- fatty acids and coronary heart disease. The final verdict? Curr Opin Lipidol. 2012;23(6):554-559. doi:10.1097/MOL.0b013e328359515f
  8. Blasbalg TL, Hibbeln JR, Ramsden CE, Majchrzak SF, Rawlings RR. Changes in consumption of omega-3 and omega-6 fatty acids in the United States during the 20th century. Am J Clin Nutr. 2011;93(5):950-962. doi:10.3945/ajcn.110.006643 
  9. Kawakami N. Epidemiology of depressive disorders in Japan and the world. Nihon Rinsho. 2007;65(9):1578-1584.
  10. Centers for Disease Control and Prevention (CDC). Mental illness surveillance among adults in the United States. Morbidity and Mortality Weekly Report (MMWR). 2011;60(03):1-32.
  11. Freeman MP, Hibbeln JR, Wisner KL, et al. Omega-3 fatty acids: evidence basis for treatment and future research in psychiatry. J Clin Psychiatry. 2006;67(12):1954-1967.
  12. 12.   McNamara RK, Strawn JR. Role of long-chain omega-3 fatty acids in psychiatric practice. PharmaNutrition. 2013;1(2):41-49. doi:10.1016/j.phanu.2012.10.004

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