Brain on Fire Dr. Erin Wiley 1 July 2013 Brain on Fire - Connection between Inflammation and Depression By: Erin Wiley HBHSC, ND Integrative Health Institute 46 Sherbourne St at King St. – Second Floor Toronto, ON. M5A 2P7 www.integrativehealthinstitute.ca firstname.lastname@example.org Jump to: Part 1 Part 2 Part 3Part 4 Part I: the Connection between Inflammation and Depression North America is suffering from an epidemic of chronic inflammatory disease, caused by changes in our food supply, diet, and lifestyle. While you may be very familiar with joint or muscle inflammation, or with inflammatory diseases such as diabetes, heart disease and arthritis, you may not realize that we experience inflammation in our brain, or that when we look at the biochemistry behind depression, inflammation is considered a major contributing factor. Therefore, the North American inflammation epidemic could contribute to a dramatic increase in depression and mental illness. Inflammatory markers are directly correlated with body fat percentage, waist circumference and insulin insensitivity.(1) The populations most at risk include those with metabolic syndrome and those with type II diabetes.(1) Approximately 59% of Canadian adults are overweight or obese and a growing number of our children are becoming obese. If current trends continue, by 2040 it is estimated that 70% of adults over the age of 40 will be overweight or obese.(2) A population trending towards an obesity epidemic is a population suffering from inflammation. That population is also physiologically at greater risk for developing depression. An appropriate inflammatory response is when the body attacks foreign bacteria, a virus or damaged cells as a method of protection. An inappropriate response is when the inflammation becomes chronic and the immune system attacks and damages its own cells, including brain tissue! As a mechanism of action for depression, inflammation decreases 5-HTP, increases glutamate, causes microglia cells to release neurotoxic substances that damage brain tissue and lowers the number of astrocytes, thus decreasing the brain’s ability to protect and repair itself.(3) This creates an environment of increasing damage and decreased repair of brain tissue, which promotes depression. The good news is that it is within our ability to promote an anti-inflammatory lifestyle, which can help prevent and treat depression. This four-part article will consider three main areas of influence. Part I is an overview of the connection between inflammation and depression. In Part II, we will look at lifestyle components such as nutrition, exercise, and stress reduction. In Part III, we will explore key foundational nutrients such as fish oil and probiotics that decrease inflammation. Finally, in Part IV we will look at supplements such as anti-oxidants and Nrf2 activators that repair cellular damage and activate the genes in our body that regulate the production of antioxidants, regulate the production of detoxification enzymes, and promote signaling in the body that down-regulates factors that promote inflammation. Exploring the inflammatory mechanisms behind depression give us a powerful opportunity to promote healthy lifestyle change and decrease the rates of depression in our population. An integrative approach also gives individuals suffering with depression the opportunity to explore a synergy of treatment options or choose the ones that are best suited to their level of readiness for lifestyle change. Under the supervision of a licensed Naturopathic Doctor, many of these treatment options are well suited to be used in conjunction with standard medical treatments for depression, such as cognitive behavioral therapy and anti-depressant medications. References 1. Festa, A, D’Agostino R, Howard G, Mykkanen L, Tracey R, Haffner S, Chronic Subclinical Inflammation as Part of the Insulin Resistance Syndrome. Circulation. 2000;102:42-47 2. Statistics Canada, Canadian Community Health Survey, 2009, 2010. 3. McNally L, Bhagwagar Z, Hannestand J. Inflammation, Glutamate, and Glia in Depression: A Literature Review. CNS Spectr. 2008;13(6):501-510 Brain on Fire - Connection between Inflammation and Depression Part II: Lifestyle influences on inflammation and depression by: Erin Wiley HBHSC, ND Integrative Health Institute 46 Sherbourne St at King St. – Second Floor Toronto, ON. M5A 2P7 www.integrativehealthinstitute.ca email@example.com Our environment is largely responsible for the degree to which we experience inflammation. The high carbohydrate diet, which is high in saturated fats and low in nutrient dense foods such as vegetables, fruit and whole grain fiber, is directly linked to inflammatory disease(1) A high stress and sedentary lifestyle dominated by technology with limited exercise and “activities of daily living” promotes inflammatory hormones and poor body composition. The result is inflammation. While the task of decreasing inflammation may seem insurmountable under these circumstances, your Naturopathic doctor can help you develop a lifestyle modification plan that is simple to follow and has many health benefits. Let’s start by taking a look at nutrition. Our diet lays the foundation for either promoting or reducing inflammation. The one of the biggest contributing factors to inflammation in or diet is sugar. The average Canadian consumes over 23.1 kg of sugar per year. Sugar can be found in high concentration in many hidden places from cereal to white bread, bagels, pasta, potatoes, rice, candy, and processed foods. In contrast, low carbohydrate diets such as the Paleo diet and Ketogenic (2,3) diet are associated with a reduction in inflammation. Similarly, healthy dietary fats such as coconut oil and olive oil have been show to have ant-inflammatory properties while saturated animal fats and hydrogenated or chemically-modified fats promote inflammation(2,3) Thus, consuming a low carbohydrate diet that is rich in healthy fats is a great place to start. The brain-gut connection is also something that needs to be considered. Our immune system is in direct communication with our digestive system, scanning for foreign invaders and ready to mount an inflammatory response. If we chronically expose ourselves to foods or allergens that irritate our digestive-immune system we will promote inflammation.(4) Our brains are sensitive to this inflammation, which is why many individuals report improvement in their mental health when they remove food sensitivities from their diet.(5) Your naturopathic doctor can teach you how to identify and eliminate your food sensitivities. Exercise or simply moving your body has powerful anti-inflammatory effects. Research has shown that exercise is an effective treatment for mild to moderate depression.(6) In Japan the practice of “shinrin-yoku” meaning forest bathing has demonstrated a huge benefit to a population struggling with an epidemic of exhaustion and depression. In one study, forest walking reduced inflammatory cytokines and lowered cortisol levels.(7) Here in Toronto, Dr. Mike Evans, a family physician at St. Michael’s Hospital, synthesized research in a presentation entitled “23 and ½ hours: What is the single most important thing for your health”. The research documents many of the powerful anti-inflammatory effects of simply walking for 30 minutes a day.(8) When we consider how these activities affect inflammation on a cellular level, we see that exercise not only decreases the levels of pro-inflammatory cytokines and C-reactive protein but also simultaneously enhances the concentrations of anti-inflammatory cytokines when compared with controls.(9) Many different types of exercise have been studied with great success and the secret is that the activity does not need to be complicated. From running to cycling, strength training to yoga, all types of activity can have benefit so it is best to choose activities that you like and can sustain. There is no doubt about it, stress is inflammatory and is associated with depression. Stress rates among Canadians continue to increase. According the Stats Canada’s Community Health Survey, in 2011 approximately 23.6% of Canadians 15 years of age or older reported that most days felt “extremely or quite a bit stressful”.(10) Psychological stress is strongly associated with depression and fuels pro-inflammatory cytokine production.(11) How we manage our stress and the support systems available to us go a long way to support depression treatment and prevention. In particular, practices such as Mindfulness Meditation, Yoga , and Tai Chi have consistent show benefit in the reduction of perceived stress levels and depression.(12, 13, 14) A comprehensive lifestyle approach to decreasing inflammation is necessary for addressing the environmental links to the development depression, and implementation of these tools can help treat and alleviate symptoms. The safety profile for these interventions is impeccable and the interventions have numerous additional health benefits. Optimal nutrition, such as consuming a low carbohydrate diet that is rich in healthy fats, avoiding food sensitivities, exercising for thirty minutes a day, and participating in stress reducing activities offers choice in a variety of supportive treatment options. Your Naturopathic doctor can help you develop an individualized plan designed to meet your health goals and set you on the path to decreasing inflammation and preventing or treating depression. While these lifestyle interventions are necessary to address the root cause of our susceptibility to inflammation, they are not the only tool we have available as we build our anti-inflammatory lifestyle. References 1. Giugliano D, Ceriello A, Esposito K. The effects of diet on inflammation - Emphasis on the metabolic syndrome. J Am Coll Cardiol. 2006;48:677–85. 2. Lee M, The use of ketogenic diet in special situations: expanding use in intractable epilepsy and other neurologic disorders. Korean J Pediatr. 2012 September; 55(9): 316–321. 3. Farrés J, Pujol A, Coma M, Ruiz JL, Naval J, Mas JM, et al. Revealing the molecular relationship between type 2 diabetes and the metabolic changes induced by a very-low-carbohydrate low-fat ketogenic diet. Nutr Metab (Lond). 2010; 7: 88. 4. Ho MH, Wong WH, Chang C. Clinical Spectrum of Food Allergies: a Comprehensive Review. Clin Rev Allergy Immunol. 2012 Nov 16. 5. Lillestøl K, Berstad A, Lind R, Florvaag E, Arslan Lied G, Tangen T. Anxiety and depression in patients with self-reported food hypersensitivity. Gen Hosp Psychiatry. 2010 Jan-Feb;32(1):42-8. 6. Pauline Anderson. Exercise May Beat Mental Activity in Preserving Cognition. Medscape. Oct 24, 2012 7. Mao GX, Lan XG, Cao YB, Chen ZM, He ZH, Lv YD, et al. Effects of short-term forest bathing on human health in a broad-leaved evergreen forest in Zhejiang Province, China Biomed Environ Sci. 2012 Jun;25(3):317-24 8. Evans M. 23 and ½ Hours: What is the single most important thing for your health. http://www.youtube.com/watch?v=aUaInS6HIGo and http://www.myfavouritemedicine.com/about-dr-mike/ 9. Lakka TA, Lakka HM, Rankinen T, Leon AS, Rao DC, Skinner JS, et. al. Effect of exercise training on plasma levels of Creactive protein in healthy subjects: the HERITAGE Family Study. Eur Heart J 2005;26:2018–2025. 10. Statics Canada: Canadian Community Health Survey, 2011. 11. Kiecolt-Glaser J. Stress, Food, and Inflammation: Psychoneuroimmunology and Nutrition at the Cutting Edge. Psychosom Med. 2010 May; 72(4): 365–369. 12. Marchand WR. Mindfulness-based stress reduction, mindfulness-based cognitive therapy, and Zen meditation for depression, anxiety, pain, and psychological distress. J Psychiatr Pract. 2012 Jul;18(4):233-52. 13. Michalsen A, Jeitler M, Brunnhuber S, Lüdtke R, Büssing A, Musial F, et. al .Iyengar yoga for distressed women: a 3-armed randomized controlled trial. Evid Based Complement Alternat Med. 2012;2012:408727. 14. Wang C, Bannuru R, Ramel J, Kupelnick B, Scott T, Schmid CH. Tai Chi on psychological well-being: systematic review and meta-analysis. BMC Complement Brain on Fire - Connection between Inflammation and Depression Part III: Probiotics and Fish Oil in Inflammation and Depression by: Erin Wiley HBHSC, ND Integrative Health Institute 46 Sherbourne St at King St. – Second Floor Toronto, ON. M5A 2P7 www.integrativehealthinstitute.ca firstname.lastname@example.org Fish oil has had a long track record of good evidence supporting its ability to decrease inflammation, influence mood and support mental health. The active nutrients in fish oil are Omega -3 Fatty acids: EPA and DHA. EPA is the primary anti-inflammatory omega 3 in the brain, while DHA is the primary structural component. When omega-3 fatty acids levels are low in the brain, increased neuro-inflammation occurs. Studies on fish oil vary. but the focus is on finding the best therapeutic dose and balance between EPA and DHA. One study has compared the therapeutic effects of EPA to a common anti-depressant fluoxetine. The results showed that taking both an antidepressant and EPA had the greatest therapeutic effect. When compared side-by–side, participants taking 1000mg of EPA saw the same benefits as participants taking 20mg of the antidepressant alone and both treatment groups saw significant improvements over placebo.(1) When we look at larger meta-analysis of studies on fish oil and depression across the board, again we see that results vary based on the therapeutic dose but that there is a consistent therapeutic effect across the board.(2) The key thing to keep in mind when choosing fish oil as a therapeutic option is that the therapeutic dose for inflammation is a concentration of EPA that is greater than 2000mg/day. While the therapeutic dose for improved mood is achieved at concentrations of EPA above 1000mg per day, the ratio of EPA to DHA is very important and needs to be greater than 6:1. Fish oil has an outstanding safety profile. This fact cannot be ignored. Compared to conventional options, fish oil offers little to no safety risk outside of food allergy and does not pose a threat to drug interactions with antidepressant medications. However, the product should be checked to ensure that is it does not contain mercury or other heavy metals and pollutants. The product should not be exposed to the air as it will oxidize and the product should be made from an environmentally sustainable source. Due to the great number of benefits from omega-3 fatty acids, clients often ask my opinion on two main areas: Can we get enough omega-3s from eating fish and can I choose other oils that are high in omega-3 such as flax oil. The answer to both of these questions comes down to therapeutic dose. While eating fish and consuming flax oil as part of a healthy diet are generally recommended, it would seem impractical to consume enough fish daily to achieve 2000mg per day of EPA and impossible to convert enough flax oil to the proper dose and ratio to have the specific anti-depressant effects. Another supplement that has been well established for its effects on inflammation are probiotics, or the healthy bacteria that live in your gut. Recent studies on a particular strain of bacteria, Lactobacillus Rhamnosus, suggest a direct connection between the health of the gut and the health of the brain. Studies on mice showed that Lactobacillus Rhamnosus reduced inflammatory markers, lowered corticosteroid hormone release and elevated GABA,(3) thus having a direct effect on neurotransmitters by reducing inflammation, decreasing stress hormone production and producing calming brain chemicals. Probiotics also have an amazing safety profile with little side effects and no evidence that they would interfere with anti-depressant medications. Both fish oil and probiotics are recommended by most Naturopathic doctors as either a preventive strategy for depression or as part of a comprehensive treatment plan. These supplements can be taken daily and are safe to use long term. References 1. Jazayeri S, Tehrani-Doost M, Keshavarz SA, Hosseini M, Djazayery A, Amini H, et al. Comparison of therapeutic effects of omega-3 fatty acid eicosapentaenoic acid and fluoxetine, separately and in combination, in major depressive disorder. Aust N Z J Psychiatry. 2008 Mar;42(3):192-8. 2. Lin PY, Su KP. A meta-analytic review of double-blind, placebo-controlled trials of antidepressant efficacy of omega-3 fatty acids. J Clin Psychiatry. 2007 Jul;68(7):1056-61. 3. Bravo JA, Forsythe P, Chew MV, Escaravage E, Savignac HM, Dinan TG, et al. Proc Natl Acad Sci U S A. 2011 Sep 20;108(38):16050-5. Epub 2011 Aug 29. Brain on Fire - Connection between Inflammation and Depression Part IV: Antioxidants and Nrf2 Activators in Inflammation and Depression by: Erin Wiley HBHSC, ND Integrative Health Institute 46 Sherbourne St at King St. – Second Floor Toronto, ON. M5A 2P7 www.integrativehealthinstitute.ca email@example.com We live in an environment that promotes inflammation. Even after we do our best to decrease our exposures to the causes of inflammation, tissue damage may occur and repair needs to be done for our brain to function at its best. Fortunately, the body has many self-healing mechanisms. Natural substances in our environment can be used to help the body with the task of recovery and repair. We will explore two categories or support: “antioxidants” and “Nrf 2 Activators”. Antioxidants by name and by nature repair oxidative damage to tissues in the body. Two of the top anti-oxidants used in my practice to support depression include Alpha Lipoic Acid and N- Acetyl- Cysteine. Alpha Lipoic Acid is a powerful antioxidant that prevents and repairs damage. Its mechanism of action improves insulin sensitivity, increases tryptophan in the brain and promotes serotonin synthesis.(1) Studies show that this nutrient specifically protects neurons and brain tissue .(2) Alpha Lipoic Acid also participates in the induction of glutathione synthesis (glutathione is considered to be the most powerful antioxidant in the body). Alpha Lipoic Acid can be given by mouth or by IV administration. N-Acetyl Cysteine is also another powerful antioxidant that repairs damaged brain tissue and promotes the body’s primary anti-oxidant, Glutathione. N-acetyl cysteine has been demonstrated to be neuroprotective in a variety of neurodegenerative disease models.(3) Both Alpha Lipoic Acid and N-Acetyl- Cysteine should be used under the supervision of your Naturopathic Doctor, as the dose is dependant on the client and client’s need to be monitored for side effects and interactions. Another route of support for tissue repair is to become your own genetic architect through Nrf2 Activation and gene expression. The body has the ability to produce its own antioxidant and detoxification enzymes internally. Nrf2 is a genetic pathway that regulates the production of antioxidants such as glutathione and superoxide dismutase (SOD). This genetic pathway also regulates the production of detoxification enzymes and down regulates signaling factors that promote inflammation. You can influence your own genetic ability to repair tissue, support detoxification and calm inflammation just by consuming foods and supplements that promote this pathway! One primary activator of this pathway is Sulforaphane, and primary component of cruciferous vegetables like broccoli, cabbage, and Brussels sprouts. Sulforaphane is most concentrated in broccoli seed extract. While changes in your diet to include more cruciferous vegetables are highly recommended, sulforaphane can also be taken as a supplement that protects brain tissue and decreases inflammation.(4, 5, 6) Curcumin is another nutrient that has been promoted for its anti-inflammatory activity. Curcumin has been studied for its effect on many neurodegenerative diseases, including a neuroprotective effect on major depression. While its action is not fully explained, it is believed to be effective due to its powerful anti-inflammatory and anti-oxidative properties.(7) While Curcumin is found in Tumeric and is considered part of an anti-inflammatory diet, it can be limited by the body’s ability to absorb the nutrient from the digestive system. Science has helped us improve its absorptive capacity by creating supplements made from a supra-critical extract, containing 95% curcuminoids, or by adding black pepper to enhance absorption. Through simple nutrient supplementation with anti-oxidants and Nrf2 activators that promote the production of detoxification enzymes and down regulate inflammation, we have the opportunity to repair the neural damage that leads to, and is caused by, inflammation. On a long term basis, supplements such as fish oil and probiotics support an anti-inflammatory effect on the entire body and promote optimal mood and anti depressant effects that are extremely safe. On an individual level we can play our part by promoting stress reduction, increasing exercise, and eating a diet that is low in carbohydrates and rich in healthy fats. These steps help support a healthy lifestyle that can decrease the rates of depression in our population. An integrative approach offers choice to individuals suffering with depression and the synergistic effects of these combined treatment options cannot be ignored. You can choose the interventions that are best suited to your level of readiness for lifestyle change and your Naturopathic Doctor can help you choose the integrative therapeutic options that work in conjunction with standard medical treatments for depression. References 1. Salazar MR. Alpha lipoic acid: a novel treatment for depression. Med Hypotheses. 2000 Dec;55(6):510-2. 2. Packer L, Tritschler HJ, Wessel K. Neuroprotection by the metabolic antioxidant alpha-lipoic acid.Free Radic Biol Med. 1997;22(1-2):359-78. 3.Berk M, Malhi GS, Gray LJ, Dean OM. The promise of N-acetylcysteine in neuropsychiatry. Trends Pharmacol Sci. 2013 Jan 28. 4. Chen H, Wu J, Zhang J, Fujita Y, Ishima T, Iyo M, Hashimoto K. Protective effects of the antioxidant sulforaphane on behavioral changes and neurotoxicity in mice after the administration of methamphetamine. Psychopharmacology (Berl). 2012 Jul;222(1):37-45. 5. Chen G, Fang Q, Zhang J, Zhou D, Wang Z. Role of the Nrf2-ARE pathway in early brain injury after experimental subarachnoid hemorrhage. J Neurosci Res. 2011 Apr;89(4):515-23. d 6. Brandenburg LO, Kipp M, Lucius R, Pufe T, Wruck CJ. Sulforaphane suppresses LPS-induced inflammation in primary rat microglia. Inflamm Res. 2010 Jun;59(6):443-50. doi: 10.1007/s00011-009-0116-5. 7. Kulkarni SK, Dhir A. . Overview of Curcumin in Neurological Disorders. Indian J Pharm Sci. 2010 Mar-Apr; 72(2): 149 15412.