The Ketogenic Diet and Depression
It is well known that a ketogenic diet is one of the oldest forms of medical treatment to control seizures in people with epilepsy. It has been comprehensively researched since the 1920s and has since also been used for other purposes, like weight loss and the treatment of diabetes type 2.
Over the recent years, the relationship between a ketogenic diet and the improvement of mental health has spiked major interest among doctors and allied health care professionals. There has been some research on to what extent a ketogenic diet could be beneficial to people who have been affected by depression. It has to be mentioned that this article focuses on studies that have been conducted on the effects of a ketogenic diet on depression-related symptoms and on the role of fructose in the development of depression.
Depression is becoming more common, and is a serious mood disorder causing severe symptoms that affect both a person’s physical and mental health. Many factors (may) contribute to developing symptoms of depressions. Genetics, personal problems and certain medications can play a role but since depression is an extremely complex disease, there is no simple one fits all answer. Nutrition might also play a significant role in the development of depression-related symptoms (Sathyanarayana Rao, Asha, Ramesh, Jagannatha Rao, 2008; El-Mallakh, R.S., Paskitti, M.E., 2001).
The link between ketones, neurotransmitters and depression
Several studies have shown that depression may be associated with an increased risk of epilepsy (Bostock, Kirkby & Taylor, 2017). The effectiveness of traditional antidepressant therapies is often researched in animal model studies, but there has only been a couple of rat studies so far on the effectiveness of a ketogenic treatment.
To examine if a ketogenic diet can be implemented as an antidepressant therapy, 20 Wistar rats were given this diet and compared to 20 rats that were fed a standard diet. This 7 day study showed that the rats on a ketogenic diet spent less time immobile than the rats in the control group (Murphy, Likhodii, Nylen & Burnham, 2004). This shows some evidence for potential antidepressant effects. During this study, researchers also measured the levels of beta-hydroxybutyrate, a ketone that exert anti-inflammatory effects. Neuro-inflammation plays a critical role in the development of depression (Hashmi, Aftab, Mazhar, Umair & Butt, 2013; Yamanashi, Iwata, Kamiya, et al., 2017). Despite the fact that currently there are little to no reports published indicating that beta-hydroxybutyrate produces antidepressant-like effects, a study showed that adult offspring mice living on a prenatal ketogenic diet were less sensitive to anxiety and depression (Sussman, Germann, Henkelman, 2015). In other rat studies, it has been found that this ketone together with acetoacetate, decreases the death of neurons and prevents negative changes caused by glutamate excitotoxicity (Maalouf, Sullivan, Davis, et al. 2007).
The neurotransmitter, GABA, which is responsible for countering the neurotransmitter glutamate, acts as an inhibitory neurotransmitter and reduces neuronal excitement in the nervous system while glutamate does the opposite of this, and therefore induces neuronal excitement. Both of these neurotransmitters are needed for a proper functioning of the brain. If they are not in balance, neural problems may occur. To maintain a balance, the amount of glutamate must be controlled by the brain. Too much excitement, and thus too much glutamate, provokes neurotoxicity and in high rates this can cause seizures in people with epilepsy. Neurotoxicity is also linked to other neurological diseases whereof depression is one. During a situation in which the brain uses energy efficiently, it is easier for their cells to pull back the glutamate. Glutamate itself can develop into GABA or aspartate. Aspartate is an excitatory neurotransmitter and can be neurotoxic when there is too much of it circulating in the nervous system. It seems like following a ketogenic diet leads to glutamate developing into GABA rather than aspartate which means less neurotoxicity. It is suspected that this has to do with the way how ketones are metabolized and how ketosis uses acetate as a fuel which becomes glutamine, an essential precursor for GABA (Deans, 2011; Maalouf, Sullivan, Davis, et al. 2007).
In children with epilepsy, following a ketogenic diet has been linked to significant alterations in the neurotransmitters serotonin and dopamine, both which are important parameters for anxiety and depression (Bostock, Kirkby & Taylor, 2017).
The role of fructose in the development of depression
Implementing a ketogenic diet means eliminating refined, high-carbohydrate foods. Consuming an excessive amount of sugar or refined carbohydrates does not only increase the chance of developing obesity and diabetes type 2, but also of major depression. Table sugar, sucrose, consists of two components, namely glucose and fructose and doesn’t contain any nutritional value. White (table) sugar, high fructose syrup and even natural sweeteners like honey, agave and maple syrup consist roughly of half glucose and half fructose. A spiking blood sugar level after consuming too much added fructose from refined products increases the risk of heart, liver and kidneys diseases (Kretowicz, Johnson, Ishimoto, Nakagawa, Manitius, 2011) and obesity and type 2 diabetes. In addition, a high level of sugars in your body plays a role in developing chronic inflammation, a cause of a wide range of psychiatric and neurodegenerative disorders including major depression (Westover & Marangell, 2002). There are different theories known on how consuming too much sugar contributes to developing depression, namely that sugar causes a serotonin crash, that sugar increases brain inflammation and that sugar depresses the natural antidepressant brain-derived neurotrophic factor (BDNF) (Alban, n.d.).
Although there is still little scientific evidence available to proof whether a ketogenic diet is beneficial to people who are affected by depression, it is well-acknowledged that a ketogenic diet is used as a powerful treatment for other neurological conditions like epilepsy. According to several animal model studies, the diet might have antidepressant properties, because of the anti-inflammatory effects. In addition, consuming an excessive amount of sugar promotes the development of depression. Since sugar is removed from a ketogenic diet, this is an important benefit of following a low-carb high-fat diet. The exact role of a ketogenic diet in mental health problems is unclear since most of the published studies are based on animal models with limited generalizability to humans. Future research in depressed humans should focus on long-term, prospective, randomized, placebo-controlled crossover dietary trials to examine the effect of a ketogenic diet in various mental health problems.
Although there are many factors contributing to the development of depression-related symptoms, and different expressions of depression ask for different levels of treatment, it is well researched that biochemical issues like an imbalance in neurotransmitters play a role.
Note: This article hasn’t looked into the specific role of particular nutrients in food and their relation the development of depression, but as reported in several studies, omega 3, tryptophan, l-glutamine, tyrosine, phenylalanine and methionine play a role in the decrease of depression-related symptoms (Sathyanarayana Rao, Asha, Ramesh, Jagannatha Rao, 2008). These components are mostly found in animal-based products like grass-fed beef, fish, eggs, nuts and cheeses and these products form the foundation of the ketogenic diet.
About the author:
Lotte Damen, recently graduated with a Bachelor of Science, as a Nutrition & Dietetics student at The Hague University of Applied Sciences in the Netherlands. She joined the Noakes Foundation in January 2018 as an intern. As part of her internships she assisted with several projects, including the launch of the Nutrition Network and with the development of LCHF meal plans and program development. She also wrote LCHF relevant articles and content, and developed marketing materials. During her time as an intern she learned about the many benefits of a LCHF/ketogenic diet and and are excited to apply her obtained knowledge in the future as a registered dietitian. Lotte is also an avid runner, adventurous cook and always reading up on the latest research in nutrition and enjoys spending quality time with her friends and family.
About the Noakes Foundation, Eat Better South Africa! and the Nutrition Network:
The Noakes Foundation is a Public Benefit Organization founded for public benefit which aims to advance medical science’s understanding of the benefits of a low-carbohydrate healthy high fat (LCHF) diet by providing evidence-based information on optimum nutrition. The Foundation’s key goal is to change the way South Africa eats because the epidemics of obesity and type 2 diabetes are set to cripple national health care within the next 10 years. The Foundation relies purely on funding to carry out this mandate; visit our website to find out how you can help: www.thenoakesfoundation.org/donate.
Eat Better South Africa! (EBSA) is the community outreach branch of The Noakes Foundation, and is an intervention programme aimed at educating people from lower income areas, teaching them to get better by eating better. EBSA’s mission is to educate underresourced community members about the dangers of excessive sugar and carbohydrate consumption, and to teach them how to make better food choices through dietary education, meal and budget planning, and general nutritional awareness.
The Nutrition Network is an independent initiative inspired by The Noakes Foundation and is an online learning platform designed exclusively for medical practitioners and allied health workers across all disciplines, presenting the latest and most up-to-date science and research in the field of Low Carb nutrition. On completion of the course, practitioners will receive a certificate signifying their ability to prescribe LCHF to their patients.
Alban, D. The role sugar plays in depression and anxiety. Retrieved from https://bebrainfit.com/sugar-depression-anxiety/#how-sugar-can-cause-depression
Bostock, E.C.S., Kirkby, K.C., Taylor, B.V.M. (2017). The current status of the ketogenic diet in psychiatry. Front Pyschiatry, 8: 43. Doi: 10.3389/fpsyt.2017.00043
Deans, E. (2011, April 18). Your Brain on Ketones – How a high-fat diet can help the brain work better. Retrieved from https://www.psychologytoday.com/intl/blog/evolutionary-psychiatry/201104/your-brain-ketones
El-Mallakh, R.S., Paskitti, M.E. (2001). The ketogenic diet may have mood-stabilizing properties. Medical Hypotheses, 57(6), 724-726. Doi: 10.1054/mehy.2001.1446
Hashmi, A.M., Aftab, M.A., Mazhar, N., Umair, M., Butt, Z. (2013). The fiery landscape of depression: A review of the inflammatory hypothesis. Pakistan Journal of Medical Sciences, 29(3): 877-884.
Ketosis for depression. Retrieved from https://www.perfectketo.com/ketosis-for-depression/
Kretowicz, M., Johnson, R.J., Ishimoto, T., Nakagawa, T., Manitius, J. (2011). The impact of fructose on renal function and blood pressure. International Journal of Nephrology, Article ID 315879. Doi:10.4061/2011/315879
Maalouf, M., Sullivan, P.G., Davis, L., Kim, D.Y., Rho, J.M. (2007). Ketones inhibit mitochondrial production of reactive oxygen species production following glutamate excitotoxicity by increasing NADH oxidation. Neuroscience, 145(1): 256-264. Doi: 10.1016/j.neuroscience.2006.11.065
Mergenthaler, P., Lindauer, U., Dienel, G.A., Meisel, A. (2013). Sugar for the brain: the role of glucose in physiological and pathological brain function. Trends in Neurosciences, 36(10): 587-597. Doi: 10.1016/j.tins.2013.07.001
Murphy, P., Likhodii, S., Nylen, K., Burnham, W.M. (2004). The antidepressant properties of the ketogenic diet. Biological Psychiatry, 56(12): 981-983. Doi: 10.1016/j.biopsych.2004.09.019
Sathyanarayana Rao, T.S., Asha, M.R., Ramesh, B.N., Jagannatha Rao, K.S. (2008). Understanding nutrition, depression and mental illnesses. Indian Journal of Psychiatry, 50(2): 77-82. Doi: 10.4103/0019-5545.42391
Sussman, D., Germann, J., Henkelman, M. (2015). Gestational ketogenic diet programs brain structure and susceptibility to depression & anxiety in the adult mouse offspring. Brain and Behavior, 5(2): e00300. Doi: 10.1002/brb3.300
Westover, A.N., Marangell, L.B. (2002). A cross-national relationship between sugar consumption and major depression? Depression and Anxiety, 16: 118-120. Doi: 10.1002/da.10054
Yamanashi, T., Iwata, M., Kamiya, N., Tsunetomi, K., Kajitani, N., Wada, N., Iitsuka, T., Yamauchi, T., Miura, A., Pu, S., Shirayama, Y., Watanabe, K., Duman, R.S., Kaneko, K. (2017). Beta-hydroxybutyrate, an endogenic NLRP3 inflammasome inhibitor, attenuates stress-induced behavioral and inflammatory responses. Scientific Reports, 7: 7677. Doi: 10.1038/s41598-017-08055-1