New theories on how inflammation may be a cause of depression, and how the ketogenic diet may be a novel treatment option

Depression is the most commonly diagnosed neuropsychiatric disorder, ^{(Chen, 2017)} characterized by a persistent feeling of sadness, loss of interest and hopelessness. Is it estimated that >16 million people in the US have suffered from a depressive episode in the past year, which represents 6.7% of all American adults.

The cause of depression has typically been blamed on a chemical imbalance in the brain, specifically a decrease in the monoamine neurotransmitters (serotonin, noradrenaline, and dopamine). Most of the anti-depressant medications work by increasing the levels of these monoamines neurotransmitters. It is estimated that a third of depressed patients treated with these anti-depressant medications, however, do not improve. ^{(Miller, 2016) (Yamanashi, 2017)} So maybe the pathophysiology of depression is not that simple.

Scientific evidence now suggests that inflammation plays a role in the pathophysiology of depression.

Psychosocial stress is a very common risk factor for the development of depression. Studies have shown that stress, especially early life-trauma, is associated with an increased risk of developing depression. ^{(Miller, 2016)} Stress has been shown to cause many pathological changes in the body including increased inflammation. When the body is stressed, the NLRP3 inflammasome is activated. When activated the NLRP3 inflammasome causes the release of the pro-inflammatory cytokines (interleukin 1 beta, interleukin -6 and tumor necrosis factor alpha). These pro-inflammatory cytokines, which are markers of inflammation, have been noted to be significantly higher in the brains of patients with depression and in people who have committed suicide. The amount of inflammatory present correlates to the number of life stressors that one experiences. This then directly correlates to a higher risk of developing depression. ^{(Miller, 2016)}

It is this increased amount of inflammation in the brain that is believed to be the underlying cause of depression. ^{(Yamanashi, 2017)} Inflammation may cause depression thru several different mechanisms. First of all, studies have indicated that the inflammatory in the brain causes a decrease in the amount of the anti-depressant monoamines neurotransmitters. Next, high level of inflammatory also results in the increase the amount of glutamate in the brain. Elevated glutamate level in the brain has also been correlated with causing depressive symptoms. ^{(Miller, 2016)} Not only does having increased inflammation increase depressive symptoms but also may limit the antidepressant medications from working as well. ^{(Miller, 2016)}

So does decreasing the levels of this inflammation result in improvement in the depression symptoms?

The answer is yes. Studies have indeed shown that blocking the release of these inflammatory cytokines can reverse the depressive behaviors induced by stress and the levels of inflammation in the brain. ^{(Yamanashi, 2017) (Miller, 2016)} Since the NLRP3 inflammasome is such a critical factor in the development of this inflammation, blocking of this inflammasome is a potential target. Ketones, specifically Beta-hydroxybutyrate (BHB) has been shown to have to exert an anti-inflammatory effect via inhibition of the NLRP3 inflammasome. ^{(Yamanashi, 2017)} Ketones are the breakdown products of fats. They are produced naturally in your liver during times of starvation or while on a ketogenic diet. The ketogenic diet has been used since the 1920s as a treatment for neurological disorders such as hard to treat seizures. Many believe that is the benefits of the ketogenic diet are due to the neuroprotective and anti-inflammatory properties of ketones.

To date, the benefits of ketones or a ketogenic diet in depression have only been studied in animal models. The first study showed that rats that were pretreated with a ketogenic diet showed less depressive activities compared to the rats on a standard diet. ^{(Murphy, 2004)} In 2017, two studies were published using ketone supplementation in animal models of depression. One study by Chen showed that exogenous BHB improved depressive behaviors in mouse models. This improvement was similar to the benefits seen with treatment of the anti-depressant medication imipramine. ^{(Chen, 2017)} Another study, using rat models of stress, looked the anti-inflammatory and antidepressant effects of ketone supplementation with BHB. They found that the rats that were pretreated with BHB had less depressive and anxiety behaviors than would typically be seen with stress. Also, the amount of inflammation in the brains of the stressed rats has decreased in the BHB treated rats. ^{(Yamanashi, 2017)}

Ketones have also been shown to have other benefits that may also help with depression symptoms. The ketone BHB has been shown to increase the levels of brain-derived neurotrophic factor (BDNF), which has been shown to be decreased in psychiatric diseases including depression. ^{(Chen, 2017)} Additionally, BHB has been shown to decrease the excitatory neurotransmitter glutamate and increase the levels of the calming neurotransmitter GABA. This increased ratio of GABA to glutamate also reduces anxiety. ^{(Ari, 2016)}

These animal studies and research suggest that the ketone, beta-hydroxybutyrate, may have an antidepressant effect. So can something as simple as changing your diet, or using a ketone supplement* improve depression? That question in humans has not been formally studied. However wouldn’t it be worth a try? If you would like to give it a try, I will be happy to help.

Bibliography

Ari, C. (2016). Exogenous Ketone Supplements Reduces Anxiety-Related Behaviors in Sprague-Dawley and Wistar Albino Glaxo/Rijswijk Rats. Frontiers in Molecular Neuroscience, 9, 1-10.

Chen, L. (2017). Beta-hydroxybutyrate alleviates depressive behaviors in mice possibly by increasing the histone3-lysine9-Beta-hydroxybutyrylation. Biochemical and Biophysical Research Communications, 490, 117-122.

Miller, A. H. (2016). The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nature, 16, 22-34.

Murphy, P. (2004). The Antidepressant Properties of the Ketogenic Diet. Biological Psychiatry, 56, 981-983.

Yamanashi, T. (2017). Beta-hydroxybutyrate, an endogenic NLRP3 inflammasome inhibitor, attenuates stress-induced behavioral and inflammatory responses. Nature, 7, 1-10.

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