RESEARCH REVIEW: KETO THERAPY FOR MAJOR DEPRESSIVE DISORDER

As people are becoming more savvy to the big drug companies, many are choosing to forgo pharmaceuticals in exchange for more natural approaches. 

And of course, one of the most natural approaches is finding therapeutic value in your diet. 

One of the emerging areas of interest in the natural health space is brain health — including neurological issues like Alzheimer’s disease as well as psychiatric disorders like anxiety and clinical depression.

In a literature review published in the Recent Progress in Nutrition journal, researchers provide an up-to-date summary on the ketogenic diet’s potential to alleviate major depressive disorder (MDD). In the review, the investigators searched several top databases for literature related to the ketogenic diet and symptoms of depression published between the dates of August 2021 and January 2022.

With this data, the authors provide us with a neurological basis for the ketogenic diet, along with preliminary clinical evidence for its use in MDD.

Let’s dive in. 

How Can a Ketogenic Diet Help With Major Depressive Disorder?

The literature survey uncovered five potential avenues in which a low-carb, high-fat ketogenic diet may be therapeutic for MDD:

• Glucose metabolism 
• Gaba and glutamate balance
• Mitochondrial function
• Inflammation
• Gut microbiome homeostasis

Impaired Glucose Metabolism

Accumulating evidence shows that individuals with depression exhibit alteration in glucose metabolism in the brain. Under normal circumstances, glucose is the brain's primary source of fuel, which means a deficiency in glucose (low blood sugar) could directly impact mitochondrial function and all neurological processes. 

While this can happen in the case of insulin resistance (type 2 diabetes), individuals that are generally healthy may also struggle with blood sugar regulation.

Various studies show that depending on the type of depression, different areas of the brain may be starved for glucose including the insula, temporal cortex, frontal cortex, and so on.

The researchers believe that one mechanism behind impaired glucose metabolism in depressed people may be inhibition of a glucose transporter called GLUT 1. GLUT 1 is responsible for shuttling glucose out of your blood and into your cells to be used as fuel. Research shows that in depressed people this transporter (and likely others similar to it), are inhibited and therefore block the uptake of glucose. 

By replacing glucose as a form of energy, ketones circumvent deficiencies in cellular metabolism in the brain. In other words, they replace the missing glucose and therefore allow for balanced energy metabolism throughout all areas of the brain. 

Gaba and Glutamate Balance

While serotonin is the neurotransmitter most commonly associated with depression, research suggests that glutamate may also play a role. Studies show that when this neurochemical is inhibited, patients experience antidepressant effects. On the other hand, high levels of glutamate can be excitatory in the brain, causing imbalance. 

In this review, the researchers note evidence that ketosis may modulate brain function by altering cerebral glutamate metabolism. Specifically, ketosis appears to increase the conversion of glutamate into a new compound called glutamine. When glutamate activity is calmed, it allows for enhanced GABA activity in the brain. 

While glutamate is an excitatory neurotransmitter, GABA is an inhibitory neurotransmitter, Similarly, while high glutamate is associated with increased depression, GABA is associated with reduced depression. 

Therefore, by assisting in the exchange of glutamate for GABA, ketones may help calm the brain and bring about a greater sense of peace. 

Mitochondrial Dysfunction and Oxidative Stress

Mitochondria are crucial for energy metabolism, but they also play a critical role in maintaining the balance of oxidative stress and antioxidant systems  in your brain. In this way, healthy mitochondrial function is crucial for the health of your brain and nervous system.

Research shows that through various processes, ketones regulate mitochondrial function and may provide assistance in generating antioxidants that combat damaging oxidative stress. 

In fact, an interesting hypothesis is that the alleviation of mitochondrial dysfunction and oxidative stress could be among the mechanisms through which ketosis reduces epileptic seizures.

Inflammation

There is significant research supporting the association between inflammation and depression. While the authors note that depression is likely not solely caused by inflammation, there is good reason to believe that inflammation plays a role. 

Several studies show that following a ketogenic diet results in lower pro-inflammatory chemicals, with higher levels of anti-inflammatory compounds. 

Furthermore, in animal models the ketone body ​β-hydroxybutyrate not only shows anti-inflammatory activity, but it also alleviates depressive symptoms. The researchers believe this is due to the impact on brain-specific immune cells called microglia, which are proposed to play a critical role in the pathophysiology of depression.

Gut Microbiome 

As research into the gut microbiome continues to grow, the relationship between gut health and mental health is becoming one of the most intriguing subjects. 

Research already shows a correlation between certain types of gut bacteria and a range of neurological issues, including depression.  

While the exact mechanisms underlying this connection remain uncertain, researchers have proposed several hypotheses:

• Metabolites released from bacteria have a bidirectional interaction from the gut to the brain via the hypothalamus–pituitary–adrenaline (HPA) axis and the immune system.
• The signaling of these intestinal metabolites to the enteric nervous system (a part of your nervous system that lives in the gut).
• Bacterial metabolites modulate behavior via the vagus nerve (which runs from the gut all the way up to your brain).

Meanwhile, growing evidence suggests that a low-carbohydrate diet helps to rebalance the gut microbiome in favor of healthier bacteria. Specifically bacteria that are associated with neurological conditions and depression. Therefore, a ketogenic diet may alleviate depressive symptoms by restoring the balance of gut microbiota.

It should be noted that when considering the ketogenic diet for gut health, it’s vital that your diet be full of whole foods, as opposed to processed packaged foods.

What Could This Mean For You?

In the neuroscience space, the ketogenic diet continues to gain popularity far beyond it‘s ability to curb cravings, boost energy levels, and support weight loss.

The investigators in this study report that although more high-quality clinical research is needed before a firm conclusion can be made, the emerging research is showing positive correlations and providing us with a range of potential mechanisms for the positive impact of the keto diet on depressive symptoms. 

One example would be evidence which shows that when people with epilepsy switch to a low-carb diet they often experience reduced depression along with a reduction in seizures.  

In this review, the authors conclude that the current research on the ketogenic diet provides sufficient preclinical evidence supporting its beneficial systemic impact, including neurotrophic, antioxidant, neuroprotective, and anti-inflammatory effects.   

Therefore, other researchers should now have strong rationale for conducting randomized controlled trials involving the use of the ketogenic diet in individuals with depression and other mood disorders.

As always, be sure to work with a healthcare professional when considering a new diet, especially if you are currently managing a metabolic imbalance.