Understanding the Science Behind Ketogenic Therapy for Major Depressive Disorder

Estimated reading time: 6 minutes

Let’s explore the outcomes of a study that explored the neurobiological evidence supporting improvement in depression with a ketogenic diet and find out what underlying biological mechanisms they uncovered through in vitro and in vivo studies in the scientific literature.

Shamshtein D, Liwinski T. Ketogenic Therapy for Major Depressive Disorder: A Review of Neurobiological Evidence. Recent Progress in Nutrition2022;2(1):003; doi:10.21926/rpn.2201003.

Basically, they did a literature review from August 2021 to January 2022. This means they searched peer-reviewed studies looking for data on use of the ketogenic diet for depression and trying to find possible underlying mechanisms to explain the effects.

Here’s what they found.

Impaired Glucose Metabolism

Another term for this is brain hypometabolism. People with depression may have changes in glucose metabolism in the brain. This is a condition called brain hypometabolism. The ketogenic diet boosts cellular energy metabolism by raising ketone bodies and replacing glucose as the main fuel source.

Ketones restore mitochondrial function and help maintain energy balance. The ketogenic diet, which relies on ketone bodies instead of glucose, could obviously, be a promising approach.

GABA and Glutamate Balance

The glutamate/GABA neurotransmitter system is implicated in depression. Studies have shown altered glutamate levels in depressed individuals, suggesting excessive glutamate-induced excitation in depression.

Reduced GABAergic activity accompanies depression, similar to epilepsy. Ketosis, which enhances astrocyte metabolism and increases glutamate removal, might explain the efficacy of ketosis in treating both epilepsy and depression.

Mitochondrial Dysfunction and Oxidative Stress

Mitochondria are responsible for energy metabolism in cells, and their reduced function is implicated in the pathogenesis of neurodegenerative diseases, which may contribute to depression.

Ketosis may help alleviate depression by impacting mitochondrial and oxidative processes, ultimately improving brain function.

The induction of low redox signaling molecules triggered by ketone bodies may increase the levels of antioxidants and detoxification enzymes, and it is thought that this potentially reduces oxidative stress and mitochondrial dysfunction associated with depression.

Ketosis and Inflammation

The authors found many studies suggesting a strong association between depression and inflammation and also acknowledged it is likely not a purely inflammatory condition.

Microglial alterations are thought to play a critical pathophysiological role in depression. β-hydroxybutyrate promoted microglial ramification in mice with depressive behavior. This finding, and many more outlined in their investigation of the scientific literature, provide evidence for the antidepressant effects of ketone bodies via their immunomodulatory actions. (13/36) #depression #inflammation #immunomodulation

Depression may have a causal link with the gut microbiota, as shown in animal model-based studies. Microbiome alterations seen in depressed patients are similar to those found in other chronic diseases such as metabolic syndrome.

Feeling a little confused about the differences between neuroinflammation and oxidative stress and how they are related? You may find this article below helpful:

If Your Brain Were a City: Understanding Oxidative Stress and Neuroinflammation

Ketosis and Gut Microbiome

A ketogenic diet may help restore microbial balance in the gut, potentially alleviating the burden of depressive symptoms. Animal models and patients with brain disorders have shown promising results.

These findings identified in the scientific literature provide a strong rationale for studying the effects of a ketogenic diet on the gut microbiota and symptom improvement in patients with depression and animal models with depression-like behaviors.

Ketogenic Diet and Mood

Depression is a complex human phenomenon that can be difficult to study. Still, animal studies have provided valuable insights into potential pathophysiological mechanisms and clues for novel treatments for Major Depressive Disorder.

In rat models of depression-like behaviors, a ketogenic diet improved “behavioral despair”, indicating that ketosis could improve depressive symptoms. In other animal studies, feeding ketone salt and ketone salts mixed with medium-chain triglycerides improved anxiety-associated behaviors in Sprague-Dawley and WAG/Rij rats, achieving ketosis within seven days.

Interestingly, in a mice study, exposure to a gestational ketogenic diet modulated the offspring’s brain structures and protected them against anxiety and depression-associated behaviors later in adulthood, even though the offspring were fed a standard chow after birth.

Furthermore, recent animal studies demonstrated that a ketogenic diet with regular exercise decreased anxiety and depressive behaviors in mice. The reduction in depression burden was correlated with BHB levels, linking mood improvement to favorable metabolic changes.

Clinical Evidence

While the evidence for the improvement in depressive symptoms and the underlying mechanisms is limited, the existing data are encouraging and warrant further mechanistic studies on the beneficial neuromodulator effects of ketosis.

When this research article was published, there were no RCTs investigating ketogenic diets and depression! But I know of at least one going on as I write this post! So what did this study find out based on what was currently out there at the time around ketogenic diets for mood and cognition?

A randomized controlled study found that a ketogenic diet reduced anxiety and improved mood and cognition in children and adolescents with refractory epilepsy compared to a regular diet with standard care.

And in adult patients with chronic epilepsy, a ketogenic diet was associated with lesser anxiety and depression. The longer they were on the diet, the more favorable impact on their psychological state. I think that’s pretty cool.

A case study demonstrated that a ketogenic diet might act as a mood stabilizer in patients with type II bipolar disorder. Patients achieved mood stabilization superior to that accomplished using medication.

The authors who reviewed all of these studies carefully go on to say that In humans, the ketogenic diet is a safe and affordable therapy with multiple benefits. They understandably call for more research in order to understand the effects of the ketogenic diet on neurometabolic dysfunction, inflammation, and commensal microbiota alterations associated with depression. They would like to see studies demonstrating a direct correlation between the ketogenic diet and reducing symptoms of depression.

But let’s be honest. It’s going to take some time for those studies to be done. And people are suffering now.

They end their review of the literature with the following conclusion.

Nevertheless, the available evidence strongly supports the implementation of randomized controlled trials involving the use of the ketogenic diet in depressed populations.

And while these randomized controlled trials on depressed populations are being organized and going on, I don’t know about you, but I am going to make sure my clients are aware of the literature. They deserve to know that ketogenic diets show potential benefits in the typical comorbidities and pathologies seen in Major Depressive Disorder.

There isn’t a lot of funding available for dietary intervention unless you count the Baszucki Group and their partners who will change countless lives by funding the studies needed to mainstream this powerful metabolic therapy for mental illness and neurological disorders.

Despite this wish list of further research, the researchers of the study go on to say that existing data suggest potential benefits of the ketogenic diet against Major Depressive Disorder (MDD) in typical comorbidities or intersecting pathological features.

I can tell my patients it is not the standard of care after offering them the standard of care. And still remain in an ethical stance. Because not sharing this therapy showing so much promise to those suffering from Major Depressive Disorder would, in my mind, potentially do harm and not be an ethical stance.

Here is the study for your convenience in case you want more detail. So you can have the information you need to make your own ethical choice as a practitioner, Or maybe you are watching someone you love suffer. And you would like them to know all the ways they can feel better.

If you would like to learn more about the potential underlying mechanisms of action in a ketogenic diet on depression, you may enjoy these other blog articles available here on the Mental Health Keto Blog.

Neuroinflammation and depression

Can keto treat my depression without medication?

3 Reasons you are Depressed and why Keto can fix them

Because you have the right to know all of the ways that you can feel better.