Can the ketogenic diet treat bipolar disorder?

Mounting evidence supports the use of ketogenic diets for bipolar disorder because of the ketogenic diet’s ability to modify underlying pathological mechanisms such as brain hypometabolism, neurotransmitter imbalances, brain inflammation, and oxidative stress. There are numerous anecdotal reports, published case studies in peer-reviewed journals, articles reviewing the literature on the topic, and randomized controlled trials being conducted evaluating the ketogenic diet as a treatment for bipolar disorder.

Introduction

Manic episodes in BPD are generally considered to be fairly well-managed through medications. But major depressive episodes are still considered to be recurrent and a significant clinical challenge. People with bipolar disorder suffer from a burden of significant depressive symptoms, even for those whose manic episodes feel well controlled with medication.

These phases can create persistent functional impairment and disability and increase the risk of suicide. Relying on ineffective medications to treat the depressive phases of bipolar disorder is both cruel and potentially dangerous. Even if it is the standard of care. Existing mood stabilizers for the depressive phase of bipolar disorder are only effective in 1/3 of bipolar patients and standard antidepressants repeatedly fail to show benefit in RCTs for this condition and may even worsen the condition. Atypical antipsychotics are reportedly more effective but have devastating metabolic disorder effects that make long-term use unhealthy and side-effects often intolerable for patients.

I write the above to illustrate the plight of many suffering from bipolar disorder, and to point out that even if someone with bipolar disorder has gotten their manic symptoms under control with medication (many have not), there is still a significant portion of the bipolar population suffering from residual symptoms.

And they deserve to know all of the ways they can feel better.

Several biological mechanisms have been proposed as potential underlying causes of BD. These include mitochondrial dysfunction, oxidative stress and neurotransmitter disruption.

Yu, B., Ozveren, R., & Dalai, S. S. (2021). Ketogenic diet as a metabolic therapy for bipolar disorder: Clinical developments. https://www.researchsquare.com/article/rs-334453/v2

As we discuss glucose hypometabolism, neurotransmitter imbalances, inflammation, oxidative stress, and how a ketogenic diet modifies those factors, you will begin to understand why people are doing the ketogenic diet for bipolar disorder.

Let’s get started!

Bipolar Disorder and Hypometabolism

Key underlying metabolic pathologies thought to play a role include dysfunction in energy metabolism.

Yu, B., Ozveren, R., & Dalai, S. S. (2021). The use of a low carbohydrate, ketogenic diet in bipolar disorder: systematic review. https://www.researchsquare.com/article/rs-334453/v1

What is brain hypometabolism? And do people with bipolar disorder have hypometabolism?

Brain hypometabolism simply means that brain cells are not using energy well in some parts of the brain or in specific structures. 

  • hypo = low
  • metabolism = energy use

People with bipolar disorder have regions of brain hypometabolism, meaning those brain areas are not as active as they should be. Brain hypometabolism is really about mitochondrial dysfunction, which is basically how the brain uses fuel and how well it produces energy.

It is not just one particular area of the brain in which we see accumulated mitochondrial dysfunction play out as energy deficits. Some of the brain areas identified as hypometabolic through different neuroimaging technologies include the insula, brainstem, and cerebellum.

There is also ample evidence of hypometabolism causing disrupted connectivity within the frontal white matter. These disruptions of cell structure and metabolism occur deep in the brain’s white matter between the front-limbic network. For those new to all these brain structure names, your limbic system is an emotional center of the brain. But it is important to understand that your emotions can come from your appraisal of a situation (oh that’s a tiger and they eat people!) and that that message goes to your limbic system to initiate a response (RUN!). In bipolar disorder, we see white matter connectivity problems in major cognitive networks that include the dorsolateral prefrontal cortex, temporal and parietal regions. Which are basically all very important parts you need to function and burn energy well.

These identified areas of brain structure hypometabolism are not surprising when we think about the manifestation of affective and behavioral symptoms in bipolar disorder. For example:

  • disrupted connectivity between dorsal cingulate cortex, and precuneus, cuneus.
    • It is thought that this disrupted connectivity may play a role in subsequent over-reactivity during emotional processing in bipolar patients
  • dorsolateral prefrontal cortex
    • controls executive functions like planning tasks, working memory, and selective attention.
  • dorsal cingulate cortex
    • executive control (which you need to regulate emotion), learning, and self-control.
    • hypometabolism in the cingulate cortex is seen in individuals with substance use disorders
  • precuneus
    • perception of the environment, cue reactivity, mental imagery strategies, episodic memory retrieval, and affective responses to pain.

But wait a minute, you may say. Over-reactivity? How can that happen in a brain with hypometabolism when we expect not enough energy for over-activity to occur? And also, don’t some phases of bipolar disorder make everyone sort of hyperactive? Like they can’t stop or sleep? How does this apply?

Well, the answer is a little paradoxical. When some brain areas do not have enough energy to function, it can cause downstream effects that disrupt neuronal balancing in other regions. So hypometabolism in some parts of the brain throws the delicate system of the brain off, and it ends up perpetuating neurotransmitter imbalances throughout or in neighboring structures, causing hyperexcitability on a neurotransmitter level. which we will discuss more in later sections (see Neurotransmitter Imbalances). Hypometabolism in one area of the brain can cause the brain to make too many connections to other parts of the brain, trying to compensate. You can end up with connectivity between areas that don’t really belong being quite so connected.

The inability of brain cells to have adequate energy from a stable fuel source perpetuates mitochondrial dysfunction. Mitochondria are the batteries of your cells, and they are needed to accomplish all the things that a neuron needs to do. If your brain fuel is no longer working for you, which in the case of glucose and bipolar disorder may very well be the case, those batteries cannot work. The neurons do not have enough energy to function and start to just not work right! A malfunctioning neuron is unable to do basic cell housekeeping, make neurotransmitters, or even keep those neurotransmitters around for the right amount of time in the synapse, or even be able to communicate well with other cells.

Because they are in distress, they create their level of inflammation and oxidation, using up precious cofactors (vitamins and minerals) trying to fight the inflammation occurring because the cell is in distress from an energy deficit. Depleting the cell further and adding to the poor energy cycle in the neuron.  

One of the theories why this happens is that the metabolism of glucose is impaired in the brain due to poor conversion of an important enzyme called pyruvate dehydrogenase complex (PDC). Problems with converting glucose as a fuel source for energy in the brain have grave consequences.

This hypometabolism, and subsequent mitochondrial dysfunction, is so relevant in the bipolar brain, that researchers can make transgenic mice with specific brain mitochondrial dysfunction, and completely recreate the symptoms that a bipolar human experiences!

And, when they medicate these transgenic mice with lithium or even regular antidepressants, they respond in the same way as human bipolar patients do to those medications.

So my point is this. Hypometabolism is a HUGE factor in the creation and perpetuation of bipolar symptoms. It deserves attention as a direct target of intervention in bipolar disorder.

Now, let’s discuss how a ketogenic diet, a known therapy for metabolic disorders, can help.

How keto treats hypometabolism in bipolar disorder

Ketogenic diets are a neuron’s best friend. Not only do they provide an alternative fuel source to glucose in the form of ketones, this ketone energy just slips right into the neuron, bypassing any special enzyme processes or faulty transporter functions. This improved energy metabolism gives the bipolar brain energy to do all the things it needs to, much better than it could before.

As if having a better fuel source that brains could use better was not enough, the ketones themselves are gene signaling bodies. this means they can turn genes on and off in various pathways. And one of the things these ketones do is encourage the cell to make more mitochondria. Ketones literally increase brain energy by making more of those cell batteries and then providing the fuel to burn in them.

If you are still unconvinced that a ketogenic diet should be considered as a treatment for the hypometabolism seen in bipolar disorder, it may benefit you to learn about how some of the symptoms of bipolar disorder are similar to what we see in neurodegenerative diseases.

The pattern of hypometabolism in the brain in bipolar disorder, is so similar to Alzheimer’s disease, that in older patients a differential diagnosis is very challenging and sometimes not possible.

…our results unveil shared common neurocognitive features in bipolar patients with cognitive impairment of suspected neurodegenerative origin they suggest a participation of various underlying pathologies…

Musat, E. M., et al., (2021). Characteristics of Bipolar Patients with Cognitive Impairment of Suspected Neurodegenerative Origin: A Multicenter Cohort. https://doi.org/10.3390/jpm11111183

In fact, bipolar disorder features many of the same abnormalities, both in brain metabolism and signaling pathways as many neurodegenerative diseases, including Alzheimer’s disease (AD), Lewy Body Dementia, and even some aspects of Parkinson’s disease.

Ketogenic diets are an evidence-based treatment for Alzheimer’s disease, with several RCTs showing benefits. Why would it not help these same brain regions struggling with energy and metabolism? Especially when we can see that many of the very same brain regions are involved.

How do we know this? Do we have RCT brain imaging studies yet showing improved activity in the brain specifically in people with bipolar disorder who adopt a ketogenic diet? Not that I found. But I am pretty sure they are coming. Because we see a huge reduction in symptoms in many people with bipolar disorder that move to a ketogenic diet. And some of that symptoms reduction is defiantly coming from improved brain energy.

A ketogenic diet allows the bipolar brain to gobble up ketones for fuel and use them instead of primarily glucose for fuel. This increased fuel is a rescue mechanism for brain metabolism. Allowing more energy in the cell allows cell repair, maintenance, improved neuron transmission, better action potentials, you name it. Your brain needs adequate energy to do it.

There is a sweet spot in future research to tease out metabolisms’ relationship with different neurotransmitter systems. So until that research is done, we will have to discuss each in separate sections. It’s time to move from hypometabolism to neurotransmitter imbalances.

BIpolar Disorder and Neurotransmitter Imbalances

There are many different kinds of neurotransmitter chemicals in the brain. The neurotransmitters implicated in bipolar illness include dopamine, norepinephrine, serotonin, GABA (gamma-aminobutyrate), and glutamate. Acetylcholine is also implicated but will not be reviewed in this blog post. When we talk about neurotransmitter imbalances, it is important to understand that we are not just talking about too much or too little of any in particular. 

That might be the case to some extent, with the making less of one and more of another could be helpful. But what we are talking about is how neurotransmitters are made and used. Are the receptors designed to take the neurotransmitters into the cells working well? Can the cell membrane do its part in making the neurotransmitter or storing the nutrients it needs to make neurotransmitters? 

Are there too many receptors for one kind of neurotransmitter? If so, what does that mean for how long a neurotransmitter stays around in the synapse to be of benefit? Are there genetic polymorphisms that affect the enzymes that are supposed to make neurotransmitters or do the work of breaking them back down?

You get the idea. My point is that when I discuss particular neurotransmitters below, I am writing about a complex system. And system thinking takes a shift in perspective. So keep that in mind as you read about neurotransmitter imbalances in bipolar disorder.

Dopaminergic System

Dopamine (DA) receptor and transporter dysfunctions play a significant role in the pathophysiology of bipolar disorder in both manic and depressive states.
One very consistent finding comes from dopaminergic agonists in research studies. Dopaminergic agonists block dopamine receptors, so dopamine stays active in the synapse longer and exerts a more substantial effect. When researchers do this, they can simulate episodes of mania or hypomania in bipolar patients, or even just those who have an underlying predisposition to develop the disease.

Some studies have found that bipolar patients have higher dopaminergic system activity and that this activity may be due to increased release of the neurotransmitter and problems managing it through synaptic functions. These factors may be associated with developing manic symptoms in bipolar patients. And it is important to note that increased levels of dopamine have been associated with increases in oxidative stress. While this is not the oxidative stress section of the blog, oxidative stress is highly relevant to the neurotransmitter system. It interferes with important enzymatic processes and creates more reactive oxygen species, and this disrupts the environment in which neurotransmitters are trying to be made, having significant downstream effects.

Norepinephrinergic System

Norepinephrine is a key neurotransmitter in bipolar disorder. Dopamine is converted to norepinephrine by the enzyme Dopamine-β-hydroxylase (DβH). When there is less of this enzyme activity, and therefore less dopamine converted into norepinephrine, study participants report higher bipolar symptomology on checklists.

MHPG, a byproduct made by the metabolic process of creating norepinephrine (called a metabolite), is considered a potential biomarker for identifying mood states. This metabolite is proposed to represent clinical characteristics as a bipolar patient switches between depressed and manic states. And when lithium is used, there is a decrease in this very same biomarker.

Norepinephrine activity appears to fluctuate based on the bipolar phase. Lower norepinephrine levels and receptor (a2) sensitivity are reported during depressed states and higher activity during manic phases.

Glutamatergic System

Glutamate is an excitatory neurotransmitter with roles in many complex and essential processes. We see higher amounts of glutamate activity in bipolar disorder.

You want some glutamate, but not too much, and you want higher concentrations in the right areas. When conditions are not optimal in the brain, for whatever reason but most likely due to inflammation (as you will learn about later), the brain will make too much glutamate (up to 100x more than normal levels). Glutamate at these levels is neurotoxic and causes neurodegenerative aging. Too much glutamate causes damage to neurons and synapses and creates damage that the brain must then attempt to heal (and a workload of damage repair it will not be able to keep up with when high glutamate is chronic).

Studies consistently show a decrease in the expression of molecules involved in glutamate transmission between neurons in the brains of people who have bipolar disorder. One hypothesis is that the constant excess of glutamate in the brain of bipolar disorder patients changes receptors to reduce the damaging effects.

Glutamate is a neurotransmitter that affects mood. We see higher glutamate levels in a host of mental illnesses, like anxiety, pain disorder, PTSD, and bipolar disorder is no exception in sharing this common neurotransmitter imbalance. Except in bipolar disorder, instead of creating a panic attack as it might in someone with generalized anxiety, glutamate can be seen in elevated levels, specifically during the manic stage of the illness.

GABAergic System

GABA is an inhibitory neurotransmitter that acts as the brakes for excitatory neurotransmitters like glutamate. GABA is implicated in bipolar disorder and is associated with manic and depressive states, and clinical data indicate that decreased GABA system activity is associated with depressive and manic states. Psychiatrists will often prescribe GABA-modulating medications because this appears to have a mood-stabilizing effect on bipolar disorder.

There are consistently lower markers (measurements) of GABA in the brains of bipolar individuals, and while this is not exclusive to bipolar disorder and occurs in other psychiatric illnesses, it is a consistent finding. The use of drugs targeting the GABA system is used to help treat the depressive phase of bipolar disorder. Both gene association and postmortem studies show evidence of abnormalities in the GABA signaling system.

Patients who have a reduction in GABA present as having more significant cognitive impairments and specifically in inhibitory control of behavior.

Serotoninergic System

We know that serotonin plays a role in bipolar disorder. Evidence supporting that serotonin (also called 5-HT) deficits are involved in mania and that increasing or enhancing serotonin has a mood-stabilizing effect have been done in a variety of studies using different markers (e.g., tryptophan depletion, postmortem, platelet, and neuroendocrine).

The decreased release and activity of serotonin are associated with suicidal ideation, suicide attempts, aggression, and sleep disorders. There are all symptoms that are experienced by people with bipolar disorder. But as we discussed in the blog post introduction, medications that attempt to alter this system are often insufficient in reducing these symptoms in this population.

Cell membrane function and BDNF

You cannot discuss neurotransmitter balancing without a discussion of membrane function. As you already learned, cells need the energy to fire an action potential (cell firing). And important things happen when neurons fire, such as the ability to regulate calcium concentrations. You have to have a healthy cell membrane to have good energy production and control amounts of essential minerals the brain needs to generate action potentials, maintain the health of the cell, store nutrients for neurotransmitter production and enzyme function.

In bipolar disorder, the loss of sodium/potassium function and subsequent loss of (sodium) Na+/ (potassium) K+-ATPase Function (critical enzyme functions to create energy) occurs and contributes to cells’ energy deficit. Resulting changes in membrane function could influence manic and depressed states of bipolar disorder.

Brain-derived neurotrophic factor (BDNF) is a substance made in the brain that helps repair cells and makes new connections for learning and between brain structures. Remember how we discussed the neural circuitry abnormalities in the white matter? You need BDNF to help rewire something like that. And people with bipolar disorder do not have enough BDNF to do that well or to keep up with repairs needed from chronic states of neuroinflammation.

Hopefully, this blog post is beginning to answer the question of Can the ketogenic diet treat bipolar disorder? You can see how the effects on neurotransmitter balance make the ketogenic diet treatment for bipolar disorder.

How keto balances neurotransmitters

Ketogenic diets have direct effects on several neurotransmitters. There are plenty of studies showing an increase in serotonin and GABA, and balancing of glutamate and dopamine. There is some interaction between ketogenic diets and norepinephrine that is currently being investigated in research on epilepsy. There does not appear to be an influence of ketones on norepinephrine directly, but downstream as it is converted into dopamine.

Ketogenic diets balance neurotransmitter production and activity, so you won’t get too much of one or too little of another, and end up getting side effects as you sometimes would with medications.

The upregulation of certain neurotransmitters, such as GABA, is obviously beneficial to mood and its increase helps balance out excitatory glutamate production. This is likely a mechanism by which we see the improved mood in bipolar individuals, and could also directly influence a reduction in manic states.

Another important mechanism by which we see improvements in neurotransmitter balance is in improved cell membrane function. Ketogenic diets strengthen communications between cells and help regulate the influx of micronutrients (remember sodium, potassium, and calcium?) needed for cell firing. Improved membrane function also occurs through a mechanism that upregulates (makes more) BDNF, so cells and cell membranes are better able to repair themselves. And as an added bonus, this improvement in cell membrane function allows membranes to store important micronutrients needed to produce neurons and initiate repairs (using that fantastic extra supply of BDNF).

But as we will learn below, neurotransmitters cannot be made well or in balanced amounts in an environment that is constantly under attack and dysregulated by inflammation. And so we end our discussion of neurotransmitters but only in relation to the other pathological mechanisms happening in the bipolar brain, which include inflammation and oxidative stress.

Bipolar Disorder and Inflammation

Inflammation is such an issue in bipolar disorder that it is an important body of research all by itself and is identified as a significant underlying mechanism of the illness.

  • Micronutrient deficiency
    • resulting in the inability of the cell to maintain health and function)
  • Viruses and bacteria
  • Allergies
    • food or environemntal
  • Environmental toxins
    • pollution, pesticides, heribcide, plastics, mold
  • Gut microbiome
    • overgrowth of generally negative species that create gut permiability and inflammation
  • Inflammatory diets
    • standard American diet, highly processed carbohydrates, industrialized oils, uncontrolled high blood sugars

Chronic neuroinflammation is an immune response to one or more of these types of assaults. This immune response results in the activation of microglial cells that then produce inflammatory cytokines, particularly, TNF-α and IL-1β, to neutralize what is perceived as dangerous. But in doing so, there is damage done to surrounding tissues from these cytokines. The brain then needs to repair, which is challenging to accomplish when there is constant and nonstop inflammation.

One fascinating theory of the depressive symptoms seen in bipolar disorder has to do with the seasons. There is a higher rate of depressive symptoms in bipolar disorder in the spring. One interesting study found that depressive symptoms correlated with blood serum immune marker immunoglobulin E. It is thought that in the spring, as pollen goes up, symptoms of depression in bipolar individuals can become exacerbated due to the pro-inflammatory cytokine response triggered by allergies.

Microglial production of inflammatory cytokines is particularly relevant in bipolar disorder because they offer an explanatory mechanism for symptoms we see in bipolar disorder. Inflammatory mediators, like cytokines, shape synaptic transmissions and even strip away connections between brain cells (a usually normal process called pruning that gets out of hand with chronic neuroinflammation). These alterations in the brain impair attention, executive function (planning, learning, controlling behavior and emotion), and memory deficits. The hippocampus, which is a part of the brain with important functions in memory formation, is particularly hit hard by neuroinflammation. Unrestrained production of inflammatory cytokines results in premature brain cell death.

Increased inflammatory cytokine production has a strong role in why we see progressive worse dysfunction in the population over tie and in several areas of measurement. The overactivation of microglial cells leads to increased cognitive impairment, progressively worsened functioning, medical comorbidities that include chronic illness, and finally, premature mortality in those with bipolar disorder.

So inflammation and the reduction of inflammation, and hopefully fixing the root cause of inflammation for the individual patient, becomes a very important target of intervention on their journey to wellness.

How keto reduces inflammation

I don’t think a better intervention for inflammation exists than the ketogenic diet. I know that is a lofty statement but bear with me. Ketogenic diets create something called ketones. Ketones are signaling bodies, meaning they are able to talk to genes. Ketone bodies have been seen to literally turn genes off that are a part of chronic inflammatory pathways. Ketogenic diets are so effective at inflammation they are being used for arthritis and other chronic pain conditions.

But wait a minute, you may say, those are not conditions of brain inflammation. Those are diseases of peripheral inflammation so they don’t count. Touche.

But we know that ketogenic diets are so good for neuroinflammation that we use them with traumatic brain injury. After an acute traumatic brain injury, there is a huge cytokine storm in response to the injury, And this response does more damage often than the initial assault. Ketogenic diets quiet that response If a ketogenic diet can mediate brain injury neuroinflammation, I don’t see why it would not be a stellar option for bipolar disorder. We also use it for several neurodegenerative diseases like Alzheimer’s, Parkinson’s disease, and ALS. All conditions with a very significant neuroinflammation component.

So why wouldn’t we use a well-formulated, anti-inflammatory ketogenic diet to treat the underlying inflammatory mechanisms we see in bipolar disorder?

Bipolar Disorder and Oxidative Stress

Oxidative stress is what happens when there are too many reactive oxygen species (ROS). ROS happens no matter what we do. But our bodies know what to do about it. We even have endogenous (made in our body) antioxidant systems in place that help us deal with them and mitigate the damage of being alive and breathing, and eating. But in people with bipolar disorder, these antioxidant systems are not working optimally or cannot keep up with the damage going on. And so, in people with bipolar disorder, oxidative stress markers are consistently higher than normal controls in the research literature. It is not just one marker that is particularly high; it is many of them.

Oxidative stress, and the body’s inability to adequately quell neuroinflammation, are responsible for the hippocampal aging proposed to underlie the neurocognitive dysfunctions observed in BD patients. Oxidative stress causes accelerated brain aging in BD and is even responsible for high levels of mitochondrial (cell batteries) DNA mutations seen in post mortem studies.

But just giving people with bipolar disorder antioxidant treatments to reduce oxidative stress has mixed results, and researchers believe this may be because oxidative stress levels are being influenced by mitochondrial dysfunction. Remember what we learned about brain hypometabolism and the energy deficit and mitochondrial dysfunction we see in bipolar disorder? Bipolar disorder is a metabolic disorder of the brain, and there is just not enough energy for the brain to use?

That same issue may be responsible for the oxidative stress levels seen by researchers. At least in some portion of those with bipolar disorder and oxidative stress.

Regardless of whether it is the primary cause or a secondary mechanism of pathology in bipolar disorder, we know that oxidative stress is instrumental in creating the symptoms we see in bipolar disorder. And for that reason, we need an intervention that directly reduces oxidative stress, preferably by several mechanisms.

How keto reduces oxidative Stress

My favorite system is endogenous antioxidant system is glutathione. This is a very powerful antioxidant system that ketogenic diets actually upregulate. This upregulation in glutathione helps you reduce oxidative stress, and may improve the functioning and health of the bipolar brain. The improved nutrition that occurs with a well-formulated ketogenic diet also improves glutathione production. So added bonus.

Two types of ketones—β-hydroxybutyrate and acetoacetate—were found to reduce ROS levels in isolated neocortical mitochondria (Maalouf et al., 2007)

Further investigation is required to determine specific mechanisms of a KD on oxidative stress through influences on ROS and antioxidant levels. It is likely that the anti- inflammatory effects of ketone bodies are achieved by affecting multiple biochemical pathways.

Yu, B., Ozveren, R., & Dalai, S. S. (2021). Ketogenic diet as a metabolic therapy for bipolar disorder: Clinical developments.
DOI: 10.21203/rs.3.rs-334453/v2

As the quote communicates so well, ketogenic diets are affecting multiple pathways that modulate oxidative stress. Besides ketone bodies, the improved neuronal health that occurs with a ketogenic diet, such as increased BDNF, balanced neurotransmitters that don’t cause neuronal damage (I am looking at you, glutamate and dopamine!), and healthier function cell membranes all do their part in reducing oxidative stress. That improved membrane potential and function, along with improved nutrient intake from a well-formulated ketogenic diet, really improve enzyme and neurotransmitter production, which play a role in fighting oxidative stress.

And you already know and understand that ketogenic diets upregulate the production of mitochondria, improving their functioning, but also encourage brain cells to make more of them. And imagine how much better a brain cell can manage ROS with so many more little cell powerhouses humming along making energy. This might be the mechanism by which oxidate stress has the potential to be reduced the most in the bipolar brain.

Conclusion

Now that you have learned the powerful effects of the ketogenic diet on brain hypometabolism, neurotransmitter balance, inflammation, and oxidative stress I will leave you with this quote discussing the current hypothesized around the disease processes we see in bipolar disorder.

A pathophysiological hypothesis of the disease suggests taht dysfunctions in intracellular biochemical cascades, oxidative stress and mitochondrial dysfunction impair the processes linke to neuronal plasticity, leading to cell damage and the consequent loss of brain tissue that has been identified in postmortem and neuroimaging.

Young, A. H., & Juruena, M. F. (2020). The Neurobiology of Bipolar Disorder. In Bipolar Disorder: From Neuroscience to Treatment (pp. 1-20). Springer, Cham. https://link.springer.com/chapter/10.1007%2F7854_2020_179

At this point, I feel confident you can make those connections and have a better understanding of how a ketogenic diet may be a powerful treatment for your bipolar disorder or that of someone you love.


I would have been afraid to write this blog post a few years ago, even though there were a lot of anecdotal reports coming out from people reporting significantly improved symptoms and functioning. I am so excited to see so much research being done.

The reason I am feeling more confident in writing a blog post like this is that there are peer-reviewed case studies showing remission of bipolar symptoms using the ketogenic diet and RCTs underway looking at the ketogenic diet as a treatment for bipolar disorder. There is even work by researchers analyzing in the comments in forums where people with bipolar disorder discuss using the ketogenic diet to feel better (see Ketosis and bipolar disorder: controlled analytic study of online reports).

There is an excellent table (Table 1) in the journal article Ketogenic diet as a metabolic therapy for bipolar disorder: Clinical developments that neatly outlines the mechanisms by which a ketogenic diet could help treat bipolar disorder. Since you have just taken the time to read this article, you will understand so much better what this table is communicating! I have recreated it here:

BD MechanismsBD SymptomsPotential KD Effects
Mitochondrial DysfunctionDecrease in energy level productionInduces mitochondrial biogenesis
Na/K
ATPase loss of function
Impaired ATP production via Oxidative phosphorylationprovides alternative energy production pathway via ketosis
PDC DysfunctionUnsustainable ATP levels due to glycolysis-only productionProvides alternative energy production pathway via ketosis
Oxidative StressIncrease in ROS leading to neuronal damageReduces ROS levels with ketone bodies; Increases HDL cholesterol levels for neuroprotection
Monoaminergic ActivityChanges in behavior and emotion due to imbalanced neurotransmitter concentrationsRegulates neurotransmitter metabolites via ketone bodies and intermediates
DopamineIncrease in receptor activation inducing mania symptomsDecreases dopamine metabolites
SerotoninReduced levels inducing depressive symptomsDecreases serotonin metabolites
NorepinephrineReduced levels inducing depressive symptomsNo significant changes observed in prior studies
GABAReduced levels related to depressive and mania symptomsIncreases GABA levels
GlutamateIncrease in levels leading to unsustainable energy requirements and neuronal damageDecreases glutamate levels
GSK-3 Enzyme Dysfunction / DeficiencyApoptosis and neuronal damageIncreases antioxidants to provide neuroprotection
(Table 1) in the journal article Ketogenic diet as a metabolic therapy for bipolar disorder: Clinical developments

If you found this blog post helpful or interesting, you may also enjoy learning how the ketogenic diet can play a role in modifying gene expression.

If you have comorbidities with other disorders, you may find it helpful to search my blog (search bar at the bottom of the page on desktops) and see if the ketogenic diet has beneficial effects on those disease processes as well. Some of the more popular ones that may be relevant to bipolar disorder include:

As a mental health practitioner who helps people transition to a ketogenic diet for mental health and neurological issues, I can tell you that I see improvements very often in those who are able to use the ketogenic diet consistently. And that is the majority of my patients. It is not an unsustainable therapeutic for bipolar disorder or any of the other disorders I treat using the ketogenic diet, psychotherapy, and other nutritional or functional psychiatry practices.

You may enjoy reading my small sample of Case Studies here. For some of my clients, it is about trying something other than medications to treat their bipolar disorder. For most, it is about reducing the prodromal symptoms they continue to live with, and many stay on one or more medications. Often at a lower dose.

You may also enjoy these other posts about bipolar disorder and using the ketogenic diet here:

If you would like to contact me you may do so here. I am happy to help you find resources or guide you on your wellness journey while coordinating with your prescriber. I hope this article has been helpful in your ability to know all the ways you can feel better!

Like what you are reading on the blog? Want to learn about upcoming webinars, courses, and even offers around support and working with me towards your wellness goals? Sign up!


References

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Brady, R. O., McCarthy, J. M., Prescot, A. P., Jensen, J. E., Cooper, A. J., Cohen, B. M., Renshaw, P. F., & Ongür, D. (2013). Brain gamma-aminobutyric acid (GABA) abnormalities in bipolar disorder. Bipolar Disorders, 15(4), 434–439. https://doi.org/10.1111/bdi.12074

Campbell, I., & Campbell, H. (2019). A pyruvate dehydrogenase complex disorder hypothesis for bipolar disorder. Medical Hypotheses, 130, 109263. https://doi.org/10.1016/j.mehy.2019.109263

Campbell, I. H., & Campbell, H. (2019). Ketosis and bipolar disorder: Controlled analytic study of online reports. BJPsych Open, 5(4). https://doi.org/10.1192/bjo.2019.49

Ching, C. R. K., Hibar, D. P., Gurholt, T. P., Nunes, A., Thomopoulos, S. I., Abé, C., Agartz, I., Brouwer, R. M., Cannon, D. M., de Zwarte, S. M. C., Eyler, L. T., Favre, P., Hajek, T., Haukvik, U. K., Houenou, J., Landén, M., Lett, T. A., McDonald, C., Nabulsi, L., … Group, E. B. D. W. (2022). What we learn about bipolar disorder from large-scale neuroimaging: Findings and future directions from the ENIGMA Bipolar Disorder Working Group. Human Brain Mapping, 43(1), 56–82. https://doi.org/10.1002/hbm.25098

Christensen, M. G., Damsgaard, J., & Fink-Jensen, A. (2021). Use of ketogenic diets in the treatment of central nervous system diseases: A systematic review. Nordic Journal of Psychiatry, 75(1), 1–8. https://doi.org/10.1080/08039488.2020.1795924

Coello, K., Vinberg, M., Knop, F. K., Pedersen, B. K., McIntyre, R. S., Kessing, L. V., & Munkholm, K. (2019). Metabolic profile in patients with newly diagnosed bipolar disorder and their unaffected first-degree relatives. International Journal of Bipolar Disorders, 7(1), 8. https://doi.org/10.1186/s40345-019-0142-3

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