Is there a genetic component to bipolar disorder?
There is definitely a genetic component to bipolar disorder. Hereditability is estimated to be between 60–85%. Some of the genes have been identified as important targets for pharmacological intervention. Ketones are active mediators in some of these gene pathways, either in expression or in expression further downstream. Ketogenic diets are currently being investigated as a treatment for bipolar disorder.
Usually, when I write about mental illness and the use of the ketogenic diet as a treatment, I focus on the aspects of glucose hypometabolism, neurotransmitter imbalances, inflammation, and oxidative stress. But in doing my research for a blog post on bipolar disorder, I was excited to see so much research being done on genetic mechanisms. As I read through some of the genes identified, I recognized many of them or the pathways they influence as being influenced by ketones.
My genetic biochemistry is not what I would call solid. But I decided that because bipolar disorder and subsequent mood disturbances are found to have high heritability, it may be helpful to talk about it.
On the basis of twin and family studies, the heritability of BD is estimated at 60–85%.Mullins, N. et al., (2021). Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology.
Why would I want to talk about genetic influences in bipolar disorder?
Because sometimes when we are told that our mental illness is genetic, we feel powerless to change symptoms. And if I am able to convince you that there is something you may be able to do to moderate some of the gene expression found to be highly associated with bipolar disorder, it might give you some hope that you can feel better.
I know that if you have bipolar disorder and are reading this blog post, you may be one of the two-thirds of BPD sufferers who, while medicated, still suffer from prodromal symptoms and even episodic depression. And so, because I want you to know all the ways you can feel better, I will share with you what I learned.
As you read below, keep in mind that the bipolar brain struggles with higher levels of inflammation and oxidative stress, brain energy (glucose hypometabolism), and neurotransmitter imbalances. This will help you understand how a ketogenic diet and its effects on gene signaling and beneficial downstream effects may provide an effective treatment option.
Genes, ketones and bipolar disorder
It is of great interest to note, that BPD-associated genes are being found and identified all the time. Four of the most promising targets for new drug development for BPD are influenced by β-Hydroxybutyrate or other ketone bodies. And it just so happens that ketones are produced as part of a ketogenic diet. A search of the literature showed that the effects were either direct or downstream affecting a related mechanism seen in the pathology of bipolar disorder. These include GRIN2A, CACNA1C, SCN2A, and HDAC5.
β-Hydroxybutyrate, a ketone body, reduces the cytotoxic effect of cisplatin via activation of HDAC5. Inhibition of HDAC5 is shown to be neuroprotective by inhibiting apoptosis pathways. Why would ketones not assist in treating genetic variations of HDAC5 by inducing neuroprotective effects? Do we really need new drugs to influence HDAC5 mutations to treat bipolar disorder?
Could HDAC5 mutations and the neuroprotective effects of ketones on this pathway be one of the mechanisms that make a ketogenic diet treatment for bipolar disorder? I think it could be. And these are all questions I am hoping to see debated and answered in the research literature over the next decade.
Let’s next discuss the GRIN2A gene. This gene makes the GRIN2A protein. This protein is a component of N-methyl-D-aspartate (NMDA) receptors (ion channels). NMDA receptors are controlled, in part, by glutamate and send excitatory signals in the brain. NMDA receptors are involved in synaptic plasticity (learning and memory) and play a role in deep sleep. I include the effects of ketones on the NMDA pathway here, mostly because the receptors are glutamate-regulated.
But I could just as easily put it in the inflammation or oxidative stress section of this post. Because when glutamate is high, it is often due to neuroinflammation affecting neurotransmitter production and balance. Just know that imbalances in neurotransmitter systems (e.g., increased glutamate levels and NMDA receptor activity; increased NMDA-excitotoxicity) are associated with bipolar disorder. Ketones mediate inflammation directly and influence glutamate production so that the inflammation is downregulated and glutamate is made in the right amounts and ratios.
SCN2A is a gene that provides instructions for making a sodium channel protein called NaV1.2. This protein allows neurons to communicate using electrical signals called action potentials. Ketogenic diets have long been used to treat epilepsy and are used specifically to treat those with specific genetic mutations in SCN2A. I do not believe that it is an unreasonable stretch to imagine that ketogenic diets may help treat the genetic variations in the SCN2A gene that we see in bipolar populations.
CACNA1C is also identified as having a strong association with bipolar disorder. It also affects voltage-dependent calcium channels, which are important for membrane function in the neuron. You need healthy neuronal cell membranes to accomplish important goals such as nutrient storage, neurotransmitter production, and communication between cells.
CACNA1C is instrumental in subunit alpha1 calcium channel function. And while my current level of genetic biochemistry does not allow me to perfectly trace this path, I do know that something called paroxysmal depolarization shifts (PDS) are thought to be involved in epileptic seizures. Ketogenic diets appear to stabilize depolarization shifts in populations with epilepsy, and this is thought to be one of the mechanisms by which ketogenic diets work in this population. And by work, I mean literally reduce and sometimes stop the seizures.
Improved repolarization and membrane stabilization may also occur indirectly by increasing cell energy and bypassing dysfunctional brain metabolism. Ketones provide this improved energy source, and so while ketones may not directly affect the CACNA1C pathway expression, they may provide the remedy for the influence of a CACNA1C snip influencing bipolar symptoms.
Seizure disorders have been treated using the ketogenic diet since the 1920s, and these effects are well documented and irrefutable at this point. The influence of ketones on calcium channels and repolarization of neuronal membranes is well-documented in the epilepsy literature.
But my point is that ketogenic diets treat calcium channel dysfunction and improve neuronal membrane health and functioning. So why would it not work to help those with bipolar disorder? Could this not be another mechanism by which the ketogenic diet could help reduce bipolar symptoms?
These are examples of genes identified as having influence in the disease process of bipolar disorder, potentially being regulated through the act of ketones directly or downstream in the biologically active products being made and how they are used. So while there is a significant genetic component to bipolar disorder, there are also ways to influence those genes and how they are expressed, modifying how they are expressed further down important pathways.
It’s important to me that you know all the ways that you can feel better, and that you understand that just because something is genetic, it does not mean you cannot turn some of those genes on and off with your lifestyle or other factors. And it does not mean your genes get to dictate your destiny when it comes to chronic illness – even chronic psychiatric illness, like bipolar disorder.
Bipolar disorder (BD) is a severe psychiatric disorder characterized by repeated conflicting manic and depressive states. In addition to genetic factors, complex gene-environment interactions, which alter the epigenetic status in the brain, contribute to the etiology and pathophysiology of BD.(emphasis added) Sugawara, H., Bundo, M., Kasahara, T. et al., (2022). https://doi.org/10.1186/s13041-021-00894-4
If you liked this blog post regarding genetic components to bipolar disorder, you will likely find my blog post on ketogenic diets for bipolar disorder helpful.
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As always, this blog post is not medical advice.
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