Quieting the bipolar mind: can a ketogenic diet stabilize mood?

Disclaimer: Please note that I am in no way endorsing nutritional ketosis as a supplement to, or a replacement for medication. There is very little data actually supporting the use of a ketogenic diet as a treatment for bipolar, and a well-documented case where a bipolar patient on valporic acid developed full-blown mania with psychosis after starting a ketogenic diet (thanks to @neurocritic for pointing me to this report; read about it below).  This post talks about the theory behind using keto for bipolar disorder and a few recorded clinical cases.

Bipolar disorder is often described as a dizzying, sinister and emotionally draining roller-coaster ride. It is marked by dark periods of severe depression interspersed with mania or hypomania – insane energy levels, difficulty concentrating, distorted thinking, euphoria and thoughts that tumble around and around in the brain.

To date there is no cure for bipolar disorder, but mood swings can be managed effectively with lithium or anti-seizure medication, such as valporic acid. While effective in many cases, these drugs unfortunately come with a price: in some women lithium may lower thyroid levels causing rapid cycling of depressive-maniac cycles; valporic acid may increase the level of testosterone in young women leading to disruption of menstrual cycles and excess body hair. Many drugs also suffer from the “rebound effect”, where suddenly stopping the medication may worsen bipolar symptoms. In many cases, using a lower drug dose may minimize side effects, but sometimes at the cost of decreased efficacy.

What if there’s an alternative way –say, a diet – to stabilize mood in conjunction with drugs? Lucky for mood clinicians, there is in fact a successful pre-existing case: the use of the ketogenic diet to treat drug-resistant epilepsy. Originally introduced as a therapy for epilepsy in the 1920s, the ketogenic diet (“keto”) is a high-fat, moderate protein and very low carbohydrate diet. The diet triggers a metabolic state called ketosis, in which the body begins to generate acetone and ketone bodies to use as alternative fuels in place of glucose. Although this sense-defying style of eating accrued many skeptics and naysayers, increasing evidence is showing that keto may be used in other neurological disorders. In fact, the therapeutic potential of the diet is currently being investigated in several clinical trials for strokebrain cancer and Parkinson’s Disease.

The theory: how can a ketogenic diet stabilize mood?

Researchers have good reasons to believe that keto may alleviate bipolar symptoms. Remember that many currently used mood stabilizers are actually anticonvulsants; lithium also possess mild anti-seizure activity. Along the same lines, electroconvulsive therapy (ECT) increases seizure threshold (making it harder to trigger an attack) and is effective for both mania and depression. Finally, artificially stimulating the peripheral vagus nerve – an anticonvulsant procedure – is also effective at managing depressive and bipolar symptoms. These observations suggest that epilepsy and bipolar disorder may share certain disrupted neurobiological pathways that are targeted by the above therapies.

One idea of how mood stabilizers work is that they make neurons less excitable. The reason neurons can transmit electrical signals is because of ions (sodium, potassium, calcium) moving through their membrane. Ions cannot normally pass through the membrane; they rely on protein tunnels (called ion channels) that connect the inside of a neuron to the outside. At rest, the channels are closed and the neurons build up drastically different levels of ions across the membrane, thus forming an electrical-chemical gradient (left, graph below). When stimulated, the channels open and sodium rushes in changing the chemical gradient (middle, below), which in turn causes nearby channels to open and so on; if the neuron reaches a certain threshold of open channels, it fires an electrical impulse. This "action potential" propagates down the long axon (right, below) and triggers the release of chemical messengers stored at the synaptic terminals – where neurons talk to each other. The messengers are then captured by the next neuron, and can either excite or inhibit it depending on their chemical makeup. In a nutshell, sodium rushing in makes a neuron excited; an firing neuron can either excite or inhibit its neighbours.

Mood stabilizers reduce the amount of sodium that goes into the neurons after stimulation, decreasing its ability to pass on information. In the case of epilepsy and bipolar where neurons tend to be overly excitable, less activity is a good thing. Coincidentally, a ketogenic diet reduces intracellular sodium concentration as well, mainly due to slightly increased acidity of the blood; it also decreases the level of excitatory neurotransmitters (which excites the next neuron), further dampening neuronal activation.

Another way keto may improve bipolar symptoms is through better energy production. Patients with bipolar disorder often show deficient glucose metabolism and energetics. Since keto increases energy production in the brain as it changes the fuel source from glucose to ketones, it may solve this energy deficiency problem. Finally, a rather fringe theory proposes that a certain type of ketone can itself be euphoric as it’s chemically related to GHB, the notorious date-rape drug. While somewhat amusing, this theory will probably remain just a theory for a very long time.

The practice: can a ketogenic diet truly relieve bipolar symptoms?

Theoretically, keto can act as a mood stabilizer. But is there any actual evidence?

Unfortunately to date there are only two clinical case reports using the ketogenic diet for bipolar disorder. The first one was a face-palming fail. In 2002, a team of clinicians put a 49-year-old woman with drug-resistant bipolar disorder on a month-long ketogenic diet. The lady did not show any improvement of symptoms, but researchers also couldn’t detect any urinary ketones, weight loss or changes in liver function, suggesting that somehow she managed to resist going into ketosis.

A case report from 2013 presented far more encouraging results. The report documented two patients with Type II Bipolar. That is, they suffer from hypomania (“below mania”) and depressive episodes rather than full-blown mania. Both patients were women whose bipolar symptoms manifested in their young adulthood and had previously responded badly to medication, including drug-induced suicidal thoughts and attempts. Before the diet, both ladies had tried an anticonvulsant called lamotrigine, which worked decently for one but not the other.

Mrs. A began her diet in January of 2010 and maintained it for two years, eating a diverse range of high quality keto-friendly food (free range meats, diary, seafood). She was able to lower and ultimately stop her medication and control her symptoms with diet alone. In her words: ...I have not lost my temper once [since establishing ketosis], nor have I felt like it…I believe that being in ketosis has been life changing for me. Her serum lipid profile was similar to periods when she was on a vegetarian diet or an omnivore diet. Interestingly, she reported that her symptoms seemed better controlled with 15mg/dL of urine ketones compared to 5mg/dL, suggesting that the degree of ketosis may be important for bipolar management.

Mrs. B had previously tried the diet to control flare-ups for irritable bowel syndrome and serendipitously noticed its mood stabilizing effect. In preparation for pregnancy she stopped lamotrigine and went back on the diet. Within 3 days of achieving ketosis, she reported “ a sense of calm, confidence and kindness” and her symptoms have remained stable on the diet for 3 years. Both ladies were medically monitored and given supplements to decrease the risk of keto-related kidney stones. Neither ladies reported any adverse effects or symptoms of anxiety.

A final word: can a ketogenic diet stabilize mood?

While intriguing, it’s very difficult to generalize from two anecdotes. The studies were completely open label, so both patients and clinicians knew of the desired result. Both ladies were extremely motivated and dedicated to the n=1 experiments "wanting" the intervention to work – hence placebo effects may play a large role in the self-reported improvements. The ladies both took a paleo-like approach to their diet, eliminating processed foods, gluten and sugar and supplementing with of omega 3s and probiotics; any or all of these could have accounted for the perceived mood stabilization. The ladies were closely monitored for any sign of medical problems, so don't try this at home without talking to your physician. And one has to wonder: are there any cases where a ketogenic diet did not improve bipolar symptoms, but they just weren’t reported?

It's also important to realize that keto can come with nasty side effects. Common complaints include constipation, dehydration and micronutrient and electrolyte deficiencies – the latter is no joke as it may induce irregular heartbeats. Other serious complications include increased chance of kidney stones, gallbladder problems and bone fractures, especially in children. But perhaps more disturbingly, keto may backfire in its use for bipolar disorder. A report from 2005 documented the case of a 54-year old man who started the Atkins diet while on valproate medication. Two weeks later, he reported sleeping problems; a months after that, his family voiced concern over his escalating bizarre behaviours and paranoia. In the end, two months into the Atkins diet, he was finally admitted to the hospital after being evicted from his apartment for causing extreme damage to the building. At the time of admission his thoughts were rambling and tangential and his mood irritable and expansive. The doctors placed him on a regular diet and continued his pre-admission medications for roughly 3 weeks until his mood stabilized and delusions improved.

From these highly contradictory reports it's clear that we don't know whether keto is beneficial for bipolar disorder, and if so, under what circumstances. For answers, we will have to wait for results from large-scale, randomized control experiments exploring the effects of keto on mood swings in bipolar disorder. But it's definitely an interesting field to keep an eye on.

Disclaimer: Once again, please don't try a ketogenic diet without talking to your doctor first. As you can see there is very little evidence that keto is beneficial for bipolar disorder, and that going into ketosis may trigger full-blown mania in some. 

Phelps JR, Siemers SV, & El-Mallakh RS (2013). The ketogenic diet for type II bipolar disorder. Neurocase, 19 (5), 423-6 PMID: 23030231
El-Mallakh RS, & Paskitti ME (2001). The ketogenic diet may have mood-stabilizing properties. Medical hypotheses, 57 (6), 724-6 PMID: 11918434