Metabolism and Mental Health

Obesity and mental illness

Major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia are all associated with increased rates of obesity. Obese individuals were more likely to have mood disorders than those of healthy weight. ¹ After their first hospitalization for psychosis, almost two-thirds of patients with schizophrenia and over half of those with BD became obese within 20 years. ²

Obesity worsens the course of bipolar I disorder and impairs cognition. ³ Obese people are 25% more likely to have a mood or anxiety disorder. ⁴ Diets high in junk food lead to higher rates of obesity and depression. ⁵ Why is this so? Perhaps it can be explained by this finding: individuals with higher body mass index exhibit alterations in brain circuit connectivity, causing disturbances in mood and cognition. ⁶

Diabetes, depression, and BP

About 5% of the global population is diagnosed with depression. Among diabetics, however, the incidence of depression is 25%.

Patients with schizophrenia are three times more likely to develop diabetes than the general population. ⁷ Patients diagnosed with depression are 60% more likely to develop diabetes than the general population. ⁸ People who present with new-onset schizophrenia often have glucose dysregulation as well, even if they do not yet meet the criteria for diabetes. ⁹

BD is a complex disorder of which we have a poor understanding. Over the past several decades, no novel treatments have been developed for BD specifically. However, there is increasing evidence of elevated brain lactate levels compared with healthy controls as a biological marker for BD. ¹⁰

Increased lactate levels occur with mitochondrial dysfunction. The cause is the switch from mitochondrial oxidative phosphorylation or respiration to cytoplasmic glycolysis, as described by Warburg.

Fifty percent of BD patients have impaired glucose metabolism. Brain imaging shows a similar (although milder) decrease in brain glucose utilization in BD compared with Alzheimer’s. ¹¹

Diabetes often comes before obesity in people with severe mental illness. ¹²

Cardiovascular disease, schizophrenia, and BD

People with schizophrenia and BD are much more likely to have cardiovascular disease (CVD) than the general population. ¹³ Depression is also a major risk factor for CVD. In healthy people, depression increases the risk of CVD by 50%–100%, while in people with CVD, depression increases the risk of another CV event by 50%–150%. ¹⁴ Twenty percent of people with coronary artery disease and 33% of people with congestive heart failure also have depression.

Longevity

Mental health affects longevity because mental disorders are associated with increased mortality. Schizophrenia reduces life expectancy by 10–30 years, BD by 9–25 years, and MDD by 7–18 years. ¹⁵ The average decrease overall is 10 years for men and 7 years for women. While suicide rates are higher in this population, the leading causes of death are diabetes, CVD, and cancer. ¹⁵ The former two and possibly the third are metabolic diseases associated with mental disorders.

Keto and epilepsy

One of the first applications of metabolic therapy was in treating brain disorders such as epilepsy. Fasting has been known as an effective means of stopping seizures since the days of Hippocrates. However, a person can fast only so long.

In 1921, a diet that mimicked fasting was developed. It was a ketogenic diet low in carbohydrates and high in fats that turned TOR (target of rapamycin) down. It achieved results similar to fasting and caused a remission of seizures over a sustained period.

However, once drugs (with significant side effects) were developed, ketogenic diets fell out of favor. Metabolic treatment for seizures stopped when antiseizure medications appeared. Diabetes was likewise once managed with similar diets, but then insulin injections replaced the dietary approach.

It is interesting that many of the drugs used to treat epilepsy are also effective at treating mental illness and vice versa. These include Valium, Librium, and sodium valproate. In fact, mitochondrial dysfunction and metabolic abnormalities have been documented in schizophrenia, BD, and depression. Abnormalities in glucose metabolism are often seen in untreated schizophrenia.

As a result, cutting-edge psychiatrists led by Georgia Ede, another pioneer in this space, decided to review the use of a ketogenic diet to treat mental health. Evidence shows that a potential primary metabolic intervention for mental illness is to reduce TOR with a ketogenic diet.

Researchers conducted a retrospective analysis of a group of 31 psychiatric inpatients admitted to the Clinique du Castelviel, a psychiatric hospital in France. Despite intensive management, their symptoms were poorly controlled.

The patients were placed on a strict ketogenic diet: 75%–80% fat, 15%–20% protein, and only 5% carbohydrates. They were restricted to a maximum of 20 g of carbohydrates per day. The intervention lasted from 6 to 248 days, depending on the patient’s needs. Of the 31 patients, 28 managed to adhere to the diet. Twelve of these patients had BD, 6 had MDD, and 10 had schizophrenia. Twenty-seven out of the 28 patients were later assessed.

At the end of the intervention, every patient reported improvement in symptoms. Nearly all (96%) lost weight. Twelve patients (44%) achieved clinical remission. More than half (64%) were discharged with reduced medication. ¹⁶

Sadly, we do not have large clinical trials. Yet early evidence supports the therapeutic benefits of ketogenic diets in epilepsy and other neurological conditions. This suggests this same metabolic approach may also benefit mental health conditions. Today, there are about 500 metabolic–ketogenic diet centers around the world for the treatment of seizures.

Keto and depression

Depression is now the leading cause of disability. As we have seen earlier, obesity is correlated with mental illness, and obesity is rising around the world. The good news is that weight loss alone is associated with improvements in depression. ¹⁷

Numerous studies into the use of ketogenic diets in epilepsy report improved mood, energy, sleep, and mental clarity. This suggests possible applications for treating depression. In rats, a ketogenic diet showed antidepressant effects in a standard test for depression. ¹⁸

Another clinical trial compared a group of patients following a ketogenic diet with another group that adopted a low-fat diet for 24 weeks. Health-related quality-of-life metrics were tracked every four weeks. The low-fat group reported less body pain, but not the ketogenic diet group. There were no other differences in physical component scores. However, the ketogenic diet group showed improvements in vitality and mental health. ¹⁹

Clinical trials for the treatment of major depression through metabolic therapy are underway.

Keto and alcohol use disorder

Alcohol use disorder (AUD) is associated with brain glucose hypometabolism. Ethanol (found in alcohol) generates ketones on which the brain becomes dependent. The theory behind the use of metabolic therapy is that a ketogenic diet helps to maintain ketones while allowing the patient to discontinue the use of alcohol.

A three-week inpatient trial compared the health outcomes of AUD patients who adopted a ketogenic diet versus those who followed the standard high-carb diet. A ketogenic diet was found to reduce alcohol withdrawal symptoms and change brain metabolism. The ketogenic diet group required fewer benzodiazepines to detox than the standard American diet group. ²⁰

As of time of writing, there is now a large multimillion-dollar study underway to measure the effect of a ketogenic diet on AUD.