The Current Status of the Ketogenic Diet in Psychiatry

Question
How strong is the evidence supporting the use of the ketogenic diet in psychiatric and neurological conditions?
Takeaway
Currently, the evidence indicating a ketogenic diet may be beneficial in patients with certain psychiatric and neurological conditions is preliminary but promising. In addition to the diet’s well-established benefits in patients with epilepsy, early studies suggest it may be beneficial in patients with Alzheimer’s, Parkinson’s, bipolar disorder, schizophrenia, autism, ADHD, anxiety, and depression. The majority of this evidence, however, is derived from small animal studies and human case studies. Further research is needed to better understand the nature, extent, and consistency of any benefits the diet might have.

The ketogenic diet (KD) has been used to treat epilepsy since the 1920s, an indication for which it is well-supported (1). This 2017 review assessed evidence supporting the use of the KD to treat other psychiatric and neurological conditions. There were few trials testing the KD in each condition, so the assessment is brief.

The KD is known to have effects on serotonin and dopamine (2) and therefore has been hypothesized to affect anxiety and depression. In rats, ketone supplementation reduced markers of anxiety and depression, but it is unknown how well these markers map to the same conditions in humans (3).

Two case studies tested the KD in women with bipolar disorder. In the first, two women who complied with the KD reported subjective mood stabilization beyond any effects they had experienced with medication (4). The second trial did not indicate any KD-related improvement in mood or other symptoms, but the trial was only one month long and the patient may not have actually achieved ketosis (4).

Similarly, two case studies have indicated the KD may help resolve schizophrenia. A 1965 study found the ketogenic diet significantly reduced symptomology in schizophrenic patients (5). A more recent case study found use of a KD completely reversed schizophrenic symptoms in a 70-year-old overweight woman (6). These improvements may be related to remediation of aberrant brain glucose metabolism observed in schizophrenia, though these defects are difficult to study given that many schizophrenic medications affect metabolism (7).

It has been proposed that defective brain mitochondrial function may lead to or exacerbate autism (8). Multiple rodent models have indicated a KD increases social behavior in autistic rodents (9). In one case study, an autistic child with epilepsy followed a ketogenic diet for multiple years, during which he experienced a 70-point IQ increase and the resolution of autistic symptoms and seizures (10). A larger trial testing this diet in 30 children found inconsistent effects, but subject compliance with the diet was poor (11).

One prospective trial found children with ADHD following a KD showed significant improvements in attention and social functioning (12). At the time of this review, no clinical trials testing the use of the KD in ADHD existed.

Finally, two small, uncontrolled trials found the use of a KD and/or supplementation with exogenous ketones led to a subjective improvement in symptoms in patients with Alzheimer’s and Parkinson’s (13).

There are multiple theories suggesting how or why the KD may be beneficial in these or other psychiatric and neurological conditions. Cellular energy deficits have been linked to many of the conditions (14), and a KD may be able to maintain or restore cellular energy balance and mitochondrial function (15). Ketones may also have direct effects on neurotransmitter function (16). Given the high frequency of sleep disruption in psychiatric disorders (16), the beneficial effects of a KD on sleep may also play a role (17).

In sum, the evidence suggesting a KD can support psychiatric and neurological health remains preliminary, but early findings suggest beneficial effects may be present. Further research will be needed to explore these effects and understand whether they indicate, more broadly, that metabolic defects play a role in the development and/or progression of these and other similar conditions.

Notes

1. History of the ketogenic diet; A multicenter study of the efficacy of the ketogenic diet; The ketogenic diet for the treatment of childhood epilepsy: A randomized controlled trial; Ketogenic diet for the treatment of refractory epilepsy in children: A systematic review of efficacy; Efficacy of the ketogenic diet as a treatment option for epilepsy: Meta-analysis; Ketogenic diet and other dietary treatments for epilepsy
2. CSF levels of dopamine and serotonin, but not norepinephrine, metabolites are influenced by the ketogenic diet in children with epilepsy
3. Exogenous ketone supplements reduce anxiety-related behavior in Sprague-Dawley and Wistar Albino Glaxo/Rijswijk rats; The antidepressant properties of the ketogenic diet; Behavioral despair in mice: A primary screening test for antidepressants; Antidepressant-like properties of zinc in a rodent forced swim test 
4. Ketogenic diet in bipolar illness
5. A pilot study of the ketogenic diet in schizophrenia
6. Schizophrenia, gluten and low-carbohydrate, ketogenic diets: A case report and review of the literature
7. The role of energy metabolism dysfunction and oxidative stress in schizophrenia revealed by proteomics; Schizophrenia: Metabolic aspects of aetiology, diagnosis and future treatment strategies; Glucose metabolism in relation to schizophrenia and antipsychotic drug treatment
8. Mitochondrial dysfunction in autism spectrum disorders: A systematic review and meta-analysis
9. The ketogenic diet modifies social and metabolic alterations identified in the prenatal valproic acid model of autism spectrum disorder; Genetic modifications associated with ketogenic diet treatment in the BTBRT+ Tf/J mouse model of autism spectrum disorder; Ketogenic diets improve behaviors associated with autism spectrum disorder in a sex-specific manner in the EL mouse
10. Nutrition and aging: Changes in the regulation of energy metabolism with aging
11. Metabolic mechanisms in heart failure
12. Effects of ketogenic diet on development and behavior: Preliminary report of a prospective study
13. Study of the ketogenic diet agent AC-1202 in mild to moderate Alzheimer’s disease: A randomized, double-blind, placebo-controlled, multicenter trial; Treatment of Parkinson’s disease with diet-induced hyperketonemia: A feasibility study
14. Mitochondrial dysfunction and psychiatric disorders; Mitochondrial dysfunction in autism spectrum disorders: A systematic review and meta-analysis; Effects of a ketogenic diet on ADHD-like behavior in dogs with idiopathic epilepsy
15. The neuroprotective properties of calorie restriction, the ketogenic diet and ketone bodies; Energy, the driving force behind good and ill health; Cancer as a metabolic disease
16. Sleep and psychiatry
17. Ketogenic diet improves sleep quality in children with therapy-resistant epilepsy; The effects of the ketogenic diet on behavior and cognition; Effects of diet on sleep quality