In a case study of a 70-year-old overweight woman with a diagnosis of schizophrenia, KD was initiated by her treating physician. The patient remained on KD for 12 months and reportedly had no recurrences of auditory or visual hallucinations, and the patient lost weight. The patient reported eating mainly lean proteins and low-carbohydrate vegetables (the lipid:non-lipid ratio was not listed), ketosis was not confirmed and perhaps not established due to the lack of dietary fats listed; therefore, this case report is of indeterminate value.
Some studies suggest that abnormal glucose and energy metabolism may underlie the pathophysiology of schizophrenia, which may provide some potential pointers into the hypothesized mode of action of KD in the disorder. Others have noted that abnormal glucose metabolism may occur secondary to antipsychotic medications alongside significant treatment side effects such as weight gain, hyperglycemia, and diabetes. The high metabolic risk associated with schizophrenia is due to genetic and environmental factors.
Features of patients with ASD include compromised social interaction and communication. It is estimated that between 5 and 40% of patients with autism will develop epilepsy, and while most patients will respond to pharmacotherapy, in one study, 34% of 170 patients had medically refractory epilepsy. The precise pathogenesis of ASD remains unknown, but genetic and environmental factors have been known to contribute to its onset. One such factor is exposure to valproic acid (VPA) in utero, which is associated with a 12% incidence of ASD in children and is used as an animal model of induction of ASD.
Using the animal model of autism induced by prenatal exposure to VPA in mice, the effects of KD were examined. Pregnant Swiss mice received a single intraperitoneal injection of 600 mg/kg of VPA (n = 26) or saline (n = 18) on gestational day 11. At day 21, 16 VPA treated and 16 control mice were used. Half of each group was fed KD (lard 690 g/kg, sunflower oil 5 g/kg, protein 250 g/kg, fiber 10 g/kg, ash 5 g/kg), while the other received a standard diet. Ketone levels were not measured. After 70 days on KD, a statistically significant result was found in mice with VPA in behaviors such as social deficits and stereotypies that are common behaviors in those with ASD. It is also believed that mitochondrial dysfunction may play a role in the onset of ASD. Ahn et al. aimed to determine if KD could reverse the social deficits and mitochondrial dysfunction seen in a prenatal VPA animal model of autism using Wistar rats. On postnatal day 21, rats were placed on either KD (6:1 lipid:non-lipid ratio) or standard diet for 10-14 days. Beta-hydroxybutyrate was measured. KD had a significant effect and was able to modify complex social behaviors in VPA and control rats and mitochondrial respiration.
Another animal model of autism using the inbred BTBR mouse strain that exhibits three core features of autism, including reduced sociability, communication, and increased repetitive behavior, was studied. In another study, 33 genes were differentially expressed in the temporal cortex and 48 in the hippocampus suggesting deficits in the stress response and in neuronal signaling and communication in BTBR mice. After 14 days on KD (6.3:1 lipid:non-lipid ratio), both brain regions showed improvements on autistic deficits associated with myelin formation and white matter development. One study has found that in BTBR mice, KD reduces total gut microbial and compositional remodeling of the mouse microbiome providing a potential explanation as to its efficacy in this model.
In an animal model with behavioral characteristics of ASD and comorbid epilepsy in male and female EL mice, the effect of KD was assessed. Testing occurred at 8-9 weeks postpartum following 3-4 weeks of dietary treatment. Animals were fed either a standard diet or one of two KDs (3.0:1 or 6.6:1 lipid:non-lipid ratio). KD raised ketones in all groups, but the higher fat ratio deepened ketosis. Both KDs significantly increased sociability, time spent in the chamber with another mouse, in females and males. Social novelty, preference for a newly introduced mouse was higher in females fed the higher KD ratio. The test of repetitive behavior (self-grooming) was significantly decreased in males but was non-significant in females. This study provides some intriguing results regarding the effects of sex and KD in a mouse model of ASD and idiopathic epilepsy.
The role of KD in ASD has been examined in a pilot study of 30 children. The diet (30% of energy as MCT oil, 30% fresh cream, 11% as saturated fat, 19% carbohydrates, and 10% as protein) was administered for 6 months with intervals of 4 weeks with 2 diet-free weeks. Of the total sample, 40% did not comply or did not tolerate the diet. Urinary ketones were measured. In the remaining sample, two children showed significant improvements on the Childhood Autism Rating Scale, while the rest showed mild-to-moderate improvements. As observed in patients with epilepsy, after the termination of KD the benefits persisted, which raise intriguing questions regarding the effects of plasticity.
In a case study of a child with autism and epilepsy, following standard treatment non-response, the individual was placed on KD (1.5:1 lipid:non-lipid ratio) with adjunct anticonvulsant therapy. The patient was in ketosis. After initiation of the diet several benefits ensued including the resolution of morbid obesity and the improvement of cognitive and behavioral features of the disorder. After several years on the diet, the patient's score on the Childhood Autism Rating Scale decreased from 49 to 17, a change from a rating of severe autism to non-autistic, and IQ increased by 70 points. Fourteen months following the initiation of the diet the patient was also seizure free.
The suggested mechanisms of action of KD in ASD include that it may reduce pain sensitivity through the reduction of glucose and may have anti-inflammatory properties as it reduces swelling and plasma extravasation. In a systematic review of KD in ASD it was concluded that the limited number of reports of improvements after treatment with the diet is not sufficient to attest to the practicability of KD as a treatment for the disorder.
Attention deficit hyperactivity disorder is characterized by a lack of behavioral inhibition and by neuropsychological deficits in four areas, including working memory, self-regulation of affect-motivation-arousal, internalization of speech, and behavioral analysis and synthesis. ADHD is the most commonly occurring mental disorder in children and adolescents with epilepsy occurring in 16 (29.1%) of 78 patients. Children with ADHD have a high frequency of epileptiform discharges as observed by EEG. In a prospective study of children with epilepsy (n = 34) on KD it was found that after 1 year on the diet there was a statistically significant improvement of attention and social functioning.
There is little evidence examining ADHD and KD, but a 6-month prospective, randomized, double-blinded, placebo-controlled, crossover dietary trial compared the effects of KD (10% moisture, 28% protein, 15% fat, 6% ash, 2% crude fiber, and MCT oil) or a standard diet on behavior in 21 dogs with comorbid ADHD and idiopathic epilepsy. It was hypothesized that there were three specific behaviors related to ADHD in dogs including excitability, chasing, and trainability. ADHD in dogs is manifested as inattention and excitability/impulsivity, which have been likened to the disorder in humans. When compared with the standard diet, KD resulted in a significant improvement in ADHD-related behaviors. Serum beta-hydroxybutyrate was measured. The mechanisms of behavioral improvements during KD remain unknown. The authors postulated that alterations of energy metabolism in the brain may contribute to behavioral changes. Research into humans with ADHD and KD is lacking.