The effects of ketogenic metabolic therapy on mental health and metabolic outcomes in schizophrenia and bipolar disorder: a randomized controlled clinical trial protocol

Calogero Longhitano; Sabine Finlay; Isabella Peachey; Jaymee-Leigh Swift; Flavia Fayet-Moore; Toby Bartle; Gideon Vos; Donna Rudd; Omer Shareef; Shaileigh Gordon; Mostafa Rahimi Azghadi; Iain Campbell; Shebani Sethi; Christopher Palmer; Zoltan Sarnyai

doi:10.3389/fnut.2024.1444483

The effects of ketogenic metabolic therapy on mental health and metabolic outcomes in schizophrenia and bipolar disorder: a randomized controlled clinical trial protocol

Front Nutr. 2024 Aug 21:11:1444483. doi: 10.3389/fnut.2024.1444483. eCollection 2024.

Authors

Calogero Longhitano^#^{1

2

3}, Sabine Finlay^#^{2

4}, Isabella Peachey^#^{2

3}, Jaymee-Leigh Swift⁵, Flavia Fayet-Moore^{6

7}, Toby Bartle^{2

4}, Gideon Vos^{2

8}, Donna Rudd⁴, Omer Shareef^{1

2}, Shaileigh Gordon^{1

2}, Mostafa Rahimi Azghadi⁸, Iain Campbell⁹, Shebani Sethi¹⁰, Christopher Palmer¹¹, Zoltan Sarnyai^{2

4}

Affiliations

¹ Townsville University Hospital and Health Service, Mental Health Service Group, Queensland Health, Townsville, QLD, Australia.
² Laboratory of Psychiatric Neurosciences, Australian Institute of Tropical Health and Medicine, College of Public Health, Medical and Veterinary Science, James Cook University, Townsville, QLD, Australia.
³ College of Medicine and Dentistry, James Cook University, Townsville, QLD, Australia.
⁴ College of Public Health, Medical and Veterinary Sciences, James Cook University, Townsville, QLD, Australia.
⁵ Mater Hospital, Aurora Healthcare and James Cook University, Townsville, QLD, Australia.
⁶ School of Environmental and Life Sciences, College of Engineering, Science and Environment, University of Newcastle, Callaghan, NSW, Australia.
⁷ FoodiQ Global, Sydney, NSW, Australia.
⁸ Electrical and Electronics Engineering, College of Science and Engineering, James Cook University, Townsville, QLD, Australia.
⁹ Centre for Clinical Brain Sciences, Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom.
¹⁰ Metabolic Psychiatry, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, CA, United States.
¹¹ McLean Hospital, Harvard Medical School, Belmont, MA, United States.

^# Contributed equally.

Abstract

Background: Schizophrenia, schizoaffective disorder, and bipolar affective disorder are debilitating psychiatric conditions characterized by a chronic pattern of emotional, behavioral, and cognitive disturbances. Shared psychopathology includes the pre-eminence of altered affective states, disorders of thoughts, and behavioral control. Additionally, those conditions share epidemiological traits, including significant cardiovascular, metabolic, infectious, and respiratory co-morbidities, resulting in reduced life expectancy of up to 25 years. Nutritional ketosis has been successfully used to treat a range of neurological disorders and preclinical data have convincingly shown potential for its use in animal models of psychotic disorders. More recent data from open clinical trials have pointed toward a dramatic reduction in psychotic, affective, and metabolic symptoms in both schizophrenia and bipolar affective disorder.

Objectives: to investigate the effects of nutritional ketosis via a modified ketogenic diet (MKD) over 14 weeks in stable community patients with bipolar disorder, schizoaffective disorder, or schizophrenia.

Design: A randomized placebo-controlled clinical trial of 100 non-hospitalized adult participants with a diagnosis of bipolar disorder, schizoaffective disorder, or schizophrenia who are capable of consenting and willing to change their diets.

Intervention: Dietitian-led and medically supervised ketogenic diet compared to a diet following the Australian Guide to Healthy Eating for 14 weeks.

Outcomes: The primary outcomes include psychiatric and cognitive measures, reported as symptom improvement and functional changes in the Positive and Negative Symptoms Scale (PANSS), Young Mania Rating Scale (YMS), Beck Depression Inventory (BDI), WHO Disability Schedule, Affect Lability Scale and the Cambridge Cognitive Battery. The secondary metabolic outcomes include changes in body weight, blood pressure, liver and kidney function tests, lipid profiles, and markers of insulin resistance. Ketone and glucose levels will be used to study the correlation between primary and secondary outcomes. Optional hair cortisol analysis will assess long-term stress and variations in fecal microbiome composition. Autonomic nervous system activity will be measured via wearable devices (OURA ring and EMBRACE wristband) in the form of skin conductance, oximetry, continuous pulse monitoring, respiratory rate, movement tracking, and sleep quality. Based on the encouraging results from established preclinical research, clinical data from other neurodevelopment disorders, and open trials in bipolar disorder and schizophrenia, we predict that the ketogenic metabolic therapy will be well tolerated and result in improved psychiatric and metabolic outcomes as well as global measures of social and community functioning. We additionally predict that a correlation may exist between the level of ketosis achieved and the metabolic, cognitive, and psychiatric outcomes in the intervention group.

Keywords: bipolar disorder; dietary intervention; ketogenic diet; mental health disorders; metabolic therapy; nutrition; randomized control trial (RCT); schizophrenia.

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This project is funded by a philanthropic grant donated by the “Baszucki Brain Research Fund”, California, USA. Additional funding is provided by the Donald and Joan Wilson Foundation, Australia. Author CL received a Research Fellowship from his Employer (THHS SERTA research grant 2021_26).