Ketogenic Metabolic Therapy in Schizophrenia, Bipolar Disorder, Major Depressive Disorder: Deep Omic Profiling

The ketogenic diet is a low carbohydrate, moderate protein, higher fat diet to help individuals improve energy and mood and to obtain nutrients from fats and protein. Schizophrenia, bipolar disorder, and major depressive disorder, collectively affect about 344 million individuals worldwide, (24 million with schizophrenia, 40 million people with BD, and 280 million with depression World Health Organization). These illnesses 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 comorbidities, resulting in reduced life expectancy of up to 25 years (Xie et al., 2023). Reductions in cerebral glucose uptake are seen in both schizophrenia and bipolar disorder. While glucose is the brain's default fuel, ketone bodies are 27% more efficient, improve brain metabolism, and promote neural stability, as seen in childhood epilepsy (Sethi \& Ford, 2022). The ketogenic diet (KD, also known as metabolic therapy) has been successful in the treatment of obesity, type 2 diabetes, and epilepsy (Sethi et al., 2024, Liu et al., 2018, Martin-McGill et al., 2020). Nutritional ketosis has been successfully used to treat a range of neurological disorders. Metabolic disorders, which include conditions such as obesity and metabolic syndrome, more commonly occur in individuals with severe mental illness (between 40-60%). The investigators aim to study the effect of ketogenic metabolic therapy on various markers including:

* Metabolic health measurements and cardiovascular risk factors including: insulin resistance, advanced lipid analysis, weight, glucose regulation, dyslipidemia, absolute body fat chang, inflammation, waist circumference, blood pressure, skeletal muscle mass, and omega index * Psychiatric symptom measures include: mood, psychosis, cognition, and quality of life * Deep omic profiling including metabolic and proteomic data. Through identifying patterns, changes, and pathways of molecular, psychiatric, physiologic, and metabolic markers, the investigators aim to assess how this intervention may impact individuals with serious mental illnesses and symptoms/conditions related to serious mental illnesses.

• Cambridge Cognition (CANTAB Assessment) [Time frame: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).]
• Quality of Life in Neurological Disorders (Neuro-QOL, Cognitive Function) [Time frame: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).]
• Brief Psychiatric Assessment Scale (BPRS) [Time frame: Screening; Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).]
• Patient Health Questionnaire (PHQ-9) [Time frame: Screening; Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).]
• Clinical Global Impressions Scale (CGI)/ Clinical Mood Monitoring [Time frame: Screening; Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).]
• Perceived Stress Scale 4 (PSS-4) [Time frame: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).]
• Generalized Anxiety Disorder Scale (GAD-7) [Time frame: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).]
• Pittsburgh Sleep Quality Index (PSQI) [Time frame: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).]
• Epigenome [Time frame: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).]
• Mitochondrial Function [Time frame: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).]
• Metabolome [Time frame: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).]
• Proteome [Time frame: Baseline through study completion, an average of 12 weeks (Arm 1: Ketogenic Diet Only) or 24 weeks (Arm 2: DAU-Ketogenic Diet Crossover).]