Ketogenic Intervention for Bipolar Depression

Inclusion criteria

• Age 18-50 years
• Willingness to change the current diet to a high fat, low carbohydrate diet
• Diagnosis of bipolar I or II disorder, or BP schizoaffective Disorder by DSM-IV (SCID- confirmed). If a participant has already completed a structured diagnostic interview within the last 2 years or in any of the Department of Psychiatry and Psychology Mood Unit studies, existing SCID results can be used for this study; thus, they will not be required to repeat the SCID assessment. If a structured diagnostic interview was completed more than 2 years ago, the current mood state sections of the SCID must be repeated to ensure accuracy of current mood state assessment.
• Depressive symptom severity of at least mild (MADRS \> 6) with steady and stable (ie, at least 2 weeks) mood stabilization (eg, lithium, valproate, lamotrigine, carbamazepine/oxcarbamazepine, and/or atypical antipsychotic therapy) and non-psychotropic medication.
• Urine drug screen is negative except for allowable drugs that they have been prescribed, such as benzodiazepines.
• Pregnancy test is negative.
• Established birth control practice for sexually active individuals.
• Medical comorbidity is stable (hypertension, T2D, gout - uric acid in normal limits).

Exclusion criteria

• No access to smartphone or internet (unless provided by sponsor)
• Inability to provide written, voluntary, informed consent and pass (80%) comprehension assessment related to study goals, risks, and benefits.
• Structured clinical interview confirmation of schizophrenia or presence of psychotic symptoms (both SCID and YMRS question 8\>5).
• Clinical diagnosis of personality disorder that, upon review by the study psychiatrist, of all available information (SCID, electronic health record), is the primary psychiatric diagnosis.
• Mixed symptoms of depression defined as a YMRS ≥12 (i.e., hypomania).
• Active suicidal ideation as defined by MADRS score \>4 on question #10 or Columbia Suicide Severity Scale (C-SSRS), yes response to Question #4 (ideation, intent, but no plan) or Question #5 (ideation, intent, and plan).
• Any current drug and alcohol use disorder (excluding nicotine); complete (not partial) remission ≥3 months.
• Positive toxicology screen for cannabis and cannabis use disorder by structured clinical interview. Participants who use cannabis for recreational or medicinal purposes and fail the toxicology screen can potentially be included if the Cannabis Use Disorder Identification Test (CUDIT-R) score is \< 12.
• Currently undergoing ECT, transcranial magnetic stimulation, or deep brain stimulation as an acute or maintenance treatment. Maintenance vagal nerve stimulation is allowed if the placement of device is \> 1 year.
• Current involuntary psychiatric hospitalization.
• Already in ketosis or on a medication that causes acidosis, such as carbonic anhydrase inhibitors (e.g., acetazolamide "Diamox" and topiramate).
• BMI \< 18.5; (m) baseline LDL-c \> 190.
• Any active or unstable medical condition judged by the principal investigator as conferring significant medical risk to allow inclusion in the study, such as active severe infection.
• Acute pancreatitis or history of lipid-associated pancreatitis.
• Type I diabetes.
• SGLT2 inhibitor use
• Rare inborn errors of metabolism affecting fatty acid processing (typically diagnosed in infancy or, rarely, adolescence), such as Pyruvate carboxylase deficiency and Porphyria
• Primary carnitine deficiency
• Chronic renal failure, significant renal disease defined as creatinine clearance \<30 or in dialysis.
• Severe vitamin D deficiency (serum levels of 25-hydroxyvitamin D \[25(OH)D\] \< 12 ng/mL or 30 nMol/L).
• A diagnosis of osteopenia, defined as a bone mineral density (BMD) T-score between -1.0 and -2.5 on a dual-energy X-ray absorptiometry (DEXA) scan or with a history of fragility fractures
• Clinically significant laboratory test abnormality
• Anticipated elective surgical procedure within the next 18 weeks
• Family history of premature coronary artery disease defined as atherosclerotic cardiovascular events (e.g., heart attack, stroke) before 55 and 65 years of age in male and female first-degree relatives, respectively.
• History of familial hypercholesterolemia (note -current or start of statin or lipid-lowering drug as part of clinical care is not an exclusion provided managed by a primary care provider) or LDL-C\>190 mg/dl (or LDL\>160 mg/dl if on lipid lowering therapy) or triglycerides\>500 mg/dl.
• History of coronary disease or coronary calcifications or coronary stenosis found in invasive cardiac catheterization or imaging.
• History of ischemic stroke or carotid plaque found on baseline common carotid intima-media thickness (IMT) ultrasound.
• History of peripheral atherosclerotic arterial disease or any other form of clinical atherosclerosis.
• History or current diagnosis of respiratory failure defined as a PaO₂ \< 60 mmHg or SpO₂ \< 90% on room air or any condition leading to clinically significant respiratory impairment
• History or current diagnosis of liver failure or chronic liver disease with significant impairment, defined as ALT or AST \> 5 times the upper limit of normal, or total bilirubin \> 3 mg/dL.