Ketogenic Diet Therapy Major Depressive Disorder

Major Depressive Disorder Clinical Trial

— KETOMDD  

Official title:

Effects and Mechanistic Aspects of Ketogenic Diet in Individuals With Major Depressive Disorder: A Pilot Study

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05558995
• Other study ID #: KETOOPEN
• Status: Recruiting
• Phase: N/A
• Start date: January 2, 2024
• Est. completion date: December 30, 2024

Study information

• Verified date: November 2023
• Source: Queen's University
• Contact: Elisa Brietzke, MD,Ph.D
• Phone: +1 (613) 548- 3232
• Email: Elisa.brietzke[@]queensu.ca
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This research program will examine the feasibility as assessed through rates of adherence, tolerability, and safety of the ketogenic diet for individuals with Major Depressive Disorder (MDD) who are not achieving symptomatic remission with first line antidepressants such as the Serotonin Selective Inhibitors (SSRIs). Driven by robust data on the benefits of ketogenic diet in epilepsy and by preliminary data in animal models demonstrating its effects on depressive behaviors, there is a hypothesis that ketogenic diet could be useful to treat residual depressive symptoms. As deficits in reward and pleasure (anhedonia) are the most common residual symptoms in MDD individuals with partial response to SSRIs, the ketogenic diet could be a potential adjuvant in the treatment for depression. In addition, a preliminary assessment of neuroplasticity-related biomarkers in the plasma to determine possible biological substrates for the mechanism of action of ketogenic diet in the brain will be conducted.

Description:

This is a 12-week, open-label study of the feasibility, safety, and tolerability of adjunctive ketogenic diet for the treatment of individuals with Major Depressive Disorder (MDD). The study will consist of a 2-weeks ketogenic diet induction phase, followed by a 10-week maintenance phase until study endpoint (week-12). For this feasibility study, 15 participants that successfully meet the requirements for inclusion in the study will be enrolled. With an expected patient dropout rate of approximately 15% at 12-weeks, this sample size will be effective in reliably estimating patient adherence and tolerability to the ketogenic diet, and patient recruitment and dropout rates. The results of this feasibility study will facilitate the calculation of an appropriate sample size for a subsequent randomized controlled trial. Research individuals will be recruited from the Mood Disorders Outpatient Unit at Providence Care Hospital and the W.J. Henderson Centre for Patient-Oriented Research at Kingston General Hospital (KGH) both located in Kingston, ON, Canada. Male and female participants with ages between 18 and 50 who have had a confirmed diagnosis of a major depressive episode and currently meeting all inclusion and exclusion criteria, and which are able to provide written informed consent will be eligible for inclusion in the study. A virtual appointment will be arranged for participants interested in participation with research staff members and a registered dietitian also will interview the individual to ensure that participants fully understand the study. Details on the ketogenic diet, the foods involved, and other dietary questions, will be answered by a registered dietician. If complete eligibility is confirmed, patients will be given 48 hours to decide on participation. If willing to participate in the study, written informed consent will be obtained. The study consists in weekly visits involving psychiatric assessments, general medical assessments, and dietetic assessments. The first two will be conducted by trained psychiatrist and the third one by a registered dietician. In every visit the psychiatrists will conduct assessments of severity of depressive symptoms and anhedonia and treatment-emergent side effects. The computer based task Effort Expenditure for Rewards Task (EEfRT) will be used to evaluate reward motivation at the baseline and at the endpoint. Weight, height, Body Mass Index, waist circumference, and hip circumference will be evaluated in all visits. The individuals will be asked to fill a food diary that will be checked at each weekly consultation. The quantities of food will be recorded by each patient. The exact macronutrient consumption will be analyzed and recorded for each patient by the registered dietician. The dietician will analyze all foods and drinks consumed by participants to ensure each individual is abiding to the medically supervised ketogenic diet. Urine will be collected in each visit for assessment of ketonuria, a parameter of adherence to the intervention. A blood sample will be collected at the baseline and endpoint consultations for biological analysis of neuroplasticity-related biomarkers in plasma. The results of this study will demonstrate whether consumption of the medically supervised ketogenic diet for 12 consecutive weeks by individuals with MDD is a feasible and tolerable intervention.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 10
• Est. completion date: December 30, 2024
• Est. primary completion date: December 30, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

Inclusion Criteria:

• Diagnostic criteria for single episode or recurrent MDD, without psychotic features, according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), and confirmed by the Mini International Neuropsychiatric Interview (MINI).

-- Moderate or severe depressive syndrome, as defined by a Montgomery-Asberg Depression Rating Scale (MADRS) total score greater than or equal to (>=) 20 at baseline.

• Treatment with SSRIs for at least 6 weeks, with no changes in dosing for the past 3 weeks.

• Must be capable of providing informed consent, based on the opinion of the participating physician.

• No vitamin and mineral deficiencies, specifically: vitamin B (B1, B3, B6, B9, and B12), vitamin D, iron, zinc, electrolytes (Na, K), calcium, and magnesium.

Exclusion Criteria:

• Has a current or prior diagnosis of schizophrenia spectrum disorders or bipolar disorder or related disorders, or intellectual disability, according to DSM-5.

• Has current or prior diagnosis of epilepsy

• Has homicidal ideation/intent or is at imminent risk of suicide per the physician's clinical judgment and/or based on the Columbia-Suicide Severity Rating Scale (C-SSRS) corresponding to a response of "Yes" on Item 4 (active suicidal ideation with some intent to act, without specific plan) or Item 5 (active suicidal ideation with specific plan and intent)

• Has received electroconvulsive therapy in the past 6 months. - Made use of caloric restriction, intermittent fasting, and carbohydrates restriction in the 4 weeks prior the inclusion.

• Adoption of specific dietetic habits: vegan, gluten-free, lactose-free diets or currently doing fasting for religious purposes.

• Has evidence of alcohol or drug dependence (except for nicotine and caffeine) according to DSM-5 or within 6 months prior to enrolment

• Has participated in or is currently enrolled in any clinical trial or observational study within the current episode.

• Has a medical contra-indication for ketogenic diet (e.g. metabolic disorder, cardiac arrhythmia, pregnancy or breastfeeding).

Related Conditions & MeSH terms

• Depression
• Depressive Disorder
• Depressive Disorder, Major
• Major Depressive Disorder

Intervention

Other:
• ketogenic diet
All the subjects will be instructed by a nutrition professional to have at least 3 meals per day consisting of 20 g to 30 g of carbohydrate in the form of green vegetables and salad, and 80 g to 100 g of protein in the form of meat, fish, fowl, eggs, shellfish and cheese for 12 weeks. Polyunsaturated and monounsaturated fats will also be included in the diet. Micronutrients (vitamins and minerals) will be given to each subject in the form of one capsule per day. The adherence to diet will be confirmed weekly through a food log and urinary ketones assessment using dipstick to ensure that all individuals remain in a ketotic state.

Locations

Country	Name	City	State
Canada	Queen's University - Kingston General Hospital	Kingston	Ontario

Sponsors (1)

Lead Sponsor	Collaborator
Queen's University

Country where clinical trial is conducted

Canada, 

References & Publications (6)

Brietzke E, Mansur RB, Subramaniapillai M, Balanza-Martinez V, Vinberg M, Gonzalez-Pinto A, Rosenblat JD, Ho R, McIntyre RS. Ketogenic diet as a metabolic therapy for mood disorders: Evidence and developments. Neurosci Biobehav Rev. 2018 Nov;94:11-16. doi: 10.1016/j.neubiorev.2018.07.020. Epub 2018 Jul 31. — View Citation

Ceolin G, Breda V, Koning E, Meyyappan AC, Gomes FA, Moreira JD, Gerchman F, Brietzke E. A Possible Antidepressive Effect of Dietary Interventions: Emergent Findings and Research Challenges. Curr Treat Options Psychiatry. 2022;9(3):151-162. doi: 10.1007/s40501-022-00259-1. Epub 2022 Apr 23. — View Citation

Cooper JA, Arulpragasam AR, Treadway MT. Anhedonia in depression: biological mechanisms and computational models. Curr Opin Behav Sci. 2018 Aug;22:128-135. doi: 10.1016/j.cobeha.2018.01.024. — View Citation

Grigolon RB, Gerchman F, Schoffel AC, Hawken ER, Gill H, Vazquez GH, Mansur RB, McIntyre RS, Brietzke E. Mental, emotional, and behavioral effects of ketogenic diet for non-epileptic neuropsychiatric conditions. Prog Neuropsychopharmacol Biol Psychiatry. 2020 Aug 30;102:109947. doi: 10.1016/j.pnpbp.2020.109947. Epub 2020 Apr 17. — View Citation

Malhi GS, Mann JJ. Depression. Lancet. 2018 Nov 24;392(10161):2299-2312. doi: 10.1016/S0140-6736(18)31948-2. Epub 2018 Nov 2. — View Citation

Shelton RC, Tomarken AJ. Can recovery from depression be achieved? Psychiatr Serv. 2001 Nov;52(11):1469-78. doi: 10.1176/appi.ps.52.11.1469. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Participant Adherence	Number of participants that completed the trial/Total number of participants enrolled	Baseline (week 0), week 1, week 2, week 3, week 4, week 5, week 6, week 7, week 8, week 9, week 10, week 11, week 12.
Secondary	Changes in the Effort-based decision making	the Effort-Expenditure for Rewards Task (EEfRT or "effort"), a novel behavioral paradigm as a means of exploring effort-based decision-making in humans. The proportion of hard-task choices indicates a more active reward system.	Baseline (week 0), week 1, week 2, week 3, week 4, week 5, week 6, week 7, week 8, week 9, week 10, week 11, week 12.
Secondary	Changes in the serum levels of the brain-derived neurotrophic factor	The BDNF levels will be determined in plasma with the enzyme-linked immunosorbent assay (ELISA), as part of the biomarkers assessments. Results are expressed in pg/mL.	Baseline (week 0) and week 12.
Secondary	Changes in the serum level of TNF-alpha	The TNF-alpha blood levels will be determined by ultrasensitive ELISA. The results will be expressed in pg/mL.	Baseline (week 0) and week 12.
Secondary	Changes in the serum level of Interleukin-1(IL-1)	The IL-1 blood levels will be determined by ultrasensitive ELISA. The results will be expressed in pg/mL.	Baseline (week 0) and week 12.
Secondary	Changes in the serum level of Interleukin-6 (IL-6)	The IL-6 blood levels will be determined by ultrasensitive ELISA. The results will be expressed in pg/mL.	Baseline (week 0) and week 12.
Secondary	Changes in the serum level of Interleukin-6 (IL-10)	The IL-10 blood levels will be determined by ultrasensitive ELISA. The results will be expressed in pg/mL.	Baseline (week 0) and week 12.
Secondary	Changes in depressive symptoms severity	Montgomery-Asberg Depression Rating Scale to assess changes in severity of depressive symptoms. The scores of this scale varies from 0-60 with higher scores indicating more severe depressive symptoms.	Baseline (week 0), week 1, week 2, week 3, week 4, week 5, week 6, week 7, week 8, week 9, week 10, week 11, week 12.
Secondary	Changes in anxiety symptoms severity	Generalized Anxiety Disorder-7 to assess severity of anxiety symptoms. The scores in this instrument vary from 0-21 with higher scores indication greater severity of anxiety symptoms.	Baseline (week 0), week 1, week 2, week 3, week 4, week 5, week 6, week 7, week 8, week 9, week 10, week 11, week 12.
Secondary	Changes in functioning	Clinical Global Impression. The score of this scale varies from 1-7, with higher scores indicating poorer functioning	Baseline (week 0), week 1, week 2, week 3, week 4, week 5, week 6, week 7, week 8, week 9, week 10, week 11, week 12.
Secondary	complete blood count (CBC) baseline	complete blood count (CBC) as part of safety assessment	Baseline (week 0)
Secondary	complete blood count (CBC) endopoint	complete blood count (CBC) as part of the safety assessment	Endpoint (week 12)
Secondary	Sodium blood level baseline	Sodium blood level blood expressed in mEq/L as part of the safety assessment	Baseline (week 0)
Secondary	Sodium blood level endpoint	Sodium blood level blood expressed in mEq/L as part of the safety assessment	Endpoint (week 12)
Secondary	Potassium blood level baseline	Potassium blood level blood expressed in mEq/L as part of the safety assessment	Baseline (week 0)
Secondary	Potassium blood level endpoint	Potassium blood level blood expressed in mEq/L as part of the safety assessment	Endpoint (week 12)
Secondary	Vitamin B blood level baseline	Vitamin B blood level expressed in pg/mL as part of the safety assessment	Baseline (week 0)
Secondary	Vitamin B blood level endpoint	Vitamin B blood level expressed in pg/mL as part of the safety assessment	Endpoint (week 12)
Secondary	Vitamin D blood level baseline	Vitamin D blood level expressed in pg/mL as part of the safety assessment	Baseline (week 0)
Secondary	Vitamin D blood level	Vitamin D blood level expressed in pg/mL as part of the safety assessment	Endpoint (week 12)
Secondary	Iron serum level baseline	Iron serum level expressed in mcg/dL as part of the safety assessment	Baseline (week 0)
Secondary	Iron serum level endpoint	Iron serum level expressed in mcg/dL as part of the safety assessment	Endpoint (week 12)
Secondary	Zinc blood level baseline	Zinc blood level expressed in mcg/mL as part of the safety assessment	Baseline (week 0)
Secondary	Zinc blood level endpoint	Zinc blood level expressed in mcg/mL as part of the safety assessment	Endpoint (week 12)
Secondary	Blood level of aspartate aminotransferase (AST) baseline	Blood level of aspartate aminotransferase (AST) expressed in U/L	Baseline (week 0)
Secondary	Blood level of aspartate aminotransferase (AST) endpoint	Blood level of aspartate aminotransferase (AST) expressed in U/L as part of the safety assessment	Endpoint (week 12)
Secondary	Blood level of alanine aminotransferase (ALP) baseline	Blood level of alanine aminotransferase (ALP) expressed in U/L as part of the safety assessment	Baseline (week 0)
Secondary	Blood level of alanine aminotransferase (ALP) endpoint	Blood level of alanine aminotransferase (ALP) expressed in U/L as part of the safety assessment	Endpoint (week 12)
Secondary	Blood level of albumin baseline	Blood level of albumin (ALB) expressed in g/dL as part of the safety assessment	Baseline (week 0)
Secondary	Blood level of albumin endpoint	Blood level of albumin (ALB) expressed in g/dL as part of the safety assessment	Endpoint (week 12)
Secondary	Blood prothrombin time (PT) baseline	Prothrombin time (PT) expressed in prothrombin time/international normalized ratio (INR) as part of the safety assessment	Baseline (week 0)
Secondary	Blood prothrombin time (PT) endpoint	Prothrombin time (PT) expressed in prothrombin time/international normalized ratio (INR) as part of the safety assessment	Endpoint (week 12)
Secondary	Total serum bilirubin baseline	Total serum bilirubin expressed in mg/dL as part of the safety assessment	Baseline (week 0)
Secondary	Total serum bilirubin endpoint	Total serum bilirubin expressed in mg/dL as part of the safety assessment	Endpoint (week 12)
Secondary	Serum blood urea nitrogen (BUN) baseline	blood urea nitrogen (BUN) expressed in mmol/L as part of the safety assessment	Baseline (week 0)
Secondary	blood urea nitrogen (BUN) endpoint	blood urea nitrogen (BUN) expressed in mmol/L as part of the safety assessment	Endpoint (week 12)
Secondary	Urinalysis (UA) baseline	Urinalysis (UA) for ketonuria as part of the safety assessment	Baseline (week 0)
Secondary	Urinalysis (UA) endpoint	Urinalysis (UA) for ketonuria as part of the safety assessment	Endpoint (week 12)
Secondary	Blood glycated hemoglobin (HbA1c) in the baseline	Blood glycated hemoglobin (HbA1c), expressed in % as port of the safety assessment	Baseline (week 12)
Secondary	Blood glycated hemoglobin (HbA1c) in the endpoint	Blood glycated hemoglobin (HbA1c), expressed in % as part of the safety assessment	Endpoint (week 12)
Secondary	Lipid panel baseline	lipid panel as part of the safety assessment	Baseline (week 0)
Secondary	Lipid panel endpoint	lipid panel as part of the safety assessment	Endpoint (week 12)
Secondary	Pregnancy test (for female participants)	Pregnancy test (for female participants)	Baseline (week 0)
Secondary	Pregnancy test (for female participants)	Pregnancy test (for female participants)	Endpoint (week 12)
Secondary	Changes in severity of anhedonia	Snaith-Hamilton Pleasure Scale (SHAPS) to assess severity of anhedonia. The scores varies from 0-14. A higher total score indicates higher levels of anhedonia.	Baseline (week 0), week 1, week 2, week 3, week 4, week 5, week 6, week 7, week 8, week 9, week 10, week 11, week 12.