Clinical trial NCT05558995: Ketogenic Diet Therapy Major Depressive Disorder
Official title: Effects and Mechanistic Aspects of Ketogenic Diet in Individuals With Major Depressive Disorder: A Pilot Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Major Depressive Disorder
Keywords: Ketogenic Diet
Major depressive disorder
Lead sponsor: Queen's University
Sponsor class: OTHER
First posted: 2022-09-29
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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).

Primary outcomes:
measure: Participant Adherence
timeFrame: 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 outcomes:
measure: Changes in the Effort-based decision making
timeFrame: 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.
measure: Changes in the serum levels of the brain-derived neurotrophic factor
timeFrame: Baseline (week 0) and week 12.
measure: Changes in the serum level of TNF-alpha
timeFrame: Baseline (week 0) and week 12.
measure: Changes in the serum level of Interleukin-1(IL-1)
timeFrame: Baseline (week 0) and week 12.
measure: Changes in the serum level of Interleukin-6 (IL-6)
timeFrame: Baseline (week 0) and week 12.
measure: Changes in the serum level of Interleukin-6 (IL-10)
timeFrame: Baseline (week 0) and week 12.
measure: Changes in depressive symptoms severity
timeFrame: 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.
measure: Changes in anxiety symptoms severity
timeFrame: 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.
measure: Changes in functioning
timeFrame: 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.
measure: complete blood count (CBC) baseline
timeFrame: Baseline (week 0)
measure: complete blood count (CBC) endopoint
timeFrame: Endpoint (week 12)
measure: Sodium blood level baseline
timeFrame: Baseline (week 0)
measure: Sodium blood level endpoint
timeFrame: Endpoint (week 12)
measure: Potassium blood level baseline
timeFrame: Baseline (week 0)
measure: Potassium blood level endpoint
timeFrame: Endpoint (week 12)
measure: Vitamin B blood level baseline
timeFrame: Baseline (week 0)
measure: Vitamin B blood level endpoint
timeFrame: Endpoint (week 12)
measure: Vitamin D blood level baseline
timeFrame: Baseline (week 0)
measure: Vitamin D blood level
timeFrame: Endpoint (week 12)
measure: Iron serum level baseline
timeFrame: Baseline (week 0)
measure: Iron serum level endpoint
timeFrame: Endpoint (week 12)
measure: Zinc blood level baseline
timeFrame: Baseline (week 0)
measure: Zinc blood level endpoint
timeFrame: Endpoint (week 12)
measure: Blood level of aspartate aminotransferase (AST) baseline
timeFrame: Baseline (week 0)
measure: Blood level of aspartate aminotransferase (AST) endpoint
timeFrame: Endpoint (week 12)
measure: Blood level of alanine aminotransferase (ALP) baseline
timeFrame: Baseline (week 0)
measure: Blood level of alanine aminotransferase (ALP) endpoint
timeFrame: Endpoint (week 12)
measure: Blood level of albumin baseline
timeFrame: Baseline (week 0)
measure: Blood level of albumin endpoint
timeFrame: Endpoint (week 12)
measure: Blood prothrombin time (PT) baseline
timeFrame: Baseline (week 0)
measure: Blood prothrombin time (PT) endpoint
timeFrame: Endpoint (week 12)
measure: Total serum bilirubin baseline
timeFrame: Baseline (week 0)
measure: Total serum bilirubin endpoint
timeFrame: Endpoint (week 12)
measure: Serum blood urea nitrogen (BUN) baseline
timeFrame: Baseline (week 0)
measure: blood urea nitrogen (BUN) endpoint
timeFrame: Endpoint (week 12)
measure: Urinalysis (UA) baseline
timeFrame: Baseline (week 0)
measure: Urinalysis (UA) endpoint
timeFrame: Endpoint (week 12)
measure: Blood glycated hemoglobin (HbA1c) in the baseline
timeFrame: Baseline (week 12)
measure: Blood glycated hemoglobin (HbA1c) in the endpoint
timeFrame: Endpoint (week 12)
measure: Lipid panel baseline
timeFrame: Baseline (week 0)
measure: Lipid panel endpoint
timeFrame: Endpoint (week 12)
measure: Pregnancy test (for female participants)
timeFrame: Baseline (week 0)
measure: Pregnancy test (for female participants)
timeFrame: Endpoint (week 12)
measure: Changes in severity of anhedonia
timeFrame: 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.
Other outcomes:
Locations:
city: Kingston
country: Canada
facility: Queen's University - Kingston General Hospital
state: Ontario
Study officials:
affiliation: Queen's University
name: Elisa Brietzke, MD,PhD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.
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.
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.
citation: 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.