Single-dose Ketamine Treatment to Improve Depression in Mild Cognitive Impairment

Study Overview
=================
Brief Summary
-----------------
Ketamine is a NMDA-receptor antagonist that promotes synapse formation and has been shown to rapidly improve symptoms in depression. Even a single dose of ketamine has been shown to improve depression and cognition with short-term memory, inhibitory control, cognitive flexibility, and processing speed showing improvements within days of treatment. The mechanism behind ketamine's rapid action is not clear but some groups have speculated it may be related to enhanced neuroplasticity, particularly in the frontal areas and the hippocampus. If this mechanism is accurate, ketamine may be especially effective in treating mild cognitive impairment and depression (MCI-D) where changes in the hippocampus and frontal areas have been implicated. Although few studies have been published on the effects of ketamine in older adults, some small pilot studies suggest that ketamine treatment might be effective in improving depression in older adults and relatively safe. There are no studies looking at the effects of ketamine treatment in patients with MCI-D. The research team hypothesize that IV ketamine treatment will be well-tolerated and will improve depression and cognition in patients with MCI-D. The study team will explore the effects of brain imaging abnormalities and amyloid biomarker status on the responsiveness to ketamine. The study team will conduct an open-label pilot study designed to gather data to support an application for a larger NIH-funded study.

Detailed Description
-----------------
Ketamine is a rapid-acting antidepressant thought to work, at least in part, by the enhancement of neural plasticity and the growth of new synapses. A single dose of ketamine has been shown to improve depression and cognition with short-term memory, inhibitory control, cognitive flexibility, and processing speed showing improvements within days of treatment. The mechanism behind ketamine's rapid action is not clear but some groups have speculated it may be related to enhanced neuroplasticity, particularly in the frontal areas and the hippocampus. If this mechanism is accurate, ketamine may be especially effective in treating individuals with mild cognitive impairment and depression (MCI-D) where changes in the hippocampus and frontal areas have been implicated. Although few studies have been published on the effects of ketamine in older adults, they suggest that ketamine treatment might be effective in improving depression in older adults and relatively safe. There are no studies looking at the effects of ketamine treatment in patients with MCI-D. A key hypothesis of this study is that IV ketamine treatment will be well-tolerated and will improve depression and cognition in patients with MCI-D. The effects of brain imaging and activity abnormalities and amyloid biomarker status on the responsiveness to ketamine will be explored. This open-label pilot study is designed to gather data to support an application for a larger NIH-funded study. This study is an open-label trial to determine the safety and tolerability of a single sub-anesthetic (0.5 mg/kg) intravenous (IV) ketamine treatment in individuals with mild cognitive impairment and depression (MCI-D). As secondary endpoints, whether treatment with a single dose of ketamine may improve mood or cognition in individuals with MCI-D will be examined. In exploratory analyses, whether AD biomarker status has any influence on the effectiveness of ketamine treatment in MCI and brain connectivity changes after ketamine treatment will be examined. The entire study period will be approximately 1 month from start to finish. The study begins with screening followed by a baseline visit. Then there will be a single visit where an infusion of 0.5 mg/kg of IV ketamine will be performed. There will be follow-up visits 1 day, 2 days, 3 days, 7 days, and one month after the infusion. Baseline visit will include questionnaires, blood draw, cognitive evaluation, clinical evaluation, neuroimaging (specifically a non-contrast magnetic resonance image (MRI)), and an optional electroencephalogram (EEG). Follow-ups will include questionnaires, cognitive evaluation, and clinical evaluation. Additionally, blood draw and imaging (MRI) follow-up may be performed.

Official Title
-----------------
KET-MCI: An Open-label Trial of Single-dose Ketamine Treatment to Improve Depression in Mild Cognitive Impairment

Conditions
-----------------
Mild Cognitive Impairment, Depression

Intervention / Treatment
-----------------
* Drug: IV Ketamine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age 50-90 Able to give consent Montgomery Asberg Depression Rating Scale (MADRS) score of ≥20 consistent with at least moderate depression Clinical diagnosis of mild cognitive impairment or mild Alzheimer's Disease Exclusion Criteria: Serious unstable medical illness Uncontrolled hypertension Abnormal electrocardiogram Renal impairment defined as BUN 20 mg/dl and/or creatinine clearance >1.3 Current drug or alcohol use disorder History of seizures without a clear or resolved etiology Lifetime history of schizophrenia, schizoaffective disorder, or bipolar 1 or 2 disorder Montreal Cognitive Assessment (MoCA) score <18 Presence of psychotic symptoms or lifetime psychotic disorder Recreational ketamine or phencyclidine use in the last 2 years BMI>40 Serious or imminent suicidal or homicidal risk Systolic blood pressure >165 or diastolic blood pressure >95 on infusion day

Ages Eligible for Study
-----------------
Minimum Age: 50 Years
Maximum Age: 90 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>Single dose of IV ketamine administered at the standard dose used for depression treatment (0.5 mg/kg) | Drug: IV Ketamine<br>* 0.5 mg/kg IV Ketamine<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and severity of symptom events as assessed by the Patient Rated Inventory of Side Effects (PRISE) | Number of symptom events as assessed by the patient in a self-report measure. PRISE assesses the presence of treatment side effects in nine organ/function systems (gastrointestinal, nervous system, heart, eyes/ears, skin, genital/urinary, sleep, sexual functioning, and other) | end of study, at 1 month | 
| Severity of symptom events as assessed by the Patient Rated Inventory of Side Effects (PRISE) | Severity of symptom events as assessed by the patient in a self-report measure. PRISE assesses the presence of treatment side effects in nine organ/function systems (gastrointestinal, nervous system, heart, eyes/ears, skin, genital/urinary, sleep, sexual functioning, and other) | end of study, at 1 month | 
| Frequency of symptoms measured using PRISE | Frequency of observed adverse events as captured by the PRISE; assesses the presence of treatment side effects in nine organ/function systems (gastrointestinal, nervous system, heart, eyes/ears, skin, genital/urinary, sleep, sexual functioning, and other) | end of study, at 1 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Depressive symptoms as assessed with the Montgomery-Asberg Depression Rating Scale (MADRS) | The number of depressive symptoms will be assessed using the Montgomery-Asberg Depression Rating Scale (MADRS). The Montgomery Asberg Depression Rating Scale (MADRS-S) has 10-items which are based on mood symptoms over the past 7 days. Each items is scored 0 (normal) to 6 (severe depression) with overall score ranges from 0 (normal) to 60 (severe depression) | end of study, at 1 month | 
| Level of cognition as assessed with the NIH Toolbox Cognition Battery | The NIH Toolbox Cognition Battery (NIHTB-CB) is a 30 minute long cognitive evaluation consisting of 7 tests done via iPad that has been developed to allow for quick and robust measurement of multiple cognitive domains including executive function, memory, language, and processing speed using a series of well-validated assessments. Scoring for the NIH Toolbox Cognition Battery is automated and individuals are assigned a T-score (mean = 50, SD = 10) representing their cognitive performance compared to age, education, gender, and ethnicity-matched peers. | end of study, at 1 month | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Depression, Mild Cognitive Impairment, Intravenous Ketamine, Cognition, Neuroplasticity, Geriatric Psychiatry