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

Mount Sinai Health System

Status and phase

Active, not recruiting

Phase 2

Conditions

Mild Cognitive Impairment

Depression

Treatments

Drug: IV Ketamine

Study type

Interventional

Funder types

Other

Identifiers

NCT06069843

STUDY-23-00160

Details and patient eligibility

About

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.

Full 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.

Enrollment

15 patients

Sex

All

Ages

50 to 90 years old

Volunteers

No Healthy Volunteers

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