Ketamine Treatment Effects on Synaptic Plasticity in Depression
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT04091971|
Recruitment Status : Not yet recruiting
First Posted : September 17, 2019
Last Update Posted : April 24, 2020
|Condition or disease||Intervention/treatment||Phase|
|Major Depressive Disorder||Drug: Ketamine||Phase 4|
Depression is the leading cause of disability globally (1, 2). One-third to one-half of patients suffering from major depressive disorder (MDD) do not achieve remission even after multiple antidepressant trials (3). Ketamine is a commonly-used FDA-approved anesthetic and non-competitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonist. Recent randomized trials demonstrate that subanesthetic doses of ketamine lead to rapid antidepressant and antisuicidal ideation effects in individuals with MDD and bipolar depression (reviewed in (9)). In contrast to current FDA-approved antidepressants, ketamine exerts antidepressant effects in hours, rather than weeks, following administration. Despite these promising findings, a key limitation of ketamine treatment is that it only yields an antidepressant response in approximately 50% of those treated. In addition, ketamine's clinical utility is limited by its acute dissociative side effects, a one to two-week duration of action as monotherapy, its addictive potential, and long term safety concerns related to cognition and interstitial cystitis (9-11). Given the profound benefit of ketamine for some individuals yet these key limitations, developing a precision medicine research strategy for ketamine's antidepressant effects could be of tremendous scientific and clinical benefit, in order to A) elucidate ketamine's mechanism of action, to advance the development of safer alternative agents and B) identify biomarkers predicting treatment outcome to ketamine, which could be used to match patients to treatment based on the likelihood of effectiveness at the individual level.
There is evidence of brain atrophy in depression: gray matter volume is reduced in the prefrontal cortex (PFC) and in the hippocampus (HC) in depressed individuals (12). Postmortem studies in depression show low expression of several genes related to synaptic function and decreased synapse number in the dorsolateral PFC (13). Chronic stress, a risk factor for depression, precipitates neuronal atrophy and dendritic spine loss in HC and PFC (14, 15). Preclinical work in rodents suggests that ketamine may exert antidepressant effects by reversing neuronal atrophy, specifically through the formation of new dendritic spine synapses in the brain. In rodents, ketamine induces rapid synaptogenesis via stimulation of mechanistic target of rapamycin (mTOR) and brain-derived neurotrophic factor (BDNF), leading to a reversal of chronic, stress-induced neuronal atrophy (4-7).
A recently developed research tool enables examination of synaptic density in vivo in humans. [11C]UCB-J is a PET radiotracer that is specific for synaptic vesicle glycoprotein 2A (SV2A) (16, 17), providing a quantitative measure of synaptic density in vivo in the brain in humans. A recent PET imaging pilot study identified low [11C]UCB-J binding in the PFC of individuals with current MDD as compared to healthy volunteers, providing early evidence that this synaptic density biomarker may quantify a disease-relevant process in depression (18). Furthermore, PET imaging with [11C]UCB-J displays outstanding test-retest reliability, with absolute test-retest variability of only 4-5% in brain regions of interest in this study (19), making it an outstanding tool for longitudinal studies of the effects of treatment interventions. We therefore propose to directly quantify synaptic density in depressed patients to investigate whether it is increased by treatment with ketamine in a regionally-specific manner. Moreover, we will examine synaptic density as a mediator of the sustained antidepressant effects of ketamine and as a predictor of treatment outcome. We will quantify synaptic density using PET imaging before and after a course of 4 sequential intravenous infusions of ketamine administered over a two-week period.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||20 participants|
|Intervention Model:||Single Group Assignment|
|Intervention Model Description:||Depressed adults with current major depressive disorder|
|Masking:||None (Open Label)|
|Official Title:||Examining the Effects of Ketamine Treatment on Synaptic Plasticity in Depression Using PET Imaging|
|Estimated Study Start Date :||July 1, 2020|
|Estimated Primary Completion Date :||March 1, 2022|
|Estimated Study Completion Date :||March 1, 2022|
Experimental: Depressed adults with current MDD
Subjects will undergo 4 sequential intravenous infusions of ketamine administered over a two week period.
See arm description.
- Synaptic Density [ Time Frame: Baseline scan: ≤1 week prior to first ketamine infusion. Post-treatment scan: approximately 24-48 hours after final (4th) ketamine infusion ]Change in PET imaging measure of synaptic density ([11C]UCB-J binding)
- 17-item Hamilton Depression Rating Scale [ Time Frame: Conducted at screening, 24 hours pre-infusion, 24 hours post-infusion, 3 days post infusion 4, and during weekly follow ups on Weeks 1, 2 and 3 ]
The 17-item Hamilton Depression Rating Scale (HDRS) is a clinician-administered scale that quantifies depression severity, and includes items assessing mood, suicidal thinking, insomnia, feelings of guilt, work and activities, somatic symptoms, and insight. It is a well-characterized scale with excellent psychometric properties. The total score is the sum of the individual scores of the 17 scale items. Higher scores indicate greater depression severity. Published norms for interpretation of the 17-item HDRS use a different version of the scale with a total possible score of 52, and are listed below. Interpretation is comparable (but not identical) with the 17-item HDRS version used in this study, which has a maximum score of 51.
None: 0-7 Mild: 8-13 Moderate: 14-19 Severe: 20-25 Very Severe: 26-52
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04091971
|Contact: Jeffrey Miller, MDemail@example.com|
|Contact: John J Mann, MDfirstname.lastname@example.org|
|Principal Investigator:||Jeffrey Miller, MD||New York State Psychiatric Institute|