Ketamine Treatment Effects on Synaptic Plasticity in Depression
Condition: Major Depressive Disorder
MeSH terms: Depressive Disorder; Depressive Disorder, Major
Study type: Interventional
Phase: Phase 4

Summary: 
      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
      medication that at subanesthetic doses leads to rapid antidepressant and anti-suicidal
      ideation 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. The goal of this project is to
      A) elucidate ketamine's mechanism of action 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. Data from animal models suggests that
      ketamine acts by enhancing the connections between neurons through a process known as
      synaptic plasticity (4-7), and that these biological changes are responsible for the
      sustained behavioral effects of ketamine (8). A newly available tool allows us to image the
      density of these synaptic connections in the living brain using PET (positron emission
      tomography) imaging with a radiotracer called [11C]UCB-J, which is a marker of synaptic
      density. We propose to directly quantify synaptic density in depressed patients before and
      after a course of ketamine, to examine changes in density following treatment. In exploratory
      analyses, we will examine synaptic density as a mediator of the sustained antidepressant
      effects of ketamine and as a predictor of treatment outcome. To study these questions, 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 participation
      involves an inpatient stay of approximately three weeks at the New York State Psychiatric
      Institute at no cost.
    

Detailed description: 
      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 participation
      involves an inpatient stay of approximately three weeks at the New York State Psychiatric
      Institute at no cost.
    

Intervention name(s): Ketamine
Intervention type(s): Drug
Intervention description(s): Subjects will undergo 4 sequential intravenous infusions of ketamine administered over a two week period.
Ketamine is administered at a dose of 0.5mg/kg intravenously as a slow continuous infusion over approximately 40 minutes, with 4 sequential infusions over an approximately two week period (two infusions per week for two weeks).
Intervention MeSH terms: Ketamine
Intervention model: Single Group Assignment
Intervention model description: Depressed adults with current major depressive disorder
Masking: None (Open Label)
Primary purpose: Other