Biomarkers of Fast Acting Therapies in Major Depression
Condition: Major Depressive Disorder
MeSH terms: Depression; Depressive Disorder; Depressive Disorder, Major
Study type: Interventional
Phase: Phase 1

Summary: 
      The drug Ketamine, available in medical practice since the late 1960s, is currently used for
      inducing general anesthesia or sedation during medical procedures. When given slowly as an
      injection into a vein, ketamine is shown to produce a very rapid effect on depression and to
      improve depressive symptoms within hours to days. By studying patients who receive a ketamine
      IV infusion, as an add-on treatment for depression, investigators may start to understand how
      changes in the brain or in gene function relate to getting better over a very short period of
      time. In this study, the investigators will enroll 60 patients currently ill with major
      depression selected to receive IV ketamine therapy under medical supervision. To study
      neurobiological changes relating to symptom improvement, the investigators will use advanced
      brain scans to measure brain structure, chemistry and function. Blood samples will measure
      changes in gene regulation and immune system response. Although some people have a rapid
      antidepressant response to ketamine, others do not respond. Also, antidepressant effects
      after ketamine usually wear off within days to weeks. We will determine if up to four doses
      of ketamine delivered two to three times a week may prolong antidepressant response to
      ketamine therapy. To determine the durability of ketamine treatment for depression, patients
      will be monitored by phone and via electronic devices twice a week for up to five weeks and
      will return for a final assessment when their symptoms return. For this trial, brain and
      blood sample measurements will occur before and after a patient receives their first ketamine
      infusion. Patients who do not remit after an initial dose of ketamine, will receive up to
      three additional ketamine treatments. Mood will be measured 24-hours after each subsequent
      ketamine infusion and brain and blood measurements be repeated at the time of remission or
      after the fourth ketamine infusion if remission does not occur. Patients will return for a
      final brain scan and blood sample when their depressive symptoms return or at five weeks if
      they continue remission. Investigators will able to see how changes brain measurements, gene
      regulation and immune response relate to improvements and relapse of depressive symptoms with
      ketamine IV therapy. The ketamine infusion sessions will occur at a special research unit
      (CTRC) at UCLA.
    

Detailed description: 
      Growing evidence implicates the glutamatergic system in the pathogenesis of depression, and
      receptor antagonists may provide a new generation of compounds for MDD treatment. In
      particular, the finding that the NMDA antagonist, ketamine, induces a rapid antidepressant
      response within hours to days has led to research investigating the neural mechanisms
      producing rapid antidepressant action and makes ketamine a valuable tool to identify
      biomarkers of depression response and of risk of relapse. The study of biomarkers for
      understanding the mechanistic actions of ketamine may serve to enhance emerging treatment
      approaches and provide new breakthroughs for translation of other drug targets.

      Recently, the investigators of this trial have begun to offer off-label ketamine infusion
      treatment to clinical patients with treatment-resistant depression (TRD) and have developed a
      local treatment protocol for systematic clinical assessment, infusion monitoring and
      follow-up, which has been well-received and tolerated. The overarching goal of this study is
      to investigate imaging, gene expression and immune system biomarkers to help determine the
      underlying mechanisms and predictors for treatment response and relapse in MDD patients
      receiving ketamine and to compare these with the same biomarkers obtained from patients
      receiving ECT. The investigators aim to collect data from a sample of 60 patients who will
      receive serial infusions of ketamine, occurring 2-3 times a week, until they achieve
      remission or a total of 4 infusions. To study changes during or after ketamine treatment, we
      will use advanced brain scans that will allow us to measure brain structure, chemistry and
      function. We will also collect blood samples to measure changes in gene regulation and immune
      system response at the same time. Patients will also be assessed for basic cognitive function
      and mood. Brain and blood sample measurements will occur before ketamine infusion, 24 hours
      after the first infusion, after the 4th or last infusion, and at a final follow-up session
      approximately 5 weeks after ketamine treatment. We are also including remote mood assessment
      after treatment to more efficiently track relapse. We will therefore be able to see how
      changes over time in brain measurements and gene regulation, or immune response relate to
      improvements and relapse in depressive symptoms.

      The investigators will address the following aims:

      Aim 1: To use a comprehensive multimodal magnetic resonance imaging (MRI) battery including
      a) single voxel proton magnetic resonance spectroscopy (1HMRS), b) structural MRI (sMRI), c)
      arterial spin-labeling (ASL), d) resting state functional MRI (rs-fMRI) and e) diffusion MRI
      (dMRI) sensitive to different aspects of brain plasticity to isolate neurobiological markers
      linked with and predictive of ketamine response and subsequent relapse.

      Hypothesis 1: Neuroplasticity in cortico-limbic (prefrontal and anterior cingulate cortex and
      hippocampus) and striatal networks, including changes in glutamate and other brain
      metabolites, in blood perfusion and in structural and functional connectivity will associate
      with therapeutic response to ketamine.

      Aim 2: To use peripheral blood to measure inflammatory cytokines and their soluble receptors
      previously linked with depression or treatment outcome for the examination of relationships
      with ketamine response and subsequent relapse.

      Hypothesis 2: Ketamine-induced symptom improvement will associate with altered concentrations
      of proinflammatory cytokines to indicate modulation of the immune response system.

      Aim 3: To conduct transcriptome profiling using peripheral blood samples to identify gene
      expression correlates of ketamine response.

      Hypothesis 3: Gene expression profiles will signal biological pathways underlying therapeutic
      response to ketamine.

      Description of outcome measures:

        1. Clinical outcome: The Hamilton Depression Rating Scale

        2. Imaging markers: Image analysis will incorporate both standard and custom image analysis
           software and processing streams to measure changes neurochemistry, and structural and
           functional plasticity and connectivity occurring across time and in association clinical
           response. Specifically, outcome measures will include:

             1. Structural imaging and connectivity measures: combined volumetric and shape and
                diffusion metrics obtained from sMRI and dMRI data.

             2. Functional connectivity measures: Combined functional imaging measures obtained
                from resting state functional imaging data

             3. Neurochemistry: Brain metabolites including glutamate, choline, and NAA.

             4. Gene expression: Gene expression markers obtained from differential expression
                analyses.

      Analyses: General linear mixed models and regression analyses will be used to determine
      changes across time and in association with clinical response for imaging markers. Weighted
      Gene Coexpression Network analysis (WGCNA) and Ingenuity Pathways analysis (IPA) will be used
      to identify functions and pathways associated with identified transcripts.
    

Intervention name(s): Ketamine
Intervention type(s): Drug
Intervention description(s): Approved FDA indications for ketamine include use as an adjunct in the induction and maintenance of general anesthesia and for procedural sedation. For general anesthesia, ketamine is given at dosages ranging from 1-2mg/kg and given either as bolus injection or run continuously (0.1 to 0.3mg/kg/min) in conjunction with another anesthetic or sedation agent. In this study, ketamine at a subanesthetic dose of 0.5mg/kg will be diluted in 60cc of normal saline and administered via a slow IV infusion over 40 minutes at each treatment session in patients while undergoing hemodynamic monitoring. When used in this manner, ketamine infusion does not induce general anesthesia or states of unconsciousness, and patients remain fully awake, responsive to commands, and do not lose respiratory drive.
Intervention MeSH terms: Ketamine
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: ketamine; major depression; imaging; gene expression