Biomarkers of Fast Acting Therapies in Major Depression
| Status: | Recruiting |
|---|---|
| Conditions: | Depression, Depression, Major Depression Disorder (MDD) |
| Therapuetic Areas: | Psychiatry / Psychology, Pulmonary / Respiratory Diseases |
| Healthy: | No |
| Age Range: | 18 - 64 |
| Updated: | 8/30/2018 |
| Start Date: | June 2014 |
| End Date: | August 2021 |
| Contact: | Katie Patel |
| Email: | DGCBiomarkerStudy@mednet.ucla.edu |
| Phone: | 310-794-0305 |
Translational Biomarkers of Fast Acting Therapies in Major Depression
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.
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.
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.
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.
Inclusion Criteria:
- Age between 18 to 64 years, inclusive
- Diagnosis: DSM-IV TR criteria for non-psychotic major depression
- Hamilton Depression Rating Scale-17 item ≥ 18 or Montgomery Asberg Depression Scale ≥
20
- A history of at least one previous major depressive episode prior to the current
episode
- Recurrent Depression - in the current episode, have not responded to at least 2
adequate antidepressant trials (using Antidepressant Treatment History Form criteria)
- Have been continuously depressed for between 6-12 months
- Receiving approved monoaminergic antidepressant therapy
- No changes in antidepressant medication(s) in the past one (1) month
- Voluntary patient receiving ketamine
- Capacity to provide informed consent
- Have no contraindications to an adjunctive trial of ketamine infusion
- Be under the current care of a treating Psychiatrist
- If outpatient, a responsible driver available for transportation to and from scanning
sessions
- Live locally, within travelling distance to UCLA
- Be available to participate for a 5-week research follow-up
Exclusion Criteria:
- Younger than 18 or older than 64
- Serious and imminent suicidal or homicidal risk (active suicidal ideations with or
without a plan, HAM-D score ≥ 3 on item 3)
- Mental retardation or other developmental disorder
- Diagnosis of dementia of any type
- History of current substance abuse or dependence
- Psychotic reactions to medications, alcohol or illicit substances in the past
- Current or past history of psychosis, schizophrenia, bipolar disorder, delusional
disorder or other psychotic disorder
- Treatment with medications with NMDA and NMDAR action
- Contraindication to ketamine
- Depression related to serious medical illness (i.e., mood disorder due to general
medical condition)
- History of neurological disorder or other physical disorder (i.e. significant head
injury) that could affect brain functioning
- Serious or unstable medical or neurological condition(s) that in the opinion of the
treating physician or PI renders ketamine unsafe to administer
- Any condition that would contraindicate scanning (metal implants, claustrophobia or a
breathing or movement disorder)
- Pregnancy (as confirmed by positive urine pregnancy test) or planning on becoming
pregnant
- Non-English speaking (due to scales administered)
- Live outside of the Los Angeles area
We found this trial at
1
site
Los Angeles, California 90095
Principal Investigator: Katherine Narr, Ph.D.
Phone: 310-267-5119
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