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Advancing Personalized Antidepressant Treatment Using PET/MRI

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ClinicalTrials.gov Identifier: NCT02623205
Recruitment Status : Recruiting
First Posted : December 7, 2015
Last Update Posted : November 8, 2019
Sponsor:
Information provided by (Responsible Party):
Stony Brook University

Brief Summary:
Despite current medications, morbidity and mortality of Major Depressive Disorder (MDD) remain high. According to the World Health Organization, MDD affects 121 million people worldwide, and is projected to be the second leading cause of global disability by 2020. Monotherapy with SSRIs is the most widely used treatment for MDD. However, on average, SSRIs require six weeks for onset of action, and two-thirds of those on SSRIs fail to achieve remission.Compounding this problem, patients with residual symptoms are significantly more likely to discontinue treatment or relapse, be hospitalized for medical and psychiatric conditions, or die of suicide and other causes. Although eliminating ineffective treatment trials would significantly reduce patient suffering and healthcare costs,clinicians currently do not have the tools to objectively select treatment based on an individual's likelihood of remission. Therefore, there is an urgent need to identify markers predictive of an individual's SSRI treatment outcome. Developing this personalized treatment requires increased understanding of the relationship between pretreatment neurobiology, SSRI-induced biological changes, and the corresponding symptom improvements.

Condition or disease Intervention/treatment Phase
Depression Drug: Escitalopram Drug: Placebo Phase 4

Detailed Description:

Aim 1: Determine a Pretreatment Marker of SSRI Effectiveness Using PET. With the goal of reducing MDD burden, many studies have assessed the utility of FDG-PET in antidepressant treatment prediction. However, due to the limitations listed above, there is no consensus on which brain regions are predictive of treatment efficacy. In addition to serving as a biomarker of SSRI effectiveness, only conclusive determination of these regions will provide insight into depression pathophysiology, helping uncover SSRI mechanism of action, and aiding in the search of novel therapeutics. Based on the investigators' preliminary data and other, similar studies, the investigators hypothesize that SSRI-induced change in the Hamilton Depression Rating Scale (deltaHDRS) will be correlated with pretreatment metabolic rate of glucose (MRGlu, quantified using arterial blood analysis) in three potential regions: (1) midbrain, (2) right anterior insula, and/or (3) left ventral prefrontal cortex.

Aim 2: Isolate the Neurobiological Basis of the "Loss" Research Domain Criteria (RDoc) and the Change Associated with Treatment. Using a factor analysis of the HDRS, the investigators have previously demonstrated that the "loss" RDoC criteria is significantly correlated to MRGlu in frontal cortical areas. The investigators therefore hypothesize that change in MRGlu (pre to post treatment) in these regions will be correlated with symptom improvement specifically in "loss" symptoms. As an exploratory extension, the investigators will determine whether these changes are treatment-specific (i.e. to SSRI or placebo). A validation of the hypothesis suggests a targeted mechanism of action, and provides a significant step forward for precision treatment. If regional changes in MRGlu are not correlated to improvement in this RDoC category, it suggests that SSRI (or placebo) induced changes may be a downstream effect that should be examined further.

Aim 3: Validate NonInvasive Full Quantification of MRGlu Using Simultaneous Estimation. Full quantification of brain MRGlu with FDG (as performed in this study) requires measuring FDG in arterial plasma (input function) from arterial catheter insertion and blood analysis. This costly and invasive procedure creates a barrier to widespread PET use. The investigators have developed an innovative method for Simultaneous Estimation (SimE) of input information and PET outcome measures (e.g. MRGlu). SimE fully quantifies brain MRGlu without requiring an arterial catheter. In the case of FDG, the investigators' data suggests that SimE used with a single venous sample can provide accurate results. The investigators further hypothesize that the venous sample may be entirely replaced by study data (e.g., injected dose) and biometrics (e.g., body surface area, lean body mass index). Using two different approaches (statistical imputation and physiological parametric modeling) and previously collected data, the investigators will train the SimE for accurate quantification in the absence of blood data. The rich data collected in this study will then provide a robust benchmark for validation of the SimE approach.

Aim 4: Validate Noninvasive Estimates of Plasma Radioactivity from a Novel miniPET Scanner. In parallel to SimE (algorithm/software) development, the investigators will test a noninvasive method of plasma analysis using hardware. FDG concentration will be measured at the wrist, arm, ankle or leg with a novel synchronized PET scanner developed by co-Investigator, Dr. Paul Vaska.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 150 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Advancing Personalized Antidepressant Treatment Using PET/MRI
Actual Study Start Date : May 2015
Estimated Primary Completion Date : January 1, 2020
Estimated Study Completion Date : January 1, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Antidepressants

Arm Intervention/treatment
Active Comparator: Escitalopram
Active Comparator: Escitalopram (Lexapro) 10mg Week 1, 20mg Weeks 2 and 3, and 30mg for Weeks 4 to 8 (or until 12 for patients close to remission)
Drug: Escitalopram
Participants randomized to the escitalopram group will be given the medication for 8 weeks, after which they will be given the option to continue for 4 more weeks if they are close to remission.
Other Name: Lexapro

Placebo Comparator: Placebo
Lactose pill manufactured to mimic Escitalopram pill
Drug: Placebo
To reduce the burden of the patients on placebo, the placebo trial will have a target of 8 weeks. To provide an opportunity for placebo non-responders to receive active drug and to aid in recruitment, we will provide 8-12 weeks of SSRI treatment to placebo non-responders.
Other Name: Lactose pill




Primary Outcome Measures :
  1. Change from Baseline in Hamilton Depression Rating Scale at 8 weeks [ Time Frame: 8 weeks ]

Secondary Outcome Measures :
  1. Change from Baseline in MRGlu (quantified using arterial blood analysis) at 8 weeks [ Time Frame: 8 weeks ]
  2. Quantification of brain MRGlu without an arterial catheter by training SimE [ Time Frame: 8 weeks ]
  3. FDG concentration measured at the wrist, arm, ankle, or leg with a novel synchronized PET scanner [ Time Frame: 8 weeks ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age range: over 18 years old
  2. Capacity to consent
  3. Diagnosis of MDD and suffering from a major depressive episode
  4. Score of at least 22 on the MADRS

Exclusion Criteria:

  1. Significant active physical illness, particularly those that may affect the brain
  2. Need for use of medication during the study that will interact with the study medication. Need to start medication that will affect study results (anti epileptics, antidepressants, beta blockers, medications with serotonergic or GABAergic modes of action)
  3. Patients considered at significant risk for suicide
  4. Patient is unlikely to be able to tolerate medication washout or the ~3 week interval (5 for fluoxetine) following washout (drug free period). Medication washouts will be supervised by a study physician.
  5. For females: Pregnancy, currently lactating; planning to conceive during the course of study participation, or abortion in the past two months.
  6. Coumadin treatment within 10 days of PET scanning
  7. Any MRI contraindications, including metal implants, pacemaker, metal prostheses, orthodontic appliances, or presence of shrapnel that are contraindicated for MRI.
  8. Bipolar Disorder
  9. Current psychosis
  10. High potential for excessive drug/alcohol use during the treatment period (excluding nicotine or cannabis)
  11. Currently taking effective antidepressant
  12. Currently taking an effective antidepressant
  13. Prior intolerance escitalopram (ESC) for ≥ 4 weeks taking ≥ ⅔ PDR maximal dose
  14. Significant neurological deficits
  15. ECT within the past 6 months

Information from the National Library of Medicine

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): NCT02623205


Contacts
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Contact: Nichole Hoehn, MA 631-638-2053 nichole.hoehn@stonybrookmedicine.edu
Contact: Study Coordinator 631-638-2053 imaging.study@stonybrookmedicine.edu

Locations
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United States, New York
Stony Brook University Hospital Recruiting
Stony Brook, New York, United States, 11794
Contact: Nichole Hoehn, MA    631-638-2053    Nichole.Hoehn@stonybrookmedicine.edu   
Contact: Juhayer Alam    631-638-2053    imaging.study@stonybrook.edu   
Principal Investigator: Christine DeLorenzo, PhD         
Sponsors and Collaborators
Stony Brook University
Investigators
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Principal Investigator: Christine DeLorenzo, PhD Stony Brook University

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Responsible Party: Stony Brook University
ClinicalTrials.gov Identifier: NCT02623205    
Other Study ID Numbers: 2014-2911-F
First Posted: December 7, 2015    Key Record Dates
Last Update Posted: November 8, 2019
Last Verified: November 2019
Additional relevant MeSH terms:
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Depression
Behavioral Symptoms
Dexetimide
Antidepressive Agents
Citalopram
Psychotropic Drugs
Serotonin Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Serotonin Agents
Physiological Effects of Drugs
Antidepressive Agents, Second-Generation
Antiparkinson Agents
Anti-Dyskinesia Agents
Parasympatholytics
Autonomic Agents
Peripheral Nervous System Agents
Muscarinic Antagonists
Cholinergic Antagonists
Cholinergic Agents