Advancing Personalized Antidepressant Treatment Using PET/MRI

Sponsor
Stony Brook University (Other)
Overall Status
Completed
CT.gov ID
NCT02623205
Collaborator
(none)
85
1
2
58
1.5

Study Details

Study Description

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 selective serotonin reuptake inhibitors (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
Phase 4

Detailed Description

Aim 1: Determine a Pretreatment Marker of SSRI Effectiveness Using Positron Emission Tomography (PET). With the goal of reducing MDD burden, many studies have assessed the utility of 18F-2-fluoro-2-deoxy-D-glucose fluorodeoxyglucose (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 mini-Positron Emission Tomography (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.

Study Design

Study Type:
Interventional
Actual Enrollment :
85 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 1, 2015
Actual Primary Completion Date :
Mar 1, 2020
Actual Study Completion Date :
Mar 1, 2020

Arms and Interventions

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. This additional 4-week treatment option is something offered to participants outside the clinical trial, and therefore was not treated as part of the main study.
Other Names:
  • 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. This treatment option is something offered to participants outside the clinical trial, and therefore was not treated as part of the main study.
    Other Names:
  • Lactose pill
  • Outcome Measures

    Primary Outcome Measures

    1. Change From Baseline in Hamilton Depression Rating Scale at 8 Weeks [8 weeks]

      Comparison of Hamilton Depression Rating Scale-17 score at pretreatment and post-treatment. Minimum score 0, maximum possible score 52, with remission defined as <=7. The higher the score on the scale, the more severe the degree of depression.

    Secondary Outcome Measures

    1. Change From Baseline in Metabolic Rate of Glucose (MRGlu), Quantified Using Arterial Blood Analysis, at 8 Weeks [8 weeks]

      Difference between MRGlu Metabolism in Right Insular Cortex before treatment (baseline) and after treatment (week 8). Details on methods and criteria used to assess brain glucose metabolism rates can be found here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8551925/

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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 Physician's Desk Reference (PDR) maximal dose

    14. Significant neurological deficits

    15. Electroconvulsive Therapy (ECT) within the past 6 months

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Stony Brook University Hospital Stony Brook New York United States 11794

    Sponsors and Collaborators

    • Stony Brook University

    Investigators

    • Principal Investigator: Christine DeLorenzo, PhD, Stony Brook University

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Christine DeLorenzo, Associate Professor of Psychiatry, Associate Professor of Biomedical Engineering, Stony Brook University
    ClinicalTrials.gov Identifier:
    NCT02623205
    Other Study ID Numbers:
    • 2014-2911-F
    First Posted:
    Dec 7, 2015
    Last Update Posted:
    Jun 2, 2022
    Last Verified:
    May 1, 2022
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Escitalopram Placebo
    Arm/Group Description 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) 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. Lactose pill manufactured to mimic Escitalopram pill 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 selective serotonin reuptake inhibitor (SSRI) treatment to placebo non-responders.
    Period Title: Overall Study
    STARTED 42 43
    COMPLETED 38 40
    NOT COMPLETED 4 3

    Baseline Characteristics

    Arm/Group Title Escitalopram Placebo Total
    Arm/Group Description 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) 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. Lactose pill manufactured to mimic Escitalopram pill 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. Total of all reporting groups
    Overall Participants 42 43 85
    Age (Count of Participants)
    <=18 years
    0
    0%
    0
    0%
    0
    0%
    Between 18 and 65 years
    42
    100%
    43
    100%
    85
    100%
    >=65 years
    0
    0%
    0
    0%
    0
    0%
    Sex: Female, Male (Count of Participants)
    Female
    27
    64.3%
    29
    67.4%
    56
    65.9%
    Male
    15
    35.7%
    14
    32.6%
    29
    34.1%
    Race/Ethnicity, Customized (Count of Participants)
    Caucasian - White
    26
    61.9%
    26
    60.5%
    52
    61.2%
    Caucasian - Non-white
    2
    4.8%
    1
    2.3%
    3
    3.5%
    African American / Black
    2
    4.8%
    2
    4.7%
    4
    4.7%
    Asian - South Asian
    5
    11.9%
    2
    4.7%
    7
    8.2%
    Asian - East Asian
    3
    7.1%
    4
    9.3%
    7
    8.2%
    Asian - Southeast Asian
    0
    0%
    1
    2.3%
    1
    1.2%
    Pacific Islander
    0
    0%
    1
    2.3%
    1
    1.2%
    Mixed
    4
    9.5%
    6
    14%
    10
    11.8%
    Region of Enrollment (participants) [Number]
    United States
    42
    100%
    43
    100%
    85
    100%
    Hamilton Depression Scale (HAM-D) Rating (Scores on Scale) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Scores on Scale]
    18.86
    (5.09)
    16.79
    (3.84)
    17.81
    (4.59)

    Outcome Measures

    1. Primary Outcome
    Title Change From Baseline in Hamilton Depression Rating Scale at 8 Weeks
    Description Comparison of Hamilton Depression Rating Scale-17 score at pretreatment and post-treatment. Minimum score 0, maximum possible score 52, with remission defined as <=7. The higher the score on the scale, the more severe the degree of depression.
    Time Frame 8 weeks

    Outcome Measure Data

    Analysis Population Description
    Disparity in Week 8 Number Analyzed versus Baseline Number Enrolled due to participants lost to follow up or instances of discontinued intervention (Escitalopram Group: n = 4, Placebo Group: n =3), and participants who were excluded from analysis for one of the following: Greater than 20% blood glucose change between pre-scan and post scan sampling, Diabetes, Motion Interference, & Instrument Failure (Escitalopram Group: n = 7, Placebo Group: n = 8)
    Arm/Group Title Escitalopram Placebo
    Arm/Group Description 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) 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. Lactose pill manufactured to mimic Escitalopram pill 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.
    Measure Participants 31 32
    Mean (Standard Deviation) [score on a scale]
    11.81
    (7.02)
    9.41
    (5.66)
    2. Secondary Outcome
    Title Change From Baseline in Metabolic Rate of Glucose (MRGlu), Quantified Using Arterial Blood Analysis, at 8 Weeks
    Description Difference between MRGlu Metabolism in Right Insular Cortex before treatment (baseline) and after treatment (week 8). Details on methods and criteria used to assess brain glucose metabolism rates can be found here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8551925/
    Time Frame 8 weeks

    Outcome Measure Data

    Analysis Population Description
    Total n = 15 excluded from analysis for the following: Greater than 20% blood glucose change between pre-scan and post scan sampling, Motion, Instrument failure. In addition, several participants in each group were lost to follow up or discontinued intervention.
    Arm/Group Title Escitalopram Placebo
    Arm/Group Description 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) 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. Lactose pill manufactured to mimic Escitalopram pill 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.
    Measure Participants 29 29
    Mean (Standard Deviation) [mg/(min*100 ml)]
    0.507489448
    (0.102327217)
    0.068629964
    (0.048866182)

    Adverse Events

    Time Frame Adverse event data were collected over a period of up to 6-weeks during the pre-treatment washout phase (when necessary), and for the complete 8-week treatment period.
    Adverse Event Reporting Description
    Arm/Group Title Escitalopram Placebo
    Arm/Group Description 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) 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. Lactose pill manufactured to mimic Escitalopram pill 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.
    All Cause Mortality
    Escitalopram Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/42 (0%) 0/43 (0%)
    Serious Adverse Events
    Escitalopram Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/42 (0%) 0/43 (0%)
    Other (Not Including Serious) Adverse Events
    Escitalopram Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/42 (0%) 0/43 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Kathryn Hill
    Organization Department of Psychiatry, Renaissance School of Medicine at Stony Brook University
    Phone 904-252-3449
    Email kathryn.hill@stonybrookmedicine.edu
    Responsible Party:
    Christine DeLorenzo, Associate Professor of Psychiatry, Associate Professor of Biomedical Engineering, Stony Brook University
    ClinicalTrials.gov Identifier:
    NCT02623205
    Other Study ID Numbers:
    • 2014-2911-F
    First Posted:
    Dec 7, 2015
    Last Update Posted:
    Jun 2, 2022
    Last Verified:
    May 1, 2022