An Investigation of Early Life Stress and Depression

Sponsor
Mclean Hospital (Other)
Overall Status
Completed
CT.gov ID
NCT01701258
Collaborator
National Institute of Mental Health (NIMH) (NIH), Massachusetts General Hospital (Other)
153
2
8
45
76.5
1.7

Study Details

Study Description

Brief Summary

The purpose of this study is to investigate brain pathways within adult females (with a history of CSA that occurred between the ages of 5-14) with and without a current diagnosis of major depressive disorder (MDD).

Hypotheses:

The CSA/MDD participants will be characterized by (1) reduced reward responsiveness and prefrontal cortex activity, but increased cortisol levels, (2) reduced dopamine activity, and (3) reduced dopamine transporter binding. The over-arching purpose of the study is to (1) identify individuals at risk for psychopathology and maladaptive behavior, (2) prevent re-victimization, and (3) develop more targeted therapeutic interventions.

Condition or Disease Intervention/Treatment Phase
Phase 1

Detailed Description

This study will include four sessions:

Session 1 (SCID Session) The first session takes place at the Center for Depression, Anxiety, and Stress Research (CDASR) or Neuroimaging Center (both at McLean Hospital) and involves consenting, a clinical evaluation, a series of questionnaires, and a medical assessment.

Session 2 or 3 (fMRI Session) The third session takes place at the Neuroimaging Center. Using a double-blind design, participants will be administered either amisulpride (50 mg) or placebo. Participants will complete the Monetary Incentive Delay (MID) task during functional magnetic resonance imaging (fMRI) and the Probabilistic Stimulus Selection Task (PSST) afterwards.

Session 2 or 3 (PET Session) This session takes place at Massachusetts General Hospital. 9 mCi of [11C] altropane will be injected by a trained nuclear medicine technician and positron emission tomography (PET) scanning will begin. Prior to the PET scan, a blood serum pregnancy test will be administered for females.

Session 4 (ERP Session) The fourth session takes place at the CDASR and involves an electroencephalography (EEG) recording, the Probabilistic Reward Task (PRT), and collecting saliva samples to assess cortisol levels.

Study Design

Study Type:
Interventional
Actual Enrollment :
153 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Intervention Model Description:
There were four groups of subjects: those with a history of child sexual abuse that are currently experiencing a major depressive episode, those with a history of child sexual abuse without a current or past diagnosis of major depressive disorder, those without a history of child sexual abuse that are currently experiencing a major depressive episode, and those with without a history of child sexual abuse and without a current or past diagnosis of major depressive disorder. Within each group, half of the subjects were assigned to receive the study drug (amisulpride) and half to receive a placebo for the fMRI session (session 2 or 3).There were four groups of subjects: those with a history of child sexual abuse that are currently experiencing a major depressive episode, those with a history of child sexual abuse without a current or past diagnosis of major depressive disorder, those without a history of child sexual abuse that are currently experiencing a major depressive episode, and those with without a history of child sexual abuse and without a current or past diagnosis of major depressive disorder. Within each group, half of the subjects were assigned to receive the study drug (amisulpride) and half to receive a placebo for the fMRI session (session 2 or 3).
Masking:
Triple (Participant, Care Provider, Investigator)
Primary Purpose:
Basic Science
Official Title:
Early Life Stress and Depression: Molecular and Functional Imaging Approaches
Actual Study Start Date :
Aug 1, 2013
Actual Primary Completion Date :
May 1, 2017
Actual Study Completion Date :
May 1, 2017

Arms and Interventions

Arm Intervention/Treatment
Active Comparator: CSA/MDD-amisulpride

Subjects experiencing a current episode of major depression (MDD) with a history of child sexual abuse (CSA) are randomized to receive a single low-dose pharmacological challenge, 50mg amisulpride tablet during the fMRI session.

Drug: Amisulpride
single low-dose pharmacological challenge, 50 mg amisulpride during the fMRI session only
Other Names:
  • Solian
  • Placebo Comparator: CSA/MDD-placebo

    Subjects experiencing a current episode of major depression (MDD) with a history of child sexual abuse (CSA) are randomized to receive a placebo during the fMRI session.

    Drug: Placebo
    single-dose placebo capsule during the fMRI session only

    Active Comparator: CSA/RES-amisulpride

    Subjects with a history of child sexual abuse (CSA) without a current or past diagnosis of major depressive disorder (RES) are randomized to receive a single low-dose pharmacological challenge, 50mg amisulpride tablet during the fMRI session.

    Drug: Amisulpride
    single low-dose pharmacological challenge, 50 mg amisulpride during the fMRI session only
    Other Names:
  • Solian
  • Placebo Comparator: CSA/RES-placebo

    Subjects with a history of child sexual abuse (CSA) without a current or past diagnosis of major depressive disorder (RES) are randomized to receive a placebo during the fMRI session.

    Drug: Placebo
    single-dose placebo capsule during the fMRI session only

    Active Comparator: MDD-amisulpride

    Subjects without a history of child sexual abuse that are currently experiencing a major depressive episode are randomized to receive a single low-dose pharmacological challenge, 50mg amisulpride tablet during the fMRI session.

    Drug: Amisulpride
    single low-dose pharmacological challenge, 50 mg amisulpride during the fMRI session only
    Other Names:
  • Solian
  • Placebo Comparator: MDD-placebo

    Subjects without a history of child sexual abuse that are currently experiencing a major depressive episode are randomized to receive a placebo during the fMRI session.

    Drug: Placebo
    single-dose placebo capsule during the fMRI session only

    Active Comparator: Control-amisulpride

    Subjects without a history of child sexual abuse and without a current or past diagnosis of major depressive episode are randomized to receive a single low-dose pharmacological challenge, 50mg amisulpride tablet during the fMRI session.

    Drug: Amisulpride
    single low-dose pharmacological challenge, 50 mg amisulpride during the fMRI session only
    Other Names:
  • Solian
  • Placebo Comparator: Control-placebo

    Subjects without a history of child sexual abuse and without a current or past diagnosis of major depressive episode are randomized to receive a placebo during the fMRI session.

    Drug: Placebo
    single-dose placebo capsule during the fMRI session only

    Outcome Measures

    Primary Outcome Measures

    1. Dopamine Active Transporter Binding Potential [1 hour PET scan (Session 3)]

      Utilizing 11C-altropane during positron emission tomography (PET) scanning allows us to measure dopamine active transporter (DAT) binding potential. Our outcome measure is Nondisplacable Binding Potential (BPND). BPND refers to the ratio at equilibrium of specifically bound radioligand to that of nondisplaceable radioligand in tissue. *Higher BPND scores indicate greater binding potential

    2. The Effects of CSA and Diagnosis on PRT Performance Under Acute Stress [3 hour EEG Session (Session 4)]

      The participant's performance on the Probabilistic Reward Task (PRT) was assessed both before and after an acute stressor. The PRT is a behavioral task that measures an individual's ability to learn from rewarding stimuli and incorporate this learning into their response style (response bias). The acute stressor was the Maastricht Acute Stress Test (MAST). The score obtained is a ratio of the number of times participants correctly choose the high reward stimuli versus the low rewarding stimuli. Response bias scores range between -1 and +1. Higher response bias scores indicate a stronger response bias toward high reward stimuli. A negative response bias indicates a stronger bias toward low reward stimuli.

    3. The Effect of Major Depressive Disorder and Childhood Abuse History on a Reward-related EEG Component (Reward Positivity Component) While Under Stress [3 hour EEG Session (Session 4)]

      EEG was recorded during the probabilistic reward task (the PRT task). Participants completed the Probabilistic Reward Task (PRT) twice throughout the experiment, once before stress and once after stress. The stressor was the Maastricht Acute Stress Test (MAST). This statistic shows the effect that childhood sexual abuse (CSA) and diagnosis had on a reward-related positivity EEG component recorded during the PRT, before and after stress. Higher reward positivity amplitudes indicate a stronger neural response to reward and lower amplitudes indicate a lower neural response to rewards.

    4. Cortisol Output in Response to a Stress Manipulation [3 hour EEG Session (Session 4)]

      This statistic shows the impact of the stress manipulation on the participant's salivary cortisol output. Saliva samples were collected at 5 distinct time points throughout the study session. The first saliva sample (Cort 1) was collected when the participant began the eeg session. The second (Cort 2)was taken at the end of the acute stressor. The third (Cort 3) was taken approximately fifteen minutes after the second. The fourth (Cort 4) was taken approximately ten minutes after the third. The fifth (Cort 5) was taken approximately 40 minutes after the fourth.

    5. Effects on Major Depressive Disorder and Childhood Sexual Abuse History on Striatal Activity in Response to Neutral and Reward Cues [3 hour Drug & fMRI Session (Session 2)]

      This statistic shows the influence of major depressive disorder and childhood sexual abuse history on the strength of striatal activation (caudate, putamen, accumbens) in response to neutral and reward cues during the monetary incentive delay task (MID). Striatal activation is measured using a statistic called a beta weight. A beta weight is a standardized regression coefficient. Higher beta weights mean greater striatal activation and lower beta weights mean less striatal activation. A negative beta weight would indicate a deactivation.

    6. Effects on Major Depressive Disorder and Childhood Sexual Abuse History on Striatal Activity in Response to Neutral and Reward Feedback [3 hour Session 2 (fMRI session)]

      This statistic shows the influence of major depressive disorder and childhood sexual abuse history on the strength of striatal activation (caudate, putamen, accumbens) in response to neutral and reward feedback during the monetary incentive delay task (MID). Striatal activation is measured using a statistic called a beta weight. A beta weight is a standardized regression coefficient. Higher beta weights mean greater striatal activation and lower beta weights mean less striatal activation. A negative beta weight would indicate a deactivation.

    7. The Effect of Diagnosis on Cortisol Reactivity [3 hour EEG Session (Session 4)]

      This is a measure of area under the curve in relation to ground, a measure of total cortisol output, in response to acute stress. The acute stressor was the Maastricht Acute Stress Test (MAST). The area under the curve includes all 5 cortisol measures, with one measure before the stressor and the other four measures collected after the stressor. Given that the cortisol data were positively skewed, the cortisol measures were normalized via a log transformation prior to calculating the area under the curve. Area under the curve with respect to ground (AUCG) is calculated AUC_g=(((cort2_log + cort1_log) * cort_t1_time) / 2)+(((cort3_log+cort2_log)*cort_t2_time)/2)+(((cort4_log+cort3_log)*cort_t3_time)/2)+(((cort5_log+cort4_log)*cort_t4_time)/2). Cort_logs are the log transformed cortisol output data (ng/ml) and the cort_times are the time spans in between each cortisol assessment.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    20 Years to 45 Years
    Sexes Eligible for Study:
    Female
    Accepts Healthy Volunteers:
    Yes
    General Inclusion Criteria:
    • Females of all ethnic origins, age between 20 and 45; right-handed (Chapman & Chapman 1987);

    • Absence of any psychotropic medications for at least 2 weeks (6 weeks for fluoxetine; 6 months for neuroleptics; 2 weeks for benzodiazepines; 2 weeks for any other antidepressants);

    Inclusion Criteria for Childhood Sexual Abuse/MDD (CSA/MDD) Group:
    • At least one incident of contact sexual abuse1 between the ages 5-14 years;

    • Current DSM-IV diagnostic criteria for MDD (as diagnosed with the use of the SCID);

    Inclusion Criteria for Childhood Sexual Abuse/Resilient (CSA/RES) Group:
    • At least one incident of contact sexual abuse1 between the ages 5-14 years;

    • Absence of past or current DSM diagnosis, including MDD or alcohol/substance abuse;

    Inclusion Criteria for Non-traumatized, MDD (MDD) Group:
    • No incidents of sexual, verbal, or physical abuse (ascertained using the Traumatic Antecedents Questionnaire);

    • Current DSM-IV diagnostic criteria for MDD (as diagnosed with the use of SCID);

    Non-traumatized, healthy controls (controls):
    • No incidents of sexual, verbal, or physical abuse (ascertained using the Traumatic Antecedents Questionnaire);

    • Absence of any medical, neurological, and psychiatric illness (including alcohol/substance abuse)

    Exclusion Criteria:
    • Participants with suicidal ideation where study participation is deemed unsafe by the study clinician;

    • Pregnant women or women of childbearing potential who are not compliant with the requirements of a urine and blood pregnancy test.

    • Failure to meet MRI or PET safety requirements.

    • Serious or unstable medical illness, including cardiovascular, hepatic, renal, respiratory, endocrine (hypothyroidism), neurologic or hematologic disease;

    • Past/current DSM diagnosis of: OCD, ADHD, schizophrenia, schizoaffective disorder, delusional disorder, bipolar disorder, mood congruent/incongruent psychotic features, substance dependence, substance abuse within the last 12 months (with the exception of cocaine or stimulant abuse, which will lead to automatic exclusion);

    • Simple phobia, social anxiety disorder and generalized anxiety disorders will be allowed only if secondary to MDD and only in the CSA/MDD and MDD groups (which will be matched for comorbidities);

    • History of seizure disorder; renal insufficiency; history of adverse reactions to amisulpride;

    • History of cocaine, stimulant, and other DA drug use [e.g., (meth)amphetamine), methylphenidate].

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 McLean Hospital Belmont Massachusetts United States 02478
    2 Massachusetts General Hospital Boston Massachusetts United States 02114

    Sponsors and Collaborators

    • Mclean Hospital
    • National Institute of Mental Health (NIMH)
    • Massachusetts General Hospital

    Investigators

    • Principal Investigator: Diego Pizzagalli, PhD, Mclean Hospital

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Diego A. Pizzagalli, Associate Professor of Psychiatry, Harvard Medical School, Mclean Hospital
    ClinicalTrials.gov Identifier:
    NCT01701258
    Other Study ID Numbers:
    • 2012P002593
    • 5R01MH095809
    First Posted:
    Oct 5, 2012
    Last Update Posted:
    May 18, 2018
    Last Verified:
    May 1, 2018
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Keywords provided by Diego A. Pizzagalli, Associate Professor of Psychiatry, Harvard Medical School, Mclean Hospital
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details Participants were recruited at McLean Hospital (Belmont, MA) between August, 2013, and June, 2017. The study was advertised using flyers, and on a number of internet bulletin boards available to the general public. Study visits were conducted in research facilities at McLean Hospital and Massachusetts General Hospital.
    Pre-assignment Detail In session 1, subjects had a diagnostic interview, a physical exam, provided a blood sample, and completed surveys, to determine eligibility. Those eligible were invited to participate in the other sessions. Participants did not need to complete all sessions. The order depended on facility availability and convenience for participants.
    Arm/Group Title All Participants Control Group Control-amisulpride (fMRI Session) Control-placebo (fMRI Session) MDD Group MDD-amisulpride (fMRI Session) MDD-placebo (fMRI Session) CSA/RES CSA/RES-amisulpride (fMRI Session) CSA/RES-placebo (fMRI Session) CSA/MDD Group CSA/MDD-amisulpride (fMRI Session) CSA/MDD-placebo (fMRI Session)
    Arm/Group Description All participants that went through the assessment (session 1) regardless if they were eligible or ineligible. Subjects without a history of child sexual abuse and without a current or past diagnosis of major depressive episode. After the screening visit, eligible control subjects without a history of child sexual abuse and without a current or past diagnosis of major depression were invited to participate in the fMRI session. Those that were interested were randomized to receive a single low-dose pharmacological challenge, 50mg amisulpride tablet during the fMRI session. This arm is specific to those that competed the fMRI session. Many eligible baseline control participants did not complete this session. After the screening visit, eligible control subjects without a history of child sexual abuse and without a current or past diagnosis of major depression were invited to participate in the fMRI session. Those that were interested were randomized to receive a placebo during the fMRI session. This arm is specific to those that competed the fMRI session. Many eligible baseline control participants did not complete this session. Subjects without a history of child sexual abuse that are currently experiencing a major depressive episode . After the screening visit, eligible subjects without a history of child sexual abuse that are currently experiencing a major depressive episode were invited to participate in the fMRI session. Those that were interested in participating, were randomized to receive a single low-dose pharmacological challenge, 50mg amisulpride tablet during the fMRI session. This arm is specific to those that competed the fMRI session. Many eligible MDD baseline participants did not complete this session. After the screening visit, eligible subjects without a history of child sexual abuse that are currently experiencing a major depressive episode were invited to participate in the fMRI session. Those that were interested in participating, were randomized to receive a placebo during the fMRI session. This arm is specific to those that competed the fMRI session. Many eligible MDD baseline participants did not complete this session. Subjects with a history of CSA but no psychopathology ("resilient group"; CSA/RES). After the screening visit, eligible subjects with a history of CSA but no psychopathology ("resilient group"; CSA/RES) were invited to participate in the fMRI session. Those that were interested in participating, were randomized to receive a single low-dose pharmacological challenge, 50mg amisulpride tablet during the fMRI session.This arm is specific to those that competed the fMRI session. Many eligible CSA/RES baseline participants did not complete this session. After the screening visit, eligible subjects with a history of CSA but no psychopathology ("resilient group"; CSA/RES) were invited to participate in the fMRI session. Those that were interested in participating, were randomized to receive a placebo during the fMRI session. This arm is specific to those that competed the fMRI session. Many eligible CSA/RES baseline participants did not complete this session. Subjects experiencing a current episode of major depression (MDD) with a history of child sexual abuse (CSA). After the screening visit, eligible subjects with a current episode of major depression (MDD) with a history of child sexual abuse (CSA) were invited to participate in the fMRI session. Those that were interested in participating, were randomized to receive a single low-dose pharmacological challenge, 50mg amisulpride tablet during the fMRI session.This arm is specific to those that competed the fMRI session. Many eligible CSA/MDD baseline participants did not complete this session. After the screening visit, eligible subjects with a current episode of major depression (MDD) with a history of child sexual abuse (CSA) were invited to participate in the fMRI session. Those that were interested in participating, were randomized to receive a placebo. This arm is specific to those that competed the fMRI session. Many eligible CSA/MDD baseline participants did not complete this session.
    Period Title: Assessment and Scheduling
    STARTED 153 0 0 0 0 0 0 0 0 0 0 0 0
    Eligible After Screening Visit 96 0 0 0 0 0 0 0 0 0 0 0 0
    Returned for Drug+fMRI (Session 2) 68 0 0 0 0 0 0 0 0 0 0 0 0
    Returned for PET (Session 3) 73 0 0 0 0 0 0 0 0 0 0 0 0
    Returned for EEG (Session 4) 66 0 0 0 0 0 0 0 0 0 0 0 0
    COMPLETED 70 0 0 0 0 0 0 0 0 0 0 0 0
    NOT COMPLETED 83 0 0 0 0 0 0 0 0 0 0 0 0
    Period Title: Assessment and Scheduling
    STARTED 0 0 11 11 0 9 8 0 6 6 0 10 7
    Received Drug Challenge 0 0 11 11 0 9 8 0 6 6 0 10 7
    COMPLETED 0 0 11 11 0 9 8 0 6 6 0 10 7
    NOT COMPLETED 0 0 0 0 0 0 0 0 0 0 0 0 0
    Period Title: Assessment and Scheduling
    STARTED 0 20 0 0 16 0 0 19 0 0 18 0 0
    COMPLETED 0 20 0 0 16 0 0 19 0 0 18 0 0
    NOT COMPLETED 0 0 0 0 0 0 0 0 0 0 0 0 0
    Period Title: Assessment and Scheduling
    STARTED 0 19 0 0 14 0 0 16 0 0 17 0 0
    COMPLETED 0 19 0 0 14 0 0 16 0 0 17 0 0
    NOT COMPLETED 0 0 0 0 0 0 0 0 0 0 0 0 0

    Baseline Characteristics

    Arm/Group Title Control Group MDD Group CSA/RES Group CSA/MDD Group Total
    Arm/Group Description Subjects without a history of child sexual abuse and without a current or past diagnosis of major depressive episode. Subjects without a history of child sexual abuse that are currently experiencing a major depressive episode are randomized to receive a single low-dose pharmacological challenge. Subjects with a history of CSA but no psychopathology ("resilient group"; CSA/RES). Subjects experiencing a current episode of major depression (MDD) with a history of child sexual abuse (CSA) are randomized to receive a single low-dose pharmacological challenge. Total of all reporting groups
    Overall Participants 26 17 24 29 96
    Age (Count of Participants)
    <=18 years
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Between 18 and 65 years
    26
    100%
    17
    100%
    24
    100%
    29
    100%
    96
    100%
    >=65 years
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    22.44
    (6.64)
    27.19
    (5.99)
    25.61
    (4.94)
    29.95
    (6.91)
    26.63
    (6.08)
    Sex: Female, Male (Count of Participants)
    Female
    26
    100%
    17
    100%
    24
    100%
    29
    100%
    96
    100%
    Male
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    1
    3.8%
    0
    0%
    0
    0%
    0
    0%
    1
    1%
    Asian
    2
    7.7%
    2
    11.8%
    0
    0%
    4
    13.8%
    8
    8.3%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    3
    11.5%
    4
    23.5%
    9
    37.5%
    5
    17.2%
    21
    21.9%
    White
    18
    69.2%
    11
    64.7%
    14
    58.3%
    13
    44.8%
    56
    58.3%
    More than one race
    2
    7.7%
    0
    0%
    1
    4.2%
    5
    17.2%
    8
    8.3%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    2
    6.9%
    2
    2.1%
    Region of Enrollment (Count of Participants)
    United States
    26
    100%
    17
    100%
    24
    100%
    29
    100%
    96
    100%
    BDI II (units on a scale) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [units on a scale]
    1.68
    (2.79)
    27.23
    (8.44)
    3.83
    (5.77)
    31.49
    (9.05)
    15.95
    (15.14)
    MASQ total (units on a scale) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [units on a scale]
    93.04
    (16.27)
    167.86
    (22.60)
    101.82
    (26.19)
    180.57
    (21.89)
    135.42
    (44.65)

    Outcome Measures

    1. Primary Outcome
    Title Dopamine Active Transporter Binding Potential
    Description Utilizing 11C-altropane during positron emission tomography (PET) scanning allows us to measure dopamine active transporter (DAT) binding potential. Our outcome measure is Nondisplacable Binding Potential (BPND). BPND refers to the ratio at equilibrium of specifically bound radioligand to that of nondisplaceable radioligand in tissue. *Higher BPND scores indicate greater binding potential
    Time Frame 1 hour PET scan (Session 3)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Control Group MDD Group CSA/RES Group CSA/MDD Group
    Arm/Group Description Subjects without a history of child sexual abuse and without a current or past diagnosis of major depressive episode. Subjects without a history of child sexual abuse that are currently experiencing a major depressive episode are randomized to receive a single low-dose pharmacological challenge. Subjects with a history of CSA but no psychopathology ("resilient group"; CSA/RES). Subjects experiencing a current episode of major depression (MDD) with a history of child sexual abuse (CSA) are randomized to receive a single low-dose pharmacological challenge.
    Measure Participants 20 16 19 18
    Caudate
    3.191
    (0.124)
    3.161
    (0.139)
    3.175
    (0.130)
    3.216
    (0.136)
    Putamen
    3.361
    (0.120)
    3.359
    (0.134)
    3.241
    (0.125)
    3.318
    (0.131)
    Accumbens
    2.159
    (0.109)
    2.103
    (0.122)
    2.103
    (0.122)
    2.149
    (0.119)
    2. Primary Outcome
    Title The Effects of CSA and Diagnosis on PRT Performance Under Acute Stress
    Description The participant's performance on the Probabilistic Reward Task (PRT) was assessed both before and after an acute stressor. The PRT is a behavioral task that measures an individual's ability to learn from rewarding stimuli and incorporate this learning into their response style (response bias). The acute stressor was the Maastricht Acute Stress Test (MAST). The score obtained is a ratio of the number of times participants correctly choose the high reward stimuli versus the low rewarding stimuli. Response bias scores range between -1 and +1. Higher response bias scores indicate a stronger response bias toward high reward stimuli. A negative response bias indicates a stronger bias toward low reward stimuli.
    Time Frame 3 hour EEG Session (Session 4)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Control Group MDD Group CSA/RES Group CSA/MDD Group
    Arm/Group Description Subjects without a history of child sexual abuse and without a current or past diagnosis of major depressive episode. Subjects without a history of child sexual abuse that are currently experiencing a major depressive episode are randomized to receive a single low-dose pharmacological challenge. Subjects with a history of CSA but no psychopathology ("resilient group"; CSA/RES). Subjects experiencing a current episode of major depression (MDD) with a history of child sexual abuse (CSA) are randomized to receive a single low-dose pharmacological challenge.
    Measure Participants 19 14 16 17
    PRT Block1: Before MAST
    0.028
    (0.035)
    0.117
    (0.045)
    0.092
    (0.043)
    0.167
    (0.070)
    PRT Block2: Before MAST
    0.124
    (0.046)
    0.155
    (0.048)
    0.130
    (0.082)
    0.168
    (0.102)
    PRT Block1: After MAST
    0.128
    (0.026)
    0.078
    (0.055)
    0.079
    (0.042)
    0.048
    (0.042)
    PRT Block2: After MAST
    0.245
    (0.041)
    0.128
    (0.035)
    0.143
    (0.052)
    0.127
    (0.050)
    3. Primary Outcome
    Title The Effect of Major Depressive Disorder and Childhood Abuse History on a Reward-related EEG Component (Reward Positivity Component) While Under Stress
    Description EEG was recorded during the probabilistic reward task (the PRT task). Participants completed the Probabilistic Reward Task (PRT) twice throughout the experiment, once before stress and once after stress. The stressor was the Maastricht Acute Stress Test (MAST). This statistic shows the effect that childhood sexual abuse (CSA) and diagnosis had on a reward-related positivity EEG component recorded during the PRT, before and after stress. Higher reward positivity amplitudes indicate a stronger neural response to reward and lower amplitudes indicate a lower neural response to rewards.
    Time Frame 3 hour EEG Session (Session 4)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Control Group MDD Group CSA/RES Group CSA/MDD Group
    Arm/Group Description Subjects without a history of child sexual abuse and without a current or past diagnosis of major depressive episode. Subjects without a history of child sexual abuse that are currently experiencing a major depressive episode are randomized to receive a single low-dose pharmacological challenge. Subjects with a history of CSA but no psychopathology ("resilient group"; CSA/RES). Subjects experiencing a current episode of major depression (MDD) with a history of child sexual abuse (CSA) are randomized to receive a single low-dose pharmacological challenge.
    Measure Participants 19 14 16 17
    Pre MAST
    2.71
    (0.86)
    4.75
    (1.15)
    2.16
    (0.92)
    4.15
    (0.96)
    Post MAST
    2.06
    (0.91)
    4.99
    (1.22)
    2.30
    (0.98)
    3.90
    (1.01)
    4. Primary Outcome
    Title Cortisol Output in Response to a Stress Manipulation
    Description This statistic shows the impact of the stress manipulation on the participant's salivary cortisol output. Saliva samples were collected at 5 distinct time points throughout the study session. The first saliva sample (Cort 1) was collected when the participant began the eeg session. The second (Cort 2)was taken at the end of the acute stressor. The third (Cort 3) was taken approximately fifteen minutes after the second. The fourth (Cort 4) was taken approximately ten minutes after the third. The fifth (Cort 5) was taken approximately 40 minutes after the fourth.
    Time Frame 3 hour EEG Session (Session 4)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Control Group MDD Group CSA/RES Group CSA/MDD Group
    Arm/Group Description Subjects without a history of child sexual abuse and without a current or past diagnosis of major depressive episode. Subjects without a history of child sexual abuse that are currently experiencing a major depressive episode are randomized to receive a single low-dose pharmacological challenge. Subjects with a history of CSA but no psychopathology ("resilient group"; CSA/RES). Subjects experiencing a current episode of major depression (MDD) with a history of child sexual abuse (CSA) are randomized to receive a single low-dose pharmacological challenge.
    Measure Participants 19 14 16 17
    Cort1
    9.80
    (1.27)
    12.53
    (2.11)
    10.15
    (2.27)
    14.19
    (1.51)
    Cort2
    9.11
    (2.44)
    12.28
    (1.70)
    9.51
    (1.89)
    8.63
    (0.95)
    Cort3
    15.55
    (4.91)
    15.23
    (1.65)
    10.75
    (2.19)
    14.31
    (2.15)
    Cort4
    12.89
    (4.07)
    16.30
    (3.24)
    8.99
    (1.75)
    14.22
    (2.74)
    Cort5
    7.07
    (1.80)
    10.34
    (1.15)
    7.41
    (1.36)
    11.01
    (2.15)
    5. Primary Outcome
    Title Effects on Major Depressive Disorder and Childhood Sexual Abuse History on Striatal Activity in Response to Neutral and Reward Cues
    Description This statistic shows the influence of major depressive disorder and childhood sexual abuse history on the strength of striatal activation (caudate, putamen, accumbens) in response to neutral and reward cues during the monetary incentive delay task (MID). Striatal activation is measured using a statistic called a beta weight. A beta weight is a standardized regression coefficient. Higher beta weights mean greater striatal activation and lower beta weights mean less striatal activation. A negative beta weight would indicate a deactivation.
    Time Frame 3 hour Drug & fMRI Session (Session 2)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title CSA/MDD-amisulpride CSA/MDD-placebo CSA/RES-amisulpride CSA/RES-placebo MDD-amisulpride MDD-placebo Control-amisulpride Control-placebo
    Arm/Group Description Subjects experiencing a current episode of major depression (MDD) with a history of child sexual abuse (CSA) are randomized to receive a single low-dose pharmacological challenge, 50mg amisulpride tablet during the fMRI session. Amisulpride: single low-dose pharmacological challenge, 50 mg amisulpride during the fMRI session only Subjects experiencing a current episode of major depression (MDD) with a history of child sexual abuse (CSA) are randomized to receive a placebo during the fMRI session. Placebo: single-dose placebo capsule during the fMRI session only Subjects with a history of child sexual abuse (CSA) without a current or past diagnosis of major depressive disorder (RES) are randomized to receive a single low-dose pharmacological challenge, 50mg amisulpride tablet during the fMRI session. Amisulpride: single low-dose pharmacological challenge, 50 mg amisulpride during the fMRI session only Subjects with a history of child sexual abuse (CSA) without a current or past diagnosis of major depressive disorder (RES) are randomized to receive a placebo during the fMRI session. Placebo: single-dose placebo capsule during the fMRI session only Subjects without a history of child sexual abuse that are currently experiencing a major depressive episode are randomized to receive a single low-dose pharmacological challenge, 50mg amisulpride tablet during the fMRI session. Amisulpride: single low-dose pharmacological challenge, 50 mg amisulpride during the fMRI session only Subjects without a history of child sexual abuse that are currently experiencing a major depressive episode are randomized to receive a placebo during the fMRI session. Placebo: single-dose placebo capsule during the fMRI session only Subjects without a history of child sexual abuse and without a current or past diagnosis of major depressive episode are randomized to receive a single low-dose pharmacological challenge, 50mg amisulpride tablet during the fMRI session. Amisulpride: single low-dose pharmacological challenge, 50 mg amisulpride during the fMRI session only Subjects without a history of child sexual abuse and without a current or past diagnosis of major depressive episode are randomized to receive a placebo during the fMRI session. Placebo: single-dose placebo capsule during the fMRI session only
    Measure Participants 10 7 6 6 9 8 11 11
    Caudate Response to Reward Cues
    .514
    (.199)
    .054
    (.238)
    .511
    (.257)
    .079
    (.257)
    .403
    (.209)
    .608
    (.222)
    .200
    (.189)
    .468
    (.189)
    Caudate Response to Neutral Cues
    .254
    (.161)
    -.243
    (.192)
    .050
    (.208)
    -.370
    (.208)
    .047
    (.170)
    .156
    (.180)
    .222
    (.154)
    .185
    (.154)
    Putamen Response to Reward Cues
    .550
    (.175)
    .468
    (.209)
    .745
    (.226)
    .419
    (.226)
    .698
    (.185)
    .814
    (.196)
    .608
    (.162)
    .663
    (.167)
    Putamen Response to Neutral Cues
    .550
    (.175)
    .357
    (.168)
    .493
    (.181)
    .240
    (.181)
    .384
    (.148)
    .621
    (.157)
    .455
    (.134)
    .518
    (.134)
    Accumbens Response to Reward Cues
    .692
    (.206)
    .255
    (.247)
    .679
    (.267)
    .310
    (.267)
    .351
    (.218)
    .428
    (.231)
    .401
    (.197)
    .480
    (.197)
    Accumbens Response to Neutral Cues
    .385
    (.173)
    .040
    (.207)
    -.123
    (.224)
    -.381
    (.224)
    -.111
    (.183)
    .140
    (.194)
    .016
    (.165)
    .120
    (.165)
    6. Primary Outcome
    Title Effects on Major Depressive Disorder and Childhood Sexual Abuse History on Striatal Activity in Response to Neutral and Reward Feedback
    Description This statistic shows the influence of major depressive disorder and childhood sexual abuse history on the strength of striatal activation (caudate, putamen, accumbens) in response to neutral and reward feedback during the monetary incentive delay task (MID). Striatal activation is measured using a statistic called a beta weight. A beta weight is a standardized regression coefficient. Higher beta weights mean greater striatal activation and lower beta weights mean less striatal activation. A negative beta weight would indicate a deactivation.
    Time Frame 3 hour Session 2 (fMRI session)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title CSA/MDD-amisulpride CSA/MDD-placebo CSA/RES-amisulpride CSA/RES-placebo MDD-amisulpride MDD-placebo Control-amisulpride Control-placebo
    Arm/Group Description Subjects experiencing a current episode of major depression (MDD) with a history of child sexual abuse (CSA) are randomized to receive a single low-dose pharmacological challenge, 50mg amisulpride tablet during the fMRI session. Amisulpride: single low-dose pharmacological challenge, 50 mg amisulpride during the fMRI session only Subjects experiencing a current episode of major depression (MDD) with a history of child sexual abuse (CSA) are randomized to receive a placebo during the fMRI session. Placebo: single-dose placebo capsule during the fMRI session only Subjects with a history of child sexual abuse (CSA) without a current or past diagnosis of major depressive disorder (RES) are randomized to receive a single low-dose pharmacological challenge, 50mg amisulpride tablet during the fMRI session. Amisulpride: single low-dose pharmacological challenge, 50 mg amisulpride during the fMRI session only Subjects with a history of child sexual abuse (CSA) without a current or past diagnosis of major depressive disorder (RES) are randomized to receive a placebo during the fMRI session. Placebo: single-dose placebo capsule during the fMRI session only Subjects without a history of child sexual abuse that are currently experiencing a major depressive episode are randomized to receive a single low-dose pharmacological challenge, 50mg amisulpride tablet during the fMRI session. Amisulpride: single low-dose pharmacological challenge, 50 mg amisulpride during the fMRI session only Subjects without a history of child sexual abuse that are currently experiencing a major depressive episode are randomized to receive a placebo during the fMRI session. Placebo: single-dose placebo capsule during the fMRI session only Subjects without a history of child sexual abuse and without a current or past diagnosis of major depressive episode are randomized to receive a single low-dose pharmacological challenge, 50mg amisulpride tablet during the fMRI session. Amisulpride: single low-dose pharmacological challenge, 50 mg amisulpride during the fMRI session only Subjects without a history of child sexual abuse and without a current or past diagnosis of major depressive episode are randomized to receive a placebo during the fMRI session. Placebo: single-dose placebo capsule during the fMRI session only
    Measure Participants 10 7 6 6 9 8 11 11
    Caudate Response to Reward Feedback
    -.101
    (.329)
    .040
    (.393)
    -.197
    (.425)
    -.905
    (.425)
    -.819
    (.347)
    -.773
    (.368)
    -.613
    (.314)
    -.273
    (.314)
    Caudate Response to Neutral Feedback
    -.233
    (.314)
    -.608
    (.376)
    -.501
    (.406)
    -.959
    (.406)
    -.865
    (.331)
    -.733
    (.352)
    -.793
    (.300)
    -.105
    (.300)
    Putamen Response to Reward Feedback
    -.018
    (.217)
    .063
    (.260)
    -.087
    (.281)
    -.304
    (.281)
    -.031
    (.229)
    -.357
    (.243)
    -.533
    (.207)
    -.131
    (.207)
    Putamen Response to Neutral Feedback
    -.021
    (.201)
    -.418
    (.240)
    -.142
    (.260)
    -.276
    (.260)
    -.229
    (.221)
    -.108
    (.225)
    -.375
    (.192)
    .164
    (.192)
    Accumbens Response to Reward Feedback
    -.158
    (.421)
    .839
    (.503)
    -.046
    (.544)
    -.713
    (.544)
    -.554
    (.444)
    -.215
    (.471)
    .074
    (.401)
    .069
    (.401)
    Accumbens Response to Neutral Feedback
    .010
    (.308)
    -.332
    (.368)
    -.079
    (.398)
    -.819
    (.398)
    -.456
    (.325)
    -.039
    (.345)
    -.503
    (.294)
    .109
    (.294)
    7. Primary Outcome
    Title The Effect of Diagnosis on Cortisol Reactivity
    Description This is a measure of area under the curve in relation to ground, a measure of total cortisol output, in response to acute stress. The acute stressor was the Maastricht Acute Stress Test (MAST). The area under the curve includes all 5 cortisol measures, with one measure before the stressor and the other four measures collected after the stressor. Given that the cortisol data were positively skewed, the cortisol measures were normalized via a log transformation prior to calculating the area under the curve. Area under the curve with respect to ground (AUCG) is calculated AUC_g=(((cort2_log + cort1_log) * cort_t1_time) / 2)+(((cort3_log+cort2_log)*cort_t2_time)/2)+(((cort4_log+cort3_log)*cort_t3_time)/2)+(((cort5_log+cort4_log)*cort_t4_time)/2). Cort_logs are the log transformed cortisol output data (ng/ml) and the cort_times are the time spans in between each cortisol assessment.
    Time Frame 3 hour EEG Session (Session 4)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Control Group MDD Group CSA/RES Group CSA/MDD Group
    Arm/Group Description Subjects without a history of child sexual abuse and without a current or past diagnosis of major depressive episode. Subjects without a history of child sexual abuse that are currently experiencing a major depressive episode are randomized to receive a single low-dose pharmacological challenge. Subjects with a history of CSA but no psychopathology ("resilient group"; CSA/RES). Subjects experiencing a current episode of major depression (MDD) with a history of child sexual abuse (CSA) are randomized to receive a single low-dose pharmacological challenge.
    Measure Participants 19 14 16 17
    Mean (Standard Error) [[log (ng/ml)]*min]
    156.58
    (10.72)
    186.78
    (12.20)
    152.13
    (12.20)
    179.16
    (11.25)

    Adverse Events

    Time Frame 3 years, 10 months
    Adverse Event Reporting Description
    Arm/Group Title All Participants All Baseline Participants Control Group Control-amisulpride (fMRI Session) Control-placebo (fMRI Session) MDD Group MDD-amisulpride (fMRI Session) MDD-placebo (fMRI Session) CSA/RES CSA/RES-amisulpride (fMRI Session) CSA/RES-placebo (fMRI Session) CSA/MDD Group CSA/MDD-amisulpride (fMRI Session) CSA/MDD-placebo (fMRI Session)
    Arm/Group Description All participants that went through the assessment (session 1) regardless if they were eligible or ineligible. Participants that were eligible for the study after the screening visit (session 1). These participants were invited to participate in the other study sessions. Control subjects without a history of child sexual abuse and without a current or past diagnosis of major depressive episode. These participants were eligible after the screening session (session 1) and are accounted for regardless if they completed other study sessions. After the screening visit, eligible control subjects without a history of child sexual abuse and without a current or past diagnosis of major depression were invited to participate in the fMRI session. Those that were interested, were randomized to receive a single low-dose pharmacological challenge, 50mg amisulpride tablet during the fMRI session. This arm is specific to those that competed the fMRI session. Many eligible baseline control participants did not complete this session. After the screening visit, eligible control subjects without a history of child sexual abuse and without a current or past diagnosis of major depression were invited to participate in the fMRI session. Those that were interested, were randomized to receive a placebo during the fMRI session. This arm is specific to those that competed the fMRI session. Many eligible baseline control participants did not complete this session. Subjects without a history of child sexual abuse that are currently experiencing a major depressive episode. These participants were eligible after the screening session (session 1) and are accounted for regardless if they completed other study sessions. After the screening visit, eligible subjects without a history of child sexual abuse that are currently experiencing a major depressive episode were invited to participate in the fMRI session. Those that were interested in participating, were randomized to receive a single low-dose pharmacological challenge, 50mg amisulpride tablet during the fMRI session. This arm is specific to those that competed the fMRI session. Many eligible MDD baseline participants did not complete this session. After the screening visit, eligible subjects without a history of child sexual abuse that are currently experiencing a major depressive episode were invited to participate in the fMRI session. Those that were interested in participating, were randomized to receive a placebo during the fMRI session. This arm is specific to those that competed the fMRI session. Many eligible MDD baseline participants did not complete this session. Subjects with a history of CSA but no psychopathology ("resilient group"; CSA/RES). These participants were eligible after the screening session (session 1) and are accounted for regardless if they completed other study sessions. After the screening visit, eligible subjects with a history of CSA but no psychopathology ("resilient group"; CSA/RES) were invited to participate in the fMRI session. Those that were interested in participating, were randomized to receive a single low-dose pharmacological challenge, 50mg amisulpride tablet during the fMRI session.This arm is specific to those that competed the fMRI session. Many eligible CSA/RES baseline participants did not complete this session. After the screening visit, eligible subjects with a history of CSA but no psychopathology ("resilient group"; CSA/RES) were invited to participate in the fMRI session. Those that were interested in participating, were randomized to receive a placebo during the fMRI session. This arm is specific to those that competed the fMRI session. Many eligible CSA/RES baseline participants did not complete this session. Subjects experiencing a current episode of major depression (MDD) with a history of child sexual abuse (CSA). These participants were eligible after the screening session (session 1) and are accounted for regardless if they completed other study sessions. After the screening visit, eligible subjects with a current episode of major depression (MDD) with a history of child sexual abuse (CSA) were invited to participate in the fMRI session. Those that were interested in participating, were randomized to receive a single low-dose pharmacological challenge, 50mg amisulpride tablet during the fMRI session.This arm is specific to those that competed the fMRI session. Many eligible CSA/MDD baseline participants did not complete this session. After the screening visit, eligible subjects with a current episode of major depression (MDD) with a history of child sexual abuse (CSA) were invited to participate in the fMRI session. Those that were interested in participating, were randomized to receive a placebo. This arm is specific to those that competed the fMRI session. Many eligible CSA/MDD baseline participants did not complete this session.
    All Cause Mortality
    All Participants All Baseline Participants Control Group Control-amisulpride (fMRI Session) Control-placebo (fMRI Session) MDD Group MDD-amisulpride (fMRI Session) MDD-placebo (fMRI Session) CSA/RES CSA/RES-amisulpride (fMRI Session) CSA/RES-placebo (fMRI Session) CSA/MDD Group CSA/MDD-amisulpride (fMRI Session) CSA/MDD-placebo (fMRI Session)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/153 (0%) 0/96 (0%) 0/26 (0%) 0/11 (0%) 0/11 (0%) 0/17 (0%) 0/9 (0%) 0/8 (0%) 0/24 (0%) 0/6 (0%) 0/6 (0%) 0/29 (0%) 0/10 (0%) 0/7 (0%)
    Serious Adverse Events
    All Participants All Baseline Participants Control Group Control-amisulpride (fMRI Session) Control-placebo (fMRI Session) MDD Group MDD-amisulpride (fMRI Session) MDD-placebo (fMRI Session) CSA/RES CSA/RES-amisulpride (fMRI Session) CSA/RES-placebo (fMRI Session) CSA/MDD Group CSA/MDD-amisulpride (fMRI Session) CSA/MDD-placebo (fMRI Session)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/153 (0%) 0/96 (0%) 0/26 (0%) 0/11 (0%) 0/11 (0%) 0/17 (0%) 0/9 (0%) 0/8 (0%) 0/24 (0%) 0/6 (0%) 0/6 (0%) 0/29 (0%) 0/10 (0%) 0/7 (0%)
    Other (Not Including Serious) Adverse Events
    All Participants All Baseline Participants Control Group Control-amisulpride (fMRI Session) Control-placebo (fMRI Session) MDD Group MDD-amisulpride (fMRI Session) MDD-placebo (fMRI Session) CSA/RES CSA/RES-amisulpride (fMRI Session) CSA/RES-placebo (fMRI Session) CSA/MDD Group CSA/MDD-amisulpride (fMRI Session) CSA/MDD-placebo (fMRI Session)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/153 (0%) 0/96 (0%) 0/26 (0%) 0/11 (0%) 0/11 (0%) 0/17 (0%) 0/9 (0%) 0/8 (0%) 0/24 (0%) 0/6 (0%) 0/6 (0%) 0/29 (0%) 0/10 (0%) 0/7 (0%)
    Psychiatric disorders
    Other Adverse Events 0/153 (0%) 0 0/96 (0%) 0 0/26 (0%) 0 0/11 (0%) 0 0/11 (0%) 0 0/17 (0%) 0 0/9 (0%) 0 0/8 (0%) 0 0/24 (0%) 0 0/6 (0%) 0 0/6 (0%) 0 0/29 (0%) 0 0/10 (0%) 0 0/7 (0%) 0

    Limitations/Caveats

    The choice of a 50-mg dose of amisulpride was based on animal work showing low doses potentiate striatal dopamine release, have strong hedonic effects, and increase the incentive value of environmental cues. Higher doses may have different results.

    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 Diego Pizzagalli, Ph.D.
    Organization McLean Hospital
    Phone 617-855-4230
    Email dap@mclean.harvard.edu
    Responsible Party:
    Diego A. Pizzagalli, Associate Professor of Psychiatry, Harvard Medical School, Mclean Hospital
    ClinicalTrials.gov Identifier:
    NCT01701258
    Other Study ID Numbers:
    • 2012P002593
    • 5R01MH095809
    First Posted:
    Oct 5, 2012
    Last Update Posted:
    May 18, 2018
    Last Verified:
    May 1, 2018