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An Investigation of Early Life Stress and Depression

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ClinicalTrials.gov Identifier: NCT01701258
Recruitment Status : Completed
First Posted : October 5, 2012
Results First Posted : May 18, 2018
Last Update Posted : May 18, 2018
Sponsor:
Collaborators:
National Institute of Mental Health (NIMH)
Massachusetts General Hospital
Information provided by (Responsible Party):
Diego A. Pizzagalli, Mclean Hospital

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
Major Depressive Disorder (MDD) History of Childhood Sexual Abuse (CSA) Drug: Amisulpride Drug: Placebo 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 Type : Interventional  (Clinical Trial)
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).
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 : August 2013
Actual Primary Completion Date : May 2017
Actual Study Completion Date : May 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Stress

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 Name: 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 Name: 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 Name: 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 Name: 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




Primary Outcome Measures :
  1. Dopamine Active Transporter Binding Potential [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.




Information from the National Library of Medicine

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Ages Eligible for Study:   20 Years to 45 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Criteria

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].

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): NCT01701258


Locations
United States, Massachusetts
McLean Hospital
Belmont, Massachusetts, United States, 02478
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)

Documents provided by Diego A. Pizzagalli, Mclean Hospital:

Publications of Results:
Responsible Party: Diego A. Pizzagalli, Associate Professor of Psychiatry, Harvard Medical School, Mclean Hospital
ClinicalTrials.gov Identifier: NCT01701258     History of Changes
Other Study ID Numbers: 2012P002593
5R01MH095809 ( U.S. NIH Grant/Contract )
First Posted: October 5, 2012    Key Record Dates
Results First Posted: May 18, 2018
Last Update Posted: May 18, 2018
Last Verified: May 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Diego A. Pizzagalli, Mclean Hospital:
Depression
Childhood Sexual Abuse
Dopamine
MRI
PET
ERP
Stress
Reward
Childhood trauma
Amisulpride

Additional relevant MeSH terms:
Depression
Depressive Disorder
Depressive Disorder, Major
Stress, Psychological
Behavioral Symptoms
Mood Disorders
Mental Disorders
Sultopride
Sulpiride
Antipsychotic Agents
Tranquilizing Agents
Central Nervous System Depressants
Physiological Effects of Drugs
Psychotropic Drugs
Dopamine Antagonists
Dopamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Antidepressive Agents, Second-Generation
Antidepressive Agents