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An Investigation of Early Life Stress and Depression

Primary Purpose

Major Depressive Disorder (MDD), History of Childhood Sexual Abuse (CSA)

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Amisulpride
Placebo
Sponsored by
Mclean Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Major Depressive Disorder (MDD) focused on measuring Depression, Childhood Sexual Abuse, Dopamine, MRI, PET, ERP, Stress, Reward, Childhood trauma, Amisulpride

Eligibility Criteria

20 Years - 45 Years (Adult)FemaleAccepts Healthy Volunteers

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].

Sites / Locations

  • McLean Hospital
  • Massachusetts General Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm 8

Arm Type

Active Comparator

Placebo Comparator

Active Comparator

Placebo Comparator

Active Comparator

Placebo Comparator

Active Comparator

Placebo Comparator

Arm Label

CSA/MDD-amisulpride

CSA/MDD-placebo

CSA/RES-amisulpride

CSA/RES-placebo

MDD-amisulpride

MDD-placebo

Control-amisulpride

Control-placebo

Arm 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.

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.

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.

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.

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.

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.

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.

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.

Outcomes

Primary Outcome Measures

Dopamine Active Transporter Binding Potential
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
The Effects of CSA and Diagnosis on PRT Performance Under Acute Stress
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.
The Effect of Major Depressive Disorder and Childhood Abuse History on a Reward-related EEG Component (Reward Positivity Component) While Under Stress
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.
Cortisol Output in Response to a Stress Manipulation
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.
Effects on Major Depressive Disorder and Childhood Sexual Abuse History on Striatal Activity in Response to Neutral and Reward Cues
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.
Effects on Major Depressive Disorder and Childhood Sexual Abuse History on Striatal Activity in Response to Neutral and Reward Feedback
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.
The Effect of Diagnosis on Cortisol Reactivity
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.

Secondary Outcome Measures

Full Information

First Posted
October 2, 2012
Last Updated
May 16, 2018
Sponsor
Mclean Hospital
Collaborators
National Institute of Mental Health (NIMH), Massachusetts General Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT01701258
Brief Title
An Investigation of Early Life Stress and Depression
Official Title
Early Life Stress and Depression: Molecular and Functional Imaging Approaches
Study Type
Interventional

2. Study Status

Record Verification Date
May 2018
Overall Recruitment Status
Completed
Study Start Date
August 2013 (Actual)
Primary Completion Date
May 2017 (Actual)
Study Completion Date
May 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Mclean Hospital
Collaborators
National Institute of Mental Health (NIMH), Massachusetts General Hospital

4. Oversight

Data Monitoring Committee
No

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Major Depressive Disorder (MDD), History of Childhood Sexual Abuse (CSA)
Keywords
Depression, Childhood Sexual Abuse, Dopamine, MRI, PET, ERP, Stress, Reward, Childhood trauma, Amisulpride

7. Study Design

Primary Purpose
Basic Science
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
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
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
153 (Actual)

8. Arms, Groups, and Interventions

Arm Title
CSA/MDD-amisulpride
Arm Type
Active Comparator
Arm 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.
Arm Title
CSA/MDD-placebo
Arm Type
Placebo Comparator
Arm Description
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.
Arm Title
CSA/RES-amisulpride
Arm Type
Active Comparator
Arm Description
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.
Arm Title
CSA/RES-placebo
Arm Type
Placebo Comparator
Arm Description
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.
Arm Title
MDD-amisulpride
Arm Type
Active Comparator
Arm Description
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.
Arm Title
MDD-placebo
Arm Type
Placebo Comparator
Arm Description
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.
Arm Title
Control-amisulpride
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Control-placebo
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Amisulpride
Other Intervention Name(s)
Solian
Intervention Description
single low-dose pharmacological challenge, 50 mg amisulpride during the fMRI session only
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
single-dose placebo capsule during the fMRI session only
Primary Outcome Measure Information:
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)
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)
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)
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)
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)
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)
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)

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
20 Years
Maximum Age & Unit of Time
45 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility 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].
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Diego Pizzagalli, PhD
Organizational Affiliation
Mclean Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
McLean Hospital
City
Belmont
State/Province
Massachusetts
ZIP/Postal Code
02478
Country
United States
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
28942738
Citation
Kaiser RH, Clegg R, Goer F, Pechtel P, Beltzer M, Vitaliano G, Olson DP, Teicher MH, Pizzagalli DA. Childhood stress, grown-up brain networks: corticolimbic correlates of threat-related early life stress and adult stress response. Psychol Med. 2018 May;48(7):1157-1166. doi: 10.1017/S0033291717002628. Epub 2017 Sep 25.
Results Reference
result
PubMed Identifier
31784354
Citation
Liu Y, Admon R, Mellem MS, Belleau EL, Kaiser RH, Clegg R, Beltzer M, Goer F, Vitaliano G, Ahammad P, Pizzagalli DA. Machine Learning Identifies Large-Scale Reward-Related Activity Modulated by Dopaminergic Enhancement in Major Depression. Biol Psychiatry Cogn Neurosci Neuroimaging. 2020 Feb;5(2):163-172. doi: 10.1016/j.bpsc.2019.10.002. Epub 2019 Oct 22.
Results Reference
derived

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An Investigation of Early Life Stress and Depression

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