An Investigation of Early Life Stress and Depression

NCT01701258 | Completed Phase 1 Results

• 2 other identifiers: 2012P0025935R01MH095809
• Study Type: interventional
• Target: 153
• Locations: 1 country
• Sites: 2

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.

Conditions

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

Keywords

Depression; Childhood Sexual Abuse; Dopamine; MRI; PET; ERP; Stress; Reward; Childhood trauma; Amisulpride

Outcome Measures

Primary Outcomes (7)

• 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

  1 hour PET scan (Session 3)

• 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.

  3 hour EEG Session (Session 4)

• 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.

  3 hour EEG Session (Session 4)

• 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.

  3 hour EEG Session (Session 4)

• 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.

  3 hour Drug & fMRI Session (Session 2)

• 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.

  3 hour Session 2 (fMRI session)

• 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.

  3 hour EEG Session (Session 4)

Study Arms (8)

CSA/MDD-amisulpride

ACTIVE COMPARATOR

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

CSA/MDD-placebo

PLACEBO COMPARATOR

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

CSA/RES-amisulpride

ACTIVE COMPARATOR

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

CSA/RES-placebo

PLACEBO COMPARATOR

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

MDD-amisulpride

ACTIVE COMPARATOR

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

MDD-placebo

PLACEBO COMPARATOR

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

Control-amisulpride

ACTIVE COMPARATOR

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

Control-placebo

PLACEBO COMPARATOR

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

Interventions

Amisulpride DRUG

single low-dose pharmacological challenge, 50 mg amisulpride during the fMRI session only

Also known as: Solian

CSA/MDD-amisulpride; CSA/RES-amisulpride; Control-amisulpride; MDD-amisulpride

Placebo DRUG

single-dose placebo capsule during the fMRI session only

CSA/MDD-placebo; CSA/RES-placebo; Control-placebo; MDD-placebo

Eligibility Criteria

• Age: 20 Years - 45 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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);
• 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);
• 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;
• 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)

You may not qualify if:

• 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;
• 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 \[e.g., (meth)amphetamine), methylphenidate\].

Sponsors & Collaborators

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

Study Sites (2)

McLean Hospital

Belmont, Massachusetts, 02478, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Related Publications (2)

• 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.

  PMID: 28942738 RESULT

• 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.

  PMID: 31784354 DERIVED

MeSH Terms

Conditions

Depressive Disorder, Major; Depression

Interventions

Amisulpride

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders; Behavioral Symptoms; Behavior

Intervention Hierarchy (Ancestors)

Benzamides; Amides; Organic Chemicals; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons

Limitations and 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.

Results Point of Contact

• Title: Diego Pizzagalli, Ph.D.
• Organization: McLean Hospital

dap@mclean.harvard.edu

617-855-4230

Study Officials

• Diego Pizzagalli, PhD

  Mclean Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Psychiatry, Harvard Medical School

Model Details: 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).

Study Record Dates

• First Submitted: October 2, 2012
• First Posted: October 5, 2012
• Study Start: August 1, 2013
• Primary Completion: May 1, 2017
• Study Completion: May 1, 2017
• Last Updated: May 7, 2025
• Results First Posted: May 18, 2018

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)