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A Neuroimaging Study of Open-label Placebo in Depressed Adolescents (OLP)

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ClinicalTrials.gov Identifier: NCT04201106
Recruitment Status : Recruiting
First Posted : December 17, 2019
Last Update Posted : March 24, 2020
Sponsor:
Information provided by (Responsible Party):
University of California, San Francisco

Brief Summary:
Major depressive disorder (MDD) is the current leading cause of disability worldwide and adolescence is an especially vulnerable period for the onset of depression. Non-pharmacologic approaches are particularly attractive as treatment of adolescent depression due to the elevated risks of side effects related to the use of psychotropic drugs during development. A recent meta-analysis detected a positive and significant effect of non-deceptive placebos (open-label placebo, OLP) for a series of clinical conditions, including adult depression. To the investigators' knowledge, no studies of OLP have been conducted in depressed adolescents to date, although placebo response rates in adolescent depression are especially high, accounting for over 80% of the actual response to antidepressant treatment. The study's main objective is to estimate the effectiveness and understand the mechanism of OLP in depressed adolescents. The central hypothesis is that the mechanism by which OLP exerts its action in adolescent depression is by forming a positive expectation, which activates endogenous mu-opioid receptor (MOR)-mediated neurotransmission in a network of regions implicated in emotion, stress regulation, and the pathophysiology of MDD, namely, the anterior cingulate cortex (ACC) - striato - amygdalo - thalamic network. The hypothesis has been formulated on the basis of published research and preliminary data. The investigators will test the hypothesis by performing structural and functional neuroimaging in 60 untreated 13-18 year-old adolescents with mild to moderate depression. The proposed research is significant, because it is expected to elucidate the mechanism of action of OLP and advance the understanding of the neural underpinnings of positive expectations in adolescent depression.

Condition or disease Intervention/treatment Phase
Depression Behavioral: Open Label Placebo with Rationale Behavioral: Open Label Placebo without Rationale Not Applicable

Detailed Description:

This is a randomized controlled study to investigate non-deceptive placebos (open-label placebo, OLP) in depressed adolescents. Participants in this study will be randomly assigned to one of three groups: OLP with the 4-point rationale group (n=20), OLP without rationale group (n=20), and controls (n=20) who will receive the same level of supportive attention from the study clinician. MRI scanning and clinical assessments will be performed at the baseline and after the 2-week treatment or waiting period. The main objective here is to estimate the effectiveness and understand the mechanism of OLP in depressed adolescents. The central hypothesis is that the mechanism by which OLP exerts its action in adolescent depression is by forming a positive expectation, which activates endogenous mu-opioid receptor (MOR)-mediated neurotransmission in a network of regions implicated in emotion, stress regulation, and the pathophysiology of depression, namely, the anterior cingulate cortex (ACC) - striato - amygdalo - thalamic network. The investigators plan to test the central hypothesis in 60 13-18 year-old adolescents with mild to moderate depression by pursuing the following Aims:

AIM 1: To test the effectiveness of OLP in depressed adolescents. Depressed adolescents will be randomly assigned for two weeks to an OLP with the 4-point rationale group (n=20), OLP without rationale group (n=20), and controls (n=20) who will receive the same level of supportive attention from the study clinician. Hypothesis 1: The improvement in depression symptoms measured by the self-report Reynolds Adolescent Depression Scale (RADS-2) in the OLP + rationale group (that combines conscious positive expectation with conditioned response to the ingestion of medication) will be higher than in the OLP without rationale group (conditioned response only) and controls. Positive expectation of recovery will be assessed before and after group assignment and accounted for in the analyses.

AIM 2: To measure neural response to OLP. The OLP groups will receive the first dose of the OLP in the MRI scanner and changes in the cerebral blood perfusion (CBP) will be measured using arterial spin labeling (ASL) MRI. Mechanistically, the investigators expect that the MOR-mediated neurotransmission activated by placebo will be associated with a CBP increase, specifically: Hypothesis 2a: The CBP increase in the ACC - striato - amygdalo - thalamic network after the administration of the OLP + rationale to be higher than in the OLP group and controls. Hypothesis 2b: This CBP increase will correlate with the improvement in RADS-2 scores after two weeks.

AIM 3: To test neural network normalization in depressed adolescents (by comparing to the existing database of MRI scans of healthy teens). The second MRI will be performed after the two weeks. Mechanistically, the investigators expect that through the regular activation by OLP, myelination of the ACC - striato - amygdalo - thalamic network will increase, leading to a normalization of the previously demonstrated hypoconnectivity. Hypothesis 3: The increases in structural and functional connectivity of the ACC - striato - amygdalo - thalamic network after two weeks will correlate with decreases in RADS-2 depression total scores.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Primary Purpose: Basic Science
Official Title: A Neuroimaging Study of Open-label Placebo in Depressed Adolescents
Estimated Study Start Date : March 30, 2020
Estimated Primary Completion Date : May 31, 2020
Estimated Study Completion Date : May 31, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
No Intervention: Control
In the control group, the participants will not be taking any placebos or undergoing any other study-related treatments.
Experimental: Open Label Placebo Group with Rationale Behavioral: Open Label Placebo with Rationale
In the OLP + rationale group, the participants will be prescribed to take placebos for 2 weeks with the standard 4-point accompanying rationale: (1) the placebo effect is powerful, e.g. in clinical trials placebos are roughly 80% as effective as antidepressants; (2) classical conditioning is a possible mechanism for automatic self-healing - meaning that the body can automatically respond to taking placebo pills like Pavlov's dogs who salivated when they heard a bell; (3) placebo-treated patients who are more compliant have better outcomes, therefore the placebos should be taken faithfully; and (4) positive expectations increase placebo effects, but it is OK to have doubts.

Active Comparator: Open Label Placebo Group without Rationale Behavioral: Open Label Placebo without Rationale
In the OLP without rationale group, the adolescents will be asked to take placebos for 2 weeks but they will be told that the pills contain inert substance and do not have any pharmacological effect.




Primary Outcome Measures :
  1. Change in Reynolds Adolescent Depression Scale (RADS-2) Scores [ Time Frame: Baseline and 2 weeks post baseline ]
    The investigators will be looking at changes in the RADS-2 scores scores. RADS-2 was selected as the primary clinical outcome measure because it is a widely used, well-established, and standardized self-report measure of adolescent depression. The RADS-2 has a possible range of 30 to 120. Higher scores represent higher levels of depression.

  2. The cerebral blood perfusion (CBP) in the anterior cingulate cortex (ACC)- striato - amygdalo - thalamic network [ Time Frame: At Baseline ]
    Blood perfusion in a network of regions implicated in emotion, stress regulation, and the pathophysiology of depression, measured using MRI, specifically, an MRI technique known as arterial spin labeling (ASL).


Secondary Outcome Measures :
  1. Change in structural connectivity of the ACC - striato - amygdalo - thalamic network [ Time Frame: Baseline and at 2 weeks post baseline ]
    Brain connectivity in a network of regions implicated in emotion, stress regulation, and the pathophysiology of depression, measured using MRI, specifically, diffusion MRI.

  2. Change in functional connectivity of the ACC - striato - amygdalo - thalamic network [ Time Frame: Baseline and at 2 weeks post baseline ]
    Brain connectivity in a network of regions implicated in emotion, stress regulation, and the pathophysiology of depression, measured using MRI, specifically, functional MRI.



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Ages Eligible for Study:   13 Years to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

The investigators will include adolescents with mild to moderate depression who meet the following criteria.

  • Unmedicated 13-18 year-old adolescents of both sexes with mild to moderate depression, i.e. depressive symptoms corresponding to RADS-2 t-scores of 61-69, under the care of a mental health professional or a primary care doctor.
  • Fluency in English

Exclusion Criteria:

  • Subjects younger or older than 13-18 years old.
  • Psychiatric comorbidities other than anxiety disorder, severe suicidal ideation
  • MRI contraindications (ferromagnetic objects on or inside the body, e.g. braces) and pregnancy.
  • Potential subjects with an inability or unwillingness to give written informed assent whose legal guardian/representative are unable or unwilling to give written informed consent will be excluded and not allowed to enroll in the study.

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): NCT04201106


Contacts
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Contact: Namasvi Jariwala, MA 415-514-6759 namasvi.jariwala@ucsf.edu
Contact: Benjamin Sipes, MSc benjamin.sipes@ucsf.edu

Locations
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United States, California
UCSF Recruiting
San Francisco, California, United States, 94143
Contact: Olga Tymofiyeva, PhD       olga.tymofiyeva@ucsf.edu   
Sponsors and Collaborators
University of California, San Francisco
Investigators
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Principal Investigator: Olga Tymofiyeva, PhD University of California, San Francisco
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Responsible Party: University of California, San Francisco
ClinicalTrials.gov Identifier: NCT04201106    
Other Study ID Numbers: 19-29443
First Posted: December 17, 2019    Key Record Dates
Last Update Posted: March 24, 2020
Last Verified: March 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University of California, San Francisco:
Placebo
Adolescent Depression
MRI
Additional relevant MeSH terms:
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Depression
Behavioral Symptoms