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

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.

Study Overview

• Status: Recruiting
• Conditions: Depression
• Intervention / Treatment: Behavioral: Open Label Placebo with Rationale; Behavioral: Open Label Placebo without Rationale

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.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Namasvi Jariwala, MA; Phone Number: 415-514-6759; Email: namasvi.jariwala@ucsf.edu
• Study Contact Backup: Name: Benjamin Sipes, MSc; Email: benjamin.sipes@ucsf.edu

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94143
      • Recruiting
      • UCSF
      • Contact: Olga Tymofiyeva, PhD; Email: olga.tymofiyeva@ucsf.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 13 years to 18 years (Child, Adult)
• Accepts Healthy Volunteers: Yes

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Reynolds Adolescent Depression Scale (RADS-2) Scores	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.	Baseline and 2 weeks post baseline
The cerebral blood perfusion (CBP) in the anterior cingulate cortex (ACC)- striato - amygdalo - thalamic network	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).	At Baseline

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Investigators: Principal Investigator: Olga Tymofiyeva, PhD, University of California, San Francisco

Study record dates

Study Major Dates

• Study Start (Actual): May 14, 2020
• Primary Completion (Estimated): December 30, 2024
• Study Completion (Estimated): December 30, 2024

Study Registration Dates

• First Submitted: December 12, 2019
• First Submitted That Met QC Criteria: December 13, 2019
• First Posted (Actual): December 17, 2019

Study Record Updates

• Last Update Posted (Actual): April 25, 2024
• Last Update Submitted That Met QC Criteria: April 23, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: MRI; Placebo; Adolescent Depression
• Additional Relevant MeSH Terms: Behavioral Symptoms; Depression
• Other Study ID Numbers: 19-29443

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No