DepressionOLPNCT04201106
A Neuroimaging Study of Open-label Placebo in Depressed Adolescents
A study of Depression, run by University of California, San Francisco at 1 site in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 13 to 18 yearsHealthy volunteers can take part
- Conditions the study is for
- Depression
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 16 participants
- Where
- 1 siteUnited States
- Study dates
- 14 May 2020to 28 Apr 2022
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 13 to 18 years
- All sexes
- Healthy volunteers accepted
- Child, Adult
Who may be able to join
- 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
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country.
About this study
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.
Read the 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.
- Conditions
- Depression
- Being tested
- Open Label Placebo with Rationale, Open Label Placebo without Rationale
- Keywords
- Placebo, Adolescent Depression, MRI
- Medical subject headings
- Depression
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Open Label Placebo with RationaleBehavioural
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.
Open Label Placebo without RationaleBehavioural
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.
| Study group | Role | What they receive |
|---|---|---|
| Control | No intervention | In the control group, the participants will not be taking any placebos or undergoing any other study-related treatments. |
| Open Label Placebo Group with Rationale | Experimental | Not described Receives: Behavioral: Open Label Placebo with Rationale |
| Open Label Placebo Group without Rationale | Active comparator | Not described Receives: Behavioral: Open Label Placebo without Rationale |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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).
Measured: At Baseline
Secondary outcomes (2)
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.
Measured: 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.
Measured: Baseline and at 2 weeks post baseline
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 Dec 2019
- Study start14 May 2020
- Primary completion28 Apr 2022
- Study completion28 Apr 2022
Why it stopped: The study stopped because the funding ended.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for DepressionStudies of the same condition, open and under way.
- More trials run by University of California, San FranciscoThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind
- Who is masked
- Participant
- Enrolment
- 16 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of California, San Francisco
- Sponsor type
- University, hospital or other
- Collaborators
- National Center for Complementary and Integrative Health (NCCIH)
- Responsible party
- Sponsor
- Investigators
- Tony T Yang, MD, PhD, Principal investigator, University of California, San Francisco
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04201106
- Sponsor's protocol ID
- 19-29443
- Other IDs
- R61AT012028
- Acronym
- OLP
- Status last verified
- Jul 2026
- First submitted
- 12 Dec 2019
- Last updated
- 29 Jul 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 29 Jul 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Neuroimaging Study of Open-label Placebo in Depressed Adolescents
- ClinicalTrials.gov ID
- NCT04201106
- Acronym / sponsor ID
- OLP / 19-29443
- Conditions
- Depression
- Keywords
- Placebo, Adolescent Depression, MRI
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: The study stopped because the funding ended.
- Enrolment
- 16 participants (actual)
- Lead sponsor
- University of California, San FranciscoUniversity, hospital or other
- Collaborators
- National Center for Complementary and Integrative Health (NCCIH)
- Study start
- 14 May 2020 (actual)
- Primary completion
- 28 Apr 2022 (actual)
- Study completion
- 28 Apr 2022 (actual)
- First posted
- 17 Dec 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (participant)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Control | No intervention | –In the control group, the participants will not be taking any placebos or undergoing any other study-related treatments. |
| Open Label Placebo Group with Rationale | Experimental | Behavioral: Open Label Placebo with Rationale |
| Open Label Placebo Group without Rationale | Active comparator | Behavioral: Open Label Placebo without Rationale |
Who may qualify
- Ages
- 13 to 18 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult
Key inclusion criteria (3 listed)
- 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
Key exclusion criteria (4 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Open Label Placebo with RationaleIn 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. | Behavioural | Open Label Placebo Group with Rationale |
| Open Label Placebo without RationaleIn 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. | Behavioural | Open Label Placebo Group without Rationale |
Primary outcome
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.
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).
2 secondary outcomes
Change in structural connectivity of the ACC - striato - amygdalo - thalamic network
Time frame: Baseline and at 2 weeks post baseline
Change in functional connectivity of the ACC - striato - amygdalo - thalamic network
Time frame: Baseline and at 2 weeks post baseline
Results and safety
The study was stopped early (reason given: The study stopped because the funding ended.). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Jul 2026.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Tony T Yang, MD, PhD principal investigator
University of California, San Francisco
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study of Depression, run by University of California, San Francisco at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 29 Jul 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study was stopped early (reason given: The study stopped because the funding ended.). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Reynolds Adolescent Depression Scale (RADS-2) Scores (time frame: Baseline and 2 weeks post baseline). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Jul 2026.