Open-label Placebo for Depression

(OLP Trial)

Overseen By Tony T Yang, MD, PhD

Age: < 65

Sex: Any

Trial Phase: Academic

Sponsor: University of California, San Francisco

Must not be taking: Psychotropic drugs

Disqualifiers: Psychiatric comorbidities, MRI contraindications, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 3

Duration: 2 weeks

16 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial requires participants to be unmedicated, so you would need to stop taking your current medications to join.

What data supports the effectiveness of the treatment Open Label Placebo for Depression?

Research shows that in many depression studies, a significant number of patients improve with placebo treatment, suggesting that the belief in treatment can lead to real improvements in symptoms. ^{1 2 3 4 5}

Is open-label placebo safe for treating depression?

Open-label placebo treatments are generally considered safe, as they do not contain active medication and are not associated with side effects. Studies suggest that placebo treatments, including open-label ones, do not increase the risk of serious adverse events like suicide compared to active medications. ^{4 5 6 7 8}

How is open-label placebo treatment different for depression?

Open-label placebo treatment for depression is unique because it involves giving patients a placebo (a treatment with no active medication) while they are aware of its nature, which is ethically sound and avoids side effects. This approach leverages the psychological benefits of taking a treatment, even when patients know it contains no active ingredients, and can be used alongside traditional therapies like cognitive-behavioral therapy. ^{1 5 7 9 10}

Research Team

Tony T Yang, MD, PhD

Principal Investigator

University of California, San Francisco

Eligibility Criteria

This trial is for English-speaking adolescents aged 13-18 with mild to moderate depression who are not currently on medication. They must be under the care of a mental health professional or doctor and willing to give informed consent, along with their guardian if necessary.

Inclusion Criteria

You are a teenager between 13-18 years old, not taking any medication, and experiencing mild to moderate depression. A mental health professional or primary care doctor is aware of your condition.

Fluency in English

Exclusion Criteria

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.

You have mental health conditions other than anxiety disorder, or have severe thoughts about hurting yourself.

MRI contraindications (ferromagnetic objects on or inside the body, e.g. braces) and pregnancy.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Baseline Assessment

MRI scanning and clinical assessments are performed at baseline

1 week

1 visit (in-person)

Treatment

Participants receive open-label placebo (OLP) treatment for 2 weeks

2 weeks

1 visit (in-person) for MRI and OLP administration

Follow-up

Participants are monitored for changes in depression symptoms and neural connectivity

2 weeks

1 visit (in-person) for follow-up MRI and assessments

Treatment Details

Interventions

• Open Label Placebo without Rationale
• Open Label Placebo with Rationale

Trial Overview The study tests the effectiveness of open-label placebos (a 'fake' treatment that participants know doesn't contain active medication) in treating adolescent depression. It explores how positive expectations can activate certain brain networks related to emotion and stress regulation.

Participant Groups

Group I: Open Label Placebo Group with Rationale Experimental Treatment 1 Intervention

Group II: Control Active Control 1 Intervention

In the control group, the participants will not be taking any placebos or undergoing any other study-related treatments.

Group III: Open Label Placebo Group without Rationale Active Control 1 Intervention

Who Is Running the Clinical Trial?

University of California, San Francisco

Lead Sponsor

Trials

2,636

Recruited

19,080,000+

National Center for Complementary and Integrative Health (NCCIH)

Collaborator

Trials

886

Recruited

677,000+

Findings from Research

In a study of 1017 patients with major depressive disorder treated with placebo, key predictors for remission included younger age, less severe depressive symptoms, lower anxiety levels, and shorter duration of the current depressive episode.

The predictive models developed showed modest accuracy (ROC curve areas of 0.6-0.65), suggesting they may help adjust for placebo effects in clinical trials, but are not reliable for predicting remission in individual patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Predictors of remission with placebo using an integrated study database from patients with major depressive disorder. Nelson, JC., Zhang, Q., Deberdt, W., et al.[2015]

A meta-analysis of 101 studies found that using a placebo run-in period before randomization does not reduce the placebo response rate or increase the difference in response between drug and placebo treatments for antidepressants.

The findings suggest that including a placebo run-in period in acute phase efficacy trials for antidepressants offers no significant advantages, as it does not improve drug response rates for either inpatients or outpatients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Does a placebo run-in or a placebo treatment cell affect the efficacy of antidepressant medications? Trivedi, MH., Rush, H.[2022]

References

1. Germany pubmed.ncbi.nlm.nih.gov

Pretreatment neurophysiological and clinical characteristics of placebo responders in treatment trials for major depression. [2018]

2. England pubmed.ncbi.nlm.nih.gov

Predictors of remission with placebo using an integrated study database from patients with major depressive disorder. [2015]

3. United States pubmed.ncbi.nlm.nih.gov

Use of placebo control groups in evaluating efficacy of treatment of unipolar major depression. [2019]

4. England pubmed.ncbi.nlm.nih.gov

Debunking the placebo effect in depression: the effect of patient and investigator expectation on escitalopram efficacy. [2014]

5. England pubmed.ncbi.nlm.nih.gov

Does a placebo run-in or a placebo treatment cell affect the efficacy of antidepressant medications? [2022]

6. Ireland pubmed.ncbi.nlm.nih.gov

Nocebo in clinical trials for depression: a meta-analysis. [2022]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Open-Label placebo for the treatment of unipolar depression: Results from a randomized controlled trial. [2021]

8. United States pubmed.ncbi.nlm.nih.gov

Symptom reduction and suicide risk in patients treated with placebo in antidepressant clinical trials: an analysis of the Food and Drug Administration database. [2019]

9. Netherlands pubmed.ncbi.nlm.nih.gov

Open-label placebos as adjunctive therapy for patients with depression. [2022]

10. Germany pubmed.ncbi.nlm.nih.gov

[Appearances are not deceptive: clinical evidence and new research approaches to open-label placebo]. [2020]