Placebo Effects in the Treatment of Depression: Cognitive and Neural Mechanisms

February 26, 2020 updated by: Bret Rutherford, New York State Psychiatric Institute
Studies of the neural mechanisms underlying placebo effects in antidepressant clinical trials largely have been limited to demonstrating objective differences in brain activity between responders and non-responders to placebo. This 8 week Placebo-controlled and Open groups study employs a novel antidepressant trial design with integrated functional magnetic resonance imaging (fMRI) to manipulate patient expectancy and examine its neural mediators.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

The placebo effect represents a potent treatment for Major Depressive Disorder (MDD)-placebo response in acute randomized controlled trials (RCTs) of antidepressant medications averages 30%, and meta-analyses have estimated the proportion of medication response attributable to placebo to be 50-75%. Patient expectancy is the mechanism of placebo effects in antidepressant RCTs and has been positively associated with medication response. Determining how expectancy alters the course of MDD could lead to methods of optimizing placebo effects and improving the treatment of MDD. In addition, investigating the neurobiology of placebo effects has the potential to elucidate the pathophysiology of MDD and the mechanisms of action of antidepressant treatments. Brain regions implicated in expectancy and placebo effects comprise prefrontal cortical (PFC) areas, amygdala, insular cortex, rostral anterior cingulate cortex (rACC), and dopaminergic reward pathways in the striatum. Pathological decreases in PFC and striatal function, increases in limbic activity, and disordered connectivity between these regions have all been observed in MDD, and the rostral and dorsal ACC have been repeatedly linked to antidepressant treatment response.

Therefore, studying placebo effects offers a window into the functioning of the neural circuits that are disturbed in MDD and improve with effective treatment. The goals of this study are to determine whether expectancy affects the outcome of antidepressant pharmacotherapy and to investigate the neural mechanisms of expectancy effects. These will be accomplished by conducting a clinical trial randomizing adult outpatients with MDD to 8 weeks of treatment in high vs. low expectancy conditions. The high expectancy condition will be open administration of citalopram, while the low expectancy condition will be placebo-controlled administration of citalopram. The neural mechanisms of expectancy will be determined using functional Magnetic Resonance Imaging (fMRI) paradigms to investigate treatment activation differences in brain regions associated with placebo effects and MDD.

Study Type

Interventional

Enrollment (Actual)

65

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • New York
      • New York, New York, United States, 10032
        • New York State Psychiatric Institute

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

24 years to 75 years (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

Female

Description

Inclusion Criteria:

  • Men and women aged 24-75 years
  • Diagnosed with Diagnostic and Statistical Manual of Mental Disorders (DSM) IV Major Depressive Disorder, nonpsychotic
  • 24-item Hamilton Rating Scale for Depression (HRSD) score ≥ 16
  • Willing to and capable of providing informed consent and complying with study procedures
  • Subjects are right-handed
  • Using appropriate contraceptive method if woman of child-bearing age

Exclusion Criteria:

  • Current comorbid Axis I DSM IV disorder other than Nicotine Dependence, Adjustment Disorder, Panic Disorder, Generalized Anxiety Disorder, or Social Phobia
  • Diagnosis of substance abuse or dependence (excluding Nicotine Dependence) within the past 12 months
  • History of psychosis or psychotic disorder, mania or bipolar disorder
  • Subject is considered to be at significant risk of suicide based on current mental status and recent history
  • History of allergic or adverse reaction to citalopram, or nonresponse to adequate trial of citalopram (at least 4 weeks at dose of 40mg) or escitalopram (at least 4 weeks at dose of 20mg)
  • Subject is considered based on history to be unlikely to respond to the single agent citalopram (i.e., subjects with treatment resistant depression)
  • Current treatment with psychotherapy
  • Clinical Global Impression (CGI)-Severity score of 7 at baseline Clinical Interview
  • Current or recent (within the past 4 weeks) treatment with any of the following: antidepressants, antipsychotics, mood stabilizers, isoniazid, glucocorticoids, opiates, centrally active antihypertensive drugs (e.g. clonidine, reserpine)
  • Subject has metal in body or prior history working with metal fragments (e.g., as a machinist), tattoos, or unable to tolerate the scanning procedures (i.e., severe obesity, claustrophobia)
  • Acute, severe, or unstable medical illness

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Open Track
Open treatment with 20mg of citalopram, increased to 40mg if depression has not remitted at week 4.
Drug: Citalopram
Other Names:
  • Celexa
Placebo Comparator: Placebo Track
Blinded treatment with either citalopram 20mg or placebo, increased to citalopram 40mg or placebo at week 4 if depression has not remitted.
Drug: Citalopram
Other Names:
  • Celexa

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Hamilton Rating Scale for Depression
Time Frame: 8 weeks
The patient is rated by a clinician among 24 dimensions with a score on a 3 or 5 point scale. A score of 0-9 is considered to be normal. Score between 10-18 is considered as mild depression, Scores between 19-26 indicate moderate, scores between 27-34 indicate severe, and score between 35-75 indicate very severe depression.
8 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

New York State Psychiatric Institute

Collaborators

National Institute of Mental Health (NIMH)

Investigators

  • Principal Investigator: Bret R Rutherford, MD, New York State Psychiatric Institute

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 1, 2010

Primary Completion (Actual)

June 1, 2016

Study Completion (Actual)

June 1, 2016

Study Registration Dates

First Submitted

August 5, 2013

First Submitted That Met QC Criteria

August 6, 2013

First Posted (Estimate)

August 8, 2013

Study Record Updates

Last Update Posted (Actual)

March 9, 2020

Last Update Submitted That Met QC Criteria

February 26, 2020

Last Verified

February 1, 2020

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 6038/6996R
  • K23MH085236 (U.S. NIH Grant/Contract)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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