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

• Sponsor: New York State Psychiatric Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT01919216
• Collaborator: National Institute of Mental Health (NIMH) (NIH)
• Enrollment: 65
• Location: 1
• Arms: 2
• Actual Duration (Months): 77
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Major Depressive Disorder	Drug: Citalopram	Phase 4

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 Design

• Study Type: Interventional
• Actual Enrollment: 65 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Placebo Effects in the Treatment of Depression: Cognitive and Neural Mechanisms
• Actual Study Start Date: Jan 1, 2010
• Actual Primary Completion Date: Jun 1, 2016
• Actual Study Completion Date: Jun 1, 2016

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Hamilton Rating Scale for Depression [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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 24 Years to 75 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	New York State Psychiatric Institute	New York	New York	United States	10032

Sponsors and Collaborators

• New York State Psychiatric Institute
• National Institute of Mental Health (NIMH)

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Publications

• Rutherford BR, Roose SP. A model of placebo response in antidepressant clinical trials. Am J Psychiatry. 2013 Jul;170(7):723-33. doi: 10.1176/appi.ajp.2012.12040474. Review.

• Responsible Party: Bret Rutherford, Assistant Professor of Clinical Psychiatry, New York State Psychiatric Institute
• ClinicalTrials.gov Identifier: NCT01919216
• Other Study ID Numbers: 6038/6996R; K23MH085236
• First Posted: Aug 8, 2013
• Last Update Posted: Mar 9, 2020
• Last Verified: Feb 1, 2020

• Additional relevant MeSH terms: Depressive Disorder; Depressive Disorder, Major; Citalopram

Study Results

Participant Flow

Recruitment Details	This study was conducted in the Adult and Late Life Depression Research Clinic at the New York State Psychiatric Institute (NYSPI) and approved by the NYSPI Institutional Review Board. Recruitment period started January 2010 and ended in June 2016.
Pre-assignment Detail	11 enrolled participants were lost to follow up prior to randomization.

Arm/Group Title	Open Track	Placebo Track - Citalopram	Placebo Track - Placebo
Arm/Group Description	Open treatment with 20mg of citalopram, increased to 40mg if depression has not remitted at week 4. Citalopram	Blinded treatment with either citalopram 20mg, increased to citalopram 40mg at week 4 if depression has not remitted. Citalopram	Blinded treatment with either placebo
Period Title: Overall Study
STARTED	28	21	5
COMPLETED	26	20	4
NOT COMPLETED	2	1	1

Baseline Characteristics

Arm/Group Title	Open Track	Placebo Track - Citalopram	Placebo Track - Placebo	Total
Arm/Group Description	Open treatment with 20mg of citalopram, increased to 40mg if depression has not remitted at week 4. Citalopram	Blinded treatment with citalopram 20mg , increased to citalopram 40mg at week 4 if depression has not remitted. Citalopram	Blinded treatment with placebo	Total of all reporting groups
Overall Participants	26	20	4	50
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	26 100%	20 100%	4 100%	50 100%
>=65 years	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	41.4 (12)	43.8 (10.7)	34.3 (10.2)	41.79 (11.36)
Sex: Female, Male (Count of Participants)
Female	17 65.4%	10 50%	3 75%	30 60%
Male	9 34.6%	10 50%	1 25%	20 40%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	5 19.2%	2 10%	1 25%	8 16%
Not Hispanic or Latino	21 80.8%	18 90%	3 75%	42 84%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	3 11.5%	0 0%	0 0%	3 6%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	7 26.9%	6 30%	1 25%	14 28%
White	12 46.2%	13 65%	3 75%	28 56%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	4 15.4%	1 5%	0 0%	5 10%
Region of Enrollment (Count of Participants)
United States	26 100%	20 100%	4 100%	50 100%
Hamilton Rating Scale for Depression (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	25.7 (5.5)	25.7 (4.1)	23.8 (2.8)	25.55 (4.8)
Hamilton Anxiety Rating Scale (HAM-A) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	13.2 (4.9)	15.1 (4.8)	16.7 (9.2)	14.24 (5.34)
CGI Severity (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	4.4 (0.6)	4.3 (0.5)	4.3 (0.6)	4.35 (0.56)
Quick Inventory of Depressive Symptoms-Self Report (QIDS-SR) 16 Item Scale (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	19.7 (5.2)	19.8 (7.2)	17.8 (7.5)	19.59 (6.27)

Outcome Measures

1. Primary Outcome

Title	Hamilton Rating Scale for Depression
Description	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.
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

54 subjects participated in the study, of whom 4 (2 in open track, 1 in placebo track - citalopram, 1 in placebo track - placebo) were lost to follow-up prior to taking the study medication and were excluded from the analyses.

Arm/Group Title	Open Track	Placebo Track - Citalopram	Placebo Track - Placebo
Arm/Group Description	Open treatment with 20mg of citalopram, increased to 40mg if depression has not remitted at week 4. Citalopram	Blinded treatment with either citalopram 20mg, increased to citalopram 40mg or placebo at week 4 if depression has not remitted. Citalopram	Blinded treatment with placebo
Measure Participants	26	20	4
Mean (Standard Deviation) [units on a scale]	10.79 (8.96)	15.30 (9.2)	12.75 (5.188)

Adverse Events

Arm/Group Title	Open Track		Placebo Track - Citalopram		Placebo Track - Placebo
Arm/Group Description	Open treatment with 20mg of citalopram, increased to 40mg if depression has not remitted at week 4. Citalopram		Blinded treatment with citalopram 20mg, increased to citalopram 40mg or placebo at week 4 if depression has not remitted. Citalopram		Blinded treatment with placebo
All Cause Mortality
	Open Track		Placebo Track - Citalopram		Placebo Track - Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/26 (0%)		0/20 (0%)		0/4 (0%)
Serious Adverse Events
	Open Track		Placebo Track - Citalopram		Placebo Track - Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/26 (0%)		0/20 (0%)		0/4 (0%)
Other (Not Including Serious) Adverse Events
	Open Track		Placebo Track - Citalopram		Placebo Track - Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/26 (0%)		0/20 (0%)		0/4 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.