Major Depressive Disorder
Conditions
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.
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.
Interventions
DRUGCitalopram
Sponsors
National Institute of Mental Health (NIMH)
New York State Psychiatric Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
24 Years to 75 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
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 details
11 enrolled participants were lost to follow up prior to randomization.
Participants by arm
| Arm | Count |
|---|---|
| Open Track Open treatment with 20mg of citalopram, increased to 40mg if depression has not remitted at week 4.
Citalopram | 26 |
| Placebo Track - Citalopram Blinded treatment with citalopram 20mg , increased to citalopram 40mg at week 4 if depression has not remitted.
Citalopram | 20 |
| Placebo Track - Placebo Blinded treatment with placebo | 4 |
| Total | 50 |
Baseline characteristics
| Characteristic | Open Track | Placebo Track - Citalopram | Placebo Track - Placebo | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 26 Participants | 20 Participants | 4 Participants | 50 Participants |
| Age, Continuous | 41.4 years STANDARD_DEVIATION 12 | 43.8 years STANDARD_DEVIATION 10.7 | 34.3 years STANDARD_DEVIATION 10.2 | 41.79 years STANDARD_DEVIATION 11.36 |
| CGI Severity | 4.4 units on a scale STANDARD_DEVIATION 0.6 | 4.3 units on a scale STANDARD_DEVIATION 0.5 | 4.3 units on a scale STANDARD_DEVIATION 0.6 | 4.35 units on a scale STANDARD_DEVIATION 0.56 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 2 Participants | 1 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 21 Participants | 18 Participants | 3 Participants | 42 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Hamilton Anxiety Rating Scale (HAM-A) | 13.2 units on a scale STANDARD_DEVIATION 4.9 | 15.1 units on a scale STANDARD_DEVIATION 4.8 | 16.7 units on a scale STANDARD_DEVIATION 9.2 | 14.24 units on a scale STANDARD_DEVIATION 5.34 |
| Hamilton Rating Scale for Depression | 25.7 units on a scale STANDARD_DEVIATION 5.5 | 25.7 units on a scale STANDARD_DEVIATION 4.1 | 23.8 units on a scale STANDARD_DEVIATION 2.8 | 25.55 units on a scale STANDARD_DEVIATION 4.8 |
| Quick Inventory of Depressive Symptoms-Self Report (QIDS-SR) 16 Item Scale | 19.7 units on a scale STANDARD_DEVIATION 5.2 | 19.8 units on a scale STANDARD_DEVIATION 7.2 | 17.8 units on a scale STANDARD_DEVIATION 7.5 | 19.59 units on a scale STANDARD_DEVIATION 6.27 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 6 Participants | 1 Participants | 14 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 1 Participants | 0 Participants | 5 Participants |
| Race (NIH/OMB) White | 12 Participants | 13 Participants | 3 Participants | 28 Participants |
| Region of Enrollment United States | 26 Participants | 20 Participants | 4 Participants | 50 Participants |
| Sex: Female, Male Female | 17 Participants | 10 Participants | 3 Participants | 30 Participants |
| Sex: Female, Male Male | 9 Participants | 10 Participants | 1 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 26 | 0 / 20 | 0 / 4 |
| other Total, other adverse events | 0 / 26 | 0 / 20 | 0 / 4 |
| serious Total, serious adverse events | 0 / 26 | 0 / 20 | 0 / 4 |
Outcome results
Primary
Hamilton Rating Scale for Depression
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Open Track | Hamilton Rating Scale for Depression | 10.79 units on a scale | Standard Deviation 8.96 |
| Placebo Track - Citalopram | Hamilton Rating Scale for Depression | 15.30 units on a scale | Standard Deviation 9.2 |
| Placebo Track - Placebo | Hamilton Rating Scale for Depression | 12.75 units on a scale | Standard Deviation 5.188 |