Major Depressive Disorder
Conditions
Brief summary
The goal of this study is to develop new methods of administering antidepressant medications that will result in improved drug/placebo separation in randomized controlled trials (RCTs) for Major Depressive Disorder (MDD) and enhanced medication response in open clinical treatment. The highly intensive, weekly visit schedule followed in most antidepressant RCTs radically differs from how antidepressant medications are prescribed in standard clinical practice and is believed to be a major reason why the majority of studies submitted to the Food and Drug Administration (FDA) fail to show a significant difference between medication and placebo. Moreover, a one size fits all approach to psychopharmacologic management (i.e., weekly visits for all patients) does not take into account differences between patients that may predispose some individuals to respond positively to frequent follow-up visits, while others may respond negatively or not at all. Clinic visits comprise multiple components that may be therapeutic for depression, including activating patients' behavior, exposing them to medical procedures, permitting social interactions with research staff, and providing supportive meetings with clinicians. Two independent meta-analyses have associated more frequent study visits with increased antidepressant and placebo response as well as decreased separation between medication and placebo. Despite the high costs and potential disadvantages of weekly follow-up visits for patients receiving antidepressant medication, this clinical management strategy has not been studied prospectively to date. It is unknown whether weekly follow-up visits are needed to ensure treatment compliance and patient safety in clinical trials and to what degree contacts with clinicians influence medication and placebo response.
Detailed description
This study utilizes a 2 x 2, double-blind, acute, prospective design randomizing adult outpatients with MDD to Research Frequency Management (RFM, weekly study visits) vs. Community Frequency Management (CFM, every 4 weeks study visits) and antidepressant medication vs. placebo. Specifying visit frequency as the independent variable in this study has the distinct advantages of being easily operationalized for research purposes avoiding a priori assumptions about which components of study visits influence antidepressant and placebo response (i.e., behavioral activation vs. doctor-patient relationship vs. medical procedures). Close monitoring of all subjects will be assured by telephone evaluations of individuals randomized to CFM at intervals between monthly visits, and additional study contacts will be scheduled as necessary to maintain patient safety (all extra-protocol contacts will be recorded and included as a variable in outcome analyses). Additionally, subjects will be characterized extensively on clinical, demographic, and psychological measures to pilot the study assessment battery and search for predictor variables influencing the effects of contact frequency on medication and placebo response.
Interventions
DRUGEscitalopram
Escitalopram is a Selective Serotonin Reuptake Inhibitor (SSRI) medication that appears to help with symptoms of depression by increasing the availability of specific chemicals in the brain.
DRUGPlacebo
A placebo (or dummy pill) is an inert (inactive) substance, typically a tablet, capsule or other dose form that does not contain an active drug ingredient.
Sponsors
University of Haifa
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
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
\- Inclusion Criteria Method of Ascertainment 1. Men and women aged 18-75 years 1. Clinical interview 2. Diagnosis with Diagnostic and Statistical Manual (DSM) V Major Depressive Disorder (MDD) 2. Clinical interview, Structured Clinical Interview for DSM-V 3. 24-item Hamilton Rating Scale for Depression (HRSD) score ≥ 16 and ≤ 28; 17-item Hamilton Rating Scale for Depression (HRSD) score \< 25 3. HRSD by trained rater 4. Capable of providing informed consent and complying with study procedures 4. Clinical interview 5. Using appropriate contraceptive method if woman of child-bearing age and not currently pregnant 5. Clinical interview
Exclusion criteria
1. Current comorbid Axis I DSM V disorder other than Mild Substance Use Disorder, Adjustment Disorder, Anxiety Disorder or Personality Disorder 1. Clinical interview, SCID 2. Diagnosis of Moderate to Severe Substance Use Disorder within the past 12 months 2. Clinical interview, SCID, Urine tox 3. present or past history of psychosis, psychotic disorder, mania, or bipolar disorder 3. Clinical interview, SCID 4. baseline HRSD 24-item score \> 28 or HRSD suicide item \> 2 or baseline HRSD 17-item score ≥ 25 4. HRSD by trained rater 5. History of allergic or adverse reaction to escitalopram, or non-response to adequate trial of escitalopram (at least 4 weeks at dose of 20mg) during the current episode 5. Clinical interview 6. Current treatment with psychotherapy, antidepressants, antipsychotics, or mood stabilizers 6. Clinical interview 7. CGI-Severity score of 6 or greater at baseline 7. CGI based on Clinical interview 8. Acute, severe, or unstable medical illness 8. Clinical interview, Physical Exam, Screening Labs
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline Hamilton Rating Scale for Depression 24-Item Scale to Study Completion (8 Weeks) | Up to 8 Weeks | Scale for depressive symptoms administered by trained rater. The Hamilton is the standard measure of depression severity for clinical trials of antidepressants and was chosen as the primary outcome measure over other depression rating scales to ensure compatibility of study results with our meta-analyses and ongoing studies of expectancy. The scoring is based on the first 24 items of the Hamilton. Sum of the scores of the first 24 items (range from 0 to 74): 0-7 = NORMAL 8-13 = Mild Depression 14-18 = Moderate Depression 19-22 = Severe Depression \>=23 = Very Severe Depression |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline Hamilton Anxiety Rating Scale 14-item Scale | Up to 8 Weeks | Scale for anxiety symptoms administered by trained rater. The Hamilton Anxiety is a standard measure of anxiety severity in pharmacotherapy studies that has been shown to have acceptable reliability and validity in studies of depressed patients. Each item is scored on a scale of 0 (not present) to 4 (severe), with a total score range of 0-56, where \<17 indicates mild severity, 18-24 mild to moderate severity and 25-30 moderate to severe. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline Clinical Global Impressions | Up to 8 Weeks | Scales developed to measure the clinician's view of subjects' global functioning before and after initiating a study medication. The Clinical Global Impressions correlates well with other standard outcome measures for depression (e.g., HRSD), is sensitive to change in antidepressant trials, and offers clinically understandable anchor points. 7-point scale: 0 = Not assessed 4 = Moderately ill 1 = Normal, not at all ill 5 = Markedly ill 2 = Borderline mentally ill 6 = Severely ill 3 = Mildly ill 7 = Among the most extremely ill patients |
Countries
United States
Participant flow
Pre-assignment details
In total, 29 subjects were enrolled. Of the 29 enrolled, 4 subjects did not continue in the study after enrolling. These 4 subjects did not appear for their randomization visit at which they would have been assigned to a study arm. Thus, 29 patients enrolled and 25 patients started.
Participants by arm
| Arm | Count |
|---|---|
| Clinical Frequency Management: Placebo Study visits monthly (Week 0, 4, and 8), with phone visits every other week (Week 2 and 6). Double-blind, placebo-controlled treatment with escitalopram 10mg/day, raised to 20mg/day, if non-responders at week 4. If they respond, will be treated in a 3-month Continuation Phase with monthly site visits.
Placebo: A placebo (or dummy pill) is an inert (inactive) substance, typically a tablet, capsule or other dose form that does not contain an active drug ingredient. | 5 |
| Research Frequency Management: Placebo Weekly study visits, treatment with double-blind, placebo controlled escitalopram 10 mg/day, raised to 20mg/day at week 4 if non-responders. If they respond, will be treated in a 3-month Continuation Phase with monthly site visits.
Placebo: A placebo (or dummy pill) is an inert (inactive) substance, typically a tablet, capsule or other dose form that does not contain an active drug ingredient. | 7 |
| Clinical Frequency Management: Escitalopram Study visits monthly (Week 0, 4, and 8), with phone visits every other week (Week 2 and 6). Double-blind, placebo-controlled treatment with escitalopram 10mg/day, raised to 20mg/day, if non-responders at week 4. If they respond, will be treated in a 3-month Continuation Phase with monthly site visits.
Escitalopram: Escitalopram is a Selective Serotonin Reuptake Inhibitor (SSRI) medication that appears to help with symptoms of depression by increasing the availability of specific chemicals in the brain. | 5 |
| Research Frequency Management: Escitalopram Weekly study visits, treatment with double-blind, placebo controlled escitalopram 10 mg/day, raised to 20mg/day at week 4 if non-responders. If they respond, will be treated in a 3-month Continuation Phase with monthly site visits.
Escitalopram: Escitalopram is a Selective Serotonin Reuptake Inhibitor (SSRI) medication that appears to help with symptoms of depression by increasing the availability of specific chemicals in the brain. | 8 |
| Total | 25 |
Baseline characteristics
| Characteristic | Research Frequency Management: Placebo | Clinical Frequency Management: Escitalopram | Clinical Frequency Management: Placebo | Research Frequency Management: Escitalopram | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Age, Categorical >=65 years | 2 Participants | 4 Participants | 1 Participants | 3 Participants | 10 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 0 Participants | 4 Participants | 5 Participants | 14 Participants |
| Age, Continuous | 58 years STANDARD_DEVIATION 7.26 | 58.8 years STANDARD_DEVIATION 22.95 | 55.6 years STANDARD_DEVIATION 14.4 | 60 years STANDARD_DEVIATION 13.77 | 58.32 years STANDARD_DEVIATION 13.91 |
| Clinical Global Impressions Severity | 4 units on a scale STANDARD_DEVIATION 0 | 4 units on a scale STANDARD_DEVIATION 0 | 4 units on a scale STANDARD_DEVIATION 0.71 | 4 units on a scale STANDARD_DEVIATION 0.54 | 4 units on a scale STANDARD_DEVIATION 0.41 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants | 4 Participants | 5 Participants | 7 Participants | 23 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Hamilton Anxiety Rating Scale 14-item Scale | 9.57 units on a scale STANDARD_DEVIATION 2.15 | 11.4 units on a scale STANDARD_DEVIATION 4.22 | 10.2 units on a scale STANDARD_DEVIATION 3.27 | 9.62 units on a scale STANDARD_DEVIATION 2.83 | 10.08 units on a scale STANDARD_DEVIATION 2.96 |
| Hamilton Rating Scale for Depression | 20.4 units on a scale STANDARD_DEVIATION 2.07 | 19.6 units on a scale STANDARD_DEVIATION 3.65 | 18 units on a scale STANDARD_DEVIATION 4.53 | 20.8 units on a scale STANDARD_DEVIATION 4.43 | 19.88 units on a scale STANDARD_DEVIATION 3.68 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 2 Participants | 1 Participants | 3 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) White | 3 Participants | 3 Participants | 2 Participants | 4 Participants | 12 Participants |
| Region of Enrollment United States | 7 Participants | 5 Participants | 5 Participants | 8 Participants | 25 Participants |
| Sex: Female, Male Female | 4 Participants | 3 Participants | 4 Participants | 4 Participants | 15 Participants |
| Sex: Female, Male Male | 3 Participants | 2 Participants | 1 Participants | 4 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 0 / 7 | 0 / 5 | 0 / 8 |
| other Total, other adverse events | 2 / 5 | 6 / 7 | 1 / 5 | 6 / 8 |
| serious Total, serious adverse events | 0 / 5 | 0 / 7 | 0 / 5 | 1 / 8 |
Outcome results
Primary
Change From Baseline Hamilton Rating Scale for Depression 24-Item Scale to Study Completion (8 Weeks)
Scale for depressive symptoms administered by trained rater. The Hamilton is the standard measure of depression severity for clinical trials of antidepressants and was chosen as the primary outcome measure over other depression rating scales to ensure compatibility of study results with our meta-analyses and ongoing studies of expectancy. The scoring is based on the first 24 items of the Hamilton. Sum of the scores of the first 24 items (range from 0 to 74): 0-7 = NORMAL 8-13 = Mild Depression 14-18 = Moderate Depression 19-22 = Severe Depression \>=23 = Very Severe Depression
Time frame: Up to 8 Weeks
Population: Two CFM, Placebo, two RFM, Placebo, and two CFM, Escitalopram participants did not complete the Hamilton Rating Scale for Depression at Week 8, and so their change from baseline Hamilton Rating scale for Depression score could not be calculated.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Clinical Frequency Management: Placebo | Change From Baseline Hamilton Rating Scale for Depression 24-Item Scale to Study Completion (8 Weeks) | 1.33 score on a scale | Standard Deviation 3.51 |
| Research Frequency Management: Placebo | Change From Baseline Hamilton Rating Scale for Depression 24-Item Scale to Study Completion (8 Weeks) | 11.4 score on a scale | Standard Deviation 4.04 |
| Clinical Frequency Management: Escitalopram | Change From Baseline Hamilton Rating Scale for Depression 24-Item Scale to Study Completion (8 Weeks) | 5.33 score on a scale | Standard Deviation 13.65 |
| Research Frequency Management: Escitalopram | Change From Baseline Hamilton Rating Scale for Depression 24-Item Scale to Study Completion (8 Weeks) | 9.25 score on a scale | Standard Deviation 9.21 |
p-value: 0.292Regression, Linear
Secondary
Change From Baseline Hamilton Anxiety Rating Scale 14-item Scale
Scale for anxiety symptoms administered by trained rater. The Hamilton Anxiety is a standard measure of anxiety severity in pharmacotherapy studies that has been shown to have acceptable reliability and validity in studies of depressed patients. Each item is scored on a scale of 0 (not present) to 4 (severe), with a total score range of 0-56, where \<17 indicates mild severity, 18-24 mild to moderate severity and 25-30 moderate to severe.
Time frame: Up to 8 Weeks
Population: Two CFM, Placebo, two RFM, Placebo, and three CFM, Escitalopram participants did not complete the Hamilton Anxiety at Week 8, and so their change from baseline Hamilton Anxiety score could not be calculated.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Clinical Frequency Management: Placebo | Change From Baseline Hamilton Anxiety Rating Scale 14-item Scale | 3.67 score on a scale | Standard Deviation 2.52 |
| Research Frequency Management: Placebo | Change From Baseline Hamilton Anxiety Rating Scale 14-item Scale | 4.40 score on a scale | Standard Deviation 4.22 |
| Clinical Frequency Management: Escitalopram | Change From Baseline Hamilton Anxiety Rating Scale 14-item Scale | 6.50 score on a scale | Standard Deviation 4.95 |
| Research Frequency Management: Escitalopram | Change From Baseline Hamilton Anxiety Rating Scale 14-item Scale | 3.37 score on a scale | Standard Deviation 4.98 |
Other Pre-specified
Change From Baseline Clinical Global Impressions
Scales developed to measure the clinician's view of subjects' global functioning before and after initiating a study medication. The Clinical Global Impressions correlates well with other standard outcome measures for depression (e.g., HRSD), is sensitive to change in antidepressant trials, and offers clinically understandable anchor points. 7-point scale: 0 = Not assessed 4 = Moderately ill 1 = Normal, not at all ill 5 = Markedly ill 2 = Borderline mentally ill 6 = Severely ill 3 = Mildly ill 7 = Among the most extremely ill patients
Time frame: Up to 8 Weeks
Population: Two CFM, Placebo, two RFM, Placebo, and two CFM, Escitalopram participants did not complete the CGI at Week 8, and so their change from baseline CGI score could not be calculated.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Clinical Frequency Management: Placebo | Change From Baseline Clinical Global Impressions | 1.00 score on a scale | Standard Deviation 1.73 |
| Research Frequency Management: Placebo | Change From Baseline Clinical Global Impressions | 1.20 score on a scale | Standard Deviation 0.84 |
| Clinical Frequency Management: Escitalopram | Change From Baseline Clinical Global Impressions | 0.67 score on a scale | Standard Deviation 1.15 |
| Research Frequency Management: Escitalopram | Change From Baseline Clinical Global Impressions | 1.50 score on a scale | Standard Deviation 1.31 |