Depression, Inflammation
Conditions
Keywords
Depression, Geriatric, Inflammation
Brief summary
Over 18% of Americans aged 65 years and older have depression. Recent evidence suggests that there is a link between depression and inflammatory disease. This study investigates the relationship between inflammation in the brain and depression. Comparing biological and psychological differences in depressed and non-depressed people allows researchers to find better ways to treat and prevent depression. All participants will have: neuropsychological tests, an EKG, a spinal tap, a blood draw, and, if depressed, given either an antidepressant coupled with an anti-inflammatory medication or an anti-depressant coupled with a placebo for six weeks. The investigators are trying to correlate brain function with depression levels and biomarkers from the blood and spinal fluid.
Interventions
DRUGEscitalopram + Celecoxib
Participants will receive celecoxib in addition to escitalopram
Participants will receive a placebo in addition to escitalopram.
Sponsors
University of Pennsylvania
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
50 Years to 80 Years
Healthy volunteers
Yes
Inclusion criteria
1. Age 18-80, male or female, any race; 2. Absence of clinical dementia 3. English speaking 4. Blood pressure not exceeding 150/90 mmHg, treated or untreated 5. Weight greater than 110 lbs 6. Normal result on liver-function test 7. No history of ulcer disease or GI bleeding 8. No renal insufficiency Additional Inclusion Criteria for Depressed Participants: 1. DSM-IV criteria for Major Depressive Disorder 2. HAM-D greater than 18
Exclusion criteria
1. Known history of relevant severe drug allergy or hypersensitivity (e.g. to Citalopram or Escitalopram, and/or to celecoxib, aspirin, or other NSAIDs only for Phase 2; known demonstration of allergic-type reactions to sulfonamides); 2. Does not speak English; 3. Cannot give informed consent; 4. MRI contraindications (e.g., foreign metallic implants, pacemaker); 5. Known primary neurological disorders, such as Parkinson's disease, Alzheimer's disease, traumatic brain injury, cognitive impairment or dementia, 6. Known severe inflammatory disease such as systemic lupus erythematosis, known autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis; Screen + for RF, ANA, HIV, Hepatitis B or C. 7. Clinical Dementia Rating Scale score greater than 0; 8. Diagnosis of a chronic psychiatric illness other than MDD at the discretion of the study doctor; 9. Significant handicaps (e.g. uncorrected hearing or visual impairment, mental retardation) that would interfere with testing; 10. Bleeding diathesis; 11. Severe Medical problem, which in the opinion of the investigator would pose a safety risk to the subject; 12. Clinically significant cardiovascular disease that will be assessed on a case-by-case basis. Clinically significant cardiovascular disease usually includes one or more of the following: cardiac surgery or myocardial infarction within the last 4 weeks; unstable angina; acute decompensated congestive heart failure or class IV heart failure; current significant cardiac arrhythmia or conduction disturbance, particularly those resulting in ventricular fibrillation, or causing syncope or near syncope; uncontrolled high blood pressure; QTc greater than 450msec (by history for subjects with cardiac disease); documented prior stroke; 13. Clinically significant abnormalities on EKG. Primary AV block or Right bundle branch block are not necessarily exclusionary; 14. Current diagnosis of cancer 15. Current diagnosis of HIV, active Hepatitis B and/or Hepatitis C 16. Use of an Investigational medicine within the past 30 days; 17. Use of Coumadin, Warfarin within the past 2 months; 18. Current treatment with psychotropic drugs or drugs that affect the CNS such as beta-blockers, mood stabilizers, antipsychotics, steroids or non-steroidal anti-inflammatory medications or other antidepressants. No subjects will be included in the study unless they have been off all psychotropics for at least 3 weeks, except in the case of fluoxetine, where 5 weeks off treatment will be required; 19. Current alcohol or substance abuse disorder, schizophrenia or other psychotic disorder, bipolar disorder, or current OCD; 20. Abnormal liver-function test 21. History of ulcer disease, Chron's disease, GI bleeding or anemia 22. Weight less than 110 lbs 23. Renal insufficiency 24. Any other factor that in the investigator's judgment may affect patient safety or compliance (e.g. distance greater than 100 miles from this facility); Additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| IL-6 Levels | up to week 6 | IL6 levels were measured in participants by blood draw 6 weeks after the first dose was given. |
| Montgomery Asberg Depression Rating Scale (MADRS) | Week 6 | This depression rating scale will be used to determine clinical outcome for depressed participants. Scores range from 0-60. The higher the score, the worse the outcome (see below) Normal: 0-6 Mild Depression: 7-19 Moderate Depression: 20-34 Severe Depression: 35+ Very Severe Depression: 60 |
| IL10 Levels | up to 6 weeks | IL10 levels were measured in participants by blood draw 6 weeks after the first dose was given |
Countries
United States
Participant flow
Recruitment details
SEPTA and PATCO advertisements, radio advertisements on WHYY, WMGK, and WURD, Newspaper advertisements in Metro, Milestones, Golden Times, and Haddonfield Sun, recruitment flyers, iConnect, emailing doctors for referrals, and advertising in clinics
Pre-assignment details
Total recruitment was 119 but 24 screen failed so the actual recruitment was 95
Participants by arm
| Arm | Count |
|---|---|
| Healthy Control Participants do not meet DSM-IV criteria for MDD, and did not receive any medication throughout the study | 30 |
| Placebo Participants meet DSM-IV criteria for MDD, and received placebo pills for the 6 week duration of the study | 20 |
| Escitalopram Participants meet DSM-IV criteria for MDD and received a dose of escitalopram between 10-20mg, or a 10-20mg dose of escitalopram as well as a placebo pill daily for the 6 week duration of the study. | 29 |
| Escitalopram + Celecoxib Participants meet DSM-IV criteria for MDD and received a 10-20mg dose of escitalopram and a 400mg dose of celecoxib daily for the 6 week duration of the study | 16 |
| Total | 95 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 3 | 3 | 0 |
| Overall Study | Physician Decision | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 2 | 2 |
Baseline characteristics
| Characteristic | Healthy Control | Placebo | Escitalopram | Escitalopram + Celecoxib | Total |
|---|---|---|---|---|---|
| Age, Customized 18-55 | 10 Participants | 3 Participants | 8 Participants | 5 Participants | 26 Participants |
| Age, Customized 56-65 | 7 Participants | 11 Participants | 13 Participants | 11 Participants | 42 Participants |
| Age, Customized 66-75 | 10 Participants | 5 Participants | 7 Participants | 0 Participants | 22 Participants |
| Age, Customized Over 75 | 3 Participants | 1 Participants | 1 Participants | 0 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 29 Participants | 20 Participants | 28 Participants | 16 Participants | 93 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| IL-10 Levels | 4.8 pg/mL STANDARD_DEVIATION 7.64 | 43.53 pg/mL STANDARD_DEVIATION 67.4 | 13.93 pg/mL STANDARD_DEVIATION 39.18 | 17.9 pg/mL STANDARD_DEVIATION 27.49 | 20.04 pg/mL STANDARD_DEVIATION 24.98 |
| IL-6 Levels | 4.89 pg/mL STANDARD_DEVIATION 3.75 | 13.9 pg/mL STANDARD_DEVIATION 10.53 | 4.12 pg/mL STANDARD_DEVIATION 4.05 | 9.18 pg/mL STANDARD_DEVIATION 10.29 | 8.02 pg/mL STANDARD_DEVIATION 4.57 |
| Montgomery Asberg Depression Rating Scale (MADRS) | 1.27 Total score (sum of points) STANDARD_DEVIATION 1.64 | 25.53 Total score (sum of points) STANDARD_DEVIATION 5.41 | 27.08 Total score (sum of points) STANDARD_DEVIATION 5.56 | 26.21 Total score (sum of points) STANDARD_DEVIATION 4.79 | 20.02 Total score (sum of points) STANDARD_DEVIATION 1.84 |
| Race and Ethnicity Not Collected | — | — | — | — | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants | 10 Participants | 14 Participants | 5 Participants | 40 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 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 | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 18 Participants | 10 Participants | 15 Participants | 11 Participants | 54 Participants |
| Sex: Female, Male Female | 13 Participants | 9 Participants | 13 Participants | 9 Participants | 44 Participants |
| Sex: Female, Male Male | 17 Participants | 11 Participants | 16 Participants | 7 Participants | 51 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 / 30 | 0 / 20 | 0 / 29 | 0 / 16 |
| other Total, other adverse events | 0 / 30 | 1 / 20 | 7 / 29 | 9 / 16 |
| serious Total, serious adverse events | 0 / 30 | 0 / 20 | 2 / 29 | 2 / 16 |
Outcome results
Primary
IL10 Levels
IL10 levels were measured in participants by blood draw 6 weeks after the first dose was given
Time frame: up to 6 weeks
Population: Not everybody completed the last blood draw
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Control | IL10 Levels | 4.21 pg/mL | Standard Deviation 5.83 |
| Placebo | IL10 Levels | 64.9 pg/mL | Standard Deviation 82.16 |
| Escitalopram | IL10 Levels | 12.24 pg/mL | Standard Deviation 29.32 |
| Escitalopram + Celecoxib | IL10 Levels | 18.56 pg/mL | Standard Deviation 28.9 |
Comparison: IL10 levels in healthy controls pre- and post-treatment compared using a paired t-testp-value: 0.29t-test, 2 sided
Comparison: IL10 levels in the placebo group pre- and post-treatment compared using a paired t-testp-value: 0.19t-test, 2 sided
Comparison: IL10 levels in the escitalopram group pre- and post-treatment compared using a paired t-testp-value: 0.5t-test, 2 sided
Comparison: IL10 levels in the escitalopram + celecoxib group pre- and post-treatment compared using a paired t-testp-value: 0.55t-test, 2 sided
Comparison: IL10 levels at completion of study compared between all MDD groups (placebo, escitalopram, and escitalopram + celecoxib) and the healthy control groupp-value: 0.06t-test, 2 sided
Primary
IL-6 Levels
IL6 levels were measured in participants by blood draw 6 weeks after the first dose was given.
Time frame: up to week 6
Population: Not everybody completed the final blood draw
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Control | IL-6 Levels | 5.25 pg/mL | Standard Deviation 4.12 |
| Placebo | IL-6 Levels | 18.24 pg/mL | Standard Deviation 15.63 |
| Escitalopram | IL-6 Levels | 3.69 pg/mL | Standard Deviation 3.73 |
| Escitalopram + Celecoxib | IL-6 Levels | 6.84 pg/mL | Standard Deviation 4.83 |
Comparison: IL6 levels in healthy controls pre- and post-treatment compared using a paired t-testp-value: 0.44t-test, 2 sided
Comparison: IL6 levels in the placebo group pre- and post-treatment compared using a paired t-testp-value: 0.11t-test, 2 sided
Comparison: IL6 levels in the escitalopram group pre- and post-treatment compared using a paired t-testp-value: 0.42t-test, 2 sided
Comparison: IL-6 levels in the escitalopram + celecoxib group pre- and post-treatment compared using a paired t-tesp-value: 0.49t-test, 2 sided
Comparison: IL6 levels at completion of study compared between all MDD groups (placebo, escitalopram, and escitalopram + celecoxib) and the healthy control groupp-value: 0.23t-test, 2 sided
Primary
Montgomery Asberg Depression Rating Scale (MADRS)
This depression rating scale will be used to determine clinical outcome for depressed participants. Scores range from 0-60. The higher the score, the worse the outcome (see below) Normal: 0-6 Mild Depression: 7-19 Moderate Depression: 20-34 Severe Depression: 35+ Very Severe Depression: 60
Time frame: Week 6
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Control | Montgomery Asberg Depression Rating Scale (MADRS) | 1.27 Total Score (Sum of Points) | Standard Deviation 1.64 |
| Placebo | Montgomery Asberg Depression Rating Scale (MADRS) | 19.14 Total Score (Sum of Points) | Standard Deviation 7.92 |
| Escitalopram | Montgomery Asberg Depression Rating Scale (MADRS) | 14.04 Total Score (Sum of Points) | Standard Deviation 9.13 |
| Escitalopram + Celecoxib | Montgomery Asberg Depression Rating Scale (MADRS) | 12.93 Total Score (Sum of Points) | Standard Deviation 9.59 |
Comparison: MADRS scores at the final visit compared between the healthy control and escitalopram + celecoxib groupsp-value: 0.003Wilcoxon (Mann-Whitney)
Comparison: MADRS scores at the final visit compared between the healthy control and escitalopram groupsp-value: <0.001Wilcoxon (Mann-Whitney)
Comparison: MADRS scores at the final visit compared between the healthy control and placebo groupsp-value: 0.034Wilcoxon (Mann-Whitney)
Comparison: MADRS scores at the final visit compared between the placebo groups and all groups receiving escitalopram (both with and without celecoxib)p-value: 0.03ANCOVA