Anxiety, Depression
Conditions
Keywords
Cardiovascular Biomarkers, Depression, Quetiapine
Brief summary
No suitable treatment has been identified to reverse and ideally prevent, the cardiovascular disease risk associated with depression and anxiety. The purpose of this study is to determine if quetiapine treatment of depression can reverse the signs of arterial stiffening that often occurs in depression and anxiety, and which are believed to be risk factors for future heart disease.
Detailed description
The evidence that depressive and anxiety disorders confer a high relative risk (RR) for cardiovascular disease (CVD) development is clear and compelling. A cadre of inflammation, platelet activation and other biomarkers of endothelial dysfunction strongly suggest multiple and possibly interrelated mechanisms underlying this co-morbidity. Early detection of the vulnerability to develop CVD has become an urgent health issue. However, detection alone of vulnerability without proper therapeutic intervention aimed at reversing it, is merely of scientific interest. The evidence to date that antidepressant drugs, while highly efficacious in restoring euthymia, may not normalize the biomarkers of CVD vulnerability. Hence, there is a need to identify other pharmacologic interventions for depression. Quetiapine, due to its unique molecular structure and unique pharmacological profile, belongs to none of the known classes of antidepressants. However, quetiapine clearly has antidepressant and anti-anxiety efficacies. Now, we propose to explore whether quetiapine can reverse those pathophysiological changes occurring in mixed depression/anxiety that have been linked causally to the development of CVD. Accordingly, the primary purpose of this study is to compare C-Reactive Protein between the treatment and healthy control groups at 12 weeks post treatment.
Interventions
DRUGQuetiapine-XR
Quetiapine-XR (Seroquel-XR) 50-300mg daily for 12 weeks.
Sponsors
Loyola University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* A diagnosis of Major Depressive Disorder (MDD), first episode or recurrent, by Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition (DSM-IV) requiring treatment. The index episode must be at least 14 days of persistent symptoms. If first episode, patients must not have been previously treated. If recurrent, must not be receiving treatment for the recurrence. * Females and males 20-65 years of age * Female patients of childbearing potential must be using a reliable method of contraception and have a negative urine human chorionic gonadotropin (HCG) test at time of enrolment * Able to understand and comply with the requirements of the study
Exclusion criteria
* Females who are pregnant, lactating, breast feeding or on oral contraceptives * Any DSM-IV Axis I disorder not defined in the inclusion criteria except MDD co-morbid with generalized anxiety disorder (GAD) * Patients who, in the opinion of the investigator, pose an imminent risk of suicide or a danger to self or others * Known intolerance or lack of response to quetiapine (Seroquel) as judged by the investigator * Use of any of the following cytochrome P450 3A4 inhibitors in the 14 days preceding enrolment including but not limited to: ketoconazole, itraconazole, fluconazole, erythromycin, clarithromycin, troleandomycin, indinavir, nelfinavir, ritonavir, fluvoxamine and saquinavir * Use of any of the following cytochrome P450 inducers in the 14 days preceding enrolment including but not limited to: phenytoin, carbamazepine, barbiturates, rifampin, St. John's Wort, and glucocorticoids * Concomitant use of any other antidepressant, anxiolytic, or antipsychotic agent * Administration of a depot antipsychotic injection within one dosing interval (for the depot) before the study begins * Substance or alcohol dependence at enrolment (except dependence in full remission, and except for caffeine or nicotine dependence), as defined by DSM-IV criteria * History of heavy smoking within the preceding 6 months * Opiates, amphetamine, barbiturate, cocaine, cannabis, or hallucinogen abuse by DSM-IV criteria within 4 weeks prior to enrolment * Restrictions prior to blood drawings: Aspirin (previous 240 hours), antihistamines (previous 72 hours), Tylenol (previous 72 hours), Vitamin C or E (previous 72 hours), sleeping pills (previous 72 hours), caffeinated beverages (8 hours), physical exertion (8 hours) and tobacco products (2 hours). * Medical conditions that would affect absorption, distribution, metabolism, or excretion of study treatment * Unstable or inadequately treated medical illness (e.g. diabetes, angina pectoris, hypertension) as judged by the investigator * Involvement in the planning and conduct of the study * Previous enrolment in the present study. * Participation in another drug trial within 4 weeks prior enrolment into this study or longer in accordance with local requirements * A patient with Diabetes Mellitus (DM) fulfilling one of the following criteria: * Unstable DM defined as enrolment glycosylated hemoglobin (HbA1c) \>8.5%. * Admitted to hospital for treatment of DM or DM related illness in past 12 weeks. * Not under physician care for DM * Physician responsible for patient's DM care has not indicated that patient's DM is controlled. * Physician responsible for patient's DM care has not approved patient's participation in the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| C-Reactive Protein at 12 Weeks | 12 weeks | To compare C-Reactive Protein between the treatment and healthy control groups at 12 weeks post treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Hamilton Rating Scale for Depression With 17 Items (HAM-D-17) | Baseline and 12 weeks | The 17-item Hamilton Rating Scale for Depression (HAMD-17) is an objective assessment of depression administered by a trained rater. This version allows scores to range from 0 to 52, where higher scores indicate worsening mood. |
| Change in Hamilton Rating Scale for Depression With 21 Items (HAMD-21) | Baseline and 12 weeks | The 21-item Hamilton Rating Scale for Depression (HAMD-21) is an objective assessment of depression administered by a trained rater. This version allows scores to range from 0 to 52, where higher scores indicate worsening mood. |
| Change in Hamilton Rating Scale for Depression With Seven Items (HAM-D-7) | Baseline and 12 weeks | The seven item Hamilton Rating Scale for Depression (HAMD-7) is an objective assessment of depression administered by a trained rater. This version allows scores to range from 0 to 22, where higher scores indicate worsening mood. |
| Change in Beck Depression Inventory (BDI) | Baseline and 12 weeks | The 21-item Beck Depression Inventory (BDI) is a subjective self-report assessment of depression. This version allows scores to range from 0 to 63, where higher scores indicate worsening mood. |
| Change in 14-item Perceived Stress Scale (PSS-14) | Baseline and 12 weeks | The 14-item Perceived Stress Scale (PSS-14) is a subjective self-report assessment of stress. Each item is rated on a five point frequency scale ranging from 0 = never experiencing the stress symptom to 4 = Very often experiencing the stress symptom. Scores range from 0 to 56, where higher scores indicate higher stress. |
| Change in Hamilton Rating Scale for Anxiety (HAM-A) | Baseline and 12 weeks | The 14-item Hamilton Rating Scale for Anxiety (HAM-A) is an objective assessment of anxiety administered by a trained rater. This version allows scores to range from 0 to 56, where higher scores indicate worsening anxiety. |
Countries
United States
Participant flow
Recruitment details
Ninety-one individuals were consented and 47 participants received study drug while 44 participants enrolled as healthy control participants between July 2009 and October 2011. Participants were recruited using physician solicitation and advertisements.
Participants by arm
| Arm | Count |
|---|---|
| Experimental Cohort Patients will undergo baseline psychological and laboratory tests then receive Quetiapine-XR(Seroquel-XR) with flexible dosing at the discretion of the treating physician based on clinical response and tolerability. The dose range will be from 50-300mg. The total duration of the treatment will be 12 weeks.
Quetiapine-XR: Quetiapine-XR (Seroquel-XR) 50-300mg daily for 12 weeks. | 47 |
| Healthy Control Participants without major depressive disorder or anxiety are enrolled as a comparison group without intervention. They will undergo baseline psychological and laboratory tests and will be followed for 12 weeks. | 44 |
| Total | 91 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 4 | 0 |
| Overall Study | Withdrawal by Subject | 15 | 0 |
Baseline characteristics
| Characteristic | Total | Healthy Control | Experimental Cohort |
|---|---|---|---|
| Age, Continuous | 41.7 years STANDARD_DEVIATION 13.1 | 39.5 years STANDARD_DEVIATION 13.8 | 43.8 years STANDARD_DEVIATION 12.1 |
| Baseline Beck Depression Inventory | 16.50 units on a scale | 0 units on a scale | 25.50 units on a scale |
| Baseline Hamilton Rating Scale for Anxiety | 10 units on a scale | 0 units on a scale | 22 units on a scale |
| Baseline Hamilton Rating Scale for Depression with 17 Items | 17 units on a scale | 0 units on a scale | 25 units on a scale |
| Baseline Hamilton Rating Scale for Depression with 21 Items | 18 units on a scale | 0 units on a scale | 27 units on a scale |
| Baseline Hamilton Rating Scale for Depression with Seven Items | 8 units on a scale | 0 units on a scale | 15 units on a scale |
| Body Mass Index (BMI) | 29.36 kg/m^2 STANDARD_DEVIATION 6.84 | 26.51 kg/m^2 STANDARD_DEVIATION 5.77 | 31.98 kg/m^2 STANDARD_DEVIATION 6.76 |
| Concomitant Psychiatric Medication No | 58 participants | 42 participants | 16 participants |
| Concomitant Psychiatric Medication Unknown | 6 participants | 1 participants | 5 participants |
| Concomitant Psychiatric Medication Yes | 27 participants | 1 participants | 26 participants |
| Family History of Alzheimer's Disease No | 54 participants | 36 participants | 18 participants |
| Family History of Alzheimer's Disease Unknown | 12 participants | 4 participants | 8 participants |
| Family History of Alzheimer's Disease Yes | 25 participants | 4 participants | 21 participants |
| Family History of Depression No | 55 participants | 38 participants | 17 participants |
| Family History of Depression Unknown | 12 participants | 4 participants | 8 participants |
| Family History of Depression Yes | 24 participants | 2 participants | 22 participants |
| Height | 1.67 Meters STANDARD_DEVIATION 0.15 | 1.68 Meters STANDARD_DEVIATION 0.1 | 1.66 Meters STANDARD_DEVIATION 0.19 |
| Menopausal Status Not Applicable (Males) | 36 participants | 15 participants | 21 participants |
| Menopausal Status Postmenopausal | 13 participants | 10 participants | 3 participants |
| Menopausal Status Premenopausal | 42 participants | 19 participants | 23 participants |
| Perceived Stress Scale with 14 Items | 43.50 units on a scale | 27.00 units on a scale | 49.50 units on a scale |
| Race/Ethnicity, Customized African American | 21 Participants | 8 Participants | 13 Participants |
| Race/Ethnicity, Customized Asian | 4 Participants | 3 Participants | 1 Participants |
| Race/Ethnicity, Customized Hispanic White | 14 Participants | 3 Participants | 11 Participants |
| Race/Ethnicity, Customized Non-Hispanic White | 52 Participants | 30 Participants | 22 Participants |
| Sex: Female, Male Female | 55 Participants | 29 Participants | 26 Participants |
| Sex: Female, Male Male | 36 Participants | 15 Participants | 21 Participants |
| Tobacco Use Non-Smoker | 62 Participants | 40 Participants | 22 Participants |
| Tobacco Use Smoker | 3 Participants | 3 Participants | 0 Participants |
| Tobacco Use Unknown | 26 Participants | 1 Participants | 25 Participants |
| Weight | 81.86 kilograms STANDARD_DEVIATION 21.31 | 74.59 kilograms STANDARD_DEVIATION 15.45 | 88.50 kilograms STANDARD_DEVIATION 23.8 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 39 / 47 | 0 / 44 |
| serious Total, serious adverse events | 0 / 47 | 0 / 44 |
Outcome results
Primary
C-Reactive Protein at 12 Weeks
To compare C-Reactive Protein between the treatment and healthy control groups at 12 weeks post treatment.
Time frame: 12 weeks
Population: Due to the cost for the C-reactive protein assay, only 20 individuals from each cohort are analyzed (N = 40).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Experimental Cohort | C-Reactive Protein at 12 Weeks | 3.31 mg/L |
| Healthy Control | C-Reactive Protein at 12 Weeks | 0.50 mg/L |
Comparison: The null hypothesis is that C-reactive protein (CRP) is no different between the experimental and healthy control cohorts at 12 weeks.p-value: 0.001Wilcoxon (Mann-Whitney)
Secondary
Change in 14-item Perceived Stress Scale (PSS-14)
The 14-item Perceived Stress Scale (PSS-14) is a subjective self-report assessment of stress. Each item is rated on a five point frequency scale ranging from 0 = never experiencing the stress symptom to 4 = Very often experiencing the stress symptom. Scores range from 0 to 56, where higher scores indicate higher stress.
Time frame: Baseline and 12 weeks
Population: This analysis is restricted to the twenty-three individuals from the intervention cohort had valid PSS-14 responses at baseline and 12 weeks; the healthy control arm is not included, because their PSS-14 scores were recorded at baseline only (see baseline characteristics).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Experimental Cohort | Change in 14-item Perceived Stress Scale (PSS-14) | 50.00 units on a scale |
| Healthy Control | Change in 14-item Perceived Stress Scale (PSS-14) | 35.00 units on a scale |
Comparison: The null hypothesis is that there is no difference between the intervention cohort's baseline PSS-14 score and end of treatment (i.e., 12 week) PSS-14 score.p-value: <0.001Wilcoxon signed rank test
Secondary
Change in Beck Depression Inventory (BDI)
The 21-item Beck Depression Inventory (BDI) is a subjective self-report assessment of depression. This version allows scores to range from 0 to 63, where higher scores indicate worsening mood.
Time frame: Baseline and 12 weeks
Population: This analysis is restricted to the twenty-seven individuals from the intervention cohort had valid BDI responses at baseline and 12 weeks; the healthy control arm is not included, because their BDI scores were recorded at baseline only (see baseline characteristics).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Experimental Cohort | Change in Beck Depression Inventory (BDI) | 25.00 units on a scale |
| Healthy Control | Change in Beck Depression Inventory (BDI) | 6.00 units on a scale |
Comparison: The null hypothesis is that there is no difference between the intervention cohort's baseline BDI score and end of treatment (i.e., 12 week) BDI score.p-value: <0.001Wilcoxon signed rank test
Secondary
Change in Hamilton Rating Scale for Anxiety (HAM-A)
The 14-item Hamilton Rating Scale for Anxiety (HAM-A) is an objective assessment of anxiety administered by a trained rater. This version allows scores to range from 0 to 56, where higher scores indicate worsening anxiety.
Time frame: Baseline and 12 weeks
Population: This analysis is restricted to the twenty-eight individuals from the intervention cohort had valid HAM-A responses at baseline and 12 weeks; the healthy control arm is not included, because their HAM-A scores were recorded at baseline only (see baseline characteristics).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Experimental Cohort | Change in Hamilton Rating Scale for Anxiety (HAM-A) | 22.00 units on a scale |
| Healthy Control | Change in Hamilton Rating Scale for Anxiety (HAM-A) | 6.00 units on a scale |
Comparison: The null hypothesis is that there is no difference between the intervention cohort's baseline HAM-A score and end of treatment (i.e., 12 week) HAM-A score.p-value: <0.001Wilcoxon signed rank test
Secondary
Change in Hamilton Rating Scale for Depression With 17 Items (HAM-D-17)
The 17-item Hamilton Rating Scale for Depression (HAMD-17) is an objective assessment of depression administered by a trained rater. This version allows scores to range from 0 to 52, where higher scores indicate worsening mood.
Time frame: Baseline and 12 weeks
Population: This analysis is restricted to the twenty-eight individuals from the intervention cohort who had valid HAM-D-17 responses at baseline and 12 weeks; the healthy control arm is not included, because their HAM-D-17 scores were recorded at baseline only (see baseline characteristics).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Experimental Cohort | Change in Hamilton Rating Scale for Depression With 17 Items (HAM-D-17) | 24.00 units on a scale |
| Healthy Control | Change in Hamilton Rating Scale for Depression With 17 Items (HAM-D-17) | 5.50 units on a scale |
Comparison: The null hypothesis is that there is no difference between the intervention cohort's baseline HAMD-17 score and end of treatment (i.e., 12 week) HAMD-17 score.p-value: <0.001Wilcoxon signed rank test
Secondary
Change in Hamilton Rating Scale for Depression With 21 Items (HAMD-21)
The 21-item Hamilton Rating Scale for Depression (HAMD-21) is an objective assessment of depression administered by a trained rater. This version allows scores to range from 0 to 52, where higher scores indicate worsening mood.
Time frame: Baseline and 12 weeks
Population: This analysis is restricted to the twenty-eight individuals from the intervention cohort had valid HAM-D-21 responses at baseline and 12 weeks; the healthy control arm is not included, because their HAM-D-21 scores were recorded at baseline only (see baseline characteristics).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Experimental Cohort | Change in Hamilton Rating Scale for Depression With 21 Items (HAMD-21) | 26.50 units on a scale |
| Healthy Control | Change in Hamilton Rating Scale for Depression With 21 Items (HAMD-21) | 6.50 units on a scale |
Comparison: The null hypothesis is that there is no difference between the intervention cohort's baseline HAMD-21 score and end of treatment (i.e., 12 week) HAMD-21 score.p-value: <0.001Wilcoxon signed rank test
Secondary
Change in Hamilton Rating Scale for Depression With Seven Items (HAM-D-7)
The seven item Hamilton Rating Scale for Depression (HAMD-7) is an objective assessment of depression administered by a trained rater. This version allows scores to range from 0 to 22, where higher scores indicate worsening mood.
Time frame: Baseline and 12 weeks
Population: This analysis is restricted to the twenty-eight individuals from the intervention cohort who had valid HAM-D-7 responses at baseline and 12 weeks; the healthy control arm is not included here, because their HAM-D-7 scores were recorded at baseline only (see baseline characteristics).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Experimental Cohort | Change in Hamilton Rating Scale for Depression With Seven Items (HAM-D-7) | 15.00 units on a scale |
| Healthy Control | Change in Hamilton Rating Scale for Depression With Seven Items (HAM-D-7) | 3.00 units on a scale |
Comparison: The null hypothesis is that there is no difference between the intervention cohort's baseline HAM-D-7 score and end of treatment (i.e., 12 week) HAM-D-7 score.p-value: <0.001Wilcoxon signed rank test