Depression
Conditions
Keywords
Cancer, IL-2 therapy, Antidepressant, Immune system, Neuroendocrine response
Brief summary
This study will determine the effectiveness of an antidepressant in preventing or reducing depressive symptoms in people with melanoma who are receiving Interleukin-2 (IL-2) treatment.
Detailed description
Melanoma is the most serious type of skin cancer, affecting nearly 54,000 people in the United States each year. Melanomas often develop in pre-existing moles or as new moles on the body. If left untreated, the cancerous cells can spread throughout the body. Fortunately, melanoma can be cured if a person is diagnosed and treated early. Typical treatments include surgery, amputation, chemotherapy, and immunotherapy. Interleukin-2 (IL-2) treatment, a type of immunotherapy, uses the body's immune system to slow or stop the spread of cancer cells to other parts of the body. However, IL-2 treatment is typically associated with severe side effects, including depression, fatigue, and difficulty thinking. This study will evaluate whether escitalopram, an antidepressant, can help improve treatment-related depressive symptoms, reduce stress hormone levels, and increase the number of treatment cycles among people with metastatic melanoma who are receiving IL-2 treatment. Participation in this double-blind study will last up to 18 weeks and will include 5 to 14 study visits. Participants will complete four 1-week cycles of IL-2 treatment over a 12-week period. Two weeks prior to starting IL-2 treatment, participants will undergo a psychiatric interview; a computerized thinking test; questionnaires; and blood, urine, and saliva collection. Participants will also be randomly assigned to start receiving either escitalopram or placebo for the entire duration of the study. The dosage of escitalopram or placebo will vary depending on the symptom severity of each participant. Immediately prior to IL-2 treatment, participants will undergo preliminary IL-2 procedures, which will include a medical history review, physical exam, and blood collection. These same procedures will occur every day that the participant is in the hospital for IL-2 treatment. Participants will stay in the hospital when receiving all four IL-2 treatment cycles. During these hospital stays, participants will complete repeat questionnaires and computerized tasks. Blood collection will occur at selected times as well. A follow-up visit will occur 4 weeks after the final treatment dose of IL-2.
Interventions
DRUGEscitalopram
Participants will begin medication approximately 2 weeks before their first scheduled IL-2 treatment. The dosage for the first week will be 10 mg per day. If 10 mg is well tolerated by the participant, the dosage will be increased to 20 mg per day. The dosage for the remainder of the study will be 20 mg per day.
DRUGPlacebo
Participants will begin the placebo approximately 2 weeks before their first scheduled IL-2 treatment. The dosage for the first week will be 1 pill per day, if 1 pill is well tolerated by the participant the dosage will be increased to 2 pills per day. Two pills per day will be the dosage for the reminder of the study.
DRUGIL-2
IL-2 is a 12-week treatment regimen with intravenous (IV) IL-2. There will be one cycle every 3 weeks for a total of four cycles. One cycle is 720,000 units/kg every 8 hours for 5 days.
Sponsors
National Institute of Mental Health (NIMH)
Emory University
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosed with cancer and beginning Interleukin (IL)-2 treatment * Willing to use an effective form of birth control throughout the study if sexually active
Exclusion criteria
* Diagnosed with major depression or experiencing significant depressive symptoms or a Hamilton Rating Scale-Depression score of 18 or higher * Brain metastases, history of a brain injury, or seizure disorders * Meets Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV criteria for substance abuse or dependence within 3 months of study entry * Suicidal, psychotic, or received psychiatric hospitalization within 12 months of study entry * Past or current history of schizophrenia or bipolar disorder * Pregnant or planning on becoming pregnant within 1 to 2 years * Evidence of untreated or poorly controlled infectious, hormone, heart, blood, kidney, liver, or neurological disease * Use of antidepressants, glucocorticoids, guanethidine, centrally acting alpha-antagonists, beta-blockers, or anticonvulsants * Clinically significant eye abnormalities * A score lower than 28 on the Mini Mental Status Exam (MMSE) * Prior history of severe adverse events associated with escitalopram or other selective serotonin reuptake inhibitor (SSRI) antidepressants * Diagnosed with type 1 or type 2 diabetes * Any condition that might make the participant unsuitable for enrollment or that could interfere with study participation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of IL-2 Treatments Tolerated | Cycle 4 (up to 12 weeks of IL-2 treatment) | The mean number of IL-2 doses tolerated (out of the possible 60 total doses) are presented for each study arm. The standard high dose regimen of IL-2 includes 15 doses per cycle. The dose of IL-2 is reduced, or treatment is stopped entirely, if the side effects become severe. This analysis includes the total number of doses taken at the end of Cycle 4, by all participants who began the trial, regardless of how many cycles each participant completed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Concentrations of Adrenocorticotropic Hormone (ACTH) | Screening and Cycles 1 - 4 (up to 14 weeks) | Adrenocorticotropic hormone (ACTH) is a stress hormone that is synthesized by the pituitary in response to corticotropin-releasing hormone (CRH). ACTH stimulates adrenal cortisol production. ACTH levels vary throughout the day and are highest between 6am and 8am. A typical reference range is 10-50 picograms per milliliter (pg/ml) from blood drawn in the morning. Low levels of ACTH can indicate adrenal insufficiency (including adrenal cancers) while high levels may indicate several diseases or stress. IL-2 treatment stimulates the release of ACTH and this stimulation is dose dependent (rising as the dose of IL-2 increases) and tends to increase further with repeated exposure to IL-2. Blood was drawn for measuring ACTH at screening (baseline value) and once during days 1-3 of each cycle of the four IL-2 treatments. |
| Plasma Concentrations of Interleukin 6 (IL-6) | Screening and Cycles 1 - 4 (up to 14 weeks) | Immune system functioning was assessed by measuring plasma concentrations of interleukin 6 (IL-6). IL-6 is a proinflammatory cytokine that is elevated during times of inflammation, infection, in patients with advanced or metastatic cancer, and is also implicated in mood disorders. IL-2 treatments are associated with increased IL 6 levels, in a dose response manner. IL-6 values in healthy individuals are generally less than 16 pg/ml. Blood was drawn for measuring IL-6 at screening (baseline value) and once during days 1-3 of each cycle of the four IL-2 treatments. |
| Plasma Concentrations of Cortisol | Screening and Cycles 1 - 4 (up to 14 weeks) | Cortisol is a steroid hormone made in the adrenal glands in response to fear or stressful situations. A typical reference range is 6-23 micrograms/deciliter (mcg/dL) from blood drawn in the morning. Low levels of cortisol can indicate Addison's disease or a problem with the pituitary gland, while high levels may indicate tumors of the adrenal gland, among other illnesses, or increased stress. Chronic elevation of cortisol is associated with reduced immune function and increased risk of heart disease. IL-2 treatment stimulates the release of cortisol and this stimulation is dose dependent (rising as the dose of IL-2 increases) and tends to increase further with repeated exposure to IL-2. Blood was drawn for measuring cortisol at screening (baseline value) and once during days 1-3 of each cycle of the four IL-2 treatments. |
| Hamilton Depression Rating Scale (HAM-D) Score | Screening and Cycles 1 - 4 (up to 14 weeks) | Hamilton Depression Rating Scale (HAM-D) is a 21-item, observer-rated scale which quantifies the severity of depressive symptoms, including depressed mood, loss of interest in usually pleasurable activities, insomnia, anorexia, fatigue, weight loss, and psychomotor retardation or agitation. Participants rate the severity of their symptoms on a scale of 0-2 or 0-4 (depending on the item), where 0 means that the symptom is absent. Total scores are calculated by summing the first 17 items for a total score between 0 and 50. For this study a score of 0-6 indicates a normal state, a score of 7-17 indicates mild depression, a score of 18-24 indicates moderate depression, and a score of greater than 25 indicates severe depression. The HAM-D was administered at screening (baseline value) and once during days 1-3 of each cycle of the four IL-2 treatments. |
| Genetic Polymorphisms | Screening and After Cycle 4 (up to 14 weeks) | — |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from the Winship Cancer Institute in Atlanta, Georgia. Participant enrollment began in October 2006 and all study participation ended in May 2010.
Pre-assignment details
Of 67 approached about the study, 26 met eligibility criteria and consented to participate in the trial. Two individuals did not come to the screening visit leaving 24 that were randomized evenly between the study arms. An additional 4 participants were discontinued prior to beginning IL-2 therapy, resulting in 20 participants who began the study.
Participants by arm
| Arm | Count |
|---|---|
| Escitalopram Participants receiving 10-20 mg of escitalopram per day from two weeks before IL-2 treatment begins and continuing through the duration of IL-2 treatment. IL-2 treatment consists of four 3-week cycles, for 12 weeks of IL-2 treatment and a total of 14 weeks of the escitalopram intervention. | 9 |
| Placebo Participants receiving a placebo from two weeks before IL-2 treatment begins and continuing through the duration of IL-2 treatment. IL-2 treatment consists of four 3-week cycles, for 12 weeks of IL-2 treatment and a total of 14 weeks of the intervention of a placebo to match escitalopram. | 11 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Development of major depression | 0 | 1 |
| Overall Study | Progression of metastatic melanoma | 5 | 3 |
| Overall Study | Side effects of IL-2 administration | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 3 |
Baseline characteristics
| Characteristic | Escitalopram | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 50.8 years STANDARD_DEVIATION 8.4 | 44.6 years STANDARD_DEVIATION 16.1 | 47.4 years STANDARD_DEVIATION 13.3 |
| Region of Enrollment United States | 9 Participants | 11 Participants | 20 Participants |
| Sex: Female, Male Female | 2 Participants | 3 Participants | 5 Participants |
| Sex: Female, Male Male | 7 Participants | 8 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 9 | 0 / 11 |
| other Total, other adverse events | 1 / 9 | 1 / 11 |
| serious Total, serious adverse events | 5 / 9 | 3 / 11 |
Outcome results
Primary
Number of IL-2 Treatments Tolerated
The mean number of IL-2 doses tolerated (out of the possible 60 total doses) are presented for each study arm. The standard high dose regimen of IL-2 includes 15 doses per cycle. The dose of IL-2 is reduced, or treatment is stopped entirely, if the side effects become severe. This analysis includes the total number of doses taken at the end of Cycle 4, by all participants who began the trial, regardless of how many cycles each participant completed.
Time frame: Cycle 4 (up to 12 weeks of IL-2 treatment)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Escitalopram | Number of IL-2 Treatments Tolerated | 18.4 IL-2 treatments | Standard Deviation 8.22 |
| Placebo | Number of IL-2 Treatments Tolerated | 19.8 IL-2 treatments | Standard Deviation 8.96 |
Secondary
Genetic Polymorphisms
Time frame: Screening and After Cycle 4 (up to 14 weeks)
Population: Genetic polymorphisms were not analyzed due to the small sample size and insufficient funds.
Secondary
Hamilton Depression Rating Scale (HAM-D) Score
Hamilton Depression Rating Scale (HAM-D) is a 21-item, observer-rated scale which quantifies the severity of depressive symptoms, including depressed mood, loss of interest in usually pleasurable activities, insomnia, anorexia, fatigue, weight loss, and psychomotor retardation or agitation. Participants rate the severity of their symptoms on a scale of 0-2 or 0-4 (depending on the item), where 0 means that the symptom is absent. Total scores are calculated by summing the first 17 items for a total score between 0 and 50. For this study a score of 0-6 indicates a normal state, a score of 7-17 indicates mild depression, a score of 18-24 indicates moderate depression, and a score of greater than 25 indicates severe depression. The HAM-D was administered at screening (baseline value) and once during days 1-3 of each cycle of the four IL-2 treatments.
Time frame: Screening and Cycles 1 - 4 (up to 14 weeks)
Population: The population in this analysis includes participants completing the HAM-D at the indicated study visit. Participants withdrew or were terminated from the study early depending on their ability to continue IL-2 treatment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Escitalopram | Hamilton Depression Rating Scale (HAM-D) Score | Cycle 1 | 11.56 units on a scale | Standard Error 2.24 |
| Escitalopram | Hamilton Depression Rating Scale (HAM-D) Score | Cycle 3 | 14.56 units on a scale | Standard Error 1.61 |
| Escitalopram | Hamilton Depression Rating Scale (HAM-D) Score | Cycle 2 | 12.33 units on a scale | Standard Error 1.69 |
| Escitalopram | Hamilton Depression Rating Scale (HAM-D) Score | Cycle 4 | 14.56 units on a scale | Standard Error 1.77 |
| Escitalopram | Hamilton Depression Rating Scale (HAM-D) Score | Screening | 7.77 units on a scale | Standard Error 1.27 |
| Placebo | Hamilton Depression Rating Scale (HAM-D) Score | Cycle 4 | 16.00 units on a scale | Standard Error 2.45 |
| Placebo | Hamilton Depression Rating Scale (HAM-D) Score | Screening | 6.45 units on a scale | Standard Error 1.51 |
| Placebo | Hamilton Depression Rating Scale (HAM-D) Score | Cycle 1 | 12.73 units on a scale | Standard Error 1.63 |
| Placebo | Hamilton Depression Rating Scale (HAM-D) Score | Cycle 2 | 15.00 units on a scale | Standard Error 2.05 |
| Placebo | Hamilton Depression Rating Scale (HAM-D) Score | Cycle 3 | 16.64 units on a scale | Standard Error 2.38 |
Secondary
Plasma Concentrations of Adrenocorticotropic Hormone (ACTH)
Adrenocorticotropic hormone (ACTH) is a stress hormone that is synthesized by the pituitary in response to corticotropin-releasing hormone (CRH). ACTH stimulates adrenal cortisol production. ACTH levels vary throughout the day and are highest between 6am and 8am. A typical reference range is 10-50 picograms per milliliter (pg/ml) from blood drawn in the morning. Low levels of ACTH can indicate adrenal insufficiency (including adrenal cancers) while high levels may indicate several diseases or stress. IL-2 treatment stimulates the release of ACTH and this stimulation is dose dependent (rising as the dose of IL-2 increases) and tends to increase further with repeated exposure to IL-2. Blood was drawn for measuring ACTH at screening (baseline value) and once during days 1-3 of each cycle of the four IL-2 treatments.
Time frame: Screening and Cycles 1 - 4 (up to 14 weeks)
Population: The population in this analysis includes participants with ACTH measurements at the indicated study visit. Participants withdrew or were terminated from the study early depending on their ability to continue IL-2 treatment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Escitalopram | Plasma Concentrations of Adrenocorticotropic Hormone (ACTH) | Cycle 1 | 45.66 pg/ml | Standard Error 7.58 |
| Escitalopram | Plasma Concentrations of Adrenocorticotropic Hormone (ACTH) | Cycle 3 | 87.89 pg/ml | Standard Error 36.03 |
| Escitalopram | Plasma Concentrations of Adrenocorticotropic Hormone (ACTH) | Cycle 2 | 112.59 pg/ml | Standard Error 73.04 |
| Escitalopram | Plasma Concentrations of Adrenocorticotropic Hormone (ACTH) | Cycle 4 | 91.25 pg/ml | Standard Error 45.23 |
| Escitalopram | Plasma Concentrations of Adrenocorticotropic Hormone (ACTH) | Screening | 27.55 pg/ml | Standard Error 7.41 |
| Placebo | Plasma Concentrations of Adrenocorticotropic Hormone (ACTH) | Cycle 4 | 81.23 pg/ml | Standard Error 22.08 |
| Placebo | Plasma Concentrations of Adrenocorticotropic Hormone (ACTH) | Screening | 28.95 pg/ml | Standard Error 4.43 |
| Placebo | Plasma Concentrations of Adrenocorticotropic Hormone (ACTH) | Cycle 1 | 56.60 pg/ml | Standard Error 10.46 |
| Placebo | Plasma Concentrations of Adrenocorticotropic Hormone (ACTH) | Cycle 2 | 75.69 pg/ml | Standard Error 20.61 |
| Placebo | Plasma Concentrations of Adrenocorticotropic Hormone (ACTH) | Cycle 3 | 136.13 pg/ml | Standard Error 60.52 |
Secondary
Plasma Concentrations of Cortisol
Cortisol is a steroid hormone made in the adrenal glands in response to fear or stressful situations. A typical reference range is 6-23 micrograms/deciliter (mcg/dL) from blood drawn in the morning. Low levels of cortisol can indicate Addison's disease or a problem with the pituitary gland, while high levels may indicate tumors of the adrenal gland, among other illnesses, or increased stress. Chronic elevation of cortisol is associated with reduced immune function and increased risk of heart disease. IL-2 treatment stimulates the release of cortisol and this stimulation is dose dependent (rising as the dose of IL-2 increases) and tends to increase further with repeated exposure to IL-2. Blood was drawn for measuring cortisol at screening (baseline value) and once during days 1-3 of each cycle of the four IL-2 treatments.
Time frame: Screening and Cycles 1 - 4 (up to 14 weeks)
Population: The population in this analysis includes participants with cortisol measurements at the indicated study visit. Participants withdrew or were terminated from the study early depending on their ability to continue IL-2 treatment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Escitalopram | Plasma Concentrations of Cortisol | Cycle 1 | 20.60 mcg/dL | Standard Error 1.47 |
| Escitalopram | Plasma Concentrations of Cortisol | Cycle 3 | 22.44 mcg/dL | Standard Error 2.39 |
| Escitalopram | Plasma Concentrations of Cortisol | Cycle 2 | 19.53 mcg/dL | Standard Error 2.53 |
| Escitalopram | Plasma Concentrations of Cortisol | Cycle 4 | 20.58 mcg/dL | Standard Error 2.63 |
| Escitalopram | Plasma Concentrations of Cortisol | Screening | 11.51 mcg/dL | Standard Error 2.06 |
| Placebo | Plasma Concentrations of Cortisol | Cycle 4 | 18.86 mcg/dL | Standard Error 1.29 |
| Placebo | Plasma Concentrations of Cortisol | Screening | 10.62 mcg/dL | Standard Error 1.27 |
| Placebo | Plasma Concentrations of Cortisol | Cycle 1 | 17.78 mcg/dL | Standard Error 1.58 |
| Placebo | Plasma Concentrations of Cortisol | Cycle 2 | 18.46 mcg/dL | Standard Error 1.79 |
| Placebo | Plasma Concentrations of Cortisol | Cycle 3 | 19.11 mcg/dL | Standard Error 1.15 |
Secondary
Plasma Concentrations of Interleukin 6 (IL-6)
Immune system functioning was assessed by measuring plasma concentrations of interleukin 6 (IL-6). IL-6 is a proinflammatory cytokine that is elevated during times of inflammation, infection, in patients with advanced or metastatic cancer, and is also implicated in mood disorders. IL-2 treatments are associated with increased IL 6 levels, in a dose response manner. IL-6 values in healthy individuals are generally less than 16 pg/ml. Blood was drawn for measuring IL-6 at screening (baseline value) and once during days 1-3 of each cycle of the four IL-2 treatments.
Time frame: Screening and Cycles 1 - 4 (up to 14 weeks)
Population: The population in this analysis includes participants with IL-6 measurements at the indicated study visit. Participants withdrew or were terminated from the study early depending on their ability to continue IL-2 treatment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Escitalopram | Plasma Concentrations of Interleukin 6 (IL-6) | Cycle 1 | 290.77 pg/ml | Standard Error 81.63 |
| Escitalopram | Plasma Concentrations of Interleukin 6 (IL-6) | Cycle 3 | 305.41 pg/ml | Standard Error 69.95 |
| Escitalopram | Plasma Concentrations of Interleukin 6 (IL-6) | Cycle 2 | 210.90 pg/ml | Standard Error 49.96 |
| Escitalopram | Plasma Concentrations of Interleukin 6 (IL-6) | Cycle 4 | 283.34 pg/ml | Standard Error 67.55 |
| Escitalopram | Plasma Concentrations of Interleukin 6 (IL-6) | Screening | 11.68 pg/ml | Standard Error 7.09 |
| Placebo | Plasma Concentrations of Interleukin 6 (IL-6) | Cycle 4 | 308.09 pg/ml | Standard Error 57.37 |
| Placebo | Plasma Concentrations of Interleukin 6 (IL-6) | Screening | 10.12 pg/ml | Standard Error 3.36 |
| Placebo | Plasma Concentrations of Interleukin 6 (IL-6) | Cycle 1 | 270.11 pg/ml | Standard Error 71.85 |
| Placebo | Plasma Concentrations of Interleukin 6 (IL-6) | Cycle 2 | 297.94 pg/ml | Standard Error 67.94 |
| Placebo | Plasma Concentrations of Interleukin 6 (IL-6) | Cycle 3 | 332.49 pg/ml | Standard Error 52.54 |