Depression
Conditions
Keywords
Major Depression, Geriatric Major Unipolar Depression, Executive Cognitive Dysfunction, Elderly, Geriatric, Executive Cognitive Impairment, Quality of Life, Disability, Comorbidity, Medical Burden, Safety, Candidate Genes
Brief summary
This study will evaluate the safety and effectiveness of methylphenidate in improving cognition and function in older adults with depression.
Detailed description
Less than 50% of older adults with depression achieve remission and functional recovery in response to first-line antidepressant treatment. Most are left with significant residual symptoms, putting them at risk for illness relapse, frailty, and suicide. Improved understanding of the neurobiology of depression in older adults and mechanisms of treatment response may lead to better clinical management of depression. Methylphenidate (MPH) has long been used in the elderly and the medically ill to provide rapid improvement in depression, apathy, and fatigue. However, its potential beneficial effects on cognitive and functional outcomes in older adults with depression have not been studied. Combining MPH with the serotonergic antidepressant citalopram may result in better clinical outcomes than would using citalopram alone. This study will compare the safety and effectiveness of MPH combined with citalopram, MPH combined with placebo, and citalopram combined with placebo in improving thinking, memory, and speed of recovery in older adults with depression. The study will also evaluate selected dopamine- and serotonin-related gene relationships with mood, cognitive symptoms, and treatment response to MPH and citalopram. Participation in this double-blind study will last 16 weeks. All potential participants will initially undergo comprehensive medical, neuropsychiatric, and cognitive assessments and genetic testing. These initial assessments will include questionnaires about depressive symptoms, a medical history, an electrocardiogram (ECG), and a blood draw for the genetic testing. Eligible participants will then be randomly assigned to one of three groups: MPH and citalopram, MPH and placebo, or citalopram and placebo. All participants will receive 16 weeks of treatment with their assigned medications. Study visits will occur weekly for the first 6 weeks of treatment and bi-weekly for the remainder of the study. During study visits, participants will undergo vital sign and weight measurements, answer questionnaires, and report any medication side effects. Blood will again be drawn at Visits 4 and 10, and the ECG will be repeated at Visit 10 if any cardiac symptoms occur. Most initial assessments will be repeated on Visit 13, the last study visit. Participants will also be contacted weekly by phone throughout the study to answer questions on how they are feeling and any possible side effects.
Interventions
DRUGCitalopram
Citalopram dosage will be 20 to 60 mg a day prior to FDA warning limiting it to 20-40 mg in 2011. Participants will begin taking one 20-mg capsule once per day for 4 weeks, and this dosage may be increased or decreased depending on the participant's response to the medication or side-effect profile. Participants will continue on their assigned dosage of citalopram that will be titrated up after week 4 if clinical global impressions (CGI) scores were \> 2 until treatment completion.
MPH dosage will be 5 to 40 mg a day. Participants will initially take 1 capsule (2.5 mg) twice per day, which will be increased to a maximum up to 8 x 2.5 mg capsules twice per day. After Visit 11, MPH dosage will be gradually reduced over 2 weeks until participants are no longer taking any capsules.
DRUGPlacebo
Placebo pills will be taken in combination with the active pills. Participants will initially take 1 capsule twice per day, which will be increased to a maximum of 16 capsules twice per day matching methylphenidate, and 1-3 capsules matching citalopram. After Visit 11, placebo dosage will be gradually reduced over 2 weeks until participants are no longer taking any capsules.
Sponsors
National Institute of Mental Health (NIMH)
University of California, Los Angeles
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
60 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Meets Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV) criteria for major depressive disorder (recurrent and nonrecurrent course will be identified) * Score of 16 or higher on the 24-item Hamilton Depression Rating Scale (HDRS) at study entry * Score of 26 or higher on the Mini-Mental State Exam (MMSE)
Exclusion criteria
* History of psychiatric illness or a substance abuse disorder other than unipolar depression, diagnosed prior to the onset of the first depressive episode * Presence of psychotic symptoms * Severe or acute medical illness (e.g., major surgery, metastatic cancer, stroke, heart attack) 6 months prior to study entry * Acute suicidal or violent behavior or history of suicide attempt within the year prior to study entry * Presence of delirium, neurodegenerative dementia, Parkinson's disease, or any other central nervous system (CNS) diseases * Toxic or metabolic abnormalities on laboratory examination * Medications taken or medical illnesses present that could account for depression * Active heart failure categorized as Class III or greater according to New York Heart Association criteria * Heart attack or crescendo angina within the 3 months prior to study entry * Symptomatic cardiac arrhythmias or symptomatic, hemodynamically significant mitral or aortic valvular disease * Resting heart rate less than 50 beats per minute and a corrected QT (QTc) interval greater than 0.45 seconds * Second or third degree atrioventricular block * Systolic blood pressure greater than 180 mmHg or less than 90 mmHg and diastolic blood pressure greater than 105 mmHg or less than 50 mmHg at study entry * Treated with depot neuroleptic therapy within 6 months prior to study entry * Treated with any neuroleptic, antidepressant, anxiolytic medication (other than lorazepam), or over-the-counter CNS-active medications used for treatment of depression (e.g, St. John's Wort, kava-kava, melatonin) within 2 weeks (4 weeks for fluoxetine or monoamine-oxidase inhibitors (MAOIs)) prior to the first administration of study medication * Known allergy to citalopram or MPH or history of ineffective treatment with citalopram or MPH for current depressive episode * Requires concomitant therapy with any prescription or over-the-counter medications that have potentially dangerous interactions with either citalopram or MPH * Requires electroconvulsive therapy (ECT) or received ECT within 3 months prior to study entry * Initiated psychotherapy within 3 months prior to study entry or will be initiating or terminating psychotherapy during the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Hamilton Depression Rating Scale (HDRS) Maintained Scores at Week 16 | Maintained response measured at Week 16 | The Hamilton Depression Rating Scale (HDRS) is a 24-item depression scale and the total score is summed with a minimum score=0 and maximum score=76. There are no subscales and the higher values represent a worse outcome. Outcomes are measured and defined as follows: 1) Response will be defined as HDRS scores of 10 or less; 2) Sustained response will be defined as maintained response at week 16; 4) Remission will be defined as HDRS scores of 6 or less. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Quality of Life Assessment | Measured at Baseline and Week 16 | The Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form (Q-LES-Q-SF) is a 16 item self-administered questionnaire that captures life satisfaction over the past week. Each question is rated on a 5 point scale from 1 (Very Poor) to 5 (Very Good). The total score is reported for items 1-14. The minimum raw score on the Q-LES-Q-SF is 14, and the maximum score is 70 with higher values representing a better outcome. |
Countries
United States
Participant flow
Pre-assignment details
181 participants were enrolled in the study and 38 participants dropped out before randomization. A total of 143 participants were assigned to groups.
Participants by arm
| Arm | Count |
|---|---|
| 1 - Citalopram + Placebo Participants will take a combination of citalopram and placebo for 16 weeks
Citalopram: Citalopram dosage will be 20 to 60 mg a day. Participants will begin taking one 20-mg capsule once per day, and this dosage may be increased or decreased depending on the participant's response to the medication. Participants will continue on their assigned dosage of citalopram until treatment completion.
Placebo: Placebo pills will be taken in combination with the active pills. Participants will initially take 1 capsule twice per day, which will be increased to a maximum of 16 capsules twice per day. After Visit 11, placebo dosage will be gradually reduced over 2 weeks until participants are no longer taking any capsules. | 48 |
| 2 - Methylphenidate + Placebo Participants will take a combination of methylphenidate and placebo for 16 weeks
Methylphenidate (MPH): MPH dosage will be 5 to 40 mg a day. Participants will initially take 1 capsule twice per day, which will be increased to a maximum of 16 capsules twice per day. After Visit 11, MPH dosage will be gradually reduced over 2 weeks until participants are no longer taking any capsules.
Placebo: Placebo pills will be taken in combination with the active pills. Participants will initially take 1 capsule twice per day, which will be increased to a maximum of 16 capsules twice per day. After Visit 11, placebo dosage will be gradually reduced over 2 weeks until participants are no longer taking any capsules. | 48 |
| 3 - Methylphenidate + Citalopram Participants will take a combination of methylphenidate and citalopram for 16 weeks
Methylphenidate (MPH): MPH dosage will be 5 to 40 mg a day. Participants will initially take 1 capsule twice per day, which will be increased to a maximum of 16 capsules twice per day. After Visit 11, MPH dosage will be gradually reduced over 2 weeks until participants are no longer taking any capsules.
Citalopram: Citalopram dosage will be 20 to 60 mg a day. Participants will begin taking one 20-mg capsule once per day, and this dosage may be increased or decreased depending on the participant's response to the medication. Participants will continue on their assigned dosage of citalopram until treatment completion. | 47 |
| Total | 143 |
Baseline characteristics
| Characteristic | 1 - Citalopram + Placebo | 2 - Methylphenidate + Placebo | 3 - Methylphenidate + Citalopram | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 35 Participants | 31 Participants | 39 Participants | 105 Participants |
| Age, Categorical Between 18 and 65 years | 13 Participants | 17 Participants | 8 Participants | 38 Participants |
| Age, Continuous | 70.1 years STANDARD_DEVIATION 7.1 | 70.0 years STANDARD_DEVIATION 7.1 | 68.9 years STANDARD_DEVIATION 7.6 | 69.7 years STANDARD_DEVIATION 7.3 |
| Region of Enrollment United States | 48 participants | 48 participants | 47 participants | 143 participants |
| Sex: Female, Male Female | 31 Participants | 28 Participants | 19 Participants | 78 Participants |
| Sex: Female, Male Male | 17 Participants | 20 Participants | 28 Participants | 65 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 48 | 9 / 48 | 4 / 47 |
| serious Total, serious adverse events | 1 / 48 | 0 / 48 | 0 / 47 |
Outcome results
Primary
Hamilton Depression Rating Scale (HDRS) Maintained Scores at Week 16
The Hamilton Depression Rating Scale (HDRS) is a 24-item depression scale and the total score is summed with a minimum score=0 and maximum score=76. There are no subscales and the higher values represent a worse outcome. Outcomes are measured and defined as follows: 1) Response will be defined as HDRS scores of 10 or less; 2) Sustained response will be defined as maintained response at week 16; 4) Remission will be defined as HDRS scores of 6 or less.
Time frame: Maintained response measured at Week 16
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 1 - Citalopram + Placebo | Hamilton Depression Rating Scale (HDRS) Maintained Scores at Week 16 | 18.3 units on a scale | Standard Deviation 5.2 |
| 2 - Methylphenidate + Placebo | Hamilton Depression Rating Scale (HDRS) Maintained Scores at Week 16 | 18.7 units on a scale | Standard Deviation 5.1 |
| 3 - Methylphenidate + Citalopram | Hamilton Depression Rating Scale (HDRS) Maintained Scores at Week 16 | 19.8 units on a scale | Standard Deviation 6.3 |
Secondary
Quality of Life Assessment
The Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form (Q-LES-Q-SF) is a 16 item self-administered questionnaire that captures life satisfaction over the past week. Each question is rated on a 5 point scale from 1 (Very Poor) to 5 (Very Good). The total score is reported for items 1-14. The minimum raw score on the Q-LES-Q-SF is 14, and the maximum score is 70 with higher values representing a better outcome.
Time frame: Measured at Baseline and Week 16
Population: The overall analyzed at baseline and week 16 differs due to participant drop out.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 1 - Citalopram + Placebo | Quality of Life Assessment | Baseline | 45.50 units on a scale | Standard Deviation 7.59 |
| 1 - Citalopram + Placebo | Quality of Life Assessment | Week 16 | 54.45 units on a scale | Standard Deviation 7.54 |
| 2 - Methylphenidate + Placebo | Quality of Life Assessment | Baseline | 47.06 units on a scale | Standard Deviation 8.43 |
| 2 - Methylphenidate + Placebo | Quality of Life Assessment | Week 16 | 53.54 units on a scale | Standard Deviation 13.11 |
| 3 - Methylphenidate + Citalopram | Quality of Life Assessment | Baseline | 47.52 units on a scale | Standard Deviation 7.32 |
| 3 - Methylphenidate + Citalopram | Quality of Life Assessment | Week 16 | 57.79 units on a scale | Standard Deviation 9.19 |