Geriatric Depression, Late Life Depression, Major Depressive Disorder, Treatment-Refractory Depression, Treatment Resistant Depression
Conditions
Keywords
Comparative Effectiveness Research, Pragmatic Clinical Trials, Patient-Centered Outcomes Research
Brief summary
The purpose of this research study is to assess which antidepressants work the best in older adults who have treatment-resistant depression (TRD).
Detailed description
Older adult participants with treatment-resistant depression will be randomly assigned to a Step 1 medication strategy. * Adding aripiprazole to current antidepressant medication * Adding bupropion to current antidepressant medication * Replacing current antidepressant medication with bupropion If depression is not relieved at the end of 10 weeks, or if participants do not qualify for Step 1, participants will be randomly assigned to a Step 2 medication strategy: * Adding lithium to current antidepressant medication * Replacing current antidepressant medication with nortriptyline All medication strategies will be offered in collaboration with participants' own physicians with the the research team providing support and guidance. After treatment in Step 1 and/or Step 2, participants will enter the Continuation Phase to assess long term follow-up outcomes for 12 months. Participants in this clinical trial will also be asked to participate in an additional study to gather imaging and biomarker data.
Interventions
Augment current antidepressant treatment with aripiprazole (tablets). Start at 2 mg daily; increase every two weeks (i.e., to 5, 7, 10 mg) to a maximum of 15 mg daily based on symptom severity and side effects.
Augment current antidepressant treatment with bupropion once-daily extended release, starting at 150 mg daily; titrated after four weeks to 300 mg daily based on symptom severity and side effects.
Taper from current antidepressant therapy. Start bupropion once-daily extended release at 150 mg daily; titrated after four weeks to 300 mg daily based on symptom severity and side effects.
Augment current antidepressant treatment with lithium carbonate tablets starting at 300 mg daily, titrated per blood level to 0.4-0.6 meQ/L.
Taper from current antidepressant therapy. Start on nortriptyline tablets starting at 1 mg per kg of body weight daily, titrated per blood level to 80-120 ng/ml
Sponsors
Patient-Centered Outcomes Research Institute
National Institute of Mental Health (NIMH)
Washington University School of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
60 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Men and women aged 60 and older * Current Major Depressive Disorder (MDD) * Failure to respond adequately to two or more antidepressant treatment trials of recommended dose and length * Patient Health Questionnaire-9 (PHQ-9) score of 10 or higher
Exclusion criteria
* Inability to provide informed consent * Dementia * Lifetime diagnosis of bipolar I or II disorder, schizophrenia, schizoaffective disorder, schizophreniform disorder, delusional disorder, or current psychotic symptoms * High risk for suicide and unable to be managed safely in the clinical trial * Contraindication to proposed study medications, as determined by study physician including history of intolerance or non-response to proposed medications. * Non-correctable, clinically significant sensory impairment interfering with participation * Unstable medical illness, including delirium, uncontrolled diabetes mellitus, hypertension, hyperlipidemia, or cerebrovascular or cardiovascular risk factors that are not under medical management. * Moderate to severe substance or alcohol use disorder
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Psychological Well-Being | Step 1 (10 weeks), Step 2 (10 weeks), a period of up to 20 weeks | Psychological well-being was assessed using the NIH Toolbox Psychological Wellbeing subscales of Positive Affect and General Life Satisfaction, with a T score calculated as the average of these two subscales. Higher scores indicate greater positive affect and life satisfaction. Reference T-score (mean=50, SD=10). |
| Number of Participants With Remission From Depression | Step 1 (10 weeks), Step 2 (10 weeks), a period of up to 20 weeks | Remission defined as Montgomery Asberg Depression Rating Scale score ≤10. Scale ranges from 0-60 with higher scores indicating higher depressive symptoms. |
| Serious Adverse Events | Step 1 (10 weeks), Step 2 (10 weeks), a period of up to 20 weeks | Life threatening illness, hospitalization, or need of medical care. |
Countries
Canada, United States
Participant flow
Recruitment details
Patients were recruited based on referrals from primary care providers (PCPs) or psychiatrists and self-referrals. This was further checked by using tools electronic medical records (EMRs) and using EMR-launched clinical decision tools. Print, radio, and social media advertising were used too. If patients self-referred, treatment recommendations were given by their community providers or a psychiatrist associated with the study.
Participants by arm
| Arm | Count |
|---|---|
| Aripiprazole Augmentation Augment current antidepressant treatment with aripiprazole (tablets), titrated from 2-15 mg daily based on symptom severity and side effects.
Aripiprazole Augmentation: Augment current antidepressant treatment with aripiprazole (tablets). Start at 2 mg daily; increase every two weeks (i.e., to 5, 7, 10 mg) to a maximum of 15 mg daily based on symptom severity and side effects. | 211 |
| Bupropion Augmentation Augment current antidepressant treatment with bupropion once-daily extended release, titrated from 150-300 mg daily based on symptom severity and side effects.
Bupropion Augmentation: Augment current antidepressant treatment with bupropion once-daily extended release, starting at 150 mg daily; titrated after four weeks to 300 mg daily based on symptom severity and side effects. | 206 |
| Switch to Bupropion Taper from current antidepressant therapy. Start bupropion once-daily extended, titrated from 150-300 mg daily based on symptom severity and side effects.
Switch to bupropion: Taper from current antidepressant therapy. Start bupropion once-daily extended release at 150 mg daily; titrated after four weeks to 300 mg daily based on symptom severity and side effects. | 202 |
| Lithium Augmentation Augment current antidepressant treatment with lithium carbonate tablets starting at 300 mg daily, titrated per blood level to 0.4-0.6 meQ/L.
Lithium Augmentation: Augment current antidepressant treatment with lithium carbonate tablets starting at 300 mg daily, titrated per blood level to 0.4-0.6 meQ/L. | 127 |
| Switch to Nortriptyline Taper from current antidepressant therapy. Start on nortriptyline tablets starting at 1 mg per kg of body weight daily, titrated per blood level to 80-120 ng/ml.
Switch to nortriptyline: Taper from current antidepressant therapy. Start on nortriptyline tablets starting at 1 mg per kg of body weight daily, titrated per blood level to 80-120 ng/ml | 121 |
| Total | 867 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Step 1 | Death | 1 | 1 | 1 | 0 | 0 |
| Step 1 | Investigator discretion | 1 | 0 | 1 | 0 | 0 |
| Step 1 | Lost to Follow-up | 7 | 9 | 12 | 0 | 0 |
| Step 1 | Other | 0 | 0 | 1 | 0 | 0 |
| Step 1 | Withdrawal by Subject | 10 | 8 | 13 | 0 | 0 |
| Step 2 | Investigator discretion | 0 | 0 | 0 | 0 | 1 |
| Step 2 | Lost to Follow-up | 0 | 0 | 0 | 4 | 1 |
| Step 2 | Withdrawal by Subject | 0 | 0 | 0 | 7 | 3 |
Baseline characteristics
| Characteristic | Switch to Bupropion | Aripiprazole Augmentation | Bupropion Augmentation | Total | Switch to Nortriptyline | Lithium Augmentation |
|---|---|---|---|---|---|---|
| Age, Continuous | 69.68 years STANDARD_DEVIATION 7.71 | 69.07 years STANDARD_DEVIATION 6.46 | 69.13 years STANDARD_DEVIATION 7.14 | 69.29 years STANDARD_DEVIATION 7.1 | — | — |
| Age, Customized | — | — | — | 68.55 years STANDARD_DEVIATION 5.88 | 68.03 years STANDARD_DEVIATION 5.72 | 69.04 years STANDARD_DEVIATION 6 |
| Race/Ethnicity, Customized African American | 13 Participants | 16 Participants | 17 Participants | 46 Participants | 4 Participants | 7 Participants |
| Race/Ethnicity, Customized Hispanic/Latino | 13 Participants | 22 Participants | 17 Participants | 13 Participants | 10 Participants | 3 Participants |
| Race/Ethnicity, Customized Other | 189 Participants | 189 Participants | 189 Participants | 15 Participants | 111 Participants | 124 Participants |
| Race/Ethnicity, Customized White | 175 Participants | 173 Participants | 174 Participants | 222 Participants | 106 Participants | 116 Participants |
| Sex: Female, Male Female | 127 Participants | 144 Participants | 142 Participants | 173 Participants | 83 Participants | 90 Participants |
| Sex: Female, Male Male | 75 Participants | 67 Participants | 64 Participants | 75 Participants | 38 Participants | 37 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 211 | 1 / 206 | 1 / 202 | 0 / 127 | 0 / 121 |
| other Total, other adverse events | 148 / 211 | 120 / 206 | 136 / 202 | 93 / 127 | 93 / 121 |
| serious Total, serious adverse events | 15 / 211 | 15 / 206 | 19 / 202 | 12 / 127 | 11 / 121 |
Outcome results
Primary
Number of Participants With Remission From Depression
Remission defined as Montgomery Asberg Depression Rating Scale score ≤10. Scale ranges from 0-60 with higher scores indicating higher depressive symptoms.
Time frame: Step 1 (10 weeks), Step 2 (10 weeks), a period of up to 20 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Aripiprazole Augmentation | Number of Participants With Remission From Depression | 61 Participants |
| Bupropion Augmentation | Number of Participants With Remission From Depression | 58 Participants |
| Switch to Bupropion | Number of Participants With Remission From Depression | 39 Participants |
| Lithium Augmentation | Number of Participants With Remission From Depression | 24 Participants |
| Switch to Nortriptyline | Number of Participants With Remission From Depression | 26 Participants |
p-value: 0.5generalized linear model with logistic l
p-value: 0.038generalized linear model with logistic l
p-value: 0.021generalized linear model with logistic l
p-value: 0.027generalized linear model with logistic l
p-value: 0.934generalized linear model with logistic l
p-value: 0.011generalized linear model with logistic l
Primary
Psychological Well-Being
Psychological well-being was assessed using the NIH Toolbox Psychological Wellbeing subscales of Positive Affect and General Life Satisfaction, with a T score calculated as the average of these two subscales. Higher scores indicate greater positive affect and life satisfaction. Reference T-score (mean=50, SD=10).
Time frame: Step 1 (10 weeks), Step 2 (10 weeks), a period of up to 20 weeks
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Aripiprazole Augmentation | Psychological Well-Being | 10 weeks | 38.8 t-score |
| Aripiprazole Augmentation | Psychological Well-Being | baseline | 34.7 t-score |
| Bupropion Augmentation | Psychological Well-Being | baseline | 35.0 t-score |
| Bupropion Augmentation | Psychological Well-Being | 10 weeks | 38.7 t-score |
| Switch to Bupropion | Psychological Well-Being | baseline | 34.8 t-score |
| Switch to Bupropion | Psychological Well-Being | 10 weeks | 36.1 t-score |
| Lithium Augmentation | Psychological Well-Being | baseline | 33.1 t-score |
| Lithium Augmentation | Psychological Well-Being | 10 weeks | 35.7 t-score |
| Switch to Nortriptyline | Psychological Well-Being | baseline | 34.2 t-score |
| Switch to Nortriptyline | Psychological Well-Being | 10 weeks | 35.6 t-score |
p-value: 0.01ANOVA
p-value: 0.004ANOVA
p-value: 0.017ANOVA
Comparison: Repeated measure of 2\*2\*3 ANOVA with age (60 - 70, \> 70), time (baseline, end of Active phase of Step 1) by treatment group (3 levels). Tests were conducted with a Hochberg Step-down procedure. If the comparison with the lowest p-value \< 0.05/3 it is significant. If the second lowest p-value is also \< 0.05/2 then it also will be significant and if the third p-value is \< 0.05 then it also will be significant.p-value: 0.65ANOVA
Comparison: Repeated measure of 2\*2\*3 ANOVA with age (60 - 70, \> 70), time (baseline, end of Active phase of Step 1) by treatment group (3 levels). Tests were conducted with a Hochberg Step-down procedure. If the comparison with the lowest p-value \< 0.05/3 it is significant. If the second lowest p-value is also \< 0.05/2 then it also will be significant and if the third p-value is \< 0.05 then it also will be significant.p-value: 0.003ANOVA
p-value: 0.385ANOVA
Primary
Serious Adverse Events
Life threatening illness, hospitalization, or need of medical care.
Time frame: Step 1 (10 weeks), Step 2 (10 weeks), a period of up to 20 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Aripiprazole Augmentation | Serious Adverse Events | 15 Participants |
| Bupropion Augmentation | Serious Adverse Events | 15 Participants |
| Switch to Bupropion | Serious Adverse Events | 19 Participants |
| Lithium Augmentation | Serious Adverse Events | 12 Participants |
| Switch to Nortriptyline | Serious Adverse Events | 11 Participants |
p-value: 0.103Regression, Cox
p-value: 0.164Regression, Cox
p-value: 0.127Regression, Cox
p-value: 0.524Regression, Cox