Depression
Conditions
Keywords
Major Depressive Disorder, MDD
Brief summary
The primary study comparing effectiveness for suicidal ideation and/or behavior of two antidepressant medications in depressed patients who have attempted suicide or are currently experiencing suicidal thoughts has been completed. A secondary study component using functional magnetic resonance imaging (fMRI) to investigate different medication effects on reward processing in the same sample is ongoing.
Detailed description
Major depressive disorder (MDD) is a common and serious psychiatric illness. It is among the leading causes of disability and is the psychiatric disorder most often associated with suicide. The treatment of MDD with antidepressant medication remains largely trial and error. Little empirical evidence exists to guide the treatment of MDD when suicide risk is a major factor. Selective serotonin reuptake inhibitors (SSRIs) are a type of antidepressant medication that works by increasing the amount of serotonin, a natural substance in the brain that helps maintain mental balance. The study compared the effectiveness of paroxetine, an SSRI, versus bupropion, a non-SSRI, on suicidal ideation and/or behavior in depressed patients with a past suicide attempt and/or current suicidal thoughts. Results of the completed primary study have been published (Grunebaum MF et al. Neuropsychopharmacology. 2012 Feb;37(3):697-706). In the ongoing secondary neuro-imaging component of the study, Participants are randomly assigned to either paroxetine or bupropion treatment for 8 weeks with fMRI scans involving a reward processing task at baseline and Week 8. Weekly study visits include interviews with a psychologist, self-report scales, and medication monitoring. All participants will then be offered 4 additional months of open clinical treatment. If original medication assignments prove to be ineffective, participants will have the option to switch to another medication. After completing the study, participants will be referred for ongoing treatment.
Interventions
DRUGParoxetine
Dosage will be 25 mg every day for 2 weeks, then 37.5 mg every day for 2 weeks, and then optional increase to 50 mg every day for the remainder of treatment.
DRUGBupropion
Dosage will be 150 mg every day for 2 weeks, then 300 mg every day for 2 weeks, and then optional increase to 450 mg every day for the remainder of treatment.
Sponsors
National Institute of Mental Health (NIMH)
New York State Psychiatric Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Currently suffering from a major depressive episode (unipolar only) * History of a past suicide attempt or score greater than 2 on the Hamilton Depression Rating Scale (HDRS) item #3 (suicide) at in-person screening interview. Patients with suicidal plan or intent will only be enrolled as inpatients if independent inpatient treatment team agrees. * Patients 60 years of age and older must score at least 25 on MMSE at screening. * Patients 60 years of age and older must have a normal ECG within the past year.
Exclusion criteria
* Any of the following conditions: bipolar disorder; current psychotic symptoms; bulimia or anorexia that is current or within the past year, or current purging at least twice a week for three months; already taking selective serotonin reuptake inhibitors (SSRIs) or bupropion for other indications (such as anxiety disorders) * Primary disorder is an anxiety disorder (e.g., panic disorder, general anxiety disorder, obsessive compulsive disorder, social anxiety disorder), with secondary depression * Drug or alcohol dependence within 6 months prior to study entry (current drug or alcohol abuse may be permitted if study officials determine that the abuse is of lesser importance than the major depressive episode) * Systolic blood pressure greater than or equal to 140 mm Hg or diastolic blood pressure greater than or equal to 90 mm Hg * Significant active physical illness, particularly those that may affect the brain or serotonergic system (e.g., blood dyscrasias lymphomas, hypersplenism, endocrinopathies, kidney failure, severe chronic obstructive lung disease, autonomic neuropathies, active malignancy) * Active medical problems * Requires antipsychotic medication * History of hypomania or mania while taking antidepressants * Any condition that may make the use of an SSRI or bupropion medically inadvisable * Currently using Zyban * Failure to respond to adequate trials of three SSRIs, paroxetine, or bupropion within 2 years prior to study entry (failure to respond to therapeutic trial defined as at least 2/3 maximal daily dose \[PDR\] for at least 6 weeks) * Pregnant, breastfeeding, or plans to become pregnant during the course of study participation * Currently on effective treatment, requires adjunctive antipsychotic or mood stabilizing medication, or is unlikely to respond to single agent treatment for depression * Patients with ferrous metal implants in their bodies, or a history of claustrophobia that precludes MRI, will be excluded. * Patients assessed as being unlikely to tolerate the maximum 2-week delay to start of treatment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Go-No go Test | Measured at Baseline and Week 8 | Change in neuropsychological measure of impulsivity. Computer-based task involving induction of a dominant response tendency and testing of the subject's ability to withhold responding to less frequent non-target stimuli. |
| Scale for Suicidal Ideation | Baseline and Week 8 | The clinician-rated Beck Scale for Suicidal Ideation (SSI) (Beck et al 1979)was used weekly for 8 weeks. It has 19 items scaled 0 (least severe) to 2 (most severe) and total score is the sum, ranging 0 to 38 (Beck et al 1979). Items measure frequency, intensity, and attitudes toward suicidal thoughts, feelings of control over them, and suicide plans. Mean score in 90 inpatients hospitalized for suicidal ideation was 9.4±8.4, versus 4.4±5.8 in outpatients as cited in the study by Beck et al, 1979. |
| Occurrence of Suicidal Ideation or Acts Necessitating a Change in Treatment | Measured at Month 6 | Suicide attempts, other suicidal behavior, or increase in suicidal thoughts that required a change in clinical treatment. |
| Brain Activity Measured by BOLD Signal With fMRI During a Reward Processing Task. | Baseline and Week 8. | Comparison of fMRI results at baseline and after 8 weeks of antidepressant pharmacotherapy with paroxetine vs. bupropion. Percent change in contrast of parameter estimates (COPE). COPE is measured during Monetary Incentive Delay Task. Task conditions are: Reward=BOLD signal when subject wins 5 cents vs. wins 0 cents Punishment=BOLD signal when subject loses 5 cents vs. loses 0 cents |
Countries
United States
Participant flow
Recruitment details
Recruitment dates were 2/2005-7/2009 with follow-up completed in January 2010.
Pre-assignment details
N=101 subjects enrolled, but N=23 did not return after enrollment, so N=78 were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Paroxetine Participants will receive paroxetine for 8 weeks | 36 |
| Bupropion Participants will receive bupropion for 8 weeks | 38 |
| Total | 74 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Ineligibility discovered after entry | 2 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 |
Baseline characteristics
| Characteristic | Bupropion | Paroxetine | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 38 Participants | 36 Participants | 74 Participants |
| Age, Continuous | 37.9 years STANDARD_DEVIATION 11.9 | 35.2 years STANDARD_DEVIATION 12.8 | 36.4 years STANDARD_DEVIATION 12.7 |
| Region of Enrollment United States | 38 participants | 36 participants | 74 participants |
| Sex: Female, Male Female | 21 Participants | 21 Participants | 42 Participants |
| Sex: Female, Male Male | 17 Participants | 15 Participants | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 36 | 0 / 38 |
| serious Total, serious adverse events | 3 / 36 | 2 / 38 |
Outcome results
Primary
Brain Activity Measured by BOLD Signal With fMRI During a Reward Processing Task.
Comparison of fMRI results at baseline and after 8 weeks of antidepressant pharmacotherapy with paroxetine vs. bupropion. Percent change in contrast of parameter estimates (COPE). COPE is measured during Monetary Incentive Delay Task. Task conditions are: Reward=BOLD signal when subject wins 5 cents vs. wins 0 cents Punishment=BOLD signal when subject loses 5 cents vs. loses 0 cents
Time frame: Baseline and Week 8.
Population: Major depressive disorder with suicidal thoughts or past suicide attempt.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Paroxetine | Brain Activity Measured by BOLD Signal With fMRI During a Reward Processing Task. | -0.27 percentage of change in COPE |
| Bupropion | Brain Activity Measured by BOLD Signal With fMRI During a Reward Processing Task. | -0.95 percentage of change in COPE |
Primary
Go-No go Test
Change in neuropsychological measure of impulsivity. Computer-based task involving induction of a dominant response tendency and testing of the subject's ability to withhold responding to less frequent non-target stimuli.
Time frame: Measured at Baseline and Week 8
Population: These were the number with analyzable data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Paroxetine | Go-No go Test | -0.09 Commission errors | Standard Deviation 0.8 |
| Bupropion | Go-No go Test | -0.06 Commission errors | Standard Deviation 0.89 |
Primary
Occurrence of Suicidal Ideation or Acts Necessitating a Change in Treatment
Suicide attempts, other suicidal behavior, or increase in suicidal thoughts that required a change in clinical treatment.
Time frame: Measured at Month 6
Population: These were the number of subjects with analyzable data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Paroxetine | Occurrence of Suicidal Ideation or Acts Necessitating a Change in Treatment | 4 Events |
| Bupropion | Occurrence of Suicidal Ideation or Acts Necessitating a Change in Treatment | 6 Events |
Primary
Scale for Suicidal Ideation
The clinician-rated Beck Scale for Suicidal Ideation (SSI) (Beck et al 1979)was used weekly for 8 weeks. It has 19 items scaled 0 (least severe) to 2 (most severe) and total score is the sum, ranging 0 to 38 (Beck et al 1979). Items measure frequency, intensity, and attitudes toward suicidal thoughts, feelings of control over them, and suicide plans. Mean score in 90 inpatients hospitalized for suicidal ideation was 9.4±8.4, versus 4.4±5.8 in outpatients as cited in the study by Beck et al, 1979.
Time frame: Baseline and Week 8
Population: The study was powered for N=50 subjects per group based on naturalistic pilot data from our clinic. An interim data analysis showed an interaction of treatment with baseline suicidal ideation severity on follow-up ideation. After consulting with clinical colleagues, statisticians and the IRB, a decision was made to stop enrollment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Paroxetine | Scale for Suicidal Ideation | Baseline | 8.0 Points on Scale for Suicidal Ideation | Standard Deviation 6.7 |
| Paroxetine | Scale for Suicidal Ideation | Week 8 | 2.3 Points on Scale for Suicidal Ideation | Standard Deviation 4.5 |
| Bupropion | Scale for Suicidal Ideation | Baseline | 9.9 Points on Scale for Suicidal Ideation | Standard Deviation 7.4 |
| Bupropion | Scale for Suicidal Ideation | Week 8 | 4.7 Points on Scale for Suicidal Ideation | Standard Deviation 6.6 |
Comparison: Generalized least squares model of Scale for Suicidal Ideation score during 8-week acute treatment of major depressive disorder.p-value: 0.0395% CI: [-0.57, -0.023]Mixed Models Analysis