VA Augmentation and Switching Treatments for Improving Depression Outcomes (VAST-D)

• Relapse in symptoms of major depression [ Time Frame: During acute phase (up to 12 weeks) and continuation phase (from 12 weeks up to 36 weeks) ] [ Designated as safety issue: No ]
  Relapse in symptoms of major depression defined as a QIDS-C16 > 11 after remission.
• Response in symptoms of major depression [ Time Frame: During acute phase (up to 12 weeks) and continuation phase (from 12 weeks up to 36 weeks) ] [ Designated as safety issue: No ]
  Response in symptoms of major depression defined as a reduction in QIDS-C16 of 50% or greater.
• Onset or cessation of akathisia [ Time Frame: During acute phase (up to 12 weeks) and continuation phase (from 12 weeks up to 36 weeks) ] [ Designated as safety issue: No ]
  Onset or cessation of akathisia, or change in symptom proclivity to as measured by the Barnes Akathisia Scale (Barnes 1989).
• Onset or cessation of anxiety [ Time Frame: During acute phase (up to 12 weeks) and continuation phase (from 12 weeks up to 36 weeks) ] [ Designated as safety issue: No ]
  Anxiety will be assessed by Beck Anxiety Inventory (BAI) (Beck, Epstein et al. 1988).
• Onset or cessation of suicide ideation [ Time Frame: During acute phase (up to 12 weeks) and continuation phase (from 12 weeks up to 36 weeks) ] [ Designated as safety issue: Yes ]
  Suicide ideation and behaviors will be assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS).
• Change in Clinical Global Impression Scale [ Time Frame: During acute phase (up to 12 weeks) and continuation phase (from 12 weeks up to 36 weeks) ] [ Designated as safety issue: No ]
  Clinical assessment of a participant's level of depression and treatment response assessed by the Clinical Global Impression - Severity (CGI -S) Scale, a 7-point clinician rating scale of the severity of depression and the Clinical Global Impression - Improvement (CGI -I) Scale, a 7-point clinician rating scale of improvement from baseline in severity of depression (Guy 1976).
• Emergence of adverse experiences [ Time Frame: During acute phase (up to 12 weeks) and continuation phase (from 12 weeks up to 36 weeks) ] [ Designated as safety issue: Yes ]
  Side effects, tolerability and discontinuation of medications will be assessed by the patient-rated Frequency and Intensity of Side Effects Rating/Global Rating of Side-Effect Burden (FIBSER) (Wisniewski, Rush et al. 2006) and by recording the occurrence of commonly reported side effects of antidepressant and atypical -psychotic medications, and the occurrence of serious or unexpected adverse experiences.
• Cost and Cost-Effectiveness [ Time Frame: During acute phase (up to 12 weeks) and continuation phase (from 12 weeks up to 36 weeks) ] [ Designated as safety issue: No ]
  Costs will be assessed by costs of care and health care utilization, and cost-effectiveness assessed by the ratio of costs to quality-adjusted life years.

• Relapse in symptoms of major depression [ Time Frame: During acute phase (up to 12 weeks) and continuation phase (from 12 weeks up to 36 weeks) ] [ Designated as safety issue: No ]
  Relapse in symptoms of major depression defined as a QIDS-C16 > 11 after remission.
• Response in symptoms of major depression [ Time Frame: During acute phase (up to 12 weeks) and continuation phase (from 12 weeks up to 36 weeks) ] [ Designated as safety issue: No ]
  Response in symptoms of major depression defined as a reduction in QIDS-C16 of 50% or greater
• Onset or cessation of akathisia [ Time Frame: During acute phase (up to 12 weeks) and continuation phase (from 12 weeks up to 36 weeks) ] [ Designated as safety issue: No ]
  Onset or cessation of akathisia, or change in symptom proclivity to as measured by the Barnes Akathisia Scale (Barnes 1989)
• Onset or cessation of anxiety [ Time Frame: During acute phase (up to 12 weeks) and continuation phase (from 12 weeks up to 36 weeks) ] [ Designated as safety issue: No ]
  Anxiety will be assessed by Beck Anxiety Inventory (BAI) (Beck, Epstein et al. 1988)
• Onset or cessation of suicide ideation [ Time Frame: During acute phase (up to 12 weeks) and continuation phase (from 12 weeks up to 36 weeks) ] [ Designated as safety issue: Yes ]
  Suicide ideation and behaviors will be assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS)
• Change in Clinical Global Impression Scale [ Time Frame: During acute phase (up to 12 weeks) and continuation phase (from 12 weeks up to 36 weeks) ] [ Designated as safety issue: No ]
  Clinical assessment of a participant's level of depression and treatment response assessed by the Clinical Global Impression - Severity (CGI -S) Scale, a 7-point clinician rating scale of the severity of depression and the Clinical Global Impression - Improvement (CGI -I) Scale, a 7-point clinician rating scale of improvement from baseline in severity of depression (Guy 1976).
• Emergence of adverse experiences [ Time Frame: During acute phase (up to 12 weeks) and continuation phase (from 12 weeks up to 36 weeks) ] [ Designated as safety issue: Yes ]
  Side effects, tolerability and discontinuation of medications will be assessed by the patient-rated Frequency and Intensity of Side Effects Rating/Global Rating of Side-Effect Burden (FIBSER) (Wisniewski, Rush et al. 2006) and by recording the occurrence of commonly reported side effects of antidepressant and atypical -psychotic medications, and the occurrence of serious or unexpected adverse experiences.
• Cost and Cost-Effectiveness [ Time Frame: During acute phase (up to 12 weeks) and continuation phase (from 12 weeks up to 36 weeks) ] [ Designated as safety issue: No ]
  Costs will be assessed by costs of care and health care utilization; and cost-effectiveness assessed by the ratio of costs to quality-adjusted life years.

The overall purpose is to determine research based 'next-steps' for outpatients with major depressive disorder who have not had satisfactory outcomes to standard 'first-step' treatments. The primary objective is to compare the acute (up to 12 weeks) treatment effectiveness of augmenting an antidepressant with aripiprazole or with bupropion-SR vs. switching treatment to bupropion-SR monotherapy on symptom remission in Veterans with Major Depressive Disorder (MDD) who have not achieved optimal response after an adequate trial on antidepressant (SSRI or SNRI) monotherapy. The secondary objectives are to compare the acute (up to 12 weeks) and long term (up to 36 weeks) efficacy, safety, effects on functioning, suicidality, quality of life, anxiety and other associated symptoms, costs and cost-effectiveness of each of the three treatments.

The overall aim of VAST-D is to enhance treatment outcomes for representative outpatients diagnosed with nonpsychotic major depressive disorder (MDD) and treated in primary or psychiatric VA care settings. In particular, VAST-D is designed to determine the comparative effectiveness of different treatment options for participants with MDD who fail to have a satisfactory outcome to treatment with their initial antidepressants.

These options may be conceptualized as representing two overall treatment strategies: 1) Medication Switch - switching from the initial antidepressant to another antidepressant medication, specifically bupropion-SR and 2) Medication Augmentation - augmenting the initial antidepressant with a second antidepressant, specifically bupropion-SR or a second generation antipsychotic, specifically aripiprazole. VAST-D's primary goal is to determine which of these 3 treatment strategies is most likely to lead to remission. Other key objectives include comparisons of response, time to remission, time to response, relapse, anxiety symptoms, suicidal ideation and behaviors, side effects, tolerability, quality of life, health related costs and satisfaction with participation in the study.

VAST-D will enroll 1518 total patients of both genders and all ethnic/racial and socioeconomic backgrounds. All patients will meet DSM-IV-TR criteria for nonpsychotic MDD. The diagnostic criteria for eligibility will be established by clinical interview supplemented with the 9-item Patient Health Questionnaire (PHQ-9). Final determination for eligibility will be made by the study clinician. Only participants with a suboptimal outcome to a well documented, adequately delivered (dose and duration), trial with selective serotonin reuptake inhibitor (SSRI) or a serotonin and norepinephrine reuptake inhibitor (SNRI) will be eligible for the study. Failure to achieve an adequate outcome will be ascertained by a QIDS-C16 >= 16 (considered severe depression) after at least 6 weeks of treatment or >= 11 (considered moderately severe depression) after at least 8 weeks of treatment. Otherwise, the inclusion criteria are broad and the exclusion criteria are few; participants with most comorbid general medical or psychiatric disorders are generally included to provide a broadly representative sample.

Participants will be randomized (1:1:1 ratio) to switch to bupropion-SR alone (n=506), current antidepressant plus bupropion-SR (n=506), or current antidepressant plus aripiprazole (n=506). Treatment will be guided by clinician-rated symptom measures (the PHQ-9) and global side effects measures (the Frequency, Intensity, and Burden of Side Effects Rating or FIBSER) obtained at each treatment visit. Acute treatment visits will occur at baseline and at weeks 1, 2, 4, 6, 8, 10, and 12 to ensure delivery of appropriate and yet vigorous and tolerable pharmacotherapy. Participants who tolerate the acute treatment and achieve adequate response at 12 weeks will enter the 24-week Continuation Treatment phase, during which the initial treatment will continue and visits will occur every four weeks subsequently until patients have been followed for 36 weeks post-randomization. The QIDS-C16 will be administered at baseline and at each follow-up visit by an independent evaluator (who will be blinded to treatment assignment) to measure symptoms of depression for the study outcomes of remission, response and relapse. Neither the participant nor the treating clinician will be blinded to treatment.

Primary hypotheses:

Primary hypothesis 1.a: Remission rate from major depressive disorder will be higher in patients whose treatment is augmented with bupropion-SR (antidepressant + bupropion-SR) compared to those switched to bupropion-SR monotherapy.

Primary Hypothesis 1.b: Remission rate from major depressive disorder will be higher in patients whose treatment is augmented with aripiprazole (antidepressant + aripiprazole) compared to those switched to bupropion-SR monotherapy.

Secondary hypotheses:

Secondary Hypothesis 2.a: Remission rate will be greater in patients whose treatment is augmented with bupropion-SR (antidepressant + bupropion-SR) than in those augmented with aripiprazole (antidepressant + aripiprazole).

Secondary Hypothesis 2.b: Relapse rate (within 36 weeks of the initiation of treatment) will be lower in patients whose antidepressant is augmented with bupropion-SR (antidepressant + bupropion-SR) than in those whose antidepressant is switched to bupropion-SR monotherapy.

Secondary Hypothesis 2.c: Relapse rate (within 36 weeks of the initiation of treatment) will be lower in patients whose treatment is augmented with aripiprazole (antidepressant + aripiprazole) vs. those switched to bupropion-SR monotherapy.

Secondary Hypothesis 2.d: Relapse rate after 12 weeks (or after 2 consecutive visits in remission) will be lower in patients whose treatment is augmented with bupropion-SR (antidepressant + bupropion-SR) than in patients whose treatment was augmented with aripiprazole (antidepressant + aripiprazole).

Secondary Hypothesis 2.e: The proportion of patients who develop akathisia, other akathisia-like side effects (e.g., tremor, irritability, motor restlessness) and extrapyramidal side effects will be greater in the patients whose antidepressant treatment is augmented with aripiprazole (antidepressant + aripiprazole) compared to patients whose treatment is augmented with bupropion-SR (antidepressant + bupropion-SR), or switched to bupropion-SR monotherapy.

Secondary Hypothesis 2.f: The relative costs (direct and indirect) of augmenting an antidepressant with aripiprazole (antidepressant + aripiprazole) will be greater than the costs of antidepressant augmentation with bupropion-SR (antidepressant + bupropion-SR), and the costs of antidepressant augmentation with bupropion-SR (antidepressant + bupropion-SR) will be greater than the costs of switching to bupropion-SR monotherapy, and augmentation and monotherapy with bupropion-SR will be more cost-effective than aripiprazole augmentation.

• Drug: Augmenting: Antidepressant + Aripiprazole

  Current antidepressant (either a SSRI or SNRI): Continue the dose prescribed at time of enrollment or adjust depending on response or side effect profile for up to 36 weeks.

  And

  Aripiprazole (Dose: 2 mg - 15 mg taken orally once per day for up to 36 weeks): Initiating with aripiprazole dose of 2 mg for one week, then increasing dose per protocol up to 15 mg, maintaining or decreasing dose for up to 36 weeks depending on response and side effect profile through the acute and continuation phases.

• Drug: Augmenting: Antidepressant + Bupropion-SR

  Current antidepressant (either a SSRI or SNRI): Continue the dose prescribed at time of enrollment, or adjust depending on response or side effect profile for up to 36 weeks.

  And

  Bupropion-SR (Dose: 150 mg - 400 mg taken once a day orally for up to 36 weeks): Initiating with bupropion-SR dose of 150 mg, then increasing dose per protocol up to 400 mg, maintaining or decreasing dose for up to 36 weeks depending on response and side effect profile through the acute and continuation phases.

• Drug: Switching: Bupropion-SR
  Bupropion-SR (Dose: 150 mg - 400 mg taken once a day orally for up to 36 weeks): Initiating with bupropion-SR dose of 150 mg, then increasing dose per protocol up to 400 mg, maintaining or decreasing dose for up to 36 weeks depending on response and side effect profile through the acute and continuation phases.

• Active Comparator: Arm 1
  Augmenting: Antidepressant + Aripiprazole
  Intervention: Drug: Augmenting: Antidepressant + Aripiprazole
• Active Comparator: Arm 2
  Augmenting: Antidepressant + Bupropion-SR
  Intervention: Drug: Augmenting: Antidepressant + Bupropion-SR
• Active Comparator: Arm 3
  Switching: Bupropion-SR
  Intervention: Drug: Switching: Bupropion-SR

Inclusion Criteria:

1. DSM-IV diagnosis of single or recurrent, non-psychotic, major depressive disorder
2. Currently taking a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) for major depressive disorder
3. Need for "next-step" treatment based on documented suboptimal outcome from current antidepressant treatment for major depressive episode (at least 6 weeks treatment with a QIDS-C16 >= 16 or at least 8 weeks with a QIDS-C16 >= 11; and at least 3 weeks at a stable "optimal" dose
4. Age: 18 years of age or older

Exclusion Criteria:

1. Prior inadequate response or clear cut intolerance to the study medications (aripiprazole or bupropion)
2. Current treatment with aripiprazole or any other antipsychotic agent or bupropion
3. Lifetime history of bipolar disorder, schizophrenia, schizoaffective disorder, or psychosis not otherwise specified
4. Current diagnosis of Dementia
5. Current diagnosis of an eating disorder or a seizure disorder
6. High suicide risk currently requiring acute intervention (other than outpatient treatment of depression)
7. Unstable, serious medical condition or one requiring acute medical treatment, or anticipation of hospitalization for extended care
8. Requiring immediate hospitalization for psychiatric disorders
9. Physiologic substance dependence requiring detoxification (excluding nicotine) in the past 30 days (substance abuse is not an exclusion criteria)
10. Taking any concomitant medication that contraindicates any of treatment options
11. Concurrent or recent participation (within the last 30 days) in another clinical trial with an investigational drug
12. Female - pregnant or lactating or planning to become pregnant
13. Not able or not willing to provide informed consent.