Clinical trial NCT00892047
Conditions: Depression
Keywords: Depression Aripiprazole Venlafaxine Partial Remission Augmentation strategy Treatment resistance Elderly Late-life
Sponsor: University of Pittsburgh
Start date: 2009-08-01; Completion date: 2014-09-01
Enrollment: 468 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary aims of this study are to:

1. Assess the efficacy of aripiprazole augmentation for the acute and continuation treatment of TRLLD.

   Hypothesis 1: Patients with TRLLD (defined as those who do not remit after 12 weeks of acute treatment with venlafaxine XR) will have a higher rate of remission with aripiprazole than with placebo augmentation (primary outcome) and greater improvement in depressive symptoms and stability of remission (secondary outcomes).
2. Assess the tolerability of aripiprazole in TRLLD with a focus on adiposity and akathisia/restlessness.

Hypothesis 2: Aripiprazole will be associated with a higher rate of clinically significant akathisia and increased adiposity than placebo.

The Secondary/exploratory aims of this study are to:

1. Examine anxiety, medical burden, and executive impairment as moderators of aripiprazole augmentation efficacy in TRLLD.

   Hypothesis 3: Pre-levels of anxiety symptoms, medical burden, and executive impairment will be treatment-specific factors: they will moderate the efficacy of aripiprazole augmentation. The aripiprazole-placebo difference will be greater in individuals with these variables, compared to those without these variables because these three factors will be associated with a decreased likelihood that "staying the course" with venlafaxine monotherapy will achieve remission.
2. Examine genetic predictors (phase 1) and moderators (phase 2-3) of treatment outcomes, while controlling for drug exposure.

Hypothesis 4: Selected polymorphisms will reduce remission rate with venlafaxine and will reduce efficacy and tolerability with aripiprazole.

Detailed description:
Incomplete response in the treatment of late-life depression (LLD) is a large public health challenge: at least 50% of older people fail to respond adequately to antidepressant pharmacotherapy, even under optimal treatment conditions. Treatment resistant late-life depression (TRLLD) increases risk for early relapse, undermines adherence to treatment for coexisting medical disorders, amplifies disability and cognitive impairment, imposes greater burden on family caregivers, and increases the risk for early mortality, including suicide. Getting to and sustaining remission is the primary goal of treatment, yet there is a paucity of controlled studies of how best to manage TRLLD.

This is a multi-site study being conducted by 3 sites: University of Pittsburgh, University of Toronto, and Washington University. We propose to enroll 500 subjects aged 60 and older with major depressive disorder at this site and treat them openly for 12 weeks with venlafaxine XR (up to 300mg/d) (phase 1). Participants meeting criteria for incomplete response will be randomly assigned to receive either aripiprazole (2-15 mg/d; target dose: 10 mg/d) or placebo augmentation (adding a pill without active medicine) of venlafaxine for 12 weeks (phase 2), with the goal of achieving remission (MADRS≤10 for two consecutive assessments). Those who remit in phase 2 will receive continuation treatment, with the same double-blinded intervention to which they were randomly assigned (phase 3), for 12 weeks to determine the stability of remission. Efficacy and tolerability data will provide a clinically informative estimate of benefits and risks of aripiprazole augmentation for TRLLD.

In addition to the primary goal of assessing these benefits and risks, we will develop evidence relevant to personalized treatment for LLD by testing the roles of clinical (comorbid anxiety, medical burden, and executive impairment) and genetic (selected polymorphisms in serotonin, norepinephrine, and dopamine genes) variables, while controlling for variability in drug exposure for efficacy and tolerability analyses. This approach will allow us to distinguish treatment-specific resistance factors versus general prognostic factors.

Arms: arm 1: antidepressant (venlafaxine) plus aripiprazol or venlafaxine plus placebo arm 2: antidepressant (venlafaxine) plus aripiprazol or venlafaxine plus placebo
Interventions: intervention 1: venlafaxine XR plus aripiprazole intervention 2: venlafaxine plus placebo
Intervention descriptions: intervention 1: Dosage varies. Subject remains on antidepressant throughout the 36 week study. Will be randomized to aripiprazole or placebo for up to 24 weeks. intervention 2: Dosage varies. Subject remains on antidepressant throughout the 36 week study. Will be randomized to aripiprazole or placebo for up to 24 weeks.

Protocol documents: