Incomplete Response in Late Life Depression: Getting to Remission (IRL GREY)

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.