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. To address this gap, we propose a three-site collaborative R01 linking the Advanced Center for Interventions and Services Research at the University of Pittsburgh with centers of excellence for LLD research at the University of Toronto and at Washington University in St. Louis. A pilot study by our group of aripiprazole augmentation in 24 incomplete responders to sequential SSRI and SRNI pharmacotherapy found that 50% remitted over 12 weeks with the addition of aripiprazole. Based on these data, we hypothesize that aripiprazole augmentation will be superior to placebo for bringing about and sustaining remission in elderly patients who respond incompletely to venlafaxine XR. We propose to enroll 500 patients aged 60 and older with major depressive disorder at the three sites and treat them openly for 12 weeks with venlafaxine XR (up to 225 mg/d) (phase 1). Participants meeting criteria for incomplete response (N=200) will be randomly assigned to receive either aripiprazole (2.5-15 mg/d;target dose: 10 mg/d) or placebo augmentation 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 (N=80) 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. Based on efficacy and tolerability data, we will estimate number needed to treat and number needed to harm, providing 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 advancing 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.] This is the A1 resubmission of R01 MH083660. Late-life depression is an extremely common illness;with the changing demographics in the U.S. and other developed nations its public health importance will continue to increase. At least 50% of elderly persons with depression will fail to respond to first-line treatments;such individuals are at increased risk not only for continued suffering but also increased disability, mortality, recurrence of depression, complication of medical issues, and caregiver burden. Thus, treatment-resistant late-life depression (TRLLD) is a significant public health problem. There are is no evidence-based pharmacotherapy for TRLLD;thus, this study seeks to address a major gap in the evidence base for treating depression.

Public Health Relevance

Late-life depression is an extremely common illness;with the changing demographics in the U.S. and other developed nations its public health importance will continue to increase. At least 50% of elderly persons with depression will fail to respond to first-line treatments;such individuals are at increased risk not only for continued suffering but also increased disability, mortality, recurrence of depression, complication of medical issues, and caregiver burden. Thus, treatment-resistant late-life depression (TRLLD) is a significant public health problem. There are is no evidence-based pharmacotherapy for TRLLD;thus, this study seeks to address a major gap in the evidence base for treating depression.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH083648-04
Application #
8284460
Study Section
Special Emphasis Panel (ZMH1-ERB-P (01))
Program Officer
Evans, Jovier D
Project Start
2009-07-23
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$397,784
Indirect Cost
$136,084
Name
Washington University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Hsu, Jonathan H; Mulsant, Benoit H; Lenze, Eric J et al. (2016) Impact of Prior Treatment on Remission of Late-Life Depression with Venlafaxine and Subsequent Aripiprazole or Placebo Augmentation. Am J Geriatr Psychiatry 24:918-22
Smagula, Stephen F; Wallace, Meredith L; Anderson, Stewart J et al. (2016) Combining moderators to identify clinical profiles of patients who will, and will not, benefit from aripiprazole augmentation for treatment resistant late-life major depressive disorder. J Psychiatr Res 81:112-8
Lenze, Eric J; Farber, Nuri B; Kharasch, Evan et al. (2016) Ninety-six hour ketamine infusion with co-administered clonidine for treatment-resistant depression: A pilot randomised controlled trial. World J Biol Psychiatry 17:230-8
Cristancho, Pilar; O'Connor, Brendan; Lenze, Eric J et al. (2016) Treatment Emergent Suicidal Ideation in depressed older adults. Int J Geriatr Psychiatry :
Lenze, Eric J; Ramsey, Alex; Brown, Patrick J et al. (2016) Older Adults' Perspectives on Clinical Research: A Focus Group and Survey Study. Am J Geriatr Psychiatry 24:893-902
Kaneriya, Shriya H; Robbins-Welty, Gregg A; Smagula, Stephen F et al. (2016) Predictors and Moderators of Remission With Aripiprazole Augmentation in Treatment-Resistant Late-Life Depression: An Analysis of the IRL-GRey Randomized Clinical Trial. JAMA Psychiatry 73:329-36
Lenze, Eric J; Mulsant, Benoit H; Blumberger, Daniel M et al. (2015) Efficacy, safety, and tolerability of augmentation pharmacotherapy with aripiprazole for treatment-resistant depression in late life: a randomised, double-blind, placebo-controlled trial. Lancet 386:2404-12
Hall, Charles A; Simon, Kevin M; Lenze, Eric J et al. (2015) Depression Remission Rates Among Older Black and White Adults: Analyses From the IRL-GREY Trial. Psychiatr Serv 66:1303-11
Smagula, Stephen F; Butters, Meryl A; Anderson, Stewart J et al. (2015) Antidepressant Response Trajectories and Associated Clinical Prognostic Factors Among Older Adults. JAMA Psychiatry 72:1021-8
Garfield, Lauren D; Müller, Daniel J; Kennedy, James L et al. (2014) Genetic variation in the serotonin transporter and HTR1B receptor predicts reduced bone formation during serotonin reuptake inhibitor treatment in older adults. World J Biol Psychiatry 15:404-10

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