Efficacy, safety, and tolerability of augmentation pharmacotherapy with aripiprazole for treatment-resistant depression in late life: a randomised, double-blind, placebo-controlled trial

Abstract

Summary Background Treatment-resistant major depressive disorder is common and potentially life-threatening in older persons, in whom little is known about the benefits and risks of augmentation pharmacotherapy. Methods We conducted a multi-site, placebo-controlled, randomized clinical trial to test the efficacy and safety of aripiprazole augmentation for older adults with treatment-resistant depression. We treated 468 participants aged 60 and older with current major depressive episode with venlafaxine extended-release (ER); 96 (20.5%) did not complete this open phase, 191 (40.8%) remitted, and 181 (38.7%) did not remit and were randomized to 12 weeks of double-blind augmentation with aripiprazole or placebo. The computer-generated randomization was done in blocks and stratified by site. The primary endpoint was remission, defined as Montgomery-Asberg Depression Rating Scale scores ≤10 (and at least two points below the score at the start of the randomized phase) at both of the final two consecutive visits. We also assessed resolution of suicidal ideation, and safety and tolerability with cardiometabolic and neurological measures. Analyses were conducted according to the intention-to-treat principle. This trial is registered with ClinicalTrials.gov, number NCT00892047. Findings Older adults on aripiprazole had a higher remission rate than those on placebo (44% versus 29%; odds ratio [OR]=2.0, 95% CI 1.1–3.7, p=0.03; number needed to treat [NNT]=6.6 [95% CI 3.5–81.8]). Overall, remission was stable during 12 additional weeks of continuation treatment. The resolution of suicidal ideation was more marked with aripiprazole than with placebo. Akathisia was the most common adverse effect (27% of participants on aripiprazole). Compared to placebo, aripiprazole was also associated with more Parkinsonism but not with treatment-emergent suicidal ideation, QTc prolongation, or increases in adiposity, glucose, insulin, or lipids. Interpretation In older adults who fail to achieve remission from depression with a first-line antidepressant, the addition of aripiprazole is effective in achieving and sustaining remission. Tolerability concerns include potential for akathisia and Parkinsonism. Funding National Institute of Mental Health, UPMC Endowment in Geriatric Psychiatry, Taylor Family Institute for Innovative Psychiatric Research, National Center for Advancing Translational Sciences, and the Campbell Family Mental Health Research Institute.

Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder

“…Serious adverse events were reported in 4% of patients on aripiprazole and 2% on placebo, with 6% discontinuation on aripiprazole and 9% with placebo. 136 An RCT (N ¼ 338) of older adults (aged 65þ years) with MDD found that quetiapine XR monotherapy (median dose 158.7 mg) demonstrated efficacy versus placebo in depression scores, response, and remission rates. 137 However, subgroup analysis of participants aged 75þ years demonstrated only a trend-level significance for depression score reduction (P ¼ 0.068).…”

Trajectories of suicidal ideation in depressed older adults undergoing antidepressant treatment

“…We analyzed data from participants in the IRL-GRey study (Lenze et al 2015), a clinical trial conducted at three academic sites (the University of Pittsburgh, the Centre for Addiction and Mental Health/University of Toronto, and Washington University). Data were collected between 7/2009 and 12/2014.…”

“…Exclusion criteria included inability to provide informed consent; dementia; lifetime diagnosis of bipolar I or II disorder, schizophrenia, schizoaffective disorder, schizophreniform disorder, delusional disorder, or current psychotic symptoms, as diagnosed by the SCID; abuse of or dependence on alcohol or other substances within the past 3 months; unstable physical illness; high risk for suicide (e.g., active suicidal ideation or current/recent intent or plan) that could not be managed safely in the clinical trial (e.g., unwillingness to be hospitalized); contraindication to venlafaxine XR or aripiprazole; failure to respond to at least 6 weeks of venlafaxine (≥ 225 mg/d) plus aripiprazole (≥ 10 mg/d). Failure to respond to aripiprapazole was an exclusion since later phases of the trial involved randomization to aripiprazole or to placebo (see Lenze et al 2015). …”

“…We analyzed data from an NIMH-sponsored clinical trial: “Incomplete Response in Late Life Depression: Getting to Remission” (IRL-GRey; Lenze et al 2015). The primary aim of this study was to characterize the trajectories of change in suicidal ideation over time in individuals being treated for depression.…”

The effects of white matter disease on the accuracy of automated segmentation

“…The subjects participated in a five-year multi-site study of treatment of Late Life Depression (LLD) with an imaging component added to the Pittsburgh site (Lenze et al, 2015). The University of Pittsburgh IRB approved this study.…”