Abilify-Links To And Excerpts From The 2015 Lancet Article-Efficacy, safety, and tolerability of augmentation pharmacotherapy with aripiprazole for treatment-resistant depression in late life: a randomised, double-blind, placebo-controlled trial

In this post I link to and excerpt from Efficacy, safety, and tolerability of augmentation pharmacotherapy with aripiprazole [Abilify] for treatment-resistant depression in late life: a randomised, double-blind, placebo-controlled trial [PubMed Abstract] [Full Text HTML] [Full Text PDF].  VOLUME 386, ISSUE 10011P2404-2412, DECEMBER 12, 2015.

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Summary

Background

Treatment-resistant major depression is common and potentially life-threatening in elderly people, in whom little is known about the benefits and risks of augmentation pharmacotherapy. We aimed to assess whether aripiprazole is associated with a higher probability of remission than is placebo.

Methods

We did a randomised, double-blind, placebo-controlled trial at three centres in the USA and Canada to test the efficacy and safety of aripiprazole augmentation for adults aged older than 60 years with treatment-resistant depression (Montgomery Asberg Depression Rating Scale [MADRS] score of ≥15). Patients who did not achieve remission during a pre-trial with venlafaxine extended-release (150–300 mg/day) were randomly assigned (1:1) to the addition of aripiprazole (target dose 10 mg [maximum 15 mg] daily) daily or placebo for 12 weeks. The computer-generated randomisation was done in blocks and stratified by site. Only the database administrator and research pharmacists had knowledge of treatment assignment. The primary endpoint was remission, defined as an MADRS score of 10 or less (and at least 2 points below the score at the start of the randomised phase) at both of the final two consecutive visits, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00892047.

Findings

From July 20, 2009, to Dec 30, 2013, we recruited 468 eligible participants, 181 (39%) of whom did not remit and were randomly assigned to aripiprazole (n=91) or placebo (n=90). A greater proportion of participants in the aripiprazole group achieved remission than did those in the placebo group (40 [44%] vs 26 [29%] participants; 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]). Akathisia was the most common adverse effect of aripiprazole (reported in 24 [26%] of 91 participants on aripiprazole vs 11 [12%] of 90 on placebo). Compared with placebo, aripiprazole was also associated with more Parkinsonism (15 [17%] of 86 vs two [2%] of 81 participants), but not with treatment-emergent suicidal ideation (13 [21%] of 61 vs 19 [29%] of 65 participants) or other measured safety variables.

Interpretation

In adults aged 60 years or older who do not achieve remission from depression with a first-line antidepressant, the addition of aripiprazole is effective in achieving and sustaining remission. Tolerability concerns include the potential for akathisia and Parkinsonism.

Introduction

Major depressive disorder is common in adults aged 60 years and older, leading to disability, suicidality, and increased mortality, but can be mitigated by treatment.
Most older adults with depression receive treatment in general medical settings, and the geriatric mental health workforce projections show that most older adults with depression will continue to be treated chiefly in the primary care secto
A major problem is treatment resistance to first-line therapies: 55–81% of older adults with major depressive disorder fail to remit with a selective serotonin reuptake inhibitor (SSRI) or a serotonin–norepinephrine reuptake inhibitor (SNRI).
Yet, unlike adults aged younger than 60 years,
little evidence exists from controlled trials to guide second-line or augmentation pharmacotherapy.
Second-line treatments including mirtazapine, bupropion, and augmentation with lithium, psychostimulants, or second-generation antipsychotics, interpersonal psychotherapy, and electroconvulsive therapy, have been proposed. Of these treatments, replicated evidence in older adults support only lithium augmentation, which is often difficult to tolerate in this age group. Without evidence, clinicians cannot weigh the benefits and risks of these treatments in older adults.

Research in context

Evidence before this study

We searched PubMed and ClinicalTrials.gov for studies published or underway up until December 2014 that examined augmentation or second-line pharmacotherapy for treatment-resistant depression in older adults with the following search terms: “treatment resistance”, “depression”, “elderly”, “augmentation strategy”, “aripiprazole”, and “antidepressant”. The search also used our familiarity with the medical literature and research in progress in the specialty.

As described in two critical reviews of the topic, few trials of any kind and no well powered trials exist to provide evidence for clinicians to make well reasoned decisions about second-line treatment in the common scenario of treatment-resistant late-life depression.

Added value of this study

Our findings bridge a crucial gap by providing clinicians with evidence on the benefits and risks of augmenting antidepressant treatment with an atypical antipsychotic, aripiprazole, in older adults with depression that did not remit with a serotonin–norepinephrine reuptake inhibitor.

Implications of all of the available evidence

About half of older adults with a major depressive disorder do not remit with first-line antidepressant pharmacotherapy. Aripiprazole has a favourable risk–benefit ratio in these older adults, most of whom receive treatment in primary care or general medical settings. The number needed to treat (NNT) with aripiprazole of 6·6 (95% CI 3·5–81·8) is similar to the NNT in young adults of the two most well studied augmentation therapies: lithium (NNT=5) and atypical antipsychotics (NNT=9).

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