Aripiprazole augmentation versus antidepressant switching for patients with major depressive disorder: A 6-week, randomized, rater-blinded,prospective study

Highlights

• Lack of direct comparison between aripiprazole augmentation and antidepressant switching.

• Aripiprazole augmentation showed better clinical outcomes than antidepressant switching.

• Tolerability was comparable between aripiprazole augmentation and switching.

• More rigorous clinical trials will be mandatory to support current findings.

Abstract

No study has directly compared the efficacy and tolerability of aripiprazole augmentation (AA) and antidepressant switching (SW) in patients with major depressive disorder (MDD). This is the first 6-week, randomized, rater-blinded, direct comparison study between AA and SW in outpatients. An inadequate response to antidepressants was defined as a total score ≥14 on the Hamilton Depression Rating Scale-item 17 (HDRS-17) despite adequate antidepressant dosage for at least 6 weeks in the current depressive episode. The primary endpoint was change in the total score of the Montgomery–Åsberg Depression Rating Scale (MADRS) from baseline to the end of treatment. Secondary efficacy measures included the response and remission rates as priori defined at the end of treatment: changes in total scores of the HDRS-17, Iowa Fatigue Scale (IFS), and Sheehan Disability Scale (SDS) from baseline to the end of treatment and the proportion of patients who scored 1 or 2 on the Clinical Global Impression-Improvement Score (CGI-I) at the end of treatment. Tolerability was assessed with the Barnes Akathisia Rating Scale (BARS) and Arizona Sexual dysfunction scale (ASEX), and the numbers of adverse events were compared between the two groups. A total of 101 patients were randomized to either AA (n = 52) or SW (n = 49). The mean change in the MADRS score from baseline was significantly higher in the AA, with a difference in magnitude of −8.7 (p < 0.0001). The intergroup difference was first evident in week 2. The numbers of responders (p = 0.0086) and remitters (p = 0.0005) were also significantly higher in the AA (60% and 54%, respectively) compared with the SW (32.6% and 19.6%, respectively). On most secondary endpoints, AA showed better clinical outcomes compared to SW. The tolerability profiles were comparable between the two groups. Overall, AA yielded potentially beneficial clinical outcomes compared to SW. Given the methodological shortcomings of the present study, adequately powered, more rigorously controlled clinical trials are strongly warranted to confirm the present findings.

Introduction

Major depressive disorder (MDD) is a chronic and devastating mental illness characterized by high lifetime and annual prevalence rates of 16% and 7%, respectively (Kessler et al., 2003). It is also associated with high morbidity and mortality and results in significant economic burdens related to personal and work productivity, high suicide rates, and substantial impairments in quality of life (Murray and Lopez, 1996a, Murray and Lopez, 1996b).

The mainstream of MDD treatment is pharmacotherapy, although there is a recognized need to improve non-pharmaceutical treatment options. While the ultimate goal of pharmacotherapy is full resolution of depressive symptoms and restoration of psychosocial and occupational functioning, only a very small percentage of patients achieve this goal (Pae et al., 2011b, Papakostas, 2009a). In this context, there have been a number of different classes of antidepressants based on different action mechanisms, and the most recently approved antidepressant, vortioxetine (September 2013) is also indicated for the treatment of MDD. However, many patients with MDD do not achieve optimal treatment outcomes (Pae et al., 2015b, Papakostas, 2010, Warden et al., 2007, Han and Pae, 2015, Wang et al., 2015, Pae, 2015).

The limited efficacies of antidepressants have been continuously reported in large randomized, placebo-controlled clinical trials (RCTs) and studies carried out in naturalistic clinical treatment settings, such as the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) (Rush et al., 2006a). The STAR*D trial reported lower remission/response rates and higher relapse rates were observed among those who required subsequent treatment levels (Rush et al., 2006a). Several meta-analyses have also consistently described the limited efficacy of antidepressants, including those with novel mechanisms (Cipriani et al., 2009, Citrome, 2012, Huang et al., 2014, Koesters et al., 2013, Pae et al., 2015b, Papakostas and Fava, 2007, Papakostas et al., 2007, Taylor et al., 2014).

For patients who fail to achieve adequate treatment outcomes with current antidepressants, additional treatment options may include diagnosis reassessment, dose increment, psychotropic augmentation, antidepressant combination (AC), and switching (SW) to different antidepressants (Patkar and Pae, 2013, Thase, 2011b). When choosing the best treatment strategy for inadequate antidepressant responders, clinicians should consider treatment efficacy and tolerability, as well as various clinical factors affecting treatment outcomes. The risk of potential loss of partial therapeutic benefit from the initial antidepressant treatment and the risk of withdrawal symptoms should both be considered when considering SW. Similarly, the potential risk of drug–drug interactions, medical cost, and compliance issues should be taken into account when considering augmentation therapy and AC (Papakostas, 2009b).

Aripiprazole was the first drug approved by the U.S. FDA in 2007 as an augmentation therapy to treat MDD (Pae et al., 2011a). The efficacy of aripiprazole augmentation (AA) was clearly shown in a number of RCTs and meta-analyses in depressed patients with inadequate responses (Berman et al., 2009, Berman et al., 2007, Kamijima et al., 2013, Marcus et al., 2008, Nelson and Papakostas, 2009b, Spielmans et al., 2013). In fact, the use of AA in MDD has dramatically increased worldwide and continues to be one of the best available augmentation options (Han et al., 2013a, Pae et al., 2014b). Meanwhile, SW is another favored next-treatment option in clinical practice when the initial antidepressant treatment achieves an inadequate response and/or the patient is intolerant; unequivocal data has shown that it is effective in the treatment of difficult-to-treat MDD patients, although large RCTs are still insufficient (Carvalho et al., 2014).

The superiority of one treatment strategy over others has not been intensely investigated in patients with MDD who do not adequately respond to current antidepressants (Connolly and Thase, 2011). The STAR*D trial did not include atypical antipsychotic augmentation option, by which it does not properly reflect contemporary practice. Therefore, the present study is the first to directly compare AA and SW in patients with MDD with inadequate responsiveness to current antidepressants.