Aripiprazole as Adjunctive Therapy for Patients with Major Depressive Disorder

Abstract

Aripiprazole was initially approved to treat schizophrenia and later approved for bipolar mania, as a monotherapy and an adjunctive therapy (manic or mixed episodes), and for irritability associated with autism. Aripiprazole is a partial agonist at dopamine D(2) and D(3) and serotonin 5-HT(1A) receptors, and is an antagonist at 5-HT(2A) receptors. This profile, and convincing preliminary data from small-scale studies, provided the rationale for the large-scale exploration of aripiprazole for unipolar depression. Recently, three 6-week, large-scale, randomized, double-blind, placebo-controlled clinical trials demonstrated clinically meaningful efficacy for aripiprazole as an adjunctive therapy to antidepressants for treating major depressive disorder (MDD). In November 2007, aripiprazole was approved by the US FDA as an adjunctive therapy to antidepressants for treating MDD, with support from two of the above-mentioned trials. In the trials, aripiprazole was demonstrated to be safe and well tolerated, and showed a minimal trend for weight gain over the course of a 6-week treatment. The incidence of akathisia was higher than that reported in studies of patients with schizophrenia; however, most cases were mild to moderate and infrequently lead to discontinuation (5/1090 from all three trials). This comprehensive review provides an overview of the data from all three 6-week studies (including a pooled analysis) and from an unpublished 52-week, open-label extension study, to inform physicians and facilitate reasonable treatment decisions. In addition, specific issues associated with the use of aripiprazole as an adjunctive therapy in patients with MDD, including possible early treatment effect, appropriate timing of therapy initiation, appropriate dosing and duration of treatment, possible differential effect on depressive subgroups and long-term tolerability, are also discussed.

Clinical Issues in Use of Atypical Antipsychotics for Depressed Patients

“…Based on placebo controlled clinical trials, aripiprazole has clearly shown efficacy as an augmentation therapy [13]. However, it is also associated with more adverse events (AEs) than antidepressant monotherapy in patients with MDD [13].…”

Evaluating The Antidepressant Efficacy of Aripiprazole Using a Chronic Mild Stress Model: An Experimental Study

“…It is also known that dopamine activity in the frontal cortical area is impaired in depression 8 . Preclinic data supports that aripiprazole may be effective in depression treatment through partial dopamine agonism and 5-HT antagonism [40][41][42][43] . In studies with animal depression models, depression was shown to be related to dopaminergic deficiency and this condition may be reversed by dopamine agonists 8 .…”

Do We Need to Consider Ethno-cultural Variation in the Use of Atypical Antipsychotics for Asian Patients with Major Depressive Disorder?

“…Therefore, the use of anticholinergic agents for MDD patients is recommended to be short term with early discontinuation, particularly for Asians with their greater vulnerability to anticholinergic AEs. In fact, the most common interventions associated with EPS resolution were dose reduction of aripiprazole (51 %) and no intervention (36 %), in registration clinical trials of aripiprazole for MDD [7].…”

“…Consideration of different pharmacodynamic profiles, including affinity on various neurotransmitters and monoamine receptors among each atypical antipsychotic (AA), should also be beneficial for controlling such florid symptoms of MDD when current antidepressants are not adequately effective, especially concerning patient clinical status [7]. According to a recent pooled analysis, quetiapine significantly reduced the symptoms of generalized anxiety disorder, with improvements beginning from week 1; quetiapine also has a favourable profile on sleep disturbance for MDD patients [8].…”