Aripiprazole for Depression
Aripiprazole (Abilify) is FDA-approved as adjunctive therapy for major depressive disorder in adults who have not responded adequately to standard antidepressant monotherapy after 6-8 weeks of treatment. 1, 2
Role and Positioning in Treatment Algorithm
Aripiprazole should be used as a second-step augmentation strategy, not as first-line monotherapy for depression. 1 The treatment sequence follows this approach:
- Start with second-generation antidepressant monotherapy (SSRIs, SNRIs, or other agents) selected based on adverse effect profiles, cost, and patient preferences 3
- Assess response within 6-8 weeks of optimized antidepressant therapy at adequate doses 3, 1
- Add aripiprazole 2-20 mg/day if inadequate response to monotherapy persists 1, 4, 5
Evidence for Efficacy
The approval is based on robust placebo-controlled trial data demonstrating:
- Significant improvement in Montgomery-Asberg Depression Rating Scale (MADRS) scores compared to placebo when added to ongoing antidepressant therapy 5
- Response rates of 50% or higher in open-label studies, with remission rates of approximately 29% 6
- Rapid onset of benefit within 1-2 weeks of initiating adjunctive therapy 5
- Efficacy across different antidepressant classes, including SSRIs, SNRIs, and bupropion 6, 5, 7
Dosing and Initiation
The effective dose range is 2-20 mg/day, with most patients responding to lower doses (2-15 mg/day). 4, 8, 5
- Start with low doses (2-5 mg/day) to minimize side effects 4
- Titrate based on response and tolerability 8
- Maximum studied dose is 20 mg/day 5
Monitoring Requirements
Begin monitoring within 1-2 weeks of initiation and continue regularly throughout treatment. 3, 1 Specific parameters to assess:
- Suicidality and behavioral changes: Monitor daily for emergence of agitation, irritability, unusual behavior changes, worsening depression, or suicidal ideation, particularly in the first few weeks 2
- Metabolic parameters: Weight, glucose, and lipids due to potential for weight gain (though minimal in 6-week trials) 1, 8
- Extrapyramidal symptoms: Akathisia occurs more frequently in depression than schizophrenia populations (though usually mild-moderate) 8, 5
- Treatment response: Evaluate efficacy at 6-8 weeks of combined therapy 1
Safety Profile and Common Pitfalls
Akathisia is the most common side effect requiring clinical attention. 8 Key safety considerations:
- Akathisia incidence is higher in MDD patients than in schizophrenia populations, but most cases are mild-moderate and rarely lead to discontinuation (5/1090 patients across trials) 8
- Weight gain is minimal over 6-week treatment periods, though long-term data show some weight increase 8
- Black box warning for suicidality applies when used as adjunctive therapy in depression, requiring close monitoring especially in younger adults 2
- Neuroleptic malignant syndrome and tardive dyskinesia are rare but serious risks with all antipsychotics 2
Duration of Treatment
Continue combined therapy for 4-9 months after achieving satisfactory response for first-episode depression. 3
- Patients with recurrent depression (≥2 episodes) may benefit from longer maintenance therapy 3
- Long-term tolerability data from 52-week extension studies support extended use when clinically indicated 8
Critical Clinical Caveat
Aripiprazole is NOT approved for monotherapy in depression and has NOT been evaluated in pediatric major depressive disorder. 2 It should only be used as adjunctive therapy in adults who have demonstrated inadequate response to standard antidepressant treatment.
The mechanism likely involves partial D2/D3 dopamine agonism, 5-HT1A partial agonism, and 5-HT2A antagonism, though the exact basis for antidepressant augmentation remains incompletely understood. 4, 8