Does Aripiprazole (atypical antipsychotic) have antidepressant properties?

Aripiprazole as Antidepressant Augmentation

Aripiprazole does not have standalone antidepressant properties, but it is FDA-approved and highly effective as an adjunctive therapy to standard antidepressants for treatment-resistant major depressive disorder, demonstrating clinically meaningful improvements in core depressive symptoms including depressed mood, loss of interest, and psychic anxiety. 1, 2

FDA-Approved Indication

• Aripiprazole received FDA approval in November 2007 specifically as adjunctive therapy to antidepressants for treating major depressive disorder (MDD), not as monotherapy 2
• The approval was based on two large-scale, randomized, double-blind, placebo-controlled trials demonstrating superior efficacy when added to ongoing antidepressant treatment 2, 3
• Aripiprazole should never be used as monotherapy for depression—it must be combined with a standard antidepressant (SSRI, SNRI, or bupropion) 4, 5

Mechanism Supporting Antidepressant Effects

• Aripiprazole functions as a partial agonist at dopamine D2/D3 and serotonin 5-HT1A receptors, while acting as an antagonist at 5-HT2A receptors 2
• This unique pharmacological profile differentiates it from traditional antipsychotics and provides the mechanistic rationale for augmenting antidepressant response 2
• The partial dopaminergic agonism may address motivational and anhedonic symptoms that SSRIs alone often fail to improve 6

Clinical Efficacy Data

Response and Remission Rates

• In pivotal trials, adjunctive aripiprazole 2-20 mg/day produced significantly greater improvements in Montgomery-Asberg Depression Rating Scale (MADRS) scores compared to placebo when added to standard antidepressants 3
• Response rates (≥50% improvement) ranged from 55.6-58.3% in treatment-resistant patients who had failed adequate SSRI trials 4
• Remission rates reached 33.3-41.7% in patients with previously treatment-resistant depression 4
• Improvements became statistically significant as early as 1-2 weeks after initiating aripiprazole augmentation, with some patients achieving remission within the first week 3, 5

Core Symptom Improvement

• Aripiprazole augmentation produced substantial within-group effect sizes (ES=1.1-1.2) on core depression subscales, comparable to effects on total HAM-D scores 6
• Individual symptoms showing greatest improvement included: depressed mood (ES=1.03), work and activities (ES=0.86), guilt (ES=0.77), and psychic anxiety (ES=0.67)—all significantly superior to placebo 6
• Significant improvements occurred across anxiety, insomnia, and drive components, addressing symptoms beyond mood that often persist with antidepressant monotherapy 6

Dosing Algorithm

Starting Dose

• Begin with aripiprazole 2.5 mg/day, not 10 mg/day 5
• The lower starting dose reduces akathisia-related discontinuation by 50% (from 2/7 patients to 1/8 patients) 5
• Overall discontinuation rates at endpoint were lower with 2.5 mg starting dose (3/8 patients) versus 10 mg starting dose (4/7 patients) 5

Titration Schedule

• Increase gradually based on tolerability and response, with FDA-approved dosing range of 2-20 mg/day 1, 3
• Most patients in clinical trials received doses between 5-15 mg/day 2
• Allow at least 6-8 weeks to assess full therapeutic response before concluding treatment failure 2, 3

Safety and Tolerability Profile

Common Adverse Events

• Akathisia represents the most clinically significant adverse effect, occurring more frequently than in schizophrenia trials, though most cases are mild to moderate 2
• Only 5 of 1,090 patients across three pivotal trials discontinued due to akathisia when using appropriate starting doses 2
• Weight gain showed minimal trend over 6-week treatment periods, with more favorable metabolic profile than olanzapine or quetiapine 2
• Most treatment-emergent adverse events were mild to moderate in severity 3

Long-Term Safety

• A 52-week open-label extension study demonstrated continued tolerability with long-term adjunctive aripiprazole treatment 2
• No severe adverse events were observed in open-label augmentation studies 4

Critical Clinical Considerations

When to Initiate Aripiprazole Augmentation

• Consider after inadequate response to at least 8 weeks of adequate-dose antidepressant monotherapy 5
• The American College of Physicians recognizes aripiprazole among atypical antipsychotics evaluated for augmentation in patients who did not remit after initial adequate antidepressant trial 7
• Response to aripiprazole augmentation does not appear related to which specific antidepressant (SSRI, venlafaxine, or bupropion) is used as the base therapy 3, 5

Differential Use in Bipolar vs Unipolar Depression

• While aripiprazole is FDA-approved for bipolar mania and as adjunctive therapy for MDD, these are distinct indications 1
• In schizophrenia, aripiprazole augmentation can be considered for ongoing negative symptoms when added to clozapine 7
• For bipolar depression specifically, the American Academy of Child and Adolescent Psychiatry recommends olanzapine-fluoxetine combination as first-line, not aripiprazole monotherapy 8

Common Pitfalls to Avoid

• Never use aripiprazole as monotherapy for depression—it requires combination with a standard antidepressant for FDA-approved use in MDD 4, 2
• Avoid starting at 10 mg/day—this doubles the risk of akathisia-related discontinuation compared to 2.5 mg starting dose 5
• Do not conclude treatment failure before allowing 6 weeks of adequate-dose therapy, as some patients continue improving throughout this period 2, 3
• Do not assume lack of efficacy based on the specific antidepressant used—aripiprazole augmentation works across different antidepressant classes 3, 5
• Recognize that while aripiprazole improves core depressive symptoms, it does so only when combined with ongoing antidepressant therapy, not through standalone antidepressant properties 6