Objectives

To compare the efficacy, tolerability and clinical applications of aripiprazole and cariprazine as augmentation strategies in treatment-resistant depression (TRD).

Methods

The research includes PubMed/MEDLINE data from 2015 to 2025 which combines results from RCTs and meta-analyses and systematic reviews and guidelines and real-world data. Aripiprazole has demonstrated superiority over placebo in terms of treatment response and remission, with therapeutic effects emerging within weeks and persisting during long-term treatment. The most frequently reported side effects include akathisia and typically mild weight gain. The drug cariprazine produces different results in RCT studies because it shows beneficial effects at 1.5 mg doses in selected trials while preserving metabolic stability and producing minimal drowsiness as a side effect. The metabolic pathways of these drugs differ because aripiprazole depends on CYP2D6/3A4 enzymes for metabolism but cariprazine requires CYP3A4 enzymes and produces long-lasting metabolites which need special attention during medication changes.

Conclusions

Aripiprazole remains the most well-documented first-line augmentation strategy for TRD. Cariprazine serves as an effective treatment option for patients who experience severe anhedonia/apathy symptoms and for cases where doctors need to focus on metabolic stability. Additional research must be conducted to determine the best candidates for treatment and establish long-term effectiveness of cariprazine. Currently, there are no head-to-head trials comparing aripiprazole and cariprazine in TRD augmentation.