¹MIMS Pte Ltd, Services Management & Operations, MPF, Singapore, Singapore, ²Pamela Youde Nethersole Eastern Hospital, Department of Pharmacy, Hong Kong, Hong Kong, SAR of China, ³MIMS (Hong Kong) Limited, Services Management & Operations, MPF, Hong Kong, Hong Kong, SAR of China, ⁴Qualiceutic (Hongkong) Limited, Medical Department, Hong Kong, Hong Kong, SAR of China

Background: Very few psychopharmacological treatments (PPhTs) have ever been approved for post-traumatic stress disorder (PTSD). Recently, results from a few large randomized controlled trials (RCTs) investigating the combination of brexpiprazole and sertraline for PTSD have been detailed. One rationale for including brexpiprazole in the primary combination is its potent antagonism at α₁-adrenergic receptors. Brexpiprazole, its structurally related aripiprazole, and cariprazine are sometimes grouped together as dopamine receptor partial agonists (DRPAs). The 3 DRPAs each exhibit some binding affinity for α₁-adrenoreceptors.

Aims & Objectives: The current effect-size (ES) analysis is part of an overarching, evidence-based program designed to systematically derive a summary ES for a number of PPhTs that have been investigated in RCTs for the treatment of PTSD. This substudy focused on available DRPAs (aripiprazole, brexpiprazole, and cariprazine).

Method: A systematic search for primary reports of RCTs investigating DRPAs for PTSD published or presented up to 31 December 2025 was performed in MEDLINE, EMBASE, CENTRAL, and PsycINFO. All study-level ESs were calculated or retrieved as Cohen’s d for the continuous endpoint of the change in the Clinician-Administered PTSD Scale (CAPS) total score, regardless of CAPS version. All pooling of study-level ESs (meta-analysis) for a summary ES was performed using random-effects models. This review, as well as the parent review, has been registered in PROSPERO.

Results: From the literature search, 4 distinct RCTs were identified that adopted a DRPA as part of the treatment modalities for PTSD. The approaches ranged from the upfront initiation of a DRPA in combination with an antidepressant to DRPA augmentation of an antidepressant regimen. No eligible RCTs involving cariprazine were identified. Across the 4 trials, a total of 1,306 patients were randomized, of whom 981 (75.1%) provided data on changes in the CAPS total score at endpoints after 8–11 weeks of treatment. After pooling the 6 comparisons based on the 4 trials, the use of a DRPA in the treatment of PTSD yielded an ES of 0.19 (95% confidence interval [CI], −0.00 to 0.38; p=0.056). There was a moderate level of heterogeneity (I²=56.9%). When excluding the aripiprazole trial (also the smallest), the ES associated with brexpiprazole was largely unchanged at 0.18 (95% CI, −0.02 to 0.38; p=0.072; I²=63.1%).

Discussion & Conclusions: Including either aripiprazole or brexpiprazole as a PPhT for PTSD yielded a small ES that narrowly missed statistical significance. Considering that, in most included trial participants, aripiprazole or brexpiprazole was administered together with an antidepressant, this review validates the approaches that alternative PPhTs in the treatment of PTSD may partner with antidepressants rather than substitute them. Another review delineating further the treatment effect of α₁-adrenergic receptor blockade with PPhTs will be presented at an upcoming meeting.