2026 ECNP Congress

PS03-3008

Brexpiprazole vs aripiprazole in schizophrenia with comorbid substance use disorder: impulsivity and craving outcomes

Ginevra Lombardozzi — G. Trovini, G. Albanesi, Y. Sonnino, E. Amici, V. Giovanetti, G. Civita, M. Manganozzi, D. Donato, S. De Filippis · Villa Von Siebenthal, Neuropsychiatric Clinic and Hospital, Genzano di Roma RM, Italy

2026 ECNP Congress

Introduction

Schizophrenia is often complicated by comorbid substance use disorder (SUD), affecting approximately half of patients and contributing to disabling clinical course, increased relapse rates, hospitalisation burden and reduced treatment adherence [1]. Dopaminergic dysregulation underlies both psychotic symptoms and reward-seeking behaviour, making dopamine-serotonin partial agonists a pharmacologically rational treatment choice for this population. Brexpiprazole and aripiprazole share a common mechanism as D2/D3 receptor partial agonists with 5-HT1A agonism and 5-HT2A antagonism, yet differ in intrinsic D2 activity and serotonergic affinity, which may translate into clinically meaningful differences in global severity, impulsivity, and craving [2;3].

Aims

The present naturalistic study compares the longitudinal effectivness of brexpiprazole and aripiprazole in patients with schizophrenia, with or without comorbid SUD , on global clinical severity, impulsivity, and substance craving iover a 12-month- follow-up.

Methods

217 inpatients with a DMS-5 diagnosis of Schizophrenia, of whom 112 had a comorbid SUD diagnosis, hospitalized at the Villa Von Siebenthal neuropsychiatric hospital, were enrolled between January 2022 and ended on October 2022 and followed for 12 months. 86 patients received brexpirpazole (4 mg/day) and 131 received aripiprazole (30 mg/day).

Patients were assessed with Clinical Global Impression Severity scale (CGI-S), Barratt Impulsiveness Scale-11 (BIS-11), Visual Analogue Scale for craving (VAS-crav),respectevely for gloal clinica severity, impulsivity and craving in SUD patients, at baseline, 1, 3, 6 and 12 months. Statistical analysis used two-way repeated-measures ANOVA with Fisher’s LSD post-hoc test; significance was set at p<0.05.

Results

At baseline, CGI-S and BIS-11 total scores did not differ significantly between groups (CGI-S: brexpiprazole 5.01±0.08 vs aripiprazole 4.83±0.07, p=0.089; BIS-11: 77.02±2.04 vs 81.21±1.59, p=0.107). Two-way repeated-measures ANOVA confirmed significant treatment effects for both scales (CGI-S: F (1.215)=41.87, p<0.0001; BIS-11 total: F (1.215)=35.85, p<0.0001). At 12 months, brexpiprazole-treated patients showed significantly lower global severity (CGI-S: 2.27±0.07 vs 3.28±0.10; t=8.522, p<0.0001) and greater impulsivity reduction across all BIS-11 subscales (attentional: F (1.215)=47.82; motor: F (1.215)=15.96; non-planning: F (1.215)=37.21; all p<0.0001), with endpoint BIS-11 total scores of 46.24±1.23 vs 66.11±1.63 (t=9.741, p<0.0001). Brexpiprazole showed continuous improvement throughout follow-up, whereas aripiprazole exhibited a plateau after 6 months on most measures.

VAS-crav scores at baseline showed a modest but statistically significant difference (6.98±0.44 vs 8.11±0.26, p=0.030) and diverged markedly over time (F (1.120)=64.82, p<0.0001). By 12 months, brexpiprazole-treated patients showed near-complete craving resolution (0.50±0.15) compared with persistent mild craving in the aripiprazole group (5.08±0.34; t=12.25, p<0.0001). BIS-11 improvements were also superior in the SUD subgroup for brexpiprazole (F (1.120)=41.07, p<0.0001; endpoint: 47.83±1.85 vs 73.84±2.21, p<0.0001).

Conclusions

Both treatments were associated with sustained improvement in global severity and impulsivity over 12 months. Brexpiprazole showed significantly greater and more consistent improvements across CGI-S, all BIS-11 domains, and — in patients with comorbid SUD — near-complete craving suppression. These findings suggest that brexpiprazole’s distinct receptor profile, particularly its lower intrinsic D2 activity and stronger serotonergic modulation, may confer a clinically relevant advantage in managing impulsivity, global severity, and craving in this high-burden population. Larger controlled studies are needed to confirm these observations.

References

  1. Volkow ND, Michaelides M, Baler R. The Neuroscience of Drug Reward and Addiction. Physiol Rev. 2019 Oct 1;99(4):2115-2140. doi: 10.1152/physrev.00014.2018. PMID: 31507244; PMCID: PMC6890985.
  2. Citrome L. The ABC’s of dopamine receptor partial agonists - aripiprazole, brexpiprazole and cariprazine: the 15-min challenge to sort these agents out. Int J Clin Pract. 2015 Nov;69(11):1211-20. doi: 10.1111/ijcp.12752. Epub 2015 Oct 18. PMID: 26477545.
  3. Dalley JW, Robbins TW. Fractionating impulsivity: neuropsychiatric implications. Nat Rev Neurosci. 2017 Feb 17;18(3):158-171. doi: 10.1038/nrn.2017.8. PMID: 28209979.