2026 ECNP Congress

EP02-2052

Cariprazine–clozapine combination as an augmentation strategy to reduce negative, affective and cognitive symptoms in psychotic disorders

Marc Peraire — R. Gimeno-Vergara, A. Moreno-Beltrán, M. Cabañés-Suñer, A. Fillol · Consorci Hospitalari Provincial Castelló, Salud Mental, Castelló de la Plana, Spain

2026 ECNP Congress

Introduction: Clozapine remains the gold-standard treatment for treatment-resistant schizophrenia and related psychotic disorders, particularly for patients who fail to respond to at least two antipsychotic trials. However, despite adequate dosing and plasma levels, a substantial proportion of patients continue to experience persistent negative symptoms—such as blunted affect, avolition and social withdrawal—as well as affective and cognitive deficits that significantly impair functional recovery and quality of life. It is estimated that up to 40–70% of patients show only partial response to clozapine, highlighting the need for effective augmentation strategies [1]. These residual domains are often insufficiently addressed by clozapine’s pharmacological profile. Cariprazine, a dopamine D2/D3 partial agonist with preferential binding to D3 receptors, has emerged as a promising adjunctive agent due to its modulatory effects on mesolimbic and mesocortical dopaminergic pathways, which are closely linked to motivation, reward processing and cognition [1,2]. Its pharmacodynamic properties may complement clozapine’s serotonergic, anticholinergic and antiadrenergic actions [1]. This narrative review examines the emerging evidence supporting the combination of cariprazine and clozapine as a targeted strategy to address persistent symptom domains in psychotic disorders.

Aims: To synthesise current evidence regarding the clinical efficacy, neuropharmacological rationale and safety profile of the cariprazine–clozapine combination, with a particular focus on its impact on negative, affective and cognitive symptoms in schizophrenia-spectrum disorders.

Methods: A narrative review of the literature published between January 2017 and April 2026 was conducted using PubMed, Embase and Cochrane Central databases. Search terms included a combination of “cariprazine”, “clozapine”, “augmentation”, “psychotic disorders”, “negative symptoms”, “affective symptoms” and “cognition”. Eligible studies comprised case reports, case series, retrospective chart reviews and systematic reviews. Given the heterogeneity of study designs and outcome measures, the findings were synthesised qualitatively rather than through a formal meta-analysis.

Results: Available evidence suggests that adjunctive cariprazine in patients stabilised on clozapine is associated with clinically meaningful improvements in persistent negative symptoms, including reductions in anhedonia, avolition and social disengagement [2,3]. Improvements in affective domains—particularly depressive symptoms, anergia and emotional reactivity—have also been consistently reported [3,4]. In a recent retrospective chart review, approximately 75% of patients showed clinical improvement after cariprazine augmentation, with benefits observed across negative, affective and global functioning domains [4]. Emerging data also suggest potential benefits in cognitive functioning, including attention and verbal fluency, although findings remain limited by non-standardised assessments [3]. Furthermore, recent systematic evidence supports the role of cariprazine in improving negative symptoms through D3-mediated mechanisms [5]. Cariprazine is typically introduced at low doses (1.5 mg/day) and titrated up to 3–6 mg/day depending on tolerability and response, with therapeutic effects generally emerging over several weeks. The combination appears relatively well tolerated, with akathisia and mild activation being the most frequently reported adverse effects, and no consistent clinically relevant pharmacokinetic interactions described [3,4].

Conclusions: The cariprazine–clozapine combination represents a promising augmentation strategy for patients with treatment-resistant psychotic disorders who exhibit persistent negative, affective and cognitive symptoms. While preliminary evidence supports its efficacy and tolerability, larger prospective, controlled studies are needed to confirm these findings, establish optimal dosing strategies and better characterise long-term safety.

References

  1. Oloyede E, Clark I, Mace S, Whiskey E, Taylor D. Clozapine augmentation with cariprazine for negative symptoms: a case series and literature review. Ther Adv Psychopharmacol. 2022 Jan 28;12:20451253211066642. doi: 10.1177/20451253211066642. PMID: 35111297; PMCID: PMC8801710.
  2. Selvan P, Devkare P, Shetty A, Dharmadhikari S, Khandhedia C, Mane A, Mehta S, Andrade C. A review on the pharmacology of cariprazine and its role in the treatment of negative symptoms of schizophrenia. Front Psychiatry. 2024 Apr 22;15:1385925. doi: 10.3389/fpsyt.2024.1385925. PMID: 38711874; PMCID: PMC11071166.
  3. Pappa S, Csehi R, Caldwell-Dunn E, Dombi ZB, Hjorth S. Cariprazine and clozapine: a systematic review of a promising antipsychotic combination for treatment-resistant schizophrenia. Int J Neuropsychopharmacol. 2025 Aug 1;28(8):pyaf053. doi: 10.1093/ijnp/pyaf053. PMID: 40679420; PMCID: PMC12342903.
  4. Siwek M, Chrobak AA, Gorostowicz A, Król P, Dudek D. Cariprazine augmentation of clozapine in schizophrenia-a retrospective chart review. Front Pharmacol. 2024 Jan 4;14:1321112. doi: 10.3389/fphar.2023.1321112. PMID: 38239199; PMCID: PMC10794393.
  5. Selvan P, Devkare P, Shetty A, Dharmadhikari S, Khandhedia C, Mane A, Mehta S, Andrade C. A review on the pharmacology of cariprazine and its role in the treatment of negative symptoms of schizophrenia. Front Psychiatry. 2024 Apr 22;15:1385925. doi: 10.3389/fpsyt.2024.1385925. PMID: 38711874; PMCID: PMC11071166.