CASE REPORT article
Front. Psychiatry
Sec. Schizophrenia
Volume 16 - 2025 | doi: 10.3389/fpsyt.2025.1679678
MANAGING TREATMENT-RESISTANT SCHIZOPHRENIA FOLLOWING CLOZAPINE CESSATION: A CASE REPORT OF XANOMELINE–TROSPIUM AND OLANZAPINE COMBINATION THERAPY
Provisionally accepted
- Brookdale University Hospital and Medical Center, Brooklyn, United States
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Background: Clozapine is the gold standard for treatment-resistant schizophrenia (TRS) but is limited by rare, serious adverse events. Venous thromboembolism (VTE) and pulmonary embolism (PE) represent particularly challenging complications given their multifactorial pathophysiology, unpredictable recurrence risk, and lack of clear guidance on rechallenge. Case presentation: A 44-year-old man with TRS and comorbid seizure disorder achieved over 25 years of remission on clozapine (300 mg/day). In November 2023, he developed acute deep vein thrombosis and PE, leading to permanent discontinuation despite long-term tolerability and the absence of conventional risk factors. Abrupt cessation was followed by rapid relapse. Aripiprazole, titrated to 15 mg/day, and subsequent augmentation with olanzapine failed to restore stability. A muscarinic–dopaminergic approach using xanomeline–trospium (Cobenfy™) with olanzapine was initiated, producing marked improvements in positive symptoms, affective expressivity, social engagement, and daily functioning without significant adverse effects. Discussion: Most clozapine-related VTE/PE cases necessitate discontinuation, though rare continuations under anticoagulation and multidisciplinary oversight have been described. Reviews emphasize inconclusive evidence and the need for individualized risk–benefit assessment. In this case, discontinuation was chosen collaboratively with the family, prompting exploration of alternative mechanisms. Conclusion: Clozapine-related VTE/PE represents a serious clinical dilemma. This case illustrates the potential of muscarinic–dopaminergic strategies to restore stability in TRS when clozapine is no longer an option.
Keywords: treatment-resistant schizophrenia, TRS, Clozapine, Venous Thromboembolism, VTE, Pulmonary Embolism, Pe, xanomeline–trospium
Received: 05 Aug 2025; Accepted: 06 Oct 2025.
Copyright: © 2025 Sumegi Went, Alonso, Rigunay, You and Hershberger. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Nils Sumegi Went, nsumegiw@bhmcny.org
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