Transitioning from clozapine to Cobenfy (xanomeline-trospium chloride) in treatment resistant schizophrenia and clozapine induced OCD

Abstract

Background

Treatment-resistant schizophrenia (TRS) is defined as nonresponse to at least two adequate antipsychotic trials at therapeutic doses for six or more weeks. Currently, clozapine is the only antipsychotic approved for TRS by the FDA and a plethora of evidence indicates that it is the most efficacious antipsychotic for treatment of chronic and refractory cases of schizophrenia. However, its utilization is often limited by metabolic, hematologic, and anticholinergic side effects. Notably, clozapine-induced obsessive-compulsive symptoms (OCS) or obsessive-compulsive disorder (OCD) have been increasingly recognized, attributed to its potent serotonergic antagonism. In 2024, the FDA approved xanomeline-trospium, a dual agent combining a central muscarinic M1/M4 agonist with a peripheral antimuscarinic, which offers a novel approach to treating psychosis. Early evidence suggests comparable efficacy to other antipsychotics, with fewer metabolic and extrapyramidal side effects. We present a case of a woman with longstanding schizophrenia and clozapine-induced OCD successfully transitioned to xanomeline-trospium, resulting in remission of both psychotic and obsessive-compulsive symptoms.

Case presentation

A 57-year-old woman with a chronic history of schizophrenia, requiring multiple hospitalizations and maintenance electroconvulsive therapy (ECT), stabilized on clozapine 300 mg nightly after failing several antipsychotics. Despite adherence, she exhibited persistent hallucinations, negative symptoms, and later developed clozapine-induced OCD characterized by intrusive counting and numerical obsessions refractory to high-dose sertraline. Due to distressing OCD and passive suicidal ideation, she was admitted for a discontinuation of clozapine and initiation of xanomeline-trospium. Clozapine was tapered and discontinued before initiating xanomeline-trospium, titrated to 100 mg/20 mg twice daily. Within one week after starting xanomeline-trospium, her counting obsessions resolved, psychosis improved, and suicidality resolved. At discharge, three weeks post-admission, she remained stable on xanomeline-trospium, ziprasidone, and sertraline, with complete remission of hallucinations and obsessions.

Conclusion

This case highlights a successful switch from clozapine to xanomeline-trospium for management of chronic schizophrenia and clozapine induced OCD. The patient’s improvement raises important considerations regarding clozapine-induced OCD, cautious discontinuation, and the benefit of muscarinic receptor agonists. Xanomeline-trospium may represent a viable alternative for patients intolerant of clozapine.

Clinical trial number

Not applicable.

Introduction

Treatment resistant schizophrenia (TRS) is defined as a failure to respond to at least two adequate trials of antipsychotics, each at therapeutic dose for six or more weeks [1]. Currently, clozapine is the only antipsychotic approved for TRS by the FDA and a plethora of evidence indicates that it is the most efficacious antipsychotic for treatment of chronic and refractory cases of schizophrenia [2]. Despite the effectiveness of clozapine, its utilization is limited by a range of adverse effects, including sialorrhea, myocarditis, metabolic syndrome and agranulocytosis. Additionally, some patients are at risk of developing obsessive-compulsive symptoms (OCS) or frank obsessive-compulsive disorder (OCD) [3]. When attempting to transition from clozapine to a novel antipsychotic, clinicians must be cautious to avoid abrupt discontinuation, which may result in psychosis, cholinergic rebound side effects, and/or withdrawal syndromes [4]. The latest antipsychotic approved for treatment of schizophrenia by the FDA in 2024 is xanomeline-trospium (Cobenfy) - a central muscarinic M1/M4 receptor agonist (Xanomeline) combined with a peripheral anticholinergic (Trospium). This novel mechanism offers efficacy comparable to other antipsychotics, but with fewer metabolic and extrapyramidal side effects [5]. Current available data recommends using xanomeline-trospium as monotherapy and cross-tapering over a two-week period when switching from another antipsychotic [5]. We report a case of a female with longstanding schizophrenia who developed clozapine induced OCD and was successfully transitioned to xanomeline-trospium with resolution of both psychosis and obsessive-compulsive symptoms.

Case presentation

Patient history

Patient is a 57-year-old female, with a 30-year history of schizophrenia complicated by catatonia and multiple hospitalizations. She was initiated and maintained on clozapine (most recent dose of 300 mg/night) for decades, after failed trials of haloperidol, fluphenazine, risperidone, aripiprazole, and chlorpromazine. She also received maintenance electroconvulsive therapy (ECT), which improved her affect and engagement. Despite adherence to clozapine and ongoing ECT, she had chronic hallucinations and pronounced negative symptoms. Additionally, she consistently described a sensation of bilateral “eye pain”, leading to extensive ophthalmologic and neurologic investigations that identified no obvious anatomic or neurologic cause.

Approximately five years ago, the patient developed progressively worsening intrusive thoughts – most prominently regarding numbers (compulsive counting and repeatedly asking relatives to confirm simple arithmetic, perseveration on numbers), although hoarding and checking behaviors were also present. The intrusive thoughts and repetitive counting were recognized as obsessions and compulsions, and she was diagnosed with clozapine-induced OCD. She was initiated on sertraline to address the OCD symptoms, which persisted despite titration to 250 mg daily. Her outpatient regimen included clozapine 300 mg nightly, ziprasidone 60 mg twice daily, sertraline 250 mg daily and maintenance ECT.

Assessment

On outpatient assessment prior to admission, she displayed persistent psychosis (“communicates like a TV in my mind” [referring to a boyfriend, who did not exist]) and distressing obsessions involving numbers. The patient’s family corroborated that she spent many hours of the day performing arithmetic, despite frequent reassurances that she was counting correctly. She expressed feeling demoralized by decades of illness and verbalized passive suicidal ideation. Due to the severity of her treatment resistant psychotic symptoms, intolerable and distressing clozapine induced OCD, and new passive suicidal ideations, her outpatient psychiatrist planned to switch the patient from clozapine to xanomeline-trospium.

Hospital course

The patient was admitted to our inpatient unit in July 2025 for discontinuation of clozapine and initiation of xanomeline-trospium in a controlled and monitored setting. Clozapine was gradually reduced over one week with complete discontinuation. Consistent with cross taper guidance for antipsychotics, abrupt discontinuation of clozapine should be avoided to minimize rebound psychosis, withdrawal syndromes, and/or cholinergic rebound [4]. Xanomeline-trospium was started on July 21st, 2025 at 50/20 mg twice daily and titrated to 100/20 mg twice daily over a week. The patient tolerated the medication well, with prophylactic ondansetron for nausea. After one week of being initiated on xanomeline-trospium, patient’s counting obsessions abated, her psychosis diminished, and she displayed improved engagement and affective reactivity on the unit. Her passive suicidal ideation resolved, and mood had improved.

Follow-up and outcome

On discharge, three weeks after admission, the patient was stable on xanomeline-trospium 100/20 mg twice daily, ziprasidone was continued at 60 mg twice daily, and sertraline maintained at 250 mg daily. She reported no hallucinations or obsessions and expressed hopefulness about her future. Outpatient maintenance ECT was tapered given improvement in symptomatology.

Discussion

Clozapine induced OCD

Secondary onset obsessive-compulsive symptoms are well described with clozapine and other anti-serotonergic second-generation antipsychotics. clozapine’s strong antagonism at 5HT1C, 5HT2A and 5HT2C receptors may underlie this effect [3]. The severity of clozapine induced OCS is typically dose dependent and symptoms often improve after dose reduction or switching to another antipsychotic [3]. In this patient, OCD emerged after 25 years of clozapine therapy and was refractory to high dose sertraline. Reducing the current clozapine dose was limited by psychosis control and concerns for repeat decompensation. Following clozapine discontinuation, the patient’s obsessive–compulsive symptoms improved, and transition to xanomeline–trospium was not associated with a recurrence of OCD symptoms.

Cobenfy as a novel option

Xanomeline-trospium acts via agonism of muscarinic receptors (Xanomeline) and includes trospium to limit peripheral cholinergic effects [5]. Trials show comparable efficacy to other antipsychotics without metabolic side effects or extra-pyramidal symptoms [5]. Current guidance recommends using it as monotherapy and cross tapering over about two weeks when switching from another antipsychotic [5]. Highly anticholinergic drugs such as clozapine, olanzapine, and quetiapine should be avoided in combination with xanomeline-trospium due additive antimuscarinic effects with the trospium component of xanomeline-trospium, which may exacerbate adverse effects in frequency or severity (including dry mouth, constipation, or urinary retention) [6]. More importantly, potent CNS anti-cholinergic medications would be anticipated to directly oppose the proposed therapeutic mechanism of xanomeline-trospium, through agonist of M1 and M4 receptors. Additionally, abruptly stopping sedating antipsychotics can cause rebound agitation or insomnia [6] and abruptly stopping anti-cholinergic antipsychotics can cause withdrawal syndromes [4]. Our patient’s transition from clozapine to xanomeline-trospium mirrored these recommendations with completed discontinuation of clozapine before xanomeline-trospium initiation, preventing overlap and additive cholinergic side effects. The patient experienced no withdrawal or rebound psychosis, and her OCD resolved, supporting reports that OCS can improve after clozapine dose reduction or switch [3].

Revisiting treatment resistance

Although clozapine is indicated for TRS, adequate trials of at least two antipsychotics are required before establishing this diagnosis [1]. In our patient, most previous antipsychotic trials occurred overseas and were not well documented, and augmentation strategies rather than full monotherapy trials were often used. While clozapine-based combination therapy with adjunctive ziprasidone has been associated with improved outcomes in some patients, this strategy did not yield symptomatic improvement in our patient despite treatment with both agents [7]. The observed response to adjunctive xanomeline–trospium with ziprasidone supports its potential utility in treatment-resistant schizophrenia and highlights the need for further investigation.

Lessons and implications

Recognition of clozapine induced OCD requires careful assessment, as obsessions may be misinterpreted as somatic complaints or psychotic symptoms. Switching patients from clozapine to xanomeline-trospium can be feasible and effective; a gradual taper minimizes withdrawal and anticholinergic synergy [4]. Clinicians should monitor for cholinergic side effects and adjust dosing when patients are taking strong CYP2D6 inhibitors, like Sertraline [5]. Accurate documentation of prior antipsychotic trials is essential before labelling a patient as having TRS [1].

Conclusion

This case demonstrates that a patient with longstanding schizophrenia, labelled as treatment resistant, and experiencing debilitating clozapine induced OCD, achieved remission of psychosis and obsessive-compulsive symptoms following a cautious transition to xanomeline-trospium. The case underscores the importance of recognizing clozapine associated OCS, reassessing the diagnosis of TRS, and considering novel pharmacologic options. Although xanomeline-trospium showed promising efficacy and tolerability, further research is needed to determine its role in TRS and its long-term impact on obsessive-compulsive symptoms.

Author contributions

All authors equally contributed to writing and reviewing the case report.

Funding

None.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Patient has provided written informed consent for their personal and clinical details. No identifying images are required for this publication.

Competing interests

There were no competing interests at the time the patient care was established by the primary author and the manuscript was written/reviewed by all authors. One month ago, Dr. Rachel Rose became a consultant for Bristol Myer Squibb, after the case was written.