Adjunctive xanomeline/trospium in clozapine-resistant schizophrenia: two case reports demonstrating limited response

Few pharmacologic options exist for patients with clozapine-resistant schizophrenia (CRS) or schizoaffective disorder. Xanomeline/trospium represents a new class of antipsychotic medication that has efficacy as monotherapy for schizophrenia. Despite distinct mechanistic differences from standard antipsychotics, phase III evidence suggest limited benefit of xanomeline/trospium in the augmentation of non-clozapine antipsychotics. Research on the use of xanomeline/trospium in patients with clozapine-resistant illness or with partial response to clozapine is even more limited. Two cases of this combination are described with a discussion on key considerations for the management of CRS. The first case is a 42-year-old patient whose clozapine dose was limited by supratherapeutic clozapine levels in response to minor infections. She was ultimately stabilized on a combination of clozapine and xanomeline/trospium, with yet further improvements from electroconvulsive therapy (ECT). The second case is a 31-year-old patient who elected to discontinue clozapine and ECT due to cognitive side effects, despite improvement in psychosis. The addition of xanomeline/trospium to clozapine caused sialorrhea and did not produce observable clinical benefits and was thus discontinued. These case reports describe clozapine-resistant patients who were trialed on xanomeline/trospium combined with clozapine and still required consideration of ECT for symptom control. Overall, future investigation into xanomeline/trospium effectiveness as an augmentation agent or as monotherapy for CRS is necessary to guide clinical decision-making.