Beyond stabilization: Augmenting LAI aripiprazole with xanomeline–trospium in schizophrenia – A case series

Schizophrenia is a chronic psychiatric disorder characterized by positive symptoms (e.g., hallucinations, delusions), negative symptoms (e.g., avolition, blunted affect), and general psychopathology (e.g., anxiety, cognitive deficits). Long-acting injectable (LAI) antipsychotics such as aripiprazole are effective for controlling positive symptoms, yet negative symptoms and general psychopathology often persist, impairing functional recovery and quality of life. Interest has grown in treatments that target non-dopaminergic pathways. Xanomeline–trospium chloride (KarXT, Cobenfy™)—a central M1/M4 muscarinic agonist combined with a peripheral anticholinergic—represents a novel adjunctive approach. This case series describes the use of KarXT in patients maintained on LAI aripiprazole who had persistent negative and general psychopathology symptoms, with the aim of exploring potential clinical benefit through cholinergic modulation. Four male patients (ages 20–29) with schizophrenia, all stabilized on LAI aripiprazole, presented with residual negative symptoms such as avolition, blunted affect, and emotional withdrawal, along with general psychopathology symptoms, despite adequate control of positive symptoms. Adjunctive KarXT (xanomeline 50 mg / trospium 20 mg BID, titrated to xanomeline 100 mg / trospium 20 mg BID) was administered for 10 weeks. Positive and Negative Syndrome Scale (PANSS) assessments were conducted by trained raters. Across cases, reductions were observed in total PANSS scores (mean reduction 32.1%), with the largest changes in negative and general psychopathology subscales. Patients also reported subjective improvements in motivation, social engagement, and emotional expressiveness. Findings from prior randomized controlled trials have shown KarXT to reduce PANSS scores, though its effects on negative symptoms remain under investigation. In this small, uncontrolled case series, observed improvements may reflect potential benefit, but causality cannot be inferred. The absence of a control group, potential placebo effects, and concurrent treatments are important limitations. Compared with options such as clozapine, which may be limited by side effects and monitoring requirements, KarXT may represent a tolerable adjunctive strategy warranting further controlled study. Adjunctive KarXT in patients with schizophrenia stabilized on LAI aripiprazole was associated with observed improvements in negative and general psychopathology symptoms in this small case series. These preliminary findings support further investigation in larger, randomized controlled trials to determine efficacy, safety, and optimal use in real-world clinical settings.