NEI Congress 2025 | Colorado Springs, CO
Exploring Titration Strategies for a First-in-Class Non-Antipsychotic Therapy
Dose titration is an important consideration when initiating any new therapy for schizophrenia. Unlike traditional dopamine receptor–blocking antipsychotics, xanomeline–trospium (X/T) represents the first non-antipsychotic medication approved by the U.S. Food and Drug Administration for the treatment of schizophrenia in adults. Acting through selective muscarinic receptor modulation rather than dopamine antagonism, X/T offers a new treatment pathway and, notably, does not carry the boxed warning required for all antipsychotic drugs. By pairing a dual M1/M4-preferring muscarinic receptor agonist (xanomeline) with a peripherally restricted antagonist (trospium chloride), X/T leverages central muscarinic activation while minimizing peripheral cholinergic side effects.
Background and Rationale
In the pivotal EMERGENT-1, -2, and -3 trials, X/T was titrated rapidly to its target dose and demonstrated robust efficacy with predictable, transient cholinergic AEs such as nausea and vomiting, which typically peaked early and lasted on average between 4 and 20 days.
To determine whether a slower titration schedule might improve tolerability, a subsequent phase 4, inpatient, open-label study evaluated the incidence, onset, and duration of procholinergic and anticholinergic treatment-emergent adverse events (TEAEs) across different titration speeds and maximum dose levels.
Methods
The phase 4 study (NCT06572449) enrolled adults aged 18–65 years with stable schizophrenia symptoms (PANSS ≤80, CGI-S ≤4). All participants were washed out of prior antipsychotic medication before initiating X/T.
Two titration approaches were assessed:
- Slower titration to a maximum dose of 100 mg/20 mg twice daily (BID)
- Faster titration to 125 mg/30 mg BID, with optional down-titration based on tolerability
Safety results were compared with pooled data from the acute EMERGENT-1, -2, and -3 trials (n = 331), which used rapid titration to reach the same target doses.
Results
The phase 4 safety population included 173 participants, while 331 were included from the pooled EMERGENT trials. Across studies, most participants were male, Black or African American, and in their mid-40s. Mean PANSS scores, by max dose 100/20mg and 125/30mg respectively, were 62.3/65.9 in the phase 4 study and 97.4/100.3 in the pooled EMERGENT trials.
Overall, 64.5% (phase 4) and 68.6% (pooled EMERGENT) of participants experienced ≥1 TEAE, nearly all were mild or moderate in severity. The most common procholinergic events were nausea and vomiting, while constipation and dyspepsia were the most frequent anticholinergic events.
Importantly, slower titration did not reduce the incidence or severity of cholinergic events. Instead, participants who remained at 100 mg/20 mg BID experienced higher rates and longer duration of first incidence of nausea compared with those titrated more quickly to 125 mg/30 mg BID. In both the phase 4 and pooled EMERGENT datasets, the peak incidence of cholinergic events occurred early, typically during transition to the 100 mg/20 mg dose, then declined over time regardless of titration speed.
Conclusions
Slower titration of xanomeline–trospium did not improve tolerability and, in some cases, prolonged cholinergic side effects. These findings challenge conventional titration strategies and suggest that achieving the target dose (125 mg/30 mg BID) promptly may be optimal.
Because xanomeline–trospium represents a first-in-class, non-antipsychotic treatment for schizophrenia, its initiation and titration strategy differ from dopamine receptor–blocking agents. The distinct muscarinic mechanism, combined with the absence of an antipsychotic boxed warning, positions X/T as a novel option for patients and clinicians seeking an alternative approach to managing schizophrenia symptoms.
