Xanomeline/Trospium in Treatment-Refractory Bipolar I Disorder With Psychosis: A Case Report of Rapid Agitation Control and Functional Improvement

While antipsychotics are mainstays in bipolar disorder, particularly in mania, the associated risk of extrapyramidal symptoms and metabolic adverse effects limit their use. Furthermore, a significant proportion of patients do not fully respond to antipsychotics, and residual symptoms may increase the frequency of relapse, precipitating significant impairment and poor outcomes.¹ To address the gap in care of antipsychotic refractory cases, novel neurotransmission mechanisms are being investigated.

A growing body of evidence hypothesizes that imbalances in cholinergic and catecholamine neurotransmission are implicated in mood dysregulation. Specifically, hypocholinergic-hyperadrenegic states underlie mania, and hypercholinergic-hypoadrenergic states underlie depressive symptoms.^2,3 Muscarinic M₁ and M₄ receptors are highly expressed in the cortex, hippocampus, and striatum; excitatory imbalance in these regions are proposed mechanisms of mania in animal studies.⁴ M₁ agonism leads to formation of inositol triphosphate (IP₃) with subsequent induction of calcium release.⁵ Of note, inositol metabolism and intracellular calcium signaling are also targeted in lithium’s multifaceted mechanisms of action.⁶ M4 inhibits adenylate cyclase and reduces cAMP formation—mechanisms that mood stabilizers utilize to regulate disruptions in neurotransmission in cortical and limbic regions during manic episodes. Accordingly, M₁ and M₄ receptors are potential therapeutic targets for the treatment of bipolar disorder.^3,5 Furthermore, previous small trials of muscarinic agonists physostigmine and xanomeline, acetylcholine precursors lecithin and choline, and acetylcholinesterase inhibitor donepezil have demonstrated improvement in patients with manic symptoms.⁷

Xanomeline/trospium is a novel oral antipsychotic that combines xanomeline, a muscarinic M₁ and M₄ agonist, with trospium, a peripheral muscarinic antagonist, to mitigate associated cholinergic adverse effects.⁸ Xanomeline/trospium was approved by the US Food and Drug Administration in September 2024 for adults with schizophrenia but is currently not indicated for bipolar disorder. To the knowledge of the authors, no other studies exist that have evaluated the efficacy of xanomeline/trospium for patients with bipolar mania at the time of writing this case report. The authors of this article present a patient case of bipolar disorder refractory to mood stabilizers and antipsychotics that responded to xanomeline/trospium initiation. To our knowledge, this is among the first reported cases describing the use of xanomeline/trospium in treatment-refractory bipolar I mania with psychotic features and severe agitation.

Case Presentation

“Carl” is a middle-aged man with obesity (BMI 35 kg/m²) and DSM-5 bipolar I disorder with psychotic features who presented to our psychiatric emergency department with severe agitation. His presentation was refractory to multiple prior pharmacologic trials, including quetiapine, aripiprazole, haloperidol, and chlorpromazine, as well as dual mood stabilization with lithium and valproate. He had no known substance use disorder or significant medical comorbidities. His psychiatric history was notable for 5 inpatient admissions over the preceding 2 years for similar episodes of acute behavioral dysregulation.

During the first week of admission, Carl’s home regimen was restarted, including valproate 2000 mg/day (serum level 95 μg/mL), lithium 1800 mg/day (serum level 0.8 mEq/L), quetiapine 600 mg/day, and aripiprazole 20 mg/day. Despite therapeutic dosing, he showed minimal clinical improvement and continued to require haloperidol 5 mg intramuscularly every 6 hours and lorazepam 2 mg intramuscularly twice daily, along with daily physical restraints.

During the second week, aripiprazole was discontinued. Scheduled haloperidol 10 mg orally twice daily and clonazepam 1 mg twice daily were added in response to persistent agitation and suspected akathisia. As-needed chlorpromazine 50 mg twice daily was also administered, but this did not meaningfully reduce his behavioral symptoms. Carl continued to require daily physical restraints and multiple doses of chlorpromazine as needed. Repeat laboratory testing was unremarkable, aside from a mild elevation in creatine kinase, which was attributed to physical restraint use.

During the third week, xanomeline/trospium was initiated and titrated to 100 mg/20 mg twice daily over 5 days while haloperidol was cross-tapered. Quetiapine was also discontinued during this transition. Following initiation and titration of xanomeline/trospium, Carl demonstrated a temporally associated and clinically significant reduction in agitation and required fewer doses of chlorpromazine as needed. He began responding to directions and independently using the bathroom and eating appropriately. With the support of a 1:1 sitter, he became more communicative about his needs. His thought process became more linear and logical, although mild loose associations persisted. Grandiosity lessened, paranoia decreased in intensity, and he was able to engage in basic reality testing. For the first time during the admission, he described his auditory hallucinations and their intensity. Although his mental status examination was initially limited by agitation, by the end of the third week, Carl was oriented to time, place, and person.

See the Table for more information.

Discussion

This case highlights the potential role of xanomeline/trospium chloride as an adjunctive option in severe, treatment-refractory manic episodes with psychotic features. Carl had persistent agitation despite treatment with multiple antipsychotics and mood stabilizers at therapeutic doses, requiring prolonged use of intramuscular antipsychotics, benzodiazepines, and physical restraints. After initiation of xanomeline/trospium, he demonstrated gradual but clinically meaningful improvement in behavioral control, organization of thought, and ability to engage with staff. These changes suggest that the medication may have contributed to symptom reduction in a setting where conventional approaches were insufficient.

The clinical significance of this case lies in the limited evidence base for xanomeline/trospium outside of schizophrenia. Although approved for schizophrenia, its muscarinic receptor activity may be relevant to affective and psychotic symptoms in bipolar disorder, particularly in patients with marked behavioral dysregulation and poor response to dopamine-blocking agents. In this patient, improvement was observed after xanomeline/trospium was introduced while other agents were cross-tapered, making it difficult to isolate the specific contribution of each medication change. Nevertheless, the temporal association between initiation of xanomeline/trospium and subsequent reduction in agitation supports consideration of this agent as a possible adjunct in similarly refractory cases.

An additional point of interest is the apparent improvement in Carl’s capacity for reality testing and verbalization of psychotic symptoms. By the end of the third week, he was able to describe his auditory hallucinations, engage more coherently in conversation, and follow commands with less prompting. This functional improvement may be particularly meaningful in psychiatric emergency and inpatient settings, where the primary goals are not only symptom reduction but also restoration of safety, communication, and ability to participate in care.

Several limitations should be acknowledged. First, this is a single case, and spontaneous improvement related to time, containment, sleep restoration, or concurrent medication adjustments cannot be excluded. Second, Carl received multiple sedating and antipsychotic agents during the same period, including haloperidol, lorazepam, clonazepam, and chlorpromazine, which complicates attribution of benefit. Third, the diagnosis of akathisia and the contribution of restraint-related stress to the clinical picture may have influenced both symptom severity and response over time. Finally, the optimal dose and duration of xanomeline/trospium in bipolar disorder remain unknown, and there are no established guidelines supporting its routine use for this indication.

Despite these limitations, this case adds to emerging clinical interest in nontraditional mechanisms of action for severe mood and psychotic illness. Given the patient’s long-standing refractoriness to standard treatment and the improvement observed after introduction of xanomeline/trospium, further study is warranted to evaluate whether muscarinic-targeting therapy may have a role in treatment-resistant bipolar disorder with psychotic features. Prospective studies and additional case reports will be needed to clarify efficacy, tolerability, and the patient populations most likely to benefit.

Dr Sharma is a board-certified psychiatrist and a faculty member at UC Davis Medical Center.

Dr White is a clinical psychiatric pharmacist at UC Davis Health.

Dr Santos is a board-certified psychiatric pharmacist at UC Davis Health.

References

1. Fountoulakis KN, Yatham LN, Grunze H, et al. The CINP Guidelines on the definition and evidence-based interventions for treatment-resistant bipolar disorder. Int J Neuropsychopharmacol. 2020;23(4):230-256.

2. Jeon WJ, Dean B, Scarr E, Gibbons A. The role of muscarinic receptors in the pathophysiology of mood disorders: a potential novel treatment? Curr Neuropharmacol. 2015;13(6):739-749.

3. González-Campos M, Vieta E. Muscarinic acetylcholine receptor agonists in bipolar disorder. Eur Neuropsychopharmacol. 2025;95:4-5.

4. Lee Y, Zhang Y, Kim S, Han K. Excitatory and inhibitory synaptic dysfunction in mania: an emerging hypothesis from animal model studies. Exp Mol Med. 2018;50(4):1-11.

5. Bymaster F, Felder C. Role of the cholinergic muscarinic system in bipolar disorder and related mechanism of action of antipsychotic agents. Mol Psychiatry 2002;7(Suppl 1):S57-S63.

6. Kato T. Current understanding of bipolar disorder: toward integration of biological basis and treatment strategies. Psychiatry Clin Neurosci. 2019;73(9):526-540.

7. McCaffrey U, Cannon DM, Hallahan B. The muscarinic-cholinergic system as a target in the treatment of depressive or manic episodes in bipolar disorder: a systematic review and meta-analysis. J Affect Disord Rep. 2021;6:100235.

8. Xanomeline-Trospium. Prescribing Information. BristolMyers Squibb; 2025. Accessed July 8, 2026. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/216158s000lbl.pdf