FDA Approves a New-Mechanism Schizophrenia Drug (2024)

Table of Contents

1. What the FDA Did
2. Who the Approval Covers
3. How the Label Describes the Drug’s Action
4. The Trials Behind the Approval
5. What the 5-Week Results Showed
6. Contraindications and Warnings
7. Side Effects Seen in the Trials
8. Dosing as the Label Describes It
9. Studies the FDA Required After Approval
10. What the Approval Does Not Do
11. Dates and Status as of 11 October 2026
12. How the Approval Fits the FDA’s Other Steps
13. Primary Documents
14. Key Research Papers
15. Connections

1. What the FDA Did

The FDA announced the decision in a press release dated 26 September 2024, “FDA Approves Drug with New Mechanism of Action for Treatment of Schizophrenia.” It states that the agency “approved [xanomeline and trospium chloride] capsules for oral use for the treatment of schizophrenia in adults.” (Product and company names are omitted on this page; the bracketed generic names stand in for the brand name the FDA uses.)

The approval letter, dated the same day, approves new drug application (NDA) 216158. The letter records that the application was dated and received on 26 September 2023 — one year before approval — and that it was submitted under section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act. The combination is entry 33 on the FDA’s list “Novel Drug Approvals for 2024,” dated 9/26/2024, with the use “To treat schizophrenia.” The FDA describes “novel” drugs on that list as “new drugs never before approved or marketed in the U.S.”; it counts 50 such approvals by its drug center in 2024.

The director of the Division of Psychiatry in the FDA’s Center for Drug Evaluation and Research is quoted in the release: “Schizophrenia is a leading cause of disability worldwide. It is a severe, chronic mental illness that is often damaging to a person’s quality of life. … This drug takes the first new approach to schizophrenia treatment in decades. This approval offers a new alternative to the antipsychotic medications people with schizophrenia have previously been prescribed.”

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2. Who the Approval Covers

The indication in the prescribing information is one sentence: the drug “is indicated for the treatment of schizophrenia in adults.” The label adds that “the safety and effectiveness … in pediatric patients have not been established,” and that the controlled studies did not include patients older than 65.

The FDA’s press release describes the illness this way: schizophrenia “can cause psychotic symptoms including hallucinations (such as hearing voices), difficulty controlling one’s thoughts and being suspicious of others. It can also be associated with cognitive problems and difficulty with social interactions and motivation.” It states that about 1% of Americans have the illness, that globally it is one of the 15 leading causes of disability, and that people with schizophrenia are at greater risk of dying at a younger age, with “nearly 5%” dying by suicide.

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3. How the Label Describes the Drug’s Action

The capsule holds two ingredients with opposite actions on the same receptor family, the muscarinic acetylcholine receptors. The label calls the product “a combination of xanomeline, a muscarinic agonist, and trospium chloride, a muscarinic antagonist.” An agonist switches a receptor on; an antagonist blocks it.

• Xanomeline. The label’s Mechanism of Action section states: “The mechanism of action of xanomeline in the treatment of schizophrenia is unclear; however, its efficacy is thought to be due to its agonist activity at M1 and M4 muscarinic acetylcholine receptors in the central nervous system.” Its Pharmacodynamics section adds that xanomeline binds all five muscarinic receptor subtypes (M1 to M5) with comparable affinity and “exhibits higher agonist activity at the M1 and M4 receptors.”
• Trospium chloride. The label states that trospium “antagonizes the muscarinic receptors primarily in the peripheral tissues” — that is, mainly outside the brain. The label describes it as a quaternary ammonium compound.

Several of the label’s warnings follow from this pairing. Some are typical of stimulating muscarinic receptors (the overdose section lists “cholinergic” signs such as vomiting, diarrhea, sweating and salivation), and others are typical of blocking them (the label lists “anticholinergic” effects such as dry mouth, constipation, urinary retention and blurred vision). The label states that an overdose “may produce cholinergic, anticholinergic or a combination of cholinergic and anticholinergic signs and symptoms.” It also reports that at the maximum dose the drug “does not prolong the QT interval to any clinically relevant extent” (the QT interval is a heart-rhythm measurement on an electrocardiogram).

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4. The Trials Behind the Approval

The press release and label describe two studies “with identical designs” (470 patients in the efficacy analysis):

• Design: 5-week, randomized, double-blind, placebo-controlled, multi-center studies in adults with schizophrenia diagnosed by DSM-5 criteria (the American psychiatric diagnostic manual). The label registers them as Study 1 (NCT04659161) and Study 2 (NCT04738123).
• Trial dosing: 50 mg xanomeline / 20 mg trospium twice daily for 2 days, then 100 mg / 20 mg twice daily for the rest of week 1; on day 8 the dose was raised to 125 mg / 30 mg twice daily unless the patient could not tolerate it, and any patient could return to 100 mg / 20 mg.
• Who took part: median age 46 (range 19 to 65); 25% women; 68% Black or African American, 31% White, 1% other or not reported. No patient was over 65.
• Main measure: the change in the Positive and Negative Syndrome Scale (PANSS) total score at week 5. The label explains that the PANSS is a 30-item scale, each item rated by a clinician from 1 (absent) to 7 (extremely severe), so the total runs from 30 to 210, with higher scores meaning more severe symptoms.

The label’s safety section draws on a larger group: 1,594 people exposed to at least one dose, including 1,135 adults with schizophrenia and 389 healthy volunteers; 347 patients had at least 6 months of exposure and 150 at least one year (defined as at least 50 weeks), from open-label studies.

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5. What the 5-Week Results Showed

The press release states that in both studies, patients on the drug “experienced a meaningful reduction in symptoms from baseline to Week 5 as measured by the PANSS Total Score compared to the placebo group.” Table 4 of the label gives the numbers (least-squares mean change from baseline; a negative change means fewer symptoms):

• Study 1: 117 patients on the drug and 119 on placebo, baseline scores about 98. Change at week 5: −21.2 points on the drug vs −11.6 on placebo. Placebo-subtracted difference −9.6 points (95% confidence interval −13.9 to −5.2), statistically significant.
• Study 2: 114 patients on the drug and 120 on placebo, baseline scores about 97. Change at week 5: −20.6 vs −12.2. Difference −8.4 points (−12.4 to −4.3), statistically significant.

A secondary measure, the Clinical Global Impression–Severity (CGI-S) scale, a clinician’s 1-to-7 rating of how ill a patient is overall, also improved significantly more than on placebo in Study 1, according to the label. The label states that examining subgroups by age, sex and race “did not suggest differences in response.” Placebo groups also improved substantially in both studies; the drug’s effect is the extra improvement beyond placebo.

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6. Contraindications and Warnings

A contraindication is a condition in which the label states the drug is not to be used. The label lists five: urinary retention; moderate or severe liver impairment (Child-Pugh Class B or C, a standard grading of liver disease); gastric retention (a stomach that does not empty); a history of hypersensitivity to the product or to trospium chloride; and untreated narrow-angle glaucoma.

The label’s Warnings and Precautions section covers nine risks, summarized here as the label states them:

• Urinary retention. Older patients and people with bladder outlet obstruction, such as an enlarged prostate, “may be at increased risk.” The drug is not recommended in moderate or severe kidney impairment.
• Liver impairment. Xanomeline levels are higher in people with liver impairment; the drug is not recommended in mild liver impairment and is contraindicated in moderate or severe impairment. The label calls for liver enzymes to be checked before starting.
• Biliary disease. Trials saw “transient increases in liver enzymes with rapid decline,” consistent with brief bile-duct obstruction and possible gallstone passage. The drug is not recommended for active biliary disease such as symptomatic gallstones, and the label directs that it be stopped if signs of substantial liver injury appear, such as jaundice, itching, or the liver enzyme ALT rising above five times normal.
• Slowed movement of the gut, from the trospium component, with a risk of gastric retention.
• Angioedema — swelling of the face, lips, tongue or larynx — reported with the product and with trospium; the label notes that swelling of the upper airway “may be life-threatening.”
• Narrow-angle glaucoma: pupil dilation from the anticholinergic effect “may trigger an acute angle closure attack” in people with anatomically narrow angles.
• Increased heart rate, with heart rate to be assessed at baseline and during treatment.
• Anticholinergic effects in kidney impairment: trospium is “substantially excreted by the kidney,” and the label expects effects such as dry mouth, constipation and urinary retention to be greater when kidney function is reduced (estimated GFR below 60 mL/min).
• Central nervous system effects: dizziness, confusion, hallucinations and sleepiness have been reported with trospium chloride.

The label’s drug-interaction section lists four groups: strong inhibitors of the liver enzyme CYP2D6 (which can raise xanomeline levels), drugs eliminated by active tubular secretion in the kidney, oral drugs that are sensitive substrates of CYP3A4, and oral drugs that are substrates of P-glycoprotein (xanomeline briefly inhibits both in the gut). Decisions about any medicine belong with a clinician who knows the person’s full history and other prescriptions.

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7. Side Effects Seen in the Trials

The press release lists the most common side effects as “nausea, indigestion, constipation, vomiting, hypertension, abdominal pain, diarrhea, tachycardia (increased heartbeat), dizziness and gastroesophageal reflux disease.” Table 1 of the label gives the rates in the two pooled 5-week trials (251 patients on the drug, 253 on placebo):

• Nausea 19% vs 4%; indigestion (dyspepsia) 18% vs 5%; constipation 17% vs 7%; vomiting 15% vs 1%.
• High blood pressure 11% vs 2%; abdominal pain 8% vs 4%; diarrhea 6% vs 2%.
• Fast heart rate 5% vs 2%; dizziness 5% vs 2%; acid reflux 5% vs under 1%.
• Dry mouth 4% vs 2%; sleepiness 3% vs 2%; blurred vision 3% vs 0%.

Other figures from the label’s safety section:

• Stopping for side effects: 6% on the drug vs 4% on placebo in the 5-week trials; nausea (2%) and vomiting (1%) were the side effects that most often led to stopping.
• Heart rate: the rise peaked on day 8 (13.5 beats per minute on the drug vs 4.0 on placebo) and eased with continued dosing (11.4 vs 5.5 at week 5). In a separate 8-week study with 24-hour monitoring, the mean rise was 9.8 beats per minute.
• Liver enzymes: ALT or AST above three times normal in 2.8% (6 of 214) on the drug vs 0.4% (1 of 224) on placebo; most elevations came in the first month and resolved with continued use, and one case involved a rise in bilirubin.
• Urinary retention: 0.8% on the drug vs 0.4% on placebo in the 5-week trials, and 3.5% in the long-term open-label studies, more often in men, older patients and those with risk factors. Across all 1,594 people exposed, four needed a urinary catheter.

The label also lists reactions reported during post-approval use of trospium chloride on its own, including chest pain, hypertensive crisis, palpitations, fainting, rhabdomyolysis (muscle breakdown), delirium, hallucinations, anaphylactic reaction and Stevens-Johnson syndrome (a severe skin reaction).

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8. Dosing as the Label Describes It

The label’s dosing section, reported here as the FDA-approved label states it:

• Before starting: liver enzymes and bilirubin checked, and heart rate assessed.
• Starting dose: one 50 mg / 20 mg capsule (xanomeline / trospium chloride) twice daily for at least two days, then one 100 mg / 20 mg capsule twice daily for at least five days.
• Increase: the dose “may be increased” to 125 mg / 30 mg twice daily, the maximum, based on tolerability and response.
• Meals: taken at least one hour before or two hours after a meal; the capsules are not to be opened.
• Older adults: a slower increase may be considered, and the maximum is one 100 mg / 20 mg capsule twice daily, because of the urinary-retention risk.

The label notes a pregnancy exposure registry that monitors outcomes in women exposed to psychiatric medicines, including this one, and states that there are no data on its use in pregnant women and no data on its presence in human milk.

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9. Studies the FDA Required After Approval

The approval letter attaches several required postmarketing studies. Under the Pediatric Research Equity Act the FDA waived pediatric studies for ages 12 and under, “because necessary studies are impossible or highly impracticable,” and deferred them for ages 13 to 17 because the product was ready for approval in adults. Two adolescent studies are required:

• a randomized, double-blind, placebo-controlled efficacy and safety study in ages 13 to 17 (study completion due 12/2029, final report 06/2030);
• an open-label, long-term safety study of at least 52 weeks in the same age group (completion 12/2030, final report 06/2031).

Under section 505(o) of the Act, the letter states the FDA determined that routine adverse-event reporting “will not be sufficient to assess these serious risks” and requires:

• a lactation study measuring xanomeline and trospium in breast milk;
• a prospective pregnancy exposure registry and a separate retrospective pregnancy study using claims or health-record data, both looking at birth defects, miscarriage, stillbirth, preterm birth and small-for-age babies;
• a non-invasive, one-year urological safety study of effects on bladder emptying, “especially urinary retention” (completion 12/2027, final report 06/2028);
• drug-interaction studies with a CYP3A4 substrate and a P-glycoprotein substrate (completion 09/2026), and a pharmacogenetic study of how CYP2D6 gene variants affect xanomeline levels (completion 03/2027).

The letter also states that the application “was not referred to an FDA advisory committee because the clinical trial design is similar to previously approved products in the class and the evaluation of the safety data … did not raise significant safety or efficacy issues that were unexpected.”

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10. What the Approval Does Not Do

• It does not cover children or teenagers. The indication is for adults, and pediatric safety and effectiveness have not been established; studies in ages 13 to 17 are still required.
• It does not cover other psychotic disorders. The indication names schizophrenia only.
• It does not rest on long-term controlled evidence. The efficacy evidence the FDA describes is two 5-week placebo-controlled trials; longer exposure in the label comes from open-label studies without a placebo group.
• It does not include data in people over 65 from the controlled trials; the label sets a lower maximum dose for older adults.
• It does not replace the older drugs. The FDA describes it as “a new alternative” to previously prescribed antipsychotics; the press release makes no comparison with any of them.

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11. Dates and Status as of 11 October 2026

• 27 July 1992: the investigational new drug application (the exemption that allows testing in people) became effective, according to the FDA’s 2026 patent-term notice, which states this was 30 days after the FDA received an earlier application.
• 26 September 2023: the new drug application was submitted and received.
• 26 September 2024: FDA approval (NDA 216158).
• 21 November 2025: the FDA announced a new draft product-specific guidance for the trospium chloride / xanomeline tartrate combination (see section 12).
• 6 February 2026: the FDA published its regulatory review period determination for patent-extension purposes.

Status as of 11 October 2026: approved; final action. The labeling posted on the National Library of Medicine’s DailyMed service (version 6, effective January 2026) carries the same indication, “the treatment of schizophrenia in adults,” the same five contraindications and the same mechanism wording. A check of the Federal Register through 11 October 2026 found no FDA document withdrawing the approval or changing the indication. The FDA documents found that mention the drug are the 2025 product-specific guidance notice and the 2026 patent-term notice; the other Federal Register hits were Medicare payment rules issued by a different agency, not FDA actions.

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12. How the Approval Fits the FDA’s Other Steps

A long testing phase. The FDA’s patent-term notice of 6 February 2026 (91 FR 5494, Docket Nos. FDA-2025-E-0152, -0153 and -0154) sets the drug’s regulatory review period at 11,751 days: 11,384 days of testing, counted from the 1992 investigational application, and 367 days of FDA review. The notice records that the patent holder had claimed an August 2016 start date for testing and a 27 September 2024 approval date, and that FDA records show 27 July 1992 and 26 September 2024 instead. The notice explains that this period sets the maximum possible patent extension, which the U.S. Patent and Trademark Office then limits by statute; the applicant sought 1,124 or 1,191 days. Comments and requests for redetermination were open until 7 April 2026, and due-diligence petitions until 5 August 2026.

Groundwork for generic versions. On 21 November 2025 the FDA announced new draft product-specific guidances (90 FR 52681, Docket No. FDA-2007-D-0369), with “Trospium chloride; Xanomeline tartrate” on the list of new ones. The notice explains that such guidances give “product-specific recommendations on, among other things, the design of bioequivalence (BE) studies to support abbreviated new drug applications (ANDAs)” — the applications used for generic copies. A draft guidance is not an approval of any generic.

A new class among antipsychotics. The FDA presented the approval as the first antipsychotic targeting cholinergic rather than dopamine receptors. The earlier research on xanomeline alone, in Alzheimer’s disease in the 1990s and in a small schizophrenia study in 2008, is listed under Key Research Papers.

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13. Primary Documents

1. U.S. Food and Drug Administration (2024). FDA Approves Drug with New Mechanism of Action for Treatment of Schizophrenia. Press release, 26 September 2024 — fda.gov press release
2. U.S. Food and Drug Administration, CDER. Novel Drug Approvals for 2024 (entry 33, 9/26/2024) — fda.gov Novel Drug Approvals for 2024
3. U.S. Food and Drug Administration (2024). NDA approval letter, NDA 216158 (xanomeline and trospium chloride capsules), 26 September 2024 — accessdata.fda.gov approval letter (PDF)
4. Prescribing information for xanomeline and trospium chloride capsules, NDA 216158, as approved (initial U.S. approval 2024) — accessdata.fda.gov label (2024, PDF)
5. Current labeling for xanomeline and trospium chloride capsules (SPL version 6), National Library of Medicine DailyMed — DailyMed labeling
6. Food and Drug Administration, HHS (2025). Product-Specific Guidances; Draft and Revised Draft Guidances for Industry; Availability. Federal Register 90 FR 52681–52683, 21 November 2025. Docket No. FDA-2007-D-0369 — FR Doc. 2025-20548
7. Food and Drug Administration, HHS (2026). Determination of Regulatory Review Period for Purposes of Patent Extension (xanomeline tartrate and trospium chloride; product name omitted here). Federal Register 91 FR 5494–5495, 6 February 2026. Docket Nos. FDA-2025-E-0152, FDA-2025-E-0153 and FDA-2025-E-0154 — FR Doc. 2026-02388

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Key Research Papers

1. Bodick NC, Offen WW, Levey AI, Cutler NR, Gauthier SG, Satlin A, Shannon HE, Tollefson GD, Rasmussen K, Bymaster FP, Hurley DJ, Potter WZ, Paul SM (1997). Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease. Archives of Neurology 54(4):465-473. A 6-month trial of xanomeline alone in 343 people with Alzheimer’s disease; it reported reductions in hallucinations, delusions and agitation, and 52% of the high-dose group stopped because of side effects, mainly gastrointestinal — PubMed PMID: 9109749
2. Shekhar A, Potter WZ, Lightfoot J, Lienemann J, Dubé S, Mallinckrodt C, Bymaster FP, McKinzie DL, Felder CC (2008). Selective muscarinic receptor agonist xanomeline as a novel treatment approach for schizophrenia. American Journal of Psychiatry 165(8):1033-1039. A 4-week pilot trial of xanomeline alone in 20 people with schizophrenia — PubMed PMID: 18593778
3. Brannan SK, Sawchak S, Miller AC, Lieberman JA, Paul SM, Breier A (2021). Muscarinic Cholinergic Receptor Agonist and Peripheral Antagonist for Schizophrenia. New England Journal of Medicine 384(8):717-726. The 182-patient phase 2 trial of the combination; PANSS fell 17.4 points vs 5.9 on placebo over 5 weeks — PubMed PMID: 33626254
4. Kaul I, Sawchak S, Walling DP, Tamminga CA, Breier A, Zhu H, Miller AC, Paul SM, Brannan SK (2024). Efficacy and Safety of Xanomeline-Trospium Chloride in Schizophrenia: A Randomized Clinical Trial. JAMA Psychiatry 81(8):749-756. The phase 3 trial registered as NCT04738123 (Study 2 in the label), 256 participants — PubMed PMID: 38691387
5. Kaul I, Claxton A, Sauder C, Patel T, Chaturvedi S, Brown D, Zhu H, Marcus R, Sawchak S, Brannan SK (2026). Long-Term Safety and Efficacy of Xanomeline and Trospium Chloride in Schizophrenia: A 52-Week Open-Label Extension Trial. American Journal of Psychiatry 183(3):183-192. An open-label extension without a placebo group; 34 of 156 enrolled participants completed 52 weeks — PubMed PMID: 41634905

PubMed Topic Searches

1. PubMed: xanomeline-trospium
2. PubMed: muscarinic agonists in schizophrenia
3. PubMed: xanomeline

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Connections

• FDA Actions of 2024
• FDA and Regulation
• Schizophrenia
• Schizophrenia: History
• Psychiatry
• MDMA for PTSD Not Approved (2024)
• Donanemab for Early Alzheimer’s Disease (2024)
• Resmetirom for Fatty-Liver Scarring (2024)
• Nasal Epinephrine for Anaphylaxis (2024)

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