This is a Phase 3, 6-week, randomized, double-blind, placebo-controlled, multicenter, outpatient study in subjects with schizophrenia with an inadequate response to their current atypical antipsychotic treatment. The primary objective of the study is to assess the efficacy of adjunctive KarXT (a fixed dose combination of xanomeline and trospium chloride twice daily [BID]) versus placebo in the treatment of subjects with inadequately controlled symptoms of schizophrenia as measured by the Positive and Negative Syndrome Scale (PANSS) Total Score.

Inclusion Criteria:

1. Subject is aged ≥18 to <65 years at the time of randomization
2. Subject is capable of providing signed Informed Consent Form before any study assessments will be performed
3. Subject has a primary diagnosis of schizophrenia established by a comprehensive psychiatric evaluation based on the DSM-5 criteria and confirmed by Mini International Neuropsychiatric Interview for Schizophrenia and Psychotic Disorder Studies (MINI) version 7.0.2
4. Subject is currently being treated with stable dosing of monotherapy risperidone, paliperidone, aripiprazole, or their LAIs ziprasidone, lurasidone, or cariprazine and has been taking this treatment with the same dosing regimen for at least 8 weeks at the time of Day 1 (Visit 3)
5. The subject has had at least 1 previous inadequate response to above antipsychotics that was dosed appropriately (within the label) for at least 6 weeks
6. The subject has not required psychiatric hospitalization, incarceration in prison, acute crisis intervention, or other increase in the level of care due to symptom exacerbation within 8 weeks of Screening and is psychiatrically stable in the opinion of the Investigator
7. To be eligible for randomization, subjects need to have detectable levels of background antipsychotic medication (measured at Visit 1)
8. Positive and Negative Syndrome Scale (PANSS) total score ≥ 70 at Screening and randomization
9. Clinical Global Impression-Severity (CGI-S) scale with a score ≥ 4 (moderate) at Screening and randomization
10. PANSS Marder Positive symptom factor ≥ 4 on 2 (or more) items (PANSS items, delusions, hallucinations, grandiosity, suspiciousness and persecution, stereotyped thinking, somatic concern, unusual thought content or lack of judgment and insight), at Screening and randomization
11. Subjects with ≤ 20-point decrease in PANSS Total score between Visit 1 and Visit 3
12. Subject is willing and able to visit the clinic in an outpatient setting for the study duration, follow instructions, and comply with the protocol requirements
13. Body Mass Index (BMI) must be within 18 to 40 kg/m2 (inclusive of both values)
14. Subject resides in a stable living situation in the opinion of the Investigator
15. Subject has identified a reliable informant/ caregiver willing and able to assist with study activities as needed throughout the subject's participation in the study. The informant needs to be physically present at the Baseline visit, but can complete the remaining study visits assessments via phone (as needed and as per local regulations). In Bulgaria, the informant needs to physically present at the Baseline visit and should be physically present at all study visits where the Investigator determines that his/her input would be beneficial.
16. Women of childbearing potential (WOCP), or men whose sexual partners are WOCP, must be able and willing to use at least 1 highly effective method of contraception during the study and for at least 1 menstrual cycle (e.g., 30 days) after the last dose of study drug. Sperm donation is not allowed for 30 days after the final dose of the study drug. A female subject is considered to be a WOCP after menarche and until she is in a postmenopausal state for 12 months or otherwise permanently sterile (for which acceptable methods include hysterectomy, bilateral salpingectomy, or bilateral oophorectomy)

Exclusion Criteria:

1. Any primary DSM-5 disorder other than schizophrenia within 12 months before screening (confirmed using MINI version 7.0.2 at screening)

2. The subject has a history of moderate to severe substance use disorder (other than nicotine) within the past 12 months

   1. A Screening subject with mild substance use disorder within the 12 months before Screening must be discussed with the Medical Monitor before being allowed into the study
   2. Subjects who test positive for cannabis at Screening may be permitted to enroll in consultation with the Medical Monitor if the subject's pattern of use is not indicative of a moderate to severe substance use disorder

3. Subject has a history of treatment-resistant schizophrenia defined as:

   a. Failure to minimally respond to 2 adequate courses of antipsychotic drug (APD) pharmacotherapy Note: Failure to minimally respond is defined as persistence symptoms of moderate severity in 2 or more psychotic symptom domains or persistence of severe symptoms in 1 or more psychotic symptom domains despite adequate dose and duration (6 weeks or longer) of APD treatment.

4. History of symptom instability

   a. > 3 psychiatric hospitalizations over the last 12 months or 2 over the last 6 months

5. Current APD is other than aripiprazole, risperidone, paliperidone, or their LAI versions, ziprasidone, lurasidone, or cariprazine

6. Subjects who are diagnosed with schizophreniform disorder or are experiencing their first treated episode of schizophrenia

7. Significant or severe medical conditions including pulmonary, cardiovascular, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, or oncologic disease or any other condition that, in the opinion of the Investigator, could jeopardize the safety of the subject or the validity of the study results

   1. eGFR < 60 mL/min
   2. Alanine transaminase or aspartate transaminase (AST) > 1.5 x upper limit of normal (ULN)
   3. Total bilirubin > 1.5 x ULN (Subjects with Gilbert's syndrome can be included as long as direct bilirubin is ≤ 1.5 x ULN)

8. Subjects with human immunodeficiency virus (HIV), cirrhosis, biliary duct abnormalities, hepatobiliary carcinoma, and/or active hepatic viral infections as indicated by medical history, serologies or LFT results

9. History or high risk of urinary retention, gastric retention, or narrow-angle glaucoma as evaluated by the Investigator

10. History of irritable bowel syndrome (with or without constipation) or any serious constipation requiring treatment within the last 6 months

11. Risk for suicidal behavior during the study as determined by the Investigator's clinical assessment and/or C-SSRS as confirmed by the following:

    1. Answers "Yes" on items 4 or 5 (C-SSRS - ideation) with the most recent episode occurring within the 2 months before Screening or,
    2. Answers "Yes" to any of the 5 items (C-SSRS behavior) with an episode occurring within the 12 months before Screening

12. Clinically significant abnormal finding on the physical examination, medical history, ECG, or clinical laboratory results at Screening

13. Urine toxicology screen is positive for phencyclidine, amphetamines, opiates, cocaine, or alcohol (clinically significant alcohol use in the opinion of the Investigator)

14. Subject is currently taking, or plans to take while in the study, any prohibited concomitant medication.

15. Pregnant, lactating, or less than 3 months postpartum

16. If, in the opinion of the Investigator and/or Sponsor/Medical Monitor subject is unsuitable for enrollment in the study or subject has any finding that, in the view of the Investigator and/or Sponsor/Medical Monitor, may compromise the safety of the subject or affect his/her ability to adhere to the protocol visit schedule or fulfill visit requirements

17. Positive test for coronavirus (COVID-19) within 2 weeks or at Screening

18. Subjects with extreme concerns relating to global pandemics, such as COVID-19, that would obscure ratings or be expected to disrupt adherence to trial procedures

19. Unable to taper and discontinue a concomitant medication that would preclude participation in the double-blind adjunctive treatment (e.g., cannot stop anticholinergic)

20. Subjects with prior exposure to KarXT

21. Subjects who experienced any adverse effects due to xanomeline or trospium

22. Subjects who received investigational product as part of a clinical trial within 3 months of Screening

23. Risk of violent or destructive behavior as per Investigator's judgment that would interfere with subject's participation

24. Current involuntary hospitalization or incarcerationor on parole/probation

25. For all male subjects only, any one of the following:

    1. History of bladder stones
    2. History of recurrent urinary tract infections
    3. Serum prostate specific antigen (PSA) >10 ng/mL
    4. An International Prostate Symptom Score (IPSS) of 5 (almost always) on either item 1, 3, 5, or 6
    5. A sum of scores on IPSS items 1, 3, 5, and 6 of ≥9 Note: IPSS will be required only for male subjects ≥ 45 years of age. Subjects already enrolled in the study will have these assessments at their next clinic visit planned after re-consenting to determine current eligibility.