Articles

Efficacy and safety of the muscarinic receptor agonist KarXT

(xanomeline–trospium) in schizophrenia (EMERGENT-2) in
the USA: results from a randomised, double-blind, placebo-
controlled, flexible-dose phase 3 trial
Inder Kaul, Sharon Sawchak, Christoph U Correll, Rishi Kakar, Alan Breier, Haiyuan Zhu, Andrew C Miller, Steven M Paul, Stephen K Brannan

Summary
Lancet 2024; 403: 160–70 Background New treatments with new mechanisms are urgently needed for people with schizophrenia. Xanomeline
Published Online is a dual M₁ and M₄-preferring muscarinic receptor agonist that does not block D₂ dopamine receptors, unlike all
December 14, 2023 currently approved treatments for schizophrenia. Xanomeline–trospium (KarXT) combines xanomeline with the
https://doi.org/10.1016/
peripherally restricted muscarinic receptor antagonist trospium chloride with the goal of ameliorating xanomeline-
S0140-6736(23)02190-6
related adverse events associated with peripheral muscarinic receptors. The EMERGENT-2 trial aimed to assess the
This online publication has been
corrected. The corrected version
efficacy and safety of KarXT in people with schizophrenia experiencing acute psychosis.
first appeared at thelancet.com
on May 30, 2024 Methods EMERGENT-2 was a randomised, double-blind, placebo-controlled, flexible-dose, 5-week, inpatient, phase 3
See Comment page 120 trial in people with schizophrenia. Participants were adults aged 18–65 years with a diagnosis of schizophrenia who
Karuna Therapeutics, Boston, had a recent worsening of psychosis warranting hospital admission, a Positive and Negative Syndrome Scale (PANSS)
MA, USA (I Kaul MD, score of 80 or higher, and a Clinical Global Impression-Severity score of 4 or higher. The participants were recruited
S Sawchak RN, H Zhu PhD,
A C Miller PhD, S M Paul MD,
from 22 inpatient sites in the USA, and were randomly assigned (1:1) to KarXT or placebo twice per day. Participants
S K Brannan MD); Department randomly assigned to KarXT received 50 mg xanomeline and 20 mg trospium twice per day for the first 2 days and
of Psychiatry, Zucker Hillside then 100 mg xanomeline and 20 mg trospium twice per day for days 3–7. Beginning on day 8, KarXT dosing was
Hospital, Glen Oaks, NY, USA flexible with an optional increase to 125 mg xanomeline and 30 mg trospium twice per day and the option to return to
(Prof C U Correll MD);
Departments of Psychiatry and
100 mg xanomeline and 20 mg trospium based on tolerability. The primary endpoint was change from baseline to
Molecular Medicine, Donald week 5 in PANSS total score. Efficacy analyses used the modified intention-to-treat population (all randomly assigned
and Barbara Zucker School of participants who received at least one trial medication dose and had at least one post-baseline PANSS assessment).
Medicine at Hofstra/Northwell, Least squares mean change from baseline, SE, and least squares mean difference between the KarXT and placebo
Hempstead, NY, USA
(C U Correll); Department of
groups at week 5, along with the 95% CI and two-sided p values were calculated for the primary and secondary
Child and Adolescent continuous efficacy endpoints. Safety analyses included all participants receiving at least one trial medication dose
Psychiatry, Charité and used descriptive statistics. This trial is registered with ClinicalTrials.gov (NCT04659161).
Universitätsmedizin Berlin,
Berlin, Germany (C U Correll);
Segal Trials, Miami Lakes, FL,
Findings From Dec 16, 2020, to April 13, 2022, of 407 people who were screened, 252 participants meeting enrolment
USA (R Kakar MD); Department criteria were randomly assigned to the KarXT (n=126) or placebo (n=126). Baseline PANSS total scores were 98·3 (KarXT;
of Psychiatry, Indiana n=126) and 97·9 (placebo; n=125). The trial met the primary endpoint with a mean change from baseline to week 5 in
University School of Medicine, PANSS total score that favoured KarXT (–21·2 points, SE 1·7) versus placebo (–11·6 points, 1·6; least squares mean
Indianapolis, IN, USA
(Prof A Breier MD)
difference –9·6; 95% CI –13·9 to –5·2; p<0·0001, Cohen’s d effect size=0·61). All secondary endpoints were also met,
Correspondence to:
and favoured KarXT versus placebo (p<0·05). The most common adverse events with KarXT versus placebo were
Dr Steven M Paul, Karuna constipation (27 [21%] vs 13 [10%]), dyspepsia (24 [19%] vs 10 [8%]), headache (17 [14%] vs 15 [12%]), nausea (24 [19%] vs
Therapeutics, Boston, MA, USA seven [6%]), vomiting (18 [14%] vs one [1%]), hypertension (12 [10%] vs one [1%]), dizziness (11 [9%] vs four [3%]), gastro-
spaul@karunatx.com oesophageal reflux disease (eight [6%] vs zero [0%]), and diarrhoea (seven [6%] vs four [3%]). Treatment-emergent adverse
event rates of extrapyramidal motor symptoms (KarXT, zero [0%] vs placebo, zero [0%]), akathisia (one [1%] vs one [1%]),
weight gain (zero [0%] vs one [1%]), and somnolence (six [5%] vs five [4%]) were similar between the KarXT and placebo
groups, as were adverse event-related discontinuation rates (nine [7%] vs seven [6%]).

Interpretation In the EMERGENT-2 trial, KarXT was effective in reducing positive and negative symptoms and was
generally well tolerated. These results support the potential for KarXT to represent a new class of effective and well
tolerated antipsychotic medicines based on activating muscarinic receptors, not the D₂ dopamine receptor-blocking
mechanism of all current antipsychotic medications. Results from additional trials, including the identical
EMERGENT-3 trial and the 52-week, open-label EMERGENT-4 and EMERGENT-5 trials, will provide additional
information on the efficacy and safety of KarXT in people with schizophrenia.

Funding Karuna Therapeutics.

Copyright © 2023 Elsevier Ltd. All rights reserved.

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Research in context
Evidence before this trial and clinically meaningful reduction in Positive and Negative
We searched PubMed from inception to Dec 6, 2020 for Syndrome Scale total score, improvement in several secondary
randomised controlled trials published in English using the outcome measures, and was generally safe and well tolerated.
search term “xanomeline”. We identified two studies. In
Implications of all the available evidence
previous randomised controlled trials, xanomeline
This trial showed that KarXT was effective in reducing positive
demonstrated antipsychotic activity in people with
and negative symptoms and generally well tolerated in people
schizophrenia or Alzheimer’s disease, but its clinical
with schizophrenia. In the EMERGENT-2 trial, the most
development was limited by gastrointestinal adverse events.
common side-effects with KarXT were constipation, dyspepsia,
Phase 1 and 2 trials demonstrated that adding the peripherally
nausea, vomiting, hypertension, dizziness, and gastro-
restricted muscarinic receptor antagonist trospium chloride
oesophageal reflux disease, which reflect the mechanisms of
reduced the frequency and severity of gastrointestinal adverse
xanomeline and trospium. KarXT demonstrated a distinctive
events with xanomeline. In the phase 2 EMERGENT-1 trial in
safety and tolerability profile and was not associated with many
people with schizophrenia experiencing acute psychosis, KarXT
of the adverse events typically associated with current
(xanomeline-trospium) demonstrated antipsychotic efficacy
antipsychotic treatments, including extrapyramidal motor
and was generally safe and well tolerated.
symptoms, weight gain, changes in lipid and glucose
Added value of this trial parameters, and somnolence. KarXT has the potential to be the
KarXT again demonstrated efficacy and tolerability in people first of a new class of effective and well tolerated antipsychotic
with schizophrenia experiencing acute psychosis in the medicines on the basis of activating muscarinic receptors, as
EMERGENT-2 trial. In this randomised, double-blind, placebo- opposed to the D₂ dopamine-receptor blocking activity
controlled, phase 3 trial, KarXT was associated with a significant associated with all current antipsychotic medications.

Introduction Antipsychotic drugs have established efficacy in treating

Schizophrenia is a serious, disabling brain disorder that only positive symptoms, but have limited efficacy for
often begins in late adolescence or early adulthood and is negative or cognitive symptoms. Moreover, approxi­
typically followed by a chronic course marked by relapses, mately 30% of people with schizophrenia are treatment
hospital admissions, and substantial morbidity and resistant to antipsychotic drugs, defined as not responding
mortality.1,2 It is a leading cause of disability and years of to two or more antipsychotic drugs, and many more derive
life lost globally.3,4 Schizophrenia is also associated with only partial positive symptom benefit.11 One study
one of the highest mortality rates among all psychiatric found that almost one of four people with first-episode
illnesses, a life expectancy reduced by 15–30 years, and psychosis or schizophrenia will develop treatment-
an estimated lifetime suicide rate of 4·9%.5–8 resistant schizophrenia during the early stages of
The primary symptom domains of schizophrenia are treatment.12 Antipsychotic drugs are a heterogenous
positive symptoms (eg, delusions and hallucinations), class of medication and can cause a range of substantial
negative symptoms (eg, constricted affect and asociality), short-term and long-term side-effects, including
and cognitive symptoms. Cognitive symptoms are a core extrapyramidal motor symptoms or akathisia, tardive
clinical feature and people with schizophrenia commonly dyskinesia, hyperprolactinemia, weight gain, metabolic
show poor performance on measures of executive disturbances, and somnolence or sedation, each of which
function, long-term memory, sustained attention, and contributes to substantial morbidity, an estimated non-
general intellectual impairment, often at illness onset.2 adherence rate between 40% and 50%, and subsequent
The mainstays for treating schizophrenia are antipsychotic relapses.9,13 Some of these side-effects emerge after longer-
drugs. More than 30 antipsychotic drugs have been term use. An important unmet medical need exists for
approved by the European Medicines Agency, the US people with schizophrenia, and new treatments with
Food and Drug Administration, and other regulatory novel mechanisms are urgently needed.
authorities,9 and all act as direct or functional (eg, via Increasing evidence suggests that muscarinic
partial agonism) D2 dopamine receptor antagonists.10 acetylcholine receptors are involved in schizophrenia
Many have additional effects, including antagonism pathophysiology, representing promising new treatment
of serotonin (particularly 5-hydroxy-tryptamine 2A), targets for schizophrenia.14 Xanomeline is an oral
adrenergic, and histaminergic receptors.10 Currently muscarinic receptor agonist devoid of direct D2 dopamine
available antipsychotic drugs are generally divided into receptor effects.15 It is a preferential agonist of
two classes, first and second generation, with second- M₁ and M₄ muscarinic receptors, which have been
generation antipsychotic drugs in predominant use today. implicated in schizophrenia.14 In two previous placebo-
The largely conserved pharmacology across available controlled clinical trials in Alzheimer’s disease16 and
antipsychotic drugs, however, results in similar outcomes schizophrenia,17 xanomeline was associated with a
that are inadequate for many people with schizophrenia. reduction in psychotic symptoms and improved

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cognition. However, xanomeline was associated with secondary objectives of the trial were to evaluate the
high rates of primarily gastrointestinal adverse events, reduction in PANSS positive subscale, PANSS negative
which contributed to the eventual suspension of further subscale, PANSS Marder negative factor, and CGI-S score;
clinical development of xanomeline monotherapy. percentage of PANSS responders (≥30% reduction); and
Xanomeline–trospium (KarXT) combines xanomeline the safety and tolerability of KarXT compared with
with trospium chloride, with the goal of ameliorating placebo.
adverse events associated with xanomeline’s activation of
peripheral muscarinic receptors in peripheral tissues. Methods
Trospium is an oral, pan-muscarinic receptor antagonist Trial design and participants
that is peripherally restricted because of its inability to EMERGENT-2 (NCT04659161) was a phase 3, multicentre,
cross the blood–brain barrier. Trospium is approved for inpatient, randomised, double-blind, placebo-controlled
the treatment of overactive bladder in the USA and trial done at 22 inpatient sites in the USA. The trial
the EU.18 The highly polar quaternary amine structure of consisted of a 7-day to 14-day screening phase and a
trospium prevents it from entering the CNS. In a 5-week treatment period. The protocol and consent form
phase 1 trial in healthy volunteers (NCT02831231), KarXT were reviewed and approved by an independent ethics
demonstrated an approximately 50% lower incidence of committee and central institutional review board (WCG
adverse events, which were primarily gastrointestinal in IRB, Puyallup, WA, USA; tracking number 20203606),
nature, compared with xanomeline alone.19 These results and the trial was conducted in compliance with the
provide evidence that KarXT enables the administration of International Council for Harmonisation guidelines for
therapeutic doses of xanomeline with reduced adverse current Good Clinical Practice, ethical principles of the
events. In the double-blind, phase 2 EMERGENT-1 trial Declaration of Helsinki, and applicable regulatory
(NCT03697252), 182 people with acutely exacerbated requirements.
schizophrenia were randomly assigned to receive KarXT Participants were aged 18–65 years with a primary
twice per day (increased to a maximum of 125 mg diagnosis of schizophrenia established by comprehensive
xanomeline and 30 mg trospium per dose) or placebo for psychiatric evaluation on the basis of criteria in the
5 weeks.20 The mean change from baseline to week 5 in Diagnostic and Statistical Manual of Mental Disorders,
Positive and Negative Syndrome Scale (PANSS)21 total fifth edition,24 and confirmed by Mini International
score was –17·4 points with KarXT and –5·9 points with Neuropsychiatric Interview for Schizophrenia and
placebo (least squares mean difference –11·6 points; Psychotic Disorders version 7.0.2.25 Other key inclusion
95% CI –16·1 to –7·1; p<0·0001; Cohen’s d effect criteria were as follows: an acute exacerbation or relapse
size 0·75). Results for secondary outcome measures, of psychotic symptoms requiring hospital admission
namely change in PANSS positive subscale score, PANSS with onset less than 2 months before screening; a
negative subscale score, and PANSS Marder negative PANSS total score of 80–120 (range 30–210; higher
factor significantly favoured KarXT over placebo (p<0·05), scores indicate more severe symptoms) with a score
except the percentage of participants with a Clinical Global of 4 or higher (moderate or greater) on at least two of
Impression-Severity (CGI-S) score of 1 (normal, not ill at four symptoms (delusions, conceptual disorganisation,
all) or 2 (borderline ill).22 KarXT was generally safe and hallucinatory behaviour, and suspiciousness or
well tolerated; adverse events associated with KarXT were persecution; and a CGI-S22 scale score of 4 or higher,
mild to moderate and included gastrointestinal events, indicating a person who is moderately ill (range 1–7,
including nausea, vomiting, and constipation, as well as with higher scores reflecting greater severity) at
dyspepsia and dry mouth, each of which tended to be screening and baseline. Key inclusion and exclusion
See Online for appendix limited to the first 1–3 weeks.23 On the basis of the criteria are detailed in the appendix (pp 2–3). Informed
positive EMERGENT-1 trial, a phase 3 programme written consent was obtained from eligible participants
consisting of two inpatient trials in adults with acute before the start of trial procedures.
exacerbation of schizophrenia using the same
fundamental design as EMERGENT-1, designated the Randomisation and masking
EMERGENT-2 (NCT04659161) and EMERGENT-3 Eligible participants were randomly assigned 1:1 to receive
(NCT04738123) trials, and two 52-week trials of long-term oral KarXT twice per day or placebo supplied by the
safety and tolerability of KarXT, designated EMERGENT-4 sponsor as matching capsules that were identical in size,
(NCT04659174) and EMERGENT-5 (NCT04820309), were shape, colour, and appearance. Randomisation was done
initiated. In addition, the ongoing ARISE (NCT05145413) by the clinical research organisation VERISTAT
trial is assessing KarXT as adjunctive therapy in people (Southborough, MA, USA) using a computer-generated
with insufficient treatment response to antipsychotic participant identification number and randomisation
drugs. The primary objective of the EMERGENT-2 trial schedule with block randomisation, which were concealed
reported here was to evaluate the efficacy of KarXT versus from participants, trial personnel, and investigators.
placebo in reducing PANSS total score in adult inpatients Access to the randomisation schedule was limited only to
with schizophrenia experiencing acute psychosis. The independent biometrics personnel and the authorised

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pharmacy personnel or designee at each trial site. The positive subscale score (range 7–49), PANSS negative
clinical team, members of the contract research subscale score (range 7–49),21 PANSS Marder negative
organisation, statisticians, laboratory personnel, and the factor score (range 7–49),29 and CGI-S scale score
sponsor were masked to treatment group assignments. (range 1–7),22 as well as the percentage of PANSS
responders at week 5 (≥30% improvement from baseline
Procedures in PANSS total score).
Oral antipsychotic medications, monoamine oxidase Safety was assessed through adverse event (defined
inhibitors, mood stabilisers, anticonvulsants, tricyclic using preferred terms of Medical Dictionary for Regulatory
antidepressants, selective serotonin reuptake inhibitors, Activities version 23.1) monitoring and by measuring
or other psychoactive medications were required to have vital signs and weight, clinical laboratory evaluations,
a washout period of at least five half-lives or 1 week, and electrocardiogram parameters. Treatment-emergent
whichever was longer, before the baseline visit. Long- adverse events (TEAEs) were rated for severity. The SAS
acting injectable antipsychotics were stopped at least assessed extrapyramidal motor symptoms (range 0–40;
12 weeks (at least 24 weeks for paliperidone higher scores indicating greater parkinsonian symptoms),
palmitate injection every 3 months) before baseline. the BARS assessed akathisia (range 0–14; higher scores
Benzodiazepines for anxiety, agitation, or insomnia or indicating greater symptoms of akathisia), and AIMS was
sleep aids were permitted on an as-needed basis. used to assess dyskinesia (range 0–28; rating ≥2 indicating
Baseline characteristics were ascertained on the day dyskinesia). The trial included pharmacokinetic and
before randomisation and trial medication was started. exploratory endpoints that are not reported here.
The day on which trial medication was started was day 1 of
the 5-week treatment period. Participants randomly Statistical analysis
assigned to the KarXT group were given doses in the first Statistical analyses were done using SAS statistical
2 days starting from 50 mg xanomeline and 20 mg analysis software version 9.4.30
trospium twice per day and then for days 3–7 Assuming a PANSS total score difference of 8 points
100 mg xanomeline and 20 mg trospium twice per day. in the change from baseline to week 5 between KarXT
Beginning on day 8, there was flexible dosing with an and placebo and an SD of 16 on the basis of results
optional dose increase to a maximum of 125 mg from EMERGENT-1 and other similar antipsychotic
xanomeline and 30 mg trospium twice per day based on registration trials, a sample size of approximately
tolerability as assessed by the investigator, with the option 172 participants (86 evaluable participants per group) was
to return to 100 mg xanomeline and 20 mg trospium based calculated to result in a power of 90·3% for a two-sided test
on tolerability if needed. The dosing regimen was identical at a significance level of 0·05. With an estimated dropout
to that of the previous phase-2 EMERGENT-1 trial.20 rate of 30%, a total of 246 participants were estimated to be
CGI-S and PANSS scores were assessed at screening, enrolled.
baseline, and once per week until the end of the 5-week Baseline demographics and characteristics for the
treatment period, starting at week 1 after treatment intent-to-treat (ITT) population were summarised by the
initiation for CGI-S and at week 2 for PANSS. Adverse number and percentage of participants for sex and race
events were recorded at each trial visit. Orthostatic vital and mean scores with SDs were calculated for baseline
signs were measured supine and standing (after 2 min) age, BMI, PANSS score, and CGI-S score by treatment
at screening on the first day of treatment and at weekly group and for the overall population. Baseline
visits thereafter. Vital signs were recorded 2 h after the demographics and characteristics for the ITT, modified
morning dose at each visit. A resting 12-lead ITT (mITT), and safety populations were compared.
electrocardiogram was done at screening, on day 1, and Efficacy analyses were done using the mITT population,
at weeks 4 and 5. Blood to assess laboratory parameters which included all randomly assigned participants who
was collected at screening and at weeks 3 and 5. The received at least one dose of KarXT or placebo and
Simpson-Angus Scale (SAS),26 Barnes Akathisia Rating had a baseline and at least one post-baseline PANSS
Scale (BARS),27 and Abnormal Involuntary Movement assess­ment. The primary efficacy endpoint was analysed
Scale (AIMS)28 were assessed at baseline and once per using a mixed model for repeated measures (MMRM).
week during the trial. A safety follow-up visit was done at Least squares mean change from baseline, SE, and least
week 6 for all participants who did not enrol in the long- squares mean difference between the KarXT and placebo
term, rollover follow-up trial (EMERGENT-4). groups at week 5 along with the 95% CI and a two-sided
p value were calculated for the primary endpoint. A
Outcomes two-sided p value of ≤0·05 was considered statistically
The primary efficacy endpoint was change from baseline significant.
to week 5 in PANSS total score for KarXT versus placebo.21 Analyses accounted for multiplicity by using a fixed-
There was a prespecified hierarchy of secondary outcomes sequence testing procedure.31 If the primary efficacy
for hypothesis testing of KarXT versus placebo that endpoint was significantly different between the KarXT
consisted of change from baseline to week 5 in the PANSS and placebo groups at a two-sided significance level

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of 0·05, then prespecified secondary outcome measures in score from baseline at week 5 between the KarXT and
were tested using hierarchical hypothesis tests in a fixed- placebo groups divided by the pooled SD of the change.
sequence procedure in the following order: PANSS For the PANSS responder analysis, PANSS items were
positive subscale; PANSS negative subscale; PANSS rescaled from a range of 1−7 to 0−6 or, equivalently,
Marder negative factor; CGI-S; and percentage of PANSS total scores were floor-adjusted by subtracting
PANSS responders (≥30% improvement in PANSS total 30 points from baseline and post-baseline scores.33 The
score) at week 5. In addition, other PANSS response percentage of PANSS responders at each week was
thresholds of ≥20%, ≥40%, and ≥50% were assessed. A calculated and summarised by treatment group and visit.
PANSS total score reduction of ≥20% is a standard The percentage of PANSS responders at week 5 was
measure of the minimal clinically meaningful change and compared between treatment groups (KarXT and
a score reduction of ≥50% represents much better.32 The placebo) using the Cochran-Mantel-Haenszel test.
continuous-variable primary endpoint and secondary Safety analyses were done on all randomly assigned
outcome measures were analysed using an MMRM. participants who received at least one dose of KarXT or
Missing data were not explicitly imputed but were handled placebo (safety population). All safety and tolerability data
by the MMRM. The least squares mean change from were summarised descriptively by treatment group and
baseline, SE, and least squares mean difference between timepoint as appropriate. The number and percentage of
the KarXT and placebo groups at week 5, along with the participants with any TEAEs, any serious TEAE, any severe
95% CI and a two-sided p value were calculated for PANSS TEAE, and any TEAE leading to trial drug discontinuation
negative subscale, PANSS positive subscale, and PANSS were summarised by treatment group. Mean change (SD)
Marder negative factor secondary outcomes measures. from baseline to week 5 was calculated for measures of
The responder rates (in percentages) for the KarXT and body weight, prolactin, and vital signs, and the SAS, BARS,
placebo groups, the difference of responder rates between and AIMS scores, and summarised by treatment group.
the two treatment groups, and 95% CI and two-sided
p values were calculated. Role of the funding source
A Cohen’s d effect size was calculated for the primary Karuna Therapeutics designed the protocol and provided
efficacy endpoint and secondary outcome measures using the trial drug and placebo; the funder had no role in data
the absolute value of the difference in least squares change collection. The contract research organisation Syneos

407 participants screened for eligibility

155 did not meet inclusion criteria

252 randomly assigned

126 assigned to KarXT 126 assigned to placebo

1 withdrew consent before first dose

126 received at least one dose of 94 completed treatment 125 received at least one dose of 100 completed treatment
KarXT 32 discontinued treatment placebo 25 discontinued treatment
13 withdrew consent 11 withdrew consent
10 adverse events 6 adverse events
9 other reason 6 other reason
1 progressive disease
1 no reason collected

9 did not have baseline and at least 6 did not have baseline and at least
one post-baseline PANSS one post-baseline PANSS
assessment assessment

117 had baseline and at least one 119 had baseline and at least one
postbaseline PANSS assessment postbaseline PANSS assessment

Figure 1: Trial profile

ITT=intent-to-treat. KarXT=xanomeline–trospium. mITT=modified intent-to-treat. PANSS=Positive and Negative Syndrome Scale.

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ITT population mITT population

KarXT (n=126) Placebo (n=126) Total (n=252) KarXT (n=117) Placebo (n=119) Total (n=236)
Age, years 45·6 (10·4) 46·2 (10·8) 45·9 (10·6) 45·9 (10·4) 46·1 (10·8) 46·0 (10·6)
Sex
Male 95 (75%) 95 (75%) 190 (75%) 87 (74%) 91 (77%) 178 (75%)
Female 31 (25%) 31 (25%) 62 (25%) 30 (26%) 28 (23%) 58 (25%)
Race
Asian 2 (2%) 1 (1%) 3 (1%) 2 (2%) 0 (0%) 2 (1%)
Black or African American 97 (77%) 92 (73%) 189 (75%) 91 (78%) 86 (72%) 177 (75%)
White 26 (21%) 31 (25%) 57 (23%) 23 (20%) 31 (26%) 54 (23%)
Other 1 (1%) 2 (2%) 3 (1%) 1 (1%) 2 (2%) 3 (1%)
BMI, kg/m2 30·2 (5·4) 29·1 (5·4) 29·6 (5·4) 30·1 (5·5) 29·1 (5·4) 29·6 (5·5)
PANSS score
Total score 98·3 (8·9) 97·9 (9·7) 98·1 (9·3) 98·2 (8·9) 97·7 (9·4) 98·0 (9·1)
Positive subscale score 26·8 (3·7) 26·7 (4·0) 26·7 (3·9) 26·8 (3·8) 26·5 (3·7) 26·7 (3·8)
Negative subscale score 22·9 (4·0) 22·9 (3·8) 22·9 (3·9) 22·9 (4·1) 22·9 (3·9) 22·9 (4·0)
Marder negative factor score 22·9 (5·0) 22·5 (4·7) 22·7 (4·9) 22·8 (5·1) 22·5 (4·7) 22·7 (4·9)
CGI-S score 5·1 (0·6) 5·1 (0·6) 5·1 (0·6) 5·1 (0·6) 5·1 (0·6) 5·1 (0·6)
Data were mean (SD) or n (%). CGI-S=Clinical Global Improvement–Severity. ITT=intent to treat. mITT=modified intent to treat. PANSS=Positive and Negative Syndrome Scale.

Table 1: Baseline patient demographics and characteristics

Health (Morrisville, NC, USA) was responsible for overall groups (table 1) and baseline characteristics were similar
trial conduct, and VERISTAT (Southborough, MA, USA) between the mITT, ITT, and safety populations. Mean
did all data analyses. Representatives from Karuna baseline PANSS total score was 98·3 points (SD 8·9) in the
Therapeutics were involved in interpreting the data and KarXT group and 97·9 points (9·7) in the placebo group.
preparing the manuscript. All of the authors are 104 (94%) of 111 participants in the KarXT group reached
employees of or consultants to Karuna Therapeutics. the highest trial drug dose (125 mg/30 mg twice per day)
compared with 123 (98%) of 125 participants in the placebo
Results group; seven (6%) participants in the KarXT group and no
407 people at 22 inpatient sites in the USA were screened participants in the placebo group had a single per-protocol
between Dec 16, 2020, and April 13, 2022, of which reduction to a lower dose for tolerability reasons.
252 participants meeting the enrolment criteria were 119 (94%) participants in the KarXT group and
randomly assigned (1:1) to KarXT (n=126) or placebo 116 (93%) participants in the placebo group had taken at
(n=126; figure 1). Among the 155 people ineligible for least one psychoactive medication in the previous 6 months.
participation, 65% had abnormal laboratory values or Previous medication use was generally similar between
physical examination findings, 30% were not included in treatment groups. The most common previous medi­
the study because their medical or psychiatric history did cations in the two groups included lorazepam (42 [33%] in
not meet the trial eligibility criteria, and the remaining 5% the KarXT group vs 37 [30%] in the placebo group),
had several other reasons. The percentage of screened zolpidem (40 [32%] vs 41 [33%]), risperidone (28 [22%] vs
participants excluded was similar across trial sites. The 27 [22%]), and quetiapine (28 [22%] vs 35 [28%]).
safety population included 251 participants (KarXT n=126; For the primary endpoint, the KarXT group demon­
placebo n=125), who received at least one dose of trial strated a statistically significant 9·6-point greater
medication. The mITT population included reduction (95% CI –13·9 to –5·2) in PANSS total score at
236 participants (KarXT n=117; placebo n=119), who week 5 than the placebo group (table 2; figure 2A). A
received at least one PANSS assessment after predefined sensitivity analysis of PANSS total score
randomisation. 32 (25%) participants in the KarXT group change from baseline for completers was consistent with
and 26 (21%) participants in the placebo group terminated the primary analysis (appendix p 4).
the trial early. The most common reasons for discontinuing Compared with placebo at week 5, KarXT demonstrated
the trial early were withdrawn consent and adverse events, a 2·9-point reduction (95% CI –4·3 to –1·5) in PANSS
including three participants in the KarXT group and six positive-subscale score (table 2; figure 2B), a 1·8-point
participants in the placebo group who discontinued reduction (95% CI –3·1 to –0·5) in PANSS negative-
because of a psychiatric disorder. There were no deaths. subscale score (table 2; figure 2C), and a 2·2-point
No meaningful differences in baseline demographic and reduction (95% CI –3·6 to –0·8) in PANSS Marder
clinical characteristics were observed between treatment negative factor score (table 2; figure 2D). For CGI-S scale

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KarXT (n=117) Placebo (n=119) Difference (95% CI) Cohen’s d p value

Primary endpoint
PANSS total score* –21·2 (1·7) –11·6 (1·6) –9·6 (–13·9 to –5·2) 0·61 <0·0001
Secondary outcome measures
PANSS positive symptom subscale score† –6·8 (0·5) –3·9 (0·5) –2·9 (–4·3 to –1·5) 0·59 <0·0001
PANSS negative symptom subscale score‡ –3·4 (0·5) –1·6 (0·5) –1·8 (–3·1 to –0·5) 0·40 0·0055
PANSS Marder negative factor score§ –4·2 (0·5) –2·0 (0·5) –2·2 (–3·6 to –0·8) 0·44 0·0022
CGI-S scale score¶ –1·2 (0·1) –0·7 (0·1) –0·6 (–0·9 to –0·3) 0·58 <0·0001
PANSS responders (≥30% reduction from baseline in 51/93 (55%) 28/99 (28%) 27% (13 to 39) NA <0·0001
PANSS total score)||
Data are LSM change (SE) from baseline or n/N (%). CGI-S=Clinical Global Impression–Severity. mITT=modified intent-to-treat. NA=not applicable. PANSS=Positive and
Negative Syndrome Scale. KarXT=xanomeline–trospium. *PANSS total score range, 30–120 (higher score reflects greater severity). †PANSS positive symptoms subscale score
range, 7–49 (higher score reflects greater severity). ‡PANSS negative symptoms subscale score range, 7–49 (higher score reflects greater severity). §PANSS Marder negative
factor range, 7–49 (higher score reflects greater severity). ¶CGI-S scale range, 1–7 (1 indicating no illness and 7 indicating severe illness). ||On the basis of the floor-adjusted
total score (total score minus 30), assessed in patients with available week-5 scores.

Table 2: Efficacy measures at week 5 (mITT population)

scores, least squares mean change from baseline to week 5 normal, and none of the participants had elevated
was –1·2 points (SE 0·1) in the KarXT group versus bilirubin concentrations or met the criteria for Hy’s Law.
–0·7 points (0·1) in the placebo group (table 2, figure 3). KarXT was not associated with weight gain compared
Finally, 51 (55%) of 93 participants in the KarXT group with placebo. The mean change in bodyweight from
compared with 28 (28%) of 99 participants in the placebo baseline to week 5 was 1·4 kg (SD 3·31) in the KarXT
group had a ≥30% improvement from baseline to week 5 group and 2·5 kg (6·92) in the placebo group (table 3). Of
in PANSS total score (rate difference 27%; 95% CI 13 to 39; the 94 individuals in the KarXT group and 100 individuals
p<0·0001; table 2; figure 4). A higher proportion of in the placebo group for whom weight data were available
participants in the KarXT group than the placebo group at week 5, no participants in the KarXT group and one
had a ≥20% (60 [65%] of 93 vs 36 [36%] of 99; rate difference (1%) participant in the placebo group reported a TEAE of
28%; 95% CI 14 to 41; p<0·0001), ≥40% (36 [39%] of 93 vs increased weight. The number of participants who
21 [21%] of 99; rate difference 18%; 5 to 30; p=0·0068), and experienced a ≥7% increase in weight from baseline to
≥50% (19 [20%] of 93 vs 12 [12%] of 99; rate difference 8%; week 5 was six (6%) in the KarXT group and 13 (13%) in
–2 to 19; p=0·18) improvement from baseline to week 5 in the placebo group. The mean change in BMI from
PANSS total score. baseline to week 5 was 0·5 kg/m² (SD 1·09) in the KarXT
At least one TEAE was experienced by group and 0·8 kg/m² (2·17) in the placebo group. KarXT
95 (75%) participants in the KarXT group versus was not associated with greater changes than placebo in
73 (58%) participants in the placebo group (table 3). metabolic parameters (appendix p 6).
TEAEs occurring in ≥5% of participants in the KarXT The incidences of extrapyramidal motor symptoms or
group were generally gastro­intestinal in nature. The most akathisia reported were low and similar between treatment
common TEAEs (≥5%) reported in the KarXT group, and groups. No participants in either treatment group reported
at a rate at least twice that observed in the placebo group a TEAE of extrapyramidal disorder. Only one (1%)
were constipation, dyspepsia, nausea, vomiting, participant in each treatment group reported symptoms
hypertension, dizziness, and gastro-oesophageal reflux classified by the site investigator as akathisia; both cases
disease. Vomiting was intermittent and generally mild, resolved during the trial without changes in trial drug
with about a third of vomiting TEAEs consisting of only a administration. In addition, the mean change from
single episode of emesis. The rates of serious or severe baseline to week 5 in BARS score in the KarXT group was
TEAEs were low and similar between treatment groups. –0·1 points (SD 1·09) versus –0·2 points (0·98) in the
Four serious TEAEs occurred (KarXT, suicidal ideation, placebo group, and mean change in SAS score was
n=2; placebo, appendicitis, n=1, and worsening of schizo­ 0 points (0·61) in the KarXT group versus –0·1 points
phrenia, n=1), none of which were determined by the (0·70) in the placebo group (table 3). No cases of dyskinesia
investigator to be drug related. Rates of discontinuation were reported in either treatment group; mean change in
related to TEAEs were similar between KarXT (nine [7%]) AIMS score was 0 (SD 0·28) in the KarXT group and
and placebo (seven [6%]). Adverse events of special 0 (0·10) in the placebo group. No participants in the KarXT
interest have been summarised (appendix p 5). group and one (1%) participant in the placebo group were
Two participants in the KarXT group and one administered the anti-parkinsonism medication
participant in the placebo group had elevations in hepatic benzatropine.
transaminases. None of these participants had an Mean blood pressure measures were similar between
elevation of greater than five times the upper limit of KarXT and placebo at each timepoint during the trial as

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A B
0 0

PANSS positive subscale scorechange from

PANSS total score change from baseline

baseline (least squares mean change)

–5
(least squares mean change)

–2

–10 *

† –4
†
–15
§ ‡
§ –6 §
–20
KarXT
Placebo
–25 –8

C D
0 0
PANSS negative subscale score change from

PANSS marder negative factor score change

from baseline (least squares mean change)
baseline (least squares mean change)

–1
–1

–2
–2

* –3 *
† †
–3
–4

–4 –5
Baseline Week 2 Week 3 Week 4 Week 5 Baseline Week 2 Week 3 Week 4 Week 5

Figure 2: Mean change from baseline in PANSS total score (A), PANSS positive subscale score (B), PANSS negative subscale score (C), and PANSS Marder
negative factor score (D)
Error bars indicate SEM. KarXT=xanomeline–trospium. PANSS=Positive and Negative Syndrome Scale. *p<0·05. †p<0·01. ‡p<0·001. §p<0·0001.

0
were largely transient excursions of blood pressure and
most resolved during the trial. In the subset of patients
with a recorded TEAE of increased blood pressure, mean
CGI-S score change from baseline
(least squares mean change)

blood pressure at endpoint was similar to baseline

–0·5 * measures and did not lead to trial discontinuation. One
† participant in each of the KarXT and placebo groups had
‡ an increase in supine systolic blood pressure of at least
–1·0 ‡ 15 mmHg or diastolic blood pressure of at least 10 mm Hg
at day 35. KarXT treatment was associated with an
KarXT
Placebo
increase from baseline in supine heart rate compared
–1·5 with placebo that peaked at day 8 (mean 14·3 beats per
Baseline Week 1 Week 2 Week 3 Week 4 Week 5
minute [bpm], SD 13·87, vs 3·6 bpm, 12·09) and
Figure 3: Mean change from baseline in CGI-S score decreased slightly through day 28 (mean 11·6 bpm,
Error bars indicate SEM. Least squares mean changes for KarXT and placebo SD 13·86, vs 2·4 bpm, 12·75). No syncopal events were
were estimated using mixed-model repeated measures. CGI-S=Clinical Global observed. Finally, KarXT was not associated with greater
Impression–Severity. KarXT=xanomeline–trospium. *p<0·05. †p<0·001.
changes than placebo in the corrected QT interval
‡p<0·0001.
(appendix p 6).

measured 2 h after dose, corresponding to the time of Discussion

maximum plasma concentration of KarXT. Mild nominal In this phase 3 clinical trial, treatment of adults with
increases in systolic and diastolic blood pressure schizophrenia with acute psychosis with the dual M₁ and
(2–3 mmHg) in the KarXT group were observed at peak M₄ receptor preferring muscarinic agonist KarXT was
drug concentrations during the first week of KarXT associated with significant improvements in positive and
treatment and partially attenuated as treatment negative symptoms compared with placebo over the
continued; after the first week, mean blood pressure 5-week treatment period. Although demographics in
measures were generally similar between treatment international trials might be more representative, the
groups. TEAEs of hypertension (MedDRA preferred baseline demographics and clinical characteristics
term; not necessarily reflective of clinical hypertension) including age, sex, race, BMI, and symptom severity of

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100 KarXT KarXT Placebo

Participants meeting response crierion (%)

Placebo (n=126) (n=125)

80
p<0·0001 Any TEAE 95 (75%) 73 (58%)
p=0·00027
Serious TEAE 2 (2%) 2 (2%)
60 55%
p=0·0027 52% Severe TEAE 2 (2%) 4 (3%)
TEAE leading to discontinuation 9 (7%) 7 (6%)
40 36%
p=0·50 TEAE occurring in ≥5% of participants in the KarXT group
26% 28%
19% 18% Constipation 27 (21%) 13 (10%)
20 15%
Dyspepsia 24 (19%) 10 (8%)

0
Headache 17 (14%) 15 (12%)
Week 2 Week 3 Week 4 Week 5 Nausea 24 (19%) 7 (6%)
Vomiting 18 (14%) 1 (1%)
Figure 4: Percentage of participants with ≥30% reduction from baseline in
PANSS total score by trial week Hypertension 12 (10%) 1 (1%)
Based on floor-adjusted total score (total score minus 30). PANSS=Positive and Dizziness 11 (9%) 4 (3%)
Negative Syndrome Scale. KarXT=xanomeline–trospium.
Gastro-oesophageal reflux disease 8 (6%) 0
Diarrhoea 7 (6%) 4 (3%)
the EMERGENT-2 population were broadly consistent Change from baseline to week 5*
with those of clinical trials in schizophrenia done over the Body weight, kg 1·4 (3·31) 2·5 (6·92)
past decade in the USA, including in EMERGENT-1.20 On Prolactin, mg/L 1·0 (9·27) 0·8 (9·59)
the primary endpoint, KarXT treatment showed a Simpson-Angus Scale score 0 (0·61) –0·1 (0·70)
significant 9·6-point difference in mean change from Barnes Akathisia Rating Scale score –0·1 (1·09) –0·2 (0·98)
baseline to week 5 in PANSS total score compared with Abnormal Involuntary Movement Scale 0·0 (0·28) 0·0 (0·10)
placebo (p<0·0001) with an effect size of 0·61. Combining score
this result with the effect size observed in the Data are n (%) or mean (SD). TEAE=treatment-emergent adverse event.
EMERGENT-1 trial (0·75) suggests the potential for KarXT=xanomeline–trospium. *Number of participants in the KarXT and placebo
groups for which data were available at week 5: for body weight in KarXT, n=94,
KarXT to be an efficacious treatment with a unique and in placebo, n=100; for prolactin in KarXT, n=75, and in placebo, n=85; for the
pharmacology for people with schizophrenia. The KarXT Simpson-Angus Scale in KarXT, n=92, and in placebo, n=99; for the Barnes
group showed significant improvements (all p<0·05) Akathisia Rating Scale in KarXT, n=92, and in placebo, n=99; and for the
Abnormal Involuntary Movement Scale in KarXT, n=92, and in placebo, n=99.
compared with placebo at week 5 on the PANSS positive
subscale, PANSS negative subscale, PANSS Marder Table 3: TEAEs and safety during the 5-week treatment period (safety
negative factor, and CGI-S scores. The percentage of population)
participants reaching the prespecified PANSS responder
criteria of ≥30% reduction from baseline in PANSS total
score at week 5 was significantly greater with KarXT than KarXT was not associated with common problematic
placebo (p<0·0001). adverse events of currently available antipsychotic
KarXT was generally well tolerated, with a side-effect medications, such as extrapyramidal motor symptoms or
profile substantially consistent with that observed in akathisia, weight gain, metabolic changes, prolactin
EMERGENT-1.20 The overall percentage of participants elevation, or somnolence. Measures of extrapyramidal
who discontinued treatment was similar between the motor symptoms or akathisia were similar in both the
KarXT and placebo groups (25% vs 21%), as was KarXT and placebo groups and showed no significant
the percentage of people discontinuing because of changes from baseline to week 5. There were no
TEAEs (KarXT, nine [7%] of 126; placebo, seven [6%] of 125). discontinuations because of extrapyramidal motor
The most common TEAEs associated with KarXT were symptoms, nor was any pharmacological treatment of
constipation, dyspepsia, nausea, vomiting, hypertension, adverse events initiated. Adverse events associated with
dizziness, and gastro-oesophageal reflux disease, which KarXT treatment were primarily gastrointestinal in nature,
reflect the activity of xanomeline and of trospium at consistent with previous trials and the expression of
muscarinic receptors. The majority of TEAEs occurred muscarinic receptors in the gastrointestinal tract.14 Rates of
within the first 2–3 weeks, were transient, and resolved the most common adverse events in the KarXT group
before the end of the trial. Other trials of xanomeline (constipation, dyspepsia, nausea, and vomiting) generally
alone for 6 months16 or trospium alone for 9 months,35 decreased over the course of the trial.
albeit in different patient populations, do not suggest the TEAE rates of hypertension were greater in the KarXT
emergence of new safety or tolerability issues with (n=12, 10%) versus placebo group (n=1, 1%). However,
longer treatment, but results from two ongoing 52-week mean changes in systolic and diastolic blood pressure
trials of KarXT will better characterise the long-term assessed 2 h after dose (at the time of maximum plasma
safety and tolerability profile of KarXT in people with concentration) were similar between the KarXT and
schizophrenia. placebo treatment groups and remained relatively flat over

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the course of the 5-week trial, implying that hypertension (NCT04659174 and NCT04820309). Further, the trial did not
TEAEs were mostly mild transient elevations of blood include an active control group, which would allow for more
pressure in a small number of patients. An ongoing direct comparison of KarXT with other antipsychotic drugs.
ambulatory blood pressure monitoring trial in people with In conclusion, KarXT demonstrated efficacy and safety
schizophrenia will provide more insight into any effect on and was generally well tolerated in the phase 3
blood pressure. As in previous trials, an increase in supine EMERGENT-2 trial in adults with schizophrenia with
heart rate in the first week of treatment that decreased in acute psychosis treated over 5 weeks. KarXT resulted
magnitude by the end of the trial was observed in the in significantly greater improvements than placebo across
KarXT group compared with the placebo group. the primary endpoint and all secondary outcome measures,
The efficacy and safety results from this phase 3 trial which assessed overall symptoms as well as positive and
were similar to those reported for the phase 2 negative symptoms and symptomatic response status.
EMERGENT-1 trial.20 Similarities between the trials KarXT showed a distinctive safety and tolerability profile
include a flexible dose design with two groups (KarXT and and was not associated with many of the adverse events
placebo), a 5-week treatment duration in an inpatient typically observed with currently approved antipsychotic
setting, and similar inclusion and exclusion criteria. The drugs, such as extrapyramidal motor symptoms or
placebo response on the primary outcome (PANSS total akathisia, weight gain, metabolic changes, prolactin
score least squares mean change from baseline at week 5) elevations, or somnolence. Treatment with KarXT resulted
was higher in EMERGENT-2 (–11·6 points) than in predominantly gastrointestinal side-effects, which were
EMERGENT-1 (–5·9 points)20 and higher than the mean mild to moderate in severity and generally transient. These
placebo response (–6·25 points) reported in a meta­ results confirm those from the EMERGENT-1 trial and
regression analysis of 167 randomised, double-blind, represent the second positive pivotal trial with KarXT in
placebo-controlled registration trials of antipsychotic people with acutely exacerbated schizophrenia. The
drugs in schizophrenia.34,36,37 The higher placebo response antipsychotic properties of KarXT are mediated through
in the phase 3 trial might relate to the larger number M₁ and M₄ muscarinic receptors and KarXT is devoid of
of investigational sites36 and greater expectation bias direct D₂ dopamine receptor-blocking activity. Because of
following the reported efficacy of KarXT in the this unique pharmacology and clinical profile, KarXT has
phase 2 EMERGENT-1 trial. the potential to be the first in a new class of antipsychotic
Consistent with the EMERGENT-1 trial, EMERGENT-2 medications since the launch of second-generation
demonstrated statistically significant improvement in antipsychotic drugs more than 30 years ago. The
negative symptoms with KarXT compared with placebo EMERGENT-3 trial (identical design to EMERGENT-2),
based on changes from baseline to week 5 in PANSS two open-label trials of up to 52 weeks in duration
negative subscale score (1·8-point reduction vs placebo) (EMERGENT-4 and EMERGENT-5), and a trial of KarXT
and PANSS Marder negative factor score (2·2-point as adjunctive therapy (ARISE) in people with insufficient
reduction vs placebo). Together, these results support treatment response to antipsychotic drugs are ongoing to
further testing of KarXT as a treatment for primary further establish the efficacy and safety of KarXT in the
negative symptoms in an appropriately designed study in treatment of psychosis in people with schizophrenia.
people with persistent negative symptoms, as the Marder Contributors
negative factor might be less susceptible to influence by SS, IK, AB, and SKB conceptualised the trial and contributed to its
improvement in positive symptoms than the PANSS design. SS, IK, RK, and SKB were involved in the implementation of the
trial. HZ oversaw the statistical analyses. All authors were involved in
negative subscale.38 However, caution is warranted in the interpretation of the results, reviewed and commented on the paper,
interpreting these results given the acute nature of the trial had full access to all of the trial data, take responsibility for the data
and potential pseudospecific effects related to significant integrity and the accuracy of the analyses, and were responsible for the
improvements in positive symptoms. Longer-term studies decision to submit the manuscript. IK, SS, and HZ verified the data.
in people with stable positive symptoms and predominantly Declaration of interests
negative symptoms are needed to characterise the effects CUC has been a consultant, advisor, or both consultant and advisor to or
has received honoraria from AbbVie, Acadia, Alkermes, Allergan,
of KarXT on enduring primary negative symptoms. Angelini, Aristo Pharma, Biogen, Boehringer Ingelheim, Cardio
The trial had limitations typical for antipsychotic Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa,
registration trials in patients with schizophrenia and an Denovo, Gedeon Richter, Hikma, Holmusk, Intra-Cellular Therapies,
acute exacerbation of psychosis. The duration of this Janssen or Johnson & Johnson, Karuna Therapeutics, LB Pharma,
Lundbeck, MedAvante-ProPhase, MedinCell, Merck, Mindpax, Mitsubishi
trial was 5 weeks and did not assess durability of effect Tanabe Pharma, Mylan, Neurocrine Biosciences, Neurelis, Newron,
or long-term safety of KarXT treatment for what is a lifelong Noven, Novo Nordisk, Otsuka, Pharmabrain, PPD Biotech, Recordati,
illness. However, a relatively rapid improvement in Relmada, Reviva, ROVI, Seqirus, SK Life Science, Sunovion, Sun Pharma,
psychotic symptoms (2 weeks) was observed and the Supernus, Takeda, Teva, and Viatris; provided expert testimony for
Janssen and Otsuka; served on a data safety monitoring board for
superiority of KarXT versus placebo continued to increase Compass Pathways, Denovo, Lundbeck, Relmada, Reviva, ROVI, Sage,
through week 5, suggesting that a greater effect size might Supernus, Tolmar, and Teva; has received grant support from Janssen and
occur at later time points. Trials with longer-term follow-ups Takeda; received royalties from UpToDate; and is a stock option holder of
Cardio Diagnostics, LB Pharma, Mindpax, PsiloSterics, and Quantic. AB
are warranted, and two 52-week trials are underway

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has been a consultant, advisor, or both consultant and advisor for Arrivo 18 Staskin D, Kay G, Tannenbaum C, et al. Trospium chloride has no
Sirtsei, BioXcel, Karuna Therapeutics, Neumarker, and Perception effect on memory testing and is assay undetectable in the central
Neuroscience, and holds equity in Karuna Therapeutics and Perception nervous system of older patients with overactive bladder.
Neuroscience. SMP is an employee of Karuna Therapeutics, is in a Int J Clin Pract 2010; 64: 1294–300.
leadership or fiduciary role at Karuna Therapeutics, Sage Therapeutics, 19 Breier A, Brannan SK, Paul SM, Miller AC. Evidence of
and Voyager Therapeutics, and holds equity in Eli Lilly Pharmaceuticals, trospium’s ability to mitigate cholinergic adverse events related to
Karuna Therapeutics, Sage Therapeutics, and Voyager Therapeutics. IK, xanomeline: phase 1 study results. Psychopharmacology 2023;
SS, HZ, ACM, and SKB are employees of and hold equity in Karuna 240: 1191–98.
Therapeutics. RK was a principal investigator for the EMERGENT-2 study. 20 Brannan SK, Sawchak S, Miller AC, Lieberman JA, Paul SM,
Breier A. Muscarinic cholinergic receptor agonist and peripheral
Data sharing antagonist for schizophrenia. N Engl J Med 2021; 384: 717–26.
Data will be made available from the corresponding author on 21 Kay SR, Opler LA, Lindenmayer JP. The Positive and Negative
reasonable request, subject to review. Syndrome Scale (PANSS): rationale and standardisation.
Br J Psychiatry Suppl 1989; 7: 59-67.
Acknowledgments
22 Haro JM, Kamath SA, Ochoa S, et al. The clinical global
The EMERGENT-2 trial was sponsored by Karuna Therapeutics.
impression-schizophrenia scale: a simple instrument to measure
The authors thank Matthew Jacobson, Adrienne Drinkwater, the diversity of symptoms present in schizophrenia.
Paula Stuckart, and Kimberly Church of Apollo Medical Acta Psychiatr Scand Suppl 2003; 416: 16–23.
Communications for medical writing and editorial assistance, which was 23 Correll CU, Angelov AS, Miller AC, Weiden PJ, Brannan SK.
funded by Karuna Therapeutics. Safety and tolerability of KarXT (xanomeline-trospium) in a phase 2,
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