Schizophrenia Update: Navigating the Latest in Research and Treatment - Module 1: Understanding the Evolving Treatment Landscape
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Oct 30, 2025
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About This Presentation
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
Schizophrenia is a debilitating illness that shortens life expectancy and disrupts daily life. While dopamine-blocking agents are the standard treatment, their l...
Slide Content
Schizophrenia Update: Navigating the Latest in Research
and Treatment
l
Module 1: Understanding the Evolving Treatment Landscape
Christoph U. Correll, MD
Professor of Psychiatry and Molecular Medicine
Donald and Barbara Zucker School of Medicine at Hofstra/Northwell
Professor and Chair, Department of Child and Adolescent Psychiatry
Charité – University Medicine, Berlin, Germany
FOR PERSONAL USE ONLY
and Treatment
l
Module 1: Understanding the Evolving Treatment Landscape
Christoph U. Correll, MD
Professor of Psychiatry and Molecular Medicine
Donald and Barbara Zucker School of Medicine at Hofstra/Northwell
Professor and Chair, Department of Child and Adolescent Psychiatry
Charité – University Medicine, Berlin, Germany
FOR PERSONAL USE ONLY
Disclaimer
This material may not be reproduced, displayed, modified, or
distributed without the express prior written permission of i3 Health
and the chairperson, Dr. Christoph U. Correll
FOR PERSONAL USE ONLY
This material may not be reproduced, displayed, modified, or
distributed without the express prior written permission of i3 Health
and the chairperson, Dr. Christoph U. Correll
FOR PERSONAL USE ONLY
Disclosures
Advisory board or panel: AbbVie, Allergan, Angelini, Boehringer Ingelheim, Bristol
Myers Squibb, Cerevel, Compass, Gedeon Richter, Janssen/J&J, Karuna, LB Pharma,
Life Science, Lundbeck, MedInCell, Merck, Neuraxpharm, Neurelis, Neurocrine,
Newron, Novo Nordisk, Otsuka, Recordati, Rovi, Sage, Seqirus, Sunovion, Supernus,
Teva, Vertex, Viatris
Consultant: AbbVie, Allergan, Angelini, Boehringer Ingelheim, Bristol Meyers Squibb,
Cerevel, Compass, Denovo, Eli Lilly, Gedeon Richter, IntraCellular Therapies,
Janssen/J&J, Karuna, Kuleon Biosciences, LB Pharma, Life Science; Lundbeck,
MedInCell, Medlink, Merck, Mindpax, Neuraxpharm, Neurelis, Neurocrine, Newron,
Novo Nordisk, Otsuka, Recordati, Relmada, Reviva, Rovi, Sage, Seqirus, Sunovion,
Supernus, Teva, Vertex, Viatris
Grants/research support: Boehringer-Ingelheim, Janssen, Takeda
Stock/shareholder: Cardio Diagnostics, Kuleon Biosciences, LB Pharma, Medlink,
Mindpax, Quantic, Terran
i3 Health has mitigated all relevant financial relationships
FOR PERSONAL USE ONLY
Advisory board or panel: AbbVie, Allergan, Angelini, Boehringer Ingelheim, Bristol
Myers Squibb, Cerevel, Compass, Gedeon Richter, Janssen/J&J, Karuna, LB Pharma,
Life Science, Lundbeck, MedInCell, Merck, Neuraxpharm, Neurelis, Neurocrine,
Newron, Novo Nordisk, Otsuka, Recordati, Rovi, Sage, Seqirus, Sunovion, Supernus,
Teva, Vertex, Viatris
Consultant: AbbVie, Allergan, Angelini, Boehringer Ingelheim, Bristol Meyers Squibb,
Cerevel, Compass, Denovo, Eli Lilly, Gedeon Richter, IntraCellular Therapies,
Janssen/J&J, Karuna, Kuleon Biosciences, LB Pharma, Life Science; Lundbeck,
MedInCell, Medlink, Merck, Mindpax, Neuraxpharm, Neurelis, Neurocrine, Newron,
Novo Nordisk, Otsuka, Recordati, Relmada, Reviva, Rovi, Sage, Seqirus, Sunovion,
Supernus, Teva, Vertex, Viatris
Grants/research support: Boehringer-Ingelheim, Janssen, Takeda
Stock/shareholder: Cardio Diagnostics, Kuleon Biosciences, LB Pharma, Medlink,
Mindpax, Quantic, Terran
i3 Health has mitigated all relevant financial relationships
FOR PERSONAL USE ONLY
Overview of Activity Modules
Module 1: Understanding the Evolving Treatment Landscape
Module 2: Advances in Long-Acting Injectables
Module 3: Emerging Treatments for Cognitive Symptoms
Module 4: Applying the Latest Therapeutic Advances to
Patient-Centered Care
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Module 1: Understanding the Evolving Treatment Landscape
Module 2: Advances in Long-Acting Injectables
Module 3: Emerging Treatments for Cognitive Symptoms
Module 4: Applying the Latest Therapeutic Advances to
Patient-Centered Care
FOR PERSONAL USE ONLY
Learning Objective
Appraise the indications, efficacy, and safety of current and
emerging antipsychotics for the treatment of schizophrenia
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Appraise the indications, efficacy, and safety of current and
emerging antipsychotics for the treatment of schizophrenia
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Our Evolving Understanding of Schizophrenia
Howes & Onwordi (2023). Mol Psychiatry, 28(5):1843-1856.
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Howes & Onwordi (2023). Mol Psychiatry, 28(5):1843-1856.
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Schizophrenia: Therapeutic Targets, Outcomes, and
Burden
a
In antipsychotic discontinuation studies.
b
Median (interquartile range).
FES = first-episode schizophrenia. Carbon & Correll (2014a). Dialogues Clin Neurosci, 16:505-524; Diniz et al (2023). Braz J Psychiatry, 45(5):448-458; Hansen et al (2023). Schizophr Bull, 49:297-308.
Resistance
Exacerbation Relapse
Remission
Recovery
Response
37%-47% (First-episode schizophrenia (FES): 22%)
18%-65% (FES: 40%-87%)
Any duration
a
: 57.3%
Any duration: 7%-52%
(FES: 17%-81%)
11.1% [6%-22.5%]
b
(FES: 20.8% [17%-25%])Remission:
6 months: 15%
12 months: 38%
24 months: 46%
Remission:
6 months: 44%
12 months: 52%
24 months: 47%
Illness severity
Acute Stabilization Maintenance Treatment phase
FOR PERSONAL USE ONLY
Burden
a
In antipsychotic discontinuation studies.
b
Median (interquartile range).
FES = first-episode schizophrenia. Carbon & Correll (2014a). Dialogues Clin Neurosci, 16:505-524; Diniz et al (2023). Braz J Psychiatry, 45(5):448-458; Hansen et al (2023). Schizophr Bull, 49:297-308.
Resistance
Exacerbation Relapse
Remission
Recovery
Response
37%-47% (First-episode schizophrenia (FES): 22%)
18%-65% (FES: 40%-87%)
Any duration
a
: 57.3%
Any duration: 7%-52%
(FES: 17%-81%)
11.1% [6%-22.5%]
b
(FES: 20.8% [17%-25%])Remission:
6 months: 15%
12 months: 38%
24 months: 46%
Remission:
6 months: 44%
12 months: 52%
24 months: 47%
Illness severity
Acute Stabilization Maintenance Treatment phase
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a
The overall annual direct and indirect costs total does not include costs off-set which the study found to be -$6.0
which include individuals either institutionalized or homeless individuals not incurring basic living costs.
b
Law enforcement was defined as incarceration, legal and judicial services, and police protection.
B = billion; ED = emergency department; SSDI = Social Security Disability Insurance; SSI = Supplemental Security Income.
Kadakia et al (2022). J Clin Psychiatry, 83(6):22m14458.
$343.2B*
$30.2B
$20.1B
$12.1B
$35.0B
Inpatient visits
Other direct costs
Pharmacy costs
Direct non-healthcare costs
(eg, ED visits, outpatient
and long-term care, other
medical services)
(eg, ED law enforcement
b
,
SSI/SSDI, homeless shelters,
research and training)
$54.2B
Unemployment
costs
$85.3B
Other
indirect costs
(eg. productivity loss,
premature mortality)
$112.3B
Caregiver Burden
Direct
non-healthcare
costs
($35.0B)
Direct costs
($62.4B)
Indirect
costs
($251.8B)
•Direct healthcare costs were estimated based on
patients living with schizophrenia (N=131,125)
Among these patients:
–19% (n=24,881) were commercially insured
–2.1% (n=2779) were insured by Medicare
–78.9% (n=103,465) were insured by Medicaid
•Direct healthcare costs accounted for 18% of the
total cost burden of schizophrenia
–Costs were similar among patients insured by
commercial insurance ($26,904) and
Medicaid ($26,095)
–However, costs were higher among patients
insured by Medicare ($34,391)
The total annual excess costs per patient are estimated at $87,856
Total annual economic burden in the United States
Economic Burden of Schizophrenia
Schizophrenia is associated with a significant economic burden—
more than $343B
a
in direct and indirect costs annually
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The overall annual direct and indirect costs total does not include costs off-set which the study found to be -$6.0
which include individuals either institutionalized or homeless individuals not incurring basic living costs.
b
Law enforcement was defined as incarceration, legal and judicial services, and police protection.
B = billion; ED = emergency department; SSDI = Social Security Disability Insurance; SSI = Supplemental Security Income.
Kadakia et al (2022). J Clin Psychiatry, 83(6):22m14458.
$343.2B*
$30.2B
$20.1B
$12.1B
$35.0B
Inpatient visits
Other direct costs
Pharmacy costs
Direct non-healthcare costs
(eg, ED visits, outpatient
and long-term care, other
medical services)
(eg, ED law enforcement
b
,
SSI/SSDI, homeless shelters,
research and training)
$54.2B
Unemployment
costs
$85.3B
Other
indirect costs
(eg. productivity loss,
premature mortality)
$112.3B
Caregiver Burden
Direct
non-healthcare
costs
($35.0B)
Direct costs
($62.4B)
Indirect
costs
($251.8B)
•Direct healthcare costs were estimated based on
patients living with schizophrenia (N=131,125)
Among these patients:
–19% (n=24,881) were commercially insured
–2.1% (n=2779) were insured by Medicare
–78.9% (n=103,465) were insured by Medicaid
•Direct healthcare costs accounted for 18% of the
total cost burden of schizophrenia
–Costs were similar among patients insured by
commercial insurance ($26,904) and
Medicaid ($26,095)
–However, costs were higher among patients
insured by Medicare ($34,391)
The total annual excess costs per patient are estimated at $87,856
Total annual economic burden in the United States
Economic Burden of Schizophrenia
Schizophrenia is associated with a significant economic burden—
more than $343B
a
in direct and indirect costs annually
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PET = positron emission tomography.
Huhn et al (2019). Lancet, 394(10202):939-951; Grunder et al (2003). Arch Gen Psychiatry, 60(10):974-7; McCutcheon et al (2020). JAMA Psychiatry, 77(2):201-210.
Presynaptic
neuron
Postsynaptic
neuron
Receptor
occupancy
0%-60%
60%-80%
80%
D2 Antagonist
Endogenous dopamine
All current licensed treatments for schizophrenia are functional dopamine D
2 receptor blockers
(median effect size: 0.42)
Antipsychotics: Functional Dopamine D
2 Receptor Blockers
PET studies of D
2 antagonist antipsychotics suggest
presence of a therapeutic window
Striatal D
2-receptor occupancy >60% is generally
required for a higher likelihood of improving
Occupancy levels >80% are associated with a high
likelihood of motor adverse effects
High D
2 occupancy does not guarantee response
PET studies of D
2 partial agonist antipsychotics
suggest presence of a therapeutic window
Striatal D
2 receptor occupancy >90% is generally
required for a higher likelihood of improving, as
functional agonism needs to be subtracted to get to the
net functional antagonism
High D
2 occupancy does not guarantee response
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Huhn et al (2019). Lancet, 394(10202):939-951; Grunder et al (2003). Arch Gen Psychiatry, 60(10):974-7; McCutcheon et al (2020). JAMA Psychiatry, 77(2):201-210.
Presynaptic
neuron
Postsynaptic
neuron
Receptor
occupancy
0%-60%
60%-80%
80%
D2 Antagonist
Endogenous dopamine
All current licensed treatments for schizophrenia are functional dopamine D
2 receptor blockers
(median effect size: 0.42)
Antipsychotics: Functional Dopamine D
2 Receptor Blockers
PET studies of D
2 antagonist antipsychotics suggest
presence of a therapeutic window
Striatal D
2-receptor occupancy >60% is generally
required for a higher likelihood of improving
Occupancy levels >80% are associated with a high
likelihood of motor adverse effects
High D
2 occupancy does not guarantee response
PET studies of D
2 partial agonist antipsychotics
suggest presence of a therapeutic window
Striatal D
2 receptor occupancy >90% is generally
required for a higher likelihood of improving, as
functional agonism needs to be subtracted to get to the
net functional antagonism
High D
2 occupancy does not guarantee response
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Disruption of Dopamine Circuits in Schizophrenia
a
Advances in neuroimaging techniques found dopamine dysfunction in schizophrenia is greatest within nigrostriatal pathways implicating the dorsal striatum.
Dopamine overactivity in circuit from the dorsomedial substantia nigra to the associative and adjacent sensorimotor striatum is linked to positive symptoms.
Correll, Abi-Dargham & Howes (2022). J Clin Psychiatry, 83(1):SU21204IP1; McCutcheon et al (2019). Trends Neurosci, 42(3):205-220.
Underactivity in the mesolimbic
and mesocortical pathways lead to
negative and cognitive symptoms
Mesocortical Pathway
•Learning and memory
•Negative symptoms
•Cognitive symptoms
•Depression
Tuberoinfundibular
Hypothalamic Pathway
•Prolactin elevation
•Amenorrhea
•Galactorrhea
•Sexual dysfunction
Mesolimbic Pathway
a
“
Limbic Striatum”
•Negative symptoms
•Reward dysfunction
Nigrostriatal Pathway 2 /
“
Sensorimotor Striatum”
•Dystonia
•Akinesia
•Rigidity
•Tremor
•Dyskinesia
Nigrostriatal Pathway 1
“Associative Striatum”
•Psychosis
Overactivity in the nigrostriatal pathway
“Associative Striatum”
leads to positive symptoms
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a
Advances in neuroimaging techniques found dopamine dysfunction in schizophrenia is greatest within nigrostriatal pathways implicating the dorsal striatum.
Dopamine overactivity in circuit from the dorsomedial substantia nigra to the associative and adjacent sensorimotor striatum is linked to positive symptoms.
Correll, Abi-Dargham & Howes (2022). J Clin Psychiatry, 83(1):SU21204IP1; McCutcheon et al (2019). Trends Neurosci, 42(3):205-220.
Underactivity in the mesolimbic
and mesocortical pathways lead to
negative and cognitive symptoms
Mesocortical Pathway
•Learning and memory
•Negative symptoms
•Cognitive symptoms
•Depression
Tuberoinfundibular
Hypothalamic Pathway
•Prolactin elevation
•Amenorrhea
•Galactorrhea
•Sexual dysfunction
Mesolimbic Pathway
a
“
Limbic Striatum”
•Negative symptoms
•Reward dysfunction
Nigrostriatal Pathway 2 /
“
Sensorimotor Striatum”
•Dystonia
•Akinesia
•Rigidity
•Tremor
•Dyskinesia
Nigrostriatal Pathway 1
“Associative Striatum”
•Psychosis
Overactivity in the nigrostriatal pathway
“Associative Striatum”
leads to positive symptoms
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Dopamine D
2-Receptor Blocking Antipsychotics
All antidopaminergic antipsychotics are approved as monotherapy for “the
treatment of schizophrenia”
Some antipsychotics are also indicated for the treatment of agitation and
aggression associated with schizophrenia (oral or short-acting IM)
Some antipsychotics are also available in a long-acting injectable formulation
No indication for negative or cognitive symptoms or adjunctive treatment
Antipsychotic choice is based on patient and illness characteristics,
psychiatric and medical comorbidities, medication characteristics (half-life,
drug-drug interactions, efficacy, and safety/tolerability), access, and patient
preference
IM = intramuscular.
Kahn et al (2015). Nat Rev Dis Primers, 1:15067.
Current Practice
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2-Receptor Blocking Antipsychotics
All antidopaminergic antipsychotics are approved as monotherapy for “the
treatment of schizophrenia”
Some antipsychotics are also indicated for the treatment of agitation and
aggression associated with schizophrenia (oral or short-acting IM)
Some antipsychotics are also available in a long-acting injectable formulation
No indication for negative or cognitive symptoms or adjunctive treatment
Antipsychotic choice is based on patient and illness characteristics,
psychiatric and medical comorbidities, medication characteristics (half-life,
drug-drug interactions, efficacy, and safety/tolerability), access, and patient
preference
IM = intramuscular.
Kahn et al (2015). Nat Rev Dis Primers, 1:15067.
Current Practice
FOR PERSONAL USE ONLY
Dopamine D
2-Receptor Blocking Antipsychotics (cont.)
First-generation antipsychotics predominantly block postsynaptic D
2
receptors and are associated with extrapyramidal side effects (EPS), prolactin
elevation, and secondary negative and cognitive as well as depressive
symptoms
Second-generation antipsychotics that either block postsynaptic D
2 receptors
and certain serotonin receptors and/or are partial D
2 receptor agonists are
less associated with EPS and secondary negative and cognitive symptoms,
and some may even treat depression; however, varying degrees of
cardiometabolic, neuromotor, prolactin-related, and activation- or sedation-
related side effects may limit their use
Clozapine is currently the only antipsychotic approved for treatment-resistant
schizophrenia
Kahn et al (2015). Nat Rev Dis Primers, 1:15067.
Current Practice
FOR PERSONAL USE ONLY
2-Receptor Blocking Antipsychotics (cont.)
First-generation antipsychotics predominantly block postsynaptic D
2
receptors and are associated with extrapyramidal side effects (EPS), prolactin
elevation, and secondary negative and cognitive as well as depressive
symptoms
Second-generation antipsychotics that either block postsynaptic D
2 receptors
and certain serotonin receptors and/or are partial D
2 receptor agonists are
less associated with EPS and secondary negative and cognitive symptoms,
and some may even treat depression; however, varying degrees of
cardiometabolic, neuromotor, prolactin-related, and activation- or sedation-
related side effects may limit their use
Clozapine is currently the only antipsychotic approved for treatment-resistant
schizophrenia
Kahn et al (2015). Nat Rev Dis Primers, 1:15067.
Current Practice
FOR PERSONAL USE ONLY
Network Meta-Analysis of Antipsychotics for Schizophrenia
SMD = standardized mean difference; CrI = credible interval; CLO = clozapine;
AMI = amisulpride; ZOT = zotephine; THIOT = thiotixene; OLA = olanzapine;
RIS = risperidone; PERPH = perphenazine; THIOR = thioridazine; ZUC = zuclopenthixol;
PAL = paliperidone; HAL = haloperidol; SUL = sulpride; LOX = loxapine; CPZ = chlorpromazine;
FPX = flupentixol; CPX = chlopenthixol; MOL = molindone; PEN = penfluridol; QUE = quetiapine;
ARI = aripiprazole; ZIP = ziprasidone; SER = sertindole; ASE = asenapine; LUR = lurasidone;
PIM = pimozide; PERA = perazine; CAR = cariprazine; ILO = iloperidone; FLU = flupentixol;
TRIFLU = trifluoperazine; BRE = brexpiprazole; LEV = levomepromazine; PBO = placebo.
Huhn et al (2019). Lancet, 394(10202):939-951.
Overall Symptom Change
Level of confidence in the evidence:
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SMD = standardized mean difference; CrI = credible interval; CLO = clozapine;
AMI = amisulpride; ZOT = zotephine; THIOT = thiotixene; OLA = olanzapine;
RIS = risperidone; PERPH = perphenazine; THIOR = thioridazine; ZUC = zuclopenthixol;
PAL = paliperidone; HAL = haloperidol; SUL = sulpride; LOX = loxapine; CPZ = chlorpromazine;
FPX = flupentixol; CPX = chlopenthixol; MOL = molindone; PEN = penfluridol; QUE = quetiapine;
ARI = aripiprazole; ZIP = ziprasidone; SER = sertindole; ASE = asenapine; LUR = lurasidone;
PIM = pimozide; PERA = perazine; CAR = cariprazine; ILO = iloperidone; FLU = flupentixol;
TRIFLU = trifluoperazine; BRE = brexpiprazole; LEV = levomepromazine; PBO = placebo.
Huhn et al (2019). Lancet, 394(10202):939-951.
Overall Symptom Change
Level of confidence in the evidence:
FOR PERSONAL USE ONLY
Mesocortical Pathway
•Negative symptoms
•Cognitive symptoms
•Depression
Tuberoinfundibular
Hypothalamic Pathway
•Prolactin elevation
•Amenorrhea
•Galactorrhea
•Sexual dysfunction
Mesolimbic Pathway
a
(
Limbic Striatum)
•Negative symptoms
Nigrostriatal Pathway
(Associative Striatum)
•Psychosis
Nigrostriatal Pathway
(
Sensorimotor Striatum)
•Dystonia
•Akinesia
•Rigidity
•Tremor
•Dyskinesia
Underactivity of these circuits is associated with
schizophrenia; the goal is to increase the activity
Overactivity of this circuit is associated with
schizophrenia; the goal is to reduce the hyperactivity
Effects of D
2 Receptor Blockade on Neural Circuits 1, 2
a
Advances in neuroimaging techniques found dopamine dysfunction in schizophrenia is greatest within nigrostriatal pathways implicating the dorsal striatum.
Dopamine overactivity in circuit from the dorsomedial substantia nigra to the associative and adjacent sensorimotor striatum is linked to positive symptoms.
Correll, Abi-Dargham & Howes (2022). J Clin Psychiatry, 83(1):SU21204IP1; McCutcheon et al (2019). Trends Neurosci, 42(3):205-220.
FOR PERSONAL USE ONLY
•Negative symptoms
•Cognitive symptoms
•Depression
Tuberoinfundibular
Hypothalamic Pathway
•Prolactin elevation
•Amenorrhea
•Galactorrhea
•Sexual dysfunction
Mesolimbic Pathway
a
(
Limbic Striatum)
•Negative symptoms
Nigrostriatal Pathway
(Associative Striatum)
•Psychosis
Nigrostriatal Pathway
(
Sensorimotor Striatum)
•Dystonia
•Akinesia
•Rigidity
•Tremor
•Dyskinesia
Underactivity of these circuits is associated with
schizophrenia; the goal is to increase the activity
Overactivity of this circuit is associated with
schizophrenia; the goal is to reduce the hyperactivity
Effects of D
2 Receptor Blockade on Neural Circuits 1, 2
a
Advances in neuroimaging techniques found dopamine dysfunction in schizophrenia is greatest within nigrostriatal pathways implicating the dorsal striatum.
Dopamine overactivity in circuit from the dorsomedial substantia nigra to the associative and adjacent sensorimotor striatum is linked to positive symptoms.
Correll, Abi-Dargham & Howes (2022). J Clin Psychiatry, 83(1):SU21204IP1; McCutcheon et al (2019). Trends Neurosci, 42(3):205-220.
FOR PERSONAL USE ONLY
Antipsychotics for Schizophrenia: Acute Treatment Side Effects
Huhn et al (2019). Lancet, 394(10202):939-951.
FOR PERSONAL USE ONLY
Huhn et al (2019). Lancet, 394(10202):939-951.
FOR PERSONAL USE ONLY
Antipsychotics: Acute Treatment Side Effects (cont.)
Huhn et al (2019). Lancet, 394(10202):939-951.
FOR PERSONAL USE ONLY
Huhn et al (2019). Lancet, 394(10202):939-951.
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What Are Trace Amines and TAARs?
Nair et al (2022). Mol Psychiatry, 27(1):88-94; Dedic et al (2021). Int J Mol Sci, 22(24):13185;
Dodd et al (2021). Neurosci Biobehav Rev, 120:537-541; Gainetdinov et al (2018). Pharmacol Rev, 70(3):549-620.
Trace amines (TAs)
Endogenous chemical messengers, referred to as ”false
neurotransmitters” because they are not released from
synaptic vesicles when the neuron fires
Serve as true neurotransmitters in invertebrates
Structurally similar to monoamine neurotransmitters, eg,
dopamine, norepinephrine, serotonin
Expressed at levels at least 100-fold lower than corresponding
neurotransmitters
Present in food (significant amounts in seafood, cured meats,
wine, cheese, and chocolate)
Produced by human microbiota
Trace amine-associated receptors (TAARs)
In 2001, TAs were found to selectively activate a family of
receptors called TAARs that are located in the central
nervous system (CNS) and periphery
TAARs are predominantly intracellular receptors that modulate
neurotransmission of dopamine, serotonin and glutamate.
Most studied is TAAR1
Traditional TAs
β-Phenethylamine
p-Tyramine
p-Octopamine
p-Synephrine
Tryptamine
Monoamine Neurotransmitters
Dopamine
Norepinephrine
Epinephrine
Serotonin
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Nair et al (2022). Mol Psychiatry, 27(1):88-94; Dedic et al (2021). Int J Mol Sci, 22(24):13185;
Dodd et al (2021). Neurosci Biobehav Rev, 120:537-541; Gainetdinov et al (2018). Pharmacol Rev, 70(3):549-620.
Trace amines (TAs)
Endogenous chemical messengers, referred to as ”false
neurotransmitters” because they are not released from
synaptic vesicles when the neuron fires
Serve as true neurotransmitters in invertebrates
Structurally similar to monoamine neurotransmitters, eg,
dopamine, norepinephrine, serotonin
Expressed at levels at least 100-fold lower than corresponding
neurotransmitters
Present in food (significant amounts in seafood, cured meats,
wine, cheese, and chocolate)
Produced by human microbiota
Trace amine-associated receptors (TAARs)
In 2001, TAs were found to selectively activate a family of
receptors called TAARs that are located in the central
nervous system (CNS) and periphery
TAARs are predominantly intracellular receptors that modulate
neurotransmission of dopamine, serotonin and glutamate.
Most studied is TAAR1
Traditional TAs
β-Phenethylamine
p-Tyramine
p-Octopamine
p-Synephrine
Tryptamine
Monoamine Neurotransmitters
Dopamine
Norepinephrine
Epinephrine
Serotonin
FOR PERSONAL USE ONLY
Investigational TAAR1 Compounds in Clinical Trials
5-HT1A = serotonin receptor type 1A.
Dedic et al (2019). J Pharmacol Exp Ther, 371(1):1-14; Dedic et al (2021). Int J Mol Sci, 22(24):13185; Koblan et al (2020). N Engl J Med, 382(16):1497-1506;
Correll et al (2021). NPJ Schizophr, 7(1):63; NCT03669640; NCT04512066; NCT02969382; NCT0 4092686; NCT04072354; NCT05593029; NCT05729373.
2 investigational TAAR1 compounds reached phase 2/3 clinical trials
for the treatment of schizophrenia and other psychiatric conditions
Each have different receptor pharmacology:
Ralmitaront: TAAR1 partial agonist
2 recently terminated phase 2 trials in schizophrenia and
schizoaffective disorder (acute exacerbation, and augmentation for
negative symptoms)
Ulotaront: TAAR1 agonist with 5-HT
1A agonist activity
1 positive phase 2 study in schizophrenia; and 2 negative phase 3
studies with high placebo effects
Adjunctive major depressive disorder and generalized anxiety disorder
clinical trials ongoing
FOR PERSONAL USE ONLY
5-HT1A = serotonin receptor type 1A.
Dedic et al (2019). J Pharmacol Exp Ther, 371(1):1-14; Dedic et al (2021). Int J Mol Sci, 22(24):13185; Koblan et al (2020). N Engl J Med, 382(16):1497-1506;
Correll et al (2021). NPJ Schizophr, 7(1):63; NCT03669640; NCT04512066; NCT02969382; NCT0 4092686; NCT04072354; NCT05593029; NCT05729373.
2 investigational TAAR1 compounds reached phase 2/3 clinical trials
for the treatment of schizophrenia and other psychiatric conditions
Each have different receptor pharmacology:
Ralmitaront: TAAR1 partial agonist
2 recently terminated phase 2 trials in schizophrenia and
schizoaffective disorder (acute exacerbation, and augmentation for
negative symptoms)
Ulotaront: TAAR1 agonist with 5-HT
1A agonist activity
1 positive phase 2 study in schizophrenia; and 2 negative phase 3
studies with high placebo effects
Adjunctive major depressive disorder and generalized anxiety disorder
clinical trials ongoing
FOR PERSONAL USE ONLY
Signaling Selectivity Among Muscarinic
Acetylcholine M
1-M
5 Receptors
StimulatoryInhibitory
Postsynaptic
Receptor
Presynaptic
Autoreceptor
The Nicotinic vs Muscarinic (M)
Cholinergic Receptor System
Cholinergic Receptor Systems
PNS = peripheral nervous system; cAMP = cyclic adenosine monophosphate; Ca
2+
= calcium ion.
Image created at https://biorender.com.
Paul et al (2022). Am J Psychiatry, 179(9):611-627; Brown (2019). Brain Neurosci Adv, 3:1-10; Unwin (2013). Q Rev Biophys, 46(4):283-322.
Nicotinic Receptors
•Ion-gated channel receptor
•Fast synaptic transmission
•CNS and neuromuscular
junctions
Muscarinic Receptors
•G-protein–coupled receptor
Second messenger cascades
•CNS and PNS-mediating
innervation to visceral organs
Acetylcholine
Acetylcholine
G
q protein G
i/o protein
Inositol
triphosphate
Adenylate
cyclase
Ca
2+ cAMP
FOR PERSONAL USE ONLY
Acetylcholine M
1-M
5 Receptors
StimulatoryInhibitory
Postsynaptic
Receptor
Presynaptic
Autoreceptor
The Nicotinic vs Muscarinic (M)
Cholinergic Receptor System
Cholinergic Receptor Systems
PNS = peripheral nervous system; cAMP = cyclic adenosine monophosphate; Ca
2+
= calcium ion.
Image created at https://biorender.com.
Paul et al (2022). Am J Psychiatry, 179(9):611-627; Brown (2019). Brain Neurosci Adv, 3:1-10; Unwin (2013). Q Rev Biophys, 46(4):283-322.
Nicotinic Receptors
•Ion-gated channel receptor
•Fast synaptic transmission
•CNS and neuromuscular
junctions
Muscarinic Receptors
•G-protein–coupled receptor
Second messenger cascades
•CNS and PNS-mediating
innervation to visceral organs
Acetylcholine
Acetylcholine
G
q protein G
i/o protein
Inositol
triphosphate
Adenylate
cyclase
Ca
2+ cAMP
FOR PERSONAL USE ONLY
GABA = gamma-aminobutyric acid; NMDA = N-methyl-D-as partate.
Yohn et al (2022). Trends Pharmacol Sci, 43(12):1098-1112.
Regulation of DA Circuits in Psychosis by M
1 & M
4 Receptors
M
1 receptor + activator
M
4 receptor + activator
M
5 receptor
Nicotinic
acetylcholine
receptors (nACh)
NMDA receptor
GABA
Glutamate (Glu)
Acetylcholine (ACh)
Dopamine (DA)
FOR PERSONAL USE ONLY
Yohn et al (2022). Trends Pharmacol Sci, 43(12):1098-1112.
Regulation of DA Circuits in Psychosis by M
1 & M
4 Receptors
M
1 receptor + activator
M
4 receptor + activator
M
5 receptor
Nicotinic
acetylcholine
receptors (nACh)
NMDA receptor
GABA
Glutamate (Glu)
Acetylcholine (ACh)
Dopamine (DA)
FOR PERSONAL USE ONLY
Managing Peripheral Procholinergic Effects of Xanomeline
PGP = p-glycoprotein.
Correll, Angelov et al (2022). Schizophrenia, 8:109; Callegari et al (2011). Br J Clin Pharmacol, 72(2):235-246;
Geyer et al (2009). Drug Metab Dispos, 37(7):1371-1374; Chancellor et al (2012). Drugs Aging, 29(4):259-273;
Duong et al (2021). Int Urogynecol J, 32(10):2693-2702; Malcher et al (2022). J Urol, 208(4):863-871.
Issue: xanomeline induces peripheral adverse
effects, primarily related to M
1 agonism
The answer: find an anticholinergic with limited CNS
penetration to mitigate xanomeline’s
peripheral effects
The winner: trospium! Found after screening
hundreds of compounds
What is trospium? a nonselective muscarinic
antagonist available since 1974 for overactive
bladder (approved in 2004 in the United States)
Figure: passive diffusion
across cloned kidney
cells as a model for BBB
penetration
Trospium is a quaternary ammonium compound
The positively charged ammonium group makes trospium
too polar to cross the blood-brain barrier (BBB)
Trospium is also a high-affinity substrate for PGP and is
actively transported in the BBB
FOR PERSONAL USE ONLY
PGP = p-glycoprotein.
Correll, Angelov et al (2022). Schizophrenia, 8:109; Callegari et al (2011). Br J Clin Pharmacol, 72(2):235-246;
Geyer et al (2009). Drug Metab Dispos, 37(7):1371-1374; Chancellor et al (2012). Drugs Aging, 29(4):259-273;
Duong et al (2021). Int Urogynecol J, 32(10):2693-2702; Malcher et al (2022). J Urol, 208(4):863-871.
Issue: xanomeline induces peripheral adverse
effects, primarily related to M
1 agonism
The answer: find an anticholinergic with limited CNS
penetration to mitigate xanomeline’s
peripheral effects
The winner: trospium! Found after screening
hundreds of compounds
What is trospium? a nonselective muscarinic
antagonist available since 1974 for overactive
bladder (approved in 2004 in the United States)
Figure: passive diffusion
across cloned kidney
cells as a model for BBB
penetration
Trospium is a quaternary ammonium compound
The positively charged ammonium group makes trospium
too polar to cross the blood-brain barrier (BBB)
Trospium is also a high-affinity substrate for PGP and is
actively transported in the BBB
FOR PERSONAL USE ONLY
EMERGENT-1: KarXT for Schizophrenia
PANSS = Positive and Negative Symptom Scale; BID = twice daily.
Brannan et al (2021). N Engl J Med, 384(8):717-726; Correll et al (2022). Schizophrenia, 8:109; Kaul et al (2024). Schizophrenia, 10:102.
Phase 2 Clinical Trial Design
X-T 50/20
Days 1-2
X-T 100/20
Days 3-7
X-T 125/30 (Optional increase in dose based on tolerability)
Days 8-35
Flexible dosing and titration schedule of xanomeline-trospium (X-T) BID versus matching placebo BID
Week 0 Week 5
Washout and
Screening Period
≥2 weeks
Double-Blind Inpatient Treatment Period: Days 1-35
91% were able to tolerate titration the highest dose of xanomeline-trospium
Xanomeline-trospium (n=89)
Placebo (n=90)
Randomized 1:1
•5-week, double-blind, placebo-controlled inpatient trial
•Adults ages 18-60 with an acute exacerbation of schizophrenia (EMERGENT-2 & -3: adults ages 18-65)
•Mean age: 42.5 years, 70% male, 76% non-White, mean baseline PANSS 97.1
FOR PERSONAL USE ONLY
PANSS = Positive and Negative Symptom Scale; BID = twice daily.
Brannan et al (2021). N Engl J Med, 384(8):717-726; Correll et al (2022). Schizophrenia, 8:109; Kaul et al (2024). Schizophrenia, 10:102.
Phase 2 Clinical Trial Design
X-T 50/20
Days 1-2
X-T 100/20
Days 3-7
X-T 125/30 (Optional increase in dose based on tolerability)
Days 8-35
Flexible dosing and titration schedule of xanomeline-trospium (X-T) BID versus matching placebo BID
Week 0 Week 5
Washout and
Screening Period
≥2 weeks
Double-Blind Inpatient Treatment Period: Days 1-35
91% were able to tolerate titration the highest dose of xanomeline-trospium
Xanomeline-trospium (n=89)
Placebo (n=90)
Randomized 1:1
•5-week, double-blind, placebo-controlled inpatient trial
•Adults ages 18-60 with an acute exacerbation of schizophrenia (EMERGENT-2 & -3: adults ages 18-65)
•Mean age: 42.5 years, 70% male, 76% non-White, mean baseline PANSS 97.1
FOR PERSONAL USE ONLY
EMERGENT-1–3 Trials: KarXT for Schizophrenia
LS = least squares.
Kaul et al (2024). Schizophrenia, 10:102; Brannan et al (2021). N Engl J Med, 384(8):717-726; Kaul et al (2024). Lancet, 403(10422):160-170;
Kaul et al (2024). JAMA Psychiatry, 81(8):749-756.
Efficacy: PANSS Total Score Change From Baseline
EMERGENT-1 EMERGENT-2 EMERGENT-3
-25
-20
-15
-10
-5
0
PANSS Total Score Change From
Baseline (LS Mean Change
±SEM)
Baseline Week 2 Week 4 Week 5
****
****
****
Cohen’s d effect size 0.60Cohen’s d effect size 0.61Cohen’s d effect size 0.81
Placebo
KarXT
Placebo
KarXT
Placebo
KarXT
*
**
****
P<0.05
P<0.01
P<0.0001
Primary End Point
11.6-point reduction at Week 5 9.6-point reduction at Week 5 8.4-point reduction at Week 5
FOR PERSONAL USE ONLY
LS = least squares.
Kaul et al (2024). Schizophrenia, 10:102; Brannan et al (2021). N Engl J Med, 384(8):717-726; Kaul et al (2024). Lancet, 403(10422):160-170;
Kaul et al (2024). JAMA Psychiatry, 81(8):749-756.
Efficacy: PANSS Total Score Change From Baseline
EMERGENT-1 EMERGENT-2 EMERGENT-3
-25
-20
-15
-10
-5
0
PANSS Total Score Change From
Baseline (LS Mean Change
±SEM)
Baseline Week 2 Week 4 Week 5
****
****
****
Cohen’s d effect size 0.60Cohen’s d effect size 0.61Cohen’s d effect size 0.81
Placebo
KarXT
Placebo
KarXT
Placebo
KarXT
*
**
****
P<0.05
P<0.01
P<0.0001
Primary End Point
11.6-point reduction at Week 5 9.6-point reduction at Week 5 8.4-point reduction at Week 5
FOR PERSONAL USE ONLY
Pooled EMERGENT-1–3 Trials: KarXT for Schizophrenia
TEAEs = treatment-emergent adverse events; SD = standard deviation.
Fabiano et al (2025). European Neuropsychopharmacology, 92:62-73; Brannan et al (2021). N Engl J Med, 384(8):717-726;
Kaul et al (2024). Lancet, 403(10422):160-170; Kaul et al (2024). JAMA Psychiatry, 81(8):749-756.
Safety Population: TEAEs During the 5-Week Treatment Period
Variable KarXT (n=340) Placebo (n=343)
Any TEAE 231 (67.9%) 176 (51.3%)
Serious TEAE 4 (1.2%) 2 (0.6%)
TEAE leading to discontinuation 19 (5.6%) 16 (4.7%)
TEAE occurring in ≥5% of people in the KarXT group
Nausea
Constipation
Dyspepsia
Vomiting
Headache
Hypertension
Abdominal pain
Dry mouth
Tachycardia
63 (18.5%)
58 (17.1%)
54 (15.9%)
46 (13.5%)
37 (10.9%)
29 (8.5%)
20 (5.9%)
17 (5.0%)
17 (5.0%)
13 (3.8%)
21 (6.1%)
16 (4.7%)
6 (1.7%)
35 (10.2%)
6 (1.7%)
10 (2.9%)
5 (1.5%)
8 (2.3%)
Body weight (kg), mean change from baseline to Week 5 ±SD 1.41±3.18
Body weight: ≥7% increase from baseline to Week 5 13/245 (5.3%)
Simpson-Angus Scale score, mean change from baseline to Week 5 ±SD -0.1±0.62 -0.1 ±0.63
Barnes Akathisia Rating Scale score, mean change from baseline to Week 5 ±SD -0.1±0.90 -0.1 ±0.84
Abnormal Involuntary Movement Scale score, mean change from baseline to week 5 ±SD 0.0±0.66 0.0 ±0.15
FOR PERSONAL USE ONLY
TEAEs = treatment-emergent adverse events; SD = standard deviation.
Fabiano et al (2025). European Neuropsychopharmacology, 92:62-73; Brannan et al (2021). N Engl J Med, 384(8):717-726;
Kaul et al (2024). Lancet, 403(10422):160-170; Kaul et al (2024). JAMA Psychiatry, 81(8):749-756.
Safety Population: TEAEs During the 5-Week Treatment Period
Variable KarXT (n=340) Placebo (n=343)
Any TEAE 231 (67.9%) 176 (51.3%)
Serious TEAE 4 (1.2%) 2 (0.6%)
TEAE leading to discontinuation 19 (5.6%) 16 (4.7%)
TEAE occurring in ≥5% of people in the KarXT group
Nausea
Constipation
Dyspepsia
Vomiting
Headache
Hypertension
Abdominal pain
Dry mouth
Tachycardia
63 (18.5%)
58 (17.1%)
54 (15.9%)
46 (13.5%)
37 (10.9%)
29 (8.5%)
20 (5.9%)
17 (5.0%)
17 (5.0%)
13 (3.8%)
21 (6.1%)
16 (4.7%)
6 (1.7%)
35 (10.2%)
6 (1.7%)
10 (2.9%)
5 (1.5%)
8 (2.3%)
Body weight (kg), mean change from baseline to Week 5 ±SD 1.41±3.18
Body weight: ≥7% increase from baseline to Week 5 13/245 (5.3%)
Simpson-Angus Scale score, mean change from baseline to Week 5 ±SD -0.1±0.62 -0.1 ±0.63
Barnes Akathisia Rating Scale score, mean change from baseline to Week 5 ±SD -0.1±0.90 -0.1 ±0.84
Abnormal Involuntary Movement Scale score, mean change from baseline to week 5 ±SD 0.0±0.66 0.0 ±0.15
FOR PERSONAL USE ONLY
Pooled EMERGENT-1–3 Trials : KarXT for
Schizophrenia
RR = risk ratio; GERD = gastroesophageal reflux disease; GGT = gamma-glutamyl transferase; AE = adverse event; ALT = alanine transferase;
AST = aspartate transferase; ULN = upper limit of normal; CGI-S = Clinical Global Impression–Severity.
Fabiano et al (2025). European Neuropsychopharmacology, 92:62-73.
Meta-Analyzed Efficacy and Tolerability Outcomes
FOR PERSONAL USE ONLY
Schizophrenia
RR = risk ratio; GERD = gastroesophageal reflux disease; GGT = gamma-glutamyl transferase; AE = adverse event; ALT = alanine transferase;
AST = aspartate transferase; ULN = upper limit of normal; CGI-S = Clinical Global Impression–Severity.
Fabiano et al (2025). European Neuropsychopharmacology, 92:62-73.
Meta-Analyzed Efficacy and Tolerability Outcomes
FOR PERSONAL USE ONLY
EMERGENT-4: KarXT Extension Trial
Kaul et al (2024). [Poster presentation] Schizophrenia International Research Society 2024 Annual Congress. Poster F264 .
Long-Term Change in PANSS Total Score
Mean PANSS total score
change from baseline to Week 52:
KarXT/KarXT: −33.6 points
Placebo/KarXT: −32.9 points
5-Week Acute Trial 52-Week, Open-Label Extension Trial
All participants received KarXT in the open-label phase
KarXT/KarXT (n) 48 48 47 48 48 43 38 33 29 26 25 25 19 17 18 15 15 15 14
Placebo/KarXT (n) 62 62 62 61 62 54 48 36 31 27 26 24 24 21 20 18 16 15 15
FOR PERSONAL USE ONLY
Kaul et al (2024). [Poster presentation] Schizophrenia International Research Society 2024 Annual Congress. Poster F264 .
Long-Term Change in PANSS Total Score
Mean PANSS total score
change from baseline to Week 52:
KarXT/KarXT: −33.6 points
Placebo/KarXT: −32.9 points
5-Week Acute Trial 52-Week, Open-Label Extension Trial
All participants received KarXT in the open-label phase
KarXT/KarXT (n) 48 48 47 48 48 43 38 33 29 26 25 25 19 17 18 15 15 15 14
Placebo/KarXT (n) 62 62 62 61 62 54 48 36 31 27 26 24 24 21 20 18 16 15 15
FOR PERSONAL USE ONLY
Pooled Long-Term EMERGENT Trials
Marcus et al (2024). [Poster presentation] Schizophrenia International Research Society 2024 Annual Congress. Poster F74.
Safety and Tolerability During the 52-Week Open-Label Treatment Period
Safety Population
Variable All KarXT (N=718)
Any TEAE 558 (77.7%)
Serious TEAE 46 (6.4%)
TEAEs leading to discontinuation 107 (14.9%)
TEAEs occurring in ≥5% of people in the KarXT group
Nausea
Vomiting
Constipation
Hypertension
Dry mouth
Dyspepsia
Diarrhea
Headache
Dizziness
Somnolence
Abdominal pain
143 (19.9%)
132 (18.4%)
119 (16.6%)
72 (10.0%)
68 (9.5%)
67 (9.3%)
61 (8.5%)
57 (7.9%)
56 (7.8%)
52 (7.2%)
50 (7.0%)
FOR PERSONAL USE ONLY
Marcus et al (2024). [Poster presentation] Schizophrenia International Research Society 2024 Annual Congress. Poster F74.
Safety and Tolerability During the 52-Week Open-Label Treatment Period
Safety Population
Variable All KarXT (N=718)
Any TEAE 558 (77.7%)
Serious TEAE 46 (6.4%)
TEAEs leading to discontinuation 107 (14.9%)
TEAEs occurring in ≥5% of people in the KarXT group
Nausea
Vomiting
Constipation
Hypertension
Dry mouth
Dyspepsia
Diarrhea
Headache
Dizziness
Somnolence
Abdominal pain
143 (19.9%)
132 (18.4%)
119 (16.6%)
72 (10.0%)
68 (9.5%)
67 (9.3%)
61 (8.5%)
57 (7.9%)
56 (7.8%)
52 (7.2%)
50 (7.0%)
FOR PERSONAL USE ONLY
ARISE: KarXT as Adjunct for Inadequately Controlled Schizophrenia
LAI = long-acting injectable.
NCT0514513.
Trial Design
Must have at least 1 previous inadequate response to
≥6 weeks of an adequate monotherapy trial of:
Ziprasidone, lurasidone, cariprazine, or
(oral or LAI) risperidone, paliperidone, or aripiprazole
And must have a stable dose for ≥8 weeks as of Day 1 of the study, without
changes throughout the study
Unlike the monotherapy studies:
1.Outpatients with entry PANSS ≥70
2.Uses a slower titration
3.Flexible dose design
4.100/20 BID and 125/30 BID doses are optional based on tolerability and
clinical response
Estimated
Completion
Early 2025
FOR PERSONAL USE ONLY
LAI = long-acting injectable.
NCT0514513.
Trial Design
Must have at least 1 previous inadequate response to
≥6 weeks of an adequate monotherapy trial of:
Ziprasidone, lurasidone, cariprazine, or
(oral or LAI) risperidone, paliperidone, or aripiprazole
And must have a stable dose for ≥8 weeks as of Day 1 of the study, without
changes throughout the study
Unlike the monotherapy studies:
1.Outpatients with entry PANSS ≥70
2.Uses a slower titration
3.Flexible dose design
4.100/20 BID and 125/30 BID doses are optional based on tolerability and
clinical response
Estimated
Completion
Early 2025
FOR PERSONAL USE ONLY
Emraclidine: M
4-Positive Allosteric Modulator
ES = effect size (Cohen’s d); NNT = number needed to treat.
Krystal et al (2022). Lancet, 400(10369):2210-2220.
Phase 1b Study: Efficacy Results in Change From Baseline to Week
6
ES=0.68
ES=0.59
PANSS-Total CGI-S Change
NNT=5
NNT=3
NNT=15
NNT=5
NNT=5
NNT=7
CGI-S Point Change
PANSS-Positive
PANSS-Marder Negative
PANSS-Negative
PANSS-General
Response
FOR PERSONAL USE ONLY
4-Positive Allosteric Modulator
ES = effect size (Cohen’s d); NNT = number needed to treat.
Krystal et al (2022). Lancet, 400(10369):2210-2220.
Phase 1b Study: Efficacy Results in Change From Baseline to Week
6
ES=0.68
ES=0.59
PANSS-Total CGI-S Change
NNT=5
NNT=3
NNT=15
NNT=5
NNT=5
NNT=7
CGI-S Point Change
PANSS-Positive
PANSS-Marder Negative
PANSS-Negative
PANSS-General
Response
FOR PERSONAL USE ONLY
Emraclidine: M
4-Positive Allosteric Modulator (cont.)
QD = once daily.
Krystal et al (2022). Lancet, 400(10369):2210-2220.
Adverse Effect Results in Part b of a Phase 1b Study
Placebo (n=27)
Emraclidine 30 mg
QD (n=27)
Emraclidine 20 mg
BID (n=27)
Any adverse event 14 (52%) 14 (52%) 15 (56%)
Adverse events related to study drug 10 (37%) 7 (26%) 12 (44%)
Adverse events of special interest 3 (11%) 2 (7%) 4 (15%)
Serious adverse events 0 2 (7%) 1 (4%)
Adverse events leading to study discontinuation 0 2 (7%) 1 (4%)
Adverse events that occurred in at least 5% of participants
receiving emraclidine where percent incidence was greater
with emraclidine than with placebo
Headache
Nausea
Back pain
Blood creatinine phosphokinase increase
Dizziness
Dry mouth
Somnolence
7 (26%)
1 (4%)
1 (4%)
0
0
0
0
8 (30%)
2 (7%)
2 (7%)
1 (4%)
1 (4%)
3 (11%)
1 (4%)
7 (26%)
2 (7%)
1 (4%)
2 (7%)
2 (7%)
0
2 (7%)
FOR PERSONAL USE ONLY
4-Positive Allosteric Modulator (cont.)
QD = once daily.
Krystal et al (2022). Lancet, 400(10369):2210-2220.
Adverse Effect Results in Part b of a Phase 1b Study
Placebo (n=27)
Emraclidine 30 mg
QD (n=27)
Emraclidine 20 mg
BID (n=27)
Any adverse event 14 (52%) 14 (52%) 15 (56%)
Adverse events related to study drug 10 (37%) 7 (26%) 12 (44%)
Adverse events of special interest 3 (11%) 2 (7%) 4 (15%)
Serious adverse events 0 2 (7%) 1 (4%)
Adverse events leading to study discontinuation 0 2 (7%) 1 (4%)
Adverse events that occurred in at least 5% of participants
receiving emraclidine where percent incidence was greater
with emraclidine than with placebo
Headache
Nausea
Back pain
Blood creatinine phosphokinase increase
Dizziness
Dry mouth
Somnolence
7 (26%)
1 (4%)
1 (4%)
0
0
0
0
8 (30%)
2 (7%)
2 (7%)
1 (4%)
1 (4%)
3 (11%)
1 (4%)
7 (26%)
2 (7%)
1 (4%)
2 (7%)
2 (7%)
0
2 (7%)
FOR PERSONAL USE ONLY
Emraclidine: M
4-Positive Allosteric Modulator (cont.)
In the EMPOWER phase 2b trials, emraclidine was well-tolerated with a safety profile comparable to that observed in
the phase 1b trial. The most commonly reported adverse events in EMPOWER-1 and EMPOWER-2, respectively, were:
Headache (9.4% and 10.8% in placebo;14.1% in EMPOWER-1 10 mg ; 14.6% in EMPOWER-2 15 mg; 13.2% and 13.0% in 30
mg)
Dry mouth (2.3% and 0.8% in placebo; 3.9% in EMPOWER-1 10 mg; 0.8% in EMPOWER-2 15 mg; 9.3% and 5.3% in 30 mg)
Dyspepsia (3.1% and 1.5% in placebo; 3.9% in EMPOWER-1 10 mg; 3.1% in EMPOWER-2 15 mg; 7.8% and 2.3% in 30 mg)
CI = confidence interval; SE = standard error.
Krystal et al (2022). Lancet, 400(10369):2210-2220; AbbVie, 2024 [https://news.abbvie.com/2024-11-11-AbbVie-Provides-Update-on-Phase-2-Results-for-
Emraclidine-in-Schizophrenia].
Phase 2b EMPOWER Studies vs Phase 1b Study
EMPOWER-1 EMPOWER-2
Placebo
(n=127)
Emraclidine
10 mg QD (n=125)
Emraclidine
30 mg QD (n=127)
Placebo (n=128)
Emraclidine
15 mg QD (n=122)
Emraclidine
30 mg QD (n=123)
Baseline (SD) 98.3 (8.2) 97.6 (7.6) 97.9 (7.9) 97.4 (8.2) 98.0 (8.5) 97.2 (7.8)
LS mean (95% CI)
-13.5
(-17.0, -10.0)
-14.7
(-18.1, -11.2)
-16.5
(-20.0, -13.1)
-16.1
(-19.4, -12.8)
-18.5
(-22.0, -15.0)
-14.2
(-17.6, -10.8)
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Phase 1b study
Placebo
(n=27)
Emraclidine
30 mg QD (n=27)
Emraclidine
20 mg BID (n=27)
Baseline (SD) 93 (8.8) 93 (7.3) 97 (7.9)
LS mean (SE) -6.8 (3.8) -19.5 (3.9) -17.9 (3.9)
FOR PERSONAL USE ONLY
4-Positive Allosteric Modulator (cont.)
In the EMPOWER phase 2b trials, emraclidine was well-tolerated with a safety profile comparable to that observed in
the phase 1b trial. The most commonly reported adverse events in EMPOWER-1 and EMPOWER-2, respectively, were:
Headache (9.4% and 10.8% in placebo;14.1% in EMPOWER-1 10 mg ; 14.6% in EMPOWER-2 15 mg; 13.2% and 13.0% in 30
mg)
Dry mouth (2.3% and 0.8% in placebo; 3.9% in EMPOWER-1 10 mg; 0.8% in EMPOWER-2 15 mg; 9.3% and 5.3% in 30 mg)
Dyspepsia (3.1% and 1.5% in placebo; 3.9% in EMPOWER-1 10 mg; 3.1% in EMPOWER-2 15 mg; 7.8% and 2.3% in 30 mg)
CI = confidence interval; SE = standard error.
Krystal et al (2022). Lancet, 400(10369):2210-2220; AbbVie, 2024 [https://news.abbvie.com/2024-11-11-AbbVie-Provides-Update-on-Phase-2-Results-for-
Emraclidine-in-Schizophrenia].
Phase 2b EMPOWER Studies vs Phase 1b Study
EMPOWER-1 EMPOWER-2
Placebo
(n=127)
Emraclidine
10 mg QD (n=125)
Emraclidine
30 mg QD (n=127)
Placebo (n=128)
Emraclidine
15 mg QD (n=122)
Emraclidine
30 mg QD (n=123)
Baseline (SD) 98.3 (8.2) 97.6 (7.6) 97.9 (7.9) 97.4 (8.2) 98.0 (8.5) 97.2 (7.8)
LS mean (95% CI)
-13.5
(-17.0, -10.0)
-14.7
(-18.1, -11.2)
-16.5
(-20.0, -13.1)
-16.1
(-19.4, -12.8)
-18.5
(-22.0, -15.0)
-14.2
(-17.6, -10.8)
--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Phase 1b study
Placebo
(n=27)
Emraclidine
30 mg QD (n=27)
Emraclidine
20 mg BID (n=27)
Baseline (SD) 93 (8.8) 93 (7.3) 97 (7.9)
LS mean (SE) -6.8 (3.8) -19.5 (3.9) -17.9 (3.9)
FOR PERSONAL USE ONLY
NBI-1117568: M
4 Agonist
CYP2D6 = cytochrome P450 2D6.
Neurocrine Biosciences, 2022 [https://neurocrine.gcs-web.com/news-releases/news-release-details/neurocrine-biosciences-reports-second-quarter-2022-
financial]; Neurocrine Biosciences 2024 [https://neurocrine.gcs-web.com/news-releases/news-release-details/neurocrine-biosciences-reports-positive-phase-
2-data-nbi-1117568]; GlobalNewswire, 2024 [https://www.globenewswire.com/news-release/2024/08/28/2936889/0/ en/Nxera-Pharma-Notes-Positive-Phase-
2-Data-for-Partnered-Schizophrenia-Candidate-NBI-1117568.html]; NCT03244228.
Phase 1a study in 120 healthy volunteers, completed in 2019
No serious adverse events or typical muscarinic side effects reported
Some cardiovascular effects observed
Excluded CYP2D6 poor metabolizers and use of CYP2D6 inhibitors
Week 6
(Day 42)
Placebo
(n=68)
20 mg QD
(n=35)
40 mg QD
(n=38)
60 mg QD
(n=34)
30 mg BID
(n=26)
PANSS total score LS
mean change from
baseline
-10.8 -18.2 -12.6 -13.7 -15.8
LS mean difference vs
placebo
-
-7.5
(
P=0.011)
-1.9
(P=0.282)
-2.9
(P=0.189)
-5.0
(P=0.090)
Effect size - 0.61 0.27 0.39 0.23
Preliminary Phase 2 Data in Adults with Schizophrenia
FOR PERSONAL USE ONLY
4 Agonist
CYP2D6 = cytochrome P450 2D6.
Neurocrine Biosciences, 2022 [https://neurocrine.gcs-web.com/news-releases/news-release-details/neurocrine-biosciences-reports-second-quarter-2022-
financial]; Neurocrine Biosciences 2024 [https://neurocrine.gcs-web.com/news-releases/news-release-details/neurocrine-biosciences-reports-positive-phase-
2-data-nbi-1117568]; GlobalNewswire, 2024 [https://www.globenewswire.com/news-release/2024/08/28/2936889/0/ en/Nxera-Pharma-Notes-Positive-Phase-
2-Data-for-Partnered-Schizophrenia-Candidate-NBI-1117568.html]; NCT03244228.
Phase 1a study in 120 healthy volunteers, completed in 2019
No serious adverse events or typical muscarinic side effects reported
Some cardiovascular effects observed
Excluded CYP2D6 poor metabolizers and use of CYP2D6 inhibitors
Week 6
(Day 42)
Placebo
(n=68)
20 mg QD
(n=35)
40 mg QD
(n=38)
60 mg QD
(n=34)
30 mg BID
(n=26)
PANSS total score LS
mean change from
baseline
-10.8 -18.2 -12.6 -13.7 -15.8
LS mean difference vs
placebo
-
-7.5
(
P=0.011)
-1.9
(P=0.282)
-2.9
(P=0.189)
-5.0
(P=0.090)
Effect size - 0.61 0.27 0.39 0.23
Preliminary Phase 2 Data in Adults with Schizophrenia
FOR PERSONAL USE ONLY
Muscarinic Agonists and Positive Allosteric Modulators
SIGMAR1 = sigma receptor 1; mAChR = muscarinic acetylcholine receptor; PAM = positive allosteric modulator; AD = Alzheimer disease.
Kingwell (2024). Nat Rev Drug Discov, 23(9):647-649.
Status of Agents in Development
Drug Target/Properties Lead Indication Status Additional Indi cations
KarXT (xanomeline
and trospium)
M
1/M
4 agonist plus a peripheral
pan-mAChR antagonist
Schizophrenia Approved
Schizophrenia augmentation,
AD psychosis
Emraclidine M
4 PAM Schizophrenia Phase 2
NMRA-266 M
4 PAM Schizophrenia On hold
NBI-1117568 M
4 agonist Schizophrenia Phase 2
NBI-1117570 M
1/M
4 agonist CNS indications Phase 1
NBI-1117567 M
1-preferring agonist CNS indications Phase 1
NBI-1117569 M
4-preferring agonist CNS indications Phase 1
ANAVEX3-71 SIGMAR1/M
1 agonist Schizophrenia Phase 2
ML-007C-MA
M
1/M
4 agonist plus a peripheral
pan-mAChR antagonist
Schizophrenia and
AD psychosis
Phase 1
ACP-319 M
1 PAM
Schizophrenia,
cognition in AD
Stopped
Undisclosed M
4 PAM Schizophrenia Preclinical
FOR PERSONAL USE ONLY
SIGMAR1 = sigma receptor 1; mAChR = muscarinic acetylcholine receptor; PAM = positive allosteric modulator; AD = Alzheimer disease.
Kingwell (2024). Nat Rev Drug Discov, 23(9):647-649.
Status of Agents in Development
Drug Target/Properties Lead Indication Status Additional Indi cations
KarXT (xanomeline
and trospium)
M
1/M
4 agonist plus a peripheral
pan-mAChR antagonist
Schizophrenia Approved
Schizophrenia augmentation,
AD psychosis
Emraclidine M
4 PAM Schizophrenia Phase 2
NMRA-266 M
4 PAM Schizophrenia On hold
NBI-1117568 M
4 agonist Schizophrenia Phase 2
NBI-1117570 M
1/M
4 agonist CNS indications Phase 1
NBI-1117567 M
1-preferring agonist CNS indications Phase 1
NBI-1117569 M
4-preferring agonist CNS indications Phase 1
ANAVEX3-71 SIGMAR1/M
1 agonist Schizophrenia Phase 2
ML-007C-MA
M
1/M
4 agonist plus a peripheral
pan-mAChR antagonist
Schizophrenia and
AD psychosis
Phase 1
ACP-319 M
1 PAM
Schizophrenia,
cognition in AD
Stopped
Undisclosed M
4 PAM Schizophrenia Preclinical
FOR PERSONAL USE ONLY
LB-102
GlobeNewswire, 2025 [https://www.globenewswire.com/new s-release/2025/01/08/3006104/0/ en/LB-Pharmaceuticals-Announces-Positive-Topline-Results-
from-Phase-2-Trial-of-LB-102-in-Schizophrenia.html].
NOVA1 met its primary end point, demonstrating statistically significant
change from baseline in the PANSS total score at 4 weeks
The 50-mg dose arm (n=107) achieved an effect size of 0.61, and
participants experienced a 5.0-point reduction in PANSS total score
compared to placebo (P=0.0009)
Treatment with the 75-mg dose (n=108) achieved an effect size of 0.41 and
led to a 4.7-point reduction in PANSS total score compared to placebo
(P=0.0022)
The study also included an exploratory dose of 100 mg (n=36), which
demonstrated an effect size of 0.83 with a 6.8-point reduction in PANSS total
score compared to placebo (P=0.0017)
Methylated Version of D
2/3-5HT
7 Antagonist Amisulpride
FOR PERSONAL USE ONLY
GlobeNewswire, 2025 [https://www.globenewswire.com/new s-release/2025/01/08/3006104/0/ en/LB-Pharmaceuticals-Announces-Positive-Topline-Results-
from-Phase-2-Trial-of-LB-102-in-Schizophrenia.html].
NOVA1 met its primary end point, demonstrating statistically significant
change from baseline in the PANSS total score at 4 weeks
The 50-mg dose arm (n=107) achieved an effect size of 0.61, and
participants experienced a 5.0-point reduction in PANSS total score
compared to placebo (P=0.0009)
Treatment with the 75-mg dose (n=108) achieved an effect size of 0.41 and
led to a 4.7-point reduction in PANSS total score compared to placebo
(P=0.0022)
The study also included an exploratory dose of 100 mg (n=36), which
demonstrated an effect size of 0.83 with a 6.8-point reduction in PANSS total
score compared to placebo (P=0.0017)
Methylated Version of D
2/3-5HT
7 Antagonist Amisulpride
FOR PERSONAL USE ONLY
mITT = modified intention to treat; CGI-C = Clinical Global Impression of Change.
Anand et al (2025). Neuropharmacology, 266:110275.
Selective, State-Dependent Inhibitor of Voltage-Gated Sodium Channels (VGSCs)
Evenamide for Positive Symptom Partial Non-Responders
Responder
Category
FOR PERSONAL USE ONLY
Anand et al (2025). Neuropharmacology, 266:110275.
Selective, State-Dependent Inhibitor of Voltage-Gated Sodium Channels (VGSCs)
Evenamide for Positive Symptom Partial Non-Responders
Responder
Category
FOR PERSONAL USE ONLY
Evenamide: Selective, State-Dependent Inhibitor of VGSCs
Anand et al (2025). Neuropharmacology, 266:110275.
Safety
VGSCs: Voltage-Gated Sodium Channels
FOR PERSONAL USE ONLY
Anand et al (2025). Neuropharmacology, 266:110275.
Safety
VGSCs: Voltage-Gated Sodium Channels
FOR PERSONAL USE ONLY
Key Takeaways
For 7 decades, all antipsychotics have been postsynaptic antidopaminergic
agents; they work for total and especially positive symptoms for many patients
but have limited efficacy for negative or cognitive symptoms
There is no indication for negative or cognitive symptoms or adjunctive
treatment
Clozapine is currently the only agent approved for treatment-resistant
schizophrenia
Current antidopaminergic antipsychotics are associated to varying degrees with
neuromotor, neuroendocrine, cardiometabolic, and arousal-related side effects
that can limit their utility
Antipsychotic choice is based on patient and illness characteristics, psychiatric
and medical comorbidities, medication characteristics (half-life, drug-drug
interactions, efficacy and safety/tolerability), access, and patient preference
FOR PERSONAL USE ONLY
For 7 decades, all antipsychotics have been postsynaptic antidopaminergic
agents; they work for total and especially positive symptoms for many patients
but have limited efficacy for negative or cognitive symptoms
There is no indication for negative or cognitive symptoms or adjunctive
treatment
Clozapine is currently the only agent approved for treatment-resistant
schizophrenia
Current antidopaminergic antipsychotics are associated to varying degrees with
neuromotor, neuroendocrine, cardiometabolic, and arousal-related side effects
that can limit their utility
Antipsychotic choice is based on patient and illness characteristics, psychiatric
and medical comorbidities, medication characteristics (half-life, drug-drug
interactions, efficacy and safety/tolerability), access, and patient preference
FOR PERSONAL USE ONLY
Key Takeaways (cont.)
Agents with more robust or specific efficacy for certain patient subgroups or
symptom clusters are needed
Novel mechanism of action agents are needed to treat patients who are
insufficiently served by the currently available antipsychotics and to enable
rational polypharmacy
The M
1/M
4 agonist xanomeline paired with a peripherally restricted
anticholinergic trospium is (since 9/2024) the first antipsychotic approved for
the treatment of schizophrenia that regulates presynaptic excess of dopamine
release via direct muscarinic and indirect GABAergic and glutamatergic
modulation
Additional agents in the muscarinic modulator area and with other mechanisms
of action are currently under development for total, negative, and cognitive
symptoms of schizophrenia as well as for treatment-resistant schizophrenia
FOR PERSONAL USE ONLY
Agents with more robust or specific efficacy for certain patient subgroups or
symptom clusters are needed
Novel mechanism of action agents are needed to treat patients who are
insufficiently served by the currently available antipsychotics and to enable
rational polypharmacy
The M
1/M
4 agonist xanomeline paired with a peripherally restricted
anticholinergic trospium is (since 9/2024) the first antipsychotic approved for
the treatment of schizophrenia that regulates presynaptic excess of dopamine
release via direct muscarinic and indirect GABAergic and glutamatergic
modulation
Additional agents in the muscarinic modulator area and with other mechanisms
of action are currently under development for total, negative, and cognitive
symptoms of schizophrenia as well as for treatment-resistant schizophrenia
FOR PERSONAL USE ONLY
References
AbbVie (2024). AbbVie provides update on phase 2 results for emraclidine in schizophrenia. Available at: https://news.abbvie.com/2024-11-11-AbbVie-Provides-Update-on-Phase-
2-Results-for-Emraclidine-in-Schizophrenia
Anand R, Turolla A, Chinellato G, et al (2025). Efficacy and safety of evenamide, a glutamate modulator, added to a second-generation antipsychotic in adequately/poorly
responding patients with chronic schizophrenia: results from a randomized, double-blind, placebo-controlled, phase 3 international clinical trial. Neuropharmacology,
266:110275. DOI:10.1016/j.neuropharm.2024.110275
Brannan SK, Sawchak S, Miller AC, et al (2021). Muscarinic cholinergic receptor agonist and peripheral antagonist for schizophrenia. N Engl J Med, 384(8):717-726.
DOI:10.1056/NEJMoa2017015
Brown DA (2019). Acetylcholine and cholinergic receptors. Brain Neurosci Adv, 3:2398212818820506. DOI:10.1177/2398212818820506
Callegari E, Malhotra B, Bungay PJ, et al (2011). A comprehensive non-clinical evaluation of the CNS penetration potential of antimuscarinic agents for the treatment of overactive
bladder. Br J Clin Pharmacol, 72(2):235-246. DOI:10.1111/j.1365-2125.2011.03961 .x
Carbon M, Correll CU (2014a). Clinical predictors of therapeutic response to antipsychotics in schizophrenia. Dialogues Clin Neurosci, 16(4):505-524.
DOI:10.31887/DCNS.2014.16.4/mcarbon
Chancellor MB, Staskin DR, Kay GG, et al (2012). Blood-brain barrier permeation and efflux exclusion of anticholinergics used in the treatment of overactive bladder. Drugs Aging,
29(4):259-273. DOI:10.2165/11597530-000000000-00000 .
Clinicaltrials.gov (2023). A trial of the efficacy and the safety of RO6889450 (ralmitaront) vs placebo in patients with an acute exacerbation of schizophrenia or schizoaffective
disorder. NLM identifier: NCT04512066
Clinicaltrials.gov (2024a). A clinical study that will measure how well SEP-363856 works and how safe it is in adults with generalized anxiety disorder. NLM identifier:
NCT05729373
Clinicaltrials.gov (2024b). A clinical trial that will study the efficacy and safety of an investigational drug in acutely psychotic people with schizophrenia. NLM identifier:
NCT04092686
Clinicaltrials.gov (2024c). A clinical trial to study the efficacy and safety of an investigational drug in acutely psychotic people with schizophrenia. NLM identifier: NCT04072354
Clinicaltrials.gov (2024d). A study to assess efficacy and safety of adjunctive KarXT in subjects with inadequately controlled symptoms of schizophrenia (ARISE). NLM identifier:
NCT05145413
Clinicaltrials.gov (2024e). A study to assess the effects of RO6889450 (ralmitaront) in participants with schizophrenia or schizoaffective disorder and negative symptoms. NLM
identifier: NCT03669640
FOR PERSONAL USE ONLY
AbbVie (2024). AbbVie provides update on phase 2 results for emraclidine in schizophrenia. Available at: https://news.abbvie.com/2024-11-11-AbbVie-Provides-Update-on-Phase-
2-Results-for-Emraclidine-in-Schizophrenia
Anand R, Turolla A, Chinellato G, et al (2025). Efficacy and safety of evenamide, a glutamate modulator, added to a second-generation antipsychotic in adequately/poorly
responding patients with chronic schizophrenia: results from a randomized, double-blind, placebo-controlled, phase 3 international clinical trial. Neuropharmacology,
266:110275. DOI:10.1016/j.neuropharm.2024.110275
Brannan SK, Sawchak S, Miller AC, et al (2021). Muscarinic cholinergic receptor agonist and peripheral antagonist for schizophrenia. N Engl J Med, 384(8):717-726.
DOI:10.1056/NEJMoa2017015
Brown DA (2019). Acetylcholine and cholinergic receptors. Brain Neurosci Adv, 3:2398212818820506. DOI:10.1177/2398212818820506
Callegari E, Malhotra B, Bungay PJ, et al (2011). A comprehensive non-clinical evaluation of the CNS penetration potential of antimuscarinic agents for the treatment of overactive
bladder. Br J Clin Pharmacol, 72(2):235-246. DOI:10.1111/j.1365-2125.2011.03961 .x
Carbon M, Correll CU (2014a). Clinical predictors of therapeutic response to antipsychotics in schizophrenia. Dialogues Clin Neurosci, 16(4):505-524.
DOI:10.31887/DCNS.2014.16.4/mcarbon
Chancellor MB, Staskin DR, Kay GG, et al (2012). Blood-brain barrier permeation and efflux exclusion of anticholinergics used in the treatment of overactive bladder. Drugs Aging,
29(4):259-273. DOI:10.2165/11597530-000000000-00000 .
Clinicaltrials.gov (2023). A trial of the efficacy and the safety of RO6889450 (ralmitaront) vs placebo in patients with an acute exacerbation of schizophrenia or schizoaffective
disorder. NLM identifier: NCT04512066
Clinicaltrials.gov (2024a). A clinical study that will measure how well SEP-363856 works and how safe it is in adults with generalized anxiety disorder. NLM identifier:
NCT05729373
Clinicaltrials.gov (2024b). A clinical trial that will study the efficacy and safety of an investigational drug in acutely psychotic people with schizophrenia. NLM identifier:
NCT04092686
Clinicaltrials.gov (2024c). A clinical trial to study the efficacy and safety of an investigational drug in acutely psychotic people with schizophrenia. NLM identifier: NCT04072354
Clinicaltrials.gov (2024d). A study to assess efficacy and safety of adjunctive KarXT in subjects with inadequately controlled symptoms of schizophrenia (ARISE). NLM identifier:
NCT05145413
Clinicaltrials.gov (2024e). A study to assess the effects of RO6889450 (ralmitaront) in participants with schizophrenia or schizoaffective disorder and negative symptoms. NLM
identifier: NCT03669640
FOR PERSONAL USE ONLY
References (cont.)
Clinicaltrials.gov (2024g). A study to evaluate the efficacy and safety of SEP-363856 in acutely psychotic adults with schizophrenia. NLM identifier: NCT02969382
Clinicaltrials.gov (2024h). A trial of the safety and efficacy of SEP-363856 in the treatment of adults with major depressive disorder. NLM identifier: NCT05593029
Clinicaltrials.gov (2024j). A two part study to assess safety, PK, PD, and food effect of oral HTL0016878. NLM identifier: NCT03244228
Correll CU, Abi-Dargham A & Howes O (2022). Emerging treatments in schizophrenia. J Clin Psychiatry. 83(1):SU21024IP1. DOI:10.4088/JCP.SU21024IP1
Correll CU, Angelov AS, Miller AC, et al (2022). Safety and tolerability of KarXT (xanomeline-trospium) in a phase 2, randomized, double-blind, placebo-controlled study in patients
with schizophrenia. Schizophrenia, 8:109. DOI:10.1038/s41537-022-00320-1
Correll CU, Koblan KS, Hopkins SC, et al (2021). Safety and effectiveness of ulotaront (SEP-363856) in schizophrenia: results of a 6-month, open-label extension study. NPJ
Schizophr, 7(1):63 DOI:10.1038/s41537-021-00190-z
Dedic N, Dworak H, Zeni C, et al (2021). Therapeutic potential of TAAR1 agonists in schizophrenia: evidence from preclinical models and clinical studies. Int J Mol Sci,
22(24):13185. DOI:10.3390/ijms222413185
Dedic N, Jones PG, Hopkins SC, et al, (2019). SEP-363856, a novel psychotropic agent with a unique, non-D2 receptor mechanism of action. J Pharmacol Exp Ther, 371(1):1-14.
DOI:10.1124/jpet.119.260281
Diniz E, Fonesca L, Rocha D, et al (2023). Treatment resistance in schizophrenia: a meta-analysis of prevalence and correlates. Braz J Psychiatry, 45(4):448-458.
DOI:10.47626/1516-4446-2023-3126
Dodd S, Carvalho AF, Puri BK, et al (2021). Trace amine-associated receptor 1 (TAAR1): a new drug target for psychiatry?. Neurosci Biobehav Rev, 120:537-541.
DOI:10.1016/j.neubiorev.2020.09.028
Duong V, Iwamoto A, Pennycuff J, et al (2021). A systematic review of neurocognitive dysfunction with overactive bladder medications. Int Urogynecol J, 32(10):2693-2702.
DOI:10.1007/s00192-021-04909-5
Fabiano N, Wong S, Zhou C, et al (2025). Efficacy, tolerability, and safety of xanomeline-trospium chloride for schizophrenia: a systematic review and meta-analysis. European
Neuropsychopharmacology, 92:62-73. DOI:10.1016/j.euroneuro.2024.11.013
Gainetdinov RR, Hoener MC & Berry MD (2018). Trace amines and their receptors. Pharmacol Rev, 70(3):549-620. DOI:10.1124/pr.117.015305
Geyer J, Gavrilova O & Petzinger E (2009). The role of p-glycoprotein in limiting brain penetration of the peripherally acting anticholinergic overactive bladder drug trospium
chloride. Drug Metab Dispos, 37(7):1371-1374. DOI:10.1124/dmd.109.027144
FOR PERSONAL USE ONLY
Clinicaltrials.gov (2024g). A study to evaluate the efficacy and safety of SEP-363856 in acutely psychotic adults with schizophrenia. NLM identifier: NCT02969382
Clinicaltrials.gov (2024h). A trial of the safety and efficacy of SEP-363856 in the treatment of adults with major depressive disorder. NLM identifier: NCT05593029
Clinicaltrials.gov (2024j). A two part study to assess safety, PK, PD, and food effect of oral HTL0016878. NLM identifier: NCT03244228
Correll CU, Abi-Dargham A & Howes O (2022). Emerging treatments in schizophrenia. J Clin Psychiatry. 83(1):SU21024IP1. DOI:10.4088/JCP.SU21024IP1
Correll CU, Angelov AS, Miller AC, et al (2022). Safety and tolerability of KarXT (xanomeline-trospium) in a phase 2, randomized, double-blind, placebo-controlled study in patients
with schizophrenia. Schizophrenia, 8:109. DOI:10.1038/s41537-022-00320-1
Correll CU, Koblan KS, Hopkins SC, et al (2021). Safety and effectiveness of ulotaront (SEP-363856) in schizophrenia: results of a 6-month, open-label extension study. NPJ
Schizophr, 7(1):63 DOI:10.1038/s41537-021-00190-z
Dedic N, Dworak H, Zeni C, et al (2021). Therapeutic potential of TAAR1 agonists in schizophrenia: evidence from preclinical models and clinical studies. Int J Mol Sci,
22(24):13185. DOI:10.3390/ijms222413185
Dedic N, Jones PG, Hopkins SC, et al, (2019). SEP-363856, a novel psychotropic agent with a unique, non-D2 receptor mechanism of action. J Pharmacol Exp Ther, 371(1):1-14.
DOI:10.1124/jpet.119.260281
Diniz E, Fonesca L, Rocha D, et al (2023). Treatment resistance in schizophrenia: a meta-analysis of prevalence and correlates. Braz J Psychiatry, 45(4):448-458.
DOI:10.47626/1516-4446-2023-3126
Dodd S, Carvalho AF, Puri BK, et al (2021). Trace amine-associated receptor 1 (TAAR1): a new drug target for psychiatry?. Neurosci Biobehav Rev, 120:537-541.
DOI:10.1016/j.neubiorev.2020.09.028
Duong V, Iwamoto A, Pennycuff J, et al (2021). A systematic review of neurocognitive dysfunction with overactive bladder medications. Int Urogynecol J, 32(10):2693-2702.
DOI:10.1007/s00192-021-04909-5
Fabiano N, Wong S, Zhou C, et al (2025). Efficacy, tolerability, and safety of xanomeline-trospium chloride for schizophrenia: a systematic review and meta-analysis. European
Neuropsychopharmacology, 92:62-73. DOI:10.1016/j.euroneuro.2024.11.013
Gainetdinov RR, Hoener MC & Berry MD (2018). Trace amines and their receptors. Pharmacol Rev, 70(3):549-620. DOI:10.1124/pr.117.015305
Geyer J, Gavrilova O & Petzinger E (2009). The role of p-glycoprotein in limiting brain penetration of the peripherally acting anticholinergic overactive bladder drug trospium
chloride. Drug Metab Dispos, 37(7):1371-1374. DOI:10.1124/dmd.109.027144
FOR PERSONAL USE ONLY
References (cont.)
GlobeNewswire.com (2024). Nxera Pharma notes positive phase 2 data for partnered schizophrenia candidate NBI-1117568. Available at: https://www.globenewswire.com/news-
release/2024/08/28/2936889/0/ en/Nxera-Pharma-Notes-Positive-Phase-2-Data-for-Partnered-Schizophrenia-Candidate-NBI-1117568.html
GlobeNewswire.com (2025). LB pharmaceuticals announce s positive topline results from phase 2 trial of LB-102 in schizophrenia. Available at:
https://www.globenewswire.com/news-release/2025/01/08 /3006104/0/en/LB-Pharmaceuticals-Announces-Positive-Topline-Results-from-Phase-2-Trial-of-LB-102-in-
Schizophrenia.html
Grunder G, Carlsson A & Wong DF (2003). Mechanism of new antipsychotic medications: occupancy is not just antagonism. Arch Gen Psychiatry, 60(10):974-977.
DOI:10.1001/archpsyc.60.10.974
Hansen HG, Speyer H, Starzer M, et al (2023). Clinical recovery among individuals with a first-episode schizophrenia an updated systematic review and meta-analysis. Schizophr
Bull, 49(2):297-308. DOI:10.1093/schbul/sbac103
Howes OD & Onwordi EC (2023). The synaptic hypothesis of schizophrenia version III: a master mechanism. Mol Psychiatry, 28(5):1843-1856. DOI:10.1038/s41380-023-02043-w
Huhn M, Nikolakopoulou A, Schneider-Thoma J, et al (2019). Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode
schizophrenia: a systematic review and network meta-analysis. Lancet, 394(10202):939-951. DOI:10.1016/S0140-6736(19)311 35-3
Kadakia A, Catillon M, Fan Q, et al (2022). The economic burden of schizophrenia in the United States. J Clin Psychiatry, 83(6):22m14458. DOI:10.4088/JCP.22m14458
Kahn RS, Sommer IE, Murray RM, et al (2015). Schizophrenia. Nat Rev Dis Primers, 1:15067. DOI:10.1038/nrdp.2015.67
Kaul I, Cohen EA, Miller AC, et al (2024). Maintenance of efficacy of KARXT (xanomeline and trospium) in schizophrenia. [Poster presentation] Schizophrenia International
Research Society 2024 Annual Congress. Poster F264.
Kaul I, Sawchak S, Claxton A, et al (2024). Efficacy of xanomeline and trospium chloride in schizophrenia: pooled results from three 5-week, randomized, double-blind, placebo-
controlled, EMERGENT trials. Schizophrenia, 10:102. DOI:10.1038/s41537-024-00525-6
Kaul I, Sawchak S, Correll CU, et al (2024). 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. Lancet, 403(10422):160-170. DOI:10.1016/S0140-6736(23)021 90-6
Kaul I, Sawchak S, Walling DP, et al (2024). Efficacy and safety of xanomeline-trospium chloride in schizophrenia: a randomized clinical trial. JAMA Psychiatry. 81(8):749-756.
DOI:10.1001/jamapsychiatry.2024.0785
Kingwell K (2024). Muscarinic drugs breathe new life into schizophrenia pipeline. Nat Rev Drug Discov, 23(9):647-649. DOI:10.1038/d41573-024-00129-w
Koblan KS, Kent J, Hopkins SC, et al (2020). A non-D2-recepter-binding drug for the treatment of schizophrenia. N Engl J Med, 382(16):1497-1506.
DOI:10.1056/NEJMoa1911772
FOR PERSONAL USE ONLY
GlobeNewswire.com (2024). Nxera Pharma notes positive phase 2 data for partnered schizophrenia candidate NBI-1117568. Available at: https://www.globenewswire.com/news-
release/2024/08/28/2936889/0/ en/Nxera-Pharma-Notes-Positive-Phase-2-Data-for-Partnered-Schizophrenia-Candidate-NBI-1117568.html
GlobeNewswire.com (2025). LB pharmaceuticals announce s positive topline results from phase 2 trial of LB-102 in schizophrenia. Available at:
https://www.globenewswire.com/news-release/2025/01/08 /3006104/0/en/LB-Pharmaceuticals-Announces-Positive-Topline-Results-from-Phase-2-Trial-of-LB-102-in-
Schizophrenia.html
Grunder G, Carlsson A & Wong DF (2003). Mechanism of new antipsychotic medications: occupancy is not just antagonism. Arch Gen Psychiatry, 60(10):974-977.
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Howes OD & Onwordi EC (2023). The synaptic hypothesis of schizophrenia version III: a master mechanism. Mol Psychiatry, 28(5):1843-1856. DOI:10.1038/s41380-023-02043-w
Huhn M, Nikolakopoulou A, Schneider-Thoma J, et al (2019). Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode
schizophrenia: a systematic review and network meta-analysis. Lancet, 394(10202):939-951. DOI:10.1016/S0140-6736(19)311 35-3
Kadakia A, Catillon M, Fan Q, et al (2022). The economic burden of schizophrenia in the United States. J Clin Psychiatry, 83(6):22m14458. DOI:10.4088/JCP.22m14458
Kahn RS, Sommer IE, Murray RM, et al (2015). Schizophrenia. Nat Rev Dis Primers, 1:15067. DOI:10.1038/nrdp.2015.67
Kaul I, Cohen EA, Miller AC, et al (2024). Maintenance of efficacy of KARXT (xanomeline and trospium) in schizophrenia. [Poster presentation] Schizophrenia International
Research Society 2024 Annual Congress. Poster F264.
Kaul I, Sawchak S, Claxton A, et al (2024). Efficacy of xanomeline and trospium chloride in schizophrenia: pooled results from three 5-week, randomized, double-blind, placebo-
controlled, EMERGENT trials. Schizophrenia, 10:102. DOI:10.1038/s41537-024-00525-6
Kaul I, Sawchak S, Correll CU, et al (2024). 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. Lancet, 403(10422):160-170. DOI:10.1016/S0140-6736(23)021 90-6
Kaul I, Sawchak S, Walling DP, et al (2024). Efficacy and safety of xanomeline-trospium chloride in schizophrenia: a randomized clinical trial. JAMA Psychiatry. 81(8):749-756.
DOI:10.1001/jamapsychiatry.2024.0785
Kingwell K (2024). Muscarinic drugs breathe new life into schizophrenia pipeline. Nat Rev Drug Discov, 23(9):647-649. DOI:10.1038/d41573-024-00129-w
Koblan KS, Kent J, Hopkins SC, et al (2020). A non-D2-recepter-binding drug for the treatment of schizophrenia. N Engl J Med, 382(16):1497-1506.
DOI:10.1056/NEJMoa1911772
FOR PERSONAL USE ONLY
References (cont.)
Krystal JH, Kane JM, Correll CU, et al (2022). Emraclidine, a novel positive allosteric modulator of cholinergic M4 receptors, for the treatment of schizophrenia: a two-part,
randomized, double-blind, placebo-controlled, phase 1b trial. Lancet, 400(10369):2210-2220. DOI:10.1016/S0140-6736(22)019 90-0
Malcher MF, Droupy S, Berr C, et al (2022). Dementia associated with anticholinergic drugs used for overactive bladder: a nested case-control study using the French National
Medical-Administrative Database. J Urol, 208(4):863-871. DOI:10.1097/JU.0000000000002804
Marcus R, Kakar R, Miller AC et al (2024). Long-term safety of KARXT (xanomeline and trospium) in schizophrenia [Poster presentation] Schizophrenia International Research
Society 2024 Annual Congress. Poster F74.
McCutcheon RA, Abi-Dargham A & Howes OD (2019). Schi zophrenia, dopamine and the striatum: from biology to symptoms. Trends Neurosci, 42(3):205-220.
DOI:10.1016/j.tins.2018.12.004
McCutcheon RA, Reis Marques T & Howes OD (2020). Sch izophrenia—an overview. JAMA Psychiatry, 77(2):201-210. DOI:10.1001/jamapsychiatry.2019.3360
Nair PC, Miners JO, McKinnon RA, et al (2022). Binding of SEP-363856 within TAAR1 and the 5HT1A receptor: implications for the design of novel antipsychotic drugs. Mol
Psychiatry, 27(1):88-94. DOI:10.1038/s41380-021-01250-7
Neurocrine Biosciences (2022). Neurocrine Biosciences reports second quarter 2022 financial results and raises 2022 INGREZZA sales guidance. Available at:
https://neurocrine.gcs-web.com/news-releases/news-release-details/neurocrine-biosciences-reports-second-quarter-2022-financial
Neurocrine Biosciences (2024). Neurocrine Biosciences reports positive phase 2 data for NBI-1117568 in adults with schizophrenia. Available at: https://neurocrine.gcs-
web.com/news-releases/news-release-details/neurocrine-biosciences-reports-positive-phase-2-data-nbi-1117568
Paul SM, Yohn SE, Popiolek M, et al (2022). Muscarinic acetylcholine receptor agonists as novel treatments for schizophrenia. Am J Psychiatry, 179(9):611-627.
DOI:10.1176/appi.ajp.21101083.
Unwin N (2013). Nicotinic acetylcholine receptor and the structural basis of neuromuscular transmission: insights from Torped o postsynaptic membranes. Q Rev Biophys,
46(4):283-322. DOI:10.1017/S0033583513000061
Yohn SE, Weiden PJ, Felder CC & Stahl SM (2022). Muscarinic acetylcholine receptors for psychotic disorders: bench-side to clinic. Trends Pharmacol Sci, 43(12):1098-1112.
DOI:10.1016/j.tips.2022.09.006
FOR PERSONAL USE ONLY
Krystal JH, Kane JM, Correll CU, et al (2022). Emraclidine, a novel positive allosteric modulator of cholinergic M4 receptors, for the treatment of schizophrenia: a two-part,
randomized, double-blind, placebo-controlled, phase 1b trial. Lancet, 400(10369):2210-2220. DOI:10.1016/S0140-6736(22)019 90-0
Malcher MF, Droupy S, Berr C, et al (2022). Dementia associated with anticholinergic drugs used for overactive bladder: a nested case-control study using the French National
Medical-Administrative Database. J Urol, 208(4):863-871. DOI:10.1097/JU.0000000000002804
Marcus R, Kakar R, Miller AC et al (2024). Long-term safety of KARXT (xanomeline and trospium) in schizophrenia [Poster presentation] Schizophrenia International Research
Society 2024 Annual Congress. Poster F74.
McCutcheon RA, Abi-Dargham A & Howes OD (2019). Schi zophrenia, dopamine and the striatum: from biology to symptoms. Trends Neurosci, 42(3):205-220.
DOI:10.1016/j.tins.2018.12.004
McCutcheon RA, Reis Marques T & Howes OD (2020). Sch izophrenia—an overview. JAMA Psychiatry, 77(2):201-210. DOI:10.1001/jamapsychiatry.2019.3360
Nair PC, Miners JO, McKinnon RA, et al (2022). Binding of SEP-363856 within TAAR1 and the 5HT1A receptor: implications for the design of novel antipsychotic drugs. Mol
Psychiatry, 27(1):88-94. DOI:10.1038/s41380-021-01250-7
Neurocrine Biosciences (2022). Neurocrine Biosciences reports second quarter 2022 financial results and raises 2022 INGREZZA sales guidance. Available at:
https://neurocrine.gcs-web.com/news-releases/news-release-details/neurocrine-biosciences-reports-second-quarter-2022-financial
Neurocrine Biosciences (2024). Neurocrine Biosciences reports positive phase 2 data for NBI-1117568 in adults with schizophrenia. Available at: https://neurocrine.gcs-
web.com/news-releases/news-release-details/neurocrine-biosciences-reports-positive-phase-2-data-nbi-1117568
Paul SM, Yohn SE, Popiolek M, et al (2022). Muscarinic acetylcholine receptor agonists as novel treatments for schizophrenia. Am J Psychiatry, 179(9):611-627.
DOI:10.1176/appi.ajp.21101083.
Unwin N (2013). Nicotinic acetylcholine receptor and the structural basis of neuromuscular transmission: insights from Torped o postsynaptic membranes. Q Rev Biophys,
46(4):283-322. DOI:10.1017/S0033583513000061
Yohn SE, Weiden PJ, Felder CC & Stahl SM (2022). Muscarinic acetylcholine receptors for psychotic disorders: bench-side to clinic. Trends Pharmacol Sci, 43(12):1098-1112.
DOI:10.1016/j.tips.2022.09.006
FOR PERSONAL USE ONLY
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