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 impacts millions globally, presenting with diverse positive, negative, and cognitive symptoms that significantly affect patients' lives. Current treatments often fall short across these domains, underscoring the need for innovative approaches. Dr. Christoph U. Correll explores the latest evidence-based strategies, including new and emerging therapeutic agents, how to implement patient-centered approaches and how shared decision-making will optimize outcomes in this slide presentation. Statement of Need Schizophrenia is a complex psychiatric disorder that affects approximately 24 million people worldwide. The disease is characterized by heterogenous symptom trajectories which drastically impact patients’ quality of life and outcomes (Kinon et al, 2024). Schizophrenia includes three primary symptom domains: positive symptoms, such as hallucinations, delusions, illogical thought and behavior changes, hyperactivity, and thought disorders; negative symptoms, such as apathy, lethargy, and social withdrawal; and cognitive symptoms, such as difficulty in abstract thinking, poor attention, disorientation, stereotyped thinking, and conceptual disorganization (Agius et al, 2024; Kinon et al, 2024; McCutcheon et al, 2023). Currently, the approved treatments for schizophrenia are limited in their efficacy across symptom domains (Kinon et al, 2024). Therefore, it is crucial for the care team to remain up to date not only on advances in new and emerging therapeutic agents, but also on patient-centered approaches that incorporate shared decision making in order to optimize outcomes for their patients. Target Audience Psychiatrists, psychiatric nurse practitioners, psychiatric physician assistants/associates, psychiatric-mental health nurses, pharmacists, and other healthcare professionals (HCPs) involved in the treatment of patients with schizophrenia. Learning Objectives Appraise the clinical utility of new and emerging agents for the treatment of positive, negative, and cognitive symptoms associated with schizophrenia Evaluate the safety, efficacy, and indications of novel and emerging LAI formulations of atypical antipsychotics for the treatment of schizophrenia Tailor schizophrenia treatment based on patient and disease characteristics, shared decision making, and therapeutic response BIO Christoph U. Correll, MD, is a Professor of Psychiatry and Molecular Medicine at Donald and Barbara Zucker School of Medicine at Hofstra/Northwell in New York. He is also a Professor and Chair of the Department of Child and Adolescent Psychiatry at Charité – University Medicine in Berlin, Germany. Dr. Correll’s research focuses on early identification and treatment of children and adults with severe mental illness, including schizophrenia and other psychotic disorders.

1. Addressing Positive, Negative, and
Cognitive Symptoms of Schizophrenia:
New and Emerging Strategies for Success
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
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2. 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
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3. 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, Alkermes, Allergan, Angelini, Aristo, Autobahn, Boehringer-Ingelheim,
Bristol Myers Squibb, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways,
Darnitsa, Delpor, Denovo, Draig, Eli Lilly, Eumentis Therapeutics, Gedeon Richter, GH, Hikma,
Holmusk, IntraCellular Therapies, Jamjoom Pharma, Janssen/J&J, Karuna, LB Pharma,
Lundbeck, MedInCell, MedLink, Merck, Mindpax, Mitsubishi Tanabe Pharma, Maplight, Mylan,
Neumora Therapeutics, Neuraxpharm, Neurocrine, Neurelis, NeuShen, Newron, Noven, Novo
Nordisk, Orion Pharma, Otsuka, PPD Biotech, Recordati, Relmada, Response Pharmaceutical,
Reviva, Rovi, Saladax, Sanofi, Seqirus, Servier, Sumitomo Pharma America, Sunovion, Sun
Pharma, Supernus, Tabuk, Takeda, Terran, Teva, Tolmar, Vertex, Viatris, Xenon
Grants/research support: Boehringer-Ingelheim, Janssen, Takeda
Stock option holder: Cardio Diagnostics, Kuleon Biosciences, LB Pharma, Medlink, Mindpax,
Quanticel, Terran
i3 Health has mitigated all relevant financial relationships
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4. Learning Objectives
LAI = long-acting injectable.
Appraise the clinical utility of new and emerging agents for the
treatment of positive, negative, and cognitive symptoms
associated with schizophrenia
Evaluate the safety, efficacy, and indications of novel and
emerging LAI formulations of atypical antipsychotics for the
treatment of schizophrenia
Tailor schizophrenia treatment based on patient and disease
characteristics, shared decision making, and therapeutic
response
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5. Agenda
1. Burden and Pathophysiology
2. Novel and Emerging Therapies
3. Long-Acting Antipsychotics
4. Negative Symptoms
5. Cognitive Dysfunction
6. Tailoring Treatment Options
7. Case Presentation
8. Key Takeaways
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6. aThe overall annual direct and indirect costs total does not include costs offset, which the study found to be -$6.0,
which includes individuals either institutionalized or homeless individuals not incurring basic living costs.
bLaw enforcement was defined as incarceration, legal and judicial services, and police protection.
B = billion; ED = emergency department; SSI = Supplemental Security Income; SSDI = Social Security Disability Insurance.
McGrath et al (2008). Epidemiol Rev, 30(1):67-76; Kadakia et al (2022). J Clin Psychiatry, 83(6):22m14458.
$343.2Ba
$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 enforcementb,
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=2,779) 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 has a lifetime morbidity risk of ≥0.7% and is associated with a
significant economic burden – more than $343Ba in direct and indirect costs annually
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7. Functioning
Clinical Domains and Burden of Schizophrenia
EPS = extrapyramidal symptoms.
Carbon & Correll (2014). CNS Spectr, 19(suppl_1):38-52; Millan et al (2014). Eur Neuropsychopharmacol, 24(5):645-692;
Morrens et al (2014). Front Psychiatry, 5:145; Millan et al (2012). Nat Rev Drug Discov, 11(2):141-168; Ventriglio et al (2016). Front Psychiatry, 7:116;
De Hert et al (2011). Nat Rev Endocrinol, 8(2):114-126; Jääskeläinen et al (2013). Schizophr Bull, 39(6):1296-1306.
Affective Symptoms
• Depression
• Anxiety
Cognition
• Attention
• Working memory
• Verbal memory
• Visual memory
• Executive functioning
• Processing speed
• Social conditioning
Motor Symptoms
• Motor delay
• Dyscoordination
• EPS:
o Parkinsonism
o Dyskinesia
Cardiometabolic Burden
Positive Symptoms
• Hallucinations
• Delusions
• Thought disorder
• Hostility
• Excitability
Negative Symptoms
• Affective flattening
• Alogia
• Anhedonia
• Amotivation
• Asociality
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8. Antipsychotics: Functional Dopamine D2 Receptor Blockers
PET = positron emission tomography.
Huhn et al (2019). Lancet, 394(10202):939-951; Grunder et al (2003). Arch Gen Psychiatry, 60(10):974-977; 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 D2 receptor blockers
(median effect size: 0.42)
PET studies of D2 antagonist antipsychotics suggest
presence of a therapeutic window
Striatal D2 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 D2 occupancy does not guarantee response
PET studies of D2 partial agonist antipsychotics
suggest presence of a therapeutic window
Striatal D2 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 D2 occupancy does not guarantee response
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9. Disruption of Dopamine Circuits in Schizophrenia
aAdvances 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 et al (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 Pathwaya
“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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10. Mesocortical Pathway
• Negative symptoms
• Cognitive symptoms
• Depression
Tuberoinfundibular
Hypothalamic Pathway
• Prolactin elevation
• Amenorrhea
• Galactorrhea
• Sexual dysfunction
Mesolimbic Pathwaya
“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 D2 Receptor Blockade on Neural Circuits 1, 2
aAdvances 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.
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11. Agenda
1. Burden and Pathophysiology
2. Novel and Emerging Therapies
3. Long-Acting Antipsychotics
4. Negative Symptoms
5. Cognitive Dysfunction
6. Tailoring Treatment Options
7. Case Presentation
8. Key Takeaways
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12. aD1-related increase in N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamatergic transmission.
*P<0.05 vs placebo. MMRM/ITT baseline PANSS Total Scores: lumateperone 42 mg, 88.1; lumateperone 84 mg, 84.6; risperidone 4 mg, 86.1; placebo, 86.3.
PANSS = Positive and Negative Syndrome Scale.
Davis & Correll (2016). Expert Rev Neurother, 16(6):601-614; Caplyta® prescribing information, 2019; Lieberman et al (2016). Biol Psychiatry, 79(12):952-961.
Change From Baseline in
PANSS Total Score
Change From Baseline in
PANSS Positive Subscale Score
Lumateperone 84 mg (n=80)
Placebo (n=80)
Lumateperone 42 mg (n=76)
Risperidone 4 mg (n=75)
Adults with Schizophrenia: Lumateperone 42 mg
Patients Receiving Lumateperone 42 mg Demonstrated a Significant Improvement in
PANSS Total Score in Adults with Schizophrenia
Affinity Receptor Ki Valuea
(nM)
High Serotonin 5-HT2A 0.54
Moderate
Dopamine D2 32
Serotonin
reuptake
transporter (SERT)
33
Dopamine D1
a 41
Dopamine D4
<100
α1A-adrenergic
α1B-adrenergic
Low
H1-histaminergic <50% inhibition
at 100 nM
M1-muscarinic
Study Day Study Day
LS
Mean
Change
From
Baseline,
PANSS
Total
Score
LS
Mean
Change
From
Baseline,
PANSS
Positive
Subscale
Lumateperone 84 mg (n=80)
Placebo (n=80)
Lumateperone 42 mg (n=76)
Risperidone 4 mg (n=75)
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13. Efficacy of Lumateperone vs Placebo on PANSS
CGI-S = Clinical Global Impression–Severity.
Correll et al (2020). JAMA Psychiatry, 77(4):349-358.
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14. Weight gain
• Placebo: 1.3 kg
• Lumateperone: 1.6 kg
• Risperidone: 2.6 kg
≥7% weight gain
• Placebo: 9%
• Lumateperone: 9%
• Risperidone: 22%
Significantly lower change
with lumateperone than
risperidone in:
• Body weight
• Total cholesterol
• Triglycerides
• Fasting glucose
• Prolactin
Lumateperone Safety in 4-6–Week Trials
TEAE = treatment-related adverse event; SAE = serious adverse event.
Kane et al (2021). Int Clin Psychopharmacol, 36(5):244-250.
Event
Placebo
n=412
Lumateperone 42 mg
n=406
Risperidone 4 mg
n=255
Patients with ≥1 TEAE 229 (55.6%) 267 (65.8%) 175 (68.6%)
With drug-related TEAE 161 (39.1%) 212 (52.2%) 141 (55.3%)
With treatment-emergent SAE 1 (0.2%) 1 (0.2%) 0
Discontinuations due to TEAE or SAE
TEAE 2 (0.5%) 2 (0.5%) 12 (4.7%)
Drug-related TEAE 2 (0.5%) 2 (0.5%) 12 (4.7%)
Treatment-emergent SAE 0 0 0
TEAEs occurring in ≥2% of lumateperone 42 mg group and greater than placebo
Somnolence/sedation 41 (10.0%) 98 (24.1%) 61 (23.9%)
Headache 58 (14.1%) 81 (20.0%) 42 (16.5%)
Nausea 20 (4.9%) 38 (9.4%) 19 (7.5%)
Dry mouth 9 (2.2%) 24 (5.9%) 12 (4.7%)
Constipation 23 (5.6%) 24 (5.9%) 9 (3.5%)
Dizziness 11 (2.7%) 20 (4.9%) 10 (3.9%)
Blood creatine phosphokinase increased 3 (0.7%) 17 (4.2%) 11 (4.3%)
Diarrhea 11 (2.7%) 14 (3.4%) 3 (1.2%)
Vomiting 7 (1.7%) 11 (2.7%) 8 (3.1%)
Back pain 9 (2.2%) 10 (2.5%) 7 (2.7%)
Fatigue 4 (1.0%) 11 (2.7%) 3 (1.2%)
Abdominal pain 7 (1.7%) 10 (2.5%) 1 (0.4%)
Upper respiratory tract infection 5 (1.2%) 10 (2.5%) 3 (1.2%)
Pain in extremity 6 (1.5%) 9 (2.2%) 2 (0.8%)
Decreased appetite 3 (0.7%) 9 (2.2%) 4 (1.6%)
Urinary tract infection 5 (1.2%) 8 (2.0%) 3 (1.2%)
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15. Olanzapine/Samidorphan vs Olanzapine for Schizophrenia
OLZ = olanzapine.
Silverman et al (2018). Schizophr Res, 195:245-251; Martin et al (2018). Am J Psychiatry, 176(6):457-467;
Correll et al (2019). Schizophrenia International Research Society (SIRS) meeting.
Samidorphan
Antagonist at the mu-opioid receptors
Partial agonist activity at kappa-and
delta-opioid receptors
Hypothesized opioid antagonism that
mitigates olanzapine-associated weight
gain
Randomized Trial (RCT) & Open-Label Extension Study (OLE)
ALKS 3831 = olanzapine + samidorphan = mu-opioid
RCT
OLE
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16. OLZ/SAM = olanzapine/samidorphan;
SD = standard deviation;
LS = least squares.
Potkin et al (2020). J Clin Psychiatry, 81(2):19m12769.
For Acutely Exacerbated Schizophrenia: PANSS Total Score
Olanzapine/Samidorphan vs Olanzapine vs Placebo
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17. ENLIGHTEN-2
CI = confidence interval; NNT= number needed to treat.
Correll et al (2020). Am J Psychiatry, 177(12):1168-1178; Correll et al (2023). Schizophr Bull, 49(2):454-463.
6-Month Study of Olanzapine/Samidorphan vs Olanzapine/PBO
Outcome Olanzapine + PBO
Olanzapine +
Samidorphan
P Value
(Relative Advantage)
Odds Ratio
(95% CI)
Mean % weight gain 6.59% 4.21%
0.003
(↓ 37%)
-
Weight change + 5.08 kg + 3.18 kg -
≥10% weight gain 29.8% 17.8%
0.003
(NNT=7)
0.50
(0.31-0.80), P=0.003
≥7% weight gain 42.7% 27.5%
0.001
(NNT=6)
0.50
(0.33-0.76), P=0.001
Waist circumference
≥5 cm
43.2% 26.8% (NNT=6) 0.47
Incident metabolic
syndrome
16.9% 9.2% (NNT=20)
0.55
(0.31-0.99)
New stage 1/2
hypertension
36.6% 21.6% (NNT=7)
0.48
(0.24-0.96)
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18. ENLIGHTEN-2: Adverse Effects
PBO = placebo.
Correll (2020). Am J Psychiatry, 177(12):1168-1178.
6-Month Study of Olanzapine/Samidorphan vs Olanzapine/PBO
Category
Combined Olanzapine/
Samidorphan (n=274)
Olanzapine (n=276)
Any adverse event 203 74.1% 227 82.2%
Adverse event by severity
Mild 106 38.7% 125 45.3%
Moderate 87 31.8% 95 34.4%
Severe 10 3.6% 7 2.5%
Adverse event leading to treatment discontinuation 33 12.0% 27 9.8%
Any serious adverse event 10 3.6% 7 2.5%
Adverse events in ≥5% of patients in either group
Weight increased 68 24.8% 100 36.2%
Somnolence 58 21.2% 50 18.1%
Dry mouth 35 12.8% 22 8.0%
Increased appetite 30 10.9% 34 12.3%
Waist circumference increased 17 6.2% 22 8.0%
Blood creatine phosphokinase increased 14 5.1% 12 4.3%
Extra dose administered 14 5.1% 17 6.2%
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19. mAChR = muscarinic acetylcholine receptor; AD = Alzheimer disease; AP = antipsychotic; HPC = hippocampus; KO = knockout; NHP = nonhuman primate;
PAM = positive allosteric modulator; PFC = prefrontal cortex; PRZ = pirenzepine; SZ = schizophrenia; mRNA = messenger RNA;
CHRM = cholinergic receptor muscarinic; KarXT = xanomeline-trospium chloride.Yohn SE et al (2022). Trends Pharmacol Sci, 43(12):1098-1112.
Relevance of Muscarinic Agonism in Schizophrenia
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20. Signaling Selectivity Among Muscarinic
Acetylcholine M1-M5 Receptors
Stimulatory Inhibitory
Postsynaptic
Receptor
Presynaptic
Autoreceptor
The Nicotinic vs Muscarinic (M)
Cholinergic Receptor System
Cholinergic Receptor Systems
CNS = central nervous system; PNS = peripheral nervous system; cAMP = cyclic adenosine monophosphate.
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
Gq protein Gi/o protein
Inositol
triphosphate
Adenylate
cyclase
Ca2+ cAMP
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21. Regulation of DA Circuits in Psychosis by M1 & M4 Receptors
GABA = gamma-aminobutyric acid; NMDA = N-methyl-D-aspartate.
Yohn et al (2022). Trends Pharmacol Sci, 43(12):1098-1112.
M1 receptor + activator
M4 receptor + activator
M5 receptor
Nicotinic acetylcholine
receptors (nACh)
NMDA receptor
GABA
Glutamate (Glu)
Acetylcholine (ACh)
Dopamine (DA)
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22. EMERGENT-1, EMERGENT-2, and EMERGENT-3
LSM = least squares mean; BMI = body mass index.
Brannan et al (2023). American Society of Clinical Psychopharmacology Annual Meeting; Kaul et al (2024). Schizophr, 10, 102.
Xanomeline + Trospium Chloride (KarXT)
Pooled Total PANSS Treatment Efficacy from Baseline to Week 5
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23. Pooled EMERGENT-1–3 Trials: KarXT for Schizophrenia
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
F
O
R
P
E
R
S
O
N
A
L
U
S
E
O
N
L
Y

24. Pooled EMERGENT-1-3 Trials: KarXT for Schizophrenia
SMD = standardized mean difference; RR = risk ratio; GGT = gamma-glutamyl transferase; AE = adverse event; ALT = alanine transferase;
AST = aspartate transferase; ULN = upper limit of normal.
Fabiano et al (2025). European Neuropsychopharmacology, 92:62-73.
Meta-Analyzed Efficacy and Tolerability Outcomes
F
O
R
P
E
R
S
O
N
A
L
U
S
E
O
N
L
Y

25. ARISE: KarXT as Adjunct for Inadequately Controlled Schizophrenia
BID = twice daily.
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
F
O
R
P
E
R
S
O
N
A
L
U
S
E
O
N
L
Y

26. ARISE Trial: Xanomeline-Trospium (XT) vs Placebo
APD = antipsychotic background drug; PSP = Personal and Social Performance Scale; mITT = modified intent-to-treat; SE = standard error;
LSMD = least squares mean difference.
aP value is nominal, not adjusted for multiplicity.
Bristol Myers Squibb, 2025 [https://news.bms.com/news/details/2025/Bristol-Myers-Squibb-Announces-Topline-Results-from-Phase-3-ARISE-Trial-
Evaluating-Cobenfy-xanomeline-and-trospium-chloride-as-an-Adjunctive-Treatment-to-Atypical-Antipsychotics-in-Adults-with-Schizophrenia/default.aspx].
LS Mean Change From Baseline to Week 6 in PANSS, PSP, and CGI-S
Non-risperidone group includes paliperidone, aripiprazole, ziprasidone, lurasidone and cariprazine.
Outcome XT + APD Placebo + APD LSMD (95% CI) P Value
mITT Population, N 190 196
Primary Endpoint
Change in PANSS
Total Score (SE)
-14.3 (1.01) -12.2 (0.98) -2.0 (-4.5, 0.5) 0.11
Key Secondary Endpoint
Change in PSP
Score (SE)
5.3 (0.75) 5.9 (0.73) -0.6 (-2.4, 1.2) 0.52
a
Secondary Endpoint Change in CGI-S (SE) -0.6 (0.06) -0.5 (0.06) -0.1 (-0.3, 0.04) 0.14
a
Post-Hoc Subgroup Analysis
Risperidone
Change in PANSS
Total Score (SE)
(N=60) (N=69)
1.1 (-3.7, 5.9) 0.66
a
-11.3 (2.13) -12.3 (2.10)
Non-Risperidone
Change in PANSS
Total Score (SE)
(N=130) (N=127)
-3.4 (-6.3, -0.5) 0.03
a
-15.1 (1.18) -11.7 (1.17)
F
O
R
P
E
R
S
O
N
A
L
U
S
E
O
N
L
Y

27. Emraclidine: M4-Positive Allosteric Modulator
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)
QD = once daily.
Krystal et al (2022). Lancet, 400(10369):2210-2220;r 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)
F
O
R
P
E
R
S
O
N
A
L
U
S
E
O
N
L
Y

28. Muscarinic (M) Receptor Modulators in Development
PAM = positive allosteric modulator.
Yohn et al (2024). Front Psychiatry, 15:1421554.
Clinical
Compound Name Target Mode of Action Indication Stage of Development
KarXT M1/M4
Muscarinic agonists plus
peripherally restricted
mAChR antagonist
SCZ and
AD psychosis
Phase 3
Emraclidine M4 PAM SCZ Phase 2
NBI-1117568 M4 Agonist SCZ Phase 2
ANAVEX3-71 Sigma 1/M1 Agonist/PAM
SCZ and
AD cognition
Phase 2
NBI-1117570 M1/M4 Agonist SCZ Phase 1
ML-007 M1/M4
Muscarinic agonists plus
peripherally restricted
mAChR antagonist
SCZ and AD Phase 1
NMRA-266 M4 PAM SCZ Phase 1
F
O
R
P
E
R
S
O
N
A
L
U
S
E
O
N
L
Y

29. Muscarinic (M) Receptor Modulators in Development (cont.)
PD = Parkinson disease.
Yohn et al (2024). Front Psychiatry, 15:1421554.
Pre-Clinical
Compound Name Target Mode of Action Indication
– M4 PAM SCZ
NSX-0527
M1/M4 Agonist SCZ and AD
NSX-0559
NS-136 M4 PAM SCZ
– M4 Agonist SCZ and AD
NBI-1117569 M4 Agonist SCZ
SUVN-17016031 M1 PAM PD dementia
SUVN-L8203032 M4 PAM SCZ
SUVN-16107 M1 PAM Cognition
SUVNI-1307014 M1 PAM AD
- M1 Agonist Frontotemporal dementia
F
O
R
P
E
R
S
O
N
A
L
U
S
E
O
N
L
Y

30. LB-102
GlobeNewswire, 2025 [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].
NOVA1 met its primary endpoint, 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 D2/3-5HT7 Antagonist Amisulpride
F
O
R
P
E
R
S
O
N
A
L
U
S
E
O
N
L
Y

31. aResponder rates were calculated as number of observed patients meeting responder criterion divided by the total N under mITT
population in each treatment arm.
bP value from logistic regression model (chi-square) comparing proportion of responders in evenamide 30 mg BID vs placebo BID.
CGI-C = Clinical Global Impression – Corrections.
Anand et al (2025). Neuropharmacology, 266:110275.
Selective, State-Dependent Inhibitor of Voltage-Gated Sodium Channels (VGSCs)
Evenamide for Positive Symptom Partial Non-Responders
Analysis Population
Responder
Category
Responders
[n/N (%)]
Odds Ratio
(95% CI)
P Value
b
mITT populationa
PANSS ≥20%
Evenamide
27/131 (20.6%)
1.99 (1.0, 3.8) 0.037
Placebo
18/156 (11.5%)
CGI-C ≤2
Evenamide
41/131 (31.3%)
2.18 (1.2, 3.8) 0.006
Placebo
27/156 (17.3%)
mITT population:
observed cases
PANSS ≥20%
Evenamide
27/127 (21.3%)
2.04 (1.1, 3.9) 0.032
Placebo
18/154 (11.7%)
CGI-C ≤2
Evenamide
41/127 (32.3%)
2.24 (1.3, 3.9) 0.005
Placebo
27/154 (17.5%)
F
O
R
P
E
R
S
O
N
A
L
U
S
E
O
N
L
Y

32. Evenamide: Selective, State-Dependent Inhibitor of VGSCs
N = total number of subjects in the safety population; n = number of subjects meeting the category.
Anand et al (2025). Neuropharmacology, 266:110275.
Safety
Category Evenamide 30 mg BID (n=132) Placebo (n=159) Total (N=291)
No. of subjects with at least 1 TEAE 33 (25.0%) 41 (25.8%) 74 (25.4%)
No. of subjects with at least 1 treatment-related TEAE 9 (6.8%) 18 (11.3%) 27 (9.3%)
No. of subjects with any serious TEAE 2 (1.5%) 1 (0.6%) 3 (1.0%)
No. of subjects with any TEAE leading to study drug
discontinuation (excluding death)
3 (2.3%) 1 (0.6%) 4 (1.4%)
No. of subjects with any TEAE resulting in death 0 (0.0%) 1 (0.6%) 1 (0.3%)
Any TEAE by severity: mild 22 (16.7%) 30 (18.9%) 52 (17.9%)
Any TEAE by severity: moderate 11 (8.3%) 10 (6.3%) 21 (7.2%)
Any TEAE by severity: severe 0 (0.0%) 1 (0.6%) 1 (0.3%)
Most Common TEAEs by Preferred Term (≥1% in Either Treatment Group)
Preferred Term Evenamide 30 mg BID (n=132) Placebo (n=159) Total (N=291)
Headache 3 (2.3%) 4 (2.5%) 7 (2.4%)
Somnolence 2 (1.5%) 5 (3.1%) 7 (2.4%)
Insomnia 0 (0.0%) 5 (3.1%) 5 (1.7%)
Fatigue 0 (0.0%) 5 (3.1%) 5 (1.7%)
Vomiting 3 (2.3%) 1 (0.6%) 4 (1.4%)
Nasopharyngitis 3 (2.3%) 1 (0.6%) 4 (1.4%)
F
O
R
P
E
R
S
O
N
A
L
U
S
E
O
N
L
Y

33. Agenda
1. Burden and Pathophysiology
2. Novel and Emerging Therapies
3. Long-Acting Antipsychotics
4. Negative Symptoms
5. Cognitive Dysfunction
6. Tailoring Treatment Options
7. Case Presentation
8. Key Takeaways
F
O
R
P
E
R
S
O
N
A
L
U
S
E
O
N
L
Y

34. Risk for Antipsychotic Treatment Discontinuation
AHR = adjusted hazard ratio; FG = first-generation; HR = hazard ratio.
Rubio et al (2021). Schizophr Bull, 47(6):1611-1620.
Between-Individual Analysis
Predictors of Antipsychotic Treatment
Discontinuation for Olanzapine
Head-to-Head Comparison:
Monotherapy vs Oral Olanzapine
Covariate P Value AHR
Lower
95% CI
Upper
95% CI
Sociodemographic
Male gender <0.001 0.83 0.77 0.88
Age
<25
25-34
≥35
<0.001
0.0067
Reference
1.24
1.14
1.13
1.04
1.37
1.25
Duration of first hospital stay due to schizophrenia
<1 month Reference
1-2 months <0.001 0.76 0.69 0.84
2-4 months <0.001 0.68 0.62 0.75
≥4 months <0.001 0.44 0.40 0.48
History of comorbid psychiatric conditions
Substance
abuse
disorder
<0.001 1.30 1.18 1.42
Suicidality 0.0949 1.57 0.93 2.67
Intellectual
disability
0.0596 0.75 0.55 1.01
F
O
R
P
E
R
S
O
N
A
L
U
S
E
O
N
L
Y

35. Long-Acting vs Oral Antipsychotics
RCT = randomized controlled trial; OAP = oral antipsychotic; RR = risk ratio; CI = confidence interval.
Kishimoto et al (2021). Lancet Psychiatry, 8(5):387-404.
Meta-Analytic Comparison of 137 Studies (N=397,319) Across 3 Designs
N n RR 95% CI P
RCT 29 7,833 0.88 0.79-0.99 0.033
Cohort studies 44 106,136 0.92 0.88-0.98 0.004
Pre-post studies 28 17,876 0.44 0.39-0.51 <0.001
Number of studies N
RCT 32 8,577
Cohort studies 65 37,447
Pre-post studies 40 11,295
LAIs were associated with a lower risk of admission to hospital
or relapse than oral antipsychotics (OAPs) in all 3 study designs
LAIs were superior to OAPs in 60 (18.3%) of 328 comparisons,
not different in 252 (76.8%), and less beneficial in 16 (4.9%) comparisons
F
O
R
P
E
R
S
O
N
A
L
U
S
E
O
N
L
Y

36. PP6M = paliperidone 6-monthly; PP3M = paliperidone 3-monthly.
Najarian et al (2022). Int J Neuropsychopharmacol, 25(3):238-251.
Non-Inferiority Study in the Maintenance Treatment of Schizophrenia
Intramuscular Paliperidone 6-Monthly vs 3-Monthly
F
O
R
P
E
R
S
O
N
A
L
U
S
E
O
N
L
Y

37. Event/Description PP1M/PP3M (n=838) PP6M (n=478) PP3M (n=224)
Patients with ≥1 TEAEs 341 (40.7%) 297 (62.1%) 131 (58.5%)
Patients with ≥1 serious TEAEs 23 (2.7%) 24 (5.0%) 15 (6.7%)
Most common (>5 patients) serious TEAE
Schizophrenia 6 (0.7%) 8 (1.7%) 1 (0.4%)
TEAEs leading to drug withdrawal 31 (3.7%) 16 (3.3%) 6 (2.7%)
Most common (>5 patients) TEAEs leading to drug withdrawal
Schizophrenia 6 (0.7%) 8 (1.7%) 1 (0.4%)
TEAEs leading to death 1 (0.1%) 1 (0.2%) 2 (0.9%)
Most common (≥3% of patients) TEAEs
Weight increase 8 (1.0%) 40 (8.4%) 17 (7.6%)
Injection site pain 72 (8.6%) 37 (7.7%) 9 (4.0%)
Headache 16 (1.9%) 32 (6.7%) 12 (5.4%)
Upper respiratory tract infection 19 (2.3%) 24 (5.0%) 9 (4.0%)
Nasopharyngitis 22 (2.6%) 22 (4.6%) 13 (5.8%)
Akathisia 21 (2.5%) 17 (3.6%) 8 (3.6%)
Insomnia 27 (3.2%) 15 (3.1%) 5 (2.2%)
Anxiety 25 (3.0%) 15 (3.1%) 1 (0.4%)
Weight decrease 4 (0.5%) 8 (1.7%) 7 (3.1%)
Patients with ≥1 EPS-related TEAEs 53 (6.3%) 46 (9.6%) 19 (8.5%)
Most common (>5 patients) EPS-related TEAEs
Parkinsonian rest tremor 11 (1.3%) 9 (1.9%) 2 (0.9%)
Muscle rigidity 7 (0.8%) 2 (0.4%) 0 (0.0%)
Parkinsonism 7 (0.8%) 6 (1.3%) 2 (0.9%)
Akathisia 21 (2.5%) 17 (3.6%) 8 (3.6%)
Dyskinesia 11 (1.3%) 6 (1.3%) 2 (0.9%)
Patients with ≥1 injection site-related TEAEs 89 (10.6%) 59 (12.3%) 11 (4.9%)
ITT = intention to treat; DB = double-blind.
Najarian et al (2022). Int J Neuropsychopharmacol, 25(3):238-251.
Intramuscular Paliperidone
6-Monthly vs 3-Monthly
Safety Profile
F
O
R
P
E
R
S
O
N
A
L
U
S
E
O
N
L
Y

38. Risperidone LAI for Maintenance Treatment of Schizophrenia
Kane et al (2023). Lancet Psychiatry, 10(12):934-943.
Long-Acting Subcutaneous Antipsychotic (LASCA) Risperidone (TV-46000) Once Monthly or
Once Every 2 Months vs Placebo in the Maintenance Treatment of Schizophrenia
F
O
R
P
E
R
S
O
N
A
L
U
S
E
O
N
L
Y

39. Risperidone LAI for Maintenance Treatment (cont.)
CGI-I = Clinical Global Impression – Improvement.
Kane et al (2023). Lancet Psychiatry, 10(12):934-943.
F
O
R
P
E
R
S
O
N
A
L
U
S
E
O
N
L
Y

40. Olanzapine: Long-Acting Subcutaneous Antipsychotic (TV-44749)
Shulman et al (2024). [Poster presentation] Psych Congress 2024. Poster 96.
Efficacy in the Acute 8-Week Phase 1 of the SOLARIS Trial
Superiority of TV-44749 vs
placebo on all secondary
outcomes; no postinjection
somnolence sedation
(PDSS) events in
>3,300 injections
SOLARIS phase 2 open
extension study ongoing
Figure 3: LS mean change from baseline in the PANSS total score
F
O
R
P
E
R
S
O
N
A
L
U
S
E
O
N
L
Y

41. Olanzapine: Safety and Tolerability
Shulman et al (2024). [Poster presentation] Psych Congress 2024. Poster 96.
SOLARIS: Phase 1 Acute 8-Week
Parameter, n (%) Placebo
(n=167)
TV-44749
318 mg
(n=163)
TV-44749
425 mg
(n=168)
TV-44749
531 mg
(n=169)
TV-44749
Total
(N=500)
≥1 adverse event 84 (50%) 112 (69%) 117 (70%) 126 (75%) 355 (71%)
≥1 serious adverse event 3 (2%) 4 (2%) 1 (<1%) 2 (1%) 7 (1%)
≥1 severe adverse event 4 (2%) 5 (3%) 1 (<1%) 3 (2%) 9 (2%)
Overall discontinuation rates 49 (29%) 54 (32%) 48 (28%) 48 (28%) 150 (30%)
≥1 adverse event leading to stopping treatment 5 (3%) 7 (4%) 4 (2%) 5 (3%) 16 (3%)
≥1 treatment-related adverse event 40 (24%) 85 (52%) 95 (57%) 103 (61%) 283 (57%)
≥1 adverse event leading to stopping the study 6 (4%) 8 (5%) 7 (4%) 6 (4%) 21 (4%)
Adverse events in >5% of patients and being higher than in the placebo group
Weight increased 13 (8%) 49 (30%) 66 (39%) 58 (34%) 173 (35%)
Injection site induration 4 (2%) 18 (11%) 23 (14%) 23 (14%) 64 (13%)
Injection site pain 7 (4%) 14 (9%) 19 (11%) 17 (10%) 50 (10%)
Injection site erythema 1 (<1%) 12 (7%) 21 (13%) 15 (9%) 48 (10%)
Somnolence 3 (2%) 16 (10%) 10 (6%) 13 (8%) 39 (8%)
F
O
R
P
E
R
S
O
N
A
L
U
S
E
O
N
L
Y

42. Potential for TV-44749 to Eliminate PDSS Risk
aSimulated data using a population PK model that was constructed based on actual data from phase 1 trial.
PK = pharmacokinetic.
Krtalić et al (2024). [Poster presentation] Schizophrenia International Research Society 2024 Annual Congress. Poster S82;
Perlstein et al (2024). [Oral presentation] Schizophrenia International Research Society 2024 Annual Congress.
Median
(5
th
-95
th
)
concentration
(ng/mL)
Time (days)
0
20
40
60
80
100
120
0 4 8 12 16 20 24 28
Once-monthly subcutaneous TV-44749 425 mg
Oral olanzapine 15 mg/day
Controlled release
of olanzapine shown
by in vitro data
In first-in-humans phase 1 study, clinically relevant therapeutic olanzapine plasma concentrations were
attained within 1-2 days (without a loading dose or complex initiation regimen) and maintained during
the 28-day dosing interval with no confirmed or suspected cases of PDSS
Sustained release of
olanzapine shown
by simulateda
population PK data
In vitro and early clinical data show the potential for TV-44749 to
eliminate postinjection delirium/sedation syndrome (PDSS) risk
F
O
R
P
E
R
S
O
N
A
L
U
S
E
O
N
L
Y

43. Agenda
1. Burden and Pathophysiology
2. Novel and Emerging Therapies
3. Long-Acting Antipsychotics
4. Negative Symptoms
5. Cognitive Dysfunction
6. Tailoring Treatment Options
7. Case Presentation
8. Key Takeaways
F
O
R
P
E
R
S
O
N
A
L
U
S
E
O
N
L
Y

44. Measuring Negative Symptoms
Daniel (2013). Schizophr Res, 150(2-3):343-345; Marder et al (2011). Schizophr Bull, 37(2):250-254.
PANSS negative subscale
Supplanted by the negative factor score (below)
PANSS factor score for negative symptoms
NSA-16 (Negative Symptom Assessment)
Scores related to the PANSS negative symptom factor
Measures reductions in social interest and sense of purpose that are not
measured adequately in other instruments
Measures reductions in sense of purpose and global severity of negative
symptoms more adequately than the SANS or PANSS
SANS (Scale for Assessment of Negative Symptoms)
CAINS (Clinical Assessment Interview for Negative Symptoms)
BNSS (Brief Negative Symptom Scale)
Blunted Affect, Alogia, Asociality, Anhedonia, Avolition
F
O
R
P
E
R
S
O
N
A
L
U
S
E
O
N
L
Y

45. NSA-16 NSA-4
Restricted speech quantity YES
Prolonged time to respond
Impoverished speech content
Inarticulate speech
Emotion (reduced range) YES
Affect: reduced modulation of intensity
Affect: reduced display on demand
Reduced social drive YES
Poor rapport with interviewer
Sexual interest
Poor grooming and hygiene
Reduced sense of purpose
Reduced interests YES
Reduced daily activity
Reduced expressive gestures
Slowed movements
4-Item Tool for Measuring Negative Symptoms
Alphs et al (2010). Psychiatry, 7(7):26-32.
Simplified 6-point rating scale suggested
for each item of the NSA-4 scale
Not reduced compared with a healthy
young person
Minimally reduced; significance
questionable
Mildly reduced
Moderately reduced
Markedly reduced and definitely interferes
with patient’s functioning
Severely reduced or entirely absent; it is
glaring and markedly interferes with
functioning
NSA-4
F
O
R
P
E
R
S
O
N
A
L
U
S
E
O
N
L
Y

46. Primary and Secondary Negative and Cognitive Symptoms
EPS = extrapyramidal symptoms.
Carbon & Correll (2014). CNS Spectr, 19(suppl_1):38-52.
Differential Diagnosis of Schizophrenia
Mental
Retardation
Environmental
Deprivation
Chronic Pain
Sedation
Hallucinations/
Paranoia
Substance
Misuse
Primary
Negative or Cognitive
Symptoms
Stigma
Dementia
Depression
Sleep Apnea
Anxiety Disorder,
Social Anxiety
EPS
F
O
R
P
E
R
S
O
N
A
L
U
S
E
O
N
L
Y

47. Antipsychotics for PREDOMINANT Negative
Symptoms
SXS = symptoms.
Krause et al (2018). Eur Arch Psychiatry Clin Neurosci, 268(7):625-639.
c
Negative SXS Depression Positive SXS
F
O
R
P
E
R
S
O
N
A
L
U
S
E
O
N
L
Y

48. Psychopharmacologic Co-Treatment of Any Antipsychotic
AP = atypical antipsychotic; AMSTAR = A Measurement System to Assess Symptomatic Reviews; SNRI = serotonin-norepinephrine reuptake inhibitor;
SSRI = selective serotonin reuptake inhibitor; SARI = serotonin antagonist reuptake inhibitor; MAO-B = monoamine oxidase B;
NaSSA = noradrenergic and specific serotonergic antidepressant; DHEA = dehydroepiandrosterone; NSAID = nonsteroidal anti-inflammatory drug;
NRI = norepinephrine reuptake inhibitors.
Adapted from Correll et al (2017). JAMA Psychiatry, 74(7):675-684.
Negative
Symptoms
*
F
O
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O
N
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49. KarXT EMERGENT 1-3
Horan et al (2024). Schizophr Res, 274:57-65.
PANSS Marder Negative Factor LS Mean Difference Between KarXT and Placebo
A. Full Sample B. Prominent Negative Symptoms at Baseline
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50. Agenda
1. Burden and Pathophysiology
2. Novel and Emerging Therapies
3. Long-Acting Antipsychotics
4. Negative Symptoms
5. Cognitive Dysfunction
6. Tailoring Treatment Options
7. Case Presentation
8. Key Takeaways
F
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N
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O
N
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Y

51. Cognitive Impairment in Selected Neuropsychiatric Disorders
BP = bipolar; MDD = major depressive disorder; PTSD = posttraumatic stress disorder.
Millan et al (2012). Nat Rev Drug Discov, 11:141-168.
Main Characteristics
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52. How Does Cognitive Functioning Present in the Real World?
Sabbe et al (2012). Proc Belg Roy Acad Med, 1:77-82; Nuechterlein et al (2008). Am J Psychiatry, 16(2):203-213.
Cognitive Process Definition Real-World Examples
Attention/vigilance
Responding correctly to targets while not
responding to distractors during a series
of rapidly presented stimuli
Being able to read a book or pay attention to a
movie
Working memory
Maintaining and manipulating information
in the mind for brief periods of time
(approximately 5-20 seconds
Keeping a phone number in mind while dialing it
Verbal learning and
memory
Remembering verbal information over
longer periods of time (minutes to years)
Remembering the list of items to purchase at the
supermarket
Visual learning and
memory
Remembering visual information over
longer periods of time (minutes to years)
Remembering where you left something
(eg, keys)
Reasoning and
problem solving
The ability to apply strategies effectively
Arriving on time for work even though your bus
schedule has been changed
Speed of processing
Responding quickly and accurately when
executing relatively simple tasks
Using a touch-screen computer to serve people at a
restaurant
Social cognition
Effectively processing social information
such as facial expressions, emotions, and
the meaning of social interactions
Knowing by looking at someone whether they are
angry at you or not; being able to take someone
else’s perspective in a conversation
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53. Paper and Pencil Tests to Measure Cognition in Schizophrenia
Cognitive Domains
Processing
Speed
Attention/
Vigilance
Working
Memory
Verbal
Memory
Visual
Memory
Reasoning/
Problem Solving
Other
Time
(Minutes)
WAIS-III
Short Form
x x x
Acquired
knowledge
15
RBANS x x x x 30
MCCB x x x x x x
Social
cognition
60-90
BACS x x x x x 30
BCA x x x x 15
SCoRS x x x x
Motor
Skills
30
WAIS-III = Wechsler Adult Intelligence Scale 3rd
edition; RBANS = Repeatable Battery for the Assessment of Neuropsychological
Status; MCCB = Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery; BACS =
Brief Assessment of Cognition in Schizophrenia; BCA = Brief Cognition Assessment; SCoRS = Schizophrenia Cognition Rating Scale.
Measuring Cognition in Schizophrenia
Nuechterlein et al (2025). Schizophrenia Bulletin, 51(2):401-421.
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54. Effect of Individual Antipsychotics on Global Cognition
Feber et al (2025). JAMA Psychiatry, 82(1):47-56.
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N
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55. DAAO = D-amino acid oxidase; GlyT = glycine transporter; mGluR = metabotropic glutamate receptor; cAMP = cyclic adenosine monophosphate;
AMPA = ⍺-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; CREB = cAMP response element binding protein; BDNF = brain-derived neurotrophic
factor; VGluT = vesicular glutamate transporter; PAM = positive allosteric modulator; IP3 = inositol triphosphate; DAG = diacylglycerol; NAC = N-acetyl-
cysteine; EAAT = excitatory amino acid transporter.
Miyamoto et al (2012). Molecular Psychiatry, 17:1206-1227.
(DAAO) Inhibitor
Glutamate
Receptor
System
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56. Pharmacotherapies in Development for CIAS
MOA = mechanism of action; CIAS = cognitive impairment associated with schizophrenia; ASCP = American Society for Clinical Pathology.
NCT05686239; NCT04972227; NCT04457310;
Harvey et al (2023). [Poster presentation]. American Society of Clinical Psychopharmacology Annual Meeting, 2023. Abstract W77.
Therapy Class/MOA Indication Status Clinical Trial
RL-007
GABA-B receptor agonist, NMDA receptor
agonist, nicotinic receptors agonist
CIAS Phase 2 NCT05686239
CY6463
CNS-penetrant soluble guanylate cyclase
(sGC) stimulator, a key enzyme of the nitric
oxide (NO) signaling pathway
CIAS Phase 1 NCT04972227
CVL-562 Dopamine 1 partial agonist CIAS Phase 1/2 NCT04457310
KarXT M1/M4 muscarinic agonist
Schizophrenia (cognitive data
obtained in acute trials)
Phase 2/3
Harvey et al,
ASCP 2023
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57. KarXT EMERGENT-1, EMERGENT-2, EMERGENT-3
CANTAB = Cambridge Neuropsychological Test Automated Battery.
Harvey et al (2023). [Poster presentation]. American Society of Clinical Psychopharmacology Annual Meeting, 2023. Abstract W77.
Change in Cognition From Baseline to Week 5
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58. Agenda
1. Burden and Pathophysiology
2. Novel and Emerging Therapies
3. Long-Acting Antipsychotics
4. Negative Symptoms
5. Cognitive Dysfunction
6. Tailoring Treatment Options
7. Case Presentation
8. Key Takeaways
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Y

59. Collaborative Care Planning
Littrell & Littrell (1998). Psychiatric Annals, 28(7):371-377.
During the planning process, several important functions are
performed:
Setting priorities and goals
Appraising strengths
Selecting appropriate interventions
Determining resources
Everyone works together to:
Clarify personal choices
Identify environmental options
Clarify personal values
Identify personal interests
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60. Shared Decision Making
Elwyn et al (2012). J Gen Intern Med, 27(10):1361-1367.
Provides knowledge about the condition
Including etiology, prognosis,
and potential outcomes
Inquires about patient preference
Prior medication trials, lifestyle,
and limitations
Shares insight about treatment options
Prior medication trials, lifestyle,
and limitations
Shares experience and values
Preferences, socioeconomic circumstances,
and experience of illness
Voices their concerns
Including personal risk tolerance
and accessibility of treatment
Asks questions of the provider
Regarding treatment options, outcomes,
and anecdotal experience
Clinician Patients
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61. Motivational Decision Making
Correll (2020). J Clin Psychiatry, 81(3):MS19053BR2C.
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62. Tailoring Treatment in People with Schizophrenia
CYP450 = cytochrome P450; T2DM = type 2 diabetes mellitus.
Meyer et al (2007). CNS Spectr, 12(12 suppl 21):6-9; Kim et al (2025). Schizophr Res, 281:180-190; McCutcheon et al (2025). Lancet Psychiatry, 12(5):384-394;
Correll (2011). J Clin Psychiatry, 72(suppl_1):9-13; Keepers et al (2020). Am J Psychiatry, 177(9):868-872;
Pillinger et al (2023). Lancet Psychiatry, 10(11):860-876; Littrell & Littrell (1998). Psychiatric Annals, 28(7):371-377.
Drug interactions and contraindications
CYP450-mediated interactions; QTc prolongation, prolactin elevation, sedation
Metabolic and medical comorbidities
Avoid olanzapine/quetiapine in obesity, metabolic syndrome, T2DM
Prefer partial D2 agonists, lurasidone, lumateperone, xanomeline-trospium in patients w/ T2DM
risk
Adjust for hepatic/renal impairment
Psychiatric comorbidities
Depression: consider agents with antidepressant properties (eg, lurasidone, lumateperone,
partial D2 agonists)
Anxiety: consider sedating but also non-sedating antipsychotics, use adjunctive anxiolytics
cautiously
Substance use: avoid agents with misuse potential or heavy sedation or D2 blockade
Adherence concerns
Anticipate non-adherence/ history of nonadherence → offer LAIs
Simplify regimen; assess insight and support system
Collaborative, measurement-based and shared decision making–based care
Discuss treatment goals, past experiences, fears
Use simple and scalable tools, involve family/caretaker when appropriate
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63. Collaboration
Education
Communication
Expectation
Explore what goals they have for their life and what the barriers to treatment are
Elicit preferences: What do they like/not like about current and past treatments?
Give background information, describe why you think this is a good fit
Explain the MOA in clear terminology, using metaphors if necessary
Describe clinical trials data and personal clinical experience (if any)
Dosing and administration schedule
How to transition from current antipsychotic, what to expect
Rx
Benefits: realistic but hopeful; AEs: both common and rare/serious
Solicit
&
Answer
Questions
How to Talk to Patients About Novel Treatments
Rx = prescription.
Elwyn et al (2012). J Gen Intern Med, 27(10):1361-1367; Weiden (2007). J Clin Psych, 68(suppl_14):14-19; Goff (2010). J Clin Psychiatry, 71(suppl_2):20-26;
Salzmann-Erikson & Sjödin (2018). Int J Nurs Stud, 85:7-18; Haddad et al (2014). Patient Relat Outcome Meas, 5:43-62;
Street et al (2009). Patient Educ Couns, 74(3):295-301.
F
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O
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Y

64. TGI-P Scale for Psychiatric Symptom Severity
Correll et al (2024). European Neuropsychopharmacology, 88:31-39.
F
O
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P
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S
O
N
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S
E
O
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Y

65. Measurement-Based Care
Correll et al (2024). European Neuropsychopharmacology, 88:31-39.
TGI – Psychopathology Footprint: Hyper- and Hypo-Pole
F
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66. Agenda
1. Burden and Pathophysiology
2. Novel and Emerging Therapies
3. Long-Acting Antipsychotics
4. Negative Symptoms
5. Cognitive Dysfunction
6. Tailoring Treatment Options
7. Case Presentation
8. Key Takeaways
F
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N
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O
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Y

67. Case Presentation: Mr. TG
qhs = every night at bedtime.
Patient: 21-year-old male
18 months ago: acutely psychotic, paranoid; feeling his thoughts can be
heard by others, that cameras are installed to check everything he is doing,
voices cursing at him
Lower level of psychosis for 7 months, smoking cannabis 4-7 days/week to
“chill out” and calm his “anxiety”
Inpatient admission, diagnosis of schizophrenia (managed in outpatient care)
During hospitalization, aripiprazole up to 25 mg with limited success for
agitation and positive symptoms
Olanzapine up to 20 mg qhs, significant reduction in positive symptoms,
cessation of agitation, discharged into outpatient care
Part 1
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68. Case Presentation: Mr. TG (cont.)
At 1 year: 12 kg weight gain, metabolic dysfunction, blunted affect,
cognitive slowing
Switch to risperidone up to 4 mg/day, hyperprolactinemia and erectile
dysfunction, still feeling “dull” and with “brain fog”
Gradual return of paranoid ideation and mild hallucinations because of
intermittent non-adherence due to side effects
Remained engaged in outpatient psychiatric care due to assistance by
his mother
Part 1
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69. Case Presentation: Mr. TG (cont.)
DRBA = dopamine receptor blocking agent.
Initiation of xanomeline-trospium with cross-taper strategy
Patient refused further DRBAs
Xanomeline-trospium (XT) started with cross-taper of risperidone:
Week 1: XT 50/20 mg BID, risperidone reduced to 2 mg/day
Week 2: XT 100/20 mg BID, risperidone maintained at 2 mg/day
Week 3+: XT 125/30 mg BID, risperidone discontinued
Part 2
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70. Case Presentation: Mr. TG (cont.)
Side effects:
Mild nausea in the morning
Resolved after dosing ≥1 hour before meals
Outcomes by Week 4:
Improved positive symptoms
Greater emotional expressiveness and focus
2 kg weight loss
No extrapyramidal, prolactin-related, or metabolic adverse effects
Part 2
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71. Agenda
1. Burden and Pathophysiology
2. Novel and Emerging Therapies
3. Long-Acting Antipsychotics
4. Negative Symptoms
5. Cognitive Dysfunction
6. Tailoring Treatment Options
7. Case Presentation
8. Key Takeaways
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72. Key Takeaways
Schizophrenia is a severe, often chronic and debilitating illness
Postsynaptic, relatively unselective dopamine receptor
blockade has been a mainstay of treatment for 7 decades
Outcomes are mixed for symptoms, more problematic for
remission, and even more so for recovery
Non-adherence is the major, preventable mediator of poor
outcomes, making the early offering of long-acting injectable
treatments a valuable strategy
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73. Key Takeaways (cont.)
Currently, no pharmacologic treatments are approved for
negative symptoms and cognitive impairment associated with
schizophrenia, 2 domains with strong functional impact
Novel mechanism-of-action treatments, including muscarinic
agonists, may be more targeted, reducing off-target central
adverse effects, and can potentially address positive symptoms
plus other symptom domains, especially cognition
Collaborative and measurement-based care has potential to
enhance outcomes
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74. 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
Alphs L, Morlock R, Coon C, et al (2010). The 4-item negative symptom assessment (NSA-4) instrument. Psychiatry (Edgmont), 7(7):26-32.
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
Brannan S, et al (2023). Safety and efficacy of KarXT in patients with schizophrenia in the randomized, double-blind, placebo-controlled, phase 3 EMERGENT-2 and EMERGENT-3
trials. Presented at the 2023 American Society of Clinical Psychopharmacology Annual Meeting.
Bristol Myers Squibb (2025). Bristol Myers Squibb announces topline results from Phase 3 ARISE trial evaluating Cobenfy (xanomeline and trospium chloride) as an adjunctive
treatment to atypical antipsychotics in adults with schizophrenia. Available at: https://news.bms.com/news/details/2025/Bristol-Myers-Squibb-Announces-Topline-
Results-from-Phase-3-ARISE-Trial-Evaluating-Cobenfy-xanomeline-and-trospium-chloride-as-an-Adjunctive-Treatment-to-Atypical-Antipsychotics-in-Adults-with-
Schizophrenia/default.aspx
Brown DA (2019). Acetylcholine and cholinergic receptors. Brain Neurosci Adv, 3:2398212818820506. DOI:10.1177/2398212818820506
Caplyta® (lumateperone) prescribing information (2019). Intra-Cellular Therapies, Inc. Available at:
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Carbon M & Correll CU (2014). Thinking and acting beyond the positive: the role of the cognitive and negative symptoms in schizophrenia. CNS Spectr, 19(suppl_1):38-52.
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Clinicaltrials.gov (2024a). A study to assess efficacy and safety of adjunctive KarXT in subjects with inadequately controlled symptoms of schizophrenia (ARISE). NLM identifier:
NCT05145413
Clinicaltrials.gov (2024b). A study to evaluate RL-007 in the treatment of cognitive impairment associated with schizophrenia (CIAS). NLM identifier: NCT05686239.
Clinicaltrials.gov (2024c). A translational and neurocomputational evaluation of a dopamine receptor 1 partial agonist for schizophrenia. NLM identifier: NCT04457310.
Clinicaltrials.gov (2024d) Study to assess the safety and pharmacokinetics of CY6463 in participants with stable schizophrenia. NLM identifier: NCT04972227.
Correll CU (2011). What are we looking for in new antipsychotics?, J Clin Psychiatry, 72(suppl_1):9-13. DOI:10.4088/JCP.10075su1.02
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75. References (cont.)
Correll CU (2020). Using patient-centered assessment in schizophrenia care: defining recovery and discussing concerns and preferences. J Clin Psychiatry, 81(3):MS19053BR2C
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, Davis RE, Weingart M, et al (2020). Efficacy and safety of lumateperone for treatment of schizophrenia: a randomized clinical trial. JAMA Psychiatry, 77(4):349-358.
DOI:10.1001/jamapsychiatry.2019.4379
Correll CU, Dombi ZB, Barabássy Á et al (2024). The transdiagnostic global impression – psychopathology scale (TGI-P): Initial development of a novel transdiagnostic tool for
assessing, tracking, and visualizing psychiatric symptom severity in everyday practice. European Neuropsychopharmacology, 88:31-39.
DOI:10.1016/j.euroneuro.2024.07.012
Correll CU, Kahn R, Silverman B, et al (2019). Combination of olanzapine and samidorphan limits the weight gain observed with olanzapine alone: results from the phase 3
ENLIGHTEN-2 schizophrenia study. Presented at the Schizophrenia International Research Society (SIRS) meeting; April 10, 2019; Orlando, Florida, USA.
Correll CU, Newcomer JW, Silverman B, et al, (2020). Effects of olanzapine combined with samidorphan on weight gain in schizophrenia: a 24-week phase 3 study. Am J
Psychiatry, 177(12):1168-1178. DOI:10.1176/appi.ajp.2020.19121279
Correll CU, Rubio JM, Inczedy-Farkas G, et al (2017). Efficacy of 42 pharmacologic cotreatment strategies added to antipsychotic monotherapy in schizophren ia: Systematic
overview and quality appraisal of the meta-analytic evidence. JAMA Psychiatry, 74(7):675-684. DOI:10.1001/jamapsychiatry.2017.0624
Correll CU, Stein E, Graham C, et al (2023). Reduction in multiple cardiometabolic risk factors with combined olanzapine/samidorphan compared with olanzapine: post hoc
analyses from a 24-week phase 3 study. Schizophrenia Bulletin, 49(2):454-463. DOI:10.1093/schbul/sbac144
Daniel DG (2013). Issues in selection of instruments to measure negative symptoms. Schizophr Res, 150(2-3):343-345. DOI:10.1016/j.schres.2013.07.005
Davis RE & Correll CU (2016). ITI-007 in the treatment of schizophrenia: from novel pharmacology to clinical outcomes. Expert Rev Neurother, 16(6):601-614.
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De Hert M, Detraux J, van Winkel R, et al (2011). Metabolic and cardiovascular adverse effects associated with antipsychotic drugs. Nat Rev Endocrinol, 8(2):114-126.
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Elwyn G, Frosch D, Thomson R, et al (2012). Shared decision making: a model for clinical practice. J Gen Intern Med, 27(10):1361-1367. DOI:10.1007/s11606-012-2077-6
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
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76. References (cont.)
Feber L, Peter NL, Chiocchia V, et al (2025). Antipsychotic drugs and cognitive function: a systematic review and network meta-analysis. JAMA Psychiatry, 82(1):47-56.
DOI:10.1001/jamapsychiatry.2024.2890
GlobeNewswire.com (2025). LB pharmaceuticals announces 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
Goff DC, Hill M & Freudenreich O (2010). Strategies for improving treatment adherence in schizophrenia and schizoaffective disorder. J Clin Psychiatry, 71(suppl_2):20-26.
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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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Haddad PM, Brain C & Scott J (2014) Nonadherence with antipsychotic medication in schizophrenia: challenges and management strategies. Patient Relat Outcome Meas, 5:43-62.
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Harvey PD, Saunder C, Yohn SE et al (2023). The potential role of the M1/M4 muscarinic receptor agonist KarTX in the treatment of cognitive impairment in patients with
schizophrenia. [Poster presentation]. American Society of Clinical Psychopharmacology Annual Meeting, 2023. Abstract W77.
Horan WP, Targum SD, Claxton A, et al (2024). Efficacy of KarXT on negative symptoms in acute schizophrenia: a post hoc analysis of pooled data from 3 trials. Schizophr Res,
274:57-65. DOI:10.1016/j.schres.2024.08.001
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)31135-3
Jääskeläinen E, Juola P, Hirvonen N, et al (2013). A systematic review and meta-analysis of recovery in schizophrenia. Schizophr Bull, 39(6):1296-1306.
DOI:10.1093/schbul/sbs130
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
Kane JM, Durgam S, Satlin A, et al (2021). Safety and tolerability of lumateperone for the treatment of schizophrenia: a pooled analysis of late-phase placebo- and active-
controlled clinical trials. Int Clin Psychopharmacol, 36(5):244-250. DOI:10.1097/YIC.0000000000000371
Kane JM, Harary E, Eshet R, et al (2023). Efficacy and safety of TV-46000, a long-acting, subcutaneous, injectable formulation of risperidone, for schizophrenia: a randomised
clinical trial in the USA and Bulgaria. Lancet Psychiatry, 10(12):934-943.
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77. References (cont.)
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-
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