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Journal of Medical Sciences at NEOMED
Volume 2, Issue 1, May 2023
Lumateperone in the Treatment of Schizophrenia: A Review
Gabrielle T. Robinson, BS1 and Altaf S. Darvesh, MPharm, PhD2,3*
1.
Basic and Translational Biomedicine Program, College of Graduate Studies, Northeast Ohio Medical
University, Rootstown, OH 44272
2.
Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown,
OH 44272
3.
Department of Psychiatry, College of Medicine, Northeast Ohio Medical University, Rootstown, OH 44272
* Corresponding Author
ABSTRACT
Schizophrenia is a devastating mental illness that afflicts about 1% of the world’s population. This illness
distorts a person’s perception of reality and consists of positive symptoms such as hallucinations and
delusions, negative symptoms such as inattention and withdrawal, and cognitive deficits. Antipsychotic
drugs are primarily used for the pharmacotherapy of schizophrenia. In this article, we provide a succinct
review of a recently approved novel antipsychotic, lumateperone. We present an overview and history of
schizophrenia, its symptoms, epidemiology, etiology, and pathophysiology. The classification of
antipsychotic agents as first and second-generation based on their receptor affinity is discussed. The
review focuses on describing the background, development, receptor pharmacology, mechanism of action,
pharmacokinetics, clinical trials, adverse effects, therapeutic uses, and future prospects of lumateperone.
Keywords: antipsychotic, atypical, lumateperone, schizophrenia, 5-HT2A serotonin receptor
INTRODUCTION
created the term ‘schizophrenia’ to replace the term
‘dementia precox’.4,5
Schizophrenia symptoms are primarily
classified as positive and negative in nature. Positive
symptoms, primarily experienced during a psychotic
episode, include delusions, hallucinations, and
disorganized thoughts, speech, and behavior. Negative
symptoms, which are deficits in normal emotional
response, are anhedonia (inability to experience
pleasure), alogia (poverty of speech or thought),
avolition (inability to initiate and persist in goal
directed activities), apathy (lack of interest, enthusiasm,
or concern), blunted affect, and social withdrawal.
Patients with schizophrenia also show cognitive deficits
such as impaired working memory, decreased verbal
fluency, and decreased abilities in reasoning and
problem solving.3,6
Although the etiology of schizophrenia is
unclear, several risk factors have been implicated in the
pathogenesis of this chronic debilitating mental illness.
Schizophrenia is classified as a neurodevelopmental
disorder with no known precise cause. Schizophrenia is
thought to develop from complex gene-environment
interactions. Environmental risk factors such as
Schizophrenia
Schizophrenia, a severe mental disorder of
unknown etiology, afflicts about 1% of the global
population.1 In 2019, the World Health Organization
reported over 20 million cases of schizophrenia
globally.2 The Diagnostic and Statistical Manual of
Mental Disorders, Fifth Edition (DSM-5) currently
defines schizophrenia as the presence of two or more of
the following symptoms: delusions, hallucinations,
disorganized speech, grossly disorganized or catatonic
behavior, and diminished emotional expression with the
symptoms being present for a significant portion of
time during a 1-month period. At least one of these
symptoms must be delusions, hallucinations, or
disorganized speech.3 Schizophrenia has a history,
stemming back as early as the 19th century when the
French psychiatrist, Bénédict Augustin Morel, first
coined the term ‘démence précoce’. This term would
later evolve into the term ‘dementia precox’ by the
renowned German psychiatrist Emil Kraepelin. It was
in 1908 that the Swiss psychiatrist, Eugen Bleuler,
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JMS, May 2023—Volume 2, Issue 1
childhood trauma, stress, pregnancy complications,
nutritional deficiencies; genetic and hereditary factors
and family history; as well as structural abnormalities
such as hypofrontality (decreased blood flow in the
prefrontal cortex) have all been implicated in the
development of schizophrenia.7,8
The pathophysiology of schizophrenia is
extremely complex, and there is no single theory that
can explain the pathogenesis of this mental illness.9
Studies have found significant anatomical alternations
in several brain structures of high-risk youth. It is
hypothesized that abnormal neuronal pruning of
neurons, altered communication, and decreased
neuronal connectivity, contribute to the development of
schizophrenia.12,13
Genetic factors in schizophrenia
The role of genetic contribution and
heritability in the development of schizophrenia has
been widely studied. First-degree relatives of patients
with schizophrenia have a 10% risk of developing the
disease. This risk increases to 40% when both parents
have schizophrenia. About 40% identical twins of
patients with schizophrenia are affected. There is no
particular “schizophrenia gene” that has been identified,
and research continues in the area. A genetic burden
may combine with environmental and social factors to
trigger symptoms.14
Role of neurotransmitters in schizophrenia
The dopamine dysregulation hypothesis has
been fundamental in the development of antipsychotic
medications. The hypothesis states that excessive
dopaminergic activity in the mesolimbic pathway
contributes to positive symptoms such as hallucinations
and delusions. Hypodopaminergic activity in the
mesocortical pathway may contribute to negative
symptoms such as apathy and anhedonia. Besides
dopamine, dysfunction in other neurotransmitter
systems such as glutamatergic, serotonergic,
cholinergic, and GABA-ergic systems have also been
implicated in the pathogenesis of schizophrenia.10,11
Antipsychotics
Antipsychotic medications are classified as
typical and atypical agents. Typical antipsychotics,
which were introduced earlier, are also known as first
generation antipsychotics (FGAs), and atypical agents,
introduced later, are known as second generation
antipsychotics (SGAs). Both classes of antipsychotics
significantly differ in mechanism of action, adverse
effect profile, and receptor pharmacology.15,16 (Table 1)
FGAs, such as chlorpromazine, thioridazine,
Neurodevelopmental model of schizophrenia
The neurodevelopmental aspects in the
pathophysiology of schizophrenia have been
extensively studied using techniques such as imaging
and using biomarkers. Risk factors include prenatal
infection, inflammation, malnutrition, and stress.
Antipsychotics
Adverse effect
Typical Antipsychotics (FGAs)
Mechanism of action
Chlorpromazine
Akathisia
Antagonism of dopamine D2
Thioridazine
Dystonia
receptors
Fluphenazine
Tardive dyskinesia
Trifluoperazine
Drug-induced Parkinsonism
Haloperidol
Atypical Antipsychotics (SGAs)
Clozapine
Olanzapine
Agranulocytosis, weight gain, diabetes,
Antagonism of dopamine D2 and
lipid abnormalities
serotonin 5-HT2A receptors
Weight gain, diabetes, lipid
abnormalities
Quetiapine
Sedation
Risperidone
Movement disorders
Ziprasidone
Cardiac arrhythmias
Table 1. Mechanism of action and adverse effects of antipsychotics
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JMS, May 2023—Volume 2, Issue 1
and haloperidol, are primarily dopamine D2 receptor
antagonists. FGAs block the dopaminergic mesolimbic
pathway and are effective in the management of
positive symptoms. FGAs produce movement disorders
known
as
extrapyramidal
symptoms
(EPS),
pseudoparkinsonism, or drug-induced Parkinsonism by
blocking the dopaminergic nigrostriatal pathway. FGAs
produce EPS such as akathisia (motor restlessness),
dystonia (abnormal repetitive twisting muscle
movements), and tardive dyskinesia (involuntary
abnormal facial movements).17
FGAs also elevate
prolactin levels due to inhibition of the dopaminergic
tuberoinfundibular pathway which regulates prolactin
secretion. Typical antipsychotic-induced hyperprolactinemia is associated with amenorrhea,
osteoporosis, and increased risk for developing breast
cancer.18
Clozapine was the first SGA that was
developed followed by other SGAs, such as olanzapine
and risperidone. The atypicality of SGAs arises from
their antagonist properties at the D2 receptor, which
improves positive symptoms, as well as the antagonism
of serotonin 5-HT2A receptor. Blockade of the 5-HT2A
receptors in the dopaminergic mesocortical pathways
enhances dopamine levels and improves negative
symptoms. Thus, SGAs are effective in improving both
positive and negative symptoms of schizophrenia.
Besides the D2 and 5-HT2A receptors, SGAs also
display antagonism at a multitude of other
dopaminergic,
serotonergic,
muscarinic,
and
histaminergic receptors. SGAs produce several serious
adverse effects such as diabetes, obesity, and cardiac
disturbances.19,20
In this review, we describe the background,
development, receptor pharmacology, mechanism of
Figure 1A. Structure of lumateperone tosylate43
action, pharmacokinetics, clinical trials, adverse effects,
therapeutic uses, and future prospects of lumateperone.
LUMATEPERONE
Lumateperone was developed by Intra-Cellular
Therapies, New York, NY, primarily for the treatment
of schizophrenia with potential use in other
neuropsychiatric disorders such as major depressive
disorders and bipolar disorder. Lumateperone was
called ITI-007 during its development phase, both preclinical studies, and clinical trials. Based on the clinical
data, the FDA approved lumateperone for the treatment
of schizophrenia in adults in December 2019.
Lumateperone, branded as Caplyta®, was available in
February 2020 and is administered in capsule form at a
daily dose of 42 mg.21,22,23,24
Structure
Lumateperone, similar to haloperidol, is
derived from a butyrophenone core (Figure 1A, 1B,
1C). The IUPAC name for lumateperone is 1-(4fluorophenyl)-4-(4-methyl-1,4,12-triazatetracyclo
[7.6.1.05,16.010,15]hexadeca-5,7,9(16)-trien-12-yl)
butan-1-one, and it has a molecular formula of
C24H28FN3O and a molecular weight of 393.5.
Lumateperone is formulated as a tosylate salt to provide
stability to the medication. Lumateperone tosylate has
an IUPAC name 1-(4-fluorophenyl)-4-[(10R,15S)-4methyl-1,4,12-triazatetracyclo[7.6.1.05,16.010,15]
hexadeca-5,7,9(16)-trien-12-yl]butan-1-one;4methylbenzenesulfonic acid; its molecular formula is
C31H36FN3O4S and a molecular weight of
565.7.24,25,26
Figure 1B. Structure of haloperidol44
Figure 1C. Structure of butyrophenone45
Figure 1. Comparison of the structures of lumateperone and haloperidol with their butyrophenone core
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Robinson & Darvesh
JMS, May 2023—Volume 2, Issue 1
olanzapine. This accounts for decreased EPS in
lumateperone and olanzapine therapy. Risperidone can
cause significant EPS due to strong binding at the D2
receptor comparable to haloperidol. Lumateperone’s
antidepressant potential is due to its binding at SERT,
which is not present in the other antipsychotic agents. In
summary, Lumateperone’s therapeutic efficacy and
safety are due to its robust binding at the 5-HT2A
receptor, moderate binding at the D2 receptor,
inhibition of SERT, and lack of muscarinic and
histaminergic binding. Lumateperone does not cause
movement
disorders
observed
with
FGAs.
Lumateperone does not produce serious adverse effects
produced by SGAs such as agranulocytosis, weight
gain, diabetes,
lipid abnormalities, and cardiac
arrythmias. Lumateperone also is effective in
management of both positive and negative symptoms
and also improves cognition.36,37
Pharmacology
Lumateperone is an atypical antipsychotic, and
similar to other SGAs, has antagonist properties at both
the D2 and 5-HT2A receptors. Lumateperone has high
binding affinity for the 5-HT2A receptors and displays
moderate binding affinity for the D1 and D2 receptors.
It has low binding affinity for adrenergic α1 and
histaminergic H1 receptors.27,28,29 Lumateperone has a
60-fold higher affinity for the 5-HT2A receptor
compared to the D2 receptor.28,29,30,31 The high 5HT2A / D2 binding ratio, a characteristic of SGAs,
contributes to improvement of negative symptoms.32 It
acts as a presynaptic partial agonist and a postsynaptic
antagonist at the D2 receptor. This pharmacological
effect of decreased presynaptic release of dopamine and
postsynaptic D2 receptor blockade significantly
dampens dopaminergic signaling and thus improves
positive symptoms.28 Lack of binding to muscarinic and
histaminergic receptors results in fewer adverse effects
associated with muscarinic and histaminergic
antagonism in several other antipsychotics.27
Lumateperone causes increased phosphorylation of the
N-methyl-D-aspartate (NMDA) receptor GluN2B
subunit which results in indirect glutamatergic
activation.27 Lumateperone inhibits the serotonin
reuptake transporter (SERT) which may produce
antidepressant effects and also contribute to
improvement of negative symptoms.25
Safety
Lumateperone displays a favorable safety
profile due to its receptor binding profile.36 In clinical
trials, it was well tolerated and did not display the
adverse motor effects nor the metabolic, endocrine, and
cardiovascular effects typically associated with other
FGAs and SGAs.38,39 Some common adverse effects of
lumateperone are headache, dizziness, sedation, fatigue,
nausea, constipation, and vomiting. Lumateperone was
not clinically studied in patients older than 65 years old
and is not recommended for the treatment of dementiarelated psychosis.25,26,38,39
Comparison of receptor binding affinity of lumateperone
with other antipsychotics
Pharmacokinetics
The receptor binding of lumateperone is
compared with two other SGAs, risperidone33 and
olanzapine34, and a FGA, haloperidol,35 in Table 2. For
drug-receptor binding, the smaller the inhibitory
constant (Ki), the greater the binding affinity and the
smaller amount of medication needed in order to inhibit
the activity of that receptor. Lumateperone has robust
binding to the 5-HT2A receptor, which is comparable to
both the SGAs listed in Table 2. Lumateperone shows
moderate binding at the D2 receptor similar to
Lumateperone is rapidly absorbed after oral
absorption, and displays high lipophilicity, which
increases its passage through the blood brain barrier.
Peak plasma concentration is achieved in 1-2 hours and
steady state concentration is achieved in about 5 days.
Lumateperone has a bioavailability of about 4% and is
97.4% protein bound. About 58% of lumateperone is
excreted in urine as water soluble glucuronide
metabolites. Less than 1% of unmetabolized drug is
Drug
Receptors
D1
D2
5HT2A
SERT
α1
α2
H1
Lumateperone
41 nM
32nM
0.54 nM
62 nM
<100 nM
N/A
>1000 nM
Risperidone
N/A
3.13 nM
0.16 nM
>1000 nM
0.8 nM
7.54 nM
2.23 nM
Olanzapine
11 nM
31 nM
4 nM
>1000 nM
19 nM
N/A
7.0 nM
Haloperidol
83 nM
nM
N/A
N/A
N/A
3 nM
N/A
N/A- no significant binding / binding data not available
Table 2. Comparison of inhibitory constant (Ki) of lumateperone with other antipsychotics
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JMS, May 2023—Volume 2, Issue 1
excreted in the urine and 29% is excreted in the
feces.38,39
Lumateperone is a substrate for the enzymes
Cytochrome P450 3A4 (CYP3A4) and Uridine 5'diphospho-glucuronosyltransferase (UGT), and thus
there is potential for drug-drug, drug-food, and drugherb interactions. Lumateperone should not be taken
with CYP3A4 inducers such as the anticonvulsant,
carbamazepine, and the herbal supplement, St. John’s
wort, as they would reduce the plasma concentrations of
the drug. Lumateperone is also contraindicated with
CYP3A4 inhibitors, such as the antidepressant,
fluvoxamine, and grapefruit juice, as they would lead to
an increase in plasma levels of the drug and increase the
chances for toxicity. Drugs known to be UGT inhibitors
such as the anticonvulsant, valproic acid, should not be
used with lumateperone.38,39
•
•
•
The medication and placebo were administered
once daily for 28 days. The primary end point was the
Positive and Negative Syndrome Scale (PANSS). There
was a significant difference between placebo and ITI007 (60 mg). Risperidone also showed a significant
difference compared to placebo. ITI-007 (120 mg) did
not show any statistically significant difference
compared to placebo. A subgroup of patients with
symptoms of depression were evaluated with the
Calgary Depression Scale for Schizophrenia (CDSS).
Only ITI-007 (60 mg) showed a significant difference
compared with placebo for the depression symptoms. 40
Clinical Trials
Lumateperone was clinical evaluated to study
its therapeutic effectiveness and potential adverse
effects. Two clinical trials were conducted to determine
the efficacy and safety of lumateperone are discussed in
this section.
NCT02282761
This phase III clinical trial compared placebo
with two doses of ITI-007 (lumateperone tosylate), 40
and 60 mg, which are equivalent to 28 and 48 mg of
lumateperone base. This clinical study was conducted
from November 2014 to September 2015. 450 patients
with schizophrenia were enrolled in this study in a
randomized, double-blind, 1:1:1 fashion.
NCT01499563
This clinical trial was a phase II multicenter
study that compared placebo and risperidone (4 mg), as
positive control, with two doses of ITI-007
(lumateperone tosylate) (60 mg and 120 mg) which are
equivalent to 42 mg and 84 mg of lumateperone being
used to determine effects of ITI-007 on psychosis. The
study was conducted from December 2011 to November
2013. The study was conducted in a randomized doubleblind manner in a 1:1:1:1 fashion. A total of 355 acutely
psychotic patients were enrolled into the study.
Inclusion Criteria:
•
•
•
•
Inclusion Criteria:
•
•
•
“Patient's age is 18-55
Patient has current diagnosis of schizophrenia and
is experiencing an acute exacerbation of psychosis
Patient has a history of at least three months
exposure to one or more antipsychotic therapy(ies)
and a prior response to antipsychotic therapy within
the previous five years”40
•
•
“Patient’s age is 18-60
Patient has a clinical diagnosis of schizophrenia
Patient is male or female of any race
Patient is experiencing an acute exacerbation of
psychosis”41
Exclusion Criteria:
•
•
•
Exclusion Criteria:
•
depression with psychotic features
Any patient considered to be an imminent danger to
themselves or others
Any patient with hematological, renal, hepatic,
endocrinological, neurological, or cardiovascular
disease or substance abuse as defined by protocol
Any patient judged by the investigator to be
inappropriate for the study”40
“Any female patient who is pregnant or breastfeeding
Any patient unable to provide informed consent
Any patient judged by the Investigator to be
inappropriate for the study.”41
The patients were administered medication or
placebo once daily for a period of 28 days. The primary
end point was the PANSS. ITI-007 (60 mg) showed a
significant difference compared to placebo for PANSS
while the lower dose of 40 mg did not. Both doses of
ITI-007 showed significant difference compared to
placebo for secondary end points, Clinical Global
Impression-Severity of Illness (CGI-S) scores, and the
general psychopathology subscale scores.41
“Any female patient who is pregnant or breastfeeding
Any patient presenting with concurrent dementia,
delirium, mental retardation, epilepsy, druginduced psychosis, or history of significant brain
trauma
Any patient presenting with schizoaffective
disorder, bipolar disorder, acute mania, or major
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JMS, May 2023—Volume 2, Issue 1
Overall, lumateperone showed efficacy in
improving symptoms of schizophrenia as well as
depression symptoms and also demonstrated a superior
safety profile in both aforementioned clinical trials.
5.
Yuhas D. Throughout History, Defining
Schizophrenia Has Remained a Challenge
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Accessed April 27, 2022
6.
Andreasen NC, Nopoulos P, Schultz S, et al. Positive
and negative symptoms of schizophrenia: past, present,
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7.
Khan ZU, Montanez-Martin E, Muly EC. Schizophrenia:
causes and treatments. Curr Pharm Des. 2013;19
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8.
Stilo SA, Murray RM. Non-Genetic Factors in
Schizophrenia. Curr Psychiatry Rep. 2019;21
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9.
Owen MJ, Sawa A, Mortensen PB. Schizophrenia.
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CONCLUSION
Schizophrenia is an extremely complex and
debilitating mental illness with poorly elucidated
pathophysiology.
The
pharmacotherapy
of
schizophrenia is beset with serious and life-threatening
adverse effects such as movement disorders,
agranulocytosis, weight gain, diabetes, and cardiac
arrythmias. Thus, there exists a critical need for the
development of newer antipsychotic agents with an
improved therapeutic and safety profile. The receptor
pharmacology of antipsychotic agents is well
characterized and is linked to their therapeutic and
adverse effects. This knowledge is advantageous in the
development of newer antipsychotics
Lumateperone is one of the newly developed
atypical antipsychotics in recent years. It has
significantly higher binding affinity to the 5-HT2A
receptor and moderate binding at the D2 receptor. It has
a good safety profile and has been shown to be devoid
of any significant motor, metabolic, endocrine, and
cardiovascular adverse effects. It has been shown to be
effective in the management of schizophrenia
symptoms. Lumateperone’s ability to inhibit SERT
contributes to it’s ability to manage negative and
depression symptoms. Lumateperone was approved by
the FDA for the treatment of bipolar depression in
December 2021.42 Since the drug has been on the
market for less than three years, there are no studies
evaluating any possible long-term effects of
lumateperone.
10. McCutcheon RA, Abi-Darghan A, Howes OD.
Schizophrenia, Dopamine and the Striatum: From
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11. Grace AA. Dysregulation of the dopamine system
in the pathophysiology of schizophrenia and
depression. Nat Rev Neurosci. 2016;17(8):524-532.
doi:10.1038/nrn.2016.57
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profile. Clin Pharmacokinet. 1999;37(3):177-193.
doi:10.2165/00003088-199937030-00001
24. Greenwood J, Acharya RB, Marcellus V, Rey JA.
Lumateperone: A Novel Antipsychotic for
Schizophrenia. Ann of Pharmacother. 2021;55
(1):98-104. doi:10.1177/1060028020936597
35. Peprah K, Zhu XY, Eyunni SV, et al. Multireceptor drug design: Haloperidol as a scaffold for
the design and synthesis of atypical antipsychotic
agents. Bioorg Med Chem. 2012;20(3):1291-1297.
doi:10.1016/j.bmc.2011.12.019
7
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JMS, May 2023—Volume 2, Issue 1
36. Orsolini L, De Berardis D, Volpe U. Up-to-date
expert opinion on the safety of recently developed
antipsychotics. Expert Opin Drug Safe. 2020;19
(8):981-998. doi: 10.1080/14740338.2020.1795126
45. National Center for Biotechnology Information.
PubChem Compound Summary for CID 10315,
Butyrophenone. https://pubchem.ncbi.nlm.nih.gov/
compound/Butyrophenone. Accessed October 24,
2022.
37. Calabrese JR, Durgam S, Satlin A, et al. Efficacy and
Safety of Lumateperone for Major Depressive
Episodes Associated With Bipolar I or Bipolar II
Disorder: A Phase 3 Randomized Placebo-Controlled
Trial. Am J Psychiatry. 2021;178(12):1098-1106.
doi:10.1176/appi.ajp.2021.20091339
ACKNOWLEDGMENTS
The authors wish to gratefully acknowledge the
valuable insight and opinions provided by Dr.
Takhar Kasumov, Dr. Woo Shik Shin, and Dr.
Chris Paxos.
38. Intra-Cellular Therapies Inc. Caplyta (lumateperone)
capsules for oral use (package insert). New York.
https://www.intracellulartherapies.com/
Accessed
January 07, 2023.
CONFLICTS OF INTEREST
39. Blair HA. Lumateperone: First Approval. Drugs.
2020;80(4):417-423. doi: 10.1007/s40265-020-012716
All authors declare no conflicts of interest.
AUTHOR CONTRIBUTIONS
40. ClinicalTrials.gov. U.S. National Library of
Medicine. Study of a Novel Antipsychotic ITI-007
in Schizophrenia. https://clinicaltrials.gov/ct2/
show/results/NCT01499563. Updated March 10,
2017. Accessed February 15, 2022.
Review Writing: GR
Editing: AD
41. Clinical Trials.gov. U.S. National Library of
Medicine. A Trial to Assess the Antipsychotic
Efficacy of ITI-007. https://clinicaltrials.gov/ct2/
show/NCT02282761. Updated March 10, 2017.
Accessed February 16, 2022.
42. Intra-cellular Therapies Inc. Cellular therapies
announces U.S. FDA approval of CAPLYTA®
(lumateperone) for the treatment of bipolar
depression in adults: Intra-Cellular Therapies Inc.
https://ir.intracellulartherapies.com/news-releases/
news-release-details/intra-cellular-therapiesannounces-us-fda-approval-caplytar. Published Dec
20, 2021. Accessed February 17, 2022.
43. National Center for Biotechnology Information.
PubChem Compound Summary for CID
44241743, Lumateperone Tosylate. https://
pubchem.ncbi.nlm.nih.gov/compound/
lumateperone-Tosylate. Accessed October 24,
2022.
44. National Center for Biotechnology Information.
PubChem Compound Summary for CID 3559,
Haloperidol.
https://pubchem.ncbi.nlm.nih.gov/
compound/Haloperidol. Accessed October 24,
2022.
8
Volume 2, Issue 1, May 2023
Lumateperone in the Treatment of Schizophrenia: A Review
Gabrielle T. Robinson, BS1 and Altaf S. Darvesh, MPharm, PhD2,3*
1.
Basic and Translational Biomedicine Program, College of Graduate Studies, Northeast Ohio Medical
University, Rootstown, OH 44272
2.
Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown,
OH 44272
3.
Department of Psychiatry, College of Medicine, Northeast Ohio Medical University, Rootstown, OH 44272
* Corresponding Author
ABSTRACT
Schizophrenia is a devastating mental illness that afflicts about 1% of the world’s population. This illness
distorts a person’s perception of reality and consists of positive symptoms such as hallucinations and
delusions, negative symptoms such as inattention and withdrawal, and cognitive deficits. Antipsychotic
drugs are primarily used for the pharmacotherapy of schizophrenia. In this article, we provide a succinct
review of a recently approved novel antipsychotic, lumateperone. We present an overview and history of
schizophrenia, its symptoms, epidemiology, etiology, and pathophysiology. The classification of
antipsychotic agents as first and second-generation based on their receptor affinity is discussed. The
review focuses on describing the background, development, receptor pharmacology, mechanism of action,
pharmacokinetics, clinical trials, adverse effects, therapeutic uses, and future prospects of lumateperone.
Keywords: antipsychotic, atypical, lumateperone, schizophrenia, 5-HT2A serotonin receptor
INTRODUCTION
created the term ‘schizophrenia’ to replace the term
‘dementia precox’.4,5
Schizophrenia symptoms are primarily
classified as positive and negative in nature. Positive
symptoms, primarily experienced during a psychotic
episode, include delusions, hallucinations, and
disorganized thoughts, speech, and behavior. Negative
symptoms, which are deficits in normal emotional
response, are anhedonia (inability to experience
pleasure), alogia (poverty of speech or thought),
avolition (inability to initiate and persist in goal
directed activities), apathy (lack of interest, enthusiasm,
or concern), blunted affect, and social withdrawal.
Patients with schizophrenia also show cognitive deficits
such as impaired working memory, decreased verbal
fluency, and decreased abilities in reasoning and
problem solving.3,6
Although the etiology of schizophrenia is
unclear, several risk factors have been implicated in the
pathogenesis of this chronic debilitating mental illness.
Schizophrenia is classified as a neurodevelopmental
disorder with no known precise cause. Schizophrenia is
thought to develop from complex gene-environment
interactions. Environmental risk factors such as
Schizophrenia
Schizophrenia, a severe mental disorder of
unknown etiology, afflicts about 1% of the global
population.1 In 2019, the World Health Organization
reported over 20 million cases of schizophrenia
globally.2 The Diagnostic and Statistical Manual of
Mental Disorders, Fifth Edition (DSM-5) currently
defines schizophrenia as the presence of two or more of
the following symptoms: delusions, hallucinations,
disorganized speech, grossly disorganized or catatonic
behavior, and diminished emotional expression with the
symptoms being present for a significant portion of
time during a 1-month period. At least one of these
symptoms must be delusions, hallucinations, or
disorganized speech.3 Schizophrenia has a history,
stemming back as early as the 19th century when the
French psychiatrist, Bénédict Augustin Morel, first
coined the term ‘démence précoce’. This term would
later evolve into the term ‘dementia precox’ by the
renowned German psychiatrist Emil Kraepelin. It was
in 1908 that the Swiss psychiatrist, Eugen Bleuler,
1
Robinson & Darvesh
JMS, May 2023—Volume 2, Issue 1
childhood trauma, stress, pregnancy complications,
nutritional deficiencies; genetic and hereditary factors
and family history; as well as structural abnormalities
such as hypofrontality (decreased blood flow in the
prefrontal cortex) have all been implicated in the
development of schizophrenia.7,8
The pathophysiology of schizophrenia is
extremely complex, and there is no single theory that
can explain the pathogenesis of this mental illness.9
Studies have found significant anatomical alternations
in several brain structures of high-risk youth. It is
hypothesized that abnormal neuronal pruning of
neurons, altered communication, and decreased
neuronal connectivity, contribute to the development of
schizophrenia.12,13
Genetic factors in schizophrenia
The role of genetic contribution and
heritability in the development of schizophrenia has
been widely studied. First-degree relatives of patients
with schizophrenia have a 10% risk of developing the
disease. This risk increases to 40% when both parents
have schizophrenia. About 40% identical twins of
patients with schizophrenia are affected. There is no
particular “schizophrenia gene” that has been identified,
and research continues in the area. A genetic burden
may combine with environmental and social factors to
trigger symptoms.14
Role of neurotransmitters in schizophrenia
The dopamine dysregulation hypothesis has
been fundamental in the development of antipsychotic
medications. The hypothesis states that excessive
dopaminergic activity in the mesolimbic pathway
contributes to positive symptoms such as hallucinations
and delusions. Hypodopaminergic activity in the
mesocortical pathway may contribute to negative
symptoms such as apathy and anhedonia. Besides
dopamine, dysfunction in other neurotransmitter
systems such as glutamatergic, serotonergic,
cholinergic, and GABA-ergic systems have also been
implicated in the pathogenesis of schizophrenia.10,11
Antipsychotics
Antipsychotic medications are classified as
typical and atypical agents. Typical antipsychotics,
which were introduced earlier, are also known as first
generation antipsychotics (FGAs), and atypical agents,
introduced later, are known as second generation
antipsychotics (SGAs). Both classes of antipsychotics
significantly differ in mechanism of action, adverse
effect profile, and receptor pharmacology.15,16 (Table 1)
FGAs, such as chlorpromazine, thioridazine,
Neurodevelopmental model of schizophrenia
The neurodevelopmental aspects in the
pathophysiology of schizophrenia have been
extensively studied using techniques such as imaging
and using biomarkers. Risk factors include prenatal
infection, inflammation, malnutrition, and stress.
Antipsychotics
Adverse effect
Typical Antipsychotics (FGAs)
Mechanism of action
Chlorpromazine
Akathisia
Antagonism of dopamine D2
Thioridazine
Dystonia
receptors
Fluphenazine
Tardive dyskinesia
Trifluoperazine
Drug-induced Parkinsonism
Haloperidol
Atypical Antipsychotics (SGAs)
Clozapine
Olanzapine
Agranulocytosis, weight gain, diabetes,
Antagonism of dopamine D2 and
lipid abnormalities
serotonin 5-HT2A receptors
Weight gain, diabetes, lipid
abnormalities
Quetiapine
Sedation
Risperidone
Movement disorders
Ziprasidone
Cardiac arrhythmias
Table 1. Mechanism of action and adverse effects of antipsychotics
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JMS, May 2023—Volume 2, Issue 1
and haloperidol, are primarily dopamine D2 receptor
antagonists. FGAs block the dopaminergic mesolimbic
pathway and are effective in the management of
positive symptoms. FGAs produce movement disorders
known
as
extrapyramidal
symptoms
(EPS),
pseudoparkinsonism, or drug-induced Parkinsonism by
blocking the dopaminergic nigrostriatal pathway. FGAs
produce EPS such as akathisia (motor restlessness),
dystonia (abnormal repetitive twisting muscle
movements), and tardive dyskinesia (involuntary
abnormal facial movements).17
FGAs also elevate
prolactin levels due to inhibition of the dopaminergic
tuberoinfundibular pathway which regulates prolactin
secretion. Typical antipsychotic-induced hyperprolactinemia is associated with amenorrhea,
osteoporosis, and increased risk for developing breast
cancer.18
Clozapine was the first SGA that was
developed followed by other SGAs, such as olanzapine
and risperidone. The atypicality of SGAs arises from
their antagonist properties at the D2 receptor, which
improves positive symptoms, as well as the antagonism
of serotonin 5-HT2A receptor. Blockade of the 5-HT2A
receptors in the dopaminergic mesocortical pathways
enhances dopamine levels and improves negative
symptoms. Thus, SGAs are effective in improving both
positive and negative symptoms of schizophrenia.
Besides the D2 and 5-HT2A receptors, SGAs also
display antagonism at a multitude of other
dopaminergic,
serotonergic,
muscarinic,
and
histaminergic receptors. SGAs produce several serious
adverse effects such as diabetes, obesity, and cardiac
disturbances.19,20
In this review, we describe the background,
development, receptor pharmacology, mechanism of
Figure 1A. Structure of lumateperone tosylate43
action, pharmacokinetics, clinical trials, adverse effects,
therapeutic uses, and future prospects of lumateperone.
LUMATEPERONE
Lumateperone was developed by Intra-Cellular
Therapies, New York, NY, primarily for the treatment
of schizophrenia with potential use in other
neuropsychiatric disorders such as major depressive
disorders and bipolar disorder. Lumateperone was
called ITI-007 during its development phase, both preclinical studies, and clinical trials. Based on the clinical
data, the FDA approved lumateperone for the treatment
of schizophrenia in adults in December 2019.
Lumateperone, branded as Caplyta®, was available in
February 2020 and is administered in capsule form at a
daily dose of 42 mg.21,22,23,24
Structure
Lumateperone, similar to haloperidol, is
derived from a butyrophenone core (Figure 1A, 1B,
1C). The IUPAC name for lumateperone is 1-(4fluorophenyl)-4-(4-methyl-1,4,12-triazatetracyclo
[7.6.1.05,16.010,15]hexadeca-5,7,9(16)-trien-12-yl)
butan-1-one, and it has a molecular formula of
C24H28FN3O and a molecular weight of 393.5.
Lumateperone is formulated as a tosylate salt to provide
stability to the medication. Lumateperone tosylate has
an IUPAC name 1-(4-fluorophenyl)-4-[(10R,15S)-4methyl-1,4,12-triazatetracyclo[7.6.1.05,16.010,15]
hexadeca-5,7,9(16)-trien-12-yl]butan-1-one;4methylbenzenesulfonic acid; its molecular formula is
C31H36FN3O4S and a molecular weight of
565.7.24,25,26
Figure 1B. Structure of haloperidol44
Figure 1C. Structure of butyrophenone45
Figure 1. Comparison of the structures of lumateperone and haloperidol with their butyrophenone core
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JMS, May 2023—Volume 2, Issue 1
olanzapine. This accounts for decreased EPS in
lumateperone and olanzapine therapy. Risperidone can
cause significant EPS due to strong binding at the D2
receptor comparable to haloperidol. Lumateperone’s
antidepressant potential is due to its binding at SERT,
which is not present in the other antipsychotic agents. In
summary, Lumateperone’s therapeutic efficacy and
safety are due to its robust binding at the 5-HT2A
receptor, moderate binding at the D2 receptor,
inhibition of SERT, and lack of muscarinic and
histaminergic binding. Lumateperone does not cause
movement
disorders
observed
with
FGAs.
Lumateperone does not produce serious adverse effects
produced by SGAs such as agranulocytosis, weight
gain, diabetes,
lipid abnormalities, and cardiac
arrythmias. Lumateperone also is effective in
management of both positive and negative symptoms
and also improves cognition.36,37
Pharmacology
Lumateperone is an atypical antipsychotic, and
similar to other SGAs, has antagonist properties at both
the D2 and 5-HT2A receptors. Lumateperone has high
binding affinity for the 5-HT2A receptors and displays
moderate binding affinity for the D1 and D2 receptors.
It has low binding affinity for adrenergic α1 and
histaminergic H1 receptors.27,28,29 Lumateperone has a
60-fold higher affinity for the 5-HT2A receptor
compared to the D2 receptor.28,29,30,31 The high 5HT2A / D2 binding ratio, a characteristic of SGAs,
contributes to improvement of negative symptoms.32 It
acts as a presynaptic partial agonist and a postsynaptic
antagonist at the D2 receptor. This pharmacological
effect of decreased presynaptic release of dopamine and
postsynaptic D2 receptor blockade significantly
dampens dopaminergic signaling and thus improves
positive symptoms.28 Lack of binding to muscarinic and
histaminergic receptors results in fewer adverse effects
associated with muscarinic and histaminergic
antagonism in several other antipsychotics.27
Lumateperone causes increased phosphorylation of the
N-methyl-D-aspartate (NMDA) receptor GluN2B
subunit which results in indirect glutamatergic
activation.27 Lumateperone inhibits the serotonin
reuptake transporter (SERT) which may produce
antidepressant effects and also contribute to
improvement of negative symptoms.25
Safety
Lumateperone displays a favorable safety
profile due to its receptor binding profile.36 In clinical
trials, it was well tolerated and did not display the
adverse motor effects nor the metabolic, endocrine, and
cardiovascular effects typically associated with other
FGAs and SGAs.38,39 Some common adverse effects of
lumateperone are headache, dizziness, sedation, fatigue,
nausea, constipation, and vomiting. Lumateperone was
not clinically studied in patients older than 65 years old
and is not recommended for the treatment of dementiarelated psychosis.25,26,38,39
Comparison of receptor binding affinity of lumateperone
with other antipsychotics
Pharmacokinetics
The receptor binding of lumateperone is
compared with two other SGAs, risperidone33 and
olanzapine34, and a FGA, haloperidol,35 in Table 2. For
drug-receptor binding, the smaller the inhibitory
constant (Ki), the greater the binding affinity and the
smaller amount of medication needed in order to inhibit
the activity of that receptor. Lumateperone has robust
binding to the 5-HT2A receptor, which is comparable to
both the SGAs listed in Table 2. Lumateperone shows
moderate binding at the D2 receptor similar to
Lumateperone is rapidly absorbed after oral
absorption, and displays high lipophilicity, which
increases its passage through the blood brain barrier.
Peak plasma concentration is achieved in 1-2 hours and
steady state concentration is achieved in about 5 days.
Lumateperone has a bioavailability of about 4% and is
97.4% protein bound. About 58% of lumateperone is
excreted in urine as water soluble glucuronide
metabolites. Less than 1% of unmetabolized drug is
Drug
Receptors
D1
D2
5HT2A
SERT
α1
α2
H1
Lumateperone
41 nM
32nM
0.54 nM
62 nM
<100 nM
N/A
>1000 nM
Risperidone
N/A
3.13 nM
0.16 nM
>1000 nM
0.8 nM
7.54 nM
2.23 nM
Olanzapine
11 nM
31 nM
4 nM
>1000 nM
19 nM
N/A
7.0 nM
Haloperidol
83 nM
nM
N/A
N/A
N/A
3 nM
N/A
N/A- no significant binding / binding data not available
Table 2. Comparison of inhibitory constant (Ki) of lumateperone with other antipsychotics
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JMS, May 2023—Volume 2, Issue 1
excreted in the urine and 29% is excreted in the
feces.38,39
Lumateperone is a substrate for the enzymes
Cytochrome P450 3A4 (CYP3A4) and Uridine 5'diphospho-glucuronosyltransferase (UGT), and thus
there is potential for drug-drug, drug-food, and drugherb interactions. Lumateperone should not be taken
with CYP3A4 inducers such as the anticonvulsant,
carbamazepine, and the herbal supplement, St. John’s
wort, as they would reduce the plasma concentrations of
the drug. Lumateperone is also contraindicated with
CYP3A4 inhibitors, such as the antidepressant,
fluvoxamine, and grapefruit juice, as they would lead to
an increase in plasma levels of the drug and increase the
chances for toxicity. Drugs known to be UGT inhibitors
such as the anticonvulsant, valproic acid, should not be
used with lumateperone.38,39
•
•
•
The medication and placebo were administered
once daily for 28 days. The primary end point was the
Positive and Negative Syndrome Scale (PANSS). There
was a significant difference between placebo and ITI007 (60 mg). Risperidone also showed a significant
difference compared to placebo. ITI-007 (120 mg) did
not show any statistically significant difference
compared to placebo. A subgroup of patients with
symptoms of depression were evaluated with the
Calgary Depression Scale for Schizophrenia (CDSS).
Only ITI-007 (60 mg) showed a significant difference
compared with placebo for the depression symptoms. 40
Clinical Trials
Lumateperone was clinical evaluated to study
its therapeutic effectiveness and potential adverse
effects. Two clinical trials were conducted to determine
the efficacy and safety of lumateperone are discussed in
this section.
NCT02282761
This phase III clinical trial compared placebo
with two doses of ITI-007 (lumateperone tosylate), 40
and 60 mg, which are equivalent to 28 and 48 mg of
lumateperone base. This clinical study was conducted
from November 2014 to September 2015. 450 patients
with schizophrenia were enrolled in this study in a
randomized, double-blind, 1:1:1 fashion.
NCT01499563
This clinical trial was a phase II multicenter
study that compared placebo and risperidone (4 mg), as
positive control, with two doses of ITI-007
(lumateperone tosylate) (60 mg and 120 mg) which are
equivalent to 42 mg and 84 mg of lumateperone being
used to determine effects of ITI-007 on psychosis. The
study was conducted from December 2011 to November
2013. The study was conducted in a randomized doubleblind manner in a 1:1:1:1 fashion. A total of 355 acutely
psychotic patients were enrolled into the study.
Inclusion Criteria:
•
•
•
•
Inclusion Criteria:
•
•
•
“Patient's age is 18-55
Patient has current diagnosis of schizophrenia and
is experiencing an acute exacerbation of psychosis
Patient has a history of at least three months
exposure to one or more antipsychotic therapy(ies)
and a prior response to antipsychotic therapy within
the previous five years”40
•
•
“Patient’s age is 18-60
Patient has a clinical diagnosis of schizophrenia
Patient is male or female of any race
Patient is experiencing an acute exacerbation of
psychosis”41
Exclusion Criteria:
•
•
•
Exclusion Criteria:
•
depression with psychotic features
Any patient considered to be an imminent danger to
themselves or others
Any patient with hematological, renal, hepatic,
endocrinological, neurological, or cardiovascular
disease or substance abuse as defined by protocol
Any patient judged by the investigator to be
inappropriate for the study”40
“Any female patient who is pregnant or breastfeeding
Any patient unable to provide informed consent
Any patient judged by the Investigator to be
inappropriate for the study.”41
The patients were administered medication or
placebo once daily for a period of 28 days. The primary
end point was the PANSS. ITI-007 (60 mg) showed a
significant difference compared to placebo for PANSS
while the lower dose of 40 mg did not. Both doses of
ITI-007 showed significant difference compared to
placebo for secondary end points, Clinical Global
Impression-Severity of Illness (CGI-S) scores, and the
general psychopathology subscale scores.41
“Any female patient who is pregnant or breastfeeding
Any patient presenting with concurrent dementia,
delirium, mental retardation, epilepsy, druginduced psychosis, or history of significant brain
trauma
Any patient presenting with schizoaffective
disorder, bipolar disorder, acute mania, or major
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Overall, lumateperone showed efficacy in
improving symptoms of schizophrenia as well as
depression symptoms and also demonstrated a superior
safety profile in both aforementioned clinical trials.
5.
Yuhas D. Throughout History, Defining
Schizophrenia Has Remained a Challenge
[Timeline]. Scientific American Mind and Brain.
https://www.scientificamerican.com/article/
throughout-history-defining-schizophrenia-hasremained-challenge/. Published March 1, 2013.
Accessed April 27, 2022
6.
Andreasen NC, Nopoulos P, Schultz S, et al. Positive
and negative symptoms of schizophrenia: past, present,
and future. Acta Psychiatr Scand Suppl. 1994;384:5159. doi:10.1111/j.1600-0447.1994.tb05891.x.
7.
Khan ZU, Montanez-Martin E, Muly EC. Schizophrenia:
causes and treatments. Curr Pharm Des. 2013;19
(36):6451-6461. doi:10.2174/1381612811319360006
8.
Stilo SA, Murray RM. Non-Genetic Factors in
Schizophrenia. Curr Psychiatry Rep. 2019;21
(10):100. doi:10.1007/s11920-019-1091-3
9.
Owen MJ, Sawa A, Mortensen PB. Schizophrenia.
Lancet. 2016;388(10039):86-97. doi:10.1016/S0140
-6736(15)01121-6
CONCLUSION
Schizophrenia is an extremely complex and
debilitating mental illness with poorly elucidated
pathophysiology.
The
pharmacotherapy
of
schizophrenia is beset with serious and life-threatening
adverse effects such as movement disorders,
agranulocytosis, weight gain, diabetes, and cardiac
arrythmias. Thus, there exists a critical need for the
development of newer antipsychotic agents with an
improved therapeutic and safety profile. The receptor
pharmacology of antipsychotic agents is well
characterized and is linked to their therapeutic and
adverse effects. This knowledge is advantageous in the
development of newer antipsychotics
Lumateperone is one of the newly developed
atypical antipsychotics in recent years. It has
significantly higher binding affinity to the 5-HT2A
receptor and moderate binding at the D2 receptor. It has
a good safety profile and has been shown to be devoid
of any significant motor, metabolic, endocrine, and
cardiovascular adverse effects. It has been shown to be
effective in the management of schizophrenia
symptoms. Lumateperone’s ability to inhibit SERT
contributes to it’s ability to manage negative and
depression symptoms. Lumateperone was approved by
the FDA for the treatment of bipolar depression in
December 2021.42 Since the drug has been on the
market for less than three years, there are no studies
evaluating any possible long-term effects of
lumateperone.
10. McCutcheon RA, Abi-Darghan A, Howes OD.
Schizophrenia, Dopamine and the Striatum: From
Biology to Symptoms. Trends Neurosci. 2019;42
(3):205-220. doi:10.1016/j.tins.2018.12.004
11. Grace AA. Dysregulation of the dopamine system
in the pathophysiology of schizophrenia and
depression. Nat Rev Neurosci. 2016;17(8):524-532.
doi:10.1038/nrn.2016.57
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ACKNOWLEDGMENTS
The authors wish to gratefully acknowledge the
valuable insight and opinions provided by Dr.
Takhar Kasumov, Dr. Woo Shik Shin, and Dr.
Chris Paxos.
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All authors declare no conflicts of interest.
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