Comprehensive Report on Lumateperone (Caplyta)

1. Introduction to Lumateperone (Caplyta)

1.1 Overview

Lumateperone, marketed under the brand name Caplyta®, is a novel second-generation (atypical) antipsychotic agent developed for the treatment of serious central nervous system (CNS) disorders.[1] It is specifically approved for schizophrenia and bipolar depression in adults.[1] Lumateperone is distinguished by a unique receptor binding profile, which contributes to its mechanism of action and a generally favorable tolerability profile, particularly concerning metabolic disturbances and extrapyramidal symptoms (EPS), when compared to some other antipsychotic medications.[1]

Schizophrenia, a complex mental illness affecting approximately 1% of the population, presents a significant treatment challenge [User Query]. While several antipsychotics, including aripiprazole, paliperidone, and clozapine, are available, their use is often accompanied by significant metabolic and/or neurological adverse effects [User Query]. Lumateperone's development appears to be a direct response to these limitations. The emphasis on its "novel" mechanism involving the modulation of glutamate, serotonin, and dopamine, coupled with "minimal off-target activity" and a "more favourable adverse effect profile," suggests a targeted drug design strategy aimed at improving upon existing therapies [User Query]. This approach seeks to provide efficacy in managing both positive and negative symptoms of schizophrenia with enhanced safety and tolerability [User Query].

The evolution of lumateperone's approved indications, from schizophrenia (December 2019) to subsequently include bipolar depression (December 2021, as monotherapy and adjunctive therapy) [1], reflects a broadening understanding of its therapeutic utility. This expansion is likely driven by its complex pharmacology that extends beyond simple dopamine D₂ receptor antagonism, engaging multiple neurotransmitter systems relevant to the pathophysiology of both psychotic and mood disorders.[8]

1.2 Key Identifying Information

The fundamental identifying details for lumateperone are consolidated in Table 1. This information is crucial for unambiguous identification by healthcare professionals, researchers, and regulatory bodies, facilitating database searches, literature reviews, and precise communication regarding the compound.

Table 1: Lumateperone - Key Identifying Information

Attribute	Details	Reference(s)
Generic Name	Lumateperone	User Query
Brand Name	Caplyta®	1
DrugBank ID	DB06077	User Query
CAS Number	313368-91-1	User Query, 13
Type	Small Molecule	User Query
Developer	Originally: Intra-Cellular Therapies, Inc. <br> Current: Johnson & Johnson (following acquisition of Intra-Cellular Therapies, Inc., completed April 2, 2025; operates as a unit within Johnson & Johnson Innovative Medicine)	1
Chemical Name (IUPAC)	1-(4-Fluorophenyl)-4-hexadeca-5,7,9(16)-trien-12-yl]butan-1-one	13
Molecular Formula	C<sub>24</sub>H<sub>28</sub>FN<sub>3</sub>O	13

2. Pharmacological Profile

2.1 Mechanism of Action

Lumateperone's therapeutic efficacy is derived from its sophisticated multi-target engagement strategy, which involves the simultaneous and nuanced modulation of dopaminergic, serotonergic, and glutamatergic neurotransmitter systems.[3] This complex pharmacology distinguishes it from many conventional antipsychotics that primarily target dopamine D₂ receptors.

Serotonin System Modulation:

A cornerstone of lumateperone's action is its potent antagonism at serotonin 5-HT_2A receptors, evidenced by a high binding affinity (K_i = 0.54 nM).10 This affinity is approximately 60 times greater than its affinity for dopamine D₂ receptors.10 Such potent 5-HT_2A antagonism is a hallmark of atypical antipsychotics and is believed to contribute significantly to antipsychotic efficacy, particularly in addressing negative symptoms, while concurrently reducing the risk of EPS and hyperprolactinemia commonly associated with D₂ blockade.10

Furthermore, lumateperone exhibits moderate binding affinity for the serotonin transporter (SERT), with reported K_i values of 33 nM 11 or 62 nM.10 This inhibition of serotonin reuptake, especially when combined with its 5-HT_2A antagonism, is thought to play a crucial role in its efficacy for depressive symptoms, making it suitable for its indication in bipolar depression.10 The combined actions on 5-HT_2A receptors and SERT may offer synergistic antidepressant effects, potentially addressing the affective components of both schizophrenia and bipolar disorder more comprehensively than agents with more restricted serotonergic actions.

Dopamine System Modulation:

Lumateperone interacts with the dopamine system in a multifaceted manner. It functions as a dopamine D₂ receptor presynaptic partial agonist and postsynaptic antagonist (K_i = 32 nM).10 This dual action is theorized to stabilize dopamine neurotransmission. As a presynaptic partial agonist, it can modulate dopamine release, thereby preventing excessive dopaminergic hyperactivity (often linked to the positive symptoms of schizophrenia) without inducing profound dopaminergic hypoactivity (which can exacerbate negative symptoms and cognitive impairment).10

A critical aspect of its dopaminergic action is its regional selectivity. Lumateperone preferentially targets D₂ receptors in the mesolimbic and mesocortical brain pathways, which are central to psychosis and mood regulation. Conversely, it demonstrates lower affinity for D₂ receptors in the nigrostriatal pathway, the region primarily involved in motor control. This selectivity is a key factor contributing to its observed lower liability for EPS.10 The significantly higher affinity of lumateperone for 5-HT_2A receptors over D₂ receptors (K_i ratio ~1:60) likely underpins this favorable EPS profile, as potent 5-HT_2A blockade can mitigate some effects of D₂ blockade in the nigrostriatal pathway, a principle of atypicality that lumateperone appears to leverage effectively.10

Lumateperone also modulates dopamine D₁ receptor-mediated pathways, with a K_i of 52 nM for D₁ receptors.10 This interaction is instrumental in its indirect effects on the glutamate system.

Glutamate System Modulation:

Uniquely among currently available antipsychotics, lumateperone has been shown to enhance neurotransmission mediated by both N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors.8 This effect is not achieved through direct binding to glutamate receptors but is believed to be an indirect consequence of its D₁ receptor agonism and SERT inhibition. These actions synergistically lead to increased levels of dopamine and glutamate in the medial prefrontal cortex (mPFC), a brain region crucial for cognitive functions and executive control.10

Deficiencies in NMDA receptor-mediated glutamatergic neurotransmission are strongly implicated in the pathophysiology of cognitive impairments and negative symptoms in schizophrenia. Lumateperone's capacity to enhance glutamate release via D₁ agonism offers a novel and potentially more nuanced pharmacological strategy to address these often treatment-resistant symptom domains, distinguishing it from traditional antipsychotics.10 This indirect modulation may provide a safer approach than direct glutamate receptor agonism, which has faced developmental challenges.

Minimal Affinity for Other Receptors and Clinical Implications:

Lumateperone exhibits negligible binding affinity for H₁ histaminergic, 5-HT_2C serotonergic, and muscarinic cholinergic receptors.10 This "cleaner" receptor profile is clinically significant because it predicts a lower incidence of common and burdensome antipsychotic-related side effects. Specifically, the lack of affinity for H₁ and 5-HT_2C receptors reduces the likelihood of sedation and weight gain, while minimal interaction with muscarinic receptors lessens the risk of anticholinergic side effects such as dry mouth, constipation, blurred vision, and cognitive impairment. This contributes substantially to lumateperone's overall favorable tolerability.10

2.2 Receptor Binding Profile

The specific binding affinities of lumateperone for key neurotransmitter receptors and transporters are summarized in Table 2. These quantitative data provide the pharmacological basis for its mechanism of action and help to explain its clinical profile, including its efficacy and side-effect liability.

Table 2: Lumateperone Receptor Binding Affinities (K_i values)

Receptor/Transporter	K<sub>i</sub> Value (nM)	Reference(s)
Serotonin 5-HT<sub>2A</sub> Receptor	0.54	10
Dopamine D<sub>2</sub> Receptor	32	10
Serotonin Transporter (SERT)	33 / 62	11 / 10
Dopamine D<sub>1</sub> Receptor	52	10
H<sub>1</sub> Histaminergic Receptor	Negligible affinity	10
5-HT<sub>2C</sub> Serotonergic Receptor	Negligible affinity	10
Muscarinic Cholinergic Receptors	Negligible affinity	10

Note: For SERT, K_i values of 33 nM [11] and 62 nM [10] have been reported, both indicating moderate affinity.

2.3 Pharmacokinetics

The pharmacokinetic profile of lumateperone has been characterized in adults.

Absorption:

Following oral administration, lumateperone is rapidly absorbed, with median T_max (time to peak plasma concentration) achieved within 1 to 2 hours.6 With once-daily dosing, pharmacokinetic steady-state concentrations are typically reached in approximately 5 days.10 The absolute oral bioavailability of lumateperone is relatively low, reported at 4.4% 12, suggesting significant first-pass metabolism.

Lumateperone can be administered with or without food.13 However, the presence of food, particularly high-fat meals, increases the extent and slows the rate of absorption. Compared to fasted conditions, low-, moderate-, and high-fat meals increased lumateperone AUC_(0-∞) by 33%, 41%, and 66%, respectively. Correspondingly, C_max increased by 46%, 52%, and 67%, and T_max was prolonged from 2 hours (fasted) to 3 hours (low-fat), 4 hours (moderate-fat), and 5 hours (high-fat).13 This food effect, while notable, is accommodated by the flexible dosing recommendations.

Distribution:

Lumateperone is highly bound to human plasma proteins (≥98.9%), primarily to albumin and α1-acid glycoprotein, and this binding is independent of its plasma concentration. The apparent volume of distribution (Vd/F) following a 50 mg once-daily dose is estimated to be 17.4 L, based on population pharmacokinetic analysis.

Metabolism:

Lumateperone undergoes extensive metabolism through multiple pathways.7 The primary route of metabolism is glucuronidation via UGT1A1, with a substantial contribution from oxidative metabolism mediated by CYP3A4. Other enzymes involved to a lesser extent include CYP2C8, CYP1A2, other UGT isoenzymes (such as UGT1A3 and UGT1A9), and aldo-keto reductase isoenzymes 13, S_S19, 27. The significant role of CYP3A4 and UGT1A1 in its clearance makes lumateperone susceptible to drug-drug interactions with modulators of these enzymes.

Excretion:

The terminal elimination half-life (t_1/2) of lumateperone is approximately 18 hours 15, with other reports indicating a range of 13 to 29 hours. This half-life supports a once-daily dosing regimen. Following a single oral dose of radiolabeled lumateperone, approximately 53% of the total radioactivity was recovered in feces (primarily as unchanged drug) and 31% in urine (predominantly as metabolites: an ether glucuronide accounted for 18.9% of the total dose, a metabolite formed by oxidation at the benzylic carbon for 3.0%, and its hydrolytic N-dealkylation product for 3.6%). Renal elimination of unchanged lumateperone is minimal (<1% of the dose). The apparent clearance (CL/F) of lumateperone is approximately 1.0 L/h.

The pharmacokinetic characteristics of lumateperone are summarized in Table 3.

Table 3: Summary of Lumateperone Pharmacokinetic Parameters

Parameter	Value	Reference(s)
T<sub>max</sub> (Median)	1-2 hours (fasted)	6
	3-5 hours (with low to high-fat meal)	13
Oral Bioavailability	4.4%	12
Effect of Food (vs. Fasted)	AUC<sub>(0-∞)</sub> ↑ by 33% (low-fat), 41% (mod-fat), 66% (high-fat) <br> C<sub>max</sub> ↑ by 46% (low-fat), 52% (mod-fat), 67% (high-fat)	13
Protein Binding	≥98.9% (primarily albumin, α1-acid glycoprotein)	S_S260
Apparent Volume of Distribution (Vd/F)	17.4 L	S_S260
Terminal Half-life (t<sub>1/2</sub>)	Approx. 18 hours (range 13-29 hours)	S_S31, S_S27, S_S260
Apparent Clearance (CL/F)	Approx. 1.0 L/h	S_S260
Primary Metabolic Pathways	Glucuronidation (UGT1A1 primarily, also UGT1A3, UGT1A9), Oxidation (CYP3A4 primarily, also CYP2C8, CYP1A2), Aldo-keto reduction	S_S3, 13, S_S19, 27, S_S260
Primary Routes of Excretion (of total dose)	Feces: 53% (mostly unchanged drug) <br> Urine: 31% (as metabolites; <1% unchanged)	S_S260

The pharmacokinetic profile, particularly the ~18-hour half-life and achievement of steady state within 5 days, strongly supports the convenient once-daily dosing regimen. This simplicity is a notable clinical advantage, enhancing the potential for patient adherence in chronic conditions like schizophrenia and bipolar disorder, where complex medication schedules can be a barrier to effective long-term management.

3. Clinical Efficacy

3.1 Schizophrenia

Lumateperone, administered at a dose of 42 mg once daily, has demonstrated statistically significant and clinically meaningful efficacy in the treatment of adults experiencing an acute exacerbation of schizophrenia.[1] Its efficacy has been established in pivotal, randomized, double-blind, placebo-controlled, multicenter inpatient trials.[12]

Pivotal Clinical Trials (Study 1/NCT01499563 & Study 2/NCT02282761):

The primary efficacy endpoint in these studies was the change from baseline in the Positive and Negative Syndrome Scale (PANSS) total score at Week 4 compared to placebo. The PANSS is a 30-item clinician-rated scale used to measure the severity of schizophrenia symptoms, with scores ranging from 30 to 210; higher scores indicate greater overall symptom severity.16

• Study 1 Results (N=335):
• Patients were generally moderately to markedly ill, with a median age of 42 years (17% female; 19% Caucasian, 78% African American).[16]
• Baseline PANSS Total Scores (mean): Lumateperone 42 mg: 88.1; Risperidone 4 mg (active comparator): 86.1; Placebo: 86.3.[16]
• At Week 4, lumateperone 42 mg produced a mean reduction of -13.2 points in PANSS total score, compared to a -7.4 point reduction for placebo. This resulted in a Least Squares Mean Difference (LSMD) versus placebo of -5.8 points, indicating statistically superior improvement with lumateperone.[1616]
• Risperidone 4 mg, included for assay sensitivity, showed a mean reduction of -13.4 points. The study was not designed for direct efficacy comparison between lumateperone and risperidone.[16]
• The 84 mg dose of lumateperone tested in this study did not demonstrate a statistically significant effect compared to placebo.[16]
• Study 2 Results (N=450):
• Patients were generally moderately to markedly ill, with a median age of 44 years (23% female; 26% Caucasian, 66% African American).[16]
• Baseline PANSS Total Scores (mean): Lumateperone 42 mg: 90.0; Placebo: 89.0.[16]
• At Week 4, lumateperone 42 mg demonstrated a statistically significant improvement in PANSS total score compared to placebo, with an LSMD of -4.2 points (p<0.05).[16]
• An early onset of action was suggested, with lumateperone 42 mg showing separation from placebo in PANSS total score reduction as early as Week 1. However, these earlier time points were not powered for statistical comparison and are considered descriptive.[16]
• The 28 mg dose of lumateperone tested in this study did not show a statistically significant effect versus placebo.[16]

The consistent efficacy of the 42 mg dose across these two pivotal trials, while other doses (28 mg and 84 mg) did not consistently outperform placebo, strongly supports 42 mg as the optimal therapeutic dose for acute schizophrenia, suggesting a well-defined therapeutic window.[16] The inclusion of risperidone in Study 1, showing a similar magnitude of PANSS reduction, validates the trial's ability to detect an antipsychotic effect and, when considered with lumateperone's distinct safety profile, highlights its potential as a valuable alternative.[16]

PANSS Subscales:

Lumateperone treatment was associated with improvements across the various domains of schizophrenia symptoms, including the PANSS positive subscale (e.g., delusions, hallucinations, conceptual disorganization), negative subscale (e.g., blunted affect, emotional withdrawal, poor rapport, lack of spontaneity), and general psychopathology subscale (e.g., anxiety, tension, depression, poor attention).17

Secondary Efficacy Endpoints:

In Study 2, the Clinical Global Impression-Severity (CGI-S) score was a key secondary endpoint. Lumateperone 42 mg resulted in a statistically significant improvement in the CGI-S score compared to placebo at Week 4. Patients receiving lumateperone showed a mean improvement of -0.8 points from a baseline mean of 4.8, compared to -0.5 points for placebo (LSMD -0.3; p<0.05).16 The CGI-S is a 7-point scale where clinicians rate the patient's overall illness severity.16

Long-term Efficacy/Relapse Prevention:

Further supporting its utility in schizophrenia, positive topline results evaluating the efficacy and safety of lumateperone for the prevention of relapse in adult patients with schizophrenia were announced in November 2024.18

Table 4: Summary of Efficacy in Pivotal Schizophrenia Trials (Lumateperone 42 mg vs. Placebo)

Trial Identifier	Primary Endpoint (PANSS Total Score Change from Baseline at Week 4)	Baseline PANSS Total Score (Mean)	Change for Lumateperone 42 mg (Mean)	Change for Placebo (Mean)	LSMD vs. Placebo (Points)	p-value	Key Secondary Endpoint (CGI-S Change from Baseline at Week 4)	Baseline CGI-S (Mean)	CGI-S Change Lumateperone 42 mg (Mean)	CGI-S Change Placebo (Mean)	LSMD vs. Placebo (Points)	p-value
Study 1 (NCT01499563)	Change in PANSS Total Score	LMT: 88.1 <br> PLB: 86.3	-13.2	-7.4	-5.8	Significant*	Not specified as key secondary in snippet	-	-	-	-	-
Study 2 (NCT02282761)	Change in PANSS Total Score	LMT: 90.0 <br> PLB: 89.0	Not directly stated, but LSMD given	Not directly stated	-4.2	p<0.05	Change in CGI-S Score	LMT: 4.8 <br> PLB: 4.8	-0.8	-0.5	-0.3	p<0.05

*LMT: Lumateperone; PLB: Placebo. p-value for Study 1 primary endpoint implied by superiority but not explicitly stated in.[16]

3.2 Bipolar Depression

Lumateperone, at a dose of 42 mg once daily, is FDA-approved for the treatment of depressive episodes associated with bipolar I or bipolar II disorder in adults. It can be used as monotherapy or as adjunctive therapy with lithium or valproate.[1] This dual approval for both bipolar I and II depression is a notable feature, as lumateperone is one of only four treatments with this broad indication from the FDA.[2]

Monotherapy Trial (Study 404 / NCT03249376):

This was a Phase 3, randomized, double-blind, placebo-controlled outpatient trial conducted over 6 weeks in patients with a major depressive episode (MDE) associated with bipolar I or bipolar II disorder.19

• Primary Endpoint: The primary efficacy measure was the change from baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score at Day 43 (Week 6).[19]
• MADRS Total Score Results: Lumateperone 42 mg demonstrated statistically significant improvement in MADRS total score compared to placebo.[19]
• In patients with mixed features (defined by Young Mania Rating Scale items): The LSMD versus placebo was -4.4 points (p <.01).[19]
• In patients without mixed features: The LSMD versus placebo was -4.2 points (p <.001).[19] The efficacy in patients with mixed features is clinically important, as this presentation can complicate treatment and is often associated with a poorer prognosis.[19]
• Early Onset of Action: Clinically meaningful improvement in MADRS scores was observed as early as Week 1 and was maintained throughout the 6-week treatment duration.[6]
• Secondary Endpoints (Study 404):
• Clinical Global Impression Scale-Bipolar Version-Severity (CGI-BP-S) total score: Lumateperone 42 mg showed statistically significant improvement compared to placebo.[19]
• Patients with mixed features: LSMD = -0.7 (p <.05).[19]
• Patients without mixed features: LSMD = -1.0 (p <.001).[19]
• Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF) percent score: In patients with mixed features, lumateperone significantly improved the Q-LES-Q-SF percent score at Day 43 compared to placebo (LSMD = 5.9, p <.05).[19]

Adjunctive Therapy Trial (with lithium or valproate):

This randomized, placebo-controlled clinical trial evaluated lumateperone over 6 weeks as adjunctive therapy in patients with bipolar I or bipolar II disorder experiencing an MDE who had an inadequate therapeutic response to lithium or valproate alone.20

• Primary Endpoint: Change from baseline to Day 43 in MADRS Total score.[20]
• MADRS Total Score Results: Adjunctive lumateperone 42 mg demonstrated significantly greater improvement in MADRS Total score compared with adjunctive placebo (LSMD vs. placebo = -2.4; p = 0.02).[20]
• The adjunctive lumateperone 28 mg dose showed a numerical improvement but did not achieve statistical significance compared to placebo.[20]
• Key Secondary Endpoint (CGI-BP-S depression subscore): Adjunctive lumateperone 42 mg resulted in a significantly greater improvement in the CGI-BP-S depression subscore compared to adjunctive placebo (LSMD = -0.3; p = 0.01).[20]

The consistent efficacy of the 42 mg dose in both monotherapy and adjunctive settings for bipolar depression, similar to its efficacy in schizophrenia, reinforces this as the established therapeutic dose across its approved indications.[19]

Table 5: Summary of Efficacy in Pivotal Bipolar Depression Trials (Lumateperone 42 mg vs. Placebo)

Trial Setting / Identifier	Primary Endpoint (MADRS Total Score Change from Baseline at Week 6)	LSMD vs. Placebo (Points)	p-value	Key Secondary Endpoint (CGI-BP-S Change from Baseline at Week 6)	LSMD vs. Placebo (Points)	p-value
Monotherapy (Study 404 / NCT03249376)				(CGI-BP-S Total Score)
- With Mixed Features	Change in MADRS Total Score	-4.4	<.01	Change in CGI-BP-S Total Score	-0.7	<.05
- Without Mixed Features	Change in MADRS Total Score	-4.2	<.001	Change in CGI-BP-S Total Score	-1.0	<.001
Adjunctive Therapy (to Lithium/Valproate)	Change in MADRS Total Score	-2.4	0.02	(CGI-BP-S Depression Subscore)	-0.3	0.01

MADRS: Montgomery-Åsberg Depression Rating Scale; CGI-BP-S: Clinical Global Impression Scale-Bipolar Version-Severity; LSMD: Least Squares Mean Difference.

4. Safety and Tolerability

4.1 Overview

Lumateperone is generally well-tolerated across its approved indications for schizophrenia and bipolar depression.[1] A key feature of its safety profile is the low incidence of extrapyramidal symptoms (EPS), including akathisia, and minimal effects on metabolic parameters (such as weight, glucose, and lipids) and prolactin levels, with rates often similar to those observed with placebo.[3] In clinical studies, no single adverse reaction leading to treatment discontinuation occurred at a rate greater than 2% in patients treated with Caplyta.[4]

4.2 Common Adverse Events

The most frequently reported adverse events associated with lumateperone treatment are generally mild to moderate in severity.

• Schizophrenia Trials: The most common adverse reactions (≥5% and at least twice the rate of placebo) reported with lumateperone 42 mg versus placebo were somnolence/sedation (24% vs. 10%) and dry mouth (6% vs. 2%). Somnolence was predominantly mild in nature.[4]
• Bipolar Depression Trials (Monotherapy & Adjunctive Therapy):
• Monotherapy (Lumateperone 42 mg vs. Placebo): Somnolence/sedation (13% vs. 3%), dizziness (8% vs. 4%), nausea (8% vs. 3%), and dry mouth (5% vs. 1%).[4]
• Adjunctive Therapy (Lumateperone 42 mg + Lithium/Valproate vs. Placebo + Lithium/Valproate): Somnolence/sedation (13% vs. 3%), dizziness (11% vs. 2%), nausea (9% vs. 4%), and dry mouth (5% vs. 1%).[4] In both bipolar depression settings, somnolence was predominantly mild.[4]
• Headache was also reported, for instance, at a rate of 5.3% in an open-label schizophrenia study.[5]

Table 6: Common Treatment-Emergent Adverse Events (TEAEs) for Lumateperone 42 mg (Incidence ≥5% in any trial and >Placebo)

Adverse Event	Indication(s)	Lumateperone 42 mg Incidence (%)	Placebo Incidence (%)	Reference(s)
Somnolence/Sedation	Schizophrenia	24	10	4
	Bipolar Depression (Monotherapy)	13	3	4
	Bipolar Depression (Adjunctive)	13	3	4
Dry Mouth	Schizophrenia	6	2	4
	Bipolar Depression (Monotherapy)	5	1	4
	Bipolar Depression (Adjunctive)	5	1	4
Dizziness	Bipolar Depression (Monotherapy)	8	4	4
	Bipolar Depression (Adjunctive)	11	2	4
Nausea	Bipolar Depression (Monotherapy)	8	3	4
	Bipolar Depression (Adjunctive)	9	4	4
Headache	Schizophrenia (Open-label study)	5.3	N/A (Open-label)	5

4.3 Warnings and Precautions

Lumateperone, like other antipsychotic medications, carries several warnings and precautions that clinicians should be aware of.[4]

• Boxed Warnings:
• Increased Mortality in Elderly Patients with Dementia-Related Psychosis: Antipsychotic drugs are associated with an increased risk of death in elderly patients with dementia-related psychosis. Lumateperone is not approved for the treatment of patients with dementia-related psychosis.[4]
• Suicidal Thoughts and Behaviors: Antidepressant medicines, including those used for bipolar depression, may increase the risk of suicidal thoughts and actions in some children, adolescents, and young adults, particularly within the first few months of treatment or when the dose is changed. Patients and caregivers should monitor for new or worsening depression symptoms or suicidality.[21]
• Cerebrovascular Adverse Reactions: An increased incidence of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack) has been observed in elderly patients with dementia-related psychosis treated with antipsychotics.[4]
• Neuroleptic Malignant Syndrome (NMS): NMS is a rare but potentially fatal reaction associated with antipsychotic drugs, characterized by hyperpyrexia, muscle rigidity, delirium, autonomic instability, elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If NMS is suspected, lumateperone should be discontinued immediately, and intensive symptomatic treatment and monitoring provided.[4]
• Tardive Dyskinesia (TD): TD is a syndrome of potentially irreversible, involuntary, dyskinetic movements that can develop with antipsychotic treatment. The risk may increase with the duration of treatment and the total cumulative dose. TD can develop after brief treatment periods, even at low doses, or after treatment discontinuation. Lumateperone should be prescribed in a manner most likely to reduce the risk of TD, and treatment should be discontinued if clinically appropriate.[4]
• Leukopenia, Neutropenia, and Agranulocytosis: Cases of leukopenia and neutropenia, including fatal cases of agranulocytosis, have been reported with antipsychotic agents. Patients with a pre-existing low white blood cell (WBC) count or a history of drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy. Discontinuation of lumateperone should be considered if a clinically significant decline in WBC occurs in the absence of other causative factors.[4]
• Orthostatic Hypotension and Syncope: Lumateperone may cause orthostatic hypotension and syncope. Heart rate and blood pressure should be monitored, particularly in patients with known cardiovascular or cerebrovascular disease and those vulnerable to hypotension.[4]
• Falls: Somnolence, postural hypotension, and motor and/or sensory instability caused by lumateperone may lead to falls and, consequently, fractures and other injuries. Patients at risk for falls should be assessed.[4]
• Seizures: Lumateperone should be used cautiously in patients with a history of seizures or with conditions that lower the seizure threshold.[4]
• Potential for Cognitive and Motor Impairment: Lumateperone may impair judgment, thinking, or motor skills. Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that lumateperone therapy does not affect them adversely.[4]
• Body Temperature Dysregulation: Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate caution is advised when prescribing lumateperone to patients who will be experiencing conditions that may contribute to an elevation in core body temperature.[14]
• Dysphagia: Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Lumateperone should be used cautiously in patients at risk for aspiration pneumonia.[14]
• Hypersensitivity Reactions: Hypersensitivity reactions, including pruritus, rash (e.g., allergic dermatitis, papular rash, generalized rash), and urticaria, have been reported. Lumateperone is contraindicated in patients with a known hypersensitivity to lumateperone or any components of Caplyta.[4]

While these are standard class warnings for antipsychotics, the collective clinical trial data for lumateperone generally indicate a lower actual incidence of several of these concerns, such as TD, significant metabolic changes, and EPS, when compared to what might be anticipated from older antipsychotics or even some other atypical agents. This distinction reinforces the "favorable adverse effect profile" often attributed to lumateperone and is a critical consideration in clinical decision-making, especially for long-term treatment.

4.4 Metabolic Profile

Atypical antipsychotic agents have been associated with metabolic changes, including hyperglycemia, diabetes mellitus, dyslipidemia, and weight gain.[4] However, lumateperone has demonstrated a generally minimal impact on these metabolic parameters, with effects often similar to placebo in clinical trials.[3]

• Hyperglycemia and Diabetes Mellitus: Hyperglycemia, sometimes severe and associated with ketoacidosis, hyperosmolar coma, or death, has been reported in patients receiving atypical antipsychotics. Hyperglycemia has been reported in patients treated with lumateperone. Monitoring of fasting blood glucose concentrations is recommended before or soon after initiating lumateperone and periodically during long-term therapy.[4]
• Dyslipidemia: Undesirable changes in lipid parameters have been observed with antipsychotic agents. It is recommended to obtain a fasting lipid profile at baseline (prior to or soon after initiation of lumateperone) and monitor periodically during therapy.[4]
• Weight Gain: Weight gain is a common concern with antipsychotic agents. Baseline and frequent monitoring of body weight during therapy are recommended.[4] Lumateperone has been reported to cause nonsignificant weight increases [22] and has shown favorable outcomes regarding mean body weight, BMI, and waist circumference when compared to some other second-generation antipsychotics.[23] For instance, [22] notes that lumateperone is associated with nonsignificant weight increases, contrasting with the greater weight gain typically seen with agents like clozapine and olanzapine.
• Post-discontinuation Observation: An interesting finding from an open-label schizophrenia study was that two weeks after discontinuing Caplyta, there were observed increases in mean total cholesterol, LDL cholesterol, body weight, and prolactin levels.[5] This suggests that continued monitoring may be warranted even after cessation of the drug, and the mechanisms behind this rebound or unmasking effect require further elucidation.

Lumateperone's relatively neutral metabolic profile represents a significant clinical advantage. Metabolic syndrome is a major concern with many other atypical antipsychotics, profoundly impacting patients' long-term physical health and adherence to treatment. The differentiation of lumateperone in this regard, as highlighted in multiple sources [3], makes it a more attractive option for individuals at risk for, or concerned about, these metabolic complications.

Table 7: Metabolic Parameters - Changes from Baseline (Lumateperone 42 mg vs. Placebo, representative data)

(Specific pooled mean change data for all parameters across all indications were not consistently available in the provided snippets for a comprehensive comparative table. Clinical trial publications should be consulted for detailed breakdowns. The general finding is similarity to placebo for most metabolic parameters.4)

Parameter	Indication(s)	Lumateperone 42 mg Change from Baseline	Placebo Change from Baseline	Note	Reference(s)
Weight	Schiz, Bipolar Dep	Minimal / Similar to Placebo	Minimal	Generally low incidence of clinically significant weight gain.	4
Fasting Glucose	Schiz, Bipolar Dep	Minimal / Similar to Placebo	Minimal	Monitoring recommended.	4
Total Cholesterol	Schiz, Bipolar Dep	Minimal / Similar to Placebo	Minimal	Monitoring recommended. Increase noted post-discontinuation in one study.5	4
LDL Cholesterol	Schiz, Bipolar Dep	Minimal / Similar to Placebo	Minimal	Monitoring recommended. Increase noted post-discontinuation in one study.5	4
HDL Cholesterol	Schiz, Bipolar Dep	Minimal / Similar to Placebo	Minimal	Monitoring recommended.	4
Triglycerides	Schiz, Bipolar Dep	Minimal / Similar to Placebo	Minimal	Monitoring recommended.	4
Prolactin	Schiz, Bipolar Dep	Minimal / Similar to Placebo	Minimal	Low risk of hyperprolactinemia. Increase noted post-discontinuation in one study.5	4

Schiz: Schizophrenia; Bipolar Dep: Bipolar Depression.

4.5 Extrapyramidal Symptoms (EPS) Profile

Lumateperone is associated with a low incidence of EPS-related TEAEs, with rates generally similar to placebo and notably lower than some active comparators like risperidone in short-term studies.[3] This favorable EPS profile is a cornerstone of its clinical advantage.

• In pooled data from three short-term placebo-controlled schizophrenia studies (N=1073), the rates of EPS-related TEAEs were: lumateperone 42 mg (3.0%), placebo (3.2%), and risperidone 4 mg (active control in two studies, n=255) (6.3%).[24]
• The most common EPS-related TEAE reported with lumateperone was akathisia, occurring in 2.0% of patients. This was less frequent than with placebo (2.9%) or risperidone (4.7%).[24]
• The mean time to onset of EPS-related TEAEs was longer for the lumateperone group (17 days) compared to risperidone (9 days), and similar to placebo (14 days).[24]
• The use of anticholinergic medication (e.g., benztropine) to manage EPS was similar in the lumateperone (2.5%) and placebo (2.2%) groups, and substantially higher in the risperidone group (9.0%).[24] Propranolol use (often for akathisia) was similar across all groups (2.4–3.4%).[24]
• Standardized EPS rating scales (Abnormal Involuntary Movement Scale, Barnes Akathisia Rating Scale, Simpson-Angus Scale) showed no notable changes from baseline in either short-term (4-week) or long-term (1-year open-label) studies with lumateperone.[24]
• In the 1-year open-label study (Study 303, n=239 completers), where patients were switched from standard-of-care antipsychotics to lumateperone 42 mg, the incidence of EPS-related TEAEs remained low (0.8%). The mean time to onset of EPS was 38 days. Initiation rates for benztropine (1.7%) and propranolol (0.3%) were also low.[24]

The consistently low rates of EPS, comparable to placebo and significantly lower than an active comparator like risperidone, strongly support the pharmacological rationale behind lumateperone's design, particularly its D₂ receptor selectivity for mesolimbic/mesocortical pathways and its potent 5-HT_2A antagonism.[10] This profile is a key differentiator that can improve patient experience and adherence to long-term treatment.

4.6 Sexual Side Effects

Data from clinical trials in both bipolar depression and schizophrenia indicate that lumateperone has a low incidence of sexual side effects. Rates of adverse reactions such as erectile dysfunction, decreased libido, and abnormal orgasm were generally similar to or lower than those observed with placebo.[4] For example, in schizophrenia trials, erectile dysfunction was reported in 0.7% of lumateperone-treated patients versus 0.5% for placebo, with no reports of decreased libido for either group.[4] In bipolar depression monotherapy trials, erectile dysfunction was 0.0% for lumateperone vs 0.7% for placebo, and decreased libido was 1.1% vs 0.3%.[4] These low rates of sexual dysfunction are an important aspect of overall tolerability, positively impacting quality of life and potentially improving adherence to long-term antipsychotic therapy.

5. Dosage, Administration, and Drug Interactions

5.1 Recommended Dosing and Available Strengths

The recommended dosage for lumateperone (Caplyta) is straightforward for its approved indications in adults:

• Standard Dose: 42 mg administered once daily.[13] This dose is applicable for both schizophrenia and for depressive episodes associated with bipolar I or II disorder (as monotherapy or as adjunctive therapy with lithium or valproate).
• Titration: Dosage titration is not required when initiating therapy with lumateperone.[13] Patients can start at the therapeutic dose of 42 mg once daily.
• Available Capsule Strengths: Lumateperone is available as capsules containing 10.5 mg, 21 mg, and 42 mg of lumateperone (as lumateperone tosylate).[13] The lower strengths facilitate dose adjustments when necessary due to drug interactions or hepatic impairment.

5.2 Administration Guidelines

• Lumateperone should be administered orally once daily.[13]
• It can be taken with or without food, offering flexibility for patients.[13]
• The capsules should be swallowed whole and should not be opened, crushed, or chewed, as this method of administration has not been studied.[14]

5.3 Management in Special Populations

• Hepatic Impairment:
• Mild hepatic impairment (Child-Pugh class A): No dosage adjustment is necessary.[13]
• Moderate or severe hepatic impairment (Child-Pugh class B or C): The recommended dosage of lumateperone is reduced to 21 mg once daily.[13]
• Renal Impairment: No dosage adjustment is necessary for patients with renal impairment.[13]
• Pregnancy and Lactation: Newborn infants exposed to antipsychotic drugs, including lumateperone, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. Breastfeeding is not recommended while taking lumateperone.[5]
• Geriatric Patients: No specific dosage recommendations are provided, but like all antipsychotics, it carries a boxed warning regarding increased mortality in elderly patients with dementia-related psychosis.[4]

5.4 Clinically Significant Drug Interactions

Lumateperone is extensively metabolized, primarily by CYP3A4 and UGT enzymes, making it susceptible to interactions with drugs that modulate these pathways.[7] Careful medication review is essential.

• CYP3A4 Inhibitors:
• Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, clarithromycin): Concomitant use significantly increases lumateperone exposure (approximately fourfold with itraconazole). The recommended lumateperone dose should be reduced to 10.5 mg once daily.[13]
• Moderate CYP3A4 inhibitors (e.g., diltiazem, erythromycin, fluconazole, verapamil): Concomitant use increases lumateperone exposure (approximately twofold with diltiazem). The recommended lumateperone dose should be reduced to 21 mg once daily.[13]
• CYP3A4 Inducers:
• Strong or moderate CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin, St. John’s wort, efavirenz, bosentan, modafinil): Concomitant use can substantially decrease lumateperone exposure and potentially reduce its efficacy. Such concomitant use should be avoided.[527] provides an extensive list of these inducers.
• UGT Inhibitors: Lumateperone is also a substrate for UGT enzymes. Coadministration with UGT inhibitors should be avoided.[5]
• Anticholinergic Agents: Possible additive effects leading to disruption of body temperature regulation; use with caution.[13]
• Hypotensive Agents: Potential for additive hypotensive effects, which may result in orthostatic hypotension and syncope. Monitoring of orthostatic vital signs is recommended.[13]

The significant impact of CYP3A4 modulators on lumateperone exposure underscores the critical importance of thorough medication reconciliation and appropriate dose adjustments to prevent toxicity or loss of efficacy. While the "titration-free" nature of the 42 mg starting dose offers convenience, this must be balanced against the need for vigilance regarding potential interactions and patient-specific factors like hepatic function.

Table 8: Lumateperone Dosage Adjustments for Drug Interactions and Special Populations

Condition / Interacting Drug Class	Specific Examples (if applicable)	Recommended Lumateperone Dosage	Reference(s)
Drug Interactions
Strong CYP3A4 Inhibitors	Itraconazole, ketoconazole, clarithromycin	10.5 mg once daily	13
Moderate CYP3A4 Inhibitors	Diltiazem, erythromycin, fluconazole, verapamil	21 mg once daily	13
Strong/Moderate CYP3A4 Inducers	Rifampin, carbamazepine, phenytoin, St. John’s wort, efavirenz	Avoid concomitant use	5
UGT Inhibitors		Avoid concomitant use	5
Special Populations
Mild Hepatic Impairment	Child-Pugh Class A	No adjustment (42 mg once daily)	13
Moderate Hepatic Impairment	Child-Pugh Class B	21 mg once daily	13
Severe Hepatic Impairment	Child-Pugh Class C	21 mg once daily	13
Renal Impairment	All severities	No adjustment (42 mg once daily)	13

6. Regulatory Status and Development

6.1 FDA Approval History and Indications

Lumateperone, marketed as Caplyta®, was developed by Intra-Cellular Therapies, Inc..[1] It has received the following approvals from the U.S. Food and Drug Administration (FDA):

• Schizophrenia in adults: Approved in December 2019.[1] This approval was based on efficacy data from two pivotal Phase 3 trials (Study 1/NCT01499563 and Study 2/NCT02282761) and safety data from these and a third trial (NCT02469155).[12]
• Depressive episodes associated with Bipolar I or II disorder in adults: Approved in December 2021. This indication covers lumateperone as monotherapy and as adjunctive therapy with lithium or valproate.[1] With this, Caplyta became one of only four treatments FDA-approved for both bipolar I and bipolar II depression.[2]

Potential Future Indications:

Intra-Cellular Therapies submitted a supplemental New Drug Application (sNDA) to the FDA for Caplyta® as an adjunctive treatment for adults with Major Depressive Disorder (MDD). This submission was announced in December 2024 18, and the FDA accepted the sNDA for review in February 2025.28

6.2 EMA and Other Regulatory Jurisdictions

As of the latest available information from the provided sources, lumateperone's formal marketing authorization is primarily established in the United States.[1] There is no conclusive evidence from these documents indicating that lumateperone has received marketing authorization from the European Medicines Agency (EMA), or in other major jurisdictions such as Japan or Canada.[1] However, clinical trials, including those for bipolar depression, have been conducted at international sites.[1] This international trial presence suggests a potential strategy for future regulatory submissions in these regions, although a staggered approach, prioritizing the U.S. market first, is common.

6.3 Developer and Commercialization

Lumateperone (Caplyta®) was originally developed by Intra-Cellular Therapies, Inc..1

A significant development in its commercialization occurred with the acquisition of Intra-Cellular Therapies, Inc. by Johnson & Johnson. This transaction was completed on April 2, 2025, with Intra-Cellular Therapies subsequently operating as a business unit within Johnson & Johnson Innovative Medicine.18

This acquisition is viewed as a strategic move for Johnson & Johnson, expected to be a near- and long-term growth catalyst by strengthening its neuroscience portfolio.25 The transaction is anticipated to accelerate Johnson & Johnson's sales growth in 2025.28 The backing by a major pharmaceutical company like Johnson & Johnson signifies strong confidence in lumateperone's clinical value and market potential. This could lead to expanded research programs, development into further indications, and broader global commercialization efforts, leveraging Johnson & Johnson's extensive resources and global reach.

7. Conclusion and Future Perspectives

7.1 Summary of Key Attributes

Lumateperone (Caplyta®) has emerged as a significant advancement in the pharmacotherapy of schizophrenia and bipolar depression. Its key distinguishing features include:

• Unique Multi-Modal Mechanism of Action: Lumateperone simultaneously modulates serotonin, dopamine, and glutamate neurotransmitter systems. This includes potent serotonin 5-HT_2A antagonism, D₂ presynaptic partial agonism and postsynaptic antagonism with mesolimbic/mesocortical selectivity, moderate SERT inhibition, and D₁-dependent enhancement of NMDA/AMPA neurotransmission.[8]
• Established Efficacy: Clinical trials have demonstrated its efficacy in reducing symptoms of acute schizophrenia (as measured by PANSS) and depressive episodes in both bipolar I and II disorder (as measured by MADRS and CGI-BP-S).[16]
• Favorable Safety and Tolerability Profile: Lumateperone is generally well-tolerated, with a notably low incidence of extrapyramidal symptoms, akathisia, weight gain, and adverse metabolic changes (effects on glucose and lipids), often comparable to placebo and favorable when contrasted with some other antipsychotics. It also has minimal impact on prolactin levels.[3]

7.2 Place in Therapy

Lumateperone represents a valuable treatment option within the current psychopharmacological armamentarium:

• For Schizophrenia: It is a compelling choice, particularly for patients where tolerability is a primary concern, especially regarding EPS and metabolic side effects. Its efficacy in acute exacerbations is well-documented.[16]
• For Bipolar Depression: Its approval for both bipolar I and II depression, as monotherapy or adjunctive therapy, and its demonstrated efficacy in patients with mixed features, fills an important niche.[2] The once-daily, titration-free dosing further enhances its utility in this population.

The favorable side effect profile of lumateperone aligns with the broader goals of patient-centered care in psychiatry, aiming not only for symptom control but also for improved quality of life and long-term treatment adherence by minimizing the burden of adverse effects.

7.3 Future Perspectives

The development trajectory of lumateperone suggests several promising future directions:

• Indication Expansion: An sNDA for lumateperone as an adjunctive treatment for Major Depressive Disorder (MDD) is currently under FDA review.[18] If approved, this would significantly broaden its therapeutic applications.
• New Formulations/Indications: Phase 3 trials are underway to evaluate lumateperone in bipolar I disorder with manic episodes or mixed features (bipolar mania).[18] Additionally, positive topline results have been reported for its use in the prevention of relapse in schizophrenia.[18]
• Enhanced Commercialization and Research: The recent acquisition of Intra-Cellular Therapies by Johnson & Johnson is likely to provide substantial resources for further research, development into new indications or formulations, and expanded global market access.[25]
• Real-World Evidence: As lumateperone sees wider clinical use, the accumulation of real-world evidence will be crucial in further defining its long-term effectiveness, safety, and place in diverse patient populations and clinical scenarios.[1]

In conclusion, lumateperone represents a significant evolution in antipsychotic therapy, offering a unique pharmacological profile that translates into effective symptom management for schizophrenia and bipolar depression with an improved tolerability profile. Its ongoing development and the backing of a major pharmaceutical entity suggest a promising future for this agent in addressing the complex needs of individuals with serious mental illness.

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