What are the indications, dosing regimen, contraindications, and monitoring recommendations for Caplyta (lumateperone) in adults with schizophrenia and bipolar I depression?

Caplyta (Lumateperone) for Schizophrenia and Bipolar Depression

FDA-Approved Indications

Caplyta is FDA-approved for two specific indications in adults: schizophrenia and depressive episodes associated with bipolar I or II disorder (bipolar depression), either as monotherapy or as adjunctive therapy with lithium or valproate. 1

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Dosing Regimen

Standard Dosing

• The recommended dosage is 42 mg once daily, taken with or without food, and dose titration is not required. 1
• Treatment can be initiated at the full therapeutic dose without gradual escalation 1

Dose Adjustments for Drug Interactions

• When co-administered with strong CYP3A4 inhibitors, reduce the dose to 10.5 mg once daily. 1
• When co-administered with moderate CYP3A4 inhibitors, reduce the dose to 21 mg once daily. 1
• Avoid concomitant use with CYP3A4 inducers, as they may reduce lumateperone efficacy. 1

Hepatic Impairment

• For patients with moderate or severe hepatic impairment, the recommended dosage is 21 mg once daily. 1
• No dose adjustment is needed for mild hepatic impairment 1

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Contraindications

The only absolute contraindication is known hypersensitivity to lumateperone or any components of Caplyta. 1

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Boxed Warnings

Elderly Patients with Dementia-Related Psychosis

• Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at increased risk of death, and Caplyta is not approved for this population. 1

Suicidal Thoughts and Behaviors

• Antidepressants, including Caplyta when used for bipolar depression, increase the risk of suicidal thoughts and behaviors in pediatric and young adult patients. 1
• Closely monitor all antidepressant-treated patients for worsening depression and emergence of suicidal thoughts and behaviors. 1
• Safety and effectiveness have not been established in pediatric patients 1

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Critical Warnings and Precautions

Cerebrovascular Adverse Reactions

• There is an increased incidence of cerebrovascular adverse reactions (stroke and transient ischemic attack) in elderly patients with dementia-related psychosis. 1

Neuroleptic Malignant Syndrome (NMS)

• Manage NMS with immediate discontinuation of Caplyta and close monitoring. 1
• Monitor for hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability 1

Tardive Dyskinesia

• Discontinue treatment if clinically appropriate when tardive dyskinesia develops. 1
• Risk increases with duration of treatment and total cumulative dose 1

Metabolic Changes

• Monitor for hyperglycemia/diabetes mellitus, dyslipidemia, and weight gain during treatment. 1
• Lumateperone demonstrates placebo-level rates of weight gain and metabolic disruption in short-term trials (4-6 weeks) 2

Leukopenia, Neutropenia, and Agranulocytosis

• Perform complete blood counts (CBC) in patients with pre-existing low white blood cell count (WBC) or history of leukopenia or neutropenia. 1
• Consider discontinuing Caplyta if clinically significant decline in WBC occurs in the absence of other causative factors. 1

Orthostatic Hypotension and Syncope

• Monitor heart rate and blood pressure, and warn patients with known cardiovascular or cerebrovascular disease and those at risk of dehydration or syncope. 1

Seizures

• Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold. 1

Cognitive and Motor Impairment

• Use caution when operating machinery, as Caplyta may cause somnolence and sedation. 1

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Monitoring Recommendations

Baseline Assessment

• Complete blood count if patient has pre-existing low WBC or history of leukopenia/neutropenia 1
• Fasting glucose and lipid panel to establish metabolic baseline 1
• Blood pressure and heart rate 1
• Weight and body mass index 1
• Assessment for suicidal ideation, particularly in young adults 1

Ongoing Monitoring

• Monitor for suicidal thoughts and behaviors at every visit, especially during the first few months of treatment and after dose changes. 1
• Assess for extrapyramidal symptoms and tardive dyskinesia at each visit 1
• Monitor weight, fasting glucose, and lipid panel periodically during treatment 1
• Monitor blood pressure and heart rate, particularly in patients with cardiovascular disease 1
• Repeat CBC if clinically indicated based on symptoms or initial abnormalities 1

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Common Adverse Reactions

Schizophrenia

• The most common adverse reactions (incidence >5% and greater than twice placebo) are somnolence/sedation and dry mouth. 1

Bipolar Depression

• The most common adverse reactions (incidence >5% and greater than twice placebo) are somnolence/sedation, dizziness, nausea, and dry mouth. 1

Mixed Features (MDD or Bipolar Depression)

• In patients with mixed features, treatment-emergent adverse events (≥5%, twice placebo) included somnolence (12.5%), dizziness (12.0%), and nausea (9.9%) 3
• There were no mania/hypomania treatment-emergent adverse events with lumateperone and minimal extrapyramidal symptoms or metabolic risk in patients with mixed features. 3

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Unique Safety Profile

Lumateperone exhibits a favorable tolerability and safety profile with placebo-level rates of weight gain, metabolic disruption, akathisia, extrapyramidal side effects, and prolactin elevation across short-term trials. 2

• This exceptional tolerability is due to less than 50% dopamine D2 receptor occupancy, which allows for both antipsychotic and antidepressant effects at the same dose without producing dopamine-related side effects 4
• Lumateperone achieves therapeutic benefits with minimal dopamine blockade-related side effects 4

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Mechanism of Action

• Lumateperone is a first-in-class selective and simultaneous modulator of serotonin, dopamine, and glutamate neurotransmission. 5
• It has full antagonist effects at post-synaptic D2 receptors and partial agonist effects at presynaptic D2 receptors 4
• This pleiotropic mechanism of action is predictive of therapeutic benefits across multiple domains of psychopathology in schizophrenia (positive, negative, cognitive, and prosocial symptoms) 2
• Lumateperone also reduces proinflammatory cytokines and maintains blood-brain barrier integrity, which may contribute to its antidepressant effects 6

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Clinical Efficacy

Schizophrenia

• Lumateperone significantly reduces the severity of schizophrenia compared with placebo and should be conceptualized as a first-line treatment strategy for adults with schizophrenia. 2

Bipolar Depression

• Lumateperone is superior to placebo whether used alone or in combination with a mood stabilizer in patients with type I or type II bipolar disorder. 4
• It is now the only agent approved as an adjunct to mood stabilizers for bipolar II depression. 4

Mixed Features

• Lumateperone 42 mg significantly improved depression symptoms and disease severity in patients with MDD or bipolar depression with mixed features, with effect sizes of -0.64 to -0.67. 3
• Lumateperone significantly improved Clinical Global Impression Scale-Severity and Young Mania Rating Scale total scores at day 43 in populations with combined MDD/bipolar depression, individual MDD, and individual bipolar depression with mixed features 3

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Common Pitfalls to Avoid

• Do not use Caplyta in elderly patients with dementia-related psychosis due to increased mortality risk. 1
• Do not combine with strong CYP3A4 inducers, as this will reduce efficacy—avoid concomitant use entirely. 1
• Do not overlook dose reduction requirements when co-administering moderate or strong CYP3A4 inhibitors. 1
• Do not fail to monitor for suicidal ideation in young adults, particularly during the first few months of treatment. 1
• Do not assume dose titration is needed—Caplyta is initiated at the full therapeutic dose of 42 mg. 1