Lumateperone, sold under the brand name Caplyta, is an

atypical antipsychotic The atypical antipsychotics (AAP), also known as second generation antipsychotics (SGAs) and serotonin–dopamine antagonists (SDAs), are a group of antipsychotic drugs (antipsychotic drugs in general are also known as major tranquilizers and ne ...

medication A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy ( pharmacotherapy) is an important part of the medical field and ...

of the

butyrophenone Butyrophenone is an organic compound with the formula C6H5C(O)C3H7. It is a colorless liquid. The butyrophenone structure—a ketone flanked by a phenyl ring and a butyl chain—forms the basis for many other chemicals containing various sub ...

class. It is approved for the treatment of

schizophrenia Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social wit ...

as well as

bipolar depression Bipolar disorder, previously known as manic depression, is a mental disorder characterized by periods of depression and periods of abnormally elevated mood that last from days to weeks each. If the elevated mood is severe or associated with ...

, as either monotherapy or adjunctive therapy (with

lithium Lithium (from el, λίθος, lithos, lit=stone) is a chemical element with the symbol Li and atomic number 3. It is a soft, silvery-white alkali metal. Under standard conditions, it is the least dense metal and the least dense solid ...

valproate Valproate (VPA) and its valproic acid, sodium valproate, and valproate semisodium forms are medications primarily used to treat epilepsy and bipolar disorder and prevent migraine headaches. They are useful for the prevention of seizures in those ...

). It is developed by Intra-Cellular Therapies, licensed from

Bristol-Myers Squibb The Bristol Myers Squibb Company (BMS) is an American multinational pharmaceutical company. Headquartered in New York City, BMS is one of the world's largest pharmaceutical companies and consistently ranks on the ''Fortune'' 500 list of the lar ...

. Lumateperone was approved for medical use in the United States in December 2019 with an initial indication for schizophrenia, and became available in February 2020. It has since demonstrated efficacy in bipolar depression and received FDA approval in December 2021 for that indication as well.

Medical uses

Schizophrenia

On December 20, 2019, the United States

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...

(FDA) approved lumateperone for the treatment of schizophrenia in adults.

Bipolar depression

In December 2021, the FDA approved lumateperone for the treatment of bipolar depression in adults as monotherapy and as adjunctive therapy with

. The

number needed to treat The number needed to treat (NNT) or number needed to treat for an additional beneficial outcome (NNTB) is an epidemiological measure used in communicating the effectiveness of a health-care intervention, typically a treatment with medication. The ...

(NNT) for bipolar depression at a dose of 42mg daily is 7 patients.

Pharmacology

Mechanism of action

Lumateperone acts as an antagonist of 5-HT_2A receptor and antagonizes several dopamine receptors ( D₁, D₂, and D₄) with lower affinity. It has moderate serotonin transporter reuptake inhibition, supporting its antidepressant properties. It has additional off-target antagonism at alpha-1 receptors, ''without'' appreciable antimuscarinic or antihistaminergic properties, limiting side effects associated with other atypical antipsychotics.

Pharmacokinetics

After taking the medication by mouth, lumateperone reaches maximum plasma concentrations within 1–2 hours and has a terminal elimination

half-life Half-life (symbol ) is the time required for a quantity (of substance) to reduce to half of its initial value. The term is commonly used in nuclear physics to describe how quickly unstable atoms undergo radioactive decay or how long stable at ...

of 18 hours. Lumateperone is a substrate for numerous metabolic enzymes, including various

glucuronosyltransferase Uridine 5'-diphospho-glucuronosyltransferase ( UDP-glucuronosyltransferase, UGT) is a microsomal glycosyltransferase () that catalyzes the transfer of the glucuronic acid component of UDP-glucuronic acid to a small hydrophobic molecule. This is ...

(UGT) isoforms (UGT1A1, 1A4, and 2B15),

aldo-keto reductase The aldo-keto reductase family is a family of proteins that are subdivided into 16 categories; these include a number of related monomeric NADPH-dependent oxidoreductases, such as aldehyde reductase, aldose reductase, prostaglandin F synthase, xy ...

(AKR) isoforms ( AKR1C1, 1B10, and 1C4), and

cytochrome P450 Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various co ...

(CYP) enzymes ( CYP3A4, 2C8, and

1A2 The 1A2 Key Telephone System is a business telephone system developed and distributed by the Western Electric, Western Electric Company for the Bell System. The 1A2 Key Telephone System is a modular system that provided flexible solutions for a ...

). Lumateperone does not cause appreciable inhibition of any common CYP450 enzymes. It is not a substrate for p-glycoprotein.

History

The FDA approved lumateperone based on evidence from three clinical trials (Trial 1/NCT01499563, Trial 2/NCT02282761 and Trial 3/NCT02469155) that enrolled 818 adult participants with schizophrenia. The trials were conducted at 33 sites in the United States. Trials 1 and 2 provided data on the benefits and side effects of lumateperone, and Trial 3 provided data on side effects only. Three trials provided data for the approval of lumateperone. In each trial, hospitalized participants with schizophrenia were randomly assigned to receive either lumateperone or a comparison treatment (placebo or active comparator) once daily for four weeks (Trials 1 and 2) or six weeks (Trial 3). Neither the participants nor the health care providers knew which treatment was being given until after the trials were completed. Trials 1 and 2 provided data for the assessment of benefits and side effects through four weeks of therapy. Benefit was assessed by measuring the overall improvement in the symptoms of schizophrenia. Trial 3 provided data for the assessment of side effects only during six weeks of therapy. Two Phase III lumateperone monotherapy studies were conducted and completed for the treatment of bipolar depression, those being trial Study 401 and Study 404. A third trial, Study 402, aims to test lumateperone in addition to

, the data pertaining this trial is due out in 2020. Study 401 was conducted solely in the United States while Study 404 was a global study and included patients from the US. Of the entire Study 404 population (381 patients), two-thirds were from Russia and Colombia. At the completion of the two monotherapy Phase III trials only Study 404 met its primary endpoint and one of its secondary endpoints. In Study 404, patients received 42 mg lumateperone once daily or placebo for six weeks. Study 404 patients saw an improvement of depressive symptoms compared to placebo as documented by a change in MADRS total score of 4.6.

References

External links

* {{Portal bar , Medicine Atypical antipsychotics Fluoroarenes Ketones