medication
Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to medical diagnosis, diagnose, cure, treat, or preventive medicine, prevent disease. Drug therapy (pharmaco ...
of the butyrophenone class. It is approved for the treatment of
schizophrenia
Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...
as well as bipolar depression, as either monotherapy or adjunctive therapy (with
lithium
Lithium (from , , ) is a chemical element; it has chemical symbol, symbol Li and atomic number 3. It is a soft, silvery-white alkali metal. Under standard temperature and pressure, standard conditions, it is the least dense metal and the ...
or valproate). It is developed by Intra-Cellular Therapies, licensed from
Bristol-Myers Squibb
The Bristol-Myers Squibb Company, doing business as Bristol Myers Squibb (BMS), is an American multinational pharmaceutical company. Headquartered in Princeton, New Jersey, BMS is one of the world's largest pharmaceutical companies and consist ...
. 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 depressive episodes associated with both bipolar I and II disorders. Part of the drug shows structural similarity to Pirlindole.
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 respo ...
(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
lithium
Lithium (from , , ) is a chemical element; it has chemical symbol, symbol Li and atomic number 3. It is a soft, silvery-white alkali metal. Under standard temperature and pressure, standard conditions, it is the least dense metal and the ...
number needed to treat
The number needed to treat (NNT) or number needed to treat for an additional beneficial outcome (NNTB) is an epidemiology, epidemiological measure used in communicating the effectiveness of a health-care intervention, typically a treatment with me ...
(NNT) for bipolar depression at a dose of 42 mg daily is 7 patients.
Adverse effects
The most common adverse effects (≥5%) were
somnolence
Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling aslee ...
antagonist
An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.5-HT2A receptors and binds to several
dopamine
Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...
receptors ( D1, D2, and D4) with moderate affinity. It has moderate
serotonin
Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...
transporter reuptake inhibition, which is partly responsible for its antidepressant effect in bipolar disorder and reduction of negative symptoms of schizophrenia. It may also inhibit dopamine transporter reuptake, but more evidence is needed to confirm this. It has additional off-target antagonism at α1 receptors, without appreciable antimuscarinic or antihistaminergic properties, limiting side effects associated with other atypical antipsychotics, notably
metabolic syndrome
Metabolic syndrome is a clustering of at least three of the following five medical conditions: abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides, and low serum high-density lipoprotein (HDL).
Metabolic syndro ...
aripiprazole
Aripiprazole, sold under the brand name Abilify, among others, is an atypical antipsychotic primarily used in the treatment of schizophrenia, bipolar disorder, and irritability associated with autism spectrum disorder; other uses include as ...
, lumateperone acts as a partial agonist at inhibitory D2
autoreceptor
An autoreceptor is a type of Receptor (biochemistry), receptor located in the cell membrane, membranes of neuron, nerve cells. It serves as part of a negative feedback loop in signal transduction. It is only sensitive to the neurotransmitters or ...
s and an antagonist at postsynaptic D2 receptors, thereby simultaneously reducing dopamine release and binding to postsynaptic receptors, respectively. However, lumateperone only occupies around 39% of D2 receptors—compared to at least 60-80% D2 occupancy for most antipsychotics to work for
psychosis
In psychopathology, psychosis is a condition in which a person is unable to distinguish, in their experience of life, between what is and is not real. Examples of psychotic symptoms are delusions, hallucinations, and disorganized or inco ...
—and displays regioselectivity for the
mesolimbic pathway
The mesolimbic pathway, sometimes referred to as the reward pathway, is a dopaminergic pathway in the brain. The pathway connects the ventral tegmental area in the midbrain to the ventral striatum of the basal ganglia in the forebrain. The v ...
, whose hyperactivity is responsible for the positive symptoms of schizophrenia. This reduces the risk of
extrapyramidal symptoms
Extrapyramidal symptoms (EPS) are signs and symptoms, symptoms that are wikt:archetypical, archetypically associated with the extrapyramidal system of the brain's cerebral cortex. When such symptoms are caused by medications or other drugs, they ...
(EPS) from reduced dopaminergic transmission in the nigrostriatal pathway.
A mechanism that is shared by all other atypical antipsychotics is antagonism of 5HT2A receptors, but, uniquely, lumateperone’s affinity for these receptors is 60x higher than its affinity for D2 receptors. This makes it a highly effective treatment for negative and cognitive symptoms of schizophrenia since 5HT2A antagonism increases dopamine release in the mesocortical pathway, which is hypoactive in those with schizophrenia.
Interestingly, lumateperone indirectly augments glutamatergic neurotransmission through its activity at D1 receptors, which causes
phosphorylation
In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols:
:
This equation can be writ ...
of GluN2B subunits of NMDA receptors in the mesolimbic pathway. This is significant since NMDA receptor hypofunction, reduced D1 binding, and glutamatergic abnormalities have been implicated in contributing to the cognitive and negative symptoms of schizophrenia.
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 is a mathematical and scientific description of exponential or gradual decay.
Half-life, half life or halflife may also refer to:
Film
* Half-Life (film), ''Half-Life'' (film), a 2008 independent film by Jennifer Phang
* ''Half Life: ...
of 18 hours. Lumateperone is a substrate for numerous metabolic enzymes, including various
glucuronosyltransferase
Uridine 5'-diphospho-glucuronosyltransferase ( UDP-glucuronosyltransferase, UDPGT or UGT) is a microsomal glycosyltransferase () that catalyzes the transfer of the glucuronic acid component of UDP-glucuronic acid to a small hydrophobic molecu ...
cytochrome P450
Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...
(CYP) enzymes (
CYP3A4
Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...
, 2C8, and 1A2).
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
lithium
Lithium (from , , ) is a chemical element; it has chemical symbol, symbol Li and atomic number 3. It is a soft, silvery-white alkali metal. Under standard temperature and pressure, standard conditions, it is the least dense metal and the ...
or valproate, 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.