Lumateperone

{{Short description|Atypical antipsychotic}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Use dmy dates|date=October 2025}} {{Infobox drug | image = ITI-007.svg | image_class = skin-invert-image | width = 250px | alt = | caption =

<!-- Clinical data --> | pronounce = {{IPAc-en|ˌ|l|uː|m|ə|ˈ|t|ɛ|p|ə|r|oʊ|n}}<br />{{respell|LOO|mə|TE|pər|ohn}} | tradename = Caplyta | Drugs.com = {{drugs.com|monograph|lumateperone-tosylate}} | MedlinePlus = a620014 | DailyMedID = Lumateperone | pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> | pregnancy_AU_comment = | pregnancy_category = | routes_of_administration = By mouth | class = Atypical antipsychotic | ATC_prefix = N05 | ATC_suffix = AD10 | ATC_supplemental =

<!-- Legal status --> | legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled --> | legal_AU_comment = | legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F --> | legal_BR_comment = | legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII --> | legal_CA_comment = | legal_DE = <!-- Anlage I, II, III or Unscheduled --> | legal_DE_comment = | legal_NZ = <!-- Class A, B, C --> | legal_NZ_comment = | legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C --> | legal_UK_comment = | legal_US = Rx-only | legal_US_comment = <ref name="Caplyta FDA label" /> | legal_EU = | legal_EU_comment = | legal_UN = <!-- N I, II, III, IV / P I, II, III, IV --> | legal_UN_comment = | legal_status = <!-- For countries not listed above -->

<!-- Pharmacokinetic data --> | bioavailability = 4.4%<ref name="Caplyta FDA label" /> | protein_bound = 97.4%<ref name="Caplyta FDA label" /> | metabolism = Multiple UGTs, CYP450s, and AKR enzymes<ref name="Caplyta FDA label" /> | metabolites = | onset = | elimination_half-life = | duration_of_action = | excretion = <1% excreted unchanged in urine<ref name="Caplyta FDA label" />

<!-- Identifiers --> | CAS_number_Ref = {{cascite|correct|CAS}} | CAS_number = 313368-91-1 | PubChem = 9821941 | IUPHAR_ligand = | DrugBank = DB06077 | ChemSpiderID = 7997690 | UNII = 70BSQ12069 | KEGG = D11169 | ChEBI = | ChEMBL = | NIAID_ChemDB = | PDB_ligand = | synonyms = ITI-007; ITI-722

<!-- Chemical and physical data --> | IUPAC_name = 1-(4-fluorophenyl)-4-((6b''R'',10a''S'')-3-methyl-2,3,6b,9,10,10a-hexahydro-1''H''-pyrido[3',4':4,5]pyrrolo[1,2,3-''de'']quinoxalin-8(7''H'')-yl)-1-butanone | C=24 | H=28 | F=1 | N=3 | O=1 | SMILES = CN1CCN2c3c(cccc31)[C@@H]1CN(CCCC(=O)c3ccc(F)cc3)CC[C@@H]12 | StdInChI = 1S/C24H28FN3O/c1-26-14-15-28-21-11-13-27(16-20(21)19-4-2-5-22(26)24(19)28)12-3-6-23(29)17-7-9-18(25)10-8-17/h2,4-5,7-10,20-21H,3,6,11-16H2,1H3/t20-,21-/m0/s1 | StdInChI_comment = | StdInChIKey = HOIIHACBCFLJET-SFTDATJTSA-N | density = | density_notes = | melting_point = | melting_high = | melting_notes = | boiling_point = | boiling_notes = | solubility = | sol_units = | specific_rotation = }}

'''Lumateperone''', sold under the brand name '''Caplyta''', is an atypical antipsychotic medication of the pyridopyrroloquinoxaline and butyrophenone families. It is approved for the treatment of schizophrenia as well as bipolar depression, as either monotherapy or adjunctive therapy (with lithium or valproate),<ref name="Caplyta FDA label" /> and for major depressive disorder as an adjunctive therapy only (with an oral antidepressant).<ref name= "J&J MDD Approval Press Release">{{cite web | title = FDA approval of CAPLYTA® (lumateperone) has the potential to reset treatment expectations, offering hope for remission in adults with major depressive disorder | url = https://www.jnj.com/media-center/press-releases/fda-approval-of-caplyta-lumateperone-has-the-potential-to-reset-treatment-expectations-offering-hope-for-remission-in-adults-with-major-depressive-disorder | website = jnj.com | date = 6 November 2025 | publisher = Johnson & Johnson | access-date = 28 November 2025 }}</ref> It is developed by Intra-Cellular Therapies, licensed from Bristol-Myers Squibb.<ref name="CelanirePoli2014">{{cite book | veditors = Celanire S, Poli S | title = Small Molecule Therapeutics for Schizophrenia | pages = 31– | date = 13 October 2014 | url = https://books.google.com/books?id=HEzPBAAAQBAJ&pg=PA31 | publisher = Springer | isbn = 978-3-319-11502-3 }}</ref> Lumateperone was approved for medical use in the US in December 2019 with an initial indication for schizophrenia.<ref name= "FDA snapshot" /><ref name= "FDA approval" /> It became available in February 2020.<ref name= "Caplyta FDA label" />

== Medical uses == Lumateperone is indicated for the treatment of schizophrenia in adults;<ref name="Caplyta FDA label" /> and depressive episodes associated with bipolar I or II disorder (bipolar depression) in adults, as monotherapy and as adjunctive therapy with lithium or valproate.<ref name="Caplyta FDA label" />

=== Schizophrenia === In December 2019, the US Food and Drug Administration (FDA) approved lumateperone for the treatment of schizophrenia in adults.<ref name="FDA snapshot">{{cite web | title = Drug Trials Snapshots: Caplyta | date = 20 December 2019 | website = U.S. Food and Drug Administration (FDA) | url = https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-caplyta | archive-url = https://web.archive.org/web/20200804152617/https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-caplyta | archive-date = 4 August 2020 | access-date = 2 July 2020 }} {{PD-notice}}</ref><ref name="FDA approval">{{cite web | title = Drug Approval Package: Caplyta | date = 21 January 2020 | website = U.S. Food and Drug Administration (FDA) | url = https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/209500Orig1s000TOC.cfm | archive-url = https://web.archive.org/web/20200403061320/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/209500Orig1s000TOC.cfm | archive-date = 3 April 2020 | access-date = 1 July 2020 }}</ref><ref name="Caplyta PR">{{cite press release | title = FDA Approves Intra-Cellular Therapies' Novel Antipsychotic, Caplyta (lumateperone) for the Treatment of Schizophrenia in Adults | date = 23 December 2019 | publisher = Intra-Cellular Therapies Inc. | via = GlobeNewswire | url = http://www.globenewswire.com/news-release/2019/12/23/1963993/0/en/FDA-Approves-Intra-Cellular-Therapies-Novel-Antipsychotic-CAPLYTA-lumateperone-for-the-Treatment-of-Schizophrenia-in-Adults.html | access-date = 1 July 2020 }}</ref>

===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 or valproate.<ref name="Caplyta FDA label" /><ref>{{cite press release | title = Intra-Cellular Therapies Announces U.S. FDA Approval of Caplyta (lumateperone) for the Treatment of Bipolar Depression in Adults | date = 20 December 2021 | publisher = Intra-Cellular Therapies | via = GlobeNewswire | url = https://www.globenewswire.com/news-release/2021/12/20/2355071/0/en/Intra-Cellular-Therapies-Announces-U-S-FDA-Approval-of-CAPLYTA-lumateperone-for-the-Treatment-of-Bipolar-Depression-in-Adults.html | access-date = 13 October 2025 }}</ref>

===Major depressive disorder=== In November 2025, the FDA approved lumateperone for the treatment of major depressive disorder in adults as an adjunctive therapy with an oral antidepressant.<ref name="J&J MDD Approval Press Release" />

==Adverse effects== The most common adverse effects (≥5%) were somnolence and dry mouth.<ref name="Caplyta FDA label" />

Lumateperone is associated with a low rate of serum aminotransferase elevations during therapy, but has not been linked to instances of clinically apparent acute liver injury.<ref>{{cite book | chapter = Lumateperone | title = LiverTox: Clinical and Research Information on Drug-Induced Liver Injury | date = 2012 | pmid = 34648250 | publisher = National Institute of Diabetes and Digestive and Kidney Diseases | url = https://www.ncbi.nlm.nih.gov/books/NBK574493/ }} {{PD-notice}}</ref>

== Pharmacology == {| class="wikitable sortable floatright" |+ style="text-align: center;" | Receptor affinities<ref name="Caplyta FDA label" /> |- ! Site !Action!! K_i (nM) !Ref |- | |SERT |Antagonist|| 62 |<ref name="Tarzian_2023" /><ref name="Syed_2021" /> |- |DAT |Antagonist |? |<ref name="Tarzian_2023" /> |- | |5-HT_2A |Antagonist|| 0.54 |<ref name="Tarzian_2023" /> |- | |α_1A |ND|| 100- |<ref name="Syed_2021" /> |- | |α_1B |ND|| 100- |<ref name="Syed_2021" /> |- | |D₁ |Agonist|| 52 |<ref name="Tarzian_2023" /><ref name="Syed_2021" /> |- | |D_2S | Agonist (partial) || 32? |<ref name="Syed_2021" /> |- |D_2L |Antagonist |32? |<ref name="Syed_2021" /> |- | |D₄ |ND|| 100- |<ref name="Syed_2021" /> |}

=== Mechanism of action === Lumateperone acts as an antagonist at 5-HT_2A receptors and binds to several dopamine receptors (D₁, D₂, and D₄) with moderate affinity. It has moderate serotonin transporter reuptake inhibition, which is partly responsible for its antidepressant effect in bipolar disorder and reduction of negative symptoms of schizophrenia.<ref name="Caplyta FDA label" /><ref name="Cooper_2025">{{cite book | vauthors = Cooper D, Gupta V | chapter = Lumateperone | title = StatPearls | date = 2025 | pmid = 32809679 | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK560844/ | access-date = 16 April 2025 | place = Treasure Island (FL) | publisher = StatPearls Publishing }}</ref> It may also inhibit dopamine transporter reuptake, but more evidence is needed to confirm this.<ref name="Tarzian_2023">{{cite journal | vauthors = Tarzian M, Ndrio M, Chique B, Serai J, Thalackal B, Lau J, Fakoya AO | title = Illuminating Hope for Mental Health: A Drug Review on Lumateperone | journal = Cureus | volume = 15 | issue = 9 | pages = e46143 | date = September 2023 | pmid = 37900490 | pmc = 10612995 | doi = 10.7759/cureus.46143 | doi-access = free | article-number = e46143 }}</ref> 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 and hyperprolactinemia.<ref name= "Caplyta FDA label">{{cite web | title = Caplyta- lumateperone capsule | location = US | date = 27 December 2019 | website = DailyMed.nlm.nih.gov | url = https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=db730b06-6351-47fd-8183-e61e61bbead5 | publisher = National Library of Medicine, National Institutes of Health | access-date = 3 July 2020 }}</ref><ref name="Tarzian_2023" />

Similar to aripiprazole, lumateperone acts as a partial agonist at inhibitory D2 autoreceptors 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—and displays regioselectivity for the mesolimbic pathway, whose hyperactivity is responsible for the positive symptoms of schizophrenia. These qualities reduce the risk of extrapyramidal symptoms (EPS) from reduced dopaminergic transmission in the nigrostriatal pathway.<ref name="Cooper_2025" /><ref name="Syed_2021">{{cite journal | vauthors = Syed AB, Brašić JR | title = The role of lumateperone in the treatment of schizophrenia | journal = Therapeutic Advances in Psychopharmacology | volume = 11 | pages = 20451253211034019 | date = 2021 | pmid = 34377435 | pmc = 8326816 | doi = 10.1177/20451253211034019 | article-number = 20451253211034019 }}</ref>

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.<ref name="Cooper_2025" /> 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.<ref name="Cooper_2025" /><ref name="Tarzian_2023" />

Interestingly, lumateperone indirectly augments glutamatergic neurotransmission through its activity at D1 receptors, which causes phosphorylation 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.<ref name="Cooper_2025" /><ref>{{cite journal | vauthors = Edinoff A, Wu N, deBoisblanc C, Feltner CO, Norder M, Tzoneva V, Kaye AM, Cornett EM, Kaye AD, Viswanath O, Urits I | title = Lumateperone for the Treatment of Schizophrenia | journal = Psychopharmacology Bulletin | volume = 50 | issue = 4 | pages = 32–59 | date = September 2020 | pmid = 33012872 | pmc = 7511146 | doi = 10.64719/pb.4372 }}</ref>

It has also been identified as a potent vesicular monoamine transporter 2 (VMAT2) inhibitor ({{Abbrlink|IC₅₀|half-maximal inhibitory concentration}} = 62{{nbsp}}nM).<ref name="Racz_2025">{{cite journal | vauthors = Racz R, Kozell LB, Eshleman AJ, Bloom SH, Wolfrum KM, Schmachtenberg JL, Swanson TL, Ngai J, Schutzer WE, Janowsky A, Abbas AI, Stavitskaya L | title = Evaluation of the Relationship between Vesicular Monoamine Transporter 2 (VMAT2) Inhibition and Neurologic Adverse Events in Approved Drugs | journal = ACS Pharmacology & Translational Science | date = 22 December 2025 | article-number = acsptsci.5c00538 | doi = 10.1021/acsptsci.5c00538 | issn = 2575-9108 | doi-access = free }}</ref>

=== Pharmacokinetics === After taking the medication by mouth, lumateperone reaches maximum plasma concentrations within 1–2 hours and has a terminal elimination half-life of 18 hours.<ref name="Caplyta FDA label" /> Lumateperone is a substrate for numerous metabolic enzymes, including various glucuronosyltransferase (UGT) isoforms (UGT1A1, 1A4, and 2B15), aldo-keto reductase (AKR) isoforms (AKR1C1, 1B10, and 1C4), and cytochrome P450 (CYP) enzymes (CYP3A4, 2C8, and 1A2).<ref name="Caplyta FDA label" />

Lumateperone does not cause appreciable inhibition of any common CYP450 enzymes. It is not a substrate for p-glycoprotein.<ref name="Caplyta FDA label" />

==Chemistry== In terms of chemical structure, lumateperone is a pyridopyrroloquinoxaline and butyrophenone.<ref name="PubChem">{{cite web | title = Lumateperone | website = PubChem | url = https://pubchem.ncbi.nlm.nih.gov/compound/21302490 | access-date = 29 July 2025 }}</ref>

===Analogues=== Pyridopyrroloquinoxaline serotonin 5-HT_2A receptor agonists such as the psychedelic IHCH-7113 and the non-hallucinogenic IHCH-7086, IHCH-7079, and ITI-1549 have been derived via structural modification of lumateperone.<ref name="Cao_2022">{{cite journal | vauthors = Cao D, Yu J, Wang H, Luo Z, Liu X, He L, Qi J, Fan L, Tang L, Chen Z, Li J, Cheng J, Wang S | title = Structure-based discovery of nonhallucinogenic psychedelic analogs | journal = Science | volume = 375 | issue = 6579 | pages = 403–411 | date = January 2022 | pmid = 35084960 | doi = 10.1126/science.abl8615 | bibcode = 2022Sci...375..403C }}</ref><ref name="Duan_2024">{{cite journal | vauthors = Duan W, Cao D, Wang S, Cheng J | title = Serotonin 2A Receptor (5-HT_2AR) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants | journal = Chemical Reviews | volume = 124 | issue = 1 | pages = 124–163 | date = January 2024 | pmid = 38033123 | doi = 10.1021/acs.chemrev.3c00375 }}</ref><ref name="Wacker_2025">{{cite journal | vauthors = Wacker D, McCorvy JD | title = Biased Signaling in Psychedelic Action | journal = Annual Review of Pharmacology and Toxicology | date = August 2025 | pmid = 40796124 | doi = 10.1146/annurev-pharmtox-062124-012545 | doi-access = free }}</ref><ref name="Dutheil_2025">{{cite journal | vauthors = Dutheil S, Lehmann VE, Awadallah N, John N, Zhang L, Yao W, Li P, Snyder G, Davis R | title = 319. Discovery and Development of ITI-1549: A Novel Serotonin 5-HT2A Agonist, Non-Hallucinogenic Neuroplastogen, for the Treatment of Neuropsychiatric Disorders | journal = Biological Psychiatry | volume = 97 | issue = 9 | date = 2025 | doi = 10.1016/j.biopsych.2025.02.557 | page = S227 | url = https://linkinghub.elsevier.com/retrieve/pii/S0006322325006559 | access-date = 30 December 2025 | url-access = subscription }}</ref>

== History == The FDA approved lumateperone in 2019 based on evidence from three clinical trials (Trial 1/NCT01499563, Trial 2/NCT02282761 and Trial 3/NCT02469155) that enrolled 818 adult participants with schizophrenia.<ref name="FDA snapshot" /> The trials were conducted at 33 sites in the United States.<ref name="FDA snapshot" /> Trials 1 and 2 provided data on the benefits and side effects of lumateperone, and Trial 3 provided data on side effects only.<ref name="FDA snapshot" />

Three trials provided data for the approval of lumateperone.<ref name="FDA snapshot" /> 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).<ref name="FDA snapshot" /> Neither the participants nor the health care providers knew which treatment was being given until after the trials were completed.<ref name="FDA snapshot" />

Trials 1 and 2 provided data for the assessment of benefits and side effects through four weeks of therapy.<ref name="FDA snapshot" /> Benefit was assessed by measuring the overall improvement in the symptoms of schizophrenia.<ref name="FDA snapshot" /> Trial 3 provided data for the assessment of side effects only during six weeks of therapy.<ref name="FDA snapshot" />

Two Phase III lumateperone monotherapy studies were conducted and completed for the treatment of bipolar depression, those being trial Study 401 and Study 404.<ref>{{Cite press release | title = Intra-Cellular Therapies Announces Positive Top-line Results from a Phase 3 Trial of Lumateperone in Patients with Bipolar Depression | date = 8 July 2019 | url = http://www.globenewswire.com/news-release/2019/07/08/1879347/0/en/Intra-Cellular-Therapies-Announces-Positive-Top-line-Results-from-a-Phase-3-Trial-of-Lumateperone-in-Patients-with-Bipolar-Depression.html | publisher = Intra-Cellular Therapies Inc. | via = GlobeNewswire | access-date = 6 November 2019 }}</ref> A third trial, Study 402, aims to test lumateperone in addition to lithium or valproate,<ref>{{Cite press release | title = Intra-Cellular Therapies Announces Positive Top-line Results from a Phase 3 Trial of Lumateperone in Patients with Bipolar Depression | date = 8 July 2019 | url = http://www.globenewswire.com/news-release/2019/07/08/1879347/0/en/Intra-Cellular-Therapies-Announces-Positive-Top-line-Results-from-a-Phase-3-Trial-of-Lumateperone-in-Patients-with-Bipolar-Depression.html | publisher = Intra-Cellular Therapies Inc. | via = GlobeNewswire | access-date = 6 November 2019 }}</ref><ref name="cite143ec63f">{{Cite web | title = Why Intra-Cellular Therapies Is Tanking Today | date = 8 July 2019 | url = https://finance.yahoo.com/news/why-intra-cellular-therapies-tanking-153400209.html | website = Yahoo! Finance | access-date = 6 November 2019 }}</ref> the data pertaining this trial is due out in 2020.<ref name="cite318183ee">{{Cite web | title = One out of two is not enough for Intra-Cellular | date = 8 July 2019 | url = https://www.evaluate.com/vantage/articles/news/trial-results/one-out-two-not-enough-intra-cellular | website = Evaluate | access-date = 6 November 2019 }}</ref><ref name="cite143ec63f" />

Study 401 was conducted solely in the United States while Study 404 was a global study and included patients from the US.<ref name="cite318183ee" /><ref name="DeArment_2019">{{cite web | vauthors = DeArment A | title = Intra-Cellular Therapies hits one, misses another in Phase III bipolar disorder program | date = 8 July 2019 | url = https://medcitynews.com/2019/07/intra-cellular-therapies-hits-one-misses-another-in-phase-iii-bipolar-disorder-program/ | website = MedCity News | access-date = 6 November 2019 }}</ref> 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.<ref name="cite318183ee" /><ref name="DeArment_2019" /> In Study 404, patients received 42&nbsp;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.<ref>{{Cite web | title = Phase 3 data supports lumateperone for bipolar depression | date = 8 July 2019 | url = https://www.healio.com/psychiatry/bipolar-disorder/news/online/%7Be849adff-1dbf-4f3e-9642-71d78ad12195%7D/phase-3-data-supports-lumateperone-for-bipolar-depression | website = Healio | access-date = 6 November 2019 }}</ref>

== References == {{Reflist}}

{{Antipsychotics}} {{Dopamine receptor modulators}} {{Serotonin receptor modulators}} {{Monoamine reuptake inhibitors}} {{Portal bar | Medicine}} {{Authority control}}

Category:Atypical antipsychotics Category:4-Fluorophenyl compounds Category:Ketones Category:Pyridopyrroloquinoxalines Category:Serotonin-dopamine activity modulators Category:VMAT inhibitors