Lumateperone is thought to have a pharmacological profile that includes the modulation of serotonergic and dopaminergic receptors and may contribute to indirect activation of glutamatergic AMPA and NMDA receptors ^[1]. The mechanism of action of lumateperone is unknown.

Lumateperone acts as an antagonist at Serotonin-2A receptors, binding with high affinity ^{[1] [2] [3]} and a high occupancy at this receptor of over 80 percent ^[1]. Lumateperone also binds to serotonin transporter, also known as SERT, with moderate binding affinity ^{[3] [4]} . Inhibition of SERT contributes to increased serotonin in the synapse ^[3].

Lumateperone binds to dopamine D2 receptors, post-synaptically as an antagonist with moderate binding affinity and a receptor occupancy of up to 39 percent ^{[1] [3] [4]} . When there are high levels of occupancy at the D2 receptor, which is defined as greater than or equal to 80 percent, risks of extrapyramidal symptoms and elevated prolactin levels may be increased ^[3]. The molecule has moderate affinity to dopamine D1 receptors ^{[1] [5]}. This binding may contribute to indirect activation of the glutamatergic AMPA and NMDA receptors [1] [6] [7] [8]. Lumateperone has low binding affinity for off-target receptors, such as histaminergic and muscarinic receptors ^{[3] [4] [9]}.

References

1. Vanover KE, Davis RE, Zhou Y, et al. Dopamine D2 receptor occupancy of lumateperone (ITI-007): a Positron Emission Tomography Study in patients with schizophrenia. Neuropsychopharmacology. 2019;44(3):598-605. doi:10.1038/s41386-018-0251-1
2. Li P, Zhang Q, Robichaud AJ, et al. Discovery of a tetracyclic quinoxaline derivative as a potent and orally active multifunctional drug candidate for the treatment of neuropsychiatric and neurological disorders. J Med Chem. 2014;57(6):2670-2682. doi:10.1021/jm401958n Davis RE, Correll CU. ITI-007 in the treatment of schizophrenia: from novel pharmacology to clinical outcomes [published correction appears in Expert Rev Neurother. 2016 Jun;16(6):v. doi: 10.1080/14737175.2016.1188517.]. Expert Rev Neurother. 2016;16(6):601-614. doi:10.1080/14737175.2016.1174577
3. Davis RE, Correll CU. ITI-007 in the treatment of schizophrenia: from novel pharmacology to clinical outcomes. Expert Rev Neurother. 2016;16(6):601-614. doi:10.1080/14737175.2016.1174577
4. Snyder GL, Vanover KE, Davis RE, Li P, Fienberg A, Mates S. A review of the pharmacology and clinical profile of lumateperone for the treatment of schizophrenia. Adv Pharmacol. 2021;90:253-276. doi:10.1016/bs.apha.2020.09.001
5. Center for Drug Evaluation and Research. Application number: 209500Orig1s000. Multi-discipline review. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/209500Orig1s000MultidisciplineR.pdf. Accessed 02 Sept 2025.
6. Tarzian M, Ndrio M, Chique B, et al. Illuminating Hope for Mental Health: A Drug Review on Lumateperone. Cureus. 2023;15(9):e46143. Published 2023 Sep 28. doi:10.7759/cureus.46143
7. Kumar B, Kuhad A, Kuhad A. Lumateperone: a new treatment approach for neuropsychiatric disorders. Drugs Today (Barc). 2018;54(12):713-719. doi:10.1358/dot.2018.54.12.2899443
8. Jawad MY, Alnefeesi Y, Ceban F, et al. Lumateperone for the treatment of Adults With Schizophrenia: a Systematic Review. Curr Psychiatry Rep. 2022;24(8):359-368. doi:10.1007/s11920-022-01344-1
9. Li P, Zhang Q, Robichaud AJ, et al. Discovery of a tetracyclic quinoxaline derivative as a potent and orally active multifunctional drug candidate for the treatment of neuropsychiatric and neurological disorders. Supporting Information. J Med Chem. 2014;57(6):2670-2682. doi:10.1021/jm401958n