SUMMARY

• Lumateperone has high binding affinity for serotonin 5-HT_2A receptors (K_i=0.54 nM) and moderate binding affinity for dopamine D₂ (K_i=32 nM) receptors.¹
• Receptor affinity and human positron emission tomography (PET) imaging studies further characterized lumateperone’s pharmacodynamic profile, while biochemical and animal behavioral studies assessed the functional outcome of these receptor interactions.^2-4 
  • The data collectively show that lumateperone combines high potency blockade of serotonin 5-HT_2A receptors, selective and regional modulation of dopamine transmission through dopamine D₂ and D₁ receptors, serotonin reuptake inhibition at the serotonin transporter (SERT), and indirect enhancement of glutamatergic transmission via dopamine D₁ receptors.

PRODUCT LABELING

Pharmacodynamics

Lumateperone has high binding affinity for serotonin 5-HT_2A receptors (K_i=0.54 nM) and moderate binding affinity for dopamine D₂ (K_i=32 nM) receptors. Lumateperone has moderate binding affinity for dopamine D₁ (K_i=41 nM) and D₄ and adrenergic alpha_1A and alpha_1B receptors (K_i≤100 nM), serotonin transporters (K_i=33 nM), and inhibits update of serotonin in cells expressing the human serotonin transporter (IC₅₀=150 nM). Lumateperone has low binding affinity (less than 50% inhibition at 100 nM) for muscarinic and histaminergic receptors.¹

Mechanism of Action

The mechanism of action of lumateperone for the treatment of schizophrenia in adults, for the treatment of depressive episodes associated with bipolar depression (as monotherapy or as adjunctive therapy with lithium or valproate), and as adjunctive therapy with antidepressants for the treatment of MDD is unknown. However, the mechanism of action of lumateperone for these uses could be mediated through a combination of antagonist activity at central serotonin 5-HT_2A receptors and partial agonist activity at central dopamine D₂ receptors.¹

PHARMACODYNAMICS

Receptor affinity and human PET imaging studies characterized a pharmacodynamic profile of lumateperone, while biochemical and animal behavioral studies assessed the functional outcome of these receptor interactions.^2-4 

• The data collectively showed that lumateperone combines high potency blockade of serotonin 5-HT_2A receptors, selective and regional modulation of dopamine transmission through dopamine D₂ and D₁ receptors, serotonin reuptake inhibition at the SERT, and indirect enhancement of glutamatergic transmission via dopamine D₁ receptors.
• The dopaminergic effect of lumateperone appeared to be regionally selective, modulating mesolimbic/mesocortical markers of dopaminergic neurotransmission via dopamine D₂ and D₁ receptors.³
  • At striatal dopamine D₂ receptors, lumateperone is thought to act as a presynaptic partial agonist due to the absence of functional effects on multiple presynaptic measures of dopamine transmission, including dopamine synthesis, turnover, and overflow.
  • As a postsynaptic antagonist at D₂ receptors, lumateperone preferentially increases dopamine levels (micro-dialysis) or activates intracellular markers (glycogen synthase kinase 3β [GSK-3β]) in the rat medial prefrontal cortex but not in the striatum.
• Lumateperone indirectly enhances both N-methyl-D-aspartate (NMDA)- and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-induced glutamatergic currents in the rat medial prefrontal cortex via activation of dopamine D₁ receptors.⁴ 
• In mesolimbic regions, lumateperone may indirectly modulate glutamatergic activity by increasing the phosphorylation of the GluN2B-type NMDA receptors.³
• Lumateperone significantly reverses stress-induced social withdrawal in a rodent behavioral model.³
• Affinity of lumateperone for the SERT, combined with reports on the positive role of selective 5-HT_2A receptor antagonism in social defeat models, as well as synergy of 5-HT_2A receptor antagonism with SERT inhibition rather than SERT inhibition alone for greater antidepressant efficacy, support the potential antidepressant activity of lumateperone.³
• Additionally, lumateperone’s regio-selectivity of dopamine modulation may also play a role in its antidepressive effects, where inhibition of mesolimbic and activation of mesocortical pathways have been shown to play a role in resiliency to depression-related behaviors.³
  • In rats, administration of lumateperone at doses of 3 or 10 mg/kg resulted in a dose-dependent increase in dopamine efflux specifically in the medial prefrontal cortex, with a statistically significant elevation observed at the 3 mg/kg dose (P<0.05), while no change was noted in dopamine metabolite 3,4-dihydroxyphenylacetic acid levels. 
  • In mice, oral administration of lumateperone (3, 10, or 30 mg/kg) led to a dose-dependent increase (mean±standard error of mean) in GSK-3β phosphorylation at serine 9 in both the prefrontal cortex and nucleus accumbens, with maximal effects observed at the 10 mg/kg dose (126±4.9% in prefrontal cortex, P<0.001; 120.8±3.6% in nucleus accumbens, P<0.001). No significant changes on serine 9 phosphorylation were detected in the striatum across all tested doses.
  • Additionally, oral administration of lumateperone (3 mg/kg) significantly elevated phospho-Y1472 levels in the nucleus accumbens of mice, with peak effects recorded 120 minutes post-dose (180±20% of control).

Vanover et al (2019)² conducted an open-label, PET study to evaluate the dopamine D₂ receptor occupancy (D₂RO) at plasma steady state following 2 weeks of treatment with 42 mg of CAPLYTA daily in the morning in patients with schizophrenia (N=10; mean age, 39.3 years). All enrolled patients discontinued their previous antipsychotic medication to establish a drug-free baseline using a 2-week washout period. During the study, 9 patients received lorazepam as a concomitant psychotropic medication.

D₂RO Following CAPLYTA Treatment

• Following administration of a CAPLYTA dose of 42 mg, the highest D₂RO level in the dorsal striatum was observed at 1 hour, with a mean±standard deviation (SD) occupancy of 39%±12% (n=6).
• The mean±SD dorsal striatal D₂RO gradually decreased from 34%±8% at 3 to 4 hours after dosing to 19%±10% at 7.5 hours after dosing, and 7%±7% at 24 to 27 hours after dosing (n=4).
• Combined data from all patients at 1 or 3 hours revealed a mean D₂RO of 37%, with an associated mean total plasma level of 49.3 ng/mL. A statistically significant correlation was observed between D₂RO and total plasma concentration (r²=0.6; P=0.0077).

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 02 September 2025.