SUMMARY

• 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.¹ 
  • 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.
  • 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 affinity for central dopamine D₂ receptors as a partial agonist. Partial agonists can act as agonists or antagonists depending upon the dopamine tone in the synaptic environment.^1-3
  • This dual pharmacologic action allows for reduced presynaptic release of dopamine and postsynaptic blockage of dopamine receptors for more efficient reduction in dopaminergic signaling. This mechanism helps avoid increased dopamine in the synaptic cleft while concurrently blocking postsynaptic D₂ receptors.² 
• Lumateperone has moderate affinity for serotonin transporters and inhibits uptake of serotonin in cells expressing human serotonin transporters, which can contribute to increased serotonin levels in the synapse.^1,4 
• In mesolimbic regions, lumateperone may indirectly modulate glutamatergic activity by increasing the phosphorylation of the GluN2B-type N-methyl-D-aspartate (NMDA) receptors.⁵ The clinical relevance of lumateperone’s effects on glutamate activity are unknown

PRODUCT LABELING

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

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

PRECLINICAL EVIDENCE

In mesolimbic regions, lumateperone may indirectly modulate glutamatergic activity by increasing the phosphorylation of the GluN2B-type NMDA receptors.⁵ The clinical relevance of the effect of lumateperone on glutamate activity are unknown.

• In rats, administration of lumateperone (ITI-007) 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 glycogen synthase kinase-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).

clinical data

• Vanover et al (2019)² conducted an open-label, positron emission tomography 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; age [mean±SD], 39.3±9.1 years).

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±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).
• Lumateperone has shown antipsychotics effects, even at relatively low D₂RO.

Safety

• The most frequent (reported in >2 patients) AEs possibly related to CAPLYTA were mild to moderate headache (40%) and mild sedation.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 12 September 2025.