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.
• In mesolimbic regions, lumateperone may indirectly modulate glutamatergic activity by increasing the phosphorylation of the GluN2B-type N-methyl-D-aspartate (NMDA) receptors.² 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

MECHANISM OF ACTION

In mesolimbic regions, lumateperone may indirectly modulate glutamatergic activity by increasing the phosphorylation of the GluN2B-type NMDA receptors.² The clinical relevance of lumateperone’s effects 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).

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.