Lumateperone, also known as ITI-007, is approved for the treatment of schizophrenia in adults. It is also approved for the treatment of depressive episodes associated with bipolar disorder (i.e. bipolar depression) in adults, as monotherapy and/or adjunctive therapy with lithium or valproate. Unlike other antipsychotics, lumateperone has partial agonist activity at presynaptic dopamine (D2) receptors, resulting in reduced presynaptic release of dopamine, and antagonistic activity at postsynaptic dopamine (D2) receptors. Lumateperone's pre-synaptic partial agonist activity prevents positive feedback at D2 receptors while simultaneously blocking dopaminergic neurotransmission at the post-synaptic D2 receptor. This dual action at D2 receptors prevents an increase in dopamine in the synaptic cleft while simultaneously blocking post-synaptic D2 receptors. It is thought that this is responsible for the fact that lumateperone requires D2 receptor occupancy as low as 40%, an uncommon characteristic in antipsychotics. Both reduced receptor occupancy and its dual action at D2 receptors are thought to contribute to lumateperone's low incidence of extrapyramidal side effects, such as tardive dyskinesia and parkinsonian-like effects. These characteristics allow lumateperone to efficiently reduce dopamine signaling. Lumateperone also targets dopamine (D1) receptors, and a useful secondary result of D1 activation is increased glutamatergic N-methyl-D-aspartate (NMDA) GluN2B receptor phosphorylation. This is significant since NMDA mediated glutamate signaling appears to be impaired in patients who have schizophrenia. Lumateperone is capable of modulating serotonin by inhibiting serotonin transporters (SERT), and by behaving as a 5-HT2A receptor antagonist. Lumateperone has been found to augment the activities of NMDA and AMPA receptors in the prefrontal cortex. Although the exact mechanism is unknown, it has been found that this is partly through a D1-receptor-mediated mechanism that results in the phosphorylation of GluN2B subunits of NMDA receptors in the mesolimbic pathways of the brain. This correlates with lumateperone's regioselectivity for mesolimbic circuits and lower affinity for nigrostriatal dopamine pathways. It is thought that this activity may be an important contributor to its effects as an antipsychotic and antidepressant, as NMDA-receptor activity is known to be deficient in schizophrenic patients. It is an inhibitor of the serotonin reuptake transporter, which is the mechanism of action of SSRI antidepressants, resulting in potential antidepressant activity and efficacy against the negative symptoms of schizophrenia (i.e., depression).This may be an essential factor in lumateperone's efficacy in both bipolar depression as well as the negative symptoms associated with schizophrenia. lumateperone exhibits 60x greater affinity for 5-HT2A receptors than D2 receptors. This is thought to be significant in lumateperone's gradient of clinical effects, which provides lumateperone with a potentially more extensive range of clinical use. At low dosages, lumateperone's effects are mainly sedative and anti-aggressive. The ability of lumateperone to exhibit these effects at low dosages may result from a lack of D2 receptor binding and preferential, potent 5HT2A antagonism at low dosages. In contrast, increasing dosages show increasing D2 receptor binding and occupancy in addition to 5HT2A receptor binding, resulting in antipsychotic efficacy.

Lumateperone Dopamine Action Pathway References