The introduction of second-generation antipsychotics has dramatically improved the ability of healthcare professionals to manage and treat schizophrenia and to provide an increased quality of life to patients afflicted with this disease. The discovery of the role of 5HT-2A receptor antagonism in reducing the adverse motor effects caused by D2 receptor blockade has led to a significant improvement in treatment options available for those with schizophrenia. 

However, even with the repertoire of antipsychotics introduced in the past few decades, they have so far been generally more effective against positive symptoms rather than negative symptoms of schizophrenia. Additionally, they are associated with an increased incidence of adverse metabolic effects, such as weight gain and hyperprolactinemia.[1]  As a result, an antipsychotic with decreased incidence of side effects and a broader range of efficacy against schizophrenia would provide a useful addition to current treatments.[2]

One such medication, lumateperone, is a recently FDA approved antipsychotic that provides a unique mechanism of action for the treatment of schizophrenia.[3] Clinical trials have found placebo-level metabolic adverse effects, a very low incidence of extrapyramidal symptoms, and potentially improved coverage of the negative symptoms of schizophrenia.[1][4] Its current indication is for the management of acute schizophrenia, with clinical studies underway to determine its long-term safety and efficacy for this condition.[1][5] 

Lumateperone is also under evaluation in clinical trials for both bipolar depressive disorder and behavioral agitation associated with Alzheimer disease and other dementias.[6][1][4][7][8] Lumateperone effectiveness in the treatment of acutely exacerbated schizophrenia has shown to be statistically significant vs. placebo in a four-week Phase II and Phase III clinical trial at 42 mg/day as well as a 6-week phase III trial.  

There are also suggestions that patients who are currently stable on an antipsychotic may show an improvement of symptoms when adding lumateperone as an adjunctive treatment.[4][9] Lumateperone has been studied for bipolar depression with positive outcomes in one trial, and in the other trial, lumateperone did not separate from placebo. [10] A trial with lumateperone for agitation in patients with dementia was terminated researchers determined that the trial would not meet the primary endpoints.[11]

The mechanism of action of lumateperone involves simultaneous interaction and modulation of dopaminergic, serotonergic, and NMDA-receptor mediated glutaminergic neurotransmission.[7][4] The dopaminergic action of lumateperone is selective for D2 receptors, where it exhibits differential intrinsic activities at pre- and post-synaptic terminals. It acts as a dopamine phosphoprotein modulator (DPPM), with pre-synaptic D2 receptor partial-agonist and post-synaptic antagonist activities.[6] Furthermore, this D2 receptor activity shows regioselectivity for both mesocortical and mesolimbic circuits with a lower affinity for nigrostriatal dopamine pathways.[6][1][2][9] 

Post-synaptic antagonism of D2 receptors by lumateperone increases GSK-3 signaling via phosphorylation. GSK3 signaling occurs in D2R-expressing neurons located in the PFC and nucleus accumbens.[2] Lumateperone shows potent antagonistic activity at 5HT2A receptors, with a binding affinity 60 times higher than for D2 receptors.[1] Lumateperone shows a gradient of effects based on dosage and a high tolerability profile. These two characteristics appear to be the result of the combination of the synapse-specific, regioselective D2 receptor activity, and the comparatively high 60 to 1 ratio of D2 to 5-HT2A receptor affinity, respectively.[6][1] 

Furthermore, lumateperone exhibits antipsychotic efficacy at a D2 receptor occupancy as low as 40%, an uncommon characteristic in antipsychotics, and strong receptor binding for 5-HT2A receptor versus D-2 receptor thought to contribute to the low incidence hyperprolactinemia and extrapyramidal effects respectively seen with lumateperone in clinical trials.[6] Lumateperone also has additional serotonergic modulatory activity, acting as an inhibitor of the SERT, resulting in potential antidepressant activity and efficacy against the negative symptoms of schizophrenia (i.e., depression).[2] A unique feature of lumateperone is its indirect activity on glutaminergic signaling. It exhibits phosphorylative capacity at the GluN2B receptor, which may be the result of downstream signaling of the D1 receptor.[6] 

Although the exact pharmacological mechanism is unknown, glutaminergic modulation by lumateperone involves augmentation of both AMPA and NMDA receptor signaling in the PFC. 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.[2][12]

Lumateperone shows a gradient of clinical effects depending on dosage, which provides lumateperone with a potentially more extensive range of clinical use.[2] 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.[2]

Lumateperone is administered orally, at the FDA-approved dosage 42 mg in capsule form, preferably at bedtime. Dosages at 120 mg/day have been shown not to produce any statistically significant improvement in efficacy.[4] It shows rapid absorption following oral administration and has a moderate half-life of 13 to 21 hours. T-max occurs in 3 to 4 hours.[7][2] Lumateperone and its metabolites are entirely excreted in the feces.

The adverse effects associated with the administration of lumateperone are mild to moderate.[9] At the FDA approved dosage of 42mg/day, the most common side effects are somnolence, sedation, fatigue, and constipation.[7] 

In a Phase III clinical trial consisting of 148 participants who received the currently FDA approved dosage of 42 mg, 17.6% experienced somnolence, 12.7% experienced sedation, and  5.3% experienced fatigue. Overall, 64.7% of this group experienced adverse effects.[7] No greater than 5% of participants in either of the lumateperone groups (n=294) experienced extrapyramidal symptoms. Furthermore, there was no statistically significant change in median weight from placebo. Metabolic endpoints, including changes in triglycerides, blood glucose, and prolactin levels, also did not change significantly from placebo; this appears to be partially attributable to its lack of affinity to off-target receptors, including histaminergic and muscarinic receptors.[7]

Another clinical trial conducted compared lumateperone to a standard-of-care antipsychotic consisting of 302 patients for 6-weeks. Those who switched to lumateperone from their current antipsychotics experienced statistically significant improvements in parameters measuring LDL-cholesterol, triglycerides, and prolactin levels.[4][9] Although there have only been a limited number of clinical trials that have so far, evidence points to lumateperone having a reduced risk of adverse effects normally associated with second-generation antipsychotics, although long term studies are underway to determine the long-term safety and efficacy of lumateperone.[5] 

Lumateperone undergoes metabolism by the cytochrome P450-3A4 isozyme and interacts with medications that are inhibitors and/or inducers of this isozyme. Therefore, the recommendation is to avoid lumateperone in patients taking a CYP3A4 inducer or moderate to potent CYP3A4 inhibitors. Also, Lumateperone is likely to interact with alcohol and other sedatives as it produces sedation, especially at lower dosages.[7]