Lumateperone: advancing schizophrenia treatment with a new antipsychotic

Treatment-resistant schizophrenia remains a significant challenge, necessitating the development of new treatments. Lumateperone, a novel antipsychotic, offers promising benefits due to its unique pharmacological profile. It acts as a potent antagonist of the serotonin 5-HT2A receptor and a presynaptic partial agonist and postsynaptic antagonist at D2 receptors, stabilizing dopamine neurotransmission. Lumateperone also enhances NMDA and AMPA neurotransmission, which is crucial for cognitive function. Lumateperone exhibits negligible binding affinity for receptors often associated with adverse cognitive and metabolic effects, such as H1 histaminergic, 5-HT2C, and muscarinic receptors. Pharmacokinetically, lumateperone is rapidly absorbed, reaching peak concentration within 1-2 hours, and steady-state levels are achieved in about 5 days. Clinical trials demonstrate lumateperone’s efficacy in reducing schizophrenia symptoms, with significant improvements in PANSS scores. Studies show that lumateperone 42 mg/day significantly improves symptoms and is comparable to risperidone in efficacy. Additional trials confirm its effectiveness in improving depressive symptoms and social functioning, with high completion rates due to its lower incidence of adverse events. Open-label safety switching studies and post hoc analyses further support lumateperone's positive impact on symptom maintenance. Lumateperone's safety and tolerability profile is favorable, with lower incidences of metabolic side effects such as weight gain, dyslipidemia, and hyperglycemia compared to other antipsychotics. Common adverse events include somnolence and nausea, which are generally mild.
In conclusion, lumateperone represents a significant advancement in schizophrenia treatment, offering effective symptom control and a superior safety profile. Further real-world and long-term studies are necessary to fully establish its clinical utility and sustained benefits.

BACKGROUND AND AIMS

Schizophrenia is a severe and chronic psychiatric disorder affecting approximately 1% of the global population, with minor variations across different regions and cultures ^1-4. Epidemiological studies indicate that schizophrenia affects men more frequently than women. Specifically, the risk ratio between men and women is approximately 1.4:1 ⁵. The average age of onset of schizophrenia differs between sexes. In men, schizophrenia tends to manifest earlier, with an average onset age between 18 and 25 years. In women, the onset is generally later, with a peak age between 25 and 35 years ⁶.

When examining the trends in schizophrenia data over recent decades, it is evident that from 1990 to 2019, there has been a significant increase in the global burden of the disorder ⁷. During this period, the raw prevalence of schizophrenia rose from 14.2 to 23.6 million cases, the incidence increased from 941,000 to 1.3 million new cases per year, and disability-adjusted life years (DALYs) – which measure the overall burden of disease in terms of years lost due to ill-health, disability, or early death –climbed from 9.1 to 15.1 million ⁷. In countries with a high socio-demographic index (SDI), both prevalence and DALYs saw substantial growth, while in low SDI countries, the age-standardized incidence decreased, and DALYs remained relatively stable ⁷. These observations highlight a growing global trend in the raw prevalence and impact of schizophrenia, suggesting an urgent need for improved detection in low SDI regions and enhanced prevention and treatment strategies in high SDI countries ⁷. Furthermore, it is important to acknowledge that current estimates likely underestimate the true prevalence and burden of schizophrenia ⁷.

Considering schizophrenia in its complex nature, it represents a psychiatric condition characterized by a wide range of symptoms that significantly impact an individual’s functioning. These symptoms are typically categorized into two main groups – though this is a simplification of the disorder’s truly multifaceted nature: positive and negative symptoms. Positive symptoms include phenomena such as hallucinations, delusions, and disorganized thinking, while negative symptoms are marked by diminished emotional expression, reduced social engagement, and a lack of motivation ^3,8. The treatment of schizophrenia primarily involves antipsychotic medications, psychosocial interventions, and supportive therapies ⁹. Currently available antipsychotics mainly work by blocking dopamine D2 receptors. However, these antipsychotics do not satisfactorily treat the primary and persistent negative symptoms or cognitive deficits associated with schizophrenia and are linked with a range of troublesome side effects ^10,11. These side effects, including metabolic issues, contribute to a significantly reduced life expectancy in patients with schizophrenia ¹². Second-generation antipsychotics, also known as atypical antipsychotics, were developed to address some of these issues. While they offer some advantages over first-generation antipsychotics ¹³, including a lower risk of extrapyramidal symptoms, they still pose significant metabolic risks and do not fully address negative symptoms or cognitive deficits ^14-16. Emerging treatments with novel mechanisms of action (MOAs) are under investigation to address these limitations. Agents such as muscarinic receptor agonists, trace amine-associated receptor 1 (TAAR1) agonists, and glutamatergic modulators have shown promise in early clinical trials^17,18. For instance, xanomeline, a muscarinic receptor agonist, has demonstrated potential antipsychotic efficacy without direct dopamine D2 receptor activity ¹⁹. Similarly, TAAR1 agonists like ulotaront have shown significant improvements in schizophrenia symptoms without the common side effects associated with traditional antipsychotics ²⁰.

Despite advancements, the response to treatment varies significantly among patients, with notable percentages of treatment response, remission, relapse, and treatment-resistant cases. Approximately 30% of patients still exhibit treatment-resistant schizophrenia despite the availability of numerous treatments ^21-23. Therefore, due to the increased mortality and treatment resistance, it is essential to develop well-tolerated medications without side effects that also work through new mechanisms, such as lumateperone. Lumateperone, an antipsychotic medication developed for the treatment of schizophrenia, has been approved by the United States Food and Drug Administration (FDA) under the brand name Caplyta ²⁴. However, it has not received approval from other regulatory agencies such as the European Medicines Agency (EMA) and the Italian Medicines Agency (AIFA).

PHARMACODYNAMICS

Lumateperone is an antipsychotic characterized by a unique pharmacological profile, distinguishing it from traditional antipsychotic medications.

Serotonin

Lumateperone’s mechanism of action involves potent antagonism of the serotonin 5-HT2A receptor, with a Ki value of 0.54 nM, indicating a high binding affinity ^25-28. This high affinity for the 5-HT2A receptor is 60 times greater than its affinity for the D2 receptor ²⁸. The high affinity for the 5-HT2A receptor is particularly beneficial because 5-HT2A antagonism is known to enhance antipsychotic efficacy and reduce the risk of extrapyramidal side effects (EPS) and hyperprolactinemia ²⁹. Additionally, lumateperone has a moderate binding affinity for the serotonin transporter (SERT) with a Ki value of 62 nM. This moderate inhibitory effect on SERT, combined with 5-HT2A receptor antagonism, enhances its efficacy in modulating depressive symptoms ^{25,26,28,30,31}.

Dopamine

At D2 receptors, lumateperone is a presynaptic partial agonist and postsynaptic antagonist, with a Ki value of 32 nM ^26,28,32,33. This dual action at D2 receptors is crucial because partial agonism at these receptors can help stabilize dopamine neurotransmission. This stabilization is important because it may reduce the risk of dopaminergic hyperactivity, which is associated with positive symptoms of schizophrenia, and hypoactivity, which is linked to negative symptoms and cognitive impairment ³⁴. By partially activating presynaptic D2 receptors, lumateperone can modulate dopamine release more precisely, preventing the extremes of dopaminergic activity that contribute to the diverse symptoms of schizophrenia ^25,28.

In addition to its action at D2 receptors the D2 receptor activity described above demonstrates a regional preference for mesocortical and mesolimbic pathways while maintaining a low affinity for the nigrostriatal dopamine system ^35,36.

Glutammate

Lumateperone stands out as the sole antipsychotic demonstrated to enhance both NMDA and AMPA neurotransmission. This unique capability may be attributed to its dual action of modulating D1 receptor-mediated pathways (Ki = 52nM) and inhibiting SERT activity. These mechanisms potentially enhance its therapeutic benefits for patients with schizophrenia ²⁸. In an animal model study³⁷, lumateperone showed antipsychotic-like activity: stimulating D1 receptor it enhanced NMDA- and AMPA receptor-mediated neurotransmission in pyramidal cells, and increased dopamine and glutamate levels in the rat medial prefrontal cortex (mPFC). Lumateperone’s high affinity binding to dopamine D1 receptors triggers a series of events that facilitate NMDA receptor-mediated neurotransmission in the mPFC ³⁷. The interaction between dopamine D1 and NMDA receptors in the mPFC is essential for synaptic plasticity and the formation of new synapses, which may result in lasting antidepressant effects ^38-40. Deficiencies in NMDA receptor-mediated glutamate neurotransmission are linked to cognitive impairments and negative symptoms in schizophrenia ^41,42, and lumateperone’s ability to enhance glutamate release could help restore normal glutamatergic function, thus ameliorating these deficits ⁴³.

Other neurotransmitters

Unlike many other antipsychotic medications, lumateperone exhibits negligible binding affinity for receptors often associated with adverse cognitive and metabolic effects, such as H1 histaminergic, 5-HT2C, and muscarinic receptors. The lack of significant interaction with the H1 histaminergic receptor reduces the risk of sedation and weight gain, common side effects of antipsychotics that have high affinity for this receptor. Similarly, the low binding to 5-HT2C receptors minimizes the potential for metabolic side effects like weight gain and insulin resistance, which are frequently observed with antipsychotics that strongly interact with these receptors ^28,44-47.

Furthermore, the minimal binding to muscarinic receptors helps prevent anticholinergic side effects, such as cognitive impairment, dry mouth, constipation, and blurred vision ⁴⁸. Many antipsychotics with significant muscarinic receptor affinity can cause these undesirable side effects, leading to discomfort and potential non-compliance in patients ⁴⁹.

PHARMACOKINETICS

Time course of absorption, bioavailability and distribution

Lumateperone exhibits rapid absorption, with a bioavailability rate of 4.4% and extensive protein binding at 97.4%, indicating that the compound might remain in the body for a prolonged period. When administered orally once daily, its peak concentration (Cmax) in the bloodstream is typically reached within 1 to 2 hours, with an average time to reach maximum concentration (Tmax) of 3 to 4 hours ^30,46,50. It is noted that the pharmacokinetics of lumateperone exhibit individual variability, with the coefficient of variation for Cmax and area under the curve (AUC) at steady state ranging from 68% to 97% ^51-53.

The drug reaches steady-state levels in about 5 days and has an elimination half-life ranging from 13 to 21 hours. After intravenous administration, the volume of distribution is approximately 4.1 L/kg ^53,54.

Metabolism

Lumateperone undergoes extensive metabolism through various enzymatic pathways, including uridine 5’-diphospho-glucuronosyltransferases (UGTs), 1A1, 1A4, and 2B15, aldoketoreductases 1C1, 1B10, and 1C4, as well as cytochrome P450 enzymes CYP3A4, 2C8, and 1A2 ^25,51,53. It produces more than 20 metabolites but the major active one is IC200131 which results from reduction by ketone reductases ^31,51. Additionally, CYP3A4 is responsible for the formation of the active metabolites IC200161 and IC200565 through dealkylation in the liver ^30,32. These metabolites have half-lives of 10.8 hours, 2.3 hours, and 15.5 hours respectively, with a mean Tmax of 1.5 hours ^33,55.

Excretion

Studies using radioactive tracing reveal that 58% of lumateperone is eliminated in urine and 29% in feces, with less than 1% excreted unchanged in urine ³³. The terminal half-life after intravenous administration is around 18 hours, and the clearance rate is approximately 17.9 L/h ^52,56.

Toxicokinetics

Due to its metabolic pathways involving CYP3A4 and UGT enzymes, lumateperone poses a risk for drug-drug interactions ^25,51,52 It is recommended to avoid concomitant use with the CYP3A4 inducers such as carbamazepine, as well as with moderate or strong CYP3A4 inhibitors like fluvoxamine. Similarly, concurrent use with the UGT enzyme inhibitors such as valproic acid should be strictly monitored ^51,57.

CLINICAL EFFICACY

Several studies have been conducted demonstrating both the efficacy of lumateperone as an antipsychotic and testing the optimal daily dosage for administration.

The registrational studies that demonstrate lumateperone’s efficacy and appropriate daily dosage as an antipsychotic are Study 301 and Study 005 ^54,58.

In Study 301 ⁵⁴, a randomized, double-blind, placebo-controlled trial involving 450 patients with acute schizophrenia, participants received placebo, lumateperone 28 mg, or lumateperone 42 mg daily for 4 weeks. Lumateperone 42 mg significantly improved symptoms from baseline, showing effects by day 8 and a notable reduction in the Positive and Negative Syndrome Scale (PANSS) by day 28. This dose also outperformed placebo in Clinical Global Impression-Severity (CGI-S) evaluations ⁵⁴.

In Study 005 ⁵⁸, another randomized, double-blind, placebo- and active-controlled trial with 335 patients, participants were given placebo, lumateperone 42 mg, lumateperone 84 mg, or risperidone 4 mg daily for 4 weeks. Lumateperone 42 mg showed comparable antipsychotic efficacy to risperidone, with significant reductions in PANSS scores and greater improvements in depressive symptoms and social functioning, especially in patients with comorbid depression. Both studies reported high completion rates due to lumateperone’s efficacy and lower incidence of adverse events compared to other antipsychotics.

Other information on efficacy derives from additional studies: for example, in an open-label safety switching study ⁵⁹, patients switching to lumateperone maintained or improved symptoms, evidenced by PANSS and CGI-S scores. Those who discontinued early saw a mean worsening in PANSS, primarily due to adverse events or withdrawal. Additionally, a post hoc analysis investigating the efficacy and tolerability of lumateperone in patients with schizophrenia showed positive results, confirming its effectiveness and safety ⁶⁰.

SAFETY AND TOLERABILITY

Lumateperone’s favorable safety and tolerability profile is one of its most compelling attributes. Compared to other second-generation antipsychotics, lumateperone is associated with a lower incidence of metabolic side effects such as weight gain, dyslipidemia, and hyperglycemia ⁶¹.

In Study 005 ⁵⁸, lumateperone at 42 mg/day and 84 mg/day, as well as risperidone 4 mg/day, were assessed for adverse events (AEs) compared to placebo. AEs were more frequent with the 84 mg/day dose, with the 42 mg/day dose showing a more favorable profile. The number needed to harm (NNH) for nausea with the 42 mg/day dose was 17, and for somnolence/sedation, it was 27, similar to risperidone. Weight gain was less common with lumateperone than risperidone, and lumateperone had more favorable outcomes for prolactin elevation. In Study 301 ⁵⁴, somnolence/sedation was the primary significant AE, with NNH values of 9 for the 28 mg/day dose and 5 for the 42 mg/day dose. In Study 302 ⁶¹, fewer patients on lumateperone 42 mg/day discontinued due to AEs compared to placebo. Rates of somnolence/sedation were higher in all treatment groups than placebo, with NNH values of 12, 8, and 7 for lumateperone 14 mg/day, 42 mg/day, and risperidone, respectively. A pooled analysis of Studies 005, 301, and 302 ⁶¹ revealed that discontinuation due to AEs was rare for lumateperone 42 mg/day, with somnolence/sedation being the most frequent AE (NNH = 8). Other AEs, such as dry mouth and dizziness, were less frequent, and the pooled data did not show significant metabolic or ECG abnormalities compared to placebo, reinforcing lumateperone’s favorable safety and tolerability profile.

DOSAGE AND FORMULATION

Lumateperone is available in oral capsule form. The recommended dosage for the treatment of schizophrenia in adults is 42 mg taken once daily with or without food ⁵¹. This straightforward dosing regimen enhances patient compliance and simplifies treatment protocols. For other potential indications, such as bipolar depression, the specific dosage and formulation are currently under investigation in clinical trials. Initial data suggest that the 42 mg dose may also be effective in these conditions, but formal approval and guidelines are pending ⁵⁴.

LIMITATIONS OF EXISTING LITERATURE ON LUMATEPERONE

While clinical trials have demonstrated the efficacy and safety of lumateperone, there are several limitations in the current literature. In particular, real-world studies will be essential to confirm the efficacy of this drug in more complex patient populations and to fully understand its practical clinical utility. Real-world data can provide valuable insights into how lumateperone performs outside the controlled settings of clinical trials, offering a clearer picture of its effectiveness and safety in routine practice. Additionally, considering the chronic nature of schizophrenia, long-term studies are essential to evaluate the sustained benefits and potential risks of prolonged lumateperone use. These studies would help determine its true impact on patient outcomes over extended periods, addressing the limitations of current short-term trial data.

CONCLUSION AND FUTURE PERSPECTIVES

Lumateperone represents a significant advancement in the treatment of schizophrenia, offering a novel mechanism of action, proven efficacy, and a superior safety profile ^60,61. Its unique effects on the glutamatergic system and favorable pharmacodynamic properties distinguish it from other antipsychotics ³⁷. Moreover, clinical trials have demonstrated that lumateperone is both effective and safe for patients experiencing depressive episodes within the context of bipolar I or II disorder, both as monotherapy and as an adjunctive therapy with lithium or valproate ^62-64. Additionally, lumateperone has been shown to normalize pathological levels of acute inflammation through pathways involved in mood regulation ⁶⁵. As more data become available, it will be crucial to further elucidate lumateperone’s long-term benefits and to explore its potential applications in other psychiatric disorders. Furthermore, gaining a deeper understanding of the specific symptoms of schizophrenia for which lumateperone may be particularly effective is essential. For now, lumateperone stands out as a promising option for patients seeking an effective and tolerable antipsychotic therapy.

Conflict of interest statement

Andrea Fagiolini has received research grants and/or has been a consultant for, and/or has been a speaker for: Allergan, Angelini, Apsend, Generici DOC, Lundbeck, Italfarmaco, Janssen, Otsuka, Pfizer, Recordati, Roche, Sanofi Aventis, Sunovion; Alessandro Cuomo is/has been a consultant and/or a speaker for Angelini, Glaxo Smith Kline, Lundbeck, Janssen, Otsuka, Pfizer, Recordati.

Funding

None.

Authors contributions

S.P.: methodology, investigation, writing - original draft; C.P.: investigation, writing - original draft; M.P.: investigation, writing - original draft; M.C.: investigation; A.F.: conceptualization, validation, writing-review & editing, supervision; A.C.: conceptualization, validation, writing-review & editing, supervision