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Drug Review
Published Online: 1 March 2023

Lumateperone: A Truly Innovative Antipsychotic Medication?

Publication: American Journal of Psychiatry Residents' Journal
Lumateperone (Caplyta, Intra-Cellular Therapies) is a new antipsychotic medication, approved by the Food and Drug Administration (FDA) in 2019 for adults with schizophrenia and approved in 2021 for adults with depressive episodes associated with bipolar I or II disorder. Lumateperone has properties that potentially make it more than just a “me-too” drug.

Administration and Pharmacokinetics

Lumateperone is available in 10.5-, 21-, and 42-mg strengths. It is typically dosed at 42 mg daily in the morning or evening (1). The 42-mg daily dose is the usual starting and maximum dose. According to the manufacturer, it can be taken with or without food, but ingestion with a high-fat meal can modestly decrease absorption (1).
Lumateperone reaches peak plasma concentrations 1–2 hours after oral ingestion, and its half-life is 18 hours (1). It is metabolized by the liver via a variety of enzymes, and persons with liver impairment should take half the standard dose. The package insert recommends against using this medication along with CYP3A4 inducers and recommends the lower-strength formulations for persons who are also taking CYP3A4 inhibitors (1).

Mechanism of Action

The mechanism of action of lumateperone for each of its indications is likely due to its effects on the serotonergic and dopaminergic systems and possibly the glutamatergic system as well (2, 3). Lumateperone binds to 5-HT2A, D1, and D2 receptors and serotonin transporters (24). Lumateperone has 60-fold higher affinity for 5-HT2A receptors than for D2 receptors and acts as a 5-HT2A antagonist (24). This difference in affinity contrasts with other second-generation antipsychotics, including those noted for low affinity at dopamine receptors; for example, clozapine has a 30-fold higher affinity for 5-HT2A receptors than for D2 receptors (4, 5). At the recommended dose of lumateperone, this binding profile translates to much lower dopamine receptor occupancy—that is, <40% at steady state—than the classic 60%–70% occupancy thought to be required for efficacy of most antipsychotics in treating psychosis (3). One possible reason why lumateperone works for schizophrenia despite its low D2 receptor occupancy is its effects on the glutamatergic system, although this remains speculative (3). Another possibility is that although lumateperone acts as an antagonist at postsynaptic D2 receptors, it acts as a partial agonist at presynaptic D2 receptors—the implication being that it does not increase dopamine release because, unlike most other antipsychotics, it does not stop feedback inhibition via activity at this presynaptic receptor (6).
The clinical relevance of these pharmacodynamic features is still under investigation. As discussed below, lumateperone’s receptor-binding profile may explain the rates of side effects observed in clinical trials. Moreover, for patients with schizophrenia who fail to respond to their first medication trial, there is limited evidence for the efficacy of switching to a second non-clozapine antipsychotic (7) and even less evidence to support dual antipsychotic therapy (8). These data, however, predate the introduction of lumateperone. The unique pharmacodynamic profile of lumateperone provides theoretical support for either switching to this drug or combining it with other antipsychotics when previous trials have failed. At the very least, this strategy is worthy of further study.

Clinical Studies in Schizophrenia

Lumateperone appears efficacious in the treatment of schizophrenia, as established in two randomized controlled trials. In the first trial, lumateperone was compared with placebo and risperidone in patients (N=355) experiencing acute psychosis who had responded to antipsychotics in prior episodes (9). Reductions in Positive and Negative Syndrome Scale (PANSS) scores after 4 weeks, the primary endpoint, were significantly superior with 42 mg of lumateperone compared with placebo (effect size=0.42) and equivalent to the effects with 4 mg of risperidone. Further analysis revealed that lumateperone performed significantly better than placebo or risperidone for negative symptoms, especially in patients with prominent negative symptoms at baseline. Importantly, higher doses were no better than placebo on all measures—a notable observation for clinicians who may otherwise consider a dose increase for nonresponders. These results were confirmed in a second study in which 42 mg of lumateperone outperformed placebo in reduction of PANSS scores after 4 weeks in a similar patient population (N=450) (10). However, in a third, unpublished trial (NCT02469155) that lasted 6 weeks, which is longer than the two positive trials, the effects with lumateperone were not different from those with placebo and were inferior to effects with risperidone (11).

Clinical Studies in Bipolar Disorder

Lumateperone recently joined four other drugs approved for the treatment of depression in bipolar I disorder, and it is the second drug approved for the treatment of depressive episodes in bipolar II disorder. In the phase 3 registration trial, 377 patients, ages 18–75, with a diagnosis of bipolar I or II disorder who were experiencing a depressive episode were randomly assigned to treatment with drug or placebo. The active drug showed a significantly greater reduction in scores on the Montgomery-Åsberg Depression Rating Scale (MADRS)—4.6 points better than placebo at the end of 6 weeks (effect size=0.56)—which is similar to data supporting other bipolar depression treatments (12). Remarkably, though, when the outcome was calculated as a remission rate, lumateperone led to 39.9% remission, compared with 33.3% for placebo. The study found that for remission, the number needed to treat was 15; this number is higher than that for other drugs used for bipolar depression, such as quetiapine, lurasidone, and lamotrigine, the last of which does not have FDA approval for acute bipolar depressive episodes but is often used off-label because of maintenance efficacy (13, 14).
For the bipolar II group in particular, the reduction in MADRS score at 6 weeks with lumateperone was 7 points better than with placebo, which is a high number for depression studies in general and translated to an impressive effect size of 0.81 (12). However, only a small portion of patients in this study were in the bipolar II category (38 per arm), which tempers excitement regarding these results. In addition to this trial, a similar one (NCT02600507) found comparable efficacy for lumateperone in bipolar I and II disorder when used in combination with lithium or valproate, a feature shared by lurasidone in the treatment of bipolar I disorder (1, 15).

Side Effects

The side-effect profile of lumateperone is still under investigation because it is a new drug with limited head-to-head comparisons or long-term data available. The most common side effects in the schizophrenia studies that were observed at an incidence of >5% included somnolence (24%), dry mouth (9%), dizziness (6%), and nausea (5%) (1). The data for studies in bipolar depression were similar, except headache was also observed (14%) and somnolence was less frequent (14%) (1). In the initial clinical trials, rates of discontinuation attributable to side effects were low (912).
Notable side effects of other second-generation antipsychotics include metabolic side effects (e.g., weight gain, dyslipidemia, and hyperglycemia) and neurological side effects (e.g., dystonia and tardive dyskinesia). Although long-term data remain limited, there is no evidence that lumateperone causes weight gain in the first year of treatment (16). In short-term placebo-controlled studies, lumateperone fared no worse than placebo in metrics for hyperglycemia or dyslipidemia (912). However, some data from uncontrolled conditions indicated that a small portion of patients taking lumateperone over the course of a year will have a modest increase in hyperglycemia and dyslipidemia while on the medication (16). It is impossible, however, to attribute these changes to the medication with certainty.
Short-term studies with lumateperone show frequencies of extrapyramidal symptoms consistent with its weak D2 receptor affinity. When a variety of metrics were assessed, rates of these symptoms were low (<10% of patients in each trial) and comparable to rates obtained with placebo (912). It is noteworthy that rates of extrapyramidal symptoms in the trials of lumateperone were much lower in the active drug arm, compared with rates obtained in trials of other metabolically neutral drugs that are approved by the FDA for bipolar depression—i.e., cariprazine and lurasidone (17, 18). However, it would be premature to draw definitive conclusions because no head-to-head trials between these agents have been completed, and extrapyramidal symptoms often reveal themselves over a long period (e.g., tardive dyskinesia). Therefore, lumateperone carries a warning for tardive dyskinesia because the incidence of this side effect remains unknown.
Like similar drugs, lumateperone has warnings for rare but serious side effects, including mortality in elderly persons, neuroleptic malignant syndrome, falls, seizures, cognitive impairment, cerebrovascular events, leukopenia, agranulocytosis, and increased suicidal thoughts in children, adolescents, and young adults (1). The reason for this labeling is the drug class, and it is unknown how applicable these warnings are to lumateperone. Lumateperone does not yet have a formal warning for QTc prolongation; however, theoretical concern exists because of the drug class (1).

Contraindications and Special Populations

Lumateperone is contraindicated in persons with hypersensitivity to the drug (1). It has not been studied in children and only minimally studied in geriatric patients. Other antipsychotics increase the risk of death among the elderly population, and lumateperone shares a black box warning for this possibility, even though this risk has not been established with lumateperone. Moreover, the binding profile, which includes lower D2 receptor occupancy, very minimal alpha-adrenergic receptor blockade, and no noticeable muscarinic activity, suggests that lumateperone may pose lower risk than other antipsychotics in the elderly population, but this has yet to be confirmed in head-to-head trials (2). On the basis of preclinical data, the manufacturer advises against breastfeeding while taking lumateperone. There are no known birth defects associated with the drug, but caution is advised based on the fact that third-trimester exposure to other antipsychotics is associated with extrapyramidal symptoms and withdrawal in neonates (1).

Conclusions

Lumateperone is an easy-to-administer antipsychotic with a potentially novel mechanism of action. Data thus far indicate that it is metabolically safe and has limited extrapyramidal side effects. Evidence supporting its use in schizophrenia is mixed but promising (19). Moreover, lumateperone provides an alternative option for bipolar depression, an illness with important unmet need. Currently, however, lumateperone remains on patent, and long-term data are sparse. Further study will show how well this drug truly fares, compared with others.

Key Points/Clinical Pearls

Lumateperone is a recently approved antipsychotic with a unique pharmacodynamic profile that has clinical implications for side effects and efficacy.
Lumateperone has shown evidence of efficacy in the treatment of schizophrenia and targets both negative and positive symptoms.
Lumateperone became the fifth drug approved by the Food and Drug Administration for bipolar I depression and only the second for bipolar II depression, conditions with significant unmet need.
Its pharmacological profile and preliminary evidence indicate that lumateperone causes few metabolic or extrapyramidal side effects.

References

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Information & Authors

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Go to American Journal of Psychiatry Residents' Journal
American Journal of Psychiatry Residents' Journal
Pages: 18 - 20

History

Published online: 1 March 2023
Published in print: March 1, 2023

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Thomas DePietro, D.O.
Dr. DePietro, a lieutenant in the U.S. Navy, is a second-year resident in psychiatry at Walter Reed National Military Medical Center, Bethesda, Md. His views are his own and not necessarily representative of those of Walter Reed National Military Medical Center, the U.S. Navy, or the Department of Defense.

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