Sage Journals: Discover world-class research

Abstract

Schizophrenia is a devastating mental disorder resulting in marked morbidity and mortality despite the optimal use of all currently available interventions. For this reason, the release of lumateperone (Captyla^R), also known as ITI-007, an orally administered, atypical antipsychotic provided a welcome novel tool for clinicians to utilize precision medicine to tailor an optimal treatment plan to the specific needs of each person with schizophrenia. To generate a foundation for clinicians to assess the risks and benefits of lumateperone in relation to other interventions for schizophrenia, we conducted a search of items for ‘ITI-007’ and ‘lumateperone’ on PubMed, ScienceDirect, Web of Science, Google Scholar, and www.clinicaltrials.gov. We present a critical evaluation of the limited information about lumateperone for schizophrenia, its use approved by the US Food and Drug Administration. Lumateperone merits consideration for patients with treatment-resistant schizophrenia and for patients with schizophrenia who are vulnerable to developing metabolic dysfunction and movement disorders. On the other hand, lumateperone should not be used for (a) women who are pregnant or breastfeeding, children, adolescents, and elderly patients with dementia-related psychosis, (b) patients who are at risk for cerebrovascular diseases, (c) patients who use inducers and moderate or strong inhibitors of the cytochrome P450-3A4 (CYP3A4) isozyme, and (d) patients who use alcohol and other sedating agents. Clinical trials from multiple centers without financial conflicts of interest to market lumateperone are needed to directly compare and contrast lumateperone and other antipsychotic agents to generate trustworthy evidence to be assessed objectively by clinicians treating patients with schizophrenia. Future investigations will provide the foundations to identify the evidence for comprehensive evaluations of the role of lumateperone in the treatment of people with schizophrenia and other conditions.

Keywords

antipsychotic agents clinical trials evidence pharmacodynamics pharmacokinetics psychosis serotonin transporter

Introduction

Schizophrenia

Schizophrenia is a devastating mental health disorder affecting how a person interprets reality, expresses emotions, thinks, and behaves, and involving a variety of positive, negative, and cognitive symptoms with onset in adolescence or early adulthood.¹ Positive symptoms include hallucinations (auditory, visual, gustatory, olfactory, and tactile), delusions (persecutory, referential, somatic, erotomanic, grandiose, and religious), confused thoughts, disorganized speech, trouble concentrating, catatonic behavior,² and movement disorders.^1,3 Negative symptoms include anhedonia, apathy, asociality, alogia, flattening of affect, withdrawal, affective blunting, and inattention.^4,5 Cognitive symptoms include deficits in attention, working memory, concentration, and executive functions.¹

Schizophrenia is the eighth leading cause of disability worldwide in people aged 15–44 years.⁶ The prevalence rate of schizophrenia is 2%.^7,8 Men are 1.4 times more likely to be diagnosed with the condition than women.⁹ There are 1.5 new cases per 10,000 annually.⁸ Both genetic and environmental influences may precipitate the development of schizophrenia in vulnerable individuals.

The dopamine hypothesis

The dopamine hypothesis conjectures that hyperfunctionality of dopamine D₂ receptor neurotransmission in limbic and subcortical brain regions attributes to positive symptoms of schizophrenia, while hypoactivity of dopamine D₁ receptor neurotransmission contributes to negative and cognitive symptoms of the disease.^10–15

Antipsychotics

Antipsychotics, dopamine D₂ receptor blocking drugs, constitute a major therapeutic tool for the treatment of schizophrenia. However, Parkinsonism, akathisia,¹⁶ and other movement disorders are common adverse effects of traditional (first-generation) antipsychotics.¹⁷ Newer atypical (second-generation) antipsychotics modulate neurotransmission of 5-hydroxytryptamine (serotonin) and dopamine by acting as both serotonin 5-HT_2A receptor antagonists and dopamine D₂ receptor antagonists to treat both positive and negative symptoms of schizophrenia.¹⁸ In contrast to first-generation antipsychotics, second-generation antipsychotics provide superior treatment for negative symptoms, cognition, mood, and aggression¹⁹ and reduced risks of movement disorders.²⁰

The hallmark of currently available atypical antipsychotic medications, high levels of occupancy of striatal dopamine D₂ receptors, produces Parkinsonism, akathisia,¹⁶ and other extrapyramidal symptoms.²¹ Another issue with current antipsychotic drugs is the high affinity for off-target receptors such as serotonin 5-HT_2c, muscarinic, histamine H₁, and adrenergic α-1_A receptors, as well as excessive antagonism of dopamine receptors. Targeting of these receptors has caused serious side effects such as akathisia,¹⁶ weight gain, dyslipidemia, hyperglycemia, type II diabetes, and cardiac conduction issues.²¹

The clinical actions of antipsychotics result from their pharmacokinetic properties. First-generation antipsychotics are well absorbed orally and parentally. Peak plasma levels of first-generation antipsychotics are attained 15–30 min after parenteral administration and 1–4 h after oral administration. First-generation antipsychotics are protein-bound. Antipsychotics are highly lipophilic and are primarily metabolized by cytochrome P450 2D6 and P450 3A systems in the liver. They are excreted in urine and feces.²⁰ Both first- and second-generation antipsychotics provide some symptomatic improvement but also result in a variety of cardiometabolic, endocrine, and neurologic side effects. Their inability to treat effectively both positive and negative symptoms and resulting side effects requires more research into agents for schizophrenia with a risk-to-benefit ratio with more benefits and fewer risks.^22,23

Methods

Data sources and searches

A search of items for ‘ITI-007’ and ‘lumateperone’ on PubMed, ScienceDirect, Web of Science, Google Scholar, and www.clinicaltrials.gov generated extant publications on lumateperone in schizophrenia. As several reviews of lumateperone have utilized the available publications from investigators who have financial conflicts of interest to present articles that emphasize the potential benefits,^5,24–31 we sought to construct a selective review assessing the trustworthiness of the available evidence on the pharmacodynamics, pharmacokinetics, pharmacotherapy, and clinical trials of lumateperone in schizophrenia in order to provide expert insight for the possible role of this agent for people with schizophrenia. To enhance the trustworthiness of this article, we have limited ourselves to published articles and abstracts.^5,24

To enhance the trustworthiness of the available evidence for lumateperone, we sought to identify the risk of bias, inconsistency, indirectness, or publication bias.²³ The current literature about lumateperone is hindered by the dearth of data from authors who are not supported by the pharmaceutical company that markets lumateperone.^26,32 Thus, published studies emphasize the putative promise of lumateperone by tilting the risk-to-benefit ratio of articles in favor of the benefits.³³ The paucity of available evidence for extant clinical studies for lumateperone in schizophrenia is inadequate for a definitive systematic review³⁴ of the topic. However, because lumateperone offers great promise to alleviate the suffering of people with schizophrenia, we seek to share our objective assessment to aid clinicians, administrators, policy planners, and advocates to apply precision medicine to the development of optimal treatment plans for people with schizophrenia.

Introduction to the compound

Lumateperone is an orally administered, atypical antipsychotic developed by Intra-Cellular Therapies (New York, NY, USA) for the treatment of schizophrenia and other neurologic and neuropsychiatric disorders.³⁵ Lumateperone is the first in class selective and simultaneous modulator of dopamine, serotonin, and glutamate,^{5,18,22,30,32,36–41} approved by the US Food and Drug Administration for the treatment of schizophrenia.⁴²

Chemistry

Lumateperone (4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolol[1,2,3-de]-quinoxalin-8-yl)-1-(4-fluoro-phenyl)-butan-1-one 4-methylbenzenesulfonate),⁴³ also known as ITI-007 and ITI-722, exists as the tosylate salt^{5,20,36,37,44} (Figure 1). The principal metabolite of lumateperone, ICI200131, is the alcohol produced by the reduction of the carbonyl side-chain by ketone reductase.^21,38,43,44

Figure 1.

Chemical structure of the principal metabolite of lumateperone (4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolol[1,2,3-de]-quinoxalin-8-yl)-1-(4-fluoro-phenyl)-butan-1-one 4-methylbenzenesulfonate) tosylate.^43,44

Mechanism of action

Lumateperone is a serotonin transport inhibitor and a potent antagonist at serotonin 5-HT_2A receptors^5,24,45–49 acting as a presynaptic partial agonist and a postsynaptic antagonist at dopamine D₂ receptors,^5,50,51 and as a dopamine receptor phosphoprotein modulator.^{5,22,28,45–49} It is also a dopamine D₁ receptor-dependent indirect modulator of glutamatergic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid⁵² and N-methyl-_D-aspartate (NMDA) GluN_2B receptors.^{5,19,24,53,54}

Routes of administration

The once-daily recommended dose is 42 mg administered orally with food.^24,55 In addition, a 26-year-old man with treatment-resistant paranoid schizophrenia required escalation of the dose of lumateperone to 84 mg/day to experience amelioration of auditory and visual hallucinations without adverse effects after 6 months of sustained therapy.⁵⁶ Thus, lumateperone could be a beneficial intervention for treatment-resistant schizophrenia.⁵⁵

Preclinical development of a long-acting injectable formulation of lumateperone for schizophrenia is ongoing in the USA.²⁴

Lumateperone comes with a black box warning that states that elderly patients with dementia-related psychosis are at an increased risk of death. The drug is not approved for the treatment of dementia-related psychosis.^24,43

Other indications for lumateperone

Clinical development of lumateperone for possible use in major depressive disorders, behavioral disorders associated with Alzheimer’s disease and dementia, bipolar disorder, and sleep maintenance is underway in many countries around the world.^5,24 The use of lumateperone for conditions other than schizophrenia is beyond the scope of this review.

Pharmacodynamics

Lumateperone displays a high binding affinity for serotonin 5-HT_2A receptors and moderate binding affinity for dopamine D₁ receptors, dopamine D₂ receptors, and serotonin transporters. It also demonstrates a moderate binding affinity for dopamine D₄, and α-1_A and α-1_B adrenergic receptors along with a low binding affinity for muscarinic and histaminergic receptors.^5,24

Dopamine D₂ receptor

Lumateperone has a high affinity for dopamine D₂ receptors (Ki = 32 nM) selectively in mesolimbic and mesocortical regions.²² The drug acts as a postsynaptic dopamine D₂ receptor antagonist and a presynaptic partial agonist at dopamine D₂ receptors. The dosage of lumateperone correlates well with D₂ receptor occupancy.²¹ Lumateperone rapidly penetrated the brain in healthy volunteers (n = 16) with long-lasting, dose-related, and plasma concentration-related striatal dopamine D₂ receptor occupancy.^21,24 A dose of 10 mg of lumateperone displayed low occupancy (≈12%) of striatal dopamine D₂ receptors, while 40 mg of lumateperone displayed peak occupancy up to 39% of striatal dopamine D₂ receptors.²¹ In a phase II positron emission tomography (PET) study (NCT02288845), patients with schizophrenia who received 60 mg of lumateperone once daily showed peak dorsal striatal dopamine D₂ receptor occupancy (mean 39%) at 1 h post-dose.^21,24

Dopamine D₁ receptor and glutamate GluN2B receptor

Lumateperone acts upon dopamine D₁ receptors with dose-dependent high affinity (Ki = 52 nM) phosphorylating the GluN2B (NR2B) subunit of the NMDA receptor.^5,36,52,57

Dopamine transporter

Inhibition of the dopamine transporter represents a special characteristic of lumateperone that may lead to beneficial effects in schizophrenia.⁵⁸

Serotonin 5-HT_2A receptor

Lumateperone acts as a strong serotonin 5-HT_2A receptor antagonist (Ki = 0.54 nM).⁵ In a study of 16 healthy men who had a mean age of 30.7 years with an average basal metabolic index of 24.6 with a standard deviation of (±3.0), 5-HT_2A receptors were fully saturated (>80%) by oral doses of lumateperone as low as 10 mg.²¹ A dose of 40 mg of lumateperone demonstrated occupancy up to 33% of striatal serotonin transporters.^21,31

Serotonin transporter

At medium doses, lumateperone acts as a potent serotonin transporter inhibitor (Ki = 62 nM). 5-HT_2A receptor antagonism exerts a synergistic effect with serotonin transporter inhibition for greater antidepressant efficacy.^5,21

Off-target actions

Lumateperone displays minimal affinity for off-target receptors, ion channels, neurotransmitter transporters, and enzymes. Those are common targets of other antipsychotic drugs that may cause adverse effects like weight gain, sedation, and orthostatic hypotension.³⁷ It displays a moderate binding affinity for dopamine D₄ and α-1_A and α-1_B adrenergic receptors (Ki protected at <100 nM), with a low binding affinity (<50% inhibition at 100 nM) for muscarinic and histaminergic receptors.²⁴

Pharmacokinetics

Key aspects of the pharmacokinetics of lumateperone include the absorption of lumateperone by the body, the distribution of lumateperone throughout the body, the conjugation of lumateperone in the liver, and the excretion of lumateperone from the body.⁵⁹

Time course of absorption

T_max occurs at 3–4 h after the oral administration of lumateperone. At 8 h after oral administration, plasma concentrations of 0.05–50 ng/ml of lumateperone and 0.2–100 ng/ml of metabolites were detected.^5,21

Bioavailability

In ≈1–2 h, the peak plasma concentration of lumateperone is achieved.⁴³ Steady-state concentrations are achieved in ≈5 days. Steady-state exposure of lumateperone increases in an approximately dose-proportional manner, with multiple doses in the range 21–56 mg. The pharmacokinetics of lumateperone is variable among individuals, with a coefficient of variation for C_max and area under the curve (AUC) ranging at steady state from 68% to 97%. This drug has an absolute bioavailability of ≈4.4%. C_max increases by 33%, AUC increases by 9%, and the median time to C_max is delayed by ≈1 h (from 1 h in fasting state to 2 h in presence of food) when lumateperone is given with a high-fat meal.^24,43

Distribution

Following intravenous administration, the volume of distribution for lumateperone is ≈4.1 L/kg.²⁴ It is bound to 97.4% plasma proteins at 5 µM (≈70 times higher than therapeutic concentrations).

Metabolism

Lumateperone produces more than 20 metabolites by undergoing metabolism by different enzymes. These include uridine diphosphate (UDP) glycosyltransferase (UGT)1A1, UGT1A4, UGT2B15, aldo-keto reductase (AKR)1C1, AKR1B10, AKR1C4, CYP3A4, CYP2C8, and CYP1A2.^24,43

Excretion

Lumateperone and glucuronidated metabolites represent ≈2.8% and 51% of the total plasma radioactivity following a single dose of radiolabeled lumateperone. Around 58% of the radioactivity is excreted in the urine, <1% of the drug is excreted in the urine in unchanged form, and 29% is excreted in the feces. After intravenous administration, the terminal half-life is ≈18 h and the clearance is ≈17.9 L/h.^24,43

Toxicokinetics

Age, sex, or race does not affect pharmacokinetics to a significant clinical extent.⁴³ Lumateperone should not be given with moderate or strong CYP3A4 inhibitors and UGT inhibitors. Co-administration will increase the risk of toxicity.⁴³ Since inducers and inhibitors of CYP34A increase the concentration of lumateperone, co-administration of these compounds is contraindicated.⁶⁰

The high plasma protein binding (97.4%) in humans suggests that this compound may be retained in the body for an extended duration.³⁸

Dosing routes

Currently, the dosing route of lumateperone is orally in a capsule containing lumateperone developed as a crystalline, tosylate salt. (NCT01499563).³⁸

Adverse effects

Common side effects of lumateperone are headache, somnolence, dizziness,²⁹ sedation, fatigue, and constipation (4–6.7%).⁶⁰

Contraindications

Due to interactions with the cytochrome P450-3A4 (CYP3A4) isozyme, clinicians should cautiously administer lumateperone to patients who take inducers and inhibitors of CYP3A4. In addition, to avoid sedation, clinicians should discourage the use of lumateperone with alcohol and other agents for sedation.^5,25,61 Clinicians should avoid prescribing lumateperone for those at risk of cerebrovascular diseases.⁶²

Clinical trials

Multiple clinical trials conducted by the pharmaceutical company marketing lumateperone have reported beneficial effects without safety issues.^39,45-49 Key clinical trials for lumateperone for schizophrenia are summarized in Table 1.

Table 1.

Clinical trials of lumateperone for schizophrenia.

No.	Name	Sponsors and collaborators	Indication	Phase	Stage of development	Clinicaltrials.gov/Identification	Site
1.	Lumateperone, oral administration	Intra-Cellular Therapies	Pediatric patients with schizophrenia or schizoaffective disorder	1	Not yet recruiting	NCT04779177	USA
2.	Lumateperone, long-acting injectable	Intra-Cellular Therapies	Patients with schizophrenia	1	Recruiting	NCT04709224	USA
3.	ITI-007 (lumateperone tosylate)	New York State Psychiatric Institute and Intra-Cellular Therapies	Schizophrenia	2	Completed	NCT03817528	USA
4.	ITI-007 (lumateperone tosylate)	Intra-Cellular Therapies	Patients with stable schizophrenia	2	Completed	NCT02288845	USA
5.	ITI-007 (lumateperone tosylate), risperidone, placebo	Intra-Cellular Therapies	Schizophrenia	2	Completed	NCT01499563	USA
6.	ITI-007 (lumateperone tosylate), risperidone, placebo	Intra-Cellular Therapies	Patients with schizophrenia having an acute exacerbation of psychosis	3	Completed	NCT02469155	USA
7.	ITI-007 (lumateperone tosylate), placebo	Intra-Cellular Therapies	Patients with schizophrenia	3	Completed	NCT02282761	USA

Phase II trials

Stable schizophrenia

A phase II, open-label PET study (NCT02288845) was conducted to determine the relationship between lumateperone dose, plasma levels, and brain receptor occupancy in patients with stable schizophrenia. A total of 14 participants with stable schizophrenia were enrolled in the study; 10 patients aged 26–57 years received lumateperone 60 mg and completed the study. Nine (90%) patients were Black/African and one (10%) was Asian. Among these patients only one was female (10%). Patients were stable at baseline with a mean Positive and Negative Syndrome Scale (PANSS)⁶³ total score of 72.7 with a standard deviation of (+/−7.39) and a mean Clinical Global Impressions Severity (CGI-S)⁶⁴ score of 3.8 with a standard deviation of (+/−0.63). Before the washout period, all of the patients took at least one antipsychotic. Quetiapine (eight patients, 80%) and risperidone (three patients, 30%) were the most popular ones, while haloperidol, olanzapine, lurasidone, and paliperidone were among the others taken. During the study and washout period, none of the other antipsychotics were taken. Lorazepam (nine patients, 90%) was the only psychotic medication that was taken simultaneously. A dose of 60 mg lumateperone was administered orally open-label in the morning once daily for 2 weeks in patients with schizophrenia (n = 10) and at least after a washout period of 2 weeks. [¹¹C]raclopride was used as a radiotracer with PET to determine dopamine D₂ receptor occupancy. Patients who received 60 mg of lumateperone once daily showed peak dorsal striatal dopamine D₂ receptor occupancy (mean 39%) at 1 h post-dose. This study showed that lumateperone has a favorable safety profile and is well tolerated.^5,46

Acute exacerbation of psychosis in schizophrenia

Another phase II (NCT01499563) randomized clinical trial was conducted in a double-blind, placebo-controlled, multi-center manner in patients with schizophrenia having an acute exacerbation of psychosis. The study was conducted to assess the efficacy and safety of two dose levels of lumateperone compared with placebo. Risperidone was included as a positive control. Patients aged 18–55 years were randomized to receive lumateperone 42 mg (n = 84), lumateperone 84 mg (n = 84), risperidone 4 mg (n = 82), or placebo (n = 85) once daily for 4 weeks. The least squares (LS) mean change from baseline in the PANSS⁶³ total score (primary endpoint) was −13.22, −8.3, −13.4, and −7.4 in the above groups, respectively, on day 28. After 28 days of inpatient treatment, patients were started on standard antipsychotic medication and were stabilized over 5 days before being discharged from the study clinic. Patients were assessed for final outpatient safety evaluation at the end of the study visit 2 weeks after discharge. While the difference between lumateperone 84 mg once daily and placebo was not significant, there was statistical significance between lumateperone 42 mg once daily and placebo (p = 0.017) and between risperidone and placebo (p = 0.013). Both risperidone and lumateperone 42 mg once daily significantly (p =< 0.05) improved positive symptoms and general psychopathology on the PANSS⁶³ subscales compared with placebo. Lumateperone 42 mg once daily improved depressive and psychotic symptoms in a subgroup of severely ill patients with comorbid depression.^5,18

Phase III trials

Acute exacerbation of psychosis in schizophrenia

A phase III (NCT02282761) randomized, double-blind, parallel-group, placebo-controlled, multi-center study was conducted in patients diagnosed with schizophrenia having an acute exacerbation of psychosis. The goal of the study was to determine the efficacy and safety of lumateperone for the short-term treatment of schizophrenia. A total of 450 patients aged 18–60 years were enrolled in the study from 12 clinical sites in the USA. A total of 150 patients were randomized in each group to receive lumateperone tosylate 60 mg or 40 mg (corresponding to 42 mg or 28 mg of the active moiety) or placebo once daily for 4 weeks. The change from baseline to day 28 in the PANSS⁶³ score versus placebo was the main endpoint. The LS mean change from baseline in the PANSS⁶³ total score at day 28 was −14.5 in the lumateperone 42 mg once daily group compared with −10.3 in the placebo group (LS mean difference −4.2; p = 0.02) in the prespecified modified intention-to-treat analysis (n = 435). The treatment effect of lumateperone 28 mg once daily versus placebo was not statistically noteworthy (LS mean difference −2.6). Significant improvements (p < 0.05) with lumateperone 42 mg versus placebo were also presented on the PANSS⁶³ positive symptom and general psychopathology subscales, and in psychosocial function, as measured by the PANSS-derived prosocial factor score and personal and social performance (PSP)⁶⁵ scale at day 28.⁶¹ Both doses of lumateperone were well tolerated without changes in cardiometabolic or endocrine factors or significant treatment-emergent motor adverse effects versus placebo. The drug demonstrated a favorable safety profile and efficacy for improving symptoms of schizophrenia.^5,61

Acute exacerbation of psychosis in schizophrenia

A phase III (NCT02469155) clinical trial was conducted to evaluate the antipsychotic efficacy of lumateperone in a randomized, double-blind, parallel-group, placebo- and active-controlled, multi-center study in patients with schizophrenia having an acute exacerbation of psychosis. A total of 696 patients were randomized to receive lumateperone 42 mg, lumateperone 14 mg, risperidone 4 mg, or placebo once daily for 6 weeks.³⁶ Concerning the change in baseline score on PANSS,⁶³ there was no significant difference among doses. A high placebo response was noticed.^5,45

Stable schizophrenia

A phase III (NCT03817528) 12-month open-label safety study of lumateperone was conducted in patients with stable symptoms of schizophrenia. In part one of this study, 303 patients with schizophrenia were switched from standard of care (SOC) antipsychotic therapy to 6 weeks of 42 mg lumateperone once daily. The patients were then switched back to SOC for 2 weeks. Part one of the study showed that lumateperone was associated with improvements from baseline in the PANSS total score,⁶³ Marder et al.⁶⁶ negative factor scale scores, positive symptom and general psychopathology subscale scores, and on the PSP scale.^65,67 Greater improvements were visible in patients with comorbid symptoms of depression and prominent negative symptoms at baseline.⁶⁷

In the second part of this study, 602 patients with schizophrenia were moved from SOC to 42 mg lumateperone once daily for up to 1 year.^48,49,68 The mean change in the Calgary Depression Scale for Schizophrenia score⁶⁹ from the baseline was −0.6 (p = 0.01) and the mean change from SOC baseline in the PANSS total score⁶³ was −4.0 (p < 0.001) at day 368. In patients with moderate to severe depression, improvements were more noticeable at baseline.^68,70–72

Phase II and phase III pooled trials

By combining results from multiple studies, the sponsors of lumateperone argued that overall lumateperone was effective for patients with schizophrenia. Since the authors have a financial interest in the marketing of lumateperone, there may be biases in the publications.²³ A pooled analysis (n = 520) showed that 42 mg of lumateperone once daily reduced the PANSS total score⁶³ (LS mean difference versus placebo −4.76; p < 0.001) and established comparable efficacy to risperidone (LS mean difference versus placebo −4.97; p = 0.014).⁷⁰ Lumateperone was associated with significant improvements on PANSS⁶³ subscales and the CGI-S⁶⁴ scale and significantly higher PANSS⁶³ response rates. On combining all three studies together, the ability of lumateperone 42 mg once daily to demonstrate statistical dominance over placebo was not impacted by the negative results of one study.⁷³

Relevance to clinical practice

Key questions need answers. Does lumateperone have greater or equivalent efficacy when compared with other antipsychotics? Is lumateperone more metabolically friendly? Further research is needed to determine its comparative ranking. Due to the dearth of trustworthy evidence²³ to assess the role of lumateperone in the treatment of people with schizophrenia, we utilize the available indirect assessment to provide guidance to providers for patients with schizophrenia.

Antipsychotics such as brexpiprazole, cariprazine, and lurasidone, which are known better for their tolerability than efficacy, have comparable effect sizes as lumateperone. The higher efficacy antipsychotics (i.e. olanzapine and clozapine) come with increased metabolic side-effect profiles.⁷⁴ Lumateperone’s strongest selling points are its novel mechanism of action and its tolerability.^74–77 Lumateperone is well tolerated with a low risk of extrapyramidal and cardiometabolic side effects and improves or maintains schizophrenia symptoms in outpatients with stable schizophrenia.⁷¹ For patients who are not tolerant of current antipsychotic medications either because of extrapyramidal side effects or metabolic adverse effects, lumateperone may be proven as a good choice of medication as it is not significantly associated with metabolic and extrapyramidal symptoms.²⁹

However, the high cost of lumateperone should also be considered. Some healthcare systems with financial limitations might not be able to consider lumateperone as the first choice because of the financial costs.⁷⁶ In a multi-country comparison study, lifetime costs associated with anti-psychotics (cost related to adverse effects, relapse, drug cost, schizophrenia management, and treatment discontinuation) were compared. Costs of 10 antipsychotics including aripiprazole, brexpiprazole, cariprazine, lumateperone, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, and ziprasidone were assessed. Costs from seven countries (France, Hungary, Italy, Slovenia, Spain, Sweden, and the UK) were obtained. The results showed that the lifetime costs are greatly driven by diabetes and the cardiovascular side effects of antipsychotics. These effects were lowest for lurasidone, second lowest for ziprasidone, and third lowest for lumateperone.⁷⁶ To make an informed treatment choice, costs must be considered before prescribing antipsychotics to patients.

Expert insight

Although the literature contains recommendations that may reflect the marketing strategies of the authors and lacks multi-center comparisons between lumateperone and other atypical antipsychotics,⁵¹ we seek to provide clinicians guidelines to apply the principles of precision medicine to structure treatment plans tailored to the needs of individuals with schizophrenia. A frank discussion with patients of the risks and benefits of available antipsychotic agents can then result in obtaining informed consent based on the extant evidence. Lumateperone merits consideration for patients who are vulnerable to developing metabolic adverse effects⁷² and movement disorders.^27,70,71,78

There are several issues that lead clinicians to avoid prescribing lumateperone to patients with schizophrenia. Due to the increased risk of death, lumateperone must be avoided in the treatment of elderly patients with dementia-related psychosis.⁴³ To avoid unwanted drug interactions, lumateperone should not be used for patients who are taking inducers of the CYP3A4 isozyme or moderate or strong inhibitors of the CYP3A4 isozyme.⁴³ Due to the sedative property of lumateperone, it should be avoided in the treatment of patients who take alcohol and other soporific agents.^5,25 To avoid the increased risk of stroke and transient ischemic attacks, clinicians should avoid administering lumateperone to those at risk of cerebrovascular diseases.⁶² Due to the unknown effects on developing organs and children, lumateperone should be avoided in women who are or may become pregnant or breastfeeding, and in children and adolescents.

Discussion

The role of lumateperone in the treatment of people with schizophrenia can be estimated utilizing limited available evidence²³ and indirect comparisons with other available agents. To personalize prescription, efficacy and side-effect profiles of antipsychotics should be considered.⁷⁹ A good overall safety profile is demonstrated by the newer antipsychotics.^60,79 Lumateperone has the advantageous properties of relatively low risks of common antipsychotic adverse effects, including weight gain, Parkinsonism, and akathisia.^78,80

New antipsychotics should be compared with older ones because the newer antipsychotics are not always the most efficacious. Older drugs may have a higher efficacy but newer ones are important when it comes to the side-effect profile.^79–82 The available literature is limited by the use of pooled studies and statistical arguments to explain the negative results of some clinical trials.^81–82 In addition, the current evaluation of some clinical trials is limited to examination of abstracts and posters because the findings have not been published as original research articles.

Limitations

The trustworthiness of the available evidence for lumateperone is hindered by the risk of bias, inconsistency, indirectness, or publication bias.²³ The conduct of studies by the pharmaceutical company with a financial interest to market lumateperone confirms the risk of bias, inconsistency, indirectness, or publication bias²³ in the extant literature. The current literature about lumateperone is hindered by the dearth of data from authors who are not supported by the pharmaceutical company that markets lumateperone. Low to very low confidence in published articles limits the ability to assess the value of lumateperone and other antipsychotics in comprehensive reviews.^34,83,84

Future directions

Future clinical trials to detect relapse will benefit from the careful design, checking cognitive⁸⁵ and other adverse effects,^78,86,87 cautious discontinuation, and measurement of environmental influences to minimize the confounding effects of withdrawal.⁸⁸

When data from multiple centers without financial interest in lumateperone for schizophrenia are available, well-conducted systematic reviews^34,83,84 can be conducted. Future reviews will be enhanced by the inclusion of postmarketing surveillance for adverse effects.⁵

Future investigations may be enhanced by the identification of subtypes of schizophrenia incorporating genetic and environmental influences,^19,41 as well as specific indications and optimal doses,³² utilizing valid, reliable, and responsive single-item global impression⁸⁹ and other rating scales in order to apply the principles of precision medicine to tailor an optimal treatment plan to the specific needs of individual patients. Head-to-head comparisons of newer and older agents for efficacy and adverse effects will enhance objective assessments of pharmaceuticals for schizophrenia.³²

Future investigations will be enhanced by the use of biomarkers to provide quantitative measurements of receptor expression before, during, and after treatment with lumateperone. PET provides an invaluable tool to determine precisely the occupancy of each receptor affected by lumateperone.^21,46 The utilization of PET along with behavioral, cognitive, physiological,⁹⁰ and environmental measurements^14,89,91 provide a foundation for optimal clinical trials of schizophrenia,^10,15 and other neuropsychiatric disorders^92–100 and medical disorders.^101–103 PET will provide a tool to identify the effects of lumateperone on neurotransmitter systems already studied^21,46 and other possible pathways.^92,100 Comprehensive multi-modal investigations by teams of experts around the world will facilitate the identification of biomarkers for clinical phenotypes of schizophrenia¹⁰⁴ to provide clinicians with the foundations to apply precision medicine to individuals with schizophrenia.

Conclusion

Lumateperone, a first in class selective and simultaneous modulator of dopamine, serotonin, and glutamate,²² received its first global approval in the USA on 20 December 2019 for the treatment of schizophrenia in adults.³⁰ Lumateperone has demonstrated efficacy against both positive and negative symptoms of schizophrenia and has a good tolerability and safety profile.⁸⁰ Lumateperone has proven to be a promising drug in clinical trials for bipolar depression, dementia, and sleep maintenance insomnia.³¹ It is currently being used in clinical trials around the world. While lumateperone has been approved for the treatment of schizophrenia in adults, more research is needed for its use in bipolar depression, dementia,¹⁰⁵ and sleep maintenance insomnia. Clinicians must balance the optimistic outcomes of the trials funded by the sponsor of lumateperone with a frank assessment of limited data to utilize precision medicine to generate the best treatment plan for individuals with schizophrenia.¹⁰⁶ A comprehensive evaluation of its efficacy in long-term human studies will be required to demonstrate its efficacy in the above mentioned conditions.

Footnotes

Acknowledgements

The authors thank the Welch Medical Library, Johns Hopkins University, Baltimore, MD, USA for assistance in obtaining the references.

Conflict of interest statement

The authors declare that there is no conflict of interest.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

James Robert Brašić

References

National Institute of Mental Health. Schizophrenia. www.nimh.nih.gov/health/topics/schizophrenia/index.shtml (2020, accessed 15 July 2021).

Andreasen

NC.

Scale for the assessment of positive symptoms (SAPS). Rating scale. University of Iowa, IA: Department of Psychiatry, College of Medicine University of Iowa, 1984.

D’Arrigo

Schizophrenia symptoms. WebMD, www.webmd.com/schizophrenia/schizophrenia-symptoms (2020, accessed 15 July 2021).

Andreasen

NC.

Scale for the assessment of negative symptoms (SANS). Rating scale. University of Iowa, IA: Department of Psychiatry, College of Medicine University of Iowa, 1984.

Vyas

Hwang

Brašić

JR.

An evaluation of lumateperone tosylate for the treatment of schizophrenia. Expert Opin Pharmacother 2020; 21: 139–145.

Haddad

Correll

CU.

The acute efficacy of antipsychotics in schizophrenia: a review of recent meta-analyses. Ther Adv Psychopharmacol 2018; 8: 303–318.

GBD 2016 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet 2017; 390: 1211–1259.

McGrath

Saha

Chant

, et al. Schizophrenia: a concise overview of incidence, prevalence, and mortality. Epidemiol Rev 2008; 30: 67–76.

Abel

Drake

Goldstein

JM.

Sex differences in schizophrenia. Int Rev Psychiatry 2010; 22: 417–428.

10.

Brašić

JR.

Neurotransmitter visualization in schizophrenia. J Biomed Graph Comput 2013; 3: 30–45.

11.

Toda

Abi-Dargham

Dopamine hypothesis of schizophrenia: making sense of it all. Curr Psychiatry Rep 2007; 9: 329–336.

12.

Wong

Brašić

JR.

Progress in the neuropsychiatry of schizophrenia. Psychiatr Times 2005; 22: 57, 58, 60.

13.

Wong

Gründer

Cascella

, et al. Molecular brain imaging in schizophrenia. In: Sadock

Sadock

Ruiz

(eds) Kaplan & Sadock’s comprehensive textbook of psychiatry. 9th ed. Philadelphia: Lippincott Williams & Wilkins, 2009, pp.1519–1530.

14.

Wong

Brašić

Cascella

Neuroreceptor imaging of schizophrenia. In: Shenton

Turetsky

(eds). Understanding neuropsychiatric disorders: insights from neuroimaging. Cambridge: Cambridge University Press, 2011, pp.78–87.

15.

Wong

Brašić

Horti

, et al. Molecular brain imaging in schizophrenia. In: Sadock

Sadock

Ruiz

(eds) Kaplan & Sadock’s comprehensive textbook of psychiatry. 10th ed. Philadelphia: Lippincott Williams & Wilkins, 2017, pp.1488–1501.

16.

Musco

McAllister

Caudle

Dopamine-receptor blocking agent-associated akathisia: a summary of current understanding and proposal for a rational approach to treatment. Ther Adv Psychopharmacol 2020; 10: 2045125320937575.

17.

Marder

Davis

MC.

First-generation antipsychotics. In: Sadock

Sadock

Ruiz

(eds) Kaplan & Sadock’s comprehensive textbook of psychiatry. 10th ed. Philadelphia: Lippincott Williams & Wilkins, 2017, pp.3170–3218.

18.

Lieberman

Davis

Correll

, et al. ITI-007 for the treatment of schizophrenia: a 4-week randomized, double-blind, controlled trial. Biol Psychiatry 2016; 79: 952–961.

19.

Meltzer

Gadeleta

Contrasting typical and atypical antipsychotic drugs. Focus 2021; 19: 3–13.

20.

Strassnig

Harvey

PD.

Second-generation antipsychotics. In: Sadock

Sadock

Ruiz

(eds) Kaplan & Sadock’s comprehensive textbook of psychiatry. 10th ed. Philadelphia: Lippincott Williams & Wilkins, 2017, pp.3059–3082.

21.

Davis

Vanover

Zhou

, et al. ITI-007 demonstrates brain occupancy at serotonin 5-HT2A and dopamine D2 receptors and serotonin transporters using positron emission tomography in healthy volunteers. Psychopharmacology 2015; 232: 2863–2872.

22.

Citrome

Emerging pharmacological therapies in schizophrenia: what’s new, what’s different, what’s next?

CNS Spectr 2016; 21(Suppl. 1): 4–11.

23.

Hultcrantz

Rind

Akl

, et al. The GRADE Working Group clarifies the construct of certainty of evidence. J Clin Epidemiol 2017; 87: 4–13.

24.

Blair

HA.

Lumateperone: first approval. Drugs 2020; 80: 417–423.

25.

Cooper

Lumateperone . Lumateperone. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing, 2021.

26.

Lumateperone (Caplyta) for schizophrenia. Med Lett Drugs Ther 2020; 62: 113–116.

27.

Edinoff

deBoisblanc

, et al. Lumateperone for the treatment of schizophrenia. Psycholpharmacol Bull 2020; 50: 32–59.

28.

Frampton

JE.

Lumateperone in schizophrenia: a profile of its use. Drugs Ther Perspect 2020; 36: 477–484.

29.

Greenwood

Acharya

Marcellus

, et al. Lumateperone: a novel antipsychotic for schizophrenia. Ann Pharmacother 2021; 55: 98–104.

30.

Kumar

Kuhad

Lumateperone: a new treatment approach for neuropsychiatric disorders. Drugs Today 2018; 54: 713–719.

31.

Mazza

Marano

Traversi

, et al. Evidence on the new drug lumateperone (ITI-007) for psychiatric and neurological disorders. CNS Neurol Disord Drug Targets 2020; 19: 243–247.

32.

Davis

JM.

Commentary on: Corponi

Fabbri

Bitter

Montgomery

Vieta

Kaspar

Pallanti

Serretti

Novel antipsychotics specificity profile: a clinically oriented review of lurasidone, brexpiprazole, cariprazine and lumateperone. Eur Neuropsychopharmacol 2019; 29: 1061–1062.

33.

Limandri

BJ.

Lumateperone: new drug or same old drug with a new dress?

J Psychosoc Nurs Ment Health Serv 2020; 48: 9–12.

34.

Higgins

JPT

Green

(eds) Cochrane handbook for systematic reviews of interventions. Chicester: John Wiley & Sons Ltd, 2008.

35.

Reddy

Poole

Maguire

, et al. New medications for neuropsychiatric disorders. Psychiatr Clin N Am 2020; 43: 399–413.

36.

Davis

Correll

CU.

ITI-007 in the treatment of schizophrenia: from novel pharmacology to clinical outcomes. Expert Rev Neurother 2016; 16: 601–614.

37.

Dimitrelis

Shankar

Pharmacological treatment of schizophrenia – a review of progress. Prog Neurol Psychiatry 2016; 20: 28–35.

38.

Zhang

Robichaud

, et al. Discovery of a tetracyclic quinoxaline derivative as a potent and orally active multifunctional drug candidate for the treatment of neuropsychiatric and neurological disorders. J Med Chem 2014; 57: 2670–2682.

39.

Snyder

Vanover

Davis

, et al. A review of the pharmacology and clinical profile of lumateperone for the treatment of schizophrenia. Adv Pharmacol 2021; 90: 253–276.

40.

Snyder

Vanover

Zhu

, et al. Functional profile of a novel modulator of serotonin, dopamine, and glutamate neurotransmission. Psychopharmacology 2015; 232: 605–621.

41.

Guillin

Les antipsychotiques de la future decade. [What antipsychotic drugs will be in the next decade.]

Bull Acad Natl Med 2020; 204: 1043–1046.

42.

Center for Drug Evaluation and Research. Approval package for: application number: 209500Orig1s000 2019. Silver Spring, MD: Food and Drug Administration, 2019. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/209500Orig1s000Approv.pdf (2019, accessed 15 July 2021).

43.

Intra-Cellular Therapies Inc. Caplyta (lumateperone) capsules, for oral use (package insert). New York: Intra-Cellular Therapies, Inc. https://www.intracellulartherapies.com/docs/caplyta_pi.pdf (2019, accessed 15 July 2021).

44.

Tomesch

Wennogle

4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone toluenesulfonic acid addition salt and salt crystals. Patent 9199995-B2, USA, 2015.

45.

Vanover

Glass

Kozauer

, et al. Lumateperone (ITI-007) for the treatment of schizophrenia: overview of placebo-controlled clinical trials and an open-label safety switching study [abstract no. 30]. CNS Spectr 2019; 24: 190–191. [abstract]

46.

Vanover

Davis

Zhou

, et al. Dopamine D₂ receptor occupancy of lumateperone (ITI-007): a positron emission tomography study in patients with schizophrenia. Neuropsychopharmacology 2019; 44: 598–605.

47.

Vanover

Dmitrienko

Glass

, et al. Lumateperone (ITI-007) for the treatment of schizophrenia: placebo-controlled clinical trials and an open-label safety switching study. Schizophr Bull 2019; 45(Suppl. 2): S341. [abstract]

48.

Vanover

O’Gorman

Glass

, et al. Favorable clinical safety profile for lumateperone (ITI-007) – switching from standard-of-care antipsychotic therapy in patients with schizophrenia [abstract no. T189]. Neuropsychopharmacology 2017; 42(Suppl. 1): S416–S417. [abstract]

49.

Vanover

Satlin

Durgam

, et al. Favorable long-term safety profile of lumateperone IITI-007): results from a 12 month open label safety study for lumateperone in patients with stable symptoms of schizophrenia. Schizophr Bull 2019; 45(Suppl. 2): S351. [abstract]

50.

Zhang

Hendrick

JP.

The presynaptic D2 partial agonist lumateperone acts as a postsynaptic D2 antagonist. Matters 2018; 1–4.

51.

Wang

S-M

Han

Lee

S-J

, et al. Investigational dopamine antagonists for the treatment of schizophrenia. Expert Opin Investig Drugs 2017: 26: 687–698.

52.

Svensson

Dutheil

Hendrick

, et al. Lumateperone uniquely enhances glutamatergic neurotransmission through activation of both NMDA and AMPA channels via a dopamine D1 receptor-dependent mechanism: implications for treatment of mood disorders. Neuropsychopharmacology 2017; 42(Suppl. 1): S160. [abstract]

53.

Capuzzi

Caldiroli

Ciscato

, et al. Experimental serotonergic agents for the treatment of schizophrenia. J Exp Pharmacol 2021; 13: 49–67.

54.

Titulaer

Radhe

Ström

, et al. The actions of lumateperone and single nucleotide polymorphism (SNP) converge on the glutamate-NO-cGMP pathway. Eur Neuropsychopharmacol 2020; 40(Suppl. 1): S332. [abstract]

55.

Kantrowitz

JT.

The potential role of lumateperone – something borrowed? Something new?

JAMA Psychiatry 2020; 77: 343–344.

56.

Farah

High-dose lumateperone: a case report. Curr Psychiatr 2021; 20: 42.

57.

Naguy

Alamiri

2019 FDA approved psychotherapeutic medications. Asian J Psychiatr 2020; 49: 101976.

58.

Olasupo

Uzairu

Shallangwa

, et al. Unveiling novel inhibitors of dopamine transporter via in silico drug design, molecular docking, and bioavailability predictions as potential antischizophrenic agents. Futur J Pharm Sci 2021; 7: 63.

59.

McLeod

HL.

Pharmacokinetics for the prescriber. Medicine 2016; 44: 407–411.

60.

Orsolini

De Berardis

Volpe

Up-to-date expert opinion on the safety of recently developed antipsychotics. Expert Open Drug Saf 2020; 19: 981–998.

61.

Correll

Davis

Weingart

, et al. Efficacy and safety of lumateperone for treatment of schizophrenia: a randomized clinical trial. [Erratum in JAMA Psychiatry 2020; 77(4): 438.] JAMA Psychiatry 2020; 77: 349–358.

62.

Ebied

Patel

Cooper-DeHoff

RM.

New drugs approved in 2019. Am J Med 2020; 133: 675–678.

63.

Kay

Fiszbein

Opler

LA.

The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 1987; 13: 261–276.

64.

Guy

Assessment manual for psychopharmacology revised. DHEW Publication No. (ADM)76-338. Rockville, MD: US Department of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, 1976, pp.217–222.

65.

Juckel

Personal and social performance scale. In: Michalos

(ed.) Encyclopedia of quality of life and well-being research. Dordrecht: Springer, 2014, p.206.

66.

Marder

Davis

Chouinard

The effects of risperidone on the five dimensions of schizophrenia derived by factor analysis: combined results of the North American trials. J Clin Psychiatry 1997; 58: 538–546.

67.

Davis

Dmitrienko

Glass

, et al. Lumateperone (ITI-007): favorable safety profile in an open label safety switching study from standard-of-care antipsychotic therapy in patients with schizophrenia [abstract no. F46]. Schizophr Bull 2018; 44(Suppl. 1): S236–S237. [abstract]

68.

Satlin

Vanover

Durgam

, et al. Additional results from a 12-month open-label safety study of lumateperone (ITI-007) in patients with stable symptoms of schizophrenia [abstract no. W203 plus poster]. In: 58th Annual Meeting of the American College of Neuropsychopharmacology, 2019.

69.

Addington

Maticka-Tyndall

Assessing depression in schizophrenia: the Calgary Depression Scale. Br J Psychiatry 1993; 22(Suppl.): 39–44.

70.

Correll

Vanover

Durgam

, et al. Results from a 12-month open-label safety study of lumateperone (ITI-007) in patients with stable symptoms of schizophrenia. Eur Neuropsychopharmacol 2019; 29(Suppl. 6): S454–S455. [abstract]

71.

Correll

Vanover

Davis

, et al. Safety and tolerability of lumateperone 42 mg: an open-label antipsychotic switch study in outpatients with stable schizophrenia. Schizophr Res 2021; 228: 198–205.

72.

Satlin

Durgam

Vanover

, et al. Cardiometabolic safety of lumateperone (ITI-007): post hoc analyses of short-term randomized trials and an open-label long-term study. Eur Neuropsychopharmacol 2020; 40(Suppl. 1): S265–S266. [abstract]

73.

Kane

Vanover

Durgam

, et al. Efficacy and safety of lumateperone tosylate 42 mg in the treatment of schizophrenia: a pooled analysis of phase 2 and 3 studies [abstract no. P.671]. Eur Neuropsychopharmacol 2019; 29 (Suppl. 6): S453–S454. [abstract]

74.

Kantrowitz

JT.

Managing negative symptoms of schizophrenia: how far have we come?

CNS Drugs 2017; 31:373–388.

75.

Maroney

An update on current treatment strategies and emerging agents for the management of schizophrenia. Am J Manag Care 2020; 26(Suppl. 1): S55–S61.

76.

Kearns

Cooper

Cantrell

, et al. Schizophrenia treatment with second-generation antipsychotics: a multi-country comparison of the costs of cardiovascular and metabolic adverse events and weight gain. Neuropsychiatr Dis Treat 2021; 17: 125–137.

77.

Martel

Gatti McArthur

Dopamine receptor subtypes, physiology and pharmacology: new ligands and concepts in schizophrenia. Front Pharmacol 2020; 11: 1003.

78.

Stahl

Maguire

GA.

How and when to treat the most common adverse effects of antipsychotics: expert review from research to clinical practice. Acta Psychiatr Scand 2021; 143: 172–180.

79.

Corponi

Fabbri

Bitter

, et al. Novel antipsychotics specificity profile: a clinically oriented review of lurasidone, brexpiprazole, cariprazine and lumateperone. Eur Neuropsychopharmacol 2019; 29: 971–985.

80.

Krogmann

Peters

von Hardenberg

, et al. Keeping up with the therapeutic advances in schizophrenia: a review of novel and emerging pharmacological entities. CNS Spectr 2019; 24(Suppl. 1): 38–69.

81.

Gouse

Chang

Smith

EG.

Effect size and blinding in lumateperone trial. JAMA Psychiatry 2020; 77: 650–651.

82.

Correll

Lakkis

Vanover

KE.

Effect size and blinding in lumateperone trial – reply. JAMA Psychiatry 2020; 77: 651–652.

83.

Huhn

Nikolakopoulou

Schneider-Thoma

, et al. Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis. Lancet 2019; 394: 939–951.

84.

Leucht

Cipriani

Spineli

, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 2013; 382: 951–962.

85.

MacKenzie

Kowalchuk

Agarwal

, et al. Antipsychotics, metabolic adverse effects, and cognitive function in schizophrenia. Front Psychiatry 2018; 9: 622.

86.

Hynes

McWilliams

Clarke

, et al. Check the effects: systematic assessment of antipsychotic side-effects in an inpatient cohort. Ther Adv Psychopharmacol 2020; 10: 2045125320957119.

87.

Liu

Fang

, et al. Current antipsychotic agent use and risk of venous thromboembolism and pulmonary embolism: a systematic review and meta-analysis of observational studies. Ther Adv Psychopharmacol 2021; 11: 2045125320982720.

88.

Cohen

Recalt

Withdrawal effects confounding in clinical trials: another sign of a needed paradigm shift in psychopharmacology research. Ther Adv Psychopharmacol 2020; 10: 2045125320964097.

89.

Gnanasakthy

Barrett

Norcross

, et al. Use of patient and investigator global impression scales: a review of Food and Drug Administration–approved labeling, 2009 to 2019. Value Health 2021; 24: 1016–1023.

90.

McKay

Harrigan

Brašić

JR.

A low-cost quantitative continuous measurement of movements in the extremities of people with Parkinson’s disease. MethodsX 2019; 6: 169–189.

91.

Vyas

Patel

Nijran

, et al. The use of PET imaging in studying cognition, genetics and pharmacotherapeutic interventions in schizophrenia. Expert Rev Neurother 2011; 11: 37–51.

92.

Brašić

Kim

The nicotine hypothesis. In: Madras

Kuhar

(eds) The effects of drug abuse on the human nervous system. Oxford: Academic Press, Elsevier Science, 2014, pp.313–332.

93.

Brasic

Mohamed

Human brain imaging of autism spectrum disorders. In: Seeman

Madras

(eds) Imaging of the human brain in health and disease. Oxford: Academic Press, Elsevier Science, 2014, pp.373–406.

94.

Brasic

Syed

Farhadi

, et al. PET scanning in autism spectrum disorder. Medscape Drug Dis. http://emedicine.medscape.com/article/1155568-overview (2020, accessed 15 July 2021).

95.

George

Gean

Nandi

, et al. Radiotracers used to image the brains of patients with Alzheimer’s disease In: Seeman

Madras

(eds) Imaging of the human brain in health and disease. Oxford: Academic Press, Elsevier Science, 2014, pp.407–416.

96.

Hwang

Mohamed

Brašić

JR.

Molecular imaging of autism spectrum disorder. Int Rev Psychiatry 2017; 29: 530–554.

97.

Syed

Brašić

JR.

Nuclear neurotransmitter molecular imaging of autism spectrum disorder. AIMS Mol Sci 2019; 6: 87–106.

98.

Wong

Brašić

Gean

, et al. The role of positron emission tomography (PET) in understanding addiction. In: MacKillop

de Wit

(eds) The Wiley-Blackwell handbook of addiction psychopharmacology. Chichester: John Wiley & Sons, 2013, pp.677–706.

99.

Wong

Maini

Rousset

, et al. Positron emission tomography – a tool for identifying the effects of alcohol dependence on the brain. Alcohol Res Health 2003; 27: 161–173.

100.

Wong

Nandi

Zaidi

, et al. Brain PET imaging in the cannabinoid system. In: Seeman

Madras

(eds) Imaging of the human brain in health and disease. Oxford: Academic Press, Elsevier Science, 2014, pp.27–36.

101.

Alexander

Yang

Yung

, et al. Diagnosis of benign solitary fibrous tumors by positron emission tomography. South Med J 2004; 97: 1264–1267.

102.

Alexander

Brašić

JR.

The diagnosis of esophageal cancer by 2-deoxy-2-F-18 fluoro-D-glucose positron emission tomography (F-18 FDG PET). Clin Nucl Med 2006; 31: 566–567.

103.

Alexander

Brašić

JR.

2-[¹⁸F]fluoro-2-deoxy-D-glucose ([¹⁸F]FDG) positron emission tomography (PET) for the diagnosis and treatment of Burkitt lymphoma. J Biomed Graph Comput 2013; 3: 67–72.

104.

Riva

Albert

de Filippis

, et al. Identification of clinical phenotypes in schizophrenia: the role of lurasidone. Ther Adv Psychopharmacol 2021; 11: 20451253211012250.

105.

Ahmed

Malik

Teselink

, et al. Current agents in development for treating behavioral and psychological symptoms associated with dementia. Drugs Aging 2019; 36: 589–605.

106.

Iasonos

Finding optimism in clinical trials: a numbers perspective. Oncologist 2021; 26: 84–85.

The role of lumateperone in the treatment of schizophrenia

Abstract

Keywords

Introduction

Schizophrenia

The dopamine hypothesis

Antipsychotics

Methods

Data sources and searches

Introduction to the compound

Chemistry

Mechanism of action

Routes of administration

Other indications for lumateperone

Pharmacodynamics

Dopamine D2 receptor

Dopamine D1 receptor and glutamate GluN2B receptor

Dopamine transporter

Serotonin 5-HT2A receptor

Serotonin transporter

Off-target actions

Pharmacokinetics

Time course of absorption

Bioavailability

Distribution

Metabolism

Excretion

Toxicokinetics

Dosing routes

Adverse effects

Contraindications

Clinical trials

Phase II trials

Stable schizophrenia

Acute exacerbation of psychosis in schizophrenia

Phase III trials

Acute exacerbation of psychosis in schizophrenia

Acute exacerbation of psychosis in schizophrenia

Stable schizophrenia

Phase II and phase III pooled trials

Relevance to clinical practice

Expert insight

Discussion

Limitations

Future directions

Conclusion

Footnotes

Acknowledgements

Conflict of interest statement

Funding

ORCID iD

References

Dopamine D₂ receptor

Dopamine D₁ receptor and glutamate GluN2B receptor

Serotonin 5-HT_2A receptor