Lumateperone for major depressive episodes in bipolar I or bipolar II disorder

Lumateperone (Caplyta) is a novel oral antipsychotic initially approved in 2019 for the treatment of adult patients with schizophrenia. It was approved in December 2021 for the management of depression associated with BD I or II in adults as monotherapy or when used adjunctively with the mood stabilizers lithium or VPA (Table 2).¹³ Lumateperone possesses certain binding affinities not unlike those in other newer antipsychotics, including high affinity for serotonin 5HT2A receptors (Ki 0.54 nM), low affinity for dopamine D2 receptors (Ki 32 nM), and low affinity for alpha 1-adrenergic receptors (Ki 73 nM), muscarinic and histaminergic receptors (Ki >100 nM for both).^13,14 However, there are some distinguishing features: the ratio of 5HT2A receptor affinity to D2 affinity is 60, greater than that for other second-generation antipsychotics (SGAs) such as risperidone (12), olanzapine (12.4) or aripiprazole (0.18).¹⁵ At steady state, D2 receptor occupancy remains <40%, and the corresponding rates of extrapyramidal side effects (EPS)/akathisia differed by only 0.4% for lumateperone vs placebo in short-term adult clinical schizophrenia trials,^13,16 by 0.2% for lumateperone vs placebo in the monotherapy BD depression study, and by 1.7% in the adjunctive BD depression study.^13,17,18 Lumateperone also exhibited no clinically significant impact on metabolic measures or serum prolactin during the 4-week schizophrenia trials, with mean weight gain ≤1 kg for the 42 mg dose across all studies.¹⁹ This favorable tolerability profile for endocrine and metabolic adverse effects was also seen in the BD depression studies. Across the 2 BD depression monotherapy trials and the single adjunctive study, the only adverse reactions occurring in ≥5% of lumateperone-treated patients and more than twice the rate of placebo were somnolence/sedation, dizziness, nausea, and dry mouth.¹³ There was also no single adverse reaction leading to discontinuation in the BD depression studies that occurred at a rate >2% in patients treated with lumateperone.¹³

In addition to the low risk of adverse events of all types, lumateperone has several pharmacologic features that distinguish it from other agents in its class. One unique aspect of lumateperone’s pharmacology is differential actions at presynaptic and postsynaptic dopamine D2 receptors noted in preclinical assays, a property that may explain its ability to act as an antipsychotic despite low D2 receptor occupancy.¹⁶ Preclinical assays also predicted that lumateperone was likely to have antidepressant effects.^15,19,20 Unlike every SGA except ziprasidone, lumateperone also possesses moderate binding affinity for serotonin transporters (SERT) (Ki 33 nM), with SERT occupancy of approximately 30% at 42 mg.²¹ Lumateperone facilitates dopamine D1-mediated neurotransmission, and this is associated with increased glutamate signaling in the prefrontal cortex and antidepressant actions.^14,22 While the extent of SERT occupancy is significantly below the ≥80% SERT occupancy seen with selective serotonin reuptake inhibitors, it is hypothesized that near saturation of the 5HT2A receptor might act synergistically with modest 5HT reuptake inhibition and D1-mediated effects to promote the downstream glutamatergic effects that correlate with antidepressant activity (eg, changes in markers such as phosphorylation of glutamate N-methyl-D-aspartate receptor subunits, potentiation of AMPA receptor-mediated transmission).^15,22

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