Jonathan Meyer, MD, returns to the Psychcast, this time to conduct a Masterclass lecture on treating patients with lumateperone. Dr. Meyer, of the University of California, San Diego, disclosed receiving either speaking honoraria or advising fees from several companies, including Intra-Cellular Therapies, which developed lumateperone (Caplyta). Later, Renee Kohanski, MD, discusses tailored interventions psychiatrists can incorporate into their practices to address overweight and obesity resulting from medications tied to weight gain. Take-home points Lumateperone, an atypical antipsychotic, was approved by the Food and Drug Administration for the treatment of adults with schizophrenia on Dec. 20, 2019. It has only one approved effective dose of 42 mg given with food. Further studies might define doses higher or lower, but those data are not available yet. The only adverse effect found with lumateperone was somnolence or sedation. Lumateperone was 24%; placebo was 10%. The medication has a low affinity and occupancy of the dopamine D2 receptors. This pharmacodynamic trait is reflected by the relatively low rates of extrapyramidal side effects in the clinical trial data. For now, the short-term studies of lumateperone suggest limited metabolic and endocrine effects, compared with other atypical antipsychotics. The primary indication for using lumateperone may be its tolerability profile, because nonadherence contributes to the morbidity of schizophrenia. Lumateperone is not a drug that should be used for treatment-resistant schizophrenia. The only drug that should be used for refractory patients with schizophrenia is clozapine (Clozaril). Summary Lumateperone has a unique pharmacologic profile. It has a low affinity for muscarinic, histaminergic, and alpha-adrenergic receptors. In the clinical trials, the primary side effect reported was somnolence and/or sedation. The medication also has a lower affinity for dopamine D2 receptors and occupies less than 40% of these receptors even at peak-dose timing. Conventional treatment of psychosis suggests that antipsychotic properties of D2 antagonist medications occur when 60%-80% of D2 receptors are occupied. Yet, there may be other properties of atypical antipsychotics that can increase the efficacy with lower levels of D2 blockade. Knowledge of alternative mechanisms comes from studying other antipsychotics. For example, pimavanserin (Nuplazid), an antipsychotic medication for treatment of psychosis in Parkinson’s disease, has no affinity for any dopamine receptors. Instead, it has a high affinity for serotonin 5-HT2A receptors as an inverse agonist and antagonist likely in cortical circuits with downstream glutamate signaling to dopamine circuits in the ventral tegmental area, which then decreases the amount of dopamine released in the mesolimbic pathway. Pimavanserin does not have any activity on the presynaptic D2 autoreceptors. Though counterintuitive, other atypical antipsychotics block the D2 presynaptic autoreceptor, which increases dopamine release. This mechanism is possibly why other antipsychotics require a 60%-80% D2 blockade to be effective in treating psychosis. In vitro studies suggest that lumateperone does not have presynaptic autoreceptor antagonism, which could be another reason why it doesn’t need as much D2 antagonism to be an effective antipsychotic agent. Lumateperone also is a weak inhibitor of serotonin reuptake occupying 30% of the serotonin receptors. Given its diverse pharmacologic mechanisms, lumateperone may confer antidepressant properties, and clinical trials are in the process to evaluate the use of lumateperone in bipolar depression. The drug is expected to be available at the end of March 2020. References Meltzer HY et al. Pimavanserin, a selective serotonin (5-HT)2A-inverse agonist, enhances the efficacy and safety of risperidone, 2 mg/day, but does not enhance efficacy of haloperidol, 2 mg/day: comparison with reference dose risperidon