Mar 4, 2020
Jonathan Meyer, MD, returns to the Psychcast, this time to
conduct a Masterclass lecture on treating patients with
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
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.
- 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
- 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
- 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
- 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
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 risperidone,
Schizophr Res. 2012;141(2-3):144-52.
Correll CU et al. Efficacy and safety of lumateperone for
treatment of schizophrenia: A randomized clinical trial. JAMA
Psychiatry. 2020 Jan 8.
Corponi F et al. Novel antipsychotics specificity profile: A
clinically oriented review of lurasidone, brexpiprazole,
cariprazine, and lumateperone.
Eur Neuropsychopharmacol. 2019;29(9):971-85.
U.S. National Library of Medicine.
Lumateperone drug label
Show notes by Jacqueline Posada, MD, associate producer of the
Psychcast and consultation-liaison psychiatry fellow with the Inova
Fairfax Hospital/George Washington University program in Falls
For more MDedge Podcasts, go to
Email the show: firstname.lastname@example.org