The FDA is reviewing 3 managed trials of lumateperone (Caplyta) in bipolar melancholy. The outcomes haven’t been printed, however their naked bones have been introduced at conferences. Here’s what we all know to this point.
All 3 have been giant, randomized, placebo managed, quadruple-blind trials in bipolar I and bipolar II melancholy. The primary trial was unfavourable, however lumateperone labored within the subsequent 2 with a small to medium impact dimension (0.27-0.56). As with different atypicals in bipolar melancholy, lumateperone’s efficacy was evident as early as week 1 (Desk 1).1-6
Damaging trials are a typical drawback in multicenter research like this one, which concerned 58 facilities. When every enter takes care of solely a small variety of sufferers, they have an inclination to present these sufferers extra time and a focus. This inflates the placebo response, which on this case was 1.7 instances better than the placebo response within the optimistic trial.2 Damaging outcomes didn’t maintain again the approval of different atypicals like cariprazine in bipolar melancholy, however lumateperone could not cross the end line if the FDA finds flaws with its 2 optimistic research.
The trials deliver wanted consideration to bipolar II dysfunction, which was included together with bipolar I in every of the trials. Of the 4 atypicals authorised in bipolar melancholy (cariprazine, lurasidone, quetiapine, and olanzapine-fluoxetine combo), solely quetiapine and cariprazine have been extensively studied in bipolar II melancholy, and only the quetiapine studies have been optimistic.7 Desk 2 lists 5 atypical antipsychotics in bipolar melancholy.
Lumateperone’s favorable trials remained optimistic when damaged down into bipolar I and bipolar II subgroups. A fourth trial is underway that can check the drug in a 3rd group: unipolar melancholy with combined options. At present, solely lurasidone (Latuda) has robust data in that dysfunction.8
Lumateperone is a serotonin 5-HT2A antagonist, a mechanism it shares with asenapine, clozapine, olanzapine, risperidone, and quetiapine, in addition to mirtazapine and trazodone. Not like different antipsychotics, it has low affinity for the dopamine D2 receptor. Its occupancy there’s 39%. In distinction, the subsequent lowest is 60% occupance for clozapine and quetiapine, and most different antipsychotics register at above 60% occupancy.9 To date, this has translated to a decrease charge of akathisia and extrapyramidal unwanted effects in schizophrenia, and that profit prolonged to the bipolar trials as effectively.
This profile resembles that of pimavanserin (Nuplazid), an antipsychotic with low dopamine occupancy that’s an inverse agonist at serotonin 5-HT2A (“inverse agonists” don’t block the receptor, however they trigger it to behave in methods reverse to an agonist). Pimavanserin is FDA-approved in psychosis as a result of Parkinson illness, and it has additionally shown potential in melancholy in a big, randomized, placebo-controlled augmentation trial.10
Lumateperone has a number of drawbacks in bipolar dysfunction. It’s pricey, has by no means been teste din mania, and is barely FDA-approved in schizophrenia. If authorised, its major benefit over different atypical antipsychotics is prone to be tolerability. Lumateperone had low charges of akathisia, weight achieve, metabolic disturbances, and prolactinemia within the short-term bipolar melancholy research, in addition to within the schizophrenia research which lasted as much as one yr. Its major unwanted effects are somnolence, nausea, dry mouth, and dizziness. The beginning dose is similar because the goal dose, and the identical because the schizophrenia dose: 42 mg at night time.
The Backside Line
If authorised, lumateperone will deliver a minimum of 2 qualities which are wanted within the bipolar armamentarium: Efficacy in bipolar II melancholy and cheap tolerability. Pending that, it’s price contemplating in sufferers with average to extreme bipolar melancholy who haven’t responded to different choices.
Dr Aiken is the Temper Issues Part Editor for Psychiatric InstancesTM, the Editor in Chief of The Carlat Psychiatry Report, and the Director of the Mood Treatment Center. He has written a number of books on temper issues, most just lately The Depression and Bipolar Workbook. He may be heard within the weekly Carlat Psychiatry Podcast along with his co-host Kellie Newsome, PMH-NP.
The creator doesn’t settle for honoraria from pharmaceutical corporations however receives royalties from PESI for The Depression and Bipolar Workbook and from W.W. Norton & Co. for Bipolar, Not So Much.
1. Durgam S, Satlin A, Vanover KE, et al. Lumateperone within the therapy of bipolar melancholy: Efficacy throughout signs. Poster presentation, Worldwide Society for Bipolar Issues Annual Convention, June 2020.
3. ClinicalTrials.gov. Clinical Trial Evaluating ITI-007 (Lumateperone) as a Monotherapy for the Treatment of Bipolar Depression, April 2021.
4. ClinicalTrials.gov. Clinical trial evaluating iti-007 as an adjunctive therapy to lithium or valproate for the treatment of bipolar depression, July 2020.
6. ClinicalTrials.gov. Lumateperone monotherapy for the treatment of bipolar depression conducted globally, April 2021.
7. Yatham LN, Vieta E, Earley W. Evaluation of cariprazine in the treatment of bipolar I and II depression: a randomized, double-blind, placebo-controlled, phase 2 trial. Int Clin Psychopharmacol. 2020;35(3):147-156.
8. Suppes T, Silva R, Cucchiaro J, et al. Lurasidone for the treatment of major depressive disorder with mixed features: a randomized, double-blind, placebo-controlled study. Am J Psychiatry. 2016;173(4):400-407.
9. Vanover KE, Davis RE, Zhou Y, et al. Dopamine D2 receptor occupancy of lumateperone (ITI-007): a Positron Emission Tomography Study in patients with schizophrenia. Neuropsychopharmacology. 2019;44(3):598-605.
10. Fava M, Dirks B, Freeman MP, et al. A phase 2, randomized, double-blind, placebo-controlled study of adjunctive pimavanserin in patients with major depressive disorder and an inadequate response to therapy (CLARITY).J Clin Psychiatry. 2019;80(6):19m12928.
11. Chapel S, Chiu YY, Hsu J, Cucchiaro J, Loebel A. Lurasidone dose response in bipolar depression: a population dose-response analysis. Clin Ther. 2016;38(1):4-15.