FDA Approves Milsaperidone for Acute Bipolar I Disorder, Schizophrenia

The US Food and Drug Administration (FDA) has approved milsaperidone tablets (BYSANTI) for the treatment of acute bipolar I disorder and schizophrenia.1

“The BYSANTI™ approval marks a significant step forward, offering patients and providers a reliable new treatment grounded in extensive clinical heritage," said Mihael H. Polymeropoulos, MD, president, CEO and chairman of the board of Vanda Pharmaceuticals, in a statement. "BYSANTI™ exemplifies a new era of accelerated innovation in drug development that can transform how we address unmet needs in behavioral health."

The decision, announced by Vanda Pharmaceuticals on February 21, 2026, follows the review of the new drug application (NDA) supported by bioequivalence data and the existing clinical database for iloperidone. Milsaperidone is the active metabolite of iloperidone (Fanapt), a second-generation antipsychotic previously approved for schizophrenia and manic or mixed episodes associated with adult bipolar I disorder. 2,3

Iloperidone was originally approved in 2009 for the treatment of schizophrenia in adults based on multiple randomized, double-blind, placebo-controlled trials demonstrating statistically significant improvements in Positive and Negative Syndrome Scale (PANSS) total scores compared with placebo.4 A subsequent randomized withdrawal study showed that continued iloperidone therapy significantly prolonged time to relapse or impending relapse relative to placebo in stabilized patients.5

In 2024, the FDA expanded iloperidone’s indications to include the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults, supported by randomized clinical trial data demonstrating greater reductions in Young Mania Rating Scale (YMRS) scores compared with placebo.3 These findings formed a key component of the data package supporting milsaperidone’s NDA.

Orally administered milsaperidone rapidly converts to iloperidone and achieves comparable systemic exposure at both low and high doses. An analysis reported similar area under the curve and maximum plasma concentration values relative to iloperidone.6

Iloperidone’s mechanism of action involves antagonism at dopamine D2 and serotonin 5-HT2 receptors, with additional affinity for alpha-1 adrenergic receptors.2 Clinically, its use has been associated with orthostatic hypotension, QT interval prolongation, and metabolic changes, requiring dose titration and electrocardiographic considerations in selected patients. Whether milsaperidone’s pharmacokinetic profile will translate into any differentiated safety or tolerability advantages remains to be clarified in post-marketing data or additional trials.

References

1. Inc VP. Vanda Pharmaceuticals Announces FDA Approval of BYSANTITM (milsaperidone) for the treatment of Bipolar I Disorder and Schizophrenia - A New Chemical Entity Opening New Horizons in Psychiatric Innovation. Prnewswire.com. Published February 20, 2026. Accessed February 23, 2026. https://www.prnewswire.com/news-releases/vanda-pharmaceuticals-announces-fda-approval-of-bysanti-milsaperidone-for-the-treatment-of-bipolar-i-disorder-and-schizophrenia---a-new-chemical-entity-opening-new-horizons-in-psychiatric-innovation-302693941.html

2. Montes AB, Rey JA. Iloperidone (Fanapt): An FDA-Approved Treatment Option for Schizophrenia. P T. 2009;34(11):606-613.

3. US Food and Drug Administration. FDA approves iloperidone for acute treatment of bipolar I disorder. Published 2024. Accessed February 19, 2026. https://www.hcplive.com/view/fda-approves-iloperidone-fanapt-for-bipolar-i-disorder

4. Potkin SG, Litman RE, Torres R, Wolfgang CD. Efficacy of iloperidone in the treatment of schizophrenia: initial phase 3 studies. J Clin Psychopharmacol. 2008;28(2 Suppl 1):S4-S11. doi:10.1097/JCP.0b013e3181692787

5. Weiden PJ, Manning R, Wolfgang CD, et al. A Randomized Trial of Iloperidone for Prevention of Relapse in Schizophrenia: The REPRIEVE Study. CNS Drugs. 2016;30(8):735-747. doi:10.1007/s40263-016-0345-4

6. Vanda Pharmaceuticals. Milsaperidone bioequivalence poster presented at ASCP 2025. Accessed February 20, 2026. https://www.vandapharma.com/pdfs/milsaperidone-BE-poster-ASCP-2025-v9-final-23may2025.pdf