Milsaperidone (BYSANTI): A Bad Choice for Bipolar Disorder or Schizophrenia

In February 2026, the Food and Drug Administration (FDA) approved milsaperidone (BYSANTI) for the treatment of schizophrenia in adults and the acute treatment of manic or mixed episodes associated with bipolar disorder.[1] Milsaperidone is an atypical antipsychotic that rapidly changes back and forth in the body between iloperidone (FANAPT), another antipsychotic, and milsaperidone. First approved in 2009, iloperidone and milsaperidone are manufactured and marketed by the same company.[2] Both drugs are approved for the same indications and are available in the same dosages, which depend on the indication. Both are taken twice daily.[3]

As is the case with other antipsychotic drugs, milsaperidone has a boxed warning — the FDA’s most prominent warning — for increased mortality in older adults with dementia-related psychosis.[4] Atypical antipsychotics are associated with several serious adverse events, including QTc interval prolongation that may increase the risk of arrhythmia and sudden death, tardive dyskinesia (involuntary movements, especially among elderly women), metabolic changes such as hyperglycemia, diabetes and weight gain, orthostatic hypotension, and seizures. Milsaperidone also can interfere with the body’s ability to regulate temperature and can cause somnolence, as well as cognitive and amotor impairment. To reduce the risk of hypotension, milsaperidone’s dosage needs to be incrementally increased (titrated) over several days.

Public Citizen’s Health Research Group has designated iloperidone as a Do Not Use drug due to its unfavorable benefit-risk profile compared to older antipsychotics.[5] Moreover, milsaperidone has not been demonstrated to be more effective or safer than iloperidone; for this reason, we have designated milsaperidone as Do Not Use as well. A month’s supply of iloperidone costs about $3,525. Although milsaperidone has not entered the market as of early July 2026, it will likely be more expensive than iloperidone and will also remain under patent protection for longer.[6]

Milsaperidone vs. iloperidone

Although the manufacturer claims that milsaperidone is a “unique” and “novel therapeutic option,”[7] the drug is merely an active metabolite of iloperidone.[8] To demonstrate that the drugs have similar bioavailability, the manufacturer conducted two bioequivalence studies. For an oral drug, bioavailability refers to the proportion of a drug that enters the circulation and can have an active effect.[9]

The first bioequivalence study was a randomized, open-label crossover study lasting 20 days. The study included 23 healthy volunteers aged 18 to 55 who took a single dose of three 1-mg tablets of either milsaperidone or iloperidone and switched to the same dose of the other drug after a two-week treatment break.[10] The second study was also an open-label crossover study and included 20 adults aged 18 to 65 with schizophrenia or bipolar disorder, according to the prescribing information.

Based on these studies, the FDA concluded that there are no clinically relevant differences in bioavailability between the two drugs and that the safety and efficacy of milsaperidone are “expected to be similar to iloperidone.”[11] The agency also stated that the safety assessments of the bioequivalence studies do not “suggest a new or worsened safety signal with milsaperidone.”

For these reasons, milsaperidone was approved based on the safety and efficacy data of iloperidone alone. As of June 2026, no additional clinical trials were available comparing milsaperidone with iloperidone or establishing the safety and efficacy of milsaperidone.

Safety of iloperidone

In addition to the boxed warning and general warnings associated with antipsychotic drugs, the most common adverse events of iloperidone for the treatment of schizophrenia are dizziness, dry mouth, fatigue, nasal congestion, tachycardia (fast resting heartbeat) and weight gain.[12] Adverse reactions appear to be dose dependent.

In patients with bipolar mania, the most common adverse events in the iloperidone group compared with placebo were tachycardia (23% vs. 5%), dizziness (12% vs. 1%), dry mouth (9% vs. 2%), increased hepatic (liver) enzymes (8% vs 1%), nasal congestion (6% vs. 1%) and weight gain (6% vs 1%).

Data supporting efficacy

The efficacy of iloperidone in adults with schizophrenia was assessed in three clinical trials. The first study randomized 706 participants to a daily dose of 12 to 16 mg or 20 to 24 mg of iloperidone (after titration), placebo or another antipsychotic (risperidone [RISPERDAL and generics]). After six weeks, participants who received iloperidone had significantly better outcomes on a standardized psychiatric scale than those who received placebo. However, the results for the two antipsychotics were comparable, with risperidone outperforming iloperidone in the first two weeks of the trial.

The second study randomized 604 adults to either 24 mg of iloperidone (after titration), placebo or ziprasidone (GEODON and generics), another antipsychotic. After 28 days iloperidone was superior to placebo on another psychiatric outcome scale, but the results were again comparable with the other antipsychotic.

A third study was a withdrawal study in which 303 clinically stable adult participants with schizophrenia first received between 8 mg and 24 mg of iloperidone daily (after one week of titration).[13] After 12 weeks, they were randomized to continue treatment with either iloperidone or placebo. The study was discontinued early because significantly fewer participants in the iloperidone group relapsed compared to the placebo group.

In adults with bipolar disorder, the safety of iloperidone was assessed in a double-blind, placebo-controlled trial that randomized 392 adults to receive 24 mg of iloperidone daily (after titration) or placebo.[14] After 28 days, participants who received iloperidone had statistically significantly better outcomes on a mania scale than those in the placebo group. However, these results may not be clinically meaningful because the difference between the groups was only 4 points on a scale ranging from 0 to 60 points, and participants in the placebo group also improved markedly (by 10 points).

What You Can Do

If you have schizophrenia or bipolar disorder, Public Citizen’s Health Research Group recommends that you Do Not Use milsaperidone. There are no data to suggest that milsaperidone is safer or more effective than iloperidone, and it is likely to be more expensive when it becomes available. We also recommend that you Do Not Use iloperidone because its serious harms do not outweigh its modest benefits in comparison to other antipsychotics. If you are taking any antipsychotic, do not discontinue the drug or change the dose without discussing it with your clinician first.
 

References

[1] PR Newswire. 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. February 20, 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. Accessed June 1, 2026.

[2] Vanda Pharmaceuticals. Label iloperidone (FANAPT). January 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/022192s024lbl.pdf. Accessed June 1, 2026.

[3] Food and Drug Administration. Multi-discipline review of NDA 220358. Milsaperidone (BYSANTI). February 20, 2026. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2026/220358Orig1s000MultidisciplineR.pdf. Accessed June 4, 2026.

[4] Vanda Pharmaceuticals. Label milsaperidone (BYSANTI). February 2026. https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/220358Orig1s000lbl.pdf. Accessed June 4, 2026.

[5] New iloperidone (FANAPT) is not as effective as older drugs for schizophrenia treatment. Worst Pills, Best Pills News. August 2010. https://www.worstpills.org/newsletters/view/702. Accessed June 4, 2026.

[6] Iloperidone (Fanapt)—A new indication for bipolar disorder. Med Lett Drugs Ther. 2024;66(5075):1-2.

[7] PR Newswire. 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. February 20, 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. Accessed June 1, 2026.

[8] Food and Drug Administration. Multi-discipline review of NDA 220358. Milsaperidone (BYSANTI). February 20, 2026. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2026/220358Orig1s000MultidisciplineR.pdf. Accessed June 1, 2026.

[9] Benzgalantamine (ZUNVEYL): Another bad choice for Alzheimer’s disease. Worst Pills, Best Pills News. September 2025. https://www.worstpills.org/newsletters/view/1678. Accessed June 1, 2026.

[10] Food and Drug Administration. Multi-discipline review of NDA 220358. Milsaperidone (BYSANTI). February 20, 2026. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2026/220358Orig1s000MultidisciplineR.pdf. Accessed June 4, 2026.

[11] Ibid.

[12] Vanda Pharmaceuticals. Label milsaperidone (BYSANTI). February 2026. https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/220358Orig1s000lbl.pdf. Accessed June 4, 2026.

[13] Ibid.

[14] Ibid.