Q1 2026 in Review

In a nutshell

Q1 2026 brought two FDA actions and one clinical guideline update. The FDA approved milsaperidone and removed the suicidality warning from GLP-1 receptor agonists. The ACOG issued updated guidance positioning zuranolone as the oral option for severe postpartum depression, now that brexanolone has been withdrawn from the market.

• Milsaperidone: a “new” antipsychotic without a compelling clinical case
  • Milsaperidone is an active metabolite of iloperidone; the two interconvert in vivo and share the same efficacy, safety, and tolerability profile
  • There is no evidence-based clinical reason to prescribe milsaperidone over iloperidone as of March 2026
• GLP-1 RAs: reassure patients
  • The suicidality warning originated from older weight-loss drugs, not from GLP-1 RA-specific data; it has now been removed
  • The FDA’s review found no increased risk of suicidal ideation, anxiety, depression, or psychosis
  • A 2026 national cohort study suggests semaglutide may reduce the worsening of depression, anxiety, and substance use disorder. RCTs are needed
• Zuranolone: ACOG’s updated guidance after brexanolone’s withdrawal
  • With brexanolone no longer available, ACOG issued a 2026 Clinical Practice Update positioning zuranolone as the oral alternative for severe PPD (PHQ-9 ≥20 or EPDS ≥19)
  • Practical requirements: 14-day course, once daily at bedtime with a fatty meal; patients must not care for their infant alone for 12 hours after each dose
  • Limitations:
    • No head-to-head data vs. SSRIs, SNRIs, or psychotherapy; efficacy data extend only to day 45

Milsaperidone (Bysanti) Approved for Schizophrenia and Bipolar Disorder

• The FDA approved Milsaperidone (Bysanti) in January 2026 for the treatment of schizophrenia in adults and bipolar I disorder mania and mixed mania ^[1]
• What is milsaperidone?
  • Milsaperidone is an active metabolite of iloperidone
  • It has the same pharmacodynamic properties as iloperidone
• Pharmacology
  • Milsaperidone and iloperidone rapidly interconvert in vivo
    • When milsaperidone is administered orally, it converts to iloperidone
  • Pharmacodynamics ^[2,3]
    • 5-HT2A antagonist
    • Alpha-1 antagonist
    • D2 antagonist

• Regulatory aspects: New chemical entity (NCE) ^[1,4]
  • Milsaperidone was granted NCE status: it borrows iloperidone’s entire clinical data package to establish efficacy while carrying independent patent protection through 2044
  • Bioequivalent to iloperidone across the full therapeutic dose range
  • Approved via the 505(b)(2) pathway: allows a new application to rely on existing clinical data from a previously approved drug, without running new efficacy trials
  • The efficacy basis came entirely from iloperidone’s clinical program
  • Vanda submitted pharmacokinetic bioequivalence data, not new Phase III trials
• Practical aspects
  • Titration required:
    • Iloperidone and milsaperidone require gradual titration over several days to mitigate orthostatic hypotension and syncope risk
  • Twice-daily dosing
    • Twice-daily dosing is a known adherence barrier in chronic psychiatric conditions ^[5]
• Side effects
  • Both drugs carry a risk of QTc prolongation.
    • This places them among the higher-risk atypical antipsychotics for QTc, comparable to ziprasidone ^[6]
• Commercial context
  • Iloperidone patent exclusivity expires in November 2027; three manufacturers have already filed.
  • Milsaperidone’s NCE designation extends Vanda’s commercial position ahead of iloperidone’s patent expiration in November 2027
    • Patent protection runs through 2044, providing a protected asset for pipeline development

• In the pipeline ^[1]
  • LAI formulation
    • Milsaperidone’s physicochemical properties are amenable to lipid ester development for long-acting injectable (LAI) formulations
    • Currently in preclinical/early development
  • MDD as once-daily dosing
    • Milsaperidone is currently being tested as a once-daily adjunctive treatment in treatment-resistant major depressive disorder
    • The ongoing clinical study is expected to be completed by the end of 2026
• Should we prescribe milsaperidone over iloperidone?
  • There is currently no evidence-based clinical reason for prescribing milsaperidone over iloperidone
  • Milsaperidone carries the same efficacy, safety profile, and formulation aspects as iloperidone as of March 2026.
• Why is Vanda pursuing milsaperidone if it offers no current clinical advantage over iloperidone?
  • Milsaperidone’s approval can be better characterized as a regulatory platform
  • By establishing milsaperidone as a new chemical entity before iloperidone loses exclusivity, Vanda secures an IP runway for an LAI formulation and a once-daily MDD indication
    • Both indications are technically feasible under iloperidone, but commercially unviable with only ~18 months of exclusivity remaining before generic entry

GLP-1 RA Suicidality Warning Removed

• In January 2026, the FDA requested that manufacturers remove the suicidal ideation and behavior (SI/B) warning from the labeling of GLP-1 receptor agonists ^[7]
• Affected products: Saxenda (liraglutide), Wegovy (semaglutide), and Zepbound (tirzepatide) ^[8]
• Implications:
  • GLP-1 agonists no longer carry a suicidal ideation warning
  • Patients can be reassured that the FDA found no increased risk of suicidal ideation and behavior after a comprehensive review of the available data
• Background
  • The suicidal ideation and behavior (SI/B) warning had been included in the GLP-1 RA labeling at the time of original FDA approvals
  • The warning was not based on GLP-1 RA-specific data
    • It was carried over from postmarketing reports of SI/B observed with a variety of older medicines used or studied for weight loss
    • A confounding factor: patients with obesity and diabetes carry elevated baseline rates of depression and anxiety ^[9]
      • Earlier observational studies raising psychiatric concerns about GLP-1 RAs were likely affected by this underlying burden
    • GLP-1 agonists approved for glycemic control in type 2 diabetes had never included this warning
• Regulatory history
  • July 2023: FDA initiated an investigation after receiving postmarketing reports of SI/B in GLP-1 RA users
  • January 2024: FDA issued a preliminary Drug Safety Communication; initial review did not find an association, but uncertainty remained due to small SI/B case numbers in individual trials
  • January 2026: FDA completes comprehensive review and requests label removal
• What the FDA found
  • No increased risk of: suicidal ideation and behavior, anxiety, depression, irritability, or psychosis
  • Methods:
    • Meta-analysis of 91 placebo-controlled trials, including 107,910 patients (60,338 on a GLP-1 RA; 47,572 on placebo)
    • Retrospective cohort study using healthcare claims data comparing intentional self-harm risk between GLP-1 RA users and SGLT2 inhibitor users
    • Review of published observational and pooled studies
• Emerging evidence: potential psychiatric benefits
  • A 2026 national cohort study goes further than ruling out harm ^[9]
    • Key findings:
      • Semaglutide was associated with a 42% lower risk of worsening mental illness and liraglutide with an 18% lower risk, compared with non-use periods in the same individuals
      • Semaglutide was specifically associated with reduced worsening of depression , anxiety, and substance use disorder
    • Causality cannot be established from observational data; randomized controlled trials are needed to confirm these findings
• Implications of the full evidence base
  • The available data do not support earlier concerns about GLP-1 RAs worsening psychiatric outcomes
  • Semaglutide may have meaningful benefits for mood and anxiety in patients with comorbid diabetes or obesity
  • This raises the possibility of genuine psychiatric benefit, pending confirmation from randomized controlled trials

Zuranolone for Severe PPD: ACOG’s 2026 Clinical Practice Update

• In January 2026, the American College of Obstetricians and Gynecologists (ACOG) issued a Clinical Practice Update on zuranolone (Zurzuvae)
• Recommendation: ^[10]
  • Consider zuranolone for severe postpartum depression
    • Onset: third trimester or within 4 weeks postpartum
    • Eligibility window: within 12 months of delivery
• On the severity recommendation
  • The zuranolone prescribing information carries no severity qualifier
  • ACOG’s restriction to severe PPD reflects trial design: pivotal trials required HAMD-17 >26 (consistent with severe disease)
  • Efficacy in milder presentations is unestablished
  • Clinical threshold: PHQ-9 ≥20 or EPDS ≥19
• Pharmacology
  • Zuranolone is a synthetic neuroactive steroid and positive allosteric modulator (PAM) of GABA-A receptors ^[11]
  • It shares its mechanism of action with brexanolone (Zulresso), which was the IV predecessor
• Zuranolone evidence limitations ^[12,13]
  • No head-to-head data against SSRIs, SNRIs, or psychotherapy
    • Comparative effectiveness vs. the standard of care is unknown
  • Efficacy data extend only to day 45 (4 weeks post-treatment); no data beyond that window
• FDA Approval, Scheduling, and the Brexanolone Exit
  • Zuranolone (Zurzuvae) received FDA approval in August 2023 for postpartum depression in adults
  • Schedule IV controlled substance
    • The FDA identified benzodiazepine-like reinforcing effects, dose-dependent euphoric effects, and biochemical similarity to barbiturates
  • Brexanolone (Zulresso): first FDA-approved treatment specifically for PPD (2019), sharing zuranolone’s GABA-A PAM mechanism ^[14]
    • Required a 60-hour continuous inpatient IV infusion under a REMS program
    • Complex logistics and high cost severely limited real-world access
    • Sage Therapeutics withdrew FDA approval on April 14, 2025, pivoting toward zuranolone as the oral successor
• Practical aspects ^[15]
  • 14-day treatment course, not continuous chronic therapy
  • Once-daily dosing at bedtime with a fatty meal (400–1,000 kcal, 25–50% fat)
  • Can be used as monotherapy or adjunct to stable SSRI/SNRI therapy
• Side effects
  • CNS depression: somnolence, dizziness, confusion. Most clinically significant adverse effects
  • Patients should not care for their infant alone (feeding, changing, bathing) for 12 hours post-dose
  • Embryo-fetal toxicity: effective contraception required during the 14-day course and for 1 week after the final dose

References

1. Vanda Pharmaceuticals Inc. (2026). 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. 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. Vanda Pharmaceuticals Inc. (2026). BYSANTI (milsaperidone) Tablets Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/220358Orig1s000lbl.pdf

3. Vanda Pharmaceuticals Inc. (2026). FANAPT (iloperidone) Tablets Prescribing Information. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=022192

4. U.S. Food and Drug Administration. (n.d.). 21 CFR § 314.108 — New Drug Product Exclusivity. Retrieved March 22, 2026, from https://www.law.cornell.edu/cfr/text/21/314.108

5. Medic, G., Higashi, K., Littlewood, K. J., Diez, T., Granström, O., & Kahn, R. S. (2013). Dosing Frequency and Adherence in Chronic Psychiatric Disease: Systematic Review and Meta-Analysis. Neuropsychiatric Disease and Treatment, 9, 119–131. https://doi.org/10.2147/NDT.S39303

6. Woosley, R. L., Romero, K. A., Gallo, T., Woosley, J., & Darpo, B. (2013). A Thorough QTc Study of 3 Doses of Iloperidone Including Metabolic Inhibition via CYP2D6 and/or CYP3A4 and a Comparison to Quetiapine and Ziprasidone. Journal of Clinical Pharmacology, 53(3), 289–295. https://doi.org/10.1177/0091270012442192

7. U.S. Food and Drug Administration. (2026). FDA Requests Removal of Suicidal Behavior and Ideation Warning from Glucagon-Like Peptide-1 Receptor Agonist (GLP-1 RA) Medications. https://www.fda.gov/drugs/drug-safety-and-availability/fda-requests-removal-suicidal-behavior-and-ideation-warning-glucagon-peptide-1-receptor-agonist-glp

8. Novo Nordisk. (2026). SAXENDA (liraglutide) Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/206321s022lbl.pdf

9. Taipale, H., Taylor, M., Lähteenvuo, M., Mittendorfer-Rutz, E., Tanskanen, A., & Tiihonen, J. (2026). Association between GLP-1 receptor agonist use and worsening mental illness in people with depression and anxiety in sweden: A national cohort study. The Lancet Psychiatry, 13, 119–131. https://doi.org/10.1016/S2215-0366(26)00014-3

10. Moore Simas, T. A., Hoffman, M. C., Roussos-Ross, K., Miller, E. S., Gandhi, M., & Shields, A. (2026). Zuranolone and Brexanolone for the Treatment of Postpartum Depression. Obstetrics & Gynecology, 147(1), e24–e28.

11. Sharma, R., Bansal, P., Saini, L., Sharma, N., & Dhingra, R. (2024). Zuranolone, a Neuroactive Drug, Used in the Treatment of Postpartum Depression by Modulation of GABA(A) Receptors. Pharmacology, Biochemistry, and Behavior, 238, 173734. https://doi.org/10.1016/j.pbb.2024.173734

12. Deligiannidis, K. M., Meltzer-Brody, S., Maximos, B., Peeper, E. Q., Freeman, M., Lasser, R., Bullock, A., Kotecha, M., Li, S., Forrestal, F., Rana, N., Garcia, M., Leclair, B., & Doherty, J. (2023). Zuranolone for the Treatment of Postpartum Depression. The American Journal of Psychiatry, 180(9), 668–675. https://doi.org/10.1176/appi.ajp.20220785

13. Deligiannidis, K. M., Meltzer-Brody, S., Gunduz-Bruce, H., Doherty, J., Jonas, J., Li, S., Sankoh, A. J., Silber, C., Campbell, A. D., Werneburg, B., Kanes, S. J., & Lasser, R. (2021). Effect of Zuranolone vs Placebo in Postpartum Depression: A Randomized Clinical Trial. JAMA Psychiatry, 78(9), 951–959. https://doi.org/10.1001/jamapsychiatry.2021.1559

14. Sage Therapeutics, Inc. (2025). Withdrawal of Approval of a New Drug Application for Zulresso (Brexanolone) Solution, 100 Milligrams/20 Milliliters. https://www.federalregister.gov/documents/2025/03/14/2025-04101/sage-therapeutics-inc-withdrawal-of-approval-of-a-new-drug-application-for-zulresso-brexanolone

15. Biogen MA Inc. (2026). ZURZUVAE (zuranolone) Capsules Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/217369s001lbl.pdf