Lybalvi (olanzapine/samidorphan) / Alkermes - LARVOL DELTA

Profound Remifentanil Resistance in a Patient Prescribed Olanzapine-Samidorphan (ASA 2026) - "Postoperative review revealed no alternative antagonists. This case illustrates clinically significant intraoperative opioid antagonism from samidorphan and highlights the importance of perioperative medication reconciliation and preoperative holding discussions."

Clinical • CNS Disorders • Otorhinolaryngology • Substance Abuse

Olanzapine/Samidorphan-Associated Opioid Withdrawal Reported to US Poison Centers. (PubMed, J Clin Psychopharmacol) - "Precipitated opioid withdrawal is a known concern when initiating olanzapine/samidorphan in patients using opioids. Withdrawal may last about 24 hours and require inpatient treatment. Careful screening for opioid use may reduce the risk."

Journal • CNS Disorders

An Expanded Access Program (EAP) for OLZ/SAM in Pediatric Participants With Schizophrenia or Bipolar I Disorder (ALKS 3831-315) (clinicaltrials.gov) - P=N/A | N=0 | Available | Sponsor: Alkermes, Inc.

New trial • Bipolar Disorder • CNS Disorders • Pediatrics • Psychiatry • Schizophrenia

Importance of Real-World Evidence in Clinical Decision-Making (APA 2026) - " In a claims analysis involving patients with schizophrenia, those who were initiated on a combination of olanzapine and samidorphan (OLZ/SAM) were more than twice as likely to be adherent compared with those initiated on olanzapine (odds ratio [OR] [95% CI], 2.09 [1.72, 2.54]; P<0.001) and were half as likely to discontinue treatment (OR [95% CI], 0.50 [0.40, 0.61]; P<0.001)... The integration of RWE into everyday practice can guide more informed, data-driven, patient-centered decisions and can enhance treatment decision-making when considered alongside clinical trial data."

Clinical • HEOR • Real-world • Real-world evidence • Bipolar Disorder • CNS Disorders • Schizophrenia

Samidorphan Sadness: a Case of Depressive Symptoms Following Addition of Samidorphan (APA 2026) - "Description Background: Olanzapine (Zyprexa) is a second-generation antipsychotic approved for treatment of schizophrenia in adults and adolescents ages 13 years and older; acute manic or mixed episodes of bipolar 1 disorder as well as bipolar 1 disorder maintenance in patients 13 years and older; adjunct to lithium or valproic acid treatment in adult patients with bipolar 1 disorder (FDA, 2025); It is also available in several combined formulations, including as olanzapine-fluoxetine (Symbyax) for depression associated with bipolar 1 disorder in people 10 years and older, as well as treatment-resistant depression in adults (FDA, 2025), and olanzapine-samidorphan (Lybalvi) for management of schizophrenia, bipolar 1 disorder manic or mixed episodes as monotherapy or adjunct, as well as bipolar 1 maintenance monotherapy in adults (FDA, 2025)...The mu opioid receptor is an area of interest as a potential target to treat depression, and medications including samidorphan, a..."

Clinical • Bipolar Disorder • CNS Disorders • Depression • Metabolic Disorders • Mood Disorders • Schizophrenia

Antipsychotic dose and efficacy for acute schizophrenia spectrum disorders: an updated systematic review and dose-response meta-analysis. (PubMed, EClinicalMedicine) - "Dose-response curves of most antipsychotics on overall symptoms in people with acute exacerbations of schizophrenia were hyperbolic, reaching plateau within the lower-to-medium approved dose ranges, around 3-5 mg risperidone dose equivalents. There was low to very low certainty of evidence regarding the dose-response relationships of amisulpride, blonanserin, cariprazine, clozapine, haloperidol, lumateperone and ziprasidone. We did not find enough studies to conduct dose-response meta-analysis for olanzapine/samidorphan, xanomeline/trospium, and zotepine...This meta-analysis was conducted within the framework of a larger project funded by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG; grant #468853597) and within activities of the German Center for Mental Health (Deutsches Zentrum für Psychische Gesundheit, DZPG), Munich-Augsburg partner site, funded by the Federal Ministry of Research, Technology and Space (BMFTR, grant #01EE2303B). This..."

Journal • Retrospective data • CNS Disorders • Psychiatry • Schizophrenia

The Efficacy of Olanzapine/Samidorphan on Negative Symptoms: A Post Hoc Analysis of 56-Week Treatment in Patients With Schizophrenia. (PubMed, J Clin Psychiatry) - P3 | "Trial Registration: ClinicalTrials.gov identifiers NCT02634346 (https:// clinicaltrials.gov/study/NCT02634346) and NCT02669758 (https://clinicaltrials. gov/study/NCT02669758)."

Clinical • Journal • Retrospective data • CNS Disorders • Psychiatry • Schizophrenia

Correction. The Efficacy of Olanzapine/Samidorphan on Negative Symptoms: A Post Hoc Analysis of 56-Week Treatment in Patients With Schizophrenia. (PubMed, J Clin Psychiatry) - No abstract available

Journal • Retrospective data • CNS Disorders • Psychiatry • Schizophrenia

Samidorphan sadness: does the addition of samidorphan to olanzapine have prodepressive effects? (PubMed, Int Clin Psychopharmacol) - "This case highlights the need for clinical vigilance regarding emergent depressive symptoms in patients prescribed olanzapine-samidorphan, particularly those with prior mood vulnerability. Further investigation is warranted to clarify the neurobiological mechanisms and potential risk factors for mood disturbance associated with samidorphan-containing formulations."

Journal • CNS Disorders • Fatigue • Mood Disorders • Psychiatry

Safety profile of olanzapine/samidorphan: focus on metabolic risks, opioid-related effects, and novel adverse events identified. (PubMed, Naunyn Schmiedebergs Arch Pharmacol) - "Psychiatric disorders, notably suicidal ideation, require vigilant monitoring in clinical settings. It is imperative to conduct traditional pharmacoepidemiological research to evaluate risk factors of O/S-related metabolic diseases in the future."

Adverse events • Journal • Bipolar Disorder • CNS Disorders • Diabetes • Mental Retardation • Metabolic Disorders • Psychiatry • Schizophrenia • Suicidal Ideation

Olanzapine/Samidorphan (Lybalvi) in Palliative Care: A Case Report on Medication Reconciliation, Risk-Benefit Analysis, and Psychiatric Co-Management in an Outpatient Supportive Oncology Clinic. (PubMed, J Palliat Med) - "Notably, patients with comorbid bipolar I disorder and cancer often have both significant anorexia and pain, making samidorphan less desirable, as, in addition to mitigating metabolic side effects, it can limit the efficacy of analgesia from opioids. A recommendation of transitioning to olanzapine only is discussed."

Benefit-risk assessment • Journal • Anorexia • Bipolar Disorder • CNS Disorders • Mental Retardation • Oncology • Pain • Palliative care • Psychiatry

Successful Treatment of Antipsychotic-Induced Hyperphagia With Intramuscular Naltrexone (OBESITY WEEK 2025) - " A 37-year-old gentleman presented to the primary care clinic to establish care 6 months after initiation of intramuscular haloperidol and paliperidone every 21 days for management of his severe disorganized schizophrenia...Due to the severity of his mental illness, patient was not a candidate for transition to oral samidorphan-olanzapine or addition of oral naltrexone-buproprion therapy... Treatment options for individuals with antipsychotic-associated hyperphagia who have severe mental illness and are intolerant to oral medications are currently limited, putting them at risk for the long-term health effects associated with antipsychotic-induced weight gain. This case study indicates that patients in this unique and challenging situation may benefit from injectable anti-opiate therapy such as naltrexone. Future research is needed to determine the viability and long-term effects of injectable anti-opiate therapy in this population."

Addiction (Opioid and Alcohol) • CNS Disorders • Psychiatry • Schizophrenia

Molecular determinants of the different metabolic adverse effects of antipsychotics (ECNP 2025) - "The olanzapine-samidorphan combination is presently the sole instance of co-treatment aimed at mitigating weight gain; nonetheless, the product information indicates that fasting triglycerides are elevated with olanzapine, even when samidorphan is administered concurrently.This example underscores that the processes underlying the unfavorable metabolic effects of antipsychotics are poorly understood, a knowledge gap we aim to address...Their primary targets are the enzymes that synthesize cholesterol, the lysosomal apparatus that processes endocited cholesterol, and the resulting modifications to gene transcription and metabolic control, which involve SREBPs, AMPK, and more.We have identified significant variations in the metabolic adverse action of three antipsychotics—olanzapine (high risk), risperidone (mid risk), and ziprasidone (low risk)—that may account for their varying effects on patients...While studying these antipsychotics, we found that co-treatment with..."

Adverse events • CNS Disorders

New Developments in the Treatments of Psychosis (WFSBP 2025) - "Objective: Despite the discovery of chlorpromazine over 70 years ago and substantial pharmacologic advances, postsynaptic dopamine blockade has remained the sole mechanism of action of approved drugs for schizophrenia... Newly/recently approved agents include vesicular monoamine transporter-2 inhibitors valbenazine and deutetrabenazine for tardive dyskinesia and, possibly, residual positive symptoms; olanzapine/samidorphan combination, lumateperone, new formulations, including subcutaneous injections, and ultra-long-acting injectable antipsychotics. Agents in development that have at least one positive phase 1B, 2 or 3 trial include the trace amine-associated receptor-1 (TAAR1) ulotaront, M1/M4 muscarinic agonist xanomeline plus peripherally restricted anticholinergic trospium, the M4 muscarinic positive allosteric modulator emraclidine, as well as multiple other muscarinic receptor modulators for total psychopathology, methylated amisulpride (LB-102), and evenamide, a..."

CNS Disorders • Movement Disorders • Psychiatry • Schizophrenia

Contrave, Lybalvi, Auvelity, and Cobenfy: What Do They Have in Common? (PubMed, J Psychiatr Pract) - "This column reviews 4 psychiatric combination products: Contrave (bupropion + naltrexone), Lybalvi (olanzapine + samidorphan), Auvelity (dextromethorphan + bupropion), and Cobenfy (xanomeline + trospium). In each case, the second drug in the combination enhances the efficacy and/or reduces the adverse effects of the first drug. This review illustrates how basic science in pharmacokinetics and brain circuitry was fundamental to the development of these products, particularly in the case of Contrave and Cobenfy."

Journal • Review • Psychiatry

Olanzapine/Samidorphan (Lybalvi) and Buprenorphine: Considerations for a Contradictory Combination: A Case Report. (PubMed, J Addict Med) - "This case report outlines the safety concerns of utilizing an opioid antagonist (samidorphan) in conjunction with an opioid partial agonist (buprenorphine) and demonstrates the process for safe transition to an alternative regimen."

Journal • Addiction (Opioid and Alcohol) • Bipolar Disorder • CNS Disorders • Mood Disorders • Post-traumatic Stress Disorder • Psychiatry • Schizophrenia • Substance Abuse

Healthcare Resource Utilization 6 Months Before and After Olanzapine/Samidorphan Initiation: Real-World Assessment of Patients with Schizophrenia or Bipolar I Disorder. (PubMed, Adv Ther) - "Results from this first real-world study assessing HCRU after OLZ/SAM initiation suggest that OLZ/SAM results in reductions in burden for patients, providers, and the healthcare system, as evidenced by reductions in acute all-cause, MH-related, and disease-specific HCRU among SZ and BD-I cohorts."

HEOR • Journal • Real-world evidence • Bipolar Disorder • CNS Disorders • Psychiatry • Schizophrenia

Exercise and Olanzapine-samidorphan (clinicaltrials.gov) - P4 | N=30 | Recruiting | Sponsor: New York State Psychiatric Institute | Not yet recruiting ➔ Recruiting

Enrollment open • Bipolar Disorder • CNS Disorders • Mood Disorders • Psychiatry • Schizophrenia

New Agents in the Treatment of Psychiatric Disorders: What Innovations and in What Areas of Psychopathology? (PubMed, Pharmaceuticals (Basel)) - "Our search suggested that a new antipsychotic, lumateperone, and two drug combinations, olanzapine/samidorphan (OLZ/SAM) and xanomeline/trospium (KarXT), were approved for schizophrenia...Two new agents, brexanolone and zuranolone, were approved for treatment of postpartum depression...In summary, some new psychotropic medications have been developed, in particular with the aim to improve the symptoms of resistant patients and to decrease the incidence of adverse effects. It is necessary to continue testing the effectiveness of new compounds in methodologically rigorous studies."

Journal • Review • Bipolar Disorder • CNS Disorders • Depression • Major Depressive Disorder • Mental Retardation • Mood Disorders • Obsessive-Compulsive Disorder • Postpartum Depression • Psychiatry • Schizophrenia • Suicidal Ideation

Centrally-acting opioid receptor antagonists as a treatment for antipsychotic-induced weight gain: A systematic review and meta-analysis of clinical trial data. (PubMed, J Psychopharmacol) - "CORA, specifically samidorphan, was effective at reducing weight gain in individuals prescribed olanzapine. The small effect sizes and discrepancy between samidorphan and naltrexone suggest effects may be timing dependent, not a class effect, or dependent on the antipsychotic combination."

Journal • Retrospective data • Addiction (Opioid and Alcohol) • CNS Disorders • Psychiatry • Schizophrenia

Healthcare Resource Utilization 12 Months Following Initiation of Olanzapine/Samidorphan: Real-World Assessment of Patients With Bipolar I Disorder (ISPOR 2025) - "Among patients with BD-I, OLZ/SAM initiation results in clinically meaningful reductions in disease burden, as evidenced by reductions in hospital-based HCRU. Longer OLZ/SAM treatment retention was associated with improved effectiveness. This study was sponsored by Alkermes, Inc."

Clinical • HEOR • Real-world • Real-world evidence • Bipolar Disorder • CNS Disorders • Psychiatry

Healthcare Resource Utilization 12 Months Following Initiation of Olanzapine/Samidorphan: Real-World Assessment of Patients With Schizophrenia (ISPOR 2025) - "Among patients with schizophrenia, OLZ/SAM initiation may result in clinically meaningful reductions in real-world disease burden, as evidenced by reductions in hospital-based HCRU. Longer treatment retention was associated with improved effectiveness. This study was sponsored by Alkermes, Inc."

Clinical • HEOR • Real-world • Real-world evidence • CNS Disorders • Psychiatry • Schizophrenia

A pharmacovigilance study of olanzapine/samidorphan based on FDA Adverse Event Reporting System (FAERS). (PubMed, BMC Pharmacol Toxicol) - "The long-term safety of the OLZ/SAM warrants attention, particularly concerning drug withdrawal syndrome."

Adverse events • Journal • Addiction (Opioid and Alcohol) • CNS Disorders

Alkermes plc Reports Financial Results for the Fourth Quarter and Year Ended Dec. 31, 2024 and Provides Financial Expectations for 2025 (PRNewswire) - "'This year, we have clear objectives for our pipeline as we complete the phase 2 studies for ALKS 2680 in narcolepsy, with data expected in the second half of the year, and prepare to initiate the ALKS 2680 phase 2 study in idiopathic hypersomnia...LYBALVI: Revenues for the fourth quarter were $77.0 million. Fourth quarter revenues and total prescriptions grew 37% and 30%, respectively, compared to the fourth quarter of 2023...ARISTADA: Revenues for the fourth quarter were $96.6 million. Fourth quarter revenues grew 16% compared to the fourth quarter of 2023...VIVITROL: Revenues for the fourth quarter were $134.1 million. Fourth quarter revenues grew 31% compared to the fourth quarter of 2023."

Commercial • New P2 trial • P2 data • Bipolar Disorder • CNS Disorders • Narcolepsy • Schizophrenia • Sleep Disorder

Olanzapine/Samidorphan Effects on Weight Gain: An Individual Patient Data Meta-Analysis of Phase 2 and 3 Randomized Double-Blind Studies. (PubMed, J Clin Psychiatry) - "Fewer patients treated with OLZ/SAM gained ≥7% (23.9% vs 34.6%; odds ratio [OR] = 0.58; 95% CI, 0.043-0.79) or ≥10% (13.7% vs 20.4%; OR = 0.60; 95% CI, 0.42-0.88) of their baseline body weight at week 12. In this IPD meta-analysis, OLZ/SAM treatment was associated with less weight gain and reduced risk of reaching ≥7% or ≥10% gain in body weight versus olanzapine over 12 weeks."

Clinical • Journal • P2 data • Retrospective data • Bipolar Disorder • CNS Disorders • Psychiatry • Schizophrenia