Highlights
- LYN-005, a novel long-acting oral risperidone, achieved pharmacokinetic equivalence to daily immediate-release risperidone at steady-state.
- Sustained therapeutic plasma concentrations were observed with weekly dosing, supporting its potential to mitigate adherence challenges in schizophrenia.
- Safety profile was consistent with established risperidone use, with gastrointestinal adverse events most common and no unexpected safety signals.
- The weekly oral formulation may address a critical gap for patients preferring oral therapy but struggling with daily adherence.
Study Background and Disease Burden
Schizophrenia is a chronic, disabling psychiatric disorder marked by recurrent psychosis, cognitive impairment, and significant functional decline. Medication non-adherence, estimated to affect up to half of patients at some point, is a pivotal driver of relapse, hospitalization, and poor long-term outcomes. While long-acting injectable antipsychotics (LAIs) improve adherence and outcomes, their use is limited by patient preference, access, and logistical barriers. A long-acting oral formulation could bridge the gap for patients who reject LAIs yet remain at risk for non-adherence with daily oral agents. The STARLYNG-1 trial focused on LYN-005, a weekly oral formulation of risperidone, aiming to establish its pharmacokinetic equivalence to daily immediate-release risperidone and to assess its safety and tolerability in a clinically stable population.
Study Design
STARLYNG-1 was a multicentre, open-label, non-randomised phase 3 study conducted across five U.S. inpatient facilities. Eligible participants were adults with a DSM-5 diagnosis of schizophrenia or schizoaffective disorder, clinically stable on antipsychotic therapy, and able to reside as inpatients for the 5-week study duration (except days 9–13).
After a 7-day run-in on daily immediate-release risperidone (2 mg or 6 mg), subjects transitioned to weekly oral LYN-005 (15 mg or 45 mg) for five weeks. To ensure stable plasma levels during the transition, a half-dose of daily immediate-release risperidone was provided during the first week. Primary endpoints were pharmacokinetic measures—minimum concentration (Cmin) at weeks 1 and 5, maximum concentration (Cmax), and average concentration (Cavg) at week 5—comparing LYN-005 to immediate-release risperidone at steady-state. The prespecified bioequivalence criteria were: geometric mean ratio (GMR) for Cmin ≥0.8, Cmax ≤1.25, and Cavg between 0.8 and 1.4 (all with 90% CI). Safety and tolerability were assessed throughout.
Key Findings
A total of 83 participants were enrolled (75% male, 81% Black or African American, mean age 49.3 years). Of these, 47 completed the full study course, and 44 were included in the pharmacokinetic analysis. The LYN-005 cohort included both 15 mg and 45 mg groups, directly reflecting low and high maintenance dosing typical in clinical practice.
Pharmacokinetic Outcomes
LYN-005 achieved sustained plasma risperidone levels, with geometric mean ratios versus immediate-release risperidone as follows:
- Cmin week 1: 1.02 (90% CI 0.93–1.12)
- Cmin week 5: 1.04 (0.87–1.23)
- Cmax week 5: 0.84 (0.77–0.92)
- Cavg week 5: 1.03 (0.93–1.13)
All endpoints met the prespecified bioequivalence criteria, confirming that weekly LYN-005 provides comparable exposure to daily therapy across the dosing interval. Importantly, plasma levels never fell below therapeutic thresholds, supporting the formulation’s ability to provide continuous receptor blockade necessary for relapse prevention.
Clinical Stability and Safety
Participants remained clinically stable throughout. Gastrointestinal treatment-emergent adverse events (TEAEs), such as nausea or mild GI upset, were the most common, affecting 66% of those on LYN-005. Only one serious TEAE was reported. No unexpected adverse signals emerged, and the safety profile was consistent with known effects of risperidone. There were no new extrapyramidal, metabolic, or cardiovascular signals identified.
Demographic Considerations
The sample predominantly consisted of Black or African American men in their late 40s, limiting generalizability to more diverse outpatient populations or those earlier in their disease course. Retention rates were modest (57%), consistent with the challenge of maintaining participation among individuals with severe mental illness in inpatient research settings.
Expert Commentary
The STARLYNG-1 study provides compelling pharmacokinetic evidence that LYN-005 is bioequivalent to daily risperidone, with practical implications for schizophrenia care. Adherence remains a major barrier to the long-term efficacy of oral antipsychotics; a weekly oral option offers a valuable middle ground for patients averse to injectables and unable to sustain daily pill-taking.
Dr. Leslie Citrome, a co-author of the study, has previously emphasized the clinical importance of expanding long-acting options beyond injectables, especially for populations with complex social and health needs. The sustained therapeutic levels observed suggest that weekly LYN-005 could meaningfully reduce relapse risk associated with missed daily doses.
However, the non-randomised, open-label design and inpatient setting limit extrapolation to the broader outpatient population. Additionally, high rates of gastrointestinal adverse events may warrant monitoring and patient counseling. The absence of individuals with lived experience in the trial design is a limitation, considering the importance of patient-centered care in psychiatry.
Looking ahead, real-world studies and head-to-head comparisons with LAIs are needed to clarify the relative benefit of weekly oral versus injectable long-acting antipsychotics. Mechanistically, the formulation’s extended-release profile supports consistent D2 receptor occupancy, aligning with established principles for relapse prevention in schizophrenia.
Conclusion
LYN-005 represents a significant advance in antipsychotic drug delivery, offering weekly oral dosing with proven pharmacokinetic equivalence to daily risperidone and a manageable safety profile. This innovation has the potential to enhance adherence, reduce relapse risk, and broaden therapeutic choice, particularly for patients who decline LAIs. Future research should focus on outpatient effectiveness, patient preference, and comparative effectiveness against established long-acting injectables.
References
- Citrome L, Nagaraj N, Traverso G, Dumas T, Scranton R. Long-acting oral weekly risperidone (LYN-005) for schizophrenia in the USA (STARLYNG-1): a multicentre, open-label, non-randomised phase 3 trial. Lancet Psychiatry. 2025 Jul;12(7):504-512. doi: 10.1016/S2215-0366(25)00135-X. PMID: 40506209.
- Kane JM, Correll CU. Past and present progress in the pharmacologic treatment of schizophrenia. J Clin Psychiatry. 2010;71(9):1115-1124. PMID: 20868616.
- Velligan DI, Weiden PJ, Sajatovic M, et al. The expert consensus guideline series: adherence problems in patients with serious and persistent mental illness. J Clin Psychiatry. 2009;70(suppl 4):1-46. PMID: 19570499.
- Correll CU, Citrome L, Haddad PM, et al. The use of long-acting injectable antipsychotics in schizophrenia: evaluating the evidence. J Clin Psychiatry. 2016;77(suppl 3):1-24. PMID: 27503242.
