A novel once-weekly oral formulation of risperidone has demonstrated promising results in treating schizophrenia and schizoaffective disorder, potentially addressing one of the most persistent challenges in psychiatric care: medication adherence. The STARLYNG-1 Phase 3 trial, published in The Lancet Psychiatry, represents the first successful demonstration of long-acting oral drug delivery technology for psychiatric disorders.
Breakthrough in Oral Extended-Release Technology
LYN-005 utilizes an innovative capsule design featuring a star-shaped structure that opens in the stomach and remains there for up to a week. This structure slowly releases risperidone and then breaks down naturally before exiting the body. The technology addresses a critical gap in schizophrenia treatment options, where patients have been limited to daily oral medications or long-acting injectable formulations.
"Although long-acting injectable formulations provide an alternative to daily oral medications, no long-acting oral formulations exist," the study authors noted. The only previous attempt at weekly oral antipsychotic therapy was penfluridol, a first-generation drug from the 1970s that had significant problems with inconsistent drug levels and has largely fallen out of clinical use.
Clinical Trial Results
The multicentre, open-label study enrolled 83 adults with schizophrenia or schizoaffective disorder across five US sites from April to December 2023. Participants first received daily immediate-release risperidone (2mg or 6mg) for one week, then transitioned to weekly LYN-005 (15mg or 45mg respectively) for five weeks. A half-dose of daily risperidone was administered during the first week of LYN-005 to ensure smooth transition.
The primary endpoint focused on pharmacokinetic comparisons between weekly and daily formulations. Results showed that LYN-005 matched daily risperidone in minimum and average drug levels, staying within 90% of daily dosing concentrations. Peak levels were lower with the weekly formulation, potentially indicating fewer side effects. Drug levels remained steady throughout the week, with the formulation demonstrating a long half-life of 88 to 132 hours.
Most participants remained clinically stable throughout the five-week treatment period, with no changes in symptom scores. The formulation provided "stable and therapeutic levels of the drug in the body, with efficacy and safety comparable to those of immediate-release risperidone," according to the research findings.
Safety Profile and Limitations
Side effects were primarily gastrointestinal and generally mild in nature. One serious adverse event (oesophagitis) was reported but resolved during the study period. No deaths or extrapyramidal side effects occurred, and a four-week safety follow-up revealed no new or lasting adverse effects.
However, the study faced significant challenges with participant retention. Of the 83 enrolled participants, 36 withdrew before completion - a dropout rate of approximately 43%. Sixteen participants dropped out during the initial daily risperidone phase, while seven more withdrew in the first week of LYN-005, primarily due to gastrointestinal side effects or the intensive monitoring requirements including frequent blood draws.
The study's limitations extend beyond dropout rates. The relatively short five-week duration, the structured inpatient setting rather than real-world outpatient conditions, and the high incidence of gastrointestinal effects raise questions about long-term feasibility and adherence in clinical practice.
Clinical Significance and Future Implications
This advancement represents a significant milestone in psychiatric treatment, as it is "the first Phase 3 trial to successfully demonstrate an oral extended-release technology in psychiatric disorders." The development could particularly benefit patients who struggle with daily medication adherence but prefer to avoid injectable formulations due to stigma or personal preference.
"The development of a weekly oral formulation could reduce the stigma associated with daily pill-taking and caregiver reminders, promoting greater autonomy and treatment engagement for some individuals," the authors explained.
However, experts note both the potential and limitations of this approach. While the technology offers "another option for treating schizophrenia that offers a very modest improvement," it also eliminates the flexibility of daily dose adjustments and may prolong side effects due to the extended-release mechanism.
The researchers acknowledge that larger, double-blind, randomized trials will be necessary to validate whether LYN-005 improves adherence and long-term outcomes in real-world clinical settings. If successful, this platform technology could potentially be extended to other psychiatric or chronic conditions where daily dosing presents adherence challenges.
The study represents what researchers describe as "an incremental innovation" in schizophrenia treatment, providing a new tool in the therapeutic arsenal while acknowledging that risperidone itself has been available in various formulations for many years. The weekly oral option fills a specific niche for patients who may benefit from reduced dosing frequency without requiring injectable medications.
