Once-Weekly Oral Risperidone Shows Promise in Schizophrenia Treatment

Skipping daily pills is a common problem in schizophrenia care. A new study in the US tested a once-weekly oral version of risperidone. The results show that the drug remained at therapeutic levels throughout the week and was generally well tolerated.

The study was published in The Lancet Psychiatry.

Why current schizophrenia treatments fall short

Schizophrenia and schizoaffective disorder are long-term conditions that affect thinking, emotions and behavior. For many people with these conditions, sticking to daily medication is hard due to cognitive symptoms, side effects and social stigma. When people miss doses, symptoms can return, and care becomes more complex.

Some patients are prescribed long-acting injections to reduce the number of doses they need. These can help with adherence, but not everyone wants or accepts an injection. They also require clinic visits and often carry their own stigma. So far, there hasn’t been a long-acting oral option that works reliably.

“Although long-acting injectable formulations provide an alternative to daily oral medications, no long-acting oral formulations exist,” said the study authors.

The only prior example of a once-weekly oral antipsychotic is penfluridol, a first-generation drug introduced in the 1970s. It had major problems with inconsistent drug levels in the body and has largely fallen out of use. Since then, researchers have looked for safer and more predictable long-acting oral versions of second-generation antipsychotics, which are more widely used today.

“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 said.

The new trial tested LYN-005, a once-weekly form of risperidone, to see if it could maintain stable drug levels like daily pills.

Testing weekly risperidone

The STARLYNG-1 trial was a Phase 3, open-label study carried out at five sites in the US from April–December 2023. It enrolled 83 adults diagnosed with schizophrenia or schizoaffective disorder. The aim was to test LYN-005 and see how it compared to daily dosing.

LYN-005 uses a capsule with a star-shaped structure that opens in the stomach and stays there for up to a week. This structure slowly releases the drug and then breaks down and exits the body.

All participants first switched to daily immediate-release risperidone for one week, either two milligrams or six milligrams per day, depending on their previous treatment. They then moved to once-weekly LYN-005 for 5 weeks, 15 mg or 45 mg doses, respectively. To smooth the transition, participants also received a half-dose of daily risperidone during the first week of LYN-005.

Blood samples were taken frequently during each weekly dose cycle to track how the drug moved through the body. The main goal was to compare the minimum, maximum and average concentrations of LYN-005 with those of daily risperidone.

The weekly formulation matched daily risperidone in minimum and average drug levels – matching within 90% of those from daily dosing. Peak levels were lower, which may mean fewer side effects. Drug levels stayed steady throughout the week, and the formulation had a long half-life of 88 to 132 hours.

Most participants remained clinically stable, with no change in symptom scores over five weeks.

Side effects were mainly gastrointestinal and mild. One serious event (oesophagitis) was reported but resolved. No deaths or extrapyramidal side effects occurred.

A four-week safety follow-up after the treatment period showed no new or lasting adverse effects.

What does this mean for schizophrenia treatment going forward?

LYN-005 has the potential to help people stick to their medication schedule without daily pills or monthly injections. It may also mean fewer clinic visits and more control for patients who prefer taking medications at home. A weekly oral option adds flexibility to schizophrenia care.

“To our knowledge, this phase three trial is the first successful demonstration of this long-acting oral drug delivery technology for schizophrenia and schizoaffective disorder, validating a platform that could transform daily medications into weekly formulations,” said the authors.

However, the study has clear limitations. It was small, not randomized and everyone knew what treatment they were getting. All participants were in a structured, inpatient setting, and almost half dropped out before the study ended, most during the early stages. Of the 36 participants who withdrew, 16 dropped out during the initial daily risperidone phase, and 7 more withdrew in the first week of LYN-005, mostly due to gastrointestinal side effects or intensive monitoring demands, such as frequent blood draws.

The participant group also lacked diversity. Women were underrepresented, and people with more severe or unstable illness weren’t included.

The researchers argue that the results of this study are promising; however, a larger, double-blind, randomized trial is needed. That would help test whether LYN-005 improves adherence and long-term outcomes in the real world. If successful, this technology could extend beyond schizophrenia to other psychiatric or chronic conditions where daily dosing is a barrier.

 

Reference: 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;12(7):504-512. doi: 10.1016/S2215-0366(25)00135-X

This article is a rework of a press release issued by The Lancet. Material has been edited for length and content.