No Benefit of Long-Acting Antipsychotics in Schizophrenia?

In patients with early-phase schizophrenia, long-acting injectable antipsychotics (LAIs) provide no benefit over oral antipsychotics (OAs) in preventing discontinuation of antipsychotic treatment, new research suggests.

In a multicountry, randomized, open-label study of more than 500 adults with schizophrenia, participants received either LAI paliperidone, LAI aripiprazole, or the respective oral formulation of these antipsychotics.

Results showed no significant difference between the combined oral and combined LAI treatment groups in time to all-cause discontinuation.

“We found no substantial advantage for LAI antipsychotic treatment over oral treatment, regarding time to discontinuation in patients with early-phase schizophrenia,” write investigators, led by Inge Winter-van Rossum, PhD, assistant visiting professor at Mount Sinai, New York City, and affiliated with King’s College London, United Kingdom, and UMC Utrecht, the Netherlands.

This indicates that “there is no reason to prescribe LAIs instead of oral antipsychotics if the goal is to prevent discontinuation of antipsychotic medication in daily clinical practice,” they add.

The findings were published online January 27 in The Lancet Psychiatry.

Previous Conflicting Results

Maintenance treatment with antipsychotic medication reduces risk for relapse considerably, with treatment discontinuation being “by far the most important reason for relapse,” the investigators write.

LAIs “seem theoretically to be a way to enhance medication continuation and thereby reduce the risk for relapse,” they add. This is because LAIs enable a rapid response to nonadherence and remove the need for patients to remember to take their medications on a daily basis.

However, previous research has “provided conflicting results,” regarding the effectiveness of LAIs in accomplishing this. Moreover, the subject has not been thoroughly investigated in early-stage schizophrenia, the researchers note.

Therefore, they decided to conduct the EULAST study to compare LAI and oral formulations in terms of all-cause discontinuation.

The trial was conducted at 50 general hospitals and psychiatric specialty clinics located in 15 European countries and Israel and included 511 participants in the intention to treat sample (67% men; mean age, 30.5 years).

All were randomly assigned 1:1:1 to receive either LAI paliperidone, LAI aripiprazole, or their respective oral formulations.

The combined OA treatment group consisted of 247 patients; the combined LAI group consisted of 264 patients.

Randomization was stratified by country and illness duration (5 months to 3 years vs 4-7 years). Participants were followed up to 19 months, with all-cause discontinuation during that time serving as the primary endpoint.

All-cause discontinuation was defined as the allocated treatment was stopped or used at doses outside the allowed range, medication was switched or augmented with another antipsychotic after visit four, the patient missed a monthly visit and did not show up after being reminded, the patient withdrew consent for the study, or the clinician withdrew the patient from the study.

After the baseline visit, patients already taking antipsychotics were also randomly assigned. The next 4 weeks were then used to cross-taper between pre-study antipsychotic and the agent they would be treated with during the study.

LAIs Not Superior

Results showed the LAI group did not have lower rates of hospitalization.

In addition, the discontinuation rates between the two combined groups were very similar at 71% for the oral antipsychotics group vs 64% in the LAIs group (hazard ratio [HR], 1.6; 95% CI, 0.94-1.43; P = .18).

Moreover, “no significant difference was found in the time to all-cause discontinuation between the combined oral and combined LAI treatment groups (P = .17),” the researchers report.

Reasons for discontinuation also did not differ significantly between the groups: 12% of patients in the OA group discontinued treatment because of efficacy vs 17% of patients in the combined LAI group. The difference was not significant and the time to discontinuation also did not differ.

The main reason for discontinuation in both groups was safety concerns, affecting 10% and 13% of the combined OA and LAI groups, respectively, which was not a significant between-group difference.

Illness duration had a significant effect on time to all-cause discontinuation, with patients who had longer illness duration showing a poorer response compared with those who had shorter duration (HR, 1.26; 95% CI, 1.01-1.56; P = .038).

However, stratifying participants by illness duration showed no significant difference between the subgroups (P = .25 and .34, respectively).

There was a significant between-group difference in discontinuation due to “other reasons,” with 49% vs 34% of patients in the OA and LAI groups, respectively, discontinuing (HR, 1.51; 95% CI, 1.15-1.98; P = .0034). Moreover, the LAI group showed significantly longer continued use of medication vs the OA group (P = .0029).

“After separating the reasons for discontinuation into no efficacy, safety reasons, and other reasons, we only found a significant difference in favor of LAI for the ‘other reasons’ category; although the number of patients discontinuing medication for this reason over the follow-up period did not differ, patients on LAI continued treatment for a longer time,” the investigators write.

They acknowledge that this finding is “difficult to interpret, given the wide variety of reasons for discontinuation captured in this category,” which prevented an “informative subgroup analysis.”

Nevertheless, since there is “no consistent evidence supporting the use of LAI over oral antipsychotics” in patients with early phase schizophrenia, their use should be “carefully considered on an individual risk-benefit basis,” they conclude.

No ‘Real-world’ Implications?

Commenting for Medscape Medical News, John Kane, MD, co-director and professor, Institute of Behavioral Science, Feinstein Institutes for Medical Research, Long Island, New York, said that overall, this was a “large, potentially valuable study.” However, he raised several concerns.

“I think the investigators made a much too emphatic statement about the lack of value of LAIs in early phase patients when discontinuation is the primary outcome,” he said, noting that other studies have come to the opposite conclusion.

Kane, who is also a professor of psychiatry at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, New York, was not involved with the current research.

“RCTs [randomized controlled trials] in general are not necessarily the best way to evaluate the impact of LAIs, [which] usually represent a small percentage of potentially eligible patients and are likely to include patients who are more adherent than those who would not agree to participate in an RCT,” he said. He added that the investigators “did not report on how many patients were screened and refused to be considered.”

Also, Kane noted that half of the participants were recruited from inpatient services, and so may have been “more unstable” at baseline. “Patients with residual positive symptoms are more likely to relapse on LAIs than patients who are in remission. This could potentially reduce the advantage of the LAI,” he said.

In addition, he took issue with the definition of all-cause discontinuation, which included the need for augmentation with another antipsychotic or use outside the normal range.

“This happens often in clinical practice. If someone’s symptoms aren’t sufficiently controlled by an LAI alone, for example, they often receive more of that antipsychotic or another drug. This perhaps makes the EULAST study somewhat less ‘real-world’,” Kane said.

More Information Needed

In an accompanying editorial, Martina Hahn, PharmD, PhD, Department of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital-Goethe University, Frankfurt, Germany, and Sibylle Christine Roll, MD, PHD, Department of Mental Health, Varisano Hospital in Frankfurt, note that comedications were neither documented nor analyzed by the researchers.

“Drug-drug interactions could be responsible for relapse or poor tolerability,” they write.

Moreover, pharmacogenetic information was not available nor were serum concentrations that could have been used for dose optimization after switching antipsychotic formulations, they note.

This information would have provided “a deeper understanding of why some patients do not respond or show side effects,” the editorialists write. “The use of therapeutic drug monitoring, drug interaction checks, and pharmacogenetic testing could improve treatment outcomes in both study settings and clinical practice.”

Financial support and study medication was provided by Lundbeck and Otsuka. Winter-van Rossum reports no relevant financial relationships. Disclosures for the other investigators are fully listed in the original paper. Kane is or has been a consultant to or received honoraria for lectures from Alkermes , Biogen, Boehringer Ingelheim, Cerevel, Dainippon Sumitomo, H. Lundbeck, HLS, Intracellular Therapies, Janssen, Karuna, Merck, Newron, Otsuka, Roche, Saladax, Sunovion, and TEVA. He is also a shareholder in The Vanguard Research Group, LB Pharma, Health Rhythms, North Shore Therapeutics, and Medincell. Hahn reports having received honoraria for lecture from Otsuka and advisory board participation for Rovi. Roll reports advisory board participation for Recordati, Otsuka, and Janssen.

Lancet Psychiatry. Published January 27, 2023. Abstract; editorial

Batya Swift Yasgur MA, LSW is a freelance writer with a counseling practice in Teaneck, NJ. She is a regular contributor to numerous medical publications, including Medscape and WebMD, and is the author of several consumer-oriented health books as well as Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom (the memoir of two brave Afghan sisters who told her their story).

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