Too Little, Too Late: LAIs Remain Underused

The underuse of LAIs by physicians is likely the result of multiple factors, ranging from the logistics involved in administering LAIs (for example, ordering and storing the medications) to questions over whether LAIs are superior to oral antipsychotics, Rubio said.

A large European trial that was described in Lancet Psychiatry in March suggested that patients taking LAIs were about as likely to discontinue treatment as those taking oral medications.

That trial, known as EULAST, enrolled 533 adults who had experienced a first episode of psychosis within the last seven years. The patients were randomly assigned to receive monthly LAI paliperidone, oral paliperidone, monthly LAI aripiprazole, or oral aripiprazole. They were then followed for up to 19 months, and a variety of clinical outcomes were assessed.

“A lot of the evidence of LAI superiority comes from analyses of health databases from countries like Sweden or Finland,” said study co-author Rene Kahn, M.D., the Esther and Joseph Klingenstein Professor and System Chair of Psychiatry at New York’s Icahn School of Medicine at Mount Sinai. However, such studies tend to combine different LAIs and oral medications in their analysis. “It’s not a direct apples-to-apples comparison; this study compared outcomes between people taking two forms of the exact same molecule.”

The primary outcome of interest in EULAST was medication discontinuation for any reason, which tried to capture the broad problem of medication adherence: “We let the participants vote with their feet; if they ask to stop their medication or they never show up again, then something went wrong with the treatment.”

Overall, 71% of the participants taking oral medications discontinued treatment by 19 months compared with 64% of those taking LAIs—which the authors noted was not statistically different. There were also no differences in treatment discontinuation when comparing the individual medications (aripiprazole or paliperidone).

Kahn cautioned that any one study is not definitive, but “in regard to the claim that LAIs are superior at keeping patients engaged in treatment, the jury is still out.”

Kenneth Subotnik, Ph.D., an adjunct professor of psychiatry and biobehavioral sciences at the University of California, Los Angeles, said that the EULAST study’s focus on numerous treatment discontinuation events allows for a high-level overview of whether patients with schizophrenia can be better managed on LAIs than on oral medications. However, he noted, the design of the trial may have overlooked important advantages of LAIs.

Subotnik led one of the seminal clinical trials that found patients taking LAIs experienced fewer breakthrough symptoms than those taking oral antipsychotics. In that randomized trial of 86 adults with schizophrenia, those who received LAI risperidone were less likely to experience reemergent psychosis symptoms or have a relapse over 12 months compared with adults who took oral risperidone. The participants were assessed every two weeks and pill counts were carefully monitored for the oral group. The results were published in JAMA in 2015.

Subotnik noted that since breakthrough symptoms can often be controlled with a dose adjustment or adding another medication, such symptoms may have been missed in the EULAST study.

“I think psychiatrists may overestimate how adherent their patients are to oral medications, which can contribute to some problems,” Subotnik suggested. Therein lies another advantage of LAIs, he said. “The injections maintain consistent and persistent levels of the medication in the blood, which makes it easier to differentiate a lack of drug efficacy from a lack of medication adherence.”

The thorniest barrier hindering physicians from prescribing LAIs as an early schizophrenia treatment option may be that “LAIs have been traditionally used for chronically ill patients who have recurrently demonstrated non-adherence, when it might be too late,” Rubio said.

Breaking down this barrier may require systems-level changes, he continued. “We need to get physicians to stop thinking of LAIs as a reactive tool and start seeing them as a proactive intervention to prevent relapse and other bad outcomes.”

Rubio noted that population data from Finland and Canada have shown that the effectiveness of antipsychotics drops dramatically after each relapse of psychosis, so it’s critical to step in early.

Subotnik, who is also associate director of UCLA’s outpatient clinic for patients who are in the early course of schizophrenia, agrees that LAIs need to be reframed as a preventive tool. “Studies have shown that there are so many neurochemical changes going on in the first few years after schizophrenia onset, and effective early treatment is the key to preventing further neurocognitive decline,” he said.

“Most patients do not view LAIs as a form of punishment or coercion,” he continued. “With oral antipsychotics, people with schizophrenia are reminded of their disorder every time they need to take their pill. This no longer becomes an issue with long-acting medications.”

The EULAST study was funded by Lundbeck and Otsuka. Subotnik’s clinical study was funded by the National Institute of Mental Health with supplementary funding from Janssen Scientific Affairs. Rubio’s analysis was supported by Teva Pharmaceuticals. ■