A new study has added deeper perspective on the important question of whether patients taking long-acting injectable (LAI) antipsychotic medicines after a first episode of psychosis (FEP) have a reduced risk of having a psychosis relapse in succeeding years.

A first psychotic experience in many individuals is an event that leads to a subsequent diagnosis of schizophrenia or schizoaffective disorder. The core component of any therapeutic strategy following a FEP is the prescription of an oral antipsychotic medicine. But many patients at some point stop taking oral antipsychotics—some because of the side effects of the medicine, others due to lack of insight about their condition. These patients are more likely to have psychosis relapses as well as psychiatric hospitalizations while they are not taking prescribed antipsychotics.

The problem of non-adherence inspired the creation of LAIs. For as long as a given injection is delivering active medication, the question of voluntary adherence is not a factor, although it is also commonplace for patients who have taken an LAI to decide not to return to the clinic for a subsequent injection when it is needed (dosing intervals range from every 2 weeks to every 6 months). Is there, then, any advantage with LAIs?

A team of investigators that includes 10 recipients of BBRF grants, including the two leaders of the new study, note that some (but not all) past studies have found a lower risk of psychosis relapse and hospitalization among patients receiving LAI therapy than among those receiving conventional oral antipsychotic therapy following FEP. But, they add, these results are quite difficult to interpret (and thus act upon). A host of methodological issues crop up, not only differences of approach and method between studies, but also the fact that patients receiving LAIs and oral therapies are often different in important ways, a fact that is hard to reflect in the analysis of comparative results.

The team leaders and co-first authors of the new study, which appeared in Nature Mental Health, are Alejandro G. Szmulewicz, M.D., Ph.D., of Harvard University, and Gonzalo Martinez-Ales, M.D., Ph.D., of the Icahn School of Medicine at Mount Sinai. Both are recipients of 2022 BBRF Young Investigator grants. Dr. Szmulewicz’s BBRF grant project, focusing on the comparative effectiveness and safety of different strategies for the management of early psychosis, is directly related to and helped support the current study.

The largest individually randomized clinical trial among FEP patients—called the European Long-Acting Antipsychotics in Schizophrenia Trial, or EULAST—found similar risks of therapy discontinuation and hospitalization in those taking an LAIs and those continuing on oral medicines. But the study was not able to determine comparative risks in subgroups of patients, and had a follow-up period of only 18 months. Further, it counted “hospitalizations” occurring only before individuals stopped taking their medication, while arguably the more important question is how the rate of post-discontinuation hospitalizations was either impacted or not depending on whether the patient was taking an LAI or an oral antipsychotic medicine.

The new study uses data gathered by a large consortium of FEP patients in Europe and North America called FEP-CAUSAL. The object was to compare risks of psychosis relapse and hospitalization after FEP among those who initiate LAI therapy vs. those who continue with oral therapy after FEP. The methodology of the new study enabled the authors to ask additional questions, including: estimating the comparative risks of relapse and hospitalization over a 3-year (rather than 18-month) follow-up period between LAI initiators and those who continued with oral therapy after FEP. In addition to yielding an overall differential (if any), the new study would also be able to estimate the impact (if any) in important patient subgroups, as defined according to history of any prior psychosis relapses, past history of non-adherence to antipsychotics, and a concurrent diagnosis of substance-use disorder.

In the first phase of their study, the team used data from 1,067 individuals from the FEP-CAUSAL dataset and EULAST study who were receiving oral risperidone, aripiprazole, or paliperidone. This cohort was 73% male 57% White, with a median age of 24 years. Compared with those who stayed on oral medications, those who switched to LAI therapy were, on average, more severely ill, less likely to be full-time students or workers, and more likely to have been hospitalized since their initial hospitalization for FEP. There was no significant difference in adherence (in both groups, about 45% did not stay on their treatment over 18 months of follow-up), and the 18-month risk of hospitalization was about 18% in both groups.

When the team used the data to extend the results from the EULAST study out to 3 years of follow-up, it was possible to make new comparative risk assessments. In this part of the study, the cohort consisted of 1,193 individuals with FEP, 70% of whom were White and 65% male, median age 24. Those who elected to switch to LAI were more likely to be male, White, and living alone, more likely to have a schizophrenia diagnosis concurrent with substance abuse disorder, tended to have more severe psychosis symptoms, three or more hospitalizations since FEP diagnosis, and less likely to be fulltime students or workers and to be receiving additional antidepressant drugs. Those who adhered to LAI therapy were more likely to also be taking mood stabilizers or antidepressants, and more likely not to have been hospitalized since FEP diagnosis.

About 49% at some point over the 3 years discontinued therapy in the LAI group, and just shy of 60% in the oral continuation group (some may have then re-initiated treatment, but this was not tracked in the study data). There was another significant difference between groups: the estimated 3-year risk of relapse was 46% for the LAI group and 53% for those who continued on oral therapy. The team noted, “Our findings suggest the 3-year risk of relapse is considerably lower for LAI therapy initiation than for oral therapy continuation among those with a history of psychosis relapse or non-adherence to oral medication.” The risk benefit of LAI therapy “seems to be the result of better adherence,” they said.

And while initiation of LAI medications risperidone, aripiprazole, or paliperidone decreased risk of psychosis relapse over a 3-year period, there was “little or no difference in the first 18 months, the researchers noted. Again, the expected benefit was greater for those with prior relapses and with documented non-adherence or oral antipsychotics.

The team included: Ridha Joober, M.D., Ph.D., 2000 BBRF Young Investigator; Lakshmi N. Yatham, FRCPC, MRCPsych, M.D., 2003 BBRF Independent Investigator, 1999, 1996 Young Investigator; Deepak K. Sarpal, M.D., 2017 BBRF Young Investigator; Ann K. Shinn, M.D., MPH, 2010 BBRF Young Investigator; Celso Arango, M.D., Ph.D., 2005 BBRF Independent Investigator; Dost Öngür, M.D., Ph.D., 2013 BBRF Independent Investigator, 2004 Young Investigator; Enrique Baca-Garcia, M.D., Ph.D., 2001, 1998 BBRF Young Investigator; Martin Lepage, Ph.D., 2002 BBRF Young Investigator.