Findings from the PROACTIVE study suggest why the benefits of long-acting injectable (LAI) second-generation antipsychotics may be difficult to detect in a clinical trial.
The PROACTIVE (Preventing Relapse Oral Antipsychotics Compared to Injectables Evaluating Efficacy) trial was a randomised efficacy trial, but also had pragmatic features, such as broad inclusion criteria and open clinical follow-up. The researchers aimed to bridge the gap between randomised controlled trials, which have for the most part shown little difference between second-generation LAIs and oral antipsychotics, and registry studies, which have shown reduced relapse in patients given LAIs.
“Such variances have historically hampered clinical interpretation as to the most apt positioning of LAIs in our clinical armamentarium”, say lead study author Peter Buckley (Georgia Regents University, Augusta, USA) and colleagues.
In PROACTIVE, the 153 schizophrenia patients given LAIs did not have a reduced relapse rate relative to 152 patients given oral second-generation antipsychotics, at 42% versus 32% during up to 30 months of follow-up.
Despite this, the LAI group had larger improvements over time, relative to the oral group, for Brief Psychiatric Rating Scale (BPRS) total scores (38.3 to 30.2 vs 38.1 to 38.1) and for BPRS psychosis cluster scores (2.7 to 1.8 vs 2.7 to 2.0).
All patients underwent biweekly monitoring, in line with the LAI dosing schedule, at which time patients taking oral antipsychotics were given the medication directly, rather than having to fill a prescription. Buckley et al suggest that the direct supply of medication and biweekly monitoring may have reduced nonadherence and consequently relapse in the patients assigned to receive oral antipsychotics, thus obscuring the benefits of LAIs.
“This frequency is higher than current practice, and if it were an appropriate evidence-based standard of care, it could overwhelm an already burdened community mental health services system”, the team notes in Schizophrenia Bulletin.
“However, there are ways to increase contact that do not require in-person clinic visits. A rigorous scientific evaluation of optimum frequency and model(s) of contact and interaction with follow-up and continuity of outpatient care for schizophrenia patients would be an important and timely contribution.”
The researchers also note that their patients did not have a history of nonadherence. Such patients tend to be engaged in their care and amenable to trial participation, whereas the largest anticipated benefits of LAIs are in nonadherent patients.
“Given the enormous personal suffering, family burden, disruption in functioning, and societal cost associated with preventable relapse and rehospitalization, this remains an important area of study”, concludes the team.
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