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Are long-acting injectable antipsychotics better than oral antipsychotics for preventing relapse and rehospitalization in patients with schizophrenia? You would think so, given our general acceptance of their use. However, if one looks at studies lasting 6 months or longer, the evidence for better outcomes with the long-acting vs the orals turns out to be pretty scarce. If you have patients who might warrant a long-acting injectable, you need the latest data on their efficacy.
In this Quick Take, we will look at a new meta-analysis of long-acting injectables and their efficacy. First, a quick look back to see why this new analysis is needed. In an older 2011 meta-analysis led by Claudia Leucht and colleagues, long-acting injectables were superior to orals for the prevention of relapse but not rehospitalization. And then a series of negative studies came along. So, Dr. Leucht and colleagues repeated their meta-analysis in 2014 and found no superiority of long-acting injectables relative to orals except in the early studies of first-generation antipsychotics. That was 6 years ago.
What do more recent data show? Well, that brings us to the new meta-analysis from Dr. Luisa Peters and colleagues. Here, they are looking at studies published just in the last few years and on the main question, are long-acting injectables better than orals for the prevention of relapse? There are only 4 studies to update the previous set, which, remember, ended up showing no superiority for long-acting injectables. The big new study with 444 patients was industry sponsored and showed a significant advantage for injectables over orals. The other 3, mostly government sponsored, were 1/4 to 1/8 the size and did not show superiority of long-acting injectables over orals. If you are a real skeptic, you could conclude that the only evidence for injectables over orals comes from studies sponsored by the manufacturers, and even that is pretty slim.
Nevertheless, have a look at that 1 big study run by Janssen employees. It pitted paliperidone once monthly vs clinician’s choice of oral antipsychotics in patients with a history of incarceration. The outcomes in this select population were different, with long-acting injectables superior to orals. Interestingly, the investigators lumped multiple endpoints into treatment failure. These included psychiatric hospitalization, arrest or incarceration, suicide, treatment discontinuation due to inefficacy, safety or tolerability, and the addition of another antipsychotic due to inefficacy or increased psychiatric services to prevent psychiatric hospitalization. For the long-acting injectables, the treatment failure rate was 40%. For orals, it was 54%.
However, even if you are a skeptic, which I think is warranted here, you have probably had a few patients who did well on an injectable after struggling with adherence to orals. Overall, the authors of this new review would support you. They conclude after also reviewing 5 more meta-analyses done since 2016 that the evidence for long-acting injectables is either positive or neutral, meaning no study has ever shown orals to be superior to the injectables for the select populations that entered these trials.
So, why aren’t they used more often? The authors note 5 factors: 1)The lack of familiarity on the part of many physicians; 2) incomplete or inaccurate perceptions about safety and efficacy; 3) medication costs considered in isolation without taking into account overall reductions in the cost of care due to reduced relapse and hospitalizations; 4) issues with access to treatment; and then finally, 5) negative perceptions about injectable therapy among patients’ families and prescribers. In this review, they also examined head-to-head studies comparing one long-acting injectable vs another, and there are not many of these studies. There are some comparisons of 2 versions of the same thing as paliperidone once monthly vs once 3 monthly. Moreover, 1 study compares aripiprazole and paliperidone. Overall, the results are those we would expect from oral versions of these drugs differing primarily in side effects like prolactin elevation and akathisia.
In summary, are long-acting injectables better than orals for preventing relapse and rehospitalization in patients with schizophrenia? The answer is a cautious yes, if proper patient selection is warranted. Moreover, is anyone of them any better than another? You will be the better judge of that based on your system of care, including startup time and time until the next injection. To go further, you could dig into this new paper by Luisa Peters by looking first at its structure, which is somewhat complex.
Abstract
Long-Acting Injections in Schizophrenia: a 3-Year Update on Randomized Controlled Trials Published January 2016-March 2019
Luisa Peters, Amanda Krogmann, Laura von Hardenberg, Katja Bödeker, Viktor B Nöhles, Christoph U Correll
Purpose of review: This study was conducted in order to review randomized controlled trial (RCT) data published January 2016-March 2019 on long-acting injectable antipsychotics (LAIs) for schizophrenia.
Recent findings: Thirty-one RCTs (primary studies = 7; post hoc analyses = 24; n = 4738) compared LAIs vs. placebo (studies = 11, n = 1875), LAIs vs. oral antipsychotics (OAPs) (studies = 7, n = 658), and LAI vs. LAI (studies = 13, n = 2205). LAIs included two new formulations, aripiprazole lauroxil nanocrystal dispersion and subcutaneously injectable risperidone Perseris, as well as aripiprazole lauroxil, aripiprazole once-monthly, paliperidone once-monthly, paliperidone 3-monthly, and risperidone-LAI. Regarding prevention of relapse and hospitalization, LAIs consistently outperformed placebo, being partly superior to OAPs, without relevant LAI-LAI differences. LAIs were comparable to OAPs regarding all-cause discontinuation, functioning, quality of life, and tolerability, being associated with higher patient satisfaction and service engagement. Recent meta-analyses yielded mixed results, but never favoring OAPs over LAIs. In RCTs, LAIs are superior to placebo, but only in some aspects, superior to OAPs. Comparative effectiveness of LAIs vs. OAPs requires further study, ideally in generalizable/real-world samples.
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Reference
Peters, L., Krogmann, A., von Hardenberg, L., Bödeker, K., Nöhles, V. B., & Correll, C. U. (2019). Long-acting injections in schizophrenia: A 3-year update on randomized controlled trials published January 2016–March 2019. Current Psychiatry Reports, 21(12), 124.
Related References
Peters, L., Krogmann, A., von Hardenberg, L., Bödeker, K., Nöhles, V. B., & Correll, C. U. (2019). Long-acting injections in schizophrenia: a 3-Year update on randomized controlled trials published January 2016–March 2019. Current Psychiatry Reports, 21(12), 124.
