LAI Antipsychotics: Game Changer, or Still Awaiting Evidence of Superiority?
Abstract
Randomized, controlled trials of long-acting injectable antipsychotics have had variable results. But one expert believes that studies are needed that better mimic real-world clinical situations in which compliance with medication is a ubiquitous barrier to recovery.
Are long-acting injectable antipsychotics a “game changer” in the treatment of schizophrenia, preventing relapse by ensuring better adherence to medication?
One recent randomized, controlled trial described in the August issue of JAMA Psychiatry suggests they could be. In that study, long-acting risperidone demonstrated better control of symptoms and—importantly—significant superiority compared with oral risperidone with regard to psychotic exacerbation and/or relapse in a cohort of first-episode schizophrenia patients.
(In the same edition of JAMA Psychiatry, a second study showed that a three-month formulation of paliperidone palmitate administered repeatedly over the course of a year significantly delayed time to relapse in patients with schizophrenia compared with placebo; the three-month formulation was also found to be safe and well tolerated.)
In the risperidone trial, Kenneth Subotnik, Ph.D., and colleagues at the University of California, Los Angeles, randomly assigned 86 patients with recent-onset schizophrenia to receive long-acting injectable risperidone or oral risperidone for 12 months. Of the 86 patients randomized, three refused treatment in the long-acting injectable risperidone group.
The psychotic exacerbation and/or relapse rate was 5 percent for the long-acting risperidone group compared with 33 percent for the oral group. Also, the long-acting injectable risperidone showed better control of hallucinations and delusions throughout follow-up at one year.
Subotnik and colleagues noted that the use of long-acting injectable risperidone also led to better maintenance of intracortical myelination as well as improved cognitive functioning. “If this trifecta of improved psychotic symptom control, cognition, and intracortical myelination can be replicated in longer longitudinal studies of patients with a first episode of schizophrenia, it would suggest that the use of long-acting injectable antipsychotics early in schizophrenia can modify the trajectory of the disorder and lead to better long-term outcomes,” they wrote. “This possibility would be a ‘game changer’ for the field.”
Key Points
A recent RCT comparing long-acting injectable risperidone to oral risperidone demonstrated significant superiority in preventing relapse, but meta-analyses of such trials have shown variable results.
LAI antipsychotics have not yet been widely adopted for a variety of reasons: psychiatrists’ misperception that they are for patients who are violent or have very severe mental illness, inconclusive results from RCTs, and a lack of knowledge about benefits on the part of providers and patients.
Studies mirroring real-world clinical conditions may better reveal the effectiveness of LAIs.
Adoption of LAIs may be driven by the focus on value in health care and the need to reduce rehospitalization.
A host of clinical questions remain about LAIs including dosage, choice of drug, interval time between injections, and selection of patients suitable for LAIs.
Prolonged intervals with an LAI drug should not reduce essential clinician-patient contact and communication.
Bottom Line: Long-acting injectable antipsychotics may hold promise for their effectiveness in reducing relapse and rehospitalization, but important clinical questions about their optimal use remain.
Yet findings from randomized, controlled trials (RCTs) of long-acting injectables (LAIs) have not been uniform, with a number of studies with chronic patients demonstrating no superiority over oral medications. For this reason—and several others—it appears that LAI antipsychotics have yet to achieve “game changer” status.
“Grossly underutilized” is how psychiatrist John Kane, M.D., characterized LAIs in clinical practice. He is senior vice president for behavioral Health services of the North Shore-Long Island Jewish Health System and chair of psychiatry at the Zucker Hillside Hospital.
“There are several advantages to LAIs, not the least of which is knowing when patients are taking their medications. When using oral medications, physicians very often overestimate their patients’ adherence—and the patients may do so too, either because they don’t remember to take the pills or can’t remember whether they have.
“The other advantage to LAIs is that physicians have better control over the dosage— when you give the injection, you know the exact amount of medication the patient is receiving, and there are fewer problems with bioavailability than with oral meds,” Kane told Psychiatric News.
Kane believes that the mixed results stemming from RCTs of long-acting injectables may be an artifact of the methodology of RCTs—patients who enter such trials are likely to have fewer problems with adherence, and RCTs typically involve much more monitoring. In these ways, RCTs may mask the superiority of LAIs in ensuring adherence.
More illustrative, he said, are naturalistic studies looking at large cohorts of patients that more closely resemble real-world clinical practice—where lack of adherence to medication is a ubiquitous barrier to recovery.
“Mirror image” studies, in which a period of oral medication use is followed by a period of LAI use, are likely to better represent those real-world conditions. A 2013 meta-analysis of 25 mirror image studies involving 5,940 patients worldwide followed for at least 12 months (six months on oral medications and six months using LAIs) found that LAIs performed significantly better in terms of preventing and decreasing the amount of hospitalization. (That study, of which Kane is a coauthor, appeared in the Journal of Clinical Psychiatry in October 2013.)
But Kane said there are other reasons for therapeutic neglect of LAIs. Injections may not be a routine part of some clinical practices, and there may be a perception—on the part of both clinicians and patients—that LAIs should be reserved for more severely ill patients or those who are aggressive or violent.
“I think the bigger obstacle is that physicians are not consistent in the way they approach patients,” Kane said. “When they are asked a patient may at first say ‘no.’ Many clinicians will give up at that point. This is why psychoeducation is important—you need to have a series of conversations with patients so they have enough information about the benefits and risks.”
Finally, Kane said that he believes the focus on value in health care may help to drive adoption of LAIs. “There is going to be an increasing focus on reducing rates of rehospitalization, one of the biggest drivers of cost, and so LAIs may become more attractive,” he said.
In an editorial that accompanied the Subotnik report in JAMA Psychiatry, William Carpenter, M.D., and Robert Buchanan, M.D., of the Maryland Psychiatric Research Center, echoed the barriers to LAI adoption outlined by Kane, and also stated that research is still needed to clarify a host of clinical issues around their use—dosage, interval between injections, choice of drug, and selection of patients best suited to receive LAIs. They also emphasized the critical need for ongoing engagement with patients during intervals between injections.
“Our field needs to recalibrate its attitudes and practice related to LAI drugs,” they wrote. “The [Subotnik] study indicates that LAI medications should be considered a first-line therapeutic option in people with early-phase schizophrenia. The injections every two weeks were well tolerated in this study, but an injection on a three-month schedule may be preferred by patients and should have the advantage of a prolonged period in which to address nonadherence. However, the clinical relationship and integrated therapeutics require frequent engagement between mental health professionals and patients and prolonged intervals with an LAI drug should not reduce essential patient contact.
“…A patient who objects to an LAI medication every two weeks may be interested in the once-monthly injection that can be accomplished with haloperidol or paliperidone and perhaps fluphenazine and risperidone. … Keeping in mind the absence of RCTs of more than three years and the potential advantages of dosage reductions in the long term, physicians in the field still have much to learn as LAI drug strategies are extended to being given early in the illness and to patients with a better prognosis.” ■
