The Potential Advantages of Long-Acting Injectable Antipsychotics

Non-adherence in medication-taking remains one of the major challenges in the treatment of any chronic illness.1 Schizophrenia represents a particular challenge, as it is often associated with cognitive dysfunction, lack of motivation, depression, and demoralization.

Numerous studies have found high levels of non-adherence in medication taking in patients with schizophrenia and an underestimation of the degree of it by both patients and physicians.2

There are a number of approaches that can be used to improve patient adherence. Patient and family psychoeducation is very important in providing a better understanding of the illness, its course and treatment, as well as the potential benefits and risks of treatment versus no treatment. It is often difficult for people to understand the concept of prevention and the need to continue medication even long after symptoms have subsided.

Stigma can be another important factor in reduced or nonadherence, but frequent relapse and a decline in functioning will, if anything, add to the potential stigma.

New technologies are being developed which may help facilitate adherence.3 One potentially valuable approach to enhancing adherence is the use of long-acting injectable antispychotic (LAI) medications.

The advantages of such formulations include the fact that patients do not need to be reminded of their illness every day by taking a medication or need to make the daily decision to do so. Social and professional supports can then be focused on the one occasion every two to four weeks when medication administration is necessary. There is immediate knowledge when a dose is missed, and appropriate interventions can be implemented.

Relapse is a continual risk in patients with schizophrenia and represents one of the major public health problems associated with this illness. LAIs can help reduce this risk.

The risk of relapse is three to five times higher when patients are off medication, and this is true for patients with a first episode as well as multi-episode patients.4 Relapse is not only associated with a high rate of expensive hospitalizations and/or emergency room visits, but social and work disruption, family burden and increased risks of harm to self or others.

Relapse may also be associated with changes in brain morphology and a reduction in medication responsiveness.5,6

The use of LAIs also reduces the frequent confusion and uncertainty between poor/partial response and poor/partial adherence, making treatment decisions easier and more evidence-based.

The same applies to a psychotic relapses in which there is uncertainty as to whether the relapse occurred because the medication was not having the desired effect or because the medication was not taken as prescribed.

In addition, we actually have more data on dose-response relationships in maintenance treatment with LAIs than we do with oral medications, as there has been more randomized controlled trials with the former. When studies are done with oral medications, variations in adherence can also complicate interpretation.

Though LAIs have several advantages, demonstrating their superiority over oral medications in controlled trials has not been as easy as it would seem.

Mirror image studies, in which an equal period of time before and after a switch from an oral to an LAI medication is compared to determine rates of relapse or hospitalization, have shown significant advantages for LAIs.7

Some, but not all, large-scale cohort studies – in  which a naturalistic data set is examined for patients on LAIs and patients on oral medication, and the relative relapse rates in both groups are compared – have shown significant advantages for LAIs. 8,9  

If anything, these studies might involve a conservative bias in that patients given LAIs are likely viewed as at higher risk for non-adherence.

At the same time, a recent meta-analysis involving randomized controlled trials comparing LAIs and oral medications did not show an advantage for the former.10 It is my belief that these trials in their selection criteria, consent process, follow-up retention, and assessment strategies might alter the ecology of care in such a way as to diminish the likelihood of non-adherence and relapse. This, in turn, may also diminish the potential advantages of LAIs.11

The way to test this assumption is in a large simple trial, in which naturalistic treatment is emphasized despite randomization. Such a trial is being planned.

John M. Kane, MD, is a professor and Chairman of the Department of Psychiatry at the Hofstra North Shore-LIJ School of Medicine. He serves on the Psychiatry Advisor editorial board.

Disclosures: Kane has been a consultant for Alkermes, Bristol-Meyers Squibb, Eli Lilly, EnVivo Pharmaceuticals (Forum), Forest, Genentech, H. Lundbeck Intracellular Therapeutics, Janssen Pharmaceuticals, Johnson &  Johnson, Otsuka, Reviva, and Roche. He has been on the Speaker’s Bureau for Bristol-Meyers Squibb, Janssen, Genentech and Otsuka. Kane is a shareholder in MedAvante, Inc.


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  3. Kane JM, Perlis RH, DiCarlo LA, Au-Yeung K et al.   First experience with a wireless system incorporating physiologic assessments and direct confirmation of digital tablet ingestions in ambulatory patients with schizophrenia and bipolar disorder. Journal of Clinical Psychiatry. 2013;74(6):e533-e540.
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  10. Kishimoto T, Robenzadeh A, Leucht C, Leucht S et al. Long-acting injectable vs. oral antipsychotics regarding relapse prevention in schizophrenia: A systematic review and metaanalysis. Schizophr Bull. 2014;40(1):192-213.
  11. Kane JM, Kishimoto T, Correll CU. Assessing the comparative effectiveness of long-acting injectable vs. oral antipsychotic medications in the prevention of relapse provides a case study in comparative effectiveness research in psychiatry. J Clin Epidemiol .2013;66(8 Suppl):S37-S41.