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August 2015

Expanding Therapy With Long-Acting Antipsychotic Medication in Patients With Schizophrenia

Author Affiliations
  • 1Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore
JAMA Psychiatry. 2015;72(8):745-746. doi:10.1001/jamapsychiatry.2015.0485

Long-acting injectable (LAI) antipsychotic medications are significantly underused. In light of their documented efficacy for treatment of psychotic symptoms and robust effect on relapse prevention, their relative lack of use is unfortunate. There are several reasons for this therapeutic neglect, including clinical settings where injections are not part of the usual routine; a belief that LAI medications are reserved for acute intervention or for aggressive or nonadherent patients; and the perception of stigmatization associated with their use. Moreover, randomized clinical trials (RCTs) comparing oral antipsychotic medications with LAI medications have often failed to document the expected advantage of assuring adherence with LAI medications because study participant selection often excludes those who are unable to adhere to the study protocol. Finally, physicians routinely overestimate patients’ adherence to oral medication regimens. In this context, 2 articles1,2 in JAMA Psychiatry regarding the use of LAI medications may stimulate reconceptualization of this aspect of pharmacotherapy for treating schizophrenia.

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    1 Comment for this article
    Additional Comments to the Editorial
    David Hough, MD, Larry Alphs, MD, Alberto Russu, Ph.D | Janssen Research & Development, LLC, Raritan, New Jersey (DH); Janssen Scientific Affairs, LLC, Raritan, NJ (LA); Janssen Research & Development, LLC a Division of Janssen Pharmaceutica NV, Be
    We read with interest the editorial by Carpenter and Buchanan(1) in the June 24, 2015 JAMA Psychiatry.

    We agree with the authors that long-acting antipsychotic medications (LAIs) are significantly underused and concur that consideration of LAIs as a treatment option is often overly delayed. Their use could bring value much earlier in the course of illness.

    The editorial raises important questions about use of product label-based LAI dosing in clinical practice. The commentators describe their experience with omitting doses of injectable fluphenazine without loss of efficacy. We understand that information provided in product labels must
    be individualized based on clinical assessment of efficacy and safety considerations. However, given the very long pharmacokinetic half-lives for LAIs (2 weeks to 3 months) this must be done cautiously as steady-state pharmacodynamic effects will take months or, even over a year, as in the case of paliperidone palmitate 3-month (PP3M). Advances in understanding optimal dosing have progressed considerably since the time of fluphenazine decanoate’s approval.

    For more recently developed LAIs, robust population pharmacokinetic models were validated in patients (2). Based on this work, stretching the intervals between injections or omitting doses altogether is not recommended as this lowers plasma levels below therapeutic concentrations and may lead to symptomatic relapse. Although the commentators suggest patients may have dose adjustments at regular visits, patients may relapse precipitously, as suggested by a recent comparative study in persons with schizophrenia and a recent history of incarceration (3). For all LAIswe strongly recommend adherence to the dosing recommendations in the label and in particular for PP3M, ensuring that the PP1M dose is well-established before switching to PP3M.

    Increasing the interval between injections has not been well studied. The complex and very different pharmacokinetic profiles across LAIs requires careful, often nonintuitive, procedures that would have to be individualized across drugs and patients. We recommend establishing effective doses with oral formulations and using this as a basis for establishing maintenance doses.

    The authors rightly point out that the prolonged intervals between treatments with an LAI drug should not reduce essential patient contact. Although patients may require injections as infrequently as every 3 months, monitoring patients on a more frequent basis for efficacy, tolerability, and safety is desirable. Visits in between injections could be used to address issues other than medication adherence, such as psychosocial therapies, vocational rehabilitation, cognitive remediation, or substance abuse treatment.

    1. Carpenter WT, Jr, and Buchanan, RW. Expanding therapy with long-acting antipsychotic medication in patients with schizophrenia. JAMA Psych. 2015; doi: 10.1001/jamapsychiatry.2015.0485
    2. Gopal, S; Vermeulen, A; Nandy, P; Ravenstijn, P; Nuamah, I; Buron Vidal, JA; Berwaerts, J; Savitz, A; Hough, D; Samtani, MN. Population pharmacokinetic simulations of dosing windows and missed doses of paliperidone palmitate 3-month formulation in schizophrenia. Poster presentation at: American Psychiatric Association, Toronto, Canada, 16-20 May 2015. Full manuscript submitted: CurrRes MedOpin.
    3. Alphs L, Mao L, Rodriguez SC, Hulihan J, Starr HL. Design and rationale of the Paliperidone Palmitate Research in Demonstrating Effectiveness (PRIDE) study: a novel comparative trial of once-monthly paliperidone palmitate versus daily oral antipsychotic treatment for delaying time to treatment failure in persons with schizophrenia. JClin Psych. 2014;75(12):1388-1393.
    CONFLICT OF INTEREST: All three authors are employees of Janssen