Pharmacokinetic and behavioral characterization of a long-term antipsychotic delivery system in rodents and rabbits
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Non-adherence with medication remains the major correctable cause of poor outcome in schizophrenia. However, few treatments have addressed this major determinant of outcome with novel long-term delivery systems.
The aim of this study was to provide biological proof of concept for a long-term implantable antipsychotic delivery system in rodents and rabbits.
Materials and methods
Implantable formulations of haloperidol were created using biodegradable polymers. Implants were characterized for in vitro release and in vivo behavior using prepulse inhibition of startle in rats and mice, as well as pharmacokinetics in rabbits.
Behavioral measures demonstrate the effectiveness of haloperidol implants delivering 1 mg/kg in mice and 0.6 mg/kg in rats to block amphetamine (10 mg/kg) in mice or apomorphine (0.5 mg/kg) in rats. Additionally, we demonstrate the pattern of release from single polymer implants for 1 year in rabbits.
The current study suggests that implantable formulations are a viable approach to providing long-term delivery of antipsychotic medications in vivo using animal models of behavior and pharmacokinetics. In contrast to depot formulations, implantable formulations could last 6 months or longer. Additionally, implants can be removed throughout the delivery interval, offering a degree of reversibility not available with depot formulations.
KeywordsAntipsychotic agents Treatment adherence Schizophrenia Drug delivery systems Drug implants Prepulse inhibition Haloperidol Rat Mouse Rabbit
The Stanley Medical Research Institute funded this research. Intellectual property related to haloperidol implants developed at the University of Pennsylvania is owned by the University. Research by NRS and JMS supported by MH42228 and MH01436. All experiments comply with “Principles of Laboratory Animal Care” and conform to University of Pennsylvania IACUC standards.
- Curtis H (1983) Biology, Fourth edn. Worth, New YorkGoogle Scholar
- Irani F, Dankert M, Brensinger C, Bilker WB, Nair SR, Kohler CG, Kanes SJ, Turetsky BI, Moberg PJ, Ragland JD, Gur RC, Gur RE, Siegel SJ (2004) Patient attitudes towards surgically implantable, long-term delivery of psychiatric medicine. Neuropsychopharmacology 29:960–968PubMedCrossRefGoogle Scholar
- Kane JM, Aguglia E, Altamura AC, Ayuso Gutierrez JL, Brunello N, Fleischhacker WW, Gaebel W, Gerlach J, Guelfi JD, Kissling W, Lapierre YD, Lindstrom E, Mendlewicz J, Racagni G, Carulla LS, Schooler NR (1998) Guidelines for depot antipsychotic treatment in schizophrenia. European Neuropsychopharmacology Consensus Conference in Siena, Italy. Eur Neuropsychopharmacol 8:55–66PubMedCrossRefGoogle Scholar
- Okada H, Toguchi H (1995) Biodegradable microspheres in drug delivery. Crit Rev Ther Drug Carr Syst 12:1–99Google Scholar
- Rosenheck R, Perlick D, Bingham S, Liu-Mares W, Collins J, Warren S, Leslie D, Allan E, Campbell EC, Caroff S, Corwin J, Davis L, Douyon R, Dunn L, Evans D, Frecska E, Grabowski J, Graeber D, Herz L, Kwon K, Lawson W, Mena F, Sheikh J, Smelson D, Smith-Gamble V (2003) Effectiveness and cost of olanzapine and haloperidol in the treatment of schizophrenia: a randomized controlled trial. Jama 290:2693–2702PubMedCrossRefGoogle Scholar
- Talbot K, Eidem WL, Tinsley CL, Benson MA, Thompson EW, Smith RJ, Hahn CG, Siegel SJ, Trojanowski JQ, Gur RE, Blake DJ, Arnold SE (2004) Dysbindin-1 is reduced in intrinsic, glutamatergic terminals of the hippocampal formation in schizophrenia. J Clin Invest 113:1353–1363PubMedCrossRefGoogle Scholar