title: An initial animal proof-of-concept study for central administration of clozapine to schizophrenia patients.
abstract: While clozapine is the acknowledged superior pharmacotherapeutic for the treatment of schizophrenia, the side effect profile, which includes potentially fatal complications, limits its usefulness. Central administration of clozapine directly into the brain could circumvent many of the side effect issues due to the dramatic reduction in dose and the limitation of the drug primarily to the CNS. The present study demonstrates that clozapine can be formulated as a stable solution at physiological pH, which does not have in vitro neurotoxic effects at concentrations which may be effective at treating symptoms. Acute central administration improved auditory gating deficits in a mouse model of schizophrenia-like deficits. Assessment of behavioral alterations in rats receiving chronic central infusions of clozapine via osmotic minipump was performed with the open field and elevated plus mazes. Neither paradigm revealed any detrimental effects of the infusion. While these data represent only an initial investigation, they none-the-less suggest that central administration of clozapine may be a viable alternate therapeutic approach for schizophrenia patients which may be effective in symptom reduction without causing behavioral or neurotoxic effects.
authors.affiliation: Department of Psychiatry, University of Colorado at Denver and Health Sciences Center, Aurora, CO 80045, United States.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Abrams
authors.forename: Lijun
authors.initials: L
authors.lastname: Zheng
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Choo
authors.forename: Jun J
authors.initials: JJ
authors.lastname: Yang
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Anchordoquy
authors.forename: Nasser H
authors.initials: NH
authors.lastname: Zawia
authors.forename: Karen E
authors.initials: KE
authors.lastname: Stevens
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000161:Acoustic Stimulation; D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003024:Clozapine / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D004195:Disease Models, Animal; D015195:Drug Design; D005072:Evoked Potentials, Auditory / Q000187:drug effects; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D007276:Injections, Intraventricular; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008811:Mice, Inbred DBA; D020258:Neurotoxicity Syndromes / Q000209:etiology / Q000517:prevention & control; D051381:Rats; D017207:Rats, Sprague-Dawley; D013216:Reflex, Startle / Q000187:drug effects; D012559:Schizophrenia / Q000188:drug therapy*; D012565:Schizophrenic Psychology; D047392:beta-Cyclodextrins / Q000009:adverse effects / Q000494:pharmacology
chemical_list: D014150:Antipsychotic Agents; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D003024:Clozapine