title: Clozapine as a drug of dependence.
abstract: BACKGROUND
  In schizophrenics, clozapine has been reported to induce various withdrawal signs and rapid onset relapse to psychosis on cessation of chronic treatment.
  
  
  OBJECTIVE
  The study was designed to develop an animal model of one aspect of clozapine tolerance and withdrawal using core body temperature measures.
  
  
  METHODS
  Two groups of 15 female Wistar rats were treated chronically (b.i.d.) with clozapine at 6 or 12 mg/kg per injection for 21 days prior to cessation of drug treatment, withdrawal being studied over 4 consecutive days. Body temperatures were assessed daily throughout the study.
  
  
  RESULTS
  Acutely, clozapine induced dose-related hypothermia, to which complete tolerance developed in both groups, the development of tolerance being more rapid in the group treated with 6 mg/kg per injection of clozapine. During withdrawal only the group treated chronically with 12 mg/kg per injection of clozapine showed rapid onset significant hyperthermia. This dissipated progressively over days, and was completely absent after 4 days of withdrawal.
  
  
  CONCLUSIONS
  Clozapine induced a clear somatic withdrawal sign after chronic treatment. It is suggested that, in future research in both humans and animals, it is important to attempt to differentiate between clozapine withdrawal and clozapine withdrawal-induced relapse to psychosis. It is also important to characterise the clozapine withdrawal syndrome fully in animals; to establish the neurochemical mechanisms involved in such withdrawal; and to determine which novel antipsychotics are most efficacious in inducing clozapine-like withdrawal effects, in suppressing clozapine withdrawal, and in preventing relapse to psychosis in patients being transferred from clozapine to novel atypical antipsychotic drugs.
authors.affiliation: Psychology Department, Liverpool University, UK. ajg@liverpool.ac.uk
authors.forename: A J
authors.initials: AJ
authors.lastname: Goudie
authors.forename: J A
authors.initials: JA
authors.lastname: Smith
authors.forename: A
authors.initials: A
authors.lastname: Robertson
authors.forename: C
authors.initials: C
authors.lastname: Cavanagh
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001831:Body Temperature / Q000187:drug effects; D003024:Clozapine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D005260:Female; D051381:Rats; D017208:Rats, Wistar; D013375:Substance Withdrawal Syndrome; D019966:Substance-Related Disorders
chemical_list: D014150:Antipsychotic Agents; D003024:Clozapine