Clomipramine in dogs: pharmacokinetics, neurochemical effects, and efficacy in compulsive disorder

Hewson, Caroline J.
Journal Title
Journal ISSN
Volume Title
University of Guelph

Canine compulsive disorder is a syndrome of abnormal conflict behaviours, possibly associated with central neurochemical dysfunction. There is no proven treatment for the disorder, but the human anti-compulsive drug, clomipramine, has been reported to be effective. Three experiments investigated biological and behavioural effects of clomipramine in dogs. Experiment 1 was a pharmacokinetic study. Six dogs received one oral dose (3 mg/kg) of clomipramine. After dosing, blood was taken at 0, 15, 30, 45 min, 1, 2, 4, 8, 12h, and then 12-hourly up to 120h. The dogs then received 28 daily doses (3mg/kg q 24 h); on d28, they were sampled as before. There was inter-dog variability in the elimination half-life of clomipramine (1-9h) and its metabolite, desmethylclomipramine (1-4h). Experiment 2 used six other, behaviourally normal dogs to assess the effect of clomipramine (3 mg/kg q 24 h PO) on turnover of serotonin, dopamine and norepinephrine, as indicated by concentrations of the respective metabolites in cerebrospinal fluid (CSF). The experiment had a randomised, placebo-controlled, crossover design. CSF was taken after 1, 2, 4 and 6 weeks on each treatment; there was a 2-week washout period between treatments. No effect on neurotransmitter turnover was detected. Experiment 3 was a randomised, placebo-controlled, double-blind, crossover clinical trial of clomipramine (3 mg/kg q 12h PO). Cases of canine compulsive disorder were diagnosed by a clinical ethologist, following telephone interviews with owners. An independent rater also interviewed owners, using formal criteria to diagnose compulsive disorder. Diagnostic agreement between the ethologist and the criteria was low (κ=0.02; n = 60). Fifty-one cases were enrolled in the clinical trial. They received each treatment for 4 weeks, with a 2-week washout period in-between. At the end of each treatment, owners rated the severity of the compulsive behaviour using two scales of acceptable construct validity (p<0.01). Both scales indicated a treatment effect (odds ratio = 4; p<0.015, n = 50). These experiments contribute new information about the pharmacokinetics, neurochemical effect and clinical use of clomipramine in dogs. They describe the development of a valid measure of behavioural change, and demonstrate that clomipramine is a useful treatment for canine compulsive disorder.

canine compulsive disorder, conflict behaviours, biological effects, behavioural effects, clomipramine, dogs