Effect of clomipramine on monoamine metabolites in the cerebrospinal fluid of behaviorally normal dogs.

The tricyclic antidepressant, clomipramine, is an effective treatment for canine compulsive disorder (canine CD). This disorder is a clinical syndrome of abnormal conflict behaviors and its pathophysiology is unknown. However, because clomipramine is an effective treatment, information about the drug's neurochemical effect could enhance the understanding of canine CD. The following experiment used 6 behaviorally normal dogs to assess the effect of clomipramine (3 mg/kg, q24h, PO) on the central turnover of 3 monoamines (serotonin, dopamine, and norepinephrine) as measured by the concentrations of their respective metabolites in cerebrospinal fluid (CSF). In a randomized, placebo-controlled, AB-BA crossover experiment, cisternal CSF was taken after 1, 2, 4, and 6 wk on each treatment. No effect of clomipramine was detected. This contrasts with human studies that have suggested that clomipramine affects the concentrations of monoamine metabolites in lumbar CSF. However, those papers do not address methodological assumptions, such as (i) metabolites in CSF originate only from the brain, and (ii) concentrations of metabolites in cisternal/lumbar CSF reflect the concentrations in local areas of the brain. Notwithstanding the small sample size, our results suggest that more localized sampling techniques (e.g. microdialysis) are needed when examining the effect of drugs on central monoamine metabolites. Clomipramine's efficacy for canine CD indicates the need for neurobiological research and, to our knowledge, our study is the first of its kind in dogs. The resulting data are preliminary but they can inform optimal neurobiological studies of canine CD.

The use of chance-corrected agreement to diagnose canine compulsive disorder: an approach to behavioral diagnosis in the absence of a 'gold standard'.

This study assessed the diagnostic accuracy of formal diagnostic criteria for canine compulsive disorder (canine CD). Canine CD is a syndrome of abnormal behaviors that are believed to result from conflict or frustration. Differential diagnoses include normal conflict behavior and learned behavior. In studies of canine CD, confidence in the diagnosis comes with knowing the accuracy of the diagnostic method. This accuracy may be quantified as the chance-corrected agreement between the diagnostic method and a 'gold standard' diagnostic test. The present study examined the agreement between diagnoses of canine CD made by an expert (the 'gold standard') and by using formal diagnostic criteria. The owners of 84 dogs suspected of having CD received 2 telephone interviews. The first utilized a detailed, pre-tested questionnaire; a dog was then diagnosed with CD if the behavioral history met 7 diagnostic criteria. The second interview was given by a behavioral expert whose diagnosis was based on personal experience. The interviewers were blind to each other's diagnoses. The chance-corrected agreement between diagnoses was minimal (kappa = 0.02) and disagreement was associated with 3 of the formal criteria: a history of conflict or frustration, an increase in the number of contexts that elicit the behavior, and an increase in the daily frequency of the behavior. Reasons for the disagreement include the order of the interviews, response biases, the setting of the interviews, and, possibly, the diversity of the behaviors associated with canine CD. To the authors' knowledge, this type of study is the first in clinical ethology to address validation of the diagnostic method. The results indicate 3 developmental aspects of canine CD that should be examined in future work.

Efficacy of clomipramine in the treatment of canine compulsive disorder.

OBJECTIVE: To assess the efficacy of clomipramine for treatment of canine compulsive disorder (CCD). DESIGN: Randomized, placebo-controlled, double-blind, balanced AB-BA crossover clinical study. ANIMALS: 51 dogs with CCD. PROCEDURES: Dogs were given clomipramine (3 mg/kg [1.3 mg/lb] of body weight, PO, q 12 h) for 4 weeks and placebo for 4 weeks. At the end of each treatment each owner rated the severity of their dog's behavior, using 2 validated rating scales. Statistical analysis was made by ordinal regression. Compliance, adverse effects, and the effectiveness of masking were also assessed. Each dog's behavior was reevaluated 1 to 2 years after completing the study. RESULTS: Behaviors included spinning (n = 17) and self-mutilation by licking (acral lick dermatitis, 12). Both rating scales demonstrated a treatment effect. Compliance was satisfactory, and masking was effective. Sedation and reduced appetite were reported more commonly when dogs were given clomipramine than when they were given placebo. Forty-five dogs available for follow-up evaluation still had their behaviors; 6 dogs were lost to follow-up evaluation. CLINICAL IMPLICATIONS: Results suggest that clomipramine was effective in dogs with CCD and was not associated with serious adverse effects. However, treatment for 4 weeks was not curative. Behavior modification is likely to be necessary to manage CCD.

The pharmacokinetics of clomipramine and desmethylclomipramine in dogs: parameter estimates following a single oral dose and 28 consecutive daily oral doses of clomipramine.

Clomipramine is a tricyclic antidepressant that has been recommended for the treatment of canine compulsive disorder. The pharmacokinetics of clomipramine in dogs have not been reported. This study describes the pharmacokinetics of clomipramine and its active metabolite, desmethylclomipramine, in six male dogs. Serial blood samples were collected following both a single oral dose of clomipramine (3 mg/kg) and 28 consecutive daily oral doses (3 mg/kg q 24 h). In addition, 'peak' and 'trough' samples were taken throughout the 28-day dosing period. Plasma was assayed for total (free and protein-bound) clomipramine and desmethylclomipramine, using gas-chromatography with mass spectrometric detection. Various pharmacokinetic parameters were then determined. Following a single dose of clomipramine, time of maximum plasma concentration (tmax) of clomipramine was 0.75-3.1 h, maximum plasma concentration (Cmax) was 16-310 ng/mL and elimination half-life (t1/2el) was 1.2-16 h; tmax of desmethylclomipramine was 1.4-8.8 h, Cmax was 21-134 ng/ mL and t1/2el was 1.2-2.3 h. Following multiple dosing, there was a numeric increase in these parameters; tmax of clomipramine was 3-8 h, Cmax was 43-222 ng/mL and t1/2el was 1.2-16 h; tmax of desmethylclomipramine was 1.4-8.8 h, Cmax was 21-134 ng/mL and t1/2el was 1.2-2.3 h. Clinically significant differences between dogs and humans in the pharmacokinetics of oral clomipramine are discussed.

A cross-sectional study on compulsive behaviour (stable vices) in horses.

A researcher-administered survey study was performed involving 769 horses from 32 Thoroughbred, Standardbred, and pleasure horse stables in southwestern Ontario. Data were gathered on individuals (breed, age, and sex) and at the stable level (housing, management). The effects of these factors on cribbing, stall-walking, weaving, stall-kicking, tongue playing, and pawing were assessed by unconditional analysis (Chi-square, t test) and conditionally using stepwise logistic regression. Individual level factors had significant effects on most compulsive behaviours. Some stable level factors, in most cases, those related to type and amount of exercise, had a significant effect on the prevalence of compulsive behaviours when tested unconditionally, but were not significant if entered into a logistic regression model after stable type. Stall-kicking was more common in horses which had physical contact with other horses, and this factor remained significant in the logistic regression analysis. Stable level factors should be regarded as modulating factors rather than as causes and in some cases, may reflect an attempt to treat the problem. Increased turn-out of affected horses likely reflects an ineffective attempt to treat problems, while reduced forced exercise (riding, lungeing) of affected horses is more likely to represent a cause.

Effect of dietary protein content on behavior in dogs.

OBJECTIVE: To determine the effect that feeding diets containing a low (17%), medium (25%), or high (32%) protein content would have on behavior in dogs. DESIGN: Prospective, controlled study. ANIMALS: 12 dogs with dominance aggression, 12 dogs with hyperactivity, 12 dogs with territorial aggression, and 14 control dogs without behavioral problems. PROCEDURE: Dogs were fed each of the diets for a 2-week period, and owners were instructed to score their dogs' behavior on a daily basis. RESULTS: Behavior of the dogs with dominance aggression, dogs with hyperactivity, and control dogs was unchanged by the dietary manipulations. Territorial aggression was significantly reduced when dogs were fed the low- or medium-protein diet, compared with territorial aggression when fed the high-protein diet. Post hoc analysis indicated that this effect was attributable to a marked reduction in aggression in a subset of the group (n = 7) in which territorial aggression was a result of fear. CLINICAL IMPLICATIONS: Results of this study suggest that a reduction in dietary protein content is not generally useful in the treatment of behavior problems in dogs, but may be appropriate in dogs with territorial aggression that is a result of fear.

Stereotypic or obsessive-compulsive disorders in dogs and cats.

Stereotypic and obsessive-compulsive behaviors are defined, and examples are given for both dogs and cats. The cause of these behaviors is discussed; and it is maintained that they result from conflict and are influenced by genetics, early experience, and learning. Treatment options, such as changes in environment and management, behavior modification, and the use of various drugs are reviewed.

Tail tip necrosis in Ontario beef feedlot cattle.

Studies were performed to establish the prevalence and importance of tail tip necrosis in the southern Ontario beef feedlot industry and to characterize the gross appearance and histopathology of the condition. In a mail survey, 96% of 71 feedlots with slatted floors, but only 5% of 184 feedlots with solid floors, reported a problem with tail tip necrosis from 1982-1986. Treatments reported included antibiotics, amputation of the tail (therapeutic or preventive), and slaughter. Lameness was associated with tail tip necrosis.A scoring system for severity of necrosis was developed. Repeated inspections revealed that mild lesions were unlikely to progress to more severe stages. Histological alterations such as perivascular edema and hemorrhage, dermal scarring, follicular atrophy, and paucity of leukocytes were compatible with cutaneous ischemia.Of 441 tails inspected at slaughter plants, 34.5% were affected, with 3.4% involving skin lacerations and infection, and 4.3% amputated before slaughter.