The Effects of Clomipramine Hydrochloride in Cats With Psychogenic Alopecia: A Prospective Study
A double-blind, placebo-controlled clinical trial was conducted to determine the efficacy of clomipramine hydrochloride in cats with psychogenic alopecia. Twenty-five cats were randomly assigned to receive clomipramine hydrochloride (0.5 mg/kg orally q 24 hours) or placebo for 56 days. Eleven cats in each group completed the trial. The results of this study showed that clomipramine hydrochloride failed to demonstrate significant changes in the number of grooming bouts, hair regrowth, and the area of alopecia in cats with psychogenic alopecia when compared to a placebo. It was uncertain whether these results reflected a lack of drug efficacy, insufficient treatment duration, or an insufficient number of cases enrolled.
Introduction
Grooming behavior serves several purposes, such as cleaning, body temperature control, and ectoparasite removal.1 Normally, grooming occupies 4% of a cat’s 24-hour day.1 An increase in frequency and intensity of grooming behavior may be precipitated by environmental stressors that cause anxiety, may be a component of a displacement activity, or be secondary to increased pruritus.2 Neuroendocrine reward mechanisms released during grooming may reinforce and maintain the behavioral pattern, leading to self-inflicted alopecia.3 Grooming activates serotonergic dorsal raphe nuclei, an area in the central nervous system that has been associated with compulsive disorders.4
Feline psychogenic alopecia has been compared to obsessive-compulsive disorders in humans and has been suggested as a model for this disease.5 A compatible history, typical clinical signs, and exclusion of other causes of self-induced, noninflammatory alopecia confirm the diagnosis.6 Psychogenic alopecia is a well-recognized disorder in cats, although the incidence within the feline population is unknown. Overall et al. reported that 16 of 23 cats that were presented over a period of 11 years for compulsive disorder were self-grooming or self-mutilating.7
Compulsive disorders in humans and animals are commonly treated with tricyclic antidepressants.7–11 Case reports and retrospective studies indicate that psychogenic alopecia in cats responds favorably to clomipramine hydrochloride, a tricyclic antidepressant.7–10 However, no placebo-controlled studies have been conducted to evaluate the efficacy of clomipramine hydrochloride in cats with psychogenic alopecia. Therefore, the purpose of this study was to test the hypothesis that clomipramine hydrochloride significantly reduces the clinical signs of feline psychogenic alopecia when compared to a placebo.
Materials and Methods
Selection of Cases
Cats of any breed, sex, or age referred to the Behavior or Dermatology Service of the College of Veterinary Medicine at the University of Minnesota from April 2002 through May 2003 with the history and clinical signs of noninflammatory alopecia were recruited for the study. Cases were recruited through referring veterinarians, students, newsletters, staff and faculty within the College of Veterinary Medicine, and word of mouth.
To be included in the study, dermatological causes of noninflammatory, self-inflicted alopecia were ruled out. Trichograms confirmed the self-inflicted nature of hair loss and were negative for fungal arthrospores and/or hyphae. Multiple skin scrapings from affected and nonaffected areas and fecal flotation were negative for mites (i.e., Demodex cati, Demodex gatoi, Cheyletiella spp., Notoedric cati). Dermatophyte cultures using a two-section plate containing Dermatophyte Test Media and Sabouraund’s dextrose agara yielded no fungal growth. Cats were enrolled in a food trial and had an intradermal test performed if inflammation was observed on skin biopsies of adjacent nonaffected areas. Cats were excluded if either of these tests indicated food or environmental allergies. Only two cats had inflammation of the nonaffected skin that justified enrollment in a food elimination trial. One cat did not improve during the trial and was subsequently skin-tested with 60 environmental allergens.b The skin test was negative, and this cat was included in the study. The other cat inadvertently received an injection of methylprednisolone acetate during the food trial and was excluded from the study.
Cats not enrolled in the study were those that had a previous history of sensitivity to tricyclic antidepressants; those that had received selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, and monoamino oxidase inhibitors (MAOs) within the previous 4 weeks; and cats that had received glucocorticoids within the previous 8 weeks. All cats had a normal serum biochemical profile, urinalysis (UA), complete blood cell count (CBC), serum total thyroxine concentration (T4), and electrocardiogram (ECG) before enrollment in the study. The study was reviewed, approved, and overseen by the Institutional Animal Care and Use Committee. The owners of the cats signed an informed consent prior to participation in the study.
Treatment Groups
An off-site compounding pharmacist assigned the first cat in the study to receive either a placebo or clomipramine hydrochloride. Thereafter, all subjects were assigned to the treatment groups in an alternating fashion. This process allowed for equivalent numbers of cats in the placebo and clomipramine groups. The investigators were masked to the treatments assigned to the cats.
The placebo was composed of microcrystalline cellulose that was identical in appearance to the clomipramine hydrochloride. The owners were allowed to choose among one of three presentation options to administer the placebo or clomipramine hydrochloride: size 3 gel capsules, chicken-flavored liquid, or fish-flavored liquid. Clomipramine hydrochloridec was administered at 0.5 mg/kg orally (PO) q 24 hours. The calculated dosage was placed in one capsule or 0.5 mL of the flavored liquid. Owners who experienced problems medicating their cat were allowed to switch from capsules to a liquid formulation and vice versa.
Treatment was not accompanied by specific behavior modification. Owners were asked to avoid reinforcement of the grooming behavior and to refrain from punishing the cats for the undesired behavior. Other prescription drugs for the treatment of this condition, over-the-counter medications, bandages, and Elizabethan collars were not used.
Assessments
The owners completed a questionnaire on the first day of the study that included questions regarding the cat’s age, gender, breed, origin, and total number of animals in the home. The owners were also asked about the cat’s medical history, past and present treatment, other illnesses, onset of the problem behavior, and other behavioral problems. Each cat was evaluated daily by the owners throughout the study period. Cats were also examined by a behaviorist and a dermatologist four times at set intervals during the study [see Appendix]. The owners and investigators were masked to the treatments being administered.
Evaluations by the owners were performed 7 days before enrollment, which served as the baseline assessment, and daily during the 84 days of the study. Each owner was given a form to record the following: 1) total number of episodes of licking, chewing, and hair pulling observed per day; 2) certain behaviors [e.g., anxiousness, calmness, use of litter pan, interactions with humans and household pets]; 3) special events or environmental changes [e.g., vacation, work noise from construction, unusual number of visitors, stray cats entering the house, etc.]. Additionally, the owners recorded each time the medication was given and noted if any medical problems such as vomiting, diarrhea, or lethargy occurred. In homes with more than one family member, it was recommended that the same person make the observations and notes throughout the study period. The owners were asked to observe the cat in the home environment, following guidelines that were designed to minimize observer effects and to maximize intraobserver reliability (e.g., same observer, same recorder, no variations in time of day and duration of time that the animal was observed).
Each cat was evaluated by a behaviorist, and a complete physical examination was performed on days 0, 28, 56, and 84 of the study. Each cat was also evaluated by a dermatologist on days 0, 28, 56, and 84 of the study. A complete dermatological examination was performed, and the extent of the area of alopecia and the degree of hair regrowth were assessed and recorded. An outline of the dorsum, ventrum, and lateral sides of the body were drawn on a graph paper to record the area(s) of alopecia noted at each visit. Changes in the area of the alopecia at each examination were compared to the area recorded on day 0, and a scoring system ranging from 1 to 5 was developed to qualitatively demonstrate percentages in reduction of the alopecic area [Table 1]. A score of 5 indicated no change from day 0. To evaluate qualitatively the degree of hair regrowth during the study period, the hair length adjacent to the affected area was measured at the first examination, and the hair length of the affected area was measured at each subsequent visit; then the percent reduction in the difference of hair length between these areas was determined. A scoring system ranging from 1 to 5 was devised to describe these differences [Table 2]. A score of 5 indicated no change from day 0.
A CBC, serum biochemical profile, T4, and a UA were performed on days 28 and 56 of the study. One or more tests were repeated on day 84 if any abnormality was noted on day 56. Additionally, an ECG was performed on day 28 and repeated on day 56 if deemed necessary.
On day 84 of the study, before the owners were made aware of the cat’s treatment, they were asked to gauge the overall changes in their cat’s condition during the study period. To verify compliance with treatment administration and daily observations, the owners were required to bring the medication and the daily log with them to each visit. The behaviorist reviewed the log, and a technician counted the number of capsules or the volume of liquid remaining. Cats were removed from the study if they were not returned for all the evaluations, if medications were not administered properly, if the evaluation forms were not completed, or if the cat showed any adverse clinical signs associated with the treatment.
Statistical Analysis
Two-factor analysis of variance (ANOVA) with repeated measures on one factor (i.e., time) was used to compare the numbers of grooming bouts for the placebo and treatment groups. Geisser Greenhouse-corrected P value was used to adjust for the inevitable violations of compound symmetry that accompanies this experimental design.12 Kruskal-Wallis tests were carried out to compare the mean alopecia score and the mean hair regrowth score of the placebo and treatment groups at days 28, 56, and 84 of the study. Data from 22 cats were included in the statistical analyses. For all statistical analyses, P values of =0.05 were considered significant. Statistical analyses were carried out using a computer software program.d
Results
Case Material
Twenty-five cats met the selection criteria, were included in the study, and were sequentially assigned to either the treatment (n=12) or placebo (n=13) group. Of these, 22 cats completed the study. Two cats were withdrawn from the study because of insufficient recording of data or improper treatment administration. One cat in the clomipramine group was removed from the study when it developed a urinary tract obstruction on day 18. Ages of the cats at the time of enrollment ranged from 4 to 14 years (mean 8.9 years). Fourteen cats were spayed females, and 11 were castrated males. The cats included domestic shorthairs (n=22), domestic longhairs (n=2), and one Siamese. The placebo and treatment groups each included one domestic longhair.
Owners had acquired the cats from a rescue organization or animal humane society (n=13), private source (n=5), breeder (n=1), pet store (n=1), or as strays (n=5). Twenty-two (88%) of the cats were in multicat households, with one to six additional cats. Only two cats had access to the outdoors. Nine (36%) households included one or more dogs, and six (24%) cats lived with one or more children. The onset of the problem was often unknown, and most owners were unable to associate the onset of the behavior with a specific event. Other behavioral complaints recorded by the owners included a display of anxiety or fear in the presence of loud noises, strangers, animals, or unusual situations (n=15); aggression toward humans or other animals (n=5); and elimination outside the litter box (n=2).
On presentation, alopecia was detected on the abdomen of 24 (96%) cats, on the medial thigh of seven (28%) cats, on the carpus of seven (28%) cats, and on the flank or dorsum of three (12%) cats.
Assessment Outcomes
No significant differences (ANOVA, P=0.13) in the number of grooming episodes were noted between the cats that received clomipramine and cats that received the placebo [Figure 1]. No significant differences were observed in the mean alopecia scores (Kruskal-Wallis test, P=0.44, P=0.06, P=0.39) and mean hair regrowth scores (Kruskal-Wallis test, P=0.19, P=0.48, P=0.34) between the placebo and clomipramine groups at days 28, 56, and 84 [Figures 2, 3].
No abnormalities attributed to clomipramine were observed on physical examination, auscultation, or ECG in any of the cats. Results of all CBCs, T4s, and serum biochemical profiles were within normal limits throughout the study. The UA of one cat showed struvite crystals and a pH of 8.0. This cat was diagnosed with urethral obstruction after 18 days of clomipramine and was excluded from the study. Other side effects attributed to clomipramine included lethargy (n=5), constipation (n=1), and reduced appetite (n=1). Four owners reported reduced interaction with their cats during the treatment period, and two owners had difficulties administering medication.
Of the cats that received the placebo, one cat had sporadic vomiting throughout the study (less than once weekly), one cat vomited once during week 2, and one cat sought the owner’s attention more often during the first 2 weeks of the study. Seven (64%) of 11 owners of cats that received clomipramine and three (27%) of 11 owners of cats that received the placebo reported that the cat’s hair coat and behavior improved by at least 50%.
Discussion
Feline psychogenic alopecia is a well-recognized, self-inflicted skin disorder that results from excessive grooming, chewing, and/or hair-pulling. This persistent and repetitive grooming behavior has led to the disorder being classified as compulsive.13 The disease may be triggered or aggravated by various stressors, such as anxiety, a geographic move, changes in social circumstances or relationship, trauma, etc., but the owners of cats in the study reported here were unable to identify any of these stressors with the onset of the problematic behavior.2 Fifteen cats in the current study showed other fear-related behavioral problems. This observation was consistent with other studies on pets suffering from compulsive disorders.7 Underlying anxiety that arises from real or perceived environmental stimuli may lead to conflict or frustration in the cat. Displacement activities, such as grooming, may then offer the pet a way to decrease this tension.2
Currently, very little is known about the beneficial effect of clomipramine in treating feline psychogenic alopecia. In a previous report, a cat with psychogenic alopecia that failed to respond to prednisolone, diazepam, and phenobarbital demonstrated significant improvement after treatment with clomipramine.10 In a different study, three cats with signs of psychogenic alopecia responded very well to clomipramine, and in two of these cats the behavior recurred after the dosage was reduced or the treatment was interrupted.9 Sawyer et al. reported on the beneficial effect of clomipramine in five cats with psychogenic alopecia.8 Clinical signs did not recur in four cats after discontinuing clomipramine, and three of these cats received environmental modifications to help maintain control of the condition.
The study reported here was designed as a double-blind, placebo-controlled trial to investigate the effects of clomipramine on feline psychogenic alopecia. The diagnosis of psychogenic alopecia was based on history, clinical presentation, and the exclusion of other possible causes of similar signs. All cats underwent extensive testing to rule out other possible diseases, but a food trial, an intradermal allergy test, and a parasiticide response trial were not performed in every cat before inclusion in the study.
It is unlikely that the cats enrolled in this study had flea bite hypersensitivity, because they lived in a region where fleas were rare, and none of the cats had clinical signs suggestive of this disorder. Multiple skin scrapings and a fecal flotation were performed to rule out demodicosis or cheyletiellosis, and all cats tested negative; therefore, the likelihood of these diseases causing the cats’ alopecia was reduced. It would have been preferable, however, to have performed a parasiticide response trial in all the cats before inclusion in the study, because it was possible that some cats with demodicosis or cheyletiellosis were unintentionally enrolled.
Histopathological evidence of inflammation in nonaffected skin was used as a criterion to determine if food or environmental allergies were present. This criterion was used because clinical signs of feline allergies rarely present as noninflammatory alopecia.6 However, it was possible that some of the cats enrolled in this study had food allergies and/or atopic dermatitis. It could be argued that the lack of response to clomipramine in this study was influenced by the inclusion of cats with allergic or parasitic disorders. However, the authors believe that if any of such cases were unintentionally included in the study, they were very few. Moreover, the arbitrary allocation of the cats into the placebo or treatment groups would have reduced any influence that cats with allergic or parasitic disorders might have had on the results.
When the areas of alopecia and hair regrowth during and after treatments were analyzed, no significant differences were observed between the clomipramine and placebo groups. Hair regrowth was also noted in both groups. Clomipramine also did not significantly decrease the rate of grooming behavior. Despite these results, >50% of the owners of cats that received clomipramine felt that their pets improved by at least 50%. In contrast, this level of improvement was noticed by <33% of owners of cats treated with the placebo. These findings indicated that from the owner’s perspective, clomipramine had a superior effect in reducing the excessive grooming. The validity of the owners’ comments was limited, however, since other factors may have influenced their responses and expectations.
Side effects associated with tricyclic antidepressants are commonly related to their serotonergic, anticholinergic, anti-α 1-adrenergic, and antihistamine effects.14–16 Most published reports on the side effects of clomipramine pertain to dogs. In the dog, clomipramine may cause decreased activity, nausea, and a decrease in the circulating levels of thyroid hormones.17–19 The drug does not cause cardiovascular problems in healthy dogs.17–19 In cats, reported side effects include sedation and urinary retention.14 The most common side effects observed in the study reported here were lethargy, constipation, and urinary retention, which may have arisen from the drug’s anticholinergic effects. It was uncertain if the onset of these side effects led the owners to surmise their cats received clomipramine and therefore affected their evaluations.
The results of this study showed that clomipramine failed to produce significant improvement in feline psychogenic alopecia. It is possible that if more cats were included in the study, a significant difference in skin lesions may have been reached. The level of owner compliance required by the study design and the strict inclusion and exclusion criteria may also have limited the number of cats that were recruited in the study during the 13-month enrollment period. Furthermore, a longer duration of treatment may have allowed more significant effects to be discovered.
Conclusion
Clomipramine hydrochloride administered orally at 0.5 mg/kg per day failed to demonstrate significant changes in the number of grooming bouts, hair regrowth, and degree of alopecia in cats with psychogenic alopecia. Further placebo-controlled trials enrolling larger numbers of cats to be treated for longer periods of time are necessary to confirm the results reported here.
K-800 SAB-DUET; Bacti-Lab, Mountain View, CA 94042
Allergenic extracts; Greer, Lenoir, NC 28645
Clomipramine hydrochloride; Gallipot, Inc., Mendota Heights, MN 55120
Statistical package for the Social Sciences, version 11.5.1; SPSS Inc., Chicago, IL 60606
Citation: Journal of the American Animal Hospital Association 42, 5; 10.5326/0420336
Citation: Journal of the American Animal Hospital Association 42, 5; 10.5326/0420336
Citation: Journal of the American Animal Hospital Association 42, 5; 10.5326/0420336
Citation: Journal of the American Animal Hospital Association 42, 5; 10.5326/0420336
Mean number of grooming bouts as observed by the owners from day 0 through day 84. Data were collected from 11 cats receiving clomipramine hydrochloride (0.5 mg/kg orally q 24 hours) and 11 cats receiving a placebo for 56 days.
Mean alopecia scores recorded at day 0, treatment days 28 and 56, and posttreatment day 84. Data were collected from 11 cats receiving clomipramine hydrochloride (0.5 mg/kg orally q 24 hours) and 11 cats receiving a placebo for 56 days. No significant differences were observed between the groups (P=0.44, P=0.06, P=39). See Table 1 for score definitions.
Mean hair regrowth scores recorded at day 0, treatment days 28 and 56, and posttreatment day 84. Data were collected from 11 cats receiving clomipramine hydrochloride (0.5 mg/kg orally q 24 hours) and 11 cats receiving a placebo for 56 days. No significant differences were observed between the groups (P=0.19, P=0.48, P=0.34). See Table 2 for score definitions.
Algorithm Depicting All Evaluations Performed at Various Times in a Study of Cats With Psychogenic Alopecia
