Effects of Clomipramine on Cats Presented for Urine Marking
Twenty-five cats exhibiting at least four episodes of vertical urine marking per week were assessed. Following a medical workup, a 4-week clomipramine trial was instituted, using a mean dose of 0.54 mg/kg per os q 24 hours. No concurrent behavioral or environmental modifications were applied. There was a statistically significant (P<0.0001) decrease in urine spraying when the cats were on clomipramine, with 20 of 25 cats having a ≥75% reduction in spraying within 4 weeks. Side effects were mild. Twenty cats were followed for an additional 5 months. Fifteen cats required medication to control the spraying, often at a reduced dose.
Introduction
Inappropriate elimination and urine spraying (vertical urine marking) are the most common feline behavior problems seen at behavior referral practices.1 In a study of feline behavior cases referred to the Ontario Veterinary College, 61% had a primary complaint of inappropriate elimination.1 Although sexually intact cats are most likely to spray, 12% of neutered males and 4% of spayed females may become problem sprayers.2 Spraying occurs when a cat backs up to a vertical surface and directs a stream of urine toward an object or surface. This marking behavior may be caused by territorial competition, anxiety-evoking situations, or arousing events, and it may be stimulated by novel sights, sounds, or odors, especially from other cats.2 Commonly sprayed sites include prominent objects such as plants and furniture, boundary and exit areas (such as doors, walls, or windows), and new objects in the home. Cats that spray use their litter for elimination of urine and feces, although some cats routinely use the spraying posture even in their litter boxes.
Although identifying and treating all initiating factors are essential if the urine spraying problem is to be successfully resolved, eliminating such factors may not be practical when they involve stray cats on the property or multiple cats within the home. In addition, eliminating factors such as residual urine odor may be difficult. In some cases, environmental adjustments that reduce access to the most common target areas or that decrease exposure to the inciting stimuli may be effective. Some cats are satisfied with marking a single area that is provided (allowed) by the owners. Feliway,a a synthetic facial pheromone, may also be used to induce cheek gland marking (bunting) at the targeted sites in lieu of urine spraying. Feliway may reduce arousal, excitation, and anxiety, because cheek gland marking may have a calming effect. Feliway has been reported to reduce urine spraying in 74% to 97% of cats; but in a recent study, only 33.3% of treated households had a complete resolution of the spraying.3–5
When other efforts to resolve the urine spraying are unsuccessful, pharmacological intervention may be useful. Combinations of environmental modification, pheromone therapy, and pharmacological intervention are often necessary to achieve satisfactory long-term control of urine spraying.245 For the drug trial reported here, only a single treatment modality was utilized in order to reduce the possibility of other variables affecting the outcome.
Since its introduction as a treatment for separation anxiety in dogs, the use of clomipramine hydrochloride has become increasingly common for a wide variety of behavioral problems, including urine spraying in cats.6–10 Clomipramine is licensed in Australia for this use.b In countries such as Canada and Australia, a beef-flavored tablet is available in a 5-mg size that can be administered to cats at a dose of half a tablet per day.b
Clomipramine is the most potent serotonin reuptake inhibitor of the tricyclic antidepressant class of drugs.6b Its active metabolite, desmethylclomipramine, also inhibits norepinephrine reuptake.6b Compared to amitriptyline, it appears to have fewer anticholinergic effects, although occasional urine retention, constipation, or sedation may be seen.6–8 In a study of 26 cats given 5 mg once daily, a reduction in spraying was seen in 80% of the cats within 7 days, and complete cessation occurred in 33% of cats.11 However, no long-term or follow-up data was available. In two other studies, spraying improved in some cats and resolved in others.910 In a study where clomipramine was compared to cyproheptadine for the treatment of urine spraying, clomipramine was found to be more effective.12 Preliminary results comparing clomipramine and fluoxetine found the two drugs were equally effective at controlling urine marking during the first 8 weeks of treatment; but after 16 weeks, fluoxetine induced a significantly greater reduction in spraying.13
It is recommended that clomipramine be used cautiously in animals with epilepsy, narrow angle glaucoma, or cardiac arrhythmias.b However, therapeutic doses of clomipramine in dogs do not affect cardiac rate or rhythm and cause only benign cardiovascular changes, even with doses as high as 20 mg/kg for 7 days.1415 Because of its potential anti-cholinergic effects, clomipramine should also be used cautiously in animals with a history of urine retention or reduced gastrointestinal motility.
The purpose of this study was to assess the efficacy and side effects of clomipramine administered for urine marking in cats over a short period of 30 days. Most cats were also monitored for an additional 5 months to assess long-term control and recurrence of spraying upon drug withdrawal.
Materials and Methods
Case Selection
Cats were recruited from veterinary hospitals across southern Ontario, Canada. Cats that were urine marking on vertical surfaces at least four times per week were recruited for the trial. Cats were housed indoors throughout the duration of the trial and were required to use a litter box for all other eliminations. Any previous drug therapy was withdrawn at least 30 days prior to the trial. No environmental changes or new forms of behavioral management were initiated during the trial, and no surgical procedures were allowed during the trial. A maximum of four cats was allowed for each household, provided the spraying cat could be positively identified and there was no history of intercat aggression. All cats with underlying medical conditions that might cause urinary abnormalities (e.g., hyperthyroidism, urinary tract disorders) or might preclude administration of clomipramine were discouraged from enrolling in the trial. However, five cats were admitted despite the presence of underlying medical problems, including four cats with chronic renal failure (one of which was also on corticosteroid therapy for anemia) and one cat with a grade I heart murmur and asymptomatic ventricular premature contractions (VPCs).
Cats that previously received medication for the treatment of urine marking were enrolled in the trial if the therapy had been unsuccessful or spraying had recurred after the drug was withdrawn. Fourteen cats in the trial had previously been treated with medication for urine marking. In all 14 cats, marking had recurred prior to the start of the trial. In 13 of the cats, the drugs were discontinued several months to several years earlier, well beyond any washout or withdrawal period for both behavioral and medicinal effects. In one cat that received medroxyprogesterone acetate approximately 2 months prior to the start of the trial, it is possible that some residual drug effects were still present, even though recurrence of the urine spraying occurred at least 1 month prior to the start of the trial.
Cats that met the enrollment criteria were examined by the referring veterinarian, and samples were collected and submitted to a central laboratory for a complete blood count, biochemical profile, serum thyroxine (T4) assay, and urinalysis. Each client completed a comprehensive behavioral history questionnaire, which was sent to the veterinary behaviorist (and trial coordinator) along with all laboratory results. Each owner was also required to complete 1 week of daily logs to determine the baseline (pretreatment) number of spraying events, against which future measurements would be compared. If there were four or more events of urine marking in the pretrial week, the owner was then supplied with enough drug and daily logs for the first month of the drug trial. A questionnaire to be completed at the end of the trial was also supplied. A dose of 2.5 mg clomipraminec per os (PO) per day was given to most cats, although for cats >6 kg, the suggested dose was 3.75 to 5 mg PO per day. All cats were monitored closely for adverse effects.
Treatment Course
Owners completed a daily log in which they recorded all urine marking by location, as well as any adverse events or medication side effects. At the end of 1 month, a final questionnaire was completed, all forms were returned to the behaviorist, and the laboratory tests were repeated. If a cat’s clinical signs had sufficiently improved during the 1-month trial, the clomipramine was continued for up to 5 additional months, and the cat was closely monitored. For cats in which the drug was effective, it was suggested that the drug dosage be maintained for an additional month (2 months in total) and then be reduced by 50% (by starting alternate-day therapy or reducing the daily dose by 50%) for another 2 months. If urine marking did not recur, the drug was further reduced by 50% for the next 2 months or was withdrawn. Follow-up data was collected on these cats 3 and 6 months after the start of the trial.
Data Analysis
The number of spraying events per week was recorded by owners for week 0 (pretreatment) and for the 4 weeks of therapy (weeks 1 through 4). The reduction of urine spraying was calculated as: Reduction = pretreatment spraying events at week 0 minus posttreatment spraying events at week n, where n = 1 through 4. The efficacy of treatment was calculated as: Efficacy = reduction ÷ pretreatment events × 100%.
As it could not be assumed that the data was normally distributed, applying analysis of variance (ANOVA) methods may not have been adequate; therefore, nonparametric methods were used.16 Since there was no control group, the only possible comparison was with pretrial (baseline) data, so that each animal acted as its own control. The number of spraying events at week “n” was compared to values from week 0, using the one-sample Wilcoxon signed rank test.d
Results
Twenty-five cats (18 castrated males, seven spayed females) entered and completed the trial. Nineteen of the cats came from multicat households (two to four cats per household). Cats ranged in age from 2 to 15 years (mean 7.5 years) and in body weight from 3.2 to 8.2 kg (mean 5.26 kg). The actual dose of clomipramine given at the start of the trial ranged from 0.30 to 0.83 mg/kg (mean 0.54 mg/kg) PO q 24 hours. Owners were asked to indicate the sites of urine spraying within the house. Although a variety of locations were listed, including stereo speakers and various owner possessions, the most commonly sprayed sites were (in order) walls, windows, and doors.
Ten cats had abnormalities on pretreatment laboratory tests. Three cats were diagnosed with chronic renal failure, with blood urea nitrogen (BUN) values ranging from 8.8 to 18.3 mmol/L (reference range 4.0 to 10.7 mmol/L), creatinine concentrations ranging from 151 to 201 μmol/L (reference range 50 to 177 μmol/L), and urine specific gravities of 1.016 to 1.035. Five cats had elevations in alanine amino-transferase (ALT) ranging from 67 to 96 U/L (reference range 5 to 67 U/L), and one cat had proteinuria (3+). One of the cats with chronic renal failure was receiving 10 mg prednisone PO q 72 hours to control previously diagnosed immune-mediated anemia. One cat had a grade I systolic murmur and cardiac arrhythmia, which was diagnosed on electrocardiogram (ECG) as a normal sinus rhythm with occasional VPCs. Although it was recommended that these two cats not enter the trial, the clients and referring veterinarians requested that they participate, as the cats were to be euthanized if their urine spraying continued. Since their medical abnormalities were unlikely to be the cause of the vertical urine marking, the cats were entered into the trial.
Owners were advised to report any significant side effects to their veterinarian. No adverse effects were severe enough to necessitate removal of any cat from the trial. At the 30-day recheck, no new medical abnormalities were identified in any of the cats. The renal parameters remained stable in the three cats with chronic renal failure (creatinine 181 to 182 μmol/L; BUN 9 to 13.7 mmol/L). The ALT values were virtually unchanged in four cats with elevated ALT (62 to 90 U/L) and were mildly worse in one cat (71 to 109 U/L). The proteinuria of one cat decreased from 3+ to 2+, and the cat with the arrhythmia had a normal sinus rhythm with no VPCs on a subsequent ECG.
The mean numbers of baseline (pretreatment) spraying events for males, females, and all cats were 8.56±5.04, 9.71±6.92, and 8.88±5.50, respectively. The range for all cats was 4 to 22. In analyzing the owners’ logs, a statistically significant decrease in the number of sprayings was noted for each of weeks 1 through 4 when compared to pretreatment values (P<0.0001; all cats). Twenty of the 25 cats had a ≥75% reduction in urine spraying (i.e., zero to one spraying event per week). Spraying resolved or improved by 90% in 17 (68%) of the 25 cats. Three cats had a 50% to 74% reduction in spraying, and two cats had a <50% improvement by week 4. The range and mean number of spraying events are listed in Table 1. For the 20 cats that had a ≥75% reduction, the spraying decreased to one or less event per week in seven cats by the end of week 1, in eight cats by the end of week 2, and in three more cats by the end of the third week. Two cats did not reach maximal improvement until the end of week 4 [see Figure].
There was no statistical difference between the results when age, weight, or breeds were analyzed; however, there were some differences noted between responses in males and females. The mean efficacy during weeks 1 to 4 was 77% for male cats (P<0.0001) and 80% for female cats (P<0.0156), with a mean overall efficacy of approximately 78% for all cats (P<0.0001). Responses were more or less constant for females during all 4 weeks of treatment, whereas the males showed a more gradual improvement [Table 1]. The larger P value of 0.0156 for females is likely a result of the small number (n=7) of female cats included in the trial. With seven subjects, the smallest possible P value for the Wilcoxon signed rank test is P=0.0156. This indicates that the number of spraying events was less than at baseline. There was no clinical evidence that the product was any less effective in females than in males.
Five cats sprayed >10 times during the pretrial week (range 15 to 22). Two had complete resolution of spraying by week 4 (zero events per week); one had a reduction of 95.5% (one event per week); and the remaining two cats experienced <50% improvement (44.4% and 47.6% reduction). Of the remaining 20 cats with ≤10 pretrial marking events, all cats improved by ≥50%, 85% (17/20) improved by ≥75%, and 70% (14/20) improved by ≥90%.
Fourteen cats had previously received medication in an attempt to control the urine marking. Eight of these cats had been treated with amitriptyline at 5 to 10 mg per day, and a number of owners indicated they were unable to administer the medication. Six cats had been treated with an injection of medroxyprogesterone acetate at dosages ranging from 50 to 100 mg. Feliway spray was used in four households. Three cats were treated with buspirone at 5 mg q 12 hours, and two cats were treated with diazepam at 1 mg q 12 hours. One cat was treated with megestrol acetate at 5 mg per day initially, and then the dose was reduced to once or twice weekly. One cat had been treated with an amino acid/vitamin supplement containing tryptophan.e A ≥50% improvement in urine marking was seen in 12 of these cats at the 4-week point of the study, with seven cats having no spraying [Table 2]. Of the two cats that did not improve by at least 50%, one had previously been given buspirone, medroxyprogesterone acetate, amitriptyline, and Feliway without success, and the other had not responded to diazepam therapy.
At the end of the 1-month trial, 17 owners elected to continue the clomipramine, and eight owners attempted to withdraw the medication. At the 3-month follow-up, 17 of the cats remained on medication to control the spraying. Three cats off medication had little or no recurrence of spraying, and one cat remained off medication because it was ineffective. Two cats were euthanized (one improved but was too difficult to medicate; the other did not improve sufficiently); one cat was given away when spraying recurred; and one cat was lost to follow-up (signs were controlled at last contact).
At the final 6-month follow-up, 15 cats still required medication, with the spraying either decreased or absent while on the clomipramine. Medication was discontinued in two additional cats with no recurrence of spraying. The three cats that had the medication successfully withdrawn at the 1-month follow-up continued to be normal or have only rare spraying events. For the 15 cats that remained on medication, the dose and frequency of clomipramine administration were variable. Doses ranged from 0.21 to 1.14 mg/kg PO, and frequency ranged from q 24 hours to q 72 hours. One cat was on an alternating schedule, with the drug given q 24 hours for 2 days, then q 48 hours [Table 3]. None of the treated cats received behavioral counseling or pheromone therapy, and no attempt was made to modify the household once the trial began.
Side effects, as reported by owners, occurred in 23 of 25 cats [Table 4]. Some cats had more than one clinical sign while on the medication, and some signs, such as increased sociability and decreased aggression to the other household cat, were considered desirable. Overall, side effects were mild, and only two cats (started at higher-than-recommended dosages) required a reduction in dosage for the signs to resolve. Signs in all other cats usually resolved within 1 week, despite continued administration of the clomipramine.
Discussion
Before drug therapy is started, every attempt should be made to identify and resolve the underlying causes of urine marking and to avoid the stimuli that incite the behavior. Pheromone therapy to reduce the cat’s motivation to mark territory with urine may also be tried, as well as making modifications to the environment. Increased attention must also be given to litter box location and hygiene before considering the use of drugs. In a recent study, environmental management alone (i.e., using enzymatic cleansers on previously soiled surfaces; increasing the number of litter boxes to the number of cats in the household plus one; cleaning the box daily; changing the box weekly) led to improvement in a number of cats that were vertically marking.17 In that study, owners were also advised to refrain from any form of punishment.17 Depending on a number of factors, improvement may not be achieved with these techniques alone. Poor owner compliance or inability of the owners to make significant changes to the household may make it impractical to expect significant improvement. Pharmacological therapy might be the most effective means of controlling urine spraying in such homes.
To insure consistent baseline and accurate data collection, and to minimize the possibility of owner and environmental influences on outcome, the enrollment criteria for this trial were strictly controlled. Although a double-blinded placebo trial would have been preferable, it was considered impractical, because most of the owners were desperate for some immediate improvement in the urine marking. In addition, administration of clomipramine to all cats in the study allowed more data on efficacy and side effects to be collected over a shorter period of time.
The presence of concurrent laboratory abnormalities or concomitant medical conditions in this study population is consistent with prior reports.5 In one study of urine spraying in cats, 20% of 34 cats had underlying medical conditions, while another 17% had crystalluria.5 Although such abnormalities may have had a causal relationship in some individuals, a recent study indicated there were no statistical differences in blood or urine test results of urine-marking cats compared to cats with no history of marking.18 Conversely, a study of 100 clinically normal cats ≥8 years of age, with no history of urine marking, found that 6% had elevated serum T4 values, 9% were azotemic (urine specific gravity <1.035 in five cats), one was diabetic, and one had a urinary tract infection.f
In the study reported here, the reduction in spraying in 23 of 25 cats and the ≥75% reduction in 20 cats indicated that treatment with clomipramine alone may successfully resolve many cases of urine spraying within 30 days. With no concurrent behavioral modification, most of the cats in the present study required medication (some at a reduced dose) to control the urine marking. The use of a more comprehensive behavioral assessment and modification program might provide even greater improvement and fewer episodes of recurrence upon drug withdrawal. Concurrent use of Feliway as well as environmental management might also improve both short-term and long-term success rates. The two cats that failed to improve to a level of ≥50% were among the five cats with the highest number of pretrial marking events (>10 marks per week; range 15 to 22). Three other cats with very frequent pretrial marking all improved (≥95%) with clomipramine therapy, however. While the prognosis may be worse for cats with high numbers of marking events (i.e., ≥15 per week), this study provided some evidence that cats with frequent marking might also improve significantly with clomipramine therapy.
Based upon studies in humans, it has been suggested that antidepressants such as clomipramine may require 3 to 4 weeks to achieve a therapeutic effect in animals and that up to 6 weeks may be required to achieve maximal therapeutic effects.61920 Steady-state plasma concentrations of clomipramine and its intermediate metabolite, desmethylclomipramine, are attained in dogs within 4 days.20 Clomipramine is a potent inhibitor of serotonin reuptake, and desmethylclomipramine inhibits noradrenaline reuptake, thus leading to enhanced neurotransmission of serotonin and noradrenaline.67 The initial increase in neurotransmitter concentrations in the area of the synapse leads to subsequent downregulation and inhibition of neurotransmitter release. Over time, further accumulation of neurotransmitters in the synapse causes desensitization of the autoreceptors and recovery of firing of the serotonergic neurons and a net elevation of neurotransmitter concentrations, which ultimately alters neuroreceptor function and structure.71921 The full therapeutic effect may, therefore, take ≥4 weeks to be realized.672122
Interestingly, in the study reported here, improvement occurred in some cats within the first week of treatment, and 15 of 20 cats improved by the end of the second week [see Figure]. Similar results have been demonstrated in previous studies in which 80% of cats on clomipramine exhibited less spraying after 1 week, while cats on fluoxetine showed a significant reduction by the second week of treatment.1122 Further evaluation is needed to determine whether the mechanism of action of antidepressants is different in cats than in humans and whether other factors (e.g., the initial anticholinergic side effects to which humans generally habituate in 3 to 7 days) play a role in the response.19 Five of the cats in the present study did not reach maximal improvement until the third or fourth week of the trial, which is consistent with the time that is expected in other species for stabilization of the neurotransmitter changes induced by antidepressant therapy.821
One recent study suggested that long-term therapy of ≥6 months and a slower tapering process of clomipramine may improve efficacy and reduce the chances for recurrence.g Chronic administration of serotonin reuptake inhibitors and tricyclic antidepressants in mice may lead to neurogenesis in the hippocampus, which appears to contribute to the long-term antianxiety effects of these drugs.23 Therefore, while some cats may improve within the first few weeks of therapy, extending the duration of therapy may be considered for those cats that do not immediately respond. It is also possible that an increased dosage may improve the efficacy, provided there are no adverse effects.22
Most cats (male to female ratio of 2.6:1) in this study were castrated males from multicat households. This finding was consistent with other studies of vertical urine marking, in which male cats often outnumber females by at least 2 to 1 and by as much as 10 to 1.257111724 This predominance may be related to testosterone masculinization of the brain.21725 Cats from multicat households may have been over-represented because of increased competitive marking.2451722
Of interest in this study is the number of cats that improved on clomipramine and had no previous response to a variety of other treatment modalities, including amitriptyline, medroxyprogesterone acetate injectable, megestrol acetate, buspirone, diazepam, Feliway, and tryptophan. In comparison to other drugs that have been utilized for urine marking in cats, clomipramine appeared to be an effective alternative. Clomipramine can be used once daily in comparison to the twice-daily dosing of buspirone and diazepam.679112426 It appears to be easier to administer than amitriptyline, and it may have less toxicity than either diazepam or progestins.25–27 Clomipramine is more selective for its effects on serotonin transmission than any of these other compounds, which may explain its improved efficacy.67 This supposition is further supported by the success achieved in recent studies using fluoxetine (a selective serotonin reuptake inhibitor) for urine marking in cats.22
Clomipramine caused urinary retention and constipation in some cats in the study reported here, especially when it was first initiated or when dosages >0.5 mg/kg per day were used. Cats should be monitored closely to insure normal elimination when clomipramine is first dispensed.28 Side effects were otherwise mild, with behavioral changes being the most common [Table 4]. Most of the behavioral changes reported were associated with the initial sedation or lethargy caused by the drug. While a few cats became more fearful, agitated, or less tolerant of petting, this may have been a response to the administration of the medication rather than to the medication itself. Some of the behavioral changes associated with clomipramine therapy were considered desirable by the owners [Table 4].
It is important to realize that it can be difficult to distinguish urine marking from inappropriate elimination. This difficulty can greatly affect therapy, as psychotropic drugs are not generally indicated in cases of inappropriate elimination. Little or no response can be expected in cases where pheromones and psychotropic drugs are used to treat horizontal elimination, since most of these cases do not have a marking or anxiety component.29 Clomipramine is recommended for only those cats with vertical urine marking.
Conclusion
Based on the results of this study, clomipramine was an effective and practical means of treating urine marking in cats. Eighty percent of treated cats improved ≥75% during the first 4 weeks of treatment. Side effects were minimal and generally resolved within the first week of therapy. Clomipramine is not licensed for use in cats in North America, so it must be used cautiously and with informed owner consent. Although five cats had no recurrence of urine marking when the drug was withdrawn, most cats required long-term therapy. Further investigation is needed to determine if identification and resolution of any underlying causes, increased attention to environmental management, and the concurrent use of products such as Feliway might improve treatment efficacy and allow for a greater number of cats to remain under control after the drug is ultimately withdrawn.
Feliway; Veterinary Products Laboratories, Phoenix, AZ 85013
Clomicalm package insert; Novartis Animal Health Australasia Pty Limited
Clomicalm 5 mg; Novartis Animal Health Canada Inc., Mississauga, Ontario, Canada L5N 1V9
Proc Univariate, SAS; SAS Institute Inc., Cary, NC 27511
Relaxum; Mark and Chappell Ltd., Luton, United Kingdom, LU31RJ
Garcia JL, Bruyette DS. Unpublished data, American College of Veterinary Internal Medicine Forum poster session, 1998
Hart BL. Personal communication, Annual American Veterinary Medical Association Conference presentation, Denver, CO 2003
Acknowledgments
The authors thank Dr. Wolfgang Seewalde for statistical analysis and support. The authors also thank the numerous veterinarians throughout southern Ontario who recruited and screened cases for this study.
Citation: Journal of the American Animal Hospital Association 41, 1; 10.5326/0410003
Decrease in urine marking for all cats in the trial and for cats that had a ≥75% improvement in the number of spraying events.
