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Clomipramine-induced urinary retention in a catErika Pfeiffer, Norma Guy, Alastair Cribb

Abstract A 10-year-old, female, spayed shorthair with presumed psychogenic alopecia was treatedwith clomipramine (1 mg/kg body weight/day). The cat developed urinary retention within 2 days.Clomipramine was discontinued. Clinical signs resolved over the next 7 days. The urinary retentionwas attributed to the anticholinergic effects of clomipramine.

Resume Retention urinaire provoquee par la clomipramine chez un chat. Une femelle de10 ans, castree, 'a poils courts, presentant une presumee alopecie psychogene a ete traitee 'a laclomipramine (1 mg/kg de poids corporel, par jour). La chatte a fait une retention urinaire dans lesdeux jours. La clomipramine a ete interrompue. Les signes cliniques ont disparus dans les sept jourssuivants. La retention urinaire a ete attribuee aux effets anticholinergiques de la clomipramine.

(Traduit par docteur Andr6 Blouin)Can Vet J 1999; 40: 265-267

A 10-year-old, female, spayed and declawed short-hairwas presented for ventral abdominal alopecia of

2 years' duration. The cat was reported to have been irri-table and aggressive since 1 y of age. She appeared to bedisturbed by any change in her routine, such as visitorsto the house or the absence of the owner. She would hissat or attack strangers and would groom her abdomenexcessively when upset. No specific event could belinked to the onset of the alopecia. Previous therapies,including changing the bedding and feed and treatmentwith prednisone (10 mg, PO, q24h, for 3 d; 5 mg, q24h,for 5 d; 5 mg, q48h, for 10 d), had failed to resolve theproblem. There was no evidence of flea infestation.Results of complete blood cell count (CBC) and serumthyroxine concentrations were within normal limits.Apart from hair loss, there were no apparent skin lesions.Although a conclusive diagnosis would have requiredadditional diagnostic procedures, including skin scrap-ings, fungal culture, and biopsy, a working diagnosisof psychogenic alopecia was made. Treatment withclomipramine hydrochloride (Anafranil, Geigy,Mississauga, Ontario) at 1 mg/kg body weight (BW)/dwas initiated (1).Two days after initiating therapy, the cat was returned

to the clinic with a client complaint of apparent urinaryobstruction. She had been straining to urinate for severalhours without voiding any urine. She was depressedand anorexic. On abdominal palpation, an enlarged uri-nary bladder approximately 10 to 12 cm in diameter

South Central Veterinary Clinic, Box 149, Notre-Dame,Manitoba ROG IMO (Pfeiffer), Department of Anatomy andPhysiology, Atlantic Veterinary College, University of PrinceEdward Island, 550 University Avenue, Charlottetown, PrinceEdward Island CIA 4P3 (Cribb, Guy).Address correspondence to Dr. Alastair Cribb.

could be felt. No other abnormalities were noted onphysical examination, except for the previously reportedabdominal alopecia. The cat was sedated (ketamine,atropine, xylazine) to permit cystocentesis and urinarycatheterization. After a urine sample had been obtainedby cystocentesis, the cat spontaneously voided approx-imately 200 ml of urine. Urinary catheterization was notperformed. The animal was hospitalized and given100 mL 0.9% normal saline, SC. Urinalysis revealed aspecific gravity of 1.029, pH 7.0, trace protein, a fewsquamous cells, and a few hippuric acid-resemblingcrystals. A urine sample was submitted for bacterialculture. A CBC obtained the following morning waswithin normal limits and a serum chemistry profile didnot reveal any clinically significant abnormalities.A tentative diagnosis of clomipramine-induced urinary

retention was made. Treatment with clomipramine wasdiscontinued. Additional diagnostic tests that couldhave been performed to assist in the establishment of aconclusive diagnosis through the elimination of other pos-sible causes include abdominal ultrasound, abdominalradiographs, contrast cystography or urethrography,repeat urinalyses, and cystourethrometry (bladder andurethral pressure profiles). However, some of thesespecialized diagnostic tests were not available in the gen-eral practice setting where this cat was treated, andsince there was no evidence of physical obstruction,referral for additional invasive tests was not felt to beindicated.Pending urinary culture results, treatment with

enrofloxacin (Baytril, Bayer, Etobicoke, Ontario;2.5 mg/kg BW, ql2h) had been initiated. However,urinary tract infection is uncommon in cats with lowerurinary tract disease and indiscriminate use of anti-biotics should be avoided in this condition. Therefore,enrofloxacin was discontinued when a negative urine cul-ture was returned on Day 2 of hospitalization.

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The cat was observed in hospital for 5 d. Initially, shewas stranguric with only a single large micturition in each24- to 36-hour period. By the 4th day of hospitalization,she was eating and drinking normally and appearedmore comfortable. The cat was discharged on day 5, atwhich time, she had a more normal micturition patternbut still voided large volumes infrequently. No furtherobstructive problems at home were reported by theowner.

Clomipramine is a tricyclic antidepressant used inhuman medicine to treat depression and obsessive-compulsive disorders (2). The primary mechanism ofaction of tricyclic antidepressants is to block norepi-nephrine and serotonin presynaptic neurotransmitterreuptake in the brain, reducing turnover and thus effec-tively increasing the action of these neurotransmitters.Clomipramine is distinguished from the other tricyclicantidepressants by its potent serotonin reuptake-inhibitingproperties, which resemble those of the selective serotonin-reuptake inhibitors such as fluoxetine (2). The tricyclicantidepressants as a class have been prescribed in com-panion and captive animals as anxiolytics and to treatobsessive-compulsive disorders (3-5). Only limitedclinical trials have been conducted in dogs, but they haveshown successful treatment in some cases of stereo-typical behavior, separation anxiety, or self-mutilation(3). Descriptions of the use of these drugs in cats islimited primarily to anecdotal reports. There is limitedinformation not only on the pharmacological profileof these drugs in cats and dogs, but on potential adversereactions as well.

All tricyclic antidepressants have varying degreesof anticholinergic, anti-oti-adrenergic, and antihista-minic effects that account for many of their common sideeffects, including urinary retention, hypotension, andsedation. The antimuscarinic (anticholinergic) proper-ties of clomipramine likely accounted for the observedside effects in this cat. Muscarinic blockade decreasesthe tone of the bladder musculature, which decreases theintraluminal pressure that can be achieved and allowscollapse of the trigone area, obstructing urinary outflow.Increased adrenergic activity through inhibition ofnorepinephrine reuptake may also contribute to uri-nary retention (2), but this effect may be decreasedthrough the anti-ao1-adrenergic properties.

There were several factors that led us to the presump-tive diagnosis of clomipramine-induced urinary retention.First, urinary retention is an effect that could be attributedto the known pharmacological properties of clomipramine(2). Although there are no published reports in cats,urinary retention is known to occur in other species, andthere are unlikely to be significant differences in antimus-carinic properties of clomipramine among species. Further,the temporal association with the drug was appropriate.The signs appeared 2 d after initiating therapy and werenot present prior to treatment. There were no otherdrugs being administered at the onset of clinical signs andneither physical examination nor laboratory evaluationrevealed any other explanation for the clinical signs.Finally, the clinical signs resolved on drug withdrawaland in the absence of any other treatment. Reexposure tothe drug at the same dose would have confirmed the diag-nosis but to do so was considered unethical.

Upon withdrawal of the drug, we estimated that upto 1 wk might be required for resolution of clinicalsigns. This estimate was based on the reported phar-macokinetics of clomipramine in humans because nodata are available in cats. The plasma half-life ofclomipramine in humans is 21 h following a single oraldose; clomipramine is metabolized primarily by hydrox-ylation, demethylation, and N-oxidation (2,6). Manyof the metabolites retain pharmacological activity andhave even longer half-lives than the parent compound.Although extrapolations between species can be erro-neous, we estimated that it could take S to 7 d or longer(5 times the estimated half-life) for the patient to clearthe parent drug and its active metabolites, and hence alle-viate the clinical signs. This is indeed what was observed.We did not attempt to intervene pharmacologically in

this adverse reaction. The urinary retention, althoughuncomfortable, was not life threatening to the cat, and wedid not wish to introduce other possible adverse effects.If pharmacological intervention had been desired, lowdoses of bethanechol, a muscarinic agonist, could havebeen employed. The role of an aot-adrenergic blockingdrug is not clear. Although clomipramine and its metabo-lites block the reuptake of norepinephrine and could,therefore, have enhanced the adrenergic effects, many ofthe tricyclic antidepressants, in fact, have aot-adrenergicantagonist properties. Phenoxybenzamine or prazosin,a1-adrenergic antagonist, could have been administeredto ensure that there was no enhanced internal sphinctertone due to aL -adrenergic stimulation, but they may beassociated with their own adverse effects. The use ofdiazepam, a centrally acting muscle relaxant, to relax theexternal urethral sphincter would not have been justified.The starting dose of clomipramine administered in this

case was 1 mg/kg BW/d (1). Although there is littleinformation available on appropriate dosing in cats,suggested doses range from 0.5 to 1.5 mg/kg BW/d incats (1,3,4). Starting at a dose at 1.0 mg/kg BW/d mayhave contributed to the occurrence of urinary retentionin the patient. In general, in dogs or cats, it is recom-mended to start at the low end of the dose range(0.5 mg/kg BW/d in cats) and slowly increase to aneffective dose in order to minimize the likelihood ofadverse effects. It may require at least 2 wk of treatmentto see the full behavioral effect of a given dose. Thisdelay is related both to the pharmacokinetic propertiesof the drug (probably requiring up to 1 wk to reachsteady state concentrations) and the pharmacodynamiceffects on the central nervous system, which may bedelayed. Because this was a pharmacologically mediatedadverse effect at a nonprimary target receptor, an attemptcould have been made to reintroduce clomipramine at alower starting dose (starting at 0.1-0.25 mg/kg BW/d andincreasing to an effective dose). However, we elected notto try treatment again, given the degree of urinary reten-tion previously observed.

Alternative pharmacological therapies for psychogenicalopecia are limited. Fluoxetine has been used (5),but there is currently not enough information avail-able to advocate its general use in cats. Diazepam(0.2-0.4 mg/kg BW, q8-12h) and chlorazepate(0.55-2.2 mg/kg BW, q12-24h) have been sug-gested, although diazepam has been associated

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with hepatoxicity in some cats (3). Phenobarbital(1 mg/kg BW, ql2h), an anticonvulsant, is anotherpossible option (3-5). Megestrol acetate has also beenemployed, but its side effects should preclude its use incats. In general, the prognosis remains poor unless thepsychogenic factors are resolved. The use of behaviormodifying drugs in cats is based largely on anecdotalevidence.Any practitioner considering the use of tricyclic anti-

depressant drugs should be aware of their possibleadverse effects, which may prohibit the use of thisclass of drugs in some cats. Many of the drugs sug-gested for the treatment of psychogenic alopecia alsohave significant potential adverse effects (3-5). Psy-chogenic alopecia is not a life-threatening problem,and unless there is significant self-trauma associated withit, the treatment may be worse than the disease. Poorlysocialized cats may be even more stressed by the strug-gle of daily medication. Behavior modification andenvironmental changes designed to produce a morepredictable daily routine should be considered the first

line of therapy in the treatment of compulsive disorders.Pharmacotherapy should ordinarily be reserved forthose cases that are refractory to conservative manage-ment or that involve self-mutilation. cvi

References1. Papich M. Table of common drugs: Approximate dosages. In: KirkRW, Bonagura JD, eds. Kirk's Current Veterinary Therapy XI: SmallAnimal Practice. Philadelphia: WB Saunders, 1992: 1233-49.

2. Baldessarini RJ. Drugs and the treatment of psychiatric disorders.In: Hardman JE, Limbird LE, Molinoff PB, Ruddon RW, eds.Goodman & Gilman's The Pharmacological Basis of Therapeutics,9th ed. New York: McGraw-Hill. 1996: 431-60.

3. Landsberg G, Hunthausen W, Ackerman L. Handbook of BehaviourProblems of the Dog and Cat. Oxford: Butterworth-Heinemann,1997: 45-65; 175-7.

4. Overall KL. Clinical Behavioral Medicine for Small Animals.St. Louis: Mosby-Year Book, 1997: 293-322

5. Simpson BS, Simpson DM. Behavioural pharmacotherapy. Part I.Antipsychotics and antidepressants. Compend Contin Educ Pract Vet1996; 18: 1067-81.

6. Anafranil Package Insert. In: Compendium of Pharmaceuticalsand Specialties. Ottawa: Canadian Pharmaceutical Association,1996: 73-5.

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