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doi:10.1016/j.jv

Journal of Veterinary Behavior (2009) 4, 223-229

RESEARCH

Use of fluoxetine, diazepam, and behavior modification astherapy for treatment of anxiety-related disorders in dogs

Miguel Ibaneza, Bernadette Anzolab

aUniversidad Complutense de Madrid, Facultad de Veterinaria, Clınica del Comportamiento Animal, Departamento deProduccion Animal, Ciudad Universitaria, Madrid, Spain; andbUniversidad Centrooccidental ‘‘Lisandro Alvarado,’’ Departamento de Produccion Animal Nucleo Tarabana, EstadoLara, Venezuela.

KEYWORDS: Abstract The objective of this study was to evaluate the use of fluoxetine, diazepam, and behavior

dog;anxiety;aggressive;fear;obsessive-compulsivedisorder;fluoxetine;

diazepam

modification for the treatment of a variety of anxiety disorders in dogs of different breeds, ages,and sexes that presented to a university veterinary behavior clinic. Forty dogs were enrolled in thestudy, and 34 completed it. The dogs were grouped into 2 major diagnostic categories, aggressiveand anxious, according to the presenting signs. Moreover, the dogs further subdivided into 4 groups:neutered, intact, juveniles, and adults. Diazepam was administered orally, at a dosage of 0.3 mg/kgonce a day for 4 weeks; fluoxetine was administered orally at a dosage of 1 mg/kg once a day for10 weeks. The drugs were started simultaneously. The owners were given a behavior modification planfor their dogs that started from the first week of therapy. The behavior of the subjects was evaluated at3 points in time. Clinical response was assessed by the supervising veterinarian and the owners. Therewere no significant differences (P . 0.05) between the groups studied in relation to the improvementachieved. There was a positive correlation (r . 0.44) between owner compliance with the treatmentand the values obtained for the improvement achieved for each period. Clinical signs largely improvedor were eliminated in 13 dogs (38%), 8 dogs (26%) showed moderate improvement, 5 dogs (12%) wereslightly improved, and there were 8 dogs (24%) with no changes in clinical signs.� 2009 Elsevier Inc. All rights reserved.

Introduction

Anxiety can be a normal response, but when it is out ofcontext in a given situation, and/or it is constant andexcessive, then it is likely to become a problem. Anxiety-

reprint requests and correspondence: Miguel Ibanez, Uni-

tense de Madrid, Facultad de Veterinaria, Clınica del Com-

imal, Departamento de Produccion Animal, Ciudad

8040, Madrid, Spain; Phone: 134913943760; Fax:

nez@vet.ucm.es

e front matter � 2009 Elsevier Inc. All rights reserved.

eb.2009.04.001

related conditions include aggression, separation anxiety(SA), generalized anxiety (GA), fears, phobias, and obses-sive-compulsive disorders (OCD) (Overall, 1997).

Patients with anxiety become irritable and can easilydevelop aggressiveness (Pageat, 1998). Dogs that bite theirowners may do so in social contexts, but their motivationmay be based almost entirely on anxiety (Overall 1997;Overall2005; Reisner, 2006). The American Psychiatric Associationdoes not consider aggressive behavior in humans as a separatediagnostic category, but aggression does constitute a majorproblem in a variety of psychiatric conditions, and the same ap-plies to veterinary medicine (Dodman and Shuster, 1998).

224 Journal of Veterinary Behavior, Vol 4, No 6, November/December 2009

Separation anxiety has been identified as the secondmost commonly reported behavioral disorder referred toveterinary behaviorists (all forms of aggression) in dogs(Takeuchi et al., 2000; Bamberger et al., 2006). The princi-pal signs of this disorder are excessive vocalization, inap-propriate elimination, salivation, escape attempts, anddestructive behavior when the owner is away from homeor when he or she is inaccessible to the dog (Overall,1998). Destructive behavior is usually directed toward entryand exit points such as doors or windows, as well as to ob-jects that have been in frequent contact with the owner suchas chairs, couch, pillows or clothing. Dogs with separationanxiety can be strongly attached to a person or have astrong desire to be with their owner; when this proximityis not possible, anxiety can ensue.

Fear of different phenomena such as noises or thunder,as well as fear of people, children, dogs, and other animalsis common and can be an adaptive response. Phobias areprobably quantitatively and qualitatively different fromfears, but they are so closely related that they are oftenconsidered together. Overall et al. (2001) reported thatnoise and thunderstorm phobias are among the most com-monly recognized disorders associated with panic re-sponses, although there are no data on relative incidencesof these problems. Casey (2002) indicated that extremefear reactions to noises may predispose dogs to anxietystates like phobias.

Obsessive-compulsive disorders, also referred to ascompulsive disorders (Luescher, 1998), are abnormal be-haviors that are invariant and repetitive to the extent thatthey interfere with the animal’s normal functions (Overalland Dunham, 2002). Many of these behaviors appear in re-sponse anxiety states (Landsberg et al., 2003).

Some types of behavior disorders can be reduced infrequency and severity with psychotropic drugs that selec-tively increase serotonin concentrations (Olivier et al., 1995;Fuller, 1996). There are many studies in which drugs havebeen used to treat behavioral problems in dogs. Tricyclic an-tidepressants, benzodiazepines, and other drugs with anxio-lytic properties induce a condition of continuous control ofanxiety in many dogs (Marder, 1991; King et al., 2000).

An alternative strategy for stimulating serotonin recep-tors is to administer specific inhibitors of serotoninreuptake, such as fluoxetine. Fluoxetine resulted in areduction in owner-directed dominance aggression after 3weeks of treatment in dogs (Dodman et al., 1996). The suc-cessful control by fluoxetine of interdog aggression hasbeen reported by Overall (1995), who also employed be-havior modification designed to teach the dog to relax inthe presence of other dogs and to take cues about the appro-priateness of its behavior from its owner. The effects of flu-oxetine in the reduction of clinical signs of separationanxiety were shown in recent studies (Landsberg et al.,2008; Simpson et al., 2007). Crowell-Davis et al. (2003)evaluated a combination of psychoactive drug therapy andbehavior modification for the treatment of storm phobia

in dogs. The authors used a tricyclic antidepressant (clo-mipramine) supplemented with a benzodiazepine (alprazo-lam) to offer relief from the intense fear while fluoxetinereached therapeutic levels. The combination effectively de-creased or eliminated storm phobia in dogs. Seksel and Lin-deman (2001) reported that antidepressants were effectivein controlling signs of obsessive-compulsive disorder, sep-aration anxiety, and noise phobia in dogs when used incombination with behavior modification.

Diazepam is a rapid-acting benzodiazepine with anxio-lytic properties that readily crosses the blood-brain barrierand that is widely distributed through the body (Crowell-Davis and Murray, 2006). Diazepam was used in the pre-sent study to provide an anxiolytic effect while fluoxetinereached therapeutic levels to avoid the carryover effectfrom the fluoxetine reported by Crowell-Davis and Murray(2006). The purpose of the study reported here was to eval-uate the use of fluoxetine, diazepam, and behavior modifi-cation for the treatment of anxiety disorders in dogs.

Material and methods

Subjects

The initial enrollment consisted of 40 dogs diagnosedwith a variety of behavioral disorders. Five dogs werewithdrawn between the onset and the first 4 weeks oftreatment because the owners did not provide follow-upinformation, and 1 dog was euthanized a month into thestudy (the reason for euthanasia was not given by theowner). The clinical details are presented in Table 1.

Thirty-four dogs (9 intact females, 20 intact males,1 neutered female, 4 neutered males) representing 27breeds and 7 crossbred dogs in good physical conditionwere evaluated at The Animal Behavior Clinic of theUniversidad Complutense of Madrid. The dogs werebetween 9 months and 7 years of age. Presenting com-plaints included aggressiveness, anxiety or inappropriatefear, vocalization, circling, nervousness, destructive behav-ior, pica, and house soiling.

The clinical history was completed using a standardizedquestionnaire. Dogs were included in the study if anxiety-related disorders were confirmed by the behavioral history(signs of restlessness, hyperactivity, extreme attachmentwhere to the owner the owner’s absence caused anxiety,aggression, lack of attention, nervousness, tremors, and soon were reported). Dogs were excluded if they showed anyclinical signs of any medical pathology, if they werepregnant or had been treated during the previous weekswith any psychopharmacologic treatment. The results of thebehavioral examination confirmed that dogs presented withdifferent classes of disorders (aggressiveness, separationanxiety, general anxiety, fear or phobia, and OCD). To gainstatistical power, dogs were grouped into 2 behaviorcategories according to the symptoms presented: aggressive

Table 1 Clinical details of 34 dogs treated for anxiety states

Case No. Sex Age (mos.) Primary Presenting Complaint Class of Disorder Behavior Category

1 M 12 Aggressive, destructive AGG Aggressive2 F 78 Aggressive AGG Aggressive3 FN 36 Aggressive, global fear Fear Anxious4 M 36 Aggressive AGG Aggressive5 M 60 Aggressive AGG Aggressive6 F 60 Aggressive AGG Aggressive7 MN 18 Nervousness, circling OCD Anxious8 F 36 Aggressive AGG Aggressive9 M 16 Aggressive AGG Aggressive10 M 36 Vocalization AGG Aggressive11 F 36 Fear Fear Anxious12 M 48 Vocalization SA Anxious13 M 11 Destructive GA Anxious14 F 32 Aggressive, circling OCD Anxious15 M 36 Fear Fear Anxious16 M 18 Vocalization SA Anxious17 M 24 Nervousness GA Anxious18 M 24 Aggressive AGG Aggressive19 F 60 Aggressive AGG Aggressive20 F 24 Aggressive AGG Aggressive21 F 36 Aggressive AGG Aggressive22 M 60 Inappropriate elimination GA Anxious23 MN 24 Aggressive AGG Aggressive24 MN 31 Fear, vocalization, pica Fear Anxious25 M 10 Destructive, inappropriate elimination SA Anxious26 M 9 Inappropriate elimination GA Anxious27 MN 24 Aggressive AGG Aggressive28 F 60 Fear, aggressive Fear Anxious29 M 48 Vocalization SA Anxious30 M 24 Inappropriate elimination SA Anxious31 M 12 Destructive SA Anxious32 M 24 Fear Fear Anxious33 M 12 Destructive, vocalization SA Anxious34 M 22 Aggressive AGG Aggressive

AGG, aggressiveness; F, female; FN, neutered female; GA, generalized anxiety; M, male; MN, neutered male; OCD, obsessive-compulsive disorder; SA,

separation anxiety.

Ibanez and Anzola Use of Fluoxetine, Diazepam, and Behavior Modification on anxiety in dogs 225

(this group included 15 dogs with behavior disorders thathad aggressiveness as a common symptom, mainly directedtoward unknown persons and other dogs) and anxious (thisgroup included 19 dogs that showed severe anxiety states).We divided the sample into 2 age groups, and 3 years oldwas the specific age that separated these groups (17 under 3years, n 5 17 and greater than 3 years, n 5 17) and 2groups based on reproductive status (5 neutered, 29 intact).

Treatment

Oral diazepam, given at a dosage of 0.3 mg/kg every24 hours for 4 weeks as an adjunct to fluoxetine, added ef-ficacy against extreme anxiety states. Fluoxetine was ad-ministered orally at a dosage of 1 mg/kg every 24 hoursfor 10 weeks; these dosages were unchanged for all casesthroughout the experimental period. The drugs were startedsimultaneously. During the study, the dogs could receive

any other medications that were prescribed for treatmentof any unrelated problems. The dogs received a completephysical and laboratory evaluation before the treatment.

Behavior modification plan

All dogs were included in a behavior modification planthat started on the first day of the behavioral evaluation. Thisplan consisted of 3 basic steps designed to stop unwantedbehaviors and reward preferred behaviors that were incom-patible with the performance of undesirable behaviors. Instep 1, clients were asked to cease even unintentional rewardfor the undesirable behaviors. In step 2, clients were asked tofollow a passive behavior modification program designed toteach the dogs to sit quietly, look at the person from whomthey were seeking attention or with whom the interaction wasoccurring, and wait to take cues about the appropriateness oftheir behavior from those people. The dogs followed basic

226 Journal of Veterinary Behavior, Vol 4, No 6, November/December 2009

obedience rules to increase their respect, confidence, andenhance communication between dog and owner. The mod-ification plan included: (1) rewarding only relaxed behavior;(2) eliminating reinforcement of anxious behaviors byreassuring or patting the dog when it showed clinical signsof fear or anxiety; (3) setting a routine for feeding and playingtimes; (4) spending 20 minutes per day in 4 sessions (5 min-utes each) playing or otherwise actively interacting with thedog. In step 3, clients were requested to begin active behaviormodification designed to teach the dogs to relax when theywould otherwise be engaged in the problem behavior, in ex-change for which the dog was given a food or play reward.

Follow-up

This study evaluated the effects of this treatment from thestart until the 10th week of therapy. Information from theowners was collected at 3 points in time: period 1, 14 daysafter the start of therapy; period 2, 42 days after the start oftherapy; and period 3, 70 days after the start of therapy.Response and outcome were determined by the supervisingveterinarian and the owner. Success was defined as elimina-tion or reduction of clinical signs to a level acceptable to theowner. Outcomes were categorized as 1 (worsened), 2(unchanged), 3 (slightly improved), 4 (moderately im-proved), and 5 (largely improved/eliminated), when com-pared to the initial assessment. During the assessment period,owners were questioned about their compliance with thetreatment program. This evaluation was done by people notfamiliar with the dog’s response to treatment. Compliancewas rated as variable (1), adequate (2), good (3), or excellent(4). Dog owners were encouraged to contact the supervisingclinician via telephone at the end of each period to discussprogress with the treatment program.

Statistical analyses

The data were not normally distributed and were ana-lyzed with the use of nonparametric tests. Baseline scoreswere compared with scores obtained in each follow-upperiod by use of the Wilcoxon matched-pairs signed ranktest. Groups were compared using the Wilcoxon rank-sum

Table 2 Comparison of treatment effects on studied groups by peri

Aggressive(n 5 15)

Anxious(n 5 19) P

Intact(n 5 29)

Period 1 2.9 3.2 0.36 3.1Period 2 3.2 3.5 0.48 3.4Period 3 3.4 3.6 0.61 3.5D1 0.3 0.3 0.77 0.3D2 0.2 0.2 0.77 0.1D3 0.5 0.4 0.87 0.4Com 2.1 2.7 0.08 2.5

Com, owner compliance with the behavior modification plan; D1, differenc

improvement between period 3 and period 2; D3, difference in improvement b

test. Spearman rank correlation coefficients were used todetermine interactions between the owner’s compliance andthe values obtained for the improvement for each period.All analyses were performed using Statistical AnalysisSystem (SAS)(SAS/STAT, SAS User’s Guide, Version 8.SAS Institute, Cary, NC [1996]). Differences were consid-ered significant at P , 0.05.

Results

Clinical details of 34 dogs treated for anxiety states arepresented in Table 1. Aggressiveness was a common clini-cal sign for 15 dogs. The primary presenting complaintswere aggressiveness, global fear, vocalizing, and circling.Separation anxiety was observed in 7 cases; primary pre-senting complaints were nervousness, fear, vocalization,destructive behavior, and inappropriate elimination. Gener-alized anxiety was diagnosed in 4 cases; the primary pre-senting complaints were nervousness, inappropriateelimination, pica, and aggressiveness. Fear or phobia wasthe diagnosis in 6 cases; primary presenting complaintswere fear of noise, global fear, vocalization, and pica. Ob-sessive-compulsive disorder (OCD) was diagnosed in 2cases, and the primary presenting complaints were circling,nervousness, and aggressiveness.

As noted in Table 2, there were no significant differences(Wilcoxon rank-sum test; P . 0.05) in treatment effects be-tween the 2 major diagnostic categories (aggressive andanxious) and improvement achieved, and nor were theresignificant differences (Wilcoxon rank-sum test; P .

0.05) between the neutered and intact groups and juvenilesand adult groups. Spearman rank correlation coefficients re-vealed a moderately positive correlation between ownercompliance with the treatment instructions and the valuesobtained for the improvement achieved for each follow-up period (period 1, r 5 0.44; period 2, r 5 0.55; and period3, r 5 0.47).

Largely improved or resolved clinical signs were reportedin 13 dogs (38%): 4 dogs with aggressiveness, 4 withseparation anxiety, 2 with generalized anxiety, 2 with fear,and 1 with OCD (Table 3). In addition, 9 dogs (26%) were re-ported as moderately improved: 6 with aggressiveness, 1 with

od, difference between periods and compliance

Neutered(n 5 5) P

Young(n 5 17)

Adults(n 5 17) P

3.2 0.77 2.9 3.2 0.393.2 0.74 3.2 3.5 0.523.6 0.86 3.4 3.7 0.410.0 0.20 0.3 0.2 0.510.4 0.18 0.1 0.2 0.390.4 1.00 0.4 0.5 0.762.2 0.50 2.5 2.4 0.63

e in improvement between period 2 and period 1; D2, difference in

etween period 3 and period 1.

Ibanez and Anzola Use of Fluoxetine, Diazepam, and Behavior Modification on anxiety in dogs 227

separation anxiety, 1 with generalized anxiety, and 1 withfear. Slight improvement was observed in 4 dogs (12%):1 with aggressiveness, 1 with separation anxiety, 1 with gen-eralized anxiety, and 1 with OCD. Eight dogs (24%) had nochange in symptoms: 4 with aggressiveness, 1 with separa-tion anxiety, and 3 with fear. Clinical response as reportedwith respect to disorder type revealed that 6 dogs (40%) withaggressiveness had moderate improvement. For dogs withseparation anxiety, 4 (57%) had largely improved or resolvedclinical signs. Fifty percent of dogs with generalized anxietywere gauged to have largely improved outcomes. Fifty per-cent of the cases diagnosed with fear or phobias reportedno changes in clinical signs. Finally, in the dogs with OCD,the results showed that the presenting clinical signs werelargely improved in one (50%) of the cases, and the other50% showed slight improvement.

There were no reports of worsened cases or serious sideeffects to the medication used. In some (2 dogs) cases theowner reported a transient decrease (for less than a week inboth cases) in appetite, which returned to normal with thepassage of time.

Discussion

The aim of this study was to evaluate the combination offluoxetine, diazepam, and a behavior modification programas treatment for dogs with anxiety-related behavior disor-ders. This study reported improvement in 26 of 34 patients(76%). Success was assessed by the supervising veterinar-ian and the owners, and defined as elimination or reductionof abnormal behaviors to a level acceptable to the owners.The results of the study reported here indicated thatfluoxetine has anxiolytic properties, and as reported byDodman et al. (1996), Fuller (1996), and Seksel and Liden-man (2001), anxiety in dogs can be treated successfullywith this antidepressant. This finding corroborated thatthe anxiety diagnoses were correct. In our study, as hasbeen observed by other authors (Simpson et al., 2007;Landsberg et al. 2008), fluoxetine reduced anxiety andwas observed to improve outcomes for behavioraldisorders.

Table 3 Clinical response by class of disorder in dogs treated with

LI MI

N % N

Agg 4 27 6SA 4 57 1GA 2 50 1Fear or phobia 2 33 1OCD 1 50 0

Total 13 38 9

Agg, aggressiveness; GA, general anxiety; LI, largely improved; MI, moderately i

slightly improved; UN, unchanged.

Additionally, in our study, the use of diazepam may haveprovided an axiolytic effect during the first month oftreatment in all cases. Therefore, in agreement with theresults reported by Crowell-Davis et al. (2003) that in-cluded benzodiazepines as supplemental to the effects ofother antidepressants, diazepam can be used as an adjunctto fluoxetine, leading to increased efficacy in the treatmentof severe anxiety states.

Diazepamdgiven its anxiolytic characteristics, lack ofany peripheral autonomic blocking action, rapid metabo-lism in dogs (half-life of 2.5-3.2 hours vs 3.6-10 hours fornordiazepam; Crowell-Davis and Murray, 2006), and ab-sence of side effects, combined with the favorable out-comes reported in this study (overall improvement of76%)dshows promise as a safe and effective treatmentfor anxiety disorders in dogs when used in combinationwith fluoxetine. Crowell-Davis and Murray (2006) indi-cated that although benzodiazepines sometimes decreaseaggressiveness, their use sometimes results in increasedaggression. Landsberg et al. (2003) stated that benzodiaze-pines can be considered for the treatment of any conditionthat may have a fear or anxiety component, including fearaggression, and also state that benzodiazepine’s disinhibi-tion could lead to an increase in aggression.

In this study, there were no observed effects of behav-ioral disinhibition that led to increased aggressivenessstemming from the use of diazepam to treat anxiety indogs with fear aggression. The procedures used in thisstudy to encourage compliance probably reflect those usedin general veterinary practice. This study yielded a mod-erately positive correlation between owner compliance withthe treatment recommendations and the values obtained forthe improvement achieved for each follow-up period.Although complete resolution is desirable, it may not beachievable if environmental factors that contribute toexpression of clinical signs cannot be controlled or elim-inated, or if there is incomplete owner compliance with thebehavioral modification plan or drug therapy.

The recommended treatment protocol achieved a sub-stantial improvement in clinical signs associated with ag-gressiveness, separation anxiety, general anxiety, fear orphobia, and OCD and should be considered as a treatment

fluoxetine, diazepam, and behavior modification

SI UN

% N % N %

40 1 7 4 2714 1 14 1 1425 1 25 0 017 0 0 3 500 1 50 0 0

26 4 12 8 24

mproved; OCD, obsessive-compulsive disorder; SA, separation anxiety; SI,

228 Journal of Veterinary Behavior, Vol 4, No 6, November/December 2009

option when these anxiety states are diagnosed. This studyhas shown that anxiety-related behavioral disorders occur inSpain and that owners are willing to commit to a treatmentprogram of fluoxetine in combination with diazepam andbehavior modification to improve their dogs’ behavior.

This study examined the potential effects on treatmentoutcome of reproductive status and of 2 different age groups.It was found that the effectiveness of treatment was notaffected by age or reproductive status (potential influentialfactors in states of anxiety). Moreover, by failing to findsignificant differences in level of response between the 2diagnostic categories (aggressive and anxious), which re-ceived the same treatment, it is confirmed that both categoriesmay not be independent diagnostic entities. This finding is inagreement with reports made by Dodman and Shuster (1998).

On the other hand, the effectiveness of treatment could beinfluenced by other factors given that this was an open trial.However, we observed improvement in the dogs’ anxiety-related signs from the onset of treatment with psychotropicdrugs, which we believe allowed for a better response to thebehavior modification plan. Further studies are necessary toassess recidivism rates, initiating factors, and the effect ofconcurrent behavior modification. Ideally, a double-blindstudy comparing fluoxetine and diazepam combination alone,behavior modification alone, and both therapies togethershould be undertaken to assess operator effect and identifyany placebo effect. This method was not possible in the presentstudy because of the limited number of cases available.

Conclusion

The combination of fluoxetine administered orally at adosage of 1.0 mg/kg per 24 hours, diazepam administeredorally at 0.3 mg/kg per 24 hours, and a behavior modifica-tion plan is effective in decreasing or eliminating anxiety-related clinical signs. The concurrent use of diazepamallowed the use of a lower fluoxetine dose, which waseffective enough throughout the treatment period.

Therapy based on a combination of drugs and a behaviormodification program may provide faster and more reliableimprovement of behavioral disorders than a behaviormodification plan alone. The clients of the Animal Behav-ior Clinic of the University Complutense of Madrid, Spainwere willing to commit to a treatment program of fluox-etine in combination with diazepam and behavior modifi-cation to improve their dogs’ behavior.

Acknowledgments

The Animal Behavior Clinic of the Universidad Com-plutense of Madrid funded this study. We are grateful to theCenter for Data Processing of the Universidad Complutensede Madrid for statistical advice, and to Dr. Alberto Giraldezfor his participation in the follow-up period.

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