Last time we reviewed the scientific literature on the use of fluoxetine for behavioral disorders in dogs, the data suggests this medication is generally safe and effective. While any dog can have an adverse reaction to any medication, the peer-reviewed literature on fluoxetine use in dogs does not support increases in aggression or seizure activity. Fluoxetine may be useful in canine cases of separation anxiety, compulsive disorders, aggressive behavior, other behavioral disorders and may also improve affect. In addition, fluoxetine has been tested and approved by the FDA for use in dogs. Thus, fluoxetine is often the first-choice, long-game behavior medication for dogs with a variety of behavioral issues.
A Few More SSRIs
Two other human-approved SSRIs have been most used in veterinary medicine: sertraline (Zoloft) and paroxetine (Paxil). Both sertraline and paroxetine are mentioned in various textbooks “even though there is a lack of clinical trials on their use for mental health treatments in veterinary medicine” [1]. The use of sertraline and paroxetine in veterinary medicine is based on human studies, as well as the similar, but not exactly the same, mechanism of action as fluoxetine. For example, fluoxetine frequently decreases appetite, so if an SSRI is needed, sertraline might be a better choice because it does not decrease appetite. When compared to fluoxetine, sertraline also increases dopamine, so it may increase the motivation-reward system.
Canine Model of Human OCD
In 1992, Rapaport et al. used canine acral lick as a model of human obsessive-compulsive disorder [2]. They investigated the effects of behavioral medications on, “mean licking behavior,” of dogs with acral lick dermatitis. Interestingly clomipramine, fluoxetine, and sertraline decreased “mean licking behavior” by 43%, 39%, and 21% respectively when compared to baseline, suggesting that these medications could be useful in veterinary medicine.
SSRIs Abstracts, Presentations and Case Studies
Other information about the use of sertraline and paroxetine comes from abstracts, presentations and case studies. Case studies are anecdotes of cases published in a journal. While case studies can be helpful to a clinician dealing with a specific case, a single case does not represent a population. In addition, results of abstracts not published in a peer-reviewed journal should be viewed with skepticism. Abstracts often describe preliminary observations. With further information and data collection, the conclusions drawn in abstracts may not “scientifically hold up” when all the data is analyzed.
With that in mind, Reisner [3] retrospectively assessed the effect of paroxetine on generalized anxiety in 12 dogs. Owners reported improved behavior in 6 dogs (50%) and no change in 4 dogs (33%). Increased anxiety (*n=1) and anxiety and aggression (n=1) were identified in the remaining dogs. Use of sertraline in combination with a benzodiazepine decreased compulsive behavior in 4 dogs [4], and improved generalized anxiety in 1 dog [5].
With the exception of fluoxetine, the literature on the use of SSRIs for behavior problems in dogs is scarce, however, their use can be justified based on human studies, similar mechanisms of action and clinical experience.
Tricyclic Antidepressants
Tricyclic antidepressants (TCAs). inhibit the reuptake of serotonin and norepinephrine; have antihistaminergic and anticholinergic properties (dry mouth, urinary retention); and are alpha -1 adrenergic antagonists [1]. The extent of these effects varies with the medication. Some have strong serotonin reuptake and weak norepinephrine reuptake properties, while others have the reverse. Other properties also vary, for example, amitriptyline has much stronger antihistaminergic effects than clomipramine.
You can see [Table 1] the different effects of six TCAs on the receptors involved with neurotransmission: norepinephrine (NE), serotonin (5HT), alpha-adrenergic (α 1 and 2), histamine (H1), and muscarinic (MUSC). Zero equals no biochemical effect, while ++++ equals a large biochemical effect. This data is from in vitro studies, meaning it was done using cells in a dish, not a living animal. You can see that the biochemical activity varies greatly among the TCAs, suggesting that the choice of medication can be tailored to enhance or avoid specific biochemical effects.
Clomipramine
Of the TCAs, only clomipramine (Clomicalm®) has been approved for use in dogs [Table 2]. The drug was approved in the US, Canada and the EU in 1998, and recently the FDA approved a generic form of clomipramine for use in dogs. This means that studies to evaluate efficacy and safety of clomipramine have been completed on dogs. The label “approved use in dogs,” states: Clomicalm® is to be “used as part of a comprehensive behavioral management program to treat separation anxiety in dogs greater than 6 months of age. Inappropriate barking or destructive behavior, as well as inappropriate elimination (urination or defecation), may be alleviated by the use of Clomicalm® tablets in conjunction with behavior modification.” This means that use of clomipramine for behavioral issues other than separation anxiety is “extra-label.”
Human Approved TCAs
There are six TCAs approved for use in humans; amitriptyline, clomipramine, desipramine, doxepin, imipramine and nortriptyline [Tables 1 & 2]. As mentioned, they all have a different “level of effect” on different receptors. This means that medications can be selected based on their profile of effects. So, for a dog with urinary retention who might benefit from a TCA, you would select a drug with low to zero anticholinergic effects.
Clomipramine in Canine Separation-Related Anxiety (CLOCSA) Study Group
The goal of the first three studies was to provide safety and efficacy data to the FDA for approval of clomipramine for use in dogs with separation anxiety. It is useful to remember that these studies were completed in the mid 1990s. The CLOCSA Study group was supported and organized by Novartis Animal Health, makers of Clomicalm®. Safety and efficacy data were presented at the 1st International Conference on Veterinary Behavioural Medicine in the UK in 1997 [6]. In addition to this presentation, two peer-reviewed studies were later published [7, 8].
Dogs with separation anxiety were recruited in the UK, France, and US for a prospective, randomized, double-blind, placebo-controlled, parallel-group, multicenter clinical trial [7]. Specific inclusion/exclusion criteria were used to determine eligibility. Dogs meeting the criteria were randomly assigned to one of three groups: standard dose clomipramine (1-2 mg/kg twice a day (**BID), low dose clomipramine (0.5-1 mg/kg BID) and placebo BID. Clomipramine (Clomicalm®) was supplied by Novartis Animal Health. The placebo was identical in consistency and shape. All dogs received behavioral therapy.
The efficacy of treatment was assessed by specific questions asked of the owner at 28, 56, and 84 days, and compared to baseline (day 0). Signs of separation anxiety (destruction, defecation, urination and vocalization) were rated as worse, no change, improved, disappeared or newly appeared. Improved and worse were based on severity and duration of the behavior.
Owners also rated global behavior on days 28, 56, and 84, compared to baseline (day 0). Behaviors were rated as no, little, moderate, or much improvement or cured. Frequency and severity of undesirable side effects were assessed by veterinarians.
Ninety-five dogs were included in the efficacy study: standard dose n=28; low dose n=35; placebo n=32. For three separation anxiety behaviors (destruction, defecation, and urination) there was a higher frequency of treatment success in the standard dose group at all time points. Owners’ global assessment of their dog’s behavior was significantly improved at all time points in the standard dose compared to placebo. Few undesirable side effects were reported, with vomiting, gastritis, lethargy and sleepiness reported more frequently in the standard clomipramine group than placebo. Only one severe adverse effect (collapse and disseminated intravascular coagulation) was reported, and the dog recovered. The authors conclude that the standard dose of clomipramine (1-2 mg/kg BID) when combined with behavioral therapy produced significant improvement in the signs of separation anxiety as compared to placebo, and may be a useful aid in the treatment of this disorder.
The goal of this study was to establish efficacy and safety of clomipramine in dogs with separation anxiety. Use of a two-tailed t-test for multiple comparisons (a statistical test that examines the possibility of a relationship in both directions), would likely not be the preferred method of analysis today. The data, presented in nine tables, would have been more clearly presented in graphic form. However, it appears that clomipramine is safe to use in dogs and may have some benefit for separation anxiety.
In the previously described study, neither the veterinarian nor owners were aware of the treatment and it was not divulged at the end of the study [7]. A follow-up study, by the same group, contacted the original participants, and information from 76 participants provided useful data [8]. The 28 dogs that received drug therapy were divided into two categories: (1) those that received clomipramine for more than 12 months (n=12), and (2) dogs that received no medications or medications for < 7 months. The categories seem arbitrary.
Behavioral improvement was noted in 10 of 12 dogs on clomipramine for > 12 months and adverse effects or worsening behavior were not noted. Perhaps the most important takeaway from this study is that even after 12 months of clomipramine therapy for separation anxiety, adverse effects were rare. The authors also recommend gradual discontinuation of therapy.
Multiple studies evaluating the effect of clomipramine for various behavioral issues were published in the late 1990s.
Tail Chasing Study
Moon-Fanelli and Dodson evaluated the effect of clomipramine on tail chasing in terriers (15 Bull Terriers, 1 Miniature Bull Terrier, 1 Staffordshire, 1 Jack Russel Terrier) [9]. Dogs were referred to the behavior clinic and a behavioral diagnosis was made based on the history, clinical signs, and medical assessment. For inclusion, tail chasing bouts occurred at least 3 times per day and lasted 60 seconds. All dogs were treated with clomipramine (doses varied and were adjusted) for a minimum of 3 weeks and a maximum of 1.5 years. In an effort to stabilize mood, dogs were to receive a low protein diet, enrichment of the environment, and 20-30 minutes of aerobic exercise daily.
Response to therapy was evaluated by a series of phone conversations and, in five cases, weekly diaries. Owners provided an overall score for changes in behavior: 0 = no change; 1 = minimal improvement (≥ 24%); 2 = moderate improvement (25-49%); 3 = marked improvement (50-74%); and 4 = substantial improvement (75-100% = intermittent, brief, and easily interrupted tail chasing.) Response to treatment was evaluated at three time points: weeks 1 to 4, weeks 5 to 8, and weeks 9 to 12.
The authors provide an excellent review of tail chasing behaviors. However, the interpretation of improvement related to clomipramine is complicated by the various dosing schedules, co-morbid behavioral issues, and movement of dogs during the study to different locations/homes.
At 4 weeks, 6 of the 18 dogs were reported to have substantial improvement; 4 marked improvement, 1 moderate improvement, and 7 had minimal improvement. Twelve dogs remained in the study for 12 weeks: medication was successfully withdrawn from 5 dogs with mild episodes and 7 dogs remained on medication. The authors conclude that tail chasing appears to respond to clomipramine.
Canine Compulsive Disorder
The efficacy of clomipramine on canine compulsive disorder was evaluated by Hewsen et al. [10]. This study was part of their PhD thesis and supported by Novartis Animal Health. The study was a randomized, double-blind cross-over design; dogs received clomipramine for 4 weeks, had a 2-week washout period, and then received placebo for 4 weeks (n=27) OR 4 weeks placebo, 2-week washout, 4 weeks clomipramine (n=24).
Efficacy was assessed by owners’ answers to two questions: (1) “How bad is the behavior right now” (1=extremely bad to 5=not bad at all) and (2) “Overall how would you rate the behavior over the past 5 days” (0=no “behavior” to 10=worst ever).
On the basis of question 1, dogs on clomipramine were 4 times more likely to be categorized as “better” and on the basis of question two dogs were 3.6 times more likely to be categorized as “better.” While the assessment of behavior and methods was thorough and extensive, the assessment of efficacy appears superficial. The authors conclude, “results suggest that clomipramine was effective in dogs with canine compulsive disorder 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 canine compulsive disorder.”
Separation Anxiety
In 1999, Podberscek et al. evaluated the efficacy of clomipramine on separation anxiety in a randomized controlled double-blind study [11]. Dogs with signs of separation anxiety were referred to a behavior clinic. The study design was similar to that of the CLOCSA Study group [6-8] with three groups; A=placebo BID (n=15), B=clomipramine 0.5-1 mg/kg BID (n=17), C= clomipramine 1-2 mg/kg BID (n=17).
The study lasted 8 weeks and all dogs received behavior modification. A variety of separation anxiety behaviors were assessed; just before the owner left, when the dog was left for the day and when the dog was left to sleep alone. Frequencies of separation-related behaviors were rated on a 5-point scale (0=never to 5=always). General and attachment behaviors were also investigated. Owners completed questionnaires 2, 5, and 9 weeks after the baseline questionnaire.
Of note, there was a significant difference in age and onset of separation anxiety behaviors between groups, such that dogs in group C were younger than groups A and B; and dogs in groups B and C developed separation anxiety behaviors earlier than group A. There were also significant differences in some baseline behaviors between groups. This is important because there is variability in the groups before the trial was started. Only one separation anxiety-related behavior (shivering/shaking when left alone) showed a significant improvement 1 week after treatment, and the authors attribute this to chance.
The null hypothesis (behavior modification alone = no improvement in separation anxiety behaviors) was rejected as most separation anxiety-related behaviors in group A (placebo) improved. The authors conclude that clomipramine in conjunction with behavior modification was no more effective than placebo with behavior modification in treating separation anxiety; however, this interpretation is limited by the variability of the groups prior to the onset of the study. The authors state their study shows the importance of behavior modification in the treatment of separation anxiety. They suggest that methodological differences between their study and the CLOSA studies [6, 7] may account for the lack of effect. They suggest, without evidence, that their evaluation of effect (1-5, never to always) was “more precise” than that used in the CLOCSA studies (no, little, moderate, or much improvement or cured). They do acknowledge that the larger number of dogs in the CLOCSA study may have allowed the detection of minor effects.
Obsessive-Compulsive Disorder
In 2001, Seksel and Lindeman [12] studied the effect of clomipramine on the treatment of obsessive-compulsive disorder (n=9), separation anxiety (n=14), and noise phobia (n=1) in 24 dogs. Five dogs had multiple behavioral diagnoses. The behavioral complaint was present from 10 days to 7 years 7 months. Dogs received behavior modification and clomipramine (1-2 mg/kg BID) for at least a month or until behavior was reduced. Success was defined as, “elimination,” or “reduction,” of clinical signs to a level acceptable to the owner. When compared to the initial assessment, signs were rated as: newly appeared, worsened, unchanged, slightly, moderately, or largely improved/disappeared. This study is hampered by the small number of dogs in each group, multiple behavioral diagnoses, and extremely wide time range of the presence of behavioral signs. Despite these issues, clomipramine appeared useful in ameliorating signs of separation anxiety.
Transport Fear
In 2006, Frank et al. published a paper on the effect of clomipramine on transport fear and anxiety in 24 purpose-bred Beagles [13]. One dog was excluded for “uncooperative behavior” (and replaced with a “suitable dog”). It should be noted that Beagles are social and were selected by humans to work in groups. Purpose-bred laboratory Beagles are, instead, selected for placid temperament, sociability, and size – they do not represent “generic dogs,” or the breed in either hunting or pet home situations.
Cortisol was measured before and after transport and a video camera was installed in the transport vehicle. Clomipramine was administered 3 days prior to travel, the day of travel, and 3 days post travel, in a “switch back design” (so that half the dogs in each transport received clomipramine). There were 8 groups of three same-sex dogs. Dogs were transported on three different occasions and the duration of travel was an hour. Scan sampling was used to capture behaviors. Postures and activities were recorded as “state” and reported as a percentage of observation time, and “events” were reported in terms of frequency of occurrence.
When compared to pre-transport cortisol, ground transport increased cortisol levels in both groups. The authors report that the increase in cortisol was significantly lower in the clomipramine group (pre 41.7 ± 20.1 to post 224.6 ± 110 nmol/L) when compared to placebo (36.2 ± 19.4 to 239.6 ± 90.4 nmol/L). While the lower increase in cortisol in the clomipramine group may be statistically different, it may not be biologically relevant. No differences in behavior were detected between groups. Average heart rate during transport was reported to be significantly different between groups (clomipramine = 117 bpm; placebo = 125.6 bpm), however, neither pre- or post-transport heart rate nor standard deviations were reported. The medication protocol is unusual and authors do not provide the number of dogs per data point cited or number of samples per dog for any of the data.
Client Reports vs Behavioral Observations
What one notices about these studies, and studies of pet dog behavior in general, is the reliance on owners’ reports of behavior or behavior change. This can be particularly problematic when human recall is involved, especially if the events to be recalled had occurred some time ago. Human interpretation of scales (e.g. 0=no problem to 5=huge problem) varies, so what might be mild behavior to one human might be moderate to another. We also need to consider the placebo effect and the humans’ biases, all of which can impact the reporting of behaviors.
So, does this mean we should throw out all these studies?? Not really, we have some useful information on the safety and efficacy of clomipramine as well as the clients’ perceptions of behavior. The other option for studying behavior is direct or video observation of the animals to be studied. This approach (ethology = the study of animal behavior) has been extensively used to study wildlife as well as domestic animals. While this seems like an ideal way to evaluate behavior it is time, personnel, and financially expensive.
Separation Anxiety Video Study
The study by Cannas et al. videotaped the behavior of 23 dogs diagnosed with separation anxiety before and after treatment with clomipramine [14]. The diagnosis of separation anxiety was confirmed by filming the dogs’ behaviors while home alone. Inclusion criteria included two behaviors compatible with separation anxiety, or 15 minutes of vocalization, or “destruction of exits.” All dogs received clomipramine (initial dose 1 mg/kg BID for one week, then increased to 2 mg/kg BID).
Dogs were then filmed 7, 14, 28, and 56 days after the start of treatment with clomipramine. Owners were instructed to turn on the camera before leaving; video length varied from 22 to 90 minutes. Owners filled out a multiple-choice questionnaire covering demographic, environmental, and behavioral aspects of their dog. Behavior modification was limited to clarifying human-dog communication and rewarding spontaneously offered desired behavior.
An ethogram of behaviors was developed, and behaviors “were recorded in terms of duration of occurrence or frequency. Behaviors recorded as states were exploration, locomotion, circling, passive behavior, orientation to environment, scratching, oral behavior, play, panting, grooming, ears back, barking, whining, howling, trembling, paw up, and not visible.” In addition, yawning, lip licking, and elimination were recorded as events. Inter-rater reliability was 89%,” meaning, 89% of the time different individuals observed and classified the same behavior in the same way.
Unfortunately, only three video time points (time 0, 7, 14) were analyzed, because 5 dogs were not filmed after day 14 and 3 dogs needed an increase in clomipramine dose. Data are expressed as changes in duration (%) at different time points, so if the medication was providing beneficial behavioral effects, you would expect to see increased duration of passive behaviors and decreased duration of active separation anxiety behaviors.
Passive behaviors increased with clomipramine, while barking, whining, and panting decreased [Figure 1]. The authors state, “questionnaire studies based exclusively on owner reports may underestimate the presence or absence of some signs of anxiety, as well as their severity, and may lead to errors in diagnosis or assessing pharmacological treatment response.“
They also state, “The study showed that clomipramine has efficacy in reducing signs of anxiety in dogs and improving their overall welfare. Additionally, no adverse reaction to clomipramine was reported during the treatment period in all the dogs included in the study.” While both statements are likely true, this study suffers from a lack of placebo controls. (which the authors state would be unethical), small number of dogs, and the inability to analyze the final video time points. In addition, 20% of the videos were “missing the dog” due to dogs not being secured in a room or crate, suggesting that unseen behaviors during that time might have altered the frequency or duration of measured behaviors.
Videotaping the dog in the home environment for diagnosis of separation anxiety appears to be an excellent way to confirm the diagnosis. Despite the shortcomings of this study, the results agree with most of the other studies that clomipramine is safe and may be effective, especially when combined with behavior modification for the treatment of separation anxiety. In addition, this study shows the unintended consequences and complications that often arise when observing behaviors of dogs when the cooperation of the human involved is required.
Long-Game Medications
We have covered the common “long-game” medications used in veterinary medicine. The goal with these drugs is slow and steady improvement of behavioral issues with minimal side effects. Fluoxetine and clomipramine have both been tested for safety and efficacy in dogs, thus they are likely to be the first-choice behavioral medication in many situations. Behavior veterinarians may prescribe them less often, primarily because by the time humans and their dogs make a commitment to see a specialist, they have trialed many medications without success.
Next time we will cover the major, “game-changer,” medications.Those that act rapidly and can be useful for issues that are predictable as well as in conjunction with long-game medications. Finally, we will tackle the unusual medications used (uncommonly) for behavior issues in dogs.
*n,” means “number of dogs.”
**”BID” means “twice a day.”
[1] Crowell-Davis SL, Murray TF, de Souza Dantas LM. Veterinary Psychopharmacology. Wiley & Sons, Inc. 2019.
[2] Rapoport JL, et al. Treatment of canine acral lick an animal model of obsessive-compulsive disorder. Arch Gen Psych 49:517-521, 1992.
[3] Reisner IL. Diagnosis of Canine Generalized Anxiety Disorder and Its Management With Behavioral Modification and Fluoxetine or Paroxetine: A Retrospective Summary of Clinical Experience (2001-2003). J Am Hops Assn. 39:512, 2003.
[4] Da Silva-Monteir JP, et al. The use of sertraline in dogs presenting compulsive behavior: a four-case series. J Vet Behav 78:82, 2022.
[5] Nixon SJ & Keksel K. Treatment of a case of anxiety disorder with an adverse response to medication. J vet Behav. 64-65: 25-32, 2023.
[6] Simpson B. The CLOCSA Study Group Clomipramine Proc 1st Int Conf Vet Behav Med 1997.
[7] King JN, et al. Treatment of separation anxiety in dogs with clomipramine: results from a prospective, randomized, double-blind, placebo-controlled, parallel-group, multicenter clinical trial. Appl Anim Behav Sci 67:255-275, 2000.
[8] King JN, et al. Results of a follow-up investigation to a clinical trial testing the efficacy of clomipramine in the treatment of separation anxiety in dogs. Appl Anim Behav Sci 89:233-242, 2004.
[10] Hewson JA, et al. Efficacy of clomipramine in the treatment of canine compulsive disorder. J Am Vet Med Assn. 213:1760-1766, 1998.
[11] Podberscek AL, et al. Evaluation of clomipramine as an adjunct to behavioural therapy in the treatment of separation-related problems in dogs. Vet Rec 145:365-369, 1999.
[12] Seksel K & Lindeman MJ. Use of clomipramine in treatment of obsessive-compulsive disorder, separation anxiety and noise phobia in dogs: a preliminary, clinical study. Aust Vet J. 79:252-256, 2001.
[13] Frank et al. Placebo-controlled double-blind clomipramine trial for the treatment of anxiety or fear in beagles during ground transport. Can Vet J 47:1102-1108, 2006.
[14] Cannas S et al. Video analysis of dogs suffering from anxiety when left home alone and treated with clomipramine. J Vet Behav 9:50-57, 2014.
Crowell-Davis SL, Murray TF, de Souza Dantas LM. Veterinary Psychopharmacology. Wiley & Sons, Inc. 2019.
Lana Kaiser MD, DVM
Dr. Kaiser graduated from the Michigan State College of Human Medicine as a Board Certified (human) Internist, where she is also an Emeritus Professor in the Departments of Physiology and Medicine. A graduate of the College of Veterinary Medicine MSU, she was trained as a biomedical researcher with a focus on cardiovascular pathophysiology and parasitology and is also interested in the scientific study of the interaction between humans and animals and has published in both scientific disciplines. Lana has a mobile beef cattle practice, raises Maine-Anjou and Red Angus cattle on her farm in Mason, MI and consults for several national agricultural entities. A writer and lecturer on animal welfare, animal health, genetic defects and human-livestock interactions at the state and national levels, she is involved in issues of animal behavior and welfare and was a founding member of MSU's Human-Animal Bond Initiative and coordinator of MVMAs Annual Animal Welfare Conference and Animal Behavior Conference. She has been active in the MVMA Animal Welfare, Legislative and Food Animal Practice Committee and Dean Foods Animal Welfare Advisory Council. She enjoys training her Great Pyrenees, Belgian Tervuren, ancient Beagle, horse and occasional cow.
