Journal Pre-proof

Effect of fluoxetine at a dosage of 2-4 mg/kg daily in dogs exhibiting

hypersensitivity-hyperactivity syndrome, a retrospective study

Stephane Bleuer-Elsner , Gerard Muller , Claude Beata ,

Anna Zamansky , Nathalie Marlois

PII: S1558-7878(21)00043-5
DOI: https://doi.org/10.1016/j.jveb.2021.03.007
Reference: JVEB 1393

To appear in: Journal of Veterinary Behavior

Received date: 16 June 2019

Revised date: 30 March 2021
Accepted date: 30 March 2021

Please cite this article as: Stephane Bleuer-Elsner , Gerard Muller , Claude Beata ,
Anna Zamansky , Nathalie Marlois , Effect of fluoxetine at a dosage of 2-4 mg/kg daily in dogs
exhibiting hypersensitivity-hyperactivity syndrome, a retrospective study, Journal of Veterinary Behav-
ior (2021), doi: https://doi.org/10.1016/j.jveb.2021.03.007

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition
of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of
record. This version will undergo additional copyediting, typesetting and review before it is published
in its final form, but we are providing this version to give early visibility of the article. Please note that,
during the production process, errors may be discovered which could affect the content, and all legal
disclaimers that apply to the journal pertain.

© 2021 Published by Elsevier Inc.

Highlights

 Hypersensitivity-Hyperactivity (HSHA) syndrome provides a useful model for

studying hyperactive dogs.
 Fluoxetine at a dosage of 2 to 4 mg/kg PO q. 24 h provided improvement of the
symptoms of severe HSHA for 44-68 of 89 dogs depending on sign assessed.
 Adverse events were reported for 54 of 89 dogs (61%).
Effect of fluoxetine at a dosage of 2-4 mg/kg daily in dogs exhibiting hypersensitivity-
hyperactivity syndrome, a retrospective study.

Stephane Bleuer-Elsner · Gerard Muller · Claude Beata · Anna Zamansky ·Nathalie Marlois

S. Bleuer-Elsner Research Associate in Animal Technology Lab, University of Haifa, Israel

Veterinary Hospital, Tel Aviv, Israel.
E-mail: vetbehavior.il@gmail.com , G. Muller Veterinarian Lille, C.Beata Veterinarian Toulon,
Anna Zamansky Department of Information Systems University of Haifa, N. Marlois
Veterinarian Amberieu en Bugey

Abstract

Hyperactivity in dogs is increasingly linked with human Attention Deficit Hyperactivity

Disorder (ADHD). The French veterinary psychiatry community has proposed a precise
definition of an ADHD-like syndrome in dogs called Hypersensitivity-Hyperactivity syndrome
(HSHA). Dogs suffering from severe HSHA present three main symptoms: hypermotricity,
lack of satiety, and shorter sleep duration with normal cycles. Because these symptoms
suggest involvement of the serotonergic pathway, fluoxetine is the main medication
proposed by the French veterinary psychiatry community to treat these dogs. We present
the results of a retrospective study of dogs suffering from severe HSHA syndrome and
treated with fluoxetine at dosages of 2 mg/kg/day and above. Ninety-eight dogs’ file were
studied with the help of 23 French veterinary behaviorists and 89 dogs were included in the
final sample. The three main symptoms of severe HSHA and five main adverse effects were
evaluated according to the dog’s file at the first consultation and at a follow-up four to eight
weeks later. Eighty-eight dogs showed at least some degree of improvement. Improvement
was quite high or perfect for 48 of the 89 dogs in motricity, 63 of the 89 in sleep, and 44 of
the 89 in satiety. Fifty-four of the 89 dogs (61%) showed adverse events at various levels,
with very few dogs experiencing severe adverse effects. In six cases the dosage was reduced
due to adverse effects but remained at least 2mg/kg. Given the positive reactions to the
treatment within our sample, fluoxetine at a dosage of 2 to 4 mg/kg PO q. 24 h may be
considered as a safe and effective treatment for some dogs suffering from severe HSHA.
Further prospective studies also using a lower range of dosages are required for validation.
Keywords

Hypersensitivity-Hyperactivity syndrome · Dog · Fluoxetine · ADHD

Background

Barcus et al. (1980), who was working on hyperactive children, was the first to propose a
dog model for Attention Deficit Hyperactivity Disorder (ADHD). A more recent study by
Puurunen et al. (2016) showed that dogs may spontaneously develop ADHD-like behavior
with hyperactivity, impulsivity and inattention. Veterinarians are regularly confronted with
dogs that exhibit ADHD-like behavior, where the dogs experience difficulty ending
behavioral sequences and hyper-sensitivity to stimuli in their environment. These dogs may
be difficult to live with in terms of home destruction, restlessness, lack of self-control,
including sometimes with injuries, and difficulties in learning. Such behavior can impair the
dog’s welfare and may pose a significant therapeutic challenge.

No clear consensus for the diagnosis of ADHD or ADHD-like behavior exists in either human
or veterinary medicine. Despite tools like the Diagnostic and Statistical Manual (American
Psychiatric Association, 2017), the International Classification of Diseases (ICD) 10 (World
Health Organization, 2012), or recognition by the French Haute Autorité de Santé (Haute
Autorité de Santé, 2014) there is no general agreement on how to diagnose attention deficit
hyperactivity disorder in humans (Mahajnah et al., 2016). The situation is similar in
veterinary medicine. Different signs with different names are used to describe ADHD-like
behavior in dogs, including hyperkinesis (Corson et al., 1971; Campbell, 1973),
hypermotricity, overactivity, and impulsivity ( Vas et al., 2007; Landsberg et al., 2012;
Overall, 2013).

The French veterinary psychiatry community (Mège et al., 2003) proposes a description of
an ADHD-like syndrome in dogs, which they call Hypersensitivity-Hyperactivity syndrome
(HSHA). Diagnosis of HSHA is based primary on exclusion of other causes (Marlois et al.,
2013), such as other developmental behavior disorders, emotional or mood disorders,
organic disease (neurological disorders, pain), or overactivity in a normal dog triggered by
understimulation or insufficient exercise. Vas et al. (2007) and Lit et al. (2010) provide data
about ADHD-like signs in dogs with active-impulsive and inattentive individuals. Masson et
al. (2018) proposed a complementary method of evaluation of the dogs suffering from
HSHA. According to the French veterinary psychiatry community severe HSHA dogs exhibit 3
symptoms: hypermotricity, lack of satiety, and shorter sleep duration with normal cycles.

Sleep perturbation and appetite deregulation are described in humans affected by ADHD
(Lycett et al., 2014; Hvolby, 2015; Lunsford-Avery et al., 2016; Kaisari et al., 2017; Kurz et al.,
2017). A dog’s normal sleep duration is around 12 to 16 hours per day (Lucas et al., 1977;
Zanghi et al., 2013), though sleep pattern and duration may be influenced by age or feeding
frequencies.

Stimulant medications (methylphenidate) are the most frequent medications prescribed in

human medicine (Bradley, 1937; Spencer et al., 1996; Cortese et al., 2018). In veterinary
medicine, methylphenidate is used to diagnose or treat hyperactivity (Lindsay, 2008;
Overall, 2013).

Use of fluoxetine as a treatment for human patients with ADHD is common and 60% of
patients experience at least moderate improvement with minimal adverse events
(Barrickman et al., 1991) and no modification of their appetite or weight. Fluoxetine is also
described as able to normalize the frontal lobe dysfunctions associated with ADHD
(Chantiluke et al., 2015; Carlisi et al., 2016).

In a study about the prescribing habits of 86 small animal veterinarians (Kaur et al., 2016),
only 2% of the participants reported using fluoxetine on hyperactive dogs, but it’s unclear
how cases were diagnosed, what other medication choices might have been or what the
rationale for choice was. Clinical studies of fluoxetine use in dogs for diagnoses other than
hyperactivity use a range of daily dosages from 0.5 to 2 mg/kg (Dodman et al., 1996;
Landsberg et al., 2008; Irimajiri et al., 2009; Chutter et al., 2019). The main adverse effects,
which are not common, are anorexia or decreased appetite, vomiting, apathy, diarrhea,
tremor, aggression, constipation, fear, and weight loss. Higher dosages from 2 to 4
mg/kg/day have been recommended in the treatment of severe HSHA (Mège et al., 2003;
Marlois et al., 2013), particularly for dogs showing a high level of hypermotricity and
impulsivity.
In this study we used a retrospective design to examine the effect of treatment with
fluoxetine at dosages ≥ 2mg/kg/day on three signs found in dogs suffering from severe
HSHA: hypermotricity, estimated duration of sleep below 8 hours per day, and lack of
satiety.

Materials and Method

In order to evaluate the efficiency and the adverse effects of fluoxetine at dosages ≥
2mg/kg/day, a questionnaire was sent to 152 veterinarians (identified through a mailing list)
who had graduated from the National Veterinary Schools of France with a Diploma in
Behavioral Veterinary Medicine (Diplôme de vétérinaire comportementaliste des écoles
vétérinaires françaises) or Veterinary Psychiatry (Diplôme universitaire de psychiatrie
vétérinaire). Each participating veterinarian completed one questionnaire per dog
(Appendix 1) according to the information recorded in the veterinarian’s last files of the
dogs diagnosed with severe HSHA.

Dogs were included in the study if the following criteria appeared in their files:

- Diagnosis of severe HSHA, including the three prerequisite symptoms:

hypermotricity, lack of satiety, and estimated duration of sleep below 8 hours per
day. These symptoms were evaluated by the veterinarian according to the standard
techniques of a consultation of behavioral medicine. Hypermotricity is generally
assessed during the consultation by observing the spontaneous movements of the
dogs. A dog who explores again and again the room in a compulsive way, has
tendency to explore high places like tables or workplans of the consultation room
and has difficulties to lay down and rest is suspected of hypermotricity.

Hypermotricity is also assessed by the reactions of the dog when offering a treat or a
toy. The level of excitement and impulsiveness that are triggered by the treat or the
toy, the dog’s capacity to wait before mouthing the treat or the toy, and the dog’s
tendency to chew and even destruct the toy are additional signs that help to assess
the dog’s motricity.
 Sleep and lack of satiety is generally assessed during the owner interview. Lack of
sleep during the day and frequent waking up and movements during the night
generally lead to a count of less that 8 hours of sleep per 24 hours.
Lack of satiety is generally reported by dogs’ owners, when the dogs never leave
their food bowl before emptying it, dogs that eat very quickly and are looking for
food between their meals as they can’t reach the feeling of satiety.

- Treatment with fluoxetine with a dosage ≥ 2 mg/kg.

- Fluoxetine is the only medication.

- Dogs’ owner attended at least two consultations, one on the day of diagnosis and a
follow-up four to eight weeks later.

Evolution of signs/symptomology: The questionnaire asked the veterinarians to evaluate for

each included dog and according to his medical file the evolution of the three symptoms
between the first consultation and the follow-up consultation. The veterinarian had to
assess the evolution of each symptom by using a scale from 0 to 4, where 0 represents no
improvement, 1 some improvement, 2 moderate improvement, 3 large improvement, and 4
resolution of signs. Worsening was also assessed by a yes/no question. The assessment of
the symptoms during the follow-up consultation follows the same principles than the
assessment during the first consultation. Motricity is generally assessed according to the
dog’s spontaneous movements during the consultation, capacities of laying down and
resting, level of impulsiveness and excitement with a treat or a toy. Sleep and satiety are
assessed according to the owner’s report about existence of sleep phases during the day
and quieter nights, less excitement for food and quieter food intake.

Adverse effects: The questionnaire asked the veterinarians to evaluate for each dog and
according to his medical file the adverse events of the medication during treatment. Five
main adverse events were studied: decreased appetite, weight loss, fatigability that is, loss
of strength during walks and play, sedation, namely, indifference to the environment, and
tremors.
Each adverse effect was assessed on a scale from 0 to 4, where 0 = not detected, 1 =
minimal, 2 = moderate (no dosage adjustment was needed), 3 = moderately severe, and 4
severe (for 3 and 4 dosage was adjusted when needed). Reports included the occurrence of
other adverse events or non-desired behavioral changes, any dosage’s modification
requirement, and any treatment interruption.

Statistics were performed by the software IBM® SPSS® Statistics.

Results

Description of the studied population

The survey yielded 98 dogs files from 23 veterinarians, but six did not meet the requisite
criteria or were incomplete. Of the remaining 92 dogs, three were dropped from the
analysis since their fluoxetine dosage was reduced to below 2 mg/kg per day because they
were too much sedated (in two cases it was reduced to 1.67 mg/kg, and in one to 1.88
mg/kg). The final sample was 89 dogs.

Six dogs had their fluoxetine dosage reevaluated due to adverse events, but the final dosage
remained at 2mg/kg/day or above, so they were kept for the final analysis.

In the final sample (Appendix 2) the sex ratio is 1.78/1, with 57 males for 32 females. Thirty-
five dogs were neutered. The dogs’ ages at the first consultation ranged from three months
to nine years, with an average of one year and nine months. The dogs ranged in weight from
1.4 kg to 41 kg, with an average of 22 kg. The daily fluoxetine dosage used ranged from 2 to
4.4 mg/kg, with an average dosage of 3.05 mg/kg and a median of 3.00 mg/kg.

Efficacy of treatment

Two of the 89 dogs showed complete resolution of the signs (scores of 4 for each sign). One
dog showed no improvement at all, with three scores of 0. The remaining 86 dogs showed
various levels of improvement. The participating veterinarians indicated that the condition
of 4 dogs worsened: One dog developed additional dominance aggression that was still
difficult to manage after 8 weeks, the barking of one dog increased and was still difficult to
manage after 8 weeks, and two dogs developed fear.
Table 1 summarizes the treatment’s efficacy on the 3 signs. The largest effect was for sleep
with a mean of 2.81/4. For motor activity the mean was 2.52/4 and for satiety, 2.21/4. The
global mean reaches 2.51.

Table 1: Treatment’s Efficacy

Sleep Satiety Motor activity Global
Mean 2.81 2.21 2.52 2.51
Median 3 2 3 2.67
Sample 0.9 1.49 0.71 0.64
Variance
Range 4 4 4 4
Minimum 0 0 0 0
Maximum 4 4 4 4
Count 89 89 89 89

The dosage of fluoxetine was tested against the improvement’s score for each sign of HSHA.
There is no significative correlation between the fluoxetine dosage and any of them. Sleep
improvement (Pearson: r=0.14, p=0.18), satiety improvement (Pearson: r=0.01, p=0.91) and
motor activity improvement (Pearson: r=0.05, p=0.63) are not significantly correlated to the
fluoxetine dosage between 2 to 4 mg/kg.

Adverse events

Forty-one dogs out of 89 experienced some level of adverse events. 39/89 dogs were not
affected by one of the 5 studied adverse effects, and 9/89 were highly or severely affected.
Table 2 summarizes the adverse events of the treatment. The mean for each adverse effect
remains under 1 out of 4. The highest mean is 0.85 for lack of appetite the lowest is 0.18 for
tremors. The global means of adverse effects is 0.42.
 Table 2: Treatment’s adverse effects
Lack of Fatigability Sedation Tremors Weight Global
appetite loss
Mean 0.85 0.55 0.34 0.18 0.19 0.42
Median 0 0 0 0 0 0.2
Sample 1.22
Variance 0.57 0.54 0.33 0.29 0.25
Range 4 3 4 3 3 2
Minimum 0 0 0 0 0 0
Maximum 4 3 4 3 3 2
Count 89 89 89 89 89 89

Fluoxetine dosage was tested against the severity of the adverse effects. There is no
significative correlation in this study between the fluoxetine dosage and the severity of any
adverse effect. Lack of appetite (Pearson: r=0.08, p=0.41), fatigability (Pearson: r=0.08,
p=0.46), sedation (Pearson: r=0.09, p=0.39), tremors (Pearson: r=0.06, p=0.60) and weight
loss (Pearson: r= 0.06, p=0.54) are not significantly correlated to the fluoxetine dosage
between 2 to 4 mg/kg.

Correlations between adverse events and improvement

Some improvement may be interpreted as the results of the adverse events’ expression: the
sleep improvement may be due to sedation and the satiety improvement may be due to the
lack of appetite. For these reasons sleep improvement was tested against sedation and
satiety improvement against lack of appetite.

No correlation was found between sleep improvement and sedation (Pearson: r=0.09,
p=0.39). The reported improvement of sleep is independent from the adverse effect
sedation. This result suggests that the treatment provides a substantial modification of the
amount of sleep and not just a sedation of the dog.
A correlation was found between satiety improvement and lack of appetite (Pearson: r=0.3,
p=0.004). This result suggests that a lack of appetite may be an adverse effect but also a
positive side effect of the treatment in dogs exhibiting a lack of satiety.

Discussion:

The three signs of severe HSHA on which this study focuses – hypermotricity, reduced sleep
duration and lack of satiety – seem to implicate the serotonergic system: serotonergic
projections to the basal ganglia play a role in motion control, projections to the
hypothalamus may regulate appetite and eating behaviors, and projections to the brainstem
sleep centers regulate sleep, especially slow-wave sleep. Therefore, it was reasonable to
predict that fluoxetine may be indicated for dogs showing signs of severe HSHA as it is
described in the literature with dosages from 2 to 4 mg/kg PO q. 24 h (Mège et al., 2003;
Masson et al., 2018). Our findings show that dosages of 2-4 mg/kg po q. 24 h are associated
with improvement in the three central signs of severe HSHA.

The results show that 41/89 (46%) dogs experienced some level of adverse events, and 9/89
(10%) were highly or severely affected. Simpson et al. (2007) reported adverse effects for a
1-2 mg/kg po q. 24 h dosage of fluoxetine. Our main sign, reduced appetite, was found in
43/89 dogs (48.3%), compared with 34/117 dogs (29.1%) in Simpson et al., (2007). Since the
dogs in our study exhibited a lack of satiety as a key sign, the greater frequency of this
adverse effect at high dosages could be considered as a beneficial side effect.

In our study 12/89 (13.5%) of the dogs sustained weight loss ≥ 5%. Those results are quite
similar to Simpson et al. (2007) findings where 32% of the fluoxetine-treated dogs and 16%
of placebo-treated dogs lost 5% or more of their initial body weight.

Fluoxetine may be found in several countries under the commercial name Reconcile®. This is
the only authorized fluoxetine’s use in veterinary medicine by the European Medicines
Agency and the U.S Food and Drug Administration for the indication of separation anxiety.
Fluoxetine use in France is extra-label since the Reconcile® is no longer available and use for
HSHA syndrome at any dosage is extra-label.

Limitations and further studies

The retrospective protocol used for this study shows weaknesses in the data collection.
Since there is no standardized way of collecting information the likelihood that dogs’ files
show all the necessary data was slim. Therefore, the participating veterinarians were asked
to include only files where the relevant information was complete. This may be the reason
why only 23 only out of 152 veterinarians delivered complete information (of these, 6 cases
were incomplete and therefore rejected). Furthermore, the subjectivity of the dogs’ owner
during the interview and the veterinarian’s subjectivity in assessing the dogs’ behaviors
influenced the assessments of improvements and adverse effects.

Worsening was assessed according to a yes/no question and therefore was not included in
the scale used for assessing the evolution of the 3 main symptoms of HSHA. Nevertheless,
only 4 dogs were mentioned with worsening: Two dogs developed fears, one dog,
aggression, and another dog severe barking. The reported cases of worsening didn’t directly
involve activity, sleep, or appetite. They might be side effects, adverse effects, or indirect
expression of lack of sleep or lack of activity control.

The population studied was not sex-balanced, with a sex ratio of 1.78:1 (57 males for 32
females). The sampling method might have had a significant influence on this ratio.
Nevertheless, it is interesting to note that such gender heterogeneity is often found in
human ADHD (Ramtekkar et al., 2010), with males showing more impulsivity-hyperactivity
signs. A recent study in Australia found that male dogs were generally at greater risk than
females for a number of behavior problems, in particular coprophagia, house soiling and
boisterous behavior (Barrickman et al., 1991; Col et al., 2016). Additional studies should be
designed to minimize any effect of sex.

The results of this study pertain only for the first 8 weeks of treatment. Further studies are
required to evaluate the long-term effects of 2-4 mg/kg po q. 24 h dosage of fluoxetine.

This type of retrospective study, based on clinical reports, is inherently limited. A recent
different retrospective study tend to show contrasting results than those presented here.
Chutter et al. )2019) found that the positive effects of fluoxetine on various behavioral
disorders was better when used at a dose ranged from 0.5-0.99 mg/kg and 1.0 to 1.49
mg/kg than when used at a higher dosages of 1.5 to 1.99 mg/kg. Any study of true dosage
effects would need to be randomized, double-blinded and placebo controlled, with 2
dosages (fluoxetine at 2-4 mg/kg/day and 0.5-1.5 mg/kg/day). The data collection would
also need to be standardized and to include as far as possible objective measurements as
suggested in recent studies (Bleuer-Elsner et al., 2019). It’s possible that the same or better
effects could be achieved at a lower dosage

Conclusion

This study showed a significant beneficial effect of 2 to 4 mg/kg/day of fluoxetine on the

three main signs of dogs affected by severe HSHA syndrome after four to eight weeks of
treatment. Benefits were greater for hypermotricity and sleep, but the influence on satiety
was also significant.

Acknowledgements

We thank the following for their contributions to this research: Zoopsy (the French
Association of Zoopsychiatry), Guillaume Sarcey, Claude Beata, Gerard Muller, Muriel
Marion, Nicolas Massal, Dominique Lachapele, Philippe Passelegue, Jasmine Chevalier,
Joelle Hofmans, Sylvia Masson, Vincent Dethier, Francois Laurent, Melanie Heuschen, Anne-
Marie Villars, Jenny Hameurt, Oriane Molko, Gerard Noyer, Sabine Faget, Catherine Mege,
Florence Napierala, Virginie Beugnet-Villeneuve, Coralie Blanc, Clarisse Delauney, Mary
Deluce, Anna Zamansky and Dirk van der Linden.

Authorship statement

The research was conceived by G. Muller, S. Bleuer-Elsner, N. Marlois and C. Beata. The
experiments were designed by G. Muller, S. Bleuer-Elsner, N. Marlois, and C. Beata. The
experiments were performed by N. Marlois, S. Bleuer-Elsner, G. Muller. The data were
analyzed by S. Bleuer-Elsner. The paper was written by S. Bleuer-Elsner, N. Marlois, A.
Zamansky.
Conflicts of Interest
None
References

American Psychiatric Association, 2017. Diagnostic and Statistical Manual of Mental

Disorders (DSM–5). American Psychiatric Association, Arlington.
Barcus, R., Schwebel, A. I., Corson S. A., 1980. An Animal Model of the Hyperactive-Child
Syndrome Suitable for the Study of the Effects of Food Additives. Pav. J. Biol. Sci. 15,
183–187.
Barrickman, L., Noyes, R., Kuperman, S., Schumacher, E., Verda, M., 1991. Treatment of
ADHD with fluoxetine: A preliminary trial. J. Am. Acad. Child Adolesc. Psychiatry
30, 762–767.
Bleuer-Elsner, S., Zamansky, A., Fux, A., Kaplun, D., Romanov, S., Sinitca, A., Masson, S., van
der Linden, D., 2019. Computational Analysis of Movement Patterns of Dogs with
ADHD-Like Behavior. Animals 9, 1140.
Bradley, C., 1937. The behavior of children receiving Benzedrine. Am. J. Psychiatry 94, 577–
585.
Campbell, W.E., 1973. Behavioral modification of hyperkinetic dogs. Mod. Vet. Pract. 54,
49–52.
Carlisi, C.O., Chantiluke, K., Norman, L., Christakou, A., Barrett, N., Giampietro, V., Brammer,
M., Simmons, A., Rubia, K., 2016. The effects of acute fluoxetine administration on
temporal discounting in youth with ADHD. Psychol. Med. 46, 1197–1209.
Chantiluke, K., Barrett, N., Giampietro, V., Santosh, P., Brammer, M., Simmons, A., Murphy,
D.G., Rubia, K., 2015. Inverse fluoxetine effects on inhibitory brain activation in non-
comorbid boys with ADHD and with ASD. Psychopharmacology 232, 2071–2082.
Chutter, M., Perry, P., Houpt, K., 2019. Efficacy of fluoxetine for canine behavioral disorders.
J. Vet. Behav: Clin. Appl. Res. 33, 54–58.
Col, R., Day, C., Phillips, C.J.C., 2016. An epidemiological analysis of dog behavior problems
presented to an Australian behavior clinic, with associated risk factors. J. Vet. Behav:
Clin. Appl. Res. 15, 1–11.
Corson, S.A., Corson, E.O., Kirilcuk, V., Arnold, L.E., 1971. Tranquilizing effects of d-
amphetamine on hyperkinetic untrainable dogs. In: Fed. Proc., 30, p. 206.
Cortese, S., Adamo, N., Del Giovane, C., Mohr-Jensen, C., Hayes, A.J., Carucci, S., Atkinson,
L.Z., Tessari, L., Banaschewski, T., Coghill, D., Hollis, C., Simonoff, E., Zuddas, A.,
Barbui, C., Purgato, M., Steinhausen, H.-C., Shokraneh, F., Xia, J., Cipriani, A., 2018.
 Comparative efficacy and tolerability of medications for attention-deficit
hyperactivity disorder in children, adolescents, and adults: a systematic review and
network meta-analysis. Lancet Psychiatry 5, 727–738.
Dodman, N.H., Donnelly, R., Shuster, L., Mertens, P., Rand, W., Miczek, K., 1996. Use of
fluoxetine to treat dominance aggression in dogs. J. Am. Vet. Med. Assoc. 209, 1585–
1587.
Haute Autorité de Santé, 2014. Conduite à tenir en médecine de premier recours devant un
enfant ou un adolescent susceptible d’avoir un trouble déficit de l’attention avec ou
sans hyperactivité [www. Document].
URL https://www.has-sante.fr/portail/jcms/c_1362146/fr/conduite-a-tenir-en-
medecine-de-premier-recours-devant-un-enfant-ou-un-adolescent-susceptible-d-
avoir-un-trouble-deficit-de-l-attention-avec-ou-sans-hyperactivite.
Hvolby, A., 2015. Associations of sleep disturbance with ADHD: implications for treatment.
Atten. Defic. Hyperact. Disord. 7, 1–18.
Irimajiri, M., Luescher, A.U., Douglass, G., Robertson-Plouch, C., Zimmermann, A., Hozak, R.,
2009. Randomized, controlled clinical trial of the efficacy of fluoxetine for treatment
of compulsive disorders in dogs. J. Am. Vet. Med. Assoc. 235, 705–709.
Kaisari, P., Dourish, C.T., Higgs, S., 2017. Attention Deficit Hyperactivity Disorder (ADHD) and
disordered eating behaviour: A systematic review and a framework for future
research. Clin. Psychol. Rev. 53, 109–121.
Kaur, G., Voith, V.L., Schmidt, P.L., 2016. The use of fluoxetine by veterinarians in dogs and
cats: a preliminary survey. Vet. Rec. Open. 3.1, e000146.
Kurz, S., Schoebi, D., Dremmel, D., Kiess, W., Munsch, S., Hilbert, A., 2017. Satiety regulation
in children with loss of control eating and attention-deficit/hyperactivity disorder: A
test meal study. Appetite 116, 90–98.
Landsberg, G.M., Melese, P., Sherman, B.L., Neilson, J.C., Zimmerman, A., Clarke, T.P., 2008.
Effectiveness of fluoxetine chewable tablets in the treatment of canine separation
anxiety. J. Vet. Behav: Clin. Appl. Res. 3, 12–19.
Landsberg G.M., Hunthausen W., Ackerman L., 2012. Behavior Problems of the Dog and Cat,
3rd Edition. Saunders Ltd.
Lindsay, S.R., 2008. Handbook of Applied Dog Behavior and Training. Blackwell Publishing.
Lunsford-Avery, J.R., Krystal, A.D., Kollins, S.H., 2016. Sleep disturbances in adolescents with
ADHD: A systematic review and framework for future research. Clin. Psychol. Rev.
50, 159–174.
Lycett, K., Mensah, F.K., Hiscock, H., Sciberras, E., 2014. A prospective study of sleep
problems in children with ADHD. Sleep Med. 15, 1354–1361.
Mahajnah, M., Sharkia, R., Shorbaji, N., Zelnik, N., 2016. Clinical profile of attention deficit
hyperactivity disorder: Impact of ethnic and social diversities in Israel. Isr. Med.
Assoc. J. 18, 322–325.
Marlois, N., Mège, C., 2013. Tout ce qui bouge n’est pas HS/HA. Prat. Vet. 103, 136–140.
Masson, S., Gaultier, E., 2018. Retrospective study on hypersensitivity-hyperactivity
syndrome in dogs: long-term outcome of high dose fluoxetine treatment and
proposal of a clinical score. Dog Behav. 4, 15–32.
Mège, C., Béata, C., Beaumont-Graff, E., Diaz, C., Habran, T., Marlois, N., Muller, G., 2003.
Pathologie comportementale du chien. Masson-AFVAC, Paris.
Overall, K.L., 2013. Manual of Clinical Behavioral Medicine for Dogs and Cats. Elsevier Health
Sciences, St. Louis.
Puurunen, J., Sulkama, S., Tiira, K., Araujo, C., Lehtonen, M., Hanhineva, K., Lohi, H., 2016. A
non-targeted metabolite profiling pilot study suggests that tryptophan and lipid
metabolisms are linked with ADHD-like behaviours in dogs. Behav. Brain. Funct. 12,
1–13.
Ramtekkar, U.P., Reiersen, A.M., Todorov, A.A., Todd, R.D., 2010. Sex and Age Differences in
Attention-Deficit/Hyperactivity Disorder Symptoms and Diagnoses: Implications for
DSM-V and ICD-11. J. Am. Acad. Child Adolesc. Psychiatry 49, 217-228.
Simpson, B.S., Landsberg, G.M., Reisner, I.R., Ciribassi, J.J., Horwitz, D., Houpt, K.A., Kroll,
T.L., Luescher, A., Moffat, K.S., Douglass, G., Robertson-Plouch, C., Veenhuizen, M.F.,
Zimmerman, A., Clark, T.P., 2007. Effects of reconcile (fluoxetine) chewable tablets
plus behavior management for canine separation anxiety. J. Vet. Pharmacol. Ther. 8,
18–31.
Spencer, T., Biederman, J., Wilens, T., 1996. Pharmacotherapy of attention-deficit
hyperactivity disorder across the life cycle. J. Am. Acad. Child Adolesc. Psychiatry 35,
409-432.
Vas, J., Topál, J., Péch, É., Miklósi, Á., 2007. Measuring attention deficit and activity in dogs:
A new application and validation of a human ADHD questionnaire. Appl. Anim.
Behav. Sci. 103, 105–117.
World Health Organization. (‎2015)‎. International statistical classification of diseases and
related health problems, 10th revision, Fifth edition, 2016. World Health Organization.
https://apps.who.int/iris/handle/10665/246208

Appendix 1: Survey’s questions

Dog’s Details
1- Dog's name
2- Age
3- Male/Female
4- Neutered (Yes/No)
5- Weight (in Kg)

Inclusion criteria
6- The dog exhibits hypermotricity (Yes/No)
7- The duration of the dog's sleep is less than 8 hours within 24 hours (Yes/No)
8- The dog lack of satiety (Yes/No)

Medication’s prescription details

9- Fluoxetine’s dosage prescript at the end of the first consultation (per kg or global)

Adverse events
10- Lack of appetite’s assessment during the treatment from 0 to 4 (0 no change/4 severe lack
of appetite)
11- Fatigability during the treatment from 0 to 4 (0 no change/4 severe fatigability)
12- Sedation during the treatment from 0 to 4 (0 no change/4 severe sedation)
13- Tremors during the treatment from 0 to 4 (0 no change/4 severe tremors)
14- Loss of weight during the treatment from 0 to 4 (0 no change/4 severe loss of weight)
 15- If a loss of weight occurred, precise the loss in kg.
16- Other reported or observed adverse events (free text)
17- Did you stop the treatment due to severe adverse events? (Yes/No)
18- Did you adjust the fluoxetine's dosage due to severe adverse events? (Yes/No)
19- If you adjusted the dosage, what was the new dosage per day (per kg or global)

Improvement and worsening

20- Assessment of the sleep's improvement from 0 to 4 (0 no change, 4 perfectly improved)

21- Assessment of the satiety's improvement from 0 to 4 (0 no change, 4 perfectly improved)
22- Assessment of the hypermotricity's improvement from 0 to 4 (0 no change, 4 perfectly
improved)
23- A worsening was reported or observed by you (Yes/No)
24- If a worsening was reported or observed give a description (free text)

Appendix 2: Sample Characteristics

Fluoxetine Fluoxetine
Sex Neutered Age Weight
dosage dosage
(m/f) (y/n) (yrs) (kg)
(mg/dog) (mg/kg)
1 m n 2.0 6 20 3.3
2 m n 3.0 29 70 2.4
3 f y 0.6 27 60 2.2
4 m n 1.0 8 20 2.5
5 m n 1.0 8 20 2.5
6 m y 1.0 17 40 2.4
7 f y 1.1 18 40 2.2
8 m n 0.7 27 80 3.0
9 m n 0.8 7 20 2.9
10 m n 1.3 13 30 2.3
11 m n 1.0 39 160 4.1
12 m n 1.1 6 20 3.3
13 f n 0.3 6 20 3.3
14 m y 3.5 11 30 2.7
15 m n 0.9 40 100 2.5
16 m y 2.0 6 15 2.5
17 f n 0.3 1.4 4 2.9
18 m n 0.8 35 80 2.3
19 m n 0.6 11 30 2.7
20 m n 1.3 41 80 2.0
21 m n 1.3 35 80 2.3
22 m y 1.5 29 80 2.8
23 m n 2.3 22 60 2.7
24 f y 0.6 17 40 2.4
25 f n 3.6 28 60 2.1
26 f n 0.7 24 60 2.5
27 f y 2.6 11.2 30 2.7
28 m n 1.3 34.7 100 2.9
29 f n 0.8 25.4 80 3.1
30 f n 0.9 32.5 110 3.4
31 m y 3.3 31.8 80 2.5
32 f y 0.7 20.7 50 2.4
33 m n 5.0 12 40 3.3
34 m n 1.5 24.7 80 3.2
35 m n 1.4 39 120 3.1
36 m n 1.0 40 160 4.0
37 m n 2.5 18 60 3.3
38 f y 2.5 15 40 2.7
39 f y 2.2 28 112 4.0
40 m n 1.3 17 51 3.0
41 m y 3.0 32 100 3.1
42 m n 0.5 4.7 20 4.3
43 f n 0.3 9 40 4.4
44 m n 0.6 24 80 3.3
45 f n 0.6 25 90 3.6
46 m y 5.0 34 100 2.9
47 f n 0.8 32 100 3.1
48 m n 1.5 12 40 3.3
49 f n 2.5 53 120 2.3
50 f y 1.9 23 80 3.5
51 m y 2.0 10 40 4.0
52 f y 2.0 34.7 120 3.5
53 f y 2.5 20 60 3.0
54 m y 1.5 30 100 3.3
55 m n 1.0 23 60 2.6
56 f n 2.0 13.6 40 2.9
57 f n 1.0 27.6 60 2.2
58 f y 2.0 5.8 20 3.4
59 m n 0.8 12 40 3.3
60 m n 0.7 36 140 3.9
61 f y 3.0 22 70 3.2
62 m n 0.5 20 60 3.0
63 f n 0.9 30 60 2.0
64 m y 1.2 31 120 3.9
65 m n 1.1 6 20 3.3
66 m n 0.9 39 160 4.1
67 m y 0.5 24.5 70 2.9
68 m n 0.3 14.8 40 2.7
69 m n 0.7 28.5 80 2.8
70 f n 0.8 23 80 3.5
71 m n 2.5 12 30 2.5
72 m n 0.6 24.4 50 2.0
73 m n 8.0 6 20 3.3
74 f y 3.5 22 60 2.7
75 f y 2.5 30 100 3.3
76 m y 1.5 34 120 3.5
77 m n 1.0 25 90 3.6
78 m n 0.8 33 120 3.6
79 m y 3.0 22 70 3.2
80 f y 1.1 24 80 3.3
81 m y 1.3 7 20 2.9
82 m y 4.0 33 100 3.0
83 m y 1.0 28 70 2.5
84 m n 7.0 7.3 30 4.1
85 f y 9.0 10 30 3.0
86 f y 3.0 11 30 2.7
87 f n 0.3 4 15 3.8
88 m y 1.5 18 60 3.3
89 f y 1.5 31 90 2.9
90 m y 0.7 23 70 3.0
91 m n 0.8 25 80 3.2
92 m n 2.7 36 100 2.8