Journal of Veterinary Emergency and Critical Care 22(6) 2012, pp 674–681

Retrospective Study doi: 10.1111/j.1476-4431.2012.00805.x

Retrospective evaluation of toxicosis from

selective serotonin reuptake inhibitor
antidepressants: 313 dogs (2005–2010)
Danielle E. Thomas, DVM; Justine A. Lee, DVM, DACVECC
and Lynn R. Hovda, RPH, DVM, MS, DACVIM

Abstract

Objective – To evaluate a clinical population of dogs exposed to selective serotonin reuptake inhibitor (SSRI)
antidepressant medications and describe the clinical findings, epidemiological characteristics, outcome, and
prognosis.
Design – Retrospective study (February 1, 2005–August 31, 2010).
Setting – Animal poison control helpline.
Animals – Three hundred thirteen dogs with presumed SSRI toxicosis.
Interventions – None.
Measurements and Main Results – Dogs with presumptive SSRI medication toxicosis identified by a review
of the electronic database of Pet Poison Helpline, an animal poison control center, were evaluated. No clinical
signs were reported in 76.3% (239/313) of cases. The remaining 23.6% (74/313) of cases demonstrated the
following clinical signs: neurological 79.7% (59/74), gastrointestinal 25.6% (19/74), cardiovascular 9.5% (7/74),
respiratory 8.2% (6/74), and thermoregulatory 6.7% (5/74). Of the dogs exhibiting neurological signs, 62.7%
(37/59) showed depression, 37.2% (22/59) showed hyperactivity, 10.1% (6/59) exhibited ataxia, and 1.7%
(1/59) showed other miscellaneous signs (eg, hyperesthesia). There was a significant difference between the
dose ingested by symptomatic and asymptomatic dogs for fluoxetine (P = 0.0039), but not with any other SSRI.
Ninety-four patients were confirmed to have received veterinary care. In cases where duration of veterinary care
was determined (55/313), 67.2% (37/55) of dogs were hospitalized and 32.7% (18/55) treated as outpatients.
The average duration of hospitalization was 18.5 hours, excluding outpatient visits. Of those patients that had
complete follow-up information available (136/313), overall survival was 100%.
Conclusions – The overall prognosis for animals with SSRI toxicosis is excellent with veterinary attention.
Central nervous system depression was the most common clinical sign associated with SSRI toxicosis.

(J Vet Emerg Crit Care 2012; 22(6): 674–681) doi: 10.1111/j.1476-4431.2012.00805.x

Keywords: canine, serotonin reuptake inhibitor, toxicology

SSRI selective serotonin reuptake inhibitor

Abbreviations TCA tricyclic antidepressants
CNS central nervous system 5-HT 5-hydroxytryptamine
GI gastrointestinal
MAO monoamine oxidase
MAOI monoamine oxidase inhibitors Introduction
Over the past 40 years, manipulation of concentrations
From the Section of Emergency and Critical Care, Angell Animal Medi- of the neurotransmitter serotonin in the central nervous
cal Center, 350 S Huntington Ave, Boston, MA 02130 (Thomas); Pet Poi-
son Helpline, 8009 34th Ave South, Ste 875, Bloomington, MN 55425 (Lee,
system (CNS) via medications such as serotonin reup-
Hovda). take inhibitors (SSRIs), serotonin agonists, and serotonin
The authors declare no conflict of interests. antagonists has been extensively studied and utilized
Address correspondence and reprint requests to for the treatment of human psychiatric illnesses such
Dr. Danielle E. Thomas, Angell Animal Medical Center, 350 S Huntington as clinical depression, obsessive compulsive disorders,
Ave, Boston, MA 02130, USA.
Email: dethomas@mspca.org
and anxiety disorders.1, 2 During this time, the use of an-
Submitted August 31, 2011; Accepted August 3, 2012. tidepressant medications, specifically SSRIs, has grown

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tremendously. According to the US Centers for Disease
Control and Prevention, the use of antidepressants in
adults increased 5-fold between 1988 and 2008, with 11%
of adults in the United States having reported taking
prescription antidepressants between 2005 and 2008.3
In veterinary medicine, SSRI antidepressants have also
been used off label for behavioral problems (eg, canine
separation anxiety).4 More recently, specific veterinary
medications have emerged, with the first Food and Drug
Administration approved SSRI for the treatment of ca-
nine separation anxiety obtaining licensure in 2007.a
Serotonin, a biogenic amine, is produced from the es-
sential amino acid tryptophan by the enzymes trypto-
phan hydroxylase and tryptophan decarboxylase.5 The
majority of the body’s serotonin is synthesized in the
CNS and enterochromaffin cells, but a small amount can
also be produced by platelets.5 Ninety to 95% of the
body’s serotonin is stored outside the CNS, largely in
the enterochromaffin cells and platelets.5 Platelets ab-
sorb large amounts of serotonin from the plasma, thus
keeping circulating concentrations very low.6, 7 Outside
the CNS, serotonin plays a role in platelet aggregation,8
the maintenance of vascular tone,9 and gastrointesti-
nal (GI) motility.10 In the CNS, serotonin is stored in
presynaptic vesicles of the serotonergic neurons, pineal
gland, and catechoalminergic neurons.11 Serotonin is re-
leased from the presynaptic membrane and binds to
serotonin-specific receptors on the postsynaptic mem-
brane or to autoreceptors on the presynaptic mem-
brane, which act as a negative feedback to serotonin
release.1 Serotonin is removed from the synaptic cleft
by binding to a selective serotonin transporter, which
transports it into the presynaptic cytosol.12 Once in the
cytosol of the presynaptic neuron, serotonin is metabo-
lized by monoamine oxidase (MAO) or repackaged in
vesicles.13 The effect at the postsynaptic membrane is
determined by the amount of serotonin available to bind
5-hydroxytryptamine (5-HT) receptors.14
Medications specifically aimed at altering serotonin
concentrations in the CNS fall into four categories:
medications that inhibit serotonin metabolism (eg,
monoamine oxidase inhibitors [MAOI]), medications
that inhibit reuptake of serotonin from the synap-
tic cleft across the presynaptic membrane by selec-
tive serotonin transporter (eg, SSRIs, tricyclic antide-
pressants [TCAs]), medications that augment serotonin
release (eg, 3,4-methylenedioxymethamphetamine, am-
phetamines), and serotonin precursors.2 Until the advent
of SSRIs, TCAs and MAO inhibitors (MAOIs) were the
most frequently prescribed serotonergic agents used to
treat depression and anxiety disorders.15 Adverse effects
from these medications were common, attributable to
their antihistaminergic and antimuscarinic effects, and
included clinical signs such as constipation, urine reten-

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SSRI antidepressant toxicosis in dogs
tion, sinus tachycardia, and memory loss.15 TCAs also
have quinidine-like, pro-arrhythmic effects on the my-
ocardium and may cause hypotension through alpha1 -
adrenergic blockade.2
SSRIs act specifically on synaptic serotonin concen-
trations and have minimal effects on other neurotrans-
mitters such as catecholamines, acetylcholine, and his-
tamine, minimizing the adverse effects seen with their
usage. As a result, SSRIs have largely replaced TCAs
and their comparative safety has made the occurrence of
adverse events less frequent.15
The increased use of SSRIs in both human and veteri-
nary medicine has resulted in veterinary patient expo-
sure through accidental ingestion of their owner’s med-
ications, as well as veterinary specific products. There
has been a growing frequency in the number of cases
presenting to Pet Poison Helplineb for SSRI intoxication.
As a result, the purpose of this study was to further char-
acterize the clinical signs, toxic dose, and outcome in a
large case series of SSRI toxicosis in dogs.
Materials and Methods
Criteria for the selection of cases
The electronic computer database of Pet Poison
Helplineb was searched for dogs having ingested SS-
RIs between February 2005 and August 2010. Inclu-
sion criteria were the dogs witnessed or suspected
to ingest one or more of the following SSRI antide-
pressants: citalopram, escitalopram, paroxetine, fluox-
etine, fluvoxamine, sertraline, or other/unknown SSRIs.
Cases in the other/unknown SSRI category included
serotonin-norepinephrine reuptake inhibitors, SSRIs that
the owner could not identify, and medications with sim-
ilar serotonergic action (eg, bromocriptine). Exclusion
criteria included cases where multiple animals were ex-
posed (due to the difficulty in accurately determining
dose ingested), coingestion of other medications (which
could potentially skew clinical signs observed), an in-
complete medical record (eg, absent signalment infor-
mation), or ingestion by cats.
Data were recorded in a commercially available
spreadsheet programc and medical records were re-
viewed for signalment (ie, gender, breed, age, and body
weight), clinical signs, dose ingested, time since expo-
sure, duration of clinical signs and outcome. When the
amount of medication ingested was described by the
owner as a range of possible values, the dose ingested
was calculated based on the maximum amount possibly
ingested.
General system categories of clinical signs were used
to characterize the data including: neurological–CNS
depression (with corresponding signs such as coma or
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D. E. Thomas et al.
sedation) or CNS stimulation (with corresponding signs
such as agitation, aggression, tremors, or seizures); GI
(eg, anorexia, vomiting, hypersalivation, or diarrhea);
cardiovascular (eg, tachycardia, bradycardia, arrhyth-
mias, syncope, hypotension, hypertension, or pallor);
and respiratory (eg, tachypnea and dyspnea). The pres-
ence of hyperthermia, ataxia, and hyperesthesia was also
recorded.
Follow-up with pet owners or hospital staff was per-
formed by telephone call or fax at the time of study de-
sign to obtain additional information regarding develop-
ment of clinical signs, veterinary treatment performed,
and overall outcome. In some cases, information was
available from follow-up calls made by poison control
center staff 2–7 days after the initial call. Pet owners were
contacted for follow-up information and verification of
outcome in those cases where dogs were not hospital-
ized, did not receive veterinary care, or when veteri-
nary data were not available. Both the veterinarian and
owner were contacted for information and outcome in
those animals that received outpatient veterinary care
or were hospitalized. A patient was considered to have
received veterinary care if they were evaluated by a
veterinarian. Two attempts were made to contact each
pet owner and/or veterinarian before the case was con-
sidered closed. Animals were determined to be asymp-
tomatic if they were asymptomatic at the time of the
owner’s phone call and any additional information on
the case (follow-up calls made between the veterinarian,
pet owner, and Pet Poison Helpline) did not describe the
development of any clinical signs. Patients were consid-
ered survivors if they were treated on an outpatient basis
or survived to discharge from the hospital. Patients that
died or were euthanized were considered nonsurvivors.
Statistical analysis
For parametric data, the mean and standard deviation
are reported; for nonparametric data, median values
and ranges are reported. The Student’s t-test was used
to determine the statistical significance between symp-
tomatic and asymptomatic animals with regard to age
and weight. Asymptomatic and symptomatic popula-
tions were compared based on breed and gender using
a Fisher’s exact test and a chi-square test, respectively. A
multivariable logistic regression was performed to eval-
uate the relationship between age, gender, and dose in-
gested to the development of clinical signs for each medi-
cation. A P value of <0.05 was considered significant. For
the medications with sufficient data points (eg, citalo-
pram, escitalopram, fluoxetine, paroxetine, and sertra-
line), an odds ratio was calculated for the relationship
between milligrams per kilogram dose and development
of clinical signs. A Fisher’s exact test was performed
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to compare the frequency of each clinical sign between
medications and to determine if any specific clinical sign
was more prevalent with the ingestion of one medica-
tion as compared to another. All statistical analyses were
performed with a commercially available statistical soft-
ware package.d
Results
Between February 2005 and August 2010, Pet Poison
Helpline received 362 calls concerning ingestion of SS-
RIs. Of these, 313 dogs met the inclusion criteria; 49 cases
were excluded due to multipet households, incomplete
records, or follow-up information that revealed that no
ingestion had occurred. Of the 313 dogs, 52 cases were
not included in the statistical analysis of “dose ingested”
and “development of clinical signs,” due to the inabil-
ity to accurately calculate the exact amount ingested.
The 52 excluded cases included 16 symptomatic patients
(citalopram [4], escitalopram [5], fluoxetine [1], parox-
etine [3], sertraline [3]) and 36 asymptomatic patients
(citalopram [11], escitalopram [6], fluoxetine [7], fluvox-
amine [1], paroxetine [6], sertraline [5]).
Follow-up was available for 43.5% (136/313) cases,
including 52.7% (39/74) of symptomatic patients and
40.5% (97/239) of asymptomatic patients. Overall, 48.2%
(151/313) of dogs were male and 51.7% (162/313) were
female. The median age was 2 years (n = 312/313; range
0.17–17 years), while the median weight was 11.4 kg
(n = 313; range 1.4–54.5 kg). The most common
breeds represented were mixed breed (25.8% [81/313]),
Labrador retriever (10.8% [34/313]), and beagles and
Chihuahuas (both with 3.5% [11/313]). There was no
significant difference between symptomatic and asymp-
tomatic dogs with regard to weight (n = 261, P = 0.3883),
age (n = 261, P = 0.2150), gender (n = 261, P = 0.2741),
or breed (n = 261, P = 0.3842) with any of the drugs
evaluated.
Of the 7 different medications represented in this case
series, 24.6% ingested sertraline (77/313), 24.2% ingested
fluoxetine (76/313), 20.7% ingested citalopram (65/313),
18.8% ingested escitalopram (59/313), 1.3% ingested flu-
voxamine (4/313), 8.3% ingested paroxetine (26/313),
and 1.9% ingested an unspecific SSRI (6/313).
Overall, no clinical signs were reported in 76.3%
(239/313) of cases. The remaining 23.6% (74/313) of dogs
developed clinical signs. Of the 74 symptomatic dogs,
the milligrams per kilogram dose was determined for
58 cases (78%). The median dose ingested for dogs that
developed clinical signs was 7.1 mg/kg (n = 58; range
0.13–264 mg/kg). The median dose ingested by asymp-
tomatic dogs was 3.14 mg/kg (n = 203; range 0.14–196.4
mg/kg).
 SSRI antidepressant toxicosis in dogs

Table 1: Dose ingested in symptomatic and asymptomatic animals

All ingestions Symptomatic Asymptomatic

Median dose Range Median dose Range Median dose Range Odds
Medication ( mg/kg) (mg/kg) (mg/kg) (mg/kg) (mg/kg) (mg/kg) P value ratio

Citalopram 3.2 (n = 50) 0.3–138.8 4.2 (n = 10) 1.1–29.4 2.4 (n = 40) 0.3–138.9 P = 0.8566 OR (CI) = 1
(0.96–1.04)
Escitalopram 2.0 (n = 48) 0.1–74.1 4.4 (n = 7) 0.5–74.1 1.8 (n = 41) 0.14–11 P = 0.3783 OR (CI) = 1.09
(0.9–1.34)
Fluoxetine∗ 4.3 (n = 68) 0.4–91.6 15.9 (n = 12) 1.3–91.7 3.5 (n = 56) 0.4–57.4 P = 0.0039∗ OR (CI) = 1.06
(1.02–1.1)
Fluvoxamine 2.6 (n = 3) 1.5–11.3 1.5 (n = 1) N/A 7.0 (n = 2) 2.6–11.3 Insufficient data N/A
Paroxetine 2.9 (n = 17) 0.3–25.9 7.7 (n = 5) 0.3–25.9 2.2 (n = 12) 1.2–8.8 P = 0.1239 OR (CI) = 1.42
(0.91–2.21)
Sertraline 9.2 (n = 69) 0.4–47.7 11.6 (n = 22) 0.4–264 8.5 (n = 47) 0.6–196.4 P = 0.2632 OR (CI) = 1.01
(1–1.02)
Unknown SSRI 4.9 (n = 6) 0.1–31.4 0.1 (n = 1) N/A 5.5 (n = 5) 1.4–31.4 Insufficient data N/A

SSRI, selective serotonin reuptake inhibitor.

∗
P < 0.05, statistically significant.
P value based on multivariable (age, gender) adjusted logistic regression for 261 cases for which data were complete, Odds ratio (OR) and 95% confidence
interval (CI) estimates for continuous predictor § looking at mg/kg dose as a predictor of developing clinical signs.

The median milligrams per kilogram dose ingested
was calculated for each specific SSRI ingested and com-
pared between symptomatic and asymptomatic animals
using multivariable logistic regression analysis (Table 1).
An odds ratio was calculated for the relationship be-
tween milligrams per kilogram dose ingested and the
development of clinical signs (Table 1). The median dose
ingested was directly associated with the development
of clinical signs for fluoxetine and there was a statisti-
cally significant difference in the median dose ingested
in dogs that developed clinical signs compared with dogs
that did not (P = 0.0039). An odds ratio was calculated for
the probability of developing clinical signs as it related
to the milligrams per kilogram of fluoxetine ingested.
For every 1-unit increase in the milligrams per kilogram
dose ingested for fluoxetine, the probability of becoming
symptomatic increased by 6% (Table 1).
velop clinical signs between the different medications
(Table 3).
Four patients in this study displayed clinical signs as-
sociated with the development of serotonin syndrome.
Serotonin syndrome is defined here as demonstrating
multiple signs (eg, mental status changes, agitation, my-
oclonus, hyperreflexia, diaphoresis, shivering, diarrhea,
incoordination, and hyperthermia) and tremors.16 These
patients ingested the following individual doses of med-
ication: 1.1 mg/kg of citalopram, 91.6 and 86.6 mg/kg of
fluoxetine, and 25.8 mg/kg of paroxetine.
In 66.2% (49/74) of cases, the time to onset of clinical
signs was available. Overall, the median time to devel-
opment of any clinical sign was 2 hours (n = 49/74; range
0.25–24 hours). In the 16 cases where the duration of clin-
ical signs could be determined, the median duration was
24 hours (n = 16/74; range 1–72 hours).

Clinical Presentation
Clinical signs were evaluated for each specific SSRI and
the percentage of symptomatic dogs exhibiting each clin-
ical sign was calculated (Table 2). Neurological and GI
signs were the most common clinical signs noted for all
medications (Table 2). There was no statistically signif-
icant difference between the frequency of any clinical
sign between any of the medications (Table 3). The ten-
dency to develop clinical signs was evaluated in the same
manner by comparing the incidence of asymptomatic
animals with confirmed milligrams per kilogram dose
ingested between the different medications. There was
no significant difference regarding the tendency to de-
Treatment
Information regarding care provided was available for
155 cases. Of these cases, 60.6% (94/155) of patients re-
ceived veterinary care. Duration of hospitalization could
be confirmed in 55/94 cases; of these, 67.2% (37/55)
were hospitalized and 32.7% (18/55) were treated on
an outpatient basis. Due to the limits of a retrospective
study, information about specific treatments received
was not readily available from the records nor they could
be obtained from owners or the hospital facility at the
time of follow-up call. In this study, all the dogs, for
whom follow-up information was available, survived to


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D. E. Thomas et al.

Table 2: Clinical signs associated with SSRI intoxication in 313 reported cases

All SSRIs Citalopram Escitalopram Fluoxetine Fluvoxamine Paroxetine Sertraline Unknown SSRI

Percentage of dogs 74/313 14/65 12/59 13/76 1/4 8/26 25/77 1/6
developing (23.6%) (21.5%) (20.3%) (17.1%) (25%) (30.7%) (32.4%) (16.7%)
symptoms
CNS depression 37/74 7/14 6/12 6/13 1/1 1/8 15/25 1/1
(50%) (50%) (58.3%) (46.1%) (100%) (12.5%) (60%) (100%)
CNS stimulation 22/74 5/14 2/12 6/13 0% 3/8 6/25 0%
(29.7%) (35.7%) (16.7%) (46.1%) (37.5%) (24%)
Cardiovascular 7/74 3/14 0/12 1/13 0% 1/8 2/25 0%
signs (9.5%) (21.4%) (0%) (8%) (12.5%) (8%)
Respiratory 6/74 0/14 1/12 1/13 0% 1/8 3/25 0%
signs (8.2%) (0%) (8.33%) (8%) (12.5%) (12%)
Gastrointestinal 19/74 5/14 3/12 3/13 0% 3/8 4/25 1/1
signs (25.6%) (35.7%) (25%) (23%) (37.5%) (16%) (100%)
Other signs 7/74 1/14 1/12 2/13 0% 2/8 1/25 0%
(9.5%) (7.14%) (0%) (12.5%) (25%) (4%)
Hyperthermia 5/74 1/14 1/12 0/13 0% 1/8 2/25 0%
(6.7%) (7.14%) (8.33%) (0%) (12.5%) (8%)

CNS, central nervous system; SSRI, selective serotonin reuptake inhibitor.

Table 3: Comparison of frequency of clinical signs between medications in 261 dogs with confirmed ingestion (in milligrams per
kilogram basis)

Citalopram Escitalopram Fluoxetine Fluvoxamine Paroxetine Sertraline Unknown P value

SSRI

CNS depression (n 6/50 3/48 7/68 1/3 2/17 14/69 1/6 n = 34

= confirmed (12%) (6.25%) (10.29%) (33%) (11.76%) (20.29%) (16.67%) P = 0.2396
ingestions)
CNS stimulation 2/50 2/48 6/68 0 1/17 6/69 0 n = 17
(4%) (4.17%) (8.82%) (5.88%) (8.7%) P = 0.8733
Cardiovascular 1/50 0 1/68 0 1/17 2/69 0 n=5
signs (2%) (1.47%) (5.88%) (2.90%) P = 0.6306
Respiratory signs 0 1/48 0 0 1/17 3/69 0 n=5
(2.08%) (5.88%) (4.35%) P = 0.2349
Gastrointestinal 4/50 2/48 2/68 0 3/17 4/69 1/6 n = 16
signs (8%) (4.17%) (2.94%) (17.65%) (5.80%) (16.67%) P = 0.2330
Other signs 0 0 2/68 0 0 6/69 0 n=8
(2.94%) (8.70%) P = 0.1321
Asymptomatic 40/50 41/48 56/68 2/3 12/17 47/69 5/6 n = 203
(80%) (85.42%) (82.35%) (66.67%) (70.59%) (68.12%) (83.33%) P = 0.2580

CNS, central nervous system; SSRI, selective serotonin reuptake inhibitor.

discharge (n = 136); no dogs were reported to have died
or have been euthanized as a result of ingestion.
Discussion
SSRIs are commonly prescribed for a variety of con-
ditions in human medicine and their use is becom-
ing increasingly popular in veterinary medicine. As a
result, the incidence of SSRI intoxications in animals
has increased, based on observations from Pet Poison
Helpline.
The clinical signs observed with SSRI overdose in hu-
man beings are due to the presence of excessive serotonin
in the CNS.2 These include nausea, vomiting, dizziness,
blurred vision, and less commonly CNS depression and
sinus tachycardia. The severity of clinical signs is pri-
marily related to the dose of medication ingested,1, 2, 17
but the drug ingested may also impact the clinical signs
manifested in overdose.18 The most severe manifestation
of these clinical signs is termed serotonin syndrome or
serotonin toxicity. Development of serotonin syndrome
in people is most commonly due to coingestion of sero-
tonergic agents with different mechanisms of action.19, 20
In veterinary medicine, clinical signs observed sec-
ondary to SSRI intoxication result from the presence
of excessive serotonin in the CNS.14 Currently, there is
limited information about specific SSRI intoxication in
veterinary medicine but it appears that the severity of

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clinical signs is related to the dose ingested. Mohammed-
Zadeh et al1 evaluated 189 dogs with SSRI intoxication
and reported lethargy (31.7%), vomiting (12.2%), mydri-
asis (11.6%), and agitation (11.1%) as the most common
clinical signs.1 This report found a dose-dependent rela-
tionship to clinical signs with the most minor signs (eg,
salivation and lethargy) noted at 1–3 mg/kg of parox-
etine and sertraline, whereas more severe signs such as
tremoring and hyperthermia were not seen until the dose
reached between 8 and 10 mg/kg of fluoxetine and ser-
traline. Seizure activity was not noted until the dose ex-
ceeded 25 mg/kg of fluoxetine and sertraline but was
observed when doses exceeded 3 mg/kg of paroxetine.1
The results of this retrospective study support the pre-
vious findings in human and veterinary literature re-
garding the clinical signs associated with ingestion of
supra-therapeutic doses of SSRIs. In the current study,
CNS depression, CNS stimulation, and GI upset were
the most prevalent signs in symptomatic animals. CNS
and GI signs were also the most common adverse ef-
fects noted when fluoxetine was used at therapeutic
doses for the treatment of separation anxiety,4 suggesting
that these adverse effects may represent mild serotonin
toxicity.
The aforementioned study by Mohammed-Zadeh
et al,1 along with experimental animal studies and a
number of retrospective studies in people, has iden-
tified a dose-dependent relationship with the de-
velopment and severity of clinical signs with SSRI
intoxication.4, 18, 20–24 However, in the current retrospec-
tive study, a dose-dependent relationship for the devel-
opment of clinical signs was established only for flu-
oxetine. No significant association was observed with
escitalopram, paroxetine, and sertraline. A recent study
reviewing intoxication associated with the serotonergic
agent 5-hydroxytryptophan in dogs also did not demon-
strate a correlation between the severity of clinical signs
and dose ingested.25 It is possible that with these medica-
tions individual metabolic variation and veterinary care
(eg, speed to decontamination, etc) had a greater impact
on the development of clinical signs than dose ingested.
Individual variation in MAO activity has been demon-
strated in human medicine to affect circulating concen-
trations of serotonin.26 This variability can result from
individual genetic variation or diseases that affect the
vascular endothelium, the site of the majority of MAO
activity.27 Such variability in MAO activity has been sug-
gested to predispose certain people to the development
of serotonin syndrome.27 Although it has not yet been
demonstrated in veterinary patients, it is possible that
individual variation in MAO activity, based on genet-
ics or underlying disease states, may contribute to the
likelihood of the development of clinical signs following
ingestion of an SSRI.

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SSRI antidepressant toxicosis in dogs
In the current study, the median milligrams per kilo-
gram dose for asymptomatic animals for fluoxetine,
paroxetine, and sertraline was greater than previously
published doses at which one would expect clinical
signs.1, 17, 28, 29 These findings may be due to owner’s in-
ability to correctly determine the amount ingested or
prompt implementation of therapeutic measures such as
calling a veterinary poison control helpline for treatment
recommendations, rapid onset of emesis and decontam-
ination, and/or time to presentation to the veterinarian
for treatment.
Four patients in this study displayed a collection
of clinical signs associated with the development of
serotonin syndrome. Serotonin syndrome has been
previously described in dogs following the ingestion
of the serotonergic agent 5-hydroxytryptophan29 and
dogs chronically exposed to supra-therapeutic levels of
fluoxetine.17 Despite the association with more severe
manifestations of toxicosis, all the dogs in the current
study that developed serotonin syndrome responded
well to medical attention and recovered fully (n = 4/4).
This outcome is consistent with other reports of sero-
tonin syndrome in dogs and people that suggest most
patients recover within 24 hours following discontinu-
ation of the specific SSRI medication and institution of
supportive care.18, 19, 25
Although the development of severe clinical signs has
been documented in people and other animals follow-
ing the ingestion of a single SSRI, the most serious clin-
ical manifestation, serotonin syndrome, is more com-
mon following the ingestion of multiple serotonergic
agents.19 TCAs and MAOIs are the most commonly im-
plicated coingestants in human medicine. Because these
medications are also used in veterinary medicine (eg,
amitriptyline and clomipramine), the risk for coingestion
still exists (ie, “polypharmacy toxicosis”), with the po-
tential for severe clinical consequences. Other serotoner-
gic medications used in veterinary medicine include the
phenylpiperidine opioids (eg, fentanyl and tramadol),
mirtazipine, buspirone, amitraz, and chlorpheniramine.
As multidrug ingestion was considered an exclusion cri-
terion in this study, coingestion was not evaluated in the
current study, which may explain the small number of
dogs who developed more serious clinical signs (eg, sero-
tonin syndrome and seizures) in this patient population.
As the use of SSRIs becomes more common in veterinary
medicine, the clinician will need to be conscious of the
potential for drug interactions and the clinical signs of
serotonin toxicity and serotonin syndrome.
The current study did not identify an increased preva-
lence of any specific sign in relation to any specific
individual SSRI medication. It has been reported in
people that acute overdoses of citalopram are asso-
ciated with an increased risk of electrocardiographic
679
D. E. Thomas et al.
abnormalities such as a prolonged QT interval rela-
tive to other SSRIs.18, 21 The suggested mechanism for
this prolongation is the inhibition of potassium chan-
nels in the conducting system of the heart by the citalo-
pram metabolite didesmethylcitalopram.2 In the current
study, the observed prevalence of cardiovascular abnor-
malities was low; however, electrocardiographic evalu-
ation was not available for any cases. Therefore, it is
unknown whether QT interval prolongation occurred
and went undetected. Other cardiovascular abnormali-
ties associated with excess serotonin include tachycar-
dia and hypertension.30 These effects are mediated cen-
trally through modulation of sympathetic tone via 5-HT1
and 5-HT2 receptors and peripherally through vascular
smooth muscle and platelet interactions.1 Blood pres-
sure measurements were not consistently available, so
the prevalence of hypertension could not be determined
in this study.
Seizures have been noted more frequently in people
following citalopram overdoses relative to other SSRIs.18
In this study, seizures were noted infrequently (0.6%
[2/313]). No milligram per kilogram dose was avail-
able in these 2 dogs. Mohammed-Zadeh et al1 reported
seizures in 3.2% of dogs (n = 189) following SSRI intox-
ication, but citalopram was not evaluated in this report.
Because of the low incidence of seizures in the current
study, it is not possible to draw conclusions about the
propensity of citalopram or any other SSRI to precipi-
tate seizures in veterinary patients. The low incidence
reported here may be the result of early intervention in-
cluding induction of emesis and the administration of
activated charcoal that minimized the amount of toxi-
cant absorbed.
SSRIs are metabolized by the liver through the cy-
tochrome P450 isoenzymes.1 Fluoxetine, paroxetine, and
sertraline are highly protein bound.28 As a result, SSRIs
have the potential to alter the liver’s ability to metab-
olize other drugs and may alter the plasma concentra-
tion of other compounds that are highly protein bound.
In addition, many of these compounds generate active
metabolites, which prolong their duration of effect and
may also act as either substrates for or inhibitors of var-
ious hepatic isoenzymes. The presence of these active
metabolites, which are primarily eliminated through the
urine, prolongs the half-life of these compounds and in-
creases the period during which drug interactions may
occur.2, 31 Previous exposure to medications that inhibit
the cytochrome P450 system, such as ketoconazole, may
increase a patient’s potential for developing toxicosis fol-
lowing ingestion of an SSRI. Animals with preexisting
renal or hepatic disease may be more susceptible to the
effects of these medications and more likely to develop
clinical signs following their ingestion. Due to their re-
680 
C Veterinary Emergency and Critical Care Society 2012, doi: 10.1111/j.1476-4431.2012.00805.x
duced ability to metabolize and excrete these drugs,
these patients may warrant more aggressive treatment
measures and a longer duration of treatment following
the exposure.
As previously stated, individual factors such as in-
trinsic MAO activity and the presence of vascular dis-
ease may predispose patients to SSRI toxicity.1, 19 In-
creased susceptibility to SSRIs has been documented
in humans with atherosclerosis, hyperlipidemia, and
hypothyroidism.27, 30 Although atherosclerosis is not
common in veterinary patients, other diseases which af-
fect the vasculature (eg, hypothyroidism, diabetes mel-
litus, and hyperlipidemia) are relatively common; cur-
rently, it is unknown whether these disease processes
affect the veterinary patient’s vulnerability to SSRI toxi-
cosis. The presence of such comorbidities should be con-
sidered when developing and implementing a treatment
plan following SSRI intoxication.
Limitations
The retrospective nature of this study prevented uniform
data collection for all cases. Due to uncertainty relating
to the amount of drug ingested, a number of cases were
removed from statistical analysis, thereby lessening the
statistical power of the study. The dependence on own-
ers reporting their pets’ clinical signs via telephone, as
opposed to being able to rely on results of physical ex-
amination, and the difficulty in accurately determining
the exact amount of medication ingested further limited
the study. However, history taking with any emergent
or critically ill patient is subjective and limited by the
accuracy of information provided by the pet owner or
caretaker. Another limitation of the study was the lower
number of cases with complete follow-up despite nu-
merous attempts to obtain it. As a result, it is possible
that some of the patients initially reported as asymp-
tomatic later developed unreported clinical signs. Inter-
pretation of results should be evaluated in light of these
limitations.
Conclusions
Despite the limitations, this report shows that the prog-
nosis for dogs experiencing SSRI toxicosis is excellent
with treatment. Complicating factors such as hepatic im-
pairment may potentially worsen the prognosis due to
alterations in the pharmacokinetics for the specific SSRI;
therefore, additional studies are warranted that look at
this specific patient population. In addition, further in-
formation is needed regarding the potential for interac-
tions between SSRIs and other medications commonly
prescribed for veterinary patients.

Acknowledgements
The authors thank Joe Palmisano for assistance with the
statistical analyses.
Footnotes
a chewable tablets for dogs. 2007. [Accessed 8/2010]. Available
Reconcile, fluoxetine hydrochloride, Elanco Animal Health, Greenfield,
IN.
b
Pet Poison Helpline, a division of SafetyCall international. Minneapolis,
MN.
c
Microsoft Excel (2003). Microsoft Corporation. Redmond, WA.
d
SAS Statistical Package 92. SAS Institute, Inc. Cary, NC.
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