Vol.18, No.
11 November 1996 V
Continuing Education Article
FOCAL POINT
★ Anxiolytics and mood stabilizers
that are commonly used in
human psychiatry may be useful
in veterinary behavioral medicine.
KEY FACTS
■ Benzodiazepines should be
discontinued gradually.
■ Fatal idiopathic hepatic necrosis
has reportedly followed short-
term oral administration of
diazepam to cats.
■ If fear or anxiety is restraining
aggression, an anxiolytic drug
will release the expression of
aggression.
■ Pet owners need to understand
that behavior problems are
seldom cured but frequently
improved by pharmacologic
treatment.
■ Target behaviors are defined and
quantified before drug treatment
begins.
Behavioral
Pharmacotherapy.
Part II. Anxiolytics and
Mood Stabilizers*
The Veterinary Behavior Clinic Moore Regional Hospital
Southern Pines, North Carolina Pinehurst, North Carolina
Barbara S. Simpson, PhD, DVM Dale M. Simpson, MD, PhD
M any drugs that have long been used in human psychiatry are being
tested in veterinary behavioral medicine. Part I of this two-part pre-
sentation discussed antipsychotic drugs and antidepressants. Most of
the drugs described in this presentation (Table I) have not been approved for
use in animals. Their use in companion animals is extralabel. Although the
human psychiatric literature serves as a useful reference, drugs tested and labeled
for human psychiatric problems may have different effects, side-effect profiles, or tox-
icities in companion animals.
ANXIOLYTICS
Drugs with antianxiety properties include benzodiazepines, azapirones, bar-
biturates, and antihistamines. The benzodiazepines have become the standard
drug class of choice for the treatment of anxiety in humans. A specific aza-
pirone, buspirone hydrochloride, offers a pharmacologically distinct alternative
to these drugs. The anxiolytic effect of the barbiturates is associated with a
significant degree of cortical depression; the anxiolytic effects of the anti-
histamines, although real, appear to be a nonspecific effect associated with the
sedating properties of some of these drugs. Only the benzodiazepines and bus-
pirone hydrochloride are considered in the sections below. Other drugs that
were described in Part I, such as certain tricyclic antidepressants and the atypi-
cal antidepressants trazodone hydrochloride and nefazodone hydrochloride,
may also be useful in the treatment of some anxiety states.
Benzodiazepines
Benzodiazepines have become synonymous with anxiolytics, and the vast
*Part I of this two-part presentation appeared in the October 1996 issue (Vol. 18, No.
10) of Compendium.
Small Animal
TABLE I
Anxiolytics and Mood Stabilizers Used in Veterinary Behavioral Medicine
Drug Class Examples
Anxiolytics
Benzodiazepines Diazepam, clorazepate
alprazolam
Azapirones Buspirone hydrochloride
Mood stabilizers Lithium, carbamazepine,
valproic acid
majority of pharmacologic treatments for anxiety in
humans involve benzodiazepines.1 The most commonly
used benzodiazepines are diazepam, lorazepam, alpra-
zolam, chlorazepate dipotassium, oxazepam, chlor-
diazepoxide, and clonazepam. Several others (e.g.,
temazepam and flurazepam hydrochloride) are labeled
only as sleeping pills. All benzodiazepines have great
structural similarity and appear to work through the
same mechanisms but differ widely with regard to
pharmacodynamics and pharmacokinetics. With the
exception of clonazepam, all commonly used benzodi-
azepines are available in generic form and are inexpen-
sive. They are extremely safe in overdosage and have a
limited number of side effects.1
Pharmacology and Mode of Action
Benzodiazepines have been available since chlor-
diazepoxide was introduced in 1960.1 There are now at
least 39 benzodiazepines on the market.1 These drugs
are believed to act by binding to γ-aminobutyric acid
(GABA) receptors in the central nervous system, thus
promoting the inhibitory activity of GABA. Their
anxiolytic properties seem to result from GABAergic
activity at the levels of the cerebral cortex and limbic
system. GABA receptors are widely distributed, so ef-
fects at other sites explain the side effects of benzodi-
azepines. For example, the sedating effects result from
GABA activity in the reticular activating system, mus-
cle-relaxing effects result from GABA effects at the level
of the spinal cord, and anticonvulsant effects are medi-
ated by GABA circuits at multiple levels of the central
nervous system.1
The benzodiazepines are lipid soluble and are thus
well absorbed from the gastrointestinal tract and pass
easily into the brain. In humans, they reach peak
GABA ■ ELIMINATION HALF-LIFE ■ DURATION OF BEHAVIORAL ACTION
The Compendium November 1996
Potential Applications
Indications in in Veterinary
Human Psychiatry Behavioral Medicine
Anxiety disorders Anxiety disorders, urine
marking by cats
Anxiety disorders Anxiety disorders, urine
marking by cats
Bipolar disorders, seizure Aggressive behaviors
plasma levels from 0.5 to 6 hours, depending on the
absorption rate of each particular drug and other
variables, such as the amount of food in the patient’s
stomach. After a single dose of a benzodiazepine, its be-
havioral action is reduced primarily by drug distribu-
tion. Diazepam, for example, is rapidly absorbed and
distributed following a single oral dose. Even though
diazepam has a long elimination half-life, its duration
of behavioral action is relatively brief.2
In human psychopharmacology, these drugs are clas-
sified according to whether the elimination half-lives of
the parent compound and active metabolites in humans
are short (<6 hours), intermediate (6 to 20 hours), or
long (>20 hours).1 The half-life determines the time re-
quired to achieve a steady-state concentration (approxi-
mately four half-lives). Until a drug reaches steady
state, it is accumulating and the optimal dosage for a
particular patient cannot be determined.2 Drugs with
elimination half-lives greater than 24 hours may be ad-
ministered once a day. Drugs with shorter half-lives
should be given more often.
The intermediate–half-life benzodiazepines loraz-
epam, oxazepam, and temazepam are metabolized by
conjugation to inactive glucuronides, sulfates, and
acetylated substances. They have no active metabolites
and are often used for elderly patients or those with
compromised hepatic function. Alprazolam, another
intermediate–half-life benzodiazepine, undergoes ox-
idation but has no clinically important metabolites.
Only lorazepam and midazolam are reliably absorbed
after intramuscular injection.2
Long–half-life benzodiazepines include diazepam,
chlordiazepoxide, clorazepate dipotassium, and clon-
azepam. All are biotransformed by hepatic oxidative
reactions to at least one active metabolite, desmethyl-
The Compendium November 1996
diazepam (nordiazepam). Clorazepate dipotassium re-
quires biotransformation to an active form in the gas-
trointestinal tract. The fastest absorption occurs in an
acid environment, thus clorazepate dipotassium is most
effective when administered on an empty stomach and
may be poorly absorbed in states of high gastric pH.3
Empirically, the duration of action of benzodiaz-
epines in small animals, especially dogs, appears shorter
than that in humans.4 Thus, the timetable for elimina-
tion half-lives of benzodiazepines in humans cannot re-
liably be applied to other species. Other characteristics
of the pharmacokinetics appear to differ between hu-
mans and dogs. For example, in humans but not in
dogs, clorazepate dipotassium sustained delivery
(Tranxene SD®—Abbott Laboratories) produces pro-
longed serum concentrations compared with the regu-
lar formulation (Tranxene®—Abbott Laboratories).4
Side Effects
Benzodiazepines have few side effects beyond the pre-
viously mentioned sedation, cortical depression, and
muscle relaxation. They produce little respiratory de-
pression even in overdoses, although they can potenti-
ate the respiratory depression produced by other seda-
tive hypnotics, such as the barbiturates. They have little
effect on the cardiovascular system and apparently raise
seizure threshold, although benzodiazepine withdrawal
can be associated with seizures.
In humans, intravenous use produces amnesia. Oral
dosing, particularly of the rapidly absorbed lipid-solu-
ble benzodiazepines, may also produce amnesia and
interferes with learning conditioned responses.2 Chlor-
diazepoxide administration, however, greatly facilitates
operant conditioning of nervous pointer dogs.5 Use of a
benzodiazepine may therefore reduce the effectiveness
of a behavior-modification program for some patients6
but may facilitate associative learning by extremely anx-
ious patients.
Partial tolerance to all the aforementioned side effects
may develop over time. In general, tolerance develops
to the nonspecific sedative effects of a benzodiazepine
during long-term therapy, but tolerance to its anxiolytic
effects is less common.7 Gradual withdrawal is recom-
mended after long-term use of benzodiazepines in hu-
mans and animals to avoid the discontinuation syn-
drome. In one regimen for withdrawal, the daily dose is
reduced by 25% per week.7
In cats, there are reports of fatal idiopathic hepatic
necrosis in response to short-term oral administration
of benzodiazepines, especially diazepam.8,9 This rare
phenomenon has been confirmed to be a result of oral
generic diazepam and at least four proprietary formula-
tions.9 Although questions about the dosage given to
SEDATION ■ WITHDRAWAL SEIZURES ■ AMNESIA ■ FEAR
Small Animal
affected cats and about their underlying medical status
have been raised,10 the phenomenon does not appear to
be dose related and has occurred in cats with normal
pretreatment hepatic enzyme assays.8,9 There have been
speculations that some cats produce toxic metabolites
from diazepam, possibly related to species-specific dif-
ferences in hepatic metabolism.
Applications
All benzodiazepines are more effective than placebos
for the short-term treatment of generalized anxiety dis-
order in human patients.7 Trials comparing various
benzodiazepines have failed to demonstrate consistent
differences in efficacy among drugs of this class.7 Sever-
al benzodiazepines have other applications. Alprazolam
is labeled for the treatment of panic disorder. Clon-
azepam is labeled for treatment of epilepsy and is also
used in the treatment of panic disorder. Flurazepam hy-
drochloride and temazepam are marketed for insom-
nia—likely more a marketing decision than a reflection
of unique pharmacologic profile. Because they are bio-
transformed by conjugation, not oxidation, and have
nonactive metabolites, lorazepam and oxazepam are
used with success for agitated patients with compro-
mised hepatic function.3
Despite the widespread use of benzodiazepines in
veterinary practice, there is a shortage of scientific data
for rational guidance of their use in animals. Hart
evaluated the effect of diazepam (0.7 mg/kg orally)
compared with other drugs and placebo in dogs.11 Sev-
en of 10 treated dogs (compared with controls) mildly
increased behavioral measures of excitability and de-
creased fearful responses. Chlordiazepoxide (1 mg/kg
orally) given to a few dogs showed little effect on these
measures.11 Numerous reviews have suggested the ben-
zodiazepines to be effective at reducing the intensity of
fearfulness and its associated anxiety in dogs,6,12,13 al-
though few studies have tested these effects.14 Voith
recommends diazepam (0.55 to 2.2 mg/kg orally) for
thunderstorm anxiety in dogs.6 Beaver recommends
chlordiazepoxide (0.5 to 5.0 mg orally) or diazepam
(0.5 to 2.0 mg orally) for situations involving “frustra-
tion” or social anxiety in cats.15
The effects of benzodiazepines on aggressive behav-
iors in animals are variable, possibly reflecting that dif-
ferent brain centers mediate different types of aggres-
sion.15 Chlordiazepoxide reportedly has “taming” effects
on wild cats and other zoo animals. 11,16,17 Marder
reported improvement with diazepam treatment in a
1-year-old dog exhibiting unpredictable aggression
toward its owners as well as flank-chewing behavior.12
Review articles generally indicate that benzodiazepine
can be used effectively to reduce fear-induced aggressive
Small Animal
behavior of cats.6,12 Schwartz, however, reported the un-
successful use of diazepam (0.5 to 1.0 mg orally every
12 hours) in two cases of feline aggression.18 These cats
were successfully treated with the mood stabilizer car-
bamazepine.18
Benzodiazepines have been recommended for treat-
ment of fear-related behaviors, including fear-induced
aggressive behavior.6,11 Several veterinary behaviorists,
however, report that benzodiazepines can cause a para-
doxical increase in some types of aggression in ani-
mals.6,12,13 Diazepam may escalate predation in cats.19
Benzodiazepines may actually disinhibit normal agonis-
tic responses, thus increasing the likelihood of aggres-
sion, a particular problem in fear aggression in dogs
and cats.
It is useful to think of benzodiazepines as being “dis-
inhibitors” of suppressed behavior.7 If aggression is a
manifestation of underlying fear or anxiety, reduction
in fear or anxiety will reduce aggression. In contrast, if
fear or anxiety is restraining the expression of aggres-
sion, then reduction in fear or anxiety will release the
expression of aggression. Because these underlying
states may be difficult to differentiate, benzodiazepines
should be used with caution for aggressive patients.
Several clinical studies have evaluated the efficacy of
diazepam for the treatment of urine spraying. Urine
spraying is a highly motivated behavior influenced by
social and sexual factors.20 Because urine spraying is
generally resistant to other therapeutic modalities, such
as behavior modification, pharmacotherapy is often im-
portant in the management of this behavior problem.14
In a prospective trial, Marder treated 23 cats with this
diagnosis with diazepam (1 mg orally every 12 hours; if
no response, increased to 2 mg orally every 12 hours).12
Treatment was continued at the effective dose for 1
month, then tapered over 1 month. When assessed lat-
er, 43% of the cats had completely stopped spraying
and 74% of owners expressed satisfaction, defined as a
75% or greater improvement in the problem.
Eleven of the cats that had previously been given syn-
thetic progestins without success were effectively treat-
ed with diazepam. Owners reported side effects of in-
creased affection, lethargy, appetite increase, and ataxia.
Of the cats that responded, 75% resumed the behavior
after the medication was discontinued.12
Cooper and Hart tested the clinical effect of diaz-
epam in an open trial on 20 surgically sterilized cats
presented for urine spraying.21 Eleven of the cats had
previously been treated unsuccessfully with progestins.
Diazepam (1 to 4 mg orally every 12 hours) was given
for 2 to 20 weeks in an experimental design contingent
on each cat’s response. Nine cats ceased spraying and
two others showed marked reduction in spraying for an
DISINHIBITION ■ APPETITE STIMULATION ■ SLEEP DISORDERS ■ URINE SPRAYING
The Compendium November 1996
overall response rate of 55%. All responders except one
(10 of 11) resumed spraying when the drug was discon-
tinued after 6 to 8 weeks of treatment. Reported side
effects included ataxia (8 of 20), which usually abated
as cats became tolerant to the drug; increased sleepiness
(10 of 20); increased appetite (3 of 20); weight gain (2
of 20); reduced intercat aggression (1 of 20); and in-
creased affection toward people (3 of 20).21
A case presentation of urine spraying and reclusive
behavior by a cat from a multicat household highlights
common social interactions that complicate treatment
in these cases.22 The cat was successfully treated with
diazepam (1 mg orally every 12 hours, later increased
to 2 mg orally every 12 hours) until it relapsed—over a
year later when successful treatment with the atypical
anxiolytic buspirone hydrochloride was initiated.22
Various other uses for benzodiazepines have been re-
ported. Diazepam has been used as an appetite stimu-
lant.13,15 Clonazepam has been used to correct rapid eye
movement (REM) sleep disorders in dogs, including vi-
olent movement during sleep.23
Buspirone Hydrochloride
Buspirone hydrochloride was the first nonsedating
antianxiety drug to be developed and marketed. Its an-
tianxiety effects differ markedly from those of the ben-
zodiazepines and other anxiolytics in that buspirone
hydrochloride has no immediate antianxiety effects and
requires a week or more of daily treatment to produce
measurable antianxiety effects in humans.
Pharmacology and Mode of Action
Buspirone hydrochloride is in a class of drugs called
azapirones. Its antianxiety effect is attributed to block-
ing serotonin1A presynaptic and postsynaptic receptors.
It appears that the presynaptic serotonin1A blockade in-
creases serotonergic activity when such activity is low
but reduces it by blocking postsynaptic receptors when
serotonergic activity is high.24 Buspirone hydrochloride
causes downregulation of serotonin2 receptors and ad-
ditionally acts as a dopamine agonist throughout the
brain. Unlike the benzodiazepines, it has no direct ef-
fect on GABA receptors, although it does enhance ben-
zodiazepine binding.
In large-scale, double-blind clinical studies, buspi-
rone hydrochloride has been shown to be as effective as
benzodiazepines in the treatment of generalized anxiety
disorder or other anxiety states.24 In smaller, short-term
trials, particularly in crossover experimental designs
with benzodiazepines, buspirone hydrochloride often
fails to show efficacy.25 This may be because of the slow
onset of action of buspirone hydrochloride (in compar-
ison with the benzodiazepines) or because it appears to
Small Animal
be less effective in patients that had previously received
benzodiazepines than in naive patients.24 Many clini-
cians and patients have found the overall effectiveness
of buspirone hydrochloride for the treatment of anxiety
to be disappointing.
Buspirone hydrochloride is ineffective in the control
of panic disorder, thus emphasizing that panic disorder
should be differentiated from generalized anxiety disor-
der in presentation and efficacy of drug treatment. Evi-
dence suggests that patients who experienced panic at-
tacks or social phobia showed preferential response to
medications that were not anxiolytic per se, such as tri-
cyclic antidepressants. Other drugs (e.g., buspirone hy-
drochloride and most benzodiazepines) that are effec-
tive in the treatment of generalized anxiety disorder are
ineffective in the treatment of panic attacks.24 This sug-
gests that the pathophysiology of these states may not
be the same. It may be useful to classify fearful behavior
in animals similarly.
Buspirone hydrochloride lacks sedative, muscle re-
laxant, or anticonvulsant actions and does not impair
performance of motor tasks.24 The drug has a short
elimination half-life, from 1 to 10 hours in humans.
Recommended dosing in humans is 5 to 15 mg three
times a day. Unlike benzodiazepines, buspirone hydro-
chloride can be abruptly withdrawn without complica-
tion.
Side Effects
In humans, buspirone hydrochloride has a propensity
to elevate prolactin and growth hormone at high doses
but not at standard therapeutic doses.24 Despite its ef-
fect on dopamine receptors, buspirone hydrochloride
lacks antipsychotic effects. Buspirone hydrochloride is
relatively free of serious side effects and drug interac-
tions, and it lacks abuse potential.
Applications
In humans, buspirone hydrochloride is used for the
treatment of anxiety and little else. Although there have
been some reports of the use of buspirone hydro-
chloride to augment the effectiveness of the selective
serotonin-reuptake inhibitors in the treatment of de-
pression and obsessive-compulsive disorder, well-con-
trolled studies have failed to show increased efficacy
over selective serotonin-reuptake inhibitors alone.26
Buspirone hydrochloride has been used by veterinary
behaviorists, although the doses are significantly higher
than those used for depressed human patients. Bu-
spirone hydrochloride has the disadvantages of multiple
daily dosing, relatively high cost, and extended latency
to effect. It has the advantages of being safe and well
tolerated.
PANIC DISORDER ■ ANXIETY ■ URINE SPRAYING
The Compendium November 1996
In a prospective open trial, Hart and coworkers re-
corded owner assessment of the effect of buspirone hy-
drochloride on the incidence of urine spraying and
marking by 62 surgically sterilized cats.27 The presence
or absence of concomitant therapy, such as environ-
mental control, was unspecified. Buspirone hydrochlo-
ride doses were increased if the cat failed to respond.
The dose range (2.5 to 7.5 mg orally every 12 hours)
was only slightly less than doses used in adult hu-
mans.3 Results indicated buspirone hydrochloride to
be effective in approximately 55% of cats, similar to
results of diazepam treatment by the same group,21 al-
though Marder reported diazepam to be effective in
74% of cats that sprayed urine.12 Approximately half
of the responders resumed spraying after buspirone
hydrochloride was withdrawn, in contrast to a similar
study with diazepam in which 91%21 or 75%12 of the
subjects resumed spraying, although the analysis de-
pends on how the operational terms are defined.22 Side
effects included sedation (4 of 62), increased affection
toward owners (12 of 62), and agitation after pill ad-
ministration (5 of 62).
Overall presented a case report of a cat whose prob-
lems of urine spraying and social withdrawal recurred
with long-term diazepam therapy.22 With buspirone hy-
drochloride therapy (2.5 mg orally every 12 hours), the
cat stopped spraying and exhibited more exploratory
behavior, although the behavior problems recurred
when attempts were made to withdraw the medication.
In a complex case of a dog exhibiting dominance-relat-
ed aggression and fearfulness with circling, Overall used
buspirone hydrochloride, in addition to behavior thera-
py, to reduce fearfulness and generalized anxiety, al-
though it had no effect on circling behavior.28
MOOD STABILIZERS
Lithium, carbamazepine, and valproic acid are dis-
similar compounds used in human psychiatry as mood
stabilizers in the treatment of bipolar disorder and to
reduce impulsivity, emotional reactivity, and aggression.
In humans, bipolar disorder is characterized by episodic
mood swings, typically with periods of mania and de-
pression. Carbamazepine and valproic acid also are used
as anticonvulsants, but this is not clearly related to their
mood-stabilizing effects.
Pharmacology and Mode of Action
Lithium has been used therapeutically for more than
150 years.29 Lithium is an element and is not metabo-
lized but is excreted by the kidneys. Its elimination
half-life in humans is from 18 to 24 hours and is sen-
sitive to renal function. In general, lithium enhances
serotonin neurotransmission and may also affect
The Compendium November 1996
dopamine, norepinephrine, and acetylcholine pathways
in certain brain regions.
Carbamazepine has a tricyclic structure similar to
that of the tricyclic antidepressant imipramine hydro-
chloride. As an antiepileptic, it acts on neuronal ion
channels to reduce high-frequency repetitive firing of
action potentials; and it acts pre- and postsynaptically
on multiple neurotransmitter systems, including nor-
epinephrine, dopamine, serotonin, acetylcholine, GABA,
glutamate, and others.29 The specific mechanism for
carbamazepine’s psychotropic actions is unknown.
Valproic acid has multiple effects, but the mecha-
nisms of action are not well understood. It has been
suggested that valproic acid alters the metabolism of
GABA.30
Side Effects
Lithium has a narrow therapeutic index with a rec-
ommended therapeutic serum concentration of 0.8 to
1.2 mEq/L.29 Careful monitoring of serum lithium lev-
els is necessary to reduce the risk of side effects. Toxici-
ty becomes more evident as serum concentrations ex-
ceed the recommended range. Side effects commonly
reported include polyuria, polydipsia, memory prob-
lems, weight gain, and diarrhea. At elevated serum con-
centrations, central nervous system toxicity is manifest-
ed by cognitive impairment, restlessness, fatigue, and
irritability, progressing to delirium, seizures, coma, and
death. Clinicians should consider lithium’s other side
effects and many potential drug interactions.3,29,31 In
human patients receiving lithium therapy, serum lithi-
um levels and measures of kidney function (usually
serum creatinine) are monitored regularly.
The side-effect profile of carbamazepine is more
favorable than that of lithium, although 33% to 50%
of patients taking carbamazepine experience some side
effects.30 Those most commonly reported are transient
dizziness, nausea, fatigue, and blurred vision. Some-
times liver enzymes are elevated transiently. More seri-
ous but rare are blood dyscrasias, including agranulo-
cytosis. Carbamazepine can interact with various other
drugs.30 It is generally recommended that complete
blood counts and liver chemistry profiles of patients
receiving carbamazepine therapy be routinely moni-
tored.
Valproic acid has a better side-effect profile than
lithium, other antiepileptics, and antipsychotics.30 It is
less likely to cause cognitive impairment and rarely
causes renal, thyroid, cardiac, or allergic effects. Dose-
related side effects include gastrointestinal distress,
tremor and sedation, and elevation of hepatic enzymes.
Most of these abnormalities subside with time or re-
duced dosage. Irreversible hepatic failure is rare and id-
LITHIUM TOXICITY ■ BLOOD-LEVEL MONITORING ■ AGGRESSION
Small Animal
iosyncratic. It is recommended that hepatic and hema-
tologic values be monitored periodically.
Applications
Lithium maintenance therapy has been demonstrated
to reduce mood swings in human bipolar disorder.30 Of
particular interest to veterinarians is the reported anti-
aggression effect of lithium therapy.29 Although most
studies have been conducted in institutions, lithium
has been shown to exert antiaggression effects on psy-
chiatric patients, children with behavior problems,
mentally retarded individuals, and prisoners with rage
outbursts.32
Both carbamazepine and valproic acid have been
shown to have similar mood-stabilizing effects. Both
drugs are frequently used as an alternative to lithium
therapy for the treatment of bipolar disorder in human
patients intolerant of or nonresponsive to lithium. Both
drugs have been shown in double-blind studies to be as
effective as lithium and antipsychotics in the short-term
treatment of acute mania and the long-term treatment
of bipolar disorder.30 In cases and small trials, carba-
mazepine has been used successfully in aggressive pa-
tients refractory to conventional therapies. Several of
these individuals had abnormal electroencephalograms
in the absence of seizures, thus suggesting organic dis-
ease.33
The possible value of mood-stabilizing agents in the
treatment of aggression makes them potentially of inter-
est to veterinary behaviorists33; however, these drugs
have received little attention so far. Lithium’s side-effect
profile and requirements for blood-level monitoring
make its use difficult for most practicing veterinarians.
Reisner reported the use of lithium in one dog in the
treatment of dominance-related aggression.34
Although the short elimination half-life (1 to 2
hours) of carbamazepine in dogs35 makes it an unsat-
isfactory choice for seizure control, it may be useful in
the treatment of certain behavior problems. When di-
azepam failed to control aggression in two cats,
Schwartz reported attenuation of aggression with carba-
mazepine (25 mg orally every 12 to 24 hours).18 Val-
proic acid (30 to 180 mg/kg daily in divided oral doses
every 8 hours) has been recommended in large-breed
dogs with idiopathic epilepsy resistant to more con-
ventional therapy.35 This use of valproic acid to treat
seizures in dogs suggests that the drug may be benefi-
cial for certain behavior problems.
OTHER DRUGS
This review focuses on human psychotropic drugs
and summarizes the studies to date on their use in the
treatment of veterinary behavior problems. Omitted
Small Animal
from this discussion are drugs that historically have
played an important role in veterinary behavior therapy
because of their documented psychoactive effects. Such
drugs as barbiturates, antihistamines, narcotic antago-
nists, and progestin hormones6,12,13,36,37 are familiar to
most veterinarians. They have confirmed behavioral ef-
fects but are rarely used therapeutically in human psy-
chiatry. Reasons for this include their nonspecific ef-
fects (compared with those of other drugs) or risks
associated with their use, including fatal overdose or
abuse potential.
Other drugs (e.g., such narcotic antagonists as nalox-
one hydrochloride) are of particular interest for their
role in the treatment of compulsive disorders in
animals.38–40 β-Blockers, such as propranolol or the new-
er agents naldolol or pindolol, reduce signs of fearful-
ness in humans and may have a role in the treatment of
aggression.33 Methylphenidate hydrochloride or dextro-
amphetamine may be used to treat a specific diagno-
sis of hyperactivity.36,41 The reader is referred to reviews
in the veterinary literature for a discussion of these
agents.6,12,13,27,36 Of additional interest are discussions of
specific animal behavior disorders, their applicability as
models of human behavior conditions, and their treat-
ment.42–44
PRACTICE OF BEHAVIORAL PHARMACOTHERAPY
In veterinary psychopharmacology, as in human psy-
chopharmacology, treatment is best accomplished by
initially identifying a set of problem behaviors targeted
for pharmacologic modification. These behaviors should
be quantifiable and should occur often enough that the
owner can notice changes in their frequency or severity
within a reasonable time frame (e.g., before the next vis-
it to the veterinarian).
An important part of this process is the involvement
of the pet owner as behavior observer. Rarely do behav-
ioral problems present themselves in the office, where
the treating veterinarian can effectively assess the fre-
quency and severity of the behaviors in the absence of
the owner. The pet owner needs to understand and
agree with the selection of behavioral targets and must
be able to identify and report on any changes in the be-
havioral targets attributable to the drug treatment. Fur-
ther, the owner needs to understand that behavioral
problems are rarely cured but frequently improved. This
process of establishing a realistic groundwork of under-
standing and expectations is central to the effective prac-
tice of veterinary behavioral pharmacotherapy. A solid
basis for clear communication between veterinarian and
owner about the frequency and severity of target behav-
iors before and during drug treatment must be estab-
lished from the start.
TARGET BEHAVIORS ■ THERAPEUTIC TRIALS ■ EXTRALABEL USE ■ DRUG SELECTION
The Compendium November 1996
Once target behaviors are agreed upon, the decision
about which drug to use becomes a question of which
drug is most likely to have a beneficial influence on
these target behaviors. This selection of a drug begins
with an understanding of the various types of avail-
able drugs, their general behavioral actions, side ef-
fects, and previously reported therapeutic effects in
animals. Many of these drugs have similar behavioral
effects and differ only in pharmacokinetics or side-
effect profiles. A thorough working knowledge of a
few different behaviorally active drugs will therefore
be more beneficial to the practicing veterinarian than
a less complete knowledge of a large number of simi-
lar drugs.
Drug selection in veterinary behavioral pharmaco-
therapy has in the past been guided by personal experi-
ence, extrapolation from the human literature, a few
case reports in animals, and a “best guess” approach ap-
plied case by case. Recently, there have been more at-
tempts to generate scientific studies of psychopharma-
cologic treatment of animals to help the clinician in the
selection of a therapeutic agent. Despite this trend,
finding a drug that actually improves the target be-
haviors often involves repeated therapeutic trials with
different agents.
Once a drug is selected, the expected behavioral ef-
fects and possible side effects are discussed with the
owner, and the therapeutic trial begins. If the initial
drug trial is unsuccessful, either because of lack of posi-
tive behavioral effect or intolerable side effects, an alter-
native drug should be chosen. In the case of lack of de-
sirable behavioral effect, pharmacologically different
agents should reasonably be tried on successive thera-
peutic trials. Where side effects caused problems but
positive behavioral effects were achieved, similar drugs
with different side-effect profiles should be tried.
Veterinarians have available to them an increasingly
large number of behaviorally active drugs. Many of
these drugs are relatively new in human psychiatry and
are just beginning to be applied in veterinary medicine.
Caution should be exercised in applying these drugs to
species, such as dogs or cats, for which they have not
been formally tested. Veterinarians should obtain all
available information on the effectiveness and safety of
the agent in the relevant species and discuss with their
clients the agent and its documented use in veterinary
medicine. Then, veterinarians can expect to improve or
ameliorate an increasingly large number of their pa-
tients’ behavioral problems.
ACKNOWLEDGMENTS
The authors thank Sukey Jacobsen, Donna Witt, and
Jacqueline Gadison for assistance with library research.
Small Animal
About the Authors
Dr. Barbara Simpson is affiliated with The Veterinary Be-
havior Clinic, Southern Pines, North Carolina, and is a
Diplomate of the American College of Veterinary Behav-
iorists. Dr. Dale Simpson is affiliated with the Department
of Psychiatry, Moore Regional Hospital, Pinehurst, North
Carolina, and is a Diplomate of the American Board of
Psychiatry and Neurology.
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