Download Practical Psychopharmacology for the General Practitioner Valarie V

Practical Psychopharmacology for the General Practitioner
Valarie V. Tynes, DVM, DACVB
Premier Veterinary Behavior Consulting
Sweetwater, Texas
[email protected]
The most important thing to remember about using psychotropic medications is that used
alone, they rarely solve any behavior problem. Psychotropic medications should be considered
just one of the tools in our toolbox for treating behavior problems. As is the case with most
home improvement projects, many tools are needed to successfully complete a job. In the case
of behavior problems the commonly used tools are avoidance of things that trigger the
behavior, modification of the inappropriate behavior with some form of learning (training), and
medications, if desired, to raise an animal’s threshold for performing the behavior or lower
their anxiety level making it easier for them to learn. This complete program cannot be
developed without a thorough history, an accurate diagnosis and time to explain the behavior
modification protocol. If you do not have the time or desire to do this then the only role
medication should play is as a part of behavioral triage, ie, keeping the animal safe until it can
see a qualified behaviorist.
In this presentation, psychotropic medications will be discussed according to their class. Most
classes are defined by the particular neurotransmitter/s that they affect. Which
neurotransmitter is affected also helps to explain what the common side effects and
contraindications are for each particular drug.
Benzodiazepines
Benzodiazepines work by facilitating the transmission of alpha aminobutyric acid (GABA) in the
central nervous system. GABA is the major inhibitory neurotransmitter in the brain. GABAergic
neurons are widely distributed throughout the brain where they serve important regulatory
functions such as vigilance, anxiety, muscle tension, memory and epileptogenic activity. The
primary functions for which we use benzodiazepines in veterinary medicine are: reducing
muscle movement and anxiety and controlling seizure activity.
Generally speaking, benzodiazepines have a rapid onset of action with effects that can last for a
few to several hours. Clinicians should use caution when giving benzodiazepines to animals that
may be aggressive as they have the potential to lead to disinhibition of aggression. They may
also lead to increased affiliative behavior. At low doses benzodiazepines have a calming, antianxiety affect and at higher doses they may be sedating. Paradoxical excitation seems to be a
relatively common problem noted when prescribing benzodiazepines. If this occurs, increasing
the dose should be tried first. If excitation occurs again, then switching to a different
benzodiazepine should be tried before abandoning use of the class completely in that
individual. Due to the possibility for paradoxical excitation, pet owners prescribed
benzodiazepines for their pet should always be instructed to give a “test dose” when they can
be home to observe the pet but before the pet is likely to experience exposure to what it fears.
For example, when dealing with a thunderstorm phobic patient, the “test dose” should be given
on a day when NO thunderstorms are expected.
Benzodiazepines do have the potential to produce addiction so after long term use in an
animal, the dose should be decreased slowly (decrease dose by 25-30% per week) in order to
prevent problems when stopping the drug. Tolerance to the drug is also common so be
prepared to increase the dose when the animal must be on it for an extended period of time.
Benzodiazepines are metabolized in the liver and excreted by the kidneys so their use should be
avoided if liver or kidney disease exists. Idiopathic hepatic necrosis has been documented in
cats receiving diazepam so when prescribing diazepam to cats, blood work should be rechecked
after 3-5 days of treatment Other side-effects include, ataxia, muscle relaxation, increased
appetite, anxiety, hallucinations, muscle spasticity and insomnia. Contraindications for the use
of most benzodiazepines also include glaucoma, pregnancy and lactation.
Some of the more common and practical uses for benzodiazepines include fear and anxiety, in
particular, noise phobias, separation anxiety (usually in conjunction with a TCA or SSRI), feline
urine marking and as an appetite stimulant. Benzodiazepines are an excellent first choice of
medication when dealing with a suspected fear or anxiety related problem. Once an effective
dose has been determined, their immediate action can decrease symptoms, thus slowing or
halting the damage to the human pet bond that may be occurring. The owner can then relax a
little bit while they plan for the referral.
Over dosage with a benzodiazepine may lead to ataxia, prostration, agitation, vomiting,
hyperesthesia, muscle tremors, coma, hypersalivation, aggressiveness and paresis. Treatment
of overdosage is primarily supportive but administration of flumenazil (Mazicon) a
benzodiazepine receptor antagonist may partially or fully reverse the effects. Activated
charcoal can also be administered and if presented within 3 hours of ingestion, induction of
vomiting and/or gastric lavage may also be helpful.
All benzodiazepines have the potential for human abuse so care should be taken when
prescribing and refilling prescriptions for benzodiazepines.
Table 1. Some of the benzodiazepines commonly used in veterinary medicine.
Medication
Dog dose
Cat dose
Useful information
Alprazolam
0.02-0.1 mg/kg q 4h
0.0125-0.25 mg/kg q
8h
Minimal active metabolites
Rapid onset of action
Clonazepam
(Klonopin)
0.1-0.5 mg/kg q 8-12h
0.015-0.2 mg/kg q 8h
Extensive liver metabolism but
less toxic to cats
Diazepam
0.5-2.0 mg/kg q 4h
0.1-1.0 mg/kg q 4h
Multiple active metabolites
Short half life;May potentiate
organophosphates
0.04-0.5 mg/kg q 6h
0.2-1.0 mg/kg q 1224h
No active metabolites
Slower onset but longer
duration of action
(Xanax)
(Valium)
Oxazepam
( Serax)
Tricyclic Antidepressants
The tricyclic antidepressants (TCAs) affect numerous different neurotransmitters and each TCA
has varying degrees of effect on each of these neurotransmitters. To different degrees they
may block norepinephrine and serotonin reuptake, have anticholinergic and antihistaminic
effects and act as alpha adrenergic antagonists.
The TCAs have anxiolytic, anticompulsive, antidepressant and antiaggressive effects. However,
clinicians should avoid using TCAs alone to treat aggression. The limited research that has been
done using TCAs to treat aggression, used it in combination with behavior modification and one
study found this no more effective than placebo combined with behavior modification. The side
effects of TCAs are numerous due to the wide spread affects that they have on several different
neurotransmitters. These include: appetite changes, urinary retention, sedation, constipation,
diarrhea, ataxia, decreased tear production, xerostoma, mydriasis, cardiac arrhthmias,
tachycardia, and changes in blood pressure.
The TCAs have an extremely bitter taste, making them difficult to use in animals unless well
compounded or placed within gelatin capsules. They take several days to weeks to take effect
so they should not be given on an as needed basis. Clients should be informed before beginning
treatment of their pet with a TCA that it should be given for 6-8 weeks before deciding if it has
an effect, assuming that no negative side-effects occur. If serious side effects occur, the
medication should be stopped immediately. TCAs are not addictive and withdrawal symptoms
are unlikely if the drug is withdrawn suddenly. However, if a patient has been on the drug for
several months, it should be withdrawn slowly so as to observe for return of the behavioral
symptoms. TCA’s should not be given with MAOIs (discussed below) such as selegiline and
amitraz (i.e. Certifect). They should be avoided in cases with existing cardiac disease, a history
of seizures and pregnant or lactating females.
In veterinary practice, some of the more commonly used TCAs are clomipramine, amitriptylline
and doxepin. They may be useful in the treatment of anxiety disorders and compulsive
disorders in both dogs and cats, and urine marking, hypervocalization and psychogenic alopecia
in cats. Although amitriptylline does not appear to be as cardiotoxic in dogs and cats as it is in
humans, clomipramine has less cardiogenic effects entirely. Clomipramine is more specific for
serotonin reuptake than the other TCAs so it has less of the unpleasant side effects seen with
amitriptylline. For that reason, and the fact that it is actually approved for use in dogs, it is the
TCA that this author uses first in most cases. However, amitriptylline has more antihistaminic
effects and is somewhat analgesic making it a better choice for some conditions. Clomipramine
may decrease thyroxine levels so while not necessarily contraindicated in cases of thyroid
disease, it can complicate treatment, requiring more frequent monitoring of thyroid levels. It is
simply easier to use an SSRI in those situations. Doxepin is the TCA with the most antihistaminic
effects of all medications in the class. It has less of the anticholinergic side effects and less
effects on serotonin and norepinephrine. For this reason it is not a bad choice when faced with
a case where pruritus is leading to hair loss but anxiety or compulsive behavior may be
contributing as well.
In case of overdose with a TCA, the patient should be treated with supportive therapy. There is
no antidote. Vomiting is contraindicated.
Table 2. Doses for some of the more commonly used TCAs
Medication
Dog dose
Cat dose
Amitriptylline
1.0-6.0 mg/kg q 12h
0.5-2.0 mg/kg q 12-24h
Clomipramine
1.0-3.0 mg/kg q 12h
0.25-1.3 mg/kg q 24h
Doxepin
3.0-5.0 mg/kg q 8-12h
0.5-1.0mg/kg q 12h
Selective Serotonin Reuptake Inhibitors
Selective serotonin reuptake inhibitors (SSRIs), as the name implies, lead to increased levels of
serotonin in the synaptic cleft while having minimal effects on other neurotransmitters. The
SSRIs are classified as antidepressants, however, they have anxiolytic, anticompulsive and some
antiaggressive effects as well. They contribute to mood elevation and calming, with minimal
sedation and no impairment of learning.
When pet owners report side effects of the SSRIs, anorexia and sedation are the most common.
In most cases, the side effects decrease with time and they almost always disappear completely
if the medication is discontinued. Other side effects that have been noted in a variety of species
are: constipation, diarrhea, urinary retention, anxiety, irritability, agitation, tremors, insomnia,
and decreased libido.
Serotonin syndrome is a condition that has been reported in humans taking excessive
quantities of medications that increase serotonin levels or other medications that are
incompatible with the SSRIs at the same time as SSRIs. Signs may include: tachycardia, tremors,
ataxia, restlessness, seizures, vomiting, nausea, hypotension or hypertension and sudden
death. Due to the risk of serotonin syndrome, a thorough history needs to include a list of ALL
medications being given to the animal. Supplements such as St. Johns Wort work by increasing
levels of serotonin and if the client fails to mention that this supplement is being given, the
addition of an SSRI could potentially lead to serotonin syndrome.
The SSRI fluoxetine has been shown to treat feline urine marking very effectively. The SSRIs may
also be very useful when treating fear and anxiety disorders such as canine separation anxiety
and compulsive disorders. Their anti-aggressive and anti-impulsivity effects make them useful
for treating some forms of aggression. Again, use caution when treating any animal with a
psychotropic medication for aggression. If a thorough understanding of the patients motivation
for using aggression does not exist, it may be ineffective and worse, might contribute to a
disinhibition of aggression. The legal liabilities that exist when treating aggression in pets makes
this a condition that general practitioners may want to avoid treating by referring to a
specialist.
Like the TCAs, the SSRIs should not be used on an as needed basis. They can take several weeks
to take effect, although some people note improvement within a matter of days. Telling the
client that they should give the medication at least 4-6 weeks before deciding if it has an effect,
is a good rule of thumb. The SSRIs should not be given to animals receiving selegiline, amitraz
dips (or Certifect), tryptophan or thioridazine. Treatment with fluoxetine should not be started
until two weeks after discontinuation of selegiline or amitraz treatment. The use of SSRIs
should also be avoided in geriatric patients or those with kidney or liver disease, diabetes,
glaucoma and in pregnant or lactating females. Caution should be used in prescribing them to
breeding animals because of the potential for decreased libido. The SSRIs are strongly bound to
plasma proteins so their use when prescribing other drugs that bind to plasma proteins should
be avoided. Care should be used if administering SSRIs with TCAs, carbamazepine, haloperidol
and benzodiazepines as lower doses of these medications will be required.
The SSRIs are not addictive but similar to the TCAs, gradual withdrawal is recommended. In
case of overdose with an SSRI, treat as you would an overdose of the TCAs.
Table 3. Doses for some of the more commonly used SSRIs
Drug
Dog dose
Cat dose
Fluoxetine (Prozac)
1.0-2.0 mg/kg once daily
0.5-1.5 mg/kg once daily
Paroxetine (Paxil)***
1.0-1.5 mg/kg once daily
0.5-1.5 mg/kg once daily
*** Withdrawal reactions may be more likely with paroxetine than with fluoxetine so gradual
withdrawal is highly recommended.
Monoamine Oxidase Inhibitors
The only monoamine oxidase inhibitor (MAOI) with psychotropic effects that is currently of
importance in veterinary medicine is selegiline (Anapryl). Anapryl is one of the few psychotropic
medications approved for use in dogs and has been found to be useful in the treatment of
canine cognitive dysfunction. Its primary mode of action is by increasing levels of dopamine in
the CNS. However, it also decreases serotonin and norepinephrine reuptake to a lesser degree.
It also increases free radical elimination which may be another method by which it slows
cognitive decline. Selegiline should be given at least 4 weeks before determining its efficacy.
Treat dogs with selegiline at 0.5-1.0 mg/kg once daily. Although not approved for cats, cats do
show signs of cognitive decline that may be improved by treatment with selegiline at the same
dose as dogs. Clients should be informed that since cognitive decline is irreversible, if
improvement is seen with treatment, then treatment should continue indefinitely.
Possible side effects seen with selegiline include restlessness, vomiting, agitation,
disorientation, diarrhea and diminished hearing. It should not be given with TCAs, SSRIs or
amitraz. If discontinuing treatment with selegiline so as to switch to an SSRI, you must wait 5
weeks before beginning treatment with an SSRI. Caution should be used if giving selegeline with
metronidazole, prednisone, trimethoprim sulfa, alpha-2 agonists, and meperidine. Its use
should be avoided in pregnant or lactating females.
In case of overdose with selegiline, emesis and/or gastric lavage may be tried if the patient is
presented within a few hours of ingestion. Diazepam can be used to treat the signs of CNS
overstimulation. Phenothiazines and CNS stimulants should be avoided. Other supportive
therapy should be used as needed.
Azapirones
The only azapirone of veterinary importance (the only one commercially available in the US) is
buspirone. Buspirone is a serotonin 1A agonist and is anxiolytic with virtually no sedative effect.
It is not addictive and can be used in combination with the TCAs or the SSRIs. It may be useful
when treating a variety of anxiety related conditions, such as separation anxiety, feline urine
marking and shy or fearful cats. It may also be useful when treating motion sickness in cats.
The dose for treating cats with buspirone is 2.5-7.5 mg/cat every 12 hours or 0.5-1.0 mg/kg
every 12 hours. Treat dogs with buspirone at 0.5-2.0 mg/kg every 8-24 hours.
Buspirone side effects are very uncommon but in some cases may include dizziness, insomnia,
nervousness, nausea, headache fatigue and mania. Buspirone may take several weeks to take
effect but is safe for use in geriatric and pregnant patients. It should not be given with MAOIs
and caution should be used if giving with erythromycin or itraconazole. In case of overdose,
supportive care should be offered.
Antipsychotics
The antipsychotic used most often in veterinary practice is the phenothiazine neuroleptic
acepromazine. Acepromazine blocks postsynaptic dopaminergic receptors and has some
anticholinergic, antihistaminic and alpha adrenergic blocking effects. It has an antiemetic effect
as well as a depressant effect on the CNS resulting in sedation and muscle relaxation but it has
no anxiolytic effects. While it may be useful as a preanesthetic agent or to aid in restraint, it
should not be used routinely to treat noise phobias or other fear or anxiety related problems.
Miscellaneous
Clonidine is a presynaptic alpha 2-adrenergic agonist. Its original use in humans was as a
hypertensive agent but because of its widespread actions on the noradrenergic system, it has
gained popularity as a psychopharmacologic agent. In veterinary medicine it has been used
primarily in the dog to treat fear or anxiety based problems such as noise phobias, separation
anxiety and fear of car travel. It may be especially useful when paradoxical excitation prevents
the use of benzodiazepines. Clonidine can be given regularly (2 times daily) but is most
commonly used for situational anxieties and/or as an adjunct to other longer lasting
medications such as SSRIs or TCAs. If used for situational anxiety, clonidine should be given
about 2 hours prior to the fear inducing event. The dose range for dogs is 0.01-0.05 mg/kg.
Side effects are uncommon but may include sedation, dry mouth, nausea or constipation.
Clonidine can enhance the CNS effects of other CNS antidepressants such as trazodone,
barbiturates and other sedative-hypnotics. If needed, the effects of clonidine can be reversed
using yohimbine or atipamazole.
Trazodone is structurally unrelated to the other SSRIs but is a weak inhibitor of serotonin
reuptake and a potent antagonist of some serotonin receptors. In humans it has been used
primarily to treat depression and insomnia. Similar to clonidine, trazadone has been used in
veterinary medicine as an adjunctive agent to treat anxiety related problems, when
benzodiazepines have been ineffective or not tolerated by the patient. Clonidine and trazodone
should not be used at the same time as this can lead to a hypotensive event. Trazodone
potentiates the effects of other CNS depressants and can increase levels of phenytoin and
digoxin. A wide range of doses has been reported for trazodone. Two mg/kg as needed is a
reasonable starting dose in most patients. The dose can be slowly increased up to a total of 5
mg/kg/day, depending on the problem and what other medications the animal is taking.
The most common side effects associated with trazodone use are sedation, hypotension and
nausea. Compared to other antidepressants, it is the one with the lowest risk of seizures.
Although, more studies on dose range, efficacy and safety of trazodone are needed, it provides
a therapeutic option when other medications fail to successfully control some behavioral
symptoms.