Abstract

While a limited amount of data has been published regarding the use of the psychotropic drugs in animals commonly kept in zoo environments, that does not mean that the enormous amount of data that does exist regarding these drugs cannot be cautiously extrapolated to help improve the lives of zoo animals. The mammalian brain in particular is remarkably similar from taxon to taxon, so with a knowledge of the neurotransmitters that most affect behaviors and the drugs that most affect those neurotransmitters, appropriate drug choices can be made to assist in improving the welfare of some individuals. While drugs should never be expected to make up for a poor or inappropriate environment, they can be very helpful for animals that are exhibiting maladaptive or malfunctional behaviors regardless of the inciting cause.

Introduction

A minimal amount of peer-reviewed research data has been published on the use of psychotropic drugs in wild animals, and what has been published is mostly in the form of occasional case reports. However, many of these drugs have been in development for decades, and much research exists on their use in a variety of different species, including non-human primates. Veterinary behaviorists have used many of these drugs successfully in pets over the past 20 years by extrapolating what information we do have about their use in humans and laboratory animals. While much remains to be learned about the exact mechanism of these medications, the fact is that they do help improve the quality of life for many animals when used in a rational manner.

What is the most rational manner in which to use these medications? The first and probably most important thing we can do is to change our “mindset” about psychotropic drugs. We need to stop thinking of psychotropic drugs as something that we will use to “change behavior” but rather as a tool that can be used to help put an animal in a state of mind where it can learn. Most animals with problem behaviors are, for a variety of different reasons, experiencing some degree of anxiety or fear. The ability to learn can be seriously impaired when an animal is in a constant state of anxiety. Decreasing anxiety with medication gives us the opportunity to use behavior modification to teach animals alternative behavioral responses or use desensitization and/or classical conditioning to change their response to a particular fear, anxiety, or stress-inducing stimuli.

To ensure the greatest safety for an animal being prescribed a psychotropic drug, a complete blood count and serum chemistry profile should always be performed first. While evidence of the drugs causing organ dysfunction is rare, if an animal had a pre-existing condition that was not yet diagnosed, administration of the drugs could potentially exacerbate it.

Neurotransmitters

Psychotropic drugs are believed to produce their behavioral effects due to their actions on different neurotransmitters in the central nervous system. The neurotransmitters that are particularly pertinent to behavior and behavioral problems are gamma-aminobutyric acid (GABA), glutamate, acetylcholine, norepinephrine (noradrenaline), dopamine, and serotonin.

GABA is an amino acid neurotransmitter that is synthesized from glutamate. GABA neurons are the major inhibitory neurotransmitter in the brain and are widely distributed throughout the central nervous system where they serve important regulatory functions associated with vigilance, anxiety, muscle tension, memory and epileptogenic activity. Benzodiazepines and barbiturates are examples of drugs that act on GABA neurons.

Acetylcholine is the most widely distributed neurotransmitter. Cholinergic neurons are excitatory neurons with pathways distributed throughout the central and peripheral nervous system. Muscarinic cholinergic synapses are found in smooth muscle, cardiac muscle, peripheral autonomic ganglia, and parasympathetic post-ganglionic synapses. Nicotinic cholinergic synapses are found at the neuromuscular junction. Blockade of muscarinic cholinergic receptors is responsible for atropine-like side effects of the antipsychotics and tricyclic antidepressants: dry mouth and eyes, urine retention, constipation, mydriasis, cardiogenic effects (tachycardia), and increased intraocular pressure.

The monoamine neurotransmitters (catecholamines and indoleamines) are related by their chemical structure. These neurotransmitters are concentrated within the hypothalamus, midbrain and limbic system and are stored within vesicles in the axons and nerve terminals. They are primarily inactivated by reuptake at the synaptic cleft, so drugs that block or inhibit their reuptake increase their availability and activity.

The catecholamine neurotransmitters include norepinephrine, epinephrine and dopamine. These neurotransmitters generally produce CNS stimulation. A large portion of the brain’s dopamine is located in the corpus striatum where it modulates the part of the extrapyramidal pathways concerned with coordinated motor activities. Dopamine levels are also high in some regions of the limbic system. Dopamine depletion or inactivation occurs as a result of administration of tranquilizers, neuroleptics or antipsychotics and leads to behavioral quieting, depression and extrapyramidal signs. Excess dopamine release is caused by administration of amphetamines, apomorphine or methylphenidate and has been associated with the development of stereotypies.

Norepinephrine is formed by the hydroxylation of dopamine. Centrally, norepinephrine is stimulating and is postulated to affect mood, the functional reward system and arousal. Peripherally, norepinephrine is the post-ganglionic neurotransmitter of the sympathetic nervous system. Excess noradrenergic activity has been associated with mania, while norepinephrine depletion is associated with depression.

The indoleamine neurotransmitters include serotonin, and melatonin. These neurotransmitters are synthesized from dietary tryptophan. Serotonin (also known as 5-hydroxytryptamine [5-HT]) receptors are found predominantly in the brain and act primarily in an inhibitory manner both pre- and post-synaptically. Different receptor subclasses are responsible for modulation of sleep/wake cycles, mood, and impulse control. 5-HT receptors are widely distributed throughout the brain, and much is still being learned about the far-reaching effects of this important neurotransmitter. There is growing supporting evidence for the role of serotonin in aggression. Impaired synthesis or metabolism of serotonin has repeatedly been found to be associated with increased aggression.^1,11,15 Dogs diagnosed with aggression have lower levels of 5-HIAA (a serotonin metabolite) in their cerebrospinal fluid than control dogs.¹⁴ An inverse correlation between levels of 5-HIAA in the CSF and a history of aggression has been found repeatedly in human, primate and laboratory studies.^7,10,19

Monoamine oxidase is an enzyme that metabolizes norepinephrine, dopamine, and serotonin. Monoamine oxidase inhibitors such as selegiline cause elevation in monoamine neurotransmitters by inhibiting this enzyme.

Once you have a general understanding of the neurotransmitters and their basic effects, it is simplest to speak of the psychotropic drugs by class, as most classes are defined by the neurotransmitters they affect. Knowledge of the general effects of the different neurotransmitters, then helps you to understand the drug effects and why we use them as we do, as well as why the drugs have the side effects they do.

Benzodiazepines

Benzodiazepines are one of the most widely prescribed drugs in the world. They work by facilitating the transmission of GABA in the central nervous system. 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 a variable period of time, generally under a day. Clinicians should use caution when giving benzodiazepines to animals that may be aggressive as they have the potential to lead to disinhibition of aggression.³ To confound matters, however, in laboratory studies, they have been shown to increase affiliative behaviors in some species such as rhesus macaques and they have been found to have a taming effect in some species.^5,6,16 At low doses, benzodiazepines have a calming, anti-anxiety effect, and at higher doses they may be sedating. Paradoxical excitation seems to be a relatively common problem noted when prescribing benzodiazepines in dogs, but we haven’t documented the use of these drugs enough in other species to know how common that may or may not be in other species. If it occurs, generally, we recommend increasing the dose by 25–50% and giving another test dose after the excitation of the first dose wears off. If excitation occurs again, then switching to a different benzodiazepine can be tried before abandoning use of the class completely in that individual. Due to the possibility for paradoxical excitation, it is ideal for a “test dose” of a benzodiazepine to be given at a time when a caretaker can observe the patient for a few hours and when the animal can be separated from its social group for a while, if it is safe to do so. Obviously, depending on the individual you are treating, the problem and the particular environment, it may be safer to switch drugs immediately if you have a paradoxical reaction. This is a decision that must be made by the clinician on a case-by-case basis.

There are many different kinds of benzodiazepines, ranging in duration of action from 3 hours (alprazolam) to 10 hours (clorazepate). When treating pets, benzodiazepines are often just given 30–60 minutes prior to the occurrence of a fear-inducing event. When the events that are disturbing to a particular patient cannot be predicted, a regular dosing regimen should be established.

Benzodiazepines do have the potential to produce addiction, so after long-term use in an animal, the dose should be decreased slowly (25–30% per week) in order to prevent problems when stopping the drug. Tolerance to the drug is also common, so clinicians should be prepared to increase the dose when the animal must be on it for an extended period of time.

Benzodiazepines are highly protein bound, and hypoproteinemia will lead to an increased volume of distribution. They 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 you may wish to avoid its use completely in felids. However, there is limited evidence to suggest other benzodiazepines are particularly dangerous to cats and many of them are used safely in practice on a regular basis. In laboratory studies, clonazepam specifically has been found to be substantially less toxic to cats than chlordiazepoxide, diazepam or flurazepam.³ Other side effects of the benzodiazepines 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.

Benzodiazepines can be very useful when employing multimodal drug therapies, as they can be safely used with other maintenance medications such as SSRIs and SNRIs.

Table 1. Commonly used benzodiazepines and oral dosage information in dogs and cats

GABA Analogues

These drugs work on voltage-gated calcium channels to prevent calcium influx which inhibits the release of excitatory neurotransmitters such as glutamate. This action helps to block pain, increase the seizure threshold and decrease anxiety. Gabapentin is the drug most often used in veterinary medicine. Pregabalin is also available but is still on patent and therefore much more costly. Side effects are infrequent. Withdrawal-associated seizures are reported in humans, so taper use of this medication as a precautionary measure. Avoid the use of the commercial liquid human formulation as it contains xylitol.

Selective Serotonin Reuptake Inhibitors (SSRIs)

Selective serotonin reuptake inhibitors (SSRIs) work by blocking the serotonin transport system (SERT) and as the name implies, this lead to increased levels of serotonin in the synaptic cleft while having minimal effects on other neurotransmitters. With prolonged administration, downregulation of post-synaptic autoreceptors also occurs. 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. Again, these virtually always disappear with discontinuation of the drug.

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. At this time, no case of serotonin syndrome in a pet being treated with psychotropic drugs has been documented, so it is very difficult to say how problematic it may be in any nondomestic species. To avoid serotonin syndrome, medical records need to carefully document all medications and nutraceuticals or supplements being given to an animal. For example, supplements such as St. John’s wort and L-tryptophan work by increasing levels of serotonin, so these types of products could potentially lead to serotonin syndrome if their use goes unnoticed.

The SSRIs should not be used on an as-needed basis. They should be given for at least 6–8 weeks to take effect before considering stopping the drug. At that point, if there are no negative side effects, adding an adjunctive drug may be more practical than stopping the SSRI and restarting another drug that may take 6–8 weeks to take effect. The SSRIs should not be given to animals receiving selegiline, amitraz dips (or Certifect) or thioridazine. While the use of these products may be uncommon in the zoological setting, an awareness of these contraindications could be important. Treatment with fluoxetine should not be started until 2 weeks after discontinuation of selegiline or amitraz treatment. Due to the long half-life of fluoxetine, treatment with selegiline should not be started until 5 weeks after the discontinuation of fluoxetine. 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 tricyclic antidepressants (TCAs), carbamazepine, haloperidol and benzodiazepines as lower doses of these medications will be required.

The SSRIs are not addictive, but gradual withdrawal is recommended. In case of overdose with an SSRI, treatment is supportive.

Table 2. Typical oral doses of two of the more commonly used SSRIs

Serotonin and Noradrenaline Reuptake Inhibitors (SNRIs)

These drugs increase the amounts of both serotonin and noradrenaline available at the synaptic cleft by inhibiting reuptake. As with SSRIs, down regulations of autoreceptors will occur with prolonged administration, thereby increasing efficacy. These drugs also have anticholinergic and antihistaminic effects and act as α-1 adrenergic agonists. TCAs are the most commonly used SNRIs in veterinary medicine and include amitriptyline, clomipramine, desipramine, doxepin and imipramine. Clomipramine is available in a veterinary formulation (Clomicalm®) approved for the treatment of separation anxiety in dogs, so it has received much use in the veterinary field in the last 10 years.

SNRIs are used for the same behavior problems as SSRIs, should be administered long term as a maintenance medication and are given orally once or twice daily. Because of their anticholinergic, antihistaminic and α-1 adrenergic agonistic effects, there can be pronounced side effects which include cardiac arrhythmias, decreased blood pressure, constipation, urine retention, gastrointestinal signs and sedation. As with SSRIs, SNRIs should be used with caution in animals already receiving other medications that affect serotonin levels. TCAs and SSRIs have been shown to artificially lower laboratory thyroid values, so these should be interpreted with caution if evaluated in an animal that has been receiving these medications for more than a few weeks.

Although not addictive, gradual withdrawal is recommended when using these medications.

Serotonin Antagonist-Reuptake Inhibitors (SARIs)

Trazodone is classified as a SARI. At lower doses, it antagonizes serotonin, histamine and α-1 adrenergic postsynaptic receptors.¹⁷ At higher doses it blocks SERT (serotonin transporter) and antagonizes additional postsynaptic serotonin receptors.¹⁷ Recent research indicates that it may also modulate GABA, revealing a mechanism of action separate from that of SSRIs and SNRIs.⁹ Trazodone is rapidly absorbed, reaching peak plasma levels 1 hour after administration and is therefore appropriate for both PRN and maintenance use.⁴ There is some evidence that trazodone works synergistically with SSRIs and SNRIs, and ongoing research in dogs for treatment of anxiety indicates that it is well tolerated.⁴ As with SSRIs and SNRIs, SARIs should be used with caution in animals already receiving other medications that affect serotonin levels. Trazodone is used to treat insomnia in people and has been suggested for use in addressing the sleep cycle changes seen in cognitive decline.

In dogs, a common starting dose for trazodone is about 2–3 mg/kg as needed. The dose can be slowly increased up to a total of 7 mg/kg every 12 hours, depending on the problem and what other medications the animal is taking. Trazodone has been used in cats at doses ranging from 12.5–50 mg per cat as needed.

Azapirones

Buspirone is the main drug from this category used in veterinary medicine. It is often used as an augmentation drug in conjunction with a primary maintenance medication such as an SSRI. It is a serotonin 1A partial agonist and an antagonist of dopamine receptors. It has an anxiolytic effect. It takes 6 weeks or more before reaching maximum effect and is short acting, requiring twice or three times daily dosing. One interesting side effect noted is increased social behavior in cats, and this effect deserves more study in other species.³

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.

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.

Monoamine Oxidase Inhibitors (MAOIs)

MAOIs interfere with the action of monoamine oxidase A and B which are the primary enzymes responsible for the breakdown of multiple catecholamines including serotonin, dopamine, adrenaline and noradrenaline. Increasing these substances should lead to an elevation of mood. Selegiline is the MAOI most often used in the United States. The effects of MAOIs are more extensive than just neurotransmitters. They affect many systems in the body and as such should be used with caution in combination with other drugs. Selegiline is licensed for use in cognitive decline in dogs in the United States and for other behavior disorders in Europe.^2,8 It has some effect on anxiety, but because of its delayed action and restricted use in combination with other medications, it is used less in the U.S. for behavioral problems not associated with cognitive decline.

Alpha-2 Adrenergic Agonists

Clonidine is an α-2 agonist used in humans for the treatment of hypertension, attention deficit hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD) and impulsivity. It works by blocking norepinephrine release from α-2 receptors on presynaptic neurons. A single study showed that clonidine is efficacious in the treatment of canine anxiety.¹² Clonidine takes 1–2 hours to take effect and lasts for approximately 6 hours. Side effects are rare, but the drug should be used with caution in animals with cardiac conditions, as it can cause hypotension.

Antipsychotics

Antipsychotic agents include the phenothiazine tranquilizers, acepromazine and chlorpromazine and the butyrophenones, haloperidol and azaperone. These agents block the action of dopamine. Dopamine depletion results in behavioral quieting, depression and extrapyramidal signs (EPS). EPS are Parkinsonian-like symptoms such as difficulty initiating movements, muscle spasms, motor restlessness, and increased muscle tone resulting in tremors and stiffness.³ In addition, the blockade of dopamine receptors affects brain regions responsible for controlling thermoregulation, basal metabolic rate, emesis, vasomotor tone and hormonal balance. Antipsychotics also produce a state of decreased emotional arousal and a relative indifference to stressful situations. With chronic use, tardive dyskinesia may develop as a result of upregulation of dopamine receptors. This is an inability to control movements and hyperkinesis. Chronic side effects can occur after as little as three months of treatment and are potentially irreversible even after discontinuation of the medication.

Although their effects can be quite rapid, the use of these drugs can produce very inconsistent results, especially when used to treat aggression. They have actually been known to increase aggressiveness in animals with no known history of aggression.¹³ Due to their wide-ranging dangerous side effects and the availability of several safer and likely more efficacious choices, these drugs should not be the first choice of behavioral drugs in any animal species.

Conclusion

While much remains to be learned about the role of the different neurotransmitters on behavior and the effects of the psychotropic drugs, for more than 20 years these drugs have been used successfully to decrease suffering in many animals. With careful extrapolation, the newer, safer drugs such as the SSRIs, the SNRIs and the SARIs should be used more frequently and older classes of drugs such as the antipsychotics only used as a last resort when treating problem behavior in captive wild animals.

Literature Cited

1.  Brunner HG, Nelen M, Breakefield XO, Ropers HH, van Oost BA. Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase A Science. 1993;262(5133):578–580.

2.  Campbell S, Trettien A, Kozan B. A noncomparative open-label study evaluating the effect of selegiline hydrochloride in a clinical setting. Vet Therap. 2000;2:24–39.

3.  Crowell-Davis S L, Murray T. Veterinary Psychopharmacology. United Kingdom: Blackwell Publishing; 2006.

4.  Gruen ME, Sherman BL. Use of trazodone as an adjunctive agent in the treatment of canine anxiety disorders: 56 cases (1995–2007). J Am Vet Med Assoc. 2008;233:1902–1907.

5.  Heise GA, Boff E. Taming action of chlordiazepoxide. Proceedings of the 45th Annual Meeting of the American Society of Experimental Biology. 20:393.

6.  Kumar R, Palit G, Singh JR, Dhawan BN. Comparative behavioural effects of benzodiazepine and non-benzodiazepine anxiolytics in rhesus monkeys. Pharm Res. 1999;39(6):437–444.

7.  Kyes RC, Botchin MB, Kaplan JR, Manuck SB, Mann JB. Aggression and brain serotonergic responsivity: response to slides in male macaques. Physiol Behav. 1995;57:205–208.

8.  Landsberg G. Therapeutic options for cognitive decline in senior pets. J Am Anim Hosp Assoc. 2006;42:407–413.

9.  Luparini MR, Garrone B, Pazzagli M, Pinza M, Pepeu G. A cortical GABA–5HT interaction in the mechanism of action of the antidepressant trazodone. Prog Neuropsychopharmacol Biol Psychiatry. 2004;28:1117–1127.

10.  Mehlman PT, Higley JD, Faucher I, Lilly AA, Taub DM, Vickers J, Suomi SJ, Linnoila M. Low CSF 5-HIAA concentrations and severe aggression and impaired impulse control in nonhuman primates. Am J Psychiatry. 1994;151(10):1485–1491.

11.  Nelson RJ, Chiavegatto S. Molecular basis of aggression. Trends Neurosci. 2001;24:713–719.

12.  Ogata N, Dodman NH. The use of clonidine in the treatment of fear-based behavior problems in dogs: an open trial. J Vet Behav. 2011;6:130–137.

13.  Overall KL. Behavioral pharmacology. In: Clinical Behavioral Medicine for Small Animals. Saint Louis, MO: Mosby; 1997:293–322.

14.  Reisner IR, Mann JJ, Stanley M, Huang Y, Houpt KA. Comparison of cerebrospinal fluid monoamine metabolite levels in dominant-aggressive and non-aggressive dogs. Brain Res. 1996;714(1–2):57–64.

15.  Sandou F, Amara DA, Dierich A, Le Meur M, Ramboz S, Segu L, Buhot MC, Hen R. Enhanced aggressive behavior in mice lacking 5 HT1B receptor. Science. 1994;265(5180):1875–1878.

16.  Schekel CL, Boff E. Effects of drugs on aggressive behavior in monkeys. Proceedings of the Fifth International Congress of the Collegium Internationale Neuro-Psychopharmacologicum. Washington, DC; 1966.

17.  Stahl SM. Mechanism of action of trazodone: a multifunctional drug. CNS Spectr. 2009;14:536–546.

18.  Stahl SM. Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 4th ed. New York, NY: Cambridge University Press; 2013.

19.  Van Praag HM. Serotonergic dysfunction and aggression control. Psychol Med. 1991;21:15–19.