Drug prescribing must proceed in agreement with local regulations and licensing requirements. Since most drugs used in canine and feline behavior therapy are not licensed for use in pets, they should be used cautiously. Whenever possible, medications licensed for use in the species and for the intended purpose should be used. For off-label use (use not specifically indicated on the product label) or compounded medications, the hospital should ensure full disclosure and the owner should sign a release where appropriate (see Appendix C, form C.9, client form #5, printable version available online), indicating informed consent for the use of a product not licensed for this purpose. However, a release does not absolve the practitioner from liability, particularly if the rationale for selection and use of the drug cannot be medically justified. Caution should be taken to assess carefully whether any concurrent medication, supplements, or diet is being utilized that in any way interact with the medication that has been selected. Of course, owner compliance, including ability to administer the medication, may also impact the choice of medication and whether compounding might be necessary (see below). Owners should be advised as to what behaviors are likely to be improved (i.e., intensity, frequency, severity) and over what time frame, and what side-effects or adverse events might be expected. Although the family should be advised to report any unexpected change in health or behavior immediately, the veterinary clinic should be proactive in regularly contacting the client to assess progress or potential problems. Veterinary literature should be regularly reviewed for reports of adverse effects or changes in dosage recommendations. Although human studies cannot necessarily be extrapolated to animals, it is also advisable to consult the human literature and manufacturers’ data to determine areas of potential concern. Ideally, blood and urine tests should be performed before any behavioral drug is dispensed to rule out underlying medical problems and establish a baseline against which future tests can be measured. Testing should be repeated at regular intervals (minimally once a year) based on the pet’s age and health and the potential side-effects of the medication being used. When there is more than one potentially effective treatment regimen, the safest course of action should be followed (Box 8.1).

In the European Union a standard general procedure exists for drug selection, where the drug of first choice should be one that is licensed for the species being treated, provided there is a suitable choice available. The second choice of drug to consider should be one that has been licensed in another animal species. The third choice should be one that has been licensed for use in humans, and the final choice, when the other three choices are not possible, would be a drug that is available (perhaps on trial or through another country) but is as yet an unlicensed drug.

Although some older medications, such as acepromazine and the progestins, are still in frequent use, newer drugs that are nonaddictive, relatively free of potential organ toxicity, and cause minimal sedation are now available. Many of these drugs exert their effects on the specific mechanisms of behavior regulation that may need to be altered with little or no alteration of other behaviors. In some behavior cases where alterations in physiological neurotransmitter levels or function seem to occur, these drugs may help to re-establish normal neurotransmission. Side-effects may be less common since most selectively target specific neurotransmitter systems.

Evidence-based medicine and veterinary behavioral pharmacology

Most available information on drug therapy for behavior problems in companion animals comes from clinical experience of veterinary behaviorists as well as from inferred comparisons between psychiatric conditions and behavior problems of pets. According to the Oxford Centre for Evidence-Based Medicine scoring system (www.cebm.net), the weakest levels of evidence for measuring therapeutics (levels 4 and 5) are attributed to case-based studies, in vitro research, or expert opinion without crucial appraisal. A systematic review of case-control studies with homogeneity or individual case-controlled studies would receive a higher rating in terms of evidence (level 3), while a systematic review of cohort studies, individual cohort studies, and lower-quality randomized control trials (RCTs) would receive level 2 ratings. The gold standard (level 1a) would be a systematic review with homogeneity of RCTs.¹ However, with few published trials for most veterinary behavioral therapeutics, veterinarians have little access to such rigorous research. Whenever possible, it is clear that RCTs should be the standard way to assess efficacy of drug therapy in behavioral medicine, particularly regarding the placebo effect, which may be responsible for 50% or more of the effects in some behavioral studies. For instance, in a study in which fluoxetine was compared to placebo in the treatment of separation anxiety, the effect of treatment on global improvement ranged from 58.6% to 65.1% while the placebo group had improvements ranging from 43.4% to 51.3%.² In a recent study in which a homeopathic remedy for firework phobias was compared to placebo for the treatment of noise sensitivities, both treatment groups reported a significant level of change over the course of treatment but there was no evidence that the homeopathic remedy had any effect above the control group.^3,⁴ In addition, knowledge of participating in a placebo-controlled trial appeared to have no effect on the owner’s perception of treatment effect.⁴

In prior periods, the amount of published independent clinical trials on psychopharmacology of behavior problems in companion animals was sparse. One of the main limitations for conducting proper controlled clinical trials is the ethical concern of setting up a pure placebo group on a population of owned dogs presented for behavior problems. Fortunately, over the past few years, more and more clinical trials have been conducted on drug treatment of behavior problems of dogs and cats. For example, the vast majority of available studies on the use of fluoxetine to treat canine behavior problems have been published since the year 2000. Recently, a systematic review of RCTs examining the effects of therapeutic agents on urine marking in cats has been published, representing the highest level of evidence for the use of those drugs to treat that particular condition.⁵

A trend is observed in behavioral medicine to focus research on the use of a few molecules to treat a reduced list of conditions. Most published trials on canine behavioral psychopharmacology involve fluoxetine and clomipramine. Separation anxiety is the primary focus of research in most of those papers, followed by compulsive disorders like acral lick dermatitis and tail chasing.

Recently laboratory models have been developed for a variety of behavior problems, allowing for the assessment of drugs, natural supplements, and behavior products in a controlled environment, including minimal subject variability, validated measures of behavior, and removal of owner bias. An example of this approach is the work done by CanCog Technologies (cancog.com) to develop a variety of validated models for: (1) learning and memory tasks in dogs and cats with specific applications for cognitive dysfunction and brain aging (see Chapter 13); (2) fear of noises⁶; and (3) fear of humans.⁷ These models have proven invaluable in validating the efficacy of a number of diets, natural supplements, and drugs that are now licensed for use in dogs and cats. Nevertheless, while laboratory models are an effective means of supporting the efficacy of a product over a placebo or control group, clinical trials in affected pets are necessary to support the efficacy of the product for specific behavioral applications in a real domestic environment.

Compounding might be considered when dose, compliance, or availability is an issue. However, solubility, stability, absorption, and potency are potential concerns. Specifically, drugs that are packaged in blister packs or moisture-proof barriers may not be amenable to compounding into liquid formulations, while drugs originally packaged in light-proof containers may be inactivated if exposed to light. In addition, transdermal medications can be an easy and convenient way to administer medications, particularly in cats. However, in one study the bioavailability of fluoxetine was approximately 10% of oral dosing, and in another study systemic absorption of amitriptyline and buspirone was found to be negligible (compared to oral dosing).^8,⁹ Thus, transdermal medications are not currently considered an effective method to administer psychoactive drugs in dogs and cats.

Drug dosage information is provided in Appendix D.

Understanding drug action and drug selection

In order to decide if medication is needed to treat one particular condition and in that case what drug can be more effective, the clinician needs to consider four elements:

1. What is the presenting clinical condition?

2. What elements of that particular behavior condition could be modified with drugs?

3. How are the drugs integrated in the overall treatment protocol?

4. What are the available drugs and what are their pharmacological profiles?

Target conditions for drug therapy

Clinical trials usually refer to the use of specific drugs to treat a specific diagnosis, like canine separation anxiety, noise sensitivities, or urine marking in cats. Nevertheless, it is important to realize that there are no drugs to treat specific diagnoses, but to modify some of the underlying motivational states, emotions, and mechanisms of behavior control, like fear, anxiety, or the inability to withhold a behavior response.

Most psychotropic drugs used in behavioral medicine exert their effects on the so-called diffuse modulatory neurotransmitters, including serotonin, dopamine, norepinephrine, and acetylcholine (Table 8.1).

Table 8.1 Drugs that affect neurotransmitters

Neurotransmitter	Drugs that increase effects	Drugs that decrease effects
Acetylcholine	Carbachol, bethanechol, cholinesterase inhibitors (donepezil, galantamine, neostigmine, physostigmine)	Atropine, scopolamine curare (blocks N-m nicotinic synapses)
Dopamine	l-DOPA, amphetamine, methylphenidate, apomorphine, bromocriptine, selegiline (MAO-B inhibitor), MAO inhibitors	Neuroleptics (e.g., acepromazine, risperidone)
GABA	Benzodiazepines	Flumazenil
Norepinephrine	Alpha-adrenergics (ephedrine, phenylpropanolamine), amphetamine, MAO inhibitors	Beta-blockers (pindolol, propranolol), alpha-agonist (clonidine), risperidone
Serotonin	Tryptophan, selective serotonin reuptake inhibitors, sumatriptan, MAO inhibitors, buspirone	Cyproheptadine, risperidone

GABA, γ-aminobutyric acid; MAO, monoamine oxidase.

Neurons of the diffuse systems arise from relatively small nuclei of the brainstem and project to extensive areas of the brain, from the limbic system to the neocortex. As a result, the aforementioned neurotransmitters act as modulators of broad aspects of behavior control, including motivation and emotional states, which can be the same across different behavior conditions. This mechanism of action is in clear contrast with the frequent view of neurotransmitters as quite precise and discrete ways of conveying information from one specific part of the central nervous system (CNS) to another. For this reason the same drug is often prescribed to treat apparently different diagnoses. As an example, the array of conditions that can be treated with fluoxetine includes urine marking in cats, separation anxiety in dogs, acral lick dermatitis in dogs, and aggression. The reason is that fluoxetine affects the turnover of serotonin, a neurotransmitter involved in the regulation of wide aspects of behavior, from fear and anxiety to aggression and impulse control.

In addition to the diffuse modulatory pathways, the benzodiazepines act on gamma-aminobutyric acid (GABA), which causes mostly inhibitory effects in the CNS and is involved in the control of areas of clinical relevance such as fear and anxiety.

Many psychotropic drugs act on more than one neurotransmitter system. For instance, clomipramine influences the serotonin turnover, but also has actions on norepinephrine, acetylcholine, and histamine. Furthermore, drugs acting on the same modulatory system can do so by interacting on different mechanisms or receptors for that particular neurotransmitter. The range of pharmacological actions characteristic of each drug is one of the reasons why certain drugs may be more effective to treat one condition than others with an apparently similar profile. Thus, different drugs can be used to treat the same condition and the same condition can be treated with different drugs.

Overall framework of drug therapy

From a clinical perspective, there are four situations where drug therapy might be indicated for behavioral conditions: (1) as an adjunct to behavior therapy; (2) in drug desensitization; (3) when medication is necessary as the primary mode of treatment; and (4) when an underlying pathology is present.

Adjunct to behavior therapy

Psychotropic drugs are most commonly used as an adjunct to behavior therapy. Factors to consider include whether there may be a drug that could help to resolve the problem more quickly, potential adverse effects of the medication, the owner’s commitment to the behavioral program, and the humane considerations for the pet (i.e., whether the pet’s interests might be better served with medication). The treatment of separation anxiety, fears, and phobias, and aggression are examples of conditions in which a drug might help facilitate the initiation and implementation of behavior therapy. For example, studies on the use of clomipramine for separation anxiety showed that there was greater and faster improvement in the group with drugs and behavior modification compared with the group with behavior modification alone (i.e., placebo group).¹⁰ Choosing an appropriate drug may provide an opportunity to resolve the problem in a quicker or safer manner. However, without concurrent behavioral modification, the problem may not improve significantly and is likely to recur when the drug is removed.

Drug desensitization

Drug desensitization is a technique that can be applied when the stimulus cannot be effectively controlled or reduced, or when there are multiple stimuli that lead to fear or aggression. The drug should be given at sufficient dosage so that the pet is relaxed and calm when exposed to the stimulus. By pairing exposure to the stimulus with favored treats, the association can be made even more positive (counterconditioning). Even if the drug alone does not completely calm the pet, it may still be possible to reduce its arousal enough to get the pet to respond to a training command such as focus, sit/stay, or settle, and this response can then be reinforced (response substitution). Drug-aided desensitization should be combined with other behavioral modification techniques such as systematic desensitization, controlled flooding, counterconditioning, and differential reinforcement (see Chapter 7) so that behavioral techniques, rather than the drug itself, are the principal methods of altering behavior. As soon as the successful response (and mood) can be consistently achieved in the presence of the stimulus, the drug can be gradually reduced at subsequent training sessions.

Medication is necessary as the primary mode of treatment

A third indication for drug use is when a behavior problem is unlikely to be corrected by behavioral modification techniques alone. This might be the case for urine marking, compulsive disorders (e.g., acral lick dermatitis (granuloma), tail chasing, spinning). Not only might these behavioral problems require drugs to help control the condition, but it may not be possible to withdraw the drugs without the condition recurring.

Underlying pathology present

A final indication for drug use is when underlying pathology, whether medical or behavioral, is present. Medical problems that may be involved in the expression of behavior problems include endocrinopathies (hyperthyroidism, hypothyroidism, and hyperadrenocorticism), epilepsy, hepatic encephalopathy, interstitial cystitis, cognitive dysfunction syndrome, chronic painful conditions, or neuropathic pain (see Chapter 6). Similarly, behavioral pathology (i.e., where behavioral changes may be due to altered neurotransmitter function) may only improve with appropriate drug therapy. Compulsive disorders, attention deficit hyperactivity disorders (ADHDs), generalized anxiety disorders, and some of the Pageat (French) classifications of behavior disorders (such as hypersensitivity-hyperactivity and dissociative disorders) may require medication to treat the problems effectively (i.e. mental health disorders).

Classification and selection of psychotropic drugs

A psychotropic drug can be named and classified according to different criteria, including the chemical structure, the main pharmacological action, and the most common clinical use. For instance, alprazolam can be referred to as a benzodiazepine, a drug acting on GABA, or an antianxiety agent.

When referring to a drug by the neurotransmitter involved in its main pharmacological action it is important to remember that the vast majority of agents exert secondary actions in other neurotransmitters. These secondary effects may either enhance the therapeutic value of the drug or be responsible for its adverse side-effects.

Labeling a drug for its therapeutic value might seem clear and self-explanatory but it could create some confusion for both the clinician and the patient. Many conditions in human beings, like anxiety or panic, have a clear counterpart in veterinary medicine. However, others, like depression or schizophrenia, don’t. Since most psychotropic drugs used in behavioral medicine are only licensed for humans, clinicians must emphasize to their clients that information contained on the package insert (or in books, brochures, or websites) refers to use in humans and does not necessarily apply to animals. For example, paroxetine is often classified as an antidepressant, but its use in veterinary behavioral medicine cannot be understood in terms of that diagnostic category. Furthermore, it is becoming more and more clear in veterinary behavioral medicine and human psychiatry that very few, if any, psychotropic drugs can be considered diagnosis-specific. Thus, the current trend in human psychiatry is to abandon the terminology based on indications in favor of one referring to the primary effects on neurotransmission or to the chemical structure.¹¹

Before considering the different categories of psychotropic drugs it is important to understand the neurophysiology of the main neurotransmitters involved in their action.

Neurotransmitters

Neurotransmission is a complex process, basically resulting from a dynamic interaction between the neurotransmitter, the presynaptic and postsynaptic receptors, the reuptake pump, and the degradation enzymes. Psychotropic drugs act at varying sites, presynaptically, postsynaptically, and within the synapse. The production and release of the neurotransmitter may be enhanced, drugs may block the effects of the neurotransmitter at the postsynaptic receptor, drugs may affect receptors on the presynaptic neuron as well as on the postsynaptic neuron, and drugs may block the reuptake of neurotransmitter into the presynaptic neuron. Drugs may also act by inhibiting the breakdown of neurotransmitters within the presynaptic neuron or within the synapse.

After being released by the presynaptic neuron, the neurotransmitter interacts with both presynaptic and postsynaptic receptors, resulting in major biological changes within the presynaptic and the postsynaptic neurons. Activation of these sites may influence a variety of physiological activities, including ion movement across the cell membrane, changes in cell membrane potential, and activation of intracellular enzymes, mostly through G-proteins.

Drugs that have molecular conformations similar to that of the primary neurotransmitter can attach to the receptor sites and either mimic neurotransmitter activity (agonists) or block normal neurotransmitter activity (antagonists), depending on the specific character of the molecule. Different receptor subtypes exist for each neurotransmitter, which can have different functions and may be differentially expressed in different brain regions. Many psychotropic drugs are able to target one or more specific subtypes of receptors.

Many presynaptic receptors have a self-regulatory function on the neurotransmitter (autoreceptors). Activation of these sites following attachment of neurotransmitter molecules diffusing through the intercellular space provides negative feedback by having an inhibitory influence on neurotransmitter synthesis and release. Thus, pharmacological blockage or desensitization at these sites results in less inhibition and increased synthesis and release of neurotransmitter molecules.

After detaching from receptor sites, the neurotransmitter molecules are either enzymatically degraded or diffuse to reuptake receptor sites on the presynaptic neuron, where they attach and are transferred into the cell. The reuptake pump decreases the neurotransmitter’s interneural concentration by physically removing molecules from the interneural space, but also indirectly by increasing the intracellular storage pool. This occurs because an intracellular feedback system inhibits neurotransmitter synthesis as the concentration of neurotransmitter increases within the neuron. Thus, the reuptake receptor site provides an excellent target for drug action by effectively increasing the amount of neurotransmitter available to interact with the postsynaptic cell. Many psychotropic drugs exert their action by either blocking the degrading enzyme or blocking the reuptake pump (Figure 8.1).

Figure 8.1 The stages of neurotransmission and receptor.

Up to a certain point, neurons are able to self-regulate neurotransmitter function by controlling the expression of its receptors. When neurotransmitter levels in the synaptic cleft are kept high and sustained, a process called downregulation reduces the number of receptors. If neurotransmitter levels are low, an opposite mechanism of upregulation results in an increase in the number of receptors.

From a clinical perspective, understanding the complexity of neurotransmission is necessary to explain some of the characteristics of drug action. For instance, when a serotonin reuptake inhibitor such as fluoxetine is given, blocking the reuptake of serotonin into the neuron results in an increase in serotonin in the synaptic cleft, which stimulates the postsynaptic receptors. This accumulation of serotonin also activates autoreceptors, which decreases the release of neurotransmitter from the presynaptic neuron. With time, the overstimulated autoreceptors become hyposensitized and inhibition of serotonin synthesis and release wanes, so that the net effect is increased serotonin transmission. This sequence of biochemical changes, including the downregulation of receptors, is the likely reason for the delayed effect of fluoxetine and other reuptake blockers.

The influence of the primary neurotransmitter on the effector cell may be modulated by secondary neurotransmitters, such as polypeptides, as they interact at separate modulator receptor sites on the postsynaptic cell membrane. Attachment of modulatory neurotransmitters at these sites can result in the inhibition or facilitation of the effect of a primary neurotransmitter on the postsynaptic cell. Drugs with a correct fit can also work at these sites to regulate neurotransmitter effect.

The neurotransmitters that are altered by drugs in companion animal behavioral medicine are primarily serotonin, norepinephrine, dopamine, acetylcholine, GABA, and excitatory amino acids such as glutamate. Complex dynamic relationships exist between the different neurotransmitters. For instance, attention to external stimuli results from a balance between the levels of norepinephrine and dopamine.

It is important to realize that the mechanisms of action of most psychotropic drugs have not been fully elucidated. This could be an additional factor to explain the different clinical responses to drugs apparently belonging to the same category.¹⁰

The cholinergic system

Acetylcholine

Acetylcholine’s main involvement in behavior is linked to its action within the CNS supporting mnemonic function through the activation of different structures of the cortex and the limbic system. A defect in central cholinergic transmission may lead to learning and memory deficits and has been found in human patients with Alzheimer’s disease. The adverse effects of many of the psychotropic medications are derived from their ability to block muscarinic acetylcholine receptors and include sedation, dry mouth, and constipation.

Chemistry and pharmacology

Acetylcholine is synthesized from the union of acetylcoenzyme A and choline in the axonal boutons and is stored in the synaptic vesicles. Acetylcholine action is rapidly terminated by the enzyme acetylcholinesterase and most of the choline necessary for the production of acetycholine is obtained through reuptake from the synaptic cleft. It is the only major neurotransmitter not derived directly from an amino acid.

In vertebrates, acetylcholine is the neurotransmitter at all neuromuscular junctions and is involved in preganglionic to postganglionic neurotransmission for both the sympathetic and parasympathetic nervous systems (nicotonic synapses). Nicotonic receptors are excitatory. There are both N-m nicotinic receptors, which are located at the neuromuscular junction leading to muscle contraction, and N-n receptors, which are found in the brain, adrenal medulla, and autonomic ganglia. Acetylcholine is also the postganglionic neurotransmitter of the parasympathetic nervous system (muscarinic synapses). Muscarinic stimulation leads to a decrease in heart rate and cardiac output and arteriole vasodilation, and an active digestive system. Five subtypes of muscarinic receptors have been identified, each acting on a different secondary messenger system. Acetylcholine is present in subcortical structures above the brainstem, especially in the area of the lower part of the basal ganglia named the nucleus basalis of Meynert, which is deeply involved in the neurophysiology of learning.

Atropine blocks muscarinic synapses and therefore the effect of the parasympathetic system at the target organs, while curare blocks nicotonic synapses, thereby paralyzing skeletal muscles. Acetylcholinesterase inhibitors, such as some organophosphate compounds, potentiate the effects of cholinergic activity, while atropine acts as an antidote by blocking cholinergic receptors in the brain.

Monoamines

This neurotransmitter group is divided into catecholamines, indoleamines, and histamine. The catecholamines norepinephrine (noradrenaline), epinephrine (adrenaline), and dopamine are all synthesized from the amino acids tyrosine and phenylalanine, and share a common chemical structure. The indoleamines serotonin (5-hydroxytryptamine) and melatonin are synthesized from tryptophan.

Catecholamines are the neurotransmitters associated with the arousal of the autonomic nervous system. Catecholamine depletion in the brain results in mood changes and locomotor deficits. During stressful or fearful moments, the catecholamines dopamine and norepinephrine are released, resulting in CNS stimulation and anxiety. Chronic stress might lead to exhaustion and depletion of norepinephrine and dopamine and resultant depression. Almost all classes of psychotropic drugs interact in one way or another with the monoamine system. There are numerous catecholamine receptors, including five dopaminergic receptors and four noradrenergic receptors. Many of the receptors affect the postsynaptic neurons by stimulating adenylate cyclase to convert adenosine triphosphate to cyclic adenosine monophosphate, an important secondary messenger.

Serotonin levels are controlled by cellular uptake of tryptophan and the action of tryptophan hydroxylase, which is involved in the rate-limiting step in serotonin synthesis. Tryptophan is discussed in detail in Chapter 9. Inactivation is by reuptake or by breakdown by MAO. An increase in serotonin may be associated with an activation of the pituitary–adrenal axis. A decrease in serotonin may lead to depression, increased anxiety, aggression, and decreased food intake. In humans, altered serotonergic system function is associated with hyperaggressive states, schizophrenia, affective illness, major depressive illness, and suicidal behavior. Increasing or normalizing serotonin levels may be useful in the treatment of depression in people, compulsive and stereotypic disorders, and some forms of aggression and anxiety. Selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) increase serotonin availability by decreasing reuptake, and MAO inhibitors (MAOIs) increase serotonin by decreasing serotonin breakdown. Serotonin agonists have been shown in rat studies to reduce offensive aggression, without blocking defensive aggression. Impulsivity (disinhibition, unpredictability, prolonged arousal) may be correlated with the presence of low serotonin metabolites in the cerebrospinal fluid (5HIAA).¹² This is also true in humans regarding impulsive violent offenders. Serotonin reuptake inhibitors may decrease these forms of aggression while cyproheptadine (serotonin agonist) may increase aggression. In studies of nonhuman primates increased serotonin was correlated with higher social rank but inversely correlated with aggression.¹³ In primate studies, fluoxetine inhibited impulsivity in a resident model.¹⁴ Mice lacking the 5HT1B receptor were more aggressive, while mice lacking 5HT1 receptors were more anxious.^15,¹⁶ Serotonin may act to inhibit aggression, at least in part, by antagonizing the aggression-promoting effects of vasopressin. It has also been suggested that there is a relationship between dopamine and serotonin levels in that higher levels of 5HT may inhibit dopamine release. In fact, one factor in schizophrenia in humans may be decreased inhibition of the release of dopamine by 5HT in the mesencephalon and frontal cortex, and that treatment should help to normalize the relationship between 5HT and dopamine. Recent canine studies have demonstrated differences within breed in 5HT levels between aggressive and nonaggressive dogs.¹⁷^–¹⁹

Histamine

Histamine is found in low quantities in the brain. It may help to regulate body rhythms, thermoregulation, and neuroendocrine functions. Histamine activity is high during the waking state, reduced during slow-wave sleep, and nearly absent during rapid-eye-movement (REM) sleep. Its precursor is histidine. Histamine receptors are found primarily in the hypothalamus. Histamine receptors initiate secondary messenger systems.

Amino acids

Amino acids are the most prevalent of the CNS neurotransmitters. In contrast with the diffuse modulatory systems, they are involved in rapid point-to-point communication. Glycine, glutamate, and aspartate are three of the most important of the 20 amino acids that function as neurotransmitters. Glycine is an inhibitory neurotransmitter of the hindbrain and spinal cord. Glutamate is an excitatory amino acid, which may be produced in abnormal levels in aggression and impulse control disorders. N-Methyl-d-aspartic acid (NMDA) antagonists such as memantine suppress glutamate, as do barbiturates and progestins. Tryptophan, a precursor to serotonin, has been used as a food supplement as a means of enhancing serotonin transmission. Details can be found in Chapters 9 and 11.

Gamma-aminobutyric acid

GABA causes mostly inhibitory effects and is the most widespread neurotransmitter in the brain. It is synthesized from glutamic acid. After it interacts with its receptor, there is active reuptake by the prejunctional neuron. GABA is metabolized by GABA transferase. Seizure activity and Parkinson’s disease may be associated with GABA decreases or disorders, so that GABA agonists such as benzodiazepines can be useful in the treatment of these conditions. GABA agonists may also be helpful in the treatment of anxiety disorders.

Neuropeptides

Endorphins and neurokinins (substance P and NK1)

This group is composed of molecules that are short-chained amino acids. They mainly function as modulators of other neurotransmitters, evoking facilitation or inhibition of neurotransmitter activity at the postneuron receptor site. The opioid system plays an important role in mediating both physical pain and social affective disorders.²⁰ Endogenous brain opioids may be involved in the development and maintenance of social behavior and social attachments. Opioids have been shown to reduce crying and motor agitation in puppies during social isolation. Opioid administration in socially deprived kennel dogs has also been shown to ameliorate chronic emotional distress while opioid blockade (i.e., administration of naloxone) appears to intensify emotionality. On the other hand, since morphine reduces social need, it appears to decrease social solicitation, while naloxone increases solicitive behavior, including tail wagging and face licking.²¹ Therefore opioids may play a role in the development and treatment of fear and anxiety. CNS endorphin release has been implicated in some compulsive disorders involving stereotypic behavior, although the role is still not well understood.

Substance P is a neuropeptide that is found in the spinal cord and CNS; it is a modulator of nociception involved in signaling the intensity of noxious stimuli. Along with neurokinin 1 (NK1), substance P is likely involved in the body’s response to stress, anxiety, invasion of territory, and noxious or aversive stimuli. Substance P is present in the limbic system, including the hypothalamus and amygdala, and may play a role in emotional behavior. NK1 is present in the hypothalamus, pituitary, and amygdala, which play a role in affective behavior and response to stress. In cats, NK1 substance P receptors in the midbrain periaqueductal gray potentiate defensive rage and suppress predatory aggression.²² Substance P is one of the primary neurotransmitters released during tissue and mast cell damage.²³ Blocking substance P might reduce inflammation, pain, nausea, and neuropathic pain.²⁴ Therefore, as a substance P inhibitor (NK1 antagonist), maropitant citrate (Cerenia: Pfizer Animal Health) may reduce neurogenic inflammation, and substance P inhibitors have potential applications for inflammatory conditions in humans.²⁵ Although there have been no published studies to date on its efficacy as an anti-inflammatory agent in pets, it has been reported to be used anecdotally on an extra-label basis for its anti-inflammatory effects at 1–2 mg/kg twice weekly, every other day or 5 days on and 2 days off (Mandelker, L., personal communication, 2010). It should not be used for long-term daily use as depletion of substance P could lead to depletion in dopamine and resultant parkinsonian-like tremors, although in a study of 15 days of daily injections of maropitant citrate in cats at up to 5 mg/kg for 15 days, it was well tolerated with no adverse effects, except for one cat that developed mild tremors during sleep (but no signs when awake).²⁶

For nausea or vomiting, a dose of 2 mg/kg can be used daily PO for up to 5 days; the oral product is not licensed for cats, but has been used at 0.5–1 mg/kg daily PO for 5 days (off label).²⁶ The product is also available in injectable form, and the dosage for acute vomiting is 1 mg/kg SQ once daily, for up to 5 days in dogs 8 weeks of age and older, and in cats 16 weeks of age and older (label indications may vary by country).²⁶ For motion sickness the canine dose is 8 mg/kg daily for 2 days.

Other neurotransmitters

There are numerous other mediators of neurotransmitter release (e.g., encephalins, nitric acid), but further discussion is beyond the scope of this text.

Hormones

Endogenous compounds such as hormones or other substances that are naturally produced by the body have generated renewed interest for the treatment of human psychiatric disorders. The idea is that if we administer substances that the body already has, we can rebalance underlying deficits. Recent studies have shown that estrogen supplementation, growth hormone, and even secretin, which has been trialed in the treatment of autism, may have beneficial effects in depressed patients. Although some may consider that using substances already found in the body is somehow safer, hormone excess can also lead to serious medical problems. Melatonin is covered in detail in Chapter 9.

Vasopressin

Vasopressin, in addition to its effects as an antidiuretic hormone, affects a variety of functions, including cardiovascular regulation, antipyresis, learning, memory, and arousal. In hamster and rat studies, injections of vasopressin in multiple CNS sites led to offensive aggression, while vasopressin receptor antagonists inhibit aggression. It has been hypothesized that, at least in the hamster, serotonin inhibits fighting by antagonizing the aggression-promoting action of vasopressin. A similar reciprocal relationship between vasopressin and serotonin may also exist in humans, so that in some personality disorders associated with aggression there may be elevated vasopressin, which may be inhibited by serotonin.

Main classes of psychotropic drugs

Neuroleptics/antipsychotics

Neuroleptics are drugs that block dopamine receptors in the brain, causing a nonspecific depression of the CNS with a reduction of motor function and reduced awareness of external stimuli. Classical neuroleptics include the phenothiazines, haloperidol, and thioridazine. Neuroleptics have been widely used in veterinary medicine as tranquilizers and also to control motion sickness. Nevertheless, they are currently not considered first-line drugs for any of these conditions.

Phenothiazine tranquilizers, such as acepromazine, chlorpromazine, or promazine, have been used for rapid tranquilization and also to treat the clinical signs associated with fearful, anxious, and phobic behaviors. Tranquilized pets should be cautiously assessed as phenothiazines have a variable effect on aggression, and some patients may be more reactive to noises and may easily startle. Antipsychotics may also be useful in controlling productive signs of canine anxiety such as destruction, escape, and agitation, such as in thunderstorm phobias and separation anxiety. However, they are not true antianxiety agents and their use is limited as adjuncts for behavior modification therapy. Benzodiazepines are preferable to neuroleptics whenever a rapid control of anxiety is required. They specifically target anxiety and do not have the potential side-effects of neuroleptics, which include hypotension (due to alpha-adrenergic blockade), decreased seizure threshold, bradycardia, ataxia, and extrapyramidal signs such as muscle tremors, muscle spasms, muscle discomfort, and motor restlessness. The so-called high-potency neuroleptics, such as perphenazine and haloperidol, are less sedating but with the highest potential for extrapyramidal effects. Caution should be taken in patients with liver disease because of slow hepatic clearance.

Due to their antiemetic properties, antipsychotics have been also extensively used for motion sickness. However, the NK1 antagonist maropitant citrate (Cerenia) offers a better alternative to acepromazine for this purpose, without remarkable sedative effects. The administration of neuroleptics, particularly acepromazine, is still common practice to tranquilize pets in transit. Nevertheless, it should be emphasized that neuroleptics may impair normal balance, thus increasing the risk of injury, as well as causing air obstruction due to abnormal postures. For these reasons, among others, the International Air Transport Association discourages the use of medication, particularly neuroleptics, to control panic attacks.

On the other hand, acepromazine might be particularly beneficial in the sedation of dogs that are too fearful or aggressive to handle or restrain safely and effectively. Oral combinations with benzodiazepines might be effective prior to veterinary visits, grooming, or other potentially fear-evoking events.²⁷ However, intramuscular combinations of either acepromazine or dexmedetomidine plus a narcotic and midazolam are generally highly effective for most procedures (see Chapter 23).

Risperidone has been used in some European countries to treat recently developed sociopathies toward people. Neuroleptics have been utilized in stage 3 deprivation syndrome (deprivation depression associated with sleep disturbances and self-injurious behaviors), in separation anxiety when there are motor disturbances (pipamperone in combination with clomipramine), in some cases of primary dissocialization, in social phobias (thioridazine or fluphenazine), and in stage 2 sociopathies toward humans (in combination with cyproterone and carbamazepine) (see Chapter 22).²⁸

Benzodiazepines

Benzodiazepines can be considered for the treatment of any condition that may have an underlying component of fear or anxiety, including separation anxiety, noise phobias, and some forms of feline inappropriate elimination. They potentiate the effects of GABA, an inhibitory neurotransmitter. This acts to mute the effects of glutamate, the excitatory neurotransmitter from which GABA is made.

Glutamate and GABA are, in fact, a system in balance where GABA controls glutamate, and vice versa. In general benzodiazepines cause decreased anxiety, hyperphagia, muscle relaxation, decreased locomotor activity, and varying degrees of sedation. Benzodiazepines act as mild sedatives at low doses, as antianxiety agents at moderate doses, and as hypnotics at high doses. They may also act as anticonvulsants. Studies of animal models of anxiety have shown that the inhibition related to fear and anxiety can lead to a decrease in eating, drinking, and exploratory behaviors, and an increase in avoidance or aggression, while treatment with benzodiazepines leads to disinhibition, resulting in increased exploration, resumption of appetite, and a decrease in avoidance and aggression.²⁹ However, in some instances, such as where the fear response is one of avoidance, disinhibition could lead to an increase in aggression. In humans and laboratory animals the aggression-heightening effect of benzodiazepines seems to be dose-dependent, with lower doses enhancing aggression. Some evidence from studies on laboratory rodents indicate that certain benzodiazepines such as oxazepam and clorazepate might be safer in terms of their potential aggression-heightening effect.³⁰

Benzodiazepines can cause paradoxical excitability, which can be particularly problematic in situations where a calming effect is desired and is also a concern if the drug is to be administered during periods when there is no owner supervision, such as in separation anxiety. In those situations it is advised before beginning the treatment to test the drug in the owner’s presence. Benzodiazepines may cause a variable degree of anterograde amnesia, which is an inability to create new memories. Amnesic effects of benzodiazepines can have positive or negative consequences depending on how they are integrated in the overall treatment scheme.

In one study examining the effects of diazepam in dogs with behavior problems, it was very effective or somewhat effective in 67% of anxiety-related behavior cases.³¹ Upon discontinuation of diazepam, owners reported either lack of efficacy or adverse effects, ranging from sedation to increased appetite, ataxia, agitation, activity, and aggression. Owners reported greater success when using diazepam for fear of thunderstorms than for separation anxiety. When doses of 0.8 mg/kg were used, there were greater reports of increased activity.³¹ Therefore when side-effects are seen, dose adjustments should be considered or alternative benzodiazepines selected.

Benzodiazepines might be used on an as-needed basis for the treatment of situational anxiety such as with thunderstorms, fireworks, car rides, visits to veterinary clinics, or the anxiety associated with departures in dogs with separation anxiety. They reach peak effect shortly after each dose and can be used alone or in combination with other drugs on an as-needed basis.^32,³³

Benzodiazepines might be useful to facilitate desensitization and counterconditioning in animals showing intense fear, since they decrease anxiety and increase appetite. However, since they can impair learning, the dose should be gradually reduced as the pet begins to show improvement. The amnesic effects of benzodiazepines can be useful for unavoidable exposures to the stimuli causing fear or anxiety, for they might reduce the long-term impact of those negative experiences.

All of the benzodiazepines act as anxiolytic medications and have similar therapeutic effects. But onset of action, duration of effect, intensity of effects, and metabolism differ, so that a particular benzodiazepine might be more suited to a particular application.

In humans, oxazepam and lorazepam are considered short-acting benzodiazepines, alprazolam is intermediate-acting, and diazepam, chlordiazepoxide, and clorazepate are longer-lasting. Clonazepam is also a long-acting benzodiazepine that is indicated for the control of seizures in humans. It may lead to less sedation than some other benzodiazepines. In general, clorazepate, clonazepam, and perhaps oxazepam might be preferable when a longer duration of action is required.

Benzodiazepines are absorbed unchanged from the gastrointestinal tract, with the exception of clorazepate, which is converted to its intermediate metabolite nordiazepam (desmethyldiazepam) in the gastrointestinal tract prior to its absorption. Most benzodiazepines, such as diazepam, are metabolized by the liver and some have active intermediate metabolites that may be more active than the parent compounds. The metabolites are then conjugated by the liver and excreted in the urine. For instance, nordiazepam, which in turn is converted to the active metabolite oxazepam, is an active metabolite of chordiazepoxide, diazepam, and clorazepate. Alprazolam and triazolam have short-lived metabolites with minimal activity. Diazepam and particularly its active metabolites have been reported to cause rare cases of hepatotoxicity in cats and for this reason is no longer considered the benzodiazepine of choice in that species.³⁴ Anorexia can be a sign that the cat is having a hepatic reaction and should be cause for immediate cessation of the drug. Oxazepam and lorazepam have no intermediate metabolites and therefore may be safer for the obese, elderly, or those with liver disease and have less chance of residual or cumulative effects.

In cats, diazepam has been used successfully for spraying, anxiety-motivated inappropriate elimination, anxieties, and fears (including fear aggression). It has also been used successfully to stimulate appetite, to control seizures, and to treat feline hyperesthesia. Diazepam may also decrease predation through its inhibitory effect on acetylcholine. Because of the relatively short half-life in dogs (3.2 hours compared with 5.5 hours in cats), as well as the short half-life of its active metabolite nordiazepam (3.6 hours in dogs compared with 21 hours in cats), its primary use in dogs is alone or in combination with SSRIs or TCAs as adjunct to desensitization programs for fears and fear aggression, and prior to fear- and anxiety-evoking events such as owner departures, thunderstorms, or fireworks.³⁵ However, with continued oral dosing of 1–2 mg/kg TID, steady-state plasma concentrations might be achieved.³⁶

Because of its short duration of action and high potency, alprazolam is most useful for acute fears and panic. In pets, it has been used successfully for some forms of fear- or anxiety-related aggression, as other benzodiazepines may lead to disinhibition and increased aggression. It may also be useful for pets that wake up anxious at night, and in refractory cases of feline inappropriate elimination. At low doses, it may successfully reduce fear and aggression with less effect on motor function than diazepam.

Clonazepam and clorazepate may be useful where the chronic use of a benzodiazepine is needed for the treatment of generalized anxiety states in dogs and cats. Clonazepam has a slower onset of action and may be safer for pets with compromised hepatic function since it has no active intermediate metabolite. Peak concentrations are achieved in 1–3 hours. Clorazepate may have a longer duration of effect than other benzodiazepines, with peak duration of effect of up to 6 hours.

Oxazepam is an effective appetite stimulant for cats and provides a longer duration of action than diazepam. In people, oxazepam is a favored benzodiazepine in the elderly and in patients with impaired hepatic function.

Lorazepam provides more sustained release in people but has a slower onset of action. In dogs it has been reported to maintain therapeutic blood levels for 60–90 minutes at a dose of 0.2 mg/kg.³⁵ It has been used for the control of acute agitation and aggression in people and may be effective for an overly fearful victim cat in cases of intercat aggression. Intranasal administration also maintained plasma levels consistent with anticonvulsant activity in 3/6 dogs for at least 60 minutes.³⁷

Chlordiazepoxide has also been used for urine spraying in cats. Chlordiazepoxide combined with clinidium may be effective for stress-induced colitis.

Long-term use of benzodiazepines may lead to dependence. In humans, benzodiazepines also pose a risk of dependency and abuse; therefore, while drug use by pets can be responsibly controlled by the pet owner, veterinarians should exercise some caution in dispensing and monitoring of benzodiazepine use if they suspect that there might be a potential for human abuse. All benzodiazepines, particularly those of high potency, should be withdrawn slowly (e.g., 10–25% per week). This is especially true in patients administered benzodiazepines for the control of seizures, as status epilepticus may be precipitated if the drug is not tapered slowly. Behavior problems may recur when the drug is withdrawn. In one study, 91% of cases of inappropriate urination in cats recurred when the diazepam was discontinued.³⁸