18 Margaret E. Gruen, Barbara L. Sherman, and Mark G. Papich Over the past decade, the use of drugs to influence animal behavior has expanded commensurate with that of human behavioral medicine (Crowell-Davis and Murray, 2006; Simpson and Papich, 2003). Drugs, in combination with behavior modification, have been used to manage difficult animal behavior problems. Often these problems are those insufficiently responsive to nonpharmacological approaches alone and may impact the animal’s health and welfare. In a general way, drugs may decrease arousal, excitability, and impulsivity and promote behavioral calming. More specifically, behavioral drugs may be used to attenuate repetitive compulsive behaviors, modulate aggression, and help manage organic states (Stein et al., 1994). Psychotropic drugs may be used to decrease the latency to response to behavioral treatment (King et al., 2000b). The use of behavioral drugs to reduce fears and anxieties may enhance animal welfare and promote safe and humane handling. Extrapolating from the reports of humans who suffer from anxiety disorders and from our direct observations, highly anxious or fearful animals suffer as well and should be treated, behaviorally and pharmacologically, consistent with our mission as veterinarians to reduce animal suffering. We suggest that, particularly for anxiety-related disorders, pharmacological treatment should be considered as a first, rather than last, resort. This chapter focuses on commonly used behavioral drugs, their presumed mechanism of action, their side effects and their application to clinical veterinary practice. In addition, some new agents, with potential for use in veterinary behavior, are introduced. Although the activities of behavioral drugs have been elucidated in vitro, our knowledge of their activity in the brain of humans or nonhuman animals remains imperfect. Radioactive labeling, advanced imaging, and other techniques have revealed the remarkable complexity of the brain and the interrelationships of systems previously considered distinct. For example, there is increasing evidence that affective disorders are modulated by neuroactive steroids that, in turn, modulate specific neurotransmitters, including those described in this chapter (Eser et al., 2006). In spite of recent expansion in our understanding and application of behavioral drugs, behavioral pharmacology remains in its infancy due to the complexity and multidimensional aspects of behavior. With few exceptions, the drugs discussed herein are approved for use in humans for the treatment of behavioral disorders; their use in animals is extralabel (Simpson and Voith, 1997). Without an approved claim, it has fallen upon veterinary behaviorists, pharmacologists, and other specialists to examine the relevant data and conduct studies to examine the published record on these medications to predict clinical use and response. One of the greatest challenges in evaluating the studies published in human medicine or from laboratory animal studies is to interpret the data in light of the various species differences that exist in pharmacokinetics, drug metabolism, receptor sensitivity, and susceptibility to toxicosis. Pharmacokinetics is covered in more detail in this book in earlier chapters (Chapters 2 and 3). Pharmacokinetics is the science that describes the effect of the body on a drug and a description of the absorption, distribution, metabolism, and elimination (Janicak et al., 2011). In this section are some comments regarding the importance of pharmacokinetic issues to behavior drug therapy. When there is a relationship of the plasma or serum drug concentrations to clinical effect, pharmacokinetics can be helpful to predict pharmacological response. This becomes particularly important when we have few controlled clinical trials of drugs in animals, but comparative pharmacokinetic data. Bioavailability of a drug depends on both the extent and rate of drug absorption. Since most behavior drugs discussed in this chapter are administered orally, absorption becomes a critical pharmacokinetic parameter. Drug absorption is determined by examining the relative concentrations in plasma or serum. These concentrations serve as a surrogate to predict clinical response because the availability of a drug to the central nervous system cannot be easily measured. Drugs administered orally can be absorbed quickly and avoid significant metabolism, be poorly absorbed because of unfavorable dissolution or solubility, or be absorbed from the gastrointestinal tract (GIT) and then undergo first-pass metabolism, which is the process of intestinal or hepatic metabolism prior to reaching systemic circulation. Many of the behavior drugs to be discussed in this article are weak bases, for example, the substituted amines that are the tricyclic antidepressants and other centrally acting drugs. These weak bases generally have good lipophilicity, but poor water solubility. However, most are formulated as water-soluble salts (hydrochloride salts of clomipramine, fluoxetine, buspirone). This allows for more rapid dissolution in the GIT, followed by good permeability in the intestine. Subsequently, the oral absorption of most of these drugs is good. However, these drugs – being lipophilic – are also subject to enzyme metabolism in the intestine and liver. For some drugs, extensive intestinal and hepatic metabolism may render these drugs susceptible to the first-pass metabolic effects, which reduces the overall systemic availability. Drug metabolism is the process whereby drugs are metabolized to active and inactive metabolites or an inactive drug can be metabolized to an active drug (if administered as a prodrug). For the drugs discussed in this chapter, the metabolic fate is determined primarily by hepatic and intestinal metabolism. To our knowledge, there are few drugs used in behavior therapy that are affected much by renal clearance, although the kidneys may be the ultimate route of elimination for conjugated water-soluble metabolites. Many behavioral drugs are substrates for, or affect, cytochrome P450 (CYP) enzymes, which are microsomal drug-metabolizing enzymes (DeVane, 1999; Janicak et al., 2011) located primarily in the liver and GIT. These enzymes have potential for important pharmacokinetic drug–drug interactions. They are designated by family, subfamily, and isoforms by a number and letter sequence (Tables 18.1 and 18.2). In humans the important CYP enzymes include CYP1A2, CYP2C9-10, CYP2C19, CYP2D6, and CYP3A3/4. The enzymes CYP3A3/4 and CYP2D6 are responsible in humans for 50% and 30%, respectively, of known oxidative drug metabolism. Because these enzymes can be both induced and inhibited by certain drugs, such as those classified as antidepressants, concentrations of other drugs, metabolized by the same CYP 450 enzymes, will increase. For example, in humans fluoxetine and paroxetine inhibit CYP2D6, important in the oxidative metabolism of the tricyclic antidepressants (TCAs). When fluoxetine or paroxetine is used in combination with a TCA, a significant increase of the TCA plasma concentration occurs, potentially causing toxicity unless the TCA dose is reduced (Janicak et al., 1997). Table 18.1 Psychotropic agents used in dogs See text for special considerations and side effects. All doses are per os unless otherwise noted Table 18.2 Psychotropic agents used in cats See text for special considerations and side effects. All doses are per os. q HS, at bedtime. One of the problems in veterinary medicine is that the enzymes, and subsequently their substrates and inhibitors, are not as well characterized as in human medicine (Chauret et al., 1997). The enzyme responsible for the greatest proportion of metabolism in humans is CYP3A4 oxidase. There are only low levels of CYP3A4 in dogs and cats, but other enzymes play a larger role (for example, CYP3A12) (Kuroha et al., 2002). Other enzymes present in dogs are the 1A, 2B, 2C, 3A, and 2D families and subfamilies (Chauret et al., 1997; Kuroha et al., 2002; Court, 2013). There are large interspecies differences in the P450-mediated metabolism in dog and cat microsomes compared to human. The variation is in the metabolic activity, as well as the effect of specific inhibitors on P450 enzyme activity (Chauret et al., 1997). Information on the inhibitory activity of drugs on various enzyme systems in humans should not be broadly extrapolated to dogs and cats (Kuroha et al., 2002). The other step in drug metabolism is a biosynthetic reaction called conjugation. Drug metabolic conjugation is the process whereby the drug or metabolite is linked with endogenous compounds such as amino acids, glucuronic acid, sulfate, glutathione, or acetyl (acetate). These polar conjugates are more water soluble and more easily excreted than the parent compound. The conjugated products are usually inactive, but there are exceptions. Just as with the other metabolic reactions, there are tremendous species differences in the conjugation reactions. Dogs lack the ability to acetylate drugs such as sulfonamides; cats have a deficient ability to form glucuronide metabolites with drugs such as salicylate and phenols (such as with acetaminophen metabolites). The rate of hepatic metabolism is measured by hepatic clearance. Clearance is one of the determinants of elimination half-life (T1/2), the time needed for plasma drug concentrations to decrease by 50% (Janicak et al., 2011). Drugs with short elimination half-lives must be given more frequently to maintain a consistent plasma concentration. With repeated dosing, these drugs also achieve steady-state more quickly. Usually after five half-lives, a drug reaches steady-state, the plasma concentration achieved as long as the dosing schedule or other metabolic processes remain constant. Once plasma steady-state is achieved, drug concentration in other tissues, such as the brain, is at equilibrium. The time to reach steady-state is relevant to the use of behavior drugs. Some drugs, such as diazepam in the dog, have short half-lives (T1/2 less than 1 hour) (Papich and Alcorn, 1995). Unless administered more frequently than once every five half-lives, these drugs will never reach a steady-state. On the other hand, drugs with long half-lives will accumulate with chronic dosing and attain steady-state in approximately five half-lives. But, if the half-life is 24 hours or longer, several days may be necessary before the drug accumulates to a level high enough to produce a consistent clinical response. This may be one reason that some antidepressant drugs do not have immediate effects when administered chronically in animals. The physiological distribution of drugs is determined by their lipid solubility and protein binding. The higher the lipophilicity, the greater is the ability to distribute across biological lipid membranes, as long as plasma protein binding is not so high as to limit the diffusion. Because most behavior drugs are weak bases, protein binding is expected to be low for these drugs. However, this is only assumed, because there is little or no published data documenting the true plasma protein binding for these drugs in dogs and cats. Tissue protein binding, or intracellular trapping of drugs, can increase the distribution of drugs from the plasma to tissue compartment. Most of the behavior drugs are unionized and lipophilic at physiological pH. Some may be trapped in the brain or CSF owing to pH partitioning because these spaces are relatively more acidic than the plasma. Because the tissue concentrations may be high relative to plasma concentrations of these drugs, the apparent volume of distribution for this group of drugs is usually greater than 1.0 l/kg. Relevant to the behavior drugs is the distribution across the blood–brain barrier (BBB). The BBB consists of unfenestrated capillaries, with tight junctions that prevent large or poorly lipophilic molecules from passing from the blood to the brain (Pardridge, 1999; Jolliet-Riant and Tillement, 1999). There is also a blood–CSF barrier, but it makes up a relatively smaller component to the distribution of drugs to the central nervous system. The BBB also is comprised of transmembrane pumps that effectively transport drugs (and probably other compounds) from the brain back to the blood stream. One of the best known of these transporters is p-glycoprotein. Some drugs are good substrates for p-glycoprotein and other drugs serve as inhibitors of these pumps (Jolliet-Riant and Tillement, 1999). Details of the autonomic nervous system function and transmission are covered in more detail in Chapters 6, 7, and 8. Presented here are some of the neurotransmitters that are most affected by behavior-modifying drugs. Behavioral drugs act either as stimulators (agonists) or blockers (antagonists) of neurotransmitter receptors, or as inhibitors of associated regulatory enzymes (Baldessarini, 1995; Stahl, 2013). Drugs that modulate naturally occurring neurosignals affect the monoamine neurotransmitters serotonin (5-hydroxytryptamine or 5HT), norepinephrine (NE), and dopamine (DA), as well as acetylcholine (ACh), glutamate, and γ-aminobutyric acid (GABA) receptors, among others. Neurotransmitters have multiple receptor subtypes distributed in specific areas of the body with which they interact. The most selective drugs mimic the natural neurotransmitter’s action at only one receptor subtype. Other substances, such as circulating hormones, pituitary peptides, opioid peptides, and neurokinins can also affect behavior (Stahl, 2013). At the cellular level, neurotransmission alters the function of postsynaptic target neurons. This process, in turn, affects gene expression (Stahl, 2013). The neurotransmitter released from the presynaptic neuron is considered the first messenger. It binds to its postsynaptic receptor and the bound neurotransmitter regulates a second messenger inside the cell of the postsynaptic neuron. This second messenger, in turn, forms transcription factors that, when activated, bind to regulatory regions of genes. This process activates RNA polymerase and the gene is transcribed into its mRNA, leading to translation of the corresponding protein. The protein can influence cellular processes that modulate behavior. Because multiple neurotransmitters are involved in CNS function, each working through multiple receptors, chemical signaling provides the features of both selectivity and amplification. Discussed below are neurotransmitters or regulatory enzymes known to influence behavior and be affected by commonly used behavioral drugs. The monoamine neurotransmitters include norepinephrine, dopamine, and serotonin. It is now known that many neurons respond to more than one neurotransmitter, a process called cotransmission (Stahl, 2013). This may explain why multiple drugs in combination may be particularly effective and why some beneficial drugs act on more than one neurotransmitter. At this time, there is no rational treatment approach based on cotransmission. However, a strategic multiple drug program may enhance treatment success in the future. Norepinephrine (NE) is derived from the amino acid tyrosine, which is transported from the blood and into each noradrenergic neuron by means of an active transport pump (Stahl, 2013). There, tyrosine is acted upon by three enzymes, eventually converting it to dopamine, and then to NE, which is stored in vesicles. NE can be broken down by monoamine oxidase (MAO), located in mitochondria, and catechol-O-methyl transferase (COMT), located outside the presynaptic nerve terminal. There are three postsynaptic receptors for NE that are important for the action of behavior-modifying drugs: β1, α1, and α2. Norepinephrine has little activity on β2 receptors. α2 receptors are also found presynaptically. Called autoreceptors, they regulate NE release via a negative feedback system. Most cell bodies for noradrenergic neurons are located in the locus coeruleus area of the brainstem. This region determines whether attention is focused on the external environment (as in response to a threat) or to internal signals (such as pain). There are many specific noradrenergic pathways in the brain, controlling both psychological and physiological activities. For example, projections from the locus coeruleus to the limbic cortex regulate emotions; projections in cardiovascular centers may control blood pressure. Like norepinephrine, dopamine is synthesized intraneuronally from the amino acid tyrosine. Dopamine (DA) neurons lack the third enzyme that leads to conversion to norepinephrine. The same enzymes that break down norepinephrine (MAO and COMT) break down DA. There are at least five DA receptor subtypes. Best known is the DA2 receptor, which is stimulated by dopaminergic agonists for the treatment of Parkinson’s disease in humans and blocked by DA antagonist antipsychotics. Acepromazine, which is known to most veterinarians, is a well-known dopamine antagonist. Although DA1, DA3, and DA4 receptors respond to antipsychotics, it is not clear to what extent they contribute to the behavioral effects of these drugs. When dopamine receptors are blocked, as with an antipsychotic drug, acetylcholine activity increases. This is because dopamine normally suppresses acetylcholine activity. An increase in acetylcholine activity can lead to extrapyramidal signs, discussed in Section Acetylcholine. Serotonin, is also called 5-hydroxytryptomine or 5HT. The chemistry and pharmacology of serotonin and other transmitters are covered in more detail in Chapter 19. Abnormalities in central serotonin function have been hypothesized to underlie disturbances in mood, anxiety, satiety, cognition, aggression, and sexual drives (Tollefson and Rosenbaum, 1998). Drugs that enhance serotonin are among the most effective modulators of behavior (Simpson and Simpson, 1996a). Abnormalities in serotonin production or metabolism may underlie some behavior problems in companion animals. For example, dogs that exhibit affective (dominance type) aggression have significantly lower levels of serotonin metabolites in their cerebrospinal fluid than nonaggressive control dogs (Reisner et al., 1996). Canine compulsive disorder may be linked to 5HT dysfunction, based on the responsiveness of dogs that exhibit repetitive spinning, object licking, or light chasing to treatment with drugs that inhibit serotonin reuptake (Hewson et al., 1998a; Luescher, 2003). For synthesis of serotonin, the amino acid tryptophan is transported into the brain from plasma. Two enzymes are involved in the conversion of tryptophan to 5HT. Analogous enzymes, transport pumps, and receptors exist in the 5HT neuron. Classification of 5HT receptors was reviewed thoroughly by Hoyer and colleagues (1994). There are two key presynaptic receptors, 5HT1A and 5HT1D, and at least six postsynaptic receptors, 5HT1A, 5HT1D, 5HT2A, 5HT2C, 5HT3, and 5HT4 (Hoyer et al., 1994). As with NE and DA, presynaptic receptors act as autoreceptors that detect high concentrations of 5HT, inhibit further 5HT release, and slow 5HT neuronal impulse flow. Postsynaptic 5HT receptors regulate 5HT release from the presynaptic nerve ending. The 5HT2A, 5HT2C, and 5HT3 receptors are implicated in several serotonin pathways in the CNS (Hoyer et al., 1994). Although some 5HT4 receptors are in the CNS, their action is primarily localized to the gastrointestinal tract. Additional roles of this receptor on gastrointestinal function is discussed with specific drugs in Chapter 46. Serotonergic nuclei are localized to the raphe nucleus of the brainstem (Stahl, 2013). This area has projections to the frontal cortex, which may regulate mood; the basal ganglia, which may control movement and compulsive behaviors; and the limbic area, which may be involved in anxiety and panic. There is evidence that the serotonin system may exert “tonic inhibition” on the central dopaminergic system (Tollefson and Rosenbaum, 1998). This may explain the occasional unexpected occurrence of extrapyramidal side effects during therapy with a selective serotonin reuptake inhibitor (Tollefson and Rosenbaum, 1998). Acetylcholine (ACh) is formed in cholinergic neurons from two precursors: choline, derived from dietary sources, and acetyl coenzyme A, which is synthesized in the neuron. There are two major types of cholinergic receptors: nicotinic and muscarinic. Each of these is further divided into numerous receptor subtypes. There are five muscarinic receptor subtypes, M1 through M5. M1 receptors are found at ganglia. M3 and M4 are found on smooth muscle and secretory organs, such as those of the GIT, and all five subtypes are found in the central nervous system. A nonspecific blocker of muscarinic receptors is atropine. One of the side effects of some behavior-modifying drugs (e.g. tricyclic antidepressants) is to block muscarinic receptors, thus producing cardiovascular, gastrointestinal, and other side effects. Additional discussion of the cholinergic nervous system is provided in Chapter 8. Gamma amino butyric acid (GABA) is the major inhibitory neurotransmitter in the CNS, localized particularly in the cortex and thalamus (Sheehan and Raj, 2009). GABA is synthesized from the amino acid precursor glutamate. Glutamate participates in multiple metabolic functions. The GABA neuron has a presynaptic transporter similar to those of NE, DA, and 5HT. There are two subtypes of GABA: GABAA and GABAB. GABAA subtype receptors are allosterically modulated by benzodiazepine receptors and others. Some of the anticonvulsant drugs that affect the GABA receptor are discussed in Chapter 17. Historically, behavioral drugs were classified according to their first human clinical application (for example, the antidepressant category), although such categorical descriptions have become functionally obsolete. Most behavioral drugs used in human and veterinary medicine have expanded their use well beyond their original clinical application. Traditionally, drugs are further classified according to their chemical structure and neurochemical activity. Tricyclic antidepressants (referring to a common chemical structure) and selective serotonin reuptake inhibitors (referring to neurochemical activity) are examples of drugs classified by their chemical structure and mechanism of action, respectively. The historic and functional drug classifications are retained here, since they provide a useful framework for our understanding of action and side effects of behavioral drugs. Drugs in the same category share many characteristics, including mechanism of action and common side effects. In addition, many reference sources utilize this traditional and logical categorization. The antipsychotics include a number of structurally dissimilar drugs used in humans to treat psychosis, typified by conditions such as schizophrenia, affective disorder, and psychoses associated with organic mental disorders (Nasrallah and Tandon, 2009). Most veterinarians are familiar with acepromazine, one of the drugs in this class that is approved for veterinary medicine (e.g., Atravet, PromAce, or ACE; sometimes incorrectly called acetylpromazine). Acepromazine and other sedatives in this class are discussed in more detail in Chapter 14. Since the conventional antipsychotics produce neurological side effects, they are sometimes called neuroleptics. This term is generally not applied to newer, atypical antipsychotics for which neurological side effects are less likely. Antipsychotics block central dopamine (DA) receptors, particularly of the subtype DA2. Antipsychotics produce ataraxia, a state of relative indifference to external stimuli (Baldessarini, 1995). Most antipsychotics are metabolized by the CYP 450 enzymes belonging to family 2 and 3; therefore it is possible that drug–drug interactions described for people also would be a concern for animals (Simpson and Papich, 2003). Except for acepromazine (and Prolixin for horses), antipsychotics are not commonly used in modern veterinary behavioral medicine for a number of reasons. First, small animals are rarely diagnosed with “psychosis”, and the anxiolytic properties of antipsychotics in animals are minimal. Second, side effects limit their usefulness. When animals are given traditional antipsychotics at relatively high or repeated doses, they often develop catalepsy, a syndrome with immobility, increased muscle tone, and abnormal postures, although reflexes (including the bite reflex) are preserved. Most veterinarians are familiar with the effects of acepromazine on dogs and cats. Third, spontaneous motor activity, caused by dopamine-receptor blockade in the striatum and inactivation of dopamine neurons in the substantia nigra may result from the administration of phenothiazines to animals (Nasrallah and Tandon, 2009). Finally, other important side effects of antipsychotic drugs, summarized below, can be unacceptable. Antipsychotics can cause extrapyramidal signs (EPS) because of their effect of inhibiting the action of dopamine. EPS are most likely in older, high-potency antipsychotics such as haloperidol. EPS documented in humans include pseudoparkinsonism (stiffness, tremor, shuffling gait), akathisia (motor restlessness), and acute dystonic reactions (tightening of facial and neck muscles). The involuntary muscle movements of EPS have been confused with seizures. Antipsychotic drugs may also reduce blood pressure and elevate prolactin levels. One subclass of antipsychotics, the phenothiazines, may disinhibit learned responses (Aronson, 1999) and may inhibit the learning processes necessary for behavior modification techniques. It has been reported in several textbooks that this group of drugs, particularly acepromazine, increases the risk of seizures in animals and may actually be contraindicated in animals at risk of seizures. However, clinical studies have shown that acepromazine does not increase the risk of seizures in dogs (Tobias et al., 2006; Garner et al., 2004; McConnell et al., 2007). These EPS should not be confused with another adverse effect of long-term antipsychotic medication called tardive dyskinesia. Tardive dyskinesia is characterized by oral–facial, limb, or truncal dyskinesia or twisting postures. The differentiation is that EPS usually occur soon after administration of the drugs, while tardive dyskinesia occurs after prolonged chronic treatment. The other important differentiation is that EPS are believed to be caused by a deficiency of dopamine and tardive dyskinesia is caused by an excess of dopamine, or increased dopamine receptor sensitivity caused by chronic administration. Decreasing the dose or withdrawal of the antipsychotic drug will worsen tardive dyskinesia. To our knowledge, tardive dyskinesia has not been described clinically in veterinary patients, though rodent models have been described. Historically, one phenothiazine antipsychotic, acepromazine (PromAce, ACE, Atravet), has been used in the management of veterinary behavior problems, such as noise phobia, by reducing animals’ general attendance to environmental stimuli and producing sedation. The effectiveness of acepromazine as an oral anxiolytic is often disappointing and causes undesirable side effects (Overall, 1998a). However, its intramuscular use may decrease presurgical patient apprehension and reduce the dose of other drugs used as general anesthetics (Light et al., 1993). It also may reduce the dose of other coadministered anesthetics. Owing to the sedative and extrapyramidal effects, acepromazine is not satisfactory for chronic administration. Other agents, such as the benzodiazepines or antidepressants, are preferred because they are more specific for their antianxiety effects and have fewer side effects. A small proportion of companion animals – especially cats – that are administered acepromazine orally will experience spontaneous motor activity, possibly akathisia. A unique adverse effect reported in horses is penile prolapse. It is usually of short duration, but can last as long as 4 hours and can lead to paraphimosis. Because acepromazine is not used to modify behavior in horses, and is used primarily as an anesthetic adjunct, more detailed information about this adverse effect is listed in Chapter 14. Phenothiazines have been used to treat compulsive behaviors not satisfactorily responsive to serotonergic drugs or in combination with serotonergic agents (Goodman et al., 1990). Dopamine has been implicated in some forms of stereotypic behaviors, perhaps because of the effect of serotonin (Kennes et al., 1988). Dopaminergic agents such as apomorphine and amphetamine and the dopamine precursor L-dopa can induce stereotypies in animals (Goodman et al., 1990). Thioridazine has been used in one case of aberrant motor behavior in a dog (Jones, 1987). In 2000, proprietary thioridazine (Mellaril) added a label warning that the drug has been shown to prolong the QTc interval and been associated with arrhythmias and sudden death in humans. It was recommended that thioridazine not be used concurrently with fluvoxamine, fluoxetine, paroxetine, propranolol, pindolol, or any drug that affects the QTc interval of the EKG or the CYP2D6 enzymes. At this time, there is not sufficient information available to recommend safe dosage regimens for the majority of drugs in this class. The side effects associated with the traditional antipsychotics may not apply to the newer drugs, although immobility and transient loss of conditioned responses may be observed. At present their high cost and lack of published data make them impractical for animal use. The anxiolytic drugs include benzodiazepines, azapirones, barbiturates, and antihistamines. Antidepressants (discussed separately, in Section Antidepressants) also have anxiolytic properties. Discussed here are the benzodiazepine and azapirone classes, as well as a special class, nonbenzodiazepine hypnotics. The benzodiazepines (BZDs) constitute a large class of drugs with a long history of safe and efficacious use in humans. Examples used in veterinary medicine are shown in Figure 18.1. All drugs in the class act on BZD receptors in the CNS to facilitate GABAA, an inhibitory neurotransmitter. They are not direct inhibitors of the GABA receptor site, but modulate the GABA receptor to produce the desired effects. After binding to the GABAA receptor, these drugs enhance the GABA-mediated conductance through ionic channels and stabilize excitable membranes. The effects of BZD on behavior may be attributed to potentiation of GABA pathways that act to regulate release of monoamine neurotransmitters in the CNS. Examples of drugs in this class with veterinary application are diazepam, clorazepate, alprazolam, lorazepam, oxazepam, orazepam, and temazepam. Anesthetic uses of benzodiazepines are discussed in more detail with anesthetic agents in Chapter 14. The use of benzodiazepines for treating seizures is discussed in Chapter 17 on anticonvulsant drugs. Figure 18.1 Benzodiazepines used in veterinary medicine. Lorazepam (left), diazepam (center), and clonazepam (right). There are more differences in the pharmacokinetic properties among these drugs than differences that affect the receptor (pharmacodynamic effect). BZDs are used in humans primarily for generalized anxiety disorder or panic disorder (Sheehan and Raj, 2009); they are used similarly in small animals (Simpson and Simpson, 1996b). Dosing schedule can affect pharmacokinetics. For example, diazepam given one time for anxiety will have a lower maximal nordiazepam concentration compared to the same BZD given twice daily (Sheehan and Raj, 2009; Forrester et al., 1990). After oral administration, behavioral responses to BZDs generally occur within 1 hour, although conflicting studies in animals suggest that the anxiolytic effects are greater after they have been administered for several days (File, 1985). Sedation, ataxia, muscle relaxation, increased appetite, paradoxical excitation, and memory deficits may be observed (Roy-Byrne and Cowley, 1991). Tolerance to sedation, ataxia, and muscle relaxation may develop over the first few days of therapy (Löscher and Frey, 1981). Animals may become ataxic and unstable; therefore, pet owners should be cautioned to assist older animals to avoid falls. Animals should be observed for hyperphagia when given BZDs on a regular basis. Agitation and restlessness may occur as an idiosyncratic response to BZDs. Paradoxic reactions of excitement have been observed in dogs, particularly with administration of alprazolam. If these are observed, the drug should be discontinued and another drug from another class should be selected. Amnesia from BZD has been observed in humans for many years (King, 1992). Also, in animals, memory deficits and diminished conditioned responses may be observed, that is the animal may seem to “forget” what it has been previously taught. Difficulty in learning new behaviors, such as desensitization protocols, may be affected by the memory deficits. At routine doses, BZDs have little, if any, effect on cardiovascular and respiratory systems (Sheehan and Raj, 2009). BZDs may disinhibit behavior. In humans, manifestations of disinhibition include hostility, aggressiveness, rage reactions, paroxysmal excitement, irritability, and behavioral dyscontrol (Dietch and Jennings, 1988). These effects are also reported in animals (Dodman, 2000), thus benzodiazepines should be used with caution in aggressive animals, particularly dogs, since bite inhibition may be lessened. The potential for behavioral disinhibition serves as a contraindication for the use of benzodiazepines in fearful but aggressive dogs. Bite inhibition may be diminished and the net effect may be an increased, rather than decreased, tendency to bite. Benzodiazepines are controlled substances with the potential for human substance abuse. Pet owners should be screened prior to prescribing and refill requests should be carefully scrutinized. Although BZDs have a high safety margin, occasionally animals may be exposed to overdoses (accidental ingestion, for example) or have a paradoxical, unexpected reaction. In these instances it may be necessary to reverse the effects. Flumazenil (Romazicon) is a benzodiazepine-receptor antagonist and will inhibit the effects of BZDs. Flumazenil has been used to counteract the adverse effects of large overdoses of BZDs. After daily administration for more than 1 week, a benzodiazepine should be withdrawn gradually to avoid discontinuation syndrome. Discontinuation syndrome, especially common in high-potency benzodiazepines such as alprazolam, includes nervousness, tremors, or even seizures (Roy-Byrne and Cowley, 1991; Roy-Byrne et al., 1993). The longer a BZD is administered and the higher the dose used, the greater the likelihood of withdrawal reactions when it is discontinued, especially abruptly (Janicak et al., 2011). Signs may be reversed by administration of the BZD. Discontinuation syndrome may be avoided by tapering the BZD dose 25% per week for 1 month. If a discontinuation reaction is observed, signs can be relieved by administering the implicated drug. BZDs are used in dogs to treat fears and phobias as well as generalized anxiety. Benzodiazepines may be combined with a tricyclic antidepressant such as clomipramine to decrease latency to effect and reduce the panic-like states of thunderstorm phobia (Crowell-Davis et al., 2003) and separation anxiety (Herron et al., 2008). Among cats, BZDs are used for management of urine spraying, travel, and generalized anxiety, such as anxiety associated with changes in a new home environment. Diazepam (Valium) is the best known of the BZD (Figure 18.1). It has been used for behavior disorders as a sedative, muscle relaxant, anxiolytic, anticonvulsant, and adjunct for anesthesia. Its high lipophilicity and rapid distribution make it suitable for the emergency treatment of seizures because it crosses the blood–brain barrier quickly. Its high lipophilicity also allows it to be absorbed across membranes quickly and is even rapidly and almost completely absorbed from a rectal or nasal administration (Papich and Alcorn, 1995; Musulin et al., 2011). However, the vehicle carrier is not suitable for intramuscular administration. The pharmacokinetics of diazepam are complex, but have been examined in both dogs and cats (Sheehan and Raj, 2009; Löscher and Frey, 1981; Papich and Alcorn, 1995; Cotler et al., 1984; Musulin et al., 2011). Diazepam undergoes metabolism first to a demethylated metabolite, desmethyldiazepam (also called nordiazepam), and then to oxazepam. Both of these metabolites are active, but not as active or as lipid soluble as diazepam. Desmethyldiazepam is believed to have anticonvulsant properties that are equal to (Randall et al., 1965) or about one-third of (Frey and Löscher, 1982) the potency of diazepam. The pharmacokinetics of diazepam illustrate the tremendous species differences in clearance and elimination. In people, diazepam is considered a drug with low hepatic clearance and a long half-life. The half-life in people is 43 hours, (but may range from 24 to 48 hours) and systemic clearance is 0.38 ml/min/kg. In dogs, the half-life was less than 1 hour, and clearance is in excess of liver blood flow at 57–60 ml/min/kg in one study (Papich and Alcorn, 1995), but had a longer half-life of 5.6 hours and slower clearance (11.5 ml/kg/min) in another study (Musulin et al., 2011). Cats have slower clearance than dogs with the half-life in cats of 5.5 hours and the systemic clearance is 4.7 ml/min/kg (Cotler et al., 1984). In all species, the metabolites of diazepam have longer elimination half-lives than diazepam. For example, the half-life of desmethyldiazepam is 51–120 hours in people, 21.3 hours in cats, and 2.2–2.8 or 6.7 hours for dogs (Papich and Alcorn, 1995; Cotler et al., 1984; Musulin et al., 2011). These differences show that for long-term treatment, diazepam is not suitable for dogs because frequent administration is necessary to avoid high peaks and low troughs. However, its short half-life and ability to attain therapeutic concentrations makes it suitable for short-term use. This large difference in pharmacokinetics among species for diazepam means that information published for diazepam in humans will not apply to dogs. For example, CYP 450 enzyme inhibition and other drug interactions cited for people are not likely in dogs because of the already-high systemic clearance. But, because liver clearance is dependent primarily on hepatic blood flow, changes in hepatic perfusion will drastically affect diazepam clearance. Clearance is expected to be altered in dogs with congenital or acquired hepatic vascular shunts. As an oral anxiolytic in solid form in dogs, it has a benign taste, and is relatively easy to administer directly or by mixing in moist food. However, particularly for panic-like states of thunderstorm phobia and separation anxiety, clinicians anecdotally report the anxiolytic performance of diazepam to be disappointing. Because hepatic clearance is high in dogs, oral doses are likely to be less effective than IV doses. If used orally in dogs, high doses may be sufficient to produce ataxia but insufficient to reduce anxiety. Other agents, such as alprazolam, may be more satisfactory, or a regime of daily, rather than PRN dosing, may be more effective. Alternatively, rectal or nasal administration of diazepam can be considered (Papich and Alcorn, 1995; Musulin et al., 2011). In cats, oral diazepam has been used for treatment of urine spraying (Cooper and Hart, 1992; Hart et al., 1993). In open trials, efficacy was approximately 55%, although relapse was common on discontinuation (Marder, 1991; Cooper and Hart, 1992). Concerns about side effects from oral use in cats have decreased its application in veterinary medicine. The most serious adverse reaction associated with diazepam in companion animals is that of idiosyncratic hepatic necrosis in cats. Hepatic necrosis from diazepam is a rare but often-fatal condition, and has been documented in cats given oral diazepam. The specific pathogenic mechanism is not known (Center et al., 1996; Hughes et al., 1996). Diazepam undergoes complex metabolism to intermediate compounds. It is possible that in susceptible cats, an aberrant metabolite is produced that is responsible for the hepatic toxicosis. In the cats reported, the reaction occurred within 7 days of oral administration of generic or proprietary diazepam (Center et al., 1996; Hughes et al., 1996). It is possible that the metabolites responsible for the toxicosis are more likely to be produced from oral administration because of first-pass metabolism, compared to parenteral administration (van Beusekom, 2015). Idiosyncratic hepatic necrosis has not been reported after administration of other oral benzodiazepines, although that negative finding does not eliminate the possibility. However, the adverse event may be less likely with lorazepam and oxazepam, which are conjugated directly without undergoing intermediate metabolism. Alprazolam and temazepam appear to have only one intermediate (alphahydroxy) metabolite before undergoing conjugation. Compared to diazepam, these alternative drugs may be less likely to induce hepatic toxicosis in cats but safety studies are needed to confirm this theory. The BZD clorazepate (Tranxene) is metabolized in the acidity of the stomach to its active metabolite, nordiazepam, before absorption (Sheehan and Raj, 2009; Forrester et al., 1993). Clorazepate is used in dogs for treatment of anxiety disorders, particularly thunderstorm/noise phobia. Mean peak nordiazepam levels were detected approximately 98 minutes after a single oral dose of clorazepate, and 153 minutes after multiple oral doses (Forrester et al., 1990). The elimination half-life after a single dose (284 minutes) was not significantly different than after multiple doses (355 minutes) (Forrester et al., 1990). An oral dose of 2 mg/kg q 12 h maintains concentrations of the active metabolite, nordiazepam, in the range considered therapeutic in humans (Forrester et al., 1990). Excessive ataxia and sedation are uncommon (Forrester et al., 1990). Although available in a sustained-delivery formulation, one pharmacokinetic study in dogs found no difference in the serum disposition compared to immediate-release clorazepate (Brown and Forrester, 1991). Alprazolam (Xanax) is a high-potency benzodiazepine shown in humans to be an effective treatment for panic disorder (Figure 18.1). Its use has increased since the availability of generic forms. It is used in dogs to treat the panic-like states of separation anxiety, thunderstorm phobia, and other phobias, as well as generalized anxiety. In people, it has a more rapid onset of action and shorter elimination half-life than diazepam, but these comparisons have not been reported for animals. In humans (Sheehan and Raj, 2009; Brandwein, 1993), plasma concentrations vary greatly among patients administered identical doses of alprazolam. As in humans, higher doses of alprazolam may be required for panic-like states in dogs, such as thunderstorm phobia and separation anxiety, compared to general anxiety. Thus, individualized dosing may be required to achieve treatment success with the fewest adverse effects (Sheehan and Raj, 2009). Paradoxical excitement occurs in some canine patients given alprazolam. In such cases, the drug should be discontinued and a drug in another class should be selected. The mechanism of this paradoxical reaction is not known. Canine patients receiving alprazolam at a moderately high dose once a day, as may occur with separation anxiety or thunderstorm phobia, are at risk for withdrawal-induced anxiety or tremors prior to the next day’s dose, due to its short elimination half-life (Crowell-Davis and Murray, 2006). This may be avoided by administering the drug twice a day and not skipping doses. To terminate the drug, alprazolam should be withdrawn slowly, decreasing the dose over weeks. As mentioned previously, oxazepam (Serax) and lorazepam (Ativan) are metabolized directly via phase II conjugation to inactive compounds (Sheehan and Raj, 2009). Both oxazepam and lorazepam have been used by veterinarians as sedatives, anxiolytics, and anticonvulsants, but they are not as well-known as diazepam. In cats, oxazepam has been used as an appetite stimulant. There are no active metabolites for either oxazepam or lorazepam. Because conjugation reactions are usually preserved, even when there is hepatic disease, these drugs are recommended for individuals with compromised liver function, for aged canine subjects in which metabolism may be slowed (Sheehan and Raj, 2009), and in cats, in which phase II metabolism may be less likely to trigger idiopathic hepatic necrosis. Lorazepam has the advantage of a greater and more prolonged distribution to the CNS than other BZDs. Lorazepam in healthy dogs has a half-life of 0.88 hours, a systemic clearance less than half that of diazepam at 19.3 ml/min/kg, and oral availability of 60% (Papich, unpublished research). Therefore, as an oral drug it may be a suitable alternative to diazepam. In dogs, benzodiazepines may be used with tricyclic antidepressants for treatment of thunderstorm phobia (Crowell-Davis et al., 2003) and separation anxiety (Takeuchi et al., 2000). When alprazolam is given concomitantly with fluoxetine in humans, the result is a 30% increase in alprazolam levels (but no significant increases in fluoxetine or norfluoxetine plasma concentrations) due to CYP3A inhibition (Lasher et al., 1991). Therefore, coadministration may permit a lower dose of alprazolam to be effective. Fluvoxamine inhibits the CYP3A4 enzyme and can be associated with increased levels of alprazolam (Sheehan and Raj, 2009). In fact, the use of a BZD and an SSRI is a useful strategy with panic disorder in humans refractory to single drug therapy (Stahl, 2013). Similar strategies may be helpful in animals, particularly dogs. Oxazepam has been shown in humans to decrease turnover of serotonin and norepinephrine (Sheehan and Raj, 2009). In contrast, in one pharmacokinetic study in dogs, clorazepate was used concurrently with phenobarbital (Forrester et al., 1993). The amount of the active metabolite nordiazepam in circulation during each dose interval was significantly reduced compared to administration of clorazepate alone (Forrester et al., 1990). This class of anxiolytics is represented clinically by one drug, buspirone (Buspar). Buspirone was the first nonsedating, nonbenzodiazepine anxiolytic drug to be developed and marketed (Robinson et al., 2009). Buspirone acts as a full agonist at presynaptic 5HT1A receptors, with resulting decrease in serotonin synthesis and inhibition of neuronal firing. It also acts as a partial agonist at postsynaptic 5HT1A receptors. In serotonin deficit states, buspirone acts as an agonist (Robinson et al., 2009). Buspirone also has dopaminergic effects. Buspirone is not a substrate for CYP 450 enzymes, nor does it inhibit them (Robinson et al., 2009). It has no interactions with benzodiazepines and there are no withdrawal concerns after long-term use (Stahl, 2013). In humans, buspirone has been effective for treatment of generalized anxiety disorder, but not for the control of panic disorder. Buspirone has demonstrated efficacy in certain animal models of anxiety, such as the conditioned avoidance response. In dogs, buspirone does not appear to be particularly therapeutic for the panic-like condition of thunderstorm phobia or separation anxiety, but it has been used for generalized anxiety. Because it has a short elimination half-life, buspirone must be administered two or three times per day. Buspirone has a benign taste and may be given with food. In contrast to benzodiazepines, buspirone produces no sedation, no memory or psychomotor impairment, and no disinhibition phenomenon. Unlike the benzodiazepines, buspirone produces no immediate behavioral effects. Its beneficial effects are not observed until administration for several weeks. Side effects are uncommon and mild, but may be noted immediately. They include gastrointestinal signs and alterations in social behavior (often reported as increased “friendliness”). Buspirone has no potential for human abuse. In cats, buspirone is used to modulate states of high arousal, including feline urine spraying. In an open trial, improvement was observed in 55% of cats, with a 50% relapse rate following the cessation of treatment (Hart et al., 1993). It has also been used to reduce anxiety in the “pariah” cat in cases of intercat aggression within a household (Overall, 1994a, 1999a). Buspirone can be used to augment certain antidepressants. If used with an SSRI, increased efficacy is possible if intraneuronal serotonin has been depleted. Buspirone also may act directly on autoreceptors to inhibit neuronal impulse flow, possibly allowing repletion of 5HT stores. Also, buspirone may act at 5HT1A receptors to aid in the targeted desensitization of 5HT1A autoreceptors (Stahl, 2013). In humans, buspirone may be used to augment SSRI treatment for obsessive–compulsive disorder (OCD) with success in some studies (Janicak et al., 2011) but not others (Grady et al., 1993). In dogs, buspirone has been used with tricyclic antidepressants to treat separation anxiety (Takeuchi et al., 2000) and with an SSRI (fluoxetine) to treat a complex case involving anxiety, aggression, and stereotypic behavior (Overall, 1995). In cases of acute-onset and severe phobic states, such as thunderstorm phobia and separation anxiety, there is a need for safe and rapid reduction in responsiveness to environmental stimuli and initiation of sleep, with relatively short duration of action and rapid recovery. The unpredictable and often disappointing effect of benzodiazepines and phenothiazines, and the long latency to effect of buspirone, leave a void with regard to such application. Nonbenzodiazepine hypnotics hold some promise, since they are used to facilitate and maintain sleep for 3–7 hours in humans, although no published reports on their clinical use in dogs are available to date. Drugs in this class include zaleplon (Sonata), eszopiclone (Lunesta), and zolpidem (Ambien). These drugs are sometimes referred to as the Z-drugs
Drugs Affecting Animal Behavior
Introduction
Pharmacokinetic Issues for Behavior Drugs
Absorption, Metabolism, Clearance, and Distribution
Drug class
Drug name
Dose in dogs
References
α2 agonist
Clonidine
0.007 – 0.049 mg/kg PRN or q 12–24 h
Ogata and Dodman, 2011
α2 agonist
Detomidine
0.35 mg/m2 OTM
Hopfensperger et al., 2013
α2 agonist
Dexmedetomidine
Dogs: 125 μg/m2 OTM
May re-dose q 2–3 h
Cats: 40 μg/kg OTM, IM
FDA, 2015
Slingsby et al., 2009
Benzodiazepine (BZD)
Diazepam
0.55–2.2 mg/kg PRN
Papich, 2016
BZD
Alprazolam
0.02–0.1 mg/kg q 8–12 h
0.02 mg/kg PRN (w/clomipramine)
Landsberg et al., 2013
Crowell-Davis et al., 2003
BZD
Clorazepate
2 mg/kg q 12 h
Papich, 2016
Forrester et al., 1990
BZD
Lorazepam
0.02–0.1 mg/kg q 8–24 h
Mills and Simpson, 2002
BZD
Oxazepam
0.2–1.0 mg/kg q 12–24 h
Landsberg et al., 2013
Azapirone
Buspirone
2.5–10 mg/dog q 12–24 h or
1.0–2.0 mg/kg q 12 h
Papich, 2016
Tricyclic antidepressant (TCA)
Amitriptyline
2.2–4.4 mg/kg q 12–24 h
2 mg/kg q 24 h
0.74–2.5 mg/kg q 12 h
1–2 mg/kg q 12–24 h
Juarbe-Diaz, 1997a,b
Takeuchi et al., 2000
Reich et al., 2000
Papich, 2016
TCA
Clomipramine
1–3 mg/kg q 12 h
1–2 mg/kg q 12 h
1–2 mg/kg q 12 h
1–2 mg/kg q 12 h
3 mg/kg q 12 h
3 mg/kg q 24 h
Papich, 2016
King et al., 2000b
Moon-Fanelli and Dodman, 1998
Seksel and Lindeman, 2001
Hewson and Luescher, 1998a,b
Rapoport et al., 1992
TCA
Imipramine
2–4 mg/kg q 12–24 h
Papich, 2016
Selective serotonin reuptake inhibitor (SSRI)
Fluoxetine
Start 0.5 mg/kg q 24 h, increase to 1.0 mg/kg q 24 h
1 mg/kg q 24 h
0.96 mg/kg q 24 h
20 mg/dog q 24 h
Papich, 2016
Dodman et al., 1996a
Rapoport et al., 1992
Wynchank and Berk, 1998a,b
SSRI
Paroxetine
0.5–1 mg/kg q 24 h
Papich, 2016
SSRI
Sertraline
3.42 mg/kg q 24 h
2.5 mg/kg q 24 h
Rapoport et al., 1992
N. Dodman, Pers. Comm. 2000
Larson and Summers, 2001
Monoamine oxidase inhibitor (MAOI)
Selegiline
0.5–1.0 mg/kg q am
Calves, 2000
Atypical antidepressant
Trazodone
2–5 mg/kg q 12 h and/or bolus 1+ hour prior to an anxiety-inducing event
To facilitate postsurgical calming
Gruen and Sherman, 2008; Simpson and Papich, 2003
Gruen et al., 2014
Mirtazapine
Small dogs: 3.75 mg q 24 h
20–35 pounds dogs: 7.5 mg q 24 h
40–50 pounds dogs: 15 mg q 24 h
>75 pounds: 22.5 mg q 24 h
>100 pounds: 30 mg q 24 h
Cats: 1.88 mg per cat once a day or once every other day
Quimby and Lunn, 2013
Anticonvulsant
Phenobarbital
0.45 mg/kg q 24 h
1.5–2.0 mg/kg q 12 h
5 mg/kg q 12 h (with clorazepate)
2–8 mg/kg q 12 h
Crowell-Davis et al., 1989
Dodman et al., 1992
Forrester et al., 1993
Papich, 2016
Carbamazepine
4–8 mg/kg q 12 h
Holland, 1988; Haug, 2008
Gabapentin
10 mg/kg q 8–12 h
β antagonist
Propranolol
2–3 mg/kg q 12 h (w/phenobarbital)
Walker et al., 1997
Narcotic antagonist
Naltrexone
2.2 mg/kg q 12–24 h
2.2 mg/kg q 12 h
White, 1990
Papich, 2016
Progestogen hormones
Megestrol acetate (see text)
Males: 2 mg/kg q 24 h × 7 days, then if improved 1 mg/kg × 14 days 2.2 mg/kg q 24 h × 14 days,
then 1.1 mg/kg q 24 h × 14 days, then 0.5 mg/kg q 24 h × 14 days
2–4 mg/kg q 24 h × 8 days, reduce for maintenance
Joby et al., 1984
Borchelt and Voith, 1986
Papich, 2016
Hormone
Melatonin
0.1 mg/kg q 8–24 h (w/amitriptyline)
Aronson, 1999
Drug class
Drug name
Dose in cats
References
Benzodiazepine (BZD)
Diazepam
1–4 mg/cat q 12–24 h
0.2–0.4 mg/kg q 12–24 h
1–2 mg/cat q 12 h
Papich, 2016
Cooper and Hart, 1992
BZD
Alprazolam
0.125–0.25 mg/cat q 12 h
Marder, 1991
BZD
Clorazepate
2 mg/kg q 12 h
Papich, 2016
BZD
Oxazepam
2.5 mg/cat PRN appetite stimulation
Papich, 2016
Azapirone
Buspirone
2.5–5 mg/cat q 12–24 h
5.0 mg/cat q 12 h
2.5–5.0 mg/cat q 8–12 h
Hart et al., 1993
Sawyer et al., 1999
Marder, 1991
Tricyclic antidepressant (TCA)
Amitriptyline
5–10 mg/cat q 24 h
2.5–5.0 mg/cat q 12–24 h
0.5–1.0 mg/kg q 12 h
10 mg/cat q HS
Papich, 2016
Sawyer et al., 1999
Halip et al., 1998
Chew et al., 1998
TCA
Clomipramine
0.5 mg/kg q 24 h
1.25–2.5 mg/cat q 24 h
1–5 mg/cat q 12–24 h
DeHasse, 1997 Sawyer et al., 1999
Papich, 2016
TCA
Imipramine
2–4 mg/kg q 12–24 h
Papich, 2016
Selective serotonin reuptake inhibitor (SSRI)
Fluoxetine
0.5–4.0 mg/cat q 24 h
1 mg/kg q 24 h
1–1.5 mg/cat q 24 h
2 mg/cat q 24–72 h
Papich, 2016
Pryor et al., 2001
Hartmann, 1995
Romatowski, 1998
SSRI
Paroxetine
1.25–2.5 mg/cat q 24 h
Papich, 2016
Monoamine oxidase inhibitor (MAOI)
Selegiline
0.5 mg/kg q 24 h
Atypical antidepressant
Mirtazapine
1/8–1/4 × 15-mg tablet (1.87–3.75 mg)/cat q 72 h
Trazodone
50 mg/cat PRN
Orlando et al., 2016
Stevens et al., 2016
Anticonvulsant
Carbamazepine
25 mg q 12 h
Schwartz, 1994
Megestrol acetate (see text)
2.5–5 mg/cat q 24 h × 7d, then 5 mg 1–24 × 4/week
5 mg/cat q 24 h × 7–10 days, then 5 mg EOD × 14 days, then 5 mg 2 ×/week;
2 mg/kg q 24 h × 5 days, then 1 mg/kg q 24 h × 5 days, then 0.5 mg/kg q 24 h × 5 days
Papich, 2016
Hart, 1980
Romatowski, 1989
Neurotransmitters
Norepinephrine
Dopamine
Serotonin
Acetylcholine
Gamma-Aminobutyric Acid
Major Drug Classes
Antipsychotics
Anxiolytics
Benzodiazepines
Diazepam
Clorazepate
Alprazolam
Oxazepam and Lorazepam
Azapirones
Nonbenzodiazepine Hypnotics
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