Sara L. Bennett Medications for sheltered pets can be used to address immediate welfare concerns, often stemming from the shelter environment itself. Addressing these early can help to improve adoptability, facilitate a smoother transition to the new home, and often lead to a shorter‐term treatment overall. They can also be used to address behavior disorders present in a pet within a shelter, whether the pet entered the shelter with the problem or the stress of the shelter became a trigger for an already at‐risk animal. Addressing these disorders as soon as they are recognized can improve welfare short and long term, help to make a less adoptable pet more adoptable, and help to facilitate that pet being successfully maintained in a home long term. In this chapter, the indications and goals for behavior medication use, factors to consider prior to prescribing, requirements to prescribe, monitoring, and medication choices will be discussed. A medication formulary will also be included. To understand the medications and how to select them, a brief discussion about neurotransmitters is presented. Additionally, some tips on how to set up behavior medication protocols, along with some examples, will be reviewed. And lastly, a brief discussion on non‐pharmaceutical or adjunct treatment options will wrap up this chapter. General goals of behavioral medication use include addressing specific underlying neurotransmitter alterations; to decrease underlying anxiety, fear, and emotional arousal; and to make behavioral and environmental modification easier to implement. It is important to remember that these medications do not change the animal’s behavior itself, as the behavior patterns have been learned and practiced as coping strategies. The negative emotional states underlying the motivations for the behavior are what is being affected. This chapter is not intended to provide a comprehensive list of behavioral diagnoses, clinical signs, differentials, or comprehensive treatment plans. The reader is referred to other resources for such details (see Landsberg et al.’s Behavior Problems of the Dog and Cat, 3rd ed. [2013], Overall’s Manual of Clinical Behavioral Medicine for Dogs and Cats [2013a], or Horwitz and Mills’s BSAVA Manual of Canine and Feline Behavioural Medicine, 2nd ed. [2009]). On a general level, at minimum, a working diagnosis should be made prior to prescribing pharmaceuticals. This can include a succinct description of the problem—for example, a dog that cowers, tries to hide, and struggles to get away when approached by men can be given a working diagnosis of “fear of men.” This working diagnosis can then be the basis of setting up a treatment plan, including environmental management (e.g., a hiding spot from passing men), behavior modification (all men toss treats to the dog no matter what—classical conditioning), and a fast‐acting behavior medication that does not impede learning (e.g., trazodone or gabapentin). The keys to making a working diagnosis are to identify the behavior, trigger, target (if different), and motivation for the behavior (e.g., fear or frustration being the most common in shelters). By recognizing the motivation, a more informed decision on medication choice—fast‐acting short‐term, long‐term baseline, or both—can be made, along with an understanding of which specific neurotransmitters to target. For example, the dog reacting with high physiologic arousal—hackles up, pupils dilated, panting hard, salivating heavily—with poor recovery might benefit more from clonidine than the dog previously described who might do well on trazodone. Suzanne Clothier, an experienced, qualified, force‐free trainer has an excellent article that helps to describe when to consider medications for a behavior problem (Clothier 2019). She discusses the Three Ps—provocation, proportion, and persistence, which complement the identifiers listed above when making a working diagnosis. The provocation can be considered along the same lines as the trigger—the event or environment that incited the behavior of interest. The proportion considers the intensity of the dog’s reaction to a trigger: is the behavior response extreme to a minor trigger? That is an important observation to note. Persistence can be thought of as ability to recover. A normal dog should be able to recover from a mild to moderately stressful situation within a couple of minutes at most. Longer than that, and we should consider whether that behavior pattern is abnormal or impairing welfare. By taking a few minutes to make a list of the pet’s unwanted behavior, triggers and targets for it, and the suspected motivation, and layering the Three Ps over each behavior pattern of concern, one can then create a working diagnosis and also determine if the behavior(s) in question are severe enough to warrant adding behavior medication to the treatment plan. This process is often best accomplished using a team approach in the shelter. Animal care staff play an important role in identifying behaviors of concern, and also helping to clarify targets and triggers. The shelter behavior staff (if available) can also be instrumental in helping to determine motivation and applying the Three Ps. In an ideal world, the animal care staff recognize a problem, notify the shelter behavior team, and then if they identify behaviors that are more than just a training or management problem, they can notify the shelter veterinarian that this particular case might also need their input for a diagnosis and behavioral medication intervention. A risk assessment should be performed for every pet with behavioral complaints before an outcome decision and treatment plan are created. Things that should be considered include: The same requirements for prescribing any medications can be applied to those intended to modify behavior. A valid veterinarian‐client‐patient relationship (VCPR) should be established. To make an accurate diagnosis or working diagnosis, a medical evaluation, which includes a behavioral examination in addition to a physical examination, needs to be completed. This will help to ensure the practitioner is addressing the motivation for the behavior and the accompanying diagnosis rather than just trying to treat the clinical signs. For example, if one tries to treat feline housesoiling (previously called inappropriate elimination) (Carney et al. 2014) by shutting a cat in the bathroom with his own litterbox and amitriptyline, the social conflict that might be the main contributor to the problem has been neglected. Though the problem might “resolve” while the cat is sequestered in the bathroom, it will recur as soon as the cat is reintroduced to the household and the social interactions that led to the housesoiling occur again. Always consider other treatments that can be implemented prior or in addition to pharmaceutical therapy. There should always be some type of environmental management and behavior modification included in any behavior treatment plan. These do not have to be complex, as both can be implemented in simple, inexpensive, and efficient ways (see Chapters 12 and 18). What about labwork? Although ideal, and typically recommended for an owned pet prior to prescribing pharmaceuticals, is labwork a reasonable use of shelter resources? What is the risk of prescribing without it? Do the benefits potentially outweigh the risks? Does it change what medication one might choose for a particular pet? The answers to these questions often depend on the pet and the medications considered. Realistically, the risk of an underlying problem is low in an otherwise healthy young adult pet, especially if they have already undergone surgical sterilization under anesthesia without complication. However, if a problem were to occur, there would not be a baseline available for comparison. If labwork is not available, the shelter may consider medications that have a lower risk of complications and side effects (e.g., using gabapentin instead of a benzodiazepine in cats; Hughes et al. 1996). If medications are available but labwork is not, it would not be fair to the sheltered pet to refuse medication that could help save them suffering from a behavioral problem just because pre‐medication labwork could not be performed. Prescribing medication and formulating a plan is only the beginning, never the end: a follow‐up plan must be created. There should always be a plan for monitoring the pet’s response to treatment and welfare status at regular intervals. Additionally, outcome options available to that pet might change as their behavior, shelter resources, environment, or community change. One big benefit from continuing to monitor a pet on a behavior treatment plan is that as more information about that pet’s problem is identified, including what is and is not helping the problem, additional creative transfer solutions can be considered. Perhaps a breed rescue can now take a specialized breed with separation anxiety treatment already underway, or a herding dog can be more manageable on leash in a suburban environment whereas he is still too risky to try to manage in a dense urban environment. Additionally, starting treatment of a behavior problem immediately upon identification can help the next party, regardless of role, continue to set that pet up for success. The shelter is able to clearly inform “this is what we know,” advise “this is what we’ve done so far,” and counsel “this is what you can continue to do” so the next person/organization responsible for that pet has a better understanding of what that pet needs and from what information the plan was created. Creating a follow‐up plan for behavior treatment, regardless of whether behavior medication is used, is no different than setting up a follow‐up plan for a pet diagnosed with a urinary tract infection or other medical problem. Requirements to prescribe medication can vary widely state by state. In some states, there are no requirements except for controlled substances. Additionally, the list of medications subject to controlled substance scheduling also varies state by state. For example, gabapentin is currently a schedule V drug in Kentucky, Virginia, West Virginia, Michigan, and Tennessee. It is important to check laws and regulations in your local jurisdiction and state of practice and to work within them. Additional regulatory considerations pertinent to animal shelters are presented elsewhere (Newbury et al. 2010). When deciding which medication to use for a particular pet, the goal(s) of treatment, administration requirements, cost and availability, abuse potential, and legal requirements should all be considered. What is your goal? What do you plan to accomplish by adding behavior medication to the treatment plan? If trying to manage kennel stress or an immediate welfare concern, often a short onset (fast‐acting) medication would be a rational choice. If you suspect you are dealing with an underlying behavior disorder, expect this pet to have a longer length of stay (LOS), or anticipate management of a significant behavior disorder or problem in the future, such as in a home, perhaps a longer‐term baseline medication might be more appropriate (see Table 22.1). Along with considering the goal of medication administration, one must consider what neurotransmitter system is most appropriate to address when determining which specific behavioral medication to use (see Section 22.3). Table 22.1 Behavioral medicines for shelter use. Administration requirements should take into account both the frequency and route of delivery as well as the stress that may be associated with administration. Does the organization have the manpower to medicate multiple times per day? Generally, a lower frequency of administration leads to better compliance. Most behavioral pharmaceuticals are given by an oral route, with varying levels of palatability and distaste. Some options to make administration easier for staff and increase acceptance and reduce stress for the pet include mixing oral medications in canned food, pill pockets, peanut butter, cheese, etc. Staff should consider if the stress caused by administering medication to aggressive or fearful animals is worth the benefit potentially gained by the pet, such as is often the case with fearful cats. Creative strategies or smart choice of formulation can be helpful to minimize stress and maximize success. For example, one creative strategy is to give liquid oral medications to fearful cats via a tom cat catheter attached to a syringe. This can be gently guided into the cat’s mouth without restraint and the liquid administered quickly. An excellent description of this can be found in Pankratz et al. (2018) where the researchers administered gabapentin pre‐operatively to community cats housed in humane traps when presented for sterilization (see Figure 14.15). Another option is to consider offering medication in a highly palatable food just before leaving for the evening, giving the fearful pet the opportunity to eat it overnight. Money and time are common limiting factors for sheltering organizations. What is the cost and ease of availability of the medication to be prescribed? Unfortunately, the cost of generic medications can still vary widely depending on production and sometimes surprisingly may be higher than FDA‐approved formulations (e.g., at the time of writing, the cost of generic clomipramine is frequently higher than the cost of the veterinary formulation, Clomicalm®, Elanco Animal Health, Inc., Greenfield, IN), for many canine patients. This is particularly important if a pet is likely to go to their final outcome on medication that needs to be continued long‐term. One option to set the pet and adopter up for success is giving options for price shopping of the medication after adoption. There are several websites that are set up for consumers to price shop prescriptions between retail pharmacies, such as GoodRX.com. Does the medication you wish to prescribe have staff or volunteer diversion risk? What protocols are in place to monitor and manage this risk? Are there other medications available that could meet the same need with lower risk? Always be sure to check local and state jurisdictions for an up‐to‐date list of what medications are subject to controlled drug scheduling. Similarly, depending on the state and municipality, there might be some constraints on which cases medication may be used as part of a treatment plan, even if you determine the pet’s behavior indicates a need. For example, if the medication being considered has behavioral side effects that could mimic neurologic changes seen with the rabies virus, it may not be permissible to use in pets under bite quarantine. Neurological changes, such as sedation, ataxia, altered mentation, and hypersalivation are uncommon side effects of many behavioral pharmaceuticals. However, side effects such as these will often resolve within a few days of discontinuation of the medication, whereas a primary neurologic complaint, such as rabies, would not. In the case of court‐ordered holding of animals, organizations may be required to hold the “evidence” in a manner to prevent deterioration. This should include not only physical health but also mental health. Many of these cases end up with extended LOS and managing them in a way to prevent behavioral deterioration can be challenging. It can be helpful to have discussions with the investigators, legal team, and other professionals involved in the case about welfare concerns identified and what role management options, including medications, might play in maintaining the pet’s behavioral health for the duration of the hold (see Chapter 21). There should always be a designated person or persons responsible for the regular monitoring of pets under pharmacologic therapy. In private practice, this team usually is made up of the owner, the veterinarian, and possibly an additional staff member such as a veterinary technician or assistant. In the shelter, this often consists of the team doing daily behavior and wellness rounds and might include a veterinary technician, behavior team member, or experienced handler or caregiver. This might or might not include the veterinarian. This team should know what to watch for with the particular medication prescribed and know to whom they report any concerns or observations. These observations should include monitoring appetite, water intake, urination, defecation, activity level, and level of undesired and anxiety/stress‐related behaviors, specifically noting frequency, duration, and intensity of those behaviors of interest. Post‐outcome planning is also an integral part of monitoring. Each pet prescribed medication should have a plan to go with them through their anticipated outcome, including after they leave the shelter and enter the home environment. This plan should be reviewed regularly. If progress is not being made, the diagnosis and plan should be re‐evaluated and adjusted. If resources are available, the shelter can also reach out to other qualified behavior professionals, including force‐free trainers, Certified Applied Animal Behaviorists, or veterinary behavior specialists, dependent on the individual case and where the challenges are being identified. Finally, the post‐outcome plan for animals undergoing behavioral pharmaceutical treatment should be considered prior to instituting therapy. Who performs the adoption counseling or advises the next group of the pet’s current status? These requirements vary, with some states requiring such advice to be given by the prescribing veterinarian. A written management/education plan should always accompany verbal instructions. Full disclosure of the pet’s problem and current treatment needs should be provided in a thoughtful and compassionate manner in order to fully educate the caregiver without creating undue alarm about the problem. Such plans could even include offering a recommendation for follow‐up care with a veterinarian; animal behaviorist; a member of your organization familiar with the pet; or a qualified, humane, force‐free trainer. If the pet is made available for adoption or placed in a foster home, the new owner/caregiver counseling should include education about medication, including the goals of treatment, how to give it, what side effects to watch for, and who to follow up with. A plan for continuation or weaning of the medication should be discussed and should include any risks of stopping the medication abruptly. If the new owners/caregivers have concerns about the medication or treatment at any time, they should be encouraged to speak with a veterinarian before making decisions about the medication on their own. Some organizations might consider weaning the pet’s medication before adoption; this decision should be made on an individual animal basis with consideration of the risks of prolonged stay in shelter care versus those associated with abrupt discontinuation of therapy. When animals undergoing treatment are transferred to another organization, such as another shelter or rescue group, the new organization’s philosophy and policies on behavioral medications should be considered and discussed prior to transfer. A plan for continuation or weaning should be made prior to transfer. The discussion of the risk of stopping medication abruptly should be included in this plan, as it would be for an adopter or foster home. Some organizations might consider adding behavior medications to their standard operating procedure or developing protocols for their use in specific cases that the shelter is equipped to manage. In some organizations, animals can be treated by trained staff via protocols provided by a veterinarian (Association of Shelter Veterinarians 2018). Protocols should include information about the specific problem to be addressed, including accompanying behavioral observations. How the medication can be used as part of the treatment should be briefly discussed, but other aspects of the treatment plan such as environmental management, enrichment, and behavior modification should also be included. It should be emphasized that medication alone is not the sole treatment for the problem. Doses based on body weight, time to effect, side effects, and adjustments based on side effects can also be mentioned. If dosed chronically (i.e., longer than daily for four weeks) a weaning plan should be made. This will be imperative if medication is anticipated to be reduced or discontinued after the pet has moved to their final outcome. For most medications, a weaning plan of reducing the dose (not dosing frequency) by 25–33% every one to two weeks is judicious. If at any time the pet’s behavior deteriorates, the caregiver should be instructed to go back to the last previously effective dose and contact a veterinarian for further instructions. It is prudent for the welfare organization to have a few recommendations of veterinarians within their organization or community who are well versed in common behavior medications and can be referred to in these situations. Appendices 22.A–22.E contain a formulary and example behavior medication protocols for select scenarios common in shelter practice. It will be important to keep in mind that these are merely examples, and the environmental management and behavior modification skills, tools, and resources will vary widely between organizations. The intent of these resources is to guide practitioners on how to incorporate behavioral medication into a behavior treatment protocol. Glutamate, an amino acid, is the primary excitatory neurotransmitter in the central nervous system (CNS). This is where NMDA receptor blockers, such as ketamine and memantine, act creating analgesia and addressing anxiety associated with pain. At high doses, a dissociative and/or cataleptic state can be induced (Overall 2013b; Plumb 2018). Gamma (γ)‐aminobutyric acid (GABA) is synthesized from glutamate and is the major inhibitory neurotransmitter in the CNS (Murray 2019a). It plays a role in vigilance, anxiety, muscle tension, seizure activity, and memory. Benzodiazepines have their effect via this neurotransmitter by binding to the GABA A receptor site to enhance the effect of GABA (Plumb 2018.) The monoamines make up another class of neurotransmitters, containing several well‐known compounds commonly used in behavioral pharmacology: dopamine, norepinephrine, and serotonin. Along with epinephrine, melatonin, and histamine, which will not be discussed further, these compounds make up the biogenic amines. Dopamine (DA) plays a major role in reward systems. It is released in anticipation of and response to natural rewards such as food, water, and sex, or synthetic rewards (dopamine agonists) such as amphetamines, cocaine, opioids, and nicotine. Excess dopamine transmission is associated with stereotypic/compulsive behavior and schizophrenia in humans. Decreased dopamine transmission is associated with decreased alertness, anxiety, and depression as well as cognitive deficits and Parkinsonian‐like tremors in people. Dopamine and acetylcholine have an inverse relationship (Murray 2019b). Norepinephrine (NE) is synthesized from dopamine and plays a role in the control of emotions (such as the intensity of the emotional response), arousal, and reward systems. The α‐adrenergic receptors, especially the α2 adrenergic class, are particularly useful in behavioral pharmacology. Alpha‐2 agonists such as xylazine, dexmedetomidine, and clonidine inhibit NE release via action at presynaptic autoreceptors, resulting in sedation, analgesia, muscle relaxation, and at lower doses, anxiety control. Alpha‐2 antagonists such as yohimbine, atipamezole and amphetamines, stimulate NE release, hence their role as reversal agents (Murray 2019b). Serotonin (5‐HT) is synthesized from tryptophan obtained by dietary intake. Dietary levels of tryptophan can alter brain serotonin levels, though it is not a simple linear relationship and simply supplementing tryptophan to the diet will not necessarily increase serotonin levels in the brain (Dodman et al. 1996). There are many serotonin receptors, not just in the brain but throughout the body, including the heart, gastrointestinal (GI) tract, smooth muscle lining, and platelets (see Table 22.2). Consequently, serotonin plays a role in the control of mood, impulsivity, anxiety and panic, satiety, nausea, cognition, aggression, sex drive, sleep, pain, coagulation, and even thermoregulation (Murray 2019c). Acetylcholine (Ach) is the only neurotransmitter not directly synthesized from an amino acid. It is synthesized by linking choline with acetyl coenzyme A (acetyl CoA). It is involved in signal transmission at postganglionic parasympathetic synapses (muscarinic), autonomic ganglia (Nicotinic n), and neuromuscular junctions (Nicotinic m). Anticholinergic effects such as dry mouth, dry eyes, urine retention, constipation, pupil dilation (mydriasis), and an increase heart rate can occur with medications that affect this neurotransmitter, such as tricyclic antidepressants (TCAs). This neurotransmitter’s effect at the muscarinic receptors can play a role in memory. Its effect at the nicotinic‐n receptors in the brain, adrenal medulla, and autonomic ganglia also affect learning and memory. Nicotine also binds nicotinic‐n receptors, activating the reward and dependence systems, but also improving mental alertness and memory (Crowell‐Davis 2019). This makes sense when one considers the effect of cigarettes on emotion and focus as well as addiction. Degeneration of cholinergic pathways is implicated in learning and memory decline, as occurs in Alzheimer’s disease. Table 22.2 Location and function of serotonin (5‐HT) receptors. There is a great breadth of literature on psychopharmaceuticals’ impact on behavior though the majority of studies involving animals were performed during safety studies for humans. While some medications have been more extensively reviewed, particularly with regard to use in dogs and cats, some of those with the most data may be challenging to apply to shelter behavior cases due to cost, duration of action, frequency of dosing, or route of administration. These data will be reviewed where pertinent while going through the different classes of behavior medications available. If the reader should want more extensive information about any of the below, the author recommends Veterinary Psychopharmacology, 2nd ed., by Crowell‐Davis et al. (2019), for the most extensive review in veterinary behavioral medicine. The general mechanism of action for SSRIs is inhibit reuptake of serotonin molecules from the synaptic space back into the presynaptic neuron. This prevents “recycling” of the neurotransmitter and a net increase in serotonin available in the synaptic space. However, clinical effects of this increased availability often take as long as four to eight weeks to detect. This delay is attributed to an SSRI‐induced desensitization of the serotonin 1A autoreceptors blocking negative feedback, which leads to a more normalized release of serotonin (Blier and de Montigny 1998). Common medications in this class used to help treat veterinary behavior problems include fluoxetine, paroxetine, sertraline, citalopram and escitalopram. Fluoxetine will be discussed below as it has the most extensive research background, lowest dosing frequency, and is consistently inexpensive and easily available, therefore making it suitable for shelter use. Additional information about the other SSRIs can be found in other references (Ogata 2019; Plumb 2018; Overall 2013b; Landsberg et al. 2013). Fluoxetine, an SSRI, is one of the most extensively researched behavioral medications for dogs and cats. Studies have described its use and evaluated its efficacy in generic and branded form (Reconcile®, PRN® Pharmacal, Pensacola, FL) for the treatment of separation anxiety in dogs (Simpson et al. 2007; Landsberg et al. 2008; Ogata 2016), territorial and other forms of aggression in dogs (Haug 2008, 2014; Sherman et al. 1996; Reisner 2003; Houpt and Virga 2003), urine marking in cats (Pryor et al. 2001), and compulsive disorder in dogs (Wynchank and Berk 1998; Luescher 2009; Mills and Luescher 2006; Irimajiri et al. 2009; Houpt and Virga 2003). Fluoxetine has been used clinically for many other behavior problems, with the justification of treating the underlying fear and anxiety contributing to the behavior problem. This use is due in part to genetic studies on serotonin receptors that indicate receptor polymorphism may play a role in susceptibility to affective (mental illness) diseases in people. This important change, that effectively leads to a functional difference with the serotonin autoreceptor, correlates with the degree of response to fear in the amygdala (the part of the brain that manages and immediately processes primitive emotions). Those with a particular allele for this gene may be more vulnerable to stress and at higher risk of developing clinical depression (Caspi et al. 2003; Hariri et al. 2002). In other words, a large proportion of behavior disorders with underlying fear and anxiety as motivators (including several types of aggression) are suspected to be due to low serotonin levels in the brain. Due to the extensive literature available in people, dogs, cats, and other species, the mechanism of action, effects, and side effects of fluoxetine are well known. Just as with its use in humans, though the reuptake effect is immediate, it may take several weeks (at least four to six) to see the full behavioral effect due, in part, to later presynaptic auto‐receptor downregulation (Blier and de Montigny 1998). The half‐life of fluoxetine is very long in dogs, at least five days (Ogata et al. 2019; Plumb 2018), so changes in behavioral effect, and time for it to be completely cleared from the body is much longer than other antidepressants. For example, when switching from fluoxetine to a monoamine oxidase inhibitor (MAOI), a five‐week washout period is recommended to help reduce the risk of serious side effects, including serotonin syndrome (de Souza Dantas and Crowell‐Davis 2019a; Murray 2019b, Ogata et al. 2019) (see Section 22.4.1.4). Fluoxetine is typically dosed at 1–2 mg/kg by mouth once daily for dogs and 0.5–1 mg/kg by mouth once daily for cats (Landsberg et al. 2013; Plumb 2018; Ogata et al. 2019). The most common side effects include a decrease in appetite or lethargy, though these typically are mild and should not last longer than one to two weeks. If they are severe, or if other more serious side effects such as vomiting, diarrhea, tremors, increased fear or anxiety (often identified as new fears of objects or noises), or increased irritability are noted, the veterinarian managing the case should reduce the dose or stop the medication. If given daily for more than four weeks, this medication should be weaned gradually, if possible, rather than discontinued abruptly. Because fluoxetine can alter blood glucose levels, it should be avoided, or blood glucose and insulin doses monitored carefully, in diabetic patients (Ogata et al. 2019; Plumb 2018). Tricyclic antidepressants work by inhibiting the reuptake of norepinephrine and serotonin by the presynaptic plasma membrane transporters. Additionally, they will alter the conformation and enhance the sensitivity of postsynaptic serotonin 1A receptors, which makes them more efficient. As with SSRIs, it may take several weeks to see the full effect. Because TCAs impact norepinephrine receptors in addition to serotonin receptors, this class of medication is less specific than the SSRIs. Not only is norepinephrine altered, but other neurotransmitter systems are impacted, with anticholinergic, antihistaminic and α2 antagonistic effects (Crowell‐Davis 2019). This can lead to a greater breadth of side effects, including anticholinergic effects and antihistaminic effects such as dry mouth, changes in urination pattern (increased or decreased), constipation, decreased tear production, increased ocular pressure, mydriasis, and cardiovascular changes such as arrhythmias, syncope, or hypostatic congestion. This class of medication might also reduce a patient’s seizure threshold (Crowell‐Davis 2019; Plumb 2018). However, these alternate receptor side effects can be beneficial sometimes, depending on the case. For example, a pet that urinates frequently or suffers from atopy might benefit from mild urine retention or antihistaminic effects of a TCA. The most common TCAs used in veterinary behavior include clomipramine, amitriptyline, and doxepin. It is important to note that these medications have variable effects relative to each neurotransmitter that must be considered prior to selection (Crowell‐Davis 2019). Clomipramine has the greatest serotoninergic effect and hence is one of the better choices for anxieties or behaviors whose suspected underlying pathology includes low serotonin. Though amitriptyline has historically been recommended for cats urinating outside the litterbox, this recommendation was likely initially due to cost and familiarity. There are other medications that are now easily available at a reasonable cost if the underlying motivation is anxiety (such as fluoxetine or clomipramine) (Crowell‐Davis 2019). Amitriptyline may also have some beneficial effect on feline interstitial cystitis due to pain reduction via the effect on norepinephrine, rather than anxiety reduction via the effect on serotonin (Hanno et al. 1989). Doxepin has a high antihistaminic effect relative to the others, so is more frequently used for pruritis relief, though it has a relatively low effect on serotonin (Crowell‐Davis 2019). Clomipramine is an extensively researched behavioral medication for dogs and cats. Studies have described its use and evaluated its efficacy in generic and branded form (Clomicalm) for the treatment of separation anxiety in dogs in conjunction with a behavior modification plan (King et al. 2000; Sherman and Mills 2008; Cannas et al. 2014), some forms of aggression in dogs, urine marking and other behavior problems in cats (Hanno et al. 1989; Litster 2000; Landsberg and Wilson 2005; Ellis and Wells 2010), and compulsive disorder in dogs (Luescher 2009; Mills and Luescher 2006; Seksel and Lindeman 2001). Of all of the TCAs, clomipramine has the strongest serotonin reuptake effect, which is why it is a popular and effective choice for the former and for several other behavior problems, with the justification of treating the underlying fear and anxiety contributing to the behavior problem. As mentioned above, it may take up to four to eight weeks to see the full effect of this medication, although some pets will show response earlier. Clomipramine is better tolerated with a lower rate of side effects in dogs than in people, likely due to the difference in proportion of clomipramine and its metabolite desmethylclomipramine (clomipramine is higher in dogs, vs. lower in people) (Crowell‐Davis 2019). The half‐life of clomipramine is shorter than fluoxetine, and is highly variable, reported at 16 hours (Crowell‐Davis 2019) up to 32 hours (Plumb 2018). It should be noted that a two‐week washout is recommended when switching from clompiramine to an MAOI (Landsberg et al. 2013; Plumb 2018; Crowell‐Davis 2019). Clomicalm label dose is 2–4 mg/kg PO q 24 hours; however, most clinicians have found a q 12‐hour dosing strategy more clinically effective in dogs. The current standard dose range is 1–2 mg/kg PO q 12 hours, up to 3 mg/kg PO q 12 hours (Landsberg 2013; Plumb 2018; Crowell‐Davis 2019). Similar side effects as expected with fluoxetine might be noted such as a decrease in appetite or lethargy for the first one to two weeks. Side effects such as vomiting, diarrhea, constipation, changes in urination, tremors, increased anxiety, or increased irritability are indications that the veterinarian managing the case should reduce the dose or stop the medication. If given daily for more than four weeks, this medication should be weaned gradually if possible, rather than discontinued abruptly. Clomicalm should not be given to pets with a history of dry eye, glaucoma, urinary retention, constipation, abnormal blood pressure or arrythmias due to the potential for anticholinergic and antihistaminic side effects (Crowell‐Davis 2019; Plumb 2018). Unfortunately, generic clomipramine has drastically increased in cost and the branded Clomicalm is sometimes less expensive than the generic formulation. This puts Clomicalm/clomipramine out of range for rational use in most sheltered pets due to financial constraints. It should be noted that any SSRIs or TCAs can affect thyroid hormone measurements, causing cats with hyperthyroid disease to appear euthyroid and euthyroid dogs to appear hypothyroid. This does not preclude the use of these medications in patients with thyroid disease, but it can superficially complicate diagnosis and management. It is always prudent to check thyroid hormones prior to administration, when possible, and to reassess the patient for clinical signs associated with thyroid disease prior to instituting or adjusting treatment, especially if they are already on an SSRI or TCA (Martin 2010; Shelton et al. 1993; Gulikers and Panciera 2003). Sometimes referred to as serotonin toxicity, serotonin syndrome is a serious side effect that consists of a collection of physiologic, behavioral and neuromuscular side effects that can range from mild to fatal. The clinical signs most easily observed in the dog or cat include agitation, confusion, anxiety, restlessness, tremors, increased heart rate, vomiting or diarrhea. These signs can worsen in severity to include seizures, hyperthermia, blood pressure changes, coma and death (Almgren and Lee 2013; Sinn 2018; de Souza Dantas and Crowell‐Davis 2019b). Typically, serotonin syndrome occurs when a pet accidentally ingests a large amount of their owner’s medication, or when an individual is given a combination of two or more medications/supplements that both have some impact on the level of serotonin. The most notable combination is an antidepressant (SSRI or TCA) combined with an MAOI; however, this can occur with any combination of serotoninergic medications and/or supplements. Rarely, in some sensitive individuals, serotonin syndrome can occur at standard dose ranges. Additionally, medications such as tramadol, trazodone, and mirtazapine all have some effect with serotonin, even if it is not included in their primary intended effect. It is important to note that some supplements sold over the counter, such as St. John’s Wort and Griffonia seed extract (5‐HTP), have serotoninergic effects and can be quite potent, especially in smaller animals (Gwaltney‐Brant et al. 2000
22
Behavioral Pharmacology
22.1 Appropriate Use of Behavioral Pharmacology in the Shelter Setting
22.1.1 Indications for Behavioral Pharmacology
22.1.2 Things to Consider before Prescribing
22.1.3 Requirements for Prescribing Medication
22.1.4 Medication Choices
Medication category
Dosing frequency
Indications
Drug classes and examples
Baseline medications
Daily;
Longer‐term use;
several weeks to effect
Chronic, daily, or unpredictable events
Example conditions:
Anxiety, fear,
impulsivity,
compulsive disorder,
aggression (majority based in fear/anxiety),
cognitive dysfunction syndrome
Selective serotonin reuptake inhibitors (SSRIs)
Fluoxetine, sertraline
Tricyclic antidepressants (TCAs)
Clomipramine, amitriptyline
Monoamine oxidase inhibitors (MAOIs)
Selegiline
Situational, adjunct, or secondary medications
PRN;
daily short term;
combination with baseline
Short duration; predictable events; bridging medication while waiting for baseline to take effect; additional support with baseline long term
Example conditions:
Transitional or travel stress, kennel stress (short term), noise aversion, fear on walks, etc.
Benzodiazepines
Alpha‐2 agonists
Clonidine, dexmedetomidine
Trazodone
Gabapentin
22.1.5 Monitoring
22.1.6 Outcome Considerations
22.2 Developing a Medication Protocol
22.3 Neurotransmitters
Receptor
Location/function
5‐HT 1A
Prereceptor, autoreceptor—inhibits firing of neuron; synthesis and release of 5‐HT; postreceptor
5‐HT 1B
Autoreceptor—inhibits additional 5‐HT release
5‐HT 2A
Platelet aggregation and smooth muscle contraction
5‐HT 2B
Found on human heart valves
5‐HT 2C
Regulates appetite
5‐HT 3
GI tract, chemoreceptor trigger zone (vomiting, nausea)
5‐HT 4
GI tract (secretion and peristalsis)
5‐HT 6
Limbic system
5‐HT 7
Limbic system
22.4 Impact of Psychopharmaceuticals on Behavior
22.4.1 Selective Serotonin Reuptake Inhibitors and Tricyclic Antidepressants
22.4.1.1 Selective Serotonin Reuptake Inhibitors (SSRIs)
22.4.1.2 Tricyclic Antidepressants (TCAs)
22.4.1.3 Thyroid Hormone Measurements
22.4.1.4 Serotonin Syndrome
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