Miscellaneous Serotonergic Agents

9
Miscellaneous Serotonergic Agents


Leticia Mattos de Souza Dantas and Sharon L. Crowell‐Davis


University of Georgia, Athens, GA, USA


Introduction


The psychotropic medications discussed in this chapter have different classifications and different modes of action. They are grouped together due to having in common serotoninergic properties and being the only drugs in their class to be currently used in veterinary behavioral medicine.


Azapirones


Action


Azapirones are serotonin 1A agonists.


Overview of Indications


Azapirones can be used for a variety of anxiety disorders and behaviors that may be affected by chronic anxiety and fear, including generalized anxiety disorder, urine marking, separation anxiety disorder, and anxious cats that are the regular recipients of aggression. Azapirones may be helpful in certain cases of aggression that are triggered by stress and fear signs by one animal, but should be used cautiously for this problem.


Contraindications, Side Effects, and Adverse Events


Buspirone is the only azapirone that is commercially available in the United States. See the detailed discussion under buspirone below.


Adverse Drug Interactions


Azapirones should not be given in combination with monoamine oxidase inhibitors (MAOIs).


Overdose


See information under buspirone below.


Clinical Guidelines


Buspirone is anxioselective with no substantial sedative effect. While there may be a rapid response, it may require one to four weeks to take effect. The patient should be medicated daily, rather than on an as‐needed basis. Doses for dogs, cats, and rabbits are given in Table 9.1.


Table 9.1 Dose of buspirone given orally for various species.




















Species Dose Example
Dog 0.5–2.0 mg kg−1 q8–24h 20‐kg dog
30‐mg, #30
Give 1/2 q12h
Cat 2.5–7.5 mg/cat q12h
or
0.5–1.0 mg kg−1 q12h
5‐kg cat
5 mg, #30
Give 1/2 q12h
Rabbit 0.25–1.0 mg kg−1 q12h

Azapirones are commonly combined with selective serotonin reuptake inhibitors (SSRIs) or tricyclic antidepressants (TCAs) in patients that do not respond to either of those two drugs alone. This topic is discussed in further detail in Chapter 19 (Combinations).


Specific Medications


I. Buspirone



  • Chemical Compound: 8‐[4‐[4‐(2‐pyrimidinyl)‐1‐piperazinyl]butyl]‐8‐azaspiro[4,5] decane‐7, 9‐dione monohydrochloride
  • DEA Classification: Not a controlled substance
  • Preparations: Generally available as 5‐, 10‐, 15‐, and 30‐mg tablets. The 15‐ and 30‐mg tablets are scored so that they can readily be split into two or three pieces.

Clinical Pharmacology


Buspirone is a serotonin 1A partial agonist that has been available in the United States since 1987. It is believed to exert its action by blocking presynaptic and postsynaptic serotonin‐1A (5‐HT1A) receptors. It fully antagonizes presynaptic receptors, but only partially antagonizes postsynaptic 5‐HT1A receptors. It also down‐regulates 5‐HT2 receptors (Eison 1989; Cole and Yonkers 2004). It has moderate affinity for D2‐dopamine receptors in the brain (Peroutka 1985). It does not have anticonvulsant, muscle relaxant, or sedative effects and is therefore often referred to as anxioselective. The anxiolytic effect appears to be due, at least in part, to action on neurons in the dorsal raphe (Trulson and Trulson 1986).


In humans, buspirone has extensive first‐pass metabolism. Food slightly decreases the extent of presystemic clearance of buspirone, but this effect is not known to have any clinical significance. Buspirone is given with or without food (Bristol‐Myers Squibb Co. 2000). It reaches maximum concentrations in about one hour in humans, with a subsequent elimination half‐life of about 2.5 hours.


Buspirone is primarily metabolized by oxidation by the P450 liver enzyme CYP3A4. It has one pharmacologically active metabolite, 1‐pyrimidinylpiperazine (1‐PP), and several inactive metabolites. In animal tests, there has been found to be about 20 times as much 1‐PP as the parent compound in the plasma, but 1‐PP is about one‐fourth as active (Bristol‐Myers Squibb Co. 2000). Urinary excretion of unchanged buspirone accounts for about 0.1% of the initial dose. Thus, it is eliminated almost entirely in a biotransformed state (Caccia et al. 1986).


Buspirone has nonlinear pharmacokinetics so that repeated dosing results in higher blood levels than would be predicted from studies of blood levels after a single dose is given (Bristol‐Myers Squibb Co. 2000).


Buspirone does not displace highly protein‐bound medications such as phenytoin, warfarin, and propranolol. Thus, concurrent medication with buspirone does not generate the risk of inducing higher plasma levels of such drugs (Bristol‐Myers Squibb Co. 2000).


No significant difference has been found between geriatric and younger adult subjects in the pharmacokinetics of buspirone. Both liver and kidney disease result in decreased clearance and higher levels of buspirone (Bristol‐Myers Squibb Co. 2000). Buspirone appears to have no significant effect on blood sugar levels (Dixit et al. 2001). In contrast to benzodiazepines, it stimulates rather than depresses respiration (Garner et al. 1989). Buspirone does not appear to have cardiovascular effects at clinical anxiolytic doses (Hanson et al. 1986).


In horses, buspirone and three major metabolite classes can be detected in the urine 1 to 12 hours after administration (Stanley 2000).


Uses in Humans


Buspirone is used to treat generalized anxiety disorder in humans. In humans with generalized anxiety disorder, buspirone is more effective than placebo and similar in efficacy to diazepam and clorazepate, although with a slightly slower onset of action (Goldberg and Finnerty 1979; Rickels et al. 1982, 1988). The benefit of buspirone over the benzodiazepines includes avoidance of excessive sedation and physical dependence. Use of buspirone likewise avoids the sedation and anticholinergic side effects of TCAs, which are also used in generalized anxiety disorder. It is also more effective than placebo in the treatment of major depression with moderate anxiety (Fabre 1990; Rickels et al. 1990).


Contraindications


Buspirone should be used cautiously with MAOIs (Cole and Yonkers 2004). In humans, co‐administration of buspirone and erythromycin results in substantial increases in plasma levels of buspirone with concurrent increases in side effects. The implications of this finding in nonhuman animals are unknown. Nevertheless, if a patient being chronically medicated with buspirone must be given erythromycin, the dose of buspirone should be decreased. Ideally, other antibiotics that do not exhibit this interaction should be selected. Co‐administration with itraconazole also results in substantial increases in plasma levels of buspirone (Bristol‐Myers Squibb Co. 2000).


Side Effects


Side effects are uncommon, which is one advantage to the use of buspirone. Sedation does not occur in humans, but has been reported in nonhuman animals (e.g., see Hart et al. 1993). In humans, the more common side effects are dizziness, insomnia, nervousness, nausea, headache, and fatigue. One cat placed on buspirone by one of the authors (Crowell‐Davis) began hiding in the closet. This may have been a behavioral response to increased anxiety, analogous to the nervousness reported in some human patients. Mania has also occasionally been reported in humans (Liegghio and Yeragani 1988; Price and Bielefeld 1989; McDaniel et al. 1990). As with all medications, some individuals may have unique, adverse reactions to buspirone.


Unlike the benzodiazepine anxiolytics, buspirone does not produce dependence, even after several months of treatment (Robinson 1985).


In rats and mice given high doses of buspirone for 24 and 18 months, respectively, there was no evidence of carcinogenicity. Studies of mutagenicity have also revealed no such effect (Bristol‐Myers Squibb Co. 2000).


In studies of rats and rabbits given high doses of buspirone during pregnancy, there was no impairment of fertility or damage to the fetuses (Bristol‐Myers Squibb Company 2000).


Buspirone is excreted in milk (Bristol‐Myers Squibb Co. 2000).


The LD50 given orally in dogs is approximately 300 mg kg−1. Death results from compromised respiratory function (Kadota et al. 1990).


Overdose


Conduct gastric lavage and provide supportive treatment if an overdose is given. There is no specific antidote (Bristol‐Myers Squibb Co. 2000).


Dogs given 3 or 10 mg kg−1 may exhibit emesis. The 10 mg kg−1 dose produces significantly increased urinary volume and electrolyte excretion (Hanson et al. 1986).


Other Information


Buspirone causes decreased territorial and maternal aggression in rats concurrently with a substantial decrease in social activity and interest, suggesting that the decreased aggression is nonspecific (Olivier and Mos 1992). On the other hand, it causes no significant changes in social or solitary behavior patterns of rhesus monkeys (Macaca mulatta) when given at a dose of 5–10 mg kg−1 daily PO. This is an interesting example of species differences in response because it contrasts with the increased social interaction noted clinically in the domestic cat.


Buspirone has also been observed to decrease territorial aggression in rats but not in mice (Mos et al. 1992; Gao and Cutler 1993).


Many cats on buspirone begin behaving in ways that their owners often summarize as “more affectionate.” Specifically, they will stay near the owner more, rub the owner’s limbs more, climb in the owner’s lap more, and remain in the owner’s lap for longer periods of time than before. The end point of this effect appears to be related to the baseline. Thus, cats that were already affectionate become intensely affectionate, whereas cats that were previously not very sociable begin exhibiting some degree of social behavior. While the cat is on medication, it is capable of learning, and the social dynamic between cat and owner changes so that many cats retain increased levels of social behavior even after the medication is discontinued, although it may decrease from peak levels that occur while on buspirone.


Effects Documented in Nonhuman Animals


Cats

Absorption of buspirone is poor when administered transdermally as opposed to orally. Therefore, until such time as a transdermal administration technique is developed that is proven to be effective, it is recommended that buspirone always be given orally (Mealey et al. 2004). Cháveza et al. (2015) did not see a significant difference in the reduction of urine marking between cats that received either oral (1 mg kg−1 SID for five weeks) or transdermal (4 mg kg−1 SID applied inside of the ear for five weeks) buspirone. Two patients on the transdermal treatment group (2/19) left the study due to presenting allergic reactions to the medication (itching, skin dryness, and erythema of the ear). A significant reduction in marking frequency was observed following treatment (p < 0.05) for both forms of buspirone administration. This study, however, did not evaluate the blood levels of buspirone during treatment so it remains unclear if the transdermal treatment actually achieved therapeutic doses.


At a dose of 5 mg kg−1 PO buspirone causes increased wakefulness and decreased REM sleep in cats (Hashimoto et al. 1992).


Buspirone, at an average dose of 0.46 mg kg−1, blocks motion sickness in cats (Lucot and Crampton 1987). Pet cats susceptible to car sickness and other forms of motion sickness may benefit from a dose of approximately 1.0 mg kg−1 prior to trips since this will alleviate vomiting and may help with anxiety, although the latter effect may only occur with multiple doses.


Hart et al. (1993) conducted an open trial of the effectiveness of buspirone on spraying and urine marking in cats. The subjects were 47 castrated males and 15 spayed females. Forty‐two of the males were from multiple cat households while only five were from single cat households. Thirteen of the females were from multiple cat households while only two were from single cat households. Cats were initially medicated with 2.5 mg/cat q12h PO. If this dose resulted in cessation or substantial reduction by the second week, it was maintained for eight weeks. If the initial dose was not sufficiently effective, the dose was increased to 5 mg/cat q12h PO for an additional two weeks. If the spraying or marking was substantially decreased or ceased at this higher dose, the cats were maintained on buspirone at this dose for eight weeks. Cats that initially stopped spraying on the 5‐mg dose, but subsequently resumed spraying during the eight weeks, were increased to 7.5 mg/cat q12h.


After the completion of eight weeks of treatment, the dose of buspirone was gradually decreased over a two‐week period. If the cat continued to not spray, medication was discontinued entirely. If the cat resumed spraying at a given lower dose, the cat was then treated for 6–12 months at the lowest effective dose.


Thirty‐two of the 62 cats treated with buspirone responded favorably. Thus, about one‐half of the cats had a positive response. The majority of cats (81%) were given the 5‐mg dose and 12 cats were given the 7.5‐mg dose. Twenty‐one of the responders exhibited complete cessation of spraying, whereas the remaining 11 responders exhibited a decrease of 75% or more. There was a clear effect of household type. Thirty‐two of the 55 cats from multiple cat households responded, whereas none of the 7 cats from single cat households responded. There was no significant effect of sex, although proportionately more females than males responded favorably. Further studies with larger numbers of cats would be required to determine if this trend would become significant with an adequate sample size.


Of the responders, contact was maintained with the owners of 30 cats after treatment. When treatment was discontinued, half of these resumed spraying and half did not resume spraying. When the relapsing cats were placed back on buspirone, 2 failed to respond to the second treatment, while 13 responded.


Owners of 4 of the 62 cats reported sedation. Nine of the cats exhibited increased aggression toward other cats. In at least in some of these cases, the cats that became more aggressive had previously been withdrawn and timid, particularly in their relationship with other cats. While on buspirone, they became more assertive in their social interactions. Five of the cats became agitated. Twelve owners reported increased friendliness toward humans.


Forty of the cats had been previously treated with progesterone. Of these, 30 were nonresponders to progesterone. Fourteen of the 30 that had not responded to progesterone responded to buspirone. Seventeen cats had been previously treated with diazepam, eight of these being nonresponders. Of the diazepam nonresponders, only two responded to buspirone.


While buspirone has approximately the same initial efficacy as diazepam in the treatment of spraying, there is a lower recidivism rate. Specifically, only about 50% of the cats responding to buspirone resume spraying when treatment is discontinued, while over 90% of cats that respond to diazepam relapse when treatment is discontinued (Cooper and Hart 1992). Given the lower incidence of serious side effects and lower rate of recidivism, buspirone is clearly a better choice than diazepam for the treatment of urine spraying and urine marking in cats, especially considering the risks of using diazepam in cats (see Chapter 7 for a detailed discussion).


Overall (1994) used buspirone at 2.5 mg q12h PO to successfully treat spraying in a cat that had previously responded to diazepam, but had stopped responding. The patient had also been socially isolated by its own volition from other cats in the household. While on buspirone, the cat not only stopped spraying, but began venturing into other parts of the house. The cat could not be weaned off buspirone without resumption of the spraying. At the time of publication, the cat had been on buspirone for 16 months with no adverse effects.


Sawyer et al. (1999) reported on four cats with psychogenic alopecia that were treated with buspirone at 5 mg/cat q12h PO. While the frequency of grooming decreased in one cat, the problem resumed when treatment was discontinued. The problem stopped again when treatment with buspirone was resumed at a dose of 2.5 mg kg−1 q12h PO. While the cat was on treatment for a second time, the owner moved to a new home. When medication was discontinued for a second time, the problem remained resolved. This result begs the question of whether the second treatment cured the problem or whether the problem was caused by environmental stresses at the original home. The other three cats treated with buspirone did not respond at all. While these poor results suggest that buspirone may not be a good treatment for psychogenic alopecia, the sample size is too small to come to any conclusions other than that buspirone may be effective in some cases.


Ogata (2013) treated a 2.5‐year‐old castrated male domestic shorthair presenting chronic fear‐induced behavior responses to sudden and loud noises, sudden movements, and people. Buspirone was administered at a dose of 1 mg kg−1, PO, q12h. During the second week of administration, the behavior of the cat improved and no adverse effects were observed. After three months of treatment, the medication was discontinued for one week and the cat noise phobia relapsed. One week after buspirone administration was resumed, the cat was playful and the clinical signs had again improved.


Dogs

Overall (1995) reported on one case of a dog with multiple behavior problems, including fear of approaches by strangers. As part of the overall treatment program, buspirone was used (10 mg q24h PO, 23‐kg dog; 0.4 mg kg−1 daily) for the fear of strangers. The dog became less fearful and made a clear transition to friendly behavior, jumping up and licking faces, and playing with toys with strangers. This response is similar to the increased friendliness to humans seen in cats.


Marder (1991) has used buspirone in combination with acepromazine or diazepam in intense fear‐inducing situations, such as thunderstorms, with no serious side effects, although she does not state the effectiveness of the combination. Acepromazine was also used at a lowered dose. Marder (1991) has also used buspirone in dogs with mild separation anxiety.


Horses

Because buspirone does not have sedative or muscle‐relaxant side effects, it is a better drug for treating anxiety in horses than the benzodiazepines. Dodman (personal communication, 1996) has treated horses with buspirone at up to 250 mg day−1 per horse with no adverse side effects. Although it may be useful in the treatment of anxiety disorders, it must not be used in performance horses preparing for competition. A 50‐mg dose can be detected in the urine (Stanley 2000).


Rabbits

The rabbit cerebral cortex has 5‐HT1A receptors, and the binding rate of buspirone is similar to the binding rate of buspirone in rats and humans (Weber et al. 1997). Rabbits treated with buspirone at 0.05 mg kg−1 day−1 PO for one month do not exhibit any changes in blood sugar (Dixit et al. 2001).


In a study aiming to investigate the role of 5‐HT and its receptors in mediating novelty‐elicited head‐bob behavior in rabbits, pretreatment with buspirone significantly attenuated novelty‐elicited head bobs (Aloyo and Dave 2007). Buspirone may be a useful treatment for timid, anxious rabbits.


Parrots

Juarbe‐Díaz (2000) used buspirone (0.2 mg, PO, q12h) as an adjunct agent in a treatment with clomipramine (3.6 mg, PO, q12h) and environmental modification for a Congo African Gray parrot with feather‐picking and self‐injurious behavior. Buspirone was added to treat paradoxical anxiety caused by an increase in the dose of clomipramine. Six weeks after addition of buspirone to the treatment regimen, the owner reported that intensity of the feather‐picking and self‐injurious behavior was greatly decreased and new feather growth was seen.


Other Species

Buspirone was used in an experiment that aimed to validate the marmoset (Callithrix penicillata) as a model of fear and anxiety. Seven subjects were first subjected to seven 30‐min maze habituation trials in the absence of a taxidermized wild oncilla cat (Felis tigrina). Subsequently, the subjects were randomly assigned to five treatment trials in the presence of the “predator” (three buspirone sessions at 0.1, 0.5 and 1.0 mg kg−1, saline and sham injection controls). Buspirone significantly decreased the frequency of scent marking, while increasing the time spent in proximity to the predator stimulus (Barros et al. 2001).


Serotonin Antagonist/Reuptake Inhibitors (SARIs)


Action


Serotonin antagonist/reuptake inhibitors block serotonin 2A and 2C receptors and serotonin reuptake.


Overview of Indications


SARIs, more specifically trazodone, can be used for a plethora of situations where fear and anxiety need to be controlled in companion animals (such as in surgery recovery and veterinary visits) and to treat anxiety disorders. It can be used as a single agent or as an adjunct drug to enhance another pharmacological treatment. It has also been used in the treatment of neuralgia and other painful conditions. The prescription of nefazodone, another SARI, is uncommon due to its potential liver toxicity documented in human medicine.


Contraindications, Side Effects, and Adverse Events

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