Evidence-based decision making examines the validity of the information, the design of clinical trials and the application of statistics so that the clinician can select a therapeutic option that best suits the pet, client and problem. Many drugs used in veterinary behaviour fall into the poorest level of evidence including personal experience, colleague opinion, continuing education, textbooks, in vitro studies or studies from other species. The soundest evidence (A) requires systematic reviews of randomised controlled clinical trials (RCT) or at least a single RCT with high confidence. Most drugs licensed for veterinary behavioural use have been through one or more RCTs as well as pharmacokinetic and safety studies, and have the added benefit of the manufacturer's technical support. While the practitioner must follow the prescription cascade, the best evidence may be a drug that is licensed for another application, another species or in another country (for which a human version is available). When dose, compliance or availability is an issue compounding might be considered; however, stability and storage are a concern. In addition, for transdermal medications, bioavailability of fluoxetine was 10%, while systemic absorption of amitriptyline and buspirone was minimal (compared to oral dosing). Psychotropic drugs should be used with informed consent as to any off-label use and potential adverse effects.

Drug Therapy

Recommended doses of drugs are given in Figure 1.

Figure 1.

Antidepressants

Antidepressants cause little or no sedation and are unlikely to inhibit learning or memory. While antidepressants achieve peak levels within hours, reuptake inhibition initially induces down-regulation of postsynaptic receptors. Therefore 4-8 weeks of therapy is recommended to fully assess effects. Concurrent use with monoamine oxidase (MAO) inhibitors, such as selegiline, or amitraz should be avoided and antidepressants should be used cautiously in pets with seizures.

 Tricyclic antidepressants (TCAs). TCAs block the reuptake of serotonin and noradrenaline, and also have varying degrees of anticholinergic, antihistaminic and alpha-adrenergic activity, which probably account for side effects such as lethargy, dry mouth or gastrointestinal signs. TCAs are contraindicated with cardiac disease, glaucoma or where urine retention is a concern. However, amitriptyline and clomipramine have no cardiac contraindications in healthy dogs. While doxepin, imipramine and amitriptyline are commonly suggested in veterinary literature, efficacy evidence is lacking. Clomipramine is the most selective inhibitor of serotonin reuptake of the TCAs. It also inhibits noradrenaline reuptake and has mild anticholinergic and antihistaminic effects. Clomipramine is licensed for separation anxiety in combination with a behaviour modification program (BMP) and in some countries for canine compulsive and anxiety disorders and urine marking in cats (Australia). Long-term use may be required for some cases. In one study some dogs received treatment for separation anxiety for over 13 months and many continued to improve. When the drug was stopped, some dogs relapsed. Clomipramine combined with a BMP and benzodiazepines as needed may be effective for storm phobias. Efficacy has also been demonstrated for compulsive disorders in dogs and cats, and urine marking in cats.

 Selective serotonin reuptake inhibitors (SSRIs). These are selective in their blockade of the reuptake of 5HT1A into the presynaptic neurons. Because they only affect serotonin they may have fewer side effects than TCAs. Thus they may be preferred where cardiac disease, urine retention, increased intraocular pressure, sedation or anticholinergic effects might be a concern. Paroxetine has mild anticholinergic effects. In dogs maximum plasma levels for fluoxetine are reached in 1.8 hours and in 12 hours for the active metabolite norfluoxetine. Since clearance half-life is 6.2 hours for fluoxetine and 49 hours for norfluoxetine gradual weaning is not required. However, if used for longer than 8 weeks, gradual weaning should be considered. Lethargy and anorexia were the most common side effects. Since SSRIs inhibit cytochrome P450 enzymes, they can lead to increased toxicity when combined with drugs that are metabolised by these enzymes. In dogs, a chewable fluoxetine tablet is licensed in the US for treatment of separation anxiety in combination with a BMP. In another study fluoxetine alone was more effective than placebo; however, statistical improvement was not achieved in as many parameters nor as many time points compared to the study where fluoxetine was combined with a BMP. Fluoxetine and sertraline are effective for canine compulsive disorders, and fluoxetine and paroxetine may be effective for generalised anxiety. Fluoxetine may also be effective in feline urine marking and compulsive disorders.

Anxiolytics

 Buspirone is a serotonin (5HT1A) receptor agonist and a dopamine (D2) agonist. It may be useful for mild fear and anxiety in dogs and cats, and for urine marking in cats. It is non-sedating, and does not stimulate appetite nor inhibit memory. It may take a week or more to reach effect. Any anxiolytic may cause aggression due to disinhibition.

 Benzodiazepines potentiate GABA, an inhibitory neurotransmitter. They reduce anxiety, cause muscle relaxation, decrease locomotor activity and may cause hyperphagia (which may be useful for counterconditioning with food). They may cause paradoxical excitability and can have an amnesic effect on learning and memory. Benzodiazepines reach peak effect shortly after each dose and are therefore useful on an as needed basis. With extended use, there may be a rebound effect if withdrawal is not gradual. Since clonazepam, oxazepam and lorazepam have no active intermediate metabolites, they may be safer for pets with compromised hepatic function. Diazepam has been shown to be effective for feline urine marking; however, rare cases of hepatotoxicity and death have been reported.

 Beta blockers (e.g., propranolol) have been used to reduce the physiological signs of anxiety (heart rate, respiratory rate, gastrointestinal upset) when used in combination with drugs that diminish behavioural signs.

Neuroleptics

These are dopamine antagonists that decrease motor function at the basal ganglia and elevate prolactin. Phenothiazines are used for sedation but do not reduce anxiety. They are anticholinergic and should not be used in patients with seizures, liver disease or heart problems.

Progestins

Medroxyprogesterone or megestrol acetate have been used in dogs and cats for problems ranging from aggression to feline urine marking. They are most effective for androgen-induced behaviours. However, because of the potential for mammary tumours, adrenocortical and bone marrow suppression, acromegaly and diabetes, these products are not recommended, except when other therapies have failed.

Cabergoline

This is a dopamine-2-receptor agonist that has anti-prolactin effects and which might be useful in dogs with signs of pseudopregnancy including aggression. Cabergoline may also be used for post-spay aggression, which may be due to elevated prolactin.

Selegiline

This is an MAO B inhibitor, which enhances catecholamine transmission and is licensed in North America for cognitive dysfunction and in Europe for emotional disorders. A recent study found that dogs with chronic stress and anxiety had higher prolactin levels which responded to selegiline, while mild fears and phobias were associated with lower prolactin levels which responded to fluoxetine. Selegiline in combination with propranolol and alprazolam was effective in dogs with social and sound phobias. In a placebo-controlled trial, selegiline-treated dogs performed better at lure reward tasks, and were significantly more likely to walk across a novel object.

Natural Products and Supplements

'Natural' products can have great variation in purity, quality, level of activity and, therefore, efficacy between manufacturers and between batches. Adverse effects, toxicity and contra-indications are also important considerations. While a number of supplements such as S-adenosyl methionine (SAMe), DHA, combination products and other alternative therapies have been anecdotally reported to be useful, there are few, if any efficacy studies.

 Pheromones. The feline cheek pheromone (F3) is deposited by the cat throughout the environment by facial rubbing to mark out boundaries and provide emotional stability. Synthetic F3 (Feliway^TM) may be effective in reducing marking and scratching, anxiety during car transportation and in veterinary clinics, and when introducing cats to new environments. DAP is a synthetic version of the intermammary appeasing pheromone in the lactating bitch. It may help puppies adapt to a new home, reduce arousal in puppy classes, reduce anxiety in veterinary clinics and shelters, reduce fear of fireworks (with concurrent CD desensitisation) and reduce car travel anxiety. In a placebo-controlled trial, the DAP diffuser plus a BMP was found to be comparable to clomipramine plus a BMP for the treatment of separation anxiety.

 Melatonin is a derivative of serotonin and may inhibit dopamine. Production is primarily within the pineal body. Melatonin may be useful as a sleep aid and for canine fears and phobias at 0.1 mg/kg q8h.

 Diet/tryptophan. In one canine study, reduced-protein diets with tryptophan supplementation led to reduced territoriality while high-protein diets without tryptophan resulted in higher dominance aggression.

 Alpha-casozepine is a hydrolyzate of alpha-S1 capsein, a protein in cow's milk. In a canine study it was as effective as selegiline in reducing anxiety. In a cat study, there was a significant. improvement in both behavioural and autonomic signs of fear and anxiety compared to placebo

 L-theanine plus a CD desensitisation programme has been used to successful treat storm phobias in one placebo-controlled study and was effective in reducing signs of anxiety in cats.

 In one study aromatherapy was effective in reducing travel anxiety.

References

1.  Kochevar DT, Fajt V. Evidence-based decision making in small animal therapeutics. Veterinary Clinics of North America Small Animal Practice 2006; 36: 943-959.

2.  King JN, Simpson BS, et al. Treatment of separation anxiety in dogs with clomipramine: results from a prospective, randomised, double-blind, placebo-controlled, parallel-group multicenter clinical trial. Applied Animal Behaviour Science 2000; 67: 255-275.

3.  Landsberg G, Simpson B, et al. The effectiveness of fluoxetine chewable tablets in the treatment of canine separation anxiety. In: Landsberg, G; et al. (eds). Proceedings of the 6th IVBM/ECVBM-CA. Fondazione Iniziative Zooprofilattiche e Zootechniche. Brescia, IT, 2007; 68-69

4.  Pageat P, Lafont C, et al. An evaluation of serum prolactin in anxious dogs and response to treatment with selegiline or fluoxetine. Applied Animal Behaviour Science 2007; 105: 342-350.

5.  Sherman-Simpson B, Landsberg GM, et al. Effects of Reconcile (Fluoxetine) Chewable Tablets plus behavior management for canine separation anxiety. Veterinary Therapeutics 2007; 8: 18-31.