Considerations When Using Polypharmacy to Treat Behavior Issues

Treatment with psychotropic drugs is common in veterinary patients with behavioral disorders and chronic pain.¹ Veterinary schools, however, do not routinely offer basic and applied neuroscience or clinical behavioral medicine as core fields, resulting in a psychopharmacology knowledge gap.²

The current standard of care for psychopharmacology in human and veterinary medicine is often multimodal or includes drug combination therapy.³ Neurochemistry involves multiple neurotransmitters and hormones; a single medication is thus unlikely to help a patient experiencing multiple or severe signs.^4,5

Ask the Expert: What do I need to know about using multiple drugs to treat a behavioral issue?

Diagnostic Criteria Matters

Medications should not be selected to simply match a diagnosis. Psychoactive drugs modulate behavioral, emotional, and cognitive processes secondary to the brain’s neurochemistry, as well as secondary to the stress response. The first step in diagnosis should therefore be to obtain a detailed description of all behavioral concerns.⁶ An up-to-date, evidence-based resource should be consulted to confirm the description given by the pet owner matches the correct diagnostic criteria.⁴ Severity, intensity, and frequency of observed clinical signs should then guide drug selection.^4,6

Understanding the Options

The next step is to understand the mechanism of action of currently available psychoactive medications. Even drugs in the same class can have distinct mechanisms of action.⁷ For example, serotonergic drugs (eg, selective serotonin reuptake inhibitors [SSRIs], tricyclic antidepressants) have individual affinities or interactions with different receptors.^7,8 Fluoxetine administration will thus not have the same effects as sertraline administration.⁷ Fluoxetine and trazodone are among the most commonly administered serotonergic drugs in veterinary medicine and are typically used interchangeably for the same conditions; however, these drugs have completely different mechanisms of action, pharmacokinetics, and clinical profiles.³ Understanding this concept is important for proper and safe drug selection.

Treating Stress, Fear, Anxiety, & Aggression

Discussion of the physiologic and endocrine processes that cause stress, fear, anxiety, and aggression disorders are beyond the scope of this article but are broadly available in the literature.

Basic, applied, and clinical studies have consistently demonstrated the usefulness of specific classes of medications and drug combinations for decreasing the intensity of the stress response, decreasing some forms of aggressive behaviors, and effectively treating fear, phobia, and anxiety disorders.^1,4

In general, serotonergic drugs—like SSRIs, serotonin-norepinephrine reuptake inhibitors (eg, venlafaxine), serotonin antagonist and reuptake inhibitors (eg, trazodone), and azapirones (eg, buspirone)—are considered safe and effective for treatment of stress, fear, anxiety, and aggression.^3,4 Veterinary behaviorists often administer these medications in combination with mood stabilizers, particularly alpha-2-delta calcium channel ligands (eg, gabapentin, pregabalin) and alpha-2 agonists (eg, clonidine, dexmedetomidine oral transmucosal gel).³ Although case reports and preliminary studies have been published on other drugs and drug classes (including N-methyl-D-aspartate receptor antagonists [eg, memantine], beta blockers [eg, propranolol], and specific hormonal agents [eg, oxytocin]), robust, evidence-based data in veterinary patients are lacking.⁴ Tricyclic antidepressants, benzodiazepines, and antipsychotics are used less commonly in veterinary medicine, either due to concern for adverse effects and drug interaction profile or being less specific to receptors and pathways involved with the stress response, aggression, and anxiety disorders.^1,4

Consultation with a veterinary behaviorist is advised when novel psychotropic medications are considered; patient health and owner factors (eg, financial concerns) should be incorporated as part of a shared decision-making model.

How to Get Started

A baseline health assessment with routine laboratory testing (ie, CBC, serum chemistry profile, urinalysis) should always be performed as part of patient assessment. Several metabolic, genetic, and developmental factors can determine an individual patient’s response to a specific psychoactive medication. Treatment should therefore be established with a step-by-step approach.⁴ A single medication should be administered at a time, with progressive drug additions made while progress is closely monitored. When administering a medication to a patient for the first time, the lower end of the dose range should be given to watch for adverse effects. If no adverse effects or significant clinical improvement are observed, the dose can be increased as needed with continued monitoring. Additional medications can be individually added, following the aforementioned methodology: low dose administered to watch for adverse effects, progress assessed, medication increased to effect if no adverse effects are seen.⁵

Are Adverse Effects Ever Acceptable?

Every medication has potential adverse effects that can range from common to extremely rare. For example, it is common and expected that some SSRIs are likely to cause hyporexia during the first few weeks of treatment. If the hyporexia is not severe (ie, the patient is still eating and maintaining weight) and is tolerated by the owner, the recommendation is to wait, as this adverse effect tends to be transient.⁷

For some drug classes (eg, alpha-2-delta calcium channel ligands, alpha-2 agonists), sedation may occur and can be an effect of the dose amount. Decreasing the dose may eliminate the sedative effect while still providing clinical benefit.⁹

Adverse effects that contradict the purpose of treatment (eg, increased agitation, increased aggression, increased sensitivity to touch) are potentially dangerous and can reveal serious problems (eg, serotonin syndrome, individual patient inability to metabolize certain medications). In such cases, the medication should be stopped immediately and the treatment plan re-evaluated.⁴

Conclusion

Psychopharmacology can improve quality of life and increase lifespan in veterinary patients.^3,4Drug selection and combinations can be effective and safe as the function of neurotransmitters and hormones in emotional processing, cognition and behavior, and drug mechanism of action are better understood.