14 Apr 2018
Several drugs are available for managing psychiatric disorders in small animals. Sagi Denenberg discusses why knowledge of these drugs – including applications, pharmacokinetics and side effects – is paramount when treating patients.
Sagi Denenberg
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Psychoactive drugs can improve the management of psychiatric disorders in animals. These drugs can reduce the intensity of problem behaviours, improve learning and memory, calm the animal and reduce arousal.
Choosing the appropriate medications depends on accurate diagnosis, desired effect and long-term goal.
Serotonergic drugs increase the level of serotonin at the synapse, and the number of serotonergic receptors in the brain. This can help reduce anxiety and arousal, and improve learning and sleep. These are the most commonly used medications in veterinary psychiatry.
Gamma-aminobutyric acid (GABA) drugs mimic the effects of GABA at the receptors. This can lead to increased inhibition of fear and allow the animal to settle down. These medications can be used as needed, or long term.
Monoamine oxidase type B inhibitors elevate the level of dopamine and, to a lesser extent, serotonin. These drugs can be beneficial in treating cognitive decline and chronic anxiety in pets.
Alpha-2 adrenergic receptor drugs can reduce signs related to fear – such as tachycardia, hypertension and panting – and provide an overall calming effect.
Psychopharmacologic agents are valuable in treating mental disorders1.
Drugs are most efficiently used as an adjunct to environmental management and behaviour modification protocol. They can help reduce the arousal and intensity of behaviour, accelerate the rate of improvement, increase success rates and help the pet to cope with its life2. Ultimately, the drugs contribute to improving the human-animal bond.
In several clinical trials of behavioural problems in dogs and cats, enhanced treatment success was obtained with simultaneous application of behavioural techniques and medication, compared to behavioural techniques alone1.
Psychoactive drugs may decrease arousal and intensity of behaviours, and can reduce the motivation to perform problem behaviours. Behavioural drugs may be used to treat particular anxieties and fears, such as separation anxiety and noise phobia. Still, other medications can help restore neurochemical balance and manage brain pathologies, such as compulsive behaviours and cognitive dysfunction.
Psychoactive drugs exert their effect by influencing the levels of neurotransmitters, and their respective receptors, in the brain. The most common target neurotransmitters are monoamines – serotonin, dopamine and noradrenaline – and gamma-aminobutyric acid (GABA). Most psychoactive medications can affect more than one neurotransmitter at a time. The profile and type of neurotransmitters affected account for the profile of the drug.
While psychoactive drugs are usually well tolerated and can be combined with commonly used medications – such as flea and tick control, intestinal and lungworm products, and NSAIDs – care must be used with other medications or health concerns.
Psychoactive drugs will not change behaviours – it will be prudent to remember they can attenuate the motivation to show a particular behaviour, but not necessarily eliminate it.
In other words, a dog fearful when strangers approach may still bite while receiving psychoactive drugs.
These drugs are not a substitute for an appropriate behaviour modification and management plans, and owner awareness.
The goal is to improve behaviour without adverse side effects. Therefore, diagnosis should be the first step.
Ideally, based on the diagnosis, veterinary surgeons can determine the target neurotransmitter(s) and drug selection.
Having a sound knowledge of available drugs and the cascade is a necessity. This should include knowledge of the drugs’ behavioural actions, side effects – including potential drug interactions – and previously reported therapeutic effects.
Drugs licensed for dogs and cats are:
Knowing each drug’s pharmacological properties can help distinguish between drugs, as they are likely to differ in their effects – so, if one drug is ineffective or poorly tolerated, an alternative can be selected with different mechanisms of actions, side effect profile or behavioural action.
The primary mechanism of action of tricyclic antidepressants (TCAs) is to block the reuptake of serotonin and, to a lesser extent, norepinephrine3. They also have anticholinergic and antihistaminic effects that may contribute to varying levels of sedation, urine and stool retention. Other muscarinic side effects may include dry mouth, mydriasis and reduced tear production.
The use of other TCAs – such as amitriptyline, doxepin or imipramine – is anecdotal and not well supported2. These drugs have a poor serotonergic effect, so their likely effect is due to potent antihistaminic and noradrenergic effects.
Selective serotonin reuptake inhibitors (SSRIs) are most commonly used in behaviourally abnormal dogs to control reactivity and impulsivity, reduce fear and anxiety, improve trainability and address the dog’s behavioural well-being1.
SSRIs are selective in blocking the reuptake of serotonin into the presynaptic neurons, by binding to serotonin 1A receptors8. The result is an increase of free serotonin and its receptors (serotonin 1A).
Side effects are the result of serotonin binding to different receptors. Common side effects include reduced appetite, lethargy, restlessness and agitation. Serotonin also affects the central micturition centre in the brain, so a rare – yet dangerous – side effect is urethral and dorsal sphincter spasm9–11.
Fluoxetine has been found to be effective in the management of separation anxiety in dogs12,13. Fluoxetine and paroxetine may be useful for general anxiety disorders, stabilising mood, reducing impulsivity and behaviourally pathologic aggression. Fluvoxamine and sertraline are other options for social and irritable aggression.
Serotonin and norepinephrine reuptake inhibitors are also used in veterinary behavioural medicine. These block the reuptake of both serotonin and norepinephrine equally, and, to a lesser extent, dopamine.
This group is more likely to activate withdrawn pets, reduce fear and anxiety, and enhance learning. At the time of writing, no studies exist to demonstrate efficacy in pets.
While serotonergic drugs reach peak plasma levels within hours, reuptake inhibition may induce downregulation of postsynaptic receptors that are responsible for clinical effects. Therefore, four weeks or longer is recommended to fully assess therapeutic effects.
Buspirone is a serotonin 1A receptor agonist and dopamine receptor D2 agonist8. It is used for mild fear and anxiety3, is non-sedating, does not stimulate appetite and does not inhibit memory. It takes a week or more to reach effect. Adding buspirone to an SSRI may add to the serotonin pool.
Trazodone, a serotonin 2A antagonist-reuptake inhibitor, may be useful in dogs with generalised anxiety, separation anxiety, storm phobias and some forms of aggression, including inter-dog aggression and impulse control disorders14,15. It can be used on a needed basis, in conjunction with a TCA or SSRI, or two to three times daily. Common side effects include gastrointestinal upset and lethargy.
Mirtazapine is a commonly used alpha-2 antagonist. However, mirtazapine is also a potent serotonin 2A, serotonin 2C and serotonin 3 antagonist, with mild antihistamine activity8. These properties provide both anxiolytic effect and appetite stimulation16,17. Moreover, blocking serotonin 3 receptors centrally provides antiemetic properties.
Selegiline is a monoamine oxidase type B inhibitor with dopaminergic and serotonergic properties3. Chronic stress associated with stereotypic and displacement behaviours, fear aggression, and autonomic signs may have elevated prolactin levels, which may improve with selegiline18. In addition, it may improve memory and reduce oxidative damage in the brain, so is useful for CDS in cats and dogs19,20.
Dexmedetomidine, an alpha-2 agonist, can be used as a transmucosal application for the management of noise phobia21. Other (off-label) applications include management of car travel anxiety and visits to the veterinary surgery, as needed22,23. Ideally, this drug should be applied 30 to 60 minutes before a fear-evoking event and repeated every two to three hours – up to five times, as necessary.
Clonidine is also a selective alpha-2 agonist that blocks norepinephrine, and may be used with SSRIs for situational use in fear, territorial aggression, separation anxiety and noise phobias24. At higher doses, alpha-2 agonists are sedating.
They can be used alone or as an adjunct – primarily as needed – but may be considered in select cases on an ongoing basis with multiple daily dosing. They may cause paradoxical excitability, increased activity and an amnesic effect3. Common indications include situations such as veterinary visits, car travel anxiety, and fireworks and similar loud noise events.
Lorazepam, oxazepam and clonazepam have no intermediate metabolites, so are safer to use compared to diazepam2. Alprazolam metabolism includes hydroxylation prior to final glucuronidation. This renders alprazolam safer in cats compared to diazepam.
Gabapentin is structurally related to GABA; however, it does not mimic GABA’s effect or metabolism25. The most likely mode of action is inhibition of calcium influx through the presynaptic voltage-gated calcium channels, thus inhibiting release of excitatory neurotransmitters such as glutamate and noradrenaline. Typical indications include chronic pain, seizures and anxiety. It may be useful as an adjunct to SSRIs and TCAs for refractory anxiety and in compulsive behaviours in both dogs and cats1,2. In higher doses, gabapentin can be used as a situational drug – for example, for travel, veterinary visits and fireworks. Side effects may include sedation, ataxia and gastrointestinal upset.
Beta blockers – such as propranolol – reduce physiologic signs of anxiety, including heart rate, respiratory rate and trembling. Therefore, they may be most useful if combined with drugs that reduce behavioural anxiety.
Focal seizures of the temporal lobe may present with mood alterations or hallucinatory and self-traumatic behaviours. Generalised seizures may be associated with aggression – for example, in the postictal phase. Therefore, anti-kindling may be a consideration in diagnosis and treatment. Levetiracetam may be effective for focal seizures, and anxiety, panic and mood disorders that may have comorbidity with epilepsy.
Carbamazepine is also a mood stabiliser that may be a useful adjunct to SSRIs for irritable and impulsive aggression. Phenobarbital and imepitoin are also options to use in situations of seizure-related behavioural changes.
If you are thinking of using drugs, start by evaluating the patient carefully for comorbidities, including pain and other health problems. Perform a full physical examination, including any necessary laboratory and imaging tests. Take a full behavioural history and try to establish your diagnosis. Develop a complete management plan tailored to the patient, owners and environment.
Afterwards, select the appropriate drug based on your targets and pharmacological profile. Ensure your initial dose is correct and allow sufficient time to evaluate the drug’s effect. If you see minimal effect and no side effects, you can increase the dose or add a second drug. Adjust or change as necessary.
Many behavioural drugs require one to three weeks to initiate; maximum effect may take more time. Advise owners to be patient and aware that side effects may occur immediately.
In some cases, a first-choice behavioural drug may be insufficiently effective. Another drug may be chosen to optimise treatment outcome. Clients should be advised of this possibility at the onset of therapy.
