Your guide to understanding how behavior medications work

What's your question? Send your behavior-related questions to: DVM Newsmagazine, 7500 Old Oak Blvd., Cleveland, OH 44130. Your questions will be answered by Dr. Overall in upcoming columns.

Karen L. Overall

This column is the first in a series addressing the most-common questions that veterinarians ask me about behavioral medicine.

Some of the questions are:

• What drug do you use for condition X?

• How long do we have to treat the dog with medication?

• Can we stop it abruptly?

Once veterinarians are comfortable with these issues, they usually are more willing to use medication as part of a treatment regimen for troubled patients, and can intervene before the condition worsens.

Like most endeavors, one must gain experience with behavioral medication to become adept in its use, paying attention to outcomes and patterns.

What drug do you use for condition X?

This query is one of my least favorites, because it implies a simplistic and "quick-fix" approach to behavioral medicine. We live in a world of highly engineered medications that can have very specific uses, but for many disciplines, including behavioral medicine, the pharmaceutical approach is still relatively nonspecific.

Additionally, molecular biology and genetics have opened a new world for the understanding of disease processes. Sometimes, this new knowledge changes our entire perception of diagnosis and treatment.

Nowhere is this more obvious than for retroviral diseases and medications to treat them.

I suspect that, in 20 years, the way we now treat behavioral problems will seem as if we approached them with a shotgun.

That said, our approach today is more nuanced and specific than when I started in this field. At that time, the solution was to use tranquilizers for virtually everything. Simply sedate the pet so it wouldn't exhibit the problematic behavior.

The problem with that approach is that it puts a damper on normal and desirable behaviors. No dog or cat treated competently and appropriately with currently available behavioral medications should be or feel drugged.

We don't have a drug for every condition because many involve non-specific signs (e.g., barking) that rely on activation of various regions of the brain and various neurochemical systems that are affected both by environmental inputs (e.g., how threatened does the dog feel?) and the true underlying pathology at the molecular level.

However, we can pick medications based on the behavioral patterns the dog is exhibiting, combined with understanding how these medications are thought to work.

Just how these medications work often is logical and simple enough that veterinarians can explain the process to their clients in practical terms. That will encourage clients to comply with the overall behavioral-treatment plan, bringing a high rate of success.

Commonly used drugs/medications

Most of the medications prescribed for treating behavioral problems in pets fall into one of a few classes:

• benzodiazepines (BZs)

• tricyclic antidepressants (TCAs)

• selective serotonin reuptake inhibitors (SSRIs)

• combination TCAs/SSRIs

• some newer antipsychotic agents and atypical anticonvulsants.

These compounds all act by altering levels of neurotransmitters in certain regions of the brain. They do this either by affecting activity at a neuronal receptor, or by changing the neuron's activity or metabolism by directly altering internal chemistry, or by some combination of actions.

Benzodiazepines (BZs)

BZs work by changing the balance between neurons that are excited or stimulated and neurons that are slowed or inhibited. BZs increase the neurochemical gamma amino butyric acid (GABA), which is an inhibitory neurochemical that inhibits neurons that would otherwise have been stimulated. In the case of BZs, this effect is part of a balancing act: GABA is made from an excitatory amino acid that acts as an excitatory neurotransmitter, glutamate.

A seesaw provides a good analogy of these effects because, as glutamate increases activity, the patient becomes excited, and then as GABA increases, the effect of inhibition becomes more apparent and the patient calms.

These are relatively nonspecific effects, meaning that everything calms or everything becomes excited, which is why BZs are not commonly used as daily medications, except in cases of profound panic.

BZs have three levels of effects, depending on dosage:

At high levels, they act as true sedatives; at intermediate levels, they act as anti-anxiety medications; at low levels, they have general calming effects.

When we use BZs as part of a multi-level behavioral treatment program, we are looking for either the calming or anti-anxiety effects. Different BZs have different thresholds for these effects.

(Please note: Cats can have a very rare, but weird, paradoxical response to BZs. They can become excited. This also can happen in dogs, but is very rare.)

Do not assume that one drug in this class is the same as any other. It is not.

BZs include diazepam, alprazolam, clonazepam and clorazepate, among other medications.

Almost all of these can be abused by humans, but dogs and cats cannot abuse them without human help. Accordingly, there are households into which these medications should not be placed, and veterinarians should ask questions about household risk.

If the household is one that cannot have BZ-type drugs, there are alternatives that may involve combining TCAs and SSRIs, or changing some behavioral or environmental factors in the household.

Because of the half-lives of the BZs, alprazolam and oxazepam are among the most desirable to use (see Tables 1 and 2). While Table 1 refers to half-lives of BZs in humans, similar or exaggerated patterns tend to be the rule in dogs and cats, respectively, as seen in Table 2. That also explains why cats can become so drugged on diazepam, but may achieve the desired clinical effect when treated with alprazolam or oxazepam.

Tricyclic antidepressants (TCAs)

TCAs work by inhibiting the amount of norepinephrine, a stimulating neurochemical, and serotonin, a neurochemical associated with calm, outgoing, happy behaviors recycled by the neuron that first releases it (the pre-synaptic neuron). In other words, TCAs block the neuron's own recycling system.

The brain is a truly unique organ, and few chemicals in the blood actually get into the brain because of something called the blood-brain barrier (BBB). The BBB's job is to maintain relatively constant conditions in the brain, so that only the smallest substances can go back and forth between it and the blood. This is one reason recycling of neurochemicals is so important. It is a conservation strategy for neurochemical building blocks.

Because neurochemicals work by stimulating receptors in the next neuron (the post-synaptic neuron), the extra neurochemicals hanging around the synaptic cleft remain to stimulate the next receptor that becomes available. This means that you do not have to stimulate the first cell again to stimulate the second cell. This pattern is so powerful that it overcomes the thermostatic effect experienced by the first cell.

Now that you have all this neurotransmitter hanging around, the cell's thermostat (the somatodendritic auto-receptor) tells the first cell not to move any more neurochemical to the cell's membrane because there is already more outside than is being used. Accordingly, the cell slows its production and movement of norepinephrine and serotonin.

Because the objective is to stimulate the receptors in the second cell so that they stimulate chemicals in the cell that affect overall activity, it's more important to have something available to fill the receptors than it is to have a continuous supply. After a few days, a new set-point or thermostatic level is reached and there is both high volume of neurotransmitters moving through the presynaptic cell and efficient saturation of receptors on the second cell.

Selective serotonin reuptake inhibitors (SSRIs)

SSRIs work much like TCAs, but they have little or no effect on norepinephrine. The different SSRIs (e.g., fluoxetine, paroxetine, sertraline) affect different types of serotonin receptors to a greater or lesser extent, which is why sometimes a few tries are needed before choosing the best medication for your pet.

Just like people, dogs and cats differ in receptor density, in receptor type distribution, in overall metabolism of the medication, and in which enzymes make them more or less sensitive to a drug. Unfortunately, the only way to learn or infer this is to try different medications if one is not working.

Because of their more selective effects on receptor types, SSRIs are considered to have fewer side effects than many other medications, which is why they are used so often.

SSRIs and the more specific and newer of the TCAs (e.g., clomipramine) do their best work by changing the metabolism of the second neuron and encouraging it to stimulate its genetic and protein-making machinery to make new and better receptors. This is also the process you go through when learning something new. Because of this pattern, treatment with the appropriate TCA and/or SSRI can help your patients learn the behavior modification faster than they would without the medications.

In a placebo-controlled, double-blind study, dogs treated with drugs plus behavior modification compared with those undergoing behavior modification alone improved faster and to a better level (King et al., 2000). This is one reason these medications often are used in treatment programs.

Dr. Overall, faculty member at the University of Pennsylvania, has given hundreds of national and international presentations on behavioral medicine. She is a diplomate of the American College of Veterinary Behavior (ACVB) and is board certified by the Animal Behavior Society (ABS) as an Applied Animal Behaviorist.