Combination SSRIs/TCAs: Your guide to treating behavioral disorders

Some of the newer medications (e.g., Effexor; venlafaxine) have the beneficial effects of TCAs and SSRIs combined, minimizing side effects.

This means they will stimulate both the more specific and less specific neurochemical receptors, and will affect both norepinephrine and serotonin, but at different rates than would the SSRI or TCA alone. As a result, some of these medications can have greater treatment effects for some patients. All of them still have their patents at this writing; that can make them a little pricier than some of the other older medications.

In vivo combination treatment

BZs can be used in combination with TCAs and SSRIs when called for. For example, many dogs with separation anxiety are also afraid of storms. Storms do not happen every day in most parts of the country, so giving a daily medication is unnecessary. The dog can take a TCA like clomipramine every day, and the BZ alprazolam as needed. This means that for 20 days a month the dog may get the TCA twice a day, but for 10 days it also gets the alprazolam as needed if there is a 50 percent chance or greater of storms.

Because dogs use up alprazolam quickly and have few sedative effects of repeat dosing if the dose chosen is correct, the dog may get alprazolam three or four times a day during those 10 days of storms.

If the dog lives in an area where there is a true storm season, the decision to give the dog a daily BZ plus a daily TCA might be justified. For example, alprazolam could be given twice a day during the season, and more often as needed. This raises the threshold for reactivity, and lets the dog take advantage of the pharmacokinetics of the medication by constantly boosting both parent compound and intermediate metabolites, some of which can be biologically helpful.

BZs can become the victim of physiological tolerance, meaning that the animal will need more with time, but at the levels used for routine treatment this happens less often than one might expect. If an increase in medication is required to sustain a good clinical effect, this is not a problem as long as:

• The vet is sure that it is the dog or cat who is actually getting the drugs.

• A serum biochemistry profile indicates that the patient's metabolic capabilities are not impaired by the medication(s).

In fact, this is exactly why pre-medication laboratory evaluation is needed: How will you know if your treatment is having an adverse effect if you do not have a baseline against which to compare later blood work?

So, unless my clients have to choose between buying the drug and paying for lab work, or, by obtaining blood I might make the patient behaviorally worse, I want recent lab work on all my patients.

To use BZs, TCAs and SSRIs effectively, we need to acknowledge that we actually don't know very much about the disposition of these medications in our patients, and that we lack knowledge of their effects of the cytochrome system — specifically the CPY 450 system — on metabolism of these medications.

That said, dogs appear to be much like humans: there are ultra-fast metabolizers, who will need more medication than average, ultra-slow metabolizers, who will need less, and those who are normal, fast metabolizers, for whom the target dose is just fine.

To establish these ranges in dogs and/or cats, we would need to treat a large number of patients with the same drug for the same condition, involving the same inclusion and exclusion criteria, then obtain genetic samples and intermediate metabolite samples from the patients studied. This is a project that needs to be done, and in which I have great interest. If anyone has ideas about how it could be done, they should let me know.

Only by making good clinical observations about the behavioral patterns and their changes during treatment can veterinarians use this type of knowledge to benefit their patients.

There is no ideal drug to control or treat both of the chronic and sporadic types of anxieties. The best way is to use the two different drugs in a rational way. This means that you need to understand how they interact for effect and for side effects.

For example, a dog whose only problem is thunderstorm phobia may need a higher dose of the alprazolam than a dog who also has separation anxiety and is already taking a TCA or SSRI. The choice has to do with the threshold that makes the dog react and how quickly the individual dog metabolizes the medications.

Reasons for combing TCAs and SSRIs (e.g. amitriptyline and fluoxetine) include:

• If cost is an issue, by using a less specific medication with a more specific one, the amount of the more specific — and generally costlier — drug will be decreased.

• Sometimes some amount of the less specific drug is needed to affect receptors that more specific drugs don't. Although the problem is mainly with the receptors the more specific drug addresses, clinical experience indicates that the behaviors are different when on each of the medications, but both have desired improvements. In this case, using lower dosages of both drugs, especially if they are TCAs and SSRIs, can facilitate each other or make each drug work better. This is especially true for drugs that share mechanisms for how they work.

• By using lower dosages of two drugs, the side effects of each may be minimized. However, caution is urged at the beginning of the combination treatment. Very rarely, an animal may show an exaggerated excitation response that may be equivalent to serotonin syndrome in humans. These animals are quickly recognized because they don't stop moving, don't sleep and are generally frantic. Medications should be stopped at once and supportive care instituted immediately. Treated appropriately, dogs and cats survive these episodes but may never be able to take the same amounts or types of drugs again. To repeat, this is a very rare side effect, but in the world of side effects, knowledge is power.

You cannot give TCAs or SSRIs along with an MAO-I (monoamine oxidase inhibitor). To do so increases the risk of dramatically increasing the amount of norepinephrine in the system, generating a sympathetic cascade, with concomitant physical signs (e.g., restlessness, tachycardia, anorexia, etc).

Which drug?

Veterinary medicine lacks the large population of patients that have been treated in controlled trials comparing the efficacy of various medications. Regardless, some of the patterns revealed by studies in humans may provide a first tier of guidance for treatment of veterinary patients. The gestalt of how to make the decision for a first choice of a drug is found in Table 1.

Table 1: "Gestalt" of TCA and SSRI use based on t½ of parent compounds and active intermediate metabolites, relative effects on NE and 5-HT, and extrapolations from multi-center human studies

And, because in veterinary medicine price is not divorced from treatment choice, it is important to know that the older, less-specific TCAs (amitriptyline, nortriptyline) are very cheap, but they may have a slightly greater risk of side effects because they target more classes of neurochemical receptors.

Two of the SSRIs are now generic: fluoxetine and paroxetine. This means that for some dogs the cost will be equivalent to that of the older, less-specific TCAs. Keep in mind the only one of these medications that has a veterinary formulation is clomipramine, which means that use of the other medications is considered extra-label.

This first step in understanding behavioral medications should help veterinarians integrate behavioral drugs into their overall treatment plans for distressed pets. Don't worry if you don't pick the right medication for the particular pet's condition on the first try. If dogs and cats are like people, we have a huge probability of finding a medication that will help if we are willing to try three medications before giving up. In truth, well over 75 percent of the time my first or second choice of medication is efficacious. Those are pretty good odds.

Suggested Reading

And now for the dirty little secret about behavioral medications: If we are — as I said before — shot-gunning our patients with relatively non-specific medications, we have a lot of leeway for not choosing the perfect drug. In truth, these patients are suffering so much from their behavioral problems that the vast majority of them will improve if the following things happen:

1) They are treated with a TCA or an SSRI — just pick one.

2) People stop punishing them.

3) People start praising and rewarding them for spontaneously offered desirable behaviors.

4) People are humane and consistent with behavior modification.

The easiest way to do the latter is to use passive behavior modification in all life situations. Simply ask the animal to sit or lie down calmly and defer to you. By doing so, you are encouraging the animal to ask for information about what behaviors are expected and which will be rewarded. As discussed, medication helps patients learn faster and better, but I doubt that the specific medication is more important than understanding and using these four steps. These steps teach the troubled and distressed pet that you are a reliable and trustworthy human and that you will help them through their distress. Isn't that what we all want?

The next column will focus on the questions of side effects and how long you have to treat with medication.

Most of the information in these columns is from my upcoming text: Manual of Clinical Veterinary Behavioral Medicine, and from the client handouts that will be in it.

Dr. Overall

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.