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).

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.