April 4, 2013
Originally published in the April 2013 issue of Veterinary Practice News
By now, almost everyone has heard about Prozac, though the veterinary brand name Reconcile is less well recognized.
Personally, I prefer prescribing Reconcile to manage certain behavior problems because it is licensed for use in dogs, is especially designed for use in dogs in a palatable formulation, and lists the correct canine dosing and side effects on the enclosed data sheets.
One problem is that Reconcile is somewhat expensive and finds itself in competition with off extra-label generic fluoxetine. For the purposes of this article, I will mostly refer to Prozac/Reconcile by the generic name fluoxetine.
Fluoxetine is a selective serotonin reuptake inhibitor (SSRI). That is to say, it delays re-absorption of serotonin into presynaptic nerve endings following its release by blocking the reuptake mechanism. This causes serotonin to persist for longer and thus enhances its effects.
Two other actions of fluoxetine, as opposed to other SSRIs, are that it is a potent 5-HT2C antagonist and a sigma-1 receptor agonist. Overactivity of 5-HT2C contributes to anxiety and depression so antagonism of these receptors may be advantageous. The sigma receptor agonist action may also be beneficial in some instances in producing antidepressant-like effects.
Another purported action of fluoxetine and other SSRIs is to stimulate neurogenesis (maturation of progenitor neurons) in the dentate gyrus of the hippocampus. In this way SSRIs may act like Miracle-Gro for the brain. This effect takes time and may be responsible for the longish delay before SSRIs attain their peak effects.
The newly formed neurons may then migrate and populate other brain regions, perhaps increasing memory and other brain functions. So important is this effect that when mice had their hippocampi irradiated to prevent neurogenesis, fluoxetine lost its behavioral effect (Santarelli et al, Science 2003).
Whatever its mechanism, fluoxetine has been shown to be beneficial in a wide range of behavioral issues. I tell students that if they decide to become proficient in using any behavior modifying medication, fluoxetine's the one to choose. Speaking with a Harvard Medical School-based psychiatrist colleague recently, I asked for ratification of something I had been told—that fluoxetine and other SSRIs accounted for 85 percent of psychiatric prescriptions made, whatever the diagnosis.
His reply: “More than that, I would say.” It's the same in veterinary behavioral medicine.
Fluoxetine is useful to treat aggression. The simple rule here is serotonin up, aggression down (vice versa is also true). Take one experiment in vervet monkeys to emphasize the point.
A dominant male was removed from a social group and one of the remaining males was treated with either a fluoxetine or a serotonin antagonist. When fluoxetine was given the treated male invariably became more dominant, less aggressive and engaged in more affiliative behaviors (note: dominance and aggression move in opposite directions).
When a serotonin antagonist was given, one of the other monkeys became the dominant one while the treated monkey became more aggressive and more antisocial. I have also heard that the serotonin level of army officers (more in control, less aggressive) was higher than that of enlisted men.
Same story, really. In our study of fluoxetine for treatment of aggression in dogs [Journal of the American Veterinary Medical Association 1996, 209(9):1585-1587], we found an across-the-board reduction in aggression in dogs treated with 1mg per kg of fluoxetine over the four-week study. A couple of dogs showed very dramatic and sudden deceases in aggression, while in others the reduction was more gradual. None of the dogs showed an increase in aggression, and neither should they. Increased aggression is not a feature of fluoxetine's use (or any other SSRI, for that matter).
I have been looking for a confirmed case of fluoxetine-induced aggression for 25 years now and I am still looking.
True, fluoxetine is supposed to cause increased suicidal thoughts and ideation in some teenagers but there is no way of testing this in dogs. There was one man—not my client—who thought his dog had committed suicide on fluoxetine. The case regarded a fluoxetine-treated, noise-sensitive dog whose owner, descending a high-rise stairway in New York City, accidentally dropped the Flexi-lead behind the dog and the noise caused the dog to flee—up the stairs and over the top of the skyscraper. Not really suicide, if you see what I mean.
Anyway, we continue to use fluoxetine liberally in serious cases of aggression and for the most part have great success with it (more so in owner-directed aggression than fear aggression). Of course, there are troublesome, but for the most part temporary, side effects to content with in about 25 percent of dogs.
These include appetite reduction and loginess or tiredness. They typically occur in weeks two and three after beginning treatment and are gone by week four. If they are more than mild, we discontinue the fluoxetine until the side effects dissipate and then resume treatment at a lower dose.
Almost all I have said about treating canine aggression with fluoxetine applies equally well to cats. Several authors have stated that fluoxetine or another SSRI is their first choice for treating a dominant, bully cat whether that aggression is directed toward other cats or people. That is our first approach, too.
Using fluoxetine in either situation makes sense based on what we know to be the effect across the species of increasing serotonin in the central nervous system. Appetite reduction and occasionally a lackluster personality (what I call the recluse syndrome) are potential side effects that can often be managed in the same manner as I suggested for dogs.
Often no side effects are seen and the dose can be increased without issue until the desired behavioral response is obtained. As with dogs, this approach is best used in conjunction with appropriate behavior modification therapy.
Then there's separation anxiety. A properly conducted study of the use of fluoxetine (Reconcile) for treatment of separation anxiety by Gary Landsberg et al appeared in the Journal of Veterinary Behavior: Clinical Applications and Research 2008, 3, (1): 12–19. The conclusion: Reconcile provides a “positive advance as a therapeutic option” for treatment of canine separation anxiety.
Several of the parameters they measured we improved by this treatment and as a result of this group's efforts, fluoxetine in the form of Reconcile is now approved by the FDA for treatment of this highly prevalent and troubling condition. The authors caution that Reconcile should be used in conjunction with behavior modification therapy.
Actually, years earlier, we conducted an unpublished, double-blind, placebo-controlled study of fluoxetine for treatment of separation anxiety in dogs and concluded, after a five-week study, that even without concurrent BMT, fluoxetine produced a significant reduction in clinical signs of the condition. Clearly, however, it is optimal to use fluoxetine and BMT simultaneously.
Cats can develop separation anxiety, too. The signs are often far less dramatic but one key sign is urine marking only in the owner's absence. In this case, and for urine marking in general, fluoxetine is super effective.
A study by Ben Hart et al in 2005 showed that fluoxetine (and clomipramine) produced a near 90 percent reduction in urine marking in most cats and the effect was sustained over the eight months of the study. Certainly the introduction of fluoxetine as a treatment for this otherwise refractory condition has meant the urine marking is no longer the harbinger of surrender and/or death knell for cats that it once was.
Another condition that appears to respond to fluoxetine is canine thunderstorm phobia. While a definitive study of using an SSRI like fluoxetine to treat thunderstorm phobia has not yet appeared, an earlier study, by Sharon Crowell-Davis et al, of a similarly powerful but less specific serotonin reuptake inhibitor, clomipramine, in conjunction with an “as needed” Valium-like drug, alprazolam (Xanax), did produce affirmative results [JAVMA 2003, 222 (6): 744-748].
I agree with Dr. Crowell-Davis, however, that adjunctive therapy with a situational medication is often needed in this condition to supplement the background anxiety-reducing effects of the serotonin reuptake inhibitor. Cats rarely get thunderstorm phobia but if they do I am sure fluoxetine would help cats with this condition, too.
Then there are the compulsive disorders—canine and feline (CCD and FCD). SSRIs are the first line of treatment for humans with obsessive-compulsive disorders and these animal equivalent conditions. For canine lick granuloma, fluoxetine works well for most dogs.
The anti-compulsive effects of fluoxetine have been clearly documented since the early 1990s. Other animal compulsions that respond include tail chasing, flank sucking, blanket sucking, light chasing (all in dogs), and wool sucking/pica and psychogenic alopecia (both in cats). Equine compulsions, like cribbing and wind sucking, have also been found to respond.
The bottom line is that fluoxetine is a very useful behavioral medication and it and its congeners are here to stay. Former Tufts Dean Franklin Loew used to say that Prozac is to behavioral medicine what ivermectin was to parasitology. He was right.
Homer Simpson had a neat saying, too. His was “Is there anything a doughnut can't do?” I say, “Is there anything fluoxetine can't do?”
An author and researcher, Nicholas Dodman, BVMS, Dipl. ACVB is a professor at Cummings School of Veterinary Medicine at Tufts University and is founder of Tufts' Animal Behavior Clinic.
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