ACVC 2001 - Pharmacology and Behavior: Practical Applications

Pharmacology and Behavior: Practical Applications

Karen L. Overall, MA, VMD, PhD, DACVB, ABS Certified Applied Animal Behaviorist

Introduction and some cautious words: In human psychiatry, large, multi-center treatment trials are common and serve to identify sub-populations of patients who share a phenotypic diagnosis but perhaps not a specific neurochemical mechanism for that diagnosis. For example, all SSRIs vary in structure so if one subpopulation responds better to one SSRI than to another in a repeatable way, a re-examination of the effect of the medication at the molecular level may suggest causal differences for the underlying condition and its heterogeneity. In this way clinical and bench neuromolecular pharmacology work in tandem to advance understanding of the complex integration of all organ system and environmental responses that we call "behavior". There are no large-scale studies in veterinary behavioral medicine that would permit the use of this type of empiricism that is possible in human psychiatry. However, dogs are often the models for toxicological and tolerance studies of human psychotropic medications and the areas of the brain primarily affected by TCAs and SSRIs involve ancient areas so humans can serve as treatment models for many canine conditions.

Pre-medication considerations:

Prior to incorporating behavioral pharmacology into any treatment program the following conditions must be met:

(1) A reasonable diagnosis or a list of diagnoses should be formulated. This is different from a list of non-specific signs.

(2) The clinician should have some insight into the neurochemistry relevant to the condition.

(3) The clinician should have an appreciation for the putative mechanism of action of the chosen medication.

(4) The clinician should have a clear understanding of any potential side effects.

(5) The clinician and client should have some clear concept of how the prescribed drug will alter the behavior in question. The latter is critical because it will help clients to watch for side-effects and improvements and can help the clinician confirm or reject the diagnosis.

Without these five guidelines, behavioral drugs may not be given long enough or at a sufficient dosage to attain the desired effect, the clients will be unable to participate in the evaluation process, there will be no objective behavioral criteria that will allow the veterinarian to assess improvement, and drug selection is liable to be similar to alchemy.

Prior to prescribing any drug a complete behavioral and medical history should be taken. Should the animal be older, suffer from any metabolic or cardiac abnormalities, or be on any concurrent medical therapy, caution is urged. All animals should have complete laboratory and physical examinations. Most behavioral drugs are metabolized through renal and hepatic pathways so knowledge of baseline values is essential. For example, SSRIs are often considered "safer" than many TCAs, but because of the small sizes of clinical trials necessary to bring drugs to market the exact incidence of potential side effects is often unknown in the absence of post-marketing surveillance. One recent study reports that, in contrast to the commonly held view that SSRIs are "safe", 229 cases of acute hepatitis reported by the World Health Organization (WHO) International Programme for Drug Monitoring have been attributed to the SSRI fluoxetine, 54 to the SSRI fluvoxamine, 80 to the SSRI paroxetine, and 65 to the SSRI sertraline. These data present a different picture from those portrayed by the clinical trials that indicate only a 0.5% increase in liver enzymes among 3000 patients, but still may represent a very small number of serious problems for the number of patients actually exposed to the drugs.

Many of the more commonly (and, oddly 'safer') behavioral medications can have cardiac side effects. Baseline ECGs are recommended for in any patient who has had a history of any arrhythmia, heart disease, prior drug reactions, is on more than one medication, and who may be undergoing anesthesia or sedation. Liver dyscrasias and cardiac arrhythmias may not rule out the use of a drug, but knowing that they exist can serve as a guide to dosage and anticipated side effects. Once alerted to potential adverse reactions clients are extremely willing to comply with all monitoring and with the extensive communication needs of behavioral cases. Clients should receive a complete list of all potential adverse responses and should be encouraged to communicate with the clinician at the first sign of any problem. Clients are often very distressed after a behavioral consultation and need a written reminder of situations for which they should be alert.

In the United States, extra-label use of human drugs, including psychopharmacological agents, for the treatment of pets hinges on a valid client / veterinarian / patient relationship. This means that a behavioral history was taken, a tentative diagnosis was formulated, and a treatment plan was developed. If any veterinarian is uncomfortable with complying with these guidelines, they should refer their behavioral cases to a specialist in behavioral medicine. Consultations directly with a client by fax, phone, mail, or e-mail, in the absence of actual visual inspection of the patient, most often do not meet the criteria of a valid client / veterinarian / patient relationship. Caution is urged. The preferred mode of consultation if the clinician can not have a visual inspection of the patient is for the consultation to take place directly with the specialist and the referring clinician, who is then responsible for treatment and follow-up.

Finally, the client household must be considered when the decision to use behavioral drugs is made. Substance abuse is rampant in humans and many drugs used for behavioral pharmacology have high abuse potential.

Monitoring:

Monitoring of side-effects is critical for any practitioner dispensing behavioral medication. The first tier of this involves the same tests mandated in the pre-medication physical and laboratory evaluation. Age-related changes in hepatic mass, function, blood flow, plasma drug binding, et cetera cause a decrease in clearance of some TCAs, so it is prudent to monitor hepatic and renal enzymes annually in younger animals, biannually in older, and always as warranted by clinical signs. Adjustment in drug dosages may be necessary with age.

It is preferable to withdraw most patients from one class of drug before starting another. For changing between SSRIs and MAOIs the recommended drug-free time in humans and dogs is two weeks (2 + half-lives: the general rule of thumb for withdrawal of any drug). SSRIs can be added to TCAs and may then exhibit a faster onset of action than when they are given alone. This is due to the shared molecular effects on second messenger systems of both TCAs and SSRIs. Combination treatment allows the clinician to use the lower end of the dosage for both compounds which minimizes side effects while maximizing efficacy. Furthermore, benzodiazepines can be used to blunt or prevent acute anxiety-related outbursts on an as needed basis in patients for whom daily treatment with a TCA or an SSRI is ongoing. Together, the combination of benzodiazepines and TCAs / SSRIs may hasten improvement and prevent acute anxiety-provoking stimuli from interfering with treatment of more regularly occurring anxieties.

When stopping a drug, weaning is preferred to stopping abruptly. A model for how to do this is found in Table 1. Weaning minimizes potential central withdrawal signs, and allows determination of the lowest dosage that is still effective. Long-term treatment may be the rule with many of these medications and conditions, but maintenance may be at a considerably lower level of drug than was prescribed at the outset. The only way the practitioner will discover if this is so is to withdraw the medication slowly.

Choosing specific drugs for the treatment of specific behavioral conditions:

A summary of the drugs discussed can be found in Table 2. Implicit in the recommendations for treatment are that the necessary and sufficient conditions for diagnosis are met (i.e., the practitioner is addressing a specific diagnosis, not a non-specific correlate or sign) and the relevant pharmacodynamics discussed above are understood and used in the diagnosis.

References:

1. Capella D., Bruguera M., Figueras A., and Laporte J-R. (1999) Fluoxetine - induced hepatitis: why is post-marketing surveillance needed? European Journal of Clinical Pharmacology 55, 545-546.

2. Nattal S., Mittleman M. (1984) Treatment of ventricular tachyarrhythmias resulting from amitriptyline toxicity in dogs. Journal of Pharmacology and Experimental Therapeutics 231, 430-435.

3. Overall K.L. (1997) Clinical Behavioral Medicine for Small Animals. St. Louis:Mosby.

4. Overall K.L. (2000) Behavior modifying drugs: Neurochemistry and molecular biology. Proceedings of the 18^th ACVIM Forum 18, 68-71.

5. Overall K.L. (1999a) Allow behavioral drugs ample time to take effect. Veterinary Medicine 94, 858-859.

6. Pouchelon J.L., Martel E., Champeroux P., Richard S., and King J.N. (2000) Effect of clomipramine hydrochloride on the electrocardiogram and heart rate of dogs. American Journal of Veterinary Research, in press.

7. Reich M.R., Ohad D.G., Overall K.L., and Dunham A.E. (2000) Electrocardiographic assessment of antianxiety medication in dogs and correlation with drug serum concentration. Journal of the American Veterinary Medical Association 216, 1571-1575.

Table 1: Algorithm for treatment length and weaning schedule

(1) Treat for as long as it takes to begin to assess effects

• 7-10 days for relatively non-specific TCAs

• 3-5 weeks minimum for SSRIs and more specific TCAs

PLUS

(2) Treat until "well" and either have no signs associated with diagnosis or some low, consistent level

• minimum of another 1-2 months

PLUS

(3) Treat for the amount of time it took you to attain the level discussed in (2) so that reliability of assessment is reasonably assured

• minimum of another 1-2 months

PLUS

(4) Wean over the amount of time it took to get to (1) or more slowly. Remember, if receptor conformation reverts it may take 1+ months to notice the signs of this. While there are no acute side effects associated with sudden cessation of medication, a recidivistic event is a profound "side effect". Full-blown recidivistic events may not be responsive to re-initiated treatment with the same drug and, or the same dose.

• 7-10 days for relatively non-specific TCAs

• 3-5 weeks minimum for SSRIs and more specific TCAs

TOTAL: Treat for a minimum of 4-6 months

Table 2A: Selected psychopharmacological agents that may be useful in the treatment of feline behavioral diagnoses

ALPRAZOLAM (tablets: 0.25, 0.5, 1, 2 mg [1 and 2 mg tablets scored)	0.125-0.25 mg/kg po q. 12 h
AMITRIPTYLINE (tablets: 10, 25, 50, 75, 100, 150 mg)	0.5-2.0 mg/kg po q. 12-24 h; start at 0.5 mg/kg po q. 12 h
*CLOMIPRAMINE (capsules: 25, 50, 75 mg in human formulation [Anafranil]; 20, 40, 80 mg scored tablets in veterinary formulation [Clomicalm/Novartis][5 mg scored tablets available in Australia and Europe])	0.5 mg/kg po q. 24 h
CLONAZEPAM (tablets: 0.125, 0.25, 0.5, 1.0, 2.0 mg)	0.1-0.2 mg/kg po q. 12-24 h
CLORAZEPATE (tablets: 3.75, 7.5, 11.25, 15, 22.5; capsules: 3.75, 7.5, 15 mg)	0.5-2.2 mg/kg po prn for profound distress; 0.2-0.4 mg/kg q. 12-24 h
DIAZEPAM (tablets: 1, 2, 5, 10 mg; solution: 5 mg/mL)	0.2-0.4 mg/kg po q. 12-24 h (start at 0.2 mg/kg po q. 12 h)
DOXEPIN (capsules: 10, 25, 50, 75, 100, 150 mg; solution: 10 mg/mL)	0.5-1.0 mg/kg po q. 12-24 h (start low)
FLUOXETINE (capsules: 10, 20 mg; solution: 5 mg/mL)	0.5-1.0 mg/kg po q. 24 h
FLUVOXAMINE (capsules: 10, 20 mg)	0.25-0.5 mg/kg po q. 24 h
IMIPRAMINE (tablets: 10, 25, 50 mg; capsules 75, 100, 125, 150 mg)	0.5-1.0 mg/kg po q. 12-24 h (start at 0.5 mg/kg po q. 12 h)
NORTRIPTYLINE (capsules: 10, 25, 50, 75 mg)	0.5-2.0 mg/kg po q. 12 -24 h
OXAZEPAM (tablets: 15 mg; capsules: 10, 15, 30 mg)	0.2-0.5 mg/kg po q. 12-24 h; high dose:1.0-2.5 mg/kg po q. 12-24 h; 3 mg/kg po as a bolus for appetite stimulation
PAROXETINE (tablets: 10, 20, 30, 40 mg; suspension: 10 mg/5 mL)	0.5 mg/kg po q. 24 h x 6-8 weeks to start
PROTRIPTYLINE (tablets: 5, 10 mg)	0.5-1.0 mg/kg po q. 12-24 h (start at 0.5 mg/kg po q. 12 h)
*SELEGILINE (tablets: 5, 10, 15, 30 mg [Anipryl/ Pfizer; Selgan/Sanofi/CEVA])	0.25-0.5 mg/kg po q. 12-24 h; start low
SERTRALINE (tablets: 25, 50, 100 mg)	0.5 mg/kg po q. 24 h x 6-8 weeks to start
TRIAZOLAM (tablets: 0.125, 0.25 mg)	2.5-5 mg/cat po q. 8 h

Table 2B: Selected psychopharmacological agents that may be useful in the treatment of canine behavioral diagnoses

ALPRAZOLAM (tablets: 0.25, 0.5, 1, 2 mg [1 and 2 mg tablets scored)	0.125-1.0 mg/kg po q. 12 h; range: 0.01-0.1 mg/kg po prn for phobic or panic attacks, not to exceed 4 mg/dog/day - profound lethargy and incoordination may result (0.75-4.0 mg/dog / day; may increase slowly over 4.0 mg/dog/day if obtaining some effect at a lower dose) (Start with 1-2 mg for a 25 kg dog)
AMITRIPTYLINE (tablets: 10, 25, 50, 75, 100, 150 mg)1	-2 mg/kg po q. 12 h to start
BUSPIRONE (tablets: 5, 10 mg)	1 mg/kg po q. 8-24 h (mild anxiety) 2.5-10 mg/dog q. 8-24 h (mild anxiety) 10-15 mg/dog po q. 8-12 h (more severe anxiety; use high dose for thunderstorm phobia)
CARBAMAZEPINE (tablets: 200 mg [scored]; chewable tablets: 100 mg [scored])	4-8 mg/kg po q. 12 h; 0.5-1.25 mg/kg po q. 8 h; 4-10 mg/kg/day divided q. 8 h
CHLORDIAZEPOXIDE (tablets: 5, 10, 25 mg; also available as a powder for injection)	�2.2-6.6 mg/kg po prn (start low)
*CLOMIPRAMINE (capsules: 25, 50, 75 mg in human formulation [Anafranil] ; 20, 40, 80 mg scored tablets in veterinary formulation [Clomicalm/Novartis][5 mg scored tablets available in Australia and Europe])	1 mg/kg po q. 12 h X 2 weeks, then 2 mg/kg po q. 12 h X 2 weeks, then 3 mg/kg po q. 12 h X 4 weeks and then as maintenance dose - or - 2 mg/kg po q. 12 h x 8 weeks to start. May need higher maintenance dose. Constant dosage associated with slight increase in GI side effects. NB: q. 24 h dosing insufficient for vast majority of animals, particularly those with multiple signs, early age onset, or long-standing complaint.
�CLONAZEPAM (tablets: 0.125, 0.25, 0.5, 1.0, 2.0 mg)	�0.125-1.0 mg/kg po q. 12 h; range: 0.01-0.1 mg/kg po prn for phobic or panic attacks, profound lethargy and incoordination may result at dosages over 4.0 mg/day, but higher dosages may be used incrementally if there has been some effect at a lower dose (Start with 1-2 mg for a 25 kg dog)
CLORAZEPATE (tablets: 3.75, 7.5, 11.25, 15, 22.5; capsules: 3.75, 7.5, 15 mg)	0.5-2.2 mg/kg po at least 1 hour before provocative stimulus (departure) or anticipated noise (storm, fireworks); repeat q. 4-6 h prn; 11.25-22.5 mg/dog po q. 24 h (~22.5 mg/large dogs; ~11,25 mg/medium dogs; ~ 5.6 mg/small dogs)
DIAZEPAM (tablets: 1, 2, 5, 10 mg; solution 5 mg/mL)	0.5-2.2 mg/kg po at least 1 hour before provocative stimulus (departure) or anticipated noise (storm, fireworks); repeat q. 4-6 h prn
DOXEPIN (capsules: 10, 25, 50, 75, 100, 150 mg; solution: 10 mg/mL)	3-5 mg/kg po q. 8-12 h
FLUOXETINE (capsules: 10, 20 mg; solution: 5 mg/mL)	1 mg/kg po q. 12-24 h x 6-8 weeks to start
FLUVOXAMINE (tablets: 25, 550, 100 mg)	1 mg/kg po q. 12-24 h x 6-8 weeks to start
IMIPRAMINE (tablets: 10, 25, 50 mg; capsules 75, 100, 125, 150 mg)	2.2-4.4 mg/kg po q. 12-24 h; 1-2 or 2-4 mg/kg po q. 12-24 h (start low)
NORTRIPTYLINE (capsules: 10, 25, 50, 75 mg; solution 10 mg/5 mL)	1-2 mg/kg po q. 12 h
OXAZEPAM (tablets: 15 mg; capsules: 10, 15, 30 mg)	0.2-1.0 mg/kg po q. 12-24 h
PAROXETINE (tablets: 10, 20, 30, 40 mg; suspension: 10 mg/5 mL)	1 mg/kg po q. 24 h x 6-8 weeks to start
PROTRIPTYLINE (tablets: 5, 10 mg)	�5-10 mg/dog po q. 12-24 h (narcolepsy)
*SELEGILINE (tablets: 5, 10, 15, 30 mg [Anipryl/ Pfizer; Selgan/Sanofi])	0.5-1.0 mg/kg po q. 24 h x 6-8 weeks to start
SERTRALINE (tablets: 25, 50, 100 mg)	1.0 mg/kg po q. 24 h to start
TRIAZOLAM (tablets: 0.125, 0.5 mg)	0.125-1.0 mg/kg po q. 12 h; range: 0.01-0.1 mg/kg po prn