Pharmacology and Behavior: Review of Commonly Used Drugs
Karen L. Overall, MA, VMD, PhD, DACVB, ABS Certified Applied Animal Behaviorist
Classes of drugs used and misused in behavioral medicine:
Anti-histamines, anti-convulsants, progestins / estrogens, sympathomimetics / stimulants, narcotic agonists / antagonists, and mood stabilizers / antipsychotics have been discussed elsewhere (see Overall, 1997). With the exception of the last class they have limited use in modern behavioral medicine. Focus here is on the medications affecting GABA and 5-HT: the benzodiazepine tranquilizers, MAO-Is, TCAs, SSRIs, and 5-HT agonists.
Tranquilizers: Tranquilizers decrease spontaneous activity, resulting in decreased response to external or social stimuli. They interfere profoundly with any behavioral modification. Neuroleptic butyrophenones like haloperidol decrease both appropriate and inappropriate activity, and because of side effects associated with the most effect mode of delivery (i.e., IV), have limited use. Use of phenothiazines (e.g., chlorpromazine, promazine, acetylpromazine, and thioridazine), which target the dopamine receptor, is outdated - the level and duration of tranquilization varies and both normal and abnormal behaviors are blunted. All phenothiazines have side effects from long standing use (e.g., cardiovascular disturbance, extrapyramidal signs). Acetylpromazine makes animals more reactive to noises and startle, and so is wholly inappropriate for use in noise phobic patients.
The exact mechanism of action of the benzodiazepines (e.g., diazepam, chlordiazepoxide , clorazepate, lorazepam, alprazolam, and clonazepam) is poorly understood. Calming effects may be due to limbic system and reticular formation effects. Compared with barbiturates, cortical function is relatively unimpaired by benzodiazepines. All benzodiazepines potentiate the effects of GABA by increasing binding affinity of the GABA receptor for GABA and increasing the flow of chloride ions into the neuron, affecting primarily GABAA receptors. Barbiturates also affect the GABA receptor-benzodiazepine receptor-chloride ion channel complex, but because of detrimental effects on cognition barbiturates have been superseded by benzodiazepines and tricyclic anti-depressants in the treatment of aggression. Binding of diazepam is highest in the cerebral cortex compared with the limbic system and midbrain, which are, in turn, higher than the brainstem and the spinal cord, paralleling that of GABAA receptors.
At low dosages, benzodiazepines act as mild sedatives, facilitating daytime activity by tempering excitement. At moderate dosages they act as anti-anxiety agents, facilitating social interaction in a more proactive manner. At high dosages they act as hypnotics, facilitating sleep. Ataxia and profound sedation usually only occur at dosages beyond those needed for anxiolytic effects. Benzodiazepines decrease muscle tone by a central action that is independent of the sedative effect, but may function as a non-specific anxiolytic effect. Some newer benzodiazepines like clonazepam have muscle relaxation effects at smaller dosages than those needed for behavioral effects. Many of the long-term effects and side effects of benzodiazepines are the result of intermediate metabolite function. Parent compound and intermediate metabolite t1/2 are found in Table 1 for humans and Table 2 for domestic species.
Benzodiazepines are essential for treatment of sporadic events involving profound anxiety or panic (e.g., thunderstorms, fireworks, panic associated with departures of humans signaled by an outside indicator, e.g., an alarm clock). For these drugs to be efficacious they must be given to the patient at least an hour before the anticipated stimulus, and minimally before the patients exhibit signs of distress. This timing allows repeat dosing that makes use of the t1/2 of parent compounds and intermediate metabolites and permits concomitant use with daily TCA or SSRI treatment.
Monoamine oxidase (MAO) inhibitors (I) act by blocking oxidative deamination of brain amines (dopamine, nor-epinephrine, epinephrine, 5-OH-tryptamine), increasing these substances, and elevating mood. The MAO-B inhibitor, selegiline is used to treat 'cognitive dysfunction' in aged cats and dogs, but in dogs deamination of catecholamines is controlled by MAO-A. Selegiline is fairly specific for dopamine and slows destruction of synaptic knobs of presynaptic neurons.
TCAs are structurally related to the phenothiazine antipsychotics. In humans they are commonly used to treat endogenous depression, panic attacks, phobic and obsessive states, neuropathic pain states, and pediatric enuresis. The antidepressant effect is due to inhibition of prejunctional re-uptake of norepinephrine and serotonin. There are three major effects of TCAs that vary in degree depending on the individual drug: (1) sedation, (2) peripheral and central anticholinergic action, and (3) potentiation of CNS biogenic amines by blocking their re-uptake presynaptically. The ability of TCAs to inhibit prejunctional re-uptake of norepinephrine and serotonin are largely responsible for their antidepressant effect. Many TCAs also have potent muscarinic, "1-adrenergic, and H1 and H2 blocking activity, which can account for their common side effects (dry mouth, sedation, hypotension). The H1 and H2 effects, however, may be useful in treating pruritic conditions (e.g., doxepin).
The tertiary amines (amitriptyline, imipramine, doxepin, trimipramine, and clomipramine) are metabolized to secondary amines (desipramine, nortriptyline, and protriptyline). These classes of anti-depressants are among the most widely and safely (compared with benzodiazepines, phenothiazines, barbiturates, and sympathomimetic agents) used drugs in companion animal behavioral medicine.
TCAs are incompletely absorbed from the gastrointestinal tract and have significant first-pass effects. They are over 50% protein bound and highly lipid soluble. In humans TCAs reach peak plasma levels 8-12 hours after the last dose and reach steady state levels after 5-7 days of consistent dosing. There is variation in response in humans: a 30-50 fold difference in plasma levels of individuals given the same dose has been reported. There is also considerable variation in plasma levels in dogs if the results from studies on clomipramine generalize.. Nortriptyline is a little different from other TCAs in that it has a therapeutic window: plasma levels of over 150 :g/mL may reduce efficacy in humans. TCAs act primarily through a re-uptake blockage of norepinephrine and serotonin. In the long-term they may cause a decrease in number of $-adrenergic and 5-HT2 receptors.
In general, TCA metabolites are more potent inhibitors of NE uptake, while parent compounds are more potent inhibitors of 5-HT uptake; metabolites usually have similar or longer half-lives compared with the parent compound. Imipramine's intermediate metabolite, norimipramine, is a more potent inhibitor of NE uptake than is imipramine (it is also an active intermediate metabolite of other anti-anxiety agents) and has its own active intermediate metabolite. Doxepin's intermediate metabolite, nordoxepin, fully retains the pharmacological properties of the parent compound, and its t1/2 is 33-88 h in humans compared with a t1/2 of 8-25 h with doxepin. Norclomipramine (N-desmethylclomipramine), one of the active intermediate metabolites of clomipramine, is also a more potent inhibitor of NE than is clomipramine and has an elimination t1/2 1.5 times longer than that of clomipramine. Not only does this have profound implications for calculating how long one expects effects to last, but it is interesting to note that the ability to formulate intermediate metabolites is subject to genetic polymorphism in the human population. One can only imagine the complexity for the canine and feline populations. Most dogs treated with clomipramine (Clomicalm, Novartis Animal Health) reach steady state levels in 3-5 days, attain peak plasma concentrations in approximately 1-3 h, and experience t1/2 of 1-16 h of the parent compound and 1-2 h of the active intermediate metabolites, suggesting that dogs may require higher dosages or more frequent dosing than do humans treated with such medications.
Knowledge of intermediate metabolites can be important: animals experiencing sedation or other side effects with the parent compound may do quite well when treated with the intermediate metabolite, alone. For example, cats that become sedated or nauseous when treated with amitriptyline may respond well when treated with nortriptyline at the same dose. Table 3 lists parent compounds, intermediate metabolites, and their relative effects on NE and 5-HT. Side effects in humans can include a dry mouth, constipation, urinary retention, tachycardias and other arrhythmias, syncope associated with orthostatic hypotension and "-adrenergic blockade, ataxia, disorientation, and generalized depression and inappetence. Symptoms usually abate upon decrease or cessation of drug administration. Based on over 1000 dogs treated with TCAs and SSRIs at VHUP, side effects appear rare in canine patients; the most common side effect has been GI distress. More rare side effects include profound increases in appetite and discomfort associated with unremitting tachycardia that resolves when drugs are withdrawn. One dog treated with clomipramine experienced collapse, hyperthermia, and seizure activity from which he recovered with supportive care. Other researchers report less successful use which leads one to ask about expectations and comfort level of clients and diagnostic and treatment protocols. Use of TCAs is contraindicated in animals with a history of urinary retention and severe, uncontrolled cardiac arrhythmias and a cardiac consult, including a rhythm strip, should be a part of standard, pre-dispensation work-up. The common side-effects of TCAs as manifest on ECG include: flattened T waves, prolonged Q-T intervals, and depressed S-T segments. In high doses TCAs have been implicated in sick euthyroid syndrome. In older or compromised animals complete laboratory evaluations are urged since high doses of TCAs are known to alter liver enzyme levels. Extremely high doses are associated with convulsions, cardiac abnormalities, and hepatotoxicity. TCAs can interfere with thyroid medication necessitating conscientious monitoring if administrations of both medications is concurrent. Cats are likely to be more sensitive to all TCAs than are dogs because TCAs are metabolized through glucuronidation.
These drugs are extremely successful in treating many canine and feline conditions including separation anxiety, generalized anxiety that may be a precursor to some elimination and aggressive behaviors, pruritic conditions that may be involved in acral lick dermatitis (ALD), compulsive grooming, and some narcoleptic disorders. Amitriptyline is very successful in treating separation anxiety and generalized anxiety. Imipramine has been useful in treating mild attention deficit disorders in people, and may be useful in dogs since it has been used to treat mild narcolepsy. A TCA derivative, carbamazepine, has been successfully used to control aberrant activity in psychomotor seizures. Clomipramine has been inordinately successful in the treatment of human and canine obsessive compulsive disorders. Clomipramine has one active, intermediate metabolite, clomipramine, that acts as a serotonin re-uptake inhibitor.
Serotonin agonists: The only pure 5-HT1A agonist is the serenic eltoprazine [DU 28853]). Serenics leave defensive behaviors intact without sedation or muscle relaxation and decrease aggression while concomitantly increasing social interest. Partial 5-HT1A/B agonists (e.g., buspirone) have few side effects, do not negatively affect cognition, allow rehabilitation by influencing cognition, attention, arousal, and mood regulation, and may aid in treating aggression associated with impaired social interaction. Buspirone has been used with varying, but unimpressive success, in the treatment of canine aggression of dominance or idiopathic origins, canine and feline ritualistic or stereotypic behaviors, self-mutilation and possible obsessive compulsive disorders, thunderstorm phobias, and feline spraying.
The SSRIs (fluoxetine, paroxetine, sertraline, and fluvoxamine) are derivatives of TCAs. These drugs have a long half-life, and after 2-3 weeks plasma levels peak within 4-8 hours. Treatment must continue for a minimum of 6-8 weeks before a determination about efficacy can be made since these drugs act to induce receptor conformation changes - an action that can take 3-5 weeks. Most of the SSRI effects are due to highly selective blockade of the re-uptake of 5-HT1A into pre-synaptic neurons without effects on NE, dopamine, acetylcholine, histaminic, and "1-adrenergic receptors. The SSRIs should not be used with MAOIs because of risks of serotonin syndrome.
Fluoxetine is efficacious in the treatment of profound aggressions, animal models of obsessive-compulsive disorders (wheel running, anorexia, weight loss), companion animal separation anxiety, panic, avoidance disorders, including post-traumatic stress disorder, and obsessive-compulsive disorders. Paroxetine is efficacious in the treatment of depression, social anxiety, and agitation associated with depression. Sertraline is useful particularly for generalized anxiety and panic disorder.
Most of the effect of fluoxetine seems to be via a highly selective blockade of the re-uptake of 5-HT into pre-synaptic neurons. Fluoxetine appears to have no effects on NE or dopamine, no anticholinergic, no antihistaminic, and no anti-"1-adrenergic activities, so most of the side effects associated with anti-depressants are absent or minimized. Concomitant use of TCAs or benzodiazepines increases the plasma levels of these and may prolong the excretion of fluoxetine. Co-administration of buspirone may decrease the efficacy of buspirone and potentiate extrapyramidal symptoms, but there have also been reports of synergistic effects. Fluoxetine should not be used with MAOIs. Table 4 contains a "gestalt" of which TCAs and SSRIs to use for which classes of conditions.
Beta-adrenergic receptor antagonists ($-blockers) are used in humans to treat self-injurious behavior, intermittent explosive disorder, conduct disorders, dementia, brain disease / injury, autism, and schizophrenia. Older $-blockers, like propranolol [a $-1 and $-2 blocker], have not been as successful as hoped in treating canine or feline aggression., but have been used with mixed success in combination with TCAs or SSRIs to treat some anxieties and noise phobias.
Other agents (e.g., pindolol) agents have been used successfully to potentiate the action of the TCAs and SSRIs by blocking the pre-synaptic autoreceptor. Blockade of the pre-synaptic autoreceptor - the "thermostat" - aborts the initial 'down-regulation' phase of monoamine release: the relevant monoamine continues to be produced despite accumulation in the synaptic cleft due to pre-synaptic re-uptake inhibition.
Cholecystokinin (CCK) has been postulated to act as a mediator in panic attacks, and has been implicated in situations involving self-medication with food. CCK-B receptors (central brain receptors) appear involved in the opening and closing of cat jaws and may function in obsessive-compulsive disorders such as over-grooming an wool-chewing or sucking. Agents affecting CCK are being developed and tested.
1. Allgulander C., Cloniger C.R., Pryzbeck T.R., and Brandt L. (1997) Changes on the temperament and character inventory after paroxetine treatment in volunteers with generalized anxiety disorder. Psychopharmacology Bulletin 34, 165-166.
2. Altemus M., Glowa J.R., and Murphy D.L. (1993) Attenuation of food restriction-induced running by chronic fluoxetine treatment. Psychopharmacology Bulletin 29,397-400.
3. Ananth J. (1986) Clomipramine: an anti-obsessive drug. Canadian Journal of Psychiatry 31,253-258.
4. Brown T.M., Skop B.P., and Mareth T.R. (1996) Pathophysiology and management of the serotonin syndrome. The Annals of Pharmacotherapy 30, 527-533.
5. Duman R.S. (1998) Novel therapeutic approaches beyond the serotonin receptor. Biological Psychiatry 44, 324-335.
6. Duman R.S., Heninger G.R., and Nestler E.J. (1997) A molecular and cellular theory of depression. Archives of General Psychiatry 54, 597-606.
7. Flament M.F., Rappoport J.L., and Berg C.J. (1985) Clomipramine treatment of childhood obsessive-compulsive disorder. A double-blind controlled study. Archives of General Psychiatry 42, 977-983.
8. Greenblatt D.J., Shader R.I., Divoll M., and Harmatz JS. (1981) Benzodiazepines: a summary of pharmacokinetic properties. British Journal of Pharmacology 11(Suppl), 11S-16S.
9. Greenblatt D.J., Shader R.I., and Abernethy D.R. (1983) Drug therapy: current status of benzodiazepines. New England Journal of Medicine 309, 344-358.
10. Hart B.L., Eckstein R.A., Powell K.L., and Dodman N.H. (1993) Effectiveness of buspirone on urine spraying and inappropriate urination in cats. Journal of the American Veterinary Medical Association 203, 254-258.
11. Hewson C.J., Conlon P.D., Luescher U.A., and Ball R.O. (1998a) The pharmacokinetics of clomipramine and desmethylclomipramine in dogs: parameter estimates following a single oral dose and 28 consecutive daily oral doses of clomipramine. Journal of Veterinary Pharmacology and Therapy 21,214-222.
12. Hewson C.J., Luescher A., Parent J.M., Conlon, P.D., and Ball R.O. (1998b) Efficacy of clomipramine in the treatment of canine compulsive disorder. Journal of the American Veterinary Medical Association 213, 1760-1766.
13. Hyman Rapaport M., Wolkow R.M., and Clary C.M. (1998) Methodologies and outcomes from sertraline multicenter flexible-dose trials. Psychopharmacology Bulletin 32, 183-189.
14. Kaplan H.I. and Sadock B.J. (1993) Pocket Handbook of Psychiatric Drug Treatment. Baltimore: William and Wilkins.
15. Kennedy J.L., Bradwejn J., Koszycki D., King N., Crowe R., Vincent J., and Fourie O. (1999) Investigation of cholecystokinin system genes in panic disorder. Molecular Psychiatry 4, 284-285.
16. King J.N., Simpson B.S., Overall K.L., Appleby D., Pageat P., Ross C., Chaurand J.P., Heath S., Beata C., Weiss A.B., Muller G., Paris T., Bataille B.G., Parker J., Petit S., and Wren, J. (2000a) Treatment of separation anxiety in dogs with clomipramine: results from a prospective, randomized, double-blind, placebo-controlled, parallel-group, multicenter clinical trial. Journal of Applied Animal Behavior Science 67,255-275.
17. King J.N., Maurer M.P., Altmann B., and Strehlau G. (2000b) Pharmacokinetics of clomipramine in dogs following single-dose and repeated-dose oral administration. American Journal of Veterinary Research 61, 80-85.
18. Marder A.R. (1991) Psychotropic drugs and behavior therapy. Veterinary Clinics of North America: Small Animal Practice 21, 339-342.
19. Mårtensson E., Axelsson R., Nyberg G., and Svensson C. (1984) Pharmacokinetic properties of the antidepressant drugs amitriptyline, clomipramine, and imipramine: a clinical study. Current Therapy and Research 36, 228-238.
20. McTavish D., Benfield P. (1990) Clomipramine: an overview of its pharmacological properties and a review of its therapeutic use in obsessive-compulsive behavior and panic attack. Drug 39, 136-153.
21. Meltzer-Brody S., Connor K.M., Churchill E., and Davidson J.R.T. (2000) Symptom-specific effects of fluoxetine in post-traumatic stress disorder. International Clinical Psychopharmacology 15, 227-231.
22. Moon-Fanelli A.A., Dodman N.H. (1998) Description and development of compulsive tail chasing in terriers and response to clomipramine treatment. Journal of the American Veterinary Medical Association 212, 1252-1257.
23. Overall K.L. (1994) Use of clomipramine to treat ritualistic motor behavior in dogs. Journal of the American Veterinary Medical Association 205, 1733-1741.
24. Overall K.L. (1997) Clinical Behavioral Medicine for Small Animals. St. Louis:Mosby.
25. Perse T. (1988) Obsessive-compulsive disorder: A treatment review. Journal of Clinical Psychiatry 49, 48-55.
26. 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.
27. 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.
28. Schwartz M.A., Koechlin B.A., Postma E., Palmer S., and Krol G. (1965) Metabolism of diazepam in rat, dog, and man. Journal of Pharmacology and Experimental Therapy 149, 423-435.
29. Seksel K. and Lindeman M.J. (1998) Use of clomipramine in the treatment of anxiety-related and obsessive-compulsive disorders in cats. Australian Veterinary Journal 76, 317-321.
30. Singh L., Lewis A.S., Field M.J., Hughes J., and Woodruff G.N. (1991) Evidence for involvement of the brain cholecystokinin B receptor in anxiety. Proceedings of the National Academy of Science USA 88, 1130-1133.
31. Thoren P., Asberg M., and Cronholm B. (1980) Clomipramine treatment of obsessive-compulsive disorder. Archives of General Psychiatry 37, 1281-1285.
32. Wiersma J., Honig A., and Peters F.P.J. (2000) Clomipramine-induced allergic hepatitis: a case report. International Journal of Psychiatry in Clinical Practice 4, 69-71.
33. Yokota S., Ishikura Y., and Ono H. (1987) Cardiovascular effects of paroxetine, a newly developed antidepressant, in anesthetized dogs in comparison with those of imipramine, amitriptyline and clomipramine. Japanese Journal of Pharmacology 45, 335-342.
Table 1: Half-lives of parent compounds and intermediate metabolites of target benzodiazepines in humans
Table 2: Duration of action of parent compound, diazepam, and its intermediate metabolite, nordiazepam (N-desmethyl diazepam) in selected domestic animals
Table 3: Relative effects of TCA parent compounds and intermediate metabolites on NE and 5-HT re-uptake
* does not include the specific effect of the intermediate metabolite as a selective serotonin reuptake inhibitor (SSRI)
Table 4: "Gestalt" of TCA and SSRI use based on t1/2 of parent compounds and active intermediate metabolites, relative effects on NE and 5-HT, and extrapolations from multi-center human studies