Introduction

Acceptance of veterinary behavioral medicine has been aided by developments in neuropsychopharmacology and behavioral/neuropsychiatric genetics. The addition of psychotherapeutic agents to more general treatments, such as behavioral and environmental modification, has lead to better and faster treatment outcomes. In addition to facilitating better treatment of domestic animals and humans, psychopharmacological developments have permitted hypotheses about underlying mechanistic pathology to be tested. Mere treatment of non-specific behavioral complaints and signs is outdated and has been replaced with an approach that includes necessary and sufficient criteria for diagnosis and pursuit of treatment that addresses the specific mechanism underlying the neurochemical contribution to the pathology.

The use of medication should occur and is most effective as part of an integrated treatment program. There is no substitute for the hard work involved in behavior modification; however, some medications may be able to make it easier to implement the modification (1-3). Those seeking 'quick fix' solutions will doubtless be disappointed: inappropriate drug use will only blunt or mask a behavior without alteration of processes or environments that produced the behavior. Furthermore, the newer, more specific, more efficacious drugs have a relatively long lag time between initiation of treatment and apparent changes in the patient's behavior. This delay is due to the mechanism of action of the tricyclic antidepressants (TCAs) and the selective serotonin re-uptake inhibitors (SSRIs) which employ second messenger systems to alter transcription of receptor proteins.

Neurotransmitters and neurochemical tracts

The neurotransmitters affected by behavioral medications are acetylcholine, serotonin, norepinephrine (noradrenaline), dopamine, gamma amino butyric acid (GABA), and excitatory amino acids. Common adverse effects of psychotherapeutic drugs are usually caused by a blockage of the muscarinic acetylcholine receptors, which have diffuse connections throughout the brain.

Serotonin (5-hydroxy-tryptamine [5-HT])

Serotonin receptors are all G-protein-coupled receptors. There are 14 identified classes of serotonin receptors. The 5-HT₁ receptors are linked to the inhibition of adenylate cyclase and affect mood and behavior. Presynaptic 5-HT_1A-receptors predominate in dorsal and median raphé nuclei; post-synaptic 5-HT_1A-receptors predominant in limbic regions (hippocampus and septum) and some cortical layers. Activation of pre-synaptic receptors by agonists results in decreased firing of serotonergic neurons leading to transient suppression of 5-HT synthesis and decreased 5-HT release; activation of post-synaptic receptors decreases firing of post-synaptic cells. These are 'thermostatic' effects, not integrated outcomes of receptor activation. The overall effect depends on regulation of second messengers (cAMP, Ca²⁺, cGMP, IP₃) and their effects on protein kinases which then alter neuronal metabolism and receptor protein transcription (4). The subclasses of 5-HT receptors vary in their affects. 5-HT_1A receptors affect mood and behavior. 5-HT_1D receptors affect cerebral blood vessels and appear to be involved in the development of migraine. These last two classes of receptor subtypes are the primary focus of many behavioral drugs. Urinary excretion of 5-HIAA (5-hydroxy indoleacetic acid) is a measure of 5-HT turnover and has been used to assess neurochemical abnormalities in human psychiatric patients, and has potential in this regard for veterinary behavioral medicine.

Noradrenaline / norepinephrine (NE)

The most prominent collection of noradrenergic neurons is found in the locus coeruleus of the grey matter of the pons and in the lateral tegmental nuclei. There is also a cluster in the medulla. NE has been postulated to affect (1) mood [NE decreases in depression and increases in mania], (2) functional reward systems, and (3) arousal.

Dopamine

The distribution of dopamine in the brain is non-uniform, but is more restrictive than that of NE. Dopaminergic nuclei are found primarily in: (1) the substantia nigra pars compacta which projects to the striatum and is largely concerned with coordinated movement; (2) the ventral tegmental area which projects to the frontal and cingulate cortex, nucleus acumbens, and other limbic structures; and (3) the arcuate nucleus of the hypothalamus which projects to the pituitary. A large proportion of the brain's dopamine is found in the corpus striatum, the part of the extrapyramidal system concerned with coordinated movement.

Dopamine is metabolized by monamine oxidase (MAO) and catechol-O-methyl transferase (COMT) into dihydroxyphenyl acetic acid (DOPAC) and homovanillic acid (HVA). HVA is used as a peripheral index of central dopamine turnover in humans, but this use has been little explored in veterinary medicine. All dopaminergic receptors are G-protein-coupled transmembrane receptors. The D₁ receptors exhibit their post-synaptic inhibition in the limbic system and are affected in mood disorders and stereotypies. The D₂, D₃, and D₄ receptors are all affected in mood disorders and stereotypies. Excess dopamine, as produced by dopamine releasing agents (amphetamines and dopamine agonists, like apomorphine) is associated with the development of stereotypies.

Gamma amino butyric acid (GABA)

GABA, the inhibitory neurotransmitter found in short interneurons, is produced in large amounts only in the brain and serves as a neurotransmitter in ~30% of the synapses in the human CNS. The only long GABA-ergic tracts run to the cerebellum and striatum. GABA is formed from the excitatory amino acid (EEA) glutamate via glutamic acid decarboxylase (GAD), catalyzed by GABA-transaminase (GABA-T) and destroyed by transamination. There are two main groupings of GABA receptors--GABA_A and GABA_B. GABA_A receptors, ligand-gated ion channels, mediate post-synaptic inhibition by increasing Cl^- influx. Barbiturates and benzodiazepines are a potentiators of GABA_A. GABA_B receptors are involved in the fine-tuning of inhibitory synaptic transmission: presynaptic GABA_B receptors inhibit neurotransmitter release via high voltage activated Ca⁺⁺ channels; postsynaptic GABA_B receptors decrease neuronal excitability by activating inwardly rectifying K⁺ conductance underlying the late inhibitory post synaptic potential.

GABA also has a variety of tropic effects on developing brain cells. During ontogeny GABAergic axons move through areas where other neurotransmitter phenotypes are being produced, and so may be related to later monoaminergic imbalances. The extent such ontogenic effects are relevant for behavioral conditions is currently unknown but bears investigating.

EAAs (glutamate, aspartate, and, possibly, homocysteate)

EEAs have a role as central neurotransmitters and are produced in abnormal levels in aggressive, impulse, and schizophrenic disorders. The main fast excitatory transmitters in the CNS are EEAs. Glutamate, widely and uniformly distributed in the CNS, is involved in carbohydrate and nitrogen metabolism. It is stored in synaptic vesicles and released by Ca²⁺ dependent exocytosis, so calcium channel blockers may affect conditions associated with increased glutamate. Both barbiturates and progesterone suppress excitatory responses to glutamate. Pre-synaptic barbiturates inhibit calcium uptake and decrease synaptosomal release of neurotransmitters, including GABA and glutamate.

Roles for neuronal stimulation, synaptic plasticity, and receptor protein transcription and translation

What makes TCAs and SSRIs special and why are they so useful for anxiety disorders? The key to the success of these drugs is that they utilize the same second messenger systems and transcription pathways that are used to develop cellular memory or to "learn" something. This pathway involves cAMP, cytosolic response element binding protein (CREB), brain derived neurotrophic factor (BDNF), NMDA receptors, protein tyrosine kinases (PTK)--particularly Src--which regulate activity of NMDA receptors and other ion channels and mediates the induction of LTP (long-term potentiation = synaptic plasticity) in the CA1 region of the hippocampus.

There are two phases of TCA and SSRI treatment: short-term effects and long-term effects. Short-term effects result in a synaptic increase of the relevant monoamine associated with re-uptake inhibition. The somatodendritic autoreceptor of the pre-synaptic neuron decreases the firing rate of that cell as a thermostatic response. Regardless, there is increased saturation of the post-synaptic receptors resulting in stimulation of the -adrenergic coupled cAMP system. cAMP leads to an increase in PTK as the first step in the long-term effects. PTK translocates into the nucleus of the post-synaptic cell where it increases CREB, which has been postulated to be the post-receptor target for these drugs. Increases in CREB lead to increases in BDNF and tyrosine kinases (e.g., trkB) which then stimulate mRNA transcription of new receptor proteins. The altered conformation of the post-synaptic receptors renders serotonin stimulation and signal transduction more efficient.

Knowledge of the molecular basis for the action of these drugs can aid in choosing treatment protocols. For example, the pre-synaptic somatodendritic autoreceptor is blocked by pindolol (a adrenoreceptor antagonist) so augmentation of TCA and SSRI treatment with pindolol can accelerate treatment onset. Long-term treatment, particularly with the more specific TCAs (e.g., clomipramine) and SSRIs, employs the same pathway used in LTP to alter reception function and structure through transcriptional and translational alterations in receptor protein. This can be thought of as a form of in vivo "gene therapy" that works to augment neurotransmitter levels and production thereby making the neuron and the interactions between neurons more coordinated and efficient. In some patients short-term treatment appears to be sufficient to produce continued "normal" functioning of the neurotransmitter system. That there are some patients who require life-long treatment suggests that the effect of the drugs is reversible in some patients, further illustrating the underlying heterogeneity of the patient population considered to have the same diagnosis.

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.

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 (5). 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 (6). A model for how to do this is found below (6). Weaning minimizes potential central withdrawal signs, including those associated with serotonin dyscontinuation syndrome (7-8) 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: 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.

Table 1. Half-lives of parent compounds and intermediate metabolites of target benzodiazepines in humans (6)

Table 2. Duration of action of parent compound, diazepam, and its intermediate metabolite, nordiazepam (N-desmethyl diazepam) in selected domestic animals (6)

Table 3. Relative effects of TCA parent compounds and intermediate metabolites on NE and 5-HT re-uptake (6)

* 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 t_1/2 of parent compounds and active intermediate metabolites, relative effects on NE and 5-HT, and extrapolations from multi-center human studies (6)

Table 5. Algorithm for treatment length and weaning schedule (6)

(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

References

Additional references are available upon request.

1.  King J, Simpson B, Overall KL et al. Treatment of separation anxiety in dogs with clomipramine. Results from a prospective, randomized, double-blinded, placebo-controlled clinical trial. J Appl Anim Behav Sci 2000;67:255-275.

2.  Mills D, Ledger R. The effects of oral selegiline hydrochloride on learning and training in the dog: a psychobiological interpretation. Prog Neuro Psychopharmacol & Biol Psychiatr 2001;25:1597-1613.

3.  Overall KL, Dunham AE: Clinical features and outcome in dogs and cats with obsessive-compulsive disorder: 126 cases (1989-2000). J Am Vet Med Assoc 2002;221:1445-1452.

4.  Duman R.S. (1998) Novel therapeutic approaches beyond the serotonin receptor. Biol Psychiatry 1998;44, 324-335.

5.  Reich M, Ohad D, Overall KL, Dunham AE. Assessment of anti-anxiety medication on canine patients: potential for cardiac side effects and correlation with intermediate metabolite levels. J Am Vet Med Assoc 2000;216:1571-1575.

6.  Overall KL. Pharmacological treatment in behavioral medicine: The importance of neurochemistry, molecular biology, and mechanistic hypotheses. The Veterinary Journal 2001;62:9-23

7.  Rosenbaum JF, Fava M, Hoog et al. Selective serotonin reuptake discontinuation syndrome: a randomized clinical trial. Biol Psychiatry 1998;44:77-87.

8.  Zajeka J, Fawcett J, Amsterdam J, et al. Safety of abrupt discontinuation of fluoxetine:a randomized, placebo-controlled study. J Clin Psychiatry 1998;18:193-197.