I. GENERAL CONSIDERATIONS
A. Biochemical imbalance in the monoaminergic (5-HT and NE) and GABAergic neurotransmitter system have been implicated in behavioral problems seen in companion animals.
B. Behavioral problems most commonly encountered in animals include fear, anxiety, aggression, compulsive disorder, inappropriate elimination behavior, and cognitive dysfunction in geriatric patients.
C. Oral route of drug administration is routinely used in treating behavioral disorders.
D. There is potential for adverse effects following long-term use of behavior-modifying drugs. Before starting a rational drug therapy the animals must undergo complete laboratory analysis, thorough evaluation of background medical histories, and neurological examination to determine the physiological basis of the abnormal behavior.
E. Psychotherapeutic treatment outcomes are most effective when used in combination with behavioral modification therapy and environmental management.
F. Phenothiazines should not be used to treat aggressive behavior because in some cases they may cause or induce aggressive behavior in animals that have no history of aggressive behavior.
In the present chapter, focus will be on anxiolytic drugs, drugs that modulate monoaminergic and GABAergic neurotransmission, and progestins.
G. Neurotransmitters involved in the actions of antidepressant drugs
1. Monoamine hypothesis of mood
a. According to this theory, monoamines including serotonin (5-HT) and norepinephrine (NE) are proposed to play a central role in the expression of mood. Therefore, any impairment in the activity of the amines is believed to lead to depression, while increase in activity may result in mood elevation. Accordingly, agents that enhance the actions of these neurotransmitters have proven efficacy in the management of symptoms related to depression.
b. Monoamines. Monoamines include dopamine, NE, epinephrine, and 5-HT. See Chapters 2 and 3 for information on synthesis and metabolism of monoamines.
(1) Dopamine (DA)
(a) DA is the major neurotransmitter in the brain. It plays a key role in behavioral and drug reinforcement; regulates emesis, prolactin release, mood states, cognitive, and motor functions.
(b) DA is found in several neuronal tracts including nigrostriatal, mesolimbic, and tuberoinfundibular tracts.
(c) DA exerts inhibitory actions via G-protein-coupled receptors that facilitate the activation of K+ channels. There are at least five DA receptor subtypes, namely, D1, D2, D3, D4, and D5. Activation of D1 and D5 receptors (coupled to Gs) increases cAMP levels by stimulating adenylyl cyclase, while activation of D2, D3, and D4 receptors (coupled to Gi/o) decreases cAMP levels by inhibiting adenylyl cyclase. Notably, D2 receptors are primarily presynaptic and function as autoinhibitory receptors by inhibiting DA release.
(d) A partial list of drugs that affect dopaminergic neurotransmission include CNS stimulants (e.g., amphetamines), and monoamine oxidase-B (MAO-B) inhibitors (e.g., selegiline).
(2) Norepinephrine (NE)
(a) NE plays a key role in learning, memory, mood, sensory processing, sleep, and in the regulation of anxiety.
(b) The cell bodies of the noradrenergic neurons are located in the locus coeruleus or the lateral tegmental area of the reticular formation. Several brain regions, namely, thalamus, cerebral cortex, cerebellum, and thalamus receive diffuse noradrenergic input. For example, nor-adrenergic projections to the limbic cortex are believed to regulate emotions.
(c) The excitatory effects are mediated via activation of α1– and β-receptors, which results in a decrease in K+ conductance. Conversely, the inhibitory effects are mediated via activation of α2-receptors that leads to neuronal hyperpolarization via increase in K+ conductance. Furthermore, activation of presynaptic α2-receptors is associated with decrease in calcium conductance, hence resulting in decreased presynaptic release of NE.
(d) Drugs that enhance noradrenergic neurotransmission include CNS stimulants, tricyclic antidepressants (TCAs), and monoamine oxidase inhibitors (MAOIs).
(3) Serotonin (5-HT)
(a) 5-HT has been proposed to play a central role in the regulation of sleep, body temperature, arousal, emotion, and higher cognitive functions. Dysfunction in the central serotonergic system is postulated to underlie mood disturbances, anxiety, aggression, restlessness, and obsessive compulsive disorder (OCD).
(b) The cell bodies of the serotonergic neurons are located in the raphe nuclei of the brain stem. They send diffuse projections to the entire CNS, including the spinal cord, cerebellum, and areas of diencephalon and telencephalon. Multiple subtypes of 5-HT receptors have been identified and to date the receptors have been categorized under seven different families including, 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6, and 5-HT7. All of them are G-protein-coupled receptors with the exception of 5-HT3 receptor family, which is a ligand-gated ion channel (Chapter 3 II B3).
(c) 5-HT primarily has an inhibitory role; however, depending on the receptor subtype, it can exhibit both inhibitory and excitatory effects. For example, buspirone’s partial agonist effects on 5-HT1A receptors (coupled to Gi/o) are related to elevation in K+ conductance and associated membrane hyperpolarization.
(d) 5-HT enhancing drugs are effective modulators of behavior. For example, TCAs and selective serotonin reuptake inhibitors (SSRIs) enhance 5-HT neurotransmission by elevating synaptic levels of 5-HT.
c. Acetylcholine. (ACh, see Chapter 2 for information on synthesis and metabolism)
(1) ACh is proposed to play a key role in arousal, consciousness, memory consolidation, and motor coordination.
(2) ACh is present in the neurons of somatic and visceral motor nuclei present in the brain and spinal chord that innervates the hippocampus, cerebral cortex, and basal ganglia.
(3) Most CNS responses to ACh are mediated through G-protein-coupled muscarinic receptors. At a few sites, ACh elicits its response via activation of Gi/o-coupled M2 receptors that leads to slowing of neuronal discharge by increasing K+ conductance. In addition, activation of M2 receptors inhibits adenylyl cyclase, which leads to inhibition of neurotransmitter release.
(4) A few of the undesirable side effects associated with TCAs such as dry mouth, urine retention, and decreased GI motility have been linked to their muscarinic blocking effects.
II. MAJOR DRUG CLASSES
A. Anxiolytic drugs
1. Benzodiazepines. diazepam(Valium®), clorazepate(Tranxene®), Alprazolam (Xanax®), oxazepam (Serax®), lorazepam (Ativan®), chlordiazepoxide (Librium®)
2. Buspirone (Buspar®)
B. Antidepressants
1. Tricyclic Antidepressants (TCAs). amitriptyline (Elavil®), clomipramine (Clomicalm®), imipramine (Tofranil®), doxepin (Sinequan®)
2. Serotonin Selective Reuptake Inhibitors (SSRIs). fluoxetine (Prozac®), Paroxetine (Paxil®), sertraline (Zoloft®), fluvoxamine (Luvox®)
3. Monoamine Oxidase Inhibitors (MAOIs). selegiline (Anipryl®)
4. Progestins. medroxyprogesterone acetate (Depo-Provera®), megestrol acetate (Ovaban®)
III. ANXIOLYTIC DRUGS
A. Benzodiazepines (BZDs) (See Chapter 4; Section II C and D for more information on BZDs.)
1. General considerations
a. Mechanism of action. The behavioral effects are attributed to BZD’s actions on the cerebral cortex, limbic system, and most notably thalamus. BZDs induce membrane hyperpolarization by facilitating GABA-mediated chloride conductance (see also Chapter 4).
b. Pharmacological Effects. BZDs exhibit dose-dependent, but minimal CNS depressant effects. For example, at lower doses, they exhibit mild sedative and anxiolytic effects, whereas at higher doses, they have hypnotic effects.
c. Therapeutic uses
(1) BZDs are useful in the management of fear, phobia, and anxiety particularly in situations where rapid onset may be desirable.
(2) BZDs are useful particularly for the management of fears induced by stimuli that can be predicted in advance. Examples include clinical management of inappropriate urination-submissive urination, urine marking behavior, storm phobia, separation anxiety in dogs; foal rejection in mares; and urine spraying, storm phobia, separation anxiety, and extreme timidity in cats.
(3) Several of the long term effects are attributed to intermediate metabolite functions.
(4) BZDs can be used in combination with other psychotropic drugs such as TCAs or SSRIs.
d. Pharmacokinetics
(1) BZDs include a wide array of drugs that differ in their pharmacokinetic properties.
(2) BZDs are rapidly absorbed from the GI tract and distributed throughout the body.
(3) BZDs bind avidly to plasma proteins, exhibit high lipophilicity, and readily cross the blood–brain barrier.
(4) BZDs are metabolized primarily via the hepatic microsomal system and eliminated in the urine as glucuronide conjugates or oxidized metabolites. However, cats have been reported to exhibit compromised drug metabolism.
e. Adverse effects
(1) Withdrawal of BZDs should be gradual because sudden cessation of drug treatment may result in relapse of symptoms that may be more intense than that existed before drug treatment.
(2) BZDs have the potential to cause physical addiction.
(3) Adverse effects include ataxia, sedation, muscle relaxation, anxiety, paradoxical excitement, hallucinations, and memory deficits.
(4) Owing to its ability to cross placental barrier and entry into milk, it must be used cautiously in pregnant and lactating animals.
f. Contraindications. The use of BZDs is contraindicated in cases involving aggression. Although BZDs reduce aggression, sometimes it may disinhibit behaviors, hence resulting in increased aggressiveness.
2. Diazepam
a. Mechanism of action. Diazepam has CNS depressant effects but lacks peripheral autonomic blocking effects.
b. Therapeutic uses. Diazepam is a well-characterized BZD that is used for the treatment of behavioral disorders.
(1) Diazepam reduces signs of fear in dogs. However, it is less effective in treating storm phobia and separation anxiety as compared to alprazolam.
(2) In cats, although initially beneficial in ameliorating urine spraying behavior, resumption of urine spraying behavior (50–75%) was observed when drug treatment was discontinued.
c. Pharmacokinetics
(1) It undergoes extensive first-pass metabolism and is metabolized to desmethyldiazepam (nordiazepam), temazepam, and oxazepam. In all species, the t½ of the metabolites are longer than those of the parent compound.
(2) Collectively, because of the large interspecies difference, the pharmacokinetic parameters cannot be extrapolated from other species
(3) Alprazolam may be used as a suitable alternative to minimize hepatic toxicosis associated with diazepam.
(4) The plasma protein-binding capacity of diazepam is ~98%.
(5) In cats, the t½ of diazepam is ~6 hours, whereas the t½ of desmethyldiazepam is ~21 hours. In dogs, diazepam is rapidly metabolized, t½ is ~3 hours, while the t½ of desmethyldiazepam averaged 7 hours.
d. Adverse effects
(1) In cats, behavioral changes may manifest as irritability, depression, and altered demeanor.
(2) Hepatic necrosis is the most serious adverse event reported in cats. It is postulated that a toxic intermediate metabolite may be responsible for the hepatic toxicosis.
(3) Concurrent administration with other drugs that compete for cytochrome P450 (CYP450) enzyme system, including the SSRIs, may decrease the rate of metabolism of diazepam.
3. Clorazepate
a. Therapeutic uses. In dogs, it is used in the management of anxiety, especially when long duration of action is desired, for example, separation anxiety.
b. Pharmacokinetics
(1) Clorazepate is one of the most rapidly absorbed BZDs.
(2) Clorazepate is primarily oxidized in the acidic environment of the stomach to its active metabolite desmethyldiazepam (nordiazepam) before absorption.
(3) Following oral administration, mean peak levels are reached usually within 98 minutes after a single oral dose and 153 minutes after multiple oral doses, suggesting improved management when the drug is given twice daily instead of a single dose.
(4) The plasma protein binding capacity of nordiazepam is high (~97%).
(5) The t½ is 284–355 minutes and it is the same irrespective of the frequency of dosing.
c. Adverse effects. Diazepam can cross the placental barrier and enter into the milk. There is an increased risk of teratogenicity when administered during the first trimester of pregnancy. Therefore, it should not be used in pregnant and nursing females.
4. Alprazolam
a. Therapeutic uses
(1) Its rapid response makes it a good choice in treating panic disorders in dogs where a rapid resolution is essential. For example, it is effective when the drug is administered 30–60 minutes before the storm.
(2) Higher doses of the drug are required to treat panic-like states such as separation anxiety and thunderstorm phobia as compared with generalized anxiety.
(3) In cats, it is used in the treatment of anxiety disorders and inappropriate urination behaviors.
(4) The combination of alprazolam and clomipramine has been proven to be beneficial in the management of storm phobia in dogs.
b. Pharmacokinetics
(1) The two common metabolites produced by CYP450 include α-hydroxyalprazolam and benzophenone, although the latter is an inactive metabolite.
(2) Interindividual variability in plasma steady state concentration is seen in humans.
(3) Alprazolam is moderately plasma protein bound (80%).
(4) In humans, it has a rapid onset of action and the t½ is 6–27 hours. No information is available for animals.
c. Adverse effects. Dogs receiving alprazolam at a moderately high dose to treat anxiety-related disorders are at risk for developing physical dependence, withdrawal anxiety tremors, or seizures. Hence, the drug should be withdrawn gradually over a period of several weeks.
d. Contraindications. Alprazolam should not be given in conjunction with drugs that impair CYP 450 3A, including ketoconazole and itraconazole.
5. Oxazepam
a. Therapeutic uses
(1) Oxazepam provides longer duration of action as compared to diazepam and it has been effectively used as an appetite stimulant in cats.
(2) In humans, it is particularly useful in treating elderly patients with compromised hepatic function because it does not produce long-acting active metabolites.
(3) As with other benzodiazepines, oxazepam may be useful in the management of fears and phobias in cats or dogs
b. Pharmacokinetics
(1) Oxazepam does not generate active metabolites. However, in humans and pigs, the primary metabolite is the inactive glucuronide conjugate of oxazepam, which accounts for 95% of the metabolites that are eliminated in the urine.
(2) Oxazepam has pronounced plasma protein binding (97%).
(3) In humans, the t½ is ~8 hours and peak plasma levels occur at ~3 hours. No information is available for animals.
c. Adverse effects. On rare occasions, leucopenia and hepatic dysfunction have been reported in humans.
6. Lorazepam
a. Therapeutic uses
(1) It can be orally administered as a suitable alternative to diazepam.
(2) It is also useful in cats because the chances of developing idiopathic hepatic necrosis are minimal.
(3) It is used as an appetite stimulant and in the treatment of compulsive disorders.
(4) It may be safely used in individuals with compromised liver function and in geriatric dogs, because it does not produce active metabolites.
b. Pharmacokinetics
(1) After oral administration, it is rapidly absorbed in dogs, although to a lesser degree in cats.
(2) It is primarily metabolized via glucuronide conjugation The formation of the conjugate is much faster in dogs as compared to cats.
(3) It is excreted primarily in the urine and to a lesser extent in the feces in dogs and pigs. In cats, the drug is excreted in equal parts in both feces and urine.
(4) Plasma protein-binding capacity of lorazepam is ~85%.
(5) In humans, the time to peak plasma concentrations is ~2 hours. The mean t½ is ~12 hours, whereas t½ of lorazepam glucuronide is ~18 hours. No information is available for animals.
c. Adverse effects. Increased appetite, paradoxical excitation, and anxiety have been reported to occur early in therapy, although they resolve with continued use or by decreasing the dose.
7. Chlordiazepoxide
a. Mechanism of action. It acts on the limbic system of the brain, thereby modulating emotional responses.
b. Therapeutic uses
(1) It has appetite stimulant, anti-anxiety, and sedative properties.
(2) Chlordiazepoxide is beneficial in the treatment of aggression and intense fear in a number of zoo animals.
c. Pharmacological effects. Chlordiazepoxide lacks autonomic blocking effects at moderate doses, hence it exerts minimal effects on the blood pressure or heart rate.
d. Pharmacokinetics
(1) Metabolites generated via liver metabolism include desmethyldiazepam, demoxepam, desmethylchlordiazepoxide, and oxazepam. These metabolites are active and have long t½.
(2) In dogs, plasma levels peak in 7–8 hours.
(3) Chlordiazepoxide is excreted in the urine, only 1–2% is excreted in the unchanged form.
(4) Plasma protein-binding capacity of chlordiazepoxide is ~95%.
(5) In dogs, one of the metabolites demoxepam has a t½ of 10–20 hours with considerable interindividual variability. In cats, plasma levels peak in ~90 minutes when given at a dose of 1.25 mg/kg intraperitoneally (IP).
e. Adverse effects
(1) Side effects include sedation, ataxia, and rage.
(2) Because chlordiazepoxide may induce leucopenia and liver dysfunction, blood cell counts and chemistry must be monitored on a regular basis, especially when the drug is administered for an extended period.
B. Buspirone. Buspirone is the first nonsedating anxiolytic drug to be developed and marketed.
1. Mechanism of action. Buspirone may elicit its anxiolytic effects partly via its partial agonistic effects on 5-HT1A receptors located in the dorsal raphe nucleus of the brain. Additionally, it has been reported to exhibit moderate affinity to dopamine receptors.
2. Pharmacological effects
a. The CNS depressant effects are minimal.
b. Buspirone is nonsedating and it does not produce psychomotor disturbance, or disinhibition phenomenon.
c. Therapeutic efficacy is achieved only when the drug is administered for several weeks.
3. Therapeutic uses
a. In dogs, it can be used for the management of generalized anxiety although, less successful in treating storm phobia or separation anxiety.
b. In cats, the buspirone can be used for modulating urine spraying behavior and inappropriate urination.
c. It is used to reduce anxiety in cases involving inter-cat aggression within the same household.
d. It is used as an adjunct to improve the effectiveness of SSRIs in the management of OCD, although with limited success.
e. In dogs, the buspirone and fluoxetine combination therapy has been successfully used to treat complex behavioral problems involving anxiety, aggression, and stereotypic behaviors.
4. Pharmacokinetics. It is primarily metabolized by CYP450 enzymes to one active metabolite, 1-pyrimidinylpiperazine, and several other inactive metabolites.
a. Buspirone is highly (95%) plasma protein bound.
b. In humans, the t½ is ~2.5 hours. Because of the short t½ the drug must be administered at least two to three times/day. No such information is available for animals.
c. Adverse effects
(1) The incidence of side effects is very low, which is an advantage in its use as a behavior-modifying drug. Sedation does not occur in humans; however, has been reported in animals. The most common side effects reported in humans include dizziness, insomnia, nervousness, nausea, headache, and fatigue.
(2) Unlike BZDs, long-term use of buspirone is not associated with withdrawal effects or dependence, and the potential for abuse is less likely as compared to BZDs.
IV. ANTIDEPRESSANTS
A. General considerations. Four classes of drugs are categorized under the antidepressants category. The list includes TCAs, selective SSRIs, monoamine oxidase inhibitors (MAOIs), and progestins. These drugs differ in their mechanism of action (Figure 5-1), side effect profile (Table 5-1), pharmacokinetic parameters, and relative therapeutic efficacy in treating certain behavioral disorders. Despite their inherent differences, all of these drugs except progestins share certain commonalities.
1. They modulate monoamine neurotransmission (mainly NE and 5-HT) and their respective target receptor sites.
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