ANSC 378 LECTURE 2

Behaviour Modification-Medication: An Overview for Anxiety and Aggression

Introduction to Behaviour Modification

Behaviour modification, often involving medication, aims to address undesirable behaviours that are considered manifestations of underlying issues. For example, excessive crying or howling in animals can be a manifestation of distress that requires intervention.

Goals and Principles of Intervention

The primary goal of behaviour modification, whether through drug or non-drug methods, is to minimize stress or anxiety in animals. Extreme stress and/or fear can significantly hinder a dog's ability to learn. When an animal is 'over-threshold,' meaning physiologically aroused to a high degree, it can lead to various behaviour problems such as avoidance, aggression, or panic.

Anxiety Disorders: Human Context

In humans, anxiety disorders are recognized as the most prevalent psychiatric disorders and a leading cause of disability. These include conditions like panic disorder, generalized anxiety disorder, social anxiety disorder, and various phobias.

Neurobiology of Stress and Anxiety

Both the amygdala and hippocampus play significant roles in most anxiety disorders. The amygdala processes and interprets sensory signals, alerting the brain to danger and triggering anxiety. It also stores emotional memories. The hippocampus encodes threats into memories. Chronic (pathological, severe, continuous) stress can lead to brain injury. For instance, soldiers with Post-Traumatic Stress Disorder (PTSD) have shown an $8\%$ reduction in the volume of their hippocampus.

Canine Problems Associated with Anxiety

Anxiety in dogs can manifest in a range of challenging behaviours, including:

• Aggression between household dogs

• Compulsive disorder

• Fear-related aggression

• Fears/phobias

• Inappropriate attention-seeking behaviour

• Leash reactivity

• Resource guarding

• Separation anxiety

Separation Anxiety and the Human-Animal Bond

The human-animal bond is a crucial aspect when discussing separation anxiety. Three theories underpin this bond:

1. Biophilia: An innate human tendency to connect with nature and other living systems.

2. Social Support: The emotional and practical assistance provided by social relationships.

3. Self Psychology: Focuses on the role of empathy and self-object relationships in psychological development.

Attachment Theory, originating from social support concepts, suggests that attachment relationships are vital for living in a social group, helping to keep members together. This rationale is often applied to people having companion animals. John Bowlby (1958) argued that the infant-caretaker attachment relationship was evolutionarily important for human infants. This principle is extended to the person-to-animal bond, suggesting similar dynamics apply.

Evidence for Animal-Human Attachment and Stress Reduction

Evidence supports animals bonding to people:

• Scott and Fuller (1965): A study with $10$-week-old puppies indicated that maintaining interaction with people was more important to them than searching for food. In a new environment, puppies interacted more with people than with their own mother.

• Tuber et al. (1996): Kennel dogs in a new environment exhibited less stress and lower glucocorticoid levels when in the presence of people compared to kennel mates.

Attachment Theory: Testing in Children

Attachment theory has been tested in children, measuring attachment behaviours in low and high-stress situations:

• Group 1 (Low Stress): A stranger entered a room while the mother remained present.

• Group 2 (High Stress): A stranger entered a room, and the mother then left.

• Researchers examined exploratory, contact, and proximity behaviours, vocalization, and self-injury (which was rare).

Separation Anxiety in Dogs

Separation anxiety is a significant behavioural problem in dogs, diagnosed in $14\%$ to $39\%$ of cases. Its manifestations include:

• Excessive vocalization

• Destructive behaviour

• Elimination (urination or defecation) inside the house

• Pacing

• Salivating

• Trembling

Factors Contributing to Separation Anxiety (SA) in Dogs

The following factors contribute to the likelihood of a dog developing SA, rated on a scale of $1$ (likely) to $5$ (unlikely):

(Source: Menese et al. JAVMA 2021)

Potential Treatments for Anxiety

Treatments for anxiety can include:

• Punishment: Generally not recommended for anxiety as it can exacerbate the problem.

• Confinement: Can be a management strategy but not a treatment for underlying anxiety.

• Systematic Desensitization: First described in people to treat phobias or anxiety. This involves the gradual and increasing addition of a stimulus that induces anxiety, eventually leading the individual to become 'desensitized' or to 'fade out' the response to the stimulus.

• Pharmacological (Drug) Therapy: Use of medications.

• Complimentary (Non-pharmacological Adjuncts): Used in conjunction with drug therapy.

Drug Therapy: Considerations and Principles

Drug therapy is a significant component of anxiety management, but several considerations are important:

• While 'day-to-day' drug therapy (sedation) is not the desired primary effect, it can relieve anxiety and, critically, improve the mental well-being of the dog when combined with behavioral or animal husbandry modifications.

• If behavioral modifications like learned tasks, desensitization, or counter-conditioning have reached a 'plateau of success,' drug therapy can help push further progress.

• Drug therapy alone is unlikely to cure the behavioral problem without concurrent implementation of behavioral or animal husbandry practices.

• Drugs can have short, intermediate, or long-term effects, influencing the choice of medication.

• Some drugs may take $1-2$ months to reach effective therapeutic levels.

• Abrupt discontinuation of drug therapy often leads to a 'rebound' or elevated behavioral problems and should never be done. The recommendation is to reduce the drug dose by $25\%$ every $1-2$ weeks.

Primary Drug Categories for Anti-Anxiety (Anxiolytic) Drugs (Dogs)

There are five main categories of anti-anxiety drugs:

1. Selective Serotonin Reuptake Inhibitors (SSRIs)

• Examples: Fluoxetine (Prozac), Sertraline (Zoloft), Paroxetine (Paxil). Note: Prozac may not be available for veterinary use in the USA.

• Mechanism of Action: SSRIs inhibit the reuptake of serotonin by the serotonin transporter (SERT) protein in pre-synaptic neurons. This increases the concentration of serotonin in the synaptic gap, making more serotonin available for post-synaptic neurons. Serotonin is an inhibitory neurotransmitter that regulates mood, behaviour, sleep, and memory.

• Therapeutic Use: Treat fear, anxiety, and aggression.

• Advantages: Generally fewer side effects compared to Monoamine Oxidase Inhibitors (MAOIs) and Tricyclic Antidepressants (TCAs).

• Dosages (per OS, Q24h):

  • Fluoxetine: $0.5-2 \text{ mg/kg}$ PO Q $24\text{ h}$

  • Paroxetine: $1 \text{ mg/kg}$ PO Q $24\text{ h}$

  • Sertraline: $1-3 \text{ mg/kg}$ PO Q $24\text{ h}$

• Complications: Agitation, increased anxiety, inappetence, lowered seizure threshold, sedation, tremors. These complications can be dose-dependent, so therapy usually starts at lower doses and gradually increases.

2. Serotonin Antagonist and Reuptake Inhibitors (SARIs)

• Example: Trazodone

• Role: Often used to boost primary treatments.

• Mechanism of Action:

  • At low to moderate doses, Trazodone strongly blocks (antagonizes) post-synaptic serotonin $2A$, histamine, and $\alpha$ -adrenergic receptors, leading to a hypnotic effect in people.

  • At high doses, it blocks SERT activity and serotonin $2C$ ($5HT2C$) on post-synaptic neurons.

• Advantages: Shows synergistic activity with SSRIs. Has fewer anticholinergic effects than TCAs, making it suitable for short-term anxiety events (e.g., vet visits, groomer visits, post-surgery anxiety). Considered a safe and well-tolerated drug.

• Dosage (per OS, Q8-24h or PRN): $3-5 \text{ mg/kg}$ PO Q $8-24\text{ h}$ or as needed (PRN, pro re nata).

• Complications: Paradoxical increased anxiety, sedation.

• SARI vs. SSRI (General Application): Trazodone (SARI) is commonly used for short-term, acute events like vet visits or thunderstorms. SSRIs are generally preferred for long-term management of behavioral problems such as separation anxiety.

3. Tricyclic Antidepressants (TCAs)

• Examples: Clomipramine (Clomicalm), Amitriptyline, Imipramine, Trimipramine. These are older drugs from the $1950$s with a three-ring chemical structure.

• Primary Action: Inhibit both serotonin and norepinephrine uptake, making them less selective than SSRIs.

• Additional Actions: Act as antagonists for NMDA receptors (involved in long-term memory) and agonists to sigma (opioid) receptors, which can be beneficial. They also have antihistamine, anticholinergic (antimuscarinic), and alpha-adrenergic antagonist effects, and block Na+ and Ca2+ channels. These latter actions are the major cause of their side effects.

• Dosages (per OS, daily):

  • Amitriptyline: $1-4 \text{ mg/kg}$ PO Q $12\text{ h}$

  • Clomipramine: $1-3 \text{ mg/kg}$ PO Q $12\text{ h}$

• Complications: Constipation, decreased appetite, dry mouth/eyes, paradoxical increased anxiety, lowered seizure threshold, sedation, tachycardia, tachyarrhythmia, urine retention.

4. Monoamine Oxidase Inhibitors (MAOIs)

• Example: Selegiline

• Mechanism: Monoamine oxidase is an enzyme that degrades monoamine compounds (neurotransmitters like serotonin, epinephrine, norepinephrine, dopamine, phenylethylamine). MAOIs prevent this breakdown, increasing the availability of these neurotransmitters. There are two types: MAO-A and MAO-B.

• Historical Use (People): Used after failure of SSRIs or TCAs.

• Dosage (per OS, Q24h): Selegiline: $0.5-1 \text{ mg/kg}$ PO Q $24\text{ h}$

• Complications: Agitation, disorientation, vomiting, and diarrhea.

5. Novel Anticonvulsants

• Example: Gabapentin

• Background (People): Used to treat psychiatric disorders (generalized and social anxiety, panic, phobias, PTSD) and pain disorders.

• Original Design: Gabapentin was originally designed to bind to GABAergic receptors (due to its similar structure to GABA) and used as an antispasmodic drug.

• Mechanism of Action (Current Understanding): Gabapentin does not bind to GABAergic receptors. Instead, it binds to and inhibits the ( \alpha 2 \delta ) subunit of voltage-dependent L and N calcium channels. These calcium channels can be upregulated in conditions of anxiety or chronic pain. While research is ongoing, it's suggested that gabapentin reduces the release of excitatory neurotransmitters (e.g., glutamate) from presynaptic membranes, thereby reducing the hyperactivity of postsynaptic nerves.

• Gabapentin in Dogs (Current Uses): Primarily used for epilepsy, neuropathic and chronic pain, and degenerative joint disease (osteoarthritis). Increasingly used for anxiety (e.g., separation anxiety).

  • Dosage: $5-30 \text{ mg/kg}$ TID (three times daily) or $30-60 \text{ mg/kg}$ PRN (prior to stressful events).

  • Complications: Sedation, ataxia, agitation, vomiting, diarrhea, change in appetite. Care is needed in cases of renal or hepatic deficiencies as kidney excretion is the primary method of elimination.

• Gabapentin in Cats (Study Findings): A study (Van Haffen JAVMA 2017) showed that providing gabapentin $90$ minutes prior to a vet visit reduced anxiety in cats. Cats were more relaxed during transportation, and $20\%$ were easier to handle during examination. The peak effect of the drug was $2-3$ hours post-administration.

  • Dosage: $10-20 \text{ mg/kg}$ PRN (prior to stressful events like vet visits).

  • Complications: Sedation, ataxia, hypersalivation, vomiting, muscle fasciculations.

Classical Anticonvulsants (Benzodiazepines)

• GABA Receptors: There are three subtypes: GABAA and GABAC (involved in Cl- neuron influx) and GABAB (involved in K+ neuron influx). GABA is an inhibitory neurotransmitter that reduces neuron firing by increasing Cl- channel opening, leading to an influx of Cl- into the neuron and hyperpolarizing the membrane potential, thus reducing action potential generation and neuron activity.

• GABAA Receptor: The main GABAA receptor in the brain is involved in anxiety, psychiatric disorders, epilepsy, and alcoholism. It is complex, with five ( \alpha ) receptor subunits. For example, ( \alpha 1 ) subunits (in thalamus, cerebellum) have high sensitivity to benzodiazepines, while ( \alpha 2 ), ( \alpha 3 ), ( \alpha 5 ) subunits (in hippocampus) have low sensitivity. Hyperanxious individuals may underproduce endogenous GABA, and treatment can involve agonists binding to these receptors.

• Benzodiazepines (Anxiolytic, Muscle Relaxant, Anticonvulsant): Used to boost primary treatments.

  • Mechanism of Action: Increase the efficacy of GABA binding to GABAA receptors, which in turn increases Cl- channel opening. They may also reduce the release or inhibit the effectiveness of acetylcholine and serotonin (minor effect).

  • Effects: Affect both subcortical brain regions (limbic system, thalamus, hypothalamus) and the spinal cord.

  • Advantages: Useful, easy to administer orally, and relatively safe.

  • Types and Dosages (Dogs):

    • Alprazolam: $0.02-0.1 \text{ mg/kg}$ PO Q $8\text{ h}$ or PRN. Short-acting (effective for $2-6$ hours in dogs), good for separation anxiety.

    • Clorazepate: $0.5-2.2 \text{ mg/kg}$ PO Q $8\text{ h}$ or PRN. Longer-acting (effective for $8-12$ hours in dogs), good for treatments at night (e.g., separation anxiety) and phobias (e.g., thunderstorms, construction). Needs to be administered several hours before the anticipated event.

    • Diazepam (Valium): $0.5-2.2 \text{ mg/kg}$ PO Q $8\text{ h}$ or PRN. Longer-acting.

  • Complications: Paradoxical agitation, aggression, disinhibition, ataxia, and sedation without anti-anxiety effect (may indicate a drug dose problem), polyphagia ('Munchies').

Buspirone (Anxiolytic)

• Mechanism: Serotonin $1A$ receptor agonist. It binds in vitro to presynaptic and postsynaptic serotonin receptors, as well as D$2$ dopamine receptors.

• Advantage: Non-sedating, making it suitable for generalized anxiety.

• Problem: Anecdotal evidence suggests it can cause aggression disinhibition (aggression against people or other dogs).

• Use (People): Used in combination therapy with SSRIs.

Non-Pharmaceutical Agents

These adjuncts can complement pharmacological treatments:

• L-theanine (Amino Acid Analog): Similar to L-glutamate, crosses the blood-brain barrier, and may induce ( \alpha )-wave activity (associated with restful states). Examples: Anxitane, Composure.

• Pheromone Diffusers: Release calming pheromones via collars, diffusers, or sprays. Examples: Adaptil, Feliway.

• Prescription Diets: Formulated to improve overall health, which may indirectly impact behavior (e.g., urinary balance diets in cats like IAMS, Hills).

• S-adenosylmethionine (SAM): Possesses antidepressive and analgesic properties. Example: NOVIFit.

• Vitamins & Natural Compounds: Example: Senilife.

Success Rates of Drug Therapy with Behavioral Modification

Drug therapy alone does not guarantee success. A study by Takeuchi et al. (2000) on behavioral modification with medication, including $6$ months of follow-up with specific discharge instructions (reducing anxiety triggers, no punishment, increased exercise), found that $56\%$ of cases improved, while $44\%$ did not improve.

Owner Reluctance to Drug Therapy

Owners often express reluctance regarding drug therapy for their pets due to several concerns:

• **

Physiology of Anxiety and Emotional Memory in the Brain

Both the amygdala and hippocampus play significant roles in most anxiety disorders. The amygdala processes and interprets sensory signals, alerting the brain to danger and triggering anxiety. It also stores emotional memories. The hippocampus encodes threats into memories. Chronic (pathological, severe, continuous) stress can lead to brain injury, for instance, soldiers with Post-Traumatic Stress Disorder (PTSD) have shown an $8\%$ reduction in the volume of their hippocampus.

Potential Treatments for Anxiety in Dogs

Potential treatments for anxiety in dogs involve a multi-modal approach combining:

• Behavioural modification: This includes learned tasks, desensitization, and counter-conditioning techniques.

• Drug therapy: Utilizing various categories of anxiolytic drugs.

• Non-pharmaceutical agents: Adjuncts like L-theanine, pheromone diffusers, prescription diets, S-adenosylmethionine, and other vitamins and natural compounds.

Drug Therapy Considerations

Several important considerations for drug therapy include:

• The primary goal is to relieve anxiety and improve the mental well-being of the dog, rather than just sedation, when combined with behavioural or animal husbandry modifications.

• Drug therapy can help achieve further progress if behavioural modifications have reached a 'plateau of success'.

• Drug therapy alone is unlikely to cure the behavioural problem without concurrent implementation of behavioural or animal husbandry practices.

• Drugs can have short, intermediate, or long-term effects, influencing the choice of medication.

• Some drugs may take $1-2$ months to reach effective therapeutic levels.

• Abrupt discontinuation of drug therapy often leads to a 'rebound' or elevated behavioural problems and should never be done. The recommendation is to reduce the drug dose by $25\%$ every $1-2$ weeks.

Main Drug Classes for Anti-Anxiety Drugs

1. Selective Serotonin Reuptake Inhibitors (SSRIs)

• Examples: Fluoxetine (Prozac), Sertraline (Zoloft), Paroxetine (Paxil).

• Selectivity: Highly selective, primarily inhibiting the reuptake of serotonin.

• Side Effects: Generally fewer side effects compared to MAOIs and TCAs. Complications can include agitation, increased anxiety, inappetence, lowered seizure threshold, sedation, and tremors. These are often dose-dependent.

• Prescription Order/Why: Often a primary choice for long-term management of behavioural problems like separation anxiety due to their selective action and generally fewer side effects, making them advantageous for chronic conditions.

2. Serotonin Antagonist and Reuptake Inhibitors (SARIs)

• Example: Trazodone.

• Selectivity: At low to moderate doses, it strongly blocks post-synaptic serotonin $2A$, histamine, and $\alpha$-adrenergic receptors. At high doses, it blocks SERT activity and serotonin $2C$ ($5HT2C$) on post-synaptic neurons. It's less selective than SSRIs but more so than TCAs.

• Side Effects: Complications include paradoxical increased anxiety and sedation. It has fewer anticholinergic effects than TCAs and is considered safe and well-tolerated.

• Prescription Order/Why: Commonly used for short-term, acute anxiety events (e.g., vet visits, thunderstorms) or to boost primary treatments due to its effective action and good toleration for temporary situations.

3. Tricyclic Antidepressants (TCAs)

• Examples: Clomipramine (Clomicalm), Amitriptyline, Imipramine, Trimipramine.

• Selectivity: Broad-acting, inhibiting both serotonin and norepinephrine uptake. They also act as antagonists for NMDA receptors, agonists to sigma (opioid) receptors, and have antihistamine, anticholinergic (antimuscarinic), alpha-adrenergic antagonist effects, and block Na+ and Ca2+ channels.

• Side Effects: More numerous and severe side effects compared to SSRIs (e.g., constipation, decreased appetite, dry mouth/eyes, paradoxical increased anxiety, lowered seizure threshold, sedation, tachycardia, tachyarrhythmia, urine retention). These result from their broader actions.

• Prescription Order/Why: Older drugs, typically considered if SSRIs are not effective or tolerated, due to their broader side effect profile.

4. Monoamine Oxidase Inhibitors (MAOIs)

• Example: Selegiline.

• Selectivity: Broad-acting, preventing the breakdown of various monoamine neurotransmitters (serotonin, epinephrine, norepinephrine, dopamine, phenylethylamine).

• Side Effects: Can cause agitation, disorientation, vomiting, and diarrhea.

• Prescription Order/Why: Historically, in people, MAOIs were used after failure of SSRIs or TCAs, indicating they are generally not a first-line treatment due to potential complications and complexity of use.

5. Novel Anticonvulsants (e.g., Gabapentin)

• Example: Gabapentin.

• Selectivity: Binds to and inhibits the $(\alpha 2 \delta)$ subunit of voltage-dependent L and N calcium channels, reducing the release of excitatory neurotransmitters. It has a more targeted mechanism compared to TCAs or MAOIs.

• Side Effects: Can cause sedation, ataxia, agitation, vomiting, diarrhea, and changes in appetite. Care is needed in cases of renal or hepatic deficiencies.

• Prescription Order/Why: Increasingly used for anxiety (e.g., separation anxiety), and often prescribed PRN (as needed) for stressful events or as an adjunct for chronic pain/anxiety. Its unique mechanism makes it a valuable alternative or add-on, particularly for specific acute stress events or when other treatments are insufficient.

Non-Pharmaceutical Agents

These adjuncts can complement pharmacological treatments:

• L-theanine (Amino Acid Analog): May induce $(\alpha)$-wave activity (associated with restful states). Examples: Anxitane, Composure.

• Pheromone Diffusers: Release calming pheromones via collars, diffusers, or sprays. Examples: Adaptil, Feliway.

• Prescription Diets: Formulated to improve overall health, which may indirectly impact behaviour.

• S-adenosylmethionine (SAM): Possesses antidepressive and analgesic properties. Example: NOVIFit.

• Vitamins & Natural Compounds: Example: Senilife.

Success Rates of Drug Therapy with Behavioral Modification

Drug therapy alone does not guarantee success. It is crucial to combine medication with concurrent behavioural or animal husbandry modifications. A study by Takeuchi et al. (2000) on behavioural modification with medication (including $6$ months of follow-up with specific discharge instructions like reducing anxiety triggers, no punishment, increased exercise) found that $56\%$ of cases improved, while $44\%$ did not improve. This indicates that while effective, success requires a comprehensive approach and is not guaranteed for all cases.