1.3 Behaviour modifying drugs

4 first line behavioural drugs licensed in dogs

• Clomipramine (separation anxiety only)

• Fluoxetine (separation anxiety only)

• Selegiline (wide licensing but nonspecific indications)

• Imepitoin (noise fears)

3 first line behavioural drugs not licenced in dogs

• Amitriptyline

• Sertraline

• Mirtazapine

Which factor in a serotonergic drug determines their effectiveness and withdrawal processes?

Blocking ratio between serotonin reuptake and NAd reuptake

SRI mechanism

Block serotonin reuptake in synapse → more serotonin in synapse → more synaptic transmission

h1 receptor side effects

Weight gain and sedation

• h1 = histamine receptor

m1 receptor side effects

Constipation, dry mouth, urinary retention

• m1 = ACh receptor

Alpha adrenoceptor side effects

Hypotension, sedation

Amitriptyline classification, SRI:NRI blocking ratio, usage (2)

• TCA (tricyclic antidepressant)

• 1:4

  • Favours blocking NAd reuptake

  • Therefore NOT SRI

• Not used often → lots of side effects on h1, m1, alpha receptors → lots of sedative effect!

  • Anxiolytic purposes in cats

  • Some effects on pain (e.g. cat lower UTIs)

Clomipramine classification, SRI:NRI blocking ratio, usage (3)

• SRI

• 5:1

  • NOT SSRI (ratio low)

• Less side effects VS amitriptyline:

  • Separation anxiety and repetitive compulsions (dogs)

  • Aggression (dogs)

  • Indoor marking and elimination problems (cats)

2 things to keep in mind when using clomipramine

• Risk of explosive behaviour + more aggression in some dogs

  • Do NOT use with secondary aggression due to primary separation anxiety

• Risk of discontinuation syndrome

  • Clomipramine has short half life = abrupt discontinuation brings severe reaction

  • Therefore should not be abruptly stopped past first initiation period (6-8w in dogs)

Fluoxetine classification, SRI:NRI blocking ratio, usage (4)

• SSRI

• 15:1 → very specific to serotonin therefore SSRI

• Minimal side effects (except anorexia) = therefore wide range of purposes:

  • Anxiety

  • Compulsive behaviours

  • Impulsivity VS stimuli

  • Aggression

    • Both primary or secondary → used for secondary aggression due to separation anxiety

Main side effect of SSRIs (e.g. fluoxetine)

Anorexia

• Could be due to reduced gut motility?

• Can cause nausea = therefore don’t use VS travel anxiety (motion sickness)

Selegiline classification, mechanism, speed of onset, interaction

• Dopaminergic drug

• Inhibits monoamine oxidase b (MAOb)

  • MAOb breaks down dopamine

  • More dopamine in synapse

• Low onset speed

• Inhibits MAOa (which breaks down serotonin) → therefore interacts with serotonic drugs

  • If given with TCAs or (S)SRIs → too much serotonin → severe reaction of serotonin syndrome

Selegiline usage (4)

• Primary usage = VS cognitive impairment

  • Dogs with brain ageing

• Specific fears

• Anticompulsive effects

  • Makes animals more responsive to training = therefore easier to train alternative behaviours VS compulsions

• Avoidance

  • Increases approach behaviour

  • But encourages dog to approach dangers

• Fear related aggression

  • Esp important in multidog households

Selegiline main adverse effect

Increased assertiveness and confrontation

Mirtazapine classification, initiation period, usage (3)

(Unlicenced in dogs!)

• Noradrenergic + specific sertonergic antidepressant (NaSSA)

• 3 week initiation period

  • Faster than most SSRIs

• Anxiolysis (e.g. panic)

  • Comparable VS SSRIs

• Increases motivation (esp appetite)

  • Enables faster reinforcement (for anxious dogs)

• (low doses can be used as appetite stimulant)

Mirtazapine side effects (2)

• Risk of discontinuation syndrome (like clomipramine)

• Increases chase behaviour in dogs

  • Due to increased motivation

Mirtazapine specific indications (2) and contraindication

• Failed SSRI response

• SSRI caused anorexia

• NOT AGGRESSION

  • Aggression can be increased due to higher motivation with mirtazapine

Imepitoin (pexion) mechanism, dosing, usage (2)

• Partial benzodiazepine receptor agonist

• Increase dose every 2w and titrate to effect

  • Dose range 10-30 mg/kg 2x daily

  • Midrange doses (~20) best for anxiolysis but can cause ataxia or sedation

• Anti-epileptic

• Anxiolytic

Mirtazapine (NaSSA) onset of action

1-4w (relatively quick)

Amitriptyline (TCA) onset of action

3-4w (relatively quick)

How does selectivity correspond with SRI onset of action?

More specific = takes longer to work

Selegiline onset of action

8w

• 20% dogs respond beforehand

• Abrupt change in behaviour when drug starts working

Fluoxetine (SSRI) onset of action

6-8w usually

• can be 4w

What 2 key things should selegiline never be used with?

• TCAs and (S)SRIs

  • Inhibition of MAOa → no serotonin breakdown

  • Therefore severe reaction of serotonin syndrome

• Amitraz

Which substances should never be used with selegiline, clomipramine and fluoxetine? (4)

• Amitraz

• L-tryptophan

  • Potentiates (S)SRIs

• Tramadol (seizures)

• St John’s Wort

What 2 key things should clomipramine not be used with?

• Selegiline

• Amitraz

What 3 key things should fluoxetine not be used with?

• Selegiline

• Amitraz

• NSAIDs

  • Fluoxetine and NSAIDs both increase clotting time

  • NSAIDs decrease gastric protection → gastric haemorrhage

  • Therefore use omeprazole for protection

When should adverse affects mostly be seen in treatment with TCAs and (S)SRIs? List 4 common ones.

• First 7-10d of treatment

• Anxiety

• Sedation

• Anorexia

  • Exception = can continue past 7-10d with SSRIs → indication for drug switch

• Nonspecific signs = withdrawal, inactivity, irritability

Most common persistent adverse effect (in humans) for TCAs and (S)SRIs

Nausea (and potential secondary anorexia)

• Sertraline, fluoxetine, fluvoxamine in humans have lower rates of nausea and anorexia

• Anorexia rarer in dogs = individual cases

• Indication to switch drugs in dogs?

3 ways to combat TCA/(S)SRI adverse effects

• Appetite stimulant

• Antinausea meds

• Change (S)SRI admin

  • Best way

List 4 ways to change administration of an (S)SRI to combat nausea.

• Switch drug

• Dose at night

  • Potential decreased motility of gut gone by morning

• Dose with meal

• Reduce dose temporarily

  • Nausea may be temporary

Signs of serotonin syndrome (e.g. due to SSRI + selegiline) (7)

• Can be serious = coma and death

• Clonus

• Agitation

• Tremor

• Hyperreflexia (overactive or overresponsive reflexes)

• Hypertonicity (spastic rigidity)

• Hyperpyrexia

5 augmentation drugs

• Trazodone

• A2 adrenoceptor agonists

• Gabapentin

• Beta adrenoceptor antags (e.g. propranolol)

• Memantine

Trazodone mechanism, dose, usage (2), side effects

• Serotonin receptor agonist + reuptake inhibitor (SARI)

  • Therefore interacts with SSRI

• 2-3 mg/kg PRN (taken when required) to every 8h

  • Up to 10 mg/kg 2x per day

  • Best 3x per day rather than 2x

  • Since rebound anxiety may appear when drug wears off by 8h = therefore 12h intervals even worse

  • But dose not defined = awkward to titrate to effect

• Adjunct therapy if not responsive to other drugs

• Short term anxiolytic (e.g. before vet visit)

  • Use with gabapentin?

• Sedation and ataxia at effective dose

3 A2 adrenoceptor agonists

• Clonidine (catapres)

• Dexmedetomidine (Sileo)

• Tasipimidine (Tessie)

  • Only tasipimidine interacts with SSRI!

Clonidine dose, onset of action, usage and effect on appetite

• 0.01-0.05 mg/kg

• 60-120 min

• Augmentation of SSRIs

• No effect on appetite

Dexmedetomidine administration, onset of action, usage, duration of action, cognitive effect

• Low dose gel in buccal cavity

  • Transmucosal absorption

  • Dose more predictable VS tasipimidine

• 60 mins (quick)

• Noise phobias

  • But needs to be dosed in anticipation of event

• 2-3h duration (short)

• Minimal sedation, no cognitive effect

  • Good reinforcement for future as animal calm in scary event

Tasipimidine administration, onset of action, duration of action, cognitive effect, 2 dosing considerations

• Oral liquid

• 60 mins

• 3-4h (short)

• Minimal sedation, no cognitive effect

• No constant dosing

  • Max 9 consecutive days then gap needed in between

• Reduce dose by 30% if given with SSRI

Beta blocker dosage, onset of action, usage (2), side effects

• Wide dose range, easy to titrate to effect

• 20-40 min onset (with suitable dose)

• Mainly adjunct when high arousal (but not used often)

• Mild situational anxiety

• Social phobia

Memantine mechanism (2), dosage, administration, usage (2)

• Glutaminergic NMDA receptor antagonist

• 5-HT3 receptor antagonist

  • Anti-nociceptive, antiemetic, anxiolytic

• Wide dose range, titrate to effect

• Most effective as SSRI (fluoxetine) add on

• Compulsive repetitive behaviour (VS adrenaline) or habitual response (e.g. tail chasing)

• Improves attention and cognition

  • Supports behavioural therapy

Gabapentin dosage, administration, usage (2)

• 10-30 mg/kg every 8-10h

  • Typically 3x daily

  • 2x daily = dog rebound anxiety

• Augmentation for (S)SRIs

• Pain relief

• Anxiety (e.g. vet visits)

4 reasons to combine drugs

• Slow onset of main drug

• High intensity event

• Lack of main drug efficacy

• Add effect absent in main drug

  • E.g. a2 agonist VS adrenergic arousal

List 3 ways that diet can augment TCAs/(S)SRIs.

Best diet = senior diet, worst diet = raw homemade ‘wolf’ diets

• High fiber reduces absorption = less effective

• High protein low carb = less effective

• Fish oil (DHA) = more effective

5 things to add on to SSRI (fluoxetine) VS anxiety

• Benzodiazepine

• Trazodone

• Gabapentin

• Imepitoin

• Beta blocker

Thing to add on to SSRI (fluoxetine) VS situational arousal/agitation

a2 agonist

Thing to add on to SSRI (fluoxetine) VS high arousal inducing repetitive behaviour

Memantine

2 things to add on to SSRI (fluoxetine) VS insomnia

• Trazodone

• Carbamazepine