Development of and pharmacological treatment options and future research opportunities for separation anxiety in dogs

Tia Meneses From the Department of Health Management, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, PEI, Canada C1A 4P3.

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Jessica Robinson From the Department of Health Management, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, PEI, Canada C1A 4P3.

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Jessica Rose From the Department of Health Management, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, PEI, Canada C1A 4P3.

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Jennifer Vernick From the Department of Health Management, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, PEI, Canada C1A 4P3.

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Karen L. Overall From the Department of Health Management, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, PEI, Canada C1A 4P3.

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Introduction

The first part of this 2-part series focused on the epidemiological, pathological, genetic, and epi-genetic factors that may contribute to the development of separation anxiety (SA), the most common stand-alone behavioral diagnosis in pet dogs and the second most common behavioral problem after all aggressions reported in behavior clinics.1,2,3,4,5 The second part in this series focuses on pathological changes associated with anxiety, effects of anxiety on behavioral patterns, pharmacological treatment options and their mechanisms of action, and existing efficacy data, and on introduction of a multifactorial model for assessing risk for developing SA.

Effects of various hormones and neurotrophins on the development of SA

Recent studies1,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21 have focused on possible bio-markers that may be objective indicators of anxiety-related disorders in dogs. Biomarkers are an area of active research for people and rodents. Homology and conservation of genetic code for neurochemicals and functional brain regions that are involved in anxiety-related disorders are considerable,6 such that the investigative approach for the study of anxiety-related biomarkers in people and rodents is likely to be also useful for the study of anxiety-related bio-markers in dogs.

Corticotropin-releasing factor—Fear, which originates in the amygdala, occurs acutely in response to an identifiable danger, whereas anxiety, specifically localized to the bed nucleus of the stria terminalis, occurs as a slower-onset response to a sustained state of apprehension and uncertainty.1 As a result, the primary response to fear is distance-increasing behavior such as avoidance, withdrawal, or exhibition of other behaviors that would encourage increased distance, and the primary response to an anxiogenic stimulus is vigilance, scanning, and monitoring. Fear and anxiety frequently co-occur. Corticotrophin-releasing factor has been demonstrated to play a role in sustained fear and arousal of fear and anxiety in rodents.7,8 Sustained use of selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine has been shown to decrease corticotrophin-releasing factor concentrations in people.9 At the very least, 1 outcome of long-term treatment with SSRIs may be to decrease corticotrophin-releasing factor concentrations in the CNS, thereby damping the arousal response to stressors through the hypothalamic-pituitary-adrenal axis and remodeling of regions of the brain.7 Increased circulating plasma and regional brain concentrations of cortisol interfere with learning and over time cause shrinkage of the hippocampus, the region of the brain involved in associational learning, and more easily stimulate the amygdala.10 Treatments that combat this process are warranted for those with SA.

Cortisol and ghrelin—Ghrelin receptors are located throughout various regions of the brain, and receptor agonism with ghrelin plays a role in eating during stress.11,12 Providing comfort food to rodents was found to stimulate the release of endogenous opioids and decrease plasma cortisol concentrations. Luño et al13 hypothesized that serum cortisol and ghrelin concentrations would be increased with acute and chronic stress and evaluated their hypothesis further by feeding a small amount of rich, calorie-dense food (comfort food) to dogs with SA and measuring post-prandial cortisol and ghrelin concentrations. Results were promising in that postprandial serum cortisol and ghrelin concentrations decreased, compared with concentrations for a nonstressed control group, implying that feeding comfort food to an affected dog at the time of its owner's return may faster de-escalate anxiety that it had experienced during the owner's absence. A similar effect was not found for dogs with aggression toward people and those that were situationally stressed. The sample size for this study was small (n = 6); therefore, repeating the study with a larger sample size is warranted.

Oxytocin—Oxytocin has been proposed to aid in the formation of attachment between dogs and people. Kovacs et al19 found that both dog and owner oxytocin-receptor polymorphisms affected the attachment of dogs to their owners. Oxytocin concentrations increase in both dogs and people in response to visual and physical contact with familiar people.20 Thielke and Udell20 proposed that oxytocin administration to dogs could facilitate better attachment between dogs with SA and their owners because oxytocin has been used with some success in people in the treatment of post-traumatic stress disorder, schizophrenia, and social anxiety disorder. However, a counterbalanced, double-blind study failed to demonstrate an effect of intranasal administration of oxytocin on attachment.21 Although the concept that oxytocin may play a role in SA and other social anxiety-based conditions is appealing, study methodologies and review articles are complex and varied; therefore, any conclusions should be regarded as preliminary.

BDNF—Brain-derived neurotrophic factor (BDNF) is a neurotrophin that is at high concentrations especially within the limbic system and the prefrontal cortex, regions important in the regulation of mood, emotion, and cognition. Brain-derived neurotrophic factor has been shown to increase neuronal maturation, synapse formation, and synaptic plasticity, which are essential in the molecular processes associated with learning.3,14 Also, BDNF has a complex relationship with cortisol, and concentrations of BDNF are highest at intermediate concentrations of cortisol.10 A high concentration of BDNF is a marker of the neuroendocrine response to stress, and concentrations increase with social enrichment.16 In general, expression of BDNF is increased in enriching environments and decreased in instances of stress, moderate endogenous glucocorticoid exposure, and depression.15 Moesta et al17 reported significantly lower concentrations of BDNF in dogs with SA, compared with unaffected dogs; yet, many dogs with SA had comorbidities, such that decreased BDNF concentrations may instead be indicative of generalized stress rather than specifically SA. Chronic stress that causes increased cortisol concentrations and concomitant decreased BDNF expression can result in neuronal atrophy and cell loss in the amygdala, hippocampus, and prefrontal cortex.9

Brain-derived neurotrophic factor may also play a role in the long-term success of treatment with antidepressants. Several types of antidepressants (eg, SSRIs, tricyclic antidepressants [TCAs], norepinephrine serotonin reuptake inhibitors, and monoamine oxidase inhibitors) have been shown to have a positive effect on BDNF expression through enhanced synaptic efficacy. Increased neurogenesis and cell survival may account for the long-term beneficial effects of antidepressants and the delay until they take full effect.9 N-methyl-d-aspartate receptor antagonists have also been shown to increase BDNF expression but through a different mechanism.18

Treatment recommendations

Dog owners receive information of variable quality about dog behavior from numerous sources, including family, friends, certified and hobby dog trainers, dog breeders, and the popular literature, including the internet (Supplementary Table S1). Although the causes of SA vary among dogs, 4 components are key to competent assessment and identification of optimal interventions. By standardizing the approach, clinicians will maximize the likelihood of successful treatment.

  • Obtain a comprehensive history and perform a thorough physical examination. Behavioral disorders should not be addressed in isolation. A comprehensive history and a thorough physical examination are critical during an investigation of any complaints of undesirable or abnormal behavior because what may be thought to be easily attributed to a diagnosis of an uncomplicated behavioral disorder may instead be attributed to a medical disorder, or a concurrent medical problem may exacerbate behavioral abnormalities. Dogs that are painful may be more reactive to noises and may become phobic through a feedback loop in which muscles tense with noises, leading to exacerbation of pain.22 Dogs with seizure disorders may have comorbid anxiety.23 Any condition that adversely affects health can induce or exacerbate anxiety and could cause a dog with subclinical anxiety to develop clinical anxiety. The American Animal Hospital Association behavior guidelines24 indicate that every dog at every visit should be screened for signs of SA, with young dogs screened at least 3 to 4 times/y. A standardized, detailed questionnaire should be used at each visit, and clients can be asked to complete it prior to their visit, so answers can be reviewed before the appointment or on the day of the visit. If historical or physical examination findings or questionnaire answers yield information that indicate a behavioral problem, additional screening is needed. An example is provided of a screening tool that will help detect SA and allow the veterinarian to determine its scope severity (Appendix S1). A clinician should request an owner to record a video of their dog if the clinician is uncertain about the presence of a behavioral problem.

  • Cease of all punishment-based, aversive training methods. Despite positive, reward-based training methods becoming increasingly accepted by dog owners, many still use punishment-based training. Aversive training methods have been shown to create anxiety and fear in dogs and therefore may negatively affect dogs' emotional and behavioral responses when deprived of direct contact or interaction with their owners.25 In 1 study,26 dogs that were trained with aversive methods frequently exhibited undesirable separation-related behaviors. Although the relationship may be correlational rather than causal, punishment is not useful for eliminating problematic behaviors. If an anxiety disorder causes separation-related behaviors, then anxiety induced by punishment may promote a maladaptive emotional state in dogs.26,27,28

  • Include behavioral and environmental management. Robust desensitization programs, when conducted correctly and well, can be a cornerstone of successful treatment of dogs with SA; desensitization programs have been shown to reduce the frequency and severity of undesirable separation-related behaviors.29 Dedicated owners are likely to have much success with a gradual desensitization program if they interpret their dogs' behavioral cues well.29 After a dog learns to remain calm during periods of brief separation from its owner, this calm behavior can likely be applied to longer periods of separation.27 Praising and rewarding dogs for calm behaviors combined with cognitive and aerobic exercise, social interaction, and affection from their owners can help to promote overall emotional, physical, and psychological health, all of which may help minimize or resolve signs of SA.29,30 However, dog owners and trainers need to be sufficiently skilled in interpreting their dogs' behavioral cues so that they recognize when their dogs show signs of sensitization or increased distress and arousal in response to the desensitization procedure, the location in which the procedure was performed, or any food toys intended for a dog's engagement during its owner's absence, etc. The best way to evaluate behavioral changes is through review of a video recording, such that a baseline of behaviors can be identified and quantified.

  • Dogs that exhibit signs of SA should be protected from experiencing signs of SA during the initial period of desensitization and pharmacological treatment. Day care, bringing the dog to work, or leaving the dog with a known friend or relative are options that should be considered during this period. Aggressive pharmaceutical intervention may allow behavior modification to eventually benefit the dog, if behavior modification is not possible at first. Owner compliance may be poor for the more challenging or time-consuming elements of the treatment plan, such as systematic desensitization.29 For this reason, clinicians and clients should be aware that several studies29,31,32 reveal that pharmacological intervention improves the rate at which behavior is adequately modified.

  • Consider early and aggressive pharmacological treatment. Pharmacological treatment works synergistically with behavior modification to improve outcomes and independently to address a dog's emotional state.32,33,34,35 In part because of the effects of modern medications on BDNF, modern medications can enhance the capacity to learn.36 Behavioral conditions are time-dependent; the longer time that a dog suffers from a behavioral disorder, resolving the behavioral disorder becomes more difficult. Therefore, early treatment is optimal. Pharmacological treatment that improves the acquisition rate of new behaviors may shorten the overall treatment course.

Behavioral pharmacology for SA

Medications that may be prescribed for the treatment of dogs with SA include clomipramine, fluoxetine, clonidine, alprazolam, gabapentin, and dexmedetomidine (oral transmucosal gel; Table 1). Clomipramine (Clomicalm) and fluoxetine (Reconcile) are approved by the US FDA and European Union Committee for Medicinal Products for Veterinary Use for the treatment of canine SA. Extralabel drug options include alprazolam, oral transmucosal dexmedetomi-dine gel (Sileo), clonidine, and gabapentin. The latter medications are used in combination with licensed medications to abort arousal and panic and to blunt overall excitatory stimulation associated with acute anxiety and distress.

Table 1

Medications that are commonly used for the treatment for separation anxiety (SA) in dogs.

Medication Recommended dosage range and administration Mechanism of action Adverse effects References
Clomipramine

Licensed for use in dogs for the treatment of SA
Label: 1–2 mg/kg, PO, q 12 h;

Recommended: 2–3 mg/kg, PO, q 12 h
Inhibits presynaptic uptake of serotonin Intermittent vomiting or gastritis, lethargy, sedation

All TCAs or SSRIs carry the risk for potential but rare serotonin syndrome and noradrenaline, it is more specific for serotonin in dogs and has minimal anticholinergic effects
31,33,37
Fluoxetine

Licensed for use in dogs for the treatment of SA
Label: 1–2 mg/kg, PO, q 24 h (must give for 8 wk, assuming no adverse events, to confirm nonresponse)

Recommended: 0.5-I.0 mg/kg, PO, q 24 h
Acts by selectively blocking the reuptake of 5HT-la into presynaptic neurons Seizures (not clearly linked to fluoxetine administration), weight loss, lethargy, inappetence, vomiting, diarrhea, shaking or trembling, aggression, constipation and paradoxical fear

All TCAs or SSRIs carry the risk for potential but rare serotonin syndrome
34,35
Clonidine

Extralabel use
To be used in combination with TCAs or SSRIs prior to departures and/or q 12 h

0.01–0.05 mg/kg, no more frequently than q 6 h, administered 1.5–2 h prior to departure
Prevents the release of norepinephrine by activating α2 receptors on the synaptic neurons in the locus coeruleus and thereby decreases sympathetic overflow to multiple peripheral organ systems as an acute stress response Sedation and dry mouth (according to humans that use it), paradoxical worsening of noise phobia 43
Alprazolam

Extralabel use
To be used in combination with TCAs or SSRIs prior to departures and/or q 6–12 h

0.02–0.04 mg/kg in an interventional manner when a dog becomes distressed OR given 30–60 min before departure Can be given by putting a pill in the cheek, as it will dissolve
Binds to specific sites on the gamma-aminobutyric acid A (GABAA) receptors to increase the flow of chloride ions into the neuron, which enhances the inhibitory effects of GABAergic neurons Sedation, ataxia, paradoxical excitement

May cause disinhibition in animals whose aggression is currently inhibited
44,46
Gabapentin

Extralabel use
To be used in combination with TCAs or SSRIs prior to departures and/or q 8–12 h

20+ mg/kg
Binds as a ligand to a2§ subunit Sedation, ataxia, salivation, vomiting of voltage gate calcium, channels causing a decrease in the release of neurotransmitters like the excitatory neurotransmitter, glutamate 50,51,52,53
Dexmedetomidine OTM gel

Extralabel use
To be used in combination with TCAs or SSRIs prior to departures 4.65 μg/kg for a 20-kg dog (125 μg/m2; BSA (m2) = 0.101 X (BW kg)2/3 for anxiety and/or distress Centrally acting a2-adrenergic receptor agonist which has anxiolytic, sedative, and hypnotic actions mediated through inhibiting locus coeruleus firingl Sedation, hypersalivation, vomiting 56,57

BSA = Body surface area. SSRI = Selective serotonin reuptake inhibitor. TCA = Tricyclic antidepressant.

Clomipramine—Clomipramine, as a TCA, inhibits presynaptic uptake of serotonin and norepinephrine.31,33,34,35,36 The licensing study33 was a prospective, randomized, double-blind, placebo-controlled, parallel group, international multicenter clinical trial that included 95 dogs with SA and some degree of hyper-attachment, defined in this study as preferring to be with their owners. Dogs were randomly assigned to 1 of 3 treatment groups: standard dosage group (1 to 2 mg/kg, PO, q 12 h), a low dosage group (0.5 mg/kg, PO, q 12 h), and placebo group. Each dog's behavior was passively modified (ie, dog had to look at its owner and sit for owner attention), no dog received behavioral medications other than what was prescribed in the study,33 and all punishment ceased. The study lasted for 3 months, but if owners did not observe a treatment effect, they could withdraw their dogs from the study at the end of the second month and seek other treatments (ie, those for which data regarding their effectiveness were known). Significantly more dogs that received the standard dosage showed an improvement in their signs of SA, compared with those placebo. A follow-up study by King et al37 reveals that dogs that received a low dosage of clomipramine (1 mg/kg, PO, q 12 h) were more likely to have a rapid return of their clinical signs following the drug's abrupt discontinuation, compared with dogs that received a standard dosage. In contrast, separation-related behaviors for dogs that received clomipramine long-term continued to improve.

One study38 reveals a dose-dependent effect on the signs of SA. In that study,38 locomotion (pacing) and scratching significantly lessened for dogs that received 1 mg of clomipramine/kg, PO, every 12 hours, and barking, whining, panting, and time spent in a passive state (resting or sleeping) significantly lessened and increased, respectively, for dogs that received 2 mg of clomipramine/kg, PO, every 12 hours. Whether the effectiveness of clomipramine is because clomipramine is a TCA or whether it has an active metabolite that acts as an SSRI is unclear. Time of maximum plasma concentration and elimination half-life for clomipramine are 0.75 to 3.1 hours and 1.2 to 16 hours, respectively, whereas for its active metabolite desmethylclomipramine are 1.4 to 8.8 hours and 1.2 to 2.3 hours, respectively.39 The terminal half-life increased slightly with repeated-dose administration, with a greater effect on the parent compound (1.6-fold increase for clomipramine and 1.2-fold increase for desmethylclomipramine) but was still ≤ 4 hours, and steady state is reached in 4 days.40 Clomipramine's onset of action is owing to alterations in neuronal metabolism with increases in production of translational proteins that result in neurotrophic effects and subsequently greater synaptic activity.36 Severe adverse effects (AEs) are uncommon with clomipramine. Only 1 serious AE, which resembled serotonin syndrome (clinical signs include changes in mentation, neuromuscular hyperactivity, and autonomic hyperactivity) occurred during the licensing study.33 The affected dog recovered and was subsequently successfully treated for SA with an SSRI. Less severe, more common but often transient AEs of TCAs and SSRIs are intermittent vomiting, signs of gastritis, lethargy, sleepiness, and rarely aggression.33 The FDA post-approval report41 for clomipramine includes a list in order of descending frequency of AEs: lethargy or depression, anorexia, increased liver enzyme activities, vomiting, and diarrhea.

Fluoxetine—Fluoxetine was assessed as a treatment for dogs with SA in a multicenter, placebo-controlled, double-blind, randomized, parallel-arm study34 that involved 208 client-owned dogs with SA. Dogs received placebo or 1 to 2 mg of fluoxetine/ kg, PO, every 24 hours, for 6 weeks. Although the duration of the study was short, dogs that received fluoxetine had significant improvement at a faster rate in many signs of SA, compared with placebo. Overall SA, destructive behavior, and inappropriate urination and defecation significantly improved with fluoxetine, compared with placebo.34,35 Interestingly, this study did not assess the medication's effect on vocalization, yet vocalization is one of the pivotal signs of SA, and one that is difficult to redress.31

Fluoxetine and its active metabolites have an extremely variable but generally long half-life owing to the number of contributing intermediate metabolites. The half-life of the parent compound is approximately 6 hours (range, 3.0 to 12.9 hours), but the half-life of the major intermediate active metabolite, norfluoxetine, is approximately 49 hours (range, 33 to 64 hours). Fluoxetine administration may take up to 2 weeks to achieve a steady state concentration. Similar with clomipramine, fluoxetine's onset of action is owing to alterations in neuronal metabolism with increases in production of translational proteins that result in neurotrophic effects and subsequently greater synaptic activity.36 Medications that rely on the production of translational proteins require their administration for 8 weeks before they can be considered a failure.31

Selective serotonin reuptake inhibitors such as fluoxetine are often preferred to TCAs because of their relatively minimal effects on the concentrations of norepinephrine, dopamine, acetylcholine, or histamine, or on α-adrenoreceptors.31, Rare serious AEs include seizures34 and serotonin syndrome, especially when used in combination with monoamine oxidase inhibitors and other serotonergic medications (TCAs, serotonin agonist reuptake inhibitors, serotonin antagonist reuptake inhibitor, etc).31 Less serious AEs include weight loss, anorexia, lethargy, and shaking and trembling. Vomiting and diarrhea occurred slightly more often for dogs that received fluoxetine, compared with placebo, in the licensing studies,34,35 but the difference was not signifi-cant. The FDA Center for Veterinary Medicine post-approval report42 for fluoxetine lists in order of descending frequency the following AEs: decreased appetite; depression or lethargy; shaking, shivering, or tremoring; vomiting; restlessness and anxiousness; seizures; aggression; diarrhea; mydriasis; vocalization; weight loss; panting; signs of confusion; incoordination; and hypersalivation.

Clonidine—In people, clonidine has typically been used per its label indication to treat hypertension and extralabel to treat hyperarousal, hypervigi-lance, post-traumatic stress disorder, attention-deficit hyperactivity disorder, and impulsivity. Clonidine prevents the release of norepinephrine through activation of a2-adrenoceptors on the synaptic neurons in the locus coeruleus, thereby decreasing sympathetic outflow to several organ systems.43 Clonidine was assessed for the treatment of dogs with SA in an open trial across multiple diagnostic classes43 Ten dogs with SA, noise phobia, storm phobia, or a combination of these were treated with clonidine, and most dogs had comorbidities and received other medications at the time of the study.43 Clonidine was administered as needed, which resulted in variable dosages among dogs. Despite this, however, the results indicate potential for the use of clonidine as an adjunct, as-needed treatment of dogs with SA. Seven of the 10 dogs showed improvement with clonidine administration, versus their current baseline regimen or other as-needed medications that had been trialed. Three dogs showed no improvement, with 1 that had increased sensitivity to noise at a high dose. Adverse effects are rare, especially at low doses, but may include hypotension, sedation, and paradoxical worsening of noise sensitivity.43

Alprazolam—Alprazolam, a benzodiazepine (binds to γ-aminobutyric acid receptors, leading to increased flow of chloride ions into neurons and subsequent enhancement of γ-aminobutyric acid-mediated synaptic inhibition), is commonly administered to dogs for the as-needed or intermittent treatment of behavior disorders because of its rapid onset, anxiolytic and panicolytic properties, and because it is less sedative at interventional dosages that many benzodiazepines.44 Benzodiazepines cause muscles to relax independent of their sedative effects; therefore, benzodiazepines may indirectly mitigate signs of fear and anxiety because fearful and stressed animals typically have increased muscle tone.45 Alprazolam may be helpful in the arousal phase of an anxiety response associated with an owner's departure may be most useful when administered 1 hour prior to an owner's anticipated departure.46

Gabapentin—Several studies47,48,49 are available on the use of gabapentin in cats but not in dogs. However, several studies50,51,52,53 reveal the pharmacokinetic parameters for gabapentin following its administration to dogs, and, anecdotally, starting doses of 20 mg of gabapentin/kg have been administered to dogs prior to veterinary clinic visits in an attempt to mitigate fear and anxiety associated with the visits.54 Similarly, anecdotes of gabapentin administration to dogs to decrease situational anxiety, including owner departure, have been reported. On the basis of the results of the pharmacokinetic studies,50,51,52,53 gabapentin should be administered to a dog at least 90 minutes before an owner's anticipated departure. Gabapentin binds as a ligand of the α2δ subunit of voltage-gated calcium channels that causes a decrease in the release of neurotransmitters (such as the excitatory neurotransmitter glutamate) and is commonly coad-ministered with TCAs or SSRIs and such a combination may be beneficial to dogs with SA.54 Pharmacokinetic data suggest that to maintain therapeutic plasma concentrations in dogs with SA, dosing frequency should be at least every 8 hours,50,51,52,53 although dosing frequency is sometimes every 12 hours.

Dexmedetomidine—Oral transmucosal dexmedetomidine gel55 is licensed for use in dogs for the treatment of noise aversions, reactivities, fears, and phoas,56 and it has been used extralabel to decrease anxiety associated with veterinary clinic visits.57 Because of dexmedetomidine's mechanism of action (similar to clonidine), reducing the arousal phase of distress, fear, and anxiety by preventing the release of norepinephrine through activation of a2-adrenoceptors on the synaptic neurons in the locus coeruleus and thereby decreasing sympathetic outflow, dexmedetomidine likely has applications for anticipatory anxiety and distress caused by veterinary clinic visits and, for a dog with SA, an owner's departure.

Trazodone—Anecdotally, trazodone is frequently used to treat dogs with SA and for sedation and prevention of stress, anxiety, and overall hyperarousal during transport to and examination at a veterinary clinic.58 Studies59,60,61,62 evaluating trazodone usually fail to reveal whether trazadone induces a calming, anxiolytic, or sedative effect. Trazodone's primary use is in psychiatry as a hypnotic for people with insomnia or disordered sleep because trazodone decreases sleep latency and increases sleep duration.63 Trazodone acts as a serotonin antagonist and reuptake inhibitor, primarily blocking the 5-HT receptors 2A and 2C. These receptors affect various aspects of cognition (5-HT2A) and movement (5-HT2C), with both affecting sleep in a dose-dependent manner. Trazodone only functions as an antidepressant in people at a dose that antagonizes the serotonin transporter, with the dose 10 to 50 times higher than that necessary to antagonize the 5-HT2A receptors.64 Trazodone's intermediate metabolite, meta-chlorophenylpiperazine, functions as an agonist and has high affinity for 5HT2C.64 No comparable work exists for dogs. The only double-blind, placebo-controlled canine study65 that was identified through a literature search involved an investigation of whether trazodone affected postsurgical anxiety associated with confinement; this study showed no effect of trazodone on postsurgical anxiety. Given the lack of efficacy data for trazodone for dogs with SA, controlled studies are needed and must differentiate between trazodone's anxiolytic and hypnotic effects. Its hypnotic effects may be beneficial for some dogs with SA, but identifying the effects as hypnotic is important for clinician and dog owner awareness. Anti-anxiety effects are separate from hypnotic or sedative effects and changes in behavior can occur due to both effects. Sedative effects simply suppress behaviors and can interfere with learning replacement behaviors. Dogs that are administered trazodone and an SSRI or a TCA should be closely monitored owing to an enhanced risk of serotonin syndrome.

Factors to consider for future research

Data regarding dogs with SA are incomplete, and many factors thought to be involved with SA are not involved or likely play only a minor role. Conversely, factors, such as early-life experiences,66,67 that may play an important role in the development or progression of SA and other separation-related behaviors, have been understudied. In military working dogs, early maternal care has been shown to have effects on later adult behavior66,67; yet, these are among the scarcest data for pet dogs. In pet dogs, for which some genetic contributions to behavior problems are known,68,69 early-life factors could have a more pronounced effect than in working dogs. Future research should focus on accurate assessment of any associations among specific behaviors, physiological and neurophysiological states, early-life experiences and trauma, and breed and genetic risk.

The assessment tool used a prevalence study that had the largest number of dogs to date70 included only 1 question that pertained to SA. Although comorbid anxieties share clinical signs with those for SA, well-designed, objective questionnaires about context-related behavior71,72,73,74,75,76 have been shown to have no or low false positive results. Such questionnaires are recommended for use at each veterinary clinic visit for every dog24; without completion of such a questionnaire, veterinarians must rely solely on a dog owner's observations and then interpret those observations (see Supplemental data). Lack of clinical signs and context-specific routine screening (through a questionnaire) means that false negative results for dogs with SA are likely high. However, data regarding false positive and negative results obtained in general veterinary practice are inadequate, and data regarding confirmation of behaviors exhibited by a dog as reported through a questionnaire are lacking.77,78 Lastly, also lacking is a shared repository for data that would allow sensitive detection of patterns likely relevant to dogs across various dog populations. Breed clubs could facilitate such data collection.

Early-life experiences and trauma—Early-life experiences and disruptions in early social development have been postulated to lead to separation-related behaviors in adulthood.75 A few studies77,79 reveal that an animal's age may play a role in fear; therefore, past experiences or trauma may have influence on personality and cognitive bias80,81,82 and neuroendocrine correlates of cognitive ability that facilitate behavioral change.75 A better understanding of how temporal patterns of behavioral responses and cognitive bias may be influenced by genes with small cumulative effects may suggest that the largest role for early experience is epigenetic or associated with gene regulation.

Breed and genetic risk—Whether certain dog breeds have higher or lower risk for developing SA is unknown because broad, controlled studies needed to assess true risk are lacking. Some breed-related studies76,82,83 reveal that a subset of dogs are at high risk for developing SA, but that risk may be for only a particular genetic line of dogs of 1 breed or population of dogs within a breed (eg, conformation [show] dog population vs working dog population), rather than for all dogs of that breed. van Rooy et al82 found that certain genetic polymorphisms in Australian Golden Retrievers were associated with an enhanced risk of developing SA, but their study had only a small number of dogs. Knowledge of genetic risk may inform whether a dog pair should be mated, a dog should be placed with an interested party, and the interaction between an owner of a newly adopted dog and the dog would be impacted. Any breed or breed club database should include externally validated, objective questions on behavioral conditions71,72,73,75,82 so that prevalence and risk of SA and breeding value (expected phenotypic value of a dog's offspring) can be calculated.

Model for assessing contributions to risk

With many factors that may affect the risk of developing SA, its manifestation, and its resolution, a graphical model is proposed that veterinarians, dog owners, and dog breeders could use to understand the relative contributions of various factors to the risk of developing SA (Tables 2 and 3; Figure 1). Inputs to the model are Likert-like scores based on 3-or 5-point scales for 10 factors that may contribute to the development of SA. The response surface of available behaviors changes when owner-related factors change (eg, exposure, exercise, and general attentiveness to their dog's needs) and is putatively remodeled by other factors (eg, rehoming and trauma). Types of interaction patterns can then be hypothesized and tested. Models have played only a minimal role in conceptualizing testable mechanisms of behavioral conditions or potential outcomes that could be expected when a predictive factor is present. Such models may surpass their conceptual value if quantitative data on relevant factors (eg, early nutrition [diet], maternal care, source, litter size, age at adoption, early responses to handling and veterinary care, number of owners, quality home, and environment) are collected in a standardized manner for a large number of dogs from diverse backgrounds and compared with respect to response surface profiles and presence or absence of the condition of interest. Some data for dogs with SA have been cited in this set of review articles,84 but the data are rare and largely retrospective, such that hypothesis testing was not possible. Analyses are expected to reveal how response surfaces change in the presence of various behavioral problems, thereby justifying hypothesis testing of possible contributions of salient neurodevelopmental and environmental factors on the development of SA. The interventions of licensed pharmacological agents and behavior modification are the only force-free techniques that are effective and humane ways of treating dogs with SA. Understanding and mitigating risk factors is the primary way by which prevalence of dogs with SA will decrease.

Table 2

Factors that may contribute to the development of SA and descriptions of respective Likert-like scores based on 3- or 5-point scales.

Factor Definition Likert-like scale
Temperament Degree of boldness vs shyness 1 = Profoundly shy

3 = Neither profoundly shy nor bold

5 = Profoundly bold
Maternal care Adequacy of maternal care (quality and duration) 1 = Compromised

3 = Basic, adequate care

5 = Excellent
Exposure and exercise* Degree of exposure and exercise of various kinds, without fear 1 = Inadequate

3 = Basic adequate

5 = Excellent (requires human effort)
Owner attentiveness* Degree of dog-owner awareness of and response to their dog's needs and signals 1 = Not at all

3 = Middling

5 = Excellent (requires human effort)
Genetic polymorphism CAA haplotype at the dopamine drd2 locus or GAG haplotype at the arginine vasopressin avprla locus 1 = Homozygous

3 = Heterozygous

5 = Not present
Rehomed, shelter history* No. of times in rehomed or shelter settings 1 = ≥ 4 times

2 = 3 times

3 = 2 times

4 = 1 time

5 = Never
Trauma (any kind)* Neglect, deprivation, abuse 1 = Frequent

2 = Often

3 = Occasional

4 = Rare

5 = Never
Cognitive bias Affective state (mood) that affects decision-making 1 = Negative bias

3 = Neither

5 = Positive bias
Risk of epigenetic effects (maternal stressors) Environmental (exposure to elements; commercial caging), nutritional (poor diet or insufficient amount of food), behavioral (abuse, punishment, induced fear) 1 = High risk

3 = Some risk

5 = No risk
Age at adoption 1 = < 5 wk

2 = Between 6 and 7 wk

3 = Between 7 and 8 wk

4 = Between 8 and 9 wk

5 = > 9 wk

— = Not applicable.

Likert-like scale scores indicate degree of risk or protection for human-driven factors (exposure and exercise; human attentiveness) and rescue-related factors (rehomed, shelter history; trauma).

Although considered qualitative factors, these factors are considered quantitative.

In general, a score of 5 is the best because it indicates that a dog has more choices to respond, whereas a score of 1 is the worst because it indicates that a dog has fewer options, less flexibility, or more impairment.

Scores will be used to create a graphical representation of the data such that veterinarians, dog owners, and dog breeders can use to understand the relative contributions of each factor to a dog's SA.

Table 3

Sample data set created from the Likert-like scale scores in Table 1 for the assessment of SA of 5 hypothetical dogs.

Factor Likert-like scale score
Dog 1 Dog 2 Dog 3 Dog 4 Dog 5
Temperament 5 3 1 2 2
Maternal care 5 3 1 3 3
Exposure and exercise 5 3 1 5 2
Owner attentiveness 5 3 1 5 2
Genetic polymorphism 5 3 1 3 3
Rehomed, shelter history 5 3 1 5 3
Trauma 5 3 1 5 2
Cognitive bias 5 3 1 3 3
Risk of epigenetic effects 5 3 1 3 3
Age at adoption 5 3 1 5 5

Dog 1 was perceived to have had ideal experiences, Dog 2 no ideal or horrid experiences (an average dog), Dog 3 problematic (challenging) experiences, Dog 4 an owner who made every attempt to meet and understand their dog's needs and signals (without any association with a rescue organization), and Dog 5 a rescue history and an owner who was not attentive, such that they made little attempt to expose, exercise, and meet and understand their dog's needs and signals (with association with a rescue organization).

Figure 1
Figure 1

Graphical representations of the shape of the response surfaces generated from the Likert-like scale scores for the dogs in Table 2. These response surfaces use radial graphs or radar charts as a way to compare multivariate data that start at the same position in a 2-dimensional representation. It's most useful for comparing relative tradeoffs and benefits and areas affected under different patterns (putative surfaces like “response surfaces” – the sum of all the measured effects on a phenotypic representation). Rehoming and trauma are postulated to adversely affect the response surface (decrease in the behavioral responses available to a dog). A—Graphical representation of the shape of the response surfaces with respect to history for Dogs 1, 2, and 3. B—Graphical representation of the shape of the response surfaces with respect to owner attentiveness and association with a rescue organization for Dogs 1 through 5. C—Graphical representation of the shape of the response surfaces with respect to exposure and owner attentiveness and association with a rescue organization for Dog 4. D—Graphical representation of the shape of the response surfaces with respect to exposure and owner attentiveness and association with a rescue organization for Dog 5. Note the restricted response surface area for Dog 5 that had a less attentive owner and had exposure to a rescue organization, compared with Dog 4, and that these dogs differed only with respect to these factors.

Citation: Journal of the American Veterinary Medical Association 259, 10; 10.2460/javma.20.10.0602

Interestingly, more progress has been made in developing effective behavioral and pharmaceutical treatments for SA, compared with little progress in understanding the pathologic, neurodevelopmental, environmental, and genetic contributions to the risk of developing SA. Data suggest a multifactorial process or multiple contributions that differentially affect suites or clusters of patterns in pathology (eg, neurodevelopment, adoption history, genetics). Models of risk may help to identify testable hypotheses of possible contributors of SA and indicate which data may be most useful to collect in the future.

Supplementary Materials

Supplementary materials are posted online at the journal website: avmajournals.avma.org

Acknowledgments

No external funding was used in this study.

Dr. Overall serves as a consultant for Orion Pharma, the manufacturer of Sileo, and participated in the licensing study for Clomi-calm (Elanco). No other authors declared any conflicts of interest.

The authors thank Dr. Camille Squair for proofreading this manuscript.

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