• 1. Ogata N. Separation anxiety in dogs: what progress has been made in our understanding of the most common behavioral problems in dogs? J Vet Behav. 2016;16:2835.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2. Dreschel NA. The effects of fear and anxiety of health and lifespan in pet dogs. Appl Anim Behav Sci. 2010;125(3–4):157162.

  • 3. McCrave EA. Diagnostic criteria for separation anxiety in the dog. Vet Clin North Am Small Anim Pract. 1991;21(2):247255.

  • 4. Salman MD, Hutchison J, Ruch-Gallie R, et al. Behavior reasons for relinquishment of dogs and cats to 12 shelters. J Appl Anim Welf Sci. 2000;3(2):93106.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5. Bamberger M, Houpt KA. Signalment factors, comorbidity, and trends in behavior diagnoses in dogs: 1,644 cases (1991–2001). J Am Vet Med Assoc. 2006;229(10):15911601.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6. Li Y, vonHoldt B, Reynolds A, et al. Artificial selection on brain-expressed genes during the domestication of dog. Mol Biol Evol. 2013;30(8):18671876.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7. McEwen BS. The neurobiology of stress: from serendipity to clinical relevance. Brain Res. 2000;886(1–2):172189.

  • 8. McEwen BS. Glucocorticoids, depression, and mood disorders: structural remodeling in the brain. Metabolism. 2005;54(5 suppl 1)2023.

  • 9. Duman RS, Monteggia LM. A neurotrophic model for stress-related mood disorders. Biol Psychiatry. 2006;59(12):11161127.

  • 10. Peters A, Schweiger U, Pellerin L, et al. The selfish brain: competition for energy resources. Neurosci Biobehav Rev. 2004;28(2):143180.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11. Fritz EM, Singewald N, De Bundel D. The good, the bad and the unknown aspects of ghrelin in stress coping and stress-related psychiatric disorders. Front Synaptic Neurosci. 2020;12:594484.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12. Stone LA, Harmatz ES, Goosens KA. Ghrelin as a stress hormone: implications for psychiatric illness. Biol Psychiatry. 2020;88(7):531540.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13. Luño I, Palacio J, Garcia-Belenguer S, Rosado B. Baseline and postprandial concentrations of cortisol and ghrelin in companion dogs with chronic stress-related behavioural problems: a preliminary study. Appl Anim Behav Sci. 2019;216:4551.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14. Park H, Poo M-N. Neurotrophin regulation of neural circuit development and function. Nat Rev Neurosci. 2013;14(1):723.

  • 15. Björkholm C, Monteggia LM. BDNF – a key transducer of antidepressant effects. Neuropharmacology. 2016;102:7279.

  • 16. Cirulli F, Berry A, Bonsignore LT, et al. Early life influences on emotional reactivity: Evidence that social enrichment has greater effects than handling on anxiety-like behaviors, neuroendocrine responses to stress and central BDNF levels. Neurosci Biobehav Rev. 2010;34(6):808820.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17. Moesta A, Kim G, Wilson-Frank CR, Weng H-Y, Ogata N. Comparison of serum brain-derived neurotrophic factor in dogs with and without separation anxiety. J Vet Behav. 2020;35:1418.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18. Fukumoto K, Fogaça MV, Liu R-J, et al. Medial PFC AMPA receptor and BDNF signaling are required for the rapid and sustained antidepressant-like effects of 5-HT1A receptor stimulation. Neuropsychopharmacology. 2020;45(10):17251734.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19. Kovács K, Virányi Z, Kis A, et al. Dog-owner attachment is associated with oxytocin receptor gene polymorphisms in both parties: a comparative study on Austrian and Hungarian Border Collies. Front Psychol. 2018;9:435.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20. Thielke LE, Udell MAR. The role of oxytocin in relationships between dogs and humans and potential applications for the treatment of separation anxiety in dogs. Biol Rev. 2017;92(1):378388.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21. Thielke LE, Rosenlicht G, Saturn SR, Udell MAR. Nasally-administered oxytocin has limited effects on owner-directed attachment behavior in pet dogs (Canis lupus familiaris). Front Psychol. 2017;8:1699.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22. Lopes Fagundes AL, Hewison L, McPeake K, Zulch H, Mills DS. Noise sensitivities in dogs: an exploration of signs in dogs with and without musculoskeletal pain using qualitative content analysis. Front Vet Sci. 2018;5:17.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23. Watson F, Rusbridge C, Packer RMA, Casey RA, Heath S, Volk HA. A review of treatment options for behavioural manifestations of clinical anxiety as a comorbidity in dogs with idiopathic epilepsy. Vet J. 2018;238:19.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24. Hammerle M, Horst C, Levine E, et al. 2015 AAHA canine and feline behavior management guidelines. J Am Anim Hosp Assoc. 2015;51(4):205221.

  • 25. Rooney NJ, Cowan S. Training methods and owner-dog interactions: links with dog behaviour and learning ability. Appl Anim Behav Sci. 2011;132(3–4):169177.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 26. Hiby EF, Rooney NJ, Bradshaw JWS. Dog training methods: their use, effectiveness and interaction with behaviour and welfare. Anim Welf. 2004;13(1):6369.

    • Search Google Scholar
    • Export Citation
  • 27. Blackwell EJ, Twells C, Seawrtight A, Seawright A, Casey RA. The relationship between training methods and the occur-rence of behavior problems, as reported by owners, in a population of domestic dogs. J Vet Behav. 2008;3(5):207217.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28. Ziv G. The effects of using aversive training methods in dogs—a review. J Vet Behav. 2017;19:5060.

  • 29. Butler R, Sargisson RJ, Elliffe D. The efficacy of systematic desensitization for treating the separation-related problem behaviour of domestic dogs. Appl Anim Behav Sci. 2011;129(2–4):136145.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30. Bradshaw JWS, McPherson JA, Casey RA, Larter S. Aetiology of separation-related behaviour in domestic dogs. Vet Rec. 2002;151(2):4346.

  • 31. Overall KL. Manual of Clinical Behavioral Medicine for Cats and Dogs. Elsevier; 2013.

  • 32. Takeuchi Y, Houpt KA, Scarlett JM. Evaluation of treatments for separation anxiety in dogs. J Am Vet Med Assoc. 2000;217(3):342345.

  • 33. King JN, Simpson BS, Overall KL, et al. Treatment of separation anxiety in dogs with clomipramine: results from a prospective, randomized, double-blind, placebo-controlled, parallel-group, multicenter clinical trial. Appl Anim Behav Sci. 2000;67(4):255275.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 34. Landsberg GM, Patrick M, Sherman BL, Neilson JC, Zimmerman A, Clarke TP. Effectiveness of fluoxetine chewable tablets in the treatment of canine separation anxiety. J Vet Behav. 2008;3(1):1219.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 35. Simpson BS, Landsberg GM, Reisner IR, et al. Effects of Reconcile (fluoxetine) chewable tablets plus behavior management for canine separation anxiety. Vet Ther. 2007;8(1):1831.

    • Search Google Scholar
    • Export Citation
  • 36. Duman RS. Novel therapeutic approaches beyond the serotonin receptor. Biol Psychiatry. 1998;44(5):324335.

  • 37. King JN, Overall KL, Appleby D, et al. Results of a follow-up investigation to a clinical trial testing the efficacy of clomipramine in the treatment of separation anxiety in dogs. Appl Anim Behav Sci. 2004;89(3–4):233242.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 38. Cannas S, Frank D, Minero M, Aspesi A, Benedetti R, Pales-trini C. Video analysis of dogs suffering from anxiety when left home alone and treated with clomipramine. J Vet Behav. 2014;9(2):5057.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 39. Hewson CJ, Conlon PD, Luescher UA, Ball RO. The pharmacokinetics of clomipramine and desmethylclomipramine in dogs: parameter estimates following a single oral dose and 28 consecutive daily oral doses of clomipramine. J Vet Pharmacol Ther. 1998;21(3):214222.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 40. King JN, Maurer MP, Altmann BO, Strehlau GA. Pharmacokinetics of clomipramine in dogs following single-dose and repeated-dose oral administration. Am J Vet Res. 2000;61(1):8085.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 41. Clomicalm–clomipramine hydrochloride tablet. DAILEYMED. Accessed August 17, 2020. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ee50609c-39e6-452d-94f3-0622bb8a0720

    • Search Google Scholar
    • Export Citation
  • 42. Reconcile–fluoxetine hydrochloride tablet, chewable. DAILYMED. Accessed August 17, 2020. https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=006035a8-b8da-47cb-924b-524c05da8641

    • Search Google Scholar
    • Export Citation
  • 43. Ogata N, Dodman NH. The use of clonidine in the treatment of fear-based behavior problems in dogs: an open trial. J Vet Behav. 2011;6(2):130137.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 44. Greenblatt DJ, von Moltke LL, Harmatz JS, Ciraulo DA, Shader RI. Alprazolam pharmacokinetics, metabolism, and plasma levels: Clinical implications. J Clin Psychiatry. 1993;54(10 suppl)411.

    • Search Google Scholar
    • Export Citation
  • 45. Driessen JJ, Vree TB, Booij LHD, van der Pol FM, Crul JF. Effect of some benzodiazepines on peripheral neuromuscular function in the rat in-vitro hemidiaphragm preparation. J Pharm Pharmacol. 1984;36(4):244247.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 46. Crowell-Davis SL, Seibert LM, Sung W, Parthasarathy V, Curtis TM. Use of clomipramine, alprazolam, and behavior modification for treatment of storm phobia in dogs. J Am Vet Med Assoc. 2003;222(6):744748.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 47. van Haaften KA, Forsythe LRE, Stelow EA, Bain MJ. Effects of a single preappointment dose of gabapentin on signs of stress in cats during transportation and veterinary examination. J Am Vet Med Assoc. 2017;251(10):11751181.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 48. Pankratz KE, Ferris K, Griffith E, Sherman BL. Use of single-dose oral gabapentin to attenuate fear responses in cage-trap confined community cats: a double-blind, placebo-controlled field trial. J Feline Med Surg. 2018;20(6):535543.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 49. Hudec CP, Griffin CE. Changes in the stress markers cortisol and glucose before and during intradermal testing in cats after single administration of pre-appointment gabapentin. J Feline Med Surg. 2020;22(2):138145.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 50. KuKanich B, Cohen L. Pharmacokinetics of oral gabapentin in Greyhound dogs. Vet J. 2011;187(1):133135.

  • 51. Radulovic LL, Türck D, Von Hodenberg A, et al. Disposition of gabapentin (Neurontin) in mice, rats, dogs, and monkeys. Drug Metab Dispos. 1995;23(4):441448.

    • Search Google Scholar
    • Export Citation
  • 52. Vollmer KO, von Hodenberg A, Kölle EU. Pharmacokinetics and metabolism of gabapentin in rat, dog and man. Arzneimittelforschung. 1986;36(5):830839.

    • Search Google Scholar
    • Export Citation
  • 53. Rhee Y-S, Park S, Lee T-W, et al. In vitro/in vivo relationship of gabapentin from a sustained-release table formulation: a pharmacokinetic study in the beagle dog. Arch Pharm Res. 2008;31(7):911917.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 54. Overall KL. Behavioral pharmacotherapeutics. In: Mealey KL, ed. Pharmacotherapeutics for Veterinary Dispensing. John Wiley & Sons; 2019:377390.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 55. Dexmedetomidine or medetomidine for use in treating separation anxiety in dogs. Google Patents. Accessed July 20, 2020. https://patents.google.com/patent/US20200069650A1/en

    • Search Google Scholar
    • Export Citation
  • 56. Korpivaara M, Laapas K, Huhtinen M, Schöning B, Overall K. Dexmedetomidine oromucosal gel for noise-associated acute anxiety and fear in dogs-a randomised, double-blind, placebo-controlled clinical study. Vet Rec. 2017;180(14):356.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 57. Hauser H, Campbell S, Korpivaara M, Stefanovski D, Quinlan M, Siracusa C. In-hospital administration of dexmedetomidine oromucosal gel for stress reduction in dogs during veterinary visits: a randomized, double-blinded, placebo-controlled study. J Vet Behav. 2020;39:7785.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 58. Chea B, Giorgi M. Trazodone: a review of its pharmacological properties and its off-label use in dogs and cats. Am J Anim Vet Sci. 2017;12(4):188194.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 59. Orlando JM, Case BC, Thomson AE, Griffith E, Sherman BL. Use of oral trazodone for sedation in cats: a pilot study. J Feline Med Surg. 2016;18(6):476482.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 60. Stevens BJ, Frantz EM, Orlando JM. Efficacy of a single dose of trazodone hydrochloride given to cats prior to veterinary visits to reduce signs of transport- and examination-related anxiety. J Am Vet Med Assoc. 2016;249(2):202207.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 61. Gruen ME, Roe SE, Griffith E, Hamilton A, Sherman BL. The use of trazodone to facilitate post-surgical confinement in dogs. J Am Vet Med Assoc. 2014;245(3):296301.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 62. Gilbert-Gregory SE, Stull JW, Rice MR, Herron ME. Effects of trazodone on behavioral signs of stress in hospitalized dogs. J Am Vet Med Assoc. 2016;249(11):12811291.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 63. Jaffer KY, Chang T, Vanle B, et al. Trazodone for insomnia: a systematic review. Innov Clin Neurosci. 2017;14(7–8):2434.

  • 64. Stahl SM. Mechanism of action of trazodone: a multifunctional drug. CNS Spectr. 2009;14(10):536546.

  • 65. Gruen ME, Roe SC, Griffith E, Sherman BL. The use of trazo-done to facilitate calm behavior following elective orthopedic surgery in dogs: results and lessons learned from a clinical trial. J Vet Behav. 2017;22:4145.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 66. Foyer P, Wilsson E, Jensen P. Levels of maternal care in dogs affect adult offspring temperament. Sci Rep. 2016;6:19253.

  • 67. Wilsson E. Nature and nurture—how different conditions affect the behavior of dogs. J Vet Behav. 2016;16:4552.

  • 68. Sarviaho R, Hakosalo O, Tiira K, et al. Two novel genomic regions associated with fearfulness in dogs overlap human neuropsychiatric loci. Transl Psychiatry. 2019;9(1):18.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 69. Sarviaho R, Hakosalo O, Tiira K, et al. A novel genomic region on chromosome 11 associated with fearfulness in dogs. Transl Psychiatry. 2020;10(1):169.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 70. Salonen M, Mikkola S, Sulkama S, et al. Prevalence, comorbidity, and breed differences in canine anxiety in 13,700 Finnish pet dogs. Sci Rep. 2020;10(1):2962.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 71. Overall KL, Dunham AE, Frank D. Frequency of nonspecific clinical signs in dogs with separation anxiety, thunderstorm phobia, and noise phobia, alone or in combination. J Am Vet Med Assoc. 2001;219(4):467473.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 72. Overall KL, Dunham AE, Juarbe-Diaz SV. Phenotypic determination of noise reactivity in 3 breeds of working dogs: a cautionary tale of age, breed, behavioral assessment, and genetics. J Vet Behav. 2016;16:113125.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 73. Overall KL, Dunham AE, Scheifele P, Sonstrom Malowski K. Fear of noises affects problem solving behavior and locomotion in standardized cognitive tests. Appl Anim Behav Sci. 2019;221:104863.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 74. Tiira K, Lohi H. Reliability and validity of a questionnaire survey in canine anxiety research. Appl Anim Behav Sci. 2014;155:8292.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 75. Tiira K, Lohi H. Early life experiences and exercise associate with canine anxieties. PLoS One. 2015;10(11):e0141907.

  • 76. Bellamy KKL, Storengen LM, Handegård KW, et al. DRD2 is associated with fear in some dog breeds. J Vet Behav. 2018;27:6773.

  • 77. Dinwoodie IR, Dwyer B, Zottola V, et al. Demographics and comorbidity of behavior problems in dogs. J Vet Behav. 2019;32:6271.

  • 78. Elliot O, Scott JP. The development of emotional distress reactions to separation in puppies. J Genet Psychol. 1961;99:322.

  • 79. Bennett PC, Rohlf VI. Owner-companion dog interactions: relationships between demographic variables, potentially problematic behaviours, training engagement and shared activities. Appl Anim Behav Sci. 2007;102(1–2):6584.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 80. Mendl M, Brooks J, Basse C, et al. Dogs showing separation-related behaviour exhibit a ‘pessimistic' cognitive bias. Curr Biol. 2010;20(19):R839R840.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 81. Stamps J, Groothuis TGG. The development of animal personality: relevance, concepts and perspectives. Biol Rev. 2010;85(2):301325.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 82. van Rooy D, Thomson PC, McGreevy PD, Wade CM. Risk factors of separation-related behaviours in Australian retrievers. Appl Anim Behav Sci. 2018;209:70.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 83. Overall KL, Tiira K, Broach D, Bryant D. Genetics and behavior: a guide for practitioners. Vet Clin North Am Small Anim Pract. 2014;44(3):483505.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 84. Meneses T, Robinson J, Rose J, et al. Paradigm shifts in our knowledge of separation anxiety – separating myth from fact. Part I: a review of contributory factors. J Am Vet Med Assoc. 2021;259:in press.

    • Search Google Scholar
    • Export Citation

Advertisement

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

View More View Less
  • 1 From the Department of Health Management, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, PEI, Canada C1A 4P3.

Supplementary Materials

    • Supplementary Table S1 (PDF 198 KB)
    • Supplementary Appendix S1 (PDF 218 KB)

Contributor Notes

Address correspondence to Dr. Overall (koverall@upei.ca).