Difference between revisions of "Nutraceuticals in Behaviour"

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==Overview==
 
==Overview==
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A nutraceutical is defined as "a substance that is produced in purified or extracted form and administered orally to provide agents required for normal body structure and function and administered with the intent of improving the health and well-being of animals.<ref>Anonymous. Council defines "nutraceutical." Journal of the American Veterinary Medical Association 1996; 209:1986.</ref>"
+
A nutraceutical is defined as "a substance that is produced in purified or extracted form, administered orally to provide agents required for normal body structure and function with the intent of improving the health and well-being of animals" <ref>Anonymous. Council defines "nutraceutical." Journal of the American Veterinary Medical Association 1996; 209:1986.</ref>. Nutraceuticals are not regulated in the same way as pharmaceuticals and do not have to undergo the same rigorous testing to be approved. Efficacy has not been properly evaluated for most nutraceuticals.
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The majority of nutraceuticals have possible benefits as opposed to proven benefits. Nutraceuticals are not regulated in the same way as pharmaceuticals and do not have to undergo the same rigorous testing to be approved.  
 
  
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==Alpha-casozepine==
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==Alpha-Casozepine==
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Alpha-casozepine has been found to be extremely useful in the treatment of anxiety, where its efficacy has been shown to be on a par with selegiline<ref>Beata, C., Beaumont-Graff, E., Diaz, C., et al. Comparison of the effect of alpha-casozepine (Zylkene) versus selegiline hydrochloride on anxiety disorders in dogs. J Vet Behav 2007;2:175-83.</ref> as well as fear related behaviour<ref>Beata, C., Beaumont-Graff, E., Coll, V., et al. Effect of alpha-casozepine (Zylkene) on anxiety in cats. J Vet Behav 2007;2:40-6.</ref> in cats in conjunction with behavioural modification techniques. Alpha-casozepine is available as a supplement or as part of a commercial diet. It is a trypsin hydrolysate of alpha-S1 casein found in milk.  
+
Alpha-casozepine is a trypsin hydrolysate of bovine milk casein with anxiolytic and anti-epileptic effects in laboratory rodent models<ref>Miclo, L.,  Perrin, E., Driou, A., Papadopoulos, V., Boujrad, N., Vanderesse, R., Boudier, J.F., Desor, D., Linden, G., Gaillard, J.L. (2001) Characterization of α-casozepine, a tryptic peptide from
 +
bovine αs1-casein with benzodiazepine-like activity. FASEB J.15(10):1780-2.</ref>. It has been shown to have potential anxiolytic effects in cats and dogs in two open label trials<ref>Beata, C., Beaumont-Graff, E., Diaz, C., et al. Comparison of the effect of alpha-casozepine (Zylkene) versus selegiline hydrochloride on anxiety disorders in dogs. J Vet Behav 2007;2:175-83.</ref> <ref>Beata, C., Beaumont-Graff, E., Coll, V., et al. Effect of alpha-casozepine (Zylkene) on anxiety in cats. J Vet Behav 2007;2:40-6.</ref>. However, only one of these studies included a control group, the inclusion criteria were very broad, the populations small and outcomes were measured using questionnaires that had not been validated or checked for test-retest reliability. More studies are required to confirm clinical efficacy.
  
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==Cognitive Boosters==
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==L-Theanine==
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Many products aimed at improving cognitive function of older animals are mixtures of multiple ingredients such as antioxidants, mitochondrial cofactors, fatty acids (especially polyunsaturated fatty acids - omega 3 and 6 oils) amongst others which are generally thought to have a positive effect on the development of cognitive dysfunction. Additional ingredients which may be found in a supplement or diet with the aim of slowing cognitive dysfunction include vitamins C, E and B<sub>6</sub>, choline, phosphatidylcholine, alpha-lipoid acid, resveratrol, gingkobiloba, carnitine and flavonoids and carotenoids.  
+
L-Theanine is an amino acid that is found almost exclusively in certain species of tea plant. It has been shown to have positive effects on activation and anxiety symptoms in human patients with schizophrenia<ref>Ritsner, M.S., Miodownik, C., Ratner, Y., Shleifer, T., Mar, M., Pintov, L., Lerner, V.M. (2011) L-Theanine Relieves Positive, Activation, and Anxiety Symptoms in Patients With Schizophrenia and Schizoaffective Disorder: An 8-Week, Randomized, Double-Blind, Placebo-Controlled, 2-Center Study.  J Clin Psychiatry. 72(1).</ref>, and beneficial effects on stress responses and the ability to concentrate during cognitive tasks<ref>Kimura, K., Ozeki, M., June, L.R., Ohira, H. (2006) L-Theanine reduces psychological and physiological stress responses. Biological Psychology.</ref>.  
  
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Products which are more specific and focus on an active ingredient include those with S-adenosyl-L-methionine (SAMe) which is thought to improve depression in humans<ref>Papakostas, G.I. The use of complementary and alternative medicines to achieve remission in major depressive disorder. J Clin Psychiatry 2009;70(Suppl. 5):18-22.</ref> and apoaequorin. Care should be taken when using SAMe in conjunction with behavioural drugs such as [[Clomipramine|clomipramine]] a tricyclic antidepressant (TCA) and [[Fluoxetine|fluoxetine]] a selective serotonin re-uptake inhibitor (SSRI) as it may augment serotonin levels and therefore potentially cause toxicity resulting in serotonin syndrome.
+
L-Theanine has a range of effects, including binding to glutamate receptor subtypes (AMPA, kainate, and NMDA receptors) and blocking of the binding of L-glutamic acid to the glutamate receptors in cortical neurones<ref>Kakuda, T., Nozawa, A., Sugimoto, A., Nino, H., (2002). Inhibition by theanine of binding of [3H]AMPA, [3H]Kainate, and [3H]MDL 105,519 to glutamate receptors. Bioscience, Biotechnology, and Biochemistry 66, 2683– 2686.</ref>.
  
−
==L-theanine==
+
In a small open label trial without a control group, l-theanine reduced a range of anxiety signs in cats with behavioural problems<ref>Dramard, V., Kern, L., Hofmans, J., et al. Clinical efficacy of l-theanine tablets to reduce anxiety-related emotional disorders in cats: a pilot open-label clinical trial. J Vet Behav 2007;5:85-6.</ref>. However, this study was not presented as a full article in a peer reviewed journal, and the lack of detail on the methodology or statistical significance of the findings makes the results impossible to interpret. In a study of the effects of l-theanine on fear of human beings in laboratory beagles, treated dogs showed greater human interaction and approach than the placebo control group<ref>Araujo, J.A., de Rivera, C., Ethier, J.L., et al. Anxitane tablets reduce fear of human beings in a laboratory model of anxiety-related behaviour. J Vet Behav 2010;5:268-75.</ref>. Whether this could translate into a clinical effect in dogs with fear rested problems is not known.
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Naturally found in green tea L-theanine is used to help treat anxiety. It is thought to increase GABA and block glutamate, therefore reducing its excitatory effects. In cats it has been used to treat behavioural problems including inappropriate elimination, fear and aggression both towards humans and other cats and has also been shown to help with the physical effects of anxiety<ref>Dramard, V., Kern, L., Hofmans, J., et al. Clinical efficacy of l-theanine tablets to reduce anxiety-related emotional disorders in cats: a pilot open-label clinical trial. J Vet Behav 2007;5:85-6.</ref>. To date there have been no drug interactions or side effects with use<ref>Araujo, J.A., de Rivera, C., Ethier, J.L., et al. Anxitane tablets reduce fear of human beings in a laboratory model of anxiety-related behaviour. J Vet Behav 2010;5:268-75.</ref>. Benefits are usually seen approximately after 14-30 days of use.
 
  
 
==[[Melatonin]]==
 
==[[Melatonin]]==
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There are reports that melatonin can be helpful in the treatment of anxiety, fear of loud noises<ref>Aronson, L. Animal behaviour case of the month. A dog was evaluated because of extreme fear. J Am Vet Med Assoc 1999;215:22-4.</ref> and problems with sleeping patterns in dogs and cats, however further research is needed to strengthen these claims and their level of effectiveness.
+
Melatonin has been shown to impair the acquisition of fear, but not its expression in rats<ref>Yang, Z., Li, C., Huang, F. (2013) Melatonin impaired acquisition but not expression of contextual fear in rats. Neurosci Lett. 27;552:10-4.</ref>. It has been used to treat seasonal affective disorder, and possibly other conditions such as bipolar disorder in which circadian disturbances are observed<ref>Bhattacharjee, Y., (September 2007). "Psychiatric research. Is internal timing key to mental health?". Science 317 (5844): 1488–90.</ref>. Melatonin may be used to correct sleep disturbance in people, such as multiple sclerosis patients<ref>Adamczyk-Sowa, M., Pierzchala, K., Sowa, P., Mucha, S., Sadowska-Bartosz, I., Adamczyk, J., Hartel, M. (2014) Melatonin Acts as Antioxidant and Improves Sleep in MS Patients. Neurochem Res.</ref>, and may be involved in the phenomenon of worsening clinical signs in Alzheimer's patients in the late afternoon and evening (known as "sundowning")<ref>Volicer, L., Harper, D.G., Manning, B.C., Goldstein, R., Satlin, A. (2001). "Sundowning and circadian rhythms in Alzheimer's disease". Am J Psychiatry 158 (5): 704–11.</ref>. In one study, treatment with melatonin produced improvements in cognition and sleep quality of Alzheimer's patients<ref>Wade, A.G., Farmer, M., Harari, G., Fund, N., Laudon, M., Nir, T., Frydman-Marom, A., Zisapel, N. (2014) Add-on prolonged-release melatonin for cognitive function and sleep in mild to moderate Alzheimer's disease: a 6-month, randomized, placebo-controlled, multicenter trial. Clin Interv Aging. 18;9:947-61.</ref>. This suggests a potential role in canine and feline cognitive dysfunction syndrome. There is a single report of the use of melatonin to treat fear of loud noises in a dog<ref>Aronson, L. Animal behaviour case of the month. A dog was evaluated because of extreme fear. J Am Vet Med Assoc 1999;215:22-4.</ref>.
  
 
==Tryptophan==
 
==Tryptophan==
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Tryptophan is an amino acid which is used to form serotonin. Low levels of tryptophan in the diet are thought to be linked to a fall in serotonin levels. This may have an affect on mood and can be used in alongside conventional pharmacological treatments, however care should be taken to look for any signs of serotonin syndrome. Studies have shown a reduction in behaviours related to stress and a decrease in signs of anxiety in cats supplemented with L-tryptophan<ref>Da Graca Pereira, G., Fragoso, S., L-tryptophan supplementation and its effect of multi-housed cats and working dogs. Proceedings of the 2010 European Veterinary Behaviour Meeting. Hamburg, 2010, 30-35.</ref><ref>Kato, M., Miyaji, K., Ohtani, N., et al. Effects of prescription diet on dealing with stressful situations and performance of anxiety-related behaviours in privately owned anxious dogs. 2012; 7:21-6</ref>Tryptophan can be added to the diet or is available at higher levels in some commercial diets.
+
L-Tryptophan is large neutral amino acid (LNAA) which acts as a precursor for serotonin. L-Tryptophan is actively transported across the blood brain barrier by the L1 carrier<ref>Hawkins, R.A., O’Kane, R.L., Simpson, I.A., Vin ̃az, J.R. (2006) Structure of the Blood–Brain Barrier and Its Role in the Transport of Amino Acids. J. Nutr. 136: 218S–226S.</ref>. It is therefore in competition for this carrier with other LNAAs (such as leucine, valine, methionine, histidine, isoleucine, tyrosine, phenylalanine, and threonine) leading to theories that l-tryptophan supplementation might increase serotoinin availability and therefore alter mood and behaviour. However, l-tryptophan is converted to kynurenine by the enzyme indoleamine 2,3,-dioxygenase (IDO), which is activated by cortisol or pro-inflammatory cytokines<ref>Oxenkrug, G.F. (2010) Tryptophan–Kynurenine Metabolism as a Common Mediator of Genetic and Environmental Impacts in Major Depressive Disorder: The Serotonin Hypothesis Revisited 40 Years Later. Isr J Psychiatry Relat Sci. 47(1): 56–63.</ref>. Activation of IDO leads to depletion of l-tryptophan, and therefore of serotonin, which indicates a significant role in anxiety and depression<ref> Wichers, M.C., Maes, M. (2004) The role of indoleamine 2,3-dioxygenase (IDO) in the pathophysiology of interferon-α-induced depression. J Psychiatry Neurosci. 29(1):11-7.</ref> <ref>Elovainio, M., Hurme, M., Jokela, M., Pulkki-Råback, L., Kivimäki, M., Hintsanen, M., Hintsa, T., Lehtimäki, T., Viikari, J., Raitakari, O.T., Keltikangas-Järvinen, L. (2012) Indoleamine 2,3-dioxygenase activation and depressive symptoms: results from the Young Finns Study.Psychosom Med. 74(7):675-81.</ref>. Through IDO there is therefore an interaction between stress hormones (e.g. cortisol), inflammation and serotonin production. Supplementation of l-tryptophan in stressed individuals may therefore be expected to have variable effects. Supplementation with 5-hydroxytrptophan, which is converted directly to serotonin and bypasses IDO, might be expected to circumvent this problem. However, despite a large number of trials, evidence of the clinical effect of l-tryptophan supplementation in humans is weak, with a Cochrane Report concluding that evidence for effect above placebo was positive but of insufficient quality to be conclusive both for l-tryptophan and 5-hydroxytryptophan <ref>Shaw, K.A., Turner, J., Del Mar, C. (2008) Tryptophan and 5-Hydroxytryptophan for depressions.The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.</ref>.  
  
 +
Dysfunction of the serotonergic neurotransmitter system in dogs has been linked to a number of problems, including aggression<ref>Rosado, B., Garcia-Belenguer, S., Leon, M., et al. Blood concentrations of serotonin, cortisol, and dehydroepiandrosterone in aggressive dogs. Appl Anim Behav Sci 2010; 123:124-30</ref>. However, evidence for the efficacy of [[Effect of Diet on Behaviour#Protein, Tryptophan and Carbohydrate|l-tryptophan supplemented diets]] is as equivocal and unreliable as in humans.
 +
 +
In both dogs and cats fed a l-tryptophan supplement, lower levels of behaviours related to stress and fewer signs of anxiety were seen in one study, but this was not in a peer-reviewed journal<ref>Da Graca Pereira, G., Fragoso, S., L-tryptophan supplementation and its effect of multi-housed cats and working dogs. Proceedings of the 2010 European Veterinary Behaviour Meeting. Hamburg, 2010, 30-35</ref>. In another study, an anxiolytic effect was found, but the diet contained alpha-casozepine as well as l-tryptophan, so any effect cannot be ascribed to amino acid acid supplementation alone<ref name="Kato">Kato, M., Miyaji, K., Ohtani, N., et al. (2012) Effects of prescription diet on dealing with stressful situations and performance of anxiety-related behaviours in privately owned anxious dogs. Journal of Veterinary Behavior: Clinical Applications and Research. 7(1). 21–26.</ref>. A randomised double-blinded, placebo-controlled study showed no effect of an l-tryptophan enriched diet on behaviour or salivary cortisol in dogs, despite measurable increases in plasma levels of the amino acid<ref name="Kato"/><ref>Bosch, G., Beerda, B., Beynen, A.C., van der Borg, J.A.M.,  b, van der Poel, A.F.B., Hendriks, W.H.,  (2009) Dietary tryptophan supplementation in privately owned mildly anxious dogs. Applied Animal Behaviour Science. 121. 197–205</ref>.
  
 
==References==
 
==References==
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*Crane, S.W., Griffin, R.W. and Messent, P.R., 2000. Introduction to commercial pet foods. In: M.S. Hand, C.D. Thatcher, R.L. Remillard and P. Roudebush (eds), Small Animal Clinical Nutrition, 4th edition (Mark Morris Institute, Topeka, Kansas, USA)
 
*Crane, S.W., Griffin, R.W. and Messent, P.R., 2000. Introduction to commercial pet foods. In: M.S. Hand, C.D. Thatcher, R.L. Remillard and P. Roudebush (eds), Small Animal Clinical Nutrition, 4th edition (Mark Morris Institute, Topeka, Kansas, USA)
  
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[[Category:Pharmacological Approach to Problem Behaviour]]
 
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Latest revision as of 09:46, 16 July 2015

Overview

A nutraceutical is defined as "a substance that is produced in purified or extracted form, administered orally to provide agents required for normal body structure and function with the intent of improving the health and well-being of animals" [1]. Nutraceuticals are not regulated in the same way as pharmaceuticals and do not have to undergo the same rigorous testing to be approved. Efficacy has not been properly evaluated for most nutraceuticals.

Alpha-Casozepine

Alpha-casozepine is a trypsin hydrolysate of bovine milk casein with anxiolytic and anti-epileptic effects in laboratory rodent models[2]. It has been shown to have potential anxiolytic effects in cats and dogs in two open label trials[3] [4]. However, only one of these studies included a control group, the inclusion criteria were very broad, the populations small and outcomes were measured using questionnaires that had not been validated or checked for test-retest reliability. More studies are required to confirm clinical efficacy.

L-Theanine

L-Theanine is an amino acid that is found almost exclusively in certain species of tea plant. It has been shown to have positive effects on activation and anxiety symptoms in human patients with schizophrenia[5], and beneficial effects on stress responses and the ability to concentrate during cognitive tasks[6].

L-Theanine has a range of effects, including binding to glutamate receptor subtypes (AMPA, kainate, and NMDA receptors) and blocking of the binding of L-glutamic acid to the glutamate receptors in cortical neurones[7].

In a small open label trial without a control group, l-theanine reduced a range of anxiety signs in cats with behavioural problems[8]. However, this study was not presented as a full article in a peer reviewed journal, and the lack of detail on the methodology or statistical significance of the findings makes the results impossible to interpret. In a study of the effects of l-theanine on fear of human beings in laboratory beagles, treated dogs showed greater human interaction and approach than the placebo control group[9]. Whether this could translate into a clinical effect in dogs with fear rested problems is not known.

Melatonin

Melatonin has been shown to impair the acquisition of fear, but not its expression in rats[10]. It has been used to treat seasonal affective disorder, and possibly other conditions such as bipolar disorder in which circadian disturbances are observed[11]. Melatonin may be used to correct sleep disturbance in people, such as multiple sclerosis patients[12], and may be involved in the phenomenon of worsening clinical signs in Alzheimer's patients in the late afternoon and evening (known as "sundowning")[13]. In one study, treatment with melatonin produced improvements in cognition and sleep quality of Alzheimer's patients[14]. This suggests a potential role in canine and feline cognitive dysfunction syndrome. There is a single report of the use of melatonin to treat fear of loud noises in a dog[15].

Tryptophan

L-Tryptophan is large neutral amino acid (LNAA) which acts as a precursor for serotonin. L-Tryptophan is actively transported across the blood brain barrier by the L1 carrier[16]. It is therefore in competition for this carrier with other LNAAs (such as leucine, valine, methionine, histidine, isoleucine, tyrosine, phenylalanine, and threonine) leading to theories that l-tryptophan supplementation might increase serotoinin availability and therefore alter mood and behaviour. However, l-tryptophan is converted to kynurenine by the enzyme indoleamine 2,3,-dioxygenase (IDO), which is activated by cortisol or pro-inflammatory cytokines[17]. Activation of IDO leads to depletion of l-tryptophan, and therefore of serotonin, which indicates a significant role in anxiety and depression[18] [19]. Through IDO there is therefore an interaction between stress hormones (e.g. cortisol), inflammation and serotonin production. Supplementation of l-tryptophan in stressed individuals may therefore be expected to have variable effects. Supplementation with 5-hydroxytrptophan, which is converted directly to serotonin and bypasses IDO, might be expected to circumvent this problem. However, despite a large number of trials, evidence of the clinical effect of l-tryptophan supplementation in humans is weak, with a Cochrane Report concluding that evidence for effect above placebo was positive but of insufficient quality to be conclusive both for l-tryptophan and 5-hydroxytryptophan [20].

Dysfunction of the serotonergic neurotransmitter system in dogs has been linked to a number of problems, including aggression[21]. However, evidence for the efficacy of l-tryptophan supplemented diets is as equivocal and unreliable as in humans.

In both dogs and cats fed a l-tryptophan supplement, lower levels of behaviours related to stress and fewer signs of anxiety were seen in one study, but this was not in a peer-reviewed journal[22]. In another study, an anxiolytic effect was found, but the diet contained alpha-casozepine as well as l-tryptophan, so any effect cannot be ascribed to amino acid acid supplementation alone[23]. A randomised double-blinded, placebo-controlled study showed no effect of an l-tryptophan enriched diet on behaviour or salivary cortisol in dogs, despite measurable increases in plasma levels of the amino acid[23][24].

References

  1. ↑ Anonymous. Council defines "nutraceutical." Journal of the American Veterinary Medical Association 1996; 209:1986.
  2. ↑ Miclo, L., Perrin, E., Driou, A., Papadopoulos, V., Boujrad, N., Vanderesse, R., Boudier, J.F., Desor, D., Linden, G., Gaillard, J.L. (2001) Characterization of α-casozepine, a tryptic peptide from bovine αs1-casein with benzodiazepine-like activity. FASEB J.15(10):1780-2.
  3. ↑ Beata, C., Beaumont-Graff, E., Diaz, C., et al. Comparison of the effect of alpha-casozepine (Zylkene) versus selegiline hydrochloride on anxiety disorders in dogs. J Vet Behav 2007;2:175-83.
  4. ↑ Beata, C., Beaumont-Graff, E., Coll, V., et al. Effect of alpha-casozepine (Zylkene) on anxiety in cats. J Vet Behav 2007;2:40-6.
  5. ↑ Ritsner, M.S., Miodownik, C., Ratner, Y., Shleifer, T., Mar, M., Pintov, L., Lerner, V.M. (2011) L-Theanine Relieves Positive, Activation, and Anxiety Symptoms in Patients With Schizophrenia and Schizoaffective Disorder: An 8-Week, Randomized, Double-Blind, Placebo-Controlled, 2-Center Study. J Clin Psychiatry. 72(1).
  6. ↑ Kimura, K., Ozeki, M., June, L.R., Ohira, H. (2006) L-Theanine reduces psychological and physiological stress responses. Biological Psychology.
  7. ↑ Kakuda, T., Nozawa, A., Sugimoto, A., Nino, H., (2002). Inhibition by theanine of binding of [3H]AMPA, [3H]Kainate, and [3H]MDL 105,519 to glutamate receptors. Bioscience, Biotechnology, and Biochemistry 66, 2683– 2686.
  8. ↑ Dramard, V., Kern, L., Hofmans, J., et al. Clinical efficacy of l-theanine tablets to reduce anxiety-related emotional disorders in cats: a pilot open-label clinical trial. J Vet Behav 2007;5:85-6.
  9. ↑ Araujo, J.A., de Rivera, C., Ethier, J.L., et al. Anxitane tablets reduce fear of human beings in a laboratory model of anxiety-related behaviour. J Vet Behav 2010;5:268-75.
  10. ↑ Yang, Z., Li, C., Huang, F. (2013) Melatonin impaired acquisition but not expression of contextual fear in rats. Neurosci Lett. 27;552:10-4.
  11. ↑ Bhattacharjee, Y., (September 2007). "Psychiatric research. Is internal timing key to mental health?". Science 317 (5844): 1488–90.
  12. ↑ Adamczyk-Sowa, M., Pierzchala, K., Sowa, P., Mucha, S., Sadowska-Bartosz, I., Adamczyk, J., Hartel, M. (2014) Melatonin Acts as Antioxidant and Improves Sleep in MS Patients. Neurochem Res.
  13. ↑ Volicer, L., Harper, D.G., Manning, B.C., Goldstein, R., Satlin, A. (2001). "Sundowning and circadian rhythms in Alzheimer's disease". Am J Psychiatry 158 (5): 704–11.
  14. ↑ Wade, A.G., Farmer, M., Harari, G., Fund, N., Laudon, M., Nir, T., Frydman-Marom, A., Zisapel, N. (2014) Add-on prolonged-release melatonin for cognitive function and sleep in mild to moderate Alzheimer's disease: a 6-month, randomized, placebo-controlled, multicenter trial. Clin Interv Aging. 18;9:947-61.
  15. ↑ Aronson, L. Animal behaviour case of the month. A dog was evaluated because of extreme fear. J Am Vet Med Assoc 1999;215:22-4.
  16. ↑ Hawkins, R.A., O’Kane, R.L., Simpson, I.A., Vin ̃az, J.R. (2006) Structure of the Blood–Brain Barrier and Its Role in the Transport of Amino Acids. J. Nutr. 136: 218S–226S.
  17. ↑ Oxenkrug, G.F. (2010) Tryptophan–Kynurenine Metabolism as a Common Mediator of Genetic and Environmental Impacts in Major Depressive Disorder: The Serotonin Hypothesis Revisited 40 Years Later. Isr J Psychiatry Relat Sci. 47(1): 56–63.
  18. ↑ Wichers, M.C., Maes, M. (2004) The role of indoleamine 2,3-dioxygenase (IDO) in the pathophysiology of interferon-α-induced depression. J Psychiatry Neurosci. 29(1):11-7.
  19. ↑ Elovainio, M., Hurme, M., Jokela, M., Pulkki-Råback, L., Kivimäki, M., Hintsanen, M., Hintsa, T., Lehtimäki, T., Viikari, J., Raitakari, O.T., Keltikangas-Järvinen, L. (2012) Indoleamine 2,3-dioxygenase activation and depressive symptoms: results from the Young Finns Study.Psychosom Med. 74(7):675-81.
  20. ↑ Shaw, K.A., Turner, J., Del Mar, C. (2008) Tryptophan and 5-Hydroxytryptophan for depressions.The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
  21. ↑ Rosado, B., Garcia-Belenguer, S., Leon, M., et al. Blood concentrations of serotonin, cortisol, and dehydroepiandrosterone in aggressive dogs. Appl Anim Behav Sci 2010; 123:124-30
  22. ↑ Da Graca Pereira, G., Fragoso, S., L-tryptophan supplementation and its effect of multi-housed cats and working dogs. Proceedings of the 2010 European Veterinary Behaviour Meeting. Hamburg, 2010, 30-35
  23. ↑ 23.0 23.1 Kato, M., Miyaji, K., Ohtani, N., et al. (2012) Effects of prescription diet on dealing with stressful situations and performance of anxiety-related behaviours in privately owned anxious dogs. Journal of Veterinary Behavior: Clinical Applications and Research. 7(1). 21–26.
  24. ↑ Bosch, G., Beerda, B., Beynen, A.C., van der Borg, J.A.M., b, van der Poel, A.F.B., Hendriks, W.H., (2009) Dietary tryptophan supplementation in privately owned mildly anxious dogs. Applied Animal Behaviour Science. 121. 197–205
  • Crane, S.W., Griffin, R.W. and Messent, P.R., 2000. Introduction to commercial pet foods. In: M.S. Hand, C.D. Thatcher, R.L. Remillard and P. Roudebush (eds), Small Animal Clinical Nutrition, 4th edition (Mark Morris Institute, Topeka, Kansas, USA)

This article has been expert reviewed by Jon Bowen BVetMed DipAS(CABC) MRCVS.

Date reviewed: July 2, 2014


The creation of this content was made possible by Ceva Santé Animale as part of the feline behaviour project. Ceva logo.jpg


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