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Serotonin-immune interactions in major depression: lower serum tryptophan as a marker of an immune-inflammatory response

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Abstract

Serum total tryptophan and the five competing amino acids (CAA), i.e., valine, leucine, tyrosine, phenylalanine, and isoleucine were determined in 35 major depressed subjects of whom 27 with treatment resistant depression (TRD), and 15 normal controls. Twenty-five of the depressed subjects had repeated measurements of the amino acids both before and after antidepressive treatment. The following immune-inflammatory variables were assayed in the above subjects: serum zinc (Zn), total serum protein (TSP), albumin (Alb), transferrin (Tf), iron (Fe), high-density lipoprotein cholesterol (HDL-C), number of peripheral blood leukocytes, and the CD4+/CD8+ T cell (T-helper/T-suppressor) ratio. Serum tryptophan and the tryptophan/CAA ratio were significantly lower in major depressed subjects than in normal controls. The tryptophan/CAA ratio was significantly lower in patients with TRD than in patients without TRD and normal controls. There were no significant alterations in any of the amino acids upon successful therapy. There were significant correlations between serum tryptophan and serum Zn, TSP, Alb, Tf, Fe, and HDL-C (all positive), and number of leukocytes and the CD4+/CD8+ T-cell ratio (all negative). The tryptophan/CAA ratio was significantly and negatively related to the number of leukocytes and the CD4+/CD8+ T-cell ratio. The results suggest that (a) TRD is characterized by lower availability of serum tryptophan; (b) the availability of tryptophan may remain decreased despite clinical recovery; and (c) the lower availability of tryptophan is probably a marker of the immuneinflammatory response during major depression.

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References

  • American Psychiatric Association (1987) Diagnostic and statistical manual of mental disorders (DSM-III-R) 3rd edn, revised. American Psychiatric Press, Washington, DC

    Google Scholar 

  • Ashcroft GW, Blackburn IM, Eccelston D, Glen AIM, Hartley W, Kinloch NE, Lonergan M, Murray LG, Pullar IA (1973) Changes on recovery in the concentrations of tryptophan and the biogenic amine metabolites in the cerebrospinal fluid of patients with affective illness. Psychol Med 3: 319–325

    PubMed  CAS  Google Scholar 

  • Cohen J (1960) A coefficient of agreement for nominal scales. Educ Psychol Meas 20: 37–46

    Article  Google Scholar 

  • Curzon G (1990) Availability of amino acids to the brain and implication for transmitter amine function. In: Richardson MA (ed) Amino acids in psychiatric disease. American Psychiatric Press, Washington DC, pp 33–48

    Google Scholar 

  • Curzon G, Sarna GS (1984) Tryptophan transport to the brain: newer findings and older ones reconsidered. In: Schlossberger HG, Kochen W, Linzen B, Steinhart H (eds) Progress in tryptophan and serotonin research. Walter de Gruyter, Berlin, pp 145–157

    Google Scholar 

  • Deakin JF, Pennell I, Upadhyaya AJ, Lofthouse R (1990) A neuroendocrine study of 5HT function in depression: evidence for biological mechanisms of endogenous and psychosocial causation. Psychopharmacology 101: 85–92

    Article  PubMed  CAS  Google Scholar 

  • Deger O, Bekaroglu M, Orem A, Orem S, Uluutku N, Soylu C (1996) Polymorphonuclear (PMN) elastase levels in depressive disorders. Biol Psychiatry 39: 357–363

    Article  PubMed  CAS  Google Scholar 

  • Delgado PL, Charney DS, Price LH, Landis H, Heninger GR (1990) Neuroendocrine and behavioral effects of dietary tryptophan restriction in healthy subjects. Life Sci 45: 2323–2332

    Article  Google Scholar 

  • DeMyer MK, Shea PA, Hendric HG, Yoshimura NN (1981) Plasma tryptophan and five other amino acids in depressed and normal subjects. Arch Gen Psychiatry 38: 642–646

    PubMed  CAS  Google Scholar 

  • Dinarello CA (1991) Interleukin-1. In: Thompson AW (ed) The cytokine handbook. Academic Press, London, pp 47–82

    Google Scholar 

  • Fernstrom JD (1984) Tryptophan availability and serotonin synthesis in rat brain: effects of experimental diabetes. In: Schlossberger HG, Kochen W, Linzen B, Steinhart H (eds) Progress in tryptophan and serotonin research. Walter de Gruyter, Berlin, pp 161–172

    Google Scholar 

  • Fuchs D, Moller AA, Reibnegger G, Stockle E, Werner ER, Wachter H (1990) Decreased serum tryptophan in patients with HIV-1 infection correlates with increased serum neopterin and with neurologic/psychiatric symptoms. J AIDS 3: 873–876

    CAS  Google Scholar 

  • Hamilton M (1960) A rating scale for depression. J Neurol Neurosurg Psychiatry 23: 56–61

    Article  PubMed  CAS  Google Scholar 

  • Healy D, Carney PA, Leonard BE (1983) Monoamine-related markers of depression: changes following treatment. J Psychiatry Res 17: 251–260

    Article  CAS  Google Scholar 

  • Heninger GR, Delgado PL, Charney DS, Price LH, Aghajanian GK (1992) Tryptophan-deficient diet and amino acid drink deplete plasma tryptophan and induce a relapse of depression in susceptible patients. J Chem Neuroanat 5: 347–348

    Article  PubMed  CAS  Google Scholar 

  • Heyes MP, Brew BJ, Saito K, Quearry BJ, Price RW, Lee K, Bhalla RB, Der M, Markey SP (1992) Inter-relationships between quinolinic acid, neuroactive kynurenines, neopterin and beta 2-microglobulin in cerebrospinal fluid and serum of HIV-infected patients. J Neuroimmunol 40: 71–80

    Article  PubMed  CAS  Google Scholar 

  • Hirano T (1991) Interleukin-6. In: Thomson AW (ed) The cytokine handbook. Academic Press, London, pp 169–190

    Google Scholar 

  • Holmes EW, Russell PM, Kinzler GJ, Reckard CR, Flanigan RC, Thompson KD, Bermes EW (1992) Oxidative tryptophan metabolism in renal allograft recipients: increased kynurenine synthesis is associated with inflammation and OKT3 therapy. Cytokine 4: 205–213

    Article  PubMed  CAS  Google Scholar 

  • Lee WH, Woodward BD (1996) The CD4/CD8 ratio in the blood does not reflect the response of this index in secondary lymphoid organs of wealing mice in models of protein-energy malnutrition known to depress thymus-dependent immunity. J Nutr 126: 849–859

    PubMed  CAS  Google Scholar 

  • Lucca A, Lucini V, Catalano M, Alfano M, Smeraldi E (1994) Plasma tryptophan to large neutral amino acids ratio and therapeutic response to a selective serotonin uptake inhibitor. Neuropsychobiology 29: 108–111

    Article  PubMed  CAS  Google Scholar 

  • McMenamy RH, Oncley JL (1958) The specific binding of L-tryptophan to serum albumin. J Biol Chem 233: 1436–1440

    PubMed  CAS  Google Scholar 

  • Maes M (1995) Evidence for an immune response in major depression: a review and hypothesis. Progr Psychopharmacol Biol Psychiatry 19: 11–38

    Article  CAS  Google Scholar 

  • Maes M, Meltzer HYM (1995) The serotonin hypothesis of major depression. In: Bloom F, Kupher D (eds) Pschopharmacology: the fourth generation of progress. Raven Press, New York, pp 933–944

    Google Scholar 

  • Maes M, Schotte C, Scharpé S, Martin M, Blockx P (1990) The effects of glucocorticoids on the availability of L-trytophan and tyrosine in the plasma of depressed patients. J Affect Disord 18: 121–127

    Article  PubMed  CAS  Google Scholar 

  • Maes M, Bosmans E, Meltzer HY, Scharpé S, Suy E (1993 a) Interleukin-1β: a putative mediator of HPA-axis hyperactivity in major depression? Am J Psychiatry 150: 1189–1193

    PubMed  CAS  Google Scholar 

  • Maes M, Meltzer HY, Scharpe S, Bosmans E, Suy E, Minner B, Meester I de, Calabrese J, Vandervorst C, Raus J, Cosyns P (1993 b) Relationships between lower plasma L-tryptophan levels and immune variables in depression. Psychiatr Res 49: 11–27

    Article  CAS  Google Scholar 

  • Maes M, Langhe J de, Scharpé S, Meltzer HY, Cosyns P, Suy E, Bosmans E (1994 a) Haptoglobin phenotypes and gene frequencies in unipolar major depression. Am J Psychiatry 151: 112–116

    PubMed  CAS  Google Scholar 

  • Maes M, Meltzer HY, Cosyns P, Schotte C (1994 b) Evidence for the existence of major depression with and without anxiety features. Psychopathology 27: 1–13

    Article  PubMed  CAS  Google Scholar 

  • Maes M, Scharpé S, D’Haese W, Broe M de, Cosyns P (1994 c) Hypozincaemia in depression. J Affect Disord 31: 135–140

    Article  PubMed  CAS  Google Scholar 

  • Maes M, Scharpé S, Meltzer HY, Okayli G, Bosmans E, D’Hondt P, Vanden Bossche B, Cosyns P (1994 d) Increased neopterin and interferon γ secretion and lower availability of L-tryptophan in major depression: further evidence for activation of cell-mediated immunity. Psychiatr Res 54: 143–160

    Article  CAS  Google Scholar 

  • Maes M, Meltzer HY, Bosmans E, Bergmans R, Vandoolaeghe E, Ranjan R, Desnyder R (1995 a) Increased plasma concentrations of interleukin-6, soluble interleukin-6, soluble interleukin-2 and transferrin receptor in major depression. J Affect Disord 34: 301–309

    Article  PubMed  CAS  Google Scholar 

  • Maes M, Smith R, Scharpé S (1995 b) The monocyte-T lymphocyte hypothesis of major depression. Invited editorial. Psychoneuroendocrinology 20: 111–116

    Article  PubMed  CAS  Google Scholar 

  • Maes M, Vandevyvere J, Vandoolaeghe E, Bril T, Vandoolaeghe E, Neels H (1996 a) Disorders in iron metabolism and the erythron in major depression: further evidence for an inflammatory response. J Affect Disord 40: 23–33

    Article  PubMed  CAS  Google Scholar 

  • Maes M, Wauters A, Verkerk R, Neels H, Van Gastel A, Cosyns P, Scharpé S, Desnyder R (1996 b) Lower L-tryptophan availability in depression: a marker of a more generalized disorder in protein metabolism. Neuropsychopharmacol 15: 243–251

    Article  CAS  Google Scholar 

  • Marten NW, Burke EJ, Hayden JM, Straus DS (1994) Effect of amino acid limitation on the expression of 19 genes in rat hepatoma cells. FASEB J 8: 538–544

    PubMed  CAS  Google Scholar 

  • Moir ATB, Eccleston D (1968) The effect of precursor loading in the cerebral metabolism of 5-hydroxyindoles. J Neurochem 15: 1093–1108

    Article  PubMed  CAS  Google Scholar 

  • Moldawer LL, Georgieff M, Lundholm K (1987) Interleukin-1, tumour necrosis factor-alpha (cachectin) and the pathogenesis of cancer cachexia. Clin Physiol 7: 263–274

    Article  PubMed  CAS  Google Scholar 

  • Møller SE (1985) Tryptophan to competing amino acids ratio in depressive disorder: relation to efficacy of antidepressive treatments. Acta Psychiatr Scand (Suppl) 72: 1–30

    Article  Google Scholar 

  • Møller SE, Beurs P de, Timmerman L, Tan BK, Leynse-Ybema HJ, Cohen Stuart MH, Hopfner Petersen HE (1986) Plasma tryptophan and tyrosine ratios to competing amino acids in relation to antidepressant response to citalopram and maprotiline: a preliminary study. Psychopharmacology 88: 96–100

    Article  PubMed  Google Scholar 

  • Muller N (1995) Psychoneuroimtnunology: implications for the drug treatment of psychiatric disorders. CNS Drugs 4: 125–140

    Article  Google Scholar 

  • Pardridge WM (1979) Tryptophan transport through the bloodbrain barrier: in vivo measurement of free and albumin-bound amino acid. Life Sci 25: 1519–1528

    Article  PubMed  CAS  Google Scholar 

  • Perez-Cruet J, Chase TN, Murphy DL (1974) Dietary regulation of brain tryptophan metabolism by plasma ratio of free tryptophan and neutral amino acids in humans. Nature 248: 693–695

    Article  PubMed  CAS  Google Scholar 

  • Russ MJ, Ackerman SH, Banay-Schwartz M, Shindledecker RD, Smith GP (1990) Plasma tryptophan to large neutral amino acid ratios in depressed and normal subjects. J Affect Disord 19: 9–14

    Article  PubMed  CAS  Google Scholar 

  • Sainio E-L, Pulkki K, Young SN (1996) L-tryptophan: biochemical, nutritional and pharmacological aspects. Amino Acids 10: 21–47

    Article  CAS  Google Scholar 

  • Seidel A, Arolt V, Hunstiger M, Rink L, Behnisch A, Kirchner H (1996 a) Major depressive disorder is associated with elevated monocyte counts. Acta Psychiatr Scand 94: 198–204

    Article  PubMed  CAS  Google Scholar 

  • Seidel A, Arolt V, Hunstiger M, Rink L, Behnisch A, Kirchner H (1996 b) Increased CD56+ natural killer cells and related cytokines in major depression. Clin Immunol Immunopathol 78: 83–85

    Article  PubMed  CAS  Google Scholar 

  • Sluzewska A, Nowakowsky E, Gryska K, Machkiewicz A (1994) Haptoglobin levels in a chronic mild stress model of depression in rats before and after treatment. Eur Neuropharmacol P-1-18: 302

    Article  Google Scholar 

  • Sluzewska A, Rybakowski JK, Laciak M, Mackiewicz A, Sobieska M, Wiktorowiz K (1995) Interleukin-6 serum levels in depressed patients before and after treatment with fluoxetine. Ann NY Acad Sci 762: 474–476

    Article  PubMed  CAS  Google Scholar 

  • Sluzewska A, Rybakowski J, Sobieska M, Wiktorowicz K (1996) Concentration and microheterogeneity glycophorms of α1-acid glycoprotein in major depressive disorder. J Affect Disord 39: 149–155

    Article  PubMed  CAS  Google Scholar 

  • Smith SE, Pihl RO, Young SW, Ervin FR (1987) A test of possible cognitive and environmental influences on the mood lowering effect of tryptophan depletion in normal males. Psychopharmacology 91: 451–457

    Article  PubMed  CAS  Google Scholar 

  • Smith QR, Fukui S, Robinson P, Rapaport SI (1990) Influence of cerebral blood flow on tryptophan uptake into brain. In: Lubec G, Rosenthal GA (eds) Amino acids: chemistry, biology and medicine. Escom, Leiden, pp 364–369

    Google Scholar 

  • Song C, Leonard BE (1994) An acute phase protein response in the olfactory bulbectomized rat: effect of sertraline treatment. Med Sci Res 22: 313–314

    CAS  Google Scholar 

  • Song C, Dinan T, Leonard BE (1994) Changes in immunoglobublin, complement and acute phase protein levels in the depressed patients and normal controls. J Affect Disord 30: 283–288

    Article  PubMed  CAS  Google Scholar 

  • Spitzer RL, Williams JBW, Gibbon M, First MB (1990) Structured Clinical Interview according to DSM-III-R. American Press, New York

    Google Scholar 

  • Takikawa O, Yoshida R, Yasui H, Hayaishi O (1984) The relationship between plasma kynurenine and indoleamine 2,3-dioxygenase activity in the extrahepatic tissues. In: Schlossberger HG, Kochen W, Linzen B, Steinhart H (eds) Progress in tryptophan and serotonin research. Walter de Gruyter, Berlin, pp 517–520

    Google Scholar 

  • Thase ME, Rush AJ (1995) Treatment-resistant depression. In: Bloom FE, Kupfer DJ (eds) Psychopharmacology: the fourth generation of progress. Raven Press, New York, pp 1081–1098

    Google Scholar 

  • Walser M, Hill SB (1993) Free and protein-bound tryptophan in serum of untreated patients with chronic renal failure. Kidney Int 44: 1366–1371

    Article  PubMed  CAS  Google Scholar 

  • Young SN, Smith SE, Pihl R, Ervin FR (1985) Tryptophan depletion causes a rapid lowering of mood in normal males. Psychopharmacology 87: 173–177

    Article  PubMed  CAS  Google Scholar 

  • Yuwiler A, Oldendorf WH, Geller E et al. (1977) The effect of albumin binding and amino acid composition on tryptophan uptake into the brain. J Neurochem 28: 1015–1023

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Clinical Research Center for Mental Health (CRC-MH), University Department of Psychiatry, 267 Lange Beeldekensstraat, AZ Stuivenberg, B-2060, Antwerp, Belgium

    Eric Vandoolaeghe & Fran Van Hunsel

  2. Department of Psychiatry, Vanderbilt University, TN 37232-3697, Nashville, Tennessee, USA

    Michael Maes

  3. Department of Medical Biochemistry, University of Antwerp, B-2650, Edegem, Belgium

    Robert Verkerk & Simon Scharpé

  4. Laboratory of Clinical Biochemistry, Middelheim Hospital, B-2000, Antwerp, Belgium

    Hugo Neels, Annick Wauters & Paul Demedts

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  1. Michael Maes
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  2. Robert Verkerk
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  3. Eric Vandoolaeghe
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Maes, M., Verkerk, R., Vandoolaeghe, E. et al. Serotonin-immune interactions in major depression: lower serum tryptophan as a marker of an immune-inflammatory response. Eur Arch Psychiatry Clin Nuerosci 247, 154–161 (1997). https://doi.org/10.1007/BF03033069

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  • DOI: https://doi.org/10.1007/BF03033069

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