Skip to main content Accessibility help

Tryptophan metabolism in depressive illness

  • Alec Coppen (a1), Benjamin W. L. Brooksbank (a1), Eric Eccleston (a1), Malcolm Peet (a1) and Stuart G. White (a1)...


[Methylene-14C]-L-tryptophan was administered intravenously to five patients suffering from severe depression before and after clinical recovery, and to six control subjects; all subjects were tested while on a standard diet. [14C]-5-Hydroxyindoleacetic acid and [14C]-indoleacetic acid were isolated from urine during the following 48 hours and purified to constant specific radioactivity (SA). From the SA and the determination of the total excretion of the two acids their percentage conversion from labelled tryptophan was estimated. There was no consistent difference found, in patients before and after recovery, or between patients and controls, in the conversion of tryptophan to these indole acids. In another series of 11 depressive patients and 11 controls, plasma total (acid-soluble) tryptophan was measured at frequent intervals up to three hours after intravenous administration of a loading dose (1 g) of L-tryptophan. The height of the curves of plasma tryptophan throughout the three hour period was greater than in the depressive patients, even after they had recovered, than in the controls. It is concluded that the apparent volume of distribution of tryptophan is reduced in depressive individuals. This is consistent with other findings of increased protein-binding of plasma tryptophan and reduced CSF tryptophan levels in depressive patients.



Hide All
Armstrong, M. D., Shaw, K. N. F., Gortatowski, M. J., and Singer, H. (1958). The indole acids of human urine. Paper chromatography of indole acids. Journal of Biological Chemistry, 232, 1730.
Ashcroft, G. W., Crawford, T. B. B., Eccleston, D., Sharman, D. F., MacDougall, E. J., Stanton, J. B., and Binns, J. K. (1966). 5-Hydroxyindole compounds in the cerebrospinal fluid of patients with psychiatric or neurological diseases. Lancet, 2, 10491052.
Ayuso Gutierrez, J. L., and López-Ibor Aliño, J. J. (1971). Tryptophan and an MAOI (nialamide) in the treatment of depression. International Pharmacopsychiatry, 6, 9297.
Benassi, C. A., Benassi, P., Allegri, G., and Ballarin, P. (1961). Tryptophan metabolism in schizophrenic patients. Journal of Neurochemistry, 7, 264270.
Berkowitz, B. A., and Spector, S. (1971). The effect of caffeine and theophylline on the disposition of brain serotonin in the rat. European Journal of Pharmacology, 16, 322325.
Bourne, H. R., Bunney, W. E. Jr., Colburn, R. W., Davis, J. M., Davis, J. N., Shaw, D. M., and Coppen, A. J. (1968). Noradrenaline, 5-hydroxytryptamine, and 5-hydroxyin-doleacetic acid in hindbrains of suicidal patients. Lancet, 2, 805808.
Bowers, M. B. Jr. (1972). Clinical measurements of central dopamine and 5-hydroxytryptamine metabolism: reliability and interpretation of cerebrospinal fluid acid monoamine metabolite measures. Neuropharmacology, 11, 101111.
Broadhurst, A. D. (1970). 1-Tryptophan versus E.C.T. Lancet, 1, 13921393.
Burgermeister, J.-J., Dick, P., Garonne, G., Guggisberg, M., and Tissol, R. (1963). Excrétion urinaire de l'acide 5-hydroxyindolacétique (5-HIAA) chez 150 malades atteints de syndrome dépressif et d'agitation maniaque. (Ses modifications par surcharge de 5-hydroxytryptophane, et par la thérapeutique chez les dépressifs). Presse Médicale, 71, 11161118.
Carroll, B. J. (1971). Monoamine precursors in the treatment of depression. Clinical Pharmacology and Therapeutics, 12, 743761.
Cazzullo, C. L., Mangoni, A., and Mascherpa, G. (1966). Tryptophan metabolism in affective psychoses. British Journal of Psychiatry, 112, 157162.
Chiancone, F. M., and Bonollo, L. (1969). Fumo di tobacco, nicotina e metabolismo del triptofano. Acta Vitamino-logica et Enzymologica, 23, 103110.
Contractor, S. F. (1966). A rapid quantitative method for the estimation of 5-hydroxyindoleacetic acid in human urine. Biochemical Pharmacology, 15, 17011706.
Coppen, A., Brooksbank, B. W. L., and Peet, M. (1972). Tryptophan concentration in the cerebrospinal fluid of depressive patients. Lancet, 1, 1393.
Coppen, A., Eccleston, E. G., and Peet, M. (1972). Total and free tryptophan concentration in the plasma of depressive patients. Lancet, 2, 14151416.
Coppen, A., Eccleston, E. G., and Peet, M. (1973). Total and free tryptophan concentration in the plasma of depressive patients. Lancet, 2, 6063.
Coppen, A., Prange, A. J. Jr., Whybrow, P. C., and Noguera, R. (1972). Abnormalities of indoleamines in affective disorders. Archives of General Psychiatry, 26, 474478.
Coppen, A., Shaw, D. M., and Farrell, J. P. (1963). Potentiation of the antidepressive effect of a monoamine-oxidase inhibitor by tryptophan. Lancet, 1, 7981.
Coppen, A., Shaw, D. M., Herzberg, B., and Maggs, R. (1967). Tryptophan in the treatment of depression. Lancet, 2, 11781180.
Coppen, A., Shaw, D. M., and Malleson, A. (1965a). Changes in 5-hydroxytryptophan metabolism in depression. British Journal of Psychiatry, 111, 105107.
Coppen, A., Shaw, D. M., Malleson, A., Eccleston, E., and Gundy, G. (1965b). Tryptamine metabolism in depression. British Journal of Psychiatry, 111, 993998.
Coppen, A., Whybrow, P. C., Noguera, R., Maggs, R., and Prange, A. J. Jr. (1972). The comparative antidepressant value of L-tryptophan and imipramine with and without attempted potentiation by liothyronine. Archives of General Psychiatry, 26, 234241.
Curzon, G. (1969). Tryptophan pyrrolase—a biochemical factor in depressive illness? British Journal of Psychiatry, 115, 13671374.
Curzon, G., and Bridges, P. K. (1970). Tryptophan metabolism in depression. Journal of Neurology, Neurosurgery and Psychiatry, 33, 698704.
Curzon, G., Friedel, J., and Knott, P. J. (1973). The effect of fatty acids on the binding of tryptophan to plasma protein. Nature, 242, 198200.
Dencker, S. J., Malm, U., Roos, B.-E., and Werdinius, B. (1966). Acid monoamine metabolites in cerebrospinal fluid in mental depression and mania. Journal of Neurochemistry, 13, 15451548.
Denckla, W. D., and Dewey, H. K. (1967). The determination of tryptophan in plasma, liver, and urine. Journal of Laboratory and Clinical Medicine, 69, 160169.
Dunner, D. L., and Goodwin, F. K. (1972). Effect of L-tryptophan on brain serotonin metabolism in depressed patients. Archives of General Psychiatry, 26, 364366.
Eccleston, D., Ashcroft, G. W., Moir, A. T. B., Parker-Rhodes, A., Lutz, W., and O'Mahoney, D. P. (1968). A comparison of 5-hydroxyindoles in various regions of dog brain and cerebrospinal fluid. Journal of Neurochemistry, 15, 947957.
Erspamer, V. (1966). Occurrence of indolealkylamines in nature. In Handbook of Experimental Pharmacology, Vol. 19, 5-Hydroxytryptamine and Related Indolealkylamines, pp. 132181. Edited by Eichler, O. and Farah, A.. Springer: Berlin.
Fernstrom, J. D., and Wurtman, R. J. (1971). Brain serotonin content: physiological dependence on plasma trypto-phan levels. Science, 173, 149152.
Fragoso Mendes, J. M., and Lopes do Rosario, J. A. (1959). Signification et importance de la sérotonine en psychiatrie. Encéphale, 48, 501509.
Glassman, A. H., and Platman, S. R. (1969). Potentiation of a monoamine oxidase inhibitor by tryptophan. Journal of Psychiatric Research, 7, 8388.
Grahame-Smith, D. G. (1971). Studies in vivo on the relationship between brain tryptophan, brain 5-HT synthesis and hyperactivity in rats treated with a monoamine oxidase inhibitor and L-tryptophan. Journal of Neurochemistry, 18, 10531066.
Granowitz, E., and Pletscher, A. (1957). Die diagnostische Bedeutung der 5-Hydroxyindolessigsäure-Ausscheidung im Urin. Helvetica Medica Acta, 24, 2126.
Grizzle, J. E., and Allen, D. M. (1969). Analysis of growth and dose response curves. Biometrics, 25, 357381.
Hagen, P. B., and Cohen, L. H. (1966). Biosynthesis of indolealkylamines. Physiological release and transport of 5-hydroxytryptamine. In Handbook of Experimental Pharmacology, Vol. 19, 5-Hydroxytryptamine and Related Indolealkylamines, pp. 182211. Edited by Eichler, O. and Farah, A.. Springer: Berlin.
Jepson, J. B. (1969). Indoles and related Ehrlich reactors. In Chromatographic and Electrophoretic Techniques, Vol. 1, Chromatography, pp. 243273. Edited by Smith, I.. 3rd edn.Heinemann: London.
Jéquier, E. (1968). Tryptophan hydroxylation in phenyl-ketonuria. In Advances in Pharmacology, Vol. 6, Part B, pp. 169170. Edited by Garattini, S.. Academic Press: New York.
Jéquier, E., Lovenberg, W., and Sjoerdsma, A. (1967). Tryptophan hydroxylase inhibition: the mechanism by which p−chlorophenylalanine depletes rat brain serotonin. Molecular Pharmacology, 3, 274278.
Karoum, F., Anah, C. O., Ruthven, C. R. J., and Sandler, M. (1969). Further observations on the gas-chromatographic measurement of urinary phenolic and indolic metabolites. Clinica Chimica Acta, 24, 341348.
Knott, P. J., and Curzon, G. (1972). Free tryptophan in plasma and brain tryptophan metabolism. Nature, 239, 452453.
Knox, W. E. (1963). The adaptive control of tryptophan and tyrosine metabolism in animals. Transactions of the New York Academy of Sciences, Series 2, 25, 503512.
Knox, W. E., and Auerbach, V. H. (1955). The hormonal control of tryptophan peroxidase in the rat. Journal of Biological Chemistry, 214, 307313.
Knox, W. E., and Mehler, A. H. (1951). The adaptive increase of the tryptophan peroxidase-oxidase system of liver. Science, 113, 237238.
Korf, J., and Valkenburgh-Sikkema, T. (1969). Fluorimetric determination of 5-hydroxyindoleacetic acid in human urine and cerebrospinal fluid. Clinica Chimica Acta, 26, 301306.
Korf, J., Praag, H. M. Van, and Sebens, J. B. (1972). Serum tryptophan decreased, brain tryptophan increased and brain serotonin synthesis unchanged after probenecid loading. Brain Research, 42, 239242.
Lapin, I. P., and Oxenkrug, G. F. (1969). Intensification of the central serotoninergic processes as a possible determinant of the thymoleptic effect. Lancet, 1, 132136.
Leklem, J. E. (1971). Quantitative aspects of tryptophan metabolism in humans and other species: a review. American Journal of Clinical Nutrition, 24, 659672.
Lipsett, D., Madras, B. K., Wurtman, R. J., and Munro, H. N. (1973). Serum tryptophan level after carbohydrate ingestion: selective decline in non-albumin-bound tryptophan coincident with reduction in serum free fatty acids. Life Sciences, 12, Part 2, 5764.
McMenamy, R. H., and Oncley, J. L. (1958). The specific binding of L-tryptophan to serum albumin. Journal of Biological Chemistry, 233, 14361447.
Maickel, R. P., Cox, R. H. Jr., Saillant, J., and Miller, F. P. (1968). A method for the determination of serotonin and norepinephrine in discrete areas of rat brain. International Journal of Neuropharmacology, 7, 275281.
Medical Research Council (1965). Clinical trial of the treatment of depressive illness. Report by its Clinical Psychiatry Committee. British Medical Journal, 1, 881886.
Mendels, J., Frazer, A., Fitzgerald, R. G., Ramsey, T. A., and Stokes, J. W. (1972). Biogenic amine metabolites in cerebrospinal fluid of depressed and manic patients. Science, 175, 13801382.
Michael, A. F., Drummond, K. N., Doeden, D., Anderson, J. A., and Good, R. A. (1964). Tryptophan metabolism in man. Journal of Clinical Investigation, 43, 17301746.
Milne, M. D., Crawford, M. A., Girão, C. B., and Loughridge, L. W. (1960). The excretion of indolylacetic acid and related indolic acids in man and the rat. Clinical Science, 19, 165179.
Moir, A. T. B. (1971). Interaction in the cerebral metabolism of the biogenic amines: effect of intravenous infusion of L-tryptophan on tryptophan and tyrosine in brain and body fluids. British Journal of Pharmacology, 43, 724731.
Moir, A. T. B., and Eccleston, D. (1968). The effects of precursor loading in the cerebral metabolism of 5-hydroxy-indoles. Journal of Neurochemistry, 15, 10931108.
Pare, C. M. B. (1963). Potentiation of monoamine-oxidase inhibitors by tryptophan. Lancet, 2, 527528.
Pare, C. M. B., and Sandler, M. (1959). A clinical and biochemical study of a trial of iproniazid in the treatment of depression. Journal of Neurology, Neurosurgery and Psychiatry, 22, 247251.
Pare, C. M. B., Yeung, D. P. H., Price, K., and Stacey, R. S. (1969). 5-Hydroxytryptamine, noradrenaline, and dopa-mine in brainstem, hypothalamus, and caudate nucleus of controls and patients committing suicide by coal-gas poisoning. Lancet, 2, 133135.
Praag, H. M. Van, Korf, J., and Puite, J. (1970). 5-Hydroxy-indoleacetic acid levels in the cerebrospinal fluid of depressive patients treated with probenecid. Nature, 225, 12591260.
Robins, E., Robins, J. M., Croninger, A. B., Moses, S. G., Spencer, S. J., and Hudgens, R. W. (1967). The low level of 5-hydroxytryptophan decarboxylase in human brain. Biochemical Medicine, 1, 240251.
Roos, B.-E., and Sjöström, R. (1969). 5-Hydroxyindoleacetic acid (and homovanillic acid) levels in the cerebrospinal fluid after probenecid application in patients with manic-depressive psychosis. Pharmacologia Clinica, 1, 153155.
Rubin, R. T. (1967). Adrenal cortical activity changes in manic-depressive illness. Influence on intermediary metabolism of tryptophan. Archines of General Psychiatry, 17, 671679.
Schievelbein, H., Surberg, U., and Werle, E. (1962). Erhöhung der Ausscheidung von 5-Hydroxyindolessigsäure bei Rauchern. Klinische Wochenschrift, 40, 5253.
Shaw, D. M., Camps, F. E., and Eccleston, E. G. (1967). 5-Hydroxytryptamine in the hind-brain of depressive suicides. British Journal of Psychiatry, 113, 14071411.
Sprince, H., Parker, C. M., Jameson, D., and Josephs, J. A. Jr. (1969). Experimental alteration of tryptophan metabolism by methionine: neuropharmacologic implications. International Journal of Neuropharmacology, 8, 615626.
Ström-Olsen, R., and Weil-Malherbe, H. (1958). Humoral changes in manic-depressive psychosis with particular reference to the excretion of catechol amines in urine. Journal of Mental Science, 104, 696704.
Tagliamonte, A., Biggio, G., and Gessa, G. L. (1971). Possible role of “free” plasma tryptophan in controlling brain tryptophan concentrations. Rivista di Farmacologia e Terapia, 11, 251255.
Tagliamonte, A., Tagliamonte, P., Perez-Cruet, J., and Gessa, G. L. (1971a). Increase of brain tryptophan caused by drugs which stimulate serotonin synthesis. Nature New Biology, 229, 125126.
Tagliamonte, A., Tagliamonte, P., Perez-Cruet, J., Stern, S., and Gessa, G. L. (1971b). Effect of psychotropic drugs on tryptophan concentration in the rat brain. Journal of Pharmacology and Experimental Therapeutics, 177, 475480.
Weissbach, H., King, W., Sjoerdsma, A., and Udenfriend, S. (1959). Formation of indole-3-acetic acid and tryptamine in animals. A method for estimation of indole-3-acetic acid in tissues. Journal of Biological Chemistry, 234, 8186.


Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed