Abstract
The accumulation of 14C-5-hydroxytryptamine (14C-5-HT) in platelet-rich plasma (PRP) and the concentration of 5-hydroxytryptamine (5-HT) in whole blood of patients treated with the antidepressant agents zimelidine (2×100 mg. daily), desipramine (2×75 mg daily), and clomipramine (2×75 mg daily) were examined before and during the treatment. Clomipramine and zimelidine markedly reduced the accumulation of 14C-5-HT and the concentration of 5-HT in the blood. Desipramine had a weaker, but significant effect. Added to the PRP in vitro clomipramine was ten-times more potent than norzimelidine, the active metabolite of zimelidine, and 60- and 300-times more active than desipramine and zimelidine, respectively in inhibiting the accumulation of 14C-5-HT. Analysis of plasma concentrations of zimelidine and norzimelidine showed that the decreased blood 5-HT and the inhibition of 14C-5-HT accumulation in platelets was mainly produced by norzimelidine. The inhibition of the 14C-5-HT accumulation and the decrease in blood 5-HT by desipramine were significantly correlated to the log plasma concentration of desipramine. It is concluded that the decrease in blood 5-HT caused by these agents is due to the inhibition of 5-HT uptake in platelets. The half-life of the decrease in blood 5-HT after clompramine and zimelidine was about 5 days. The return to normal 5-HT level after withdrawal of the drugs was 14 days or longer. These observations might indicate that only the newly formed platelets can accumulate 5-HT.
Similar content being viewed by others
References
Åberg, A., Holmberg, G.: Preliminary clinical test of zimelidine (H102/09), a new 5-HT uptake inhibitor. Acta Psychiatr. Scand. 59:45–58 (1979)
Åsberg, M., Ringberger, V.-A., Sjöqvist, F., Thoren, P., Traskman, L., Tuck, J. R.: Monoamine metabolites in cerebrospinal fluid and serotonin uptake inhibition during treatment with chloroimipramine. Clin. Pharmacol. Ther. 21, 201–207 (1977)
Asheroft, G. W., Crawford, T. B. B., Binns, J. K., MacDougall, E. J.: Estimation of 5-hydroxytryptamine in human blood. Clin. Chim. Acta. 9, 364–369 (1964)
Brown, D., Scott, D. H. T., Scott, D. B., Meyer, M., Westerlund, D., Lundström, J.: Systemic availability of zimelidine and norzimelidine in human volunteers. Eur. J. Clin. Pharmacol. (in press, 1979)
Coppen, A., Ramarao, V. A., Swade, C., Wood, K.: Zimelidine: A therapeutic and pharmacokinetic study in depression. Psychopharmacology 63, 199–202 (1979)
Costa, J. L., Murphy, D. L.: Platet 5-HT uptake and release stopped rapidly by formaldehyde. Nature 255, 407–408 (1975)
Dawling, S., Braithwaite, R. A.: Simplified method for monitoring tricyclic antidepressant therapy using gas-liquid chromatography with nitrogen detection. J. Chromatogr. 146, 449–456 (1978)
Ebbe, S.: Origin, production and life span of blood platelets. In: The circulating platelet, S. A. Johnson, ed., pp. 19–43. New York: Academic 1971
Lemberger, L., Rowe, H., Carmichael, R., Crabtree, R., Horng, J. S., Bymaster, F., Wong, D.: Fluoxetine, a selective serotonin uptake inhibitor. Clin. Pharmacol. Ther. 23, 421–429 (1978)
Gayford, J. J., Parker, A. L., Phillips, E. M., Rowsell, A. R.: Whole blood 5-hydroxytryptamine during treatment of endogenous depressive illness. Br. J. Psychiatry 122, 597–598 (1973)
Lingjaerde, O.: Effect of doxepin on uptake and efflux of serotonin in human blood platelets in vitro. Psychopharmacology 47 183–186 (1976)
Marshall, E. F., Stirling, G. S., Tait, A. C., Todrick, A.: The effect of iproniazid and imipramine on the blood platelet 5-hydroxytryptamine level in man. Br. J. Pharmacol. 15, 35–41 (1960)
Montgomery, S., McAuley, R., Rani, G., Montgomery, D.: A double blind comparison of antidepressant efficacy of zimelidine, a new 5-HT uptake inhibitor, with amitriptyline. Seventh International Congress of Pharmacology, Paris, p. 249 (Abstracts). Paris: Pergamon 1978
Oxenkrug, G. F., Prakhje, I., Mikhalenko, I. N.: Disturbed circadian rhythm of 5-HT uptake by blood platelets in depressive psychosis. Act. Nerv. Super. 20, 66–67 (1978)
Pletscher, A.: Metabolism, transfer and storage of 5-hydroxytryptamine in blood platelets. Br. J. Pharmacol. Chemother. 32, 1–16 (1968)
Ross, S. B., Renyi, A. L.: Inhibition of uptake of tritiated catecholamines by antidepresant and related agents. Eur. J. Pharmacol. 2, 181–186 (1967)
Ross, S. B., Renyi, A. L.: Inhibition of the uptake of tritiated 5-hydroxytryptamine in brain tissue. Eur. J. Pharmacol. 7, 270–277 (1969)
Ross, S. B., Renyi, A. L.: Tricyclic antidepressants. Effects of oral administration on the uptake of 3H-noradrenaline and 14C-5-hydroxytryptamine in slices from the midbrain-hypothalamus regions of the rat brain. Acta Pharmacol. Toxicol. (Kbh.) 36, 395–408 (1975)
Ross, S. B., Jansa, S., Wetterber, L., Fyrö, B., Hellner, B.: Decreased blood level of 5-hydroxytryptamine by inhibitors of the membranal 5-hydroxytryptamine uptake. Life Sci. 19, 205–210 (1976a)
Ross, S. B., Ögren, S.-O., Renyi, A. L.: Z-Dimethylamino-1-(4-bromophenyl)-1-(3-pyridyl)propene (H 102/09), a new selective inhibitor of the neuronal 5-hydroxytryptamine uptake. Acta Pharmacol. Toxicol. (Kbh.) 34, 152–166 (1976b)
Ross, S. B., Renyi, A. L.: Inhibition of the neuronal uptake of 5-hydroxytryptamine and noradrenaline in rat brain by (Z)- and (E)-3-(4-bromophenyl) N,N-dimethyl-3-(3-pyridyl)allylamines and their secondary analogous. Neuropharmacology 16:57–63 (1977)
Shulman, N. R., Watkins, S. P., Jr., Itscoitz, S. B., Student, A. B.: Evidence that the spleen retains the youngest and hemostatically most effective platelets. Trans. Assoc. Am. Physicians 81, 302–313 (1968)
Siwers, B., Ringberger, V.-A., Tuck, J. R., Sjöqvist, F.: Initial clinical trial based on biochemical methodology of zimelidine (a serotonin uptake inhibitor) in depressed patients. Clin. Pharmacol. Ther. 21, 194–200 (1977)
Sneddon, J. M.: Blood platelets as a model for monoaminecontaining neurones. Prog. Neurobiol. 1, 151–198 (1973)
Yuwiler, A., Plotkin, S., Geller, E., Ritvo, E. R.: A rapid accurate procedure for the determination of serotonin in whole human blood. Biochem. Med. 3, 426–436 (1970)
Westerlund, D., Nilsson, L. B., Jaksch, Y.: Straight-phase ion-pair chromatography of zimelidine and similar divalent amines. J. Liquid Chromatogr. 2, 373–405 (1979)
Yates, C. M., Todrick, A., Tait, A. C.: Aspects of the clinical chemistry of desmethylimipramine in man. J. Pharm. Pharmacol. 15, 432–439 (1963)
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Ross, S.B., Aperia, B., Beck-Friis, J. et al. Inhibition of 5-hydroxytryptamine uptake in human platelets by antidepressant agents in vivo. Psychopharmacology 67, 1–7 (1980). https://doi.org/10.1007/BF00427588
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF00427588