Fluoxetine: a clinically effective non-tricyclic antidepressant

  • Louis Lemberger
  • Ray Fuller
  • David Wong
  • Paul Stark


Fluoxetine is a potent inhibitor of the neuronal uptake of serotonin (5-HT). The reuptake of 5-HT into the brain neuron from which it was released is thought to be the major means of removing 5-HT from the synaptic cleft, thereby terminating its action on synaptic receptors. Inhibition of this reuptake increases the concentration of 5-HT in the synaptic cleft and enhances the stimulation of presynaptic and postsynaptic receptors. A consequence of stimulating the presynaptic autoreceptor is a reduced rate of firing of 5-HT neurons and a reduction in 5-HT synthesis and release. Several consequences of stimulating postsynaptic receptors innervated by 5-HT neurons in various brain regions have been identified after fluoxetine administration. In laboratory animals these include activation of neuroendocrine secretion (e.g., corticosterone and prolactin when fluoxetine is combined with 5-hydroxytryptophan), reduction of food intake, alterations in sleep and behavior, enhancement of the analgesic action of morphine, and others. In humans, fluoxetine selectively inhibits the uptake of 5-HT into platelets and presumably in the neurons of the CNS.


Antidepressant Drug Uptake Inhibitor Neuronal Uptake Clinical Global Impression Serotonin Uptake Inhibitor 
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  1. Bennett, J. P., Jr. and Snyder, S. H. (1976). Serotonin and lysergic acid diethylamide binding in rat brain membranes: relationship to postsynaptic serotonin receptors. Mol. Pharmacol., 12:373–389Google Scholar
  2. Fuller, R. W., Snoddy, H. D., Perry, K. W., Bymaster, F. P. and Wong, D. T. (1977). Importance of duration of drug action in the antagonism of p-chloroamphetamine depletion of brain serotonin — comparison of fluoxetine and chlorimipramine. Biochem. Pharmacol., 27:193–198Google Scholar
  3. Horng, J. S. and Wong, D. T. (1976). Effects of serotonin uptake inhibitor, Lilly 110140, on transport of serotonin in rat and human blood platelets. Biochem. Pharmacol., 25, 865–867Google Scholar
  4. Hwang, E. C., Magnussen, I. and Van Woert, M. H. (1980). Effects of chronic fluoxetine administration on serotonin metabolism. Res. Commun. Chem. Pathol. Pharmacol., 29:79–98Google Scholar
  5. Kanof, P. D. and Greengard, P. (1978). Brain histamine receptors as targets for antidepressant drugs. Nature, 272:329–333PubMedCrossRefGoogle Scholar
  6. Lemberger, L., Rowe, H., Carmichael, R. Oldham, S., Horng, J. S., Bymaster, F. P. and Wong, D. T. (1978b). Pharmacologic effects in man of a specific serotonion reuptake inhibitor. Science, 199:436–437PubMedCrossRefGoogle Scholar
  7. Lemberger, L., Rowe, H., Carmichael, R., Crabtree, R., Horng, J. S., Bymaster, F. and Wong, D. (1978a). Fluoxetine, a selective serotonin uptake inhibitor. Clin. Pharmacol. Ther., 23:421–429Google Scholar
  8. Maggi, A., U’Prichard, D. C. and Enna, S. J. (1980). Differential effects of antidepressant treatment on brain monoaminergic receptors. Eur. J. Pharmacol., 61:91–98Google Scholar
  9. Mishra, R., Leith, N. J., Steranka, L. and Sulser, F. (1981). The noradrenaline receptor coupled adenylate cyclase system in brain. Lack of modification by changes in the availability of serotonin. Naunyn-Schmiedeberg’s Arch. Pharmacol., 316: 218–224Google Scholar
  10. Ögren, S. O., Fuxe, K., Agnati, L. F., Gustafson, J. A., Jonsson, G. and Holm, A. C. (1979). Reevaluation of the indoleamine hypothesis of depression. Evidence for a reduction of functional activity of central 5-HT systems by antidepressant drugs. J. Neural Transmission, 46:85–103Google Scholar
  11. Parli, C. J. and Hicks, J. (1974). In vivo demethylation of Lilly 110140:3-(p-trifluoromethylphenoxy)-N-methyl-3-phenylpropylamine to an active metabolite — Lilly 103947. Fed. Proc., 33:560Google Scholar
  12. Peroutka, S. J. and Snyder, S. H. (1981). Interactions of antidepressants with neurotransmitter receptor sites. In S. J. Enna, J. B. Malick and E. Richelson (eds.), Antidepressants: Neurochemical, Behavioral, and Clinical Perspectives, Raven Press, New York, pp. 75–90Google Scholar
  13. Richelson, E. (1981). Tricyclic antidepressants: interactions with histamine and muscarinic acetylcholine receptors. In S. J. Enna, J. B. Malick and E. Richelson (eds.), Anti-depressants: Neurochemical, Behavioral, and Clinical Perspectives, Raven Press, New York pp. 53–73Google Scholar
  14. Ross, S. B., Hall, H., Renyi, A. L. and Westerlund, D. (1981). Effects of zimelidine on serotoninergic and noradrenergic neurons after repeated administration in the rat. Psychopharmacol., 72:219–225CrossRefGoogle Scholar
  15. Ross, S. B. and Renyi, A. L. (1977). Inhibition of the neuronal uptake of 5-hydroxytryptamine and noradrenaline in rat brain by (Z)- and (e)-3-(4-bromiphenyl)-N,N-dimethyl-3-(3-pyridyl) allylamines and their secondary analogues. Neuropharmacology 16:57–63PubMedCrossRefGoogle Scholar
  16. Savage, D. D., Mendels, J. and Frazer, A. (1980). Monoamine oxidase inhibitors and serotonin uptake inhibitors: differential effects of 3H-serotonin binding sites in rat brain. J. Pharmacol. Exp. Ther., 212:259–263Google Scholar
  17. Schmidt, M. J. and Thornberry, J. T. (1977). Norepinephrine stimulated cyclic AMP accumulation in brain slices in vitro after serotonin depletion or chronic administration of selective amine reuptake inhibitors. Arch. Int. Pharmacodyn., 229:42–51Google Scholar
  18. Sugrue, M. F. (1980). The inability of chronic fluoxetine to potentiate a serotonin mediated effect. Commun. Psychopharmacol., 4:131–134Google Scholar
  19. Sulser, F., Okada, F., Manier, D. H., Gillespie, D. D., Janowsky, A. and Mishra, R. (1983). Noradrenergic signal transfer as a target of antidepressant therapy. This book, pp.3–17Google Scholar
  20. Wong, D. T. (1982). Neurotransmitter profiles of fluoxetine and other antidepressant drugs. Fed. Proc., 41:1636Google Scholar
  21. Wong, D. T. and Bymaster, F. P. (1981). Subsensitivity of serotonin receptors after long-term treatment of rats with fluoxetine. Res. Commun. Chem. Pathol. Pharmacol., 32:41–51Google Scholar
  22. Wong, D. T., Bymaster, F. P., Horng, J. S. and Molloy, B. B. (1975). A new selective inhibitor for uptake of serotonin into synaptosomes of rat brain: 3-(p-trifluoromethylphenoxy)-N-methyl-3-phenylpropylamine. J. Pharmacol. Exp. Ther., 193:804–811Google Scholar

Copyright information

© The contributors 1983

Authors and Affiliations

  • Louis Lemberger
    • 1
  • Ray Fuller
    • 1
  • David Wong
    • 1
  • Paul Stark
    • 1
  1. 1.Lilly Research Laboratories, Eli Lilly and Company, and the Departments of Pharmacology, Medicine, and PsychiatryIndiana University School of MedicineIndianapolisUSA

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