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The Discovery of Fluoxetine Hydrochloride (Prozac)

Abstract

In the early 1970s, evidence of the role of serotonin (5-hydroxytryptamine or 5-HT) in depression began to emerge and the hypothesis that enhancing 5-HT neurotransmission would be a viable mechanism to mediate antidepressant response was put forward. On the basis of this hypothesis, efforts to develop agents that inhibit the uptake of 5-HT from the synaptic cleft were initiated. These studies led to the discovery and development of the selective serotonin-reuptake inhibitor fluoxetine hydrochloride (Prozac; Eli Lilly), which was approved for the treatment of depression by the US FDA in 1987. Here, we summarize this research and discuss the many challenges that we encountered during the development of fluoxetine hydrochloride, which has now been widely acknowledged as a breakthrough drug for depression.

Key Points

  • The drugs that were known to be effective for the treatment of depression during the 1960s and 1970s were inhibitors of monoamine oxidase, which degraded the monoamines, or tricyclic antidepressants, which inhibited the uptake of monoamines.

  • Understanding of the activities of these drugs, in combination with other observations, provided the foundation for the monoamine hypothesis of depression, which proposes that depression results from a central deficiency of monoamine function.

  • On the basis of the hypothesis that enhancing serotonergic neurotransmission would be a viable mechanism to mediate antidepressant response, efforts to develop agents that inhibit the uptake of serotonin from the synaptic cleft were initiated at Eli Lilly in the early 1970s.

  • This article describes the research that ultimately led to the pioneering introduction of the selective serotonin-reuptake inhibitor (SSRI) fluoxetine hydrochloride (Prozac) in the United States. SSRIs are now the most widely prescribed class of antidepressants.

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References

  1. 1

    Wong, D. T., Horng, J. S., Bymaster, F. P., Hauser, K. L. & Molloy, B. B. A selective inhibitor of serotonin uptake: Lilly 110140, 3-(p-trifluoromethylphenoxy)-N-methyl-3-phenylpropylamine. Life Sci. 15, 471–479 (1974). This was the first report to describe the discovery, and give a brief characterization, of fluoxetine (LY110140) as a selective inhibitor of 5-HT uptake. The authors considered the possibility that fluoxetine would be an antidepressant drug and a useful research tool.

  2. 2

    Fuller, R. W., Perry, K. W. & Molloy, B. B. Effect of an uptake inhibitor on serotonin metabolism in rat brain: studies with 3-(p-trifluoromethylphenoxy)-N-methyl-3-phenylpropylamine (Lilly 110140). Life Sci. 15, 1161–1171 (1974). This was the first published study to show the effect of fluoxetine on the metabolism of 5-HT in the rat brain.

  3. 3

    Fuller, R. W. & Wong, D. T. Inhibition of serotonin uptake. Fed. Proc. Fed. Am. Soc. Exp. Biol. 36, 2154–2158 (1977).

  4. 4

    Fuller, R. W., Wong, D. T. & Robertson, D. W. Fluoxetine, a selective inhibitor of serotonin uptake. Med. Res. Rev. 11, 17–34 (1991).

  5. 5

    Wong, D. T., Bymaster, F. P. & Engleman, E. A. Prozac (fluoxetine, Lilly 110140), the first selective serotonin uptake inhibitor and an antidepressant drug (in US): twenty years since its first publication. Life Sci. 57, 411–441 (1995). This review provided the rationale for searching a selective inhibitor of 5-HT uptake and described the comprehensive preclinical pharmacology of fluoxetine.

  6. 6

    Stark, P. & Hardison, C. D. A review of multicenter controlled studies of fluoxetine vs imipramine and placebo in outpatients with major depressive disorder. J. Clin. Psychiatry 46, 53–58 (1985). This publication reviewed the early clinical studies that established fluoxetine as an efficacious antidepressant drug.

  7. 7

    Boyer, W. F. & Feighner, J. P. in Perspectives in Psychiatry, Volume 1: Selective Serotonin Re-uptake Inhibitors (eds Feighner, J. P. & Boyer, W. F.) 89–108 (Wiley, Chichester, England, 1991).

  8. 8

    Stokes, P. Fluoxetine: a five-year review. Clin. Ther. 15, 216–243 (1993).

  9. 9

    Molloy, B. B., Wong, D. T. & Fuller, R. W. The discovery of fluoxetine. Pharmaceutical News 1, 6–10 (1994).

  10. 10

    Bourne, G. H. The Structure and Function of Nervous Tissue, III: Biochemistry and Disease (Academic Press, New York, 1969).

  11. 11

    Gray, E. G. & Whittaker, V. P. The isolation of nerve endings from brain: an electron-microscopic study of cell fragments derived by homogenization and centrifugation. J. Anat. 96, 79–88 (1962).

  12. 12

    Whittaker, V. P. in The Structure and Function of Nervous Tissue, III: Biochemistry and Disease (ed. Bourne, G. H.) 1–24 (Academic Press, New York, 1969).

  13. 13

    Wong, D. T., Horng, J. S., Hamill, R. L. & Lardy, H. A. Effect of a new monocarboxylic acid antibiotic, A204, on the monovalent cation permeability of rat liver mitochondria. Biochem. Pharmacol. 20, 3169–3177 (1971).

  14. 14

    Wong, D. T., Wilkinson, J. R., Hamill, R. L. & Horng, J. S. Effects of antibiotic ionophore, A23187, on oxidative phosphorylation and calcium transport of liver mitochondria. Arch. Biochem. Biophys. 156, 578–585 (1973).

  15. 15

    Wong, D. T., Van Frank, R. M., Horng, J. S. & Fuller, R. W. Accumulation of amphetamine and p-chloroamphetamine into synaptosomes of rat brain. J. Pharm. Pharmacol. 24, 171–173 (1972).

  16. 16

    Page, I. in Serotonin and the Brain (ed. Bourne, G. H.) 289–307 (Academic Press, New York, 1969).

  17. 17

    Rapport, M. M., Green, A. A. & Page, I. H. Crystalline serotonin. Science 108, 329–330 (1948).

  18. 18

    Twarog, B. M. & Page, I. H. Serotonin content of some mammalian tissues and urine and a method for its determination. Am. J. Physiol. 175, 157–161 (1953).

  19. 19

    Weil-Malherbe, H. & Szara, S. I. in The Biochemistry of Functional and Experimental Psychoses 5–16 (Thomas, Springfield, Illinois, 1971).

  20. 20

    Dahlstrom, A. & Fuxe, K. Evidence for the existence of monoamine containing neurons in the central nervous system. I. Demonstration of monoamines in the cell bodies of brain stem neurons. Acta Physiol. Scand. 62 (Suppl. 232), 1–55 (1964).

  21. 21

    Fuxe, K., Hokfelt, T. & Ungerstedt, U. Localization of indolalkylamines in CNS. Adv. Pharmacol. 6A, 235–251 (1968).

  22. 22

    Lindbrink, P., Jonsson, G. & Fuxe, K. The effect of imipramine-like drugs and antihistamine drugs on uptake mechanisms in the central noradrenaline and 5-hydroxytryptamine neurons. Neuropharmacology 10, 521–536 (1971).

  23. 23

    Wong, D. T., Horng, J. S. & Fuller, R. W. Kinetics of serotonin accumulation into synaptosomes of rat brain-effects of amphetamine and chloroamphetamines. Biochem. Pharmacol. 22, 311–322 (1973).

  24. 24

    Wong, D. T., Horng, J. S. & Bymaster, F. P. DL-N-methyl-3-(o-methoxyphenoxy)-3-phenylpropylamine hydrochloride, Lilly 94939, a potent inhibitor for uptake of norepinephrine into rat brain synaptosomes and heart. Life Sci. 17, 755–760 (1975).

  25. 25

    Wong, D. T. & Bymaster, F. P. Effect of nisoxetine on uptake of catecholamines in synaptosomes isolated from discrete regions of rat brain. Biochem. Pharmacol. 25, 1979–1983 (1976).

  26. 26

    Bunney, W. E. Jr . & Davis, J. M. Norepinephrine in depressive reactions. A review. Arch. Gen. Psychiatry 13, 483–494 (1965).

  27. 27

    Schildkraut, J. J. The catecholamine hypothesis of affective disorders: a review of supporting evidence. Am. J. Psychiatry 122, 509–522 (1965).

  28. 28

    Axelrod, J. Noradrenaline: fate and control of its biosynthesis. Science 173, 598–606 (1971).

  29. 29

    Weil-Malherbe, H. & Szara, S. I. in The Biochemistry of Functional and Experimental Psychoses 57–76 (Thomas, Springfield, Illinois, 1971).

  30. 30

    Gillette, J. R., Dingell, J. V., Sulser, F., Kuntzman, R. & Brodie, B. B. Isolation from rat brain of a metabolic product, desmethylimipramine, that mediates the antidepressant activity of imipramine (Tofranil). Experientia (Basel) 17, 417–418 (1961)

  31. 31

    Hertting, G., Axelrod, J. & Whitby, L. G. Effect of drugs on the uptake and metabolism of 3H-norepinephrine. J. Pharmacol. Exp. Ther. 134, 146–153 (1961).

  32. 32

    Carlsson, A. Structural specificity for inhibition of [3H]-5-hydroxytryptamine uptake by cerebral slices. J. Pharm. Pharmac. 22, 729–732 (1970).

  33. 33

    Carlsson, A., Fuxe, K. & Ungerstedt, U. The effect of imipramine on central 5-hydroxytryptamine neurons. J. Pharm. Pharmacol. 20, 150–151 (1968).

  34. 34

    Carlsson, A., Corrodi, H., Fuxe, K. & Hokfelt, T. Effects of some antidepressant drugs on the depletion of intraneuronal brain catecholamine stores caused by 4,α-dimethyl-meta-tyramine. Eur. J. Pharmacol. 5, 367–373 (1969).

  35. 35

    Carlsson, A., Corrodi, H., Fuxe, K. & Hokfelt, T. Effect of antidepressant drugs on the depletion of intraneuronal brain 5-hydroxytryptamine stores caused by 4-methyl-α-ethyl-meta-tyramine. Eur. J. Pharmacol. 5, 357–366 (1969).

  36. 36

    Carlsson, A., Fuxe, K., Hamberger, B. & Lindqvist, M. Biochemical and histochemical studies on the effects of imipramine-like drugs and (+)-amphetamine on central and peripheral catecholamine neurons. Acta Physiol. Scand. 67, 481–497 (1966).

  37. 37

    Shaw, D. M., Camps, F. E. & Eccleston, E. G. 5-hydroxytryptamine in the hind-brain of depressive suicides. Br. J. Psychiatry 113, 1407–1411 (1967).

  38. 38

    Bourne, H. R. et al. Noradrenaline, 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in hindbrains of suicidal patients. Lancet 2, 805–808 (1968).

  39. 39

    Pare, C. M., Yeung, D. P., Price, K. & Stacey, R. S. 5-hydroxytryptamine, noradrenaline and dopamine in brain stem, hypothalamus and caudate nucleus of control and of patients committing suicide by coal-gas poisoning. Lancet 2, 133–135 (1969).

  40. 40

    Coppen, A., Shaw, D. M. & Farrell, J. P. Potentiation of the antidepressive effect of a monoamine oxidase inhibitor by tryptophan. Lancet 1, 79–81 (1963).

  41. 41

    Pare, C. M. B. Potentiation of monoamine oxidase inhibitors by tryptophan. Lancet II 35, 527–528 (1963).

  42. 42

    Kline, N. S. & Sack, W. Relief of depression within one day using an M. A. O. inhibitor and intravenous 5-HTP. Am. J. Psychiatry 120, 274–275 (1963).

  43. 43

    Shaskan, E. G. & Snyder, S. H. Kinetics of serotonin accumulation into slices from rat brain: relationship to catecholamine uptake. J. Pharm. Exp. Ther. 175, 404–418 (1970).

  44. 44

    Blackburn, K. J., French, P. C. & Merrills, R. J. 5-hydroxytryptamine uptake by rat brain in vitro. Life Sci. 6, 1653–1663 (1967).

  45. 45

    Ross, S. B. & Renyi, A. L. Inhibition of the uptake of tritiated 5-hydroxytryptamine in brain tissue. Eur. J. Pharm. 7, 270–277 (1969).

  46. 46

    Snyder, S. H. & Coyle, J. T. Regional differences in [3H]-norepinephrine and [3H]-dopamine uptake in rat brain homogenates. J. Pharmacol. Exp. Ther. 165, 78–86 (1969).

  47. 47

    Slater, I. H., Rathbun, R. C. & Kattau, R. Role of 5-hydroxytryptaminergic and adrenergic mechanism in antagonism of reserpine-induced hypothermia in mice. J. Pharm. Pharmacol. 31, 108–110 (1979).

  48. 48

    Wong, D. T. & Bymaster, F. P. in Neurochemistry in Clinical Application (eds Tang, L. & Tang, S.) 77–95 (Plenum, New York, 1995).

  49. 49

    Wong, D. T., Bymaster, F. P., Horng, J. S. & Molloy, B. B. 3-(p-trifluoromethylphenoxy)-N-methyl-3-phenylpropylamine (Lilly 110140), a selective inhibitor of serotonin uptake into synaptosomes of rat brain. Fed. Proc. 33, 296 (1974).

  50. 50

    Wong, D. T., Bymaster, F. P., Horng, J. S. & Molloy, B. B. 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, 804–811 (1975). This was the first full publication to describe fluoxetine as a selective inhibitor of 5-HT uptake in vitro and in vivo.

  51. 51

    Horng, J. S., Bymaster, F. P. & Wong, D. T. Effects of compound, Lilly 110140, a specific inhibitor of serotonin uptake on transport of monoamines in peripheral tissues of rat. Fed. Proc. 33, 560 (1974).

  52. 52

    Horng, J. S. & Wong, D. T. Effects of serotonin uptake inhibitor, Lilly 110140, on transport of serotonin in rat and human blood platelets. Biochem. Pharmacol. 25, 865–867 (1976).

  53. 53

    Fuller, R. W. & Perry, K. W. Blockade of 4-chloroamphetamine-induced depletion of brain serotonin by 3-(p-trifluoromethylphenoxy)-N-methyl-3-phenylpropylamine hydrochloride (Lilly 110140), a selective inhibitor of uptake by serotonin neurons. Fed. Proc. 33, 255 (1974).

  54. 54

    Wong, D. T. & Bymaster, F. P. The comparison of fluoxetine and nisoxetine with tricyclic antidepressants in blocking the neurotoxicity of p-chloroamphetamine and 6-hydroxydopamine in the rat brain. Res. Comm. Chem. Path. Pharmacol. 15, 221–231 (1976).

  55. 55

    Fuller, R. W. Kinetic studies and effects in vivo of a new monoamine oxidase inhibitor, N-[2-(o-chlorophenoxy)-ethyl]-cyclopropylamine. Biochem. Pharmacol. 17, 2097–2106 (1968).

  56. 56

    Mills, J., Kattau, R., Slater, I. H. & Fuller, R. W. N-substituted cyclopropylamines as monoamine oxidase inhibitors. Structure–activity relationships. Dopa potentiation in mice and in vitro inhibition of kynuramine oxidation. J. Med. Chem. 11, 95–97 (1968).

  57. 57

    Fuller, R. W., Hines, C. W. & Mills J. Lowering of brain serotonin level by chloramphetamines. Biochem. Pharmacol. 14, 483–488 (1965).

  58. 58

    Fuller, R. W. & Hines, C. W. Tissue levels of chloroamphetamines in rats and mice. J. Pharm. Sci. 56, 302–303 (1967).

  59. 59

    Fuller, R. W. & Hines, C. W. Inhibition by p-chloroamphetamine of the conversion of 5-hydroxytryptamine to 5-hydroxyindoleacetic acid in rat brain. J. Pharm. Pharmacol. 22, 634–635 (1970).

  60. 60

    Meek, J. L., Fuxe, K. & Carlsson, A. Blockade of p-chloromethamphetamine induced 5-hydroxytryptamine depletion by chlorimipramine, chlorpheniramine and meperidine. Biochem. Pharmacol. 20, 707–709 (1971).

  61. 61

    Carlsson, A., Jonason, J., Lindqvist, M. & Fuxe, K. Demonstration of extraneuronal 5-hydroxytryptamine accumulation in brain following membrane-pump blockade by chlorimipramine. Brain Res. 12, 456–460 (1969).

  62. 62

    Fuller, R. W., Perry, K. W., Snoddy, H. D. & Molloy, B. B. Comparison of the specificity of 3-(p-trifluoromethylphenoxy)-N-methyl-3-phenylpropylamine and chlorimipramine as amine uptake inhibitors in mice. Eur. J. Pharmacol. 28, 233–236 (1974).

  63. 63

    Da Prada, M. & Pletscher, A. On the mechanism of chlorpromazine-induced changes of cerebral homovanillic acid levels. J. Pharm. Pharmacol. 18, 628–630 (1966).

  64. 64

    Miller, F. P., Cox, R. H., Snodgrass, W. R. & Maickel, R. P. Comparative effects of p-chloroamphetamine and p-chloro-N-methylamphetamine on rat brain norepinephrine, serotonin and 5-hydroxyindole-3-acetic acid. Biochem. Pharmacol. 19, 435–442 (1970).

  65. 65

    Perry, K. W. & Fuller, R. W. Effect of 3-(p-trifluoromethylphenoxy)-N-methyl-3-phenylpropylamine HCl (Lilly 110140), a specific inhibitor of serotonin uptake, on 5-hydroxyindole levels and turnover in rats. Fed. Proc. 33, 560 (1974).

  66. 66

    Bymaster, F. P. & Wong, D. T. Effect of Lilly 110140, 3-(p-trifluoromethylphenoxy)-N-methyl-3-phenylpropylamine on synthesis of [3H]-serotonin from [3H]-tryptophan in rat brain. Pharmacologist 16, 244 (1974).

  67. 67

    Clemens, J. A., Sawyer, B. D. & Cerimele, B. Further evidence that serotonin is a neurotransmitter involved in the control of prolactin secretion. Endocrinology 100, 692–698 (1977).

  68. 68

    Perry, K. W. & Fuller, R. W. Effect of fluoxetine on serotonin and dopamine concentration in microdialysis fluid from rat striatum. Life Sci. 50, 1683–1690 (1992).

  69. 69

    Fuller, R. W., Snoddy, H. D. & Molloy, B. B. Potentiation of the L-5-hydroxytryptophan-induced elevation of plasma corticosterone levels in rats by a specific inhibitor of serotonin uptake. Res. Comm. Chem. Path. Pharmacol. 10, 193–196 (1975).

  70. 70

    Parli, C. J. & Hick, J. In vivo demethylation of Lilly 110140: 3(p-trifluoromethylphenoxy)-N-methyl-3-phenylpropylamine to an active metabolite, Lilly 103947. Fed. Proc. 33, 560 (1974).

  71. 71

    Fuller, R. W., Perry, K. W. & Molloy, B. B. Effect of 3-(p-trifluoromethylphenoxy). N.N.methyl-3-phenylpropylamine on the depletion of brain serotonin by 4-chloroamphetamine. J. Pharmacol. Exp. Ther. 193, 793–803 (1975). This was the first full publication to describe the blockade of p -chloroamphetamine-induced depletion of brain 5-HT by fluoxetine, showing its effect as a selective inhibitor of 5-HT uptake in vivo.

  72. 72

    Asberg, M., Bertilsson, L., Tuck, D., Cronholm, B. & Sjoqvist, F. Indoleamine metabolites in the cerebrospinal fluid of depressed patients before and during treatment with nortriptyline. Clin. Pharmacol. Ther. 14, 277–286 (1973).

  73. 73

    Lemberger, L. et al. Pharmacologic effects in man of a specific serotonin-reuptake inhibitor. Science 199, 436–437 (1978).

  74. 74

    Lemberger, L. et al. Fluoxetine, a selective serotonin uptake inhibitor. Clin. Pharmacol. Ther. 23, 421–429 (1978).

  75. 75

    Wong, D. T., Bymaster, F. P., Reid, L. R. & Threlkeld, P. G. Fluoxetine and two other serotonin uptake inhibitors without affinity for neuronal receptors. Biochem. Pharmacol. 32, 1287–1293 (1983).

  76. 76

    Montgomery, S. A. Development of new treatments for depression, J. Clin. Psychiatry 46, 3–6 (1985).

  77. 77

    Wernicke, J. F. The side effect profile and safety of fluoxetine. J. Clin. Psychiatry 46, 59–67 (1985). This report provided a comprehensive review of the side-effect profile and safety of fluoxetine.

  78. 78

    Beasley, C. M. Jr, Nilsson, M. E., Koke, S. C. & Gonzales, J. S. Efficacy, adverse events, and treatment discontinuations in fluoxetine clinical studies of major depression: a meta-analysis of the 20-mg/day dose. J. Clin. Psychiatry 61, 722–728 (2000).

  79. 79

    Bengtsson, B. O., Wiholm, B. E., Myrhed, M. & Walinder, J. Adverse experiences during treatment with zimelidine on special licence in Sweden. Int. Clin. Pharmacol. 9, 55–61 (1994).

  80. 80

    Davidson, J. R. & Meltzer-Brody, S. E. The underrecognition and undertreatment of depression: what is the breadth and depth of the problem? J. Clin. Psychiatry 60 (Suppl. 7), 4–9 (1999).

  81. 81

    Ustun, T. B., Ayuso-Mateos, J. L., Chatterji, S., Mathers, C. & Murray, C. J. Global burden of depressive disorders in the year 2000. Br. J. Psychiatry 184, 386–392 (2004).

  82. 82

    Arias, E. et al. Deaths: final data for 2001. National Vital Statistics Reports (CDC) 52, 1–116 (2003).

  83. 83

    Stokes, P. E. & Holtz, A. Fluoxetine tenth anniversary update: the progress continues. Clin. Ther. 19, 1135–1250 (1997). This publication presents a comprehensive review of the clinical experience of fluoxetine in the treatment of depression and related disorders.

  84. 84

    Stokes, P. E. Ten years of fluoxetine. Depress. Anxiety 8 (Suppl. 1), 1–4 (1998).

  85. 85

    Tranter, R., O'Donovan, C., Chandarana, P. & Kennedy, S. Prevalence and outcome of partial remission in depression. J. Psychiatry Neurosci. 27, 241–247 (2002).

  86. 86

    Mulrow, C. D. et al. Efficacy of newer medications for treating depression in primary care patients. Am. J. Med. 108, 54–64 (2000).

  87. 87

    Wernicke, J. F. Safety and side effect profile of fluoxetine. Expert Opin. Drug Saf. 3, 495–504 (2004).

  88. 88

    Stevens, J. C. & Wrighton, S. A. Interaction of the enantiomers of fluoxetine and norfluoxetine with human liver cytochromes P450. J. Pharmacol. Exp. Ther. 266, 964–971 (1993).

  89. 89

    Page, I. H. & McCubbin, J. W. Serotonin or tenure for the pharmacologist. Circulation 14, 161 (1956).

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Acknowledgements

We dedicate this article to our deceased colleagues, including R. W. Fuller, B. B. Molloy, R. C. Rathbun, D. W. Robertson and P. Stark, for their dedication and contributions to the project that led to the discovery, preclinical and clinical investigations of fluoxetine, and for their friendship during our careers in the Lilly Research Laboratories. In addition, we owe our deepest gratitude to many other collaborators in this successful project, including I. Slater, R. Kraay, L. Lemberger, C. J. Parli, J. S. Wold, D. N. Masica and J. F. Wernicke, along with the technical contributions of J. S. Horng, K. L. Hauser, H. D. Snoddy, L. R. Reid, P. G. Threlkeld, S. H. Luecke, H. Rowe and J. H. Krushinski.

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The authors declare no competing financial interests.

Correspondence to David T. Wong.

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Figure 1: Schematic of processes associated with serotonergic neurotransmission.
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