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.
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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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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