Fluoxetine (Prozac) approval: first widely used SSRI

In the two decades before fluoxetine, tricyclic antidepressants were the standard pharmacotherapy for depression. Imipramine, amitriptyline, and their congeners were effective, but their therapeutic window was narrow. A month's supply at a standard dose contained enough drug to cause fatal cardiac arrhythmias in overdose, and patients with major depression and active suicidal ideation were treated with these agents only cautiously, often requiring close monitoring or hospitalization to mitigate the overdose risk. The side effect burden, including sedation, dry mouth, orthostatic hypotension, and weight gain, also limited tolerability and long-term adherence.

The chemistry that produced fluoxetine began with systematic work at Eli Lilly in the early 1970s. Bryan Molloy, a medicinal chemist, synthesized a series of phenoxyphenylpropylamine compounds, and David Wong, a neuroscientist, screened them for selectivity at the serotonin transporter. One compound showed tight binding to the serotonin reuptake site with minimal affinity for norepinephrine, dopamine, histamine, and muscarinic receptors. Ray Fuller, a pharmacologist on the team, confirmed the compound's serotonergic activity in animal models. The molecule, eventually named fluoxetine, advanced through a decade of clinical testing before the FDA granted approval on December 29, 1987.

The clinical difference between fluoxetine and the tricyclics lay mainly in safety margin and side effects; head-to-head trials generally showed similar response rates. The main distinction was the overdose profile. Lethal toxicity with fluoxetine required far higher doses than with amitriptyline or imipramine, which substantially changed the risk calculus for prescribing in patients with suicidal ideation. For the first time, primary care physicians could initiate antidepressant treatment in this population without the same level of concern about providing a lethal means.

Adoption in primary care was rapid, and much of the drug treatment of depression moved from psychiatrists to general practitioners. Other SSRIs followed: the FDA approved sertraline on December 30, 1991, and paroxetine on December 29, 1992. By the mid-1990s, the SSRI class had largely displaced tricyclics as first-line pharmacotherapy for depression, dysthymia, panic disorder, and obsessive-compulsive disorder.

The broader cultural impact was considerable, as fluoxetine became the subject of books, public debate, and legal proceedings regarding its psychiatric effects. Later meta-analyses found that the benefit of antidepressants, SSRIs included, is modest in mild-to-moderate depression and larger in severe illness. In October 2004 antidepressants received a boxed warning about suicidal thinking and behavior in children and adolescents, and in May 2007 the FDA ordered it extended to young adults. Neither of these refinements displaced fluoxetine from clinical use; it remains on the World Health Organization's Essential Medicines List and is still widely prescribed globally.