1988: Fluoxetine (Prozac) and the SSRI Era (1988)

Although tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) effectively
treated depression from the late 1950s, both classes carried significant risks: TCAs were lethal
in overdose and caused anticholinergic side effects; MAOIs required strict dietary restrictions
to avoid hypertensive crises. The monoamine hypothesis of depression—positing a deficit of
serotonin or norepinephrine at central synapses—suggested that a drug selectively inhibiting
serotonin reuptake could produce antidepressant effects with fewer side effects.

Eli Lilly chemist Bryan Molloy and pharmacologist David Wong synthesised and characterised
fluoxetine in 1972, selecting it from among antihistamine candidates for its potent, selective
inhibition of serotonin transporter (SERT) with minimal effect on norepinephrine transporter
(NET) or muscarinic, histaminic, and adrenergic receptors. After a long development programme,
fluoxetine was approved by the FDA on 29 December 1987 (marketed from January 1988) under the
brand name Prozac.

Prozac became a cultural as well as medical phenomenon. Its favourable tolerability profile,
negligible lethality in overdose, and broader indication range (depression, OCD, bulimia,
panic disorder) drove unprecedented prescription volumes. By the late 1990s, over 35 million
people worldwide had been prescribed fluoxetine.

The SSRI class—extended by paroxetine, sertraline, fluvoxamine, citalopram, and escitalopram
—displaced TCAs as the first-line pharmacological treatment for depression globally. Despite
ongoing debates about effect size in mild depression, SSRIs remain among the most prescribed
drugs worldwide, and fluoxetine's development demonstrated the power of receptor selectivity
engineering to improve the therapeutic index of a drug class.