What was the first drug approved by the FDA to treat clinical depression?
Development and discovery of SSRI drugs
Fluoxetine
The SSRIs are the first rationally designed class of psychotropic medications. The strategy behind rational drug design is to develop a new drug that is capable of affecting a specific biological target, or in this case a special neural site of action (uptake pumps, receptors), while trying to avoid effects on other site of actions. The goal in such development is to produce pharmacological agents that are more efficacious, safer and better tolerated than older medications.[8] An initial success was achieved when medicinal chemists set out in search of the ideal SSRI with the chemical synthesis of zimelidine (figure 1) from the antihistamine drug brompheniramine,[7] which exhibited selective inhibition of 5-HT re-uptake with minimal inhibition of norepinephrine (NE) re-uptake. Most importantly, zimelidine did not come with the adverse effect profile as the TCAs and therefore it became the template for the second generation SSRIs.[5] Zimelidine was the first SSRI to be marketed, but several cases of Guillain–Barré syndrome were associated with the use of the drug which led to withdrawal from the market in 1983. Subsequently, several non-tricyclic SSRIs were discovered and marketed. Fluoxetine, which was FDA approved in 1987 and is usually thought to be the first SSRI to be marketed, paved the way for the next generation of SSRIs and was thought to be some kind of prototype.[5] Introduction of fluoxetine to the market is hailed as a miracle drug for the treatment of depression because it had fewer adverse effects, simpler dosing strategies and greater margin of safety when overdoses were consumed and thus it had better adherence, compared to the older antidepressants (TCAs and MAOIs).[5][9] Since then the number of drugs in the SSRI class has become bigger and they are now six (fluoxetine, paroxetine, citalopram, escitalopram, sertraline and fluvoxamine),[4][8] as demonstrated in table 1.