The SSRIs were the first family of antidepressants not discovered by chance. Their development was planned according to what was known about the neurochemistry of depression, which partially explains their lack of side effects and efficacy of action.

David Wong, an antibiotics researcher at Eli Lilly, had just learned a new technique that allowed him to measure uptake of chemical messengers (neurotransmitters) in neurons. Since Wong knew that current antidepressants’ side effects (such as those seen in tricyclics) were mostly due to norepinephrine uptake rather than serotonin, he decided to look for compounds that would alter serotonin uptake only, in hopes of developing a drug that would cure depression but not cause the undesirable side effects associated with the earlier classes of antidepressants.

After experimenting with several obscure compounds, Wong found that a tri-fluoridated (containing three fluoride atoms) molecule called fluoxetine had the most specific serotonin uptake inhibition.After years of tests on animal models and then in human clinical trials, Eli Lilly released fluoxetine under the
trade name Prozac in the late 1980s. Prozac went on to become the best-known and best-selling antidepressant of our time. Other companies quickly hopped onto the SSRI bandwagon, with the release of Paxil (paroxetine), Luvox® (fluvoamine),Zoloft® (sertraline), and Celexa® (citalopram). Each of these drugs had the capacity for selective serotonin uptake inhibition but also had other individual characteristics that made some better or worse than others for individual cases of depression.

studies have shown that success rates for SSRIs in alleviating moderate depression are only around 40–60 percent, and even lower for major depression. Often psychiatrists must prescribe a few SSRIs in succession to find one that works best.