What was the first drug approved by the FDA to treat clinical depression?
Development and discovery of SSRI drugs
Fluoxetine is a racemic mixture of (R)- and (S)-fluoxetine where both enantiomers contribute to its biological activity.[36] Since mono-substitution in the 4-para position of the phenoxy group (figure 4) results in selective inhibition of 5-HT re-uptake, a disubstitution i.e. 2,3- or 2,4- substitution therefore results in a loss of SERT selectivity.[5] Fluoxetine has the widest spectrum of activity since it is the least SERT selective of all the SSRIs. Fluoxetine also has a 5-HT2C antagonist activity where it blocks the 5-HT activity of 5-HT2C receptors enhancing the release of both NE and DA. A 5-HT2C antagonist do not only help out with therapeutic effects of fluoxetine but also the tolerability of the drug. The advantage of being 5-HT2C antagonist is that it has a stimulatory effect and many patients have experienced an increase in energy, concentration and focus and a decrease in fatigue from the very first dose. The stimulant activity of 5-HT2C antagonist can however, be a disadvantage for patients with agitation, insomnia and anxiety. Another feature of fluoxetine is a weak NE re-uptake inhibition which can have clinical effect in higher doses. Fluoxetine also has a long half-life which can reduce withdrawal symptoms which are characteristic for some SSRIs after abrupt discontinuation, but it also means that it takes a long time to clear the drug and its active metabolite after discontinuing fluoxetine treatment.[13]