Selective Serotonin Rewait what
The SSRIs--selective serotonin reuptake inhibitors--are a class of drugs commonly used as antidepressants. They 'work' by keeping neurons from absorbing serotonin from the synaptic cleft back into the cell, increasing the amount of available serotonin. This is good because serotonin is made of tiny pixies who want to be free, so keeping it out of
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It appears so:Fluoxetine (Prozac) was the first major breakthrough for the treatment of depression since the introduction of tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) nearly 30 years earlier. It was the first selective serotonin reuptake inhibitor (SSRI) approved by the United States Food and Drug Administration, offering superior efficacy and reduced side effects relative to TCAs and MAOIs. Though a debate remains regarding the exact mechanism by which the clinical efficacy of fluoxetine is manifested, the importance of fluoxetine and related SSRIs to the field is unquestionable. [...]
there are some classes of drugs for which not knowing the mode of action (MoA) is pretty typical; psychopharm is one of them. i'm too lazy to look up the paper, but i read an article within the past year that claimed that the SSRI activity of the class is a secondary MoA, and their main effect is due to another interaction with the CNS.
i don't think it's so bad we don't know quite what we're doing, since we do that a lot in medicine, but i'm not sanguine about giving a drug known to fiddle with brain development to kids. ISTM that's it's a huge uncontrolled experiment, and we'll figure out the results the hard way.
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(This was a sly reference to the prevalence of school shootings et al; but actually if measured over time school disasters have been fairly steady since they were first really measured with some school bombings in the 1930s. It's a naturally statistically bursty phenomenon because it's exciting and rare and it bleeds and it leads, but measured in decades the numbers haven't changed. It's just the media coverage that has amplified the attention.)
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Which suggests in turn that rational drug discovery has been a trillion-dollar voodoo ritual.
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1) my objection is only their use in children; they're a great success otherwise.
2) even if their nominal MoA is secondary to their main effect -- i haven't seen anything which says that it's irrelevant, but obviously, i can't read the whole literature -- the method works as desired.¹
3) rational drug design has worked quite well for the later NSAIDs, anti-viral protease inhibitors and NNRTIs, and other recent drug classes. it also makes french-named company quite rich via their newer rationally-designed ag chemicals.
it's not a perfect method by any measure -- i can rattle off a bunch of limitations¹ -- but it's much better than the lamp-post logic of analoging around known-good compounds or making a bunch of stuff and hoping to get lucky. current methods usually use a mixture of everything we've got (screening random compounds, in silico design of molecules based on estimates of what the target is or how it works, combinatorial synthesis of lots of somewhat-likely candidate molecules, and rational design starting from target structure). if it was an easy problem, we'd have solved it already. :)
1 (yup, used twice): the most obvious limitation is that rational design often can't say what else a drug candidate will interact with. we can make educated guesses from similar molecules, but that's usually about it. so: tissue studies, animal studies, and phase 1 clinical studies.
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