[throwaway98031]

> Now let's find out if this anti-depressant really helps anyone, or is it just another terrible drug with horrid side effects? If it doesn't help better than placebo; take it off the market?

The claim that SSRIs are no better than placebo is increasingly popular on the internet and among some researchers eager to make headlines, but the claim is not backed by the data. At best, it represents a misunderstanding of how the studies work, what they're showing, and how surprisingly effective placebo is in cases of mild depression.

Scott Alexander has already done a great job debunking these claims: http://slatestarcodex.com/2014/07/07/ssris-much-more-than-yo...

> I do know drug companies have pretty much stopped all research in new anti-depressants. Why--they were caught with their pants down, lying, hiding bad studies, and fooling doctors and patients alike with their Slick claims.

This incident is deplorable and highlights a huge problem in our clinical trials process that needs to be addressed, but your extrapolations here not only don't make sense but they are flat-out incorrect.

There is quite a huge amount of research on new antidepressants. In the past few years alone we've added Vilazodone and Vortioxetine to our arsenal, both of which are primarily SSRIs but have some additional properties that might reduce the side effects due to requiring lower doses. We also have Levomilnacipran which is the first SNRI that favors norepinephrine over serotonin, which can be very helpful in some patients.

There are many interesting compounds in the pipeline as well, from rapid-acting compounds for addressing suicidal patients (ketamine infusion, esketamine nasal spray, GABA-A5 antagonists) to completely novel antidepressant compounds: opiod-modulating drugs like ALKS-5461 which have been very impressive in clinical trials, NMDA and sigma-1 antagonists, mGluR5 antagonists, NR2B antagonists, some very impressive BDNF modulators, anti-glucocorticoid strategies, and so on.

Contrary to your claims that "ruthless drug companies" have stopped all research, this is the most exciting time for anti-depressant research we've ever seen.

[cryoshon]

How can we really be sure that they're more efficacious than placebos (which can be quite efficacious) when we aren't allowed to see negative data generated during clinical trials? We have absolutely no aperture into the internal studies that weren't submitted as proof of the drug being effective. Sure, administering these drugs will make some patients report fewer negative symptoms-- typically the worst hit patients are helped the most, so it's definitely worth employing clinically despite the hangups. Effectiveness on target isn't a reason to stop asking critical questions and finding better alternatives. We know very well that long term use of antidepressants or other psychiatric medications has permanent consequences on brain structure and plasticity. There's always long term sexual dysfunction as well, sometimes permanently. I guess people can try to dismiss these side effects, but they're nearly always downplayed by the pharmas and up-played by the actual patients who are unhappy with their treatment.

Then there's the academic problem: the monoamine hypothesis (the underlying theory behind the actions and use of SSRIs etc) is at best a crude approximation with precious little in vivo data to support ideas that are known to be inaccurate and incomplete. You can't take measurements of 5-HT concentrations inside of a patient's brain, and similar measurements based off of mouse models are moonshots, even with the fancy math which is meant to allow a parallel to be drawn. Similarly, there's not an objective test for most of these psychiatric disorders unfortunately, making a remission hard to quantify.

The human aspect is also something to remember. The pharmas have a ton of money, and intend to make more money using products they have already developed. There is a huge incentive for them to hire people with credentials to say that their drugs are more effective than placebos, and generally effective. There is a huge incentive to cover up negative data and bad side effects. There is a huge incentive to keep things the way they are.

I'm going to read through the link you posted and maybe respond again more in depth later, it looks interesting and worthy of discussion.

[throwaway98031]

> Then there's the academic problem: the monoamine hypothesis (the underlying theory behind the actions and use of SSRIs etc) is at best a crude approximation with precious little in vivo data to support ideas that are known to be inaccurate and incomplete.

The monoamine hypothesis of depression (the idea that all depressions are directly attributable to negative alterations in monoamine dynamics) has been known to be inadequate for a decade or two now in the scientific community. The idea that researchers are still operating on this basis is totally false at this point, but anti-pharma crusaders still hold it up as a convenient straw-man because it's so easy to discredit now using (ironically enough) all of the latest research that the scientific community actually uses for our current understanding of depression.

We're all very well aware that depression isn't caused by "low serotonin levels" or other such completely wrong marketing-speak of the 90s. In fact, there are quite a few very promising anti-depressants in the pipeline and stage III clinical trials that don't directly manipulate monoaminergic systems at all.

Finally, your suggestion that the monoamine hypothesis is the theory behind the actions of SSRIs is completely false. We've known for a very long time that the therapeutic effects of SSRIs lag the near-immediate alterations of monoaminergic. You can't equate discrediting the monoaminergic hypothesis of depression with discrediting SSRIs.

[cryoshon]

An uber simplified version of the monoamine hypothesis is exactly how these drugs are marketed people today, and you know it-- just watch the TV commercials advertising SSRIs and it is impossible to avoid the conclusion that they are pitching the monoamine hypothesis as correct and understood to an ignorant public.

I think it's fair to say researchers are still operating loosely within the framework of monoamine imbalance, given the predilection of pharmas to releasing new drugs which operate via modulation of monoamines rather any other action. Paradoxically if they were stepping away from the monoamine hypothesis, they would produce polymonoamine regulatory drugs which would more subtly manipulate multiple monoamines in order to get the desired modulation of maloperating neural circuits, the target du jour.

I guess we have to disagree on the science here regarding your last point... the therapeutic effects of SSRIs are certainly (100% with no wiggle room, a settled fact) a result of subtle neural circuit modulation to get therapeutic effect via monoamines.

[throwaway98031]

I'm not sure where you're getting your information from, but a lot of it is very incorrect and has a strong anti-pharma bias. For example:

> Paradoxically if they were stepping away from the monoamine hypothesis, they would produce polymonoamine regulatory drugs which would more subtly manipulate multiple monoamines in order to get the desired modulation of maloperating neural circuits, the target du jour.

The suggestion that pharmaceutical companies aren't exploring other pathways has never been more wrong, as we have quite a few very novel compounds in the pipeline that operate through very different pathways. Search for my other comment in this thread where I listed several of the other pathways and medications being explored.

Furthermore, I'm confused by your simultaneous dismissal of the monoamine hypothesis and insistence that "polymonoamine" drugs are the way to go, which isn't compatible with your assertion that the monoamine hypothesis is false. For what it's worth, there are several drugs in the pipeline that work through different combinations of monoaminergic pathways, but the most promising developments are actually in drugs that don't work through monoaminergic pathways at all (e.g. NSI-189, GABA-A5 antagonists, and so on.)

[cma]

That article is terrible to bring up here. He says suicide is a risk but would take a whole 'nother article and leaves it at that. At one point he uses anecdotal data of his own experience and gives it statistical weight by invoking the anthropic principle. What??