Posted by Couleuvre on July 6, 2019, at 7:17:25
In reply to Re: why, posted by Lamdage22 on July 4, 2019, at 5:25:08
> I am more excited about meds that have an entirely new mode of action.
I totally agree. You're right that doing too many trials of me-toos isn't worthwhile speaking from experience! Definitely it isn't worth it to try every single TCA or benzo or even SSRI. OTOH, having a few alternatives out there is nice, and it means that even for the period before the patent expires you get the benefits of competition (unlike with "orphan drugs" that aren't used much, and a lot of them are expensive-to-make biopharmaceuticals, so only one company makes one, even after the patent expires: as you might expect these tend to be super-expensive and nobody bothers to research a safer variant with fewer side effects (i.e. a me-too)).
OTOH, there are people who don't get anything from, say, Effexor, but who do well on one of the various other ones that target different (mainly serotonin) receptors in addition to blocking reuptake, like Remeron. And nobody's ever really come up with a true substitute for the old drugs, especially MAOIs but also (surprisingly) TCAs: if the TCAs weren't still available, I suspect that a lot more people who have "classic" depression would end up having to have ECT. (OTOH, if ECT were used more, maybe there'd be more research into reducing/eliminating its cognitive side fx, which would definitely be a Good Thing!)
I guess I've gotten cynical from having tried so many of the various post-SSRI ADs that combine monoamine reuptake inhibition with acting on various (mainly serotonin) receptors ("modulators" is the currently trendy term), like Serzone, Trintellix, Viibrid (is it just me or do drug brand names keep getting weirder and weirder?), etc., as well as the ones that have more noradrenergic activity (Wellbutrin, Effexor, Remeron, Strattera, etc.) and the various "adjunctive" stuff (long list). The reality is, even though they target various types of receptors and things, they're only really used as alternatives to SSRIs. Choosing one is pretty much guesswork: the main thing that seems to aid in making a genuinely rational choice is needing or wanting to minimise the risk of particular side effects.
What we really need to do is gain a real understanding of what the underlying mechanisms of different types of depression are, so that we can really diagnose it and not just sort of guess based on vague syndromes ("atypical," etc.) or comorbidity (like ADHD, various anxiety disorders (generalised anxiety (and sub-clinical anxiety symptoms), panic, PTSD (technically they DSM has moved this to a separate category for trauma disorders), social phobia, OCD, etc.), addiction and other drug problems, eating disorders, etc.). Until we can identify and diagnose types of depression objectively, we're going to be stuck with a lot of trial-and-error.
Unfortunately, although the 20th century brought us on a path in the right general direction, reaching this level of understanding is still a long way away, and will definitely require at least a few strokes of pure luck. The few non-monoaminergic ADs have pretty much all been discovered by somebody noticing that something seemed to help when people who had depression took them for some other purpose. Esketamine in particular pops to mind (probably b/c I took some yesterday).
A problem with this approach is that many (well, most) drugs have multiple different pharmacological targets. A drug that has more is considered "dirtier," compared to more selective "cleaner" drugs (SSRIs, e.g., are viewed as "cleaner" than TCAs). Often we don't know which action is responsible for which effect: some seem only to cause side effects, e.g., the anticholinergic [antagonism (blockade) of muscarinic acetylcholine receptors] effect of many TCAs. Because esketamine is a dirty drug, its antidepressant effect may have multiple mechanisms (its "dissociative" and even anaesthetic effects are something of a mystery too), and perhaps these mechanisms work synergistically (i.e., they have effects in combination that you wouldn't find on either list of all the effects that each of them has by itself). Researchers looking for "cleaner" alternatives, that work as well as ketamine as antidepressants but don't have so many side effects (and are safer, don't have its "abuse potential" (not really a big deal since the antidepressant dose range is so much lower than the recreational one, but this would be treated as an issue for something to be used orally), etc.) don't seem to be taking this into account: they're guessing which of the lengthy list of ketamine's pharmacological actions might be relevant, but they don't seem to be considering the possibility of multiple synergistic actions. Admittedly, since they're pretty much guessing, this would get rapidly more and more complicated the more different effects they wanted to try together. So anyway, as this example demonstrates, drug development is another area where it would be a lot easier if we understood the underlying causes of different kinds of depression (or even of depression in general!) and didn't have to just make slightly-educated guesses.
poster:Couleuvre
thread:1104909
URL: http://www.dr-bob.org/babble/20190513/msgs/1105176.html