22 ms·

Comparative efficacy and acceptability of 21 antidepressant drugs

133 points by rb2e 9y ago

harbie 9y ago
>"We excluded quasi-randomised trials and trials that were incomplete or included 20% or more of participants with bipolar disorder, psychotic depression, or treatment-resistant depression." Wikipedia defines treatment resistant depression as "cases of major depressive disorder that do not respond adequately to appropriate courses of at least two antidepressants." Maybe I'm unfamiliar with study methodology, but doesn't this undermine the study's conclusion? It's essentially stating that forms of deppresesion that respond well to antidepressants respond well to antidepressants.
- deleted 9y ago
  [deleted]
- tyu100 9y ago
  SSRIs are generally indicated for what's called mild/moderate depression, the most common form, not for the serious conditions that you highlighted. There were some older meta-studies that called into question their general efficacy vs. placebo even for mild/moderate depression but this new meta-study (with the additional previously unpublished data from their initial approval trials) looks like it has finally settled the matter. Reading this paper I'm amazed at the increased efficacy of some of the newer SSRI's despite not having a novel mechanism of action. This is similar to how effective some of the newer statins are at lowering LDL cholesterol despite the drug class being around for decades. edit: It looks like I'm a bit out-of-date in my knowledge but the general point still stands. DSM V has a definition of 'major depressive disorder' which seems to have replaced the old mild/moderate categorization and this study looked at all anti-depressants that treat this type of depression, not just SSRIs.
  - kqr 9y ago
    > Reading this paper I'm amazed at the increased efficacy of some of the newer SSRI's despite not having a novel mechanism of action. There are huge differences in the mechanism of action, quantitatively speaking, even within a class of antidepressants. As a particularly striking example, you're allowed to call your drug an SNRI as long as it has any detectable N effect at all -- even if the N effect is too small to practically make any sort of difference, and the drug is practically an SSRI. Don't remember well enough to cite exactly but this may have been it: https://link.springer.com/article/10.1007/s11920-013-0370-7 https://link.springer.com/article/10.1007/s11920-013-0370-7?
  - icantdrive55 9y ago
    I am obviously confused, as usual. I'm not used to reading these studies. I'm looking at the study. I'm looking at the #3 graph under Tables and Functions Tab. It says amitriptyline is the best drug? Isn't that an older drug, or am I misreading the chart?
    - kqr 9y ago
      "Best" is a complicated concept. Yes, amitriptyline has the greatest efficacy, i.e. response rate in a clinical setting. It may still have poor effectiveness (how well it works in the real world) because it belongs to a class of medications which, if you use them, you have to exclude many types of common foods from your diet. It also has less safety margins in terms of overdosing than many modern alternatives. And then there's also the odd fact that earlier trials of antidepressants show better effect than recent ones -- even for the same treatment and all else held equal. We don't know why.
      - alex_hitchins 9y ago
        What foods should I avoid? I'm been taking Amitriptaline for 8 years now for pain management and wasn't given any advise on substances to avoid. Although I'm on another Anti-Depressant, I certainly notices a positive effect from Amitriptaline that outweigh the bad effects.
        mnw21cam 9y ago
        Basically, the foods you need to avoid are any that might cause constipation, because Amitriptyline kind of does that for you already. The parent post was possibly confusing Amitriptyline with a different drug. It is very weird to be mixing two different antidepressants. Depending on what your other antidepressant is, it could be dangerous. Were your two medications prescribed by the same doctor, and if not, have the two doctors talked to each other? A very simplistic view is that some antidepressants cause the body to make more serotonin, and others prevent the body from destroying serotonin as quickly. Doing one is fine, but doing both at the same time can lead to serotonin syndrome. Amitriptyline does have higher risk from overdose than SSRIs, but has much gentler withdrawal symptoms.
  - nerfhammer 9y ago
    treatment-resistant doesn't mean severe, it means treatment resistant.
- alz 9y ago
  Right! They exclude cases where they don’t work, then conclude ‘All antidepressants were more efficacious than placebo’. This is highly misleading
random_throw 9y ago
Key bit: "In head-to-head studies, agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine, and vortioxetine were more effective than other antidepressants (range of ORs 1·19–1·96), whereas fluoxetine, fluvoxamine, reboxetine, and trazodone were the least efficacious drugs (0·51–0·84)."
- fernly 9y ago
  Also significant, the next sentence, "For acceptability, agomelatine, citalopram, escitalopram, fluoxetine, sertraline, and vortioxetine were more tolerable than other antidepressants (range of ORs 0·43–0·77), whereas amitriptyline, clomipramine, duloxetine, fluvoxamine, reboxetine, trazodone, and venlafaxine had the highest dropout rates." It appears that agomelatine[1] and vortioxetine[2] are effective and well-tolerated. Good to know. [1] https://en.wikipedia.org/wiki/Agomelatine https://en.wikipedia.org/wiki/Agomelatine : "...avoids the weight gain, sexual dysfunction, and severe withdrawal associated with the most commonly used classes of antidepressants..." [2] https://en.wikipedia.org/wiki/Vortioxetine https://en.wikipedia.org/wiki/Vortioxetine : "...Incidence of sexual dysfunction is higher in patients taking vortioxetine than in people taking placebos but appears to be lower than in people taking most other antidepressants..."
  - contingencies 9y ago
    I didn't read the paper but going off your comment and the parent - escitalopram was in both lists, whereas vortioxetine wasn't. http://en.wikipedia.org/wiki/Escitalopram http://en.wikipedia.org/wiki/Escitalopram
- joveian 9y ago
  However, agomelatine was not approved in the US due to clinical trials not showing effectiveness (withdrawn by the drug company after phase III), although regular melatonin is super easily available here and I've heard some people say it helps. For a good analysis it is important to get access to unpublished studies submitted to the FDA. I don't have links but I think there are a couple that have done that. Edit: Looks like they did include some unpublished studies at least.
ggm 9y ago
A professional I know in the field (who repudiates drugs for CBT, and so is probably biassed, but still...) says that the lack of clarity over how an antagonist and a suppressant can both be claimed to operate on the same underlying problem and have adherents, points to bad understanding of what actually causes the problem.
- amputect 9y ago
  I basically agree with your friend, but I'm pro-drugs for pepole who find them helpful. I very strongly suspect that the underlying "problem", like with cancer, is actually an enormous variety of problems that cluster into vaguely similar symptom groups. I am absolutely not an expert here, this is a layperson's opinion, but it's really hard to imagine that there's just one specific cause that we're treating. I think that's why different drug classes vary so wildly in effectiveness from person to person, there's a ton of underlying confounding variables that we simply don't understand. But what we do know is that anti-depressants can be a powerful tool for helping people who aren't responsive to other types of treatment. Even if it takes some effort to figure out which one is the best fit for the underlying disorder, that's better than nothing.
  - ggm 9y ago
    Yes, but we need professionals to be more overt we are groping in the dark I think. The recent news about why ketamine works is a very specific aha moment, they showed a focussed impact on a brain functional element which seems to re-stim negative ideation and so blocking it relieves a cycle and then permits some kind of reset. Layman's analogies.
- JamesBarney 9y ago
  True, but man found fire very useful for millennium before we understood it. And as little as we know about how drugs work we know less about how CBT works.
  - ggm 9y ago
    Yes, "push a man into a fire, and end his hunger forever" useful stuff fire.
icantdrive55 9y ago
To those struggling with the terminology, this site helped me a bit. I wasn't familiar with Odds Ratios (OR). And I'm still confused, with a headache. https://www.students4bestevidence.net/a-beginners-guide-to-interpreting-odds-ratios-confidence-intervals-and-p-values-the-nuts-and-bolts-20-minute-tutorial/ https://www.students4bestevidence.net/a-beginners-guide-to-i... I would love to have someone explain this study in a simple way, with simple percentages. For example, what is the efficacy of, say Prozac, compared to placebo? "In terms of efficacy, all antidepressants were more effective than placebo, with ORs ranging between 2·13 (95% credible interval [CrI] 1·89–2·41) for amitriptyline and 1·37 (1·16–1·63) for reboxetine." This says all antidepressants work between what percentage? And in another post, someone mentioned the newer antidepressants were better that the older ones. What percentage better? (And yes--I need to brush up on my statistics. I've taken a few of these drugs. I used to know how to read a simple study, and stopped because the results were so depressing. I am throughly confused with this study, and the charts. Then again, I'm not feeling great.)
amputect 9y ago
I think that the United States is getting better about dealing with mental health, but we still have a long way to go. This is a little soap-boxy and anecdotal, and I apologize if it's inappropriate here. If I hadn't gotten a prescription for Prozac I probably would have killed myself by now. And I definitely would have destroyed my marriage and most of my important friendships. That's not an over-dramatization, it's the honest truth just based on the direction my life was heading without them. If you can't make your own neurotransmitters, store bought are fine. I'm not writing this to say "RARGH YOU MUST USE THESE DRUGS", but I absolutely am writing it to say "hey, this worked for me and got me out of a really dark and bad place". If you are reading this from a dark and bad place, please know that you're not alone. You have a lot of options, and I promise that if you take that first step, things can get better.
- publicfig 9y ago
  As someone in the very same boat, I appreciate and can relate to the line you have to walk. My life was positively changed by going on Prozac in a way that I didn't think was possible. After years and years of trying any way of dealing with depression that didn't involve medication, I was absolutely at a dangerous place. Most of my reasoning was that I didn't really believe in the efficiency of medication, and even if so, I didn't think I was actually someone with depression, just that I had been, since i was a kid, putting myself into constant situations that caused severe anxiety and depression. It didn't all work at once, and I had a lot of weird steps between starting and being in a state that I would now consider "my normal self that I never knew I actually was", but it's been an overall life changing experience. That being said, I understand that medication, or even the same medications, can't work for some people in the way they did with me. It's difficult to explain the position of "I know medication doesn't always work and isn't always an answer, but sometimes it is an answer that I would hate to be missed out on".
- evincarofautumn 9y ago
  Likewise, if storebought doesn’t do the trick, some people (myself and my partner included) have better luck with the recreational variety—mushrooms were the thing that kicked me in the psychological ass and started me on the path to recovery from alcoholism (which was partly self-medicating for anxiety). To be clear, this is absolutely not something I’d recommend lightly. Taking (who knows how strong) mushrooms or LSD isn’t exactly the most precise or reliable way to go about it, and there are attendant risks. I just hope in the future there’s more access to psychedelics (and analogues) in a safe, professional setting, because they’ve been shown to be another potentially useful tool in the antidepressant/anxiolytic/self-care kit.
smt88 9y ago
This is consistent with my understanding, but: - how serious are the side effects? - how well would harmless placebo pills work in their place? I currently believe that there needs to be a safe, placebo-like option for people without severe illnesses. For those who are severe (and can tolerate side effects as serious as suicidality), it still seems to be a good idea to prescribe them.
- tlrobinson 9y ago
  "placebo-like option" How would that work? Do placebos work even if people know they're placebos? Could doctors just start prescribing a placebo called Fauxzac and it would work some of the time?
  - comex 9y ago
    > Do placebos work even if people know they're placebos? Sometimes, yes! See: https://www.health.harvard.edu/blog/placebo-can-work-even-know-placebo-201607079926 https://www.health.harvard.edu/blog/placebo-can-work-even-kn... But they're probably more effective if you don't know.
- icantdrive55 9y ago
  Supposedly, in Japan it's common to prescribe placebo pills to patients. In the United States, it's illegial. My hope is that they would start teaching kids about The Placebo Effect in grade school. I didn't know about it until college. Then again, I imagine millions of people are healed each you by the mind blowing phenomena. They might be better off not knowing? The person just thought they would get better, and they got better. God like?
gehwartzen 9y ago
Reading through the paper it seems like all the statistics are presented as Odds Raios vs placebo. But I couldn't find the actual efficacy of placebo. Did I miss it or does someone know? Something being twice as effective as a placebo is great when the placebo effect helps 30% of patients, not so much when it's 3%
- itschekkers 9y ago
  placebo rates would be something in the 15-40% remission rate range, in small RCTs. it varies more than you would think from one trial to another. antidepressant efficacy would be something like 20-45%. recovery rates are usually higher in smaller trials, and lower in bigger trials, partly because people get more high-touch service in smaller academic studies
gliese1337 9y ago
As another person who is on antidepressants, and tried going off them for a while: well, duh. Yeah, I know, anecdotes aren't data, and I'm glad this is being verified by more reliable statistical methods, but this is not news to the many of us who might be dead or worse if someone hadn't said "you are sick--go see a doctor" and if that doctor hadn't said "you need medication--let's see if this works". Without antidepressants, my best case scenario is being an unemployed grad-school drop-out. With anti-depressants... well, it's amazing what you can do when you actually have enough neurotransmitters in your brain!
- lawl 9y ago
  > well, it's amazing what you can do when you actually have enough neurotransmitters in your brain! This notion of chemical imbalance in the brain is wrong/misleading by the way.[0] > The fact that two efficacious classes of medications exert opposing effects on serotonin levels raises questions concerning a simplistic chemical imbalance model. [0] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4522609/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4522609/
  - gliese1337 9y ago
    Decent point. Have an upvote. I guess I'll just go with "when your brain is working properly", then.
- aianus 9y ago
  > it's amazing what you can do when you actually have enough neurotransmitters in your brain Anything except having an orgasm, in my case.
  - Jaruzel 9y ago
    Seconded. They don't actually warn you about the emotional impact of not being able to orgasm, and the added stresses it can add to a relationship. :(
  - gliese1337 9y ago
    Well, yeah, there is that. I am somewhat fortunate to be the sort of person who doesn't care too much about that, but it can definitely be a sucky tradeoff for many people.
jkmcf 9y ago
PSA: The first thing to realize is that psychiatrists, and regular practitioners, have no clue what will work for you. In my case, it took 8+ years of trying, giving up, and trying again. E.g., Prozac didn't affect me at all, but the doctor never suggested increasing the initial dose. Paxil didn't work, Lexapro kinda worked, and now on the maximum dose of Effexor. The biggest difference makers were the doctors perfectly willing to help me find a solution. Keep trying to find one like this, and don't give up.
- tinymollusk 9y ago
  This applies to everything in life. Just because an expert tells you it'll work, doesn't mean it will. Balance the possible negative effects against the possible gains, and once you have learned how it affects yourself, make your own decision. (Unless trying something creates a condition that cannot be reverted, e.g. death)
- markroseman 9y ago
  Close enough to accurate. The better ones can apply useful heuristics (symptom matching, family response, etc.) as well as more sophisticated management of dose, side effects, etc. to converge on the solution much faster, but at this point, there's definitely still trial and error involved.
- mnw21cam 9y ago
  Yeah, with me it took a few tries as well. My doctor tried me on a few, before giving up and referring me to a specialist, who basically said that none of the doses I had been given so far were very high, so why don't we just increase the one you are on now. It worked.
siliconc0w 9y ago
So it should probably be noted that given these are powerful psychotropic drugs so it's difficult to control for them with a placebo and we don't really know their longitudinal effects. Also proper diet, exercise, yoga, or meditation can all help with mood and depression but you can't patent that shit. This isn't to say the drugs have no value but the bar to use them should be high.
comex 9y ago
The problem with studies of antidepressants is that they're almost all based on short-term, fixed-length treatment courses. After all, you can't do a double blind trial that lasts years on end; it would be unethical to give someone a placebo for that long, when antidepressants are believed to work better. Yet (AFAIK) people who go on antidepressants typically stay on them for years, so the studies are reviewing a fairly artificial use case. It's like the handful of controlled trials that attempt to compare programming languages, which by necessity ask participants to solve short, fixed programming exercises, even though that bears little resemblance to the process of real software development. In the case of antidepressants - on one hand, there are some reasons to expect short-term interventions to be the best-case scenario in terms of evaluating benefit, such as the greater risk of side effects with long-term use, and drug tolerance effects. On the other hand, I suspect (but don't have data to prove) that placebos are much less effective in the long term. People think the placebo effect is in part a reaction to the social experience of interacting with a doctor, getting personal attention and concern for whatever condition is supposedly being treated. To the extent this is true, the novelty of the experience is probably a large factor, and over the long term you'd expect a reversion to the mean. So even if antidepressants are less effective in the long term than the short term, they might be more compelling as a treatment option, because the alternative (placebo) loses even more of its effectiveness. Edit: Another factor is that the effects of reduced depression may take a long time to be fully apparent. Depression tends to work in feedback loops: as an oversimplified example, you feel bad about yourself, so you lose motivation to take care of your life, so you start neglecting essential tasks, the consequences of which make you feel even worse about yourself. And lifting yourself out of depression is the same thing in reverse. So if an antidepressant has the effect of reducing your susceptibility to depression - i.e. under the same life circumstances, you wouldn't lose quite as much motivation, or see things quite as darkly - then even a small change might tip the balance and let you stay at equilibrium in a more functional state of mind. But before you can reach that equilibrium, you have to go through a long process of getting your life back in order and regaining self-confidence.
- jernfrost 9y ago
  The feedback loop is definitely a major component. It is why I've frequently entertained the thought of doing drugs. Simply because I feel a need for something to help me get started down the right path. Exercise, eat better, see friends, actually complete stuff properly at work etc. Depression has a tendency to put you in a state where you are just barely holding on to life and doing anything extra each day to improve your condition seems like an insurmountable obstacle.
djsumdog 9y ago
> meta-analysis I knew a lot of other grad students, myself included, who would throw anything with meta-analysis in the introduction in the trash. You cannot deal with controls across completely different studies in meaningful ways. I'm also hesitant about anything that tries to claim things definitively without question. Science is about continually questioning your axioms. Without doubt[1] there is no progress. As someone who has been on various anti-depressants, I will say that some of them "worked" .. but the side effects were quite high. Working only lasted the first few weeks with several different SSRIs. Eventually the side effects ended up being worse than the treatment. I found the most effective thing for me was simply a really good therapist. She did try to recommend drugs to me again after I had quit, but she did respect my wishes to not be on them. I feel that having someone who really showed me my options and truly helped examine negative thinking patterns helped a lot more than the drugs ever did. That being said, I know people who say they'd be in serious trouble or dead without SSRIs. It's a tough line to talk about. I personally would rather not ever be on them again. Dulling the pain for me also meant dulling life. There are trade offs and we need to talk about them and have full discussions on the consequences of mind alternating drugs. When things are written into pure absolutes, it is a means of killing real discussion and dialogue. [1]: https://khanism.org/science/doubt/ https://khanism.org/science/doubt/
- sjg007 9y ago
  >I knew a lot of other grad students, myself included, who would throw anything with meta-analysis in the introduction in the trash. You cannot deal with controls across completely different studies in meaningful ways. You probably need to rethink this. Meta-analysis can be quite stable and valid.
- entropyneur 9y ago
  > Dulling the pain for me also meant dulling life. I've heard quite a few people say similar things (including my therapist), but it's such a sharp contrast to my own experience. There are indeed very good reasons not to use these drugs (I currently don't and it's costing me dearly), but "dulling" is not a word that would ever come to my mind if I tried to describe the experience of being on them. The years I was medicating are actually the brightest patch of my adult life. Well, I guess such differences are to be expected when we don't know what depression is and why these drugs work.
imperio59 9y ago
Horrible side effects, no tests for diagnosis, no actual cures (have you heard of these drugs actually curing depression? No. Once you get on them you are basically on them for life...)... I think this "Science" of psychiatry has a long ways to go to actually get repeatable, scientifically proven results.
- projektfu 9y ago
  Yes, cures happen all the time. I'm an anecdote, but I was cured of depression using venlafaxine. Talk therapy was used at various times but it was not effective. I no longer take venlafaxine and I am not depressed. I will say that getting "off" of venlafaxine is troublesome and must be pursued gradually and slowly because the withdrawal is severe. Once I was cured it took about 9 months to go drug free.
  - ComputerGuru 9y ago
    I take venlafaxine for migraines and and of the many drugs I’ve tried, absolutely nothing compares to the withdrawal symptoms for venlafaxine. They start 12 hours after missing a dose and doctors have no official designation for them, besides being insanely nasty. Please for the love of all that is holy, if you are on venlafaxine and want to switch to something else: titrate. Not all doctors know about the withdrawal problems with venlafaxine. They are horrendous.
  - Jaruzel 9y ago
    I'm on Venlafaxine (300mg/day). Previously I tried Amitriptyline, and Citalopram, both of which did not suit me, so I pulled myself off them... each time the depression and anxiety returned. Although I am fairly happy on Venlafaxine (it stopped me killing myself, so that's a plus), I'd like to get off it at some point as the side affects are quite annoying. Can I ask you how you feel you were 'cured' and are there any resources I can look at? Thanks.
    - projektfu 9y ago
      I felt that I was not depressed anymore and I started working with my psychiatrist to reduce dosage until I was on the minimum dose. Then I stopped when I was feeling particularly good and kept a bottle of 5-HTP on hand. I'm not sure if that was necessary or not.
askvictor 9y ago
This analysis look at effects over 8 weeks. The first four weeks on antidepressants you're feeling terrible due to onset side effects (on top of your depression). Once that settles, you feel better. But there is no way to tell if you feel objectively better than before the medication started.
- grzm 9y ago
  > "But there is no way to tell if you feel objectively better than before the medication started." Would you elaborate at what you mean here? Two reads I have are either (a) you're getting at whether feelings like this are subjective, which is true definitionally but seems to me to be uninteresting, or (b) assessment tools (such as the Beck inventory) are imprecise, which is also true, but can still provide some basis for comparison. Or something else that I'm missing? That said, I would like to see a longer time scale to see if the changes are maintained.
- markroseman 9y ago
  Statistically, rating scales typically used in these studies have been validated as showing effect, and clinical interviews can pick up a lot of things. That said, it's normally hard for you to be able to look back eight weeks and subjectively compare how you feel then and now. Usually it's not the person being treated, but those around them (family etc.), who notice the improvements first.
  - askvictor 9y ago
    I think you mean objectively not subjectively. In any case, looking back that 8 weeks and comparing to now, _after you've just been through 4 weeks of hell_, you'll report that you're feeling a lot better, even if you've only returned to the same level you were before starting the meds. Are there studies that use family/etc as the basis for their data? That would be a lot more valuable, as long as they also include a control. The studies also need to look a lot longer than 8-12 weeks, partly due to the onset side effects, but also as a lot of depression is caused by a stress event that passes and resolves in a few months. It is interesting that a placebo has a positive effect (not as large as the meds); I wonder if they measured the effect of no treatment at all.
dmitripopov 9y ago
I don't think that researches like this make sense at all. Each depression is unique in it's pathogenesis, there are no drugs that work for everyone. For example, a depression caused by a chronic desease or the one with deep roots in your childhood - a true research needs to evaluate all 21 drugs in each situation.
SpikeDad 9y ago
I was worried as to the source of this study and the people who are claiming this "puts to rest the controversy of antidepressant drugs". It's all psychologists who naturally benefit greatly from a public perception that medication is effective. If I had seen quotes from psychologists saying "This is better than therapy - I'm stopping therapy and giving them drugs" then I would be on the bandwagon with the rest.
alz 9y ago
96 out of 522 trials identified as low risk of bias (18%)
- alz 9y ago
  Is this not an insanely low bar? How can we take this paper seriously? We are talking about brain alchemy and more than 80% of the trials under consideration have a moderate to high risk of bias?!
alz 9y ago
Authors receive consulting fees from big pharma including Merck Sharp & Dohme, LB Pharma, and Pfizer

133 points by rb2e 9y ago

>"We excluded quasi-randomised trials and trials that were incomplete or included 20% or more of participants with bipolar disorder, psychotic depression, or treatment-resistant depression." Wikipedia defines treatment resistant depression as "cases of major depressive disorder that do not respond adequately to appropriate courses of at least two antidepressants." Maybe I'm unfamiliar with study methodology, but doesn't this undermine the study's conclusion? It's essentially stating that forms of deppresesion that respond well to antidepressants respond well to antidepressants.

deleted 9y ago
[deleted]
tyu100 9y ago
SSRIs are generally indicated for what's called mild/moderate depression, the most common form, not for the serious conditions that you highlighted. There were some older meta-studies that called into question their general efficacy vs. placebo even for mild/moderate depression but this new meta-study (with the additional previously unpublished data from their initial approval trials) looks like it has finally settled the matter. Reading this paper I'm amazed at the increased efficacy of some of the newer SSRI's despite not having a novel mechanism of action. This is similar to how effective some of the newer statins are at lowering LDL cholesterol despite the drug class being around for decades. edit: It looks like I'm a bit out-of-date in my knowledge but the general point still stands. DSM V has a definition of 'major depressive disorder' which seems to have replaced the old mild/moderate categorization and this study looked at all anti-depressants that treat this type of depression, not just SSRIs.
- kqr 9y ago
  > Reading this paper I'm amazed at the increased efficacy of some of the newer SSRI's despite not having a novel mechanism of action. There are huge differences in the mechanism of action, quantitatively speaking, even within a class of antidepressants. As a particularly striking example, you're allowed to call your drug an SNRI as long as it has any detectable N effect at all -- even if the N effect is too small to practically make any sort of difference, and the drug is practically an SSRI. Don't remember well enough to cite exactly but this may have been it: https://link.springer.com/article/10.1007/s11920-013-0370-7 https://link.springer.com/article/10.1007/s11920-013-0370-7?
- icantdrive55 9y ago
  I am obviously confused, as usual. I'm not used to reading these studies. I'm looking at the study. I'm looking at the #3 graph under Tables and Functions Tab. It says amitriptyline is the best drug? Isn't that an older drug, or am I misreading the chart?
  - kqr 9y ago
    "Best" is a complicated concept. Yes, amitriptyline has the greatest efficacy, i.e. response rate in a clinical setting. It may still have poor effectiveness (how well it works in the real world) because it belongs to a class of medications which, if you use them, you have to exclude many types of common foods from your diet. It also has less safety margins in terms of overdosing than many modern alternatives. And then there's also the odd fact that earlier trials of antidepressants show better effect than recent ones -- even for the same treatment and all else held equal. We don't know why.
    - alex_hitchins 9y ago
      What foods should I avoid? I'm been taking Amitriptaline for 8 years now for pain management and wasn't given any advise on substances to avoid. Although I'm on another Anti-Depressant, I certainly notices a positive effect from Amitriptaline that outweigh the bad effects.
      - mnw21cam 9y ago
        Basically, the foods you need to avoid are any that might cause constipation, because Amitriptyline kind of does that for you already. The parent post was possibly confusing Amitriptyline with a different drug. It is very weird to be mixing two different antidepressants. Depending on what your other antidepressant is, it could be dangerous. Were your two medications prescribed by the same doctor, and if not, have the two doctors talked to each other? A very simplistic view is that some antidepressants cause the body to make more serotonin, and others prevent the body from destroying serotonin as quickly. Doing one is fine, but doing both at the same time can lead to serotonin syndrome. Amitriptyline does have higher risk from overdose than SSRIs, but has much gentler withdrawal symptoms.
- nerfhammer 9y ago
  treatment-resistant doesn't mean severe, it means treatment resistant.
alz 9y ago
Right! They exclude cases where they don’t work, then conclude ‘All antidepressants were more efficacious than placebo’. This is highly misleading

random_throw 9y ago

Key bit: "In head-to-head studies, agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine, and vortioxetine were more effective than other antidepressants (range of ORs 1·19–1·96), whereas fluoxetine, fluvoxamine, reboxetine, and trazodone were the least efficacious drugs (0·51–0·84)."

fernly 9y ago
Also significant, the next sentence, "For acceptability, agomelatine, citalopram, escitalopram, fluoxetine, sertraline, and vortioxetine were more tolerable than other antidepressants (range of ORs 0·43–0·77), whereas amitriptyline, clomipramine, duloxetine, fluvoxamine, reboxetine, trazodone, and venlafaxine had the highest dropout rates." It appears that agomelatine[1] and vortioxetine[2] are effective and well-tolerated. Good to know. [1] https://en.wikipedia.org/wiki/Agomelatine https://en.wikipedia.org/wiki/Agomelatine : "...avoids the weight gain, sexual dysfunction, and severe withdrawal associated with the most commonly used classes of antidepressants..." [2] https://en.wikipedia.org/wiki/Vortioxetine https://en.wikipedia.org/wiki/Vortioxetine : "...Incidence of sexual dysfunction is higher in patients taking vortioxetine than in people taking placebos but appears to be lower than in people taking most other antidepressants..."
- contingencies 9y ago
  I didn't read the paper but going off your comment and the parent - escitalopram was in both lists, whereas vortioxetine wasn't. http://en.wikipedia.org/wiki/Escitalopram http://en.wikipedia.org/wiki/Escitalopram
joveian 9y ago
However, agomelatine was not approved in the US due to clinical trials not showing effectiveness (withdrawn by the drug company after phase III), although regular melatonin is super easily available here and I've heard some people say it helps. For a good analysis it is important to get access to unpublished studies submitted to the FDA. I don't have links but I think there are a couple that have done that. Edit: Looks like they did include some unpublished studies at least.

ggm 9y ago

A professional I know in the field (who repudiates drugs for CBT, and so is probably biassed, but still...) says that the lack of clarity over how an antagonist and a suppressant can both be claimed to operate on the same underlying problem and have adherents, points to bad understanding of what actually causes the problem.

amputect 9y ago
I basically agree with your friend, but I'm pro-drugs for pepole who find them helpful. I very strongly suspect that the underlying "problem", like with cancer, is actually an enormous variety of problems that cluster into vaguely similar symptom groups. I am absolutely not an expert here, this is a layperson's opinion, but it's really hard to imagine that there's just one specific cause that we're treating. I think that's why different drug classes vary so wildly in effectiveness from person to person, there's a ton of underlying confounding variables that we simply don't understand. But what we do know is that anti-depressants can be a powerful tool for helping people who aren't responsive to other types of treatment. Even if it takes some effort to figure out which one is the best fit for the underlying disorder, that's better than nothing.
- ggm 9y ago
  Yes, but we need professionals to be more overt we are groping in the dark I think. The recent news about why ketamine works is a very specific aha moment, they showed a focussed impact on a brain functional element which seems to re-stim negative ideation and so blocking it relieves a cycle and then permits some kind of reset. Layman's analogies.
JamesBarney 9y ago
True, but man found fire very useful for millennium before we understood it. And as little as we know about how drugs work we know less about how CBT works.
- ggm 9y ago
  Yes, "push a man into a fire, and end his hunger forever" useful stuff fire.

icantdrive55 9y ago

To those struggling with the terminology, this site helped me a bit. I wasn't familiar with Odds Ratios (OR). And I'm still confused, with a headache. https://www.students4bestevidence.net/a-beginners-guide-to-interpreting-odds-ratios-confidence-intervals-and-p-values-the-nuts-and-bolts-20-minute-tutorial/ https://www.students4bestevidence.net/a-beginners-guide-to-i... I would love to have someone explain this study in a simple way, with simple percentages. For example, what is the efficacy of, say Prozac, compared to placebo? "In terms of efficacy, all antidepressants were more effective than placebo, with ORs ranging between 2·13 (95% credible interval [CrI] 1·89–2·41) for amitriptyline and 1·37 (1·16–1·63) for reboxetine." This says all antidepressants work between what percentage? And in another post, someone mentioned the newer antidepressants were better that the older ones. What percentage better? (And yes--I need to brush up on my statistics. I've taken a few of these drugs. I used to know how to read a simple study, and stopped because the results were so depressing. I am throughly confused with this study, and the charts. Then again, I'm not feeling great.)

amputect 9y ago

I think that the United States is getting better about dealing with mental health, but we still have a long way to go. This is a little soap-boxy and anecdotal, and I apologize if it's inappropriate here. If I hadn't gotten a prescription for Prozac I probably would have killed myself by now. And I definitely would have destroyed my marriage and most of my important friendships. That's not an over-dramatization, it's the honest truth just based on the direction my life was heading without them. If you can't make your own neurotransmitters, store bought are fine. I'm not writing this to say "RARGH YOU MUST USE THESE DRUGS", but I absolutely am writing it to say "hey, this worked for me and got me out of a really dark and bad place". If you are reading this from a dark and bad place, please know that you're not alone. You have a lot of options, and I promise that if you take that first step, things can get better.

publicfig 9y ago
As someone in the very same boat, I appreciate and can relate to the line you have to walk. My life was positively changed by going on Prozac in a way that I didn't think was possible. After years and years of trying any way of dealing with depression that didn't involve medication, I was absolutely at a dangerous place. Most of my reasoning was that I didn't really believe in the efficiency of medication, and even if so, I didn't think I was actually someone with depression, just that I had been, since i was a kid, putting myself into constant situations that caused severe anxiety and depression. It didn't all work at once, and I had a lot of weird steps between starting and being in a state that I would now consider "my normal self that I never knew I actually was", but it's been an overall life changing experience. That being said, I understand that medication, or even the same medications, can't work for some people in the way they did with me. It's difficult to explain the position of "I know medication doesn't always work and isn't always an answer, but sometimes it is an answer that I would hate to be missed out on".
evincarofautumn 9y ago
Likewise, if storebought doesn’t do the trick, some people (myself and my partner included) have better luck with the recreational variety—mushrooms were the thing that kicked me in the psychological ass and started me on the path to recovery from alcoholism (which was partly self-medicating for anxiety). To be clear, this is absolutely not something I’d recommend lightly. Taking (who knows how strong) mushrooms or LSD isn’t exactly the most precise or reliable way to go about it, and there are attendant risks. I just hope in the future there’s more access to psychedelics (and analogues) in a safe, professional setting, because they’ve been shown to be another potentially useful tool in the antidepressant/anxiolytic/self-care kit.

smt88 9y ago

This is consistent with my understanding, but: - how serious are the side effects? - how well would harmless placebo pills work in their place? I currently believe that there needs to be a safe, placebo-like option for people without severe illnesses. For those who are severe (and can tolerate side effects as serious as suicidality), it still seems to be a good idea to prescribe them.

tlrobinson 9y ago
"placebo-like option" How would that work? Do placebos work even if people know they're placebos? Could doctors just start prescribing a placebo called Fauxzac and it would work some of the time?
- comex 9y ago
  > Do placebos work even if people know they're placebos? Sometimes, yes! See: https://www.health.harvard.edu/blog/placebo-can-work-even-know-placebo-201607079926 https://www.health.harvard.edu/blog/placebo-can-work-even-kn... But they're probably more effective if you don't know.
icantdrive55 9y ago
Supposedly, in Japan it's common to prescribe placebo pills to patients. In the United States, it's illegial. My hope is that they would start teaching kids about The Placebo Effect in grade school. I didn't know about it until college. Then again, I imagine millions of people are healed each you by the mind blowing phenomena. They might be better off not knowing? The person just thought they would get better, and they got better. God like?

gehwartzen 9y ago

Reading through the paper it seems like all the statistics are presented as Odds Raios vs placebo. But I couldn't find the actual efficacy of placebo. Did I miss it or does someone know? Something being twice as effective as a placebo is great when the placebo effect helps 30% of patients, not so much when it's 3%

itschekkers 9y ago
placebo rates would be something in the 15-40% remission rate range, in small RCTs. it varies more than you would think from one trial to another. antidepressant efficacy would be something like 20-45%. recovery rates are usually higher in smaller trials, and lower in bigger trials, partly because people get more high-touch service in smaller academic studies

gliese1337 9y ago

As another person who is on antidepressants, and tried going off them for a while: well, duh. Yeah, I know, anecdotes aren't data, and I'm glad this is being verified by more reliable statistical methods, but this is not news to the many of us who might be dead or worse if someone hadn't said "you are sick--go see a doctor" and if that doctor hadn't said "you need medication--let's see if this works". Without antidepressants, my best case scenario is being an unemployed grad-school drop-out. With anti-depressants... well, it's amazing what you can do when you actually have enough neurotransmitters in your brain!

lawl 9y ago
> well, it's amazing what you can do when you actually have enough neurotransmitters in your brain! This notion of chemical imbalance in the brain is wrong/misleading by the way.[0] > The fact that two efficacious classes of medications exert opposing effects on serotonin levels raises questions concerning a simplistic chemical imbalance model. [0] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4522609/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4522609/
- gliese1337 9y ago
  Decent point. Have an upvote. I guess I'll just go with "when your brain is working properly", then.
aianus 9y ago
> it's amazing what you can do when you actually have enough neurotransmitters in your brain Anything except having an orgasm, in my case.
- Jaruzel 9y ago
  Seconded. They don't actually warn you about the emotional impact of not being able to orgasm, and the added stresses it can add to a relationship. :(
- gliese1337 9y ago
  Well, yeah, there is that. I am somewhat fortunate to be the sort of person who doesn't care too much about that, but it can definitely be a sucky tradeoff for many people.

jkmcf 9y ago

PSA: The first thing to realize is that psychiatrists, and regular practitioners, have no clue what will work for you. In my case, it took 8+ years of trying, giving up, and trying again. E.g., Prozac didn't affect me at all, but the doctor never suggested increasing the initial dose. Paxil didn't work, Lexapro kinda worked, and now on the maximum dose of Effexor. The biggest difference makers were the doctors perfectly willing to help me find a solution. Keep trying to find one like this, and don't give up.

tinymollusk 9y ago
This applies to everything in life. Just because an expert tells you it'll work, doesn't mean it will. Balance the possible negative effects against the possible gains, and once you have learned how it affects yourself, make your own decision. (Unless trying something creates a condition that cannot be reverted, e.g. death)
markroseman 9y ago
Close enough to accurate. The better ones can apply useful heuristics (symptom matching, family response, etc.) as well as more sophisticated management of dose, side effects, etc. to converge on the solution much faster, but at this point, there's definitely still trial and error involved.
mnw21cam 9y ago
Yeah, with me it took a few tries as well. My doctor tried me on a few, before giving up and referring me to a specialist, who basically said that none of the doses I had been given so far were very high, so why don't we just increase the one you are on now. It worked.

siliconc0w 9y ago

So it should probably be noted that given these are powerful psychotropic drugs so it's difficult to control for them with a placebo and we don't really know their longitudinal effects. Also proper diet, exercise, yoga, or meditation can all help with mood and depression but you can't patent that shit. This isn't to say the drugs have no value but the bar to use them should be high.

comex 9y ago

The problem with studies of antidepressants is that they're almost all based on short-term, fixed-length treatment courses. After all, you can't do a double blind trial that lasts years on end; it would be unethical to give someone a placebo for that long, when antidepressants are believed to work better. Yet (AFAIK) people who go on antidepressants typically stay on them for years, so the studies are reviewing a fairly artificial use case. It's like the handful of controlled trials that attempt to compare programming languages, which by necessity ask participants to solve short, fixed programming exercises, even though that bears little resemblance to the process of real software development. In the case of antidepressants - on one hand, there are some reasons to expect short-term interventions to be the best-case scenario in terms of evaluating benefit, such as the greater risk of side effects with long-term use, and drug tolerance effects. On the other hand, I suspect (but don't have data to prove) that placebos are much less effective in the long term. People think the placebo effect is in part a reaction to the social experience of interacting with a doctor, getting personal attention and concern for whatever condition is supposedly being treated. To the extent this is true, the novelty of the experience is probably a large factor, and over the long term you'd expect a reversion to the mean. So even if antidepressants are less effective in the long term than the short term, they might be more compelling as a treatment option, because the alternative (placebo) loses even more of its effectiveness. Edit: Another factor is that the effects of reduced depression may take a long time to be fully apparent. Depression tends to work in feedback loops: as an oversimplified example, you feel bad about yourself, so you lose motivation to take care of your life, so you start neglecting essential tasks, the consequences of which make you feel even worse about yourself. And lifting yourself out of depression is the same thing in reverse. So if an antidepressant has the effect of reducing your susceptibility to depression - i.e. under the same life circumstances, you wouldn't lose quite as much motivation, or see things quite as darkly - then even a small change might tip the balance and let you stay at equilibrium in a more functional state of mind. But before you can reach that equilibrium, you have to go through a long process of getting your life back in order and regaining self-confidence.

jernfrost 9y ago
The feedback loop is definitely a major component. It is why I've frequently entertained the thought of doing drugs. Simply because I feel a need for something to help me get started down the right path. Exercise, eat better, see friends, actually complete stuff properly at work etc. Depression has a tendency to put you in a state where you are just barely holding on to life and doing anything extra each day to improve your condition seems like an insurmountable obstacle.

djsumdog 9y ago

> meta-analysis I knew a lot of other grad students, myself included, who would throw anything with meta-analysis in the introduction in the trash. You cannot deal with controls across completely different studies in meaningful ways. I'm also hesitant about anything that tries to claim things definitively without question. Science is about continually questioning your axioms. Without doubt[1] there is no progress. As someone who has been on various anti-depressants, I will say that some of them "worked" .. but the side effects were quite high. Working only lasted the first few weeks with several different SSRIs. Eventually the side effects ended up being worse than the treatment. I found the most effective thing for me was simply a really good therapist. She did try to recommend drugs to me again after I had quit, but she did respect my wishes to not be on them. I feel that having someone who really showed me my options and truly helped examine negative thinking patterns helped a lot more than the drugs ever did. That being said, I know people who say they'd be in serious trouble or dead without SSRIs. It's a tough line to talk about. I personally would rather not ever be on them again. Dulling the pain for me also meant dulling life. There are trade offs and we need to talk about them and have full discussions on the consequences of mind alternating drugs. When things are written into pure absolutes, it is a means of killing real discussion and dialogue. [1]: https://khanism.org/science/doubt/ https://khanism.org/science/doubt/

sjg007 9y ago
>I knew a lot of other grad students, myself included, who would throw anything with meta-analysis in the introduction in the trash. You cannot deal with controls across completely different studies in meaningful ways. You probably need to rethink this. Meta-analysis can be quite stable and valid.
entropyneur 9y ago
> Dulling the pain for me also meant dulling life. I've heard quite a few people say similar things (including my therapist), but it's such a sharp contrast to my own experience. There are indeed very good reasons not to use these drugs (I currently don't and it's costing me dearly), but "dulling" is not a word that would ever come to my mind if I tried to describe the experience of being on them. The years I was medicating are actually the brightest patch of my adult life. Well, I guess such differences are to be expected when we don't know what depression is and why these drugs work.

imperio59 9y ago

Horrible side effects, no tests for diagnosis, no actual cures (have you heard of these drugs actually curing depression? No. Once you get on them you are basically on them for life...)... I think this "Science" of psychiatry has a long ways to go to actually get repeatable, scientifically proven results.

projektfu 9y ago
Yes, cures happen all the time. I'm an anecdote, but I was cured of depression using venlafaxine. Talk therapy was used at various times but it was not effective. I no longer take venlafaxine and I am not depressed. I will say that getting "off" of venlafaxine is troublesome and must be pursued gradually and slowly because the withdrawal is severe. Once I was cured it took about 9 months to go drug free.
- ComputerGuru 9y ago
  I take venlafaxine for migraines and and of the many drugs I’ve tried, absolutely nothing compares to the withdrawal symptoms for venlafaxine. They start 12 hours after missing a dose and doctors have no official designation for them, besides being insanely nasty. Please for the love of all that is holy, if you are on venlafaxine and want to switch to something else: titrate. Not all doctors know about the withdrawal problems with venlafaxine. They are horrendous.
- Jaruzel 9y ago
  I'm on Venlafaxine (300mg/day). Previously I tried Amitriptyline, and Citalopram, both of which did not suit me, so I pulled myself off them... each time the depression and anxiety returned. Although I am fairly happy on Venlafaxine (it stopped me killing myself, so that's a plus), I'd like to get off it at some point as the side affects are quite annoying. Can I ask you how you feel you were 'cured' and are there any resources I can look at? Thanks.
  - projektfu 9y ago
    I felt that I was not depressed anymore and I started working with my psychiatrist to reduce dosage until I was on the minimum dose. Then I stopped when I was feeling particularly good and kept a bottle of 5-HTP on hand. I'm not sure if that was necessary or not.

askvictor 9y ago

This analysis look at effects over 8 weeks. The first four weeks on antidepressants you're feeling terrible due to onset side effects (on top of your depression). Once that settles, you feel better. But there is no way to tell if you feel objectively better than before the medication started.

grzm 9y ago
> "But there is no way to tell if you feel objectively better than before the medication started." Would you elaborate at what you mean here? Two reads I have are either (a) you're getting at whether feelings like this are subjective, which is true definitionally but seems to me to be uninteresting, or (b) assessment tools (such as the Beck inventory) are imprecise, which is also true, but can still provide some basis for comparison. Or something else that I'm missing? That said, I would like to see a longer time scale to see if the changes are maintained.
markroseman 9y ago
Statistically, rating scales typically used in these studies have been validated as showing effect, and clinical interviews can pick up a lot of things. That said, it's normally hard for you to be able to look back eight weeks and subjectively compare how you feel then and now. Usually it's not the person being treated, but those around them (family etc.), who notice the improvements first.
- askvictor 9y ago
  I think you mean objectively not subjectively. In any case, looking back that 8 weeks and comparing to now, _after you've just been through 4 weeks of hell_, you'll report that you're feeling a lot better, even if you've only returned to the same level you were before starting the meds. Are there studies that use family/etc as the basis for their data? That would be a lot more valuable, as long as they also include a control. The studies also need to look a lot longer than 8-12 weeks, partly due to the onset side effects, but also as a lot of depression is caused by a stress event that passes and resolves in a few months. It is interesting that a placebo has a positive effect (not as large as the meds); I wonder if they measured the effect of no treatment at all.

dmitripopov 9y ago

I don't think that researches like this make sense at all. Each depression is unique in it's pathogenesis, there are no drugs that work for everyone. For example, a depression caused by a chronic desease or the one with deep roots in your childhood - a true research needs to evaluate all 21 drugs in each situation.

SpikeDad 9y ago

I was worried as to the source of this study and the people who are claiming this "puts to rest the controversy of antidepressant drugs". It's all psychologists who naturally benefit greatly from a public perception that medication is effective. If I had seen quotes from psychologists saying "This is better than therapy - I'm stopping therapy and giving them drugs" then I would be on the bandwagon with the rest.

alz 9y ago

96 out of 522 trials identified as low risk of bias (18%)

alz 9y ago
Is this not an insanely low bar? How can we take this paper seriously? We are talking about brain alchemy and more than 80% of the trials under consideration have a moderate to high risk of bias?!

alz 9y ago

Authors receive consulting fees from big pharma including Merck Sharp & Dohme, LB Pharma, and Pfizer