Comparative efficacy and acceptability of 21 antidepressant drugs
thelancet.com
thelancet.com
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.
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".
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.
Why take risks with your health when there are lots of safe, cheap and efficacious treatments that can be monitored by your doctor?
Also in my case it wasn’t depression, so I can’t really speak to that, but SSRIs are also prescribed for anxiety disorders. I chose not to go on them when they were offered because I didn’t feel that the side effects were worth it, and they weren’t the correct treatment anyway because at the time I was mainly anxious due to alcohol withdrawal. (I’m lucky I didn’t have a seizure!)
The issue here I think is that most current anti-depressants are currently of the SSRI / SNRI / tri-cyclic class. These treatments work great for some people, but do not work for everyone.
In one case (ketamine), this particular hallucinogenic drug has emerged as a candidate for anti-depression therapy (at least in mechanism) that works quite a bit different than the above (acts on glutamate). Non-hallucinogenic glutamatergic anti-depression drugs are being developed as a result, but as one is well aware, this takes time. Until one of these drugs emerges (rapastinel seems furthest along at this time), off-label ketamine clinics do exist where you can take the drug with some degree of clinical supervision.
I have not seen too much on the serotonin agonist hallucinogens in the past relieving depression, but Googling, there does seem to be a newish article on psilocybin (https://www.nature.com/articles/s41598-017-13282-7) that suggests it does offer a possible interesting anti-depression mechanism too. Possibly more exploration is needed here to confirm whether it works well (or not) and, if so, how.
I don't think we've even come close to exploring all routes to resolving depression, so I think exploring as many routes as possible is a good path. (And I do think scientists are doing this -- the parent article was for instance the first time I've heard of a melatonin receptor agonist as an anti-depressant candidate! https://en.wikipedia.org/wiki/Agomelatine )
It's not the cost of the medication that's the problem. It's access to the professional to prescribe the medication that drives people to self-medicate, IMHO.
I really think they need to have some sort required of "Life Skills" class in high school. In which they teach you how to get help, how to ask for help, how to share your feelings with friends in a safe way. And your options if you do get into a deep dark way. Based on personal evidence, almost every adult gets depressed in some way and many don't know how to get help or deal with it in a healthy way.
I didn't learn any of that till my 30s. I nearly committed suicide multiple times. Our current society and the toxic religious one i grew up in taught me that a man needs to be strong and doesn't need to rely on others. Pray to God and just pull yourself up by your bootstraps mentality.
It's amazing how helpful it is to know that you are loved and cared for. And people want to help you. You just have to ask for it.
The majority of people with depression just get better of their own accord, for no obvious reason. The NNT for most antidepressants is ~7, meaning you need to give them to about seven patients for one patient to see a clinically-significant improvement.
The evidence suggests that there's no significant relationship between SSRI use and suicide risk except for young people, for whom SSRIs may actually increase the risk of suicidal behaviours and self-harm.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3353604/
>If you can't make your own neurotransmitters, store bought are fine.
There is no evidence whatsoever that people with depression are "deficient" in neurotransmitters. We don't really understand the mechanism of action of any antidepressant. Plenty of drugs that have no effect whatsoever on serotonin are equally effective as SSRIs.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4471964/
Antidepressants can be useful for some patients, but they aren't miracle drugs - they aren't even particularly good drugs. If you're depressed then you should certainly consider pharmacological treatment, but you should regard it as only one tool among many. Talking therapy is equally effective and the combination of drugs and talk therapy is more effective than either alone. You might need to try several different drugs before you find one that works for you and has tolerable side-effects, especially if you have been depressed for some time or have comorbid conditions. If your depressive symptoms are relatively mild, you should probably look at lifestyle interventions like diet, exercise, sleep hygiene and self-help before considering drug treatment.
I could imagine that NNT might significantly improve if you consider “use antidepressants” instead of “use 1 antidepressant 1 time”
I don't want to be overly negative about antidepressant drugs - they're a useful treatment for many patients - but I do feel that the popular perception of their efficacy is far greater than the reality. Many people seem to feel extremely disheartened when antidepressant drugs don't work for them, often believing that there must be something uniquely wrong with them. The language of psychiatry doesn't help, describing these people as "treatment-resistant" rather than "people we don't know how to treat".
If you try antidepressant drugs and they don't seem to do anything, don't keep taking them just because you think you're supposed to. Speak to your doctor about alternative drug and non-drug treatments. If you have access, try a range of psychotherapies. If your symptoms are relatively mild, look at lifestyle interventions. If your symptoms are particularly severe and/or chronic, give some serious thought to rTMS or ECT.
it is less than anyone might spontaneously guess, but it is still good, considering that you will try a couple of other things in addition, like cognitive therapy.
So getting some good months long treatment by a doctor can lead to (lets say) 70% curation rate. It then becomes sad if people choose to stay away from doctors and I just commented to not discourage possible ill persons.
You probably just wanted to stress that such pills are far away from doing guaranteed miracles and you are right.
Which is fine, as long as they stay alive long enough for natural changes to occur. If a prescription gives only hope, that could be enough to keep people strong enough to battle through another day, week, month, year.
I decided late 2017, after a major depressive episode, that I needed to get help after 12 years of dealing with this depression. I kept thinking that I had a handle on it, and then it coming back weeks, months or years later.
I read The Depression Cure (https://www.amazon.com/Depression-Cure-6-Step-Program-withou...) about 5 years ago, and it helped for awhile, but it started to worsen again, and after awhile, getting the right diet, exercise and sleep seemed impossible because of the depression and anxiety.
I started therapy about 3 months ago, and finally agreed to try medication. I started taking Zoloft 3 weeks ago, and the side effects are downright awful. I made it through the first 3 weeks though, and I'm starting to feel a lot better.
Zoloft might not end up being the right medication for me, and there might be a better one, but my goal is to find something that takes 10%-20% of the depression and anxiety symptoms away so that I can start my path to curing this beast with the methods Dr. Iliardi outlines in The Depression Cure. Once I'm at a point where I'm better, I'm going to try and ween off the medication and try to live a healthy, great life without SSRIs.
For me the SSRIs completely wiped out my OCD to the point where I sometimes forget that I have problems with anxiety. Depression is downright benign compared to how bad the situation can get with other psychiatric disorders. Unfortunately the demand for competent medical professionals far outstrips what is available.
I do agree that SSRIs are over-prescribed for minor depression problems, but let's not demonize a whole class of medications which are highly useful for more serious psychiatric issues.
No - you just have no experience of comparably serious depression.
If the underlying problem is a psychosocial stressor, the meds won't fix that, though they might help you control the symptoms long enough that they give you the opportunity/resilience to address the stressor. And sometimes, while maybe not ideal, just controlling the symptoms is enough even for the long term.
I know the causes of my issues, there are at a minimum mitigations available but I can't BUY them because everything here is a business and competition and someone else took me out of the race by taking lots of money to end my capacity to compete (poor medical intervention) and I was left holding all the additional baggage with no help. I have friends who suffered catastrophes living in countries who don't think social systems are evil, and they had the tools to heal as much as possible and improve their lives and be able to contribute to the whole again. I wasn't afforded that opportunity and it's been a constant downhill slide.
Pardon the tone and it is not directed at you, it just infuriates me that American society ignores such important things and once someone is not able to WIN in the Thunderdome they are cast aside and/or expected to live with little to nothing and even more needs, while it continues focusing on pushing what are in my view largely ineffective, but very profitable "interventions". I find the predilection for painting over damage in this country over restoring/shoring up someone's foundation to be maddening.
b) Saturation marketing of psychiatric medication has caused the general public to grossly over-estimate their efficacy, even in countries where direct-to-consumer marketing is banned.
c) The wholesale price of a generic sertraline pill is about 4¢, so it's cheap enough to dole out like candy.
d) Medicalizing unhappiness is politically convenient.
If you're depressed, you go to your doctor. That's the message you've been told for decades, it's how our society is set up. In another culture, you might speak to your priest or a village elder. It's undoubtedly a net positive that we've got access to some kind of evidence-based psychiatric care, but a lot of the other structures that people used to rely on for psychosocial care have crumbled. We're less likely to know our neighbours. We have fewer close friends. Our employment is more impersonal and precarious. We're less likely to go to church. If we do go to church, it may well be a megachurch with a congregation of hundreds rather than a close-knit community church.
Doling out pills is the absolute cheapest treatment option, even if some proportion of those pills are expensive proprietary drugs. It's orders of magnitude cheaper than psychotherapy and immeasurably cheaper than building a more humane society. Your doctor can't prescribe a good friend, a sympathetic partner or a better job.
It suits your employer if you conceptualize your misery as the symptom of a "neurotransmitter deficiency" rather than a symptom of your crappy job. You probably won't be as productive, but at least you won't go on strike or burn down your office. It suits the government equally well if you see misery as a personal rather than societal problem.
Some people are just depressed for no discernible reason. Lots of people are being diagnosed with depression when they're just struggling with a shit set of circumstances that would make anyone miserable. The medical model helps some number of people in both camps. Society needs to do a better job of helping people live healthy and fulfilled lives.
The paper says: "However, in children and adolescents, there appears to be a bit of increased risk of suicidal ideations and attempts, but not of completed suicides."
I am not encouraging people not to try medication if they feel it is a good option, simply asking people to realize A. It's not a cure without a plan to fix the cause and B. Not to follow the common victim blaming that often occurs when these simple "fixes" don't work for people (OP isn't doing that and I don't intend to sound as if I am saying so...in fact they made it clear it's not a magical fix suited for all) Drugs are a tool, not a cure, and need to be wielded responsibly and properly. Sadly I don't believe that happens a lot of the time.
Also would you say the drug cured you? Are you able to function without taking it now?
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.
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.
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?
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?
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.
Although I'm on another Anti-Depressant, I certainly notices a positive effect from Amitriptaline that outweigh the bad effects.
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.
I find the ZoMorph blocked me up quite a bit, Fibrogel works well in this case.
Serotonin syndrome can be an issue with all kinds of things (most people aren't warned about being on a SSRI and having cough syrup for example), but is not very common in practice, and because it coincides with a change/increase in medication, often sorted out quickly, even if it's characterized as a "side effect" or "tolerability" problem and not actually recognized for what it is.
This study generalizes this process by discussing both efficacy (how well the drug helps with depression) and the tolerability of the treatment, as measured by how long people tend to stay on the drug (the site is down right now so I forget the actual term used). Once the paper is accessible again have a look at some of the graphs that chart both of these measures. Generally, the drugs in the upper-right quadrants are better, showing both good efficacy and tolerability.
This is basically a ranking to use in when trying drugs to statistically maximize your chance of finding one that works.
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.
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.
And as little as we know about how drugs work we know less about how CBT works.
Do you mean agonist-antagonist mechanism of action of some drugs that treat the same condition?
As far as I know different drugs can work on serotonin/dopamine/norepinephrine but in different parts of the brain and produce different results.
Drug A decreases 100ohm resistor values to 50 in a noise filter stage and "fixes" your problem with the radio.
Drug B has same 100ohm -> 50ohm effect, but in a different section of the radio and doesn't work.
Drug C increases the speaker resistance from 5ohm -> 10ohm and "fixes" your problem because you simply cannot hear the noise.
Drug D increases the microphone resistance from 5ohm -> 10ohm and the noise simply is not picked up.
Drugs A and B work the same way, drug C and D work the same way, but opposite to how drugs A and B work and they all provide the same net effect as far as I'm concerned.
Obviously therapy and other techniques should be attempted before drug prescription, but your friend is grossly oversimplifying how these drugs work and how psychiatrists portray how they work.
That they work is good. That they work about as well as CBT does, poses questions which as you observe goes to: Obviously therapy and other techniques should be attempted before drug prescription
If you want to take it a step further, think about what's causing communication via neurotransmitters to be slowed or sped up (not enough available? not being released? not being picked up by receptor?), the fact that there are multiple receptors for each neurotransmitter which drugs may or may not manipulate, the fact that there are multiple neurotransmitters (which end up affecting different areas of the brain and hence different symptoms, though some symptoms are influenced by multiple neurotransmitters), and that putting all these things together to result in the right balance of communication (not quantity of chemicals) in the brain, it would be a surprise if there weren't multiple different approaches for the "same" problem.
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.
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.
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%
"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)."
"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 : "...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 : "...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..."
Edit: Looks like they did include some unpublished studies at least.
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.
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.
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.
(Unless trying something creates a condition that cannot be reverted, e.g. death)
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.
You probably need to rethink this. Meta-analysis can be quite stable and valid.
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.
Best thing would be understanding that different solutions are right for different people, and we get in trouble by generalizing (whether it's about meds, therapy, nutrition, exercise, etc.). One illness, many root causes, many different presentations, and the appropriate solution depends on a multitude of variables.
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.
I think this "Science" of psychiatry has a long ways to go to actually get repeatable, scientifically proven results.
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.
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.
Funny enough that all the PR and talk from Pharma companies on these psychiatric drugs is all about treatment, and "living"and "coping"with symptoms... No cures, just selling you pills that don't actually work to cure your problem, just masks the symptoms or distracts you with side effects that are worse than your original issue (like obesity, loss of sexual function, etc...)
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!
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.
Anything except having an orgasm, in my case.
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.)
- 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.
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?
Sometimes, yes! See: https://www.health.harvard.edu/blog/placebo-can-work-even-kn...
But they're probably more effective if you don't know.