
Comparative efficacy and acceptability of 21 antidepressant drugs - rb2e
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)32802-7/fulltext
======
amputect
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.

~~~
jdietrich
>If I hadn't gotten a prescription for Prozac I probably would have killed
myself by now.

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/](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/](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.

[https://www.nice.org.uk/guidance/cg90](https://www.nice.org.uk/guidance/cg90)

~~~
tachyoff
I agree with all of this, and I can’t help but ask: when did we start ignoring
people’s environment and their circumstances? I have tens of thousands of
dollars of student loan debt (my monthly payment is basically a mortgage
payment) and I’m not particularly satisfied at work. Is it any wonder I find
it impossible to get out of bed? Now, I try to be careful because, sure,
perhaps the depression was already there and is just making my life
complicated, but that seems less likely. I KNOW I’m not happy at work; I KNOW
my debt burden makes me feel trapped and helpless. Look at Harlow’s monkeys.
Turns out putting creatures in helpless, depressing environments makes them
feel helpless and depressed. If seeing your friend get blown up by a roadside
bomb can give you PTSD, couldn’t falling wages, no social safety net,
stressful news media, crushing debt, and poor job mobility make you depressed?

~~~
markroseman
We're not ignoring their environment. But unfortunately, most of the time
drugs are quicker and easier for the prescribers, and therefore cheaper and
more available for the patient, than extended psychotherapy, etc.

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.

~~~
hestipod
"We" absolutely are ignoring their environment in the USA at least. People
cannot even access healthcare here without additional, significant financial
stress and burden. My entire family and the strong majority of my region and a
general majority overall oppose the policies and systems that would give
someone like me a life and future. Even seeing how it's gone for me my family
refuses to support social systems and offer help to those in need. It's
"stealing my money" to them and ruined our relationships seeing how selfish
they are turning their back on me AND society.

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.

------
harbie
>"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.

~~~
tyu100
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.

~~~
icantdrive55
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
"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
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
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.

~~~
markroseman
Being on more than one antidepressant is not unusual, and can even sometimes
be optimal. Even ones acting on the same neurotransmitter often target
different receptors and hence different symptoms. More often it's because
doctors are better at adding drugs rather than taking away ones prescribed by
other doctors "just in 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.

------
ggm
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
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
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.

------
comex
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
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.

------
gehwartzen
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
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

------
random_throw
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
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
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)

------
askvictor
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.

~~~
markroseman
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
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.

------
jkmcf
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
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)

------
djsumdog
> 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/)

~~~
tallanvor
Hopefully you and those other grad students will have learned more by the time
you finish your degree. A proper meta analysis does consider the differences
in controls across studies, and can be extremely useful in understanding why
different studies got different results and identify bad studies. Not only do
they help gain a better understanding of results, but they help find ways to
better design future studies.

------
SpikeDad
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.

------
imperio59
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
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.

~~~
Jaruzel
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
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.

------
siliconc0w
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.

------
dmitripopov
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.

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

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

~~~
alz
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?!

------
gliese1337
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!

~~~
aianus
> 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
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. :(

------
icantdrive55
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-i...](https://www.students4bestevidence.net/a-beginners-guide-to-
interpreting-odds-ratios-confidence-intervals-and-p-values-the-nuts-and-
bolts-20-minute-tutorial/)

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.)

------
smt88
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
"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
> Do placebos work even if people know they're placebos?

Sometimes, yes! See: [https://www.health.harvard.edu/blog/placebo-can-work-
even-kn...](https://www.health.harvard.edu/blog/placebo-can-work-even-know-
placebo-201607079926)

But they're probably more effective if you don't know.

