
Analysis of Antidepressant Paxil Finds Data on Teen Risk Was Held Back - pmcpinto
http://www.scientificamerican.com/article/analysis-of-gsk-s-paroxetine-antidepressant-finds-key-data-was-held-back
======
acveilleux
I use to work in pharma research (at the data acquisition and analysis side,
blinded from treatment) and the fact that pharmas are able to start clinical
trials and then shut them down without reporting result is a problem.

The folks who make those decision usually have access to unblinded data and in
the least objectionable case they do it due to lack of efficacy but you never
know. Maybe they found a side-effect and would rather it not be looked at in
the context of what the drug _is_ approved for.

There's easily the recovery of a billion dollar of R&D costs at stake.

~~~
throwaway98031
> pharmas are able to start clinical trials and then shut them down without
> reporting result is a problem.

As you've worked in the industry, I'm curious: What do you think could remedy
this situation?

Forcing all registered clinical trials to release all of their data seems like
the obvious solution. We still need the ability to shut down clinical trials
if unexpected side effects such as increased suicide rates appear, but
allowing companies to keep the results private is obviously problematic.

~~~
andreyf
One option:
[https://en.wikipedia.org/wiki/Contract_research_organization](https://en.wikipedia.org/wiki/Contract_research_organization)

~~~
acveilleux
How is that a solution? I worked for a CRO and contractually, all we did
belonged to the client, including all publishing rights on all results.

~~~
andreyf
Sorry for not expounding, that was indeed a bit opaque. I don't have first
hand experience with the industry and so would appreciate any corrections to
my understanding of it.

When research is done via contract between two companies, it can be more
effectively regulated to prevent hiding or discarding of results. I imagine
there are already laws in place saying a company can't hide research results
like this and CROs make compliance more likely because they do not benefit
from hiding bad results as pharmaceutical manufacturers do. I don't think
publication rights are the important bit here, but compliance with rules about
disclosure to the FDA.

~~~
acveilleux
That's not how CROs work usually work. Effectively, as far as the FDA is
concerned, the CRO does not exist as a distinct entity, it's an organic part
of the sponsor (i.e.: the reporting pharma.)

The sole organization reporting to the FDA is the trial sponsor.

A CRO that felt like it could just tip off the FDA could soon find itself
without further contracts.

In addition, in a properly blinded trial, most of the players (whether CRO,
sponsor or site/treating physician) have no clue who's being treated or not.
Nor do they know much more than they need to conduct their business.

The safety of a clinical trial is normally the job of a data monitoring
committee or something similar. They are normally independent and empowered to
monitor the result and, most importantly, unblinded so they can actually use
stats taking treatment into account to spot actual anomalies. They report to
and are paid for by the sponsor. The sponsor is legally required to act on the
findings and adverse events are required to be reported to the FDA. At least
that's the theory.

Gory details here:
[http://www.fda.gov/downloads/RegulatoryInformation/Guidances...](http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm127073.pdf)

~~~
andreyf
Got it. Thank you for the thorough explanation!

------
buffoon
My wife was nearly a victim of this particular drug in the late 1990s. They
have no idea how much shit they caused people by withholding this information.
Several years of people's lives destroyed. I doubt they will acknowledge it or
even apologise let alone offer compensation.

When I say they, I don't mean the faceless corporation or brand, but the
individuals who made this decision, ran the initial trials and pushed it to
start with.

~~~
phkahler
>> When I say they, I don't mean the faceless corporation or brand, but the
individuals who made this decision...

Hopefully they're scared shitless right now because of the talk around the GM
recall case. Politicians are throwing around the idea of criminal charges
because they didn't disclose safety problems soon enough. My first thought was
"what about pharma?" Not sure what I think of the idea, but some folks in
pharma are certain to be following that case.

~~~
seiji
Medical problems are difficult to class action because they are so distributed
and so private.

Earlier this year a doctor killed a family member of mine by telling her,
across multiple visits in the same week, her swollen ankle was a sprain and to
just rest. It was actually a blood clot due to being overweight and on birth
control pills. The day after her last visit, she threw a PE and died alone on
her couch.

Another doctor told another family member his chest pains were end-stage
cancer and he would die within a month. A second opinion showed it was
mesothelioma treatable by state-of-the-art radiotherapy delivered by only one
lab in the country. He's still alive two years later.

I've probably got another half dozen stories just from immediate relatives
about doctors seemingly doing random or nonsensical things instead of driving
proper diagnoses and/or treatments forward.

Doctors are in general awful unless you can afford to buy an entire private
"council of doctors" to consult and berate each other into actually getting
shit done.

~~~
phkahler
That's unfortunate and sad. But we were talking about researchers and
bureaucrats with data, whose job is making data driven decisions, and then
ignoring or hiding some of the data.

~~~
Asbostos
It's true it's a bit off topic, but I think it's closely related. Both doctors
and researchers are causing deaths and neither has any accountability. Doctors
are perhaps a bigger problem. In general, they're simply not competent at
their job as seen by examples like this. There are no checks and balances to
keep them competent. Perhaps their job really is too difficult for a human to
do but then they should be honest about that and tell the patient "I don't
really understand your condition, and all I can think of is ..."

------
DanBC
This study is more interesting. _young_ people on certain anti-depressants are
at higher risk of violence. We don't know which way causality runs. We don't
see the effect in older people.

[http://journals.plos.org/plosmedicine/article?id=10.1371/jou...](http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1001875#abstract2)

> These findings show an association between SSRIs and violent crime that
> varies by age group. They cannot, however, prove that taking SSRIs actually
> causes an increase in violent crime among young people because the
> analytical approach used does not fully account for time-varying risk
> factors such as symptom severity or alcohol misuse that might affect an
> individual’s risk of committing a violent crime (residual confounding). In
> addition, some people who committed a violent crime might have subsequently
> taken SSRIs to cope with the anxiety and stress of arrest (reverse
> causation). The lack of a significant association between SSRIs and violent
> crime among most people taking SSRIs is reassuring; the association between
> violent crimes and SSRIs among individuals younger than 25 years is
> worrying. However, this finding needs confirming in studies with other
> designs undertaken in other settings. If confirmed, warnings about the
> increased risk of violent behavior among young people when being treated
> with SSRIs might be needed. But, note the researchers, it might be
> inappropriate to restrict the use of SSRIs in this age group because
> increases in adverse outcomes associated with poorly treated depression,
> such as suicide, might outweigh the public health benefit accruing from
> decreases in violence.

~~~
throwaway98031
The study is interesting and worth following up on, but the biggest takeaway
from your post is your statement that:

> We don't know which way causality runs.

The study found a correlation, not a causation, and even the authors suggest
that reverse causation is actually a very possible explanation.

Note that the study was performed in Sweden, where they do a _much_ better job
of rehabilitating offenders than we do in the USA. So good, in fact, that the
reoffending rates in Sweden are half of other European countries. Sweden is
actually closing prisons lately because their prison population is dropping so
much.

I can't find any direct evidence to back this up, but it's not a stretch to
think that young violent offenders in Sweden are much more likely than the
general population to end up receiving psychiatric treatment, and thus are
more likely to be prescribed SSRIs than the general population.

As such, I wouldn't read too much in that study.

------
pella
-> [http://www.alltrials.net/](http://www.alltrials.net/)

and this topic: [http://www.alltrials.net/news/new-research-on-old-
data/](http://www.alltrials.net/news/new-research-on-old-data/)

-

BMJ Editorials: "Liberated trial data have enduring potential to benefit
patients, prevent harm, and correct misleading research" :
[http://www.bmj.com/content/351/bmj.h4601](http://www.bmj.com/content/351/bmj.h4601)

-

BMJ "No correction, no retraction, no apology, no comment: paroxetine trial
reanalysis raises questions about institutional responsibility"
[http://www.bmj.com/content/351/bmj.h4629](http://www.bmj.com/content/351/bmj.h4629)

~~~
mzs
That last link in particular as a very good read for me, thank you for
sharing.

------
xlm1717
I've been seeing this pop up on all the major news outlets and science
websites, but still have not seen one mention of the side effect that may be
behind both increased risk of suicide and increased risk of violent behavior:
akathisia.

Akathisia is a side effect of antidepressants that causes an intense inner
restlessness and inability to sit still. This can cause agonizing pain and
terrible anxiety, and people can resort to extreme behaviors to relieve their
symptoms, often becoming violent.

This has been known for a while now. If you look at the references on the
Wikipedia page for akathisia, you find one paper linking antidepressant-
induced akathisia to violence from 2006:

[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1564177/](http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1564177/)

Quoting from that paper on akathisia:

“Increased tenseness, restlessness, insomnia and a feeling of being very
uncomfortable”.

“On the first day of treatment he reacted with marked anxiety and weepiness,
on the second day felt so terrible with such marked panic at night that the
medication was cancelled”.

“The first few doses frequently made them anxious and apprehensive. They
reported increased feelings of strangeness, verbalised by statements such as
‘I don't feel myself’ or ‘I'm afraid of some of the unusual impulses I have'’.

"Events such as these in clinical trials of antidepressants have commonly been
coded under headings such as agitation, emotional lability, and hyperkinesis
(overactivity), and only rarely to akathisia."

The good thing is that you can treat akathisia with common medicines already
used to treat anxiety, such as benzodiazepines. The bad thing is that since
information on side effects has been suppressed, patients are not likely to
know what is happening to them and how to treat it, won't get the help they
need, and run the risk of hurting themselves or others.

~~~
existencebox
What concerns me as much as the initial side effects is your last paragraph,
and the sentiment surrounding it. Benzos have been known to have some
additional significant neurological consequences in the long term, and have
always felt to me like a rather large sledgehammer for the problems they often
treat. As such, "your behavior-modifying drugs give you a side effect so we'll
shove more powerful drugs in your face" was an attitude that I've seen
multiple times and NEVER to good effect. (I'll be very candid that I was part
of the "you have ADHD so we'll treat you with pills" generation, at a much
younger age, but will leave it at that it didn't end as planned.)

I hope I'm not a total tin foil hatter by looking askew at this trend, but
being married to a neurologist and the son of a behaviorist, I'm VERY aware of
how little we understand what we're doing when we muck around up there.

~~~
derefr
> As such, "your behavior-modifying drugs give you a side effect so we'll
> shove more powerful drugs in your face" was an attitude that I've seen
> multiple times and NEVER to good effect.

I don't see why that couldn't make perfect sense, though: someone can be
neurochemically imbalanced along multiple axes, but one imbalance can mask the
other. For example, if I have ADHD (for real) and depression, then that'll
look like I just have depression. If I'm not getting out of bed, you're not
going to observe me being very impulsive or notice when I fail to desire to
practice things.

But now, if I take an anti-depressant and the depression goes away enough for
me to get out of bed, it looks to the study like "in some people, a side-
effect of treatment X for depression is [the symptoms of ADHD]." What it
really was is that I had a comorbidity.

~~~
existencebox
Let me give a (probably very leaky) programming analogy: You have one library,
and it solves 1 class of problems. You use a second library on top of it to
try and address some bits introduced by library 1. This may well move the core
metric needle to get you what you want, but you will undoubtedly incur
unforeseen interactions, and additional potential edge cases.

When you add the brain into the equation, it removes all of the (comparatively
flawless) understanding we have of the system the libraries are running
within, and then when you add benzos, one of your libraries is now an enraged
bobcat.

In a perfect world, I'd agree with your statements. I do not think we have an
effective enough understanding of either the compounds we're using, or the
systems we're impacting, to be as laissez faire with cocktails as we often
are.

------
cryoshon
Of course the data was held back, it would hurt sales. This is extremely
typical of psychiatric drugs. Typically we only find these things out after
the drug has been on the market for a number of years, with predictable (had
we known!) consequences.

Pharmas need to be held accountable for this bad behavior and all clinical
trial results (including negative results) need to be 100% transparent. I am
going to be blunt: this would massively hurt their bottom line. Because
accountability would hurt the pharmas bottom line, it will be like pulling
teeth to get any kind of legislation to fix this problem-- they love to buy
politicians specifically because it protects them in times like these where
they have done wrong. We need to stop allowing "because money" to be a valid
reason for allowing people to get hurt.

Psychiatric drugs are huge cash cows and are very frequently (see numerous
meta-analyses) only dubiously or narrowly effective. They're a stopgap for a
missing mental healthcare system, and allowed a lot of leeway because of this.

------
refurb
For all the condemnation of GSK, it appears that the "harm coding" changed
from the original trial because _the FDA changed the system they used._ And
was a major driver for why the AEs were captured in this study and not others.

The other thing to keep in mind is that if this was a pivotal trial study, the
FDA had _the complete data set_ yet failed to recognize the increase in
suicidal ideation as well.

~~~
MichaelGG
The FDA really seems to have a bad rep. See, for instance, Ranbaxy:
[http://fortune.com/2013/05/15/dirty-
medicine/](http://fortune.com/2013/05/15/dirty-medicine/)

They were faking results and running terrible QC, to the point of shipping
glass in pills. The FDA was very slow to fine them, and then only closed
specific sites. It's obvious this company was rotten to the core, and is now
part of Sun Pharma. FDA's done a bit more since then, but they should have
issued a full ban and then started to whitelist things bit by bit. Local
health inspectors come down harder.

It creates other effects, too. By looking bad in some cases, people stop
trusting the FDA. They then decide that things like sucralose are harmful
"because you can't trust the FDA", and instead consume large amounts of sugar
(it's natural!).

------
throwaway98031
This is an egregious violation on many levels. It highlights a massive gap in
the clinical trials process (companies can stop trials without reporting
negative results) that really should be addressed. I think everyone (outside
of drug companies) can agree on that much.

I would like to say a few words on SSRIs (the class of drugs that Paxil is in)
and their risks in general, because articles like these tend to cultivate
strongly negative feelings toward SSRIs due to the deplorable drug company
actions mentioned in this article. I don't blame people for mistrusting the
drug companies after reading something like this. I also feel that SSRIs are
prescribed too quickly and with too little extra guidance from doctors,
although that trend is changing a bit as doctors become more educated.

But my biggest concern is that we're starting to see many people with severe
depression who refuse to take SSRIs because they don't trust the drug
companies and they've come to believe that their severe depression is still
better than the side effects or risks of an SSRI, which couldn't be farther
from the truth.

The bottom line is that SSRIs, while far from perfect, are still one of the
most effective first-line treatments for severe depression that we have, and
they do it with a side effect profile that is head-and-shoulders above
previous generation anti-depressants.

Perhaps the biggest problem with SSRI treatment is the delayed onset of
action. Unlike short-term rewarding drugs such as stimulants or opioids that
may boost one's mood in the short term but quickly develop tolerance, SSRIs
work through long-term adaptive changes. These changes are numerous, from
increased BDNF and hippocampal growth to HPA axis normalization and
restoration of brain connectivity back to a state that more closely matches
that of non-depressed patients. However, the problem is that all of this
happens as downstream effects of an alteration in how serotonin moves through
the brain, which is very disruptive in the short-term while the brain adapts
to the changes.

SSRI stands for selective serotonin reuptake inhibitor, which means that it
inhibits the ability of serotonin-releasing neurons to take serotonin back up
from the synapse after they release it. This doesn't "raise serotonin levels"
as many describe it (unfortunately perhaps due to some awful SSRI marketing in
the 90s and 00s) but rather alters the dynamics of how serotonin-based
circuits operate. Serotonin will now spend more time in the synaptic cleft,
activating post-synatpic serotonin receptors and synaptic transmission becomes
a bit more smoothed out as the transmission takes longer to terminate via MAO
deactivation of the serotonin or via uptake from the ~20% of uninhibited
serotonin transporters.

Over time (4-8 weeks on average) the post-synaptic receptors adjust to the
"new normal" levels of serotonin that they see in the synaptic space. This
adjustment might even be key to some of the therapeutic effects of SSRIs, as
some serotonin circuits may be too active in depressed or anxious patients,
but the chronic SSRI administration quiets those receptors down, somewhat
counter-intuitively. The big problem here is that until those receptors
compensate, the patient may actually feel _worse_ in the short-term. (Note
that some patients actually feel substantially _better_ during this phase, so
please don't take this as a given). In the worst-case, depression or anxiety
are actually worsened temporarily, combined with an increased energy due to
the SSRI's activating effects. At the extreme worst-case scenario, this can
lead to suicidal ideation, and for whatever reason this is more common in
teenagers.

I wrote all of this out because the HN crowd tends to want to know how things
work behind the scenes or under the hood when making decisions for themselves.
My goal is not to suggest that everyone who experiences depression should be
on SSRIs, because I actually feel that medication is probably best reserved as
a first-line treatment for moderate to severe depression. Instead, my goal is
to keep everyone informed such that they can work with their doctor to find
the best treatment for themselves without unnecessarily fearing SSRIs due to
these deplorable actions of drug companies a few years ago.

If you're feeling depressed, work with your doctor to find a solution. If you
question your doctor's decision, see someone else. But it's important to
explore all options if depression is taking a toll on your life, and if you
choose to go the SSRI route then be aware that therapeutic effects are 4-8
weeks out, at least, and talk to your doctor right away if you're concerned.

~~~
pfortuny
I have some experience as a patient with Escitalopram (an SSRI) and can only
say: indeed. The first two weeks it was utter confussion (I feel so worse) but
reading the prospect (a very good one in Spain) and talking to my doctor
clarified the situation.

After some weeks the "new normal" settled and to me, the medication helped.

It is good to have your doctor handy anyway.

~~~
throwaway98031
Thanks for sharing your experience.

I'm still surprised that more doctors aren't taking a proactive approach to
telling their patients what to expect. I suspect part of it stems from lack of
education, but I think some doctors are afraid to tell depressed patients that
they might get _worse_ before they get better because that suggestion alone
might make them not take the medication in the first place.

~~~
pfortuny
You are welcome. As a patient, I think it is good sharing as much of your
experience as possible (with due caution), especially in environments like
this, somewhat too prone to this type of illness and afraid to acknowledge.

------
jgalt212
What blows my mind about these clinical trials is that the truth is always
going to come out if the drug goes to market. And for big pharma, that's the
goal--get the drug to market (and the largest market possible).

While you can hide bad results when n is small. i.e. just re-run the trial
with another or smaller n. However, when n gets large as the drug comes to
market, there is nowhere to hide. The negative effects will become obvious and
compelling as the sample size grows.

How do they think they can hide this?

------
joesmo
What? A drug company hiding the fact that its drugs don't work from the
scientists assigned to oversee it to make billions of dollars? Why never would
I have thought this possible! Seems like for this segment of the market, they
could have saved billions by releasing a placebo with better effects. Amazing!

------
digikata
So why isn't there some sort of post-approval monitoring system for drugs?
With aircraft and cars we have enough data captured that problems can be
identified and traced.

~~~
cma
There is, post market monitoring.

~~~
digikata
So why didn't data from the monitoring suggest a study was needed much
earlier?

------
mzs
Depression runs in my family. Please be considerate in your replies here to
me.

I think in US every available antidepressant has that 'suicidal thoughts'
warning right at the top of the list yet antidepressants have been a very
valuable tool for our family for young and old alike.

I do not believe that any causation has been determined for currently commonly
prescribed medications. This is Reuters article reprinted at sciam does not
show that at least. What GSK did hiding studies is reprehensible of course.
Vulnerable families were hurt. The positive is the increased scrutiny now
thanks to that.

My beliefs on the matter: Antidepressants are one tool, about 20% of dealing
with the level of depression in my family. Sometimes the chemicals in our
brains are just so out of whack no amount of therapy gets to us.

For an adult like me, I have had enough experiences (bad relationships,
financial strain, health issues, legal problems, work stress, and so on) in my
life to more easily put them in healthy context to what happens three years
out say. I also remember how when I was younger that was impossible cause I
lacked that experience. This is reflected by the rest of my family.

What I believe happens is the following: People with depression are already
more likely to have thoughts of hurting themselves. There are some young
people that will use manipulation to get what they want that also suffer from
depression. 'You take away the only thing I like and I will hurt myself,'
where that thing is not a healthy coping mechanism. So that thing gets taken
away and the kid gets a psych-eval. The social worker evaluating everything
decides this is a case of manipulation and the child is at an appropriate
level of care. The problem is that some children have used manipulation but
really do end-up hurting themselves after this since the other coping
mechanisms they have in place at the time either get ignored or are
insufficient.

Now my ire does not rest solely with GSK here. When I said the licensed state
social worker evaluates everything, aspects come into that which should not
for medical reasons but do for societal ones. One of those things have been
what other options are available. People have been denied needed care based on
there not being room in the programs (because of underfunding essentially),
there not even being the appropriate program (for example intensive outpatient
again often because of underfunding), or what insurance will pay. Thankfully
that has not effected my nuclear family too much, but has affected others in
my wider family that are unfortunate to live in other places or have worse
insurance. That said, even to this day there are limits to mental health in my
insurance program. Thankfully they are not not as onerous as they were in the
past, but it does cause us stress to navigate it and not go over what is
permitted.

The other thing is that simply you need a good team to work with you, a doctor
and a therapist. There are those with mental health illnesses that are unlucky
to not have good choices there. There are too many practitioners that are
simply overworked and can't really offer the attention that is needed for
proper care. They have known about this 'suicidal thoughts' danger, but they
also see the benefits which nothing else offers. So they get into a routine of
using one system for everyone as much as possible. But then because of time
and insurance reasons there is not enough attention to tune it then as time
goes on together with therapy. For example our insurance will only pay for a
parent to consult with a therapist once a week for a child even in intensive
outpatient care. So you have to find one willing to do that over the phone
more often and not get paid for it essentially.

Well that was rambling, sorry, but somewhat therapeutic for me currently,
thank you.

~~~
Domenic_S
SSRIs without talk therapy for depression/anxiety is like prescribing Vicodin
without a cast for a broken leg. They can both help the immediate problem, but
don't address long-term health.

What we have, at least in the US, is too many pharmacological solutions and
not enough CBT.

It was once explained to me that depression and anxiety are like a top
spinning out of control. There's too much momentum throwing it off, no amount
of self-effort will correct it and eventually it will probably crash. Meds are
like resetting the top, and talk therapy equips you to keep it spinning
correctly. Then once you're properly equipped with strategies to keep your top
spinning straight you can taper off the 'crutch'.

But it's way, way easier to write a prescription and say 'come see me again in
8 weeks when the meds take effect', leaving the patient to suffer for 2
months.

------
cs2818
Wow, I was prescribed Paxil as a teenager for a year or so. Glad the only side
effect I experienced was weight gain.

~~~
peterwwillis
I remember being on it too. But i'm not sure if my problems in school were
related to this drug, or the many other drugs I was put on in the course of
trying to discover a "cure" for being a lonely sad teenager. (They never ended
up finding a 'fix' for me, and by 18 I was an adult and could finally refuse
the medication)

------
circuit_breaker
This affected me. It's immoral and should be illegal

------
pessimizer
_Drug Patents Give Companies Like GlaxoSmithKline Incentive to Lie_

 _Published: 15 July 2010_

"A NYT editorial (
[http://www.nytimes.com/2010/07/15/opinion/15thu1.html?ref=op...](http://www.nytimes.com/2010/07/15/opinion/15thu1.html?ref=opinion)
) commented on evidence that the drug maker GlaxoSmithKline had concealed
negative research findings on its diabetes drug Avandia:

"'The clearest lesson to emerge from the hearings and other recent revelations
is that GlaxoSmithKline, the maker of Avandia, can’t be trusted to report
adverse clinical results fairly. The company must be watched like a hawk as
additional trials that it sponsors go forward.'

"Arghhhhhhhhhhhhhhhh! Doesn't the NYT believe in the profit motive and
incentives? The patent system, by granting monopolies that raise prices
several thousand percent above the cost of production, gives drug companies an
enormous incentive to conceal negative research findings. As long as these
perverse incentives exist, then we have to watch every drug company like a
hawk.

"Maybe some wacko socialists think that drug companies will act for the public
good and willingly forego vast profits, but those who believe on markets and
economics know that drug companies will try to get away with anything they can
get away with. One day maybe an iota of original thought will be allowed into
public policy debates on the patent system, but we haven't gotten there yet."

[http://www.cepr.net/blogs/beat-the-press/drug-patents-
give-c...](http://www.cepr.net/blogs/beat-the-press/drug-patents-give-
companies-like-glaxosmithkline-incentive-to-lie)

\-----

 _Pharmaceutical Company Invented Diseases, One of the Incentives Provided by
Patent Monopolies_

[http://www.cepr.net/blogs/beat-the-press/pharmaceutical-
comp...](http://www.cepr.net/blogs/beat-the-press/pharmaceutical-company-
invented-diseases-one-of-the-incentives-provided-by-patent-monopolies)

 _Tufts Economist Documents Inefficiency of Patent System for Financing Drug
Research_

[http://www.cepr.net/blogs/beat-the-press/tufts-economist-
doc...](http://www.cepr.net/blogs/beat-the-press/tufts-economist-documents-
inefficiency-of-patent-system-for-financing-drug-research)

\-----

 _Patent Monopolies and the Costs of Mismarketing Drugs_

 _April 2015, Ravi Katari and Dean Baker_

 _Abstract:_ "Patent monopolies have long been used as a mechanism for
financing innovation and research. The logic is that the government awards a
monopoly on a product or process for a limited period of time in order to
reward innovation. However, in addition to providing incentives for innovation
and research, patent monopolies also provide incentives for a wide-range of
rent-seeking behaviors, many of which can have major social costs. This paper
attempts to calculate one category of these costs for prescription drugs. It
produces estimates of the costs associated with mismarketing drugs. The
estimates are based on assessments of the costs in the form of increased
morbidity and mortality associated with five prominent cases of mismarketing
over the last two decades."

[http://www.cepr.net/publications/reports/patent-
monopolies-a...](http://www.cepr.net/publications/reports/patent-monopolies-
and-the-costs-of-mismarketing-drugs)

------
nickysielicki
Why are you ending every sentence with a question mark? It makes you sound
unsure?

~~~
totalrobe
I call it the "Bill O'Reilly".

It's the either-or fallacy, also known as the false dilemma, and commonly
employed by internet forum bullies.

[https://en.wikipedia.org/wiki/False_dilemma](https://en.wikipedia.org/wiki/False_dilemma)

~~~
mzs
I do not see marincounty being a bully in that comment, just some odd
punctuation. This discussion is derailing from the topic at hand.

~~~
totalrobe
Guys, I did not say that marincounty was being a bully. Seems like you too are
falling prey to the HASTY GENERALIZATION or maybe just a faulty correlation.

Just because some bullies use the false dilemma does not mean that marincounty
is bully.

And agreed, we are definitely derailing from the topic.

------
CaptainZapp
I think this series of articles :

[http://highline.huffingtonpost.com/miracleindustry/americas-...](http://highline.huffingtonpost.com/miracleindustry/americas-
most-admired-lawbreaker/chapter-1.html)

is relevant in this context.

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

Let's throw out all those lousy studies that were done in the 90's and later?
Let's start fresh--study these antidepressants, and get rid of
them(adolescents, adults alike) if they really don't help anyone besides
doctors, and drug companies finances?

Yes, I know it's tough when you have a suicidal person in your office, and all
you have in your arsenal is dubious drugs--marketed by ruthless companies? I
don't what a caring practitioner should do. I really hope
Psychiatry/Psychology makes some breakthroughs?

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

(If you happen to be depressed, I can guarantee it gets better as you age, or
with time. Hang in there. Don't let our rediculious, narcissistic society get
the better of you. The problems you have in your youth--just might look a lot
less serious as you get older? Yes--talk is cheap, but I have no reason to
lie. I have no agenda. I don't want your money. I'm just a dude who's been
through the system, and didn't like what I saw, or ingested. If you are really
on the verge of doing something drastic; go straight to,the emergency room.
There's one procedure that actually has a high cure rate--if you are really
that desperate? I am obviously not a doctor, nor would ever want to be one.)

~~~
throwaway98031
> Now let's find out if this anti-depressant really helps anyone, or is it
> just another terrible drug with horrid side effects? If it doesn't help
> better than placebo; take it off the market?

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

Scott Alexander has already done a great job debunking these claims:
[http://slatestarcodex.com/2014/07/07/ssris-much-more-than-
yo...](http://slatestarcodex.com/2014/07/07/ssris-much-more-than-you-wanted-
to-know/)

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

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

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

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

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

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

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

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

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

~~~
throwaway98031
> Then there's the academic problem: the monoamine hypothesis (the underlying
> theory behind the actions and use of SSRIs etc) is at best a crude
> approximation with precious little in vivo data to support ideas that are
> known to be inaccurate and incomplete.

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

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

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

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

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

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

~~~
throwaway98031
I'm not sure where you're getting your information from, but a lot of it is
very incorrect and has a strong anti-pharma bias. For example:

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

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

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

