Analysis of Antidepressant Paxil Finds Data on Teen Risk Was Held Back
scientificamerican.com
scientificamerican.com
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.
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.
However, I think Phase 2 trials for new use of already approved compound should have a minimum publication requirement if they don't follow on to a phase 3. The safety (side effects and adverse events) should at least get aired.
1) Have full transparency of the placebos being used. Many studies that are published don't fully disclose the placebo being used. Full release should really mean full release.
2) Movement way from the for-profit journal system to a not-for-profit system, to prevent obvious conflicts of interest. Full release means nothing if the means in which information travels is biased.
3) Reining in the benefits pharmaceutical companies can give researchers and doctors. A number of studies have shown even the smallest of gifts can change a doctor's propensity to prescribe a specific drug. Surprisingly this can be as powerful as a journal article.
4) Passing real legislation to reduce the revolving door between the FDA and the rest of the medical industry to prevent a number of other problems.
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.
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...
This Cherry Picking should become a felony? Spit out the data you have on hand, even if incomplete? Give the results of the studies to the FDA, or make whatever data you have available to the scientific community at large?
Why don't they make this information available; because usually the study didn't prove their hypothesis, and they need to start another study hoping the data just might magically change? And with the right 3rd party researchers, in the right foreign countries--poof the data magically seems to turn around? And the company has a new money maker?
Frequently those sub-populations lack statistical power.
So then a new trial will be made targeting that sub-population if it looks promising enough (i.e.: cost vs. potential benefit/market size).
Is that a bad thing? It's variable whether the study that failed to get statistical results will get published and if so, how.
The legally required filings with the FDA are done in any case.
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.
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.
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.
With the pharmaceutical industry, however, there is no such check. To go against Pharma as a Republican is to go against big business. To go against Pharma as a Democrat is to go against "Science." Add millions and millions spent on lobbying and deceptive PR, you have a very powerful lobby.
There are very, very few true ideologues in Congress. The real reason is more prosaic - they won't cross big pharma because they need money for reelection.
Incidentally, the other industries you've listed don't have parties against them. They spread money around on both sides of the aisle.
How many Democrats are critical of pharmaceutical companies? Barely any.
Let's say the Congress wants to pass something the banks like, and they have 50 more votes than they need. The party leaders figure out who represents districts that won't like the legislation and those representatives get to vote against. In the end it's a super close vote, on paper, so 49 Congressmen can go back to their district and say "Gosh, I did my best, but we just couldn't stop it."
Look at the Iran deal. Treaties need 60 votes to pass the Senate. Now, Republican voters don't like the treaty, but the Republican establishment wants it to pass. So what do they do? They pass a bill that assumes consent and sets up a second vote that will only stop the treaty if 60 vote against it. Then they go back to their districts and pretend the second vote was the real one.
They do.
http://journals.plos.org/plosmedicine/article?id=10.1371/jou...
> 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.
> 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.
and this topic: http://www.alltrials.net/news/new-research-on-old-data/
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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
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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
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/
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.
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.
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.
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.
I've heard this is used as a form of torture in some countries. Being strapped down and injected with a medication that induces akathisia would make the most hardened individual talk.
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.
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.
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!).
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.
> 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.
I see this more as a godsend than a problem. Other meds I've taken, such as mirtazapine, work fast but poop out as soon as I develop a tolerance. Citalopram seems to work indefinitely once those adaptive changes take place.
My psychiatrist a few years back took this into account and prescribed both, and it worked brilliantly. As soon as the mirtazapine's effects were wearing off, the citalopram started kicking in.
To add, my opinion is that true suicidal ideation can be misinterpreted as manipulation in teens by it being more common at that age. Taken together with less life experience and impulse control at that age the teen is less likely to cope effectively otherwise. But this is simply a personal observation, I hope research gets to real crux of the matter.
After some weeks the "new normal" settled and to me, the medication helped.
It is good to have your doctor handy anyway.
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.
Do you have a source for this?
Some of these studies are difficult to interpret without the appropriate background, though, because it's easy to see phrases like "antidepressants decrease resting-state functional connectivity" and assume that decreasing functional connectivity in your brain is necessarily a bad thing. In reality, some types of depression might stem from detrimental alterations in functional connectivity in certain areas that are reversed by anti-depressants.
The most exciting aspect of these types of studies is that researchers are just starting to scratch the surface of being able to tailor antidepressant treatment to different types of depression.
This study: http://www.ncbi.nlm.nih.gov/pubmed/21205435 for example, found that resting state connectivity in certain areas was correlated with treatment outcome, suggesting that it might be possible to actually measure some of these things and prescribe medications that have a higher chance of working in a given patient.
Very exciting stuff!
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?
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.
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.
Published: 15 July 2010
"A NYT editorial ( http://www.nytimes.com/2010/07/15/opinion/15thu1.html?ref=op... ) 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...
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Pharmaceutical Company Invented Diseases, One of the Incentives Provided by Patent Monopolies
http://www.cepr.net/blogs/beat-the-press/pharmaceutical-comp...
Tufts Economist Documents Inefficiency of Patent System for Financing Drug Research
http://www.cepr.net/blogs/beat-the-press/tufts-economist-doc...
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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...
It's the either-or fallacy, also known as the false dilemma, and commonly employed by internet forum bullies.
Just because some bullies use the false dilemma does not mean that marincounty is bully.
And agreed, we are definitely derailing from the topic.
[1] I am aware that my punctuation, spelling, and grammar are terrible. I welcome help! My email is in my profile.
But ending every single sentence with a question mark is very confusing to the reader. I still have no idea if marincounty is agreeing with the parent, calling them out on those statements, or something in between.
Responding to criticism by inventing hyperbolic scenarios and punctuating them with questions marks is not a minor grammatical error. It is a rhetorical technique that usually, if not always, signals bad faith.
marincounty may not be a troll, but he sure writes like one. If he wants to be taken more seriously, he'd be well advised to find a style of engagement that hasn't become synonymous with dubious intent.
http://highline.huffingtonpost.com/miracleindustry/americas-...
is relevant in this context.
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.)
This is a dangerous myth.
Suicide is a leading cause of death. Suicide is the leading cause of death for men aged between 20 and 49 in the UK. 12 men die by suicide each day in the UK (and about 3 or 4 women); one person dies by suicide every 12 minutes in the US.
> Hang in there.
Unfortunate phrasing, when "hanging, strangling, and suffocation" is the leading method of death by suicide, followed closely by poisoning.
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...
> 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.
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.
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.
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.
> 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.)
These are very powerful drugs, and are almost certainly grossly overprescribed. But they definitely work for "major depression" (which has a clinical meaning behind it).
Just another anecdotal data point.
Not always, people can be depressed for long periods.