Seroxat/Paxil Study 329 – the truth at last.

I’m feeling re-energised today for a number of reasons, one of them being the fact that I’ve discovered the final chapter in the story of Study 329 has arrived.

I suggest you visit Restoring Study 329 for the latest news.

Also have a look here at Bob Fiddaman’s excellent take on today’s news.

If you don’t already know, Study 329 is arguably the most controversial drug study ever, published in July 2001.

In a nutshell Study 329:

– concluded that Seroxat was a safe and effective medication for treating major depression in adolescents;
– is still widely cited in the medical literature, providing physicians with assurance about the usefulness of paroxetine;
– was criticised by a few alert and concerned journalists, academics and bloggers. (However, their voices were buried by a tsunami of positive marketing and promotion by vested interests);
– resulted in a successful New York state fraud lawsuit against GSK;
– resulted in 2012 in the biggest fine in corporate history – $3 Billion,
and
– remains unretracted.

I have written about the scandal of Study 329 for many years and this link collects my posts about the Study 329.

From one blunt Yorkshireman to another – I hope you’re paying attention Andrew Witty, this hasn’t gone away… oh, and I don’t just mean Study 329.

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Inside Paxil Study 329, Courtesy the Justice Department

This is from Dr Howard Brody’s blog – Hooked: Ethics, Medicine, and Pharma

It sums up the story of Study 329 (with links to the original DoJ documents) and dovetails with the current scandal over Glaxo’s record $3 billion fine for witholding negative drug trial data for Avandia, the illegal marketing of drugs and bribing doctors to prescribe Glaxo products.

Remember, Study 329 was not covered by the latest $3 billion fine – Study 329 was yet another example of Glaxo’s lying and cheating to sell its drugs.

Now read on:

I’ve previously discussed the now-infamous Study 329, which took discouraging data on the efficacy and safety of paroxetine (Paxil) in kids and spun it into an article claiming excellent results:
http://brodyhooked.blogspot.com/2011/11/will-brown-university-investigate.html

Thanks to the U.S. Justice Dept. complaint in the suit recently settled by GlaxoSmithKline for a record $3B: http://www.justice.gov/opa/documents/gsk/us-complaint.pdf
–we can follow the history of this study in more detail, based on the internal GSK documents discovered during the proceedings, and see just how the data were manipulated for marketing purposes.

Study 329, directed by Dr. Martin Keller of Brown University, was one of 3 clinical studies in children and adolescents that were all interpreted by GSK scientists between August and October, 1998 to be discouraging. Study 329’s protocol specified two primary endpoints, and on neither measure did Paxil do better than placebo. The study also logged in 11 serious adverse reactions to Paxil, much more than in the placebo group, including 5 with agitated or suicidal behavior, the major risk for which eventually the FDA issued a black-box warning for the SSRI class of antidepressants.

Undaunted, GSK contracted in April 1998 with Scientific Therapeutics Information, Inc. to prepare an article for journal publication based on 329. As we know from other sources, STI writers basically wrote the paper and later did revisions, with minimal input from the supposed scientific authors, meaning that the paper was largely if not completely ghostwritten. As part of the laundering process, STI decided to downplay the primary endpoints and instead inserted 8 “efficacy measures,” none of which had been specified in the original study protocol. By what’s called data-dredging, STI was able to show that Paxil was statistically better than placebo on 4 of the 8 newly invented measures.

Initially the purported authors sent the paper to JAMA, claiming in the abstract that Paxil was “a safe and effective treatment for major depression in adolescents.” In December, 1999 JAMA rejected the paper, and reviewers’ comments indicated that the scientific reviewers had seen through the fog and realized that there were no solid data to show the superiority of Paxil. One internal memo then indicated that GSK and Dr. Keller agreed to send the manuscript to “a less demanding journal.”

Even the less-demanding Journal of the American Academy of Child and Adolescent Psychiatry originally couldn’t swallow the revised manuscript that Keller and company sent them in June 2000. Their reviewers detected some of the same problems as the earlier JAMA review.  GSK had STI go back to work responding to the reviewers’ comments and eventually JAACAP accepted the manuscript in February 2001.

According again to the Federal complaint, even with the recommended changes, GSK and STI (with the willing acquiescence of Dr. Keller and his co-authors, we presume) managed to slip in a number of incorrect and misleading statements. The abstract stated that the drug “is generally well tolerated and effective for major depression in adolescents.” The article mentioned the primary endpoints but failed to make clear that by neither was Paxil statistically superior to placebo. The article falsely implied that Paxil was superior on one of the primary endpoints by deliberately conflating one of the later “efficacy measures” with that endpoint. The article consistently downplayed all the measures where Paxil failed to show superiority to placebo and focused on the few, invented-later measures where a statistically significant result had been found.

More important, the 11 patients with serious adverse reactions due to Paxil, and the 5 of them with specifically suicidal or agitated symptoms, magically disappeared. In the revised manuscript the investigators suddenly decided that only one of the reactions (headache) was actually caused by Paxil, and the other bad outcomes were unrelated to the drug. When the FDA got its hands on the raw data from 329, it eventually determined that 10 of 93 patients taking Paxil had experienced a potentially suicidal reaction–a far different and scarier picture than that portrayed in any of the drafts or in the final manuscript.

To be sure that child psychiatrists heard the correct marketing message, GSK sponsored 8 “Forum” meetings at lavish resorts such as Rio Mar Beach Resort in Hawaii and Renaissance Esmerelda Resort in Palm Springs, CA. The psychiatrists who attended had their airfare and hotel paid plus a $750 honorarium, and in many cases their spouses were also paid for (a practice supposedly prohibited in the 2002 PhRMA code of conduct). The hired speakers who told them how wonderful Paxil was for treating kids received $2500 honoraria in addition.

Talking of speakers’ bureaus, another media summary of the complaint:
http://finance.yahoo.com/news/glaxosmithklines-gsk-3-billion-whistleblower-154800879.html
–reported that GSK had enrolled 49,000 health professionals to be on its speakers’ bureau for Paxil and other drugs. Two conclusions are possible: 1) there are 49,000 really excellent and scientifically informed speakers out there whose talents are needed to inform their fellow practitioners; or 2) a “speaker’s bureau” is really nothing but a disguised bribe to get all those docs to prescribe a lot of the drugs they are paid to speak about.

Hat tip to Dr. Roy Poses of Health Care Renewal blog for sending me the link to the full complaint (all 76 pages, for anyone who wants some fun reading).

Brown University, Keller and Study 329 – cracks beginning to show at last?

I’ve written a lot before about Marty Keller and Study 329 and so has Aubrey Blumsohn at Scientific Misconduct – in fact Dr Blumsohn has written to Brown University about Keller and his ‘research’.

It’s about time someone from Brown and/or Keller himself had the balls to stand up and explain themselves.

Now at last we might be starting to see some cracks begining to show thanks to student journalists at Brown University. This from Healthcare Renewal:

Brown University Student Journalists Dare to Report on Paxil/ Seroxat, Study 329 and GSK

We have published a few posts about the controversy about the clinical research supporting the use of paroxetine (Paxil, Seroxat in the UK, made by GlaxoSmithKline) in depression (here, here, here, and here.) This controversy includes allegations that clinical research funded by GSK was manipulated, and that the company’s marketing for the drug was unsupported by clinical evidence. GSK settled a case alleging fraud in the marketing of Paxil by then NY Attorney General Eliot Spitzer in 2004. A recent article provided arguments and evidence that Study 329, a clinical trial of paroxetine for adolescents, was manipulated , allegedly at least with the acquiescence of Brown University Psychiatry Chair Dr Martin Keller. [Jureidini JN, McHenry LB, Mansfield PR. Clinical trials and drug promotion: selective reporting of study 329. Int J Risk Safety Med 2008; 20: 73-81. Link here.] A book entirely devoted to this controversy, Side Effects by Alison Bass, who started reporting on the case in 1999 for the Boston Globe, was just published.

I am a still proud alumnus of Brown University (undergraduate and medical). I was a full-time faculty member at the University from 1994-2004, and am still a clinical faculty member. Despite Dr Keller’s and the University’s central role in the case, at least as alleged by Ms Bass and by Jureidini et al, there has only been silence about the case here in Rhode Island.

That just changed. Intrepid reporters from the Brown Daily Herald published two stories on the GSK/ Paxil/ Keller controversy. Both included some important original reporting, as well as providing clear summaries of the issues at hand.

The first article dealt mainly with Keller’s alleged conflicts of interest. This article provided confirmation that Senator Charles Grassley (R-Iowa) and the US Senate Finance Committee is, in fact, investigating Dr Keller and Brown University in connection with the controversy. It also included other original reporting, including an acknowledgement from GlaxoSmithKline Director of US Media Relationships Sarah Alspach that the company had provided the committee with full information about the compensation it gave Dr Keller.

The second provided a quite clear explanation of the allegations about the manipulation of Study 329. This article also included results of an interview with Dr Jon Jureidini, the author of an article that dissected study 329, and suggested that it had been manipulated to enhance the apparent benefits of paroxetine, and diminish its apparent risks. The reporters noted that Jureidini was “confident that data in Study 329 were deliberately misrepresented.” They were also able to obtain an internal GSK document that acknowledged that study 329 did not prove the efficacy of the drug.

The BDH reporters, Chaz Firestone and Chaz Kelsh, in my opinion, did a fine job, clearly explaining the issues, and digging out some new facts on the case.

Nonetheless, the BDH reporters were not able to get Dr Keller to talk to them, despite several attempts. They were not able to get anyone in the University administration to discuss any substantive aspects of the case. The highest ranking University official who would talk to them was Provost David Kertzer. He asserted that the University “can’t discuss particular cases of possible claims of wrongdoing and what we do about them.”

In my opinion, and as I said to the reporters, one of the most distressing aspects of this case is the refusal of Dr Keller or anyone in the University to deal with the content of the case. Very serious allegations have been made. If they can be refuted, they should be. If not, stonewalling only increases the impression that the University administration has something to hide.

Furthermore, the case raises important issues about science and clinical medicine. Universities are supposed to be where people can conduct free enquiry. There seems to be no free enquiry at Brown into the issues raised by this case. University administrators should be encouraging free enquiry. Here, they seem to be doing their best to avoid, if not stifle it.

Today, the BDH published its own editorial on the case, suggesting that Dr Keller’s “actions directly affect the integrity of the University.” If so, the University community should, at the very least, be discussing these actions, how they affect this integrity, and what ought to be done about it. Unfortunately, I am not optimistic that there will be an open discussion of these issues, even after the brave publication of these articles. The University administration seems to have some reason they want to clamp a lid on this case, and I am afraid they will continue to do so. The medical school faculty, lacking tenure and remembering what happened to previous dissenters like Dr David Kern, are likely to be too scared to push that lid away. Woe unto Brown.

See also comments on the Alison Bass Blog, PharmaGossip, and Pharmalot.

Marty Keller – Key Opinion Leader – do the FBI want to talk to him about Study 329?

It seems the FBI might want to know more about Study 329 and it’s ‘author’ ‘Marty’ Keller… The prosecutor and FBI “were quite interested in how Study 329 was used to promote Paxil for teenagers and kids by clinical researchers Glaxo had underwritten”.

If the FBI are looking in and want more information, can I suggest typing “Study 329” or “Keller” into the search box on the left. Happy reading!

GlaxoSmithKline’s Study 329 of medication for adolescent depression failed to demonstrate any benefit for paroxetine over placebo in adolescents and demonstrated a worrying profile of adverse events for paroxetine.

The study was ultimately published in 2001 by the Journal of the American Academy of Child and Adolescent Psychiatry with Keller as the primary author. This misleading paper has been a focus of interest for Healthy Skepticism since 2002. In 2003 they wrote to the Editor of JAACAP raising concerns about the misleading reporting by the authors that exaggerated benefit and downplayed adverse effects. (They also questioned editorial functioning, which drew an angry response from the Editor).

In 2004 CMAJ published an Editorial which showed that in 1998 an internal GSK document clearly acknowledged that GSK were aware that 329 was negative. A subsequent law suit by New York Attorney General, Eliot Spitzer, was settled out of court.

In 2006, HS wrote to the Lancet to point out that internal documents from another United States law suit (Smith versus GSK) revealed further concerns about study 329:

The study was ghostwritten – see here.

Misleadingly positive interpretations of the study were promoted to drug reps and other GSK staff – see here.

An illusion of efficacy was achieved by re-inventing primary and secondary end points – see here.

Eventually GSK had to acknowledge the failure of all three of their child and adolescent paroxetine depression studies – see here.

Click here for Peter Mansfield’s summary of all trials of newer antidepressants in children and adolescents.

Click here for J & E Jureidini’s summary of citations of the Keller paper.

Paxil Study 329 – lest we forget

Thanks to Healthy Skepticism and Pharmagossip for this:

GlaxoSmithKline’s Study 329 of medication for adolescent depression failed to demonstrate any benefit for paroxetine over placebo in adolescents and demonstrated a worrying profile of adverse events for paroxetine.

The study was ultimately published in 2001 by the Journal of the American Academy of Child and Adolescent Psychiatry with Keller as the primary author. This misleading paper has been a focus of interest for Healthy Skepticism since 2002. In 2003 they wrote to the Editor of JAACAP raising concerns about the misleading reporting by the authors that exaggerated benefit and downplayed adverse effects. (They also questioned editorial functioning, which drew an angry response from the Editor).

In 2004 CMAJ published an Editorial which showed that in 1998 an internal GSK document clearly acknowledged that GSK were aware that 329 was negative. A subsequent law suit by New York Attorney General, Eliot Spitzer, was settled out of court.

In 2006, HS wrote to the Lancet to point out that internal documents from another United States law suit (Smith versus GSK) revealed further concerns about study 329:

The study was ghostwritten – see here.

Misleadingly positive interpretations of the study were promoted to drug reps and other GSK staff – see here.

An illusion of efficacy was achieved by re-inventing primary and secondary end points – see here.

Eventually GSK had to acknowledge the failure of all three of their child and adolescent paroxetine depression studies – see here.

Click here for Peter Mansfield’s summary of all trials of newer antidepressants in children and adolescents.

Click here for J & E Jureidini’s summary of citations of the Keller paper.

Yet more on Paxil Study 329, Keller et al

This is from the always excellent CL Psych. As usual I have reproduced the whole of his article – it’s all here and a real eye opener.

If you need to catch up on Study 329, then read this. Otherwise just carry on:

A bombshell has just appeared [April 2008] in the International Journal of Risk & Safety in Medicine. The subject of the paper is Paxil study 329, which examined the effects of the antidepressant paroxetine in adolescents. The study findings were published in the Journal of the American Academy of Child and Adolescent Psychiatry in 2001. These new findings show that I was wrong about Paxil Study 329. You know, the one that I said overstated the efficacy of Paxil and understated its risks. The one that I claimed was ghostwritten. Turns out that due to legal action, several documents were made available that shed more light on the study. The authors (Jureidini, McHenry, and Mansfield) of the new investigation have a few enlightening points. Let’s look at the claims and you can then see how wrong I was, for which I sincerely apologize.

The story is actually worse than I had imagined.

Here’s what I said then:

Article [quote from the study publication]: Paroxetine is generally well-tolerated and effective for major depression in adolescents (p. 762).

Data on effectiveness: On the primary outcome variables (Hamilton Rating Scale for Depression [HAM-D] mean change and HAM-D final score < 8 and/or improved by 50% or more), paroxetine was not statistically superior to placebo. On four of eight measures, paroxetine was superior to placebo. Note, however, that its superiority was always by a small to moderate (at best) margin. On the whole, the most accurate take is that paroxetine was either no better or slightly better than a placebo.

I went on to bemoan how the authors took differences either based on arbitrary cutoff scores or from measures that assessed something other than depression to make illegitimate claims that paroxetine was effective. Based upon newly available data from the study, here’s what happened.

  • The protocol for the study (i.e., the document laying out what was going to happen in the study) called for eight outcome measurements. To quote Jureidini et al: “There was no significant difference between the paroxetine and placebo groups on any of the eight pre-specified outcome measures.” So I was wrong. Paxil was not better on 4 of 8 measures — it was better on ZERO of eight measures. My sincerest apologies.
  • Another quote from Jureidini and friends: “Overall four of the eight negative outcome measures specified in the protocol were replaced with four positive ones, many other negative measures having been tested and rejected along the way.

Let’s break this thing down for a minute. The authors planned to look eight different ways for Paxil to beat placebo. They went zero for eight. So, rather than declaring defeat, the authors then went digging to find some way in which Paxil was better than a placebo. Devising various cutoff scores on various measures on which victory could be declared, as well as examining individual items from various measures rather than entire rating scales, the authors were able to grasp and pull out a couple of small victories. In the published version of the paper, there is no hint that such data dredging occurred. Change the endpoints until you find one that works out, then declare victory.

How About Safety?

I was incensed about the coverage of safety, particularly the magical writing that stated that a placebo can make you suicidal, but Paxil could not. I wrote:

It gets even more bizarre. Remember those 10 people who had serious adverse psychiatric events while taking paroxetine? Well, the researchers concluded that none of the adverse psychiatric events were caused by paroxetine. Interestingly, the one person who became “labile” [i.e., suicidal] on placebo – that event was attributed to placebo. In this magical study, a drug cannot make you suicidal but a placebo can. In a later document, Keller and colleagues said that “acute psychosocial stressors, medication noncompliance, and/or untreated comorbid disorders were judged by the investigators to account for the adverse effects in all 10 patients.” This sounds to me as if the investigators had concluded beforehand that paroxetine is incapable of making participants worse and they just had to drum up some other explanation as to why these serious events were occurring.

Turns out I missed a couple things. Based on looking at an internal document and doing some calculations, Jureidini et al. found that serious adverse events were significantly more likely to occur in patients taking paroxetine (12%) vs. placebo (2%). Likewise, adverse events requiring hospitalization were significantly disadvantageous to paroxetine (6.5% vs. 0%). Severe nervous system side effects — same story (18% vs. 4.6%). The authors of Study 329 did not conduct analyses to see whether the aforementioned side effects occurred more commonly on drug vs. placebo.

Funny how they had time to dredge through every conceivable efficacy outcome but couldn’t see whether the difference in severe adverse events was statistically significant.

One quote from the discussion section of the paper sums it all up:

There was no significant efficacy difference between paroxetine and placebo on the two primary outcomes or six secondary outcomes in the original protocol. At least 19 additional outcomes were tested. Study 329 was positive on 4 of 27 known outcomes (15%). There was a significantly higher rate of SAEs with paroxetine than with placebo. Consequently, study 329 was negative for efficacy and positive forharm.

But the authors concluded infamously that “Paroxetine is generally well-tolerated and effective for major depression in adolescents.”

Enter Ghostwriters. Documentary evidence as shown on indicated that the first draft of the study was ghostwritten. This leaves two roles for the so-called academic authors of this paper:

  • They were willing co-conspirators who committed scientific fraud.
  • They were dupes, who dishonestly represented that they had a major role in the analysis of data and writing of the study, when in fact GSK operatives were working behind the scenes to manufacture these dubious results.

Remember, this study was published in 2001, and there has still been no apology for the fictional portrayal of its results, wherein a drug that was ineffective and unsafe was portrayed as safe and effective. Physicians who saw the authorship line likely thought “Gee, this is a who’s who among academic child psychiatrists — I can trust that they provided some oversight to make sure GSK didn’t twist the results.” But they were wrong.

By the way, Martin Keller, the lead “independent academic” author of this tragedy of a study said, when asked about what it means to be a key opinion leader in psychiatry:

You’re respected for being an honorable person and therefore when you give an opinion about something, people tend to listen and say – These individuals gave their opinions; it’s worth considering.

So is completely misrepresenting the data from a study “honorable”? Is Keller’s opinion “worth considering?” As you know if you’ve read this blog for long, such behavior is, sadly, not a fluke occurrence. Many others who should be providing leadership are leading us on a race to the scientific and ethical bottom. What will Brown University, home of Keller, do? Universities don’t seem to care at all about scientific fraud, provided that the perpetrators of bad science are bringing home the bacon.

Not one of the “key opinion leaders” who signed on as an author to this study has said, “Yep, I screwed up. I didn’t see the data and I was a dupe.” Nobody. Sure, I don’t expect that every author of every publication can vouch for the data with 100% certainty. I understand that. But shouldn’t the lead author be taking some accountability?

This is a Fluke (?) Some may be saying: “But this is just a fluke occurrence.” Is it? I’ve seen much evidence that data are often selectively reported in a manner like this — looks like (sadly) it takes a lawsuit for anyone to get a whiff of the bastardization of $science that passes for research these days. If GSK had not been sued, nobody would have ever known that the published data from Study 329 were negative. A reasonably educated person could see that the writeup of the study was a real pimp job — lots of selling the product based on flimsy evidence, but nobody would have seen the extent of the fraud. Apparently lawyers need to police scientists because scientists are incapable of playing by some very basic rules of science.

See for Yourself. Documents upon which the latest Jureidini et al. paper are based can be found here. Happy digging.

And while we’re talking about Study 329 – here are some real Seroxat Secrets

I know it’s going over old ground, but I’m prompted to write this by the recent posts at Scientific Misconduct and Seroxat Sufferers about Marty Keller and Study 329.

Firstly we must go back to October 1998 to an internal, confidential SmithKline Beecham document about studies 329 and 377. In summary it says “… the data do not support a label claim for the treatment of Adolescent Depression… efficacy had not been demonstrated.”

Specifically about Study 329 “…the study failed to demonstrate a statistically significant difference from placebo on the primary efficacy measures.” In other words – it didn’t work.

About Study 377 we read “… failed demonstrate [sic] any separation of Seroxat/Paxil from placebo.” In other words – it didn’t work.

“Data from these 2 studies are insufficiently robust to support a label change and will therefore not be submitted to the regulatory authorities.”

Feel free to download a copy of this document and read the rest of the interesting conclusions (especially page 6) – SB internal

Now we move on to March 1999, to a fuller manuscript of Study 329 being prepared for publication. This was written by Sally K Laden but was attributed to Marty Keller, Neil Ryan and colleagues. (I believe this is what is known as ghostwriting).

Please download a copy of this manuscript – Sally/Marty draft 3

If you go page 4 you will see the conclusion reads “Paroxetine is a safe and effective treatment of major depressive disorder in the adolescent patient.”

You can see that Sally/Marty’s spin has quickly moved on from that of SmithKline Beecham only 5 months previously. In fact you might be forgiven for wondering how these two different conclusions could be reached from the same data…

Now on to March 2001 – internally at least SmithKline Beecham seem to have understood what the data from Study 329 really said. In an email to Cohn and Wolfe, the company said: “Originally we planned to do extensive media relations surrounding this study [329] until we viewed the results. essentially the study did not really show Paxil was effective in treating adolescent depression, which is not something we want to publicize.”

Download a copy here – SB to Cohn Wolfe

However, by August 2001 SmithKline Beecham Paxil Product Management was writing to all sales representatives selling paxil and telling them about Marty Keller’s “cutting edge, landmark study which was the first to compare efficacy of an SSRI and a TCA with placebo in the treatment of major depression in adolescents. Paxil demonstrates REMARKABLE Efficacy and Safety in the treatment of adolescent depression.”

Download this memo here – Sales reps memo

As I said none of this is new. The last Panorama programme, Secrets of the Drug Trials was where all of this first broke.

Just a thought – I wonder if this is the kind of data that the big pharma apologists would have us rely on?

Drs. Keller, Ryan & study 329…

More from the Evelyn Pringle here. The entire article can be read here Trail Of Paxil Suicides Leads To Glaxosmithkline.

Glaxo needed to find a way to ‘use’ Study 329 – you know, the one that showed Paxil wasn’t safe and didn’t actually work in children. Enter Drs. Keller and Ryan. By using opinion leaders in the field, academics who everybody looks up to, doctors would be far more influenced to prescribe Paxil than they would be if approached by Glaxo salespersons.

At the time, the name of Dr Martin Keller, a professor of psychiatry at a prominent university in the US was apparently worth a lot to drug makers and specifically Glaxo. In a single year, Panorama reports, Dr Keller earned a half a million dollars from drug companies, including Glaxo.

Study 329 was finally published in the July 2001, Journal of the American Academy of Child and Adolescent Psychiatry, with Dr Keller’s name as the lead author (with Dr Neal Ryan and Dr Karen Wagner), but Keller’s actual input has been seriously questioned. In one memo, Dr Keller thanked a ghost writer from a PR firm hired by Glaxo for preparing the manuscript stating: “You did a superb job with this. Thank you very much. It is excellent. Enclosed are some rather minor changes from me…”

The study drew criticism from around the world: one letter to the Editor by Professors, Dr Jon Jureidini and Dr Anne Tonkin, from Adelaide, Australia, stated: “We believe that the Keller et al. study shows evidence of distorted and unbalanced reporting that seems to have evaded the scrutiny of your editorial process. Given that the research was paid for by GlaxoSmithKlien it is tempting to explain the mode of reporting as an attempt to show the drug in the most favorable light. Given the frequency with which it is cited in other scientific papers, at conferences and educational functions, and in advertising, this article may have contributed to the increased prescribing of SSRI medication to children and adolescents.”

Another highly critical editorial was published on June 12, 2004, in The Lancet, which stated in part that Glaxo “appears to be floundering in the semantic depths. While it has been earnestly parsing the meaning of ‘suicidal thinking and acts’ and ‘publicly,’ it appears to have forgotten what lies behind those words – people.”

By 2004 even the European Medicines Agency (EMA) and the FDA were in on the Act – the FDA ordering the re-evaluation of all SSRI studies… including 329.

A February 4, 2004, email from another highly paid Glaxo academic, Dr Neal Ryan, to fellow Study 329 authors, Dr Karen Wagner and Dr Keller, illustrates their alarm over the FDA’s order for drug companies to re-evalute all SSRI studies. The email states:
FDA made each company go line by line through absolutely all documentation of all kids in all their studies. This is where 4 more subjects in our joint study fell out, unfortunately all the Paxil group. Don’t know severity or more information about this yet.

In a curious Glaxo email titled, ‘Study 329 Update,’ to Dr Ryan, Dr Wagner and Dr Keller, the investigators who supposedly reviewed the data and authored the report, a GSK employee wrote: “We want to update you, as investigators on Study 329, about additional potential pediatric suicidality cases that were recently discovered. In a manual review of all SAE narratives and ‘trauma’ cases, 10 additional events potentially suggestive of intentional self injury, suicidal ideation, or suicide attempt were identified. Four of the 10 events occurred in study 329, all in the paroxetine group. Consequently, this could potentially change the number of paroxetine suicide-related adverse events for that study from 6 to 10.” “These cases,”the email states, “included among those undergoing blinded review by Dr. Wagner, Dr. Ryan, and Dr. Apter for the pediatric suicidality manuscript.”

This message apparently caused Dr Ryan to panic because he was being contacted by reporters. In an email response he stated:
“With your email yesterday (appended below) about 4 additional ‘events’ in Study 329 on the Paxil arm, those of us involved in writing the recent letter to the reporter asking about details of our article need very very quickly to get absolutely as much information as you have and understand what part of this we need to pass on to her. Otherwise we are in the challenging position of sending her a good-faith effort at directly answering her questions that we find very shortly thereafter is no longer the most complete information available to us and which therefore might appear misleading.”

“Can we get a much fuller explanation in email?” Dr Ryan asks. “Should we quickly set up a conference phone call?”

The truth about long-term antidepressant use

A great piece today in the Guardian by . Good to see such a comprehensive piece of reporting in the mainstream media.

This what you and I know has happened to many of us, but at the same time GSK continues to deny is a major health crisis because of Seroxat (and other SSRIs). In the UK, as the High Court action moves ever closer to trial, GSK and their expensive legal team still have their collective head in the sand – at least that’s their public stance. I believe that for many years GSK has known about the problems Seroxat causes while you take it, about the terrible problems people have withdrawing from the drug and also about the long-term problems ‘survivors’ are left with for the rest of their lives.

Here’s the article:

Sarah never planned to take antidepressants for 14 years. Three years after she began taking them, when she was 21, she went to her GP and asked to stop: 20mg of Seroxat a day had helped her live with anxiety and panic attacks, but she began to feel uncomfortable about being on medication all the time. Her doctor advised her to taper down her medication carefully.

At once, “I was a mess,” she says. “I thought I was losing my mind. My appetite completely went. I lost the best part of two stone. I was anxious constantly. My mouth was dry. It was difficult to sit and be calm.” She became withdrawn, refusing to see friends, and remembers asking her mother to get her a couple of boxes of paracetamol, thinking, “I’m going to have to take all these tablets, because I can’t live like this.”

Sarah’s doctor encouraged her to go back up to 20mg. “Within a week, I was much better. I feel anger when I look back. That wasn’t me relapsing, that was withdrawal. But I was so unwell, I didn’t stop to think, ‘I’ve never had this before.’ I truly thought it was me. Now the only reason I am on the drug is because I am dependent upon it. And that is not good enough.”

Prescriptions of SSRIs (selective serotonin reuptake inhibitors), the most common type of antidepressant, have doubled in the past decade. There are now more than 70m prescriptions dispensed in the UK in a year, the “greatest rise” of any drug in the last year, according to NHS research. But while the side-effects of starting and then withdrawing from these drugs are reasonably well known (the patient information leaflet accompanying the SSRI Seroxat is six pages long), there is very little research into the long-term effects of using antidepressants.

Last year, an all-party parliamentary group began hearing evidence as to whether there is a link between a measurable rise in mental health disability claims – 103% between 1995 and 2014 – and that in antidepressant prescriptions. (Claims for other conditions fell by 35% in the same period.) “We need to have a serious rethink about current levels of prescribing, because it may well be that the drugs are in fact contributing to the disability burden,” Dr Joanna Moncrieff, a consultant psychiatrist and senior lecturer at University College London, told the committee.

Reports both anecdotal and clinical have included side-effects such as constant pain, an altered sense of smell, taste or hearing, visual problems, burning hands and feet; food or drug intolerances and akathisia (the medical term for a deep inner restlessness). When a patient begins tapering down their dosage, these effects are generally ascribed to the drug leaving their system; if it is long after withdrawal is supposed to be over, however, patients are often disbelieved (according to the drug companies, withdrawal should take just two weeks for most people, though they acknowledge that for some it can be months).

Professor David Healy, director of the department of psychological medicine at Cardiff University and author of 22 books on psychopharmacology, believes that antidepressants are overprescribed. “If you go into your average doctor – if you’ve been off the drug for half a year or more – and you complain [of a range of symptoms] and say, ‘I think it’s caused by this pill I was on’, he or she would say, ‘It’s been out of your body for months. You’re neurotic, you’re depressed. All we need to do is put you on another pill.’”

GPs, Healy says, are “relying on your word, and if it’s a choice between believing what you say and relying on what drug companies say to them, they [tend to] believe the drug companies”. Healy, who has been a consultant for, and expert witness against, most of the major pharmaceutical companies, has long argued that long-term side-effects are routinely ignored or misunderstood.

But many experts believe these drugs do more good than harm. “Most of the people I see who have moderate to severe depression benefit from them,” says Daniel Smith, a professor of psychiatry and researcher into bipolar disorder at the University of Glasgow. For some, medication can be no less than “transformative. It can get them through a really critical period of their life.”

However, when it comes to long-term impact, especially after a person stops taking SSRIs, Smith says it can be hard to work out which symptoms relate to the drug use and which to the underlying conditions. “There’s obviously an issue of cause and effect. How can we be certain the SSRI caused it? Depression affects libido and sexual interest. How much [of the reported effects] is depression and/or anxiety symptoms coming back?”

SSRIs have been around for more than 40 years, but grew in popularity in the late 1980s and 90s after pharmaceutical company Eli Lilly launched fluoxetine, otherwise known as Prozac. Time magazine put the drug on its cover twice, asking, “Is Freud finished?” and describing SSRIs as “mental health’s greatest success story”. In 2001, a landmark report on a clinical trial into paroxetine (sold as Seroxat in North America and Paxil in the UK), called Study 329, concluded that it demonstrated “remarkable efficacy and safety”. Study 329 led directly to a massive increase in prescriptions: by 2003, worldwide sales of Seroxat (manufactured by GlaxoSmithKline) were worth £2.7bn.

But concerns were raised about the study –the US food and drug administration (FDA) officer who reviewed the data disagreed with the findings, calling it a failed trial – and in 2015 the British Medical Journal published a re-evaluation. Seven authors went through as many of the thousands of individual case reports as they could, and found not only that “the efficacy of paroxetine… was not statistically or clinically different from placebo”, but that “there were clinically significant increases in harms, including suicidal ideation and behaviour”. The original study reported 265 adverse reactions; the BMJ found 481. The re-evaluation also found that psychiatric responses were grouped together with “dizziness” and “headaches”, rather than given their own category. In 2003, the UK banned the use of Seroxat by anyone under 18; and in 2004 the FDA required a “black box warning” on all antidepressants, its strictest level of patient warning.

“Patient safety is our number one priority,” a GlaxoSmithKline (GSK) spokesperson tells me. “We believe we acted responsibly in researching paroxetine, monitoring its safety once it was approved and updating its labelling as new information became available.”

Many SSRI users report blunted emotions, even long after they have ceased taking pills, and an impact on sexual function. “They should be called anti-sex drugs rather than antidepressant drugs,” says Jon Jureidini, a child psychiatrist of 30 years’ standing, a professor of psychiatry and paediatrics at the University of Adelaide and co-author of the BMJ study, “It’s more reliably predictable that they’re going to get rid of sexual function than it is that they’re going to get rid of depression.” Again, some people find this persists long after they cease taking the drug. One person I spoke to, Kevin, had taken Prozac for six months when he was 18; now 38, he hasn’t had an erection since.

Last September, Healy and colleagues published a further examination of the data gathered for Study 329. This data followed the trial participants for six months after they started taking paroxetine (the “continuation phase”) and while they were tapered off it. GSK, which in 2004 published a clinical study report, had argued that “the long-term safety profile of paroxetine in adolescents appears similar to that reported following short-term dosing”. Healy and co, however, concluded that the “continuation phase did not offer support for longer-term efficacy”. More alarmingly, they found that the taper phase, when patients were being taken off the drugs, was the riskiest of all, showing a “higher proportion of severe adverse events per week of exposure”. This, they said, opens up the risk of a “prescribing cascade”, whereby drug side-effects are thought to be symptoms, so are treated with further drugs, causing further side-effects and further prescriptions – thus increasing the risk of long-term prescription drug-dependency.

In October, the British Medical Association published its response to a two-year fact-finding exercise into long-term use of psychoactive drugs. It noted that while benzodiazepines, z-drugs, opioid and antidepressants are “a key therapeutic tool”, that their use can “often lead to a patient becoming dependent or suffering withdrawal symptoms… the evidence and insight presented to us by many charity and support groups… shows us that the ‘lived experience’ of patients using these medications is too often associated with devastating health and social harms”; it was therefore, the report concluded, a “significant public health issue”.

The BMA made three key recommendations: first, and most urgently, that the UK government establish a 24-hour helpline for prescribed drug dependence; second, that it establish well-resourced specialist support units; and third, that there should be clear guidance on prescription, tapering and withdrawal management (they found the current approach to antidepressants, in particular, to be inconsistent: too many patients were suffering “significant harm”). There are also increasingly urgent calls for studies into long-term effects that are not funded by drug companies, because, Moncrieff says: “We don’t have very much data. This research is really important, but hasn’t been done. It’s a massive blind spot. It’s extraordinary – or maybe, given the pressures and interests at work, not extraordinary at all – that it hasn’t been filled.”

In March this year, members of the BMA, along with MPs and researchers from Roehampton University, went to parliament to lobby Public Health England, armed with research estimating that there are 770,000 long-term users of antidepressants in England alone, at a cost of £44m to the NHS per year (a figure that does not account for the cost of GP appointments, or the impact of side-effects, withdrawal effects and disability payments).

“I think you have to adopt a very conservative approach,” says psychiatrist Jon Jureidini. “These are brain-altering drugs, and our overall experience with brain-altering drugs of all kinds is that they tend to have a detrimental effect on some proportion of people who take them long term. All we know about the benefits is from short-term symptom-reduction studies. The careful prescriber needs to say, ‘Well, in balancing the likely benefits and harms, I need to be very cautious about how much benefit I’m expecting, and I need to be very generous about the possibility that the harms might be more than they appear to be.’”

Quite a few long-term users, such as those I spoke to below (and who wished to be anonymous), would agree.

‘Tapering off is the hardest thing I’ve ever done’: Sarah, 32; has taken Seroxat for 14 years I was prescribed Seroxat when I was 18, the year I started university. I grew up with a disabled sister, so things at home were very stressful, and I had a history of anxiety and panic attacks. I had counselling, but the problems persisted, so I went back to the GP. I don’t remember everything that was said, but there was no conversation about side-effects.

Within the first two weeks of starting Seroxat, I remember I was sitting in the front room watching TV when out of nowhere I had this intense feeling of heat, like an electric shock. It started in my hands, went all the way up my arms and through to my head.

The GP said it was probably just my body getting used to the drug. And after a few weeks the weird sensations did ease off. I had a fabulous time at university. I still had panic attacks, and there were certain situations I would avoid – as I still do – so it wasn’t a wonder drug, but there were no major problems.

But in 2006 I tried to come off it. There were a couple of Panorama documentaries about the side-effects and I was starting to become concerned. The GP said, “That’s fine, but do it gradually, over three weeks.”

I immediately became incredibly unwell. I thought I was losing my mind. I was going to work, but it was difficult to get through the day. My mouth was so dry, I was constantly drinking water. I had bizarre thoughts – not hallucinations – that were frightening or distressing. I had a strong sense of detachment from reality.

Eventually, the doctor said, “Look, you coming off is obviously not working: we need to get you back to 20mg.” Within a week I was much better.

A few years later, when I realised my mental health was getting worse, even though I was on the medication, I started to do some research, reading case studies about withdrawal. I find it so offensive when a GP says, “This is who you are.” I didn’t have these symptoms 10 years ago. I didn’t have this sense of detachment. I saw various psychiatrists. They just kept saying, “The drug is safe, you need to be on it.” A couple of others told me the reason I was having these problems was because I wasn’t taking enough. Another said, “If you were diabetic, you’d take insulin and you wouldn’t have an issue. Why are you so bothered about taking this drug?”

I’ve been on it since I was 18, so I don’t know who I am without it, as an adult. Who knows? I might have all kinds of problems, but I need to know I’ve tried. Tapering off is the hardest thing I’ve ever done. It’s taken me three years just to get from 20mg to 5mg. I’m no longer with my partner – we were together for six years. I believe Seroxat has played a part: it affected my moods, it made my anxiety worse and, by necessity, I’ve had to be selfish, really. I don’t want to say all my problems are to do with Seroxat, because they’re not. But I do believe that it has caused me harm.

‘I don’t have much of an interest in interacting romantically or physically with the opposite sex’: Jake, 24; took SSRIs for eight years I had been dealing with symptoms of OCD and anxiety for a lot of my childhood. It’s in my family, affecting two siblings and one parent. I was prescribed Zoloft when I was 12; I took a variety of SSRIs, Zoloft to Prozac to Lexapro, and then two others, for eight years.

Did they help? You know, I can’t really tell you, because I got through school. I got high marks, I had a lot of friends. So, in that sense, they must have helped. That’s the thing: for people with major depression, it’s easy to say, this has a measurable effect. But I kept taking them just because that’s what I’ve always done.

I went to university right out of school. I did very poorly. I had a bit of a breakdown, isolating myself, not sleeping. I was still on medication. I came home and enrolled at a community college. That was my worst period – I was very depressed. And I started to think, “I’ve been on these medications a long time. I’m not doing well – why not get off them?” I don’t recommend this at all to anyone, but I stopped going to a psychiatrist and took myself off.

For months I had trouble sleeping. I was jittery. I had brain zaps. My anxiety was pretty ramped up. I would feel numbness in my extremities – generally my arms. My psychiatrist told me these were just normal withdrawal symptoms, and they’d be gone in four to six weeks: “Anything you feel beyond that is your anxiety and depression returning.” Basically, if you still feel anything beyond this window that the medical community has established, it’s all in your head.

Eventually I went back to school full-time, and I remember doing OK, feeling somewhat better.

I’ve now been drug-free for four years. What’s lasted are the sexual side-effects. They were definitely worse in withdrawal than they had been on the drug, even though I didn’t really realise or understand it at the time, primarily because I started to take SSRIs at 12. While my brother took the same medicine over the same period and had a normal sexual life, I had a lack of sexual interest. I had erections, and I have regularly masturbated my entire life. But I don’t have much of an interest in interacting romantically or physically with the opposite sex.

I didn’t even start thinking about sex until a couple of years ago. It’s almost like I woke up one day and thought, “OK!” I started getting these windows – days or weeks – when normal sexual feelings would appear. But they’re new to me and I don’t know what to do about them. And because I don’t know what to do, I get anxious, and the anxiety kills any feeling – and then I’m anxious because I’ve lost all my feeling.

Online, I’ve come across a big asexual community. Some also took antidepressants; I think there are a lot of people like me out there. I’d like to think that if I keep going to counselling and sleeping and eating properly, I can rectify these things.

In the end, it’s about pros and cons. If you’re lying in bed and can’t get up, is it better to function? If it was up to me, I’d say that, barring extreme circumstances, nobody under 18 should be prescribed these things. Your brain develops around them. Drug companies should be thinking of the long-term effect on people who can’t even consent.

‘If I missed a dose, I’d get shocks down the side of my body’: Chris, 43; has been taking Seroxat for 26 years I was originally prescribed Seroxat for mild anxiety about my GCSEs. It was 1991, about the time GlaxoSmithKline released Seroxat. I was one of the first people to be given it.

I was prescribed 20mg, the basic dose, to start with. It helped me: I got through school, I went to uni, I went to work. But I had side-effects from the off: profuse sweating, low libido. I’m quite a placid person, but I became aggressive. I never suffered, in the beginning, with the suicidal thoughts that people talk about now, but what I did notice was that if I missed a dose – especially after eight years of taking it – I’d get shocks down the side of my body. I’d be nauseous, my limbs would become weak. I’d be in a constant state of confusion and was very impatient. I couldn’t communicate well with people. I said this to the doctor, and he said, “We’ll up the dose to 40mg.” That was 1998.

The 10 years after that weren’t too bad. I managed to work, as a sales rep, for 18-20 years. But by 2012, by which time I was up to 60mg, I had tried on numerous occasions to withdraw. I tried to go back to 20mg, but my words became slurry, so the doctor put me back up to 60mg.

By the time I was 38, even that wasn’t enough. I tried to take my life. The doctor wouldn’t prescribe a higher dose. I couldn’t do my job, I couldn’t concentrate, I couldn’t drive. A psychiatrist once said to me that coming off Seroxat is harder than quitting heroin. That really hit home.

I have now been unable to work for four years. I’m still seeing a psychiatrist. I’ve also been diagnosed with fibromyalgia: constant tiredness, aches in the neck, and in the lower back and lower limbs. I’m 43 and still live with my mum and dad.

I also have no libido. Since the age of 30, I have had no feelings in that regard whatsoever. I have had relationships, but they’ve all failed. I haven’t been in a relationship for 10 years, which is a long time to go without sex, but I just don’t get the urge.

I don’t really have emotions, to tell you the truth. The drug takes your emotions away. I’m sort of existing, not living.

And when the drugs do work…

‘I wanted to be able to feel good when good things were happening, bad when bad things were happening’ By Simon Hattenstone I suppose I was a depression snob. A purist. Why should I take antidepressants? Yes, there was something rubbish about crying all the time, not functioning, being unable to answer simple questions because of the fug in my head. But, hey, at least I was true to myself.

My depression went back to my late teens. I didn’t like to think of myself as depressive, because depressives were losers. And I didn’t think I fitted the bill: I was pretty funny and able, and I could get girlfriends. I guess most depressives don’t think they fit the bill.

It might have been genetic. My dad had paralysing depression, and so did his father. As a young boy, I’d spent three years off school with encephalitis – an inflammation of the brain that is often fatal. Survivors are often left with depression.

I remember as a teenager being on holiday in Greece with friends. The weather was gorgeous, and I thought, “Why can’t it piss down, because then at least I’d have a reason to feel this way?”

That is what I always craved – objectivity. To be able to feel good when good things were happening, to feel bad when bad things were happening. I hated the fact that my feelings rarely correlated to what was going on in my outer world.

In my 20s, I got by. I held down a good job, fell in love, had kids, made friends, had a pretty good life. But things came to a head when my best friend killed herself. I’d find myself weaving in between traffic wondering what the impact would be like. I took a period off work and gratefully accepted my Prozac prescription.

Things had changed since I first rejected them. Prozac looked cool (lovely green-and-white pills) and rock bands wrote great songs about it (even if REM’s Shiny Happy People was supposed to be dystopic). After telling people I was off work with depression, I ended up feeling like a priest at confessional. It turned out that virtually everybody I knew was a depressive and pilling their way out of it; now it was “our secret”.

I would try to come off the pills and felt rubbish again – not more rubbish than before, but the same. So I returned

Initially, Prozac made me feel sick. And then magically, after a couple of weeks, I felt lighter, as if something had been lifted. I could hear questions properly, answer logically, enjoy a sunny day.

My partner said I was transformed. Occasionally, I would try to come off the pills and felt rubbish again – not more rubbish than I had before, but the same. So I returned, and after a while, I thought, “What’s the point of even thinking about coming off the pills if they make life work for me?”

There are times now when I wonder if I weep and fret and withdraw too much, and whether I’m becoming immune to the Prozac. But on balance I think not, because life is still so much better than it was.

If Prozac was no longer working for me, would I stop taking it? Probably. Would I stop taking antidepressants full stop? I doubt it. I’d simply look for another super pill.

How addictive is Seroxat?

All this talk about Seroxat addiction and withdrawal reminded me of a post that I wrote back in 2007… I think it would be very interesting to see the data from the studies that Dr Wheadon spoke about while under oath in California.

Especially given what we now know about the lies GSK told about Study 329.

seroxat secrets...

You might think that after all the years of doctors and patients all around the world saying Seroxat is highly addictive – oops, sorry, causes dependence and severe withdrawal reactions – that Glaxo would simply undertake the definitive study to prove us all wrong and to show the world once and for all really how safe and non-addictive Seroxat is…

Well, the truth is Glaxo could have done this years ago but it has not. Why? I leave that simple question to you to answer.

In fact, the official Paxil prescribing information (produced by Glaxo, current version) confirms this by saying:

DRUG ABUSE AND DEPENDENCE
Controlled Substance Class: PAXIL is not a controlled substance.
Physical and Psychologic Dependence: PAXIL has not been systematically studied in animals or humans for its potential for abuse, tolerance or physical dependence…

Again, I ask Glaxo why have no systematic studies been done? Why not…

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