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Adverse drug events are now the fourth leading cause of death in hospitals.

It’s a reasonable bet they are an even greater cause of death in non-hospital settings where there is no one to monitor things going wrong and no one to intervene to save a life. In mental health, for instance, drug-induced problems are the leading cause of death — and these deaths happen in community rather than hospital settings.

There is also another drug crisis — we are failing to discover new drugs. [Read more...]

Author Archive for Jo

Restoring Study 329: Letter to BMJ Jan 2016

Portrait of Fiona Godlee. Photo: Magda Rakita

Editorial Note: This was our final letter in the correspondence that began here and ran through here. There has been no response from Dr Godlee.

28 January 2016

Dr Fiona Godlee
Editor, BMJ

Re: BMJ handling of conflict of interest

Dear Dr Godlee

Thank you for your email response of January 11 2016 to our letter of July 8 2015 about Dr Elizabeth Loder’s conflict of interest in relation to editing our Restoring Study 329 paper. However, we are disappointed with the outcome.

When Dr Loder and reviewers of our submitted paper suggested that we had conflicts of interest, we argued in our responses that conflict of interest is less important than access to data. With access to the data, others can decide whether or not perceptions of conflicting interests might have translated into actual bias. However BMJ made several more comments during the review process about our conflicts, and on July 6 2015 required that the most important part of our work, the reporting of adverse events, be independently checked because of perceived bias.

It was against this background that we wrote our letter of concern about Dr Loder’s apparent COI, intending to point out the double standards that appeared to us to be operating. We had hoped that you and Dr Loder would concede that there was indeed a perceptual issue with her organisation’s present and past relationship with GSK and that of her husband’s law firm, but would reassure us that there was no actual conflict because Dr Loder had worked hard for the publication of the paper. Instead BMJ dismissed the issues we raised as ‘so attenuated’ that requiring their declaration would be ‘absurd’, a dismissal that seemed inconsistent with BMJ’s attitude towards our perceived bias.

Study 329 will be an object of study for years to come, and it is important that the full story be available. The BMJ reviews and correspondence are the data about the handling of our paper. Reading them will make it possible for others to make a judgement as to whether any bias may have been involved. Yet these documents are not included under the ‘Peer review’ tab for our published paper http://www.bmj.com/content/351/bmj.h4320/peer-review, contrary to BMJ policy http://www.bmj.com/content/349/bmj.g5394. We request that they be posted there.

Meanwhile, the correspondence is available on the Restoring Study 329 website. We would be happy to include on that site a BMJ view as to how readers should read the various reviews and correspondence, or any other commentary that you might want to add.

Yours sincerely

Jon Jureidini
On behalf of 329 RIAT team

 

Restoring Study 329: Letter to BMJ

godlee-or-not

Editorial Note: The posts have gotten slightly out of sequence. This post should have preceded the responses from BMJ. It is the letter to which they were responding. This and other letters are on Study329.org.

8 July 2015

Dr Fiona Godlee
Editor
BMJ

Dear Dr Godlee

Re: “Restoring Study 329: A randomised, controlled trial of the efficacy and harms of paroxetine and imipramine in the treatment of adolescent major depression”

I note your earlier comment about BMJ’s risks being ‘more editorial than legal’. Coincidentally when we were looking up Dr Elizabeth Loder’s profile in relation to her concerns about our handling of headache in our adverse events analysis, we became aware of a potential conflict of interest.

BMJ staff have understandably been very careful about any perceived conflict of interest on the part of our team, given that some of us have previously criticized GSK’s Study 329; we now have concerns about Dr Loder’s indirect but significant links with GSK.

  • Her hospital (Brigham and Women’s) received over $12 million in research funding from GSK in 2014, up from just over $100,000 in 2003

(https://openpaymentsdata.cms.gov/company/100000005449).

  • Dr Loder has made public statements favourable to GSK products, including: ‘For all of these reasons my mantra is that “You haven’t failed sumatriptan until you have failed to respond to a full dose of injectable sumatriptan given early in an attack!” There is also evidence that combining a triptan with an anti-inflammatory drug might improve the likelihood it will be effective’.

(http://live.washingtonpost.com/how-serious-are-migraines.html ). This article was published just before GSK’s Treximet (combination triptan and anti-inflammatory) came on to the market.

  • Dr Loder’s husband, John M. Loder, is a partner in Ropes & Gray, a law firm retained by GSK in the US Department of Justice’s action against them, in which Study 329 was a central element

(http://www.law360.com/articles/250821/how-they-won-it-steptoe-gets-rare-acquittal-for-gsk-atty ).

More recently, the law firm has supported GSK with its difficulties in China

(http://www.legalweek.com/legal-week/news/2284819/ropes-gray-takes-lead-role-on-gsk-probe-into-china-bribery-claims).

Although, as Dr Loder’s COI declaration at BMJ points out, John Loder’s work is not in the healthcare field, as a partner in Ropes & Gray, he presumably profits directly from such work.

We believe that Dr Loder’s interests have been incompletely declared and that it might have been appropriate for her to recuse herself from involvement in the assessment of our paper to avoid any perception that GSK’s interests were being considered in BMJ’s deliberations.

While the timing for bringing these concerns to your attention is not ideal, we wanted to inform you as soon as possible after we became aware of these potential conflicts.

I look forward to hearing from you soon.

Yours sincerely

Jon Jureidini
On behalf of the RIAT 329 group

BMJ Award

Restoring Study 329: Correspondence with BMJ Jul 15 to Jan 16

thrill

Editorial Note: The letter from the Study 329 team to BMJ re Dr Loder featured in 50 Shades of Gray and in Conflicts of Interest. The actual letter and related correspondence is all on Study329.org.  The emails below and in the next post tell you what happened next.

From: Jureidini, Jon (Health)

Sent: Wednesday, 8 July 2015 10:32 PM

To: fgodlee@bmj.com

Subject: 329 and COI

Dear Dr Godlee

Please find attached a letter that raises some COI issues.

Thanks

Jon Jureidini

__________________________________________________________________

On Wednesday, 30 September 2015, 23:52, “Jureidini, Jon (Health)” <Jon.Jureidini@sa.gov.au> wrote:

Dear Fiona

Thank you for publishing and promoting our paper. We are very pleased that we and you saw this difficult process through.

We have not received a reply to the attached letter we sent you on 8 July, about our concerns about potential conflict of interest on the part of Dr Loder. We still think that the issues we raised are important, so we are seeking a response from you.

Thanks

Jon

_____________________________________________________________ 

From: Fiona Godlee [mailto:fgodlee@bmj.com]

Sent: Thursday, 1 October 2015 6:46 PM

To: Jureidini, Jon (Health)

Subject: Re: Confidential

Dear Jon.

Thank you for your message. My apologies for not replying to your earlier message. I’m not sure how I missed it.

Let me discuss your concerns with Dr Loder. I will get back to you as soon as I have had a chance to do so.

All best wishes. Fiona

Dr Fiona Godlee FRCP

Editor in chief, The BMJ

London WC1H 9JR

http://www.thebmj.com/

fgodlee@bmj.com

44 (0)207 383 6002

 

__________________________________________________________

 

—–Original Message—–

From: Jureidini, Jon (Health)

Sent: Wednesday, 4 November 2015 9:37 AM

To: fgodlee@bmj.com

Subject: FW: Confidential

Hi

Have you had a chance to evaluate our concerns?

Cheers

Jon

_________________________________________________________

 

On 14 Dec 2015, at 2:07 am, Jureidini, Jon (Health) <Jon.Jureidini@sa.gov.au> wrote:

Hi

Just tidying things up before Christmas, and wanting to check if I will hear back from about this potential COI issue.

Happy new year

Jon
_______________________________________________________________ 

From: “fgodlee@bmj.com” <fgodlee@bmj.com>

Date: Wednesday, 16 December 2015 4:46 am

To: “Jureidini, Jon (Health)” <Jon.Jureidini@sa.gov.au>

Subject: Re: Confidential

Dear Jon.

So sorry not to have got back to you about this. I referred it to our ethics committee which meets three times a year, but the last meeting was cancelled. They meet tomorrow and I should be able to give you their conclusion shortly afterwards. All best wishes. Fiona Dr Fiona Godlee FRCP

Editor in chief, The BMJ

London WC1H 9JR

http://www.thebmj.com/

fgodlee@bmj.com

44 (0)207 383 6002

________________________________________________________

From: Fiona Godlee [mailto:fgodlee@bmj.com]

Sent: Sunday, 3 January 2016 11:09 PM

To: Jureidini, Jon (Health)

Subject: Re: Confidential

Dear Jon,

Just to give you an update.

The ethics committee’s agenda was rather full for its December 16 meeting – having missed a meeting earlier in the year, and I am afraid we didn’t get to this item. However, I have asked our chair, Professor Marion McMurdo, to convene an additional meeting, which I hope will take place in the next few weeks, in order that we can get you a response to your concerns. My apologies for this further delay. I will be in touch again as soon as possible.

All best wishes,

Fiona

Dr Fiona Godlee FRCP Editor in Chief, The BMJ BMJ, BMA House, Tavistock Square, London, WC1H 9JR T: 020 7383 6002 E: fgodlee@bmj.com W: bmj.com/company

Personal assistant:

Julia Burrell

T: 020 7383 6102

E: jburrell@bmj.com

____________________________________________________________________

From: Fiona Godlee [mailto:fgodlee@bmj.com]

Sent: Monday, 11 January 2016 3:42 AM

To: Jureidini, Jon (Health)

Subject: Fwd: response to the Jureidini allegations

Dear Jon,

I am now able to respond in full to the concerns you raised last year about Elizabeth Loder’s possible conflicts of interest in relation to your reanalysis of the data from Study 329.

The ethics committee convened on Friday 8 January, 2015. It was chaired by the committee chair Professor Marion McMurdo, attended by committee members Julian Sheather, Elizabeth Wager, and Dr Adrian Sutton. Committee members who were unable to attend – Dr Rubin Minhas, John Coggon, and Dr Richard Hain – sent their comments by email. Also attending were myself, the BMJ’s Executive Editor Dr Theo Bloom, and the committee’s secretary Laura Templar who took the minutes.

The committee were in receipt of your letter and a response from Dr Loder, which is appended with attachments below.

The committee reviewed the issues you raised and, by a large majority, concluded that the possible conflicts you have identified are so attenuated by distance from Dr Loder – by virtue of the size and scope of her and her husband’s organisations, as to be highly unlikely to have impacted on her decision making. The committee felt that to require an individual to consider, manage or declare such attenuated links would take declaration of conflicts of interest to an absurd level, since such potential conflicts would be near impossible for an individual to keep track of or to be held responsible for. The committee was satisfied with Dr Loder’s response.

On the basis of this advice I therefore intend to take no further action on this matter.

Thank you again for raising it.

All best wishes, Fiona

 

Dr Fiona Godlee FRCP Editor in Chief, The BMJ BMJ, BMA House, Tavistock Square, London, WC1H 9JR T: 020 7383 6002 E: fgodlee@bmj.com W: bmj.com/company

Personal assistant:

Julia Burrell

T: 020 7383 6102

E: jburrell@bmj.com

———- Forwarded message ———-

From: Elizabeth Loder <eloder@bmj.com> Date: 16 December 2015 at 11:11 Subject: response to the Jureidini allegations To: Fiona Godlee <FGodlee@bmj.com>

Dear Fiona,

You asked me to respond to Dr. Jureidini’s accusations of conflict of interest regarding connections to GSK. These were 1) that my hospital, Brigham and Women’s, receives research money from GSK; 2) that my husband is a partner in the law firm Ropes & Gray, which has done work for GSK and thus he profits directly from this connection; and 3) that I have made public statements favorable to GSK products.

With regard to the first matter, I don’t keep track of nor do I have any practical way of knowing about the hospital’s many sources of research support. BWH is one of the largest academic medical centers in the US and receives millions of dollars of research support from a vast array of companies and government agencies.

With regard to the second matter, Ropes & Gray is a huge international law firm with thousands of clients. The firm has approximately 1200 lawyers working from 11 different offices around the world and well over $1 billion in annual revenues. I didn’t have any knowledge of their work for GSK. My husband does not work in their healthcare division. He is a securities lawyer. He works exclusively with firms that manage money. He advises the management of these firms or their independent boards of directors and represents them in government enforcement matters.  Ropes & Gray’s work for GSK and the firm’s relationship with GSK accordingly had no influence on the editorial process. It seems entirely unreasonable to expect that any journal would make disclosures of all of their editors’ spouses’ employers’ business relationships. Those relationships are much too attenuated to be likely to have any bearing on the objectivity of the editorial process. Furthermore, there is no practical mechanism for gathering information about such remote relationships.

With regard to the third matter, the examples provided by Dr. Jureidini are taken out of context. They do not illustrate that I have spoken favorably about GSK products. You will note that in the live Q&A with the Washington Post, from which he pulled a quote, I use the generic name sumatriptan, and am answering a question posed by a reader who used the brand name.

http://live.washingtonpost.com/how-serious-are-migraines.html

The question was specifically about sumatriptan so it made sense to speak of that drug. It is a matter of fact not opinion that the injectable version of the drug, and early administration, improve outcome. Furthermore, sumatriptan is the only one of the seven marketed triptans that is available in an injectable formulation. The injectable formulation is produced by a number of generic manufacturers in addition to GSK. GSK makes a branded version of sumatriptan which is called Imitrex or Imigran but I did not use the brand name.  Additionally, you will see in the attached review article I wrote for NEJM that I specifically recommend the use of a generic version of sumatriptan because it is the least expensive treatment.

With regard to the statement about combinations of triptans and NSAIDs being more effective than either drug alone, again this is a matter of fact and not opinion. There are many trials comparing combination treatment to the single drugs — see attached editorial I wrote about the combination of frovatriptan and an NSAID. It is hard to understand how a statement about the effectiveness of combination therapy constitutes an endorsement for a particular fixed dose combination. In practice I do not use the GSK product treximet (sumatriptan + naproxen) because I think aspirin is a better choice than naproxen for use in combination therapy.

I hope these answers are satisfactory. Let me know if you have any other questions.

Elizabeth

 

BMJ advances healthcare worldwide by sharing knowledge and expertise to improve experiences, outcomes and value. This email and any attachments are confidential. If you have received this email in error, please delete it and kindly notify us. If the email contains personal views then BMJ accepts no responsibility for these statements. The recipient should check this email and attachments for viruses because the BMJ accepts no liability for any damage caused by viruses. Emails sent or received by BMJ may be monitored for size, traffic, distribution and content. BMJ Publishing Group Limited trading as BMJ. A private limited company, registered in England and Wales under registration number 03102371. Registered office: BMA House, Tavistock Square, London WC1H 9JR, UK.

 

_______________________________________________________________________

On Thursday, 28 January 2016, 6:08, “Jureidini, Jon (Health)” <Jon.Jureidini@sa.gov.au> wrote:

Hi

Please find attached a response to this email.

Cheers

Jon

The Archers: Rob and Helen

The Archers

Editorial Note: There is no-one I know who admits to listening to The Archers. But everyone in Britain knows of it – the longest running British radio soap. It begins with a horrible theme tune that has me hitting off instantly.

But all changed in the last week or two. The Archers is now featuring on the news and in the newspapers. The build-up began nearly two years ago when Rob met Helen. Whether the scriptwriters intentions were set for them then, now at least they find themselves caught in a domestic abuse script – that everyone figures is done pretty well. It’s subtle and it’s creepy. Last week things came to a head when Helen stabbed Rob – several days after starting an antidepressant (the reason for this digression from Study 329).

We invite readers old or new to offer thoughts. Did the antidepressant cause her to do it. Can she use an antidepressant as a defense? Was Rob on an antidepressant? Or is the earth round and this is just a story about domestic abuse?

There are huge overlaps here with Jane Green’s Saving Grace.

The story so far

p01sshqh

The pair meet in 2013 – Rob is married to Jess; Helen has a son, Henry.

They end up having an affair and Rob eventually leaves Jess in early 2014.

He’s very charming to Helen’s friends and family and becomes a local hero for his help during an episode of flooding.

But there are subtle signs that things might not be as they seem – Rob refuses a meal she’s spent a long time preparing; he starts to dictate what she wears and how she does her hair.

They marry in 2015 and Rob gains parental responsibility of Henry. Rob has a more strict idea of discipline which isn’t quite in line with Helen.

There is a suggestion of abuse/rape following a ‘date night’ between the couple. After which Helen falls pregnant. There is another incident further into her pregnancy.

He preys on her history of an eating disorder as her pregnancy develops – ‘you look blooming’ ‘you’re filling out’; he forces her to eat puddings she doesn’t want and buys her clothes that don’t fit.

He consistently tells her she’s not coping and puts doubts in other people minds regarding her mental health. People start to notice she’s acting strangely at times – snappy, tired, memory problems, ‘touchy’.

Kirsty is the only friend who seems suspicious of Rob. Helen confides in her that she thinks she’s going mad and that she keeps upsetting everyone. Eventually she admits that Rob hit her during an argument (‘but it was my own fault’). Rob discourages Helen from having anything to do with Kirsty. She hides the fact that she’s in touch with her friend.

Rob undermines her memory of events, either not telling her things or lying about what might have happened, causing Helen to feel confused. Helen runs Henry a bath which Rob tops up with boiling water while Helen is out of the room, resulting in Henry getting scolded. Rob allows Helen to think it was her mistake.

After a minor car accident, Rob takes away Helen’s car keys, contributing to her feelings of isolation.

Helen has an episode of sleepwalking one night, after which Rob tells her that she was verbally aggressive and abusive towards Henry and terrified him. He suggests that something needs to be done as it seems like she’s having a breakdown. She agrees she’s not feeling herself and Rob takes her to a psychiatrist, who prescribes antidepressants. Helen refuses to take them due to her pregnancy but accepts the prescription anyway. (14th March).

Rob makes firm plans to send Henry to boarding school behind Helen’s back. When Helen finds out she loses it in front of her mother and friend, saying ‘He’s gone too far’. ‘If this is true I’m going to kill him’. To others she seems irrational. When she confronts Rob he tells her he doesn’t think she will be able to cope with two children and was looking into boarding school just as an option. Helen apologizes.

Helen’s mother doubts she’s coping. Rob drops hints that things aren’t right with Helen’s mental health, that she’s been prescribed antidepressants and referred for CBT. Helen’s mother thanks him for being such an understanding husband.

Rob encourages Helen to have a home birth against medical advice and her own feelings. She tries to hide having spoken to the midwife about a hospital birth.

After a row over Henry, where Rob throws away a favorite toy because Henry ate chocolate without permission, Rob tells Helen it’s high time she starts taking her medication (31st March), as she isn’t coping and failing as a mother. ‘It’s not about what you want, it’s about what you need’. It is later confirmed that it is around this time that she does start taking the antidepressants.

Helen contacts Jess who admits he was cruel and abusive in their relationship. Helen decides to leave Rob and tries to tell him over dinner. She admits to talking to Jess and Rob is furious and becomes verbally abusive. They argue and he hands her a knife telling her to kill herself – ‘no-one will even be surprised’. When Henry appears, Rob starts toward him and Helen stabs Rob in a short but frantic attack (3rd April).

Rob suffers severe wounds but with treatment in intensive care, he survives. Helen is arrested and is now charged with attempted murder.

Back to Study 329 our long-running scientific abuse saga (that began about two years ago curiously) next week.

Study 329: Response to Keller & Colleagues

AllData

Editorial Note: This post offers our response to the Keller letter. It was published in BMJ in early February. Again all material is available on Study329.org. The response does not make much of the fact that not all of the Als in Keller et al have lined up to sign their letter. One of the intriguing points in all this is tracking the line taken by GSK and by Keller and colleagues.

Jon N Jureidini, David Healy, Mickey Nardo, Melissa Raven, Elia Abi Jaoude, Catalin Tufanaru, Joanna Le Noury

Re: Restoring Study 329: Response to Keller

The response by Keller and selected colleagues [1] to our Restoring Study 329 article alleges three overarching faults[2]: bias and lack of blind ratings in relation to harms; lack of detailed methodology; and failure to consider the available methodological knowledge regarding paediatric depression from twenty-four years ago. Regarding the second issue, there is in fact a detailed explanation of all the methods in our paper and its RIAT Audit Record (appendix 1). We tackle the first and third issues below.

Efficacy

While there was uncertainty twenty-four years ago about the appropriate rating scale to use in pediatric depression trials, there were serious methodological problems in the conduct and reporting of Study 329 that have nothing to do with that uncertainty. Instead, in their reporting of efficacy in Study 329[3], and their defence of it, Keller and colleagues have asked that the field suspend many widely held tenets about clinical trial analysis, by asking us to do the following:

  • accept that the a priori protocol is not binding, and that changes can be made to the outcome variables while the study is ongoing, without amending the protocol with the IRB or documenting the rationale for the change
  • ignore the requirement to correct the threshold of significance for the analysis of multiple variables
  • ignore the requirement that when there are more than two groups, preliminary omnibus statistical analysis needs to be done prior to making any pairwise comparisons between groups – an integral part of the ANOVA analysis declared in the Study 329 protocol
  • allow the parametric analysis of rank-order, ordinal rating scales [CGI, HAM-D and K-SADS-L Depressed Mood Items] rather than the expected non-parametric methods specifically derived for this kind of data
  • allow 19 outcome measures to be added to the original eight at various times up to and after the breaking of the blind, purportedly according to an analytical plan ‘developed prior to opening of the blind’ (In spite of multiple requests, neither GSK nor Keller and colleagues have ever produced this analytic plan, suggesting that either it does not exist, or that it contains information unsympathetic to their claims.)
  • accept the dismissal of protocol-specified secondary outcomes and the introduction of rogue variables on the grounds that ‘the Hamilton Depression Rating Scale (our primary outcome measure) had significant limitations in assessing mood disturbance in younger patients’, when none of the protocol-specified secondary outcome measures that they discarded were based on the HAM-D, and two of the rogue measures that they introduced were HAM-D measures
  • accept the clinically dubious improvements in four of these rogue variables as evidence of efficacy. (Although these measures achieved statistical significance in the pre-defined eighth (final) week of the acute phase of the study, they did not do so in the weekly assessments over the previous seven weeks, a pattern unseen in any known antidepressant; we are working on another manuscript analysing Keller et al’s rogue variables.)

There was no ambiguity about the appropriateness of these methodological manoeuvres when Study 329 was conducted and reported. However, although some of these problems were obvious when the paper was first published, others were not apparent until we had access to the raw clinical data. This lack of transparency erodes confidence that RCTs will be conducted, analysed and reported free from covert manipulation.

Furthermore, Keller and colleagues also failed to report on the continuation phase of Study 329, even though that was a protocol-specified outcome. A report of this phase is almost ready for submission by us.

Harms

With regard to harms, Keller and colleagues are simply incorrect in many of their claims about our purported bias and lack of blind ratings.

First, our paper makes it clear that both coders in the re-analysis were blind to randomisation status.

Second, there was no ‘re-scoring’. This odd choice of words raises doubts that Keller et al have much expertise in analysing harms. We used a dictionary that adhered much more closely to the verbatim terms used by the face-to-face interviewers. The fact that Keller and colleagues say that we have labelled emotional lability as suicidality makes us wonder if they have seen the individual patient level data; it was the SKBs coders who came up with the term ‘emotional lability’, not the face-to-face interviewers, whose verbatim terms were of suicidal thoughts and behaviour. Simply using the verbatim terms that the named authors or their colleagues had used when faced with these adolescents reveals a striking rate of suicidal events. To argue that our return to these verbatim terms was arbitrary is bizarre.

Third, we made it clear there is unavoidable uncertainty in coding, and we invited others to download the data we have made available and juggle it to see if they can improve on our categorisation of the data. In our correspondence with BMJ, we made it clear that there are items that GSK could argue are more appropriately coded differently. We would be receptive to a rationale for alternate coding of certain items that is cogently argued rather than simply asserted, but our hunch is that a disinterested observer reviewing the coding as presented by GSK across all 1500 adverse effects in this study (or 2000+ if we include the continuation phase) would conclude that our efforts are a better representation of the data.

Fourth, reading our paper makes it clear why we reviewed the clinical records of 93 subjects; these were the subjects who dropped out or became suicidal. Our claims about underreporting of adverse events stand independently of that non-random sub-sample.

With regard to suicidal ideation and attempts, Keller et al. refer to a reanalysis by Bridge and colleagues, which found that there was no significant difference in suicidality between paroxetine and placebo. But Bridge et al. relied on Keller et al.’s misleading 2001 report.

With regard to bias, our point was that the best protection against bias is rigorous adherence to predetermined protocols and making data freely available. We, like everyone, are subject to the unwitting influence of our bias. The question is whether the Keller et al publication of 2001 manifests unconscious bias or deliberate misrepresentation.

The original and restored studies, the study data, reviews and responses are all available at Study329.org, offering a broad range of options when it comes to consideration of authorship, research misconduct and the newly described species, ‘research parasite’[4].

References

1 Keller MB, Birmaher B, Carlson GA, Clarke GN, Emslie GJ, Koplewicz H, Kutcher S, Ryan N, Sack WH, Strober M. Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence. Response from the authors of the original Study 329. BMJ 2015;351:h4320

2 Le Noury J, Nardo JM, Healy D, Jureidini J, Raven M, Tufanaru C, Abi-Jaoude E. Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence. BMJ. 2015 Sep 16;351:h4320.

3 Keller MB, Ryan ND, Strober M, et al. Efficacy of paroxetine in the treatment of adolescent major depression: a randomized, controlled trial. J Am Acad Child Adolesc Psychiatry 2001;40:762-72.

4 Longo DL, Drazen JM. Data sharing. N Engl J Med. 2016;374:276-7.

Competing interests: As noted in our RIAT paper

Restoring Study 329

Study 329: Nobody Pinned Anything on Us

Three amigos

Editorial Note: Following the publication of Study 329 Restored, Martin Keller and his co-authors gave an initial response in which they said Nobody Pinned Anything on Us and also that they would respond in more detail later. It took four months for this response to appear. Our Response will follow in the next post and after that we will update our background correspondence with BMJ.

This and earlier correspondence and all the data from the Study 329, BMJ reviews of the study, a timeline of the history of SSRIs and all controversies linked to these drugs is all available on Study329.org.

There are two further Study 329 articles making Study 329 the most intensively studied Clinical Trial ever. The Study 329 website will make all this material available for anyone who wants to see how clinical trials operate – this study is not an anomaly, it is standard industry practice.

The picture above was dubbed Three Amigos by its creator. It features Charlie Nemeroff, Marty Keller and Alan Schatzberg. A picture that is at least as appropriate is below linked to the conflict of interest declaration.

BMJ 2015; 351 doi: http://dx.doi.org/10.1136/bmj.h4320 (Published 16 September 2015) Cite this as: BMJ 2015;351:h4320

18 January 2016

Martin B Keller, Boris Birmaher, M.D., Gabrielle A. Carlson, MD, Gregory N. Clarke, Ph.D., Graham J. Emslie, M.D., Harold Koplewicz, M.D., Stan Kutcher, M.D., Neal Ryan, M.D., William H. Sack, M.D., Michael Strober, Ph.D.

attn: Martin B Keller, MD, 700 Butler Drive, Blumer 120, Providence, RI 02906, USA

Re: Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence. Response from the authors of the original Study 329

The BMJ article entitled “Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence”[1] reanalyzed data from the original Paroxetine 329 study[2], a double-blind placebo controlled comparison of paroxetine to imipramine. Paroxetine 329 was designed between 1991 and 1992. Subject enrollment began in 1994, and was completed in 1997. Academic psychiatrists designed the study, with very little change by GSK, which funded the study in an academic / industry partnership. The goal of the study was to advance the treatment of depression in youth, rather than primarily as a drug registration trial.

Overarching issues with the “Restoring Study 329” include:

  1. Authors of “Restoring Study 329” evidenced both bias and a lack of blind ratings. In a recent article about “Restoring Study 329” in the Chronicle of Higher Education, Dr. Jureidini is quoted as saying: “We don’t think we’ve done the definitive analysis. It’s not something that can be done absolutely objectively, particularly the interpretation of harms. We can’t protect ourselves completely from our own biases.”[3]     Biases are a serious consideration for Restoring Study 329 because Dr. Jureidini, as he declares in a Footnote on the subject of “Competing interests”, served as an expert witness for plaintiff’s lawyers in legal suites against GSK related to Study 329. In that work Dr. Jureidini would have studied all available data looking at both efficacy and suicidal side effects, using many different approaches to best capture any potential harms.
  2. The “restoring invisible and abandoned trials” (RIAT) approach to reanalyzing published studies may provide general guidelines but we could not find publications or available working RIAT documents on detailed protocols. Lack of detailed methodology is a serious concern because there is general consensus in the field that there is not, nor never will be a single correct approach to reanalysis. Small differences in analysis frequently make big differences in statistical results and conclusions.
  3. “Restoring Study 329” did not consider available knowledge 24 years ago, when Paroxetine 329 was developed and performed. Clinical research methodology has evolved considerably in the past two decades. These aspects are addressed in comments by established investigators not involved in Paroxetine 329. For example, Referring to “Restoring Study 329” as reported in Psychiatric News Alert [4] Mark Olfson said, “However, the new reanalysis does not alter the totality of clinical trial evidence that continues to support the safety and efficacy of SSRIs for adolescent depression.” And Daniel Pine said “We have known for some time that antidepressant medications have both significant benefits for some children as well as significant risks for other children. This new analysis really does nothing to change this knowledge, and provides no new insights into what we have known about these medications for the past few years.”

Efficacy

Antidepressants considered as a group are superior to placebo for the treatment of anxiety disorders and for depression in adolescents, with similar overall response rates in anxiety and depression. [5]

The two primary outcome measures in Paroxetine 329, did not reach statistical significance. The abstract of the published paper noted: (1), “The two primary outcome measures were endpoint response (Hamilton Rating Scale for Depression [Ham-D] score ≤ 8 or ≥50% reduction in baseline HAM-D) and change from baseline HAM-D score.” In Table 2, the p value for the first primary endpoint (Ham-D score ≤ 8 or ≥50% reduction in baseline HAM-D) was reported at p < 0.11 for paroxetine versus placebo. In the same table, the p value for change in HAM-D total score is reported at p < 0.13. While both outcomes were in the direction of a better response for paroxetine over placebo; neither reached our critical alpha level of 0.05. This is clear in the abstract and text of the publication.

In the interval from when we planned the study to when we approached the data analysis phase, but prior to the blind being broken, the academic authors, not the sponsor, added several additional measures of depression as secondary outcomes. We did so because the field of pediatric-age depression had reached a consensus that the Hamilton Depression Rating Scale (our primary outcome measure) had significant limitations in assessing mood disturbance in younger patients. Taking this into consideration, and in advance of breaking the blind, we added secondary outcome measures agreed upon by all authors of the paper. We found statistically significant indications of efficacy in these measures. These secondary outcomes were clearly reported as separate from the negative primary outcomes.

Thus, the authors of “BMJ-Restoring Study 329” were incorrect in stating that “Both before and after breaking the blind, however, the sponsors made changes to the secondary outcomes as previously detailed. We could not find any document that provided any scientific rationale for these post hoc changes and the outcomes are therefore not reported in this paper.” Rather, secondary outcomes were decided by the authors prior to the blind being broken. Secondary outcome measures are frequently, and appropriately, included in study reports even when the primary measures do not reach statistical significance. The authors of “Restoring Study 329” state “there were no discrepancies between any of our analyses and those contained in the CSR [clinical study report]”. The disagreement on treatment outcomes rests on this arbitrary and non-blind dismissal of our secondary outcome measures.

In the abstract we stated “Conclusions: Paroxetine is generally well tolerated and effective for major depression in adolescents.” In this sample and with the state of knowledge at the time, it was justified and appropriate.

Our goal was to learn as much as possible about the use of this compound in youth, so that we could understand what role it (and by extension other SSRIs) could play in the treatment of adolescents with MDD. For us the question was given (1) the data distribution and statistical results for efficacy and side effects that we saw in the study, and (2) that there was well replicated research evidence of efficacy and relative safety of paroxetine in adults, what conclusions should be drawn from our data? The clinical outcomes were substantially in the right direction, with a number of them reaching the 0.05 level of statistical significance. The clinical results comparing paroxetine placebo to and imipramine to placebo paralleled those reported in adults. Side effects were similar to what was known in adults. Thus we reached, the conclusions reported.

Harms

The “Restoring Study 329” reanalysis uses the FDA MedDRA approach to side effect data, which was not available when our study was done. That one can do better reanalyzing adverse event data using refinements in approach that have accrued in the 15 years since a study’s publication is unsurprising and not a valid critique of Paroxetine 329 study as performed and presented.

We emphatically disagree with the “Restoring Study 329” position that statistics are not useful in understanding adverse side effects and that each individual reader should decide for herself when a difference in rates of adverse side effects is meaningful. Statistics offer several approaches to the question of when is there a meaningful difference in the side effect rates between different treatments.

Specific methodology problems in the reanalysis of the “harm” data are as follows: 1) The authors choose a non-random subsample of 85 subjects who were withdrawn from the study plus 8 subjects whom the authors labeled “suicidal” based on their inspection of the data; 2) a different instrument was utilized to re-score the harm effects and only one of the authors was trained in the scoring of the instrument; 3) some side effects were arbitrarily interpreted (e.g., upper respiratory symptoms were labeled as “dystonia” and emotional lability labeled as “suicidality”); 4) in the original paper, side effects were analyzed only during the acute phase, but in the reanalysis, the authors analyzed them during the acute phase, as well as the tapering and follow up phases of the study; and 5) in the original study patients were interviewed face-to-face whereas the reanalysis was based only on the interpretation of the data; and 6) importantly, the two authors were not blind to patients’ randomization status.

Suicidal ideation and attempts

Our field’s understanding of how to approach analysis of suicidal ideation, suicide attempts, and completed suicide has advanced enormously since publication of study 329. Two definitive reanalyses of the suicidality with antidepressants in adolescents include: 1). The 2003 FDA reanalysis of all RCT data of SSRI studies in youth for all indications.[6] In the FDA analysis the average risk ratio for SSRI versus placebo treated subjects was 1.96 (CI: 1.28-2.98). Considered separately Study 329 did not reach statistical significance for increased suicidality (CI: 0.42-33.21). 2). The methodologically superior reanalysis by Bridge and colleagues also found that in study 329 there was no significant risk difference between paroxetine and placebo. [7]

Paroxetine treatment in youth does not appear to significantly differ from other SSRIs in the risk of suicidal ideation or attempts and whether SSRIs increase or decrease completed suicide remains an open question. [8-12]

Summary

We strongly support efforts to make anonymized raw data from scientific studies available for reanalysis. The validity of “Restoring 329”, however, is doubtful because of author bias and substantial problems with RIATT methodology. To describe Paroxetine 329 as “misreported” is pejorative and wrong based on both state-of-the-art research methods 24 years ago, and retrospectively from the standpoint of current best practices.

Sincerely,

Martin B. Keller, M.D. Boris Birmaher, M.D. Gabrielle A. Carlson, MD Gregory N. Clarke, Ph.D. Graham J. Emslie, M.D. Harold Koplewicz, M.D. Stan Kutcher, M.D. Neal Ryan, M.D. William H. Sack, M.D. Michael Strober, Ph.D.

  1. Le Noury J, Nardo JM, Healy D, et al. Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence. BMJ 2015;351:h4320.
  2. Keller MB, Ryan ND, Strober M, et al. Efficacy of paroxetine in the treatment of adolescent major depression: a randomized, controlled trial. J Am Acad Child Adolesc Psychiatry 2001;40(7):762-72.
  3. Basken P. Landmark analysis of an infamous medical study points out the challenges of research oversight. Secondary Landmark analysis of an infamous medical study points out the challenges of research oversight 2015. http://chronicle.com/article/Landmark-Analysis-of-an/233179.
  4. Reanalysis of JAACAP Study on Paroxetine Sparks Controversy. Secondary Reanalysis of JAACAP Study on Paroxetine Sparks Controversy 2015. http://alert.psychnews.org/2015/09/reanalysis-of-jaacap-study-on.html.
  5. Bridge JA, Iyengar S, Salary CB, et al. Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: a meta-analysis of randomized controlled trials. Jama 2007;297(15):1683-96.
  6. Hammad TA, Laughren T, Racoosin J. Suicidality in pediatric patients treated with antidepressant drugs. Arch Gen Psychiatry 2006;63(3):332-9.
  7. Bridge JA, Birmaher B, Iyengar S, et al. Placebo response in randomized controlled trials of antidepressants for pediatric major depressive disorder. Am J Psychiatry 2009;166(1):42-9.
  8. Gibbons RD, Brown CH, Hur K, et al. Early evidence on the effects of regulators’ suicidality warnings on SSRI prescriptions and suicide in children and adolescents. Am J Psychiatry 2007;164(9):1356-63.
  9. Olfson M, Shaffer D, Marcus SC, et al. Relationship between antidepressant medication treatment and suicide in adolescents. Arch Gen Psychiatry 2003;60(10):978-82. 10. Gibbons RD, Hur K, Bhaumik DK, et al. The relationship between antidepressant prescription rates and rate of early adolescent suicide. Am J Psychiatry 2006;163(11):1898-904. 11. Valuck RJ, Libby AM, Sills MR, et al. Antidepressant treatment and risk of suicide attempt by adolescents with major depressive disorder: a propensity-adjusted retrospective cohort study. CNS Drugs 2004;18(15):1119-32. 12. Gibbons RD, Mann JJ. Strategies for quantifying the relationship between medications and suicidal behaviour: what has been learned? Drug Saf 2011;34(5):375-95.

We merely supplied the patients

This picture comes from Carl Eliot based on Johanna Ryan’s noting a curious phrase in the conflict of interest statement from Gabrielle Carlsson below.

Competing interests: Please see attachments to this response – the attachments are available on Study329.org.

 

Guilty

guilty

Days of Reckoning?

A little over a year ago, there was consternation in psychiatric circles as a French psychiatrist, Daniele Canarelli was found guilty after her patient hacked a man to death. She had not recogized the hazard he posed. Doctors didn’t like the implications they saw.

In a series of lectures I have raised the question as to how long it might be before a doctors would be found guilty for a suicide or homoicide linked to an antidepressant, given that we have known that these drugs can cause suicide or homicide for over 50 years. See RxISK’s Violence Zone.

New Zealand

In March 2008 17-year old Toran Henry who was on Fluoxetine (Prozac) committed suicide, fifteen days after starting the drug. Maria Bradshaw, his mother, convinced that the drug had caused the problem refused to have his death attributed to a depression or other disorder he didn’t have.

Unbeknownst to her, the company that marketed it in New Zealand, Mylan, had looked internally at the case and decided their drug had caused Toran’s death. Maria had to fight to get this information. Mylan withheld their assessment and forced her to get the High Court to agree she was her child’s legal representative.

Following her efforts for her son, Maria and others formed CASPER, a New Zealand based organization aimed at raising awareness of suicide and the role that treatments like the antidepressants can play in provoking this. It is now spreading to other countries and its profile is rising steadily.

Old Zealand

Meanwhile in 2011 in Old Zealand (Denmark), Danilo Terrida, 20, committed suicide eleven days after he was prescribed antidepressants following an eight-minute-long conversation with a doctor.

The doctor never followed up on the consultation and was recently found responsible for the suicide by the National Agency for Patients’ Rights and Complaints.

The health agency, Sundhedsstyrelsen, has decided to make it harder for doctors to prescribe antidepressants to 18-to-24-year-olds after Danilo’s suicide.

From now on, young patients will have to face an assessment and an in-depth conversation with a doctor before antidepressants can be prescribed.

“Along with the Danilo case, there have been other cases that we, as the oversight authority, are not satisfied with. That is why we are now tightening the rules for this vulnerable group,” Sundhedsstyrelsen spokesperson Anne Mette Dons told TV2 News.

Danilo’s family said that they were pleased that the rules had been tightened for prescribing antidepressants.

“It doesn’t change the fact that we have lost our son,” Danilo’s mother, Marianne Terrida, told Jyllands-Posten newspaper. “The fact that it’s a dangerous drug is not new, it’s been known a long time.”

Guilty?

The case has sparked a debate in Zealand about the dangers of psychiatric drugs, and in Politiken newspaper today Peter Gøtzsche, medical researcher and leader of the Nordic Cochrane Center at Copenhagen’s Rigshospitalet, wrote that antidepressants have caused healthy people to commit suicide.

“It is true that depression increases the risk of suicide, but antidepressants increase it even more, at least up until the age of 40,” he wrote.

He added that psychiatric medication often does more harm than good and that patients would often be better off without medication.

“Doctors cannot cope with the paradox that drugs that can be useful for short-term treatment can be highly dangerous when used for years and even create the illnesses that they were supposed to prevent, or even bring on an even worse illness,” Gøtzsche wrote.

Editorial Note: The risk of suicide and violence affects all age groups – up to 100. If they go wrong, these drugs are likely to be highly dangerous in the short term.

RxISK Stories: Go Ask Alice

Editorial Note: RxISK is all about people discovering things for themselves and alerting others to something that can make a real difference.

There have been some wonderful examples outlined in posts here on RxISK from Anne-Marie Kelly’s discovery of a cure for Alcoholism – stop your SSRI and perhaps try a serotonin-3 antagonist like mianserin or ondansetron – to Samantha Dearnaley’s discovery that Champix (Chantix) had caused her epileptic convulsions. These were things that none of the experts knew.

Johanna Ryan gives another example below. As the resident psychiatric and psychopharmacologic expert, it’s worth noting that I had never heard of ‘Alice in Wonderland Syndrome’. It just shows that putting people with interest and/or motivation together can do far more to solve problems than going to see an expert – there are far too many things out there for one expert to know. Even if you think your expertise doesn’t amount to much, we have reached a point where pooling our expertise is a much better bet than relying on experts. (DH)

Go ask Alice

One pill makes you larger, and one pill makes you small
And the ones that Mother gives you don’t do anything at all
Go ask Alice, when she’s ten feet tall.

“White Rabbit,” by the Jefferson Airplane

Alice-in-Wonderland

I first heard of “Alice in Wonderland Syndrome” last year while reading Oliver Sacks’ book, Hallucinations. Sacks is a neurologist who is fascinated with the range of experiences, good, bad and strange, that the human nervous system can give rise to.

In Alice in Wonderland Syndrome (AIWS), objects in the environment and even parts of your own body are strangely distorted. Just like Alice, you may perceive your own head or arms as huge, while the people around you seem tiny – or you may feel suddenly shrunk, while the furniture in the room towers over you. It’s best known as a rare effect of migraine headaches and Sacks speculates that Lewis Carroll may have gotten some of the trippy inspirations for his classic story from his own chronic migraines. It’s also been known to occur in epilepsy and in viral infections, especially in children. Anticonvulsant drugs used to control epilepsy and migraines are a standard treatment. Which was why it startled me to stumble across a case on RxISK.org – as a side effect of an anticonvulsant drug!

RxISK patient narratives link Topamax & hallucinations

On the Patient Narrative page for Topamax, someone reported the following:

“Intense visual hallucinations. Objects in the visual field (e.g., computer monitor, hands, arms, desk, etc.) would move far, far away in regular time then come back and be grossly enlarged. It is almost like making an MS Word document change font sizes, from 12 pt to 2 pt to 350 pt, but it was everything I saw.”

Using RxISK.org’s features gave me some clues about this person’s experience, and how common it might be. Using the “A-Z Search” function under Reported Side Effects I found the FDA had eight reports of Alice in Wonderland Syndrome on Topamax, with a “PRR” of 438.8. That means the odds were overwhelming that the drug and the AIWS were connected.

The “Location” tab in Reported Side Effects told me that six of these were from Germany! One was from the UK, but absolutely none from the USA, even though Topamax is widely used here. Checking the Location tab for All Side Effects, well over half have come from America, with no other country even coming close.

Checking “Gender” and “Age” told me that all eight were female, and seven were teenagers.

Our friend on RxISK sounded more like an American adult than a teenage girl from Germany. Was she (or he) the first? Well, she’d probably never heard of Alice, so she reported this as a “visual hallucination.” Maybe others had too.

Back to the Reported A-Z side effects, where I found 69 reports (PRR 4.9) for Visual Hallucination, 103 (PRR 1.6) for plain old Hallucination, and 73 (PRR 3.2) for Visual Disturbance. “Disorientation” might be relevant too, and there were 106 reports of that (PRR 2.4).

Fifteen of the 69 Visual Hallucination reports came from the USA, 18 from the UK, and only two from Germany. Two-thirds were female. There were nine children and 21 teenagers, but there were also twenty adults, and nineteen cases were “age unknown.”

Going to the “Outcomes” tab, I found that 39 of these 69 people had been hospitalized! That told me that probably only the more extreme cases were being reported – those where the person was terrified by their experience or it happened alongside more serious side effects.

Treatment of migraines

By now I was hooked, so I went to Google. I found one professional paper on Alice in Wonderland Syndrome as a side effect of Topamax – a case report on a teenage girl in Germany who was taking the drug to prevent migraines. The authors had probably made that initial report to the FDA and may have alerted other German headache specialists to a symptom that certainly breaks up a dull workday.

There were a couple of American papers as well, though, including one about two patients with “palinopsia” and one with AIWS. All were taking Topamax for migraines. Fellow medical wonks can Google palinopsia – it’s even stranger than AIWS but I could not find a single report to the FDA.

Another paper described “Steroid-induced Psychosis Presenting as Alice in Wonderland Syndrome” and implied that the patient, who was on heavy steroids for severe asthma attacks, had been misdiagnosed with “schizophrenia.”

I also found several reports on patient discussion boards of AIWS on Topamax, including both Epilepsy.com  (“Feeling a Bit Like Alice in Wonderland on Topamax”) and the psych board CrazyMeds. They were mixed in with reports of other strange symptoms – hallucinations, delusions, feelings of unreality or of standing outside one’s own body.

I was struck by something the moderator of CrazyMeds (who by the way is resolutely pro-med and will not tolerate any psychiatry-bashing on his board) said: “As with all anticonvulsants, anything Topamax can fix is also a potential side effect.” In other words, a range of symptoms of epilepsy, migraine and even bipolar disorder could also be side effects of an anticonvulsant drug taken to treat these conditions.

‘RxISK allows us to describe what’s going on and how it affects us’

If this is true then RxISK and similar efforts could make a huge contribution. As Kalman Applbaum noted, many FDA reports filed by doctors consist only of ticking a box on a list, say for “hallucination” or “anxiety.” RxISK allows us to describe what’s going on and how it affects us, as the Alice in Wonderland sufferer did. If we know people taking anticonvulsants for one condition (say, depression) experience symptoms typical of other conditions (weird visual effects associated with migraine auras), the link to the drug becomes clearer.

In the case of Cymbalta, another drug highlighted on RxISK, people taking the drug for back pain have experienced the same side effects (nightmares, moodswings, etc.) as those taking it as an antidepressant. Observations like this could teach us more about the drug and help prevent patients from being misdiagnosed with new “diseases”, like that asthma patient with AIWS.

Reporting to RxISK

I looked at a few of the other anticonvulsants (Neurontin, Lyrica, Lamictal). No reports of AIWS. However, all have a fair amount of Visual Hallucination and Visual Disturbance reports and all include far more Americans and adults as opposed to German teenagers. So who knows! The FDA has a category called “Feeling Abnormal” which is very large and could be hiding almost anything including Alice. We need people to report to RxISK to find out what’s going on – FDA is like Humpty Dumpty for whom words where what he chose them to mean.

RxISK reporting could help bring together communities of doctors and patients who seldom talk to each other, even though we are increasingly prescribing or taking the exact same drugs. Reading the discussion boards, I noticed psychiatry patients complained that their doctors denied these problems could be happening or connected to the drugs. Neurology patients found that their doctors were much quicker to concede that these effects were drug related, although they complained of being told to just ‘hand in there’ by doctors who didnt take the side effects seriously enough. We can also share reports from various countries where the drug-use practices can be very different, even for the same illnesses.

Reports to RxISK could also reveal a lot about the brain and the mind. Oliver Sacks first made me aware how much neurologists owe to accidents, breakdowns and “side effects”, and the reports of non-scientists who had lived through them. Who could forget poor Phineas Gage, the railroad worker who survived a sharpened crowbar being driven through his left frontal lobe? Doctors and experts flocked to examine and quiz him, trying to learn more about the brain works. Fortunately, most people logging on to RxISK don’t have anything nearly as awful as Phineas Gage had but because we know more now about the brain than we did then, reports of much less dramatic things can teach us a huge amount.

Editorial Note: The only thing a psychiatry expert can add to this is that it’s not a surprise that the recognition that this is ‘Alice in Wonderland Syndrome’ came from Germany. For well over a century, the Germans have been much interested in paying close attention to superficially similar things and distinguishing between them than anyone else has.

Left Hanging: Suicide in Bridgend

suicide

The Figures

In the England and Wales there are roughly 5000 suicides in roughly 60 million people per year. This would until recently have led to around 2000 hangings per year, 34 hangings per million people per year, 3.5 per 100,000 people per year.

Bridgend in South Wales has a population of 40,000. The greater Bridgend area has a population of 130,000. There should be 18 hangings per 100,000 people over a 5 year period, 24 per 130,000 per year.

In recent years however in both the US and UK there has been a rise in the number of hangings so that this mode of death now accounts for 50% of cases. If this applies in the Bridgend area, we might expect 28 hangings per 130,000 over a 5 year period, roughly 6 per year.

There were in fact 79 hangings in Bridgend between January 2007 and February 2012. The hangings continue unabated, so the true figure may be in the 90s. This means there have been 16 per year – an excess of 10 or more hangings per year.

Vanishing suicides

There have likely been a lot more self-destructions than this in Bridgend. Coroners have considerable discretion and recently a great deal of encouragement to use narrative, open or death by misadventure verdicts rather than to record a verdict of suicide. To record a suicide verdict they should be satisfied that the person intended to kill themselves. One of the primary indicators of intent is a suicide note. In the Bridgend cases, there have been few suicide notes. This has made it easy for coroners to manage perceptions of what might be going on.

Having a narrative or open verdict can be extremely important for families. I have written reports in over 20 inquests arguing that it would be appropriate to return a narrative rather than a suicide verdict, in the case of people whose suicide has been triggered by an antidepressant.

But this use of narrative verdicts has produced a situation where suicide figures are close to worthless. The British suicide rate is comprised of cases recorded as suicides along with a proportion of narrative, open or other verdicts, with the proportion chosen down to bureaucratic whim. We do not have a self-destruction rate and absolutely no idea as to how many verdicts, either suicide or narrative, are linked to antidepressant or other drug intake.

A website antidepaware was recently set up to track deaths by suicide or misadventure or related that are related to antidepressants. It has logged over 1600 UK suicides involving antidepressants of which 43% were recorded as suicides by the coroner, 26% as narrative verdicts, 19% as open verdicts, 5% as death by misadventure and 7% as accidental.

Hanging & kneeling

While the suicide rate has become ambiguous, it is not possible to conceal the number of hangings.

Bridgend has had an unusual number of hangings. An apparently odd feature is that these hangings have involved a lot of kneeling. The fact that many victims have been found hanging but with their feet on the ground or close to kneeling has given rise to speculation about internet or other cults, and about serial killing rather than self-destruction.

I had been exposed to relatively few SSRI suicide cases when Linda Hurcombe came to me telling me of her daughter Caitlin, who after 6 weeks on Prozac hung herself using her horses’ lanyard (see Let Them Eat Prozac).

Soon after that with colleagues I ran a healthy volunteer study designed to test how antidepressants work. In this study, two completely normal women while taking the SSRI sertraline (Zoloft) became suicidal. One of these two had vivid imagery of hanging herself.

Around this time too I got involved in the Miller case. Matt Miller was a 13 year old boy who had just changed schools and was feeling nervous. His parents prompted by the teacher brought him to a doctor who put him on Zoloft. Seven days later he hung himself in the bathroom between his parent’s bedroom and his bedroom.

Pfizer, the makers of Zoloft argued that this was not suicide but auto-erotic asphyxiation gone wrong. As evidence, they pointed to the fact he was not suspended several feet above the floor but had his feet on the ground, almost kneeling. They went so far as to scour the carpet in the bathroom to collect potential evidence for seminal stains.

It was Yvonne Woodley’s case in 2010 that explained the hanging issue to me – something that anyone with an interest in the area could in fact have found from Wikipedia.

Yvonne Woodley was a 42 year old woman who was having marital difficulties. She presented to her doctor with sleep problems. The doctor viewed her as being under stress, and as posing absolutely no suicide risk. She gave Yvonne citalopram. A week later the doctor noted that Yvonne was more agitated and there were fleeting thoughts of suicide – so she doubled the dose of citalopram. After a suicide attempt, she doubled it further and a short while afterwards Yvonne hung herself.

She hung herself in the attic of her house. Given the kind of person she was, the rest of her family found it unbelievable that she would have hung herself in the house with her two daughters downstairs but a common feature of SSRI suicides is the apparent lack of concern for the effect on others.

The fact that Yvonne was close to kneeling enabled the coroner to return a narrative rather than a suicide verdict. The pathologist explained that when people are weighing up the possibility of hanging themselves, wondering about it, they might put a rope in place and test themselves against it. If they do this, it is in fact very easy by putting pressure on the carotid sinuses that are in the side of the neck to slip out of consciousness and falling forward to end up asphyxiated. If you have begun with your feet on the ground you can end up kneeling or close to kneeling.

The first cases in bridgend

Dale Crole, 18 Found hanged, 5 January 2007
David Dilling, 19 Found hanged in his home, February 2007
Thomas Davies, 20 Found hanged from a tree, 25 February 2007
Allyn Price, 21 Found hanged in his bedroom, April 2007
James Knight, 26 Found hanged at his home, 17 May 2007
Leigh Jenkins, 22 Found hanged, June 2007
Zachery Barnes, 17 Found hanged from a washing line, August 2007
Jason Williams, 21 Found hanged at home, 23 August 2007
Andrew O’Neill, 19 Found hanged at home, September 2007
Luke Goodridge, 20 Found hanged, November 2007
Liam Clarke, 20 Found hanged, 27 December 2007
Gareth Morgan, 27 Found hanged, 5 January
Natasha Randall, 17 Found hanged, 17 January
Angie Fuller, 18 Found hanged, 4 February
Kelly Stephenson, 20 Found hanged on 14 February while on holiday
Nathaniel Pritchard, 15 Kelly’s cousin, found hanged, died 15 February

Reports in the media

Jenna Parry was the next person to die. She was found hanging, almost kneeling. Her death triggered the list above and this account in the Independent in February 2008:

“Bridgend was yesterday mourning yet another addition to the alarming number of suicides in the area, after a 16-year-old girl was found hanged in a wood five miles from the town.

Police insisted there was no link between the 17 deaths in the past 13 months and no evidence of a suicide pact or an internet cult.

Jenna’s death came just days after two cousins died after apparent suicide attempts. Kelly Stephenson, 20, was found dead in a bathroom during a family holiday. Hours earlier she had learnt that her 15-year-old cousin, Nathaniel Pritchard, had hanged himself. The two lived a few doors away from each other in Bridgend…….

Following the deaths, a suicide prevention strategy has been announced for Wales. The Welsh Assembly has said it wants a 10 per cent reduction in suicides by 2012.  [As of 2012, the rate has in fact gone up despite the many abilities of coroners and bureaucrats to lower it].…

However, despite the spate of suicides around Bridgend – a county with a population of 130,000 people – police have said there is nothing to link the deaths….

[The coroner] Mr Morris criticized the media’s reporting of the deaths. “The media reporting is influencing young people in the Bridgend area.

“I have noticed an increase in sensationalist reporting, and the fact that Bridgend is becoming stigmatised. The link between the deaths isn’t the internet – it is the way the media is reporting the news.”

Death by coroner?

Fourteen deaths in Bridgend are logged on antidepaware. There are nine hanging verdicts in which antidepressants are mentioned. There are no hanging verdicts where antidepressants or other prescription medications are ruled out.

What’s happening? One contributory factor to these deaths is coroners. I have been writing to UK coroners for 15 years making the case that they should note where people have been on antidepressant or other drugs at the time of death. The list of drugs now linked to suicide and homicide up to and including school shootings includes anticonvulsants, weight loss pills, some asthma medications, some analgesics, some contraceptives, some medication for acne, a number of antibiotics, medications for malaria, in addition to antipsychotics and antidepressants. See below.

But coroners often do not record drug intake, unless the person has actually died from a drug overdose. In the case of Liam Clarke above he had had some cannabis, and alcohol and was on antidepressants.  The coroner decided that the alcohol he had had affected his judgement. Coroners are under no obligation to explain their thinking on a matter like this and are rarely if ever challenged. There is little doubt that antidepressants can lead to a craving for and increased consumption of alcohol – did this happen in Liam Clarke’s case?

Many of the cases listed above were on antidepressants but we only know this because the police or families mentioned it at the inquest and reporters from the media then reported it. Unless the antidepressant or other pill was the cause of death by poisoning coroners typically don’t mention medication.

In Bridgend, the coroner seemed to play down the role of antidepressants. In one of the inquests involving antidepressants, he refers to “lack of anything in the system that would have altered his judgement”. In others he makes similar comments.

Gary Speed the former manager of the Welsh soccer team is Wales’s most famous recent suicide. A common feature in the extensive reporting of his death was that family and friends found it baffling. The coroner opted not to reveal if there were prescription drugs in his system. Why?

The role of the media

The idea that the media reporting of suicides might cause copycat suicides in Britain stems in part from the work of Keith Hawton in Oxford. As a result students in Cardiff University, which is near to Bridgend, are steered to regard the report in the Independent above as sensationalist. Other countries have more striking suicide cohorts – Japan being the most famous – and in the case of copycat suicides by pairs of lovers jumping into Mount Fuji there is a good case for thinking the media might fuel events.

But equally decent and proper media reporting may do just the opposite and bring to light what is going on. There is probably more chance that a good journalist, or someone who has lost a family member or a friend to suicide, is going to solve this rather than bureaucrats or experts brought in to work out what is going on. In this case neither the experts nor bureaucrats linked to this case seem interested to respond to emails from me.

Having coroners refuse to keep a public record of drug intake and browbeat the media into keeping silent seems like the worst of all possible worlds.

What’s happening?

We have an excess of 60 hangings to explain in Bridgend. The number is growing by the month. If some have happened by accident as outlined above, it needs a public education campaign through the media to alert people to the risks.

Some of these suicides may be copycat. In the same way school shootings may have a copycat component to them. But a copycat needs an original or several original examples to get them going. The distress that leads to school shootings or clusters of hangings needs an original exemplar to shape it into more shootings and hangings – an original event to open this door to others.

There are obvious factors to explain some clusters like a pair of well-known Japanese loves committing suicide together by jumping into Mount Fuji. In the Bridgend case, if we are going to invoke a chemical – a medicine – the scale of the problem almost suggests that some factory in the Bridgend area must be pumping out some chemical that is having the same kind of effect as drugs like Cymbalta or Pristiq. This might seem improbable. But looking at the list of drugs that cause suicide and homicide, below, the improbable begins to look possible. It almost looks probable that this array of drugs will give rise to a cluster like this somewhere if not in Bridgend.

What to do next?

The problem of drug induced suicide and homicide is not vast like climate change or famine in Africa. You can make a difference. As things stand your Human Rights are being infringed. The supposed rights of some unspecified group of people to use (doctors) or take (patients) without having to be deterred by warnings that these drugs can cause suicide or homicide are being used to justify the deaths of people that you know that could be avoided with proper warnings. This is a breach of the Human Rights Act.

The drugs listed below are not listed as a matter of personal judgement. They are either drugs that companies are obliged to state can cause suicide or for which there is convincing evidence that they have in fact caused suicide. There are likely many more drugs that some government officials and company personnel know cause suicide but about which they keep quite.

  1. Some coroners are wonderful. Others are misguided. You do not want to assume your coroner knows what they are doing. You need to establish if they are bringing biases to bear on the issue. You have a right to interview them before an inquest.
  2. Drug regulators deal in the wording of advertisements. Public health is not their brief. If you are waiting for a regulator or a drug company to suggest a drug may have contributed to a death, you will be waiting for ever.
  3. These problems are rarely solved by outside experts. Communities need to take the issues into their own hands and to this end the media are their allies not the enemy.
  4. Contribute details of any deaths by someone’s own hand, accidental or on purpose, to Antidepaware. Contact brian@antidepaware.co.uk
  5. Be aware that the following drugs and likely many others can all cause suicide and in many cases homicide. The statement cause here is based on compelling challenge-dechallenge-rechallenge cases – see Doxycycline causes suicide – or clinical trial data or legal requirements for companies to agree their drug can cause suicide for instance

Drugs that can trigger & cause suicide or homicide

 Anti-Infectives

Mefloquine Lariam
Doxycyline Doryx
D-cycloserine Seromycin
Fluoroquinolones Levaquin, Cipro
Oseltamivir Tamiflu

 Contraceptives

Drospirenone Yasmin
Drospirenone Yaz
Cyproterone and ethinyl estradiol Dianette

 Anti-Smoking

Varenicline Chantix
Champix
Buproprion Zyban

 Anti-Asthma

Montelukast Singulair
Roflumilast Daxas
Zafirlukast Accolate

 Anti – Acne

Isotretinoin Roaccutane
Doxycycline Doryx

 Antihistamines

Diphenhydramine Benadryl, Sominex
Chlorphenamine Chlortimeton
Cyproheptadine Periactin

 Urinary Drugs

Duloxetine Yentreve
Tamsulosin Flomax
Finasteride Propecia
Dutasteride Avodart

 Anti-Nausea

Prochlorperazine Stemetil, Compro
Metoclopramide Maxolon, Reglan

 Antihypertensives

Clonidine Catapres
Doxazosin Cardura
Guanabenz Wytensin
Guanfacine Tenex
Hydralazine Apresoline
Methyldopa Aldomet, Aldoril, Dopamet
Prazosin Minipress

 Statins

Atorvastatin Lipitor
Fluvastatin Lescol
Lovastatin Mevacor
Mevastatin Compactin
Pravastatin Pravachol
Rosuvastatin Crestor
Simvastatin Zocor

 Stimulants

Methylphenidate Ritalin
Focalin
Metadate
Concerta
Amphetamine Dexedrine
Adderall
Vyvanse

 Benzodiazepines

Lorazepam Ativan
Diazepam Valium
Alprazolam Xanax
Chlordiazepoxide Librium
Bromazepam Lexotan
Oxazepam Serenid, Serax
Cloabazam Frisium
Medazepam Nobrium
Clorazepate Tranxene
Clonazepam Klonopin

 Antidepressants

Citalopram Cipramil, Celexa
Escitalopram Cipralex,   Lexapro
Duloxetine Cymbalta
Fluvoxamine Luvox,  Faverin
Fluoxetine Prozac
Paroxetine Paxil, Seroxat, Deroxat, Aropax
Sertraline Zoloft
Venlafaxine Effexor
Desvenlafaxine Pristiq
Mirtazapine Remeron
Trazodone Desyrel
Buproprion Wellbutrin, Zyban
Amitriptyline Tryptizol, Elavil
Imipramine Tofranil
Nortriptyline Allegron, Aventyl
Desipramine Pertrofran, Norpramin
Clomipramine Anafranil
Dosulepin Prothiaden
Lofepramine Gamanil
Doxepin Sinequan
Trimipramine Surmontil

 Anticonvulsants

Phenytoin Epanutin
Sodium Valproate Epilim, Depakene
Divalproex Depakote
Carbamazepine Tegretol
Oxcarbazapine Trileptal
Lamotrigine Lamictal
Gabapenin Neurontin
Pregabalin Lyrica
Leviracetam Keppra
Topiramate Topamax
Tiagabine Gabitril
Felbamate Felbatol

 Antipsychotics

Chlorpromazine Thorazine, Largactil
Perphenazine Fentazine
Trifluoperazine Stelazine
Haloperidol Haldol
Flupenthixol Fluanxol
Pericyazine Neulactil
Sulpiride Sulpitil
Molindone Moban
Aripiprazole Abilify
Olanzapine Zyprexa
Risperidone Riserpdal
Ziprasidone Geodon
Quetiapine Seroquel
Paliperidone Invega
Zotepine Zoleptil
Iloperidone Fanapt
Amisulpiride Solian
Tetrabenazine Xenazine

RxISK Stories: If You’re Going To Look After Patients, Man Up

Man up!

This post also appears on RxISK.org and can be viewed here.

Pharmalot has just posted a piece – ‘Controversial FDA official, Tom Laughren, retires.’

This is a must read for anyone with anything to do with mental health – both the post and the comments afterwards where some have posted that they still believe the Black Box warnings on antidepressants arose because of pressure from the Church of Scientology rather than in response to the data.

Despite my billing as a must-read, the Pharmalot post will likely seem boring to many. But the comments won’t – they seethe with anger. This is one of those cases in which if you weren’t there its hard to appreciate the depth of feeling this man generated in many as he – and a few others including Paul Leber and Bob Temple – appeared to stand in the way of natural justice and patient safety. The most comprehensive cover is on the AHRP website where Vera Sharav dubs Laughren a double-agent.

He seemed a quiet man. He was grey. He behaved like a functionary. But he was the focus of one of  the most dramatic moments I have ever witnessed. This was at the FDA hearings about antidepressants and suicide in children, some 8 years ago now. Because of FDA procedures, the public get a chance to offer views. There were 73 three-minute slots. At this hearing a range of doctors and other men usually with affiliations to pharma spoke against the Black Box warnings and it was down to a series of mothers to plead for warnings.

Many of the pleas were aimed straight at the bureaucrats – Laughren and Temple. The moment is at the center of Pharmageddon, where I compared what happened then and happens over and over to the Greek Myth in which Demeter implores Zeus to restore her child to life. It is appropriate perhaps in that unlike the other Gods, who were dashing and colorful, Zeus often seems to have the character of the bureaucrat who ran Olympus rather an all-powerful Jehovah.

Demeter’s stories

Demeter was the Greek goddess of the Earth and of fertility whose daughter, Cora, was forcibly abducted and carried off to the underworld by Hades. Demeter protested to Zeus, who professed himself helpless, until Demeter threatened Earth with permanent Winter. Zeus intervened and restored Cora to her mother as Persephone. Because Persephone had eaten some pomegranate seeds while in the underworld, however, she must return to Hades each year, the several months of Winter each year.

Winter’s tale

Mary Ellen Winter confronted Laughren and the FDA about her 23-year-old daughter, Beth:

“Beth was looking forward to a career in communication and was experiencing some anxiety and having trouble sleeping when she consulted our family physician. He prescribed Paxil and said she would start feeling better in two weeks. Seven days later Beth took her own life.

We, like most of you in this room, grew up with confidence in the strides made in medicine and accepted with faith antibiotics and vaccinations prescribed. We believed the FDA would always act to protect our family’s well being. When my daughter went to our family GP last year, we trusted that our doctor was well educated and informed. We were wrong. We now know that pharmaceutical sales are a high stake business, driven to increase shareholder wealth. The consolidation of pharmaceutical companies like GlaxoSmithKline has resulted in increased sophistication in the quest to market and distribute pharmaceutical products. Priority has moved from health to profit. Not all doctors are equipped to understand the marketing targets they have become. The FDA has allowed our daughter to be the victim of a highly commercial enterprise that selectively releases clinical data to maximize sales efforts and seeks only to gain corporate profits…

As residents of the State of New York, we thank our Attorney General, Elliot Spitzer, for addressing issues that the FDA has been unwilling to address…”

[This action on the part of Ruth Firestein within Spitzer’s department in many ways triggered the Access to Data issues that have since engulfed GSK and gave rise to the recent EMA hearings and a debate within RxISK and its supporters about what to do with the data that arises from people reporting to RxISK].

Thy neighbour’s child

But Demeter came right into the room in the last but one slot when Mathy Downing singled out Tom Laughren:

“On January 10, 2004 our beautiful little girl, Candace, died by hanging four days after ingesting 100 mg of Zoloft. She was 12 years old. The autopsy report indicated that Zoloft was present in her system. We had no warning that this would happen. This was not a child who had ever been depressed or had suicidal ideation. She was a happy little girl and a friend to everyone. She had been prescribed Zoloft for generalized anxiety disorder, by a qualified child psychiatrist, which manifested in school anxiety… . She had the full support of a loving, caring, functional family and a nurturing school environment.

Her death not only affected us but rocked our community… When Candace died her school was closed for the day of her memorial service, a service that had to be held in the school gym in order to seat the thousand or so people who attended. How ironic, Dr. Laughren, that your family attended Candace’s memorial service. Our daughters had been in class together since kindergarten. How devastating to us that your daughter will graduate from the school that they both attended for the past eight years and that Candace will never have the opportunity to do so.

Candace’s death was entirely avoidable, had we been given appropriate warnings and implications of the possible effects of Zoloft. It should have been our choice to make and not yours. We are not comforted by the insensitive comments of a corrupt and uncaring FDA or pharmaceutical benefactors such as Pfizer who sit in their ivory towers, passing judgments on the lives and deaths of so many innocent children. The blood of these children is on your hands. To continue to blame the victim rather than the drug is wrong. To make such blatant statements that depressed children run the risk of becoming suicidal does not fit the profile of our little girl.” [1]

Laughren’s defence

I cannot remember seeing anything ever about or by Tom Laughren where I have thought you know the man’s right on that – except the bits where he has been dragged screaming to a table and been forced to agree. But in the Pharmalot obituary on his career there for the first time was something where I jumped and said “Yes, he’s right on that”.

In another setting, faced with a barrage of criticism of FDA, “Tom Laughren, director of the FDA’s division of psychiatry products, told the panel that the agency could do little to fix the problem and, instead, pointed the finger at medical specialty societies, which he insisted must do a better job educating doctors about side effects”.

He’s right. Doctors are failing patients far more than FDA. (See Professional SuicideModel DoctorsWe need to talk about DoctorsScaremongers of the world uniteSo Long and Thanks for all the Fish). Doctors have become infantilized for whatever reason and turn to a parental figure, a Zeus, to rescue them. If you take on the responsibility of looking after people the very least you can do is Man up – or better again Mother up.

Crusoe

The next two Crusoe posts will deal with these issues. It seems right to mark the end of one year and the start of the next by stepping back from the realm of real human drama and place these in their mythic context. Taking the issues out of the domain of data, science and real clinical histories into the realm of myth seems to confuse some readers – the hope is rather to engage with a wider readership and get artists or story-tellers or poets to engage with RxISK and its issues – as Bill James has done with his cartoons and images. We are dealing here with lives and in particular the fact that we each have one life only. The two Crusoe posts will attempt to capture the spirit of RxISK.

[1] Joint Meeting of the CDER Psychopharmacologic Drugs Advisory committee and the FDA Pediatric Advisory Committee, Bethesda, Monday Sept 13th 2004, p 435.

[2] Joint Meeting of the CDER Psychopharmacologic Drugs Advisory committee and the FDA Pediatric Advisory Committee, Bethesda, Monday Sept 13th 2004, p 332.