The Review on Antidepressant Withdrawal That Cochrane Won’t Publish

Editor’s note: This article was co-authored by Anders Sørensen.

Abstract

About half of the patients on depression pills, or over 50 million people worldwide, will experience withdrawal symptoms when they try to come off them, and in half of these, the symptoms are severe. This dependency is a major reason why many people continue taking the pills for decades or even lifelong. A review of methods for safe withdrawal of depression pills would therefore be hugely important. We describe here what happened when we tried to get a protocol for a Cochrane review approved. The process took two years and we did not succeed. It seems to us that the Cochrane group sent us on a mission that was impossible to accomplish, raising their demands along the way to absurd levels with many irrelevant requirements in a face-saving operation aimed at protecting the psychiatric guild and its false beliefs.

Introduction

Usage of depression pills amounts to over 10% of the entire population in some countries, e.g. 13% in England in 2016-17. This means than more than 100 million people worldwide receive these pills every year. About half of the patients, or over 50 million people, will experience withdrawal reactions when they try to stop, and in half of these, the symptoms are severe.¹

This dependency is a major reason why many people continue taking the pills for decades or even lifelong. In Denmark, the percentage of current users in 2006 who redeemed a prescription for the same or a similar drug in each of the following years dropped slowly from 100% to 33% after ten years.² In the US, nearly 7% of adults have taken depression pills for at least 5 years.

A review of methods for safe withdrawal of depression pills would therefore be hugely important. In 2016, Peter Gøtzsche contacted psychiatrist Rachel Churchill, the co-ordinating editor of the Cochrane depression group, who showed great interest in his proposal to do a review. He employed a psychologist, Anders Sørensen, as a PhD student and temporarily involved another psychologist. However, when we submitted a protocol for the review, it was not welcomed. It took nine months before we got any feedback. We promptly responded to five pages of comments and submitted a revised protocol. Seven weeks later, we were told that further improvement was needed. We submitted a third version and were informed that we would hear from the group “shortly.” Three months later, we asked for an update and were told we would hear from the group “by the end of the week.”

The end of the week became another month. The managing editor wrote that she had prioritised our project and done everything in her power to speed up the process. This message made us suspect that her superiors had deliberately obstructed the process to wear us out so that we would withdraw the review ourselves while the group would not be seen as being unhelpful.

As over 18 months had now passed, we contacted Churchill, on 1 March 2019. We provided a timeline showing that the group had caused unbelievably long delays and wrote that we expected her to send the protocol for peer review without further delay.

The First Seven Peer Reviews

Churchill responded in April, seven weeks later, that they had had received extensive peer reviewer feedback except one, due to be submitted when the referee was back from leave. The peer reviewers had “highlighted the lack of detail provided around scope and methods” and she attached a 30-page document with 86 points.

No less than four editors and three peer reviewers had provided individual comments, and the document took up 12,044 words including our replies to earlier comments. This was seven times more words than our original protocol from 2017. Sørensen wrote to Gøtzsche that our review was quite simple and that we just wanted to help people who wished to come off their drugs but weren’t allowed to do so: “What kind of world is this?”

In her email to Gøtzsche, Churchill emphasized that she was sure that “we both still feel strongly that a clear and thorough assessment of the evidence base in this area is essential”, and she invited him “to try and address the feedback.”

Churchill sent the 8^th review five weeks later, in May, but her invitation from April to address the feedback had metamorphosed into an outright rejection: “I’m sorry that we cannot proceed with this protocol. I hope that all the peer review feedback we have sent will be helpful to you should you wish to submit elsewhere.”

The Final Peer Review: One of the Worst Ever

Sørensen and I felt that the 8^th, final peer review was an excuse to get rid of us. It was one of the worst Gøtzsche had seen in his whole career, which spans over 40 years. It was as long as a research article, 1830 words, and, in contrast to the other seven reviews, it was anonymous. We asked for the identity of the reviewer, but this was not granted. We appealed Churchill´s rejection, responded to the comments from all eight reviewers (see appendix 1 and appendix 2) and submitted a fourth version of our protocol (appendix 3).

Very few changes to the protocol were needed. We felt the final reviewer’s mission was to protect psychiatrists’ guild interests, which was done by denying a long array of scientific facts and by using several strawman arguments accusing us of things we had never claimed (appendix 2). We describe here the main issues.

We were accused of “painting a picture” about avoiding using antidepressants, which did not represent the scientific consensus, but our review would not be a consensus report and it would not address the benefits of antidepressants. It was about helping people come off them safely when they wanted to.

We had written that, “Some patients refer to the discredited hypothesis about a chemical imbalance in their brain being the cause of their disorder and therefore also the reason for not daring to stop.” The reviewer opined that we dismissed many decades of evidence relating to neurochemical changes observed in depression and wanted us to document that neurochemical theories of depression were incorrect. We responded that our review was not the place for such discussions and that the hypothesis of a lack of serotonin being the cause of depression had been discredited by many convincing studies.³

In relation to this, the reviewer accused us of having suggested with no evidence that prescribers perpetuate untruths to justify drug prescription. There is plenty of evidence for this,^3,4 and in some countries, over 80% of the patients ascribe their depression to a chemical imbalance.⁵ They did not invent this myth; the psychiatrists did.³

The reviewer wanted us to “Start with a statement as to why antidepressants are considered by the scientific community to be beneficial … in treating a broad range of highly disabling and debilitating mental health problems.” We responded that our review was not an advertisement for the drugs and that it was not relevant to discuss their effect in a review about stopping using them.

We were asked to explain the concept of ongoing prophylactic antidepressant treatment, “a well-accepted clinical strategy,” but this was outside the scope of our review. Furthermore, the randomised trials comparing maintenance therapy with withdrawal are flawed because harms are introduced by abstinence symptoms in the latter group.³

The reviewer wrote that we conflated disease reappearance with withdrawal symptoms. We did not (appendix 3), but many psychiatrists do,³ which is a major reason why many patients are treated for decades or for life.

The reviewer argued that it is not an acceptable definition of dependence when a drug that has been effective stops being effective when stopped. This is a strawman. We would never postulate anything so foolish.

The reviewer argued that most people who had taken antidepressants for extended periods could stop safely without either rebound of the disease or withdrawal symptoms. This is totally false,¹ which we had documented and referenced in our protocol. The reviewer ignored recent research results, including that the Royal College of Psychiatrists in the UK reported in 2012 that of 817 people who had stopped taking depression pills, 63% experienced withdrawal symptoms.⁶

As the reviewer seemed to believe in the chemical imbalance nonsense and mentioned thyroid diseases and insulin, we explained that antidepressants cannot be compared with drugs used to treat such diseases. People with myxoedema and diabetes lack thyroid hormones and insulin, respectively, whereas people with depression do not lack serotonin.

The reviewer accused us of having implicated very clearly – even though not having expressly stated it – that antidepressants are “bad medications” to be avoided, “especially as there is no mention whatsoever of the beneficial effects … I find this argument to be unscientific, and unacceptable in the context of the current evidence base.” Another strawman argument. 

The reviewer wanted us to remove this sentence: “the patients’ condition is best described as drug dependence” arguing, with reference to the DSM-IV drug dependence criteria, that it is an unreasonable misappropriation of a term. We responded: “The official definitions of dependence are ridiculous and self-serving, in addition to serving the drug companies that have benefitted hugely from the false perception that only benzodiazepines cause dependence, not the SSRIs.⁴ Craving larger and larger doses as a criterion for dependence is absurd, as it means that no one who smokes 20 cigarettes every day is dependent on smoking cigarettes!”

We ended our letter to Churchill by pointing out that the Cochrane Collaboration is about collaborating and being helpful to each other: “Some of the comments we have received from you have been very helpful and have improved our protocol. Some have not been helpful, some have been counterproductive, some have been irrelevant, and we have carefully explained why.”

Our Three Appeals

Churchill ignored us. After two and a half months of waiting for a reply, we complained to Cochrane’s Editor-in-Chief, Karla Soares-Weiser, who is a psychiatrist, about the inappropriate, definitive rejection of our protocol. We flagged that our review was very important; that we had done huge work with it and could finalise it in a matter of days (there are only a handful of relevant trials); that we had the expertise and were members of networks of people interested in this issue (Gøtzsche co-founded two such organisations, and is on the board in both); and that it was a very hot topic right now, in the UK in particular.⁷

We emphasized that the Cochrane Collaboration should not mount ever increasing obstacles along the way for those who volunteer to do the work to help suffering patients but should be forthcoming and helpful.

Soares-Weiser replied that we should use the official process and appeal to Chris Eccleston, Senior Editor for the Mental Health and Neuroscience Network and a professor of medical psychology. Before we did this, we appealed again to Churchill and noted that, although, according to Cochrane rules, we should have heard from the group within three days, we had received no reply.

Two weeks later, Churchill wrote that our protocol was finally rejected already in April and that she only forwarded the final peer review in May to be helpful in case we would publish elsewhere. This was not true. As noted above, she invited us in April to revise our protocol: “I’m sorry to have to inform you that we are unable to accept this protocol for publication as it stands. I’m aware this will be unwelcome news, but I’m wondering whether you and the rest of the author team would wish, once again, to try and address the feedback. Any new submission would clearly need to attend to the comments and feedback attached, but I hope these will be helpful to you.”

Our long-held suspicion that Cochrane wasn’t interested in helping patients come off their psychiatric drugs now rose to almost certainty.

Earlier, we had written to the editors that they “are making something, which is very simple, highly complicated. Our review has a very simple aim: to help patients come off drugs they want to come off” (appendix 1). When asked if reducing withdrawal symptoms or coming off the drugs was most important, we had replied that, “the most important outcome for patients wanting to come off drugs is whether they succeeded coming off the drugs. Reducing withdrawal symptoms is a means to achieve this.” Even though we had already stated in our protocol that, “Studies of interest are those aimed at helping patients, through various interventions, come off any antidepressant drug completely,” three editors and one reviewer wanted us to specify whether reducing the dose was also an objective. We explained that, “it is very easy to reduce the dose, as virtually all patients are overdosed, so this is not of any interest to us.” An editor wrote that our primary outcome of “complete cessation of antidepressant drug use” should be more clearly defined, as it might not be cessation for life. We responded that we could not define a yes/no outcome more clearly: “It is not a matter of complete cessation for life, as a patient might fall ill again.” Apart from this, no studies follow all patients till they are all dead.

Our appeal to Churchill was not assessed by her but by a co-ordinating editor from another Cochrane group, Rebecca Fortescue from the Airways group, who upheld the rejection decision.

Three days later, we appealed to Eccleston. We wrote that the demands on the protocol had increased steadily over two years and that we had tried our best to comply with them. We also noted that, even though Fortescue had provided a list of 11 documents she received from the review group in her 2.5-page assessment, it was not possible to see what all of them were about. However, it was clear that she had not received our reply to the final peer reviewer or our revised protocol, as we had already complied with many of the issues she raised in the version we submitted to Churchill on 13 June.

Fortescue mentioned a few new issues we could easily address. For example, we had written that, “Cutting the dosage in half as the first step is often possible because most patients are overdosed.” Halving the dose each time is the official recommendation in the UK and other countries as well,⁸⁹ and the hyperbolic receptor binding curves show that most patients are overdosed and that such rapid linear dose reductions are dangerous.^3,8

According to Fortescue, “a reader can be left in little doubt about the review authors’ stance on the relative harms and benefits of psychiatric drugs, which does not fully reflect the current international consensus and could cause alarm among review users who rely on Cochrane’s impartiality.” We noted in our appeal that, “We are a bit surprised about this comment.” Cochrane is not about consensus but about getting the science right. And assessing the harms and benefits of psychiatric drugs was outside the scope of our review. So, we did not write about this issue in our protocol or offered any “stance.”

Fortescue repeated criticism she had seen we had already responded to (appendix 1), and some of her criticism was plain wrong, e.g. “Lack of clear structure in the background, which fails to make proper use of the preferred sub-headings.” We had used all the preferred sub-headings and our background section was very clear (appendix 3).

Even though we had pointed this out repeatedly, Fortescue, the editors and the peer reviewers did not seem to understand that “Types of participants” were people taking pills who wanted to come off them. As the withdrawal symptoms are similar for any type of patient, disease or drug, this suggested a broad approach. However, Fortescue wanted to have a clearer description of the population, intervention and comparators, e.g. if we would include trials in migraine prophylaxis, chronic pain or urinary incontinence, and an editor asked for details about which ages, sexes, settings, diagnoses of depression, and types of antidepressants we would include, as if we were planning to do a randomised trial. The answer: everything!

Although we explained to Eccleston that there was very little that separated us and the Cochrane Common Mental Disorders group after our latest revision, which Fortescue had not seen, he summarily rejected our appeal without a single comment. Apart from formalities, he offered only 56 words:

“I am very sorry that this title did not succeed because I agree with the importance of the question. I sincerely hope that you will both take what is done and complete it in another outlet. We need to stimulate a discussion on this important topic and it has become more important over time not less.”

We appealed to Cochrane’s Editor-in-Chief on 2 October. An automated reply said that Soares-Weiser was occupied with meetings on 2 and 3 October, but already on 5 October, she sent her reply, in 118 words:

“I have had a chance to look carefully at the protocol, the editorial and the peer-review comments, together with your replies and the email exchanges between your team and the Review Group editors. The comments obtained from the open peer review process consistently indicated a lack of clarity regarding the review methods proposed and, despite more than one opportunity to address this, the protocol did not show sufficient evidence that this progressed.

“I recognise that delays in the editorial process made for uncomfortable exchanges between the editorial office and you as authors, and I have communicated this to the Review Group. However, having considered all the information, my final decision is to uphold the rejection of the protocol.”

We wonder how Soares-Weiser can call it an “open peer review process” when the final reviewer was anonymous, and we were ignored when we asked for his/her identity? We cannot even check if this reviewer has unacceptable conflicts of interest.

Discussion

It seems that Cochrane has no interest in a review of safe withdrawal of depression pills and that they sent us on a mission that was impossible to accomplish, raising their demands along the way to absurd levels with many irrelevant requirements in a face-saving operation aimed at protecting the psychiatric guild and its false beliefs.¹⁰

The very fact that patients are organising themselves in survivor groups and various withdrawal-related initiatives around the world is a clear sign that psychiatrists ignore them, and Cochrane is no exception.

It is not correct that there was a lack of clarity about our review methods (appendix 3), and, although we found many of the demands totally unreasonable, we did our best to adhere to them.

The editors asked us to write about the benefits of antidepressants and mention that “some antidepressants may be more effective than others”, with reference to a recent meta-analysis in Lancet by Cipriani and colleagues.¹¹ However, this network meta-analysis is seriously flawed, which I demonstrated in the article, “Rewarding the companies that cheated the most in antidepressant trials.” Later, a re-analysis showed a high risk of bias and that the outcome data reported by Cipriani et al. differed from the clinical study reports in 12 (63%) of 19 trials.¹² Despite the flaws, the mean difference between depression pills and placebo on the Hamilton depression rating scale (range 0-52 points) was only 2 points, which is far below the smallest effect that can be perceived (5-6 points),¹³ and these 6 points are not even clinically relevant.

It is irrelevant to discuss the effect in depression in a review about coming off these drugs, in any disease. Our review was not about proper prescription of the drugs but about proper deprescription. One editor asked us to describe how antidepressants work and what the differences are between them, and a reviewer asked us to explain when it was appropriate and inappropriate to use antidepressants, but we were not writing a textbook in clinical pharmacology.

The level of denial was very high. We were asked by a reviewer to give references on rates of dependency but had already done this to such an extent that an editor asked us to shorten this information. When we wrote that, “Psychological dependency can also be important, and some patients refer to the myth about a chemical imbalance in their brain being the cause of their disorder and therefore also the reason for not daring to stop (Lucassen 2014),” co-ordinating editor Sarah Hetrick asked us to write: “People on antidepressants may believe that this is necessary because they have a belief that the difficulties they are experiencing are due to a chemical imbalance in the brain” (appendix 1). However, the patients did not invent this myth; the psychiatrists did.³ As is typical for mainstream denying psychiatrists,³ Hetrick takes the blame away from her colleagues and blame the patients instead. Although it is true that “some people get terrible withdrawal symptoms,” a reviewer wanted us to trivialise this by writing that, “some people get withdrawal symptoms that can negatively impact the quality of life of the patient.” We changed “terrible” to “severe” and noted that the UK Royal College of Psychiatrists was recently forced to change their position totally, after the College had previously trivialised these symptoms.⁷

Cochrane protected psychiatry’s guild interests and the specialty’s false beliefs also in 2015 when Gøtzsche explained in a BMJ paper why long-term use of psychiatric drugs causes more harm than good and that we should therefore use these drugs very sparingly.¹⁴ The same day, Cochrane’s then Editor-in-Chief, David Tovey, who is not a psychiatrist, and the three editors in charge of the three Cochrane mental health groups, Rachel Churchill included, attacked my scientific credibility in a rapid response to my article.¹⁵ Several editors of other Cochrane groups told me they were dismayed that these editors had appealed to authority rather than reason, to denigrate my research, which they felt shouldn’t happen in Cochrane.

The Cochrane Collaboration has developed from being an idealistic grassroots organisation to a self-serving juggernaut whose leaders do not seem to care about the ever-increasing workload they create for the unpaid volunteers who produce all the wealth Cochrane has.^15,16 It is very sad. This pattern often develops over time, not only in religious sects but also in charities like Cochrane.

Conflicts of interest: none.

Funding: none.