The following attempts to summarise the main points arising in two further letters exchanged on this subject - SA to MGH on 5 January 1999, and the MGH reply a week later. 

1. Re "the initial publication of your work in the name of two Lilly employees, one year in advance of your definitive report".

There has been only one publication; we do not consider a 12 minute oral presentation on an interim report a publication, even if the meeting syllabus contained an abstract of that presentation.

I agree that such a presentation scarcely counts as a publication - but then it is all the more perplexing to see Dr Rosenbaum (as co-author) actually citing his own findings to Blomgren et al., 1997. (See Ref. 9, in Zajecka et al., 1988).

At the time of the writing of the Zajecka paper, the APA abstract was the only available reference to the work and the (preliminary) findings.

 

2. Re: authors' names omitted from the report published as Rosenbaum, Fava et al., 1998.

Your statement is incorrect, as the APA abstract (page 118 of the New Research Abstract book) included only one co-author that was not included in the final Biological Psychiatry manuscript.

The abstract I have, also the citation previously mentioned, include two names omitted from your publication - the principal author, S L Blomgren, and M Wilson.

No, we are correct, in that SL Blomgren and S Hoog (nee Blomgren) are one and the same. Wilson was a biostats guy who left the project for a new life in osteoporosis, and a new biostats guy signed on for work on the data for the manuscript.

 

3. Re: qualification of Lilly employees as authors

The exclusion of that author (Michael Wilson, M.S.) is simply due to the fact that, although he had helped putting together the abstract submission, he was assigned to other projects within Eli Lilly and Company (he now works with the osteoporosis team) and he had no input on the development of the final manuscript published in Biological Psychiatry.

In that case, Wilson (and presumably also Blomgren) do not meet the criteria for authorship laid down by NEJM. "Each author should have participated sufficiently in the work to take public responsibility for the content" and "authorship credit should be based only on substantial contributions to (inter alia) final approval of the version to be published". I cannot reconcile your claim to be fully in control of publication if your findings are cited to a non-publication whose principal author, and one other author, appear not to have been qualified as authors.

See 2. above. Perhaps Wilson's earlier efforts might have qualified for later authorship, but inasmuch as he had left the project and a new statistician did the bulk of the work for the paper, the latter contributor was given authorship.

 

4. Re: input of Lilly employees into writing of the manuscript.

The inclusion of the other Eli Lilly and Company employees as co-authors of the Biological Psychiatry publication simply reflects their involvement in the coordination of the study and in the writing of the manuscript (we had several conference calls between Boston and Indianapolis to refine the manuscript). We can assure you that from the beginning of the process that led to the publication of the report we were free to say or add whatever we felt appropriate as we were fully in charge of the publication.

My point was simply that Eli Lilly & Company had a major input into the interpretation and presentation of your data, and that it clearly shows. It is good that you felt free to say or add whatever you felt appropriate, but my queries would relate only to how you chose to exercise that freedom.

Since we had collaborators at Lilly, it is fair to examine our report of the findings to determine if the conclusions from our data reflect commercial bias. We felt our discussion was balanced and that the three peer reviewers helped ensure fair reporting of our results as well.

 

5. Re: the influence of trial design on the conclusion that there was little or no risk of withdrawal symptoms with fluoxetine.

Again, despite your belief otherwise, research means taking a risk of testing, rather than just asserting, one's beliefs.

My point was that research carried out to this design could be expected to quantify the obvious - to point to the relative lack of withdrawal symptoms, within one week of drug discontinuation, with a drug (plus active metabolites) having a half-life of several weeks.

Our results did prove your hypotheses. Other work (e.g. Zajecka) would be necessary to address the issue of sustained discontinuation rather than interruption of fluoxetine.

 

6. Re: similarities between withdrawal problems with SSRIs and benzodiazepines (BDZs)

We were certainly not concerned with this issue as we were proposing to do the study. Dr. Rosenbaum was and is an internationally recognized authority on benzodiazepine therapy and we can assure you there was no impression of correspondance between the two issues.

I accept what you say, though it greatly surprised me. In the early 1990s, you were among the first to recognise that withdrawal symptoms with SSRIs could be a problem, and you say you were concerned that others were not aware of this. Presumably you suspected that, with SSRIs, "physiological adaptation develops and discontinuance symptoms can appear after regular daily therapeutic dose administration ... in some cases after a few days or weeks of administration". This was how the APA (1990) defined dependence on benzodiazepines - a problem that had been also overlooked for years, which had only just come to light. I cannot understand why you concluded there was no possibility of some link between the two.

As articulated in prior communications, that symptoms emerge following discontinuation of medication to which there has been physiological adaptation is a commonplace in medicine. So perhaps the hypertensive is dependent on medicines in that sense. The differences between SSRIs and sedative-hypnotics are enormous, however, in terms of drug-seeking, dose escalation, rapid as opposed to delayed (weeks) therapeutic effects, reward or pleasurable sensations from acute dosing, toxicity etc

 

6. Re: BDZs and SSRIs - continued

With respect to the risk of a sedative-hypnotic "abstinence" syndrome or similarities between antidepressant use and BZD dependence, we believe your position is rather idiosyncratic and has not been shared by clinical researchers in the field, whether academic, federal or industry based. So, it was not likely the company's concern.

When you first came across withdrawal symptoms with SSRIs in clinical practice, you had detected something that had not been uncovered by years of federally-supervised testing, and whose clinical significance had been missed by the manufacturers, academics and your colleagues alike. That is par for this particular course with just about every mainstream drug prescribed for psychic distress; see my 1992 book, Power & Dependence (enclosed). Orthodoxy rather than idiosyncrasy has always been the problem in the past.

Thank you for sending along your publications

 

6. Re: BDZs and SSRIs - continued

As we described in our prior response, consequences of abrupt discontinuation of many classes of medicines are commonplace and generally call for taper when discontinuing.

If withdrawal problems are such a commonplace with all kinds of medicines, it seems all the more extraordinary that the authorities should have missed the point for years. Do you not think, for example, that the federal authorities should have anticipated some risk of withdrawal problems with SSRIs and required tests to be done?

We would support studies of abrupt discontinuation with new drugs since these would help accomplish our goal of alerting colleagues to situations where abrupt cessation of treatment is ill-advised and taper particularly recommended

 

6. Re: BDZs and SSRIs - continued

This does not imply dose escalation, drug seeking, or impairment or other issues associated with dependence on drugs of potential abuse. 

In this context, dose escalation and drug seeking are bright red herrings. Twenty years ago, Hoffman La Roche among many others were arguing the identical point to emphasise that BDZs could not be drugs of dependence. Depression clearly is an impairment, and clearly is induced by antidepressant drug withdrawal.

The relative lack of dose escalation in therapeutic use of BZDs (as opposed to use by substance abusers) and the drugs' rather low rating for drug-seeking preference, especially where considered in light of their anxiolytic efficiency, are important contributors to their extensive prescribing by physicians and usefulness for those impaired by anxiety disorders. 

 

6. Re: BDZs and SSRIs - continued

Depression clearly is an impairment, and clearly is induced by antidepressant drug withdrawal.

You confuse "depression", a transient dysphoric mood state, with major depressive disorder.

 

7. Re: methodology used to evaluate withdrawal reactions to SSRIs having very different half-lives.

Yes, prospective hypothesis testing is superior to testing hypotheses with existing data-sets, but the latter can still offer data of interest to the field.

My point was that you used sharp instruments and a limited time-frame to investigate withdrawal reactions with paroxetine and sertraline, but not fluoxetine.

The main difference between the Zajecka paper describing spontaneously reported adverse effects and the Rosenbaum paper describing spontaneously reported adverse effects is that the latter was prospective. The DESS certainly influenced solicited reports, so simply compare the spontaneously reported data

 

8. Re: depression as a symptom of withdrawal

You are selective in your citation from the study, and fail to note that there was no increase in DESS events in the fluoxetine group overall after discontinuation. Within those data, some had an increase in DESS symptoms (14% on fluoxetine vs 60% and 66% on comparators); you are eager to conclude the smaller number is evidence of a discontinuation syndrome rather than just week to week variation (noise in the administration of the assessment instruments) in which patients have certain symptoms. We don't believe our data supports your assertion. This much variation is seen in those who simply remain on treatment.

You previously participated in trials in which 30% of patients became measurably depressed, following withdrawal from fluoxetine - and yet you developed a 43-item list of Discontinuation-Emergent Signs and Symptoms (DESS) which doesn't mention the word depression. Not much prospect of agreement here.

You are confusing the issues of a discontinuation symptom per se and emergent depression as a result of discontinuation. Our effort was to determine whether a discontinuation syndrome, apart from the loss of therapeutic benefit, could be demonstrated. Including "depression" as evidence of discontinuation would have been criticised for simply recording loss of benefit. We did, as you will recall, include two measures of severity in our assessments of patients after treatment interruption

 

8b. Re: what if the study reported in Biological Psychiatry had been extended for several weeks?

We suspect that if fluoxetine was discontinued permanently, we might pick up a signal of mild dizziness in 5% or 6% of patients at 4-6 weeks..

What you would see would seem to depend very much on what you were looking for, and how you went about it. You seem to be reasoning that dizziness would be the hallmark withdrawal symptom to look for, simply because it was the most often reported DESS both with paroxetine alone and for paroxetine and sertraline combined. But you already knew that 30% of patients became measurably depressed, following withdrawal from fluoxetine - whereas dizziness hardly featured as a withdrawal symptom at all. Therefore you might have expected to see a higher incidence of reports of psychic distress of the kind reported in your study in Table 2. See how low in the order dizziness comes, by contrast with symptoms linked with depression:

Our answer to your question about an extended interruption of fluoxetine was based on data from an experiment that had been done several years earlier as you know

 

9. Re: predominance of depression as a withdrawal symptom

One problem with your argument is your assumption that any symptom reported is discontinuation related, and does not account for the presence of these symptoms in those who do not discontinue.

On the contrary, I am challenging your assertion that depression should never be regarded as a withdrawal symptom with fluoxetine. You clearly demonstrated the predominance of depression as a withdrawal symptom with sertraline and paroxetine - though you label it 'relapse' - and the same symptoms (notably sudden worsening of mood, irritability, agitation) predominate with fluoxetine too.

We are interested in the research question of whether the discontinuation syndrome as we conceptualize it in fact might conduce to relapse; that is would relapse of major depressive disorder occur more often after discontinuation in those who suffer the discontinuation syndrome compared to those who do not? Perhaps the discontinuation syndrome, emerging as it does in some and not other patients, might identify those at higher risk for relapse

 

10. Re: Your emphasis on withdrawal symptoms other than those linked to depression.

If we understand your point here, you are restating our hypothesis.

My main point was that your emphasis on withdrawal symptoms that would typically be attributed to the 'flu' or to some other medical illness, seemed highly inappropriate given the prevalence of depression resulting from fluoxetine withdrawal.

We are impressed at your readiness to conclude that depression after treatment withdrawal is provoked by treatment withdrawal rather than reflecting the loss of a therapeutic benefit. Your certainty and passion for this belief is a worry, since you must acknowledge as you appear to do in your letter that you may be wrong; to the extent that you have a following, your asserted concern for public health seems disingenuous given the enormous pain and suffering of untreated depression and the likelihood that your followers would avoid or neglect treatment as a consequence of your assertions.

 

11. Re: the timing of onset of depression, in relation to drug discontinuation, as indicators of either a withdrawal problem or relapse.

From the above, we take your point to be that depression is not a recurrent disorder, or at least that for those who have been on antidepressants, the return of depression after stopping treatment represents discontinuation rather than relapse. To test your hypothesis, we should randomize patients to drug or placebo treatment, then slowly taper treatment and follow subjects over time to compare relapse rates.

I was drawing your attention to well-established advice to the effect that "withdrawal syndromes developing within a few days of withdrawal cannot be attributed to a relapse of the disorder for which the antidepressant was first prescribed, because this would take several weeks to appear …" You did not comment on this, and appear to have disregarded it in your study - and essentially on this basis you concluded there is no significant risk of withdrawal with fluoxetine, and that fluoxetine is effective in the long term. These conclusions seem quite unwarranted to me.

We did not see evidence of a significant risk of a discontinuation syndrome in a one week interruption of fluoxetine; we believe, and there is some evidence to support us, that the long half-life of fluoxetine provides a gradual brain and plasma level taper that protects against significant difficulties from abrupt discontinuation

 

12. Re: defining as a "depressive relapse" more severe cases of depression occurring during the period of drug withdrawal.

If this is really depressive relapse, then we have a novel treatment for depression that works within hours of starting medication, since these new symptoms melt with restoration of medication.

I'm afraid you have completely lost me. My point was that this was not depressive relapse but that depression should be counted a withdrawal symptom. If depression 'melts' with restoration of medication, it adds to the evidence that depression is a withdrawal symptom, and nothing to do with 'relapse'.

We were confused by your use of "depression" which we usually take to stand for "major depressive disorder". It would help if you were specific then about what you mean by depression, which we assume now to be "depressed mood". If you are simply representing that a depressed mood might be a discontinuation symptom then we agree this can occur

 

13. Re: risks resulting from the failure to recognise depression as a major symptom of withdrawal.

It is unclear to us what are the additional risks that you see. Furthermore, if fluoxetine was in fact associated with a significant risk for discontinuation-emergent symptoms, we would expect to see many more clinicians observe this and report it in the literature, as there are countless reports with shorter acting agents.

The risks are of widespread drug-induced depression, compounded by the mistaken belief that antidepressants are effective in the long-term. The risk with fluoxetine is so much the greater because depression (rather than 'flu-like symptoms) is the most distinctive withdrawal symptom, and readily mistaken for 'relapse'. The data in the four Lilly-sponsored trials clearly points to this risk, even if the interpretation and presentation of data point studiedly elsewhere.

See 10 above

--- END ---

 

From: Charles Medawar
Date: 13 January1999  15:38
To: Rosenbaum Jerrold F., Md
Re: Your comments of 12 January

 

Dear Drs Rosenbaum & Fava,

Thank you for your email. It was helpful to get clarification on points 1 through 4, though it seems there are profound disagreements between us on the substantive issues. I would also think there was little chance of resolving them through further correspondence but perhaps, if you had a chance to read the documents I sent, you might get a better idea of my perspective.

If you would like me to respond to your further points, please let me know. I'm quite prepared to spell out in more detail why I remain very concerned, but would be reluctant to do so unprompted because I fear this dialogue must already seem pretty indigestible to most website visitors. Incidentally, they are hardly a "following", and few are patients. Though patients have commented and contributed much more, most visitors seem to come from pharmaceutical companies and from professional backgrounds - mainly in medicine, academe and government. It is of course open to any of them to raise any queries they may have with any or all of us.

Yours sincerely,
Charles Medawar

 

From: Rosenbaum Jerrold F., Md
Date: 13 January1999  17:45
To: Charles Medawar
Re: Your comments of 12 January

> Dear Drs Rosenbaum & Fava,

Thank you for your email. It was helpful to get clarification on points 1 through 4, though it seems there are profound disagreements between us on the substantive issues. I would also think there was little chance of resolving them through further correspondence but perhaps, if you had a chance to read the documents I sent, you might get a better idea of my perspective. [Rosenbaum, Jerrold F.,Md] We'll try to have a look when there is an opportunity to do so. If you would like me to respond to your further points, please let me know. I'm quite prepared to spell out in more detail why I remain very concerned, but would be reluctant to do so unprompted because I fear this dialogue must already seem pretty indigestible to most website visitors. [Rosenbaum, Jerrold F.,Md] [Rosenbaum, Jerrold F.,Md] Perhaps you're right, but if questions come up, we can try to address them; indeed, we may have questions for you. Incidentally, they are hardly a "following", and few are patients. Though patients have commented and contributed much more, most visitors seem to come from pharmaceutical companies and from professional backgrounds - mainly in medicine, academe and government. It is of course open to any of them to raise any queries they may have with any or all of us.

Yours sincerely,

Charles Medawar

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