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Dear Dr. Price,

I am writing to you in connection with the paper, A comparison of the post-marketing safety of four selective serotonin reuptake inhibitors including the investigation of symptoms occurring on withdrawal (Br. J. Clin. Pharmacol., 1996, 42, 757-763), also the presentation "Comparison of the post-marketing safety profiles of fluoxetine, fluvoxamine, paroxetine and sertraline using spontaneous adverse drug reaction reporting (Pharmacoepidemiol. & Drug Safety, 1995, 4, Suppl. 1, S62, Abstract from the 11th International Conference on Pharmacoepidemiology, Montreal). I am writing to you as the nominated correspondent, but my queries arise because the findings and interpretations in this paper evidently represent the thinking of the Medicines Control Agency and Committee on Safety of Medicines. I would appreciate your comments on the following points:

1. The paper does not say whether or not evidence of withdrawal effects was apparent from any of the license applications submitted for these four drugs, nor whether the MCA requested applicants to formally investigate the possibility of either this or other evidence of the dependence potential of the drug in normal therapeutic use. These seem to be important points and it would be helpful to have some information on them.

2. The abstract of the paper concludes: "there was no evidence of a physical drug dependency syndrome" with SSRIs. Could you please specifically identify the syndrome to which the paper referred ?

3. The paper does not mention benzodiazepines, but clearly invites comparison with them - if only because the number of Yellow Cards reports of withdrawal symptoms for SSRIs greatly outnumber those for benzodiazepines. Could you please therefore indicate whether or not, on the criteria applied in this paper, there would be any evidence of a physical dependency syndrome with benzodiazepines and, if so, on what basis would one differentiate benzodiazepines from SSRIs in this respect ?

4. On what basis was the conclusion reached that "the withdrawal symptoms observed do not appear to be severe" and that "this study suggests that they are relatively mild ...", when 4 out 5 doctors whose opinions were canvassed described the symptoms they observed as "moderately severe" (58%) or "severe" (21%) ?

5. What is the meaning of the term "true dependence", as used in the 1995 presentation, and would the MCA/CSM consider benzodiazepines to be ‘true’ drugs of dependence, on the criteria applied?

6. Given that withdrawal symptoms from tricyclics are experienced by long-term users often enough to justify a general recommendation for gradual withdrawal, and that Yellow Card reports of withdrawal symptoms from SSRIs greatly outnumber similar reports for tricyclics, how should I interpret the conclusion in this paper that "overall, symptoms due to stopping an SSRI are rare"?

7. Similarly, the paper concludes that "The absolute risk of a withdrawal reaction with any of the SSRIs may be so low that differences are undetectable except through spontaneous reporting where drug exposure is high." ? Again, I find it hard to accept this statement, given that the MCA/CSM have received overwhelmingly more Yellow Card reports of withdrawal reactions to SRRIs than for either benzodiazepines or tricyclics.

8. Has there been any significant change in the MCA/CSM’s understanding and/or definition of "dependence", since publication of the note on Benzodiazepines, dependence and withdrawal symptoms in Current Problems No 21 (January 1988) and, if so, what has changed?

9. The survey reported in the 1996 paper found that 19% of patients experiencing withdrawal symptoms on paroxetine had restarted the drug, and were continuing to take it at least three months later. How can this finding be reconciled with the conclusion that there is "no evidence of a physical drug dependency syndrome" and "no evidence of habituation" ?

10. Experience with the benzodiazepines underlined that the essence of the dependence problem was not that some people experienced sometime severe symptoms on withdrawal, but that many more continued to take these drugs in order to avoid them. This accords with Hollister’s observations, described in Power & Dependence (enclosed) at page 122. His investigations into the dependence liability of benzodiazepines, in the early 1960s, had convinced him there would be "a flood of reports of withdrawal reactions" for diazepam (Valium) and chlordiazepoxide (Librium), but the flood never came: "The probable reason is that patients abort these reactions early on because they think their original symptoms are returning, and they get back on the drug. So we rarely see the full-blown picture." Before concluding that SSRIs were not "true" drugs of dependence, would it not be essential to establish that the same thing was not happening again, and was this a factor that you and your colleagues took fully into account ?

Thank you very much for considering these points; I shall look forward to hearing from you.

Yours sincerely,

Charles Medawar

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