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Social audit's charles medawar, the uk's drugs watchdog, pieces together new evidence demonstrating that the new, so-called safer antidepressants like prozac could be habit-forming.

MagazineMarch 1998 (Vol. 8 Issue 12)Social audit's charles medawar, the uk's drugs watchdog, pieces together new evidence demonstrating that the new, so-called safer antidepressants like prozac could be habit-forming.

Over the past 200 years, doctors have prescribed an almost uninterrupted succession of 'addictive' drugs, always in the belief they would not cause dependence or that patients would be mainly responsible if they did

Over the past 200 years, doctors have prescribed an almost uninterrupted succession of 'addictive' drugs, always in the belief they would not cause dependence or that patients would be mainly responsible if they did. From alcohol and opium to barbiturates and benzodiazepine (BZD) tranquillisers, all these drugs have been prescribed as sedatives for mental distress and, except for alcohol, also as weaning treatments for addiction to other drugs.

The antidepressant market has changed recently with the introduction of a new class of antidepressant, the selective serotonin reuptake inhibitors (SSRIs), exemplified by fluoxetine (Prozac). These drugs have started to overtake the more traditional antidepressants, the tricyclics and the monoamine oxidase inhibitors (MAOIs). The tricyclics, in particular, have been the mainstay of drug treatment for years, but have lost some ground since the late 1980s when the SSRIs began to make their mark.

For all the differences between them, all of these antidepressants have one important thing in common, and the evidence for it is overwhelming and has never been in dispute. When you carefully measure the effects of any of these drugs on whole populations, none proves more effective than any other in treating depression. Over the years, scores of different antidepressants have been tried, but patients generally respond (some very well, others less so) in about 60-70 per cent of cases. This compares with a 30-35 per cent response rate reported with placebo.

The first SSRI (zimeldine) was introduced in 1980, but withdrawn soon afterwards when found to cause a very small but unacceptably high number of serious neurological and other reactions. Fluoxetine, or Prozac, was launched in 1988/89. Prozac became a 'buy-word' and the main driving force behind the huge expansion of the depression market.

Along with fluoxetine, there are now several other SSRIs and related drugs, and the value of the world market is about three billion pounds a year. In the last five years, Prozac and other drugs have secured a 50 per cent increase in the English market (Department of Health, 1991-1995).

Underlying the success of the SSRIs was the still widely promoted theory that depression was in effect a serotonin-deficiency disease. The thrust of the message was that depression is just as biological in origin as lack of insulin for diabetics - the implication being that drugs like Prozac might be considered essential supplements for people with depression.

The notion that depression is basically caused by lack of brain serotonin (or some simple imbalance with other neurotransmitters) is clearly problematic. It does not explain, for example, why drugs which have an immediate effect in raising brain serotonin levels nevertheless usually take at least a couple of weeks to exert an antidepressant effect. Nor would it explain why SSRIs have no more effect on depression than other antidepressants, which hardly act on serotonin. And how would one explain the lack of effect of antidepressants on the most clear-cut cases of depression, the roughly one-quarter of all cases most resistant to treatment with drugs?

Much of the bedrock evidence put before the regulators appears suspect. Publicly available data from the US Food and Drug Administration (FDA) show that fluoxetine was licensed in spite of, rather than because of, clear-cut evidence of efficacy from controlled trials:

* The FDA relied on four pivotal studies designated as 'adequate and well-controlled trials which provided evidence of efficacy' of fluoxetine (FDA, Fluoxetine Hydrochloride, Summary Basis of Approval, 1988).

* Of these four placebo-controlled trials, three permitted the use 'of concurrent psychotropic medication', and one-quarter of the enrolled patients (135/ 540) took benzodiazepines (or chloral) as well as fluoxetine.

* If these 135 patients are excluded from the analysis in these three trials, fluoxetine does not show statistically significant efficacy over placebo (Breggin and Breggin, Talking Back to Prozac, New York, 1994).

* The one study that did prohibit the use of other such medicines was also the only one of the four to find no statistically significant difference between fluoxetine and placebo.

None of the SSRIs has any more specific effect on 'depression' than any other drugs, some in use for 40 years. This would not be for want of trying to prove a difference, since any manufacturer who could demonstrate his drug was in fact more effective than the rest would sweep the board.

The SSRIs arrived on the scene at the end of the 1980s, just as benzodiazepine prescribing went into sharp decline because of concern about widespread dependence problems and the mass litigation arising from it. The companies marketing SSRIs, of course, wished to take advantage of this. Firmly labelling their products 'antidepressants', they set out to convince doctors of the value of their drugs and their advantages over tranquilisers like Valium, particularly as drugs which don't cause dependence.

One of the key factors in revealing the benzodiazepine-dependence problem was the introduction to the UK market of lorazepam (Ativan, Wyeth). Two features of this drug made withdrawal problems more conspicuous. One was that the UK recommended dose for lorazepam was the equivalent of twice the dose of other BDZs (and double the recommended dose in the US), and this increased the severity of dependence. Also, unlike the well-established brands (such as Librium, Valium, Mogadon or Damane), lorazepam had a relatively short half-life. As the drug cleared the body quite fast, withdrawal effects became evident soon after stopping it and were more acutely felt. By contrast, the leading drugs had much longer half-lives, so withdrawal effects were attenuated, delayed and disguised. Clinical experience with lorazepam in effect gave the game away: this is what prompted the investigation of the whole problem of BDZ withdrawal.

This seems relevant today, first because SSRIs are usually prescribed at higher equivalent doses than alternatives and, secondly, because the exemplar, fluoxetine, has an exceptionally long half-life. Significant amounts of the drug usually persist in the body for weeks, which explains why the manufacturers say that withdrawal problems are rare.

It is true that reported withdrawal problems with fluoxetine are rare, especially in relation to the huge volume of prescribing. However, bearing in mind the low reporting rate for adverse reactions in general - and that patients may abort withdrawal reactions and stay on the drug - one might not expect to encounter more than a handful of reported cases per several million patient months.

Paroxetine (with a much shorter half-life) appears to be the greater culprit, with 84 per cent of Yellow Cards filled on the drugs relating to problems on withdrawal. Nevertheless, fluoxetine has attracted over twice the number of Yellow Card reports about suspected withdrawal problems as diazepam, in many fewer years, so it is hardly in the clear (Eur J Clin Pharmacol, 1997).
Though paroxetine is associated with more acute and recognisable withdrawal symptoms, it would not necessarily follow that a higher proportion of users stay on the drug. Evidence from general practice suggests that about 30 per cent of patients stay on both paroxetine and fluoxetine for over six months, but it is not known how many can't or won't stop, if indeed they want to.

The numbers of Yellow Card reports do suggest a problem. After 17 years of use, the benzodiazepines had attracted 28 Yellow Card reports of suspected withdrawal problems, while the numbers of reports relating to SSRIs (as of March 1997) were pushing the 1000 mark and increasing. Probably all SSRIs present some risk, though the numbers of reports of suspected withdrawal problems with paroxetine must be unprecedented for any drug. This problem was quietly acknowledged in a note from the CSM/MCA in early 1993, when the number of Yellow Card reports were one-tenth the level they had reached by March 1997:

'We have received 78 reports of symptoms occurring on withdrawal of paroxetine, including dizziness, sweating, nausea, insomnia, tremor and confusion. Such reactions have been reported more often with paroxetine and in several patients resolved on reinstating treatment. Paroxetine should not normally be discontinued abruptly' (CSM/ MCA, 1993).

Since then, the CSM/MCA have reported the results of a more detailed investigation (Br J Clin Pharmacol, 1996; 42: 757-63). This involved a follow-up questionnaire to doctors who had reported suspected withdrawal reactions with paroxetine and included a brief review of reactions with fluoxetine, fluvoxamine and sertraline as well. This was a more searching study than the 'systematic review' of the benzodiazepines (CRM, 1980), but reached broadly similar conclusions. Again, the cardinal error was to assume that the scale of the problem could be assessed by the numbers of Yellow Cards received, and to produce an absurd underestimate as a result.

Doctors in the follow-up survey had reported that eight out of 10 paroxetine withdrawal reactions were quite severe but, inexplicably, the CSM/MCA concluded the opposite.

Doctors in the follow-up survey had reported that untreated withdrawal symptoms lasted for an average 10 days (range one to 52 days), and about one in five patients needed treatment with another drug (mainly an SSRI or another antidepressant, or a major or minor tranquilliser). About the same proportion had restarted paroxetine and had not been able to withdraw from it within three months. The CSM/MCA's conclusion was: 'There was no evidence of a physical drug dependency syndrome.' This literature also includes one or two reports of suspected neonatal withdrawal reactions resulting from maternal SSRI use in pregnancy (Br J Psychiatry, 1995; 167: 412-3).

In the many Internet discussions of Prozac, there are frequent references to two phenomena which traditionally signal some increased risk of dependence: escalation of dosage and drug tolerance.

When practised unilaterally by patients, dose-raising behaviour is regarded as clear evidence of dependence. Dose-raising can be achieved by different means. It may involve a variety of 'dosage augmentation' strategies - adding new drugs to the existing regimen, instead of/as well as increasing the dosage of the old ones; or adding other agents to 'boost' the effects of the main medication, or switching patients to a higher equivalent dose of another drug.

Switching patients from one SSRI to another appears to be commonplace, and is in line with recommendations often made in medical journals. In discussion groups, some patients describe this as being on the SSRI 'merry-go-round', and often the reason for it is the waning effect of a particular drug after a period of use ('SSRI poop out').

The authorities are unanimous: with antidepressants, the question of dependence doesn't arise. The Royal Colleges of Psychiatrists and General Practitioners have emphasised there is no risk of dependence and recommend that doctors reassure their patients about this. The manufacturers of SSRIs clearly also considered such risks remote and did not test their drugs for therapeutic dependence potential, and neither the UK nor US regulators required such tests to be done. The FDA (but not the CSM/MCA) has required that this be stated on the label. This would largely explain why withdrawal effects came to light only several years after licensing.

Since then, the CSM/MCA have concluded that withdrawal symptoms from the main SSRIs are limited and not severe. Accordingly, not all SSRI manufacturers have been required to warn doctors (or patients) about any element of risk, nor to advise gradual withdrawal. The data sheet for fluoxetine hints that patients might be expected to glide off Prozac because it tapers its own withdrawal (Physicians' Desk Reference, 1996: 919-23) and, with sertraline (Lustral), suggests no problems would arise (Comp Data Sheets, 1996). An appreciable minority of users would not agree.

Risk and severity of dependence on psychotropics tend to increase with higher doses and long-term use. But because dependence is not considered a problem with antidepressants (BMJ, 1996; 313: 858-9), long-term treatment is recommended to prevent either reemergence of an underlying condition or the onset of a new one.

Evidence relating to possible adverse effects with long-term use is sparse, but there is little evidence of concern, probably because the risks of non-intervention are considered far greater. In addition, patients who experience the worst unwanted effects tend either to quit early on or develop tolerance to them if they persist.

The relatively few studies of long-term use mainly focus on efficacy and most last for one year. Research into long-term adverse effects would be complicated, expensive and hard to fund. Also bearing in mind that SSRIs have not yet been used long enough to be sure of their effects, risks associated with indefinite use can only be guessed at. Unexpected problems and the risk of insidious harm cannot be ruled out. They could become apparent only well into the future, as they have with the tricyclics and many other drugs.

Charles Medawar

'The Antidepressent Web' by Charles Medawar has been extracted from The International Journal of Risk & Safety in Medicine. The full paper costs lb6 and is available from Primrose Hill Books' 24-hour orderline: 0171 586 2035.


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