This is the draft of a short paper, intended for print publication.
Please feel free to comment on it, if possible by mid-May 1998.
See below.

How not to defeat depression?

The consumer movement was first to spot the dependence problem with the benzodiazepines (BDZs) - tranquillisers like Valium (diazepam) and Ativan (lorazepam). But for years it met with official inertia and resistance because, at the time, government, industry and most doctors believed there would be only a few cases of dependence for every million prescriptions. That was how it was until the early 1980s, but eventually common sense prevailed. By the mid-1980s, it was clear that perhaps 500,000 people were effectively hooked. Many, especially elderly people, still are.

Two other factors helped this breakthrough in understanding. One was that "therapeutic dependence" was confirmed in controlled studies: some people got severe symptoms after withdrawing from normal doses of BDZs, especially after long-term use. The other factor was the realisation that many withdrawal symptoms positively mimicked the symptoms of anxiety, insomnia etc for which the drugs were originally prescribed. So, for over 20 years, the BDZ dependence problem went unnoticed: instead of recognising withdrawal symptoms for what they were, doctors and patients usually saw them as signs of relapse. This meant patients went back on their drugs, hardening the addiction. And of course every time this happened, it also seemed to give evidence that the drugs really went on working.

Once the penny officially dropped, in the late 1980s, prescriptions for BDZs went into sharp decline; this was one of the factors that helped to launch the SSRI antidepressants, the so-called Selective Serotonin Reuptake Inhibitors, exemplified by Prozac (fluoxetine). Though never tested for their dependence potential, these new SSRIs were widely acclaimed and often adopted as substitutes for BDZs - not least because of ringing endorsements from the Royal College of Psychiatrists (RCPsych). Their "Defeat Depression Campaign" emphasised how effective drug treatment had become, also insisting that, unlike the old BDZs, antidepressants were not drugs of dependence. The Campaign ran from 1992 to 1997, in large part funded by the manufacturers of SSRIs themselves.

SSRI antidepressants are now extensively prescribed and Prozac has become the legend that Valium once was. The RCPsych again had a lot to do with this, by urging more treatment - for example, warning "of the tragedy that, despite the availability of effective treatments, 70% of suffers go untreated". There is now, nevertheless, perhaps some glimmer of concern about the extent of SSRI prescribing - not only for the 307 official kinds of "depression", but for many other "disorders" as well. NHS antidepressant prescriptions have doubled in the past six years.

Cracks start to appear   The benzodiazepine dependence problem wasn't the first of its kind. For some 200 years, doctors have prescribed a succession of addictive drugs for anxiety, insomnia, depression and related problems - always in the belief they could not cause dependence, or that patients were responsible if they did. Originally, this happened with alcohol and opium, then with morphine, cocaine and heroin. Then there was chloral, the bromides and numerous barbiturates and related drugs, and then the BDZs. In their day, all these drugs have been prescribed for mental distress and, except for alcohol, also as weaning treatments for other drugs on the list. The question now is whether antidepressants will join this list as well.

This question only recently arose, though antidepressants of one kind or another have been used for nearly 40 years. The question first surfaced in the early 1990s, with the introduction of a new SSRI, paroxetine (Seroxat/Paxil). Reports began to suggest that, when the drug was stopped (especially suddenly), sometimes severe withdrawal reactions set in - and slowly it is becoming clearer that the same can happen with other SSRIs. I say "slowly" because most SSRIs still carry no warnings about this at all.

Looking back, it is now clear that withdrawal reactions have always been more or less of a problem with all antidepressants, if barely recognised as such. The first warning about the need for gradual withdrawal didn't appear in the British National Formulary until 1990, in spite of sporadic reports about the problem over the previous 30 years. It is now known (if not to many doctors) that perhaps one-quarter of long-term users may have real difficulties coming off antidepressants - though there was little more than a hint of the problem, until the advent of the newer SSRI antidepressants a few years ago.

Over 50 published reports of withdrawal problems with SSRIs have since been published; some cases required hospitalisation. Also, the numbers of Yellow Card reports of suspected reactions, reported to the Committee on Safety of Medicines (though just the top of the tip of the iceberg), far exceed the numbers ever reported for all benzodiazepines combined:

Reports of suspected adverse reactions,  to March 1997


No. NHS scripts Yellow Cards re: Yellow Cards re:


withdrawal reactions dependence-all forms
Temazepam 1977 50m 5


Diazepam 1963 180m 20


Fluoxetine 1989 9m 59


Paroxetine 1991 6m 802


The official response to all this has been to hide behind the new formal definition of "dependence" in the Manual (DSM-IV, 1994). The nub of it is that, in the 1980s, withdrawal symptoms on their own demanded a formal diagnosis of dependence (DSM-III). Then, because of the BDZ problem (legal complications too) the goalposts were moved. Nowadays, "therapeutic dependence" doesn't exist (some sort of reinstatement for the benzodiazepines) and a diagnosis of dependence requires evidence of frank abuse, notably self-destructiveness manifested in drug-seeking behaviour. This would be most unusual, when doctors mostly readily prescribe and actively encourage antidepressant drug use.

The implications of this go far beyond the concern that many SSRI users will find it hard to quit without medical help when the time comes - or even that many more will go on consuming. I don't see dependence, as such, as the real problem; it might not be too high a price to pay for an effective treatment for severe depression. The question is, do antidepressants work?

Do they really work?  The evidence for SSRI effectiveness has of course been grossly hyped; the reality is that no one antidepressant has ever been shown to have any greater effect on depression than any other. For all the talk about serotonin deficiency as the cause of depression, it is quite clear that, whether they target serotonin or not, all antidepressants are remarkably unspecific in their action on depression, and often no more effective than a placebo (an inert, usually identical-looking drug).

My main concern is that many claims for the SSRIs, in particular, have been based on non-science. This is especially true of recent clinical trials that "prove" that antidepressants go on working. These are of key importance, because they underpin the new consensus that depression should be treated much more aggressively than in the past. New standards, actively promoted in the "Defeat Depression Campaign", call for higher doses and suggest long-term drug treatment for depression should be the norm. However, the evidence for this comes largely from trials organised along the following basic lines:

1. Identify from among patients, a large group of "good responders" to antidepressants, who have been on their drugs for some time;

2. Randomly divide these patients into two different groups, leaving one group still taking the antidepressant drug, as before;

3. For patients in the other group, surreptitiously substitute a placebo for the active drug, to precipitate withdrawal.

4. A year or so later, see how many people in each group have "relapsed" - and rate antidepressants "effective" if significantly more have "relapsed" in group from which antidepressants were withdrawn.

Yes, perhaps you've guessed it, though the authorities apparently have not. Even the leading expert with the government's Committee on Safety of Medicines concluded that antidepressants went on working on the basis of a study that completely discounted the possibility of withdrawal reactions - and therefore found much more evidence of "relapse" in the group switched to placebo. The long-term effectiveness of antidepressants may be as much of an illusion as it was with BDZs.

Watch this space   The risk is of another fiasco of the BDZ kind, as described in Power & Dependence (Social Audit, 1992). I see my new paper, The Antidepressant Web, as something of a sequel to this, yet another example of something resembling an addiction to the prescribing of dependence-producing drugs.

But you can make up your own mind on this - especially if you can reach the Internet, to access our website:  From here you can download the evidence, with regular updates; you can also follow the (now batches of) correspondence with the powers that be, notably with the RCPsychs and the Medicines Control Agency. I have yet to be convinced of the competence of either in this matter. How about you?

Charles Medawar, 20 April 1998

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Section 5.1 - Editorial notes & What's New?