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Bristol and District Tranquilliser Project AGM


Professor C Heather Ashton, DM, FRCP

October 2005

School of Neurosciences
Division of Psychiatry
The Royal Victoria Infirmary
Queen Victoria Road
Newcastle upon Tyne NE1 4LP

Thank you for that kind introduction and for asking me to speak today. First of all I would like to offer my congratulations to all involved with the Bristol and District Tranquilliser Project on this special 10th Anniversary AGM. I am proud to be the patron of this project which has clearly worked wonders since its modest inception in 1985 and has helped so many people.

But actually it is a tragedy that there ever was, and even more that there still is, a need for projects such as this. Why, in this age of so-called scientific medicine, should we require charitable organisations with non-medical staff to help people having problems with drugs prescribed by their doctors? It is surely crazy.

It happens that I am old enough to have witnessed the start of the Era of Psychopharmacology - of drugs that affect the mind. Around the 1950s a whole host of such psychotropic drugs - all discovered by chance - entered the medical scene. These included the major tranquillisers such as chlorpromazine (Largactil), since developed into a range of antipsychotic drugs; it included the first antidepressants, the tricyclics and monoamine oxidase inhibitors, now joined by the SSRIs such as Prozac; and it included the so-called minor tranquillisers, the benzodiazepines Valium and Librium, now including a number of Z-drug hypnotics such as zopiclone and others.

These early discoveries were very exciting at the time, as they seemed to promise a cure for all psychiatric diseases. Schizophrenics taking antipsychotics could be, and were, let out of hospital to live in the community. Patients with depression could, allegedly, be freed from suicidal thoughts and from the perceived threat of electroconvulsive therapy (ECT). And the minor or major anxieties of life could be universally replaced with tranquillity and peaceful sleep induced by benzodiazepines. One eminent neurologist, Sir Henry Miller, even wrote that from now on all mental illness could be cured by a handful of pills and there would be no need for psychiatrists. He also memorably said that medical practice would now be so easy that it could safely be left entirely to women doctors!

At the same time it was believed, by a sort of backwards logic, that the cause of mental illness would be revealed by these drugs. Antipsychotics were found to block brain receptors for the neurotransmitter dopamine; therefore schizophrenia must be due to an excess of dopamine. Antidepressants were shown to increase the activity of the neurotransmitter serotonin; therefore depression must be due to a lack of serotonin. Benzodiazepines increased the activity of the neurotransmitter GABA, so anxiety must be due to lack of GABA.

Of course these na´ve and simple hopes turned out to be in vain. 50 years later we still do not know the cause of schizophrenia or depression or even how the drugs work. The prognosis of these illnesses has changed little. And anxiety and insomnia are as common as ever. It has become clear that the drugs do not cure anything; they do, often usefully it must be said, control some symptoms but have little effect on the underlying processes. And, as everyone here knows, the drugs carry their own disadvantages. But these same drugs have made millions for drug companies.

One activity that the new discoveries engendered was a neurotransmitter hunt. There was a search, mainly in the pharmaceutical industry, for new drugs acting on dopamine, serotonin or GABA. Once the basic work had been done, drug companies did not have to foot the cost of developing new drugs. It was much cheaper to manufacture "me too" drugs with similar actions but perhaps fewer side-effects. As a result, the world ended up with over 20 different but similar compounds in each class of antipsychotics, antidepressants and sedative/hypnotics. "You have to go where the market is", remarked one scientist working for a drug company.

And there was a change in the way drug companies were run. This is a quote from Pierre Simon, a pharmacologist working for Sanofi Pharmaceuticals, taken from David 's book The Pharmacologists: "In the beginning, the pharmaceutical industry was run by chemists... This was not so bad. [But] now most of them are run by people with MBAs, or things like that, people who could be the chief executive of Renault, Volvo or anything. They don't know anything about drugs." But, clearly, they do know where the market is.

Another quote from the same pharmacologist: "When you find a drug that is really active on one receptor... The problem comes when you present it to the financial analyst. You say 'I have a new drug, a very interesting antagonist of [receptor X]." 'Good', says the financial analyst, 'what is the market?' So you have to decide for what indication the drug should be developed at what dosage, what will be the price of the drug, and so on. This is totally stupid, but it's what you have to do." So the chemist or pharmacologist has to decide for what indication the drug will be developed. If the indication is not there, it must be created - in other words a disease suitable for the drug must be invented.

One of the many examples of this process was the development in the 1970s of Xanax (alprazolam), a very potent benzodiazepine, for panic disorder. According to Dr. David Sheehan at the Institute of Research and Psychiatry in Tampa, Florida, the marketing of this drug involved "a clear strategy" to take advantage of the medical profession's current confusion about the classification of anxiety disorders and (I quote:) "to create a perception that the drug had special and unique properties that would help it capture a market share of benzodiazepines and would displace diazepam from the top position... There was in fact nothing unique in this regard about Xanax... All the benzodiazepines were good for panic disorder." Nevertheless, Xanax was marketed by Upjohn with approval of the FDA (US Food & Drug Administration) in doses of up to 6mg (equivalent to 120mg of Valium).

Some vignettes provided by Dr. Sheehan give an insight into the rather cavalier way in which trials with alprazolam were conducted. There was no suitable animal model of panic disorder so it was decided to try it out on a small group of patients who had panic attacks. "It was dark; it was fall in Boston" said Dr. Sheehan. "I particularly remember two sisters who were so phobic of medication, especially that they might die of the medication at home, they they asked if they might take the medication in the unit so that I could rescue them if anything bad happened... So they took two alprazolam tablets in the waiting room, waited for 30 minutes and then felt ok and decided to take the subway home. I was still in my office when I got a phone call. It was the two sisters; one of them had got a phenomenal effect, was sedated and ataxic and had to be helped off the train and got home by her sister. They called me up and one sister said 'This is incredible, she's cured'. The sister who telephoned had experienced no effect at all."

"Another patient in this group, a dynamic executive type, phoned the next day and said 'Doc, I am lying here on the couch in my office'. "Oh my god, that's terrible", I replied. 'No Doc this is not terrible at all', he said, 'I haven't felt this good in 10 years, you have no idea what a relief this is. I feel so calm, I just don't feel any anxiety, it's really wonderful'.

"Then a further group of these patients in the study said 'Doc, this is amazing - there are so many panic patients out there in the world... the company that makes this is going to make a fortune... You should buy stock in this company - you won't have another opportunity like this."

History does not relate what happened to these patients if they continued to take Xanax long-term. But there is no doubt that Upjohn had a field day. Xanax duly overtook Valium as the most widely prescribed benzodiazepine. Xanax was dropped from the NHS limited list in 1985, but it is still widely prescribed in 4-6mg doses in the US and I get calls every week from people having long-term problems with this potent drug.

Alongside the development of Xanax, the confused psychiatrists were working on a new classification of anxiety disorders. Panic disorder became a new separate anxiety state in the new Diagnostic and Statistical Manual (DSM III) published by the American Psychiatric Association and at present anxiety, under a later DSM IV, is still split into separate categories which include panic disorder, agoraphobia, social phobia, other specific phobias and generalised anxiety disorder or GAD. But of course people with generalised anxiety get panics and develop agoraphobia and people with panics have generalised anxiety and other phobias. The inference of the new classification was that these separate disorders respond to different drugs, but in fact they merge together and they all respond to the same drugs include all the benzodiazepines and also to all the antidepressants including the old ones and the SSRIs like Prozac. If they all respond to the same drugs and the symptoms are common to all types, they clearly cannot be separate entities.

But of course you don't have to have anxiety to be prescribed a benzodiazepine. They have been prescribed for sports injuries, muscle spasms, premenstrual tension, exam nerves, depression, general malaise and much else. Because they make some people feel good at first, like the ladies on Xanax, these prescriptions tend to be continued long-term. I am sure everyone here knows how the long-term patients themselves - not the doctors - discovered that if you take benzodiazepines long-term you become dependent on them or, in common parlance, addicted.

How the dependence potential of the benzodiazepines was overlooked by doctors when it was clear that they could replace their predecessors such as the barbiturates is a matter for amazement and casts shame on the medical profession which claims to be scientifically based. Cross tolerance between different drugs, for instance between barbiturates and alcohol, was well understood at the time and clearly implied that if one drug could replace another it must have common characteristics and usually a common mode of action. In fact barbiturates and alcohol, like benzodiazepines, act on GABA receptors. The similarity between benzodiazepines and barbiturates was ignored (despite a few warning voices, including my own, which went unheard) and doctors were urged to prescribe benzodiazepines instead of barbiturates. They complied with such zeal that benzodiazepines became for a time the most commonly prescribed drugs in the world. Incidentally, they were helped by Roche who attacked barbiturates in order to sell their first benzodiazepines Librium and Valium.

The backlash came, as I have mentioned, when the patients themselves complained that the drugs were addictive, mainly because they got withdrawal symptoms if they tried to stop. Eventually, in the early 1980s controlled trials of such patients by Malcolm Lader, Peter Tyrer and others demonstrated beyond doubt that withdrawal symptoms from regular therapeutic doses of benzodiazepines were real and that they indicated physical dependence on the drugs. Eventually the medical profession accepted officially, on the grounds that they produced a withdrawal syndrome, that benzodiazepines were dependence-producing, i.e. addictive.

Not to be outdone, the drug companies rapidly produced a series of drugs that were not chemically benzodiazepines but produced the same effects. These were the Z-drugs zopiclone, zolpidem, zaleplon and now eszopiclone (Lunesta). They were marketed as sleeping pills but in fact have similar properties to benzodiazepines. They act on GABA receptors, cause dependence and, like benzodiazepines, cause a withdrawal syndrome.

With declining popularity of the benzodiazepines came a renewed interest in antidepressant drugs which led eventually to the SSRIs (selective serotonin reuptake inhibitors) - that we have today. It started as a deliberate tactic to displace benzodiazepines. Drug companies sponsored large international symposia attended by 100s, sometimes 1000s, of physicians where speakers warned of the harm benzodiazepines were doing because of dependence and suggested that serotonergic drugs would work not only for depression but were also good anti-panic drugs and good in generalised anxiety, social phobia and even in post-traumatic stress disorder (PTSD) and obsessive compulsive disorder (OCD).

The first serotonergic drug was a flop, but then Prozac came on the scene and was an immense success. So successful was Prozac that five different drug companies vied to corner some of the market with me-too SSRIs that are cheaper to make. Dr. Sulser of Vanderbilt University noted that if a drug company could get just 20% of the Prozac market it could make 400-500 million dollars a year with very little investment in research and development. He added sadly: "I don't know how to solve this dilemma in an industrial society that is so heavily driven by profits". The outcome of this is that we now have 5 other SSRIs in addition to Prozac: fluvoxamine, paroxetine, sertraline, citalopram and the newest escitalopram. According to David Healy, the effective incidence of depression, OCD, social phobia, and PTSD has increased a thousand-fold worldwide since 1980.

But there is a sting in the tail of this story too. After a while it became apparent from patients' experiences that SSRIs, like benzodiazepines, produced a withdrawal syndrome when they were stopped - in fact the withdrawal reaction is quite similar to benzodiazepine withdrawal. This is another example of surprising ignorance and lack of thought on the part of physicians. It was known that the older antidepressants, tricyclics and MAOIs (which were also beneficial for both depression and anxiety disorders) produced a withdrawal reaction - this had been well described by Peter Tyrer as long ago as 1984. Yet the doctors appeared to be taken by surprise by SSRI withdrawal reactions. Furthermore, doctors were not good at managing either benzodiazepine or SSRI withdrawal. It is no wonder that the Bristol project became involved with antidepressants. Here at last patients could find someone who listened to them.

As I mentioned before, the benzodiazepines had been accepted as being dependence-producing, or addictive, on the basis of their withdrawal effects. Now there were clear withdrawal effects from SSRIs. In a scramble to prove that SSRIs were not addictive, psychiatrists changed the definition of drug dependence. Criteria for substance dependence were altered in the 1994 DSM IV by the American Psychiatric Association. In this edition, withdrawal effects alone were not enough. A patient now also had to have evidence of tolerance, dosage escalation, continued use despite efforts to stop and other characteristics to qualify for dependence. And the withdrawal syndrome was replaced by the patronising euphemism "discontinuation reaction". As if a patient would think there was some subtle difference between "discontinuation" and "withdrawal".

I can't help feeling there is something Orwellian in these manipulations like the slogan in Animal Farm which started as "4 legs good; 2 legs bad" but when pigs started walking on their hind legs the slogan was changed to "2 legs good; 4 legs bad". Or the addition to another slogan "All animals (or withdrawal effects) are equal - but some (e.g. discontinuation effects) are more equal than others".

So where are we now, 50 years into the Era of Psychopharmacology? We still don't know the causes of mental diseases and we still don't know how or if the drugs work. The antidepressants appear to have relatively little effect on depression and are only marginally better than a placebo. The SSRIs, though they are safer, are no more efficacious than the older antidepressants, or than drugs which act on noradrenaline with little effect on serotonin. Bipolar depression (manic depression) used to be treated just with lithium; now bipolar patients usually take at least 5 drugs - lithium, an antidepressant, an antipsychotic, an anticonvulsant and usually a benzodiazepine. This is supposed to keep their mood stable, but the course and prognosis of bipolar depression has actually not changed since the patients only took lithium. The new antipsychotics such as clozapine are not much more effective than the older drugs. The over-prescription of benzodiazepines has led to them entering the drug scene. There is now a growing problem of benzodiazepine abuse which carries all the risks of drug abuse in general, including, for injectors, hepatitis C, HIV infection and AIDS. Antidepressants are also abused by people taking illicit drugs including young people taking ecstasy or amphetamines.

It is clear that money, not science, is driving pharmacology. Yet the drug companies are the only ones with the funds to conduct drug trials and doctors persist in the belief that a drug will be found that is the answer to each mental illness. Meanwhile, the few projects like this are left to pick up the pieces left by drug companies and doctors.

Well - this is not meant to be a diatribe against drug companies, drugs or doctors. It is simply a statement of some published facts which attempts to highlight some failures in the whole system under which we have insidiously come to operate.

So in conclusion, what can we do? I have only a few suggestions.

One measure we could take is to separate the pharmaceutical industry from health care policies. This year the House of Commons Health Committee issued a report entitled "The Influence of the Pharmaceutical Industry". The conclusions were damning. The report states: "The Department of Health has for too long assumed that the interests of health and the [pharmaceutical] industry are one". In practice the industry affects every level of health care provision from the licensing of new drugs, to the promotion of drugs to prescriber and patient groups, to the prescription of new medicines and the compilation of clinical guidelines. The Committee cited evidence that industry-sponsored clinical trials are specifically designed to show new drugs in the best light, that negative trial results and adverse drug reactions are suppressed (as with heart complications from Vioxx and suicides with SSRIs), and that selective publication strategies and ghost writing of articles are common. The crux of the problem is that the Department of Health sponsors both the drug industry and public health matters. The Committee recommended that the sponsorship of the industry should pass to the Department of Trade and Industry while the Department of Health Committee should concentrate solely on public health.

This seemed to be a hopeful development but the government's response was to ignore this recommendation the medical profession should take much responsibility for allowing the present situation to arise. They have been guilty of decades of thoughtless prescribing which persists for benzodiazepines despite national and international guidelines recommending that benzodiazepines are indicated for short-term use (2-4 weeks) only. Therefore we need to increase our efforts to train medical personnel better in more careful prescribing and also in the management of withdrawal in patients who have already become dependent on benzodiazepines. Arguably we should perhaps train more clinical psychologists to improve non-drug or psychological therapies, particularly for anxiety disorders and depression.

Secondly, we also need to train doctors and nurses and drug company personnel to listen to patients more. Listening to patients seems to be a lost art. In the present system, doctors do not have enough time with 10-20 minute appointments and are more influenced by results from high-powered investigations than by what patients say. Many are overworked by the need to keep up with government targets. Nurses are too few and have too many rules to abide by. In a recent case, nurses in a busy orthopaedic ward failed to notice that an old lady was blind; and an old man with asthma in a resuscitation ward couldn't talk intelligibly and the nurses failed to notice that it was because he hadn't got his false teeth with him. Yet it was nurses who first noticed the psychological effects of the first major tranquilliser chlorpromazine (Largactil) and one of the first antidepressants, imipramine. And it was patients who first drew attention to withdrawal effects of benzodiazepines and SSRIs.

Under the present NHS system there are more hospital administrators than there are nurses and more managers than there are physicians or surgeons. There is little communication between all these different supposed health care workers. Where are the "joined up" policies the government is always recommending? It seems that it is only in projects like this that people actually listen to individuals.

In addition, perhaps we should turn our attention beyond the idea of drugs as cures for mental disease and look more in our research towards causes and prevention. These days it is very hard to get a grant in universities, either from independent bodies like the MRC or from drug companies, for research which explores new and original ideas and does not have an immediate application or clearly lead to a defined or possibly lucrative outcome. Yet it is basic research that leads to scientific breakthroughs.

Finally, the public, that is all of us, should keep up the pressure on the authorities and should publicise what we see and hear every day. I don't think that the powers that be who set government targets about hospital turnover, waiting lists, NHS spending and who have appointed so many administrators, have any idea what goes on in the lives of individuals who, through failures of the whole present system, are driven outside the system to seek advice from poorly funded support groups and organisations like this one.

In the words of the anthropologist Margaret Mead: "Never doubt that a small group of thoughtful citizens can change the world. Indeed, it is the only thing that ever has." Well, at least we can keep on trying.

Bristol and District Tranquilliser Project - www.btpinfo.org.uk, Suite 5A, Westbury Court, Church Road, Westbury On Trym, Bristol, BS9 3EF - 0117 9500058 (office) and 0117 9500020 (helpline) open Monday to Thursday 10am to 3pm · Email bristranx@hotmail.com.

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