Ashton on SSRI 'discontinuation' and drug development, 2007

[Barbarannamated]

Posting this as new topic so it doesn't get buried. GREAT speech! I'm tring to find any published info on SSRI WITHDRAWAL by Dr. Ashton.

Note her explanation of the term 'discontinuation' vs. 'withdrawal'. Are we playing into the hands of the DSM by using 'discontinuation syndrome'? My answer is YES, we are.

 

Heather Ashton speaks on drug development and SSRI withdrawal ('discontinuation'), 2007

 

With the 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 from the market.

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 reaction when they were stopped. This is another example of the surprising ignorance on the part of the physicians. It was already known that the older antidepressants, tricyclics and MAOIs, produced a withdrawal syndrome which had been well described in 1984. Yet the doctors appeared to be taken by surprise by SSRI withdrawal effects. As 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 actually 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, dose 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".

 

THE ROLE OF THE PHARMACEUTICAL COMPANIES IN THE TREATMENT OF MENTAL ILL HEALTH

Mental Health North East (MHNE) AGM and Conference,

Bowburn Community Centre, Durham

 

Professor C Heather Ashton, DM, FRCP

May 18, 2007

 

I have been asked to talk about the role of pharmaceutical companies in the treatment of mental health. There is indeed an extraordinary entanglement between drug companies and the medical profession. On the one hand the drug industry develops new drugs and promotes drug use in order to make money. On the other hand the medical profession prescribes these drugs in order to help people. One might think that there would be a healthy symbiotic relationship between these two organisations. But sadly there is emerging evidence that this is not the case and that the relationship is especially unhealthy in the case of drugs used for mental ill health. This situation stems from faults on both sides, and also from government policy.

 

In the 1950s a whole host of psychotropic drugs - drugs that affect the mind - entered the medical scene. These included major tranquillisers such as chlorpromazine (Largactil), since developed into a range of antipsychotic drugs; antidepressants, tricyclics and monoamine oxidase inhibitors, now joined by the SSRIs such as Prozac; and 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 mental illnesses. Schizophrenics taking antipsychotics could be let out of hospital to live, apparently safely, 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.

 

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.

 

These naïve and simple hopes turned out to be false. 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 is as common as ever. It has become clear that the drugs do not cure any mental illness. They do control some symptoms but have little effect on the underlying processes. And, of course, the drugs carry their own disadvantages. But these same drugs have made billions of dollars for drug companies.

 

Following the new drug discoveries, there was a search 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. 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. A pharmacologist working for Sanofi Pharmaceuticals said: "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 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 it is the drug company chemist or pharmacologist who decides 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. 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 to create a perception that the drug (Xanax) had special and unique properties that would capture a market share of benzodiazepines that would displace diazepam (Valium) from the top position. There was in fact nothing unique in this regard about Xanax. All the benzodiazepines including Valium were good for panic attacks.

 

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). There was no animal model of panic disorder so it was decided to try it out in a rather cavalier fashion on a small group of patients who had panic attacks. "It was dark; it was fall in Boston" recalled Dr. Sheehan, a doctor carrying out the first trial. "I particularly remember two sisters who were so phobic of medication that they asked if they might take it in my 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 to get home. The second sister said "This is incredible, she's cured'". (She couldn't walk straight, but she was not panicking.)

 

"Another patient in this group, a dynamic executive type, phoned the next day and said to Dr. Sheehan: 'Doc, I am lying here on the couch in my office'. "Oh my god, that's terrible", he 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 (because of adverse effects), 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.

 

Meanwhile alongside the development of Xanax, the confused psychiatrists were working on a new classification of anxiety disorders. Panic disorder (invented by the makers of Xanax) became a new separate anxiety state in the new Diagnostic and Statistical Manual (DSM III) published by the American Psychiatric Association in which, incidentally, 60-100% of the panel members had financial ties to the drug companies and today anxiety is still split into separate categories which include panic disorder, agoraphobia, social phobia, other specific phobias and generalised anxiety disorder. 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 (opening a market opportunity for the drug companies), but in fact they merge together and they all respond to the same drugs including 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.

 

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. But the similarity between benzodiazepines and barbiturates was ignored and doctors were urged to prescribe benzodiazepines. They complied with such zeal that benzodiazepines became for a time the most commonly prescribed drugs in the world. They were greatly helped by Hoffman-La Roche who attacked barbiturates in order to sell their first benzodiazepines Librium and Valium.

 

The backlash came 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 in the UK demonstrated beyond doubt that withdrawal symptoms from regular therapeutic doses of benzodiazepines were real and that they indicated physical dependence on the drugs. Finally, 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 lead to dependence and, like benzodiazepines, cause a withdrawal syndrome. Yet 4-6 million of these are at present prescribed in the UK each year.

 

With the 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 from the market. 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).

 

Thus Prozac came on the scene and was so successful that five different drug companies vied to corner some of the market with "me-too" SSRIs that are cheaper to make. Calculations showed 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. The outcome of this is that we now have 5 other SSRIs in addition to Prozac including paroxetine, sertraline and others.

 

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 reaction when they were stopped. This is another example of the surprising ignorance on the part of the physicians. It was already known that the older antidepressants, tricyclics and MAOIs, produced a withdrawal syndrome which had been well described in 1984. Yet the doctors appeared to be taken by surprise by SSRI withdrawal effects. As 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 actually 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, dose 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 George Orwell's Animal Farm which started as "4 legs good; 2 legs bad" but when pigs started walking on their hind legs like men, 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 animals (e.g. pigs or discontinuation effects) are more equal than others".

So it seems that Big Pharma is slowly strangling the medical profession, like ivy growing up a tree, and forcing medical complicity with drug company aims, resulting in new definitions of dependence and even new classes of mental illness. How has the industry obtained this insidious stranglehold on the profession?One method is to sponsor drug trials which are published in high impact medical journals. These trials are very carefully designed. They appear to be properly controlled trials but the new drug is often compared to a drug or treatment known to be inferior, or against a non-equivalent dose of a competitor drug. Then only the favourable results are published. Negative results are suppressed, such as those recently showing the suicidal tendency with SSRIs. Positive results from the same trial are published in multiple journals, giving them added weight. Drug companies will often purchase thousands of reprints of an article, giving the journal a profit margin of 70%. According to Richard Smith, editor of the British Medical Journal for 25 years, an editor may face a "stark conflict of interest: publish a trial that will bring in $100,000 of profit, or fire an editor to meet the end-of-year budget." A second method is to woo doctors by funding conferences for academics at attractive resorts, upgrading their seats to business class on the plane, paying honoraria for talks, handing out free gifts and paying for expensive dinners. In 2005 Roche Products spent more than 71,000 Australian dollars on lavish dinners for 330 doctors at one symposium in Sydney. Doctors say that they are not influenced by such blandishments, but you can be sure that the companies would not go to such expense if it were not shown to be productive.

And then there are the drug reps who visit doctors in their offices. In the US drug firms employ around 100,000 reps at a cost of $5 billion/year. The tactics pay off - successful rep campaigns bring in more than $10 for every $1 spent.

The fourth method is by advertisement. There is abundant evidence that advertisement works. The more heavily advertised a drug the greater the sales, and the greater the number of prescriptions, compared to similar but less advertised drugs. More worryingly, the apparent incidence of the illness at which the drugs are aimed also increases. According to Professor David Healey, the effective incidence of depression, OCD, social phobia and PTSD has increased one thousand-fold worldwide since 1980. And now there is direct-to-consumer advertising, at least in America, which has increased the demand of patients to their doctors, who are often compliant with patients' wishes. Furthermore, prescription drugs can be obtained on the internet and some herbal products surreptitiously include prescription drugs.

A combination of drug company promotions and doctors' overprescribing has led to some tragic results, such as prescribed drugs entering the illicit drug scene. Nowadays most illicit drug abusers also take, and may inject, benzodiazepines - which can result in limb amputations, HIV infections and hepatitis C - among other complications.

It seems clear that money, not science, is driving pharmacology. Yet the drug companies are the only ones with the funds to conduct large drug trials and to develop new drugs which can, and have, saved many lives; and doctors persist in the belief that a drug will be found that is the answer to each mental illness. There appear to be failures in the whole system under which we have insidiously come to operate. What can be done about it?

One measure we could take is to separate the pharmaceutical industry from health care policies. In 2005 the House of Commons Health Committee issued a definitive 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 crux of the problem is that the Department of Health sponsors both the drug industry and public health matters. The Health Committee wisely recommended (among other things) that the sponsorship of the drug industry should pass to the Department of Trade and Industry while the Department of Health should concentrate solely on public health.

This seemed like a sensible and hopeful development but the government rejected this recommendation. So the same Department, indeed the same Minister, responsible for negotiating drug prices for the NHS is also responsible for ensuring that Health Service spending on drugs is sufficient to keep the UK drug industry profitable. Sadly, patients' welfare will remain vulnerable while government health policies and practice are dominated by the will of Big Pharma.

However, the medical profession should take much responsibility for allowing the present situation to arise. They have been too easily persuaded by the drug industry and have been guilty of decades of thoughtless prescribing. 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 dependent on benzodiazepines or SSRIs. We should perhaps train more clinical psychologists and counsellors to improve non-drug or psychological therapies, particularly for anxiety disorders and depression, and to improve social adjustment in schizophrenia.

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, GPs do not have enough time with 10-20 minute appointments (at which the patient is allowed to voice only one complaint) and doctors are more influenced by results from high-powered investigations and drug advertisements than by what patients say. Many are overworked by the need to keep up with government targets.

Nurses are too few and 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? There is a need for projects like this one to foster better communications between the different people involved in mental health care.

In addition, perhaps we should turn our attention beyond the idea of drugs as cures for mental illness 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 lucrative outcome. Yet it is basic research that leads to scientific breakthroughs. There have been no breakthroughs in mental health for 50 years.

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 from patients and health care workers. 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 voluntary organisations. I am sure that this organisation has the potential to improve mental health care in many spheres.

[Altostrata]

Very interesting account of the history of a coverup.

 

Correct, the term "discontinuation syndrome" was coined to make antidepressant withdrawal seem more benign than withdrawal.

 

The origin of antidepressant "discontinuation syndrome" is usually attributed as follows ( from http://en.wikipedia.org/wiki/SSRI_discontinuation_syndrome ):

 

In 1996, Eli Lilly and Company sponsored a symposium to address the increasing number of reports of patients who had difficult symptoms after going off their antidepressants:

 

By then it had become clear that drug-company estimates that at most a few percent of those who took antidepressants would have a hard time getting off were far too low. Jerrold Rosenbaum and Maurizio Fava, researchers at Massachusetts General Hospital, found that among people getting off antidepressants, anywhere from 20 percent to 80 percent (depending on the drug) suffered what was being called antidepressant withdrawal (but which, after the symposium, was renamed “discontinuation syndrome”).

(This is attributed to Bruce Stutz's 2007 article in the NYTimes, a secondary source.)

 

However, from a Pubmed search for "discontinuation syndrome," you can see the term was used in connection with antihypertensives since at least 1980 (Weber 1980) and applied to benzodiazepine withdrawal in 1988 (Miller 1998) and fluvoxamine withdrawal in 1993 (Black 1993).

 

It's possible that at the 1996 Lilly symposium, the attendants agreed to use "discontinuation syndrome" as an obfuscation. It becomes more commonly used in the antidepressant literature after that, by the usual suspects, i.e.:

J Clin Psychiatry. 1997;58 Suppl 7:5-10.

Serotonin reuptake inhibitor discontinuation syndrome: a hypothetical definition. Discontinuation Consensus panel.

Schatzberg AF, Haddad P, Kaplan EM, Lejoyeux M, Rosenbaum JF, Young AH, Zajecka J.

 

Source

 

Department of Psychiatry, Stanford University School of Medicine, Calif 94305, USA.

 

Abstract at http://www.ncbi.nlm.nih.gov/pubmed/9219487

 

Adverse events following discontinuation from serotonin reuptake inhibitors (SRIs) are being reported in the literature with increasing frequency; the frequency and severity of these symptoms appear to vary according to the half-life of the SRI, e.g., the incidence appears higher with the shorter half-life agents than with fluoxetine, which has an extended half-life. Yet, there have been no systematic studies of the phenomenon to date. Therefore, a group of experts convened in Phoenix, Arizona, to develop a clear description or definition of the phenomenon based on these reports. The SRI discontinuation syndrome, referred to as "withdrawal symptoms" in many anecdotal case reports, is distinctly different from the classic withdrawal syndrome associated with alcohol and barbiturates. Anti-depressants are not associated with dependence or drug-seeking behavior. SRI discontinuation symptoms tend to be short-lived and self-limiting, but can be troublesome. They may emerge when an SRI is abruptly discontinued, when doses are missed, and less frequently, during dosage reduction. In addition, the symptoms are not attributable to any other cause and can be reversed when the original agent is reinstituted, or one that is pharmacologically similar is substituted. SRI discontinuation symptoms, in most cases, may be minimized by slowly tapering antidepressant therapy, but there have been several case reports where symptoms occurred consistently even through repeated attempts to taper therapy. Physical symptoms include problems with balance, gastrointestinal and flu-like symptoms, and sensory and sleep disturbances. Psychological symptoms include anxiety and/or agitation, crying spells, and irritability. Further analyses of data bases and clinical studies are needed to define this proposed syndrome more clearly.

 

"Withdrawal syndrome" is more widely used in publications from Europe.