Chapter 1. Medicines out of control?

This book tells a story that reveals some of the workings of medicine and medicines and their impact on personal, community and global health. The story is rooted in general practice and psychiatry and revolves around the main drugs prescribed for anxiety, insomnia, depression and related mental distress.

The action runs from the mid-19th century to the foreseeable future. Over the years, the drugs in the story change and different ideas and actors hold sway. But the same patterns of behaviour emerge and the outcome is much the same. Users consistently emerge as losers - by no means universally, but always on a grand scale.

Both literally and metaphorically, all the drugs in this story cause some degree of dependence. People get hooked not only on the drugs, but also on the idea of drugs as solutions for mental distress. Subtle interplays of power and dependence nurture this process of medicalisation, as if through a ‘Conspiracy of Goodwill’.

At the heart of medicine is this delicate but mighty interdependency, based on unfathomable mixtures of fear, inspiration, trust, hope and dreams. The basis of the Conspiracy of Goodwill is the fervent wish of all parties (health professionals, government, manufacturers and users) that drugs should be safe and effective, and never anything less. The downside is the risk of insatiable demand, unmet need, disappointed expectations and often far-fetched denial when things go wrong.

The case history
The story that unfolds in the first three chapters spans the last 150 years. Throughout this time, doctors have prescribed an uninterrupted succession of drugs for mental distress, each time believing they were not addictive and that patients had only themselves to blame if addiction set in. A pattern emerged - it continues to this day - in which one drug after another, officially proclaimed as not addictive, has later proved to be just that.

Between the 1860s and 1960s, doctors treated mental distress by prescribing alcohol and opium, then morphine, heroin and cocaine. Later came chloral, bromides, barbiturates and many similar drugs. Chapter 2 explains how each of these drugs, bar alcohol, was also used to treat addiction - and later found to cause it too.

The story in Chapter 3 begins around 1960, as the reality began to sink in - that ‘iatrogenic’ dependence (caused by medical intervention) had become widespread and damaging. This realisation spurred a wholesale switch to a new class of drugs - ‘tranquillisers’, like Valium, Librium, Ativan, Xanax and Halcion. It took over 20 years to establish that they too were addictive and another decade to address the problem. Until the 1980s, the risk of becoming addicted to a tranquilliser was officially described as remote, but the opposite again proved true.

Present day remedies for anxiety, depression and mental distress date from the 1990s. By this time, tranquillisers had been internationally ‘scheduled’ as drugs of dependence and prescribing was restricted to the short-term; their use slowly declined. Chapter 4 tells how doctors then began to prescribe a new class of ‘antidepressants’ instead - for longer and in larger doses than before. Prozac started this trend; it spawned other ‘blockbusters’ - Paxil/Seroxat, Zoloft/Lustral, Celexa/ Cipramil and Efexor/Effexor - all still with us today.

This time round, the risk of addiction was denied, in effect by burying the goalposts. The drugs themselves were promoted as if they were essential supplements, badly needed to help to restore levels of a key, mood-regulating, brain chemical: serotonin. At the same time, the authorities formally redefined the concept of dependence to ensure that drug prescribing couldn’t possibly cause it. This meant that most doctors recognised ‘dependence’ only in the context of uncontrolled drug use, something close to abuse. That explains why, today, dependence on antidepressants seems painfully obvious to many users, though the problem doesn’t officially exist.

Crisis unfolding
Officially there is still no antidepressant ‘dependence’ problem, but a crisis is now clearly looming. The turning point can be quite precisely dated - it came with a heavy flurry of revelations between October 2002 and the summer of 2003. If there was a pivotal moment, it was probably 25 June - when GlaxoSmithKline quietly published a small-print amendment to the prescribing instructions for Seroxat. The company had upwardly revised its 2002 estimate of the risk of withdrawal reactions - from 0.2% to 25%. The official risk of Seroxat/Paxil withdrawal problems had increased overnight from 1 in 500 to one in four.

This 125-fold increase signalled that ‘science’ was catching up with common sense - and that sets the scene for the later chapters in this book. The case history gives way to a critical analysis of how and why the crisis arose, and its wider implications. Two related questions become central:

What does it reveal about the quality and direction of medical science, and the reliability of the medicines control system that - in spite of all the fuss and the precedents - it took over a decade to identify a prominent and potentially hazardous adverse drug reaction that affects one user in every four?

When the Internet was groaning with evidence of the problem in store, why were users’ comments and complaints ignored? This is a good moment in history to be asking that question: the more this antidepressant crisis unfolds, the more it seems that narrative evidence from users can never credibly be ignored again.

The story that started to unfold as a crisis in late 2002 began in earnest in the mid-1990s: the growth of the Internet had begun to change history, as antidepressant users began to compare notes and exchange ideas. Vivid and revealing accounts of serious withdrawal and other problems began to surface, then dedicated websites began to appear, all discussing the same thing. Users were hooked once again.

Of science and common sense
During the five-year window, 1998 to 2002, the powers-that-be did all they could to deny the miserable realities that antidepressant users increasingly described. During this period, the authorities entrenched their position; they went on digging and made the hole deeper still.

Secrecy played a key part in maintaining the official denial: Chapter 5 outlines the extent and effect of it. Towards the end of this five-year window, the element of cover-up became more obvious as the weight of scientific evidence got stronger and as public protest grew. Legal actions increased the pressure, and then the media weighed in. Finally, two BBC-TV Panorama programmes (2002, 2003) tipped the balance, and the endgame began.

The events that unfolded thereafter - and led to consideration of a third Panorama programme scheduled for early 2004 - underline the value and power of user drug intelligence. These developments also challenge the relationship between ‘
narrative evidence’ and science - the orthodox view that ‘science’ might be debased and compromised by patients’ views.

The present day model of medicines control, regards ‘science’ as the gold standard, and narrative as a base metal. But what should be driving medicine - the quest for alloyed knowledge, or something closer to shared understanding of sense and meaning? Make up your own mind on the basis of the user intelligence that emerged from 1,370 emails sent in response to the Panorama programme, ‘Secrets of Seroxat’ (BBC-TV, October 2002).

Our point is that science in medicine is a means to an end - the attainment of health and well-being. Science at its best is glorious, the cleanest known method of producing knowledge. But it is far from being the only way of distinguishing between appearance and reality, and does not in itself produce solutions or outputs that are necessarily either desirable or ‘right’. Science plays a crucial part in medicine, but democratic impulse must lead the way:

“... science and technology can contribute to the improvement of health standards only if the people themselves become full partners of the health-care providers in safeguarding and promoting health ... people have not only the right to participate individually and collectively in the planning and implementation of health care programmes, but also a duty to do so.” (WHO, 1983)

The analysis that proceeds from Chapter 5 develops this theme, in trying to explain the dynamics of the antidepressant story as it unfolds into a present-day drug crisis. With medicine now on the brink of designing life itself, the same question seems more urgent than before: why is this dependence problem happening over and over again?

The answers turn out to have much less to do with molecular performance than with human motivation and organisational behaviour. What decides drug safety and effectiveness, above all, is the performance of pharmaceutical companies, government agencies and professional institutions - and the relationships between them and with users. So how did this powerful triumvirate of conspirators contribute to the health dependencies of today?

Role of the Pharmas
Central in the analysis is the role of the Pharmas, the handful of giant, mostly US-based companies that dominate international drug trade. The Pharmas’ behaviour has been widely attributed to simple greed, but the underlying problem is that they have become theoretically unsustainable - no longer able to compete and grow by inventing new drugs that improve on the old. Strange at it may seem, the Pharmas are in crisis, staring down gun barrels, driven by uncertainty about their ability to survive.

Chapter 6 explains how the Pharmas became so huge that they could hope to survive only by rapidly creating mass markets for ‘blockbuster’ and ‘lifestyle’ drugs. The advent of Prozac and related antidepressants heralded an era in which drug innovation gave way to intensive drug marketing: this was the only way the Pharmas could secure the return on investment they needed to be able to operate on their scale. Part of the problem is to do with the Pharmas’ sheer size - ‘institutional obesity’ one might say - and by repeatedly merging, the Pharmas are getting bigger all the time.

This new and imperative emphasis on marketing involves relentless demonstrations of the triumph of benefit over risk, and the promotion of drugs for much more than they are worth. In this case, it also meant that the Pharmas tackled problems by challenging perceptions of risk and by ignoring or denying evidence of harm. In so doing, they systematically exploited the dependencies of governments and the medical establishment. There was little resistance, partly because the Pharmas were also dependent on them.

In the last quarter of the 20th century, commerce took over the reins of medicine and began to steer health towards trade. The Pharmas carefully arranged the tests and trials of their drugs; they came to dominate medical education and communication, and they sponsored more and more. From behind the scenes, the Pharmas orchestrated the widespread promotion of their products and views, through the placement and advancement of the experts and leaders they chose. In time, the imperatives of trade and the impact of commercial messages became overwhelming. “Just how tainted has medicine become?” asked a Lancet editorial (2002). The answer was, “heavily and damagingly so”.

Commercial sponsorship both sustained and undermined the reputation and independence of political, professional and academic institutions, drug regulatory systems, even patient organisations and the World Health Organization. Through relentless lobbying, marketing, promises and threats, the Pharmas came to excel in letting others get their own way. Along the way, they began to change the face of medicine, promoting drugs directly to patients, and going to ever-greater lengths to inform people about the extent of their need.

Medicalisation and ‘disease awareness’
The Pharmas’ determination to expand markets led to intense pressure on national governments to relax the laws that prevented them from promoting their products directly to consumers. In 1997, the US Food & Drug Administration (FDA) finally gave way, introducing new rules for ‘Direct-To-Consumer Advertising’ (DTCA); they allowed Prozac and other medicines to be widely advertised, even on TV.

This hugely increased the demand for antidepressant and other drugs, helping to satisfy the considerable US appetite for health and pharmacological solutions. Even in the face of global health calamity, the US leads the world in ‘disease awareness’ and concern about unmet medical need. America officially reveres 170 official ‘Health Observances’, including 74 ‘awareness months’ and 64 ‘awareness weeks’, each year.

Direct-To-Consumer Advertising or promotion (DTCA) helped the Pharmas both to extend and segment markets, allowing them to repeatedly relaunch their antidepressants for an expanding range of states of mind. In this way, the new antidepressants came to dominate the market for stress and anxiety: Valium out, Prozac in. By the early 21st century, prescribing levels for antidepressants in England had reached those of the tranquillisers at their peak.

Chapter 7 describes how the Pharmas applied pressure on other countries to get them to allow DTCA. The narrative explains in some detail how the UK and European governments responded to this pressure, in the face of conflict between trade and health needs. DTCA led to an explosive growth in the market, producing handsome returns on investment - but that translated as hyperinflationary growth in the drugs bill.

The battle for DTCA in Europe became most intense between 2000 and 2003. The way in which it unfolded revealed the workings of democracy at its worst and best. Much more attention was paid to patients’ views - but their views were increasingly orchestrated by marketing departments, public relations agencies and Pharma-sponsored patient organisations.

Government regulation of medicines
By the 21st century, global standards for drug regulation prevailed; they mainly reflected the values of the major drug-producing nations, and notably the US. Trade and health imperatives increasingly came into conflict, as market forces, national interests and political pressures led the way.

From the early 1990s, nations began to compete among themselves in earnest, to develop partnerships with the Pharmas, to attract investment and help to share the wealth. This naturally affected the style of drug control, as did the trend to get the Pharmas to pay for it. By 2000, all major industrial nations paid for drug regulation from the fees the Pharmas paid governments for the licensing of their drugs.

This case history touches on the role of conflicts of interest, endemic secrecy and political, economic and bureaucratic pressures as factors that helped to build the dependence problem. However, the regulatory failure to see and contain the problem can be also traced to the design of the regulatory process itself - in particular to the emphasis on pre-marketing rather than post-marketing drug evaluation.

Drug regulation has traditionally focused on scrutiny of company-sponsored clinical trials that are performed before drugs come to market. There is much less emphasis on monitoring what happens when drugs are used in practice. But pre-marketing trials often have major limitations and may leave quite basic questions unanswered. Many of the drugs in this case history, for example, were first marketed at a dosage that later proved too high - a problem compounded by the tendency to define the recommended dose on the basis that ‘one-size-fits-all’. None of the drugs in this story could have been safely prescribed in that way; indeed about half of all Prozac users may still get up to four times the dose they seem to need.

Chapter 8 contrasts the pattern of antidepressant safety regulation in the US and UK. The US FDA had the theoretical advantage of huge resources; it also had in place a system for user reporting of adverse drug reactions (ADRs). However, the FDA relies rigorously on the evidence from pre-marketing clinical trials, treating it rather like legal precedent. Because the US regulators require new and strictly ‘scientific’ data to supplant pre-marketing evidence, ADR reports made little difference. They were regarded as ‘anecdotal’.

By contrast, the UK regulators operate what is widely regarded as one of the best ADR reporting systems in the world, relying on it as “the cornerstone of drug safety monitoring”. In this case, however, the system operated mainly to dignify the notion that no evidence of risk signals evidence of no risk. The UK drug regulators still eschew reports from patients, in the absence of ‘medical interpretation’. Ironically, but predictably, it was the wealth of evidence from antidepressant users that finally caused the regulators to confront the reality: a substantial risk of dependence, among other damaging drug effects. In particular, the risk of drug-induced violence and self-harm had been a worry for years.

Scientific standards
Science does not and cannot operate independently of economic, political and professional imperatives. The close links between academic and clinical experts with both the Pharmas and regulators underline this, and has much to do with the quality of medical science.

The antidepressant story suggests that precious little of what passes for science amounts to honest seeking after truth - indeed the editors of the leading US and UK medical journals believe that the scientific quality is generally rather bad. In this case, as in others, the science seemed mainly directed at pointing to marginal and notional drug advantages and to papering over the cracks. The emphasis on ‘new and improved’ and on discovery and innovation largely obscured the contribution that science might have made by revealing quite basic misunderstanding.

Chapter 9 reviews some of the techniques used in designing and interpreting clinical trials, to produce the desired results. This chapter also looks at clinical trial standards from the standpoint of patient safety. Almost all the evidence on this is secret, but one shining piece of data suggests that standards are nowhere near as high as people have been led to believe.

Good science in medicine is in short supply, but policing is mainly directed at the prosecution of isolated cases of outright fraud, rather than mainstream slipshod research. The quest for scientific integrity stops far short of encouraging individual conscience, commitment and initiative, let alone whistleblowers. Their fate gives evidence of the grip of orthodoxy in the Conspiracy of Goodwill.

The antidepressant story also reveals how a combination of scientific fundamentalism and triumphalism has obscured the importance of a range of vital human factors. The scientific community has lost sight of their importance, not only in the treatment of depression, but also in relation to its own behaviour. The influence of reward and punishment systems and pressures to conform and comply, evidently have a profound effect on the conduct of medical science and on perceptions of benefit and risk.

Iatrogenesis
Among other examples of medicalisation, this case history asks how far the damage done by medicines goes, beyond the direct harm of intervention. What does the antidepressant story reflect of what Ivan Illich called ‘social’ and ‘cultural’, iatrogenesis - implying loss of personal autonomy, reduced confidence in health and diminished opportunity for making sense of illness and disease?

Adverse drug reactions exemplify direct ‘iatrogenesis’ - harm from medical intervention. However, the first, faltering, credible estimates of the overall impact of ADRs on health only began to appear at the turn of the 21st century. Meanwhile, the indirect effects - the impact of medicalisation on the health of people and community - have barely been explored. Irrational belief in the goodness of medicines is contained through the Conspiracy of Goodwill.

Chapter 10 brings the story back to the unfolding of the antidepressant crisis. Much of this chapter details the findings of a unique analysis of the operation of the UK adverse drug reaction reporting system - based on a survey of over 1,500 (anonymised) ADR reports sent to the regulators by health professionals. These reports matched the Panorama sample of reports from users: both focused on the two main worries with the new antidepressants, and Seroxat (paroxetine) in particular. Along with the risk of withdrawal symptoms, there had for years been strong, nagging concerns about drug-induced violence and suicidal behaviour.

This analysis revealed this ADR reporting system to be “chaotic and misconceived”, ensnared by process and jargon, and starved of the resources and imagination needed to make it work. The combination of low levels and standards of reporting, flawed data processing, uncritical interpretation and lack of follow-up had a devastating effect on perceptions and understandings of benefit and risk. In spite of conducting several formal reviews, the regulators had systematically failed to follow-up even reports of suspected drug-induced suicide.

Beyond lack of scrutiny, closer inspection of the data revealed systematic burial of evidence of risk, notably by crunching numbers and mincing words. One striking feature of the antidepressant story - but it applies widely - was the difference between the words of patients who speak their minds, and the approved terminologies that left meanings far behind.

The 1990s saw ‘depression’ formally redefined as a serotonin-deficiency disease and the scourge of millions - a convenient and seductive, but deeply simplistic view. The term, drug ‘dependence’ was redefined, to propose that loss of personal autonomy could never arise in a therapeutic setting, but only within a few blocks of ‘Skid Row’. The ubiquitous term, ‘discontinuation symptoms’ - newspeak for withdrawal symptoms - implied that antidepressants carried no risk of dependence. Wishful thinking proposed ‘discontinuation symptoms’ as evidence of the effectiveness of vital remedies, important for reducing overwhelming risks. Then suicides became routinely described as ‘non-accidental overdose’; and the broad-spectrum term, ‘emotional lability’, was employed – as if to fail to distinguish between a drug-induced attempted suicide and an outburst of tears.

User reports of adverse reactions attempted to describe some human reality. Collectively, they were often more informative than the reports the regulators relied on.

Towards resolution
Chapter 11 anticipates the outcome and the limitations of a major UK government review of the risks of antidepressants. This was originally intended to last only a couple of months, but then the review committee found they had opened a can of worms. The review that was finally set up in the summer of 2003 is due to report in early 2004.

At the time of writing, there is even talk of the unthinkable - perhaps major prosecutions to come - but the terms of reference of the review seem to guarantee that its major output will be in the form of more prudent small-print warnings to promote safer drug use. It is already clear that the review will miss the wider point - the need for new management in medicines’ control, for a coherent policy on drug safety and for standards of public accountability that will sweep this dismal past away.

The antidepressant story is specifically about drugs that work on the mind, but it illustrates what seems to be happening with medicines of many kinds. All drugs go through the same mill. The same companies make them, and teach the same doctors what and how to prescribe. All medicines are tested, recommended, marketed and regulated in much the same way - and the same standards of science prevail.

To that extent, this story underlines some linkage between the two major crises in health: under- and over-consumption of drugs. Health inequalities and lack of access to essential drugs dominate the world order. At the same time, the US market exemplifies what is fast becoming a global trend: increasingly people are persuaded that health is the product of assiduous risk aversion, acute disease awareness and routine drug consumption.

What happens when everyone is constantly alerted to this threat or that affliction, and urged to screen body and mind for every sign of disease? Does it really promote personal responsibility, health awareness, empowerment and choice? Or does it help to make people feel ill and create burdens that no national health service can withstand?

Market-driven medicine seems now to have surpassed the point of diminishing health returns. If health is the desired outcome, can it really make sense to invest in drug innovation and consumption on the Pharmas’ terms? This story suggests no end of better alternatives - none more radical than the notion that medicine produces most health when conducted within a framework of honest science and decent human and democratic values.

The reality seems to be that community is the bedrock of individual health. Drug response, personal health and the ability to negotiate the trials of life all reflect your uniqueness as an individual. On the other hand, what you experience of the quality of medicine and medicines is overwhelmingly decided by factors beyond your control. In the end, personal health is largely predicted by the health and well-being of others, above all by their example, attitudes and behaviour. No one escapes if other people feel ill or are impoverished, desperate, miserable or insecure.

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