Big Pharma and the Manufacture of Madness

 Mental illness was once an esoteric affliction. Now we’re told that it’s a nearly universal experience. Witness the proliferation of psychoanalysis, psychotherapy, group therapy, counselling, behaviour therapy, rehab and pills. It seems that the few of us who aren’t in treatment are at least candidates for it. Transnational drug companies, known by the sobriquet, Big Pharma, offer drugs for almost every mental health problem and for an increasing number of non-problems. This article is a critical analysis of the mental illness industry with particular emphasis on the use of drugs that claim to be psychotherapeutic. Drug treatment is based upon archaic and fanciful views of brain function. Processes crucial to the effects of drugs on the brain cannot be measured; instead, they are inferred and, as such, are pseudo-scientific. Rather than alleviate mental illness, psychotherapeutic drugs appear to cause it. The mental health industry is manufacturing madness.

The first drugs to treat serious mental illness appeared in the 1950s. It is significant that they were all accidental discoveries. In one case, researchers developing a synthetic anti-histamine noted that the drug seemed to cause emotional indifference in normal subjects. This chance observation led to an informal test of the drug in schizophrenics. As a result, chlorpromazine became the first anti-psychotic drug and the first blockbuster hit for psychiatry. About the same time, a few other experimental drugs also turned out to have unexpected therapeutic effects in patients suffering from depression and bipolar disorder. Seemingly overnight, biological psychiatry was upon us.

The benefits of the early drugs were wildly exaggerated and the adverse effects downplayed or ignored. Rigorous evaluations of these drugs were rare, largely because they painted pictures that were bad for sales. Advocates maintained that these drugs would empty the mental hospitals and make mental illness a relic of the past. The truth is rather different, and altogether less rosy.

Following the commercial success of the discoveries of the 1950s, thousands of new drugs were developed. Despite claims of genuine improvements, independent analysis suggests that they are no more effective than their predecessors. The original drugs were sometimes better than placebos, but only just. Their “success” must be qualified in so many and such fundamental ways that it may be questioned whether it is success at all. There are no data supporting any broad-based effectiveness of these drugs. Moreover, although their side effects may be somewhat different from those of the originals, it is questionable whether the new drugs are better even in this limited respect. (Miyamoto et al., 2005) Doubts about safety and efficacy notwithstanding, for Big Pharma the new drugs are an attractive financial proposition. Anti-psychotic drugs are neck and neck with cholesterol drugs on the best-seller list and it’s a multi-billion-dollar business.

The Diagnostic and Statistical Manual of the American Psychiatric Association (DSM) is the bible of the mental health industry. However, its guidelines are certainly not graven in stone. Even the major diagnostic categories of the DSM are subject to continuing dispute. Mental disorders come and go with changes in fashion and the political landscape. The irrational desire of slaves to abscond was classified as the mental illness, drapetomania. Victimisation disorder was dropped from DSM since the term was demeaning to women. War neurosis, which was a reincarnation of combat fatigue, which was a reincarnation of shellshock, had disappeared from DSM until Vietnam veterans lobbied to get it reinstated as post-traumatic stress disorder. Addiction enjoyed a long run until it was replaced by substance use disorder, but the newer term has fallen into disrepute and committees are casting about for a replacement. Such semantic shuffling reflects the intrusion of politics into science. Whereas it has long been hoped that diagnostic difficulties would be circumvented by objective biological techniques, we will see below that this approach has failed badly. 

Given that drugs are now the first-line treatment for most mental disorders, one would expect the DSM to indicate which drugs should be used for a given diagnosis; it doesn’t. In marked contrast with mainstream medicine, psychiatric diagnosis does not entail any form of treatment. Physicians are left to prescribe drugs with little help apart from the ubiquitous Physicians’ Desk Reference (PDR) and brochures provided by the drug companies. The PDR has come in for considerable criticism since it relies on the drug companies for virtually all of its data. This situation presents a clear conflict of interest.

Drugs are frequently administered according to a principle called “shotgun pharmacology”. In this dubious practice, patients are given drug after drug in the hope that something will work. Dosage is cranked up and down in the search for therapeutic effects while trying to avoid nasty side effects. Difficult cases may be given scores of drugs, singly or in bewildering combinations. There are no guidelines for this other than guesswork, which is sometimes called “clinical intuition”. 

Big Pharma has been criticised for inventing new categories of mental illness purely to boost drug sales. From the howling mad to the slightly annoyed, there is a drug that can improve our lives, or so we are told. There’s no longer any need to suffer the slings and arrows of everyday life. The illusion of a life free from annoyance may be good for drug sales, but it is shoddy science and even worse public health. Absurd beliefs and dangerous practices persist and grow because Big Pharma exerts unparalleled control over scientific research. Others must discover the truth; Big Pharma can create it. 

The current obsession with therapy for everything and everyone undermines our sense of self-efficacy. We are told that without assistance we risk becoming psychological roadkill. Toddlers are counselled to ease them into the grim world of pre-school. Pre-death and, more intriguing, post-death counselling are also on offer. The world is becoming an outpatient. Health authorities are driving us crazy with alarms and irrational apprehension about nearly everything. 

Something is badly wrong with current approaches to mental health. Mental health in the community is deteriorating and has been for a long time. Many claim we are in the throes of an epidemic. Since the introduction of anti-psychotic drugs in the 1950s, the number of people disabled by mental illness has increased sixfold. (Whitaker, 2005) Since the introduction of Prozac in 1987, the number of people disabled by mental illness has doubled. 

Treatments ranging from old-fashioned talk therapy through to modern cognitive-behavioural therapy are typically little better than placebos. Almost any treatment produces some benefit in the short term. Alas, this therapeutic honeymoon is often short-lived. Therapy typically becomes less effective over time. More is not better; it is worse. Strange medicine.

Debriefing is common after psychological trauma. Given its widespread use and the fact that it may be required by law, one could be forgiven for assuming that it was effective. Sadly, this is not the case. This was shown in a comprehensive evaluation in the Cochrane Database of Systematic Reviews, which is the gold-standard of health care reviews. (Bisson and Wessely, 2003) Eleven separate trials showed no beneficial effects. In fact, after three to five months, debriefed subjects were 22 per cent more likely to suffer post-traumatic stress disorder. One study found that twelve months after the intervention the debriefed subjects were nearly three times more likely to suffer post-traumatic stress disorder. Authorities are under legal pressure to administer a “therapy” that is more likely to harm than to help. This is a bizarre misuse of public funds.

Various sorts of psychotherapy are legally mandated in many countries. The coercive nature of treatment is indicated by the fact that the alternative to therapy is usually incarceration. Mandated therapy is common with alcohol-related offences. This is in spite of the fact that a recent Cochrane review (Ferri et al., 2009) found no evidence that Alcoholics Anonymous (AA) and related forms of treatment reduced drinking or the likelihood of re-offending. Nor were there improvements in any other measures of functioning. It is astonishing that such a discredited treatment should be used at all, let alone mandated. 

Diverse types of counselling are used for mental health problems. As with debriefing and other forms of psychotherapy, counselling may be mandated. Another Cochrane review compared the effects of counselling as opposed to simply seeing a general practitioner. (Bower and Rowland, 2006) Counselling improved symptoms in the short term but at longer durations of treatment the effect vanished. Significantly, the patients reported that they liked counselling even though it was ineffective. Everyone seems to appreciate a little attention. 

The explosive growth of pharmacotherapy partly reflects the poor results of traditional psychotherapy. Drugs are said to offer the promise of putting the vague and insubstantial material of mental health on a solid, scientific footing. In addition, psychotherapy is far more labour intensive than pharmacotherapy. In the time that a physician takes to talk to a patient, she can write several prescriptions. Further, having armed the patient with a prescription, she hardly ever needs to see the patient again. This approaches the commercial ideal of vending-machine psychiatry.

Rational intervention in the brain with drugs requires that we know how the brain works so that we can tweak its function to our advantage. The idea is to find out what is wrong in the brain of the mentally ill and use drugs to rectify the problem. At this point a major problem rears its head. Current knowledge of the brain is so sketchy and incomplete that hopes of being able to intervene rationally are ill-founded, delusional. It is a matter of numbers; numbers that are far beyond our abilities to imagine, let alone deal with. 

The brain contains about 100 billion nerve cells which interconnect at about 100 trillion specialised junctions called synapses. The latter figure is about the same as the estimated number of stars in the entire universe. The most important characteristics of nerve cells are that they are excitable and they can communicate their excitation to other cells. Understanding how nerve cells communicate is the heart of the problem. The difficulties here begin with the fact that individual nerve cells communicate with millions or even billions of other cells. The brain consists of networks of nerve cells within networks of nerve cells, within networks, and so on. Some networks are vast, consisting of billions of cells. Others may consist of only dozens. We have no idea as to how many networks there are, let alone how they work. Nor do we know if they are similar in different individuals, or if they remain stable over time. In fact, we don’t really even know how to identify a network. Networks are yet another theoretical concept awaiting verification. The brain is not a place to look for quick answers. The brain may be beyond our ability to comprehend, now or ever. There is great reluctance even to acknowledge this as a possibility.

Progress in neuroscience is limited by the extremely crude tools that are available. The crudeness results from the small size of nerve cells and the fact that they are crammed together with an average density of about 50,000 in the volume of a pinhead. Further, each nerve cell may have hundreds or even thousands of filamentous extensions, rather like the branches and roots of a tree. The extensions of adjacent and remote cells are intertwined so completely that it is impossible to dissect individual cells from the tangle. Experimenters can’t remove living human nerve cells and investigate them in test tubes. Even if they could, it is unlikely that an isolated cell would behave in anything like the way it does in its normal community of billions of other cells. Thus, most of what we know is inferred from bits of nerve tissue investigated in test tubes. The scientific method absolutely requires measurable evidence. However, in the brain most processes cannot be measured. Lacking direct and measurable evidence, neuroscience relies instead on inference. Thus the science in neuroscience is often difficult to discern. The essence of the brain is its startling dynamic properties, whereas current cellular-level techniques can only investigate tissue that is static, dead. 

There are techniques for investigating the living brain, but they are not the boon they are made out to be. Functional magnetic resonance imaging (fMRI) permits the observation of the activity of the living human brain. Enthusiasts claim that fMRI allows the visualisation of thoughts, emotions, perhaps even consciousness and mind. Whereas brain imaging provides an abundance of information, it is uncertain whether this information is useful or meaningful. The popular press continues to rhapsodise breakthroughs lurking just around the next set of brain scans. As with the wonder drugs of the neurochemical revolution, the miracles of brain imaging have failed to appear. How can we have been so thoroughly deceived?

Much too much has been expected of brain imaging. First, brain imaging does not even measure the activity of nerve cells. Instead, it measures blood flow and glucose utilisation. The images indicate the energy consumption of aggregations of billions of cells, countless networks and bits of networks. The imaging may tell us how much energy the tissue is using, but not what that energy use means. Whether changes in metabolic activity indicate increased, decreased or unchanged functional activity of nerve cells is unknown. (Barber, 2008) 

In order for the data to have adequate statistical power, brain images of numerous individuals are combined and averaged. The result is certainly information, but what it means is anybody’s guess. Trying to infer function from brain images is not science, it is haruspication. A simple conversation remains by far the best way to get psychological information.

In spite of over a century of research, we know little about how various functions are organised in the brain. Memory and cognition remain as mysterious as when our species first discovered that we had brains. It is commonly believed that little chunks of the brain control various functions in what amounts to a functional mosaic. However, this is wishful thinking. It has only the advantage that it lends itself nicely to illustration. There is no reason why functionality could not be scattered diffusely throughout the brain, in which case there would be no recognisable scheme. 

As with the functional organisation of the brain, the problem of cell-to-cell communication remains largely unaddressed. In some cases, nerve cells communicate via chemicals released at synapses. There may be a hundred or more different neurotransmitter chemicals. Cells may also communicate by electrical signals transmitted directly from one cell to another. For generations, chemical and electrical signals at the synapse were thought to be the only way nerve cells communicated. This has recently changed dramatically and this change has enormous implications. 

The puzzle of communication between nerve cells is made vastly more complex by the recent discovery of new types of cell-to-cell communication that do not use the traditional synaptic mechanisms. They take place mainly in the fluid outside cells and are referred to as volume transmission. Volume transmission allows direct cell-to-cell exchange of genetic information, viruses, bacteria, proteins, neurotransmitters, gases and who knows what else. These remarkably diverse signals are communicated between cells in exotic ways, such as tunnelling nanotubes which are direct physical conduits between cells. 

The discovery of volume transmission is creating a whole new branch of neurophysiology. How it interacts with the “old” neurophysiology can only be guessed at. As with classical synaptic transmission, it has yet to be demonstrated that volume transmission occurs in the human brain, let alone is important. Once again, we must rely on inference since we can’t measure the processes in question. This is a poor substitute for the scientific method.

The molecular approach promised simplification; instead, it has opened unfathomable vistas of brain-shredding hypercomplexity. (Agnati et al., 2010) As Dorothy said to her dog in The Wizard of Oz: “Toto, I’ve a feeling we’re not in Kansas any more ...” The scientific landscape has changed suddenly and dramatically. Kansas isn’t even on the map.

The discovery of volume transmission has enormous implications for psychotherapeutic drugs. Until now, speculation as to how these drugs work has centred on neurotransmitters and their actions at synapses. This seems to have been a dead end. Now it seems that synaptic transmission is only one of many very different forms of neural communication. Volume transmission suggests a dizzying array of new ways that drugs may affect nerve cells. However, at the moment there are no data on how drugs affect volume transmission since, once again, we can’t measure the relevant processes.

Methodological problems preclude a quick resolution to the problem of understanding communication between nerve cells. Ideally, we would begin by studying communication between two human nerve cells. We would excite one cell and see if this excitation was communicated to the next cell. However, as explained above, it is impossible to study even one living human nerve cell, let alone a pair of cells, let alone a pair along with thousands of synapses and other communication channels. This is a crushing weakness since even the simplest types of human behaviour probably involve millions of nerve cells and billions of synapses. 

The complexity and miniaturisation in the human brain mean that we must rely on data from simple invertebrates such as the giant squid. Some invertebrate nerve cells are large enough to permit direct investigations that are not possible in human tissue. Such preparations show the release of transmitter chemicals and it is possible that they could also reveal aspects of volume transmission. However, we can only infer that similar processes occur in the human brain since we can’t actually measure them. Yet, even if these processes do operate in the human brain, we have no way of telling if they are functionally significant, let alone important. 

Mental illness is commonly portrayed as a problem in brain chemistry for which the treatment of choice is drugs. The initial assumption here is that psychopathology is caused by a biochemical pathology, usually a neurochemical imbalance. The ancillary assumption is that certain drugs normalise the imbalance, thereby restoring normal behaviour. In order to make this a scientific statement as opposed to pseudo-scientific speculation, it is crucial to demonstrate that neurochemical imbalances exist and that they cause psychopathology. Our inability to measure the relevant synaptic events means that these most elementary demonstrations have not been made. Decades of intensive investigation have failed to uncover any problem in the brain which could plausibly cause mental illness. 

Not content with selling drugs which are of dubious effectiveness for their prescribed use, drug companies have been accused of encouraging the use of these drugs for conditions that are not approved. For example, anti-schizophrenic drugs are frequently prescribed for depression, dementia, post-traumatic stress disorder and other problems. Unauthorised use is a matter of concern since these drugs can be very dangerous. Their use is associated with risks which range from minor nuisances through to sudden fatal complications. Mortality in users of these drugs is much higher than in non-users. In addition, drugs often have severe psychological side effects and have been associated with greatly increased incidence of suicide. They produce long-term, even permanent, changes in the brain. (Harrison, 1999) 

Many anti-psychotic drugs block the effects of the neurotransmitter dopamine in the brain. This has led to speculation that schizophrenia is caused by too much brain dopamine. Note that excessive dopamine activity has never been measured, it is merely inferred. There is no direct evidence which supports the dopamine hypothesis and there is a lot of evidence which is glaringly inconsistent with it. The notion that schizophrenia represents the effects of too much dopamine in the brain remains a theory which persists not because of the evidence, but in spite of it. (Siebert, 1999) 

The serotonin hypothesis of depression parallels the dopamine hypothesis of schizophrenia. This theory is based on observations that drugs which enhance transmission in nerve cells using serotonin may have beneficial effects on depression. The logic is that low serotonin levels lead to neural dysfunction and this causes depression. As with the putative dopamine excess in schizophrenia, a serotonin deficiency in depression is inferred. It has never been measured. (Leventhal and Antonuccio, 2009) 

No neurochemical pathology has been convincingly implicated as a cause of mental illness. Thus, it is absurd to suggest that drugs be used to normalise a non-existent pathology. Instead, it is clear that psychotherapeutic drugs induce neurochemical pathologies. Drugs are chemical spanners tossed into the delicate machinery of the brain. It is not surprising that people taking these drugs suffer serious side effects. It would be miraculous if untoward effects did not occur following a massive and crude intervention in the chemistry of the brain.

Neurochemicals and other signalling agents in the brain affect transmission in billions of nerve cells in countless ways which change irregularly over time. It is irrational to expect any drug to produce anything vaguely resembling the myriad co-ordinated symphonies of activity in the normal brain. It would be like expecting a drug to suddenly allow you to speak a foreign language or perform calisthenics on a tightrope. It would be lovely if a drug could overcome the genetic predispositions and a lifetime of experience which may make certain people crazy, but drugs don’t work like that. All they do is induce their own forms of pathology. The miracle in this is that occasionally drugs do have genuine therapeutic effects. This raises the question, how?

It has long been known that convulsions caused by camphor, insulin and a variety of drugs may have therapeutic effects on certain forms of mental illness. (Gazdag et al., 2009) Safety considerations have led to these treatments being replaced by electroconvulsive shock. Although relatively safe, electroconvulsive shock is a sledgehammer treatment which massively disrupts brain function. Even though stigmatised by Hollywood as a form of torture, it remains one of the most effective treatments for serious psychopathology. It is effective for depression, bipolar disorder, schizophrenia and other problems as well. It’s the Swiss Army knife of mental health treatments. The fact that such a blunderbuss treatment seems to be as good as it gets speaks volumes for the competition. 

People with mental health problems often get better merely with the passage of time. This natural healing process is called spontaneous recovery. Unfortunately, psychotherapeutic drugs may impair spontaneous recovery as well as cause long-term, even permanent, changes in the brain. (Siebert, 1999) Such treatment-induced changes could well be disastrous in the mentally ill. The dark side of psychotherapeutic drugs keeps getting darker.

Problems with drinking, gambling and drugs are all characterised by high rates of spontaneous recovery. The therapy industry overlooks the fact that most people who deal successfully with these problems do so on their own. Assistance from therapeutic communities like AA, or from psychotherapeutic drugs, decreases success rates. Current practices are counterproductive in still another way. Diagnosing someone with a serious problem, particularly when it’s said to be a brain problem, is a major psychological challenge. Just becoming a patient reinforces beliefs about the gravity of their situation and this is likely to lead to adverse outcomes. Psychiatric diagnoses tend to become self-fulfilling prophecies.

Billions are spent on nicotine replacement therapy in the belief that it makes it easier to quit smoking. This belief is ill-founded. A recent review of the literature bodes ill for the conventional wisdom of smoking cessation. (Chapman and MacKenzie, 2010) Those who successfully quit smoking simply stop. Those who get into the therapy system, whether by joining support groups or using nicotine replacement or other drugs, are much more likely to resume smoking than those who are left to their own devices. Once again, therapy hurts. 

The present analysis suggests that it is absurd to try to solve problems of mental health by making vague and unsubstantiated reference to the most complex and ill-understood organ in the universe. Neuroscience is plagued with conceptual and measurement problems that are not just daunting, but overwhelming. Nor are these problems likely to be rectified soon, perhaps ever. Neuroscience has failed to produce any breakthrough treatments. Worse, people treated with psychotherapeutic drugs have a poorer long-term prognosis than those who are left alone. They are more likely to be re-hospitalised and to become chronically ill. Drugs may also result in the appearance of new and more severe symptoms. 

Big Pharma is manufacturing madness. Rather than being a part of the answer to mental illness, drugs have become a major part of the problem. Tinkering with the brain has enormous possibilities to harm which we are just beginning to appreciate. Pretending otherwise is delusional; it is unhealthy. 

Dr Dale M. Atrens is Reader Emeritus in Psychobiology at the University of Sydney. 

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