22nd August 2005
We have crossed swords in the past about the role of genes in behaviour, an area where it is all too easy to drift into a phoney "nature vs nurture" argument. This time I am glad that we are debating a subject that is not only intellectually intriguing but is also of enormous public health importance—the roots of disorders such as depression, bipolar disorder (what used to be called manic depression) and schizophrenia.
Although I have spent most of my career researching psychiatric genetics, it was reading the works of Sigmund Freud when I was a teenager that spurred me to become a psychiatrist. Freud, of course, believed that he had invented a new branch of science, psychoanalysis, and in the late 1960s this seemed more exciting than the science I was studying. And what particularly interested me were the writings of people who challenged the whole basis of orthodox psychiatry. I admired RD Laing and his followers, who argued that disorders such as schizophrenia were actually sane responses to a crazy society. I even had time for the more right-wing Thomas Szasz, who proposed that mental illness was a myth: there were no demonstrable brain abnormalities or lesions in most cases, he argued, so how could these be real diseases? It was only when I got to see psychiatric patients for myself that the light began to dawn. The people I saw were sick and suffering. If what they had was a myth, it was a myth of an astonishingly debilitating variety.
I also discovered that the treatments that worked were the ones that had a rational scientific basis and (to my initial horror) that Freudian analysis was not one of these. Some of my teachers regarded Freud not as a scientist at all but rather a purveyor of sometimes useful metaphors about mental life and the therapist-patient relationship. Over the years I came to realise that they were right. The real pioneer of effective "talking cures" was Ivan Pavlov, not Freud. Pavlov's discovery of classical conditioning and the subsequent discovery by others of "operant" (reward-based) conditioning paved the way for the development of behaviour therapy and later cognitive behaviour therapy (CBT), the two most strikingly successful types of treatment for mental disorders. CBT is not only based on sound scientific principles derived from experimental psychology, it also lends itself to scientific scrutiny. In randomised controlled trials where patients are allocated to either an active treatment—CBT—or a "dummy" treatment (like chatting to a therapist), CBT has consistently come out on top in the treatment of depression. And it has not stopped there. Therapies based on CBT are being developed and refined to treat phobias, obsessive compulsive disorder and even bipolar disorder and schizophrenic symptoms.
And what about medication? Effective antidepressants and anti-psychotic drugs had already been available for about a decade when I first studied psychiatry as a student. I was struck by how doctors and nurses who had worked with psychiatric patients before these drugs were introduced welcomed the dramatic impact that they had on previously untreatable conditions. There was an element of luck in the discovery of the new medications, but once their efficacy was established they began to provide a new window on the chemistry of the brain. The Nobel prize-winning Swedish scientist Arvid Carlson showed that all of the first-generation of antipsychotics blocked the action in the brain of the chemical messenger dopamine, providing new insights into the neurochemical basis of schizophrenia. It was also discovered that antidepressants increased the availability of one or both of two other chemical messengers in the brain: serotonin and noradrenaline. This new science of psychopharmacology has flourished since, and we are now witnessing a new generation of more selective antidepressants, safer antipsychotics and better mood stabilisers.
However, the two hottest fields in psychiatric research—brain imaging and molecular genetics—promise even more. Magnetic resonance imaging provides pictures of great clarity and detail of the living brain. It is possible to study not only the structure of the brain but also observe it in action and see specific parts "light up" when the subject performs intellectual tasks, feels emotions or experiences abnormal perceptions such as hallucinations. Experts can also observe the connections between different parts of the brain as messages flow between them. Such techniques are beginning to demonstrate not lesions but functional differences between the ill and the healthy, some of which are reversible by medication.
In genetics we have long known from twin and adoption studies that there is an inherited component to most psychiatric disorders, but the genes have been difficult to pin down, almost certainly because common disorders involve multiple genes in interplay with the environment. You have been critical of such evidence in the past and suspicious of concepts such as "heritability." I hope you will now agree that the picture is changed by the recent well-replicated discoveries of susceptibility genes associated with schizophrenia and depression. A final example: much work, including my own, has suggested that clinical depression is substantially heritable but that social "stressors," such as unpleasant events, also play a role. We now know that one of the relevant genes codes for the serotonin transporter, a protein that regulates the uptake of serotonin by brain cells. The gene exists in two common forms, causing either high or low activity. Recent studies show that depressive symptoms in the face of life stresses are more likely in those who have the low-activity form. Moreover, imaging studies show that a "fear centre" in the brain called the amygdala lights up more readily in response to frightening stimuli in those people with the low form.
Real advances have been made, and the pace is quickening. This is good news for those suffering from mental disorders, not only because a better understanding of neuropsychology and neurobiology means better treatments, but because deeper knowledge of causes must surely reduce the mystery and fear that surrounds mental illness.
Yours
Peter
Dear Peter
24th August 2005
Unlike you, I have neither the privilege nor responsibility of working with patients. I grew up with the belief that the prospect and potential of science was to understand and change the world. Trained as a biochemist, I left university convinced that the human brain was the last great mystery, and have spent the last 45 years exploring the molecular mechanisms involved in learning and memory in animals, using biochemical, pharmacological and genetic techniques, and more recently brain imaging in humans. So I am certainly not dismissive of the claims of genetics and neurochemistry to have something to say about the psychic distress you treat in the clinic.
Let me start by stating what I take as axiomatic, that to all psychic states there are corresponding brain states. Of course, when a person is depressed, manic or hallucinating, his or her brain processes will differ from those when that person is "normal." And of course, manipulating brain chemistry—especially the chemistry of the neurotransmitters that carry signals between nerve cells—can help to alleviate such symptoms, as can talking therapies such as those you describe. Indeed one of the most interesting experiments I ever did was to study a group of depressed patients going through such therapies; over the course of six months their depression lifted, and one of the key biochemical markers associated with depression (serotonin reuptake) improved correspondingly.
So where's the disagreement? The title for this exchange is: "Will science explain mental illness?" Each of these words is mired in complexity. What does it mean to explain something? By science, do we mean merely the reductionist techniques of current biological psychiatry, or do we include the wider framing of sociology, politics and economics? And how do we define mental illness?
Like most of your biologically oriented psychiatric colleagues, you seem to take it for granted that there are relatively clear-cut entities—classifiable according to the latest edition of the Diagnostic and Statistical Manual—called schizophrenia, bipolar affective disorder and so on. A patient can be given an appropriate label and treated accordingly—by drugs, cognitive therapy or whatever. Yet in real life, we know such labels are rarely so obvious. I have just received a letter from a hospitalised patient describing how—"at the whim of" whichever psychiatrist she is seeing—she has sometimes been called schizophrenic, sometimes manic depressive. Your colleagues at the Institute of Psychiatry (where I did my PhD) will agree that this is a common occurrence. Where does the borderline lie between depression and anxiety? The experience of patients is that they are routinely switched from category to category and drug to drug. This is why many psychiatrists would agree with Richard Bentall in Madness Explained when he argues for abandoning such labels and instead listening to the patient and trying to treat the symptoms. If the entities that psychiatrists treat are so fuzzily categorised, how can they serve as subjects for the exquisitely precise techniques of the molecular and genetic sciences?
Second, from which of the sciences should we seek an explanation? I suggest that a starting point is epidemiology. We know that depression is more than twice as common in women than men. Brown and Harris, in their classic studies in Camberwell, found that the best predictors of such depression were to be a woman living in conditions of economic and social insecurity, with children, and in an unstable relationship. Similarly we know that schizophrenia is much more likely to be diagnosed in working-class than middle-class patients, and, in Britain, among people whose parents are Caribbean in origin—and even more so if they are of so-called "mixed race" parentage. Such patterns defy simplistic genetic analyses, but point to complex social, economic and, yes, also political and cultural causations.
Which brings me to the third term in our discussion: "explain." What would constitute an explanation of, for instance, a diagnosis of depression in a working-class woman in Camberwell, or of schizophrenia in an 18-year-old black British lad in Brixton? Would you want to look for lower serotonin reuptake levels in the former, or changes in dopamine metabolism in the latter? Or would you look to deprivation in a profoundly unequal and still racist society? As I have said, I take for granted that there will be such biochemical differences, and multiple causal factors, but in science we seek determining causes: those with the greatest explanatory power. The fact that a drug such as Prozac, which affects serotonin reuptake, will alleviate the depression in many patients, is sometimes taken to mean that the depression is caused by a deficit in serotonin metabolism. Yet the flaw in the logic of such an argument is clear; aspirin alleviates the pain of toothache, but we don't conclude that the cause of the toothache is too little aspirin in the brain.
So where do the determining causes lie? Clearly with some types of mental disease they are biochemical—which may also point to genetic factors. Over the last decade, my work on the molecular processes involved in memory formation has led me into efforts to develop a potential memory-enhancing drug for patients suffering from Alzheimer's disease (AD). There are many risk factors for AD, some associated with a gene called ApoE, others with environmental causes. But the determining sequence of events is a set of biochemical changes in the brain that results in the death of nerve cells. AD is clearly a molecular disease, whatever the origin of the faulty biochemical cascade. Although there are some social predisposing factors, I do not think—I may be wrong—that these are the most useful to explore when in search of a determining explanation of the disease. And by analogy, while I do not doubt that there are biochemical factors at play in helping to explain why it is that one person rather than another in similar circumstances becomes depressed, I think it unlikely that in most cases the major determinant is biochemical.
You mention your earlier enthusiasm for RD Laing. Like Freud, Laing pointed to the rich subjective experience of people suffering from schizophrenia, and asked that we listen to their own words. Such words are framed in the language of hopes and fears, of motives and goals: the normal discourse of everyday life. There is a tendency among some cognitive psychologists to dismiss all of this as "folk psychology"—to be abandoned as neuroscience advances. I disagree. For most purposes, the best explanations for our thoughts and behaviours may not lie in science, but in the common sense of everyday talk.
Yours
Steven
Dear Steven
25th August 2005
I would first like to disabuse you of any notion that I am complacent about our current systems of diagnosis and classification in psychiatry. Here is what I said in 1997 in a textbook edited by Robin Murray, Peter Hill and myself: "[Psychiatric disorders] are defined purely in terms of their signs and symptoms. As yet there is no known pathophysiology and no reliable objective diagnostic tests. Consequently we must accept that modern definitions remain provisional and they too will be subject to evolution and change." So I agree that current classification is far from perfect—the same is true of several other branches of medicine—but the way forward is not to abandon diagnosis but to try to refine and improve it. Abandoning diagnosis in the management of mental illness was advocated long before the idea was revived by Richard Bentall. The most distinguished critic of diagnosis was Adolph Meyer, one of America's most influential psychiatrists in the first half of the 20th century. But despite Meyer's eminence, clinicians found that they could not devise a workable system that did not involve categories based on recognisable and recurring clusters of symptoms.
One of the issues that seems to worry you most about categories such as schizophrenia, manic depression, depression and anxiety is that there are not always clear-cut boundaries between disorders and that diagnoses sometimes change. This is also true of common disorders elsewhere in medicine, and part of the reason is that the same causal factors may underlie more than one disorder. A good example is that some of the genes that have been recently found to confer susceptibility to type II diabetes also increase the risk of various inflammatory diseases. Another example is one that you yourself give, concerning the gene ApoE. It is indeed involved in susceptibility to Alzheimer's disease but it is also involved in atherosclerosis, or hardening of the arteries, the process that underlies coronary heart disease and strokes. Some of my own work suggests that the genes that confer a risk of schizophrenia also contribute to manic depression. The message, however, is not that we should abandon these categories but that we should explore and refine them.
I also admire the work of Brown and Harris, but it seems to me that their singular contribution was to tease out the types of social adversity that are commonly involved in explaining onsets of depressive disorder. You asked what it means to explain. In answering this I am at one with the German philosopher-psychiatrist Karl Jaspers. He pointed out that there is a difference between meaningful understanding and causal explanation. Most of what Freud was really doing, wrote Jaspers, was an attempt to discover meaningful connections between his patients' experiences and the mental states that they developed. This is what I meant when, earlier, I mentioned Freud's "useful metaphors." Freud's error was that he believed he was discovering not just connections, but causes. By contrast, going back to Brown and Harris, they devised a methodology to measure and classify types of social adversity and showed that life events that are threatening (loss or humiliation, for example) and "independent" (uncontrollable by the patient, for example) are associated with the onset of depression. This is an explanatory finding in Jaspers's sense: the scientific method, whether it is applied in genetics, brain imaging or in the study of social adversity, is the way we will eventually explain mental illness.
Yours
Peter
Dear Peter
30th August 2005
You came so close to accepting my concerns in the first part of your letter that I began to doubt whether we had a serious disagreement. I certainly agree with the quote from your textbook—I have watched over the decades as one after another specific biomarker for schizophrenia—from abnormal metabolites in the urine to disordered glutamate transmission in the brain—has been proposed, only to die the death. But as I read on, the issues between us became clearer. You end your letter by praising "the scientific method" as the way to advance in this complex area. But the key question is which scientific method, for there are many. You recognise that the Brown and Harris studies were "scientific," but you dismiss Freud even though he believed that his approach was also scientific. He was, you say, convinced that his "meaningful connections" were causal, but today, you imply, we know better.
I do not defend Freud's classifications or his claims to have identified causes. But I am inclined to think that 100 years from now—sooner if we are lucky—today's similar attempts to locate causes in terms of genes will seem similarly misguided. It really won't do first to agree that diagnostic categories are very fluid, but then to go on to suggest that this is because the relevant genes are pleiotropic (that is, they have multiple effects). All genes are pleiotropic, which is why there is no simple "one gene/one character" relationship. The fluidity of the classification of psychic distress is not a result of pleiotropy but of the attempt to shoehorn the complexities of such distress into forms amenable to genetic analysis—and therapy. But if the phenotypes are ambiguous, you can't use the exquisite mathematical and DNA-analytical techniques that genetic science has made available. To do so will always produce GIGO (garbage in, garbage out) results.
There is a form of logic often used in medicine known as ex juvantibus, which essentially works backwards to the diagnosis of the disease from the treatment which alleviates it. Thus, if in two patients diagnosed with depression one improves with Prozac and the other does not, the difference in the response is interpreted as meaning that there are two distinct forms of the disease, a Prozac-susceptible and a Prozac-resistant form. I have the feeling that this is the type of logic you are seeking to impose with the genetic studies. As you well know, despite the strong claims that schizophrenia is a "genetic disease," and some rather convoluted efforts to provide an evolutionary explanation for its persistence, attempts to identify "the gene" for the disease have to date been unsuccessful. In the most optimistic scenario, we will end up having identified a handful of genes which, in particular combination and in the appropriate developmental context, will result in the early onset of the type of distress we can call schizophrenia. What I am not clear about is how this helps, other than in the most general biological sense, to "explain" the condition or, more seriously, to provide guidance as to its treatment.
I discussed this question once with Jim Watson, the co-discoverer of the structure of DNA. His argument was simple: other approaches to the disease had failed, and we know how to do genetics. This is the old story of the drunk looking for his lost door key under the lamppost because that's where the light is.
I appreciate the complexity of the problem and applaud your persistence in attempting to tackle it, but I won't hold my breath.
Yours
Steven
Dear Steven
2nd September 2005
I would not want you to hold your breath. Although I am optimistic about the rate of progress in psychiatric research, right now it is a story of a steady march onward rather than a stream of dramatic breakthroughs. I also have a Jim Watson anecdote. He visited our lab in Cardiff about ten years ago. Mike Owen and I had just started a project to search systematically the whole genome (the 23 pairs of chromosomes) in about 200 families containing brother or sister pairs both affected by schizophrenia with the aim of locating genes. "Should work, Peter," was Jim's reassuring comment. As it happened, it did not work. But a few years on the strategy has proved successful, and several of the genes involved in schizophrenia have been identified. We also have some promising findings on depression and bipolar disorder. This is because the detailed genome searches now becoming possible will not only look where the light is, they will floodlight the entire street.
The question of different types of depression that are responsive to different types of antidepressant is not at all far-fetched. Every GP comes across patients with common ailments—not just psychiatric ones—where the first treatment to be tried does not succeed and the right medication has to be found by trial and error. My prediction is that we can improve on this for many disorders in the foreseeable future. We know that many of the individual differences in the ways that people respond to medications or develop side-effects are influenced by genes, and some of these have been identified. It is likely that GPs of the future, as well as psychiatrists, will be able to tailor the treatments they prescribe to individual patients more carefully, informed by tests of their genetic make-up.
Most clinicians strive to take an evidence-based approach that depends on going beyond calling everything "psychic distress." It does not mean that working hard to listen, to comfort and to empathise with the patient is unimportant. On the contrary, empathy is central to the doctor-patient relationship and comfort was almost all that psychiatry, indeed medicine as a whole, could offer until quite recently. To our great fortune we have progressed beyond that and it is every psychically distressed person's right to receive not just comfort but scientifically informed management of their plight.
Yours
Peter
Dear Peter
7th September 2005
We agree that categories in mental illness are notoriously slippery. One explanation for this, the one our exchange started with, and that I thought we had agreed, is that the phenomena—the experiences—of mentally distressed people, are complex and varied and that diagnoses change with fashion. However, you have now moved somewhat away from that agreement to the suggestion, shared, I know, by many geneticists, that the varieties of phenomena essentially reflect the activities of several or many different genes, so that what we call schizophrenia, for instance, will turn out to be three or six or however many different diseases, each characterised by a specific genetic profile. This will make rigorous diagnosis—and hence the development of appropriately tailored treatment regimes—possible.
This is the hope of what has been called pharmacogenetics in other areas of medicine. Our DNA-on-a-chip will enable GPs to prescribe one rather than another of the several different drug families available for reducing blood pressure, each of which works by a different biochemical route. I remain sceptical about this, especially in the case of mental illnesses, where the multiple interactions between many different genes and the complexities of a person's psychosocial development is likely to make such gene-based rationality a chimera.
Our discussion, however, was intended to focus not on treatment but on "explanation." I'm still not sure whether you would want to argue that, once you have catalogued all your genes of small effect, you would say you have "explained" the "causes" of schizophrenia. The phenotypic effect of any one of your genes will be probabilistic. I doubt that, presented with a new-born baby's genetic profile, you would want to claim the ability to predict with any degree of certainty whether, or when, he or she would exhibit symptoms you would call schizophrenic. Of course, as a researcher, I can see the attraction of applying all these shiny new technologies to the problem that concerns us. It may be that your techniques will point to new drug prospects, but I fear that "explanation" will still elude simple reductionism. Meanwhile, happy gene-hunting, and I will go on working on my hoped for Alzheimer therapy.
Yours
Steven
