How we fell for antidepressants

The French novelist, Michel Houellebecq, with his accustomed acuity about modern culture, titled his last novel but one Serotonin. By then, of course, this famous neurochemical had become the key to a perfect human existence, too little or too much of it resulting in all the little problems that continue to plague mankind. If only we could get the chemical balance in our brains right, all would be well, life would return to its normal bliss!

After the commercialisation of Prozac, people started talking about the chemical balance in their brains in much the same way as they talked about the ingredients of a recipe. As Peter D. Kramer put it in his book published in Britain in 1994, Listening to Prozac:

By now, asking about the virtue of Prozac… may seem like asking whether it was good thing for Freud to have discovered the unconscious… Like psychoanalysis, Prozac exerts influence not only in its interaction with individual patients, but through it influence on contemporary thought. 

You can say that again. Prozac and its competitors (known collectively as the SSRIs) soon drove unhappiness from the lexicon and replaced it with depression. A relatively rare condition became a common one, so common that up to a sixth, and a constantly increasing proportion, of adults in the western world are now taking antidepressants (prescriptions doubled in Britain between 2008 and 2017 alone). As Dr Colin Brewer once put it, misery increases to meet the means available for its alleviation. Or perhaps more accurately, the reputed means of its alleviation, for it is far from certain that antidepressants alleviate misery, if the question is regarded more broadly rather than on a case-by-case basis. I doubt that anyone has observed the world growing much happier since the introduction of these drugs.

One possible measure of general misery and prevalence of depression is the suicide rate. In Britain, at any rate, it has remained relatively stable, oscillating slightly at around a figure of ten per 100,000 of the population per year. In the United States, by contrast, it has risen almost by a third during the last 20 years in which antidepressant use has also increased. One can say that, at least, mass drugging has not altered the suicide rate very favourably.

Such broad statistics are always capable of more than one interpretation, of course. It might be argued that the rate of depression in the western world has really risen and that in Britain, for example, but for the increase in the rate of antidepressant prescriptions, the suicide rate would have risen rather than remained relatively constant, while in the United States depression may have increased by even more than antidepressant prescription, and therefore the response to the rise in suicide rate should be the prescription of even more antidepressants. Why, on this hypothesis, depression should have increased so greatly is a question that is not discussed as often as its importance would suggest that it should be.

The widespread use of antidepressants encourages a curious form of alienation

The matter is further complicated by the suspicion that SSRIs themselves may provoke suicidal thoughts, by means of side-effects (and withdrawal effects) such as agitation and akathisia, an intense and deeply distressing feeling of restlessness that results in constant movement and that is associated statistically with suicide.

This is not quite the same as saying that the drugs never work; controlled trials show that they can, though not dramatically well. However, the results of such trials, conducted with a care impossible in everyday practice, are not automatically transferable to what we doctors sometimes call the real world, in contradistinction to the rarefied world of carefully conducted research, especially with an inherently vague (and, dare one say it, fashionable) diagnosis such as depression.

Nor does the variable effect of the drugs prove that the theory on which they marketed is necessarily false, though a recent review of the serotonin theory of depression suggests that it is far from firmly founded on scientific evidence.

This review, which has been itself criticised as incomplete, was published in Molecular Psychiatry, an important journal in the field of the biochemistry of psychiatric disorders. The authors examined the various strands of evidence put forward in favour of the serotonin hypothesis, that depression is the result of a morbid alteration of serotonin metabolism, and found them wanting in scientific conviction. For example, the measurement of serotonin metabolites in the cerebrospinal fluid of those who are depressed fails to show any difference from that in people who are not depressed. In summary, the authors conclude:

Our comprehensive review of the major strands of research on serotonin shows there is no convincing evidence that depression is associated with, or caused by, lower serotonin concentrations or activity… and methods to reduce serotonin availability… do not consistently lower mood in volunteers.

Here it is worth remembering that the first generation of effective antidepressants discovered were believed to alter noradrenaline rather than serotonin metabolism (imipramine was initially tried on patients with tuberculosis, some of whom were noticed to have grown cheerful on it), and in the experience of many psychiatrists they are more effective in preventing severe depression than the SSRIs. But the noradrenaline hypothesis was driven from the field by the serotonin hypothesis for some reason (possibly not unconnected with commercial propaganda) capturing the public imagination in the way that the noradrenaline hypothesis never had. As Einstein said, theories should be as simple as possible, but not simpler than possible.

It is worth reflecting also on the pressures on doctors to prescribe these drugs. Patients arrive in their consulting rooms who believe that their unhappiness is a deviation not only from normal but from health. The doctor has but a short time to expend on such a patient. The reasons for the patient’s misery cannot be gone into deeply and, if they exist, are in any case likely to prove refractory to the doctor’s ministrations.

The doctor has to draw a consultation to an end somehow, and a prescription is a natural way to do it, like the death of the heroine in a tragic romantic opera. He knows that placebos have a powerful effect in elevating patients’ moods, but he is no longer allowed to prescribe coloured water or some such as he once might have done.

In addition, it is probable that the antidepressant exerts an antidepressant effect on at least some patients, but so loose is the diagnosis now that he does not know which. For him, it is safer to prescribe than not to do so, for one untreated patient might cause him more problems than 99 patients treated unnecessarily, many of whom in any case will benefit from the placebo effect.

The patient also benefits in a certain way, even in the absence of that placebo effect. He is pleased that his misery is validated as an illness, thus removing some of the need for self-examination or the making of difficult decisions about his existence. He has successfully transferred some of the responsibility for his life from himself to the doctor and this is always gratifying.

Fortunately for the doctor, antidepressants are said to take some time to work. Moreover, there are various increased doses that can be given a try and that also requires a delay before they can be said not to have been effective. But this is not all: there are many antidepressants on the market, and some people respond to one and not the others. Thus trials of drugs can go on for months, by which time the feeling of depression may have evaporated, as it frequently does. The whole pas de deux between doctor and patient can last for months before drawing to a successful or unsuccessful conclusion as the case may be. At least everything has been tried.

A bonus for the drug companies is that patients often feel worse when stopping the antidepressants that they have been taking for a long time. This, of course, is an indication to stay on them for even longer. It is claimed that withdrawal effects after chronic use can last up to 18 months.

A fundamental problem is that there is no indisputable biological marker to distinguish trivial and fleeting unhappiness from serious depression, the kind that develops into the melancholia that has been described for centuries and which, once witnessed, is never forgotten. The first melancholic patient I ever saw suffered from Cotard’s syndrome, named for the French neurologist, Jules Cotard (1840 – 1889). The patient, a man of about 60, lay in his bed believing that he was already dead, the whole of his body having rotted away except for the tip of his nose, which mysteriously remained alive, though not, according to him, for very long. A successful businessman, he recovered with treatment with amitriptyline, one of the first-generation antidepressants of the noradrenaline hypothesis type.

Melancholia is varied in its manifestations, from near catatonia (patients may literally turn their faces to the wall) to unassuageable agitation. Such patients often believe themselves to be guilty of some terrible moral fault, though they may have lived exemplary lives – insofar as any human lives are exemplary. The cause that allegedly excites such melancholia is often grossly out of proportion to its supposed effects, and the successful in life are as susceptible to it as the failure.

Melancholia easily becomes a medical emergency, but is now rarely seen, possibly because of the widespread use of antidepressants. Electro-convulsive therapy (ECT) may produce dramatic effects. One patient I remember went straight from profound retarded depression to a state of mania, overactive, grandiose, and with unstoppable logorrhoea. His wife said to me, ‘Can’t you make him depressed again, doctor?’

Irrespective of the benefits of antidepressants in individual cases, which can be considerable, I suspect that their overall cultural effect, when prescribed almost in the way that hypochondriacs take vitamin supplements, has been, like that of psychoanalysis, negative or harmful. They have reinforced the facile hope that there is a technical or psychological solution to the problems of living, and that any deviation from a supposedly normal state of happiness is always pathological. The American psychiatrist, the late Thomas Szasz, once proposed that happiness should be considered an illness, on the grounds that it was rarely justified by circumstances and was usually based on delusion.

The widespread use of antidepressants encourages a curious form of alienation of patients’ thoughts and behaviour from themselves, insofar as they begin to describe themselves as objects rather than subjects, and as if they were merely an amalgam of chemicals even to themselves. They do not make decisions, their neurotransmitters make their decisions for them, at least when these decisions are bad (no one complains of his good behaviour or ascribes it to anything but himself). They thereby encourage a form of bad faith, special pleading and an avoidance of true self-reflection.