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2.3 Treatment of depression: the first 30 years

In the 1960s, the lack of any defined, mass market for depression inevitably meant that pharmaceutical companies were reluctant to try to develop drugs for it. Nevertheless, they had begun to see opportunities. Early on, one of the pioneers in this field published a small, helpful and hopeful volume, Recognising the Depressed Patient (Ayd, 1961; Raach, 1961) and "Merck Sharpe & Dohme bought 50,000 copies of it and distributed it not just to psychiatrists, but to family doctors and internists and so forth". (Ayd, 1996)

In those early days, no one knew how common depression was: "There were no epidemiological studies worth a tinker’s damn. In fact, epidemiology as we know it today in psychiatry didn’t exist then." (Ibid) An important turning point came with the publication of a widely-circulated estimate from the WHO that "at least one hundred million people in the world ... suffer from depressive disorders amenable to treatment". (Sartorius, 1974, 1978)

With these changes came new and different kinds of antidepressant drugs with confident claims of effectiveness, plus more defined ideas about what depression was and how antidepressants worked. Two trends accelerated the commitment to use drugs. One was the ascendancy of biological theories of depression over psychoanalytically-oriented views:

"If there is one central intellectual reality at the end of the twentieth century, it is that the biological approach to psychiatry - treating mental illness as a genetically influenced disorder of brain chemistry - has been a smashing success. Freud’s ideas, which dominated the history of psychiatry for the past half century, are now vanishing like the last snows of winter" (Shorter, 1997).

The other factor was the decline in use of ECT, but not so much because of the risks (Drill, 1958, Pippard, 1992), nor because it was thought ineffective. (APA, 1997) Medical texts tend to attribute the decline of ECT to public resistance fuelled by misconceived portrayals, notably in the book ( Kesey, 1962) and film (Forman, 1975) One Flew Over the Cuckoo’s Nest. However, the evidence that ECT treatment is sometimes poorly performed (Wise, 1997) and high costs may have also played some part. In the US, a single ECT session is costed at 200-500 (mainly the cost of anaesthesia) and a typical course of treatment might be 6 - 12 sessions over several weeks. (APA, 1997)

Though drugs were usually cheaper and more convenient to use, their use has always been limited by poor compliance and unwanted effects. Patients usually experienced uncomfortable rather than serious side effects, though there were also significant risks. For example, recognition of a potentially dangerous interaction between MAOIs and certain foods (eg cheese, yeast extracts) helped to promote the tricyclics, and later the tricyclics lost some ground to the "quadricyclics", newer drugs promoted as safer in overdose. Very severe depression carries some risk of suicide, and it has often and long been argued that the greatest risk lies in not treating depression at all.

The scientific medical literature of the 1960s suggests that the original antidepressants were given a rather cautious welcome, though this should be seen in the context of those times. In those days, the market was quite small and the buzz in the journals (advertisements too) was mainly about anxiety, stress and insomnia. This was a huge and growing market, but strictly reserved for the "tranquillisers", and notably the benzodiazepines. Drugs like Librium (chlordiazepoxide) and Valium (diazepam) dominated, from 1960 and for the next 30 years.

Nor did "depression" mean what it means today. Then (endogenous) depression was exemplified by the mentally and physically immobilised patient, sitting with his head in his hands. This was well-recognised as a serious illness but it also carried quite a stigma; it was "not fashionable to be depressed" (Kline, 1964). At the same time, most cases of "depression" were thought self-limiting: until the 1980s, the great medical textbooks and most experts emphasised that up to 80% of all cases of depression would cure themselves. If the implication was that depression often needed no drug treatment, such views come close to heresy today:

" ... depression is, on the whole, one of the psychiatric conditions with the best prognosis for eventual recovery with or without treatment. Most depressions are self-limited and the spontaneous or placebo-induced improvement rate is often high. For example, in a series of nine controlled studies on hospitalised patients, 57% of the patients given placebo therapy showed improvement in two to six weeks." (Cole, 1964)

"In the treatment of depression one always has as an ally the fact that most depressions terminate in spontaneous remission. This means that in many cases regardless of what one does the patient eventually will begin to get better." (Kline, 1964)

" ... most depressed patients get better anyway and the patients who improve after one has prescribed tablets have done so post hoc but not necessarily proper hoc." (Leyburn, 1967)

The physician "must also weigh the fact that perhaps 80% or more of depressed patients will eventually recover without treatment" (Byck, 1975) ... and "affective disorders have a very high rate of spontaneous remission, provided sufficient time passes" (Baldessarini, 1980).

Then as now it was recognised that a significant minority (around 25%) did not respond to drug treatment. The standard response to "resistant depression" today would be to increase the dose and to prescribe other drugs, as well or instead. In those days, resistant cases would usually be treated with electro-convulsive therapy (ECT); many experts believed this to be the most effective of all and some still do.

 Less was known then about how antidepressant drugs worked and about the biochemical rationales for using them and, in those days, psychodynamic understandings of depression held much greater sway. (Lehmann, 1996; Shorter, 1997) Moreover, evidence had accumulated since the early 1960s of a gulf between the advertised benefits of antidepressants and their actual effects, when assessed in controlled clinical trials. As a whole, the hard evidence looked thin: it did suggest that the MAOIs and tricyclics could be distinguished from placebo, but the difference was not great. This was the rather low opinion of one of the pioneers, a man still prominent in the field:

"The newer antidepressant drugs have now been used experimentally and clinically for approximately seven years. Their place in the physician’s armamentarium is still far from clear, although many clinicians feel that the drugs are useful and effective. However, controlled clinical trials of these agents have not always led to unequivocally positive findings. Even when the findings have been favourable to the drugs under study, the differences between the efficacy of the drug and a placebo have not been as great as one might wish, or as one might have anticipated after reading published reports of uncontrolled trials." (Cole, 1964)

Soon after, the US National Institutes of Health reported the results of a systematic analysis of 490 studies published in 71 leading medical journals between 1955 and 1966. The conclusion was that: "the methodology of drug research is of more significance to the outcome of a clinical trial than is the drug being studied ... In well-designed studies, the differences between the effectiveness of antidepressant drugs and placebo are not impressive". (Smith et al., 1969) The effect of these original antidepressants on depression has nevertheless become one of the main yardsticks for efficacy by which each successive generation of antidepressants has been proved.

Successive editions of a leading UK textbook on clinical pharmacology suggest that the quality of such trials "has got only a little better since"; (Laurence, 1966, 1974, 1980; Laurence & Bennett, 1987); indeed, low standards seem commonplace today (Gore et al., 1992; Wise and Drury, 1996). Meanwhile, the number of tricyclic and related antidepressants proliferated, albeit to little effect. The 1970s and 1980s saw numerous attempts to manipulate drug molecules, but antidepressant drug therapy "developed a bewildering complexity" as a result. "None of these changes (has) produced an antidepressant that is more effective; approximately 80% of a heterogeneous population will respond to adequate treatment with any tricyclic compound", (Blackwell & Simon, 1988) and the same has proved true of the rest.

In time, the controversy quietened and antidepressant drug prescribing became routine, in spite of the uncertainties and probably because of them too. One factor which would have contributed to uncertainly was the complexity and cost of rigorous drug testing. Other factors would include the lack of evidently better alternatives; the lower cost and convenience of drug treatment; the "rewarding" and "gratifying" results sometimes obtained; growing belief in the biological basis of depression; the tendency to discount placebo and nocebo factors at work (Merry, 1972); confusion over the limitless opportunities for diagnoses, with possibilities for always trying something new; and perhaps above all, the intensity of drug promotion.

Given the essential similarities between the dozens of different drugs, attention was mainly focused on safety and on the prevalence of depressive conditions, and its many and subtle manifestations. These included phenomena labelled as "masked", "smiling" and "hidden" depression; thus the many diagnostic uncertainties were simultaneously increased and also largely dispelled.

"I am sure many colleagues have shared with me the following embarrassing experience. I prescribe a tricyclic drug for an outpatient with a typical or "classical" endogenous depression. The patient returns to see me three or four weeks later. She is very much better. When I remind her of the importance of continuing drug therapy despite the improvement, she smiles and says ‘Oh doctor, the tablets did not agree with me, so I stopped taking them after the first two or three days’." (Merry, 1972)

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