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2.2. When antidepressants were first used

The first of the antidepressants in use today came on the market about 40 years ago, so why does the question arise now ? The short answer is that things changed recently with the introduction of a new class of antidepressant, the Selective Serotonin Reuptake Inhibitors (SSRIs), exemplified by fluoxetine (Prozac). These drugs have started to overtake the more traditional antidepressants, the tricyclics and the monoamine-oxidase inhibitors (MAOIs). The tricyclics, in particular, have been the mainstay of drug treatment for years, but have lost some ground since the late 1980s when the SSRIs began to make their mark.

For all the differences between them, all of these antidepressant have one important thing in common and the evidence for it is overwhelming and has never been in dispute. When you carefully measure the effects of any of these drugs on whole populations, none proves more effective than any other in treating depression. Over the years, scores of different antidepressants have been tried, but patients generally respond (some very well, others less so) in about 60% - 70% of cases. This compares with a typical 30% - 35% response rate reported with placebo.

The implications of this are fundamental to the analysis, first, because there is no difference in the quality of response between antidepressants and placebo. The difference is that active drugs can be expected to elicit that same response apparently about twice as often as placebo; when placebos work in depression, they are as effective as the best active drugs. Secondly, when many different drugs elicit a similar and only partial response, it suggests lack of specificity and that the effects on depression are unlikely to result from these drugs’ distinguishing chemical characteristics. One might conclude that the effects of antidepressants are comparable to those of a strong placebo, a double-strength placebo to be precise.

There is, however, much discussion about the relative risks of different antidepressants and about their benefits for particular patients, though such debates are ritual in any ‘new vs old’ drug evaluations and whenever clinicians have a range of treatments to chose from. The same sort of debates were in progress at about the time this story begins, when the following letter to The Lancet was published in 1955. This was immediately before the advent of the original antidepressants, the tricyclics and MAOIs. In those days, barbiturates + amphetamines had taken over from opium as the bedrock of antidepressant drug treatment and old habits took longer to die:

Sir,- Your annotation of May 21 does not mention opium. I think this is still a valuable drug in the treatment of minor depressive syndromes, many of them with anxiety, which are so commonly seen in psychiatric practice ... I have been prescribing (it) for many years. I have never seen a patient become addicted to it (it is extremely unpleasant to take) and only once has a patient attempted to use it for ostensible suicidal purposes ... Considering, too, the ease with which patients may hoard barbiturate tablets and the frequency with which they are used in suicidal attempts, I think there is still much to be said for the old-fashioned opium mixture ... It can be used safety for many weeks at a time and it goes well with the amphetamine group of drugs. I have generally found that it is only when insomnia is severe that it is necessary to add a nocturnal barbiturate to this regime". (Scottowe, 1955)

In the same year, iproniazid was introduced as a treatment for tuberculosis, and this is also where part of the story begins. Iproniazid was found by chance to have a marked effect on depressive symptoms in TB patients, so much so that it was soon superseded by another less stimulating drug, (and finally withdrawn by the manufacturers in 1961, when found to cause liver damage):

"It was eventually displaced by isoniazid since iproniazid actually made some of the patients feel ‘too well’ with the result that they failed to observe ordinary precautions, overexerted themselves, or discontinued treatment prematurely. Retrospectively it is evident that the drug not only relieved depression but occasionally must have induced euphoria. In view of the excessive good spirits of the patients it is strange that at the time the emotional reaction was regarded as a detrimental side effect and no one tried using iproniazid for treatment of depression". (Kline, 1964)

Iproniazid had been found to somewhat inhibit the effects of monoamine oxidase and the MAOIs were developed as compounds with a more potent inhibiting effect than iproniazid itself. This led to the development of ideas about the biochemical basis of depression and about the actions of antidepressant drugs. Because the enzyme, MAO, inactivated the neurotransmitter noradrenaline, it was first postulated that depression was due to a deficiency of brain noradrenaline, and that mania resulted from excess. Later it was proposed that depression resulted from a deficit of another neurotransmitter, serotonin (5-hydroxytryptamine or 5-HT). The science indicates otherwise, (Healy, 1987) but this view is still widely promoted and generally held.

By the end of the 1950s, four MAOIs were on the market. They were originally described as "psychic energisers" but count as the earliest drugs still designated and licensed for used as ‘antidepressants’. The main tricyclics (once known as "psychostimulants"), such as imipramine, came on the market a year or two later; they were developed from work on antihistamines (classically recognised as anti-allergy drugs).


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