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The other drug tested around this time, which came to be regarded as an antidepressant, was imipramine. Unlike the tuberculostatic drugs, imipramine is not a stimulant. It is chemically similar to chlorpromazine and has sedating properties. Therefore, in contrast to stimulant drugs with their activating and euphoric effects, it was difficult to construct a drug-centred rationale for why it might be useful in depression. In other words, it was difficult to see that any of the physiological and subjective effects it induced would be useful in someone who was depressed, especially as there were many other known sedatives available to address insomnia and agitation. Therefore, its use could only be rationalised on the basis that it exerted its effects by acting on the pathological basis of a depressive illness. In this sense imipramine was the first ‘antidepressant’.

Imipramine was first used by Swiss psychiatrist Roland Kuhn. According to subsequent accounts by Kuhn himself and Alan Broadhurst of Geigy, Kuhn tried out a compound called G 22355, later named imipramine, which was given to him by the drug company because of its likeness to chlorpromazine. It was first given to a group of patients with chronic schizophrenia who were withdrawn from chlorpromazine and then started on the new drug. Many of the patients became agitated and some became euphoric. Although this makes little sense given the known pharmacological profile of imipramine, and in retrospect it seems more likely to have been due to the sudden withdrawal of chlorpromazine, the official story goes that imipramine made the patients manic or euphoric. Therefore, it was concluded that it might have beneficial effects in depressed patients. So in 1955 Kuhn started to give the drug to depressed patients. He published these results in a Swiss journal in 195 7 and in the American Journal of Psychiatry in 1958. Neither of these papers contained any figures or quantitative data on levels of improvement in patients on imipramine, or any systematic comparison with patients having other sorts of treatment. The results consisted of Kuhn’s personal impressions and opinions. In the American article he described imipramine as having ‘markedly anti-depressive properties’ and ‘potent antidepressant action’.

Kuhn comes across as a passionate advocate of imipramine. He described dramatic transformations with the drug, reminiscent, as Healy observes, of the way Prozac was described three decades later. He claimed that people who had been depressed for years were suddenly cured usually in two to three days, and that those patients and their relatives claimed ‘they had not been so well for a long time’ . He described how a homosexual man had been transformed to heterosexuality through treatment and another man had been cured of impotence. Kuhn dismissed imipramine’s side effects as ‘relatively slight’. For example, instead of noting its now well-known and potentially dangerous hypotensive effects, he suggested that it could improve hypertension. Only in passing did he mention that several instances of collapse had occurred among his patients, almost certainly due to hypotension. He also suggested imipramine could cure constipation when this was associated with depression. Only later in the paper did he note the fact that imipramine appeared to induce constipation, which is now well recognised to be a common effect.

Although Kuhn admitted that imipramine’s mode of action was uncertain, he was at pains to deny that imipramine had euphoriant effects. He did not explicitly propose a mechanism of action, but one can be inferred from certain remarks. Kuhn said that imipramine’s effects were ‘symptomatic’, by which he meant that if the drug were discontinued ‘the illness breaks out again, usually with undiminished severity’. He also believed that imipramine could induce mania in susceptible individuals, a belief that has persisted ever since in psychiatric folklore, despite the fact that controlled studies show no evidence that this occurs. Therefore, Kuhn’s report conveys the implicit idea that imipramine reverses the biochemical or physical substrate of endogenous depression. If the drug is stopped the abnormalities resurface and use of the drug may tip the patient into the opposite state of mania. Later on Kuhn expressed his views of imipramine’s action more explicitly. In 1970, describing the discovery of imipramine, he stated that ‘we have achieved a specific treatment of depressive states, not ideal but already going far in this direction. I emphasise “specific” because the drug largely or completely restores what the illness has impaired -namely the mental functions and capacity and what is of prime importance, the power to experience’. In this account he acknowledged that the side effects of imipramine are greater than he had first reported, but he maintained that ‘the neurovegetative and extra-pyramidal side effects are true side effects and clearly distinguishable from the specific antidepressive components’.

From the beginning Kuhn associated the benefits of imipramine particularly with endogenous, or what he sometimes called ‘vital’ depression. Endogenous depression replaced the idea of melancholia and referred to a state that was thought to originate from biological dysfunction in contrast to ‘reactive’ or ‘neurotic’ depression that was thought to be a response to external events. Endogenous depression is held to be characterised by symptoms that indicate its biological origins, such as sleep and appetite disturbance. These are still referred to as ‘biological’ symptoms of depression, although there is no basis for concluding that these have any more biological origin than any other features of a depressed state. Again Kuhn offered no data to support his assertion that imipramine was more effective in endogenous depression than other sorts of depression, only his overall impressions. Yet the claim that there is a particular type of depressive condition that responds to the drug also helps suggest a disease-specific notion of the effects of imipramine. It implies that the drugs’ effects are not universal, but confined to people who are believed to have a truly biological condition.

In 1958, Hans Lehmann and colleagues published a paper describing their experiences of using imipramine, which provides a transition from a drug-centred to a disease-centred view of the drug treatment of depression. They described imipramine as having ‘primarily inhibitory or depressing (in the physiological sense) action on the central nervous system’. They also noted ‘we are unable at this stage to express any opinion on the specificity of the pharmacological action of imipramine (G 22355). It is conceivable that similar results might have been obtained with other drugs’ . The authors then proceeded to formulate a physical theory of the aetiology of depression, providing a disease-specific rationale for the effects of imipramine in depressed states. Although their explanations involved the still fashionable theory of electrical circuits, interestingly they suggested the idea that depression represents a state of disturbed physiological equilibrium, which has echoes of the chemical imbalance metaphor employed so widely today. ‘A therapeutically effective drug (for depression) restores the disturbed equilibrium of excitatory gradients, either by direct influence on the disturbed focus or by acting on surrounding cerebral field.

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