Historical development of antidepressants

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The use of cocaine, extracted in a crude form from the leaves of the Andean coca plant, has been used for centuries in South America to alleviate fatigue and elevate the mood. It was only relatively recently, however, that the same pharmacological effect was discovered when the amphetamines were introduced into Western medicine as anorexiants with stimulant properties. Opiates, generally as a galenical mixture, were also widely used for centuries for their mood-elevating effects throughout the world. It is not without interest that while such drugs would never now be used as antidepressants, there is evidence that most antidepressants do modulate the pain threshold, possibly via the enkephalins and endorphins. This may help to explain the use of antidepressants in the treatment of atypical pain syndromes and as an adjunct to the treatment of terminal cancer pain. Finally, alcohol in its various forms has been used to alleviate anguish and sorrow since antiquity. Whilst the opiates, alcohol and the stimulants offer some temporary relief to the patient, their long-term use inevitably leads to dependence and even to an exacerbation of the symptoms they were designed to cure.

The development of specific drugs for the treatment of depression only occurred in the early 1950s with the accidental discovery of the monoamine oxidase inhibitors (MAOIs) and the tricyclic antidepressants (TCAs). This period marked the beginning of the era of pharmacopsychiatry.

Although the iminodibenzyl structure, which forms the chemical basis of the TCA series, was first synthesized in 1889, its biological activity was only evaluated in the early 1950s following the accidental discovery that the tricyclic compound chlorpromazine had antipsychotic properties. Imipra-mine is also chemically similar in structure to chlorpromazine, but was found to lack its antipsychotic effects. It was largely due to the persistence of the Swiss psychiatrist Kuhn that imipramine was not discarded and was shown to have specific antidepressant effects. It is not without interest that the first report of the antidepressant effects of imipramine was presented to an audience of 12 as part of the proceedings of the Second World Congress of Psychiatry in Zurich in 1957!

The introduction of the first MAOI in the early 1950s was equally inauspicious. Iproniazid had been developed as an effective hydrazide antitubercular drug, but was subsequently found to exhibit mood-elevating effects. This was shown to be due to its ability to inhibit MAO activity and was unconnected with its antitubercular action. Thus by the late 1950s, psychiatrists had at their disposal two effective treatments for depression, a TCA and an MAOI. But it was only in attempting to discover how these drugs may work, together with the evidence that the recently introduced antipsychotic drug resperine caused depression in a small number of patients, that the hypothesis was developed that depression was due to a relative deficit of biogenic amine neurotransmitters in the synaptic cleft and that antidepressants reversed this deficit by preventing their inactivation. While this hypothesis has been drastically revised in the light of research into the biochemical nature of depression, at that time it had the advantage of unifying a number of disparate clinical and experimental observations and in laying the basis for subsequent drug development.

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