Thirty‐five compounds related to the antidepressive drug imipramine in chemical structure have been examined for their capacity to inhibit the uptake of 5‐hydroxytryptamine by human platelets in vitro. Substitution by small‐sized electropositive groups in positions 2 or 3 of a benzene ring gave compounds more active than the prototype, 3‐chloroimipramine being five times as potent on this test. Alteration of the characteristic seven‐membered ring of the antidepressive drugs reduced the activity while substitution in the basic side‐chain destroyed it. The tertiary amines were more potent inhibitors than their demethylated derivatives. In this and other ways the active structure for the inhibition of 5‐ht uptake by human blood platelets differs from that for the inhibition of noradrenaline uptake by the rat heart.

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Observations are reported on the blood platelet 5-hydroxytryptamine content of six patients receiving imipramine, N-(y-dimethylaminopropyl)-iminodibenzyl hydrochloride. The response was a fall to a level of one-sixth of the original in three weeks, with little change thereafter. This is in sharp contrast to the action of iproniazid which caused a rise of some 2000% in the blood platelet 5-hydroxytryptamine level over the same period. Imipramine in a concentration of 1 mg./ml. had no inhibitory action on 5-hydroxytryptophan decarboxylase; 8 0 [kg./ml. of imipramine suppressed two-thirds of the in vitro uptake of 5-hydroxytryptamine (2-5 [tg./ml.)by normal human platelets.The recently developed pharmacological approach to the treatment of disordered mental states, particularly schizophrenia, with the so-called tranquillizing or ataractic drugs has undoubtedly achieved results (Brill and Patton, 1957), although the individual response is unpredictable and the mode of action is still not clear. Nevertheless, the degree of success has been sufficient to cause the adoption of a similar approach to the treatment of the other major functional psychosis, the manic-depressive syndrome. Of the two aspects of this illness, the depressive is the more frequent in the ratio of 10 to 1 and therefore calls for more urgent attack.

Individual variations in drug metabolism are important factors affecting both toxicity and clinical effectiveness (Brodie, 1964; Kalow, 1965; Price Evans, 1965). In most cases the best available index of the drug concentration at the site of action is the plasma level. An estimate of this will show whether the optimal concentration is present and in some cases may indicate whether new symptoms can be attributed to toxic side reactions.

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