The Tricyclic Antidepressants and the Amine Uptake Theory

As early as the 1960s, a sufficient body of evidence seemed to exist to formulate the hypothesis that the antidepressant action of imipramine and related tricyclic antidepres-sants was due to blockade of amine reuptake, leading to an increased aminergic neurotransmission. However, there were some caveats. In fact, several kinds of objections were raised but, in my opinion, some of these did not carry much weight. For example, concern was raised about the slow onset of antidepressant effect compared with the almost immediate blockade of amine uptake. However, given the powerful adaptive capacity of the brain, it is not hard to envisage that an originally distinct change, induced by a drug or a pathological process, could lead to a complex cascade of secondary changes in various neurocircuits. These changes could take weeks or even months to evolve and outlast considerably the presence of the drug or initial disturbance.

More serious was the objection dealing with the complex pharmacology of the tricyclic antidepressant drugs. Besides blocking amine reuptake they have affinity for a large number of receptors (e.g., cholinergic, adrenergic, histaminergic) and in addition they have a relatively strong so-called membrane-stabilizing action which leads to cardiotoxicity, lowering of seizure threshold etc. To exclude a role for these various mechanisms in the antidepressant action proved difficult. In fact, the general opinion in the scientific community was probably adequately expressed in Goodman and Gilman's textbook, as late as 1980 (Sixth edition),19 when they commented that there is increasing doubt that the monoamine uptake theory is "either a necessary or sufficient explanation of the antidepressant action of these drugs." In subsequent editions, this comment has been deleted and opinion has shifted in favor of the amine uptake theory. Below an account will be given of the developments leading to this shift.

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