Some current problems related to the mode of action of antidepressant drugs

An important relationship between antidepressant drugs and the monoamine transmitters of the brain is generally recognized. Major groups of established antidepressants are inhibitors of monoamine inactivation (by reuptake or monoamine oxidase) or monoamine precursors. However, the tricyclic antidepressants have many actions in addition to the blockade of monoamine reuptake, e.g. blockade of muscarinic, alpha-adrenergic and histaminic receptors and general membrane effects which may lead to cardiotoxicity. The discovery that certain antihistaminic agents devoid of condensed ring systems are fairly potent inhibitors of monoamine reuptake led to the synthesis of zimelidine, a potent and selective 5-HT reuptake inhibitor with little affinity for receptors and almost devoid of cardiotoxicity. Careful pharmacological studies and clinical trials with such selective monoaminergic agents are of considerable value for testing the possible role of monoaminergic mechanisms in various aspects of human and animal behaviour and for central nervous disorders, including depression.