The mechanism of action of antidepressants revised

  • M. Ackenheil
Conference paper
Part of the Journal of Neural Transmission book series (NEURAL SUPPL, volume 32)


The discovery of the clinical efficacy of imipramine and of the MAO-inhibitor iproniazid intensively stimulated biochemical-pharmacological research on the mechanism of action of antidepressants. Due to these investigations, until recently an enhanced activity of the central noradrenergic and/or serotonergic transmitter system was considered essential for the clinical antidepressive action. Such enhancement could be achieved either presynaptically by blocking α2-adrenergic receptors, or in the synaptic cleft by inhibiting the transmitter reuptake or the main metabolic enzyme, MAO. The common final result, especially of chronic treatment, was the down-regulation of postsynaptic β-receptors, modulated by interaction with the serotonergic system, neuropeptides, and hormones. The delay of clinical response corresponded better with such receptor alterations. However, the introduction of new, more selective antidepressants led to new reflections upon the mechanism of action. On the level of transmitters, α1upregulation, increased activity of the dopaminergic system, an alteration in the balance between the different transmitter systems, are reported and seem to be important. Most promising are recent investigations of the second messenger systems, the adenylate cyclase system and the phosphatidylinositol system. Both systems are modulated by antidepressant drugs including lithium and carbamazepine. These second messengers, in turn, modulate the phosphorylation status of neuronal proteins via protein kinase, which may lead to elevations of the above mentioned receptors and again their transduction systems.


Antidepressant Drug Messenger System Adenylate Cyclase System Presynaptic Autoreceptors Phorbol Acetate 
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Copyright information

© Springer-Verlag 1990

Authors and Affiliations

  • M. Ackenheil
    • 1
  1. 1.Psychiatrische KlinikUniversität MünchenMünchen 2Federal Republic of Germany

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