Antidepressants: Mechanisms of Action
Most antidepressants primarily enhance the action of endogenous amine neurotransmitters; they act indirectly, not binding to 5HT or NE receptors but enhancing neurotransmitter action by inhibiting metabolism or removing neurotransmitters from synapses. Increased synaptic 5HT or NE levels then counteract the abnormally low levels that produce depression. 5HT enhancement may be more important than enhancement of NE, so SSRIs have become popular. MAOIs inhibit metabolism of 5HT and NE, thus increasing amine levels. Mechanisms of newer drugs include direct binding to 5HT or NE receptor subtypes (eg, antagonist action at presynaptic α2adrenoceptors stimulates NE release). The action of bupropion does not seem to involve 5HT or NE and therefore may represent a novel mechanism. The longterm mechanism of antidepressant action is unknown. All these drugs modify neurochemical pathways and can elicit adverse effects (eg, sedation and excitation).