Antidepressants and serotonergic neurotransmission: an integrative review

The effects of acute and chronic antidepressant treatment on various aspects of 5-HT neurotransmission are reviewed, in order to assess the net effect of antidepressants on transmission across 5-HT synapses. Events considered include presynaptic effects of antidepressants (on autoreceptor function, uptake and turnover) and effects on postsynaptic receptor function (assessed by electrophysiological, neuroendocrine, behavioural, and receptor binding methods). Acute antidepressant treatment has variable effects: transmission may be enhanced, unchanged or reduced, depending mainly upon the relative contributions of 5-HT uptake blockade and 5-HT receptor antagonism. However, on chronic administration, most antidepressants appear to enhance 5-HT transmission. This effect is clearest in the case of ECS, which has little effect on 5-HT turnover, but reduces uptake and increases postsynaptic receptor function. MAOIs may be an exception: there is little evidence that MAOIs enhance 5-HT transmission following chronic treatment. Most other antidepressant drugs, including some which are powerful receptor antagonists on acute administration, reduce 5-HT receptor function briefly, but enhance receptor function if several hours elapse between the final injection and testing. Zimelidine has little effect on postsynaptic receptor function, but enhances 5-HT transmission by its powerful blockade of 5-HT uptake. Chronic treatment with antidepressant drugs has usually been found to reduce binding to 5-HT2 receptors; it is difficult to reconcile these observations with the functional studies. In general, with the possible exception of MAOIs, chronic administration of antidepressants may enhance 5-HT transmission by both pre- and post-synaptic effects, and the relative contributions vary. This conclusion supports the classical "indoleamine hypothesis of depression" rather than the more recent "hypersensitive serotonin receptor" theory.