Expanding the horizons of depression: beyond the monoamine hypothesis

The monoamine hypothesis has dominated our understanding of depression and of pharmacological approaches to its management and it has produced several generations of antidepressant agents, ranging from the monoamine oxidase i nhibitors (MAOIs), through tricyclics (TCAs) and selective serotonin reupta ke inhibitors (SSRIs), to the recently introduced selective noradrenaline r euptake inhibitor (NARI), reboxetine. Greater receptor selectivity has impr oved tolerability, but not efficacy, when newer compounds are compared with the original tricyclic antidepressants (TCAs) and monoamine oxidase inhibi tors. Essentially, the newer antidepressants have the same distinguishing f eature as older ones, i.e. acute enhancement of monoaminergic neurotransmis sion. The monoamine hypothesis cannot conclusively link the acute biochemic al action of antidepressants on monoamine levels with their delayed clinica l effect of 10-14 days, nor can it explain the mode of action of antidepres sants that are effective despite being very weak inhibitors of monoaminergi c transmission (e.g. iprindole) or, incongruously, enhancing monoamine upta ke (e.g. tianeptine). Compared with other fields of medicine, there has bee n a lack of progress in understanding the pathophysiology of depression and producing truly novel antidepressant agents. Other biological approaches t o depression, such as overactivity of the hypothalamic-pituitary-adrenal ax is. hippocampal neural plasticity in response to stress, and the link betwe en the inflammatory response and depression, offer new approaches to findin g pharmacological agents, aided by improved techniques for visualising the human brain, better animal models, and increased knowledge of human markers of depression. Copyright (C) 2001 John Wiley & Sons, Ltd.