Current Trends in the Development of
New Antidepressants.
Pacher, Kecskemeti, Furst, Kohegyi
Behav Pharmacol. 2001 Feb; 8
(2): 89-100
ABSTRACT
Early antidepressant medications e.g. tricyclic antidepressants (TCAs) and
monoamine oxidase inhibitors (MAOIs) are effective because they enhance either
noradrenergic or serotonergic mechanisms, or both. Unfortunately, these
compounds block cholinergic, histaminergic and alpha-1-adrenergic receptor
sites, interact with a number of other medications and bring about numerous
undesirable side effects. Several chemically unrelated agents have been
developed and introduced in the past decade to supplement the early
antidepressants. These include selective inhibitors of the reuptake of
serotonin (the selective serotonin reuptake inhibitors (SSRIs)) or
noradrenaline (reboxetine) or both (SNRIs: milnacipran and venlafaxine), as
well as drugs with distinct neurochemical profiles such as mirtazapine,
nefazodone, moclobemide and tianeptine. All these newer compounds
are the results of rational developmental strategies to find drugs that were
as effective as the TCAs but of higher safety and tolerability profile. In
spite of the remarkable structural diversity, most currently introduced
antidepressants are monoamin based¹ and modulating monoamine activity as a
therapeutic strategy continues to dominate antidepressant research. It
must be emphasised, however, that these newer antidepressants are far from the
ideal ones, also resulting in undesirable side effects and requiring 2-6 weeks
of treatment to produce therapeutic effect. Furthermore, approximately
30% of the population do not respond to current therapies. An important
new development has been the emergence of potential novel mechanisms of action
beyond the monoaminergic synapse. The results of recent novel developmental
approaches have suggested that modulation of N-methyl-D-aspartate (NMDA),
neuropeptide (substance P and corticotrophin-releasing factor) receptors and
the intracellular messenger system may provide an entirely new set of
potential therapeutic targets. This paper discusses the advances from
monoamine-based treatment strategies and looks at the future developments in
the treatment of depression.