Putative New-Generation Antidepressants: Introduction | Targeting the Stress Hormone System | Agomelatine | Glutamatergic System | Neuropeptides | Targeting Signaling Pathways | Enhancing Neogenesis of Brain Cells | Systematic Genetic Approaches | Future Directions | References
For the past half-century, antidepressant development has
been dominated by drugs that interfere with monoamine neurotransmitters.
Some progress regarding safety and adverse effects is undeniable,
and the increasing specificity of most current antidepressants targeting
exclusively monoamines accounts for this improvement. Nevertheless, existing
antidepressants exhibit limited efficacy and protracted onset of
action, and we still do not know whether the pharmacological actions
delineated thus far are those that account for the clinical benefits
of these drugs in 60%–70% of patients
with depression. Severe depression poses a particularly difficult
problem, because failure to achieve clinical remission yields the
risks of extended illness duration and chronicity (Nemeroff 2007). Elucidation of crucial steps in the mechanism of action
of current antidepressants could yield an array of new drug candidates.
The alternative route to developing better antidepressants relies
on the increasing knowledge of the pathophysiology of depression emerging
from clinical research and well-founded hypotheses derived from
animal models. Despite huge research efforts by both academic and
pharmaceutical industry investigators, none of the many discoveries
of mechanisms involved in depression-related behavior has yet been
translated into clinical application.