Monoaminergic-based drugs remain the primary focus of pharmaceutical industry drug discovery efforts for
mood disorders, despite serious limitations regarding their ability to achieve remission. The quest for novel
therapies for
unipolar depression and
bipolar disorder has generally centered on two complementary approaches: (1) understanding the presumed therapeutically relevant biochemical targets of currently available medications, and using that knowledge to design new drugs directed at both direct biochemical targets and downstream targets that are regulated by chronic drug administration; and (2) developing pathophysiological models of the illness to design
therapeutics to attenuate or prevent those
pathological processes. This review describes several promising drugs and drug targets for
mood disorders using one or both of these approaches. Agents interacting with non-
catecholamine neurotransmitter systems with particular promise for unipolar and
bipolar depression include
excitatory amino acid neurotransmitter modulators (eg,
riluzole,
N-methyl-D-aspartate antagonists, and
AMPA receptor potentiators) and
neuropeptide antagonists (targeting
corticotropin releasing factor-1 and neurokinin receptors). Potential
antidepressant and mood-
stabilizing agents targeting common intracellular pathways of known monoaminergic agents and
lithium/mood stabilizers are also reviewed, such as
neurotrophic factors, extracellular receptor-coupled
kinase (ERK)
mitogen-activated
protein (MAP)
kinase and the bcl-2 family of
proteins, and inhibitors of
phosphodiesterase,
glycogen synthase kinase-3, and
protein kinase C. A major thrust of drug discovery in
mood disorders will continue efforts to identify agents with rapid and sustained onsets of action (such as
intravenous administration of
ketamine), as well as identify drugs used routinely in non-
psychiatric diseases for their
antidepressant and mood-stabilizing properties.