Model Organisms in Drug Discovery

disease. These molecular targets are then validated further before entry into
chemical screening campaigns. For the purposes of our discussion, validated
targets are defined as molecular targets that both modify the relevant disease
biology and are druggable (e.g. the molecular target codes for a member of a
protein family with a history of successful chemistry campaigns). A molecular
target may be tested in a battery of C. elegans and mammalian assays, and
compound screens with C. elegans may be conducted to confirm the potential
to identify a chemical ligand against the target. The following is a discussion
of the utility of C. elegans for the identification of validated targets for the
treatment of depression.
Depression – a case study
FROM DISEASE TO TARGET 47
Depression and anxiety are the most frequently occurring mental disorders.
These diseases are commonly expressed together rather than as separate
syndromes. More than 20% of the adult population suffer from these
conditions at some time during their life. The Word Health Organization
(WHO) predicts that depression will become the second leading cause of
premature death or disability worldwide by the year 2020 (Buller and
Legrand, 2001). Surprisingly, depression is still underdiagnosed and undertreated
(Hirschfeld et al., 1997; Lepine et al., 1997). Consequently, only 15%
of individuals who have recovered from an initial episode of depression do not
experience relapse (Thase, 1992).
The study of tryptophan (a serotonin precursor) levels in depressed patients
has led to the hypothesis that depression arises from decreased neurological
response to, or repressed levels of, serotonin (Coppen, 1967). This implies that
increases in the level of, or sensitivity to, serotonin (5-HT) would improve
mood. The first-generation antidepressants, such as monoamine oxidase
inhibitors (MAOI) and tricyclic antidepressants (TCA), act on neurotransmission
by blocking the reuptake of monoamines, inhibiting neurotransmitter
degradation or binding directly to specific receptors. Advances in the
understanding of these mechanisms have led to the development of drugs
with enhanced specificity, such as the selective serotonin reuptake inhibitor
(SSRI) fluoxetine (launched in 1988). The clinical relevance of interruptions to
serotonin concentrations has been demonstrated with inhibitors of the
serotonin transporter. Inhibition of the serotonin transporter increases
serotonin concentration at the synaptic cleft and hence increases serotonin
activity (de Montigny et al., 1981; Blier and de Montigny, 1994; Czachura and
Rasmussen, 2000). Although the role of serotonin concentrations has been
demonstrated, the precise molecular mechanism of depression is known to be
quite complex because the onset of the therapeutic benefit of SSRIs usually
occurs only 2–3 weeks after the onset of therapy. Thus, other mechanisms in