David T. Wong, Ph.D.

 (presented at the 1998 CAMS Annual Scientific Meeting)

 Serotonin (5-hydroxytryptamine, 5-HT) was first reported in brain follow-ing its discovery in serum by Page and colleagues (Twarog and Page, Am. J. Physiol. 175:157, 1953). The function of 5 HT as a neurotransmitter was considered (Marrazzi and Hart, J. Nerv. Mental Dis. 122:435, 1955) and distribution of separate neuronal tracks of the three monoamines, 5 HT, norepinephrine (NE) and dopamine (DA) in the brain was demonstrated (Anden et al., Life Sci., 4:1275, 1965). Presynaptic uptake specific for the three monoamines terminates their neuro-tramsmitter functions. Fluoxetine was reported as a selective inhibitor of 5-HT uptake and considered therapeutically useful in the treatment of depression (Wong et al, Life Sci., 15:471, 1974). In animal studies, fluoxetine selectively inhibited 5 HT uptake without inhibiting uptake of NE or DA; increased 5 HT availability in the brain and in turn promoted 5 HT neurotransmission. In clinical studies, fluo-xetine and its congeners setraline, paroxetine and citalopram as a class of drugs known as SSRIs have been demonstrated efficacious for the treat-ment of depression and related disorders (Stokes and Holtz, Clin. Therap. 19:1135, 1997). In depressed patients, remitted from the treatment with SSRIs, would experience relapse of de-pressive symptoms upon abrupt depletion of the 5-HT precursor amino acid, tryptophan (Delgado, et al., Archs Gen Psychiat. 47: 411, 1990), demonstrating the dependence on synaptic availability of 5-HT for the anti-depressive efficacy of the SSRIs. Fluoxetine and other SSRIs are known for the ease of once a day medication and benign profile of side effects and safety in patients. The use of SSRIs for treatment of depression associated with other medical illness includes cancer, diabetes, heart disease and HIV-infection. The SSRIs have also been demonstrated to have efficacy for treatment of obsessive compulsive disorder, bulimia and panic disorder. Thus, enhancement of serotonergic neurotransmission by the SSRIs has benefitted the treatment of de-pression and other psychiatric disorders.

 Dr. Wong is Lilly Research Fellow, Lilly Research Laboratories.