Duloxetine is a potent inhibitor of serotonin (5-hydroxytryptamine, 5-HT) and noradrenaline (NE) uptake in vitro and in vivo and is 3- to 5-times more effective at inhibiting 5-HT uptake. Duloxetine is a weak inhibitor of dopamine (DA) uptake and the binding of radioligands to neurotransmitter receptors. Upon administration of duloxetine in vivo, the inhibitory effects on uptake of 5-HT and NE persist for up to 8 h. Desmethylduloxetine, a potential metabolite, is also an inhibitor of 5-HT and NE uptake. Consistent with the ability to inhibit the uptake of 5-HT, duloxetine blocks p-chloroamphetamine induced depletion of mouse and rat brain 5-HT. Duloxetine also blocks the 6-hydroxydopamine induced depletion of mouse heart NE and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced depletion of NE in frontal cortex but does not block the MPTP induced depletion of DA in rat striatum. Electrophysiological studies show that duloxetine decreases the activity of 5-HT neurones in dorsal raphe and at a 5-times higher dose also decreases the activity of NE neurones in the locus coeruleus. Microdialysis techniques have demonstrated that duloxetine effectively elevates extracellular 5-HT and NE levels in rat frontal cortex and hypothalamus. Antagonists at somatodendritic 5-HT(1A) autoreceptors or at presynaptic alpha(2)-adrenergic receptors could augment the duloxetine induced elevation of extracellular 5-HT, NE and DA levels. Duloxetine produces behavioural responses consistent with the enhancement of 5-HT and NE neurotransmission. Pharmacokinetic studies in healthy human volunteers show that duloxetine has a half-life of 10 - 15 h without the influence of food. In preliminary clinical trials, duloxetine has shown antidepressive effects in patients with major depression. Duloxetine offers an opportunity to utilise combined central 5-HT and NE neuronal pathways to improve the treatment of patients with major depression.