The effects of the addition of short-term lithium to long-term administration of antidepressants (clomipramine or citalopram) on the levels of 5-HT and 5-HIAA and serotonergic receptors were studied in the rat cortex. The addition of short-term Li to long-term antidepressant treatment potentiated an increase in 5-HIAA, although Li alone had no effect. On the serotonergic receptors, the addition of short-term Li had no effect. It is speculated that the therapeutic action of Li when added to antidepressants in the treatment of refractory depression may partly have its basis in the further activation of the presynaptic serotonergic system.