Biological variables specifically linked with serotonin deficiency were assessed in geriatric depression. Sixteen depressed patients, all > or = 60 years of age and with scores on the Montgomery-Asberg Depression Rating Scale (MADRS) > or = 20, were treated with fluoxetine (20 mg/day) for 42 days. Biological variables measured on days 1 and 42 included whole blood and plasma serotonin, plasma total and free tryptophan, and platelet paroxetine and ketanserin binding. Seven of the 16 patients showed a positive clinical response (i.e. MADRS score < or = 12 at day 42). The pre-treatment red blood cell count was the variable most related to clinical response; low levels were found in almost all responders. To a lesser extent, plasma free tryptophan before treatment was also correlated to therapeutic response, with lower values being found in responders. During treatment, plasma free tryptophan was increased in responders and decreased in non-responders. The finding that elderly depressed patients with low pre-treatment red blood cell counts subsequently responded to fluoxetine treatment is consistent with the view that tryptophan, the precursor of serotonin in brain, is taken up by red blood cells.