Several methods of platelet membrane preparation and binding conditions were screened in order to optimize the labeling of serotonergic 5-HT2 receptors on previously frozen human platelet membranes with tritiated ketanserin. Under optimal conditions, 5-HT2 receptors in normal subjects (5 males, 7 females, age range 21 to 71) have a Kd of 1.5 +/- 0.2 nM and a Bmax of 33.9 +/- 5.3 fmole/mg protein. In a group of patients with major depressive disorder exactly matched for age and sex with the normal control group, we find a significant increase in receptor density, to 66.8 +/- 11.4 fmole/mg, with no significant change in the affinity (2.3 +/- 0.5 nM). Four weeks of treatment with antidepressant drugs result in a significant decrease of Bmax, down to control levels (29.4 +/- 3.9). Thus, ketanserin can be used to monitor changes in platelet serotonin 5-HT2 receptors which may be a relevant marker for the state of depression.