Decreased platelet serotonin transporter sites and increased platelet inositol triphosphate levels in patients with unipolar depression: Effects of clomipramine and fluoxetine

Background: The central serotonergic system has been implicated in the path ophysiology of depression and in the mechanism of the action of antidepress ant drugs. The human platelet has been proposed as a peripheral model of ce ntral serotonergic neurons. Methods: Six peripheral serotonergic parameters were determined simultaneou sly in 27 patients with unipolar depression before and after 2, 4, and 12 w eeks of clomipramine or fluoxetine treatment according to the psychiatrist. Results: In patients with depression versus matched control subjects, plate let [H-3]paroxetine binding sites were found to be significantly decreased (2.10 +/- 0.70 versus 3.88 +/- 0.77 fmol/10(9) platelets; P = .0001), plate let serotonin (5-HT) content was found to be significantly decreased (1.90 +/- 1.52 versus 2.74 +/- 1.12 nmol/10(9) platelets; P = .001), and platelet inositol triphosphate levels were found to be significantly increased (2.8 5 +/- 0.70 versus 1.85 +/- 0.77 fmol/10(9) platelets; P = .0001). No signif icant difference between patients and control subjects was found for platel et [H-3]-lysergic acid diethylamide ([H-3]LSD) binding sites, aggregation t ests with 5-HT or adenosine diphosphate and plasma 5-HT levels. Treatment w ith both clomipramine and fluoxetine gradually further reduced the density of platelet [H-3]paroxetine binding sites and induced a dramatic decrease i n platelet and plasma 5-HT levels. With clomipramine, the decreased blood 5 -HT levels are associated with increased platelet [H-3]LSD binding sites an d aggregation responses. After 12 weeks, nonresponders to both treatments h ad platelet inositol triphosphate levels that were still increased (2.81 +/ - 0.75 fmol/10(9) platelets) when responders levels were not different from those of control subjects (1.41 +/- 0.45 versus 1.70 +/- 0.25 fmol/10(9) p latelets). Conclusions: Drug-free patients with depression had simultaneously decrease d 5-HT transporter (5-HTT) sites and overstimulated phosphoinositide signal ing systems. Clomipramine and fluoxetine treatments, which further decrease d the density of 5-HTT sites, allowed platelet inositol triphosphate levels to return to normal values only in responders.