AbstractBackgroundBlood platelets, due to shared biochemical and functional properties with presynaptic serotonergic neurons, constituted, over the years, an attractive peripheral biomarker of neuronal activity. Therefore, the literature strongly focused on the investigation of eventual structural and functional platelet abnormalities in neuropsychiatric disorders, particularly in depressive disorder. Given their impact in biological psychiatry, the goal of the present paper was to review and critically analyze studies exploring platelet activity, functionality, and morpho-structure in subjects with depressive disorder.MethodsAccording to the PRISMA guidelines, we performed a systematic review through the PubMed database up to March 2020 with the search terms: (1)platelets in depression [Title/Abstract]”; (2) “(platelets[Title]) AND depressive disorder[Title/Abstract]”;(3)“(Platelet[Title]) AND major depressive disorder[Title]”;(4)(platelets[Title]) AND depressed[Title]”;(5)(platelets[Title]) AND depressive episode[Title]”;(6)(platelets[Title]) AND major depression[Title]”;(7)platelet activation in depression[All fields]”;and (8)platelet reactivity in depression[All fields].”ResultsAfter a detailed screening analysis and the application of specific selection criteria, we included in our review a total of 106 for qualitative synthesis. The studies were classified into various subparagraphs according to platelet characteristics analyzed: serotonergic system (5-HT_2Areceptors, SERT activity, and 5-HT content), adrenergic system, MAO activity, biomarkers of activation, responsivity, morphological changes, and other molecular pathways.ConclusionsDespite the large amount of the literature examined, nonunivocal and, occasionally, conflicting results emerged. However, the findings on structural and metabolic alterations, modifications in the expression of specific proteins, changes in the aggregability, or in the responsivity to different pro-activating stimuli, may be suggestive of potential platelet dysfunctions in depressed subjects, which would result in a kind of hyperreactive state. This condition could potentially lead to an increased cardiovascular risk. In line with this hypothesis, we speculated that antidepressant treatments would seem to reduce this hyperreactivity while representing a potential tool for reducing cardiovascular risk in depressed patients and, maybe, in other neuropsychiatric conditions. However, the problem of the specificity of platelet biomarkers is still at issue and would deserve to be deepened in future studies.