Association of platelet function with depression and its treatment with sertraline in patients with chronic kidney disease: analysis of a randomized trial

Nishank Jain, Fei Wan, Monica Kothari, Anuoluwapo Adelodun, Jerry Ware, Ravi Sarode, S Susan Hedayati, Nishank Jain, Fei Wan, Monica Kothari, Anuoluwapo Adelodun, Jerry Ware, Ravi Sarode, S Susan Hedayati

Abstract

Background: Major Depressive Disorder (MDD) can lead to adverse cardiovascular outcomes in patients with chronic kidney disease (CKD). Although one of the proposed mechanisms is heightened platelet activation, effects of MDD and its treatment with a selective serotonin reuptake inhibitor (SSRI) on platelet function in patients with CKD remain unclear.

Methods: In a pre-specified analysis, changes from baseline to 12 weeks in whole blood platelet aggregation (WBPA) and plasma levels of E-selectin and P-selectin on treatment with sertraline vs. placebo were investigated in 175 patients with CKD (estimated glomerular filtration rate [eGFR] < 60 ml/min/1.73m2) and MDD (MDD+/CKD+) in a randomized, double-blind trial. Correlations between severity of depressive symptoms and platelet function were also analyzed. In order to investigate whether differences in platelet function were due to presence of CKD or MDD, we compared a subgroup of 49 MDD+/CKD+ patients with eGFR < 30 ml/min/1.73m2 to 43 non-depressed CKD controls (28 CKD with eGFR < 30 ml/min/1.73m2 [MDD-/CKD+] and 15 individuals with eGFR ≥90 ml/min/1.73m2 [MDD-/CKD-].

Results: In MDD+/CKD+ individuals, there were no significant correlations between severity of depressive symptoms and platelet function, and no significant changes in platelet function after 12 weeks of treatment with sertraline vs. placebo. There were no significant differences in platelet function among MDD+/CKD+ patients and controls without MDD except in WBPA to 10 μM ADP (P = 0.03). WBPA to ADP was lower in the MDD-/CKD- group (8.0 Ω [5.0 Ω, 11.0 Ω]) as compared to the MDD-/CKD+ group (12.5 Ω [8.0 Ω, 14.5 Ω]), P = 0.01, and the MDD+/CKD+ group (11.0 Ω [8.0 Ω, 15.0 Ω]), P < 0.01.

Conclusions: Heightened ADP-induced platelet aggregability was observed in CKD patients compared to controls with normal kidney function, regardless of presence of comorbid MDD, and treatment with sertraline did not affect platelet function. These findings suggest that increased platelet activation may not be a major contributory underlying mechanism by which depression may lead to worse cardiovascular outcomes in patients with CKD. Future studies should include positive MDD controls without CKD to confirm our findings.

Trial registration: ClinicalTrials.gov identifier numbers: CAST Study: NCT00946998 (Recruitment Status: Completed. First Posted: July 27, 2009. Results First Posted: January 30, 2018). WiCKDonASA Study: NCT01768637 (Recruitment Status: Completed. First Posted: January 15, 2013. Results First Posted: April 19, 2019).

Keywords: Chronic kidney disease; Depression; Platelet aggregation; Platelet function; Selective serotonin reuptake inhibitors; Sertraline.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Participant Flow Diagram. The study design of the two trials from which the cohort was formed and time points for data collection. CKD, Chronic Kidney Disease; CAST, CKD Antidepressant Sertraline Trial; MDD, Major Depressive Disorder; WICKDonASA, Whole Blood Platelet Aggregation in Chronic Kidney Disease on Aspirin study
Fig. 2
Fig. 2
Grouped Boxplot Diagram. To investigate whether differences in platelet function were due to presence of chronic kidney disease (CKD) or major depressive disorder (MDD), comparisons were made between 49 patients with MDD and CKD (MDD+/CKD+), 15 non-depressed controls with normal kidney function (MDD−/CKD-) and 28 non-depressed controls with CKD (MDD−/CKD+) using non-parametric ANOVA on ranked outcomes. Panel a Represents comparison of whole blood platelet aggregation induced by agonists including collagen, arachidonic acid (AA), adenosine diphosphate (ADP). Overall P = 0.03 for difference between 3 groups for WBPA induced by 10 μM ADP and P = 0.02 for 20 μM of ADP; Panel b Represents comparison of platelet ATP secretion induced by agonists including collagen, arachidonic acid (AA), and thrombin; and, Panel c Represents comparison of plasma levels of P-selectin (CD62P) and E-selectin (CD62E). Asterisks represent significant p-values in pairwise comparisons

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