Indices of cellular health are associated with antidepressant treatment response

Background: Accelerated cellular aging, evidenced by shortened leukocyte telomere length (LTL), has been reported in Major Depressive Disorder (MDD), and may convey an increased risk for somatic co-morbidity. Shortened LTL reflects a cell’s mitotic history, cellular “age” and cumulative exposure to inflammation and oxidation, as well as the availability of telomerase, a telomere-lengthening enzyme. Telomere shortening leads to replicative senescence and cellular malfunctions including oxidative stress, mitochondrial damage, and apoptosis. Here we present data linking indices of accelerated cellular aging to worse antidepressant treatment response in MDD. Methods: Unmedicated MDD subjects were assessed before and after 8-weeks of open-label SSRI treatment. Results: Lower antidepressant treatment efficacy was associated with i) shorter pre-treatment LTL (p<0.05, n=27), ii) smaller increases in telomerase activity over the course of treatment (p<0.01, n=16), iii) higher levels of oxidative stress markers pre-treatment (p<0.01, n=22), and iv) a greater increase in oxidative stress during treatment (p<0.05, n=22). Circulating cell free mitochondrial DNA (CCf-mtDNA), a potential marker for mitochondrial stress and cellular damage, was highly elevated was highly significantly elevated in unmedicated MDD compared to healthy controls (p<0.00001, n=105), and ccf-mtDNA increased during treatment in non-responders, but not in responders (p=0.02, n=19). Conclusions: Our data show, from multiple indices of cellular health, that accelerated cellular aging or damage is associated with poorer antidepressant response in MDD. Cellular health may be an important moderator of successful antidepressant response.