We found that resting (unstimulated) PBMC telomerase activity was significantly higher in unmedicated depressed individuals compared with matched healthy controls. The elevated telomerase activity was more apparent in those depressed individuals who responded more poorly to 8 weeks of antidepressant treatment. We also found that depressed individuals with greater increases in PBMC telomerase activity during the treatment period had better responses to the antidepressant. Specifically, depressed individuals with relatively lower baseline (pre-treatment) telomerase activity, and those whose telomerase activity increased the most with antidepressant treatment, showed the greatest benefit from antidepressant treatment. Given the relatively small sample size, it is not possible to estimate the independence of the effects of baseline telomerase activity and changes in telomerase activity in predicting treatment response. However, individuals with relatively low baseline telomerase activity and relatively greater increases in telomerase activity with treatment showed especially good antidepressant responses. These findings are novel and need to be replicated with a larger sample, but they do raise the possibility of the involvement of telomerase, a cell viability promoting enzyme, in depression and in antidepressant responses.
Our finding of higher PBMC telomerase activity in depressed individuals is consistent with related findings from some studies, but not others, although, to our knowledge, ours is the first study to assess telomerase activity in MDD. In a study of chronically stressed (but generally not depressed) maternal caregivers, decreased PBMC telomerase activity was observed along with shortened leukocyte telomeres.13
However, in another study, stressed caregivers had shortened PBMC telomeres along with elevated telomerase activity.24
The caregivers in that study had higher depression ratings than controls, but it is not known how many, if any, had MDD. The authors of that study interpreted the elevated telomerase activity as ‘an unsuccessful attempt to compensate for the excessive loss of telomeres’.24
The possibility that increased telomerase activity reflects a compensatory response to cellular damage is consistent with preclinical and clinical data suggesting that telomerase preferentially elongates shorter telomeres,59–61
and that telomerase reverse transcriptase (the catalytic subunit of telomerase) is induced in response to certain types of cell injury, such as ischemic injury in brain cells.22,62
The prediction of antidepressant response by PBMC telomerase activity, both before treatment and during treatment, has not previously been reported. We found that relatively low telomerase activity before treatment, and relatively greater increases in telomerase activity with treatment, predicted better response to antidepressants. It is possible that telomerase activation is beneficial in the treatment of depression, as suggested by the observed correlation between telomerase activity increases and degree of antidepressant response. Especially high baseline telomerase activity, however, could indicate more underlying depression-related pathology, which could have induced greater telomerase activation. 22,44,63
Individuals with the highest pre-treatment telomerase activity may have already sustained as much benefit as is possible from endogenous telomerase activation, whereas those individuals with normal or only mildly elevated telomerase activity at baseline may be more likely to benefit from exogenously induced telomerase activation (that is, from medication). Consistent with the possibility that telomerase activation is beneficial in depression, several recent studies have suggested that healthful lifestyle changes,64
moderate physical exercise65,66
and extended periods of mindfulness meditation67
increase PBMC telomerase activity. In the former study, increases in telomerase activity were significantly correlated with decreases in psychological distress.64
For now, explanations of our findings remain speculative, although they lay the foundation for replication studies and for future prospective mechanism-oriented studies.
In our exploratory analysis, we did not find significant relationships between telomerase activity and telomere length. The reasons for this are unknown, but telomerase activity and telomere length change along very different time lines and under different circumstances, and thus may be unrelated. 40,58
Other reasons for the lack of significant correlations between telomere length and telomerase activity have been proposed,68
including the shuttling of telomerase from the nucleus to the mitochondria under conditions of oxidative stress,69,70
and the possibility that telomerase may decrease the number of PBMC’s with ‘short’ telomeres without significantly altering average PBMC telomere length.61
It is possible that depression-related inflammation and/or oxidative stress contributed to our findings, as these may be associated both with shortened telomeres7,15,71
and with stimulatory effects on telomerase activity52–56
(although see ref. 57
). Our other exploratory analysis, however, did not support this interpretation. In sum, it is not known whether the increase in telomerase activity seen in depression reflects a salutary process (attempted protection of telomeres and recovery of telomere length), a deleterious one (direct stimulation by cytotoxic processes) or both.
The major strengths of the present study are the use of physically healthy, well characterized subjects, the exclusion of medications that might have influenced our results, the inclusion of a plasma concentration-verified antidepressant treatment component and the use of a sensitive and quantitative telomerase assay that measures activity in unstimulated PBMC’s. The major limitations are the small sample size and the open-label nature of the antidepressant treatment. Another limitation is the lack of determination of telomerase activity in specific PBMC cell types,43
as differences in PBMC telomerase activity could result either from telomerase activity changes on a per-cell basis or from different proportions of circulating PBMC types, with certain cell types having different degrees of telomerase activity than others. This possibility remains to be tested in future studies.
If the present and other emerging data are replicated, the telomere/telomerase system may emerge as a novel site of pathophysiology in MDD. Future studies would then be needed to ascertain the clinical significance of these changes and whether direct manipulation of this system might hold promise for novel therapeutics, as has been proposed for other illnesses involving telomere/telomerase dysregulation.6,42,61,72–74