Telomere Length in Schizophrenia Adrienne Maguire MS 2

  • Slides: 1
Download presentation
Telomere Length in Schizophrenia Adrienne Maguire, MS 2 and Rachel Loewy, Ph. D University

Telomere Length in Schizophrenia Adrienne Maguire, MS 2 and Rachel Loewy, Ph. D University of California Davis, School of Medicine; University of California, San Francisco Telomeres in Schizophrenia • Telomeres are tandem repeat sequences (TTAGGG) at the end of linear eukaryotic DNA (15) • These repeats protect chromosomes from being recognized as damaged DNA, help to regulate gene expression, and participate in controlling cell replication and entry into senescence (1, 2) • Cell division, and thus aging, leads to progressive telomere shortening • Critically short telomeres cause cell checkpoint genes to be activated (TP 53) and the cells with dysfunctional telomeres undergo apoptosis (2) • Shortened telomeres have been associated with CVD, stroke, obesity, cancer, T 2 DM, and other chronic illnesses (1, 2, 5, 9, 28) • Schizophrenia has been described as a disorder of aging (3, 8, 11, 18, 19) • There has been conflicting evidence on whether TL is shortened or elongated in SCZ, but a recent metaanalysis reveals there is more evidence that TL is shortened in SCZ (3, 4, 8, 11, 16, 18, 19, 26) • Some studies have found shorter TL in those with more severe disease, speculating that there could be greater lifetime exposure to oxidative stress and pathological damage, leading to accelerated ageing (11, 18, 19) • One study looked at the difference in TL between SCZ inpatients who were good responders versus poor responders to antipsychotic medications and found that the poor responders had shorter LTL compared to good responders and healthy controls (26) • Other studies have found no correlation with TL and lifetime exposure to antipsychotics (8) • Studies on telomerase activity in SCZ have also revealed conflicting evidence (20, 26) • Overall, many of these studies have had low sample sizes • Many studies have not controlled well for somatic and/or psychiatric co-morbidities, nor for lifestyle conditions (diet, exercise, smoking, BMI) Telomeres in Psychiatric Illness A meta-analysis in 2015 showed shorter TL across psychiatric disorders (3) MDD • A majority of the studies done on MDD and telomere length have found that there is shortening (3, 22) • Some studies have suggested that the shortening is more pronounced in groups that have had a longer duration of illness and a more severe manifestation of MDD, linking these findings to measures of oxidative stress and inflammation (23, 24) • Researchers are looking further into the relationship between depression, anti-depressants, treatment responsiveness and telomerase levels (13, 25) Bipolar Disorder • There is more conflicting evidence for TL in BD – some studies show longer, others show shorter, and some show no difference between BD and HC (21, 22) • Some evidence of those who are good responders to Lithium have longer TL (13) Anxiety/PTSD • Some conflicting evidence between shorter TL and no difference compared to controls (3, 6, 7, 10, 12, 17) • Some of this evidence points to shortened LTL in those exposed to childhood adversity (7) RESEARCH POSTER PRESENTATION DESIGN © 2012 www. Poster. Presentations. com Future Directions REFERENCES • There has not yet been research on telomere length in UHR versus first episode or chronic schizophrenia patients. • Further research on UHR groups could help to identify new therapeutic targets for preventing or slowing the progression to psychosis • After identifying the differences between UHR and SCZ groups, differences in telomerase activity can be explored • Not many studies have been able to elucidate the causality or temporality of telomere shortening in psychiatric disorders, especially for schizophrenia • There is limited research on how telomeres and telomerase are altered by psychotropic medications • Further investigation into the overlap between the comorbidities seen in SCZ and telomere length • Investigation on ACEs and UHR TL 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. Increase Oxidative Stress 15. UHR 16. 17. 18. Shortened TL UHR and Telomeres • Ultra-High-Risk youth have been of increasing interest in the identification and intervention for those at risk of developing schizophrenia • It is estimated that up to 35% of those identified as UHR experience a psychotic episode within 2. 5 years of identification (27) • Very little research has been done on UHR groups and telomere length • One study has been done on this group that revealed there was shorter LTL in UHR groups as compared to controls that were adjusted for age, sex, ethnicity, and education (14) • This could imply that there are, in fact, telomere erosion present early in disease before the onset of full psychosis • This study had a small sample size (n=110, only 22 UHR subjects) ; more research should be done in this group 1. 2. 19. SCZ Low TA 20. 21. 22. 23. ABBREVIATIONS TL = Telomere Length MDD = Major Depressive Disorder BD = Bipolar Disorder PTSD = Post-Traumatic Stress Disorder SCZ = Schizophrenia UHR = Ultra-High-Risk ACE = Adverse Childhood Experiences TA = Telomerase Activity 24. 25. 26. 27. 28. Anthes E. Ageing: Live faster, die younger. Nature. 2014; 508(7494): S 16 -7. Childs BG, Durik M, Baker DJ, Van deursen JM. Cellular senescence in aging and age-related disease: from mechanisms to therapy. Nat Med. 2015; 21(12): 1424 -35. Darrow SM, Verhoeven JE, Révész D, et al. The Association Between Psychiatric Disorders and Telomere Length: A Meta-Analysis Involving 14, 827 Persons. Psychosom Med. 2016; 78(7): 776 -87. Fernandez-egea E, Bernardo M, Heaphy CM, et al. Telomere length and pulse pressure in newly diagnosed, antipsychotic-naive patients with nonaffective psychosis. Schizophr Bull. 2009; 35(2): 437 -42. Fitzpatrick AL, Kronmal RA, Gardner JP, et al. Leukocyte telomere length and cardiovascular disease in the cardiovascular health study. Am J Epidemiol. 2007; 165(1): 14 -21. Hoen PW, Rosmalen JG, Schoevers RA, Huzen J, Van der harst P, De Jonge P. Association between anxiety but not depressive disorders and leukocyte telomere length after 2 years of follow-up in a population-based sample. Psychol Med. 2013; 43(4): 689 -97. Kananen L, Surakka I, Pirkola S, et al. Childhood adversities are associated with shorter telomere length at adult age both in individuals with an anxiety disorder and controls. PLo. S ONE. 2010; 5(5): e 10826. Kao HT, Cawthon RM, Delisi LE, et al. Rapid telomere erosion in schizophrenia. Mol Psychiatry. 2008; 13(2): 118 -9. Kim S, Parks CG, Deroo LA, et al. Obesity and weight gain in adulthood and telomere length. Cancer Epidemiol Biomarkers Prev. 2009; 18(3): 816 -20. Ladwig KH, Brockhaus AC, Baumert J, et al. Posttraumatic stress disorder and not depression is associated with shorter leukocyte telomere length: findings from 3, 000 participants in the population-based KORA F 4 study. PLo. S ONE. 2013; 8(7): e 64762. Lin PY. Shortened leukocyte telomere length in patients with schizophrenia is related to disease status. Schizophr Res. 2015; 168(1 -2): 597 -8. Lindqvist D, Epel ES, Mello. Ladwig KH, Brockhaus AC, Baumert J, et al. Posttraumatic stress disorder and not depression is associated with shorter leukocyte telomere length: findings from 3, 000 participants in the population-based KORA F 4 study. PLo. S ONE. 2013; 8(7): e 64762. Martinsson L, Wei Y, Xu D, et al. Long-term lithium treatment in bipolar disorder is associated with longer leukocyte telomeres. Transl Psychiatry. 2013; 3: e 261. Maurya PK, Rizzo LB, Xavier G, et al. Shorter leukocyte telomere length in patients at ultra high risk for psychosis. Eur Neuropsychopharmacol. 2017; 27(5): 538 -542. Moyzis RK, Buckingham JM, Cram LS, et al. A highly conserved repetitive DNA sequence, (TTAGGG)n, present at the telomeres of human chromosomes. Proc Natl Acad Sci USA. 1988; 85(18): 6622 -6. Nieratschker V, Lahtinen J, Meier S, et al. Longer telomere length in patients with schizophrenia. Schizophr Res. 2013; 149(1 -3): 116 -20. SCZ O'donovan A, Epel E, Lin J, et al. Childhood trauma associated with short leukocyte telomere length in posttraumatic stress disorder. Biol Psychiatry. 2011; 70(5): 465 -71. Pawelczyk T, Szymanska B, Grancow-grabka M, Kotlicka-antczak M, Pawelczyk A. Telomere length in blood cells is related to the chronicity, severity, and recurrence rate of schizophrenia. Neuropsychiatr Dis Treat. 2015; 11: 1493 -503. Polho GB, De-paula VJ, Cardillo G, Dos santos B, Kerr DS. Leukocyte telomere length in patients with schizophrenia: A meta-analysis. Schizophr Res. 2015; 165(2 -3): 195 -200. Porton B, Delisi LE, Bertisch HC, et al. Telomerase levels in schizophrenia: a preliminary study. Schizophr Res. 2008; 106(2 -3): 242 Rizzo LB, Do prado CH, Grassi-oliveira R, et al. Immunosenescence is associated with human cytomegalovirus and shortened telomeres in type I bipolar disorder. Bipolar Disord. 2013; 15(8): 832 -8. Simon NM, Smoller JW, Mcnamara KL, et al. Telomere shortening and mood disorders: preliminary support for a chronic stress model of accelerated aging. Biol Psychiatry. 2006; 60(5): 432 -5. Wikgren M, Maripuu M, Karlsson T, et al. Short telomeres in depression and the general population are associated with a hypocortisolemic state. Biol Psychiatry. 2012; 71(4): 294 -300. Wolkowitz OM, Mellon SH, Epel ES, et al. Leukocyte telomere length in major depression: correlations with chronicity, inflammation and oxidative stress--preliminary findings. PLo. S ONE. 2011; 6(3): e 17837. Wolkowitz OM, Mellon SH, Epel ES, et al. Resting leukocyte telomerase activity is elevated in major depression and predicts treatment response. Mol Psychiatry. 2012; 17(2): 164 -72. Yu WY, Chang HW, Lin CH, Cho CL. Short telomeres in patients with chronic schizophrenia who show a poor response to treatment. J Psychiatry Neurosci. 2008; 33(3): 244 -7. Yung AR, Phillips LJ, Yuen HP, Mcgorry PD. Risk factors for psychosis in an ultra high-risk group: psychopathology and clinical features. Schizophr Res. 2004; 67(2 -3): 131 -42. Zhang C, Chen X, Li L, Zhou Y, Wang C, Hou S. The Association between Telomere Length and Cancer Prognosis: Evidence from a Meta-Analysis. PLo. S ONE. 2015; 10(7): e 0133174. CONTACT Adrienne Maguire: ammaguire@ucdavis. edu Rachel Loewy: Rachel. Loewy@ucsf. edu