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. 2021 Jun 7;10(6):1423. doi: 10.3390/cells10061423

Table 1.

Study characteristics, clinical and epidemiological data analysis of depressive disorders impacts on telomere lenght.

Authors Date of Publication Country Study Design Patients Age, Years, Mean (SD) Sex, n (%) Male Main Comorbidities/ Lifestyle factors Associated Race/Ethnicity Other Associated Psychiatric Diseases in This Study Medication Telomere Measurement and Tissue Measurement of Psychiatric Disorder Level of Depression Telomere Lenght
Garcia-Rizo et al. [16] Feburary 2013 Spain Case-control study Control 70 (For telomere content, n = 48) 27.8 (6.8) (62.2%) BMI: 23.7 (2.9), Mean number of cigarettes/day: 6.2 (8.3) NA - NA mTL, Southern blot, Leukocytes SCID MDD (n = 15) Shortened telomere are present early in the course of depression independently of the confounding. Abnormal glucose tolerance and lymphopenia were also related to MDD
Case 15 (For telomere content, n = 9) 30.7 (10.0) 60% BMI: 23.4 (4.1), Mean number of cigarettes/day: 9.9 (12.7) NA
Chen et al. [17] December 2014 USA Case-control study Control 20 Patients were individually matched on age (±3 years), gender and ethnicity Full patients data were not available - NA mTL, PCR, Leukocytes QIDS, SCID MDD (n = 20) In healthy controls, greater ACE exposure was associated with shorter LTL but was unassociated with telomerase activity. In MDD, greater ACE exposure was unrelated to LTL but was associated with increased telomerase activity and with a higher telomerase:
Case 20
Tyrka et al. [18] January 2016 USA Case-control study Control 113 28.5 (9.2) 50 (44.2%) Smokers (8.3%) White (82.3%) Adversities, depression, PTSD and anxiety NA mTL, qPCR, Leukocytes SCID, STAI, PSS, CD-RISC Significantly higher mtDNA copy numbers and shorter telomeres were seen in individuals with major depression, depressive disorders, and anxiety disorders, as well as those with parental loss and childhood maltreatment.
Case 1—Adverity with no psychiatric disorder 66 31.3 (11.1) 26 (39.4%) Smokers (7.8%) White (80.3%)
Case 2—Psichyatric disorder with no adversity 39 30.7 (10.4) 15 (38.5%) Smokers (7.7%) White (92.3%) MDD (n = 6), depressive (n = 7)
Case 3—Adversity and psychiatric disorder 72 34.8 (12.0) 22 (30.6%) Smokers (17.1%) White (81.9%) MDD (n = 7), depressive (n = 18)
Prabu et al. [19] July 2020 India Case-control study Control—NGT and no depression 40 48 (10) 21 (52.5%) BMI: 26 (4.2) NA - 66 T2DM patients
were on anti-diabetic medication alone. 14 T2DM patients were on anti-diabetic plus antihypertensive/statin medication. 		RTL, rQ-PCR, blood sample PHQ-9, PHQ-12 NA Patients with type 2 diabetes and depression exhibited increased circulatory levels of miR-128 and serum cortisol and shortened telomeres.
Case 1—NGT with depression 40 50 (11) 20 (50%) BMI: 26.8 (5.8)
Case 2—T2DM and no depression 40 54 (6) 21 (52.5%) BMI: 25.4 (4.9)
Case 3—T2DM with depression 40 54 (7) 21 (52.5%) BMI: 25.5 (3.7)
Vincent et al. [20] February 2017 United Kingdom Case-control study Control 100 50.84 (16.89) F:51 (51%) M:49 (49%) BMI: 26.89 (5.39) White - NA RTL, qPCR, Leukocytes CIS-R, SCAN - Shortened RTL was specifically associated with childhood physical neglect, but not the other subtypes of maltreatment or depression case/control status.
Case 80 48.63 (13.9) F: 52 (65%) M: 28 (35%) BMI: 28.47 (6.87) Mild depression (n = 15), moderate or severe depression (55), mixed depression/anxiety (n = 10)
Hoen et al. [21] August 2012 Netherlands Case-control study Control 980 53.7 (11.3) F: 551 M: 465 Smoking (n = 225; 77%), Alcohol consumption (n = 788; 80%), Sedentarism (n = 505; 52%) NA Anxiety mTL, PCR, Leukocytes CIDI NA No association was found between depressive disorders and
shorter telomeres at follow-up. Anxiety disorders predicted shorter telomere length at follow-up in a general
population cohort.
Case 97 51.3 (10.7) F: 62
M: 36		 Smokers (n = 32; 65%); Alcohol consumption (n = 78; 80%), Sedentarism (n = 50; 52%) Antidepressant use (n = 14; 15%)
Bersani et al. [22] October 2015 USA Cross-sectional study Control 76 34.64 (9.17) All male Years of education (mean ± SD): 14.79 ± 2.44, current smokers (n): 11 Hispanic (n = 35); Non Hispanic (n = 42)* PTSD Statins (n = 2), NSAIDs (n = 5), antidepressants (n = 13), antibiotics (n = 1), hormone drugs for prostate cancer (n = 1), analgesics (n = 1) RTL, PCR, Granulocytes CAPS, BDI-II, ETI, SCL-90-GSI, PSS, PANAS PTSD associated with MDD (n = 17) Early trauma, severity of perceived stress and general psychopathological symptoms are more closely associated with shorter TL than is the severity of core diagnostic symptoms of PTSD or MDD
Hoen et al. [23] September 2011 USA Cohort study Control 746 68.1 (10.6) 634 (85%) Smoking (n = 131, 18%) White (85%) - CDIS-IV, PHQ-9 Depression is associated with reduced leukocyte telomere length in patients with coronary heart disease but does not predict 5-year change in telomere length
Case 206 61.7 (10.8) 142 (69%) Smoking (n = 58, 28%) White (60%) Antidepressant use (n = 99, 48%) mTL, qPCR, Leukocytes Major Depression
AlAhwal et al. [24] February 2019 Saudi Arabia Cross-sectional study Cohort—Patients with colorectal cancer in Saudi Arabia 50 54.5 (11.8) 26 (52%) - NA - - TL measurement not specified, rQ-PCR and tissue not specified SCID-I, HDRS MDD (10%), disthymia (10%), minor depression (4.0%) TL progressively shortened from no depressive disorder
to minor depression to dysthymia to major depressive disorder.
TL was also strongly and inversely correlated with severity of depressive
symptoms on the HDRS.
Needham et al. [11] April 2015 USA Cross-sectional study No depression 966 29.2 (5.9) 425 (44%) NA Non-Hispanic white (50.2%); African american (19.5%); Mexican American (30.3%) Anxiety Antidepressant use (n = 32, 3.3%) RTL, qPCR, Leukocytes CIDI Neither depressive nor anxiety disorders were directly associated with telomere length, in young adults. There was suggestive evidence that pharmacologically-treated MD is associated
with shorter telomere length, likely reflecting the more severe nature of MD that has come to
clinical attention.
MD or depressed affect 198 30.3 (5.8) 84 (42.4%) Non-Hispanic white (51.0%); African american (19.7%); Mexican American (29.3%) Antidepressant use (n = 20, 10.1%) Depressed affect only (n = 123, 62.1%); Major depression (n = 75, 37.9%)
Verhoeven et al. [25] April 2018 USA, Canada and The Netherlands Cohort study Year 15 977 40.5 (3.6) 338 (34.6%) Obese: 32.7%, former smoker: 18.7%, current smoker: 19%; heavy drinker: 9.3%; number of somatic diseases, mean (SD): 0.9 (1.1); physical activity, mean (SD): 336 (274) White (59.4%) - Current antidepressant use (n = 67, 6.9%) mTL, qPCR, Leukocytes CES-D CES-D score: 8.5 (7.3); Depression past year (n = 86, 8.8%); Depression life-time (n = 151, 15.5%) Evidence for a long-term, between-person relationship of depressive symptoms with LTL, rather than a dynamic and direct within-person relationship
Year 20 45.4 (3.6) Obese: 38.5%, former smoker: 21.5%, current smoker: 15.5%; heavy drinker: 10.3%; number of somatic diseases, mean (SD): 1.0 (1.2); physical activity, mean (SD): 334 (273) Current antidepressant use (n = 101, 10.3%) CES-D score: 9.0 (7.8); Depression past year (n = 111, 11.4%); Depression life-time (n = 182, 18.6%)
Year 25 50.4 (3.6) Obese: 38.5%, former smoker: 21.5%, current smoker: 15.5%; heavy drinker: 10.3%; number of somatic diseases, mean (SD): 1.0 (1.2); physical activity, mean (SD): 335 (272) Current antidepressant use (n = 109, 11.1%) CES-D score: 9.0 (7.4); Depression past year (n = 131, 13,4%); Depression life-time (n = 210, 21.5%)
Verhoeven et al. [26] June 2016 Usa and The Netherlands Cohort study Baseline 2936 41.8 (13.1) 33.6% Obese: 16.7%, former smoker: 33.2, current smoker: 38.7%; heavy drinker: 12.7% NA Current anxiety disorder (n = 535, 32.0%) Tricyclic antidepressants (n = 79, 2.7%); Selective serotonin reuptake inhibitor (n = 502, 17.1), Other antidepressants (n = 164, 5.6%) RTL, qPCR, Leukocytes CIDI Current Depressive diagnosis disorder (n = 389, 23.3%), Control (n = 644, 21.9%), Remitted (n = 620, 21.1%) Robust associations of depressive and anxiety disorders with shorter telomeres, but interestingly, it did not demonstrate that depressive and anxiety disorders and LTL change together over time, suggesting the absence of a direct within-person relationship. Short LTL is suggested to be either a long-term consequence or an underlying vulnerability factor for depressive or anxiety disorders
Year 6 1883 48.6 (12.9) 34.6% Obese: 19.8%, former smoker: 42.3%, current smoker: 28.2%; heavy drinker: 9.9% Current anxiety disorder (n = 190, 36.0%) Tricyclic antidepressants (n = 56, 3.0%); Selective serotonin reuptake inhibitor (n = 224, 11.9), Other antidepressants (n = 104, 5.5%) Current Depressive diagnosis disorder (n = 159, 30.1%), Control (n = 440, 23.4%), Remitted (n = 915, 48.6%)
Whisman et al. [27] February 2017 USA Cross-sectional study 3609 67.0 (10.0) 1404 (43.7) BMI, mean (SD): 28.4 (6.0), Diabetes (19,5%), Cancer (14.1%), Heart disease (25.0), Stroke (6.0) White (87.7%), Black (9.7%), Latin (7.4%), Other (2.6%) - NA NA, RT-qPCR, saliva sample CES-D Depressive symptoms, mean (SD): 1.5 (2.0) Higher levels of depressive symptoms were associated with shorter salivary telomeres in men, and this association was incremental to several potential confounds.
Lin et al. [28] February 2015 USA Cross-sectional study 464 64.87 (10.99) 368 (79.31) Current smoker
(n = 132, 28.45%), former smoker
(n = 199, 42.89%), Non-Muscle-Invasive Bladder Cancer (n = 234, 53.67%)		 White (93.1%), Hispanic (3.23%), Black (3.23%), Other (0.44%) - NA RTL, rQ-PCR, Lymphocytes CES-D, SCID Alive with CESD < 16 (n = 280, 84.08%), Alive with CES-D ≥16 (63, 67.74%), Dead with CES-D < 16 (n = 53, 15.92%), Dead with CES-D ≥ 16 (n = 30, 32.26%) Short telomere length and depressive symptoms
are associated with bladder cancer mortality individually and
jointly.
Zhao et al. [29] November 2016 USA Cross-sectional study 2175 40.4 (17.0) 847 (38.9%) BMI: 31.3 (7.5), smoker (36.4%), drinker (58.0%, physical activity, steps/d, mean (SD): 5845.3 (3899.9) American indians - Antidepressant use: 5.2% RTL, qPCR, Leukocytes CES-D None (50.2%), mild (21.9%), moderate (15.6%), severe (12.3%) Results showed that individuals with a
higher level of depressive symptoms had shorter LTL.
Shaffer et al. [30] October 2012 USA Cross-sectional study 2225 48.2 (18.9) 1115 (50.1%) BMI: 27.0 (5.5), Diabetes mellitus (n = 101, 4.5%), Previous ischemic heart disease (n = 160, 7.2%) NA - NA mTL, RT-PCR, Leukocytes CES-D Probable depressive disorder (CES-D ≥ 16): (n = 269, 12.1%), Elevated depressive symptoms (CES-D ≥ 10): n = 613 (27.6%) Concurrent depressive symptoms were not associated with leukocyte telomere length in a large,
representative, population-based study.
Chae et al. [31] January 2016 USA Cross-sectional study 92 43.86 (5.73) 92 (100%) Smorkers (n = 51, 55.4%) African american Anxiety, mean (SD): 5.02 (3.86) Medication use (non-specified): (n = 29, 31.5%) mTL, qPCR, Leukocytes CES-D, HADS Depression, mean (SD): 7.51 (4.86) Racial discrimination was associated with shorter LTL among those with lower levels of
depressive symptoms
Phillips et al. [32] April 2013 United Kingdom Cross-sectional study Youngest cohort 337 36.6 (0.67) 47% Smoker (n = 76, 23%) NA - Antidepressant use (n = 18, 5%) mTL, qPCR, Leukocytes HADS Depression score at wave 5: 3.2 (4.54) Depressive symptoms are longitudinally associated with shorter telomere length, but only in younger adults.
Middle cohort 441 57.1 (111) 45% Smoker (n = 111, 25%) Antidepressant use (n = 52, 12%) Depression score at wave 5: 4.1 (4.66)
Older cohort 285 76.1 (0.84) 45% Smoker (n = 38, 13%) Antidepressant use (n = 33, 12%) Depression score at wave 5: 4.4 (4.50)
Liu et al. [33] April 2014 China Case-control study Control 1—NGT and no depression 46 51.22 (8.32) 19 (41.30) Current smokers
(n = 12, 26.09%); Current drinkers
(n = 7, 15.22%)		 NA - NA RTL, qPCR, Leukocytes HADS-D NA Oxidative stress contributes to both telomere length shortening and depression development in newly diagnosed type 2 diabetic patients, while in depression status, some other mechanisms besides oxidative stress may also affect the telomere length
Control 2—NGT with depression 6 55.33 (6.56) 3 (50.00) Current smokers
(n = 2, 33.33%); Current drinkers
(n = 1, 16.67%)
Case 1—T2DM and no depression 54 54.83 (8.58) 24 (44.44) Current smokers
(n = 16, 29.63%); Current drinkers
(n = 11, 20.37%)
Case 2—T2DM with depression 17 54.71 (8.10) 10 (58.82) Current smokers
(n = 5, 29.41%); Current drinkers
(n = 2, 11.76%)
Wang et al. [34] April 2017 Sweden Case-control study Control 320 44.6 (12.5) 197 (62) Smokers—NA NA - Telomere length, as compared with healthy controls, is shortened in patients
with depression, anxiety and stress and adjustment disorders
Case 181 41.9 (11.1) 22 (12) Smokers (n = 27, 15%) Antidepressant use (n = 63, 35%) mTL, rQ-PCR, Leukocyte PHQ-9, HADS-A/HADS-D, MADRS-S Baselines—Median score (IQR): MADRS-S—20 (14–25); HAD-D—8 (6–11); HAD-A—12 (9–15); PHQ-9—13 (9–17)
Schaakxs et al. [35] June 2014 The Netherlands Case-control study Control 128 70.1 (7.2) 49 (38.3) Cigarette years, median (IQR)—170.00 (598.75); moderate drinker, n (%)—99 (77.3); heavy drinker, n (%)—12 (9.4);years of education, mean (SD): 12.5 (3.5); Obesity, n (%): 26 (20.3%); physical activity, median (IQR): 2.61 (2.96) NA - - mTL, qPCR, Leukocyte CIDI, IDS, BAI, AS - Mean TL did not
differ between depressed persons and never-depressed comparisons
Case 355 70.6 (7.4) 120 (33,8) Cigarette years, median (IQR)—100.00 (435.00); moderate drinker, n (%)—200 (56.3); heavy drinker, n (%)—15 (4.2); years of education, mean (SD): 10.3 (3.4); Obesity, n (%): 60 (16.9%); physical activity, median (IQR): 1.60 (2.96) TCA, n (%): 78 (22.0);
SSRI, n (%): 94 (26.6);
Other antidepressants, n (%): 101 (28.5);
Benzodiazepine use, n (%): 141 (39.7)		 MDD, n (%): 249 (70.1); dysthymia, n (%): 6 (1.7); Co-morbid MDD and dysthymia, n (%): 92 (25.9%)
Wolkowitz et al. [36] May 2011 USA Case-control study Control 17 36.6 (11.8) 6 (35%) BMI: 24.8 (3.7); Daily current tobacco use (6%), Years of education, mean (SD): 15.82 (2.28), Yale Physical Activity Survey, mean (SD): 3.11(0.90) Caucasian (71%),
African-American (18%),
Asian (6%)
Other or Mixed (5%)		 NA mTL, PCR, Leukocyte HDRS, SCID, ATHF The depressed group, as a whole, did not differ from the controls in telomere length. However, telomere
length was significantly inversely correlated with lifetime depression exposure, even after controlling for age
Case 18 36.8 (11.0) 6 (33%) BMI: 26.3 (5.9); Daily current tobacco use (0%), Years of education, mean (SD): 15.28 (2.06), Yale Physical Activity Survey, mean (SD): 2.10(1.26) Caucasian (72%),
African-American (17%),
Asian (6%)
Other or Mixed (5%)		 - NA
Georgin-Lavialle et al. [37] January 2014 France Cross-sectional study 19 43.42 (16.97) 4 (21%) NA Caucasian (100%) - - mTL, rQ-PCR, Leukocytes DSM-IV, BDI-II, PSS - Telomere length was correlated to perceived stress (r = 0.77; p = 0.0001) but not to depression in our
population.
Verhoeven et al. [38] November 2013 USA and The Netherlands Cohort study Control 510 40.5 (14.9) 203 (39.8%) Obesity (13.5%), former smoker (35.6%), current smoker (26.1%), heavy drinker (11.8%), Physical activity (in 1000 MET-minutes per week) (mean ± S.D.): 3.8 (3.0) NA - SSRI (0.4%), benzodiazepine use (0.4%) mTL, qPCR, Leukocyte CIDI IDS score, mean (SD): 5.4 (3.6) Within the current MDD patients, separate analyses showed that both higher depression severity and longer symptom duration in the past 4 years were associated with shorter TL. The study also confirmed the imprint of past exposure to depression, as those with remitted MDD
had shorter TL than controls.
Case 1: Remitted MDD 802 43.5 (12.5) 238 (29.7%) Obesity (16.0%), former smoker (26.9%), current smoker (39.8%), heavy drinker (12.3%), Physical activity (in 1000 MET-minutes per week) (mean ± S.D.): 3.8 (3.0) Comorbid anxiety disorder: 36.9% TCA (2.9%), SSRI (16.4%), other antidepressant (3.7%), benzodiazepine use (4.4%) IDS score, mean (SD): 18.0 (10.2)
Case 2: Current MDD 1095 40.7 (12.1) 357 (32.6%) Obesity (20.4%), former smoker (27.8%), current smoker (45.6%), heavy drinker (13.5%), Physical activity (in 1000 MET-minutes per week) (mean ± S.D.): 3.3 (3.1) Comorbid anxiety disorder: 65.7% TCA (4.1%), SSRI (29.6%), other antidepressant (11.0%), benzodiazepine use (14.6%) IDS score, mean (SD): 32.6 (12.2)
Putermanet et al. [39] October 2013 Cohort study Control 743 68.2 (10.5) 84.7% BMI: 28.29 (5.31), current smoking (17.6%), not at all physical activity (17.4%) White (60.3%) Statins (66.8%), Aspirin (72.9%), ARBs and ACEi (52.5%), Antidepressants (10.6%) RTL, qPCR, Leukocytes CDIS-IV MDD was significantly related to LTL at 1 SD below the mean of multisystem
resiliency, but not at 1 SD above the mean. This study suggests that MDD associations with biological outcomes should be examined within a psychosocial–behavioral context, because this context shapes the nature of thedirect relationship.
Case 205 61.7 (10.8) 143(69.8%) BMI: 29.01 (5.68), current smoking (28.4%), not at all physical activity (22.9%) White (60.0%) Statins (58.6%), Aspirin (73.9%), ARBs and ACEi (50.2%), Antidepressants (48.8%) NA
Blom et al. [40] November 2015 Case-control study Control 63 15.8 (0.2) 22 (35.18%) NA NA NA STL, qPCR, saliva sample Adolescents with major depressive disorder exhibited significantly shorter telomere length and significantly smaller right, but not left hippocampal volume.
Case 54 15.9 (0.2) 29 (53.97%) Generalized anxiety disorder: 16
Social anxiety disorder: 2
Panic disorder: 1
Specific phobia: 4
Posttraumatic stress disorder: 5
Adjustment disorder: 1
Attention deficit hyperactivity disorder: 8
Alcohol/substance dependence: 1
Conduct disorder: 2
Oppositional defiance disorder: 3
Eating disorder (not otherwise specified): 2		 CTQ, BDI-II, CDRS Beck Depression Inventory II: 26.7 (1.5); Children’s Depression Inventory: 24.1(1.1)
Vance et al. [41] April 2018 USA Cohort study Control 67 44.1 (14.0) 28 (42%) Highest educational level: Graduate school (33%), College graduate (42%), Partial college (19%), High school graduate or lower (6%). Living with partner/married: 46%. BMI: 24.3 (3.8). Past year exercise level, more than once a week: (91%). Lifetime alcohol or substance use disorder: (10%). Cigarette smoking pack-years, mean (SD): 8.0 (17.3) White: 73%; Hispanic/Latino: 3% RTL, qPCR, Leukocyte MADRS, HAM-A, PSS, ETISR-SF, TEQ Individuals with MDD at baseline had greater LTL shortening over two years than
individuals without MDD (p = 0.03), even after controlling for differences in age, sex, and body
mass index (BMI). In the sub-sample of individuals with MDD diagnoses at baseline, no
significant associations between LTL change and symptom severity or duration were found.
Case 50 42.7 (13.2) 24 (48%) Highest educational level: Graduate school (18%), College graduate (40%), Partial college (28%), High school graduate or lower (18%). Living with partner/married: 18%. BMI: 26.0 (4.7). Past year exercise level, more than once a week: (63%). Lifetime alcohol or substance use disorder: (22%). Cigarette smoking pack-years, mean (SD): 6.8 (12.5) White: 82%; Hispanic/Latino: 4% Antidepressant use >6 months: 52% MDD, n (%): 15(37%)
Starnino et al. [42] October 2016 Canada Cohort study 132 45.34 (11.16) 54 (40,9%) Glasses of alcohol/week, mean (SD): 3.84 (5.38); Smoker n (%): 19(14%), BMI: 25.35 (5.00) NA Anxiety and hostility - RTL, qPCR, Leukocyte BDI-II, BAI Beck Depression Inventory-II, mean (SD): 7.64 (8.21) Shorter TL was observed among individuals high in defensiveness and depressive symptoms, as well as in those with less hostility and anxiety. Telomere length is associated with psychological burden though the direction of effect differs depending on the psychological variables under study
Wang et al. [43] September 2019 China Cross-sectional study 1742 63.6 (4.9) 819 (47.0%) Education level, n (%):
Illiterate: 1020 (58.6),
Primary: 432 (24.8),
Junior: 196 (11.3),
Senior or above: 94 (5.4)		 NA - NA RTL, q-PCR, Leukocyte GDS Mild depressive, n (%): 155 (8.9)
Severe depressive, n (%) 39 (2.2)		 Depressive symptoms was negatively correlated with TL in the overall sample. Depressive symptoms significantly mediated the relationship between religiosity and TL (explaining 31.8% of the total variance) in the 65 years and older subgroup
Wikgren et al. [44] September 2011 Sweden Case-control study Control 451 58.9 (11.6) 224 (50%) BMI: 26.1 (3.5), smoking, n (%): 50 (11%) NA - - NA, qPCR, Leukocytes BDI, BAI, CES-D, PSQ CES-D, Median Score (IQR): 6 (3–10) TL was shorter among patients compared with control subjects (277 base pairs, p = 0.001). Overall, short TL was associated with a
hypocortisolemic state (low post-DST cortisol and high percentage of cortisol reduction after the DST) among both patients and control
subjects but more pronounced among patients.
Case 91 60.4 (13.1) 36 (40%) BMI: 26.6 (3.7), smoking, n (%): 14 (15%) Antidepressant use, n (%): 81 (89%) CES-D, Median Score (IQR): 11 (6–22)
Szebeni et al. [45] June 2014 USA Case-control study Control 14 51 (5) 13 (93%) NA NA - NA RTL, PCR, white matter oligodendrocytes NA Relative telomere lengths in white matter
oligodendrocytes, but not astrocytes, from both brain regions were significantly shorter for MDD donors as compared to matched control donors
Case 14 51 (5) 14 (93%) NA NA - NA MDD (100%)
Liu et al. [46] July 2017 Sweden Cross-sectional study 894 Age, years, median (IQR): 46 (39, 54) 304 (34%) Education (%): 0–12 years (51.8%), More than 12 years (48.2%), Obesity (7.4%), Smokers (22.7%), Physical exercise regularity (54.2%) NA - NA RTL, qPCR, saliva DSM-IV, AVSI, AVAT - In females, depressive status and age had direct negative effects on TL. For males, the effects of stressors and depressive status on TL were mediated by social interaction and the coping strategy worry. In females, no mediation effect of social interaction and coping strategy was detected.
Boeck et al. [47] June 2018 Germany Case-control study Control 21 57.5 (5.7) 0% BMI: 24.5 (3.0); Smoking, yes, n (%): 3(14.3%); Physical activity, yes, n (%):18 (85.7%) NA - Medication, n (%): Antihypertensive drugs: 3 (14.3%),
Tyroid hormone: 3 (14.3%),
Sedatives: 1 (4.8%)		 mTL, qFISH, PBMC BDI-II BDI-II sum score (mean ± S.D.): 2.1 ± 2.2 All of the observed TL changes were signifcantly or marginally signifcantly associated with depressive symptom severity as assessed by the Becks Depression Inventory (BDI-II) sum score. Furthermore, the BDI-II also showed a signifcant negative correlation with TL in memory T helper
cells
Case 18 59.3 (6.6) 0% BMI: 29.2 (7.5); Smoking, yes, n (%): 8(44.4%); Physical activity, yes, n (%):11 (61.1%) Medication, n (%): Antidepressants: 13 (72.2%)
Antipsychotics: 5 (27.8%)
Antihypertensive drugs: 7 (38.9%)
Tyroid hormone: 5 (27.8%)
Sedatives: 5 (27.8%)
Analgesics: 3 (16.7%)
Laxatives: 2 (11.1%)
Vitamins (B1,B6,B12): 1 (5.6%)
Statins: 1 (5.6%)		 BDI-II sum score (mean ± S.D.): 23.8 ± 10.9
Jiménez et al. [48] October 2018 Colombia Case-control study Control 52 21 (3) F:36 (69%) M:16 (31%) NA latin - NA RTL, MMqPCR, Leukocyte PHQ-9, CES-D, HADS, CTQ - Correlation in the clinically significant depressive symptoms group between TL and sexual abuse
Case 40 21 (3) F:34 (85%) M:6 (15%)
Wium-Andersen et al. [49] January 2017 Denmark Cross-sectional study Quartile 1 16,820 52 (42–61) 6943 (41%) Never smokers, No. (%): 7029 (42), Drinks/week, median (IQR):7 (3–14), Less than 3 years of
education, No. (%): 10,062 (60), Low leisure time physical activity, inactive
or less than 2–4 h light/day, No. (%): 8658 (51%), BMI, median (IQR): 25 (23–28), chronic disease, No. (%): 5647 (34%)		 - Prescription antidepressant medication, No (%): 7748 (12%) mTL, modified MMqPCR, Leukocyte ICD-8, ICD-10 NA Attendance at hospital for depression was associated with
short telomere length cross-sectionally, but not prospectively.
Further, purchase of antidepressant medication was not
associated with short telomere length cross-sectionally
or prospectively. The genetic analyses suggested that telomere
length was not causally associated with attendance at
hospital for depression or with purchase of antidepressant
medication.
Quartile 2 16,829 55 (45–65) 7391 (44%) Never smokers, No. (%): 6557 (39), Drinks/week, median (IQR):7 8 (3–15), Less than 3 years of
education, No. (%): 10,260 (61), Low leisure time physical activity, inactive
or less than 2–4 h light/day, No. (%): 8931 (53), BMI, median (IQR): 25 (23–28), chronic disease, No (%): 6415 (38)
Quartile 3 16,828 59 (49–68) 7630 (45%) Never smokers, No. (%): 6096 (36), Drinks/week, median (IQR):8 (4–15), Less than 3 years of
education, No. (%): 10,698 (64), Low leisure time physical activity, inactive
or less than 2–4 h light/day, No. (%): 9100 (54), BMI, median (IQR): 26 (23–29), chronic disease, No. (%): 7320 (44)
Quartile 4 16,829 64 (54–72) 8100 (48%) Never smokers, No. (%): 7029 (42), Drinks/week, median (IQR):7 (3–14), Less than 3 years of
education, No. (%): 10,062 (60), Low leisure time physical activity, inactive
or less than 2–4 h light/day, No. (%): 8658 (51%), BMI, median (IQR): 25 (23–28), chronic disease, No (%): 5647 (34%)		 NA
Huzen et al. [50] January 2010 The Netherlands and United Kingdom Cross-sectional study 890 73 (64–79) 535 (61%) BMI: 26 (24–30) NA - - mTL, RT-qPCR, Leukocyte CES-D, DS14, RAND-36 Severe depression, n (%): 154 (18%), depressive symptoms only, n (%): 145 (16,3%) A lower perceived mental health on the RAND-36 score was associated with shorter telomere length. Telomere length was not associated
with the CES-D or DS14 score.
Simon et al. [51] August 2015 USA Case-control study Control 166 41.3 (13.7) 77 (46%) Educational level: Graduate school: 35%, College graduate (40%), Partial college (18%), High school graduate or less (7%). Lifetime alcohol or drug abuse/dependence, N (%): 13 (8). BMI: 25.4 (4.2) White: 68%, Black or African American:17%, Asian:7%, Native American/Alaska Native: 0%, Other: 8%. Not Hispanic/Latino: 90%, Hispanic/Latino: 10% RTL, RT-qPCR, Southern blot, Leukocytes DSM-IV, SCID, MADRS, CIRS, TEQ, ETISR-SF, ICG MADRS Total Score, Mean (SD): 1.9 (2.4) Our well-characterized, well-powered examination of concurrently assessed
telomere length and telomerase activity in individuals with clinically significant, chronic MDD
and matched controls failed to provide strong evidence of an association of MDD with shorter
LTL, while telomerase activity was lower in men with MDD.
Case 166 41.3 (13.8) 77(46%) Educational level: Graduate school: 20%, College graduate (35%), Partial college (25%), High school graduate or less (17%). Lifetime alcohol or drug abuse/dependence, N (%): 47 (28%) White: 78%, Black or African American:11%, Asian:4%, Native American/Alaska Native: 1%, Other: 4%. Not Hispanic/Latino: 92%, Hispanic/Latino: 7% Current anxiety disorder (50%), litime anxiety disorder (55%) Anti-depressant use > 6 months, N (%): 65 (39),
Mood stabilizer use > 6 months, N (%): 6 (4),
Benzodiazepine use > 6 months, N (%): 19 (11)
Antipsychotic use > 6 months, N (%): 10 (6)		 MADRS Total Score, Mean (SD): 28.2 (6.0)
Harttman et al. [52] November 2010 Germany Case-control study Control 20 49.1 (15.2) 11 (55%) Smokers (n = 7, 35%) NA - Major depressive disorder is associated with shortened telomeres. However, differences in the applied therapy, the duration of illness, or the severity of depression do not seem to have any influence on telomere length.
Case 54 49.1 (14.1) 21 (39%) Smokers (n = 16, 29.6%) NA - TAD ≤ 1: n = 20, TAD > 1 n = 16 mTL, Southern blot, Leukocyte HAM-D HAM-D, (SD) [Range]: 29.9 (6.0) [7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36]
Karabatsiakis et al. [53] July 2014 Germany Case-control study Control 50 51.1 (8) 0% Years of education, mean (SD): 15.1 (2.4) NA - mTL, qFISH, Leukocyte BDI NA : A history of depression is associated with shortened telomeres in the main effector populations of
the adaptive immune system. Shorter telomeres seem to persist in individuals with lifetime depression
independently of the severity of depressive symptoms.
Case 1—Lifetime depressed with irrelevant symptoms 24 53.1 (7.2) 0% Years of education, mean (SD): 14.1 (2.1) SSRI/ SNRI intake, n (%): 10 (41.7%)
Case 2—Relevant symptoms of depression 20 53.8 (7.6) 0% Years of education, mean (SD): 14.2 (2.9) SSRI/ SNRI intake, n (%): 9 (45%)
Solomon et al. [54] July 2017 Israel Cohort study 99 63.6 (3.7) NA Years of education (M, SD): 14, 3.7, Physical exercising regularly: 62 (62.6%)
Smoking on a regular basis: 21 (21.2%)		 NA PTSD NA mTL, Southern blot, Leukocyte SCL-90 NA Ex-POWs had shorter telomeres compared to controls (Cohen’s d = 0.5 indicating intermediate effect).
Ex-POWs with chronic depression had shorter telomeres compared to those with delayed onset of depression
(Cohen’s d = 4.89), and resilient ex-POWs (Cohen’s d = 3.87), indicating high effect sizes.
Verhoeven et al. [55] November 2019 The Netherlands Cohort study 2032 42.5 (12.8) 665 (32.7%) NA European ancestry: 2032 (100%) - NA RTL, qPCR, Leukocyte CIDI, DSM-IV, IDS-SR, NEO-FFI Lifetime depression diagnosis (% yes, N): 83.1, 1688
Depression severity (average 6-year IDS score) (mean ± S.D.): 19.0 (12.0)		 The use of genetic methods in this paper indicated that the established phenotypic association between telomere length and depression is unlikely due to shared underlying genetic vulnerability. These findings
suggest that short telomeres in depressed patients may simply represent a generic marker of disease or may
originate from non-genetic environmental factors
Mamdani et al. [56] September 2015 USA Case-control study Control 10 48 (13.0) 7 (70%) NA NA Schizofrenia and bipolar disorder NA RTL, qPCR, brain tissue UCCIB psychological autopsy
protocol		 A significant decrease in telomere length was observed specifically in the HIPP of MDD subjects even after controlling for age. In the HIPP of MDD subjects, several genes involved in neuroprotection and in stress response showed altered levels of mRNA.
Case 10 47.3 (11.5) 3 (30%) NA NA MDD: 10 (100%)

List of abbreviations: mTL—mean telomere length; RTL—relative telomere length; PCR—Polymerase Chain Reaction; qPCR—Quantitative PCR; RT-PCR—real-time PCR; rQ-PCR or RT-qPCR—real-time quantitative PCR; MMqPCR—monochrome multiplex quantitative PCR; qFISH—Quantitative Fluorescent in situ hybridization; T2DM—Type 2 diabetes mellitus; NGT—normal glucose tolerant; mtDNA—mitochondrial DNA; TCA—tricyclic antidepressants; SSRI—selective serotonin reuptake inhibitor; ARBs—Angiotensin II receptor blockers; ACEi—Angiotensin Converting Enzyme inhibitors; TAD—Total antidepressant dose; HIPP—hippocampus. POW—prisoners of war; ACE—adverse childhood experiences: DST—dexamethasone suppression test; BMI—Body Mass Index—Mean, (SD).