Table 1.

Studies of Leukocyte Telomere Length in Major Depressive Disorder (MDD)

Referenc e	Study Population Diagnosis; (Method of Diagnostic Assessment)	Sample Size: Psychiatric subjects/ Healthy Controls (% Female)	Mean Age (Yrs): Psychiatri c subjects /Healthy Controls	Mean Duration of illness in psychiatri c subjects (Yrs)	Mean telomere length; psychiatric subjects/healt hy controls (Telomere Assay Method)	Effect Size: Cohen’s d	Main Findings	Co-morbidity	Notes and Limitations
Simon etal., 2006	Chronic MDD/BD with or without Anxiety Disorder (Patients by SCID-DSM- IV; Controls by simple questioning)	44(48%)/ 44(43%)	51/ 51	32	6.98/7.64 (kb) (Southern blot)	0.73	Shorter LTL in mood disorders	Psychiatric: Chronic MDD/BD with or without Anxiety Disorder Somatic: Excluded “all active diseases”	Analyses reported on the combined mood disorder group, not the MDD sample alone. No data were given regarding possible associations between telomere length and duration of illness. DNA was collected from banked samples collected for other studies, and the MDD and control subjects’ DNA may have derived from different DNA repositories. The authors did not have data to control for trauma, stressful life events, socioeconomic status, obesity, medications, or stress levels. No structured diagnostic interviews were conducted for the control subjects – some subjects with mood disorders may have been included in the control group, according to the authors. Subjects were primarily Caucasian.
Lung etal., 2007	MDD (Patients by SCID-DSM- IV; Controls by undocumente d method)	253 (64%) /411 (57%)	44 /45	Unknown	8.17/9.13 kbp (Southern blot)	0.78	Shorter LTL in MDD	Psychiatric: None Somatic: not reported	The sample was not characterized with regards to number of depressive episodes or duration of illness. No data on medications or somatic co-morbidity.
Hartmann et al., 2010	MDD inpatients (Patients by DSM-IV; Controls by undocumente d method)	54 (61%)/ 20 (45%)	49/ 49	15	7.20/7.55 (kb) (Southern blot)	0.59	Shorter LTL in MDD	Psychiatric: This study excluded subjects with manic, mixed or hypomanic episodes, schizoaffective or dysthymic disorders, and dementia. But they did include patients with other (unspecified) psychiatric disorders. Somatic: This study included subjects with neurological, and (unspecified) somatic disorders and patients with substance abuse in the past	No significant correlations between LTL and duration of illness, number of hospital stays, severity of depressive symptoms or current antidepressant doses. None of the subjects were untreated (medication or ECT) at the time of study. Duration of illness was defined as length of time from anamnestic onset until blood sampling without excluding intervening periods of euthymia. The authors did not control for potential confounds such as obesity, stress, socioeconomic status, somatic disorders. Past substance abuse or other psychiatric diagnoses (except for manic/hypomanic/mix ed episodes, schizoaffective syndrome, dysthymia, and dementia) were not exclusion criteria. All patients were inpatients, and all were Caucasian.
Hoen etal., 2011	MDD in outpatients with stable CHD (MDD by CDIS-IV- DSM-IV. Controls had stable coronary heart disease without current MDD. Past history of MDD was not assessed in cases or controls).	206 (31%)/ 746 (15%)	62/ 68	Unknown	0.86/0.90 (T/S) (Q-PCR)	0.15	Significantly shorter LTL in MDD, controlling for age and sex; trend after controlling for additional covariates,	Psychiatric: Approximately 1/3 (in both groups) used alcohol on a regular basis. Somatic: Subjects had a history of myocardial infarction or coronary revascularizatio n, angiographic evidence of at least 50% stenosis in at least one coronary vessel, or a diagnosis of CHD. Exclusion was a history of myocardial infraction in past 6 months, unable to walk one block.	The study sample was comprised of stable coronary heart disease patients and mainly older men, which may limit generalizability. The association between LTL and depression may have been confounded by greater cardiac disease severity in the depression group, per the authors. The sample had relatively low depression severity. When full covariates were entered, LTL difference just missed significance (p=0.06)
Wolkowitz et al., 2011a	MDD, unmedicated outpatients (Patients and controls by SCID-DSM- IV)	18 (67%)/17 (65%)	37/ 37	13	5101/5141 (bp) (Q-PCR)	0.11	No difference in LTL across all MDD subjects. Shorter LTL was observed in MDD subjects with more chronic MDD (those with lifetime depression exposure greater than the median for the sample)	Psychiatric: No psychiatric co- morbidity except for co- morbid anxiety disorders (except PTSD) when MDD was considered the primary diagnosis. 39% of MDD subjects had co-morbid anxiety disorder.. Somatic: no uncontrolled medical illness; no illnesses or medications that could affect variables. Free of psychiatric medication for at least 6 weeks.	LTL was inversely correlated with lifetime days of untreated depression. LTL was inversely correlated with peripheral inflammatory cytokines and oxidative stress markers. Mean duration of illness was defined as lifetime years of active depression, excluding intervening periods of euthymia. The study had a relatively small sample size.
Wolkowitz et al., 2012	MDD, “severe depression phenotype” (Patients by DIGS/FIGS- DSM-IV). 90% had melancholia	91 (60%)/ 451 (50%)	60/59	28	5261/5538 (bp) (Q-PCR)	0.40	Shorter LTL in MDD	Psychiatric: Bipolar disorders, dysthymia, substance abuse, alcohol abuse, organic brain disorder, neurologic disorder, PTSD and anxiety disorder were excluded. Somatic: Not reported	LTL was not significantly related to basal cortisol levels but was directly correlated with post- dexamethasone cortisol levels. This was interpreted as short LTL being associated with overly sensitive HPA axis negative feedback and with hypocortisolism. LTL was not significantly correlated with duration or severity of depression Duration of illness was defined as time from anamnestic onset until the time of blood collection.
Teyssier et al., 2012	MDD patients by SCID- DSM-IV and MINI)	17 (100%) / 16 (100%)	40/38	12 of the MDD subjects were first episode. Mean duration: 11.4 years, range 0– 32 years)	13.42/13.60 (mean Ct) (Q-PCR)	0.58	No significant difference in LTL.	Psychiatric: Comorbid psychiatric disorders were excluded, except for “anxiety symptoms” Somatic: Somatic pathology was excluded, especially cardiovascular and metabolic	In MDD subjects, there was increased expression of p16INK4a and stathmin (STMN1) genes, which are associated with telomere dysfunction, cell senescence, microtubule dynamics, biological aging and regulation of cell cycle dynamics. Moreover, MDD subjects displayed increased expression of OGG1, a DNA/telomere oxidative damage- repairing enzyme, consistent with exposure to oxidative stress. Small sample. All female, all Caucasian, most were relatively recent onset depressive episode (< 6 months in all cases). No subjects reported early life stress, but this was not systematically assessed. 70% received antidepressant medication.
Garcia-Rizo etal., 2013	MDD, medication- naïve (patients and controls by SCID-DSM- IV)	9/48 (unknown gender distribution but reported as “similar”)	Unknown for the subset in which telomere data were available. In the entire study: 31/ 28	Unknown, all subjects were newly diagnosed	89.0/103.7 (telomere content) (Fluorimetric assay)	0.98	Lower telomere content in MDD compared to controls	Psychiatric: MDD subjects had no other axis 1 disorders Somatic: no history of diabetes or other conditions associated with glucose intolerance or insulin resistance	MDD subjects were first episode, medication-naïve. Homogeneous sample of middle/upper class subjects. Very small MDD sample. Important information such as age, sex, symptom severity were not reported.
Verhoeven et al., 2014a	MDD patients from the Netherlands Study of Depression and Anxiety (NESDA), longitudinal cohort study (MDD by CIDI-DSM-IV)	1095 current MDD (67% women) + 802 remitted MDD (70% women)/51 0 controls (60% women)	41 (current MDD)/44 (remitted MDD)/41 (controls)	Remitted MDD: 11 months of depressio n during the past 4– 5 years. Current MDD: 21 months during the past 4–5 years.	5474 (current MDD)/5433 (remitted MDD)/5553 (controls) (bp) (Q-PCR)	0.13 (current MDD vs controls) 0.14 (remitted MDD vs controls)	Shorter LTL in current and remitted MDD compared to controls	Psychiatric: Other severe psychiatric conditions, such as bipolar disorder, obsessive– compulsive disorder, severe substance use disorder or psychotic disorder were excluded.. Somatic: Between 33% controls) and 46% (current MDD) had at least one comorbid somatic disorder.	LTL was similar in current and remitted MDD. The number of years in remission and the current use of antidepressants were not correlated with TL. Within the current MDD subjects, both higher depression severity and longer symptom duration (in the past 4–5 years) were associated with shorter LTL. Group differences were significant even after adjusting for somatic co-morbidity.
Needham et al., 2014	MDD (Composite International Diagnostic inventory)	75 MDD (58.6%*)/96 6 controls (56.0%)	30.3*/29.2	Not reported	1.12/1.14 (T/S) (Q-PCR)	0.06	No overall group effect on LTL, but among subjects taking antidepressant s, those with MDD had shorter LTL than controls	Psychiatric: Significant co- morbidity with anxiety disorders . Somatic: No information regarding somatic co- morbidity or substance abuse	Relatively young sample (age range 20–39 years, mean of approximately 30 years). The study oversampled for low income and Mexican American and African American participants. There was along duration between DNA extraction and analyses.
Shalev etal. 2014	Longitudinal study in a complete birth cohort (the Dunedin Multidisciplina ry Development Study). Subjects had “internalizing disorders” including MDD, generalized anxiety disorder and PTSD. Subjects were combined due to high co- morbidity of these diagnoses. Diagnoses by the Diagnostic Interview Schedule for Children and life history calendars.	Analysis plan 1: Internalizin g disorder from age 11 to 38: 455 (58%)/ 372 (65%) Number of MDD not specified. Analysis plan 2: Internalizin g disorder between age 26 to 38: 234 (58%)/ 524 (45%) 193 had MDD	Longitudin al study from 11– 38 years old.	Not reported	Estimated from graphs in (T/S, PCR). Analysis 1 (based on phases of internalizing disorder): 0 phases (men=1.075, women=1.09), 1 phase (men=1.03, women=1.08), 2 phases (men=1.0, women=1.0), 3 phases (men=0.98, women=1.0), 4 phases (men=0.9, women=1.14), 5+ phases (men=0.78, women=1.03) Analysis 2: No diagnosis (men=1.05, women=1.05), any diagnosis (men=0.97, women=1.035), MDD (men=0.97, women=1.025), GAD (men=0.94, women=1.045), PTSD (men=0.98, women=1.05)	Insufficien t informatio n	The persistence of “internalizing disorder” diagnoses between ages 11– 38 predicted shorter LTL at age 38 in a dose-response manner in men, but not in women. LTL assessed at ages 26 and 38 showed an accelerated rate of LTL shortening in men (but not women) with “internalizing disorder” diagnoses in the interim.	Psychiatric: High co- morbidity between different internalizing disorders although exact numbers are not given. Somatic: Approximately 75% had exceeded clinical cut-off for one or more of the following physical health indicators: Metabolic abnormalities, cardiorespirator y fitness, pulmonary function, periodontal disease, and systemic inflammation.	The sample was primarily Caucasian – limited generalizability? Approximately 1/3 took psychiatric medications There was no information on other treatments.
Schaakxs et al., 2015	Late-life depression (defined by current age, not by age at onset): MDD or dysthymia (DSM-IV, CIDI)	355 depressed (within past 6 months) (66.2%)/12 8 never depressed (61.7%)	70.6/70.1 (Range 60–93)	Not specified, but mean age at onset= 49.1 yrs (range 4– 86 yrs)	5,036 bp/ 5055 bp (unadjusted) (Q-PCR)	0.04	No significant difference in LTL	Psychiatric: Primary dementia was excluded. 4% in the depression group and 9% in the control group were “heavy drinkers”. Somatic: Chronic somatic diseases not excluded	In this elderly sample, age and the number of chronic medical diseases were significantly inversely correlated with LTL, but depression diagnosis, depression severity, number of depressive episodes, and duration of longest depressive episode were not. Controlling for medication use, chronic medical illnesses, lifestyle factors and depression onset before or after 50 or 60 years old did not change the results.

Note: Studies of individuals with depressive symptoms but without MDD diagnoses are not included here, but they are briefly discussed in the text.

^*This includes MDD subjects and subsyndromal depression

ABBREVIATIONS I

BD=Bipolar Disorder

BP=base pairs

CDIS=Computerized Diagnostic Interview Schedule

CHD=Coronary Heart Disease

CIDI= Composite International Diagnostic Interview

Ct=cycle threshold for telomeric signal relative to cycle threshold for single copy gene

DIGS=Diagnostic Interview for Genetic Studies

DSM=Diagnostic and Statistical Manual of Mental Disorders

FIGS= The Family Interview for Genetic Studies

LTL=Leukocyte Telomere Length

MDD=Major Depressive Disorder

MINI= The Mini International Neuropsychiatric Interview

PCR=Polymerase chain reaction

PTSD=Post-traumatic stress disorder

SCID= the Structural Clinical Interview for DSM