Table 2.

Studies on telomere length (TL) in subjects with psychiatric disorders other than MDD

Reference	Study Population (Diagnostic Method)	Sample Size: Psychiatric subjects/ Healthy Controls (% Female)	Mean Age (Yrs): Psychiatric subjects /Healthy Controls	Mean Duration of illness in psychiatric subjects (Yrs)	Mean Telomere Length: Psychiatric Subjects/ Healthy Controls (Telomere Assay Method)	Effect Size: Cohen’s d	Main Findings	Co-morbidity	Notes and Limitations
	Bipolar disorder (BD)
Simon et al., 2006	BD with or without concurrent Anxiety Disorder (SCID)	Total sample: 44 /44 total. Of these, 15 had MDD (53% female), 15 had BD with a concurrent anxiety disorder (47% female), and 14 had BD with no anxiety disorders (43% female). In the control group there were 43% female	BD + Anxiety: 51.6/ All controls: 50.5 BD alone: 51.5 / All controls: 50.5	BD + Anxiety: 33.5 ± 6.3 BD alone: 36.7 ± 11.8	BD + Anxiety: 7100 ± 860 bp BD alone: 6960 ± 810 bp Controls (all): 7640 ± 1100 bp (Southern blot)	0.55 (BD + anxiety vs controls) 0.70 (BD alone vs controls)	Across all mood disorder subjects, LTL was significantly shorter than in controls (Individual mood disorder groups not reported separately)	Psychiatric: Chronic MDD/BD with or without Anxiety Disorder Somatic: Excluded “all active diseases”	Results are not reported separately for BD or BD plus Anxiety Disorder groups, so the effects of BD alone cannot be inferred. Lifetime psychiatric history of the controls was assessed by unstructured interview. No data on potential confounders of lifetime stress exposure, medication use, subjective stress levels or BMI. Sample was primarily Caucasian.
Elvsåshagen et al., 2011	BD II, outpatient sample. Sixteen subjects were euthymic and 12 were mildly- moderately depressed. (MINI)	28 (68) / 28 (68)	35/35	19 (time from anamnestic onset until the time of blood withdrawal)	Percentage of “short: telomeres: Bipolar II: 15.04%, vs. Controls: 13.48%. Telomere length: BD II: 10,067 bp, vs. Controls: 10,619 bp (High- throughput quantitative fluorescence in situ hybridization with automated fluorescence)	Insufficient information to calculate	The load of short telomeres (<3000 bp) was significantly greater in the bipolar subjects, compared to the controls, using one- tailed testing (p<0.04). The difference in telomere length was not statistically significant (p=0.08, one- tailed).	Psychiatric: Social phobia and panic disorder were frequent comorbid psychiatric disorders. One subject met the criteria for current alcohol abuse. Somatic: Neurological and severe chronic somatic disorders excluded.	Load of short telomeres was defined as the number of telomeres below 3,000 base pairs. Significance tests used one-tailed tests. Small sample size. No control for early life stress. The load of short telomeres and telomere length were not significantly correlated with illness duration (current age minus age at onset, including euthymic periods), but the load of short telomeres was significantly positively correlated with the number of depressive (but not hypomanic) episodes. The number of depressive episodes was negatively correlated with telomere length at trend level (p= 0.08).
Mansour et al., 2011	BD I (SCAN).	108/114	24.9 (50%)/ 27.5 (44%)	Unknown	0.95 ± 0.40/ 0.97 ± 0.40 (T/S) (PCR)	0.05	No significant differences in TL between cases and controls	No information on co-morbid conditions, somatic or psychiatric.	Subjects had high rates of consanguinity, with higher rates in the cases vs. the controls. Subjects were generally younger than those in the other studies. No data were available to co-vary for medications, comorbid illnesses, BMI, lifestyle factors or early life stress.
Rizzo et al., 2013	BD I (SCID)	22/17	39.5 (100)/44.6(100)	9.45 (range 1–25)	0.71±0.20 (T/S) vs. 0.90±0.19 (T/S) (q-PCR)	0.97	BD subjects had significantly shorter LTL than controls.	Psychiatric: Psychotic disorders, mood disorders, anxiety disorder, or substance-related disorder were exclusion criteria. Somatic: Other exclusion criteria were a history of brain injury or severe medical illness or neurological disorders; use of substances that might induce immune or endocrine changes	The sample was female only. CMV IgG levels were higher in BD subjects than in controls. CMV IgG levels were associated with expansion of senescent CD8+CD28− T cells and with shorter LTL
Martinsson et al., 2013	BD (SCAN)	202/135	Samples were matched for age and sex (age range 33–77). Mean age for psychiatric subjects/controls not reported	Not reported for whole sample	Exact values not reported (Q-PCR)	N/A	LTL was significantly longer in BD compared to controls. Lithium treated BD subjects had longer TL than controls (p<0.0005).	No information on co-morbid conditions, somatic or psychiatric.	TL correlated significantly and positively with lithium treatment duration of >30 months (p=0.031) and was negatively associated with number of depressive episodes (p<0.007). Lithium responders had significantly longer TL than lithium non- responders (p=0.047). This study did not control for smoking, obesity, inflammation and somatic disorders.
Lima et al 2014	BD type 1 and type 2 (MINI Plus 5.0)	85 (25) / 95 (37)	39/38	Information not available	Absolute values not given. (PCR)	0.36	BD subjects had significantly shorter TL than controls (p<0.001). No significant difference between BD subtype. Short LTL was associated with panic disorder co- morbidity	Psychiatric: Relatively high co- morbidity for GAD, Panic Disorder, Borderline, Alcoholism, Drug abuse, Eating disorder, and OCD. Somatic co- morbidity not reported.	No information regarding illness duration was provided. Smoking, BMI, medication use and somatic illnesses were not controlled for.
	Psychotic disorders
Kao et al., 2008 (two analyses; S1 & S2)	Schizophrenia, outpatients (13 from cohort A and 18 from cohort B. Cohort A: SCID interviews. Cohort B: structured modified Schedule for Affective Disorders and Schizophrenia combined with Structured Interview for DSM-III-R Personality Disorders and Diagnostic Interview for Genetic Studies.	S1 (schizophreni a subjects from cohorts A and B): 31(23)/41(32) S2 (all male sample matched or age, all were from cohort A): 33(0)/26(0) The two analyses were analyzed separately in independent laboratories but using same protocol	S1: 39/26 S2: 36/33	Approximately 20 years	Telomere length given in T/S: S1: 1.14/1.51 S2: 1.09/1.50 (PCR)	1.17 (S1 vs controls) 0.72 (S2 vs controls)	Significantly shorter TL in schizophrenia in S1 (p=0.002) and S2 (p=0.008)	No information on co-morbid conditions, somatic or psychiatric.	No significant correlations between current or lifetime antipsychotic dose and TL. No information on co-morbidity (psychiatric or somatic) was given, nor information regarding health behaviors such as exercise or smoking.
Yu et al., 2008	Schizophrenia, inpatients (SCID). Schizophrenia subjects were subdivided into good vs poor responders for TL analysis	68 /76	38 (78) /38 (72)	16	7.41 + 0.97 (poor responders)/8.8 8 0.90 (good responders) 8.91 + 1.36 (controls). (Terminal restriction fragment assays were used)	1.22 (poor responder s vs. controls). 0.03 (good responders vs controls)	Significantly shorter TL in schizophrenics with poor treatment response compared to controls (p<0.001) and schizophrenia subjects with good treatment response (p<0.001). There was no significant difference in TL between good responders and controls (p>0.05)	Psychiatric: No DSM-IV diagnosis of alcohol or substance abuse or neurodegenerative disorder Somatic: Physically healthy with normal laboratory parameters.	It is unclear if all schizophrenia subjects as a group differed significantly from controls in terms of TL. No information was given on potential confounders such as smoking and BMI.
Fernandez-Egea et al., 2009	“Non-affective psychosis” (SCID)	41(32)/41(32)	29/28	0	Telomere content: 93.1%/101.9% (relative to a reference DNA standard (fluorometric assay)	N/A	Psychotic patients had significantly decreased telomere content compared to controls (p=0.011)	Psychiatric: no lifetime diagnosis of schizophrenia or MDD, or a current diagnosis of adjustment disorder. Substance abuse data not reported. Somatic: no diabetes or other serious medical or neurological condition associated with glucose intolerance or insulin resistance and	No antipsychotic use 30 days prior to the study. The participants had maximum lifetime antipsychotic exposure of 1 week. Small sample size. Information regarding diet and health behaviors was not available.
Mansour et al., 2011	Schizophrenia or schizoaffectiv e disorder (SCAN).	60 / 60	28.2 (35%)/ 27.0 (35%)	Unknown	0.89 ± 0.30/ 0.87 ± 0.26 (T/S) (PCR)	0.07	No significant differences in TL between cases and controls	No information on co-morbid conditions, somatic or psychiatric.	Subjects had high rates of consanguinuity, with higher rates in the cases vs. the controls. Subjects were generally younger than those in other studies. No data were available to co-vary for medications, comorbid illnesses, BMI, lifestyle factors or early life stress.
Nieratschker et al., 2013	Schizophrenia (SCID, the Operational Criteria Checklist for Psychotic Illness, medical records, family history)	539/519	36.9 (44)/39.1 (49)	Not reported	Not reported (q-PCR)	N/A	LTL was significantly longer in schizophrenia subjects than controls	No information on co-morbid conditions, somatic or psychiatric.	The authors excluded outliers more than 3 SD from the mean, which resulted more schizophrenia subjects being excluded than controls. All subjects received medications, which the authors suggest may account for their findings.
Malaspina et al., 2014	Schizophrenia (DIGS)	53 (40%)/ 20 (45%)	42/37	Not available	Schizophrenia: males: 1.98 T/S, females: 1.80; Controls: males: 1.92, females: 1.65 (PCR)	Males: 0.08; Females: 0.24	No significant difference in LTL between schizophrenic subjects and controls or between males and females. No significant diagnosis × gender interaction.	No information on co-morbid conditions, somatic or psychiatric.	Small control sample size. Healthy control group only verified as having no Axis I diagnosis for the previous 2 years. Schizophrenia subjects were on stable doses of antipsychotic medication. Schizophrenia group was significantly older and had significantly more current tobacco use than controls. Paternal age was positively correlated with LTL in male cases but was negatively correlated with paternal age in female cases.
Kota et al., In press	Schizophrenia (DSM-IV). Unremitted or remitted	71 (36 unremitted, 35 remitted) (38%)/ 73 (53%)	31.7/ 32.1	5.5	Schizophrenia: 0.59 T/S (Remitted: 0.56 T/S; Unremitted: 0.42 T/S); Controls: 0.85 T/S (PCR)	Not available	Mean LTL shorter in schizophrenia compared to controls. This difference was significant in the unremitted schizophrenia subjects but not in the remitted ones.	No information on co-morbid conditions, somatic or psychiatric.	Schizophrenia subjects had been treated with antipsychotic medication for at least six months before blood sampling. Analyses controlled for age and sex but not for tobacco use.
	Anxiety disorders
Kananen et al., 2010	Anxiety disorders and “sub-threshold” disorders (Including Panic disorder, Generalized Anxiety Disorder, Social Phobia, Agoraphobia, and Phobia Not Otherwise Specified). Diagnoses were determined with the Munich Composite International Diagnostic Interview.	321(63)/653 (64)	50 /50	Not reported	Not reported (Q-PCR)	Not available	No significant differences in TL between cases and controls in the entire sample. Significant difference in TL between cases and controls only in individuals>48 years (p=0.013)	Psychiatric: 28% of the anxiety disorder subjects had concurrent MDD diagnosis. Comorbid alcohol use disorder in 22% of cases. Somatic: Frequency of somatic co- morbidity was not reported	LTL was significantly associated with childhood adversities but not with current perceived stress, psychiatric co- morbidity, or the use of psychotropic medication. Psychiatric diagnoses were only obtained for the preceding 12 months.
Hoen et al., 2013	Mixed anxiety disorders (panic disorder, GAD, social phobia, agoraphobia); Mixed depressive disorders (MDD and dysthymia) (CIDI, self- report computerized)	Anxiety disorders: 108 (63%)/ 970 (53%) Depressive disorders: 97 (64%)/ 980 (53%)	Anxiety disorders: 52/ 54 Depressive disorders: 51/ 54	Not reported	Not reported (PCR)	Not available	The presence of an anxiety disorder diagnosis (panic disorder, agoraphobia or social phobia, but not GAD) over the preceding year significantly predicted shorter LTL 2.2 years later. Depressive disorder diagnoses did not significantly predict LTL.	Psychiatric: 3.3% of all subjects had both an anxiety and a depressive disorder. Somatic: The study was performed in a cohort investigating risk factors for renal and cardiovascular disease. The cohort was oversampled for albuminuria.	This was a longitudinal study. Diagnoses were heterogeneous, and the depressive disorder group included dysthymia. Diagnoses were not based on clinician interview and were based on a one year window; therefore controls may have had psychiatric diagnoses prior to that one year period. . Diagnosis and LTL measurement were not contemporaneous (separated by an average of 2.2 years). Psychiatric patients were from a general population, and may have been of mild severity.
O`Donovan et al., 2011a	PTSD (SCID and CAPS)	42/46	30 (48%)/ 31 (54%)	>3 months	6,594 ± 528.1 bp /6,798 ± 528.3 bp (q-PCR)	0.39	LTL significantly shorter in PTSD, but this was accounted for by the significant correlation between cumulative exposure to childhood trauma, which was seen only in the PTSD group.	Psychiatric: Exclusion criteria included alcohol abuse or dependence in the previous 2 years; substance abuse or dependence in the previous year; any psychiatric disorder with psychotic features; bipolar disorder or obsessive-compulsive disorder; and pregnancy. Somatic: Medically healthy and medication- free. Exclusion criteria included neurologic disorders or systemic illness; use of psychiatric, anticonvulsant, antihypertensive, sympathomimetic, estrogen replacement therapy, steroidal, statin or other prescription medications; obesity (BMI > 30);	The control sample lacked individuals with childhood trauma, leaving unanswered the question of whether PTSD or childhood trauma accounted for the shorter LTL.
Ladwig et al., 2013	PTSD (partial and full), Post- Traumatic Diagnostic Scale; Impact of Event Scale	Partial PTSD: 262; Full PTSD: 51; Controls: 2687	Partial PTSD: 52.5 (61.8%); Full PTSD: 54.5 (62.7%); Controls: 56.5 (50.5%)	Not reported	Partial PTSD: 1.85 + 0.29 T/S Full PTSD: 1.78 + 0.29 T/S Controls: 1.85 ± 0.33 T/S (PCR)	0.0 (partial PTSD vs controls) 0.23 (full PTSD vs controls)	Although raw TL values were nearly identical, both PTSD groups had significantly shorter TL than controls when age was co-varied.	Psychiatric: Between 17% (no PTSD) and 24% full PTSD) had high alcohol consumption. Somatic: History of MI, diabetes, stroke, or cancer between 17% (no PTSD) and 23% (partial PTSD). Hypertension between 24% (partial PTSD) and 32% (no PTSD).	Age-adjusted “full PTSD” had shorter TL than age-adjusted subjects with “partial PTSD,” but the statistical significance of this difference was not reported. Controlling for depressive symptoms (PHQ- 9) did not alter the main findings.
Zhang et al. 2014	“Probable PTSD” in US Army Special Operations Units (self- report PCL and Life Events Checklist)	84/566. An age-matched control group (N=84) was also compared to the PTSD group.	29.2 ± 7.3 (not separated by group) (12.9%)	Not reported	Nor reported (PCR)	N/A	Significantly shorter LTL in PTSD vs. controls	No information on co-morbid conditions, somatic or psychiatric.	Analyses did not co-vary for age, sex, BMI, and tobacco use, but the significant LTL finding remained in an age-matched sub-sample. Duration of illness was not reported. Scant details were provided about the subjects. Childhood trauma was not correlated with LTL.
Needham et al., 2014	General Anxiety Disorder, and Panic Disorder (Composite International Diagnostic Interview)	52 (55.7*)/952 (56.6)	30.0*/29.3	Not reported	1.12*/1.14 (T/S ratio) Q-PCR	0.06	No overall significant difference between groups. However, females with GAD or panic disorder had shorter TL than the controls.	Psychiatric: Significant co- morbidity with MDD 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.
Verhoeven et al., in press	NESDA; DSM-IV Included: panic +/− agoraphobia, social phobia, GAD and agoraphobia. Excluded: OCD, PTSD, bipolar, substance abuse, psychosis	128 current anxiety d/o; 459 remitted anxiety d/o/ 582 controls; 67% female	Mean 41.7 +/− 13.1 Range 18–65 y.o.	Not reported	5431 bp (Current) vs. 5506 bp (Control); 5499 bp (Remitted) qPCR	0.12– 0.22	Current anxiety disorder subjects had shorter LTL compared to controls and to remitted anxiety disorder subjects. Remitted anxiety disorder subjects’ LTL did not differ from that in controls.	Psychiatric: Excluded primary diagnosis of other severe psychiatric conditions, such as bipolar disorder, obsessive– compulsive disorder, severe substance use disorder or psychotic disorder. Somatic: Somatic disorders not excluded but covaried for in the analyses	Lifestyle, health variables and all demographics were controlled. LTL was not associated with symptom duration in the past 4 years. The time since remission was positively correlated with LTL in the remitted subjects. Subjects in remission for over 10 years had significantly longer LTL than subject in remission for only 6 months- 9 years, raising the possibility (per the authors) that cellular aging associated with anxiety disorders may eventually be reversible. The anxiety/ control difference in LTL persisted even after excluding comorbid MDD diagnoses. Among the current anxiety disorders, panic with agoraphobia, social phobia and generalized anxiety disorder (but not agoraphobia or panic disorder without agoraphobia) were associated with significantly shorter LTL. Symptom clusters that correlated with shorter LTL across the whole sample included: anxiety arousal, social phobic symptoms and worrying.
Jergovic et al., 2014	PTSD, ICD-9 by MINI. and CAPS	28 combat- PTSD/ 17 non-combat- exposed controls Middle-aged men (0% female)	45.9 + 1.12/ 47.2 + 1.7	Not reported	0.86 + 0.03 / 1.03 + 0.04	Unknown	PTSD, compared to age-matched controls, had significantly decreased LTL. No difference in PBMC basal TA	Psychiatric: Only four patients were without any comorbid psychiatric condition, 24 (80%) had major depression, 13 (43%) had panic disorder, 9 (30%) had obsessive compulsive disorder, and 7 (23%) were diagnosed with social phobia. 65% of healthy controls and 20% of PTSD subjects used alcohol. Somatic: Substance abuse, acute or chronic physical illnesses were exclusion criteria. 60% of the subjects took NSAID, 10% opiod analgesics, 10% hypollipidemics, 10% antihypertensives, 3% proton pump inhibitors.	PTSD subjects were described as severely traumatized in war and having had “several forms of psychiatric treatment”Many of the PTSD subjects were taking opioid analgesics, non-steroidal anti-inflammatory drugs, statins, psychotropics, or anti-hypertensive drugs. 80% of PTSD subjects had comorbid MDD. MDD was accounted for in the regression models, and the significant difference in TL remained. There was no assessment of early life adversity. LTL and TA did not significantly correlate with CAPS severity or sub-scales or with depressive symptoms.

^*This includes subsyndromal anxiety symptoms and DSM verified anxiety disorders

ABBREVIATIONS

BD=Bipolar Disorder

BMI=Body Mass Index

BP=base pairs

CAPS=Clinician Administered PTSD Scale

CMV=Cytomegalovirus

DIGS=Diagnostic Interview for Genetic Studies

DSM=Diagnostic and Statistical Manual of Mental Disorders

GAD=Generalized Anxiety Disorder

LTL=Leukocyte Telomere Length

MDD=Major Depressive Disorder

MINI= The Mini International Neuropsychiatric Interview

PCR=Polymerase chain reaction

PCL= PTSD Checklist

PBMC=Peripheral Blood Mononuclear Cell

PTSD=Post-traumatic stress disorder

SCAN= Schedule for Assessment in Neuropsychiatry

SCID= the Structural Clinical Interview for DSM

TA=Telomerase activity