History of mental disorders and leukocyte telomere length in late adulthood: The Helsinki Birth Cohort Study (HBCS)

Journal of Psychiatric Research 46 (2012) 1346e1353

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History of mental disorders and leukocyte telomere length in late adulthood: The Helsinki Birth Cohort Study (HBCS) Katri Savolainen a, *, Katri Räikkönen a, Laura Kananen b, c, Eero Kajantie d, e, Iiris Hovatta b, c, f, Marius Lahti a, Jari Lahti a, Anu-Katriina Pesonen a, Kati Heinonen a, Johan G. Eriksson d, g, h, i, j a

Institute of Behavioural Sciences, University of Helsinki, Finland Research Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, Finland Department of Medical Genetics, Haartman Institute, Faculty of Medicine, University of Helsinki, Finland d Diabetes Prevention Unit, Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland e Hospital for Children and Adolescents, Helsinki University of Central Hospital, Finland f Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare, Helsinki, Finland g Folkhälsan Research Centre, Helsinki, Finland h Unit of General Practice, Helsinki University of Central Hospital, Finland i Vasa Central Hospital, Vaasa, Finland j Department of General Practice and Primary Health Care, University of Helsinki, Finland b c

a r t i c l e i n f o

a b s t r a c t

Article history: Received 9 January 2012 Received in revised form 28 June 2012 Accepted 4 July 2012

Shorter leukocyte telomere length (LTL) has been linked with mental disorders and with other manifestations of chronic non-communicable diseases. Mental disorders are associated with increased morbidity and premature mortality. It remains unclear if shorter LTL characterizes patients who have been diagnosed with mental disorders in the past, and who have survived till late adulthood. 1051 women and 905 men of the Helsinki Birth Cohort Study participated in this study. LTL was measured by using the real-time quantitative PCR method for subjects and patients at the mean age of 61.5 years. Patients with a mental disorder severe enough to warrant hospitalization (n ¼ 116) were identified by their case records in the Finnish Hospital Discharge Register and the use of psychotropic medication by reimbursement entitlements or prescription fills (n ¼ 665) data in the Finnish Social Insurance Register. Participants hospitalized for any mental or substance use disorders had longer LTL than non-hospitalized controls (p-values < 0.042). Moreover, only those any mental disorder patients who had psychotropic medication use had longer LTL than non-hospitalized controls (p ¼ 0.02). Adjustment for a number of covariates did not attenuate the association. Our findings suggest that shorter LTL may not be an intrinsic feature of mental disorders. Future research is needed to elucidate if psychotropic medication is involved in leukocyte telomere length maintenance in subjects with mental disorders. Ó 2012 Elsevier Ltd. All rights reserved.

Keywords: Leukocyte telomere length Mental disorder Substance use disorder Psychotropic medication Antidepressant medication

1. Introduction Telomeres are specialized DNA-protein complexes (consisting of the DNA repeat sequence TTAGGG) that are located at the ends of eukaryotic chromosomes (Blackburn, 2000). They are involved in preventing chromosome fusion and maintaining genome stability (Blackburn, 2004). In most human cells, telomere length decreases with subsequent cell divisions (Blackburn, 2000). In the normal population, the length of leukocyte telomeres decreases with age (Frenck et al., 1998; Nordfjäll et al., 2009; Valdes et al., 2005). When the telomere reaches a critical length it loses its capping ability and

* Corresponding author. E-mail address: katri.savolainen@helsinki.fi (K. Savolainen). 0022-3956/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jpsychires.2012.07.005

the cell faces replicative senescence (Blackburn, 2004; Wong and Collins, 2003; Chan and Blackburn, 2004). Age-corrected leukocyte telomere length (LTL) can be seen to reflect both, a cumulative measure of the history of oxidative damage that the cell has undergone and its replicative potential. Therefore, LTL has been acknowledged as a biomarker of cellular ageing (von Zglinicki et al., 2000; Aviv, 2009) Recent studies have associated longer LTL to better survival (Kimura et al., 2008; Bakaysa et al., 2007), a family history of longevity (Atzmon et al., 2010) and healthy ageing (Njajou et al., 2009). In contrast, shorter LTL has been linked with chronic inflammation (Damjanovic et al., 2007) and common age-related disorders, such as cardiovascular disease (Fitzpatrick et al., 2007), hypertension (Yang et al., 2009) and type 2 diabetes (Salpea et al., 2010; Demissie et al., 2006). Yet, there are conflicting results for

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which LTL does not predict all-cause mortality (Bischoff et al., 2006) or mortality from infectious diseases, cancer, or cardiac or cerebrovascular diseases among the elderly (Njajou et al., 2009; Houben et al., 2011) and among the oldest cohorts (Martin-Ruiz et al., 2005). In addition to the association with common age-related disorders, there exists evidence that shorter LTL also associates with mental disorders, including schizophrenia (Kao et al., 2008; Yu et al., 2008), nonaffective psychoses (Fernandez-Egea et al., 2009), mood disorders (Simon et al., 2006), major depressive disorder (Hoen et al., 2011; Hartmann et al., 2010; Lung et al., 2007), alcohol abuse (Pavanello et al., 2011) and anxiety disorder among patients over 48 years of age (Kananen et al., 2010). This is not surprising given that mental disorders are shown to increase the risks of all-cause (Harris and Barraclough, 1998; Miller et al., 2006) and cardiometabolic mortality (Mitchell and Lawrence, 2011; Colton and Manderscheid, 2006; Miller et al., 2006) and morbidity (Hennekens et al., 2005; Rugulies, 2002, Vogelzangs et al., 2010; Krishnan, 2005; Spencer and Hutchison, 1999). However, the findings on LTL and mental disorders are contradictory. To the best of our knowledge only two previous studies have reported no associations for LTL with schizophrenia, with bipolar disorder (Mansour et al., 2011) or with major depressive disorder (Wolkowitz et al., 2011). The number of depressed patients in the study by Wolkowitz et al. (2011) was small (n ¼ 18) for detecting significant changes in LTL but the study by Mansour et al. (2011) recruited enough psychotic disorder patients (n > 60) to detect differences in LTL compared to controls. Methodological differences such as sample size, whether the cases were inpatients or outpatients, newly or previously diagnosed with mental disorder, how well the samples were characterized for other age-related disorders including cardiometabolic health or lifestyle may partly explain the conflicting findings. The populations of the previous studies have also varied in age. Some studies used younger populations (Fernandez-Egea et al., 2009; Mansour et al., 2011) and some have used wide age ranges (Hartmann et al., 2010; Wolkowitz et al., 2011). Obviously, the findings of these studies cannot be generalized to elderly populations. The age range of a cohort is particularly important for generalization since the association between age and LTL may be nonlinear (Frenck et al., 1998). Further, not all studies provided information on psychotropic medication use (Fernandez-Egea et al., 2009; Mansour et al., 2011; Pavanello et al., 2011; Lung et al., 2007; Simon et al., 2006; Yu et al., 2008). Against this background we studied if shorter LTL associates with the history of hospitalization for a mental disorder in a wellcharacterized cohort of 57 to 70-year-old women and men in Finland between 2001 and 2004. Moreover, an animal study reported that antidepressants can decrease oxidative stress at the cellular level (Zafir et al., 2009). Therefore, we examined if LTL associates with indicators of antidepressant and psychotropic medication use as antidepressant or psychotropic medication reimbursement entitlements and medication purchases. We also investigated if psychotropic medication use modulated the associations of mental disorder hospitalizations and LTL. Finally, we examined if LTL shortening associates with recently reported sub-clinical symptoms of mental disorders including depression, anxiety and loss of vitality. 2. Materials and methods 2.1. Participants The Helsinki Birth Cohort Study (HBCS) comprises 13,345 men (n ¼ 6975) and women (n ¼ 6370) born between 1934 and 44 in one of the two public maternity hospitals in Helsinki, who attended

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child welfare clinics in the city of Helsinki and who were still living in Finland in 1971 when unique personal identification numbers were assigned to all residents of Finland. Over 2001e2004 inclusive period a randomly selected sample of 2003 (69.0% of 2902 invited) subjects (men n ¼ 928 and women n ¼ 1075) participated in a detailed clinical examination including blood sampling for LTL measurement. Of these participants, LTL data were available for 1964 participants (men n ¼ 912 and women n ¼ 1052) with a mean age of 61.5 (SD ¼ 2.9, Range ¼ 56.7e69.8) years. Detailed descriptions of the cohort can be found elsewhere (Osmond et al., 2007; Eriksson et al., 2001). The HBCS was approved by the Ethics Committee of the National Public Health Institute. All study participants gave their written informed consent. 2.2. Telomere length measurements Relative telomere length from peripheral blood DNA was determined by a quantitative real-time PCR-based method (Cawthon, 2002), as described in detail by Eerola et al. (2010), with the following modifications. Based on O’Callaghan’s method (2008), a synthetic oligomer (Sigma) dilution series, hgb-120-mer and tel14x (0.0002; 0.002; 0.02; 0.2; 1.0; 3.0 and 6.0 pg) were included on every plate to create reaction specific standard curves. Plasmid DNA (pcDNA3.1) was added to each standard to maintain a constant 10 ng of total DNA concentration per reaction. Quality control (QC) was carried out with the Bio-Rad CFX Manager software v.1.6. At this point, triplicates with amplification curve standard deviations above 0.5 at the threshold level were omitted (N ¼ 38). One subject had missing blood sample data and was therefore excluded. The final number of T/S measurements that passed QC and whose relative telomere data available was N ¼ 1964. All plates included four genomic DNA control samples for the plate effect calibration and for monitoring the repeat measures correlation coefficient of variation (CV). The quantities of the control samples were used for calculating CV values as the ratio of the standard deviation to the mean, which gave means of 21.0% for the telomere reaction, 6.0% for the b-haemoglobin reaction, and 24.8% for their ratio (T/S). The plate effect was taken into account by normalizing the telomere signal and reference gene signal to the corresponding mean of 4 control samples that were analyzed for every qPCR plate before taking the T/S ratio. Three outlier samples of T/S ratio were removed before statistical analyzes commenced. 2.3. Mental disorders Mental disorders severe enough to warrant hospitalization were identified from the Finnish Hospital Discharge Register (HDR). The HDR covers all inpatient episodes of residents in Finland in the general and psychiatric hospitals from 1969 onwards. Mental disorders were coded by the International Classification of Diseases (ICD) system. ICD-8 was used for the 1969e1986 inclusive period, ICD-9, according to the Diagnostic and Statistical Manual of Mental Disorders, Third Revision (DSM-III-R), for the years 1987e1995 inclusive and ICD-10 from the year 1996 onwards. Both the primary and subsidiary hospitalization diagnoses were used, except in the case of acute substance-intoxication (ICD-9: 305 and ICD-10: F1x.0). In such cases only primary diagnoses were used because intoxication is a frequent subsidiary diagnosis in Finnish medical practice and does not automatically indicate a substance use disorder per se. Mental disorders were categorized according to the ICD codes into the following groups: Any mental disorder, Substance use disorder, (Non-affective) Psychotic disorders, Mood disorders, Anxiety disorders and Personality disorders. For more details see Räikkönen et al. (2011). The number of specific mental disorder diagnoses does not equate to any mental disorder, because

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of co-morbidity. Participants who have been hospitalized for any of the mental disorder diagnoses are hereafter referred to as the mental disorder group. We included only those mental disorder patients (n ¼ 116) whose first hospitalization was prior to clinical examination whereupon blood samples for measurement of LTL were obtained. We thus excluded eight participants who had been hospitalized for the first time only, after the clinical examination. Participants who had not been hospitalized for mental disorders between 1969 and the clinical examination that was carried out between 2001 and 2004 are hereafter referred to as the control group (n ¼ 1840). 2.4. Psychotropic medication Information of psychotropic medication that belongs to the World Health Organization (WHO) Anatomical Therapeutic Chemical (ATC) Classification System codes N05 (psycholeptics) and N06 (psychoanaleptics), was derived from the Finnish National Social Insurance Institution (SII) register. This register covers all medication reimbursement entitlements and purchases throughout the follow-up between 1995 and 2002. We identified a total of 665 individuals with psychotropic medication reimbursement entitlements and purchases. This included 391 individuals with antidepressant medication reimbursement entitlements and purchases. Psychotropic medication reimbursement entitlements and purchases are hereafter referred to as psychotropic medication use whereas antidepressant medication reimbursement entitlements and purchases are referred to as antidepressant use. 2.5. Sub-clinical symptoms of mental disorders Depressive symptoms that occurred within the two-week period prior to the clinical examination were measured by using the self-reported Beck Depression Inventory (BDI) (Beck et al., 1988) at the clinical examination visit. The BDI consists of 21 items. Each item contains four statements that reflect varying degrees of symptom severity. Respondents were instructed to circle the number that corresponds with the statement that best describes them. The numbers ranged from zero to three, indicating the increasing severity of the symptom. Ratings were summed to calculate a total BDI score, which can range from 0 to 63. Two subscales from the SF-36/RAND, namely the Mental Health Index (MHI) and the Vitality Scale (VS) were used to capture the following symptoms: depression, anxiety, loss of behavioural/ emotional control and psychological well-being, loss of vitality and energy during the four weeks prior to the clinical examination. The five items of the MHI and the four items of the VS were measured against a 6-point scale that ranged from “all the time” (1) to “none of the time” (6). In measuring a series of sub-clinical symptoms of mental disorders, the MHI has been shown to have a high sensitivity and specificity for detecting clinical depression (Berwick et al., 1991; Arroyo et al., 2004; Ware et al., 1993). Further, a Finnish validation study of SF-36 concluded that the VS items are also important in capturing depression in a Finnish population (Aalto et al., 1999). 2.6. Covariates Other variables that are known to associate either with LTL and/ or mental disorders were treated as covariates. These included the history of hospitalizations for Coronary Heart Disease (CHD) and stroke identified from the HDR between year 1969 and clinical examination. Diabetes mellitus, which was defined according to the World Health Organization criteria (Report of WHO, 1999) by using

the standard 75-g oral glucose tolerance test at the time of clinical examination. Body mass index (BMI, kg/m2) was calculated by dividing the weight of the participant in kilograms by the square of the participant’s height in metres, measured at the clinical examination. Personal data including the highest attained education, smoking habits, leisure time physical activity and alcohol consumption were self-reported by the participants in conjunction with the clinical examination. Subjects were identified as nonsmokers if they had never smoked or had quit (vs. current smoker), physically active when they exercised at least moderately three or more times per week (vs. physically inactive), and moderate alcohol users when they used alcohol two times or less per week (vs. frequent alcohol use). 2.7. Statistical analysis Associations between relative LTL and mental disorders, psychotropic medication use and sub-clinical symptoms of mental disorders were examined using multiple linear regression analyzes with relative LTL as the outcome. We contrasted the subjects who had any and specific mental disorders with the controls. By entering three dummy coded interaction variables of ‘mental disorder/control  medication/no-medication’ into the regression equation, we examined if psychotropic medication or antidepressant medication use modulated associations between mental disorder and LTL. BDI, MHI and VS scores were used both as continuous and as dichotomous variables. A score of 10 was used for the BDI as the cutoff for at least mild depressive symptoms. The lowest tertile was used as the cutoff points for the MHI and the VS. We presented associations adjusted for age, sex and stock DNA concentration (Model 1) and thereafter adjusted for CHD, stroke, diabetes mellitus, BMI, education level, smoking status and alcohol consumption (Model 2). Continuous variables for LTL, BDI, BMI and stock DNA concentration, the number of psychotropic medication entitlements/purchases and the number of antidepressant medication entitlements/purchases were natural log (Ln) transformed and the MHI and the VS scores were squared to attain normality. LTL was then standardized to the mean of 0 and standard deviation of 1. All the statistical tests were two-tailed and all the analyzes were carried out with PASW 18 software for Windows. 3. Results Table 1 presents the characteristics of the sample according to the mental disorder status. Subjects with mental disorders had used psychotropic medication more frequently, they had been hospitalized with CHD more frequently and they reported current smoking more frequently than the controls. As predicted, we found that older age correlated with shorter relative LTL (B ¼ 0.040, 95% Confidence Interval (95% CI) ¼ 0.055, 0.026, p < 0.001), and that men had shorter LTL than women (B ¼ 0.145, 95% CI ¼ 0.050, 0.013, p ¼ 0.001). Table 2 shows that those with any mental disorder or substance abuse disorder had longer relative LTL than the controls. Model 2 adjustments did not change the significant associations (pvalues < 0.03). We also examined if psychotropic medication or antidepressant use associated or modulated the association between mental disorder hospitalizations and relative LTL. Any psychotropic or antidepressant medication use did not associate with relative LTL (p-values > 0.79). However, those participants who had been hospitalized for any mental disorder and who in addition had psychotropic medication use had 0.31 SD longer relative LTL compared with controls who had psychotropic medication use (95% CI ¼ 0.082, 0.535, p ¼ 0.008) and 0.26 SD longer relative LTL compared with controls without psychotropic

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Table 1 Characteristics of the study population. Mental disorder

Control

N ¼ 116

N ¼ 1840

P

M (SD) or N (%)

M (SD) or N (%)

Relative telomere length Standardized relative telomere length

1.45 (0.3) 0.19 (1.0)

1.39 (0.3) 0.01 (1.0)

Age (years) Male Current smoking Alcohol  3times/week BMI (kg/m2) Exercise  3 times/ week Education: elementary school or less Vocational school High school diploma University degree

62.0 63 41 13 27.1 48 46 23 28 19

(3.1) (54) (35) (11) (4.6) (41) (40) (19) (24) (16)

61.5 842 425 310 27.6 817 596 363 478 398

(2.9) (46) (23) (17) (4.7) (45) (33) (20) (26) (22)

0.11 0.07 0.003* 0.11 0.25 0.51 0.35

11 4 16 81 60

(10) (3) (14) (71) (52)

77 44 285 584 331

(4) (2) (15) (32) (18)

0.008* 0.48 0.61 <0.001* <0.001*

Coronary heart disease Stroke Diabetes mellitus Any psychotropic medication use Any antidepressant medication use Duration from the most recent hospitalization for mental disorder (years) Duration from first ever hospitalization for mental disorder (years)

12.9 (8.9)

e

16.0 (9.3)

e

M ¼ mean, SD ¼ standard deviation, N ¼ number of cases. *P < 0.05.

medication use (95% CI ¼ 0.041, 0.478, p ¼ 0.020) (Fig. 1, Panel A). In contrast, those mental disorder patients who did not have psychotropic medication use did not differ from controls with or without psychotropic medication use (p-values > 0.32) (Fig. 1, panel A). Psychotropic medication mediated associations were similar with antidepressant medication use (Fig. 1, Panel B). Mental disorder patients with or without psychotropic medication use and also those with or without antidepressant medication use did not differ in LTL from each other (p-values > 0.16). Controls with and without psychotropic medication use or with and without antidepressant medication use did not differ from each other either (pvalues > 0.17). Model 2 adjustments did not change any of the significant associations summarized in the Fig. 1 (p-values < 0.01). Further analyzes revealed that when subjects who had used antidepressants were excluded from the analyzes, neither the mental disorder patients with (n ¼ 21) or without (n ¼ 35) nonantidepressant psychotropic medication use differed from the controls (p-values > 0.47). Neither the number of psychotropic medication entitlement and purchases (B ¼ 0.002, 95% CI ¼ 0.051, 0.050, p ¼ 0.935) nor the number of antidepressant entitlement and purchases (B ¼ 0.002, 95% CI ¼ 0.047, 0.112, p ¼ 0.419) associated with LTL. The associations were also non-significant when mental disorder patients

Table 2 Associations between mental disorders and relative leukocyte telomere length. Mental disorder diagnoses

N (%)

B

95% CI

Any mental disorder Mood disorders Substance abuse disorders Anxiety disorders Psychoses Personality disorders

116 49 40 30 9 6

0.232 0.042 0.319 0.327 0.237 0.153

0.050, 0.234, 0.012, 0.024, 0.401, 0.630,

(5.9) (2.5) (2.0) (1.5) (0.5) (0.3)

P 0.425 0.317 0.626 0.678 0.875 0.937

0.013* 0.766 0.042* 0.068 0.466 0.701

N ¼ number of cases, B ¼ mean difference in relative leukocyte telomere length in standardized z score units, 95% CI ¼ 95% confidence interval. *P < 0.05.

and controls were analyzed separately (p-values > 0.38). Moreover, the time from the most recent hospitalization within the mental disorder hospitalized participants group did not associate with LTL (B ¼ 0.032, 95% CI ¼ 0.209, 0.144, p ¼ 0.717). However, when LTL of the mental disorder patient group according to the time from the most recent hospitalization for mental disorder for the three tertiles were compared with LTL of the controls, only the patients hospitalized for less than 8.3 (n ¼ 39, mean ¼ 4.08, SD ¼ 2.8) years ago had longer LTL (p ¼ 0.045) than controls. In contrast, LTL did not differ from the controls (p-values > 0.10) for subject hospitalized 8.3 to 14.3 (n ¼ 39, mean ¼ 11.06, SD ¼ 1.76) years or over 14.3 (n ¼ 38, mean ¼ 23.8, SD ¼ 5.2) years before. Model 2 adjustments did not change the results. Self reported sub-clinical symptoms of depression, anxiety and loss of vitality were not associated with relative LTL when these variables were treated either as continuous or as dichotomous variables (Table 3). The subclinical symptoms did not have significant associations on LTL either, when mental disorder patients (pvalues > 0.35) or subjects with any psychotropic medication use (pvalues > 0.13) were excluded from the analyzes. 4. Discussion Our findings demonstrate that in a large epidemiological sample of 57 to 70-year-old women and men, a past history of any mental disorder severe enough to warrant hospitalization was associated with longer relative leukocyte telomere length when compared with non-hospitalized controls. Any psychotropic or antidepressant medication use, however, modulated these associations. Longer LTL was particularly characteristic of those mental disorder patients who also had any psychotropic or antidepressant medication use. It was only the patients with any psychotropic or antidepressant medication use that differed from the controls. The associations were not explained by age, sex, BMI, current smoking, alcohol consumption, physical activity, highest attained level of education, diabetes or hospitalization for CHD or stroke.

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Fig. 1. Patients with mental disorder severe enough to warrant hospitalization who in addition had psychotropic (Panel A) or antidepressant (Panel B) medication use had longer leukocyte telomere length compared to controls with no mental disorder hospitalizations, where in contrast mental disorder patients without psychotropic (Panel A) or antidepressant (Panel B) medication use did not differ from the controls.

Our findings contradict the existing evidence, which show that mental disorders and shorter LTL are associated. Differences in methodology and study design may provide some understanding of our seemingly counterintuitive findings. Our study offered a life-course perspective into mental disorders by identifying Table 3 Associations between sub-clinical symptoms of mental disorders and relative leukocyte telomere length. N

Mean (SD) B

(95% CI)

Beck depression inventory 1950 5.8 (5.3) 0.013 (0.040, 0.066) total score <10 vs.10 0.058 (0.052, 0.168) Mental health index 1954 81.1 (15.2) 0.000 (0.000, 0.000) total score <80 (lowest tertile) vs.80 0.001 (0.088, 0.089) (upper two tertiles) Vitality scale total score 1954 70.3 (19.8) 0.000 (0.000, 0.000) <65 (lowest tertile) vs.65 0.018 (0.073, 0.109) (upper two tertiles)

P 0.624 0.303 0.550 0.990 0.950 0.700

N ¼ number of cases, B ¼ mean difference in relative leukocyte telomere length in standardized z score units, 95% CI ¼ 95% confidence interval.

hospitalizations from the Finnish HDR across nearly four decades and combined these data with measurement of relative LTL of those who had survived to older age. Previous studies for which mental disorders were found to be associated with shorter LTL have mainly been cross-sectional and conducted on inpatients (Hartmann et al., 2010; Lung et al., 2007; Yu et al., 2008), or on patients with newly diagnosed disorder (Fernandez-Egea et al., 2009; Hoen et al., 2011) or on patients who were actively taking part in a treatment programme (Pavanello et al., 2011). In addition the participants of our study were older and the age range of our sample was also narrower than in most of the previous studies (Wolkowitz et al., 2011; Fernandez-Egea et al., 2009; Simon et al., 2006). The finding of longer LTL in our study was most prominent among substance abusers. We did not exclude subjects with multiple mental disorder diagnoses because substance abuse disorders have been shown to have high comorbidity with other mental disorders (Najt et al., 2011). It may be that the positive associations we found between any mental disorders and LTL are partly explained by the subjects with substance abuse disorders. The finding of patients with substance use disorders having longer LTL contradicts that of a previous study in which alcohol abuse was associated with shorter LTL (Pavanello et al., 2011). It has been well documented that shorter LTL is associated with age-related disorders, such as CHD (Fitzpatrick et al., 2007), hypertension (Yang et al., 2009) and type 2 diabetes (Salpea et al., 2010; Demissie et al., 2006): that are also common among patients with mental disorders (Miller et al., 2006). Moreover, it has been hypothesized that chronic oxidation and/or inflammation, assessed by shorter LTL, could underlie the higher risk for age related diseases seen in mental disorder patients (Wolkowitz et al., 2011; Hoen et al., 2011). Our contradictory findings show that shorter LTL is not characteristic among elderly subjects with a history of mental disorder and suggest that excess cellular ageing, as measured by short LTL (von Zglinicki et al., 2000; Aviv, 2009), is not an intrinsic feature of mental disorders. Most importantly, our study design allowed us to examine if psychotropic medication modulated the associations between mental disorder and LTL. We found that those mental disorder patients who had received at least one psychotropic or antidepressant reimbursement entitlement or purchase had longer LTL compared to controls. Intriguingly, those mental disorder patients who did not have any psychotropic or antidepressant medications reimbursement entitlements or purchases, did not differ in LTL from the controls. Therefore, it seems that these associations could be mediated through the antidepressant medication use. Interestingly, Wolkowitz et al. (2011) found that a lifetime exposure to depression but without self-reported antidepressant use was correlated with shorter LTL. However, those authors also reported that those patients with a lifetime exposure to depression and who did receive antidepressant treatment did not differ in LTL from controls. We did not find associations between the number of any psychotropic or antidepressant medication entitlement and purchases with LTL. This finding is in line with the previous studies in which the impacts of psychotropic medication dosages on LTL in mental disorder populations were examined. For example, neither antipsychotic doses (Kao et al., 2008) nor antidepressant doses (Hartmann et al., 2010) were associated with LTL. In conclusion, the amounts taken of any psychotropic or antidepressant medication seems to have no impact on LTL. Nevertheless, our results indicate the overall use (vs. no use) of antidepressants, seem to modulate LTL in mental disorder populations. It is worth pointing out that we did not find any mediated effects for those subjects who had received psychotropic or antidepressant medication but who had not suffered from mental disorders severe enough to warrant hospitalization when compared to non-medicated controls.

K. Savolainen et al. / Journal of Psychiatric Research 46 (2012) 1346e1353

We cannot directly address the underlying mechanisms that explain these associations. Without baseline LTL measurement we do not know if psychotropic or antidepressant medication in our study increased LTL, or slowed down the LTL erosion or if the mental disorder patients who also had any psychotropic or antidepressant medication use also had longer telomeres at baseline. Telomeres are highly sensitive to oxidative stress (Kawanishi and Oikawa, 2004) and telomere shortening is believed to be affected by the balance of oxidative stress and antioxidant defence (von Zglinicki, 2002). An animal study demonstrated that antidepressants can decrease oxidative stress at the cellular level (Zafir et al., 2009) and therefore it is possible that psychotropic medications, especially antidepressants, are involved in oxidative stress or antioxidant mediated LTL protection. Telomere length dynamics offer another possible mechanism. Recent studies have provided evidence that LTL is a dynamic process: telomeres do not merely shorten, they can also lengthen (Farzaneh-Far et al., 2010; Aviv et al., 2009) and in longitudinal studies subjects with the shortest telomeres were more likely to experience telomere attrition than subjects with longer telomeres (Farzaneh-Far et al., 2010; Nordfjäll et al., 2009). In our study, a mean of 12.9 years had elapsed between the most recent hospitalization and the LTL measurement. We found that only those subjects whose hospitalization had occurred less than 8.3 years prior to LTL measurement had longer LTL, whereas subjects who had been hospitalized more than 8.3 years ago, did not differ in LTL from controls. This is interesting, since Hoen et al. (2011) have shown that LTL lengthening is more frequent among depressed patients compared with non-depressed subjects. Conversely, non-depressed subjects exhibited LTL shortening more frequently, during a 5-year follow up period (Hoen et al., 2011). Although speculative, there may be remedial cellular processes targeted especially at short telomeres (Britt-Compton et al., 2009) that psychotropic medication or other aspects of recent mental disorder treatments activate in patients who have mental disorders. There are also other possible underlying mechanisms that might explain our findings. Longer LTL confers better survival (Kimura et al., 2008; Bakaysa et al., 2007). On the other hand, mental disorders are linked to excess and early mortality (Colton and Manderscheid, 2006; Miller et al., 2006). Men and women with mental disorders in the Nordic countries were shown to live 20 and 15 years less, than their counterparts in the general population (Wahlbeck et al., 2011). The subjects of the present study had a mean age of 62 years at the time of the telomere measurement. Consequently, an interesting possibility is that LTL is longer in those mental disorder patients who have survived to older age. Recent genome wide association studies have identified novel loci for LTL (Codd et al., 2010; Atzmon et al., 2010) that also associates with longevity (Atzmon et al., 2010). Therefore, it is possible that the same genetic basis may partly explain longer LTL and better survival from mental disorders. Our results on self-reported depression, anxiety and loss of vitality indicate that these recently reported sub-clinical symptoms of mental disorders were not associated with LTL. Neither did they associate with LTL when mental disorder patients or subjects with any psychotropic medication use were excluded from the analyzes. Previous studies on depressive symptoms and LTL are contradictory. In a recent study, Huzen et al. (2010) found that depressive symptoms assessed by the MHI were associated with shorter LTL. However, the same study found that depressive symptoms when assessed by using another commonly used questionnaire, the Centre for Epidemiologic Studies Depression scale had no association with LTL. In the small sample studied by Wolkowitz et al. (2011) no associations between severity of depressive symptoms and LTL were found. Age-corrected LTL is seen to reflect a cumulative measure of the history of oxidative damage that a cell has undergone (von

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Zglinicki et al., 2000; Aviv, 2009) and it may be that two to four weeks of self-reported depression, anxiety and loss of vitality is too short a period of time for measurable LTL shortening to occur. There are some limitations in our study. Without baseline telomere measurements, we can only speculate about the direction of effects and what role a combination of mental disorders and psychotropic or antidepressant medication plays on LTL dynamics, and vice versa. Some of our results may be explained by a survival bias, as we do not have LTL measurements from those participants who had died before the clinical follow-up examination when blood samples were drawn for LTL measurement. One of the limitations of using the q-PCR method for LTL measurement is its relatively high inter-assay variability. However, this method is fast, cheap, and does not require much DNA and for these reasons, it is much used in epidemiological research. It should also be noted that psychotropic medication, including antidepressant medication entitlements and prescription fills do not necessarily represent actual medication use and that they can be prescribed for other than mental disorder treatment purposes. The HDR recorded diagnoses from 1969 onwards; thus the individuals in this present study who were hospitalized for mental disorders only before the age of 25e35 remain undetected for having mental disorder. The interpretations drawn from the associations between specific mental disorder diagnoses and LTL are somewhat limited due to the relatively small number of cases and inclusion of subjects with multiple mental disorders diagnoses. Finally, we do not have information on those mental disorders that did not warrant admission to hospital, and therefore our findings apply only to the most severe cases and to self-reported symptoms that do not necessarily indicate the presence of a mental disorder diagnosis. 5. Conclusions Our findings contradict previous studies in which mental disorders were linked to shorter LTL. Our results show that a history of mental disorders associates with longer LTL in a population that survived into late adulthood, particularly when they have had a history of antidepressant medication use. This finding suggests that shorter LTL, a biomarker of cellular ageing, may not be an intrinsic feature of mental disorders. Longitudinal studies are needed to elucidate if antidepressant medication is involved in leukocyte telomere length maintenance in subjects with mental disorders. Role of the funding source The study was funded by grant from Academy of Finland. The sponsor had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. Contributors 1. Conception and design, or acquisition or interpretation of data (Katri Savolainen, Katri Räikkönen, Laura Kananen, Eero Kajantie, Iiris Hovatta, Marius Lahti, Jari Lahti, Kati Heinonen, Anu-Katriina Pesonen, Johan G. Eriksson). 2. Literature searches, statistical analysis and writing the first draft of the manuscript (Katri Savolainen). 3. Telomere measurements (Laura Kananen, Iiris Hovatta). 4. Revising the manuscrips (Katri Savolainen, Katri Räikkönen, Laura Kananen, Eero Kajantie, Iiris Hovatta, Marius Lahti, Jari Lahti, Kati Heinonen, Anu-Katriina Pesonen, Johan G. Eriksson). 5. Final approval of the version to be published (Katri Savolainen, Katri Räikkönen, Laura Kananen, Eero Kajantie, Iiris Hovatta,

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