Telomeres consist of tandem repeats of TTAGGG and DNA binding proteins that form a cap to protect chromosomal termini from the loss of genetic material. The shortening of telomeres to a critical length leads to genomic instability and cellular apoptosis. In somatic cells such as leukocytes, telomeres gradually shorten with each cell division because of low telomerase activity.
Meanwhile, it is also well-known that various psychiatric conditions may lead to aberrant telomere shortening beyond age effect (e.g., depression, posttraumatic stress disorder, childhood adversity, and suicide). However, whether patients with schizophrenia also have shorter telomeres remains inconclusive, because the results of previous studies investigating an association between leukocyte telomere length and schizophrenia have been largely inconsistent.
This inconsistency may be partially due to the relatively small sample sizes in each study and heterogeneity caused by various uncontrolled confounders (e.g., duration of illness or hospitalization, lifetime antipsychotic dose, and telomere length assay methods). Indeed, only one study has recruited more than 1,000 patients with schizophrenia (and a sufficient sample of controls), although this was a meta-analysis, including different telomere length assay protocols.
Here, we investigate the association of leukocyte telomere length with schizophrenia with the quantitative polymerase chain reaction method in independent Japanese cohorts consisting of 1,241 patients with schizophrenia and 1,042 controls, which we believe is the largest ever as an independent sample set of telomere studies in schizophrenia. Furthermore, we examined whether the duration of hospitalization and lifetime antipsychotic dose had an effect on telomere length in schizophrenia. This study design may have overcome some potential biases that could not be controlled in previous studies (e.g., small sample size, varying LTL assay protocols, different biological bases in young, middle-aged, and elderly patients with schizophrenia, the effect of duration of illness or hospitalization, and antipsychotic dose).
Surprisingly, we observed longer (not shorter) telomeres in schizophrenia compared to controls, and further analyses clarified as follows: significantly longer telomeres were only visible in elderly patients over 50 years old with long-term hospitalization (more than 1 year), but not patients under 60 years old, outpatients, or patients with short-term hospitalization (< 1 year). Meanwhile, the lifetime antipsychotic dose had no effect on telomere length.
Figure 1. Correlations between leukocyte telomere length and age in patients with schizophrenia and healthy controls. Black dots represent patients with schizophrenia and white dots represent healthy controls. The red and blue dashed lines show non-linear relationships between leukocyte telomere length and age in patients with schizophrenia and healthy controls, respectively. Republished with permission from Elsevier from: https://doi.org/10.1016/j.jpsychires.2018.05.014
Consistent with our results, the Helsinki Birth Cohort Study published in 2012 comprising nearly 2,000 participants reported that patients hospitalized for various psychiatric disorders had longer LTL than did non-hospitalized patients.
Why, then, did long-term hospitalization appear to maintain telomeres in our elderly schizophrenia cohort? Several unique aspects of the psychiatric care system in Japan may provide clues. Mental health care in Japan remains hospital-based, and the country has the largest number of psychiatric beds per person in the world. In Japan, the average length of stay is 8.5 years, and 71% of psychiatric inpatients remain in the hospital for ≥1 year, far longer than in other countries. The majority of long-term inpatients in Japan are elderly patients with schizophrenia who are more than 50 years old.
Figure 2. Dot plot of leukocyte telomere length in controls, short-term inpatients/outpatients with schizophrenia (schizophrenia; Short/Out), and long-term inpatients with schizophrenia (Long) aged ≥50 years old. Black lines represent the mean leukocyte telomere length in each group. P values were derived from generalized linear models with age and sex as covariates. Republished with permission from Elsevier from: https://doi.org/10.1016/j.jpsychires.2018.05.014
It is well known that unhealthy lifestyle in patients with schizophrenia (such as high rates of tobacco smoking, excessive alcohol use, unbalanced diet, low exercise, overweight, or obesity) and antipsychotic medication can lead to worse physical health than in the general population and can lead to metabolic syndrome (MetS). Indeed, many studies report a higher prevalence of MetS in patients with schizophrenia compared to the general population. Meanwhile, in Japan, long-term hospitalized patients with restricted smoking and alcohol use, regular diet, and proper exercise seem to be healthier than the short-term hospitalized or outpatients.
Interestingly, a Japanese nationwide survey including nearly 8,000 patients with schizophrenia revealed that inpatients with schizophrenia had a 2- to 3-fold lower prevalence of MetS than outpatients. Furthermore, this large-scale survey indicated that elderly inpatients with schizophrenia had a lower risk of MetS even in comparison with the Japanese general population. Some studies have also reported that MetS and its components are significantly associated with shorter telomeres. Considering these findings, we posit that health characteristics in elderly patients with schizophrenia with long-term hospitalization could maintain longer telomeres than short-term hospitalized or outpatients and even than controls. Looked at from another perspective, our results suggest that schizophrenia itself does not have robust effects on telomere shortening, unlike other psychiatric conditions with strong evidence for an association with shorter telomeres.
Schizophrenia has been documented with a loss of approximately 15-25 years of life expectancy compared to the general population. Our findings indicate that this short life might not be particularly derived from pathophysiology of schizophrenia itself but from bad health and related disorders such as cardiovascular disease. In other words, we again realize that providing health improvement in patients with schizophrenia may directly contribute to extending their lifespan.
These findings are described in the article entitled Longer telomeres in elderly schizophrenia are associated with long-term hospitalization in the Japanese population, recently published in the Journal of Psychiatric Research. This work was conducted by Yuan Zhang, Akitoyo Hishimoto, Ikuo Otsuka, Shuken Boku, Tadasu Horai, and Ichiro Sora from Kobe University, Yuichiro Watanabe and Toshiyuki Someya from Niigata University, Shusuke Numata and Tetsuro Ohmori from Tokushima University, and Hidenaga Yamamori and Ryota Hashimoto from Osaka University.