Telomere attrition and inflammatory load in severe psychiatric disorders and in response to psychotropic medications

Abstract

Individuals with severe psychiatric disorders have a reduced life expectancy compared to the general population. At the biological level, patients with these disorders present features that suggest the involvement of accelerated aging, such as increased circulating inflammatory markers and shorter telomere length (TL). To date, the role of the interplay between inflammation and telomere dynamics in the pathophysiology of severe psychiatric disorders has been scarcely investigated. In this study we measured T-lymphocytes TL with quantitative fluorescent in situ hybridization (Q-FISH) and plasma levels of inflammatory markers in a cohort comprised of 40 patients with bipolar disorder (BD), 41 with schizophrenia (SZ), 37 with major depressive disorder (MDD), and 36 non-psychiatric controls (NPC). TL was shorter in SZ and in MDD compared to NPC, while it was longer in BD (model F_{6, 137} = 20.128, p = 8.73 × 10^-17, effect of diagnosis, F₃ = 31.870; p = 1.08 × 10^-15). There was no effect of the different classes of psychotropic medications, while duration of treatment with mood stabilizers was associated with longer TL (Partial correlation controlled for age and BMI: correlation coefficient = 0.451; p = 0.001). Levels of high-sensitivity C-Reactive Protein (hsCRP) were higher in SZ compared to NPC (adjusted p = 0.027), and inversely correlated with TL in the whole sample (r = -0.180; p = 0.042). Compared to NPC, patients with treatment resistant (TR) SZ had shorter TL (p = 0.001), while patients with TR MDD had higher levels of tumor necrosis factor-α (TNFα) compared to NPC (p = 0.028) and to non-TR (p = 0.039). Comorbidity with cardio-metabolic disorders did not influence the observed differences in TL, hsCRP, and TNFα among the diagnostic groups. Our study suggests that patients with severe psychiatric disorders present reduced TL and increased inflammation.

Fig. 1. Fluorescence intensity of telomeres among diagnostic groups.

The figure shows diminished fluorescence intensity of telomeres of a representative partcipant among patients with schizophrenia (a) compared to major depressive disorder (b), bipolar disorder (c) and non-psychiatric controls (d). Telomere probe (red); DAPI-stained metaphases (blue). Note: no evidence of FISH signal randomly observed mainly in SZ chromosomes indicates that telomere shortening reached a size of the exameric sequence that is under the PNA-FISH resolution (200base pairs).

Fig. 2. Difference in telomere length among diagnostic groups.

a shows the difference in telomere length (TL) among the four diagnostic groups (effect of diagnosis F₃ = 31.87, p = 1.08 × 10⁻¹⁵). b shows the difference in levels of high sensitivity C-reactive protein (hsCRP) among the four diagnostic groups (effect of diagnosis F₃ = 4.680, p = 0.004). Levels are expressed as mg/L. Figure c shows the difference in levels of tumor necrosis factor alpha (TNFα) among the four diagnostic groups (effect of diagnosis F₃ = 1.217, p = 0.306). Levels are expressed as pg/mL. Graphs were obtained using the raw values (unadjusted), while the statistical significance for TL, hsCRP and TNFα is based on post-hoc analysis with Bonferroni correction of the univariate models controlling of age, sex, and BMI as covariates. *p < 0.05; **p < 0.005; ***p < 0.0005; ns, not significant. Bars represent mean and standard errors on the mean. NPC non-psychiatric controls, BD bipolar disorder, SZ schizophrenia, MDD major depressive disorder.

Fig. 3. Correlation between hsCRP and telomere length.

Partial correlation between hsCRP and TL in the whole sample controlled for Body Mass Index (BMI) and age. Correlation coefficient = −0.180, p = 0.042. TL telomere length, hsCRP high sensitivity C-reactive protein.

Fig. 4. Association between telomere length and treatment-resistant schizophrenia or treatment-resistant depression.

a shows the difference in TL among non-psychiatric controls (NPC), patients with treatment-resistant schizophrenia (TR), and patients with non-treatment resistant schizophrenia (non-TR) (effect of diagnosis F₂ = 6.927; p = 0.002). b shows the difference in levels of tumor necrosis factor alpha (TNFα) among non-psychiatric controls (NPC), patients with treatment-resistant major depressive disorder (TR), and patients with non-treatment resistant major depressive disorder (non-TR) (effect of diagnosis F₂ = 3.998; p = 0.023). Graphs were obtained using the raw values (unadjusted), while the statistical significance for TL, hsCRP and TNFα is based on post-hoc analysis with Bonferroni correction of the univariate models controlling of age, sex, and BMI as covariates. *p < 0.05; **p < 0.005; ns, not significant. Bars represent mean and standard errors on the mean.