# Telomerase activity and telomere homeostasis in major depressive disorder, schizophrenia and bipolar disorder: a systematic review

Johanna Thurin, Bruno Etain, Frank Bellivier, Cynthia Marie-Claire

## ► To cite this version:

Johanna Thurin, Bruno Etain, Frank Bellivier, Cynthia Marie-Claire. Telomerase activity and telomere homeostasis in major depressive disorder, schizophrenia and bipolar disorder: a systematic review. Journal of Psychiatric Research, 2025, 186, pp.98-107. 10.1016/j.jpsychires.2025.04.013. hal-05108297

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Submitted on 11 Jun 2025

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# Telomerase activity and telomere homeostasis in major depressive disorder, schizophrenia and bipolar disorder: a systematic review

Johanna Thurin<sup>a</sup>, Bruno Etain<sup>a,b,c</sup>, Frank Bellivier<sup>a,b,c</sup>, Cynthia Marie-Claire<sup>a,*</sup>

## ARTICLE INFO

**Keywords:**

Telomere

Telomerase activity

Shelterin complex

Bipolar disorder

Major depressive disorder

Schizophrenia

## ABSTRACT

**Introduction:** Life expectancy is decreased in individuals diagnosed with Major depressive disorder (MDD), Schizophrenia (SCZ) or Bipolar disorder (BD), which suggests cellular ageing. Telomere length (TL), a biomarker of cellular ageing, has been consistently reported as shorter in these individuals, but the mechanisms involved remain unknown.

**Method:** A literature search was conducted which included studies focusing on telomerase activity and markers involved in telomere homeostasis (Single nucleotide polymorphisms, gene expression, protein levels). We also searched for articles investigating the impact of psychotropic medications and other interventions on any of these markers.

**Results:** We identified 25 articles among which individuals with MDD were overrepresented (n = 16). Telomerase was the most studied marker in terms of activity and gene expression, and few studies included analyses of other markers. Five studies out of seven reported an elevated telomerase activity in individuals with MDD. Seven of the twelve clinical trials identified, measured the impact of interventions in MDD (antidepressants, electroconvulsive therapy and yoga) with heterogeneous designs.

**Conclusion:** Literature suggests that telomerase activity is increased in MDD, with no major changes following exposure to antidepressants. Case-control and clinical intervention studies in BD and SCZ are too scarce to conclude. Furthermore, this review highlights that the complexity of telomere homeostasis has been overlooked in the literature thus limiting the understanding of the underlying molecular mechanisms. Future research should include larger and trans-nosographic samples, adopt more homogeneous designs for clinical trials, and perform more comprehensive analyses of the TL homeostasis markers.

## 1. Introduction

Major depressive disorder (MDD), schizophrenia (SCZ) and bipolar disorder (BD) are severe mental disorders. MDD and BD are mood disorders with prevalences reaching approximately 10 % and 2 % of the general population respectively (Marx et al., 2023; Merikangas et al., 2011). Schizophrenia is a psychotic disorder with a prevalence of approximately 1 % of the general population (Jauhar et al., 2022). These disorders are part of the leading causes of global burden worldwide and share substantial genetic determinants (Steinmetz et al., 2024; Hindley et al., 2022).

All three disorders are associated with premature mortality. Meta-analyses showed a loss of 14.5 years of life expectancy for individuals

with SCZ and 12.9 years in those with BD (Hjorthøj et al., 2017; Chan et al., 2022), while there is a reported loss of 7–14 years for individuals with MMD (Bitter et al., 2024; Laursen et al., 2016) compared to the general population. This premature mortality is partially attributed to a 10 to 30 times higher rate of death by suicide than the general population (Monson et al., 2021; Sher and Kahn, 2019). However, this phenomenon is also due to an increased risk of developing medical age-related comorbidities. Cardiovascular diseases remain the primary cause of death among individuals with severe mental disorders, who experience 85 % higher mortality rate from these conditions compared to the general population (Correll et al., 2017). Additionally, they are also more affected by other chronic conditions including diabetes, infections and cancers.

<footnote><sup>a</sup> Université Paris Cité, INSERM, Optimisation Thérapeutique en Neuropharmacologie, OPTEN U1144, 75006, Paris, France</footnote>

<footnote><sup>b</sup> Département de Psychiatrie et de Médecine Addictologique, Hôpitaux Lariboisière-Fernand Widal, GHU APHP.Nord – Université Paris Cité, Paris, F-75010, France</footnote>

<footnote><sup>c</sup> Fondation Fondamental, F-94010, Créteil, France</footnote>

<footnote>* Corresponding author.
E-mail address: cynthia.marie-claire@u-paris.fr (C. Marie-Claire).</footnote>
Early mortality and multiple medical age-related comorbidities are indicators of premature cellular ageing. There are several biomarkers of cellular ageing (López-Otín et al., 2023) of which telomere length (TL) is the most well-established and studied one in psychiatric disorders. Telomeres are non-coding nucleotide sequences at the ends of chromosomes that shorten with each cell cycle. Telomeres maintain genome integrity but when they become critically short, they induce cellular senescence or genomic instability, triggering the development of age-related disorders or cancers (Liao et al., 2023).

Telomeres are meticulously protected by a specific group of proteins among which three multiprotein complexes play primary roles in their maintenance. The Shelterin complex, attached to the ends of the telomeres, protects them from environmental stressors and coordinates their elongation when they become critically short through the recruitment of the telomerase enzyme complex and the CST complex composed of the proteins CTC1-STN1-TEN1 (Lim and Cech, 2021). An alteration in any protein of the telomerase complex can impair its activity, and may cause early telomere attrition (Roake and Artandi, 2020). Additionally, allelic variations in genes encoding a protein within any of the three complexes may modulate their expression and alter their function, ultimately leading to shorter telomeres (Burren et al., 2024).

It has been well established in numerous meta-analyses that TL is significantly reduced in individuals with severe psychiatric disorders compared to the general population. In MDD, a meta-analysis including 16 case-control studies (N = 7207 participants) found that TL is significantly shorter in affected individuals as compared to control individuals (Hedges' g = -0.42, p = 1 10⁻⁵) (Lin et al., 2016). In addition, another meta-analysis in MDD including 38 studies (N = 34,347 participants) found an association between depression and shorter TL with a Cohen's d effect size of -0.20 (p < 0.0001) (Ridout et al., 2016). In SCZ, a meta-analysis including 22 case-control studies (N = 3588 participants) found that TL was shorter in affected individuals compared to controls with a small to medium ES (ES, -0.39; 95% CI, -0.49 to -0.28; p < 0.001) (Ayora et al., 2022). In a meta-analysis including 10 studies (N = 1130 participants), TL was found shorter in individuals with BD compared to control individuals (Hedges' g = -0.54, 95% CI = -0.84 to -0.28, p < 0.001) and this effect was independent of the individual's mood status (Huang et al., 2018).

The main reference pharmacological treatments are antidepressants for MDD, antipsychotics for SCZ, and mood stabilizers or atypical antipsychotics for BD (Stępnicki et al., 2018; Nierenberg et al., 2023; Goes, 2023). Few clinical studies explored the impact of these pharmacological agents on TL in individuals with severe mental disorders. In MDD, 2 studies did not observed any association between leukocyte TL and lifetime exposure to antidepressants (ATDs) (Schaakxs et al., 2015; Pisanu et al., 2020). Concerning SCZ, a recent review of 10 studies drew contradictory conclusions. However, individuals who received antipsychotics had mostly longer TL than those not on antipsychotics (Apetroaei et al., 2024). In a recent review of 10 studies evaluating the effect of medications on TL in individuals with BD, the vast majority identified an increased TL in the blood of those on lithium (Li) treatment (Courtes et al., 2024). In contrast, a more recent study found no evidence that the number of Li prescriptions, the total duration of use, or the duration of the first prescription period of Li were associated with TL in individuals with BD (Mutz et al., 2024).

The literature on shorter TL in individuals with MDD, SCZ or BD is well-established and there are also few studies investigating the association between medication use and TL in these populations. However, literature remains very limited regarding the understanding of the mechanisms underlying this phenomenon, even though conclusions of these articles often mentioned that the observed alteration in TL might be due to abnormalities in telomere maintenance. Therefore, in this review, we aim to review evidence from clinical studies exploring Single-nucleotide polymorphism (SNPs) or gene expression (GE) of proteins involved in telomere homeostasis mechanisms and telomerase activity (TA) in individuals with MDD, SCZ or BD, in retrospective,

prospective and interventional studies.

## 2. Materials and methods

Two authors (CMC and JT) conducted independent investigations between July and November 2024. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) framework was followed, and the review was registered in PROSPERO, with registration number CRD42024605852. The following MESH terms combinations were applied in searches within the PubMed and Google Scholar databases: "telomerase and bipolar disorder", "telomerase and major depressive disorder", "telomerase and depression", "telomerase and schizophrenia", "telomere homeostasis and bipolar disorder", "telomere homeostasis and major depressive disorder", "telomere homeostasis and depression", "telomere homeostasis and schizophrenia". Research included articles published up to November 2024.

Inclusion criteria were: (1) original peer-reviewed articles written in English, (2) involving individuals diagnosed with Schizophrenia, Bipolar disorder, Major depressive disorder, (3) including one or more of the following analyses: SNPs or gene expression related to any protein involved in the telomere homeostasis system (either included in the telomerase enzyme complex, the Shelterin complex and the CST complex or as an accessory protein), or telomerase activity, (4) articles investigating the impact of pharmacological or non-pharmacological interventions on any of the mentioned markers.

Exclusion criteria were: (1) articles not written in English, (2) articles that included only TL analyses, (3) studies involving preclinical or in vitro models, (4) diagnoses not following DSM-III, DSM-IV, DSM-V (American Psychiatric Association, 1980; ibid, 2013) or ICD8 and ICD10 (International Classification of Diseases coding system, developed by the World Health Organization (WHO)) criteria of BD, MDD or SCZ, (5) review articles, (6) SNPs from genes not exclusively related to telomere homeostasis, (7) p-values not detailed for analyses, (8) enrolling individuals diagnosed with a co-occurring disease that affected TL.

The data extracted include: (1) the name of the first author, the publishing year and name of the journal, (2) the cohort characteristics (number of participants, age, sex, diagnosis), (3) the study design (type of sample, controls, type of drugs analyzed or description of intervention used in terms of duration for instance) (4) the type of analyses (TA, SNPs, GE), (5) and the main outcomes.

## 3. Results

### 1. Results of literature search

Initially, 311 studies were identified in the two databases, from which 185 duplicate articles were excluded. Abstract screening was conducted on the remaining 126 articles, and full-text analysis for eligibility was performed on 33 studies. The final list of included studies comprised 25 articles. The flowchart of study inclusion process is presented in Fig. 1.

Of the included studies, 5 investigated Single nucleotide polymorphisms (SNPs), 9 focused on gene expression and 11 studied telomerase activity (TA). Regarding treatments, 9 studies assessed the effects of various drugs (ATDs, lithium, atypical antipsychotics), while 3 explored other types of interventions (electroconvulsive therapy, yoga and oil supplementation). Articles including individuals with MDD were the most frequent (n = 16), followed by those with individuals with SCZ (n = 6) and BD (n = 4).

### 2. Genetic studies

The characteristics of included genetic studies are summarized in Table 1. We identified 5 studies examining SNPs in genes involved in telomere maintenance mechanisms. Among these, TERT or TERC were
<figure><img src="image_3.png" /><figcaption>**Fig. 1.** Flowchart of the review methodology
TL: telomere length.</figcaption></figure>

investigated in 4 studies, however, none of the studies focused on the same SNPs. The largest study examined rs1317082 in *TERC* (n = 65,107), rs7726159 in *TERT* (n = 65,719) (both from the telomerase complex) and rs2487999 in *OBFC1* (STN1) (n = 65,488) from the CST complex (n = 65,096) in Caucasian individuals with MDD. The study found no association between these genotypes and hospital attendance for depression or death by depression (Wium-Andersen et al., 2017). Similarly, in a case-control study with Caucasian individuals (n = 1628 MDD and n = 1140 HC), the rs10936599 SNP in *TERC* was not associated with MDD. However, these authors found that this SNP was associated with childhood-onset MDD (p = 0.012) (Michalek et al., 2017). In addition, the within-case comparison showed that this SNP was associated with childhood-onset versus adult-onset (p = 0.001) and childhood/adolescent-onset MDD relative to adult-onset MDD (p = 0.02). The same study did not find any association with a SNP in *TERT* gene. In a case-control study conducted in another Caucasian cohort (n = 436 MDD and n = 1590 HC), rs2736100 in *TERT* was associated with depression only in individuals who had not experienced childhood adversity (p = 0.013). The risk of depression was higher in homozygotes for the minor frequency allele compared with other genotypes (p = 0.010) (Wei et al., 2016).

Rao and colleagues performed a case-control study (n = 1072 SCZ, n = 1284 HC) of 8 SNPs within the *TERT* gene in a Han Chinese cohort. They identified 3 SNPs associated with paranoid SCZ: rs207586 (p = 0.00091), rs4975605 (p = 0.0026) and rs10069690 (p = 0.0044). In addition, an haplotype based on the combination of rs2736118-rs2075786 showed an association with paranoid SCZ (p = 0.0013) (Rao et al., 2016). Wang and colleagues studied 8 SNPs within *NVL*,

encoding an essential protein in telomerase assembly, among Han Chinese individuals, including individuals with MDD (n = 1045), SCZ (n = 1235), and HC (n = 1235). Only rs16846649 (p = 0.014) showed an association with MDD. In contrast, 3 SNPs (rs16846649 p = 7.40 10⁻⁶, rs10799541 p = 8.10 10⁻³, and rs10916583 p = 1.08 10⁻²) showed significant associations with SCZ. A combined analysis of controls vs cases (MDD + SCZ) revealed that rs16846649 (p = 8.9 10⁻⁶) and rs10916583 (p = 9 10⁻³) were strongly associated with both MDD and SCZ (Wang et al., 2015).

### 3. Gene expression

*TERT* expression was evaluated in all the 7 case-control studies identified. Table 2 summarizes the characteristics of included studies analyzing GE. Teissier and colleagues examined *TERT* expression in blood samples from individuals with MDD and healthy controls (HC). They observed no difference in *TERT* transcript levels between individuals with MDD (n = 17) and HC (n = 16) (Teissier et al., 2012). This study however found a linear relationship between depression scores and *TERT* expression (p = 0.03). *TERT* gene expression was also analyzed in MDD in human brain tissues. For this purpose, glia cells from the uncinate fasciculus (UF) and white matter (WM) were collected at the time of death from brain donors with MDD (n = 12 for UF and n = 11 for WM) and age-matched HC (n = 12 for UF and n = 11 for WM). Oligodendrocytes and astrocytes were collected using laser capture micro-dissection. The results showed a significant decrease in *TERT* gene expression in oligodendrocytes from both brain structures in individuals with MDD compared with HC (p < 0.0005 and p = 0.002). However, no
<table><caption>**Table 1**
Studies analyzing SNPs.</caption><thead><tr><th>Reference</th><th>Diagnosis</th><th>Study design</th><th>Population</th><th>N</th><th>Study sample</th><th>Method</th><th>SNP</th><th>Main outcome</th></tr></thead><tbody><tr><td>(Wium-Andersen et al., 2017)</td><td>MDD</td><td>Cohort</td><td>Caucasian</td><td>TERC n = 65107<br>OBFC1 n = 65488<br>TERT n = 65719<br>Combined n = 65096</td><td>Blood</td><td>TaqMan SNP genotyping</td><td>rs1317082 (TERC)<br>rs2487999 (OBFC1)<br>rs7726159 (TERT)</td><td>No significant association</td></tr><tr><td>Michalek et al. (2017)</td><td>MDD</td><td>Case-control</td><td>Caucasian</td><td>MDD n = 1628<br>CS n = 1140</td><td>Blood</td><td>TaqMan SNP genotyping</td><td>rs10936599 (TERC)</td><td>No significant association</td></tr><tr><td>Wei et al. (2016)</td><td>MDD</td><td>Case-control</td><td>Caucasian</td><td>MDD n = 436<br>CS n = 1590</td><td>Saliva</td><td>TaqMan SNP genotyping</td><td>rs2736100 (TERT)</td><td>rs2736100 in TERT associated with MDD only among individuals without experience of childhood adversity - the minor allele associated with higher risk of depression for homozygotes compared to other genotypes</td></tr><tr><td>Rao et al. (2016)</td><td>SCZ</td><td>Case-control</td><td>Chinese Han</td><td>SCZ n = 1072<br>CS n = 1284</td><td>Blood</td><td>TaqMan SNP genotyping</td><td>rs2736118, rs2075786,<br>rs4246742, rs4975605,<br>rs10069690, rs2853676, and<br>rs2736098 (all TERT)</td><td>3 SNPs associated with paranoid SCZ: rs207586, rs4975605, rs10069690<br>The rs2736118-rs2075786 haplotype showed strong association with paranoid SCZ</td></tr><tr><td>Wang et al. (2015)</td><td>MDD/ SCZ</td><td>Case-control</td><td>Chinese Han</td><td>MDD n = 1045<br>SCZ n = 1235<br>CS n = 3515</td><td>Blood</td><td>TaqMan SNP genotyping</td><td>8 SNPs in NVL regions (rs16846649, rs4653581, rs6664230, rs10916544, rs10799541, rs10799551, rs10916583, rs3767732)</td><td>In MDD, statistical association of rs16846649 and rs10916583<br>In SCZ, rs16846649, rs10799541, and rs10916583 showed statistical significance<br>MDD + SCZ: rs16846649 and rs10916583 showed a strong association</td></tr></tbody></table>

MDD: Major depressive disorder, SCZ: Schizophrenia, CS: Control subjects, SNP: Single Nucleotide Polymorphism, TERC: Telomerase RNA component, TERT: Telomerase reverse transcriptase, OBFC1: Oligonucleotide/oligosaccharide binding fold-containing protein 1, NVL: Nuclear valosin-containing protein-like.

<table><caption>**Table 2**
Studies analyzing Gene expression.</caption><thead><tr><th>Reference</th><th>Diagnosis</th><th>Study design</th><th>N</th><th>Study sample</th><th>Method</th><th>Gene analysis</th><th>Main outcome</th></tr></thead><tbody><tr><td>Teyssier et al. (2012)</td><td>MDD</td><td>Case-control</td><td>MDD n = 17<br>HC n = 16</td><td>Blood</td><td>RT-qPCR</td><td>TERT</td><td>No significant association</td></tr><tr><td>Szebeni et al. (2014)</td><td>MDD</td><td>Case-control</td><td>UF: MDD n = 12<br>CS n = 12<br>WM: MDD n = 11<br>HC n = 11</td><td>Brain: astrocytes/oligodendrocytes in Ucinate fasciculus (UF)/White matter (WM)</td><td>RT-qPCR</td><td>TERT</td><td>↓ TERT expression in oligodendrocytes MDD vs Controls in UF and WM<br>NS astrocytes in UF and not detected in WM</td></tr><tr><td>Mlakar et al. (2024)</td><td>SCZ</td><td>Case-control</td><td>SCZ n = 357<br>CS n = 401</td><td>Blood</td><td>Whole-genome expression profiling</td><td>TERT/TERC</td><td>↓ TERT expression in SCZ vs HC<br>NS TERC</td></tr><tr><td>Lundberg et al. (2020)</td><td>BD</td><td>Case-control</td><td>BD I n = 100<br>HC n = 100</td><td>Blood</td><td>RT-qPCR</td><td>TERT</td><td>No significant association</td></tr><tr><td>(Köse Çinar, 2018)</td><td>BD</td><td>Case-control</td><td>Bd n = 21<br>HC n = 20</td><td>Blood</td><td>RT-qPCR</td><td>TERT</td><td>↑ TERT expression in manic BD vs HC</td></tr><tr><td>Gardiner et al. (2013)</td><td>SCZ</td><td>Case-control</td><td>SCZ n = 114<br>HC n = 80</td><td>Blood</td><td>Whole-genome expression profiling</td><td>Gene expression profiling</td><td>↓ CTC1 in SCZ<br>TERT NS</td></tr><tr><td>Spano et al. (2024)</td><td>BD</td><td>Case-control</td><td>BD n = 68<br>BD controls n = 45</td><td>Blood</td><td>RT-qPCR</td><td>29 genes related to telomere homeostasis</td><td>↓ POT1 in BD with shorter telomeres vs BD controls<br>NS for other genes including TERT</td></tr></tbody></table>

MDD: Major depressive disorder, SCZ: Schizophrenia, BD: Bipolar disorder, HC: Healthy controls, RT-qPCR: Quantitative reverse transcription polymerase chain reaction, TERC: Telomerase RNA component, TERT: Telomerase reverse transcriptase, POT1: Protection of telomeres 1, CTC1: Conserved telomere capping protein 1, NS: Not significant.

differences were found in UF astrocytes, and *TERT* expression was not detected in WM astrocytes (Szebeni et al., 2014).

In a large Norwegian cohort (n = 357 SCZ, n = 401 HC), *TERT*

expression levels were significantly decreased in the peripheral blood of individuals with SCZ (p = 0.03), while no difference in *TERC* expression was observed (Mlakar et al., 2024). In the same study, neither *TERT* nor
TERC expression levels were associated with the duration of illness in individuals with SCZ (Mlakar et al., 2024).

In the study by Lundberg and colleagues, the analysis of *BERT* gene expression levels in the peripheral blood of individuals with BD type 1 (n = 100) compared with control individuals (n = 100) did not show any significant difference (Lundberg et al., 2020). Only one longitudinal study included medication-free manic male individuals with BD (n = 21), and age- and gender-matched healthy controls (n = 20). The results identified a significant (p = 0.03) increase of *BERT* gene expression at baseline in manic individuals compared with the controls (Köse Çinar, 2018). This increase remained significant even when individuals with BD met the remission criteria (p = 0.01) suggesting that this phenomenon is common to both manic and remission phases.

Two other studies did not identify *BERT* as differentially expressed between cases (SCZ or BD) and controls (Gardiner et al., 2013; Spano et al., 2024), but performed analyses for other proteins from the CST and the Shelterin complexes. The *CTC1* (CST complex) transcript was identified as downregulated (p = 0.024) in mRNA expression profiling using microarrays in Peripheral Blood Mononuclear Cells (PBMCs) in SCZ (n = 114) compared with HC (n = 80) (Gardiner et al., 2013). Spano and colleagues identified a subgroup of young individuals with BD (mean age ~29 years, n = 68) who had shorter telomeres than age-matched individuals with BD (n = 45), and found that mRNA levels of *POT1*, a Shelterin complex protein, were decreased in the first subgroup (p = 0.003) (Spano et al., 2024).

## 4. Telomerase activity

Literature screening identified 9 case-control studies measuring TA. The characteristics of the included studies measuring TA are summarized in Table 3. Seven of these studies included individuals with MDD. Two studies found no association between TA and depression. The study with the largest sample included 332 individuals in total (n = 166 MDD, n = 166 HC) and found no significant differences in TA between the two groups and no association with the duration of mood episodes or duration of MDD within the MDD group. However, the authors observed a significant increase in TA in male patients compared with male controls (p = 0.007), but these results were not observed with females (Simon et al., 2015). Similarly, a case-control study including individuals with MDD (n = 20) and HC (n = 33) found no difference in TA between groups. Additionally, within the MDD subgroup, no association was observed between TA and any available socio-demographic or clinical variables (Ryan et al., 2021). The other 5 case-control studies

consistently identified elevated TA in individuals with MDD compared with control individuals. Wolkowitz and colleagues conducted 3 studies with overlapping samples. The first one included participants with MDD (n = 20) vs HC (n = 18) and found a significantly higher TA in the PBMCs from cases (p = 0.007) (Wolkowitz et al., 2012). In another study, TA was also higher in PBMCs from individuals with MDD (n = 25) than in controls (n = 18) (p = 0.025) (Wolkowitz et al., 2015). A third case-control study including individuals with MDD (n = 20) and HC (n = 20) observed a higher TA in cases than in controls (p = 0.016). In this study, adverse childhood experiences (ACEs) were positively correlated with TA in the MDD subgroup (p < 0.05) but not in controls (Chen et al., 2014). In another study, TA was reported to be higher in individuals with MDD (n = 39) compared with HC (n = 39) (p = 0.001) (Bürhan-Çavuşoğlu et al., 2021). Additionally, TA was positively correlated with both depression severity (p = 0.001) and anxiety severity (p = 0.001). The last case-control study that found an elevated baseline TA in cases (n = 35) compared with HC (n = 35) (p = 0.001) also found a positive correlation between TA and depression severity as assessed by the Hamilton Rating Scale for Depression (HAM-D) score at baseline (p = 0.012) and during the 8 weeks of follow-up (Walia et al., 2023).

We found one study measuring TA in SCZ that recruited 3 groups: individuals with SCZ (n = 53), unaffected family members (n = 31), and unrelated HC (n = 59). While combining the unaffected groups (controls and unaffected family members), the comparison showed that individuals with SCZ had lower TA (p = 0.01) (Porton et al., 2008).

Finally, only one study assessed TA in individuals with BD. It included 28 individuals with BD matched with 23 HC. TA was not significantly different between the two groups. No differences were found between the subtypes of BD (n = 8 BDI and n = 13 BDII), nor in symptom severity within the BD group (Soeiro-de-Souza et al., 2014).

## 5. Interventions

Twelve clinical trials were included after literature screening. Of these studies, 9 involved drug interventions and 3 other types of interventions: Electroconvulsive therapy (ECT), or yoga therapy in MDD and oil supplementation in SCZ. The characteristics of the included studies are summarized in Table 4.

### a) MDD

Three prospective cohort studies were identified, in which

<table><caption>**Table 3**
Studies analyzing Telomerase activity.</caption><thead><tr><th>Reference</th><th>Diagnosis</th><th>Study design</th><th>N</th><th>Study sample</th><th>Method</th><th>Main outcome</th></tr></thead><tbody><tr><td>Simon et al. (2015)</td><td>MDD</td><td>Case-control</td><td>MDD n = 166HC n = 166</td><td>Blood</td><td>TRAP</td><td>No significant association</td></tr><tr><td>Ryan et al. (2021)</td><td>MDD</td><td>Case-control</td><td>MDD n = 20HC n = 33</td><td>Blood</td><td>TRAP</td><td>No significant association</td></tr><tr><td>Wolkowitz et al. (2012)</td><td>MDD</td><td>Case-control</td><td>MDD n = 20HC n = 18</td><td>Blood</td><td>TRAP</td><td>↑TA in MDD vs HC</td></tr><tr><td>Wolkowitz et al. (2015)</td><td>MDD</td><td>Case-control</td><td>MDD n = 25HC n = 18</td><td>Blood</td><td>TRAP</td><td>↑TA in MDD vs HC</td></tr><tr><td>Chen et al. (2014)</td><td>MDD</td><td>Case-control</td><td>MDD n = 20HC n = 20</td><td>Blood</td><td>TRAP</td><td>↑TA in MDD vs HC</td></tr><tr><td>Bürhan-Çavuşoğlu et al. (2021)</td><td>MDD</td><td>Case-control</td><td>MDD n = 39HC n = 39</td><td>Blood</td><td>TRAP</td><td>↑TA in MDD vs HC</td></tr><tr><td>Walia et al. (2023)</td><td>MDD</td><td>Case-control</td><td>MDD n = 35HC n = 35</td><td>Blood</td><td>TRAP</td><td>↑TA in MDD vs HC</td></tr><tr><td>Porton et al. (2008)</td><td>SCZ</td><td>Case-control</td><td>SCZ n = 53Unaffected controls unrelated n = 59Unaffected family members n = 31</td><td>Blood</td><td>TRAP</td><td>↓TA SCZ vs HC (unrelated and family combined)</td></tr><tr><td>(Soeiro-de-Souza et al., 2014)</td><td>BD</td><td>Case-control</td><td>BD n = 28HC n = 23</td><td>Blood</td><td>TRAP</td><td>No significant association</td></tr></tbody></table>

MDD: Major depressive disorder, SCZ: Schizophrenia, BD: Bipolar Disorder, HC: Healthy controls, TA: Telomerase activity, TRAP: Telomeric repeat amplification protocol.
<table><caption>**Table 4**
Studies analyzing Interventions.</caption><thead><tr><th>Reference</th><th>Diagnosis</th><th>Study design</th><th>N</th><th>Study sample</th><th>Analysis</th><th>Method</th><th>Type of intervention</th><th>Study design</th><th>Main outcome</th><th>Illness Severity</th><th>Rs/NRs status</th></tr></thead><tbody><tr><td>Walia et al. (2023)</td><td>MDD</td><td>Prospective cohort study</td><td>MDD n = 35</td><td>Blood</td><td>TA</td><td>TRAP</td><td>ATD</td><td>8 weeks escitalopram</td><td>No significant change of TA from baseline to week 8</td><td>TA at baseline negatively correlated with changes in depression between baseline and week 8<br>Treatment-associated changes in TA (week 8 activity minus baseline activity) were inversely correlated with changes in HDRS<br>Lower baseline TA was correlated<br>With ↓ HDRS over the course of 8 weeks treatment</td><td>lower TA in Rs versus NRs both at baseline and 8 weeks<br>↓ TA Rs vs NRs</td></tr><tr><td>Wolkowitz et al. (2012)</td><td>MDD</td><td>Prospective cohort study</td><td>MDD n = 15</td><td>Blood</td><td>TA</td><td>TRAP</td><td>ATD</td><td>8 weeks sertraline</td><td>No significant change of TA from baseline to week 8</td><td>Lower TA associated with ↑ absolute improvement in depression severity after 8 weeks</td><td>No significant association</td></tr><tr><td>Rampersaud et al. (2023)</td><td>MDD</td><td>Prospective cohort study</td><td>MDD n = 32</td><td>Blood</td><td>TA</td><td>TRAP</td><td>ATD</td><td>8 weeks open-label SSRI<br>Fluoxetine n = 6, sertraline n = 13, citalopram n = 4, escitalopram n = 11</td><td>Measure at baseline only</td><td>↑ TERT expression from baseline to week 24</td><td></td></tr><tr><td>(da Silva et al., 2022)</td><td>MDD</td><td>Prospective cohort study</td><td>MDD n = 12</td><td>Blood</td><td>GE: TERT</td><td>RT-qPCR</td><td>ATD</td><td>24 weeks sertraline or Escitalopram</td><td></td><td></td><td></td></tr><tr><td>(Wium-Andersen et al., 2017)</td><td>MDD</td><td>Cross-sectional cohort study</td><td>N = 67306 (3genotypes)<br>N = 65107 (TERC)<br>N = 65488 (OBFC1)<br>N = 65096 (TERT)</td><td>Blood</td><td>SNP: TERT - TERC - OBFC1</td><td>TaqMan SNP genotyping</td><td>ATD</td><td>Comparison of individuals with prescription antidepressants medication or not</td><td></td><td></td><td></td></tr><tr><td>Ryan et al. (2021)</td><td>MDD</td><td>Prospective case-control study</td><td>MDD n = 20</td><td>Blood</td><td>TA</td><td>TRAP</td><td>ECT</td><td>Comparison before after a mean of 11 ECT sessions</td><td>No significant association</td><td></td><td>No significant association</td></tr><tr><td>Tolahunase et al. (2018)</td><td>MDD</td><td>Prospective case-control study</td><td>MDD Yoga n = 29<br>MDD control n = 29</td><td>Blood</td><td>TA</td><td>TRAP</td><td>12-week yoga- and meditation- based lifestyle intervention</td><td>Comparison before/ after 12 weeks</td><td>↑ TA in the Yoga intervention group more than in the control group</td><td></td><td></td></tr><tr><td>Mlakar et al. (2024)</td><td>SCZ</td><td>Cross-sectional cohort study</td><td>SCZ n = 357</td><td>Blood</td><td>GE: TERT/ TERC</td><td>RT-qPCR</td><td>2.22 % on Lithium 24.6 % ATD 83.5 % AP</td><td>Comparison of individuals according to medication use</td><td>No significant association</td><td></td><td></td></tr><tr><td>Pawelczyk et al. (2018)</td><td>SCZ</td><td>Prospective case-control study</td><td>SCZ intervention n = 32<br>SCZ controls n = 33</td><td>Blood</td><td>Protein levels: TERT</td><td>ELISA</td><td>Fish oil (EPA + DHA) versus control oil (olive oil) supplements for 26 weeks</td><td>Comparison fish oil versus control oil from baseline to week 26</td><td>↑ TERT expression in both groups. mean change of TA from baseline to week 26 was significantly higher in the intervention group</td><td></td><td></td></tr><tr><td>(Soeiro-de-Souza et al., 2014)</td><td>BD</td><td>Prospective cohort study</td><td>BD n = 28</td><td>Blood</td><td>TA</td><td>TRAP</td><td>Lithium</td><td>6 weeks of Lithium</td><td>No significant change of TA from baseline to week 6</td><td>↓depressive symptoms = ↑TA</td><td>No significant association</td></tr></tbody></table>

(continued on next page)
<table><caption>Table 4 (continued)</caption><thead><tr><th>Reference</th><th>Diagnosis</th><th>Study design</th><th>N</th><th>Study sample</th><th>Analysis</th><th>Method</th><th>Type of intervention</th><th>Study design</th><th>Main outcome</th><th>Illness Severity</th><th>Rs/NRs status</th></tr></thead><tbody><tr><td>Lundberg et al. (2020)</td><td>BD</td><td>Cross-sectional cohort study</td><td>BD type I total n = 65<br>BD I on Li n = 22<br>BD I not on Li n = 41</td><td>Blood</td><td>GE: TERT</td><td>RT-qPCR</td><td>Lithium</td><td>Comparison of individuals with or without lithium</td><td>↑ TERT BD I on Li vs not on Li<br>No correlation with duration of lithium treatment (except for those >24months of treatment)<br>Not provided</td><td></td><td></td></tr><tr><td>(Köse Çinar, 2018)</td><td>BD</td><td>Prospective case-control study</td><td>BD manic n = 21<br>HC n = 20</td><td>Blood</td><td>GE: TERT</td><td>RT-qPCR</td><td>AP - Lithium</td><td>Open label study of 8 weeks of Li plus AP</td><td></td><td></td><td></td></tr></tbody></table>

MDD: Major depressive disorder, SCZ: Schizophrenia, BD: Bipolar Disorder, HC: Healthy controls, TA: Telomerase activity, GE: Gene expression, SNP: Single nucleotide polymorphism, ATD: Antidepressant, AP: Antipsychotic, ECT: Electroconvulsive therapy, HDRS: Hamilton depression rating scale, Rs: Responders, NRs: Non-responders, EPA: Eicosapentaenoic acid, DHA: Docosahexaenoic acid.

individuals were prescribed antidepressants (ATD) for 8 weeks. The largest cohort included individuals with MDD (n = 35) treated with escitalopram and found no significant changes for TA between pre-treatment and post-treatment. (Walia et al., 2023). There was a negative correlation between baseline TA and change in depressive symptoms between baseline and week 8. These authors also found that responders had lower TA compared to non-responders at baseline and after 8 weeks (respectively p = 0.001 and p = 0.012). The second study recruited individuals with MDD (n = 15) who completed an open-label treatment with sertraline. TA did not change after ATD treatment, and no correlations were found between the concentrations of sertraline and/or N-desmethylsertraline and changes in TA. In line with the previous study, responders exhibited significantly lower baseline TA than non-responders (p = 0.02). In addition, changes in TA (week 8 activity minus baseline activity) were inversely correlated with changes in HAM-D ratings (p = 0.004) (Wolkowitz et al., 2012). Moreover, in this study, lower baseline TA was directly correlated with a decrease in HAM-D ratings over the course of 8 weeks of treatment with sertraline and lower absolute HAM-D ratings (p < 0.03). These results are consistent with Rampersaud and colleagues' study describing that lower baseline TA was associated with greater absolute improvement in depression severity after completing 8 weeks of treatment with selective serotonin reuptake inhibitors (SSRI) (n = 32 MDD) (p = 0.05) (Rampersaud et al., 2023). However, this study did not find any association between the levels of TA and response to ATD 8 weeks after SSRI treatment (Rampersaud et al., 2023). In this study, no change for TA before/after treatment can be reported, since the measure was performed at baseline only. In another prospective cohort study, the effect of sertraline and escitalopram on TERT expression was measured in individuals with MDD (n = 12). After 24 weeks of treatment, an increase in TERT expression was observed (p < 0.0001) (da Silva et al., 2022). The last cross-sectional study performed in a Caucasian cohort including individuals with MDD found no association between ATD medication use and any of the three polymorphisms in the following genes: TERC (n = 65,107), OBFC1 (n = 65,488) TERT (n = 65,719), or the three genotypes combined (n = 65,096) (Wium-Andersen et al., 2017).

Ryan and colleagues conducted an open-label prospective cohort study of ECT (Electroconvulsive therapy) in individuals with MDD (n = 20). ECT was administered twice a week (individuals remained on their prescribed medications). No effects of time, group or time x group were found on TA after the intervention. Similarly, no association was identified between baseline TA or the change in TA and the change in the HAM-D score post-ECT. However, they identified that baseline HAM-D was negatively correlated with TA at baseline in a small subsample of ECT non-remitters (n = 9) (p = 0.038) (Ryan et al., 2021).

A prospective case-control study evaluated the impact of 12 weeks of yoga- and meditation-based lifestyle intervention therapy in a MDD cohort, including 29 individuals in the intervention group and 29 in the control group, both on routine drug treatments. After 12 weeks of yoga practice, a significant increase of TA was observed in the intervention group compared with the control group (p < 0.05) (Tolahunase et al., 2018).

## b) SCZ

In a cross-sectional study that included subjects with SCZ (n = 357 – 83.5 % with antipsychotics, 24.6 % with antidepressants, and 2.22 % with Li), neither TERT nor TERC expression correlated with medication use (Mlakar et al., 2024). A prospective case-control study enrolled participants with SCZ (n = 65) and randomly assigned them into two groups: one intervention group (n = 32) and one control group (n = 33). The intervention group received fish oil supplementation (0.33g of EPA - eicosapentaenoic acid and 0.22g of DHA - docosahexaenoic acid) each day, while the control group received placebo oil (olive oil). TERT protein levels were measured after 26 weeks of treatment. A significant increase in TERT protein levels were found in both groups (p < 0.001, p < 0.05).
< 0.001). However the mean change in these protein levels from baseline was significantly higher in the intervention group than in the placebo group (p = 0.002), even after controlling for additional potential confounding variables such as sex, age and Body Mass Index (BMI) (p < 0.001). Moreover, a significant correlation was observed between disease severity (CGI-S) and TERT levels in both the EPA + DHA and control groups (p = 0.87 10⁻⁹ and 8.1 10⁻⁹ respectively) (Pawełczyk et al., 2018).

### c) BD

The impact of Li on TA was evaluated in a prospective cohort study by Soeiro and colleagues. They recruited medication-free individuals with BD (n = 28) who were prescribed lithium treatment for 6 weeks. They found no change in TA after 6 weeks nor correlation between serum Li levels and TA at the endpoint or during follow-up (Soeiro-de-Souza et al., 2014). Nevertheless, they observed a negative association between improvement in depressive symptoms and TA at the endpoint (p = 0.007). This study did not identify any changes in TA related to Li responder status or remission criteria after 6 weeks of Li treatment (with a total of 16 responders out of 21 individuals). Furthermore, in a cross-sectional study including individuals with BD I (n = 63) on Li treatment, Lundberg and colleagues observed that individuals with BD I currently on Li treatment (n = 22) had higher TERT expression compared with those not on Li treatment (n = 41) (p = 0.043). Li treatment duration was not correlated with TERT expression in all treated individuals but was positively correlated with the subgroup of individuals treated for 24 months or more (n = 17) (p = 0.042) (Lundberg et al., 2020). Finally, the prospective case-control study by Köse Çinar and colleagues included medication-free manic individuals with BD (n = 21), showing increased TERT expression compared with HC (n = 20) at baseline (p = 0.03). They observed that after 8 weeks of combined treatment with Li and one antipsychotic the increase in TERT expression was still significant compared with HC (Köse Çinar, 2018). These authors did not provide statistical analyses between individuals with BD in remission vs at baseline.

## 4. Discussion

Meta-analyses have shown a robust association between psychiatric disorders and shortened TL. Telomere maintenance is a sophisticated system that involves various multi-protein complexes (Telomerase, Shelterin, CST) and accessory proteins. Alteration of any of these key components can cause serious damage to telomeres. While many studies have explored TL in association with psychiatric disorders, current research exploring the underlying mechanisms in such conditions remains scarce. Our literature screening identified 25 clinical studies on this topic focusing on i) variants of the genes encoding the proteins involved; ii) gene expression of these genes; iii) telomerase activity or telomerase levels and iv) the effects of medications and therapies on these mechanisms.

### - Studies in MDD

MDD is the most studied disorder. Of the four studies analyzing SNPs in TERT, TERC or NVL, only one reported a significant association with TERT. Further studies are needed, as some of them had moderate sample sizes, potentially leading to power issues. Noteworthy, the largest study (>65,000 participants) failed to find any association (Wium-Andersen et al., 2017). The picture is similarly inconclusive with TERT expression in case-control studies, with one blood study being non-significant while one brain study was significant (decreased TERT expression). Here again, further studies are warranted. Of note these studies were limited by small cohort sizes, with fewer than 20 participants in each group and a variability in sample types (a post-mortem brain sample and two blood samples).

Interestingly, TA was the most studied parameter in individuals with MDD. We identified seven case-control studies, most of them (n = 5) suggesting an increased TA in MDD. Of note, among these 5 significant studies, we identified 3 overlapping samples from the same research group. Since the largest study (n = 332) failed to report significant associations (Simon et al., 2015), we encourage further replications.

### - Studies in SCZ and BD

As illustrated, the study of the biomarkers in SCZ and BD remains scarce, with a total of 8 studies (4 in SCZ and 4 in BD). One genetic study in SCZ found an association with SNPs in TERT and one with SNPs in NVL regions (an accessory protein involved in telomerase assembly). Genetic variants have not been studied in BD. TA has been studied only once in SCZ and once in BD. Participants with SCZ had lower TA than healthy controls, whereas no significant association was observed in individuals with BD. Gene expression studies were also very scarce, with only 2 and 3 studies including individuals with SCZ or BD respectively. No decrease in TERT expression was found in schizophrenia in 2 studies and 2 out 3 studies also found no decrease in BD. Interestingly, when associations with SCZ or BD were found, they involved genes other than TERT (i.e. TERC, POT1, CTC1). This suggests that future studies should include all genes encoding for proteins of the three main complexes involved in telomere maintenance and not only TERT. However, replications are warranted given the small number of available studies.

### - Methodological issues

We identified significant heterogeneity in multiple aspects of study designs and methodological approaches. First, the literature is skewed towards depression with 12 out 21 case-control studies including individuals with MDD. Since telomere shortening is common to MDD, BD and SZ, the underlying mechanisms should be investigated through trans-nosographic studies to identify any specificity.

Secondly, sample sizes were a common limitation across studies. Sample sizes cannot be compared given the various markers being measured. Nevertheless, SNPs analyses included moderate to very large cohort sizes. Only 3 studies included a relatively large sample size for gene expression (Mlakar, Lundberg, Gardiner) (with more than 100 cases) and only 1 study in TA did so (Simon). We therefore cannot exclude a lack of power, in particular for GE and TA studies. Replications are therefore warranted in larger samples.

Third, telomerase activity was the most frequently evaluated parameter and seems to be the most promising marker. Studies about TA had the most uniform designs in this review, with TRAP being used in all studies. TA was mostly found higher in MDD cases compared to controls. Since only two studies assessed TA in BD and SCZ, replications are warranted with larger cohort sizes and include more participants with BD or SCZ.

Fourth, only 7 of the case-control studies assessed gene expression, all including TERT either as the only studied gene or with additional genes. Most of the results on TERT expression in case-control studies were non-significant, except for one brain study in MDD, and one blood study in BD (both in manic and in remitted patients) and one in SCZ. Only three studies included genes from the Shelterin, telomerase and CST complexes in addition to TERT. This observation highlights that the complexity of telomere homeostasis has been overlooked in the literature. Interestingly, these three studies suggested the involvement of TERC or CTC1 in SCZ and POT1 in BD. Nevertheless, since telomere maintenance involves highly complex interactions of multi-protein complexes, futures clinical investigations in gene expression should expand their scope of analyses to evaluate and elucidate these interactions.

### - Intervention studies
Concerning interventions in MMD, this review highlights that measurement of pre-vs post-treatment TA was the most studied marker, with 2 non-significant studies on antidepressants, one non-significant study on ECT, and only one significant study on yoga- and meditation-based lifestyle intervention. *TERT* expression was found to be increased with antidepressants in MMD (only in 12 participants), while no association was found with studied SNPs and the use of antidepressants. Interventions using lithium in BD, antipsychotics or fish oil in SCZ are too scarce to conclude.

Regarding interventions, the interpretations are utmost difficult due to 1) the different types of disorders being studied, 2) the heterogeneity of interventions (antidepressants, lithium, antipsychotics, yoga, ECT), 3) the design of the studies, including both cross-sectional and longitudinal ones, in addition with different follow-up durations, 4) the heterogeneity of outcomes, 5) the markers being investigated (TA, *TERT* expression, telomerase levels, SNPs) and 6) the different sample sizes (from dozens to thousands of participants). We can here claim for more research with robust designs, such as randomized controlled trial for instance.

## 5. Conclusion

This systematic review primarily found studies on MDD, mainly focusing on TA, either in case-control studies or in association with antidepressant treatments or other types of interventions. Studies on TA in BD and SCZ remain rare, as do studies of gene expression in MDD, BD or SCZ. Genetic studies remain even more scarce. Similarly, very few studies have been published on the effects of interventions and with an important heterogeneity in terms of design, markers and outcomes, preventing to draw any conclusions. This review suggests that TA might be increased in MDD, with no major changes following exposure to antidepressants. Further studies should be performed adopting a transnosographic approach, analyzing both TA and gene expression with larger sample sizes. More importantly, since the literature mainly focuses on *TERT* expression and TA, investigations of proteins other than those directly involved in the telomerase complex are warranted. Finally, the evaluation of diverse intervention approaches is also required in well-designed studies to clarify how pharmaceutical or non-pharmaceutical interventions may influence telomere homeostasis, to optimize personal treatment management.

### CRediT authorship contribution statement

**Johanna Thurin:** Writing – review & editing, Writing – original draft, Investigation. **Bruno Etain:** Writing – review & editing, Supervision. **Frank Bellivier:** Writing – review & editing, Supervision. **Cynthia Marie-Claire:** Writing – review & editing, Writing – original draft, Supervision, Investigation.

### Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

### Acknowledgements

This work was supported by INSERM (Institut National de la Santé et de la Recherche Médicale). C. Marie-Claire is supported by the Centre National de la Recherche Scientifique.

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