Sleep is associated with telomere shortening: A population-based longitudinal study.

As the chronological age increases, there is a decrease in the telomere length (TL). Associations between TL and age-related diseases have been described. Since the major pathophysiological factors related to inadequate sleep (including sleep complaints and sleep disorders) contribute to the exacerbation of inflammation and oxidative stress, an association of sleep and TL has been proposed. The aim of this study was to evaluate the association between sleep-related variables with TL in a longitudinal framework. We used data derived from the EPISONO cohort, which was followed over 8 years. All individuals answered sleep-related questionnaires, underwent a full-night polysomnography (PSG), and had their blood collected for DNA extraction. The TL was measured through a quantitative real time polymerase chain reaction. Age, sex, body mass index (BMI), smoking, physical activity status, and the 10 principal components (ancestry estimate) were considered covariables. Of the 1042 individuals in the EPISONO cohort, 68.3% agreed to participate in the follow-up study (n = 712). Baseline SpO2 (ß = 0.008, p = 0.007), medium SpO2 (ß = 0.013, p = 0.013), and total sleep time <90% (ß = -0.122, p = 0.012) had an effect on TL from the follow-up. The 8 year TL attrition was inversely associated with total sleep time, sleep efficiency, sleep architecture variables, wake after sleep onset, arousal index, oxygen-related variables baseline, and the presence of obstructive sleep apnea (OSA). We conclude that individuals with worse sleep quality, alterations in sleep architecture, and OSA had greater TL attrition over the 8 years. Using a longitudinal approach, these findings confirm previous cross-sectional evidence linking sleep with accelerated biological ageing.

Shared genetic mechanisms underlying association between sleep disturbances and depressive symptoms.

OBJECTIVES: Polygenic scores (PGS) for sleep disturbances and depressive symptoms in an epidemiological cohort were contrasted. The overlap between genes assigned to variants that compose the PGS predictions was tested to explore the shared genetic bases of sleep problems and depressive symptoms. METHODS: PGS analysis was performed on the São Paulo Epidemiologic Sleep Study (EPISONO, N = 1042), an adult epidemiological sample. A genome wide association study (GWAS) for depression grounded the PGS calculations for Beck Depression Index (BDI), while insomnia GWAS based the PGS for Insomnia Severity Index (ISI) and Pittsburg Sleep Quality Index (PSQI). Pearson's correlation was applied to contrast PGS and clinical scores. Fisher's Exact and Benjamin-Hochberg tests were used to verify the overlaps between PGS-associated genes and the pathways enriched among their intersections. RESULTS: All PGS models were significant when individuals were divided as cases or controls according to BDI (R2 = 1.2%, p = 0.00026), PSQI (R2 = 3.3%, p = 0.007) and ISI (R2 = 3.4%, p = 0.021) scales. When clinical scales were used as continuous variables, the PGS models for BDI (R2 = 1.5%, p = 0.0004) and PSQI scores (R2 = 3.3%, p = 0.0057) reached statistical significance. PSQI and BDI scores were correlated, and the same observation was applied to their PGS. Genes assigned to variants that compose the best-fit PGS predictions for sleep quality and depressive symptoms were significantly overlapped. Pathways enriched among the intersect genes are related to synapse function. CONCLUSIONS: The genetic bases of sleep quality and depressive symptoms are correlated; their implicated genes are significantly overlapped and converge on neural pathways. This data suggests that sleep complaints accompanying depressive symptoms are not secondary issues, but part of the core mental illness.

Sleep patterns according to genetically determined ethnicity in the population of São Paulo, Brazil.

Sleep is a behavior expressed differently for each individual. However, studies have shown that some ethnic groups express common sleep patterns, which can be observed in different ethnic groups. Previous studies have shown the existence of sleep disparities in populations of different ethnicities. Most of these studies have considered self-reported ethnicity and assessed sleep subjectively. Therefore, the aim of this study was to evaluate sleep disparities in different ethnic groups based on an analysis of genetic ancestry and the use of objective sleep evaluation. To do this, we used data from the São Paulo Epidemiologic Sleep Study (EPISONO), which was undertaken in Brazil, a country that is known for its ethnic/racial diversity. All individuals completed a series of questionnaires, underwent full polysomnography and had their blood collected for DNA extraction. After genotyping and identifying samples with high-quality DNA suitable for genetic analysis, 31 ancestry-informative markers (AIMs) were selected. These markers exhibited substantial allelic frequency differences, enabling the characterization of the three primary founding populations of modern Brazil - Europeans, West-Africans, and Native Americans. Through this analysis, the genetic contribution of each of these ancestral groups was identified in respect of each participant. Based on this, a latent class cluster analysis (LCCA) was performed to define the three clusters that best classified the sample according to ethnic group: African (n = 255), Caucasian (n = 668) and Native American (n = 83). Applying the adjusted model for the confounding variables (age, socio-economic class and sex), statistically significant differences in sleep variables between ethnicities were found. Africans had higher sleep latency compared to the other groups (ß = 4.46, CI = 1.18 to 7.74 and ß = 7.83, CI = 3.50 to 12.15), while Caucasians had longer total sleep time (ß = -16.47, CI = -29.94 to -2.99) and better sleep efficiency (ß = -2.19, CI = -4.35 to -0.02) compared to Africans. Regarding the respiratory arousals index (ß = -1.11, IC = -2.07 to -0.16) and periodic leg movements index (ß = -7.48, CI = -12.08 to -2.88), both were higher among Caucasians compared to Africans. We were able to conclude that genetic ancestry might modulate sleep structure and the occurrence of sleep disorders.

What is the Effect of CPAP Treatment With Humidifier on Vocal Quality?

OBJECTIVE: Evaluate vocal quality in patients with OSA before and after continuous use of CPAP with a humidifier using subjective patient perception and clinical assessment. The hypothesis was that CPAP treatment with a humidifier would benefit voice quality. STUDY DESIGN: Randomized, sham-controlled, blinded clinical trial. METHODS: Forty-three natal males with obstructive sleep apnea for whom CPAP treatment was recommended following polysomnography were randomized into two therapy groups: CPAP and Sham-CPAP. Participants completed questionnaires on voice use, a voice self-assessment with the ten-item vocal handicap index (VHI-10), and complementary questionnaires: the Epworth sleepiness scale (ESS), Pittsburgh sleep quality index (PSQI), reflux symptoms index (LPRSI) and oral dryness visual analog scale (DRY). Their voices were recorded at three different times: before CPAP therapy, and after 3 and 6 months of continuous CPAP use. The acoustic voice quality index (AVQI), and an auditory-perceptual judgment (APJ) were also applied before and after the CPAP and Sham treatments. RESULTS: After 6 months of treatment, the CPAP group presented improvements in their sleep patterns; however, no statistically significant differences were observed between the groups in respect of the results of the voice-related questionnaires, the AVQI values, and the APJ of the voice quality. All of the participants had some degree of vocal deviation at baseline. CONCLUSIONS: CPAP therapy with a humidifier did not improve vocal quality as evaluated by the clinician or patient self-assessment. However, it did not have any significant negative effects on voice quality, so can be considered safe to use in male OSA patients.

Endocrine and Epigenetic Regulation as Common Pathways Underlying the Genetic Basis of Sleep Traits and Longevity.

The amount of sleep needed over one's lifespan is age dependent and not sleeping enough or sleeping in excess is associated with increased morbidity and mortality. Yet, the convergent molecular mechanisms that link longevity and sleep are largely unknown. We performed a gene enrichment study that (1) identified genes associated with both longevity and sleep traits and (2) determined molecular pathways enriched among these shared genes. We manually curated two sets of genes, one associated with longevity and aging and the other with sleep traits (e.g., insomnia, narcolepsy, sleep duration, chronotype, among others), with both gene lists heavily driven by hits from recent large-scale Genome-Wide Association Studies. There were 47 overlapping genes between the gene list associated with sleep traits (1064 genes total) and the genes associated with longevity (367 genes total), indicating significantly more overlap than expected by chance. An overrepresentation analysis identified enriched pathways that suggest endocrine and epigenetic regulation as potential shared mechanisms between sleep traits and longevity. Concordantly, functional network analysis retrieved two clusters, being one associated with proteins of nuclear functions and the other, with extracellular proteins. This overlapping gene set, and the highlighted biological pathways may serve as preliminary findings for new functional investigations of sleep and longevity shared genetic mechanisms.

Genetic basis of sleep phenotypes and rare neurodevelopmental syndromes reveal shared molecular pathways.

Sleep-related phenotypes have been frequently reported in early on-set epileptic encephalopathies and in developmental delay syndromes, in particular in syndromes related to autism spectrum disorder. Yet the convergent pathogenetic mechanisms between these comorbidities are largely unknown. We first performed a gene enrichment study that identified shared risk genes among rare epileptic encephalopathies/neurodevelopmental disorders, rare developmental delay genetic syndromes and sleep disturbances. We then determined cellular and molecular pathways enriched among genes shared between sleep phenotypes and those two early onset mental illnesses, aiming to identify genetic disparities and commonalities among these phenotypic groups. The sleep gene set was observed as significantly overlapped with the two gene lists associated to rare genetic syndromes (i.e., epileptic encephalopathies/neurodevelopmental disorders and developmental delay gene sets), suggesting shared genetic contribution. Similarities across significantly enriched pathways between the two intersect lists comprehended mostly synapse-related pathways, such as retrograde endocannabinoid signaling, serotonergic, and GABAergic synapse. Network analysis indicates epileptic encephalopathies/neurodevelopmental disorders versus sleep-specific clusters and developmental delay versus sleep-specific clusters related to synaptic and transcriptional regulation, respectively. Longstanding functional patterns previously described in epileptic encephalopathies and neurodevelopmental disorders genetic architecture were recaptured after dissecting the overlap between the genes associated to those developmental phenotypes and sleep disturbances, suggesting that during neurodevelopment different molecular and functional mechanisms are related to alterations on circadian rhythm. The overlapping gene set and biological pathways highlighted by this study may serve as a primer for new functional investigations of shared molecular mechanisms between sleep disturbances and rare developmental syndromes.

The genetic etiology of periodic limb movement in sleep.

STUDY OBJECTIVES: Periodic limb movement in sleep is a common sleep phenotype characterized by repetitive leg movements that occur during or before sleep. We conducted a genome-wide association study (GWAS) of periodic limb movements in sleep (PLMS) using a joint analysis (i.e., discovery, replication, and joint meta-analysis) of four cohorts (MrOS, the Wisconsin Sleep Cohort Study, HypnoLaus, and MESA), comprised of 6843 total subjects. METHODS: The MrOS study and Wisconsin Sleep Cohort Study (N = 1745 cases) were used for discovery. Replication in the HypnoLaus and MESA cohorts (1002 cases) preceded joint meta-analysis. We also performed LD score regression, estimated heritability, and computed genetic correlations between potentially associated traits such as restless leg syndrome (RLS) and insomnia. The causality and direction of the relationships between PLMS and RLS was evaluated using Mendelian randomization. RESULTS: We found 2 independent loci were significantly associated with PLMS: rs113851554 (p = 3.51 × 10-12, ß = 0.486), an SNP located in a putative regulatory element of intron eight of MEIS1 (2p14); and rs9369062 (p = 3.06 × 10-22, ß = 0.2093), a SNP located in the intron region of BTBD9 (6p12); both of which were also lead signals in RLS GWAS. PLMS is genetically correlated with insomnia, risk of stroke, and RLS, but not with iron deficiency. Pleiotropy adjusted Mendelian randomization analysis identified a causal effect of RLS on PLMS. CONCLUSIONS: Because PLMS is more common than RLS, PLMS may have multiple causes and additional studies are needed to further validate these findings.

The reproducibility of clinical OSA subtypes: a population-based longitudinal study.

PURPOSE: The identification of subgroups of obstructive sleep apnea (OSA) is critical to understand disease outcome and treatment response and ultimately develop optimal care strategies customized for each subgroup. In this sense, we aimed to perform a cluster analysis to identify subgroups of individuals with OSA based on clinical parameters in the Epidemiological Sleep Study of São Paulo city (EPISONO). We aimed to analyze whether or not subgroups remain after 8 years, since there is not any evidence showing if these subtypes of clinical presentation of OSA in the same population can change overtime. METHODS: We used data derived from EPISONO cohort, which was followed over 8 years after baseline evaluation. All individuals underwent polysomnography, answered questionnaires, and had their blood collected for biochemical examinations. OSA was defined according to AHI ≥ 15 events/h. Cluster analysis was performed using latent class analysis (LCA). RESULTS: Of the 1042 individuals in the EPISONO cohort, 68% agreed to participate in the follow-up study (n = 712), and 704 were included in the analysis. We were able to replicate the OSA 3-cluster solution observed in previous studies: disturbed sleep, minimally symptomatic and excessively sleepy in both baseline (36%, 45% and 19%, respectively) and follow-up studies (42%, 43%, and 15%, respectively). The optimal cluster solution for our sample based on Bayesian information criterion (BIC) was 2 cluster for baseline (disturbed sleep and excessively sleepy) and 3 clusters for follow-up (disturbed sleep, minimally symptomatic, and excessively sleepy). A total of 45% of the participants migrated clusters between the two evaluations (and the factor associated with this was a greater delta-AHI (B = - 0.033, df = 1, p = 0.003). CONCLUSIONS: The results replicate and confirm previously identified clinical clusters in OSA which remain in the longitudinal analysis, with some percentage of migration between clusters.

Aging biological markers in a cohort of antipsychotic-naïve first-episode psychosis patients.

Schizophrenia is a severe and multifactorial disorder with an unknown causative pathophysiology. Abnormalities in neurodevelopmental and aging processes have been reported. Relative telomere length (RTL) and DNA methylation age (DMA), well-known biomarkers for estimating biological age, are both commonly altered in patients with schizophrenia compared to healthy controls. However, few studies investigated these aging biomarkers in first-episode psychosis (FEP) and in antipsychotic-naïve patients. To cover the existing gap regarding DMA and RTL in FEP and antipsychotic treatment, we aimed to verify whether those aging markers could be associated with psychosis and treatment response. Thus, we evaluated these measures in the blood of FEP antipsychotic-naïve patients and healthy controls (HC), as well as the response to antipsychotics after 10 weeks of treatment with risperidone. RTL was measured in 392 subjects, being 80 FEP and 312 HC using qPCR, while DMA was analyzed in a subset of 60 HC, 60 FEP patients (antipsychotic-naïve) and 59 FEP-10W (after treatment) using the "Multi-tissue Predictor"and the Infinium HumanMethylation450 BeadChip Kit. We observed diminished DMA and longer RTL in FEP patients before treatment compared to healthy controls, indicating a decelerated aging process in those patients. We found no statistical difference between responder and non-responder patients at baseline for both markers. An increased DMA was observed in patients after 10 weeks of treatment, however, after adjusting for blood cell composition, no significant association remained. Our findings indicate a decelerated aging process in the early phases of the disease.

Obstructive sleep apnea and the retina: a review.

CITATION: This review's objective was to synthesize the literature on the repercussions of obstructive sleep apnea (OSA) in the retinal vascular system. Two independent investigators conducted a search using the MEDLINE/PubMed database using the following terms: sleep apnea syndrome, obstructive sleep apnea, retina, vascular tortuosity, central serous chorioretinopathy, diabetes mellitus, and subfoveal choroidal thickness. Patients with OSA present increased vascular tortuosity compared with patients without OSA, decreased parafoveal and peripapillary vessel density, and increased retinal vein occlusion incidence. In central serous chorioretinopathy patients and patients who are poor responders to intravitreal anti-VEGF (-vascular endothelial growth factor) treatment for macular edema, OSA is more frequent. Macular choroidal thickness alterations are controversial, and OSA may worsen diabetic maculopathy, thus being a risk factor for diabetic retinopathy, proliferative diabetic retinopathy, and macular edema. OSA is a prevalent syndrome with many systemic vascular changes. The retina and choroid are the most affected ocular structures, with primarily vascular changes. New noninvasive technologies such as optical coherence tomography and optical coherence tomography angiography could help to better understand retinal structures and help clarify the ophthalmological repercussions of OSA. CITATION: Nakayama LF, Tempaku PF, Bergamo VC, et al. Obstructive sleep apnea and the retina: a review. J Clin Sleep Med. 2021;17(9):1947-1952.

Klotho genetic variants mediate the association between obstructive sleep apnea and short telomere length.

The core features of obstructive sleep apnea (OSA) can potentially contribute to the acceleration of telomere shortening mechanisms. Other factor associated with telomeres is Klotho gene as it can negatively regulates telomerase activity. Noteworthy, KLOTHO protein level has recently been associated with OSA. In this sense, it was plausible to hypothesize that OSA would be associated with short telomere length and those with OSA plus risk single nucleotide polymorphisms (SNPs) in Klotho gene would present even shorter telomere length. As part of the EPISONO cohort, 1042 individuals answered questionnaires, underwent polysomnography and had blood collected for DNA extraction. OSA was defined according to AHI≥ 15 events/hour. Leukocyte telomere length (LTL) was measured through real-time polymerase chain reaction (qPCR) and Klotho SNPs were genotyped by array. Mediation analyses considered the presence of SNPs in Klotho gene and how this interaction can affect OSA and its consequence in telomere length. All the analyses were corrected for multiple comparisons. LTL was significantly shorter in OSA compared to controls in a severity-dependent manner (B = 0.055; CI = 0.007-0.102; p = 0.02). Among the 43 Klotho SNPs analyzed, we observed that 4 SNPs (rs525014, rs7982726, rs685417 and rs9563124) significantly mediated the association between OSA and short LTL. Klotho gene opens a new venue in OSA research since it can contribute in the increase of knowledge of the mechanisms involved in the consequences of short telomeres in individuals with OSA.

Genome-wide association study reveals two novel risk alleles for incident obstructive sleep apnea in the EPISONO cohort.

OBJECTIVE/BACKGROUND: Obstructive sleep apnea (OSA) is a sleep-related breathing disorder that has a complex phenotype. Currently, few genes have been linked with OSA. Thus, the aim of this study was to conduct a genome-wide association study (GWAS) of the apnea-hypopnea index (AHI) variation along time (delta-AHI) in a prospective cohort. METHODS: We used data derived from the São Paulo Epidemiologic Sleep Study (EPISONO) (n = 1074) cohort, which was followed over eight years (n = 712). Our phenotype of interest was delta-AHI and incident OSA. Further, we were interested on the time-dependent effect of genetic variants. Our final GWAS model used delta-AHI as a dependent variable and the SNPs and covariates as independent variables. We also performed a gene-set and pathway analysis. RESULTS: The delta-AHI increased on average 6.1 events/hour (standard deviation = 14.9) over the follow-up. We found two significant and 21 suggestive variants associated with delta-AHI. The strongest association (rs12415421) was observed at ST8SIA6 gene and the other significant hit (rs4731117) was in an intergenic region in linkage disequilibrium with our third hit (rs12669165) in the ASB15 gene. We found an effect of the allele rs12415421 for the OSA incidence. Additionally, we observed that individuals with both risk alleles presented a higher incidence of OSA when compared to those with one or without any risk alleles. CONCLUSIONS: This study has identified genes in these associated regions with delta-AHI, which seem to be involved in growth and stability of muscle and bone. We also observed an effect of both allele frequencies in the incidence of OSA.

Sleep deprivation decreases the reproductive capacity by affecting the arrival of morulas in the uterus.

A previous animal study by our group found that sleep deprivation during preimplantation was associated with decreased pregnancy maintenance. Given its impact on human society, we aimed in the current study to assess whether sleep deprivation affects blastocyst gene expression and/or the implantation process. For this, pregnant mice (gestational day 0 [GD 0]) were assigned into paradoxical sleep deprivation (SD, 72 hr; multiple platform method) and, a control (CT) group. Animals were euthanized on GD 3.5 and blood, uterus (embryos) and fallopian tube were collected. Then, 89% of CT presented blastocysts in the uterus versus 25% from SD group. Compared to CT, SD presented lighter relative uterus weight, increased plasma concentrations of corticosterone and testosterone, decreased concentrations of progesterone and luteinizing hormone, but no statistical differences in plasma concentrations of 17ß-estradiol and follicle stimulating hormone. There were no differences in uterus and blastocyst gene expression related to embryo implantation and development, and no alteration in blastocysts global DNA methylation. Considering this, the decreased pregnancy maintenance after sleep deprivation seems not to be associated with implantation losses or developmental problems related to the blastocysts. It is likely that complications in morula development and/or its movement through the fallopian tubes affect the pregnancy rate, since only 25% of SD females presented a blastocyst on the GD 3.5. In fact, three out of four females without blastocysts in the uterus presented morula in the fallopian tubes due to a phase delay. Additionally, we suggest that the observed hormonal changes may play a role in this outcome.

Long Sleep Duration, Insomnia, and Insomnia With Short Objective Sleep Duration Are Independently Associated With Short Telomere Length.

STUDY OBJECTIVES: We aimed to determine the association between short telomere length, sleep parameters, and sleep disorders in an adult general population sample. METHODS: As part of the EPISONO cohort (São Paulo, Brazil), 925 individuals answered questionnaires, underwent a full-night polysomnography and clinical assessment, and had peripheral blood collected for DNA extraction. Insomnia was diagnosed based on the Diagnostic and Statistical Manual of Mental Disorders, 4th edition; and obstructive sleep apnea was defined according to apnea-hypopnea index. For the objective insomnia phenotype, we combined insomnia diagnosis with total sleep time from polysomnography with a cutoff of 360 minutes, allowing the classification of six groups. Self-reported sleep duration was used to classify the individuals as short (< 6 hours), average (6 to 8 hours) and long (> 8 hours) sleepers. The leukocyte telomere length was measured using quantitative real-time polymerase chain reaction. Based on its distribution, we considered leukocyte telomere length < 10th percentile as short telomere and leukocyte telomere length ≥ 10th percentile as non-short telomere. RESULTS: After adjusting for sex, age, and body mass index, only insomnia disorder (odds ratio [OR] = 2.654, 95% confidence interval [CI] = 1.025-6.873, P = .044), insomnia disorder total sleep time < 360 minutes (OR = 4.205, 95% CI = 1.097-16.117, P = .036) and long sleepers (OR = 2.177, 95% CI = 1.189- 3.987, P = .012) were associated with short telomere. CONCLUSIONS: Our findings support the existence of an association among insomnia, insomnia phenotype, and self-reported long sleep duration with the maintenance of telomere length. COMMENTARY: A commentary on this article appears in this issue on page 1975.

Effect of male-specific childhood trauma on telomere length.

Child maltreatment (CM) is a global issue with serious lifelong consequences. In fact, maltreatment during childhood might be an important risk factor for the development of psychiatric disorders. Furthermore, previous studies showed a strong relationship between telomere length (TL) and early life stress. Considering that only a few studies have evaluated this relationship in children and that even fewer considered the sex as a possible moderator, we investigated whether TL in the blood of both children and adolescents was associated with psychopathology and with a history of CM, and whether these associations were moderated by the sex. In this cross-sectional study, 561 individuals (ranging between 6 and 14 years of age) from a large prospective community school-based study, i.e., the Brazilian High-Risk Cohort (HRC), were evaluated. The Child Behavior Checklist (CBCL) score was used to assess psychopathology, whereas a latent variable encompassing some questions about history of adverse environment and trauma was employed to determine the CM history. TL was measured in blood cells using a multiplex quantitative polymerase chain reaction. Additionally, TL was inserted in two moderation models, in which the CBCL score/CM, TL and sex were the independent variables, the outcome, and the moderator variable, respectively. Although an association between psychiatric symptoms and TL was not observed, a relation between CM and TL moderated by the sex was seen, indicating that males with higher CM scores presented with shorter telomeres than did females. Our results suggest that child maltreatment could influence telomere length in both children and adolescents and that this effect is mediated by the sex.

Leukocyte telomere length variation in different stages of schizophrenia.

Recent research has demonstrated that telomere maintenance might be a key integrating point for the cumulative effect of genetic and environmental factors in patients with first-episode psychosis (FEP) and schizophrenia (SCZ). Eighty-one participants with antipsychotic-naïve FEP, 173 with SCZ and 438 HC were enrolled in this study. Psychiatric diagnosis was assessed using the Semi-Structured Clinical Interview for DSM-IV Axis-I (SCID-I). The Positive and Negative Syndrome Scale (PANSS), Young Mania Rating Scale (YMRS) and Calgary Depression Scale for Schizophrenia (CDSS) were used to measure symptoms severity. Telomere length (TL) was determined using a multiplex qPCR assay. After adjustment for age, years of education, and smoking status, we found that patients with SCZ had longer TL (relative ratio (RR) = 1.08) than the HC group (RR = 1.00, Wald χ2 = 12.48, p = 0.002). Further, non-remitted SCZ patients presented longer TL (RR = 1.00) compared to remitted SCZ (RR = 0.88, Wald χ2 = 7.20, p = 0.007). TL in patients also correlated to psychopathology assessment in terms of total (p = 0.003) and positive PANSS scores (p = 0.001). No correlation with negative PANSS, YMRS, and CDSS or effects of medication was found on TL. Although the exact pathways underlying longer TL in SCZ patients remain unclear, these findings raise more questions than answers and suggest that TL may be of immense value on SCZ progression. Further studies are required to investigate the association of TL in FEP and SCZ.