Longitudinal stability of serum neurofilament light chains in psychiatric disorders

Longitudinal stability of serum neurofilament light chains in psychiatric disorders | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Longitudinal stability of serum neurofilament light chains in psychiatric disorders Ishana Rue, Sherri Jones, Mahdie Soltaninejad, Charlotte Teunissen, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7557288/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Serum neurofilament light (sNfL) is a biomarker of axonal integrity which is elevated in neurodegenerative diseases. Although common psychiatric disorders are not neurodegenerative, some studies have found slightly higher levels of sNfL in psychiatric disorders compared to healthy controls. The reason for this elevation is unknown, and it is unclear whether this difference persists over time, or if it varies in relationship to symptom severity. Longitudinal serum samples and clinical data from a large dataset of psychiatric patients (n = 836; ages 40+, M = 478, F = 358) were obtained from the Signature Biobank at up to four time points over up to 2 years (from emergency room admission to outpatient follow-up or remission). sNfL was measured using SiMoA assay technology. Repeated measures analyses were used to test sNfL over time, adjusting for age, BMI, blood creatinine and sex. Linear regressions were used to test associations between sNfL levels and depression, anxiety and psychosis symptoms. sNfL levels did not change significantly over time for subjects with all 4 available timepoints (n = 73), nor from baseline to the last available timepoint (n = 268). Males had slightly higher sNfL than females (Cohen’s d = 0.38, p = 0.003). Depression, anxiety and psychosis symptoms improved over time, but there were no clinically significant correlations between sNfL and symptom severity. This study did not detect a significant change in sNfL in psychiatric disorders over time, despite overall improvement in symptom severity. These results suggest that the mild elevation in sNfL reported in psychiatric disorders is a disease trait rather than state dependent. Health sciences/Biomarkers/Diagnostic markers Health sciences/Diseases/Psychiatric disorders Figures Figure 1 Figure 2 INTRODUCTION Neurofilament light (NfL) is a marker of neuronal integrity. When an axon is damaged, neurofilaments can be released into the cerebrospinal fluid (CSF) and proportionally, in lower concentrations, into the bloodstream 1 . Single-molecule array (SiMoA) assay technology allows reliable quantification of blood NfL levels, facilitating longitudinal monitoring 1 . In previous work analyzing a large sample of patients with psychiatric disorders presenting to a psychiatric emergency room, Light et al. reported that the mean serum NfL (sNfL) measured in psychiatric disorders was higher compared to healthy controls 2 . sNfL was elevated in all types of psychiatric disorders, without inter-group differences 2 . This is an unexpected finding given that psychiatric disorders are not traditionally thought to involve neurodegenerative processes. The reason for the elevation in sNfL in psychiatric disorders compared to controls is unclear, and it is unknown whether this difference persists over time, or whether it is correlated with psychiatric symptom severity. Previous studies on differences in NfL levels between psychiatric disorders and healthy controls have been inconsistent 3 – 7 . Increased NfL has been reported in depression and bipolar disorder in some studies 6 , 8 – 10 , but others found no significant difference 3 – 5 , 7 , 11 . These prior studies often included small samples of patients with psychiatric disorders recruited from a secondary or tertiary care setting. Where Light et al. did report a 12.7% elevation in sNfL in psychiatric disorders compared to controls, this study comprised a large sample of patients in an acute care state, when their symptoms are most severe 2 . If sNfL is related to symptom severity in psychiatric disorders, there could be a transient rise in sNfL during the acute episode, followed by a decline as symptoms stabilize and patients are discharged. Indeed, some studies have found a positive cross-sectional association between sNfL and depressive symptom severity 12 – 14 , and blood NfL was inversely correlated with cognitive functioning in patients with depression 8 , 9 . These results suggest a possible relationship between sNfL and symptom severity in psychiatric disorders, but this relationship needs to be confirmed with longitudinal measures. This study explored the longitudinal behavior of sNfL in a large, mixed diagnosis cohort of patients with psychiatric disorders, throughout their trajectory of care. We also explored the relationship between sNfL levels and measures of anxiety, depressive and psychotic symptoms in this group. We hypothesized that 1) sNfL levels would decrease over time as patients transitioned from an acute state upon admission to the emergency room, to a more stable disease state in outpatient care, and that 2) sNfL would be positively correlated with psychiatric symptom severity. SUBJECTS AND METHODS Study population This study was approved by the McGill University Health Centre Research Ethics Board (2022–7585). The dataset for this study was acquired from the Signature Biobank 15 . Patients were recruited upon admission to the psychiatric emergency services at the Institut Universitaire en Santé Mentale de Montréal (IUSMM) in Montreal, Quebec, Canada between 2012 and 2020. Clinical information, questionnaires and biospecimen data (including blood) were collected at 4 timepoints: at psychiatric emergency admission (T1), at hospital discharge (T2), at the first outpatient clinic appointment (T3), and a final clinic follow up appointment up to 2 years (mean: 471 days) after the initial recruitment, or at clinical remission (T4) 15 . The psychiatric diagnosis by the treating psychiatrist based on standard clinical assessment at T2 was used as the main diagnostic classification 15 . Only participants who completed their participation without interruption due to a rehospitalization (Track A) were included in this study 15 . Our initial dataset included 872 subjects, ages 40 and above 2 . We included the same participants with psychiatric disorders as Light et al. at T1 2 . In addition, all listed diagnoses at hospital discharge (T2) were reviewed; participants with no formal psychiatric diagnosis, a neurocognitive disorder or other non-psychiatric diagnosis (for example, medical causes) were excluded (n = 12). Our final sample included data from 836 subjects with sNfL available at T1 and 394 participants with at least one longitudinal sNfL sample available. sNfL measurement The longitudinal (T2, T3, T4) serum samples (n = 732, 200ul each) were shipped in January 2024 from the Signature Biobank to the Neurochemistry Laboratory at the Amsterdam University Medical Centre. Sample processing and storage prior to shipment followed the Signature Biobank protocol for peripheral blood sample serum separation and aliquot storage at -80C 15 . Sample shipment and sNfL analysis was completed following identical methods as Light et al. for the baseline samples at T1 2 . sNfL levels were measured using SiMoA assay technology on a HD-X analyser according to the manufacturer’s instructions (Quanterix, Billerica, MA, USA). Repeat baseline samples (n = 20) were also analyzed as a reference for the longitudinal measurements to correct for any batch differences. Assessment of psychiatric symptom severity Data on psychiatric symptom severity was obtained from 3 questionnaires: the 9-item Patient Health Questionnaire (PHQ-9), the 6-item short form of the Spielberger State-Trait Anxiety Inventory Form Y (STAI-Y6), and the Psychotic Symptom Rating Scales (PSYRATS). The PHQ-9 is a self-administered diagnostic instrument and a validated measure of depression severity 16 , 17 . The PHQ-9 total score ranges from 0 to 27 and evaluates patient symptoms over the previous 2 weeks 16 , 17 . Second, the STAI-Y6 is a self-report anxiety questionnaire which collects information on how the patient is currently feeling 18 . The total score ranges from 20–80, where higher scores indicate greater anxiety. Third, the Psychotic Symptom Rating Scales (PSYRATS) was collected via semi-structured interview with a nurse from the Signature Biobank study. This scale assesses the severity of the different dimensions of auditory hallucinations (11 items) and delusions (6 items) from the previous week 19 – 22 . Total scores are calculated for each subscale and higher scores indicate greater severity 21 . These 3 questionnaires were completed by participants at each timepoint (T1-T2-T3-T4). The PHQ-9 and STAI-Y6 were included in the Signature Biobank protocol from the beginning of the project in November 2012 15 . The PSYRATS questionnaire was added to the protocol in 2017, so the sample of participants who completed this questionnaire is smaller 15 . We obtained the questionnaire data from the Signature Biobank at T1 and the last available sNfL timepoint (T2, T3 or T4) for each participant. Statistical analysis Statistical analyses were completed using IBM SPSS Statistics Version 29.0.1.1 (IBM SPSS Statistics, Armonk, NY). We completed descriptive statistics using frequencies for categorical data and means and standard deviations (SD) for continuous variables. Median sNfL is also reported to allow comparisons with other studies. Assumptions for each statistical analysis were verified and met. sNfL was not normally distributed at any timepoint, so all sNfL analyses were duplicated using log (sNfL) to confirm our results (data not shown). Raw sNfL values are reported for interpretation. Longitudinal sNfL We conducted a one-way repeated measures ANCOVA to test if sNfL (pg/ml) changes over time in psychiatric disorders. Time was evaluated as a within-subjects factor, and sex was entered as a between-subjects factor. Age, body mass index (BMI) and blood creatinine were included as covariates, given their known associations with NfL 1 , 2 , 23 . In sensitivity analyses, the interval in days between T1 and the last timepoint was included as an additional covariate in each analysis because the interval from T1 to subsequent timepoints varied between participants. First, sNfL was evaluated for participants with sNfL available at all 4 timepoints (T1, T2, T3, T4), from emergency admission to the last follow up appointment, and measurements for all covariates (n = 73). The Greenhouse-Geisser correction was applied to correct for sphericity violations in this analysis. Second, to increase statistical power by maximizing the sample size, sNfL was evaluated for all subjects with at least 2 time points, using T1 and the last available timepoint of sNfL measurement available after T1 (T2, T3 or T4), and measurements for all covariates (n = 268). Error bars with 1 standard error of the mean (SEM) for the covariate adjusted means are shown in figures. Independent samples t-tests and the Pearson’s chi-square test were conducted to check for differences between the included participants with only 1 sNfL value available (n = 442) vs participants with at least 2 sNfL values available (n = 394). None of the variables tested (age, sex, sNfL at T1, BMI, blood creatinine, or depression/anxiety/psychosis symptoms at T1) were significantly different between the samples. This confirms that our subgroup of participants for longitudinal analysis is representative of the entire sample. Additional exploratory analyses also considered the gender index score as a predictor of longitudinal sNfL. The gender index score was included with sex as a factor and interaction term in both repeated measures analyses because the correlation between the gender index score and sex in our sample was moderate (n = 688, r = 0.303, p < 0.001), demonstrating the partial but not complete overlap of these variables. This composite gender index score was developed based on sociodemographic and psychosocial variables showing sex differences in this Signature Biobank psychiatric cohort 24 . Symptom severity measures First, dependent samples t-tests were completed to test the change in each symptom severity questionnaire total score from T1 to the last timepoint (T2/T3/T4). The number of participants with scores available at both timepoints varied by questionnaire. Only participants with at least 1 follow up sNfL measurement were included, so up to 394 participants were included per analysis. Second, linear regressions were completed to test the associations between sNfL and each symptom severity indicator (PHQ-9 total score, STAI-Y6 total score, PSYRAT auditory hallucinations subscale total score, PSYRAT delusions subscale total score), at both T1 and the last timepoint, controlling for both age and sex. Up to 836 participants with both sNfL and a questionnaire measure available were included at T1, and up to 394 participants were included at the last timepoint. Next, the numerical change value (Δ) was calculated from T1 to the last timepoint for each questionnaire total score (Δ = Total score (Last) – Total score (T1)), and the change in sNfL (pg/ml) was calculated from the T1 to last timepoint (Δ = sNfL (Last) – sNfL (T1)). Linear regressions were completed to test associations between Δ sNfL and the Δ total score for each questionnaire, controlling for age and sex. Up to 394 participants were included per analysis. The significance values for all beta coefficients were calculated using a two-tailed t-test. The 95% confidence intervals were also reported for each analysis. The Bonferroni correction for multiple comparisons was applied to the significance level to control the type 1 error rate (alpha level = 0.0125). RESULTS Clinical characteristics The characteristics of the included participants with sNfL measurements available are shown in Table 1 . The diagnostic categories of participants are shown in Supplementary Table 1. Table 1 Characteristics of Signature Biobank participants with psychiatric disorders. Mean ± SD, [%], n Minimum 1 sNfL timepoint, n = 836 1 Minimum 2 sNfL timepoints, n = 268 2 All 4 sNfL timepoints, n = 73 3 Sex, % male [57.2%], n = 478 [50.3%], n = 135 [43.8%], n = 32 Gender index score 0.58 ± 0.14, n = 688 0.57 ± 0.14, n = 222 0.54 ± 0.14, n = 59 Covariates Age 52.8 ± 8.3 53.9 ± 8.0 53.1 ± 7.5 Body Mass Index (BMI) 27.7 ± 6.5, n = 832 28.1 ± 6.6 28.5 ± 6.6 Blood creatinine (µmol/L) 72.7 ± 24.3, n = 493 73.9 ± 26.0 72.3 ± 21.7 1 n=836 participants with at least 1 serum neurofilament light (sNfL) value available (T1). 2 n=268 participants with at least 2 sNfL values available (T1 + T2/T3/T4) and measurements for all covariates (Age, BMI, blood creatinine). 3 n=73 participants with all 4 sNfL values available and measurements for all covariates. Longitudinal sNfL The descriptive statistics for the longitudinal sNfL values are shown in Table 2 . There were 394 participants with at least 2 sNfL values available. The mean raw sNfL is 14.0pg/ml at T1 and 13.7pg/ml at the last timepoint. There were no high outliers for sNfL at any timepoint (T1-T4) in this final sample. Table 2 Longitudinal serum neurofilament light (sNfL) values in Signature Biobank psychiatric participants. sNfL (pg/ml) T1 T2 T3 T4 Last Δ Last-T1 n 836 283 255 171 394 394 Mean 14.0 15.5 13.2 12.3 13.7 -0.58 SD 9.6 10.9 9.6 7.4 8.7 7.5 Median 11.5 12.8 10.3 10.0 10.9 -0.24 Sex, % male 57.2% (n = 478) 51.2% (n = 145) 52.5% (n = 134) 49.7% (n = 85) 54.1% (n = 213) n/a Note. n/a: not applicable. Last: the last available follow up sNfL timepoint (T2/T3/T4). There were 73 participants with sNfL values available at all 4 timepoints and measurements for all covariates. The longitudinal behavior of sNfL from ER admission to the last follow up is shown in Fig. 1 . sNfL did not demonstrate a statistically significant change over the four time points, F (2.67, 181.79) = 0.795, p = 0.485, η p 2 = 0.012. Also, there was no significant sex effect or interaction of sex and time. Given that sNfL increases with age, we conducted sensitivity analyses to include the interval in days from T1 to T4 (mean = 471 ± 96, ranging from 319 to 720 days) as an additional covariate. This did not change our results, we found that sNfL did not change over time, η p 2 = 0.009. Next, there were 268 participants with sNfL available for at least 2 timepoints and measurements for all covariates. sNfL did not change significantly over time, from the 1st sample to the last blood collection timepoint available (between hospital discharge and the last follow up appointment), F(1,263) = 0.384, p = 0.536, η p 2 = 0.001. There was a small but significant effect of sex on sNfL; males had a significantly higher mean sNfL than females (Cohen’s d = 0.38, p = 0.003). The interaction effect of sex and time was not significant. The longitudinal behavior of sNfL from T1 to the last available timepoint is shown in Fig. 2 . In sensitivity analyses, the interval in days from T1 to the last timepoint (mean = 248 ± 224, range: 2-783 days) was included as an additional covariate. This did not change our results, we found that sNfL did not change over time, η p 2 = 0.003. In additional sensitivity analyses for the T1-last repeated measures model (n = 268), we ran the model with only the participants with a time interval from T1-last > 1 year included (n = 115). This did not change our results, sNfL did not change significantly over time, η p 2 = 0.005. Finally, we completed exploratory analyses to include the gender index score with sex as a factor and interaction term in both repeated measures models. There was not a significant main effect of gender, and the interaction of the gender index score with time was not significant in either model. Associations between sNfL and symptom severity The descriptive statistics for the symptom severity measures at T1 and the last available timepoint, and the results of the dependent samples t-tests are shown in Supplementary Table 2. There was a significant mean decrease in total score for all 3 questionnaires, meaning that on average participants demonstrated a significant improvement in depression, anxiety and psychosis symptoms over time. The cross-sectional beta coefficients between sNfL and each symptom severity measure were not significant at T1 or the last timepoint, controlling for age and sex. The results of these regression analyses are shown in Table 3 . Table 3 Serum neurofilament light (sNfL) predicted from symptom severity, controlling for age and sex, at T1 and the last available timepoint: sNfL = β₀ + β₁ (Symptom severity) + β₂(Age) + β 3 (Sex). PHQ-9 STAI-Y6 PSYRAT- Auditory Hallucinations PSYRAT - Delusions T1 sNfL -0.029 ± 0.037 [-0.101,0.044] -0.035 ± 0.017 [-0.069,0.001] -0.047 ± 0.049 [-0.145,0.051] -0.033 ± 0.092 [-0.215,0.149] Last sNfL 0.023 ± 0.059 [-0.092,0.139] -0.034 ± 0.026 [-0.086,0.017] -0.051 ± 0.104 [-0.262,0.159] 0.010 ± 0.62 [-0.317,0.337] Note . Unstandardized beta coefficient (β₁) for symptom severity ± standard error [95% confidence interval]. Alpha level = 0.0125 (Bonferroni). PHQ-9: 9-item Patient Health Questionnaire. STAI-Y6: 6-item short form of the Spielberger State-Trait Anxiety Inventory Form Y. PSYRATS: Psychotic Symptom Rating Scales. T1: emergency room admission. Last: Last available sNfL timepoint for each participant (from hospital discharge to the last follow up timepoint). Next, the beta coefficients to predict Δ sNfL from Δ symptom severity, controlling for age and sex, are shown in Table 4 . There was a statistically significant negative relationship between Δ anxiety symptoms and Δ sNfL between T1 and the last timepoint, meaning that sNfL decreased over time as anxiety symptoms increased over time. This was an unexpected finding, however, only 2.3% of the variation in Δ sNfL was predicted from the longitudinal change in anxiety symptoms (controlling for age and sex). When controlling for age and sex; as sNfL declined by 1 pg/mL, anxiety symptoms increased by 0.06. The relationships between Δ sNfL and the longitudinal change in depressive and psychosis symptoms were not significant. Table 4 Longitudinal Δ serum neurofilament light (sNfL) predicted from Δ symptom severity, controlling for age and sex: Δ sNfL = β₀ + β₁ (Δ Symptom severity) + β₂(Age) + β 3 (Sex). Δ PHQ-9 Δ STAI-Y6 Δ PSYRAT- Auditory Hallucinations Δ PSYRAT - Delusions Δ sNfL -0.082 ± 0.044 [-0.169,0.005] -0.058 ± 0.020 [-0.097, -0.020] -0.043 ± 0.120 [-0.295,0.209] -0.118 ± 0.149 [-0.428,0.191] p-value 0.066 0.003* 0.723 0.436 Note . Unstandardized beta coefficient for symptom severity ± standard error [95% confidence interval]. * p < 0.0125 (Bonferroni). Δ = Last – T1. PHQ-9: 9-item Patient Health Questionnaire. STAI-Y6: 6-item short form of the Spielberger State-Trait Anxiety Inventory Form Y. PSYRATS: Psychotic Symptom Rating Scales. DISCUSSION In this study, we investigated the longitudinal profile of sNfL in this large cohort of patients with psychiatric disorders, in a real-life patient trajectory over up to 2 years of clinical follow up. Contrary to our hypotheses, we did not detect a significant change in sNfL over time when controlling for age as patients progressed in their treatment pathway, despite significant improvements in symptomatology. Moreover, we did not find meaningful associations between sNfL levels and measures of psychiatric symptom severity, only a subtle inverse relationship between change in anxiety symptoms and change in sNfL. Overall, these findings suggest that the mild elevation in sNfL observed in psychiatric disorders 2 , and previously reported in cross-sectional studies 6 , 8 , may reflect a stable disease trait rather than a transient state associated with psychiatric symptom fluctuations. The absence of longitudinal variation in sNfL, even among participants who received treatment and experienced clinical improvement, indicates that this biomarker may not be sensitive to short- or medium-term fluctuations in psychiatric symptom severity. The previously reported elevation in sNfL in psychiatric disorders compared to controls 2 could indicate chronic neuroaxonal stress or injury, potentially attributable to disease duration, metabolic factors, neuroinflammation, medical comorbidities, psychotropic medications or even subclinical neurodegenerative processes. This still requires furthers investigation. Notably, we found that males had significantly higher sNfL levels than females (18%) after adjustment for covariates, which is in line with results from recent studies 2 , 25 , 26 . There was no significant effect of the gender index score on the longitudinal behavior of sNfL in psychiatric disorders, so biological sex appears to be a more important predictor than gender for sNfL. Some recent studies have reported positive correlations between sNfL and depressive symptoms 12 – 14 , but in our large, heterogenous sample with repeated measures, our findings did not support a similar relationship between sNfL and psychiatric symptom severity. While we observed a statistically significant correlation between longitudinal change in anxiety symptoms and Δ sNfL in an unexpected direction, the effect size was very small, which suggests that it is not clinically meaningful. These results align with recent work from Hvid et al., a large sample size study which also did not detect significant associations between NfL and depression symptoms or cognitive functioning in patients with depression 27 . Other studies have also failed to detect meaningful relationships between NfL and measures of psychiatric severity in patients with bipolar disorder and schizophrenia 8 , 10 , 28 . These findings suggest that any link between sNfL and symptom severity in psychiatric disorders is weak and likely influenced by other factors, such as medical comorbidities or neurobiological heterogeneity. A recent review from Bavato et al. suggested a future role for NfL in the assessment of treatment interventions or as monitoring tool in psychiatric populations 28 , but the stability of sNfL and the lack of association with symptom severity in the current study suggests that sNfL may not be useful for this purpose in psychiatric populations alone. This study has important implications for sNfL as a promising biomarker for differentiating psychiatric disorders from neurodegenerative diseases, in particular behavioral variant frontotemporal dementia (bvFTD). The stable longitudinal behavior of sNfL in psychiatric disorders is in sharp contrast to the increases in NfL over time in bvFTD and other neurodegenerative disorders. Gendron et al. demonstrated that plasma NfL associates with markers of disease severity in bvFTD patients, and the rate of change of NfL over time was significantly higher in bvFTD patients (median = 2.8pg/ml per year) compared to controls (median = 0.3 pg/ml per year) 29 . Therefore, the rate of change of sNfL in bvFTD vs psychiatric disorders may offer greater diagnostic accuracy compared to cross-sectional sNfL, but this would need to be addressed in future studies with longitudinal sNfL values collected in both populations, as well as controls. Moreover, if the rate of change in sNfL is progressively larger in bvFTD than in psychiatric disorders, a longer clinical follow up period than 1–2 years may provide increased diagnostic accuracy for blood-based NfL. The strengths of this study are the large sample size, the collection of biological and psychosocial measures, repeated measures design, and adjustment for key covariates such as age, BMI, and creatinine, which enhanced the robustness of our findings. The large sample size and comprehensive dataset allowed us to consider biological sex as well as psychosocial indicators of gender (gender index score). However, some limitations must be acknowledged. The variability in follow-up intervals and number of available timepoints across participants may have introduced noise, although sensitivity analyses accounting for time interval did not change the main findings. Also, though all sNfL measurements were conducted by a single lab and technology, there were two different batches for 1) T1 and 2) all longitudinal timepoints. This is not ideal, but control analyses were performed on a small batch of repeat T1 samples to confirm the reliability of our results. Additionally, comparisons to a longitudinal control group, as well as more extensive psychiatric symptom assessments and longer follow-up measures could have improved the interpretation of our findings. In conclusion, our study found that sNfL levels are stable over time in psychiatric disorders, and do not track symptom severity. These results suggest that mildly elevated sNfL in psychiatric disorders compared to controls 2 may reflect a chronic, trait-level neurobiological characteristic rather than dynamic changes related to psychiatric symptom fluctuations. Future research should explore the relationship between sNfL and neurobiological contributors to psychiatric illnesses such as neuroinflammation to investigate factors potentially responsible for the elevation of sNfL in this population. Supplementary information is available at MP’s website. Declarations ACKNOWLEDGEMENTS This study was funded by the Canadian Institutes of Health Research (CIHR) grant to the Canadian Consortium on Neurodegeneration in Aging (CCNA) Phase II. Ishana Rue receives salary support from the Canada First Research Excellence Fund, awarded to the Healthy Brains, Healthy Lives initiative at McGill University . Dr Simon Ducharme receives salary support from the Fond de recherche du Québec– Santé. The data for this study were obtained from the Signature Biobank database. Serum sample analyses were completed by Hans Heijst at the Neurochemistry Laboratory at the Amsterdam University Medical Centre, led by Dr. Charlotte E. Teunissen. Conflict of interest. Dr. Ducharme has research contracts with Biogen, Novo Nordisk, Janssen, Passage Bio, Alnylam, Roche, Voyager Therapeutics and Eli Lilly. He has received advisory/speaker fees from Eisai, Eli Lilly, Voyager Therapeutics and QuRALIS. He is a member of the DSMB of Aviado Bio. Dr. Teunissen’s work has supported by the European Commission (Marie Curie International Training Network, grant agreement No 860197 (MIRIADE) and No 101119596 (TAME), Innovative Medicines Initiatives 3TR (Horizon 2020, grant no 831434) EPND ( IMI 2 Joint Undertaking (JU), grant No. 101034344) and JPND (bPRIDE, CCAD), European Partnership on Metrology, co-financed from the European Union’s Horizon Europe Research and Innovation Programme and by the Participating States ((22HLT07 NEuroBioStand), Horizon Europe (PREDICTFTD, 101156175), CANTATE project funded by the Alzheimer Drug Discovery Foundation, Alzheimer Association, Michael J Fox Foundation, Health Holland, the Dutch Research Council (ZonMW), Alzheimer Drug Discovery Foundation, The Selfridges Group Foundation, Alzheimer Netherlands. CT is recipient of ABOARD, which is a public-private partnership receiving funding from ZonMW (#73305095007) and Health~Holland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). Dr. Teunissen is recipient of TAP-dementia, a ZonMw funded project (#10510032120003) in the context of the Dutch National Dementia Strategy. Dr. Teunissen has research contracts with Acumen, ADx Neurosciences, AC-Immune, Alamar, Aribio, Axon Neurosciences, Beckman-Coulter, BioConnect, Bioorchestra, Brainstorm Therapeutics, C2N diagnostics, Celgene, Cognition Therapeutics, EIP Pharma, Eisai, Eli Lilly, Fujirebio, Instant Nano Biosensors, Merck, Muna, Novo Nordisk, Olink, PeopleBio, Quanterix, Roche, Toyama, Vaccinex, Vivoryon. She is editor in chief of Alzheimer Research and Therapy, and serves on editorial boards of Molecular Neurodegeneration, Alzheimer’s & Dementia, Neurology: Neuroimmunology & Neuroinflammation, Medidact Neurologie/Springer, and is committee member to define guidelines for Cognitive disturbances, and one for acute Neurology in the Netherlands. She has consultancy/sp eaker contracts for Aribio, Biogen, Beckman-Coulter, Cognition Therapeutics, Danaher, Eisai, Eli Lilly, Janssen, Merck, Novo Nordisk, Novartis, Olink, Roche, Sanofi and Veravas. Ishana Rue, Dr Sherri Lee Jones and Mahdie Soltaninejad declare no potential conflict of interest. References Khalil M, Teunissen CE, Lehmann S, Otto M, Piehl F, Ziemssen T et al. Neurofilaments as biomarkers in neurological disorders — towards clinical application. Nature Reviews Neurology 2024; 20(5): 269–287. Light V, Jones SL, Rahme E, Rousseau K, de Boer S, Vermunt L et al. Clinical Accuracy of Serum Neurofilament Light to Differentiate Frontotemporal Dementia from Primary Psychiatric Disorders is Age-Dependent. Am J Geriatr Psychiatry 2024. Eratne D, Loi SM, Walia N, Farrand S, Li QX, Varghese S et al. 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Neurofilaments as Emerging Biomarkers of Neuroaxonal Damage to Differentiate Behavioral Frontotemporal Dementia from Primary Psychiatric Disorders: A Systematic Review. Diagnostics 2021; 11(5): 754. Liu X, Chen X, Chen J. Relationship between serum neurofilament light chain protein and depression: A nationwide survey and Mendelian randomization study. Journal of Affective Disorders 2024; 366: 162–171. Guo M, Zhu C. Serum neurofilament light chain, markers of systemic inflammation and clinically relevant depressive symptoms in US adults. Journal of Affective Disorders 2024; 363: 572–578. Song Y, Jiao H, Weng Q, Liu H, Yi L. Serum neurofilament light chain levels are associated with depression among US adults: a cross-sectional analysis among US adults, 2013–2014. BMC Psychiatry 2024; 24(1): 527. Kerr P, Le Page C, Giguère C, Marin MF, Trudel-Fitzgerald C, Romain AJ et al. The Signature Biobank: A longitudinal biopsychosocial repository of psychiatric emergency patients. Psychiatry Res 2024; 332: 115718. Kroenke K, Spitzer RL, Williams JBW. The PHQ-9: Validity of a brief depression severity measure. Journal of General Internal Medicine 2001; 16(9): 606–613. Furukawa TA. Assessment of mood: Guides for clinicians. Journal of Psychosomatic Research 2010; 68(6): 581–589. Marteau TM, Bekker H. The development of a six-item short-form of the state scale of the Spielberger State-Trait Anxiety Inventory (STAI). Br J Clin Psychol 1992; 31(3): 301–306. Haddock G, McCarron J, Tarrier N, Faragher EB. Scales to measure dimensions of hallucinations and delusions: the psychotic symptom rating scales (PSYRATS). Psychological Medicine 1999; 29(4): 879–889. Drake R, Haddock G, Tarrier N, Bentall R, Lewis S. The Psychotic Symptom Rating Scales (PSYRATS): Their usefulness and properties in first episode psychosis. Schizophrenia Research 2007; 89(1): 119–122. Woodward TS, Jung K, Hwang H, Yin J, Taylor L, Menon M et al. Symptom dimensions of the psychotic symptom rating scales in psychosis: a multisite study. Schizophr Bull 2014; 40 Suppl 4(Suppl 4): S265-274. Favrod J, Rexhaj S, Ferrari P, Bardy S, Hayoz C, Morandi S et al. French version validation of the psychotic symptom rating scales (PSYRATS) for outpatients with persistent psychotic symptoms. BMC Psychiatry 2012; 12(1): 161. Akamine S, Marutani N, Kanayama D, Gotoh S, Maruyama R, Yanagida K et al. Renal function is associated with blood neurofilament light chain level in older adults. Sci Rep 2020; 10(1): 20350. Cipriani E, Samson-Daoust E, Giguère C-E, Kerr P, Consortium, Lepage C et al. A step-by-step and data-driven guide to index gender in psychiatry. PLOS ONE 2024; 19(1): e0296880. Sukhonpanich N, Ongphichetmetha T, Uawithya E, Jitprapaikulsan J, Rattanathamsakul N, Prayoonwiwat N et al. Reference range for serum neurofilament light chain: findings from healthy Thai adults. Brain Communications 2025; 7(3). Beltran TA. Normative Values for Serum Neurofilament Light Chain in US Adults. J Clin Neurol 2024; 20(1): 46–49. Hviid CVB, Benros ME, Krogh J, Nordentoft M, Christensen SH. Serum glial fibrillary acidic protein and neurofilament light chain in treatment-naïve patients with unipolar depression. Journal of Affective Disorders 2023; 338: 341–348. Bavato F, Barro C, Schnider LK, Simrén J, Zetterberg H, Seifritz E et al. Introducing neurofilament light chain measure in psychiatry: current evidence, opportunities, and pitfalls. Molecular Psychiatry 2024; 29(8): 2543–2559. Gendron TF, Heckman MG, White LJ, Veire AM, Pedraza O, Burch AR et al. Comprehensive cross-sectional and longitudinal analyses of plasma neurofilament light across FTD spectrum disorders. Cell Rep Med 2022; 3(4): 100607. Additional Declarations Yes Conflict of interest statement is included in the manuscript. 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Jones","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Sherri","middleName":"","lastName":"Jones","suffix":""},{"id":517326325,"identity":"dfa1c933-8e11-4b2a-bc12-700abb2188da","order_by":2,"name":"Mahdie Soltaninejad","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Mahdie","middleName":"","lastName":"Soltaninejad","suffix":""},{"id":517326326,"identity":"8eed7912-5bda-4904-ae96-b8d693af0a89","order_by":3,"name":"Charlotte Teunissen","email":"","orcid":"https://orcid.org/0000-0002-4061-0837","institution":"Neurochemistry Laboratory and Biobank","correspondingAuthor":false,"prefix":"","firstName":"Charlotte","middleName":"","lastName":"Teunissen","suffix":""},{"id":517326327,"identity":"401789fa-0e4c-4404-9771-0f91ee126702","order_by":4,"name":"Simon Ducharme","email":"","orcid":"https://orcid.org/0000-0002-7309-1113","institution":"McGill 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10:22:56","extension":"xml","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":97521,"visible":true,"origin":"","legend":"","description":"","filename":"2025MP0022170structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7557288/v1/fa78b548d38ad6047b35660a.xml"},{"id":92495059,"identity":"ed1e59e4-5230-496e-bece-a9f841e3dfc4","added_by":"auto","created_at":"2025-09-30 10:22:56","extension":"html","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":106054,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7557288/v1/02e0b4b986c533a589e9412b.html"},{"id":92495048,"identity":"be9572fa-4763-4983-b5c5-78cbf126629f","added_by":"auto","created_at":"2025-09-30 10:22:56","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":14933,"visible":true,"origin":"","legend":"\u003cp\u003eLongitudinal serum neurofilament light (sNfL) in psychiatric participants from emergency room admission to last follow up (n=73).\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-7557288/v1/fd23c36882f7bd84ee42aae7.png"},{"id":92495051,"identity":"f8d2d11d-14ac-4016-8caf-605cb31b73cf","added_by":"auto","created_at":"2025-09-30 10:22:56","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":225998,"visible":true,"origin":"","legend":"\u003cp\u003eLongitudinal behavior of serum neurofilament light (sNfL) from T1 to the last available timepoint (n=268).\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-7557288/v1/04a01063317b8e31d6f422da.png"},{"id":94985577,"identity":"326b6dd6-dad9-401a-8087-c5cf31c1f4c4","added_by":"auto","created_at":"2025-11-03 06:58:27","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":956584,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7557288/v1/373e5d42-7529-4404-8485-acc63cdfeb93.pdf"},{"id":92496620,"identity":"0268e601-99a0-4d8e-81ea-7df35a5985f3","added_by":"auto","created_at":"2025-09-30 10:30:56","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":19592,"visible":true,"origin":"","legend":"Supplementary Information","description":"","filename":"SupplementaryInformation.docx","url":"https://assets-eu.researchsquare.com/files/rs-7557288/v1/d5365a9b46b9c1a3e54931ec.docx"}],"financialInterests":"\u003cb\u003eYes\u003c/b\u003e\nConflict of interest statement is included in the manuscript.","formattedTitle":"Longitudinal stability of serum neurofilament light chains in psychiatric disorders","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eNeurofilament light (NfL) is a marker of neuronal integrity. When an axon is damaged, neurofilaments can be released into the cerebrospinal fluid (CSF) and proportionally, in lower concentrations, into the bloodstream\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Single-molecule array (SiMoA) assay technology allows reliable quantification of blood NfL levels, facilitating longitudinal monitoring\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. In previous work analyzing a large sample of patients with psychiatric disorders presenting to a psychiatric emergency room, Light et al. reported that the mean serum NfL (sNfL) measured in psychiatric disorders was higher compared to healthy controls\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. sNfL was elevated in all types of psychiatric disorders, without inter-group differences\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. This is an unexpected finding given that psychiatric disorders are not traditionally thought to involve neurodegenerative processes. The reason for the elevation in sNfL in psychiatric disorders compared to controls is unclear, and it is unknown whether this difference persists over time, or whether it is correlated with psychiatric symptom severity.\u003c/p\u003e\u003cp\u003ePrevious studies on differences in NfL levels between psychiatric disorders and healthy controls have been inconsistent \u003csup\u003e\u003cspan additionalcitationids=\"CR4 CR5 CR6\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. Increased NfL has been reported in depression and bipolar disorder in some studies \u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e, but others found no significant difference\u003csup\u003e\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. These prior studies often included small samples of patients with psychiatric disorders recruited from a secondary or tertiary care setting. Where Light et al. did report a 12.7% elevation in sNfL in psychiatric disorders compared to controls, this study comprised a large sample of patients in an acute care state, when their symptoms are most severe\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. If sNfL is related to symptom severity in psychiatric disorders, there could be a transient rise in sNfL during the acute episode, followed by a decline as symptoms stabilize and patients are discharged. Indeed, some studies have found a positive cross-sectional association between sNfL and depressive symptom severity \u003csup\u003e\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e, and blood NfL was inversely correlated with cognitive functioning in patients with depression\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. These results suggest a possible relationship between sNfL and symptom severity in psychiatric disorders, but this relationship needs to be confirmed with longitudinal measures.\u003c/p\u003e\u003cp\u003eThis study explored the longitudinal behavior of sNfL in a large, mixed diagnosis cohort of patients with psychiatric disorders, throughout their trajectory of care. We also explored the relationship between sNfL levels and measures of anxiety, depressive and psychotic symptoms in this group. We hypothesized that 1) sNfL levels would decrease over time as patients transitioned from an acute state upon admission to the emergency room, to a more stable disease state in outpatient care, and that 2) sNfL would be positively correlated with psychiatric symptom severity.\u003c/p\u003e"},{"header":"SUBJECTS AND METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStudy population\u003c/h2\u003e\u003cp\u003e This study was approved by the McGill University Health Centre Research Ethics Board (2022\u0026ndash;7585). The dataset for this study was acquired from the Signature Biobank\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. Patients were recruited upon admission to the psychiatric emergency services at the \u003cem\u003eInstitut Universitaire en Sant\u0026eacute; Mentale de Montr\u0026eacute;al\u003c/em\u003e (IUSMM) in Montreal, Quebec, Canada between 2012 and 2020. Clinical information, questionnaires and biospecimen data (including blood) were collected at 4 timepoints: at psychiatric emergency admission (T1), at hospital discharge (T2), at the first outpatient clinic appointment (T3), and a final clinic follow up appointment up to 2 years (mean: 471 days) after the initial recruitment, or at clinical remission (T4)\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. The psychiatric diagnosis by the treating psychiatrist based on standard clinical assessment at T2 was used as the main diagnostic classification \u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. Only participants who completed their participation without interruption due to a rehospitalization (Track A) were included in this study\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eOur initial dataset included 872 subjects, ages 40 and above\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. We included the same participants with psychiatric disorders as Light et al. at T1\u003csup\u003e2\u003c/sup\u003e. In addition, all listed diagnoses at hospital discharge (T2) were reviewed; participants with no formal psychiatric diagnosis, a neurocognitive disorder or other non-psychiatric diagnosis (for example, medical causes) were excluded (n\u0026thinsp;=\u0026thinsp;12). Our final sample included data from 836 subjects with sNfL available at T1 and 394 participants with at least one longitudinal sNfL sample available.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003esNfL measurement\u003c/h3\u003e\n\u003cp\u003eThe longitudinal (T2, T3, T4) serum samples (n\u0026thinsp;=\u0026thinsp;732, 200ul each) were shipped in January 2024 from the Signature Biobank to the Neurochemistry Laboratory at the Amsterdam University Medical Centre. Sample processing and storage prior to shipment followed the Signature Biobank protocol for peripheral blood sample serum separation and aliquot storage at -80C\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. Sample shipment and sNfL analysis was completed following identical methods as Light et al. for the baseline samples at T1\u003csup\u003e2\u003c/sup\u003e. sNfL levels were measured using SiMoA assay technology on a HD-X analyser according to the manufacturer\u0026rsquo;s instructions (Quanterix, Billerica, MA, USA). Repeat baseline samples (n\u0026thinsp;=\u0026thinsp;20) were also analyzed as a reference for the longitudinal measurements to correct for any batch differences.\u003c/p\u003e\n\u003ch3\u003eAssessment of psychiatric symptom severity\u003c/h3\u003e\n\u003cp\u003eData on psychiatric symptom severity was obtained from 3 questionnaires: the 9-item Patient Health Questionnaire (PHQ-9), the 6-item short form of the Spielberger State-Trait Anxiety Inventory Form Y (STAI-Y6), and the Psychotic Symptom Rating Scales (PSYRATS). The PHQ-9 is a self-administered diagnostic instrument and a validated measure of depression severity\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. The PHQ-9 total score ranges from 0 to 27 and evaluates patient symptoms over the previous 2 weeks\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. Second, the STAI-Y6 is a self-report anxiety questionnaire which collects information on how the patient is currently feeling\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. The total score ranges from 20\u0026ndash;80, where higher scores indicate greater anxiety. Third, the Psychotic Symptom Rating Scales (PSYRATS) was collected via semi-structured interview with a nurse from the Signature Biobank study. This scale assesses the severity of the different dimensions of auditory hallucinations (11 items) and delusions (6 items) from the previous week\u003csup\u003e\u003cspan additionalcitationids=\"CR20 CR21\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. Total scores are calculated for each subscale and higher scores indicate greater severity\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eThese 3 questionnaires were completed by participants at each timepoint (T1-T2-T3-T4). The PHQ-9 and STAI-Y6 were included in the Signature Biobank protocol from the beginning of the project in November 2012\u003csup\u003e15\u003c/sup\u003e. The PSYRATS questionnaire was added to the protocol in 2017, so the sample of participants who completed this questionnaire is smaller\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. We obtained the questionnaire data from the Signature Biobank at T1 and the last available sNfL timepoint (T2, T3 or T4) for each participant.\u003c/p\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eStatistical analyses were completed using IBM SPSS Statistics Version 29.0.1.1 (IBM SPSS Statistics, Armonk, NY). We completed descriptive statistics using frequencies for categorical data and means and standard deviations (SD) for continuous variables. Median sNfL is also reported to allow comparisons with other studies. Assumptions for each statistical analysis were verified and met. sNfL was not normally distributed at any timepoint, so all sNfL analyses were duplicated using log (sNfL) to confirm our results (data not shown). Raw sNfL values are reported for interpretation.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eLongitudinal sNfL\u003c/h3\u003e\n\u003cp\u003eWe conducted a one-way repeated measures ANCOVA to test if sNfL (pg/ml) changes over time in psychiatric disorders. Time was evaluated as a within-subjects factor, and sex was entered as a between-subjects factor. Age, body mass index (BMI) and blood creatinine were included as covariates, given their known associations with NfL\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. In sensitivity analyses, the interval in days between T1 and the last timepoint was included as an additional covariate in each analysis because the interval from T1 to subsequent timepoints varied between participants.\u003c/p\u003e\u003cp\u003eFirst, sNfL was evaluated for participants with sNfL available at all 4 timepoints (T1, T2, T3, T4), from emergency admission to the last follow up appointment, and measurements for all covariates (n\u0026thinsp;=\u0026thinsp;73). The Greenhouse-Geisser correction was applied to correct for sphericity violations in this analysis. Second, to increase statistical power by maximizing the sample size, sNfL was evaluated for all subjects with at least 2 time points, using T1 and the last available timepoint of sNfL measurement available after T1 (T2, T3 or T4), and measurements for all covariates (n\u0026thinsp;=\u0026thinsp;268). Error bars with 1 standard error of the mean (SEM) for the covariate adjusted means are shown in figures.\u003c/p\u003e\u003cp\u003eIndependent samples t-tests and the Pearson\u0026rsquo;s chi-square test were conducted to check for differences between the included participants with only 1 sNfL value available (n\u0026thinsp;=\u0026thinsp;442) vs participants with at least 2 sNfL values available (n\u0026thinsp;=\u0026thinsp;394). None of the variables tested (age, sex, sNfL at T1, BMI, blood creatinine, or depression/anxiety/psychosis symptoms at T1) were significantly different between the samples. This confirms that our subgroup of participants for longitudinal analysis is representative of the entire sample.\u003c/p\u003e\u003cp\u003eAdditional exploratory analyses also considered the gender index score as a predictor of longitudinal sNfL. The gender index score was included with sex as a factor and interaction term in both repeated measures analyses because the correlation between the gender index score and sex in our sample was moderate (n\u0026thinsp;=\u0026thinsp;688, r\u0026thinsp;=\u0026thinsp;0.303, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), demonstrating the partial but not complete overlap of these variables. This composite gender index score was developed based on sociodemographic and psychosocial variables showing sex differences in this Signature Biobank psychiatric cohort\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eSymptom severity measures\u003c/h2\u003e\u003cp\u003eFirst, dependent samples t-tests were completed to test the change in each symptom severity questionnaire total score from T1 to the last timepoint (T2/T3/T4). The number of participants with scores available at both timepoints varied by questionnaire. Only participants with at least 1 follow up sNfL measurement were included, so up to 394 participants were included per analysis.\u003c/p\u003e\u003cp\u003eSecond, linear regressions were completed to test the associations between sNfL and each symptom severity indicator (PHQ-9 total score, STAI-Y6 total score, PSYRAT auditory hallucinations subscale total score, PSYRAT delusions subscale total score), at both T1 and the last timepoint, controlling for both age and sex. Up to 836 participants with both sNfL and a questionnaire measure available were included at T1, and up to 394 participants were included at the last timepoint.\u003c/p\u003e\u003cp\u003eNext, the numerical change value (Δ) was calculated from T1 to the last timepoint for each questionnaire total score (Δ\u0026thinsp;=\u0026thinsp;Total score (Last) \u0026ndash; Total score (T1)), and the change in sNfL (pg/ml) was calculated from the T1 to last timepoint (Δ\u0026thinsp;=\u0026thinsp;sNfL (Last) \u0026ndash; sNfL (T1)). Linear regressions were completed to test associations between Δ sNfL and the Δ total score for each questionnaire, controlling for age and sex. Up to 394 participants were included per analysis.\u003c/p\u003e\u003cp\u003eThe significance values for all beta coefficients were calculated using a two-tailed t-test. The 95% confidence intervals were also reported for each analysis. The Bonferroni correction for multiple comparisons was applied to the significance level to control the type 1 error rate (alpha level\u0026thinsp;=\u0026thinsp;0.0125).\u003c/p\u003e\u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\u003ch2\u003eClinical characteristics\u003c/h2\u003e\u003cp\u003eThe characteristics of the included participants with sNfL measurements available are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The diagnostic categories of participants are shown in Supplementary Table\u0026nbsp;1.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eCharacteristics of Signature Biobank participants with psychiatric disorders.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e\u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD, [%], n\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMinimum 1 sNfL timepoint, n\u0026thinsp;=\u0026thinsp;836\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMinimum 2 sNfL timepoints, n\u0026thinsp;=\u0026thinsp;268\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAll 4 sNfL timepoints, n\u0026thinsp;=\u0026thinsp;73\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSex, % male\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e[57.2%], n\u0026thinsp;=\u0026thinsp;478\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e[50.3%], n\u0026thinsp;=\u0026thinsp;135\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e[43.8%], n\u0026thinsp;=\u0026thinsp;32\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGender index score\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.58\u0026thinsp;\u0026plusmn;\u0026thinsp;0.14, n\u0026thinsp;=\u0026thinsp;688\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.57\u0026thinsp;\u0026plusmn;\u0026thinsp;0.14, n\u0026thinsp;=\u0026thinsp;222\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.54\u0026thinsp;\u0026plusmn;\u0026thinsp;0.14, n\u0026thinsp;=\u0026thinsp;59\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eCovariates\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e52.8\u0026thinsp;\u0026plusmn;\u0026thinsp;8.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e53.9\u0026thinsp;\u0026plusmn;\u0026thinsp;8.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e53.1\u0026thinsp;\u0026plusmn;\u0026thinsp;7.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBody Mass Index (BMI)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e27.7\u0026thinsp;\u0026plusmn;\u0026thinsp;6.5, n\u0026thinsp;=\u0026thinsp;832\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e28.1\u0026thinsp;\u0026plusmn;\u0026thinsp;6.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e28.5\u0026thinsp;\u0026plusmn;\u0026thinsp;6.6\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBlood creatinine (\u0026micro;mol/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e72.7\u0026thinsp;\u0026plusmn;\u0026thinsp;24.3, n\u0026thinsp;=\u0026thinsp;493\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e73.9\u0026thinsp;\u0026plusmn;\u0026thinsp;26.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e72.3\u0026thinsp;\u0026plusmn;\u0026thinsp;21.7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e\u003cp\u003e\u003csup\u003e1\u003c/sup\u003en=836 participants with at least 1 serum neurofilament light (sNfL) value available (T1).\u003c/p\u003e\u003cp\u003e\u003csup\u003e2\u003c/sup\u003en=268 participants with at least 2 sNfL values available (T1\u0026thinsp;+\u0026thinsp;T2/T3/T4) and measurements for all covariates (Age, BMI, blood creatinine).\u003c/p\u003e\u003cp\u003e\u003csup\u003e3\u003c/sup\u003en=73 participants with all 4 sNfL values available and measurements for all covariates.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eLongitudinal sNfL\u003c/h2\u003e\u003cp\u003eThe descriptive statistics for the longitudinal sNfL values are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. There were 394 participants with at least 2 sNfL values available. The mean raw sNfL is 14.0pg/ml at T1 and 13.7pg/ml at the last timepoint. There were no high outliers for sNfL at any timepoint (T1-T4) in this final sample.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eLongitudinal serum neurofilament light (sNfL) values in Signature Biobank psychiatric participants.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"7\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003esNfL (pg/ml)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eT1\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eT2\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eT3\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eT4\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eLast\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eΔ Last-T1\u003c/p\u003e \u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003en\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e836\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e283\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e255\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e171\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e394\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e394\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMean\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e14.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e13.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e12.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e13.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-0.58\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e9.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e10.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e9.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e7.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e8.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e7.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedian\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e10.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e10.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e10.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-0.24\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSex, % male\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e57.2% (n\u0026thinsp;=\u0026thinsp;478)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e51.2% (n\u0026thinsp;=\u0026thinsp;145)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e52.5% (n\u0026thinsp;=\u0026thinsp;134)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e49.7%\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;85)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e54.1%\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;213)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003en/a\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003cem\u003eNote.\u003c/em\u003e n/a: not applicable. Last: the last available follow up sNfL timepoint (T2/T3/T4).\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eThere were 73 participants with sNfL values available at all 4 timepoints and measurements for all covariates. The longitudinal behavior of sNfL from ER admission to the last follow up is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. sNfL did not demonstrate a statistically significant change over the four time points, F (2.67, 181.79)\u0026thinsp;=\u0026thinsp;0.795, p\u0026thinsp;=\u0026thinsp;0.485, η\u003csub\u003ep\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.012. Also, there was no significant sex effect or interaction of sex and time.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eGiven that sNfL increases with age, we conducted sensitivity analyses to include the interval in days from T1 to T4 (mean\u0026thinsp;=\u0026thinsp;471\u0026thinsp;\u0026plusmn;\u0026thinsp;96, ranging from 319 to 720 days) as an additional covariate. This did not change our results, we found that sNfL did not change over time, η\u003csub\u003ep\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.009.\u003c/p\u003e\u003cp\u003eNext, there were 268 participants with sNfL available for at least 2 timepoints and measurements for all covariates. sNfL did not change significantly over time, from the 1st sample to the last blood collection timepoint available (between hospital discharge and the last follow up appointment), F(1,263)\u0026thinsp;=\u0026thinsp;0.384, p\u0026thinsp;=\u0026thinsp;0.536, η\u003csub\u003ep\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.001. There was a small but significant effect of sex on sNfL; males had a significantly higher mean sNfL than females (Cohen\u0026rsquo;s d\u0026thinsp;=\u0026thinsp;0.38, p\u0026thinsp;=\u0026thinsp;0.003). The interaction effect of sex and time was not significant. The longitudinal behavior of sNfL from T1 to the last available timepoint is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eIn sensitivity analyses, the interval in days from T1 to the last timepoint (mean\u0026thinsp;=\u0026thinsp;248\u0026thinsp;\u0026plusmn;\u0026thinsp;224, range: 2-783 days) was included as an additional covariate. This did not change our results, we found that sNfL did not change over time, η\u003csub\u003ep\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.003.\u003c/p\u003e\u003cp\u003eIn additional sensitivity analyses for the T1-last repeated measures model (n\u0026thinsp;=\u0026thinsp;268), we ran the model with only the participants with a time interval from T1-last\u0026thinsp;\u0026gt;\u0026thinsp;1 year included (n\u0026thinsp;=\u0026thinsp;115). This did not change our results, sNfL did not change significantly over time, η\u003csub\u003ep\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.005.\u003c/p\u003e\u003cp\u003eFinally, we completed exploratory analyses to include the gender index score with sex as a factor and interaction term in both repeated measures models. There was not a significant main effect of gender, and the interaction of the gender index score with time was not significant in either model.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eAssociations between sNfL and symptom severity\u003c/h2\u003e\u003cp\u003eThe descriptive statistics for the symptom severity measures at T1 and the last available timepoint, and the results of the dependent samples t-tests are shown in Supplementary Table\u0026nbsp;2. There was a significant mean decrease in total score for all 3 questionnaires, meaning that on average participants demonstrated a significant improvement in depression, anxiety and psychosis symptoms over time.\u003c/p\u003e\u003cp\u003eThe cross-sectional beta coefficients between sNfL and each symptom severity measure were not significant at T1 or the last timepoint, controlling for age and sex. The results of these regression analyses are shown in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eSerum neurofilament light (sNfL) predicted from symptom severity, controlling for age and sex, at T1 and the last available timepoint: sNfL\u0026thinsp;=\u0026thinsp;β₀ + β₁ (Symptom severity) + β₂(Age) + β\u003csub\u003e3\u003c/sub\u003e(Sex).\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePHQ-9\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSTAI-Y6\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePSYRAT- Auditory Hallucinations\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003ePSYRAT - Delusions\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003eT1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003esNfL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-0.029\u0026thinsp;\u0026plusmn;\u0026thinsp;0.037\u003c/p\u003e\u003cp\u003e[-0.101,0.044]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-0.035\u0026thinsp;\u0026plusmn;\u0026thinsp;0.017\u003c/p\u003e\u003cp\u003e[-0.069,0.001]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-0.047\u0026thinsp;\u0026plusmn;\u0026thinsp;0.049\u003c/p\u003e\u003cp\u003e[-0.145,0.051]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-0.033\u0026thinsp;\u0026plusmn;\u0026thinsp;0.092\u003c/p\u003e\u003cp\u003e[-0.215,0.149]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003eLast\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003esNfL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.023\u0026thinsp;\u0026plusmn;\u0026thinsp;0.059\u003c/p\u003e\u003cp\u003e[-0.092,0.139]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-0.034\u0026thinsp;\u0026plusmn;\u0026thinsp;0.026\u003c/p\u003e\u003cp\u003e[-0.086,0.017]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-0.051\u0026thinsp;\u0026plusmn;\u0026thinsp;0.104\u003c/p\u003e\u003cp\u003e[-0.262,0.159]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.010\u0026thinsp;\u0026plusmn;\u0026thinsp;0.62\u003c/p\u003e\u003cp\u003e[-0.317,0.337]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003cem\u003eNote\u003c/em\u003e. Unstandardized beta coefficient (β₁) for symptom severity\u0026thinsp;\u0026plusmn;\u0026thinsp;standard error [95% confidence interval]. Alpha level\u0026thinsp;=\u0026thinsp;0.0125 (Bonferroni). PHQ-9: 9-item Patient Health Questionnaire. STAI-Y6: 6-item short form of the Spielberger State-Trait Anxiety Inventory Form Y. PSYRATS: Psychotic Symptom Rating Scales. T1: emergency room admission. Last: Last available sNfL timepoint for each participant (from hospital discharge to the last follow up timepoint).\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eNext, the beta coefficients to predict Δ sNfL from Δ symptom severity, controlling for age and sex, are shown in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. There was a statistically significant negative relationship between Δ anxiety symptoms and Δ sNfL between T1 and the last timepoint, meaning that sNfL decreased over time as anxiety symptoms increased over time. This was an unexpected finding, however, only 2.3% of the variation in Δ sNfL was predicted from the longitudinal change in anxiety symptoms (controlling for age and sex). When controlling for age and sex; as sNfL declined by 1 pg/mL, anxiety symptoms increased by 0.06. The relationships between Δ sNfL and the longitudinal change in depressive and psychosis symptoms were not significant.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eLongitudinal Δ serum neurofilament light (sNfL) predicted from Δ symptom severity, controlling for age and sex: Δ sNfL\u0026thinsp;=\u0026thinsp;β₀ + β₁ (Δ Symptom severity) + β₂(Age) + β\u003csub\u003e3\u003c/sub\u003e(Sex).\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eΔ PHQ-9\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eΔ STAI-Y6\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eΔ PSYRAT- Auditory Hallucinations\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eΔ PSYRAT - Delusions\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eΔ sNfL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-0.082\u0026thinsp;\u0026plusmn;\u0026thinsp;0.044\u003c/p\u003e\u003cp\u003e[-0.169,0.005]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-0.058\u0026thinsp;\u0026plusmn;\u0026thinsp;0.020\u003c/p\u003e\u003cp\u003e[-0.097, -0.020]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-0.043\u0026thinsp;\u0026plusmn;\u0026thinsp;0.120\u003c/p\u003e\u003cp\u003e[-0.295,0.209]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-0.118\u0026thinsp;\u0026plusmn;\u0026thinsp;0.149\u003c/p\u003e\u003cp\u003e[-0.428,0.191]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ep-value\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.066\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.003*\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.723\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.436\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003cem\u003eNote\u003c/em\u003e. Unstandardized beta coefficient for symptom severity\u0026thinsp;\u0026plusmn;\u0026thinsp;standard error [95% confidence interval]. * p\u0026thinsp;\u0026lt;\u0026thinsp;0.0125 (Bonferroni). Δ\u0026thinsp;=\u0026thinsp;Last \u0026ndash; T1. PHQ-9: 9-item Patient Health Questionnaire. STAI-Y6: 6-item short form of the Spielberger State-Trait Anxiety Inventory Form Y. PSYRATS: Psychotic Symptom Rating Scales.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eIn this study, we investigated the longitudinal profile of sNfL in this large cohort of patients with psychiatric disorders, in a real-life patient trajectory over up to 2 years of clinical follow up. Contrary to our hypotheses, we did not detect a significant change in sNfL over time when controlling for age as patients progressed in their treatment pathway, despite significant improvements in symptomatology. Moreover, we did not find meaningful associations between sNfL levels and measures of psychiatric symptom severity, only a subtle inverse relationship between change in anxiety symptoms and change in sNfL. Overall, these findings suggest that the mild elevation in sNfL observed in psychiatric disorders\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e, and previously reported in cross-sectional studies\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e, may reflect a stable disease trait rather than a transient state associated with psychiatric symptom fluctuations. The absence of longitudinal variation in sNfL, even among participants who received treatment and experienced clinical improvement, indicates that this biomarker may not be sensitive to short- or medium-term fluctuations in psychiatric symptom severity. The previously reported elevation in sNfL in psychiatric disorders compared to controls\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e could indicate chronic neuroaxonal stress or injury, potentially attributable to disease duration, metabolic factors, neuroinflammation, medical comorbidities, psychotropic medications or even subclinical neurodegenerative processes. This still requires furthers investigation.\u003c/p\u003e\u003cp\u003eNotably, we found that males had significantly higher sNfL levels than females (18%) after adjustment for covariates, which is in line with results from recent studies\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e. There was no significant effect of the gender index score on the longitudinal behavior of sNfL in psychiatric disorders, so biological sex appears to be a more important predictor than gender for sNfL.\u003c/p\u003e\u003cp\u003eSome recent studies have reported positive correlations between sNfL and depressive symptoms\u003csup\u003e\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e, but in our large, heterogenous sample with repeated measures, our findings did not support a similar relationship between sNfL and psychiatric symptom severity. While we observed a statistically significant correlation between longitudinal change in anxiety symptoms and Δ sNfL in an unexpected direction, the effect size was very small, which suggests that it is not clinically meaningful. These results align with recent work from Hvid et al., a large sample size study which also did not detect significant associations between NfL and depression symptoms or cognitive functioning in patients with depression\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. Other studies have also failed to detect meaningful relationships between NfL and measures of psychiatric severity in patients with bipolar disorder and schizophrenia\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. These findings suggest that any link between sNfL and symptom severity in psychiatric disorders is weak and likely influenced by other factors, such as medical comorbidities or neurobiological heterogeneity. A recent review from Bavato et al. suggested a future role for NfL in the assessment of treatment interventions or as monitoring tool in psychiatric populations\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e, but the stability of sNfL and the lack of association with symptom severity in the current study suggests that sNfL may not be useful for this purpose in psychiatric populations alone.\u003c/p\u003e\u003cp\u003eThis study has important implications for sNfL as a promising biomarker for differentiating psychiatric disorders from neurodegenerative diseases, in particular behavioral variant frontotemporal dementia (bvFTD). The stable longitudinal behavior of sNfL in psychiatric disorders is in sharp contrast to the increases in NfL over time in bvFTD and other neurodegenerative disorders. Gendron et al. demonstrated that plasma NfL associates with markers of disease severity in bvFTD patients, and the rate of change of NfL over time was significantly higher in bvFTD patients (median\u0026thinsp;=\u0026thinsp;2.8pg/ml per year) compared to controls (median\u0026thinsp;=\u0026thinsp;0.3 pg/ml per year)\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e. Therefore, the rate of change of sNfL in bvFTD vs psychiatric disorders may offer greater diagnostic accuracy compared to cross-sectional sNfL, but this would need to be addressed in future studies with longitudinal sNfL values collected in both populations, as well as controls. Moreover, if the rate of change in sNfL is progressively larger in bvFTD than in psychiatric disorders, a longer clinical follow up period than 1\u0026ndash;2 years may provide increased diagnostic accuracy for blood-based NfL.\u003c/p\u003e\u003cp\u003eThe strengths of this study are the large sample size, the collection of biological and psychosocial measures, repeated measures design, and adjustment for key covariates such as age, BMI, and creatinine, which enhanced the robustness of our findings. The large sample size and comprehensive dataset allowed us to consider biological sex as well as psychosocial indicators of gender (gender index score). However, some limitations must be acknowledged. The variability in follow-up intervals and number of available timepoints across participants may have introduced noise, although sensitivity analyses accounting for time interval did not change the main findings. Also, though all sNfL measurements were conducted by a single lab and technology, there were two different batches for 1) T1 and 2) all longitudinal timepoints. This is not ideal, but control analyses were performed on a small batch of repeat T1 samples to confirm the reliability of our results. Additionally, comparisons to a longitudinal control group, as well as more extensive psychiatric symptom assessments and longer follow-up measures could have improved the interpretation of our findings.\u003c/p\u003e\u003cp\u003eIn conclusion, our study found that sNfL levels are stable over time in psychiatric disorders, and do not track symptom severity. These results suggest that mildly elevated sNfL in psychiatric disorders compared to controls\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e may reflect a chronic, trait-level neurobiological characteristic rather than dynamic changes related to psychiatric symptom fluctuations. Future research should explore the relationship between sNfL and neurobiological contributors to psychiatric illnesses such as neuroinflammation to investigate factors potentially responsible for the elevation of sNfL in this population.\u003c/p\u003e\u003cp\u003e\u003cb\u003eSupplementary information is available at MP\u0026rsquo;s website.\u003c/b\u003e\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eACKNOWLEDGEMENTS\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was funded by the Canadian Institutes of Health Research (CIHR) grant to the Canadian Consortium on Neurodegeneration in Aging (CCNA) Phase II. Ishana Rue receives salary support from the \u003cem\u003eCanada First Research Excellence Fund, awarded to the Healthy Brains, Healthy Lives initiative at McGill University\u003c/em\u003e. Dr Simon Ducharme receives salary support from the Fond de recherche du Québec\u0026ndash; Santé.\u003c/p\u003e\n\u003cp\u003eThe data for this study were obtained from the Signature Biobank database. Serum sample analyses were completed by Hans Heijst at the Neurochemistry Laboratory at the Amsterdam University Medical Centre, led by Dr. Charlotte E. Teunissen.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDr. Ducharme has research contracts with Biogen, Novo Nordisk, Janssen, Passage Bio, Alnylam, Roche, Voyager Therapeutics and Eli Lilly. He has received advisory/speaker fees from Eisai, Eli Lilly, Voyager Therapeutics and QuRALIS. He is a member of the DSMB of Aviado Bio.\u003c/p\u003e\n\u003cp\u003eDr. Teunissen\u0026rsquo;s work has supported by the European Commission (Marie Curie International Training Network, grant agreement No 860197 (MIRIADE) and No 101119596 (TAME), Innovative Medicines Initiatives 3TR (Horizon 2020, grant no 831434) EPND (\u0026nbsp;IMI 2 Joint Undertaking (JU), grant No. 101034344) and JPND (bPRIDE, CCAD), European Partnership on Metrology, co-financed from the European Union\u0026rsquo;s Horizon Europe Research and Innovation Programme and by the Participating States ((22HLT07 NEuroBioStand), Horizon Europe (PREDICTFTD, 101156175), CANTATE project funded by the Alzheimer Drug Discovery Foundation, Alzheimer Association, Michael J Fox Foundation, Health Holland, the Dutch Research Council (ZonMW), Alzheimer Drug Discovery Foundation, The Selfridges Group Foundation, Alzheimer Netherlands. CT is recipient of ABOARD, which is a public-private partnership receiving funding from ZonMW (#73305095007) and Health~Holland, Topsector Life Sciences \u0026amp; Health (PPP-allowance; #LSHM20106). Dr. Teunissen is recipient of TAP-dementia, a ZonMw funded project (#10510032120003) in the context of the Dutch National Dementia Strategy.\u003c/p\u003e\n\u003cp\u003eDr. Teunissen has \u003cstrong\u003eresearch contracts\u003c/strong\u003e with Acumen, ADx Neurosciences, AC-Immune, Alamar, Aribio, Axon Neurosciences, Beckman-Coulter, BioConnect, Bioorchestra, Brainstorm Therapeutics, C2N diagnostics, Celgene, Cognition Therapeutics, EIP Pharma, Eisai, Eli Lilly, Fujirebio, Instant Nano Biosensors, Merck, Muna, Novo Nordisk, Olink, PeopleBio, Quanterix, Roche, Toyama, Vaccinex, Vivoryon. She is \u003cstrong\u003eeditor\u003c/strong\u003e in chief of Alzheimer Research and Therapy, and serves on editorial boards of Molecular Neurodegeneration, Alzheimer\u0026rsquo;s \u0026amp; Dementia, Neurology: Neuroimmunology \u0026amp; Neuroinflammation, Medidact Neurologie/Springer, and is committee member to define guidelines for Cognitive disturbances, and one for acute Neurology in the Netherlands. She has \u003cstrong\u003econsultancy/sp\u003c/strong\u003e\u003cstrong\u003eeaker contracts\u003c/strong\u003e for Aribio, Biogen, Beckman-Coulter, Cognition Therapeutics, Danaher, Eisai, Eli Lilly, Janssen, Merck, Novo Nordisk, Novartis, Olink, Roche, Sanofi and Veravas.\u003c/p\u003e\n\u003cp\u003eIshana Rue, Dr Sherri Lee Jones and Mahdie Soltaninejad declare no potential conflict of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eKhalil M, Teunissen CE, Lehmann S, Otto M, Piehl F, Ziemssen T \u003cem\u003eet al.\u003c/em\u003e Neurofilaments as biomarkers in neurological disorders \u0026mdash; towards clinical application. \u003cem\u003eNature Reviews Neurology\u003c/em\u003e 2024; 20(5): 269\u0026ndash;287.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLight V, Jones SL, Rahme E, Rousseau K, de Boer S, Vermunt L \u003cem\u003eet al.\u003c/em\u003e Clinical Accuracy of Serum Neurofilament Light to Differentiate Frontotemporal Dementia from Primary Psychiatric Disorders is Age-Dependent. \u003cem\u003eAm J Geriatr Psychiatry\u003c/em\u003e 2024.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eEratne D, Loi SM, Walia N, Farrand S, Li QX, Varghese S \u003cem\u003eet al.\u003c/em\u003e A pilot study of the utility of cerebrospinal fluid neurofilament light chain in differentiating neurodegenerative from psychiatric disorders: A 'C-reactive protein' for psychiatrists and neurologists? \u003cem\u003eAust N Z J Psychiatry\u003c/em\u003e 2020; 54(1): 57\u0026ndash;67.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAl Shweiki MR, Steinacker P, Oeckl P, Hengerer B, Danek A, Fassbender K \u003cem\u003eet al.\u003c/em\u003e Neurofilament light chain as a blood biomarker to differentiate psychiatric disorders from behavioural variant frontotemporal dementia. \u003cem\u003eJ Psychiatr Res\u003c/em\u003e 2019; 113: 137\u0026ndash;140.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eEratne D, Janelidze S, Malpas CB, Loi S, Walterfang M, Merritt A \u003cem\u003eet al.\u003c/em\u003e Plasma neurofilament light chain protein is not increased in treatment-resistant schizophrenia and first-degree relatives. \u003cem\u003eAust N Z J Psychiatry\u003c/em\u003e 2022; 56(10): 1295\u0026ndash;1305.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eEratne D, Kang M, Malpas C, Simpson-Yap S, Lewis C, Dang C \u003cem\u003eet al.\u003c/em\u003e Plasma neurofilament light in behavioural variant frontotemporal dementia compared to mood and psychotic disorders. \u003cem\u003eAustralian \u0026amp; New Zealand Journal of Psychiatry\u003c/em\u003e 2024; 58(1): 70\u0026ndash;81.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKang MJY, Eratne D, Wannan C, Santillo AF, Velakoulis D, Pantelis C \u003cem\u003eet al.\u003c/em\u003e Plasma neurofilament light chain is not elevated in people with first-episode psychosis or those at ultra-high risk for psychosis. \u003cem\u003eSchizophrenia Research\u003c/em\u003e 2024; 267: 269\u0026ndash;272.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBavato F, Cathomas F, Klaus F, G\u0026uuml;tter K, Barro C, Maceski A \u003cem\u003eet al.\u003c/em\u003e Altered neuroaxonal integrity in schizophrenia and major depressive disorder assessed with neurofilament light chain in serum. \u003cem\u003eJournal of Psychiatric Research\u003c/em\u003e 2021; 140: 141\u0026ndash;148.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChen MH, Liu YL, Kuo HW, Tsai SJ, Hsu JW, Huang KL \u003cem\u003eet al.\u003c/em\u003e Neurofilament Light Chain Is a Novel Biomarker for Major Depression and Related Executive Dysfunction. \u003cem\u003eInt J Neuropsychopharmacol\u003c/em\u003e 2022; 25(2): 99\u0026ndash;105.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJakobsson J, Bjerke M, Ekman CJ, Sellgren C, Johansson AGM, Zetterberg H \u003cem\u003eet al.\u003c/em\u003e Elevated Concentrations of Neurofilament Light Chain in the Cerebrospinal Fluid of Bipolar Disorder Patients. \u003cem\u003eNeuropsychopharmacology\u003c/em\u003e 2014; 39(10): 2349\u0026ndash;2356.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDavy V, Dumurgier J, Fayosse A, Paquet C, Cognat E. 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The Psychotic Symptom Rating Scales (PSYRATS): Their usefulness and properties in first episode psychosis. \u003cem\u003eSchizophrenia Research\u003c/em\u003e 2007; 89(1): 119\u0026ndash;122.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWoodward TS, Jung K, Hwang H, Yin J, Taylor L, Menon M \u003cem\u003eet al.\u003c/em\u003e Symptom dimensions of the psychotic symptom rating scales in psychosis: a multisite study. \u003cem\u003eSchizophr Bull\u003c/em\u003e 2014; 40 Suppl 4(Suppl 4): S265-274.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFavrod J, Rexhaj S, Ferrari P, Bardy S, Hayoz C, Morandi S \u003cem\u003eet al.\u003c/em\u003e French version validation of the psychotic symptom rating scales (PSYRATS) for outpatients with persistent psychotic symptoms. \u003cem\u003eBMC Psychiatry\u003c/em\u003e 2012; 12(1): 161.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAkamine S, Marutani N, Kanayama D, Gotoh S, Maruyama R, Yanagida K \u003cem\u003eet al.\u003c/em\u003e Renal function is associated with blood neurofilament light chain level in older adults. \u003cem\u003eSci Rep\u003c/em\u003e 2020; 10(1): 20350.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCipriani E, Samson-Daoust E, Gigu\u0026egrave;re C-E, Kerr P, Consortium, Lepage C \u003cem\u003eet al.\u003c/em\u003e A step-by-step and data-driven guide to index gender in psychiatry. \u003cem\u003ePLOS ONE\u003c/em\u003e 2024; 19(1): e0296880.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSukhonpanich N, Ongphichetmetha T, Uawithya E, Jitprapaikulsan J, Rattanathamsakul N, Prayoonwiwat N \u003cem\u003eet al.\u003c/em\u003e Reference range for serum neurofilament light chain: findings from healthy Thai adults. \u003cem\u003eBrain Communications\u003c/em\u003e 2025; 7(3).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBeltran TA. Normative Values for Serum Neurofilament Light Chain in US Adults. \u003cem\u003eJ Clin Neurol\u003c/em\u003e 2024; 20(1): 46\u0026ndash;49.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHviid CVB, Benros ME, Krogh J, Nordentoft M, Christensen SH. Serum glial fibrillary acidic protein and neurofilament light chain in treatment-na\u0026iuml;ve patients with unipolar depression. \u003cem\u003eJournal of Affective Disorders\u003c/em\u003e 2023; 338: 341\u0026ndash;348.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBavato F, Barro C, Schnider LK, Simr\u0026eacute;n J, Zetterberg H, Seifritz E \u003cem\u003eet al.\u003c/em\u003e Introducing neurofilament light chain measure in psychiatry: current evidence, opportunities, and pitfalls. \u003cem\u003eMolecular Psychiatry\u003c/em\u003e 2024; 29(8): 2543\u0026ndash;2559.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGendron TF, Heckman MG, White LJ, Veire AM, Pedraza O, Burch AR \u003cem\u003eet al.\u003c/em\u003e Comprehensive cross-sectional and longitudinal analyses of plasma neurofilament light across FTD spectrum disorders. \u003cem\u003eCell Rep Med\u003c/em\u003e 2022; 3(4): 100607.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7557288/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7557288/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eSerum neurofilament light (sNfL) is a biomarker of axonal integrity which is elevated in neurodegenerative diseases. Although common psychiatric disorders are not neurodegenerative, some studies have found slightly higher levels of sNfL in psychiatric disorders compared to healthy controls. The reason for this elevation is unknown, and it is unclear whether this difference persists over time, or if it varies in relationship to symptom severity. Longitudinal serum samples and clinical data from a large dataset of psychiatric patients (n\u0026thinsp;=\u0026thinsp;836; ages 40+, M\u0026thinsp;=\u0026thinsp;478, F\u0026thinsp;=\u0026thinsp;358) were obtained from the Signature Biobank at up to four time points over up to 2 years (from emergency room admission to outpatient follow-up or remission). sNfL was measured using SiMoA assay technology. Repeated measures analyses were used to test sNfL over time, adjusting for age, BMI, blood creatinine and sex. Linear regressions were used to test associations between sNfL levels and depression, anxiety and psychosis symptoms. sNfL levels did not change significantly over time for subjects with all 4 available timepoints (n\u0026thinsp;=\u0026thinsp;73), nor from baseline to the last available timepoint (n\u0026thinsp;=\u0026thinsp;268). Males had slightly higher sNfL than females (Cohen\u0026rsquo;s d\u0026thinsp;=\u0026thinsp;0.38, p\u0026thinsp;=\u0026thinsp;0.003). Depression, anxiety and psychosis symptoms improved over time, but there were no clinically significant correlations between sNfL and symptom severity. This study did not detect a significant change in sNfL in psychiatric disorders over time, despite overall improvement in symptom severity. These results suggest that the mild elevation in sNfL reported in psychiatric disorders is a disease trait rather than state dependent.\u003c/p\u003e","manuscriptTitle":"Longitudinal stability of serum neurofilament light chains in psychiatric disorders","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-30 10:22:51","doi":"10.21203/rs.3.rs-7557288/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"eb90e35b-2c62-45e0-ae8a-6e19fb3b3fe4","owner":[],"postedDate":"September 30th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":54974678,"name":"Health sciences/Biomarkers/Diagnostic markers"},{"id":54974679,"name":"Health sciences/Diseases/Psychiatric disorders"}],"tags":[],"updatedAt":"2025-10-31T08:01:44+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-30 10:22:51","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7557288","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7557288","identity":"rs-7557288","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}