Elevated plasma neurofilament light chain protein in alcohol use, anorexia nervosa, mania, psychosis and other acute psychiatric disorder presentations

Elevated plasma neurofilament light chain protein in alcohol use, anorexia nervosa, mania, psychosis and other acute psychiatric disorder presentations | medRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var j=j||B.errorTimeout,l=b.createElement(a),o=0,r=0,u={t:d,s:c,e:f,a:i,x:j};1===y[c]&&(r=1,y[c]=[]),"object"==a?l.data=c:(l.src=c,l.type=a),l.width=l.height="0",l.onerror=l.onload=l.onreadystatechange=function(){k.call(this,r)},p.splice(e,0,u),"img"!=a&&(r||2===y[c]?(t.insertBefore(l,s?null:n),m(k,j)):y[c].push(l))}function j(a,b,c,d,f){return q=0,b=b||"j",e(a)?i("c"==b?v:u,a,b,this.i++,c,d,f):(p.splice(this.i++,0,a),1==p.length&&h()),this}function k(){var a=B;return a.loader={load:j,i:0},a}var l=b.documentElement,m=a.setTimeout,n=b.getElementsByTagName("script")[0],o={}.toString,p=[],q=0,r="MozAppearance"in l.style,s=r&&!!b.createRange().compareNode,t=s?l:n.parentNode,l=a.opera&&"[object Opera]"==o.call(a.opera),l=!!b.attachEvent&&!l,u=r?"object":l?"script":"img",v=l?"script":u,w=Array.isArray||function(a){return"[object Array]"==o.call(a)},x=[],y={},z={timeout:function(a,b){return b.length&&(a.timeout=b[0]),a}},A,B;B=function(a){function b(a){var a=a.split("!"),b=x.length,c=a.pop(),d=a.length,c={url:c,origUrl:c,prefixes:a},e,f,g;for(f=0;f<d;f++)g=a[f].split("="),(e=z[g.shift()])&&(c=e(c,g));for(f=0;f<b;f++)c=x[f](c);return c}function g(a,e,f,g,h){var i=b(a),j=i.autoCallback;i.url.split(".").pop().split("?").shift(),i.bypass||(e&&(e=d(e)?e:e[a]||e[g]||e[a.split("/").pop().split("?")[0]]),i.instead?i.instead(a,e,f,g,h):(y[i.url]?i.noexec=!0:y[i.url]=1,f.load(i.url,i.forceCSS||!i.forceJS&&"css"==i.url.split(".").pop().split("?").shift()?"c":c,i.noexec,i.attrs,i.timeout),(d(e)||d(j))&&f.load(function(){k(),e&&e(i.origUrl,h,g),j&&j(i.origUrl,h,g),y[i.url]=2})))}function h(a,b){function c(a,c){if(a){if(e(a))c||(j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}),g(a,j,b,0,h);else if(Object(a)===a)for(n in m=function(){var b=0,c;for(c in a)a.hasOwnProperty(c)&&b++;return b}(),a)a.hasOwnProperty(n)&&(!c&&!--m&&(d(j)?j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}:j[n]=function(a){return function(){var b=[].slice.call(arguments);a&&a.apply(this,b),l()}}(k[n])),g(a[n],j,b,n,h))}else!c&&l()}var h=!!a.test,i=a.load||a.both,j=a.callback||f,k=j,l=a.complete||f,m,n;c(h?a.yep:a.nope,!!i),i&&c(i)}var i,j,l=this.yepnope.loader;if(e(a))g(a,0,l,0);else if(w(a))for(i=0;i (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];var j=d.createElement(s);var dl=l!='dataLayer'?'&l='+l:'';j.src='//www.googletagmanager.com/gtm.js?id='+i+dl;j.type='text/javascript';j.async=true;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-P4HH5NV'); Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search Elevated plasma neurofilament light chain protein in alcohol use, anorexia nervosa, mania, psychosis and other acute psychiatric disorder presentations View ORCID Profile Dhamidhu Eratne , View ORCID Profile Matthew JY Kang , Charles B Malpas , Samantha M Loi , Alexander F Santillo , Henrik Zetterberg , Naveen Thomas , Ian Everall , Chad Bousman , Christos Pantelis , Kruti Patel , Jeffrey Smith , Michael Christie , Cherie Chiang , Dennis Velakoulis , The MiND Study Group doi: https://doi.org/10.1101/2025.11.19.25340633 Dhamidhu Eratne 1 Neuropsychiatry Centre, The Royal Melbourne Hospital; Department of Psychiatry, The University of Melbourne 2 Department of Psychiatry, The University of Melbourne Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Dhamidhu Eratne For correspondence: deratne{at}unimelb.edu.au Matthew JY Kang 1 Neuropsychiatry Centre, The Royal Melbourne Hospital; Department of Psychiatry, The University of Melbourne 2 Department of Psychiatry, The University of Melbourne Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Matthew JY Kang Charles B Malpas 3 Department of Medicine (Royal Melbourne Hospital), University of Melbourne 4 Melbourne School of Psychological Sciences, University of Melbourne Find this author on Google Scholar Find this author on PubMed Search for this author on this site Samantha M Loi 1 Neuropsychiatry Centre, The Royal Melbourne Hospital; Department of Psychiatry, The University of Melbourne 2 Department of Psychiatry, The University of Melbourne Find this author on Google Scholar Find this author on PubMed Search for this author on this site Alexander F Santillo 5 Clinical Memory Research Unit, Department of Clinical Sciences, Faculty of Medicine, Lund University , Lund/Malmö, Sweden Find this author on Google Scholar Find this author on PubMed Search for this author on this site Henrik Zetterberg 6 Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg , Mölndal, Sweden 7 Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital , Mölndal, Sweden 8 Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health , Madison, WI, USA 9 Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison , Madison, WI, USA 10 Department of Neurodegenerative Disease, UCL Institute of Neurology , Queen Square, London, UK 11 UK Dementia Research Institute at UCL , London, UK 12 Hong Kong Center for Neurodegenerative Diseases , InnoHK, Hong Kong , China 13 Centre for Brain Research, Indian Institute of Science , Bangalore, India Find this author on Google Scholar Find this author on PubMed Search for this author on this site Naveen Thomas 14 Mental Health and Wellbeing Services, Western Health , St Albans, Victoria, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site Ian Everall 15 King’s College London , London, UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site Chad Bousman 16 Department of Medical Genetics, Cumming School of Medicine, University of Calgary , AB, Canada Find this author on Google Scholar Find this author on PubMed Search for this author on this site Christos Pantelis 2 Department of Psychiatry, The University of Melbourne 17 Florey Institute of Neuroscience and Mental Health, The University of Melbourne , Parkville, VIC, Australia 18 Monash Institute of Pharmaceutical Sciences (MIPS), Monash University , Royal Parade, Parkville, Victoria, Australia 19 Western Centre for Health Research & Education (WCHRE), University of Melbourne & Western Health, Sunshine Hospital , Furlong Road, St Albans, Melbourne, Victoria, Australia 20 Mental Health and Wellbeing Services, Western Health , St Albans, Victoria, Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site Kruti Patel 21 Colonial Foundation Diagnostics Centre, New Medicines and Diagnostics Division, Walter and Eliza Hall Institute Find this author on Google Scholar Find this author on PubMed Search for this author on this site Jeffrey Smith 21 Colonial Foundation Diagnostics Centre, New Medicines and Diagnostics Division, Walter and Eliza Hall Institute Find this author on Google Scholar Find this author on PubMed Search for this author on this site Michael Christie 21 Colonial Foundation Diagnostics Centre, New Medicines and Diagnostics Division, Walter and Eliza Hall Institute 22 Department of Pathology, Royal Melbourne Hospital; Department of Endocrinology, Royal Melbourne Hospital, University of Melbourne Find this author on Google Scholar Find this author on PubMed Search for this author on this site Cherie Chiang 22 Department of Pathology, Royal Melbourne Hospital; Department of Endocrinology, Royal Melbourne Hospital, University of Melbourne Find this author on Google Scholar Find this author on PubMed Search for this author on this site Dennis Velakoulis 1 Neuropsychiatry Centre, The Royal Melbourne Hospital; Department of Psychiatry, The University of Melbourne 2 Department of Psychiatry, The University of Melbourne Find this author on Google Scholar Find this author on PubMed Search for this author on this site Abstract Full Text Info/History Metrics Data/Code Preview PDF Abstract Objective To investigate plasma neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) levels across a range of acute psychiatric disorder presentations, and to determine whether elevations are specific to certain diagnoses. Methods We analysed biobanked lithium heparin plasma samples from 121 patients with acute psychiatric presentations (including mania, psychosis, alcohol use disorder, anorexia nervosa, depression, and adjustment disorder), and 59 healthy controls. NfL and GFAP were measured using Simoa assays. Group differences were compared via bootstrapped general linear models adjusted for age, sex, and weight. Results NfL was significantly elevated in alcohol use disorder, anorexia nervosa, mania, and psychosis compared to controls, but not in depression or adjustment disorder. GFAP was elevated only in alcohol use disorder. Conclusions Plasma NfL and GFAP are not uniformly elevated across psychiatric disorders. Elevations in specific acute disorders likely reflect underlying neuronal and astroglial injury. These results support nuanced, biologically grounded, diagnosis and stage-specific roles for these biomarkers in psychiatry. Statistical analysis conducted by: Dr Dhamidhu Eratne Introduction Blood biomarkers that reflect central nervous system pathological processes, such as neurofilament light chain protein (NfL, a marker of neuronal injury) and glial fibrillary acidic protein (GFAP, a marker of glial activation and neuroinflammation), are increasingly recognised for their diagnostic and broader value in neurodegenerative disorders. More recently, there has been growing interest in whether these markers may be relevant in primary psychiatric disorders (PPD), particularly in severe or acute presentations where there may be neurobiological changes that overlap with neurodegeneration or neuroinflammation ( Abu-Rumeileh et al., 2023 ; Bavato, Barro, et al., 2024 ; Bavato, Seifritz, et al., 2024 ; Dai et al., 2022 ). The validation and use of such blood tests could facilitate improved understanding of underlying biological processes, help identify unique subtypes, and serve as markers of treatment response and poorer prognosis. Given the increasing awareness of this association between diverse psychiatric disorders and dementia ( Baudouin et al., 2025 ; Livingston et al., 2024 ), they may also enable early identification of individuals at greater risk for neurodegeneration and dementia,. Several studies have demonstrated elevated plasma NfL in bipolar affective disorder (BPAD) depression ( Aggio et al., 2022 ; Kang, Eratne, et al., 2025 ), major depressive disorder (MDD) ( Bavato et al., 2021 ), and psychotic disorders ( Ceylan et al., 2023 ; Rodrigues-Amorim et al., 2020 ). However, findings have not been consistent ( Squitti et al., 2024 ), with other studies not finding elevated levels in BPAD ( Queissner et al., 2024 ), MDD ( Eratne, M Kang, et al., 2024 ), or treatment-resistant schizophrenia and first-episode psychosis ( Eratne et al., 2022 ; Eratne, M Kang, et al., 2024 ; Kang et al., 2024 ). A recent meta-analysis found elevated NfL levels in bipolar disorder, but not major depressive disorder ( Kang, Grewal, et al., 2025 ). NfL and GFAP have been found to be elevated in bipolar depression ( Kang, Eratne, et al., 2025 ) and anorexia nervosa ( Doose et al., 2023 ; Hellerhoff et al., 2021 ; Nilsson et al., 2019 ). Neither biomarker was elevated in treatment-resistant schizophrenia ( Eratne, MJY Kang, Lewis, Dang, Malpas, Ooi, et al., 2024 ). A major limitation in the literature has been the lack of research in different phases of PPD, particularly acute phases of illness. Recent studies of NfL in a large group of psychiatric emergency presentations found elevated levels across a diverse range of broad diagnostic categories, from personality to anxiety to mood disorders, however, their mood disorders cohort was not further characterised (i.e. in to unipolar vs bipolar disorder), and did not provide any findings in patients with mania ( Light et al., 2024 ; Zarglayoun et al., 2025 ). Ceylan et al. investigated adolescent patients with bipolar mania, however analyses were not adjusted for important covariates such as weight, age, and sex, known to affect blood biomarker levels. To our knowledge, only two studies have reported biomarkers in mania, n=4 in each study. ( Al Shweiki et al., 2019 ; Steinacker et al., 2021 ), but only Steinacker et al. reported findings in mania specifically (n=4; NfL and GFAP levels were not elevated). Despite this growing literature, there remain several key unanswered questions. First, few studies have examined individuals during acute psychiatric presentations, when symptoms are most severe and biological changes such as neuronal injury and neuroinflammation may be most pronounced. Second, very few studies have focused on mania and acute psychosis, owing to recruitment challenges during the acute phases of illness. Third, potential confounders, such as age and body weight, have not always been adequately addressed. Finally, no studies to our knowledge have yet described GFAP levels in a diverse range of acute psychiatric disorder presentations. This study aimed to examine plasma NfL and GFAP levels in individuals presenting to hospital with a range of acute psychiatric disorders, including mania, psychosis, anorexia nervosa, alcohol use disorder, depression, and adjustment disorder, and compare these to levels in healthy controls. We hypothesised that NfL and/or GFAP would be elevated in some acute psychiatric presentations — particularly mania and psychosis – but not across all diagnostic groups – potentially reflecting differing degrees of neuronal injury and neuroinflammation in acute phases of severe disorders compared to acute presentations of less severe disorders. Methods Recruitment and sample analysis Patients in this study had been admitted with acute psychiatric presentations to acute settings at The Royal Melbourne Hospital (RMH), including the emergency department, an acute adult psychiatry inpatient unit, and an eating disorder inpatient unit. The broad admission category was reviewed, and patients with manic, depressed, psychotic, anorexia nervosa and other psychiatric presentations were identified. People admitted with alcohol use disorder were identified as a comparator, positive control group, given the evidence of NfL and GFAP elevations in this alcohol use disorder (Hou et al., 2025; Huang et al., 2024; Requena-Ocaña et al., 2023). Routine admission pathology samples from the identified inpatients were retrieved, and de-identified prior to analysis. Waiver of consent was approved by the hospital ethics committee for the use of routine de-identified blood samples and data for the development of in-house biomarker testing (HREC/65332/mh-2020). Aliquots were stored at - 80C, and analysed for NfL and GFAP using N2PB kits on Quanterix Simoa HD-X analysers. The primary discharge diagnosis was extracted from file review and was categorised into one of the following: adjustment disorder, alcohol use disorder, anorexia nervosa, depression, mania (bipolar mania), other PPD, psychosis (schizophrenia spectrum disorders). Sex, weight and age were linked to each sample episode. The control group consisted of unrelated, age, sex and sociodemographic matched healthy controls recruited from the general community, through the CRC psychosis study, as described in detail previously ( Bousman et al., 2019 ; Eratne et al., 2022 ; Mostaid et al., 2017 ). Statistical analyses All statistical analyses were performed in R version 4.5.0 (2025-04-11). A number of cases had missing values for weight (n=46). Due to weight having a significant influence on plasma biomarkers, missing weight data was imputed using multiple imputation by chained equations (MICE) with predictive mean matching, based on age, sex, and diagnostic group (mice package), with imputed values replacing missing ones in the main dataset. General linear models (GLMs) were fitted separately for logliltransformed plasma NfL and GFAP concentrations, with diagnostic group as the primary predictor and age, sex, and weight as covariates. Model coefficients and confidence intervals were estimated using nonlilparametric bootstrapping with 10,000 replicates (parameters package), due to small sample sizes and to ensure robust inference. Estimated marginal means (EMMs) were obtained using the emmeans package to calculate adjusted mean log values for each diagnostic group. Biomarker data from the control group were analysed in a separate batch using plasma EDTA samples using NfL and GFAP single-plex kits and Simoa SR-X analysers. Using data from samples that were analysed in both batches (n=72 from a separate study), we were able to determine a strong linear correlation between batches (Pearson’s correlations 0.97 and 0.96 for NfL and GFAP, respectively) and harmonise the control data. Results The final study cohort included 180 participants with the following primary diagnoses: adjustment disorder (n=9), alcohol use disorder (n=10), anorexia nervosa (n=21), mania (n=17), depression (n=15), other PPD (n=13), psychosis (n=36), and controls (n=59). As illustrated in Table 1 , there were age, weight, and sex differences between the groups. People with anorexia nervosa were the youngest (mean age 25 years). People with alcohol use disorder and depression were older (mean 48 years and 44 years, respectively), compared to the other groups (means 32-40 years). Imputed weights were similar to weights without imputation. Anorexia nervosa had the lowest weight (mean 43kg). Adjustment disorder and mania had higher weights compared to controls (87kg and 82kg, respective, vs 76kg). View this table: View inline View popup Download powerpoint Table 1. Study cohort details and biomarker levels. Data is Mean (SD) or n / N (%) z: Adjusted levels are estimated marginal means derived from general linear model with age, sex, and imputed weight as covariates (see Supplementary Material for further details) GFAP: glial fibrillary acidic protein; NfL: neurofilament light chain protein NfL in acute psychiatric presentations As demonstrated in Table 1 and Figure 1 , raw, unadjusted NfL levels were higher in alcohol use disorder (mean 43pg/mL) and anorexia nervosa (mean 20pg/mL), compared to controls (mean 9pg/mL). Descriptively, unadjusted levels in other groups were slightly higher compared to controls (psychosis 13pg/mL, other PPD 13pg/mL, mania 10pg/mL), or similar to controls (depression, adjustment disorder). Download figure Open in new tab Figure 1. Plasma neurofilament light chain protein (NfL) levels in acute psychiatric disorder presentations and controls. + : unadjusted mean level X = adjusted mean level To account for differences between groups, standardised bootstrapped GLMs with age, sex, and weight as covariates were performed, and adjusted log means derived for additional description ( Table 1 , Figure 1 , and further details in Supplementary Material). These demonstrated markedly elevated NfL levels compared to controls in alcohol use disorder (adjusted mean log NfL 1.31 vs 0.91; β=1.32 95%CI:[0.53, 2.20], p=0.002) and anorexia nervosa (1.17 vs 0.91; β=0.86 [0.43, 1.32], p<0.001). NfL levels were also elevated in mania (1.04 vs 0.91; β=0.44 [0.08, 0.83], p=0.015), and psychosis (1.01 vs 0.91; β=0.34 [0.03, 0.66], p=0.034). None of the other groups were statistically different compared to controls. Comparing only PPD to each other, with depression as the reference group, NfL levels were elevated in alcohol use disorder (1.31 vs 0.79; β=1.53 [0.80, 2.30], p<0.001) and anorexia nervosa (1.17 vs 0.79; β=1.15 [0.61, 1.64], p<0.001), mania (1.04 vs 0.79; β=0.81 [0.33, 1.27], p=0.002), psychosis (1.01 vs 0.79; β=0.68 [0.28, 1.07], p=0.003), and other PPD (1.02 vs 0.79; β=0.73 [0.12, 1.33], p=0.022). NfL levels between adjustment disorder and Depression were not statistically different. GFAP in acute psychiatric presentations Unadjusted GFAP levels were markedly elevated in alcohol use disorder (180pg/mL) and anorexia nervoca (127pg/mL), compared to controls (73pg/mL), with less pronounced elevations in other groups (92-107pg/mL, Table 1 and Figure 2 ). Download figure Open in new tab Figure 2. Plasma glial fibrillary acidic protein (GFAP) levels in acute psychiatric disorder presentations and controls. + : unadjusted mean level X = adjusted mean level Adjusted log mean GFAP levels were only elevated in Alcohol use disorder compared to controls (2.09 vs 1.82; β=1.01 [0.16, 1.80], p=0.024). Comparing only PPD to each other, with Depression as the reference group, GFAP levels were not elevated in any groups compared. Discussion This study investigated plasma NfL and GFAP levels in people with acute psychiatric presentations and alcohol use disorder. The main finding after adjusting for important covariates (age, sex, and weight), was of elevated NfL levels in several acute psychiatric disorder presentations: markedly elevated significant levels in alcohol use disorder and anorexia nervosa, with more modest but significant elevations in mania and psychosis. To our knowledge, no previous study has described NfL and GFAP levels in bipolar mania and acute psychosis in adults. Our findings provide important evidence of neuronal injury during the acute phases of these severe psychiatric disorders. Furthermore, this study reinforces the association between alcohol use disorder, anorexia nervosa, and significant neuronal injury. Our study is the first to describe GFAP levels in a diverse range of acute psychiatric presentations, not finding elevated levels in any of the disorders (except alcohol use disorder) compared to controls, or compared to each other. Strengths of our study include the inclusion of patients who are traditionally extremely challenging to recruit, robust statistical and imputation methods to mitigate against smaller sample sizes and missing weight data, and adjust for important covariates. Our findings differ from recent large-scale studies such as Light et al. and Zarglayoun et al. ( Light et al., 2024 ; Zarglayoun et al., 2025 ), who reported broad elevations in NfL and GFAP across nearly all major psychiatric categories, also including anxiety disorders and personality disorders. By contrast, our study did not find uniform elevations. NfL levels in adjustment disorder and depression were comparable to controls, and GFAP elevations were limited to alcohol use disorder. Our findings that peripheral markers of neuronal and glial injury are elevated only in certain severe subgroups or clinical states, is more plausible in that it may more accurately reflect underlying biological processes. NfL elevations in mania and psychosis may reflect acute neurotoxicity associated with extreme mood dysregulation, sleep-wake disruption, and agitation. This interpretation is supported by longitudinal neuroimaging evidence showing that a greater number of manic episodes is associated with progressive cortical thinning, particularly in prefrontal regions ( Abé et al., 2022 ). GFAP elevations in alcohol use disorder are consistent with prior evidence of astroglial activation and blood-brain barrier permeability changes in this population ( Nadler et al., 2025 ). Normal NfL and GFAP levels may reflect either the lower biological burden in states such as adjustment disorder, or in the case of depression the possibility that such changes emerge only in chronic, severe, recurrent illness. Importantly, the presence of normal biomarker levels in some psychiatric groups adds credence to the signal observed in others – elevated levels in severe psychiatric disorders like bipolar disorder, and normal levels in milder disorders like adjustment disorder – are biologically plausible. If all groups had shown elevated NfL or GFAP, regardless of diagnosis or severity, it would raise concerns about the specificity or utility of these markers. Instead, our results suggest that blood-based biomarkers could potentially identify differences between psychiatric presentations, reflecting plausible underlying biological processes, and may even help identify pro-neuronal injury and pro-inflammatory subtypes within our current heterogeneous diagnostic categories. We have previously described elevated NfL levels in bipolar depression ( Eratne, M Kang, et al., 2024 ; Kang, Eratne, et al., 2025 ). Along with this study’s findings of elevated levels in mania as well, suggest neuronal injury at different phases of the illness. The finding of normal biomarker levels in depression in this study is similar to our previous findings of normal NfL levels in unipolar depression ( Eratne, M Kang, et al., 2024 ). We have now also described NfL levels in all stages of psychosis ultra-high risk and first-episode ( Kang et al., 2024 ), treatment-resistant ( Eratne et al., 2022 ), and now acute psychosis. In another study, we found lower levels of NfL in younger people with TRS ( Wannan et al., 2024 ). In contrast, in similarly aged people with acute psychosis in this study, we found elevated levels. This study’s findings of elevated levels in acute psychosis contrasts to our negative findings in other phases/stages of the illness, and might suggest dynamic changes and processes, with elevated neuronal injury only during acute phases. This could be consistent with findings of cortical thinning in psychosis occurs in the first few years following onset ( Cropley et al., 2017 ; Sun et al., 2009 ), with evidence from neuropathology of highest brain iron elevations during early stages of schizophrenia patients, consistent with higher oxidative stress load ( Lotan et al., 2023 ). Future studies should in larger groups try and identify clusters that are driving these changes in the possibility that these different clusters have different underlying biological mechanisms. It is important to note that the elevations seen in this study were subtle, between 5-15% elevations compared to controls. These differences are markedly lower than the around 250% elevations seen in neurodegenerative disorders ( Eratne, MJY Kang, Lewis, Dang, Malpas, Keem, et al., 2024 ). While this suggests lower degrees and rates of neuronal injury compared to neurodegenerative disorders, the cumulative effects of these still increased rates of neuronal injury, over a longer period of time and/or with repeated episodes, could contribute to the recognised increased risk with psychiatric disorders, of dementia later on in life ( Baudouin et al., 2025 ; Livingston et al., 2024 ). Therefore, biomarkers such as NfL could play a role as an objective biomarker identify individuals at high risk of developing dementia, to lead to earlier interventions to reduce risk and delay or prevent dementia, and as a marker of treatment response and prognosis. There are several important limitations to this study. This was a cross-sectional study, limiting causal inference and precluding any conclusions about longitudinal change or biomarker dynamics over time. The waiver of consent ethics meant that while we could include patients who traditionally are extremely hard to recruit (e.g., acute manic and psychotic presentations), we had very limited data available to investigate for other important covariates and associations, such as disease duration, substance and medication use. While the manic and psychosis groups were comparable to or larger than other studies, sample sizes in each group were still relatively small, and it is possible that we were underpowered to detect true differences, reflected by several analyses trending towards significance. Unfortunately, we were unable to harmonise our data to be able to directly compare acute mania and psychosis, to other stages of bipolar and schizophrenia disorders from our previous studies. We used a separate control group and robustly harmonised data, due to not having a local control group with weight data. Our findings should be therefore considered preliminary in the context of these limitations, and should prompt larger studies with important clinical (e.g., substance use, number of episodes, medication use), neuroimaging (e.g., atrophy, white matter disease) covariates. Longitudinal follow up and serial biomarkers will help answer the question of whether prognosis, treatment-response, and clinical response can be tracked and guided by NfL and GFAP. To our knowledge, this is the first study to report elevated plasma NfL in a group of people with acute mania and psychosis, and to highlight differential NfL and GFAP changes across psychiatric disorders using carefully adjusted models. These findings challenge the idea that neurodegeneration-associated biomarkers are elevated in all psychiatric disorders, and instead suggest more nuanced, as well as stage specific roles. If replicated, these results could inform future biomarker-based tools to differentiate between psychiatric diagnoses, stratify severity, track treatment response, and identify individuals at risk of poor prognosis or neurodegenerative progression. Future work should explore longitudinal trajectories, incorporate neuroimaging or cognitive correlates, and include larger, phenotypically richer cohorts. Understanding whether these biomarker elevations persist, resolve, or predict outcomes will be critical to determining their utility in clinical psychiatry. Data Availability All data produced in the present study are available upon reasonable request to the authors DECLARATION OF INTERESTS AND FINANCIAL DISCLOSURES Conflicts of interest HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZpath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Enigma, LabCorp, Merck Sharp & Dohme, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Quanterix, Red Abbey Labs, reMYND, Roche, Samumed, ScandiBio Therapeutics AB, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures sponsored by Alzecure, BioArctic, Biogen, Cellectricon, Fujirebio, LabCorp, Lilly, Novo Nordisk, Oy Medix Biochemica AB, Roche, and WebMD, is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, and is a shareholder of CERimmune Therapeutics (outside submitted work). In the last 3 years, CP has received honoraria for talks at educational meetings and has served on an advisory boards for Lundbeck, Australia Pty Ltd., and Servier Australia. All other authors have nothing to disclose. Acknowledgements and funding sources The authors would like to thank all the participants, patients and their families, for their participation. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. Matthew Kang is supported by the Research Training Program Scholarship (stipend) from the Department of Psychiatry, University of Melbourne with contributions from the Australian Commonwealth Government and the Ramsay Health Research Foundation Translation Challenge. HZ is a Wallenberg Scholar and a Distinguished Professor at the Swedish Research Council supported by grants from the Swedish Research Council (#2023-00356, #2022-01018 and #2019-02397), the European Union’s Horizon Europe research and innovation programme under grant agreement No 101053962, Swedish State Support for Clinical Research (#ALFGBG-71320), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), the AD Strategic Fund and the Alzheimer’s Association (#ADSF-21-831376-C, #ADSF-21-831381-C, #ADSF-21-831377-C, and #ADSF-24-1284328-C), the European Partnership on Metrology, co-financed from the European Union’s Horizon Europe Research and Innovation Programme and by the Participating States (NEuroBioStand, #22HLT07), the Bluefield Project, Cure Alzheimer’s Fund, the Olav Thon Foundation, the Erling-Persson Family Foundation, Familjen Rönströms Stiftelse, Familjen Beiglers Stiftelse, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2022-0270), the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), the European Union Joint Programme – Neurodegenerative Disease Research (JPND2021-00694), the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre, the UK Dementia Research Institute at UCL (UKDRI-1003), and an anonymous donor. CP was supported by a National Health and Medical Research Council (NHMRC) L3 Investigator Grant (1196508) and NHMRC Program Grant (ID: 1150083). CRC Psychosis study was funded by a Department of Industry Co-operative Research Centre (CRC) grant (ID: 20090064; investigators included IE, CP). Appendix: collaborators/contributors On behalf of others in The MiND Study Group: Supplementary material PPD vs controls with imputed weight – adjusted log means derived from GLMs Download figure Open in new tab PPD vs controls with imputed weight (reference = Controls) – GLM results NFL Download figure Open in new tab GFAP Download figure Open in new tab Download figure Open in new tab PPDs compared to each other with imputed weights (reference = Depression) – GLM results NfL Download figure Open in new tab Download figure Open in new tab GFAP Download figure Open in new tab Download figure Open in new tab References 1. ↵ Abé C , Ching CRK , Liberg B , et al. 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The Journal of Neuropsychiatry and Clinical Neurosciences: appineuropsych 20240228 . View the discussion thread. Back to top Previous Next Posted November 20, 2025. Download PDF Data/Code Email Thank you for your interest in spreading the word about medRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. You are going to email the following Elevated plasma neurofilament light chain protein in alcohol use, anorexia nervosa, mania, psychosis and other acute psychiatric disorder presentations Message Subject (Your Name) has forwarded a page to you from medRxiv Message Body (Your Name) thought you would like to see this page from the medRxiv website. Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. Share Elevated plasma neurofilament light chain protein in alcohol use, anorexia nervosa, mania, psychosis and other acute psychiatric disorder presentations Dhamidhu Eratne , Matthew JY Kang , Charles B Malpas , Samantha M Loi , Alexander F Santillo , Henrik Zetterberg , Naveen Thomas , Ian Everall , Chad Bousman , Christos Pantelis , Kruti Patel , Jeffrey Smith , Michael Christie , Cherie Chiang , Dennis Velakoulis , The MiND Study Group medRxiv 2025.11.19.25340633; doi: https://doi.org/10.1101/2025.11.19.25340633 Share This Article: Copy Citation Tools Elevated plasma neurofilament light chain protein in alcohol use, anorexia nervosa, mania, psychosis and other acute psychiatric disorder presentations Dhamidhu Eratne , Matthew JY Kang , Charles B Malpas , Samantha M Loi , Alexander F Santillo , Henrik Zetterberg , Naveen Thomas , Ian Everall , Chad Bousman , Christos Pantelis , Kruti Patel , Jeffrey Smith , Michael Christie , Cherie Chiang , Dennis Velakoulis , The MiND Study Group medRxiv 2025.11.19.25340633; doi: https://doi.org/10.1101/2025.11.19.25340633 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Area Psychiatry and Clinical Psychology Subject Areas All Articles Addiction Medicine (572) Allergy and Immunology (864) Anesthesia (302) Cardiovascular Medicine (4448) Dentistry and Oral Medicine (444) Dermatology (383) Emergency Medicine (609) Endocrinology (including Diabetes Mellitus and Metabolic Disease) (1515) Epidemiology (15240) Forensic Medicine (30) Gastroenterology (1130) Genetic and Genomic Medicine (6614) Geriatric Medicine (669) Health Economics (1000) Health Informatics (4550) Health Policy (1372) Health Systems and Quality Improvement (1613) Hematology (543) HIV/AIDS (1268) Infectious Diseases (except HIV/AIDS) (15928) Intensive Care and Critical Care Medicine (1106) Medical Education (624) Medical Ethics (147) Nephrology (668) Neurology (6621) Nursing (346) Nutrition (999) Obstetrics and Gynecology (1147) Occupational and Environmental Health (957) Oncology (3343) Ophthalmology (977) Orthopedics (369) Otolaryngology (421) Pain Medicine (436) Palliative Medicine (130) Pathology (665) Pediatrics (1695) Pharmacology and Therapeutics (693) Primary Care Research (714) Psychiatry and Clinical Psychology (5459) Public and Global Health (9248) Radiology and Imaging (2205) Rehabilitation Medicine and Physical Therapy (1371) Respiratory Medicine (1197) Rheumatology (597) Sexual and Reproductive Health (715) Sports Medicine (530) Surgery (714) Toxicology (99) Transplantation (289) Urology (265) (function(){function c(){var b=a.contentDocument||a.contentWindow.document;if(b){var d=b.createElement('script');d.innerHTML="window.__CF$cv$params={r:'a02898d0f8b2df88',t:'MTc3OTkyMjQxOQ=='};var a=document.createElement('script');a.src='/cdn-cgi/challenge-platform/scripts/jsd/main.js';document.getElementsByTagName('head')[0].appendChild(a);";b.getElementsByTagName('head')[0].appendChild(d)}}if(document.body){var a=document.createElement('iframe');a.height=1;a.width=1;a.style.position='absolute';a.style.top=0;a.style.left=0;a.style.border='none';a.style.visibility='hidden';document.body.appendChild(a);if('loading'!==document.readyState)c();else if(window.addEventListener)document.addEventListener('DOMContentLoaded',c);else{var e=document.onreadystatechange||function(){};document.onreadystatechange=function(b){e(b);'loading'!==document.readyState&&(document.onreadystatechange=e,c())}}}})();