Overview of neurofilament light chain in mental disorders

Abstract

Neurofilament light chain (NfL), released following neuroaxonal damage, serves as a biomarker in neurological diseases and shows potential in mental disorders. This narrative review aims to clarify the current research status of NfL in five mental disorders, namely depression, bipolar disorder, schizophrenia, substance use disorder, and anxiety, as well as in electroconvulsive therapy. We conducted a literature review using articles from PubMed, EMBASE, Google Scholar, and Web of Science databases. In depression, most population-based studies supported positive associations between NfL and depressive symptoms, whereas clinical findings were mixed. For bipolar disorder, most studies reported elevated NfL levels compared to healthy controls. In schizophrenia, however, more studies found no significant elevation compared with healthy controls. For substance use disorder, studies reported dynamic changes in NfL across withdrawal stages, with most evidence derived from alcohol dependence. The only study on anxiety disorder lacked patient-control comparisons. Studies on electroconvulsive therapy consistently reported no significant changes in NfL after treatment. Overall, research on NfL in mental disorders remains at a preliminary stage and requires further validation, as well as mechanistic and longitudinal studies.

Key Words: Neurofilament light chain; Mental disorders; Biomarker; Mood disorders; Schizophrenia; Substance use disorder; Electroconvulsive therapy

Core Tip: This minireview provides an overview of current findings on neurofilament light chain (NfL) in five mental disorders and electroconvulsive therapy. Heterogeneity exists across mental disorders, with mixed findings in clinical studies on depression, more consistently elevated NfL levels observed in bipolar disorder, predominantly no significant differences noted in schizophrenia, and dynamic changes observed during substance withdrawal. In contrast, studies on electroconvulsive therapy consistently show no significant changes in NfL levels. Overall, research on NfL in mental disorders remains at a preliminary stage and warrants further validation, as well as mechanistic and longitudinal studies.

INTRODUCTION

Traditionally, mental disorders have been considered functional disorders, in contrast to neurological diseases, largely because of technical limitations in detecting underlying structural abnormalities[1,2]. Psychiatry and neurology are viewed as separate disciplines with distinct clinical and research domains[2]. Most neurological diseases are associated with identifiable pathological changes, which may be reflected in clinical manifestations like motor dysfunction (e.g., Parkinson’s disease), structural abnormalities on neuroimaging like magnetic resonance imaging (e.g., multiple sclerosis), the presence of disease-specific antibodies in cerebrospinal fluid (CSF) or blood (e.g., autoimmune encephalitis), or characteristic histopathological alterations (e.g., Alzheimer’s disease)[3-6]. In contrast, the clinical diagnosis of mental disorders still relies on descriptive diagnostic systems[1,7]. However, accumulating evidence in recent decades suggests that mental disorders are associated with underlying neurobiological and structural brain alterations, which have been reported across a range of psychiatric disorders, such as major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ)[1,7]. Scientists suggest that mental disorders and neurological diseases share a common framework within the nervous system[2]. Interdisciplinary integration and bidirectional exchange of knowledge between psychiatry and neurology need to be promoted beyond arbitrary boundaries. In this context, biomarkers successfully applied in neurological disorders may provide valuable insights into psychiatric conditions. Neurofilament light chain (NfL), a well-established biomarker in neurology, has attracted increasing interest in psychiatric research as a potential indicator of neuroaxonal injury in mental disorders[8].

In neurology, NfL has widely been acknowledged as a validated biomarker of neuroaxonal injury reflecting neurodegeneration[9]. Aided by highly sensitive analytical platforms enabling the detection of NfL in blood, the application of NfL is expanding from research settings to potential use in neurological clinical practice[9]. Clinical trials in multiple sclerosis, Alzheimer’s disease, amyotrophic lateral sclerosis, and Huntington’s disease have incorporated NfL as an endpoint[10-13]. Besides pathological conditions, the microstructural alterations indexed by NfL have also been investigated in healthy individuals and those with subclinical conditions[14,15]. Consequently, serum NfL levels were found to be correlated with multi-component behavior efficiency, which was concluded as a major determinant[14]. In this research, NfL represented the non-pathological variations in the integrity of the neuronal cytoskeleton[14]. A longitudinal population-based study showed that baseline serum NfL levels independently predicted future subclinical brain volume loss and were correlated with subtle changes in cognitive performance during follow-up[15]. Given the sensitive and dynamic characteristics of NfL, increasing attention has been directed toward differentiating neurological diseases from mental disorders[16,17]. In a systematic review, NfL showed potential utility in clinical diagnostic evaluations in distinguishing behavioral variant frontotemporal dementia from primary psychiatric disorders[16]. Studies also showed that NfL helps identify the underlying causes of psychiatric symptoms, allowing differentiation of neurodegenerative diseases from primary psychiatric disorders[18]. Recently, an increasing number of studies has focused on the role of NfL in mental disorders[8,19]. Although investigations are still at an early stage, emerging evidence has begun to accumulate.

We performed a narrative review (minireview) to summarize the structure and function of NfL and the current evidence of its role in mental disorders, including depression, BD, SZ, substance use disorder, and anxiety, as well as in the context of electroconvulsive therapy (ECT). We searched PubMed, EMBASE, Google Scholar, and Web of Science to identify relevant literature from database inception to June 2026. The main search terms included “neurofilament light chain”, “NfL”, “structure”, “function”, “mental disorders”, “psychiatric disorders”, and the disease-specific terms listed above. We selected published articles based on their relevance to the topic and their contribution to elucidating the role of NfL in mental disorders. Compared with previous reviews and systematic assessments, this minireview has several strengths, including updated coverage of recent studies, the inclusion of substance use disorder, a summary of changes in NfL levels during ECT, and a discussion of the clinical implications and future research directions.

STRUCTURE AND FUNCTION OF NFL

Intermediate filaments (IFs) are a component of the cytoskeleton and comprise a large superfamily of proteins expressed in human tissues[20]. IFs are classified into six major classes, class I to class VI[21]. Among them, neurofilaments are class IV IFs specific to neurons[21]. Neurofilaments form bundles that constitute neurofibrils, which are important structural components of neurons[21]. Neurofilaments have four subunits: (1) NfL, 68-70 kDa; (2) Neurofilament middle, 145-160 kDa; (3) Neurofilament heavy, 200-220 kDa; and (4) α-internexin, 58-66 kDa, or peripherin, 57-59 kDa[21]. Neurofilaments are instrumental in maintaining axonal organization[22]. The relationships among IF, neurofilaments, NfL, and neurofibrils are shown in Figure 1.

Figure 1  The relationships between intermediate filament, neurofilaments, neurofilament light chain, and neurofibrils.

NfL is the smallest, most abundant, and most soluble unit of neurofilaments[8]. NfL comprises three major structural domains: A head domain, a rod domain, and a tail domain[23]. NfL is highly expressed in large-caliber myelinated axons and forms the backbone of neurofilaments, providing essential structural stability for neurons[24]. Furthermore, NfL participates in the slow axonal transport system[25]. In vitro experiments have shown that healthy neurons actively secrete low baseline levels of NfL, which is a part of normal neuronal homeostasis[26]. When neuroaxonal injury occurs (e.g., neurodegeneration and traumatic brain injury), NfL, as a component of cytoskeletal proteins, is released into the interstitial fluid[9]. Subsequently, NfL diffuses into CSF, blood, and other body fluid compartments[9]. Accumulating evidence has shown that a portion of circulating blood NfL is derived from the glymphatic system, a complex system encompassing the perivascular space, extracellular space, and lymphatic-like structures within the brain[9,27]. NfL can be measured in CSF and blood (i.e., serum or plasma). There are three primary highly sensitive detection platforms that support accurate quantification of blood-derived NfL: (1) Single-molecule array (Simoa); (2) The microfluidic Ella platform; and (3) The Meso Scale Discovery platform[9]. In healthy individuals, neurofilament proteins in CSF are approximately 40 times more concentrated than in the bloodstream[8].

NFL AND DEPRESSION

Neuroimaging studies have identified gray matter and white matter microstructural changes in MDD[28,29]. These have been detected in the whole brain and at regional levels, with a severe disorganization associated with prolonged illness[28]. These changes could be related to impaired cerebral blood flow and impaired self-regulation, blood-brain barrier dysfunction, elevated inflammatory factors, and both genetic and environmental factors[30]. A series of studies investigated the relationship between NfL and depression.

Population-based articles

In this minireview, we identified nine population-based articles that examined the association between NfL concentrations and depressive symptoms in adults or older adults (Table 1). To investigate this association in adult populations, four articles used the data from the 2013-2014 cycle of the National Health and Nutrition Examination Survey (NHANES)[31-34]. NHANES is a population-based survey using a representative sample to monitor individual health in the United States; it has been widely used to investigate associations between biomarkers and health outcomes[35]. All four articles reported a positive association between NfL levels and clinically significant depressive symptoms, which was defined as a Patient Health Questionnaire-9 (PHQ-9) score ≥ 10[31-34]. One article, using Mendelian randomization, identified no causal relationship between serum NfL and depression[32]. Interestingly, one article identified a significant interaction between serum NfL levels and age group (< 60 years and ≥ 60 years; P = 0.045), with age-stratified analyses confirming this association only among participants aged ≥ 60 years[33]. However, another article found no significant interaction between NfL and age group (age < 40 years, 40 years ≤ age < 60 years, and age ≥ 60 years; P > 0.05)[34]. This discrepancy may be partly attributable to differences in age-group definitions and different covariate adjustments. However, age-stratified analysis in both studies showed that the positive correlation between NfL and depression was found only among participants aged ≥ 60 years, highlighting the importance of focusing on older populations[33,34]. Notably, the four articles using data from the 2013-2014 NHANES cycle may have included substantially overlapping participant populations and therefore should not necessarily be interpreted as four fully independent lines of evidence.

Table 1 Population-based articles examining the association between neurofilament light chain concentrations and depressive symptoms.

Ref.	Data source	Sample size	Age (years)
Song et al[31], 2024	NHANES	1301	20-75; 20-34: n = 348; 35-60: n = 643; 61-75: n = 310
Liu et al[32], 2024	NHANES	1765	Mean: 45.194; SD: 15.295; 20-59: n = 1297; ≥ 60: n = 468
Guo et al[33], 2024	NHANES	1881	20-75; < 60: n = 1412; ≥ 60: n = 469
Zhang et al[34], 2025	NHANES	1909	Mean: 47.135; SD: 15.488; < 40: n = 656; 40-59: n = 733; ≥ 60: n = 520
Gudmundsson et al[36], 2010	PPSW	78	Mean: 73.9; SD: 3.2
Schuurmans et al[37], 2024	Rotterdam Study cohort	3895	Mean: 71.78; SD: 7.37
Bellelli et al[38], 2025	MAPT	Plasma NfL levels were assessed either 1 (n = 465) or 2 years (n = 40) after the start of the trial	Median: 76; IQR: 7
Xu et al[39], 2024	NHANES	495	≥ 60; median: 66.0; IQR: 7.0
Xia et al[40], 2026	The Shanghai Aging Study	1658	Without depressive symptoms: Mean: 71.4; SD: 7.5. With depressive symptoms: Mean: 72.1; SD: 7.1

MAPT: The Multidomain Alzheimer Preventive Trial; NHANES: The National Health and Nutrition Examination Survey; PPSW: Prospective Population Study of Women in Göteborg; IQR: Interquartile range; SD: Standard deviation; NfL: Neurofilament light chain.

Five articles[36-40] explored the association between NfL concentrations and depressive symptoms in older populations. An early 2010 article including a population-based sample of 78 elderly women without dementia reported that NfL levels in CSF were elevated in women with depression relative to those without depression[36]. Data from Rotterdam Study including 3895 participants found that the increase in log2-transformed NfL levels was associated with more depressive symptoms at baseline[37]. In addition, with longitudinal follow-up, higher baseline levels of NfL predicted an increased risk of any incident depressive event[37]. However, one article including participants with normal cognition and mild cognitive impairment from the Multidomain Alzheimer Preventive Trial reported that plasma NfL levels were positively correlated with depressive symptoms only in the mild cognitive impairment group and not in the normal cognition group or the entire sample[38]. Two articles, using data from participants aged ≥ 60 years in NHANES and the Shanghai Aging Study, respectively, investigated the mediating role of NfL in the association between depressive symptoms and cognitive function[39,40]. Both articles found that NfL partially mediated the pathway from more depressive symptoms to cognitive decline, with mediation effects of 19.65% in NHANES[39] and 19.35% in Shanghai Aging Study[40].

Studies in clinical settings

Several studies have investigated NfL levels in patients with depression in clinical settings. Overall, the number of studies reporting elevated peripheral NfL levels in patients relative to healthy controls (HCs) was comparable to the number of studies identifying no significant between-group differences. Some studies were designed as case-control studies with only patients with depression and matched HCs, whereas others included depression as a condition in their investigation. Only one study[41] did not clearly present a direct comparison between patients with MDD and HCs. In this study, NfL levels were 29.3 ± 35.3 pg/mL in the MDD group and 15.2 ± 7.1 pg/mL in HCs[41].

Increasing attention has been paid to the association between NfL levels and cognitive impairment in depression. Several studies have revealed significant negative correlations between peripheral NfL and cognitive performance in patients with MDD[42-44]. These studies have assessed cognitive domains of executive function, processing speed, and working memory[42-44]. One study found that patients with depression and subsequent dementia had higher NfL levels than both depressive patients with cognitive recovery and cognitively normal HCs; although the sample size were small[45]. In a cross-sectional study using cluster analysis, one of the identified clusters showed cognitive deficits similar to those observed in patients with MDD and individuals with mild or major neurocognitive disorders of the Alzheimer’s type[46]. Patients in this cluster showed poor cognitive function with cognitive performance negatively correlated with plasma NfL levels[46]. Besides, studies have reported elevated NfL levels in adolescents with depression, with serum NfL concentrations showing positive correlations with the severity of depressive symptoms, anxiety, and suicidal ideation[47]. Another study reported that patients with treatment-resistant depression who received ketamine treatment showed elevated baseline plasma NfL levels compared to HCs[48], with higher baseline NfL levels independently predicting diminished sustained antidepressant effects to low-dose ketamine[48]. However, studies have also shown that NfL levels did not significantly differ between HCs and patients with depression, even among untreated patients[49-55]. Among them, one study found higher NfL levels to be associated with increased risks of lifetime suicide planning and suicide attempts[55].

NFL AND BD

Although most studies reported elevated NfL levels in patients with BD relative to HC, two studies found no differences in this regard[56,57]. A 2019 study confirmed significantly higher NfL levels in behavioral variant frontotemporal dementia than in psychiatric groups, while revealing no differences in serum NfL levels among BD, depression, SZ, and HC[56]. A longitudinal study that measured CSF and blood NfL in BD and HCs across euthymic and affective phases found no significant between-group differences at baseline or 1-year follow-up[57].

Using neuroimaging analyses, two studies have linked NfL to brain structural abnormalities in BD[58,59]. Elevated peripheral NfL was positively correlated with not only impaired white matter integrity, particularly axonal integrity[58], but also with abnormalities of the cerebral cortex, wherein it was found that intracortical myelin content across six brain regions, alongside age, explained 26% of the variance in NfL concentration[59].

Some studies explored the associations among disease course, episode frequency, and NfL levels in patients with BD[60,61]. A study published in 2024, including 51 BD patients and 35 HCs, after adjusting for confounding factors, revealed a significant positive correlation between previous manic episodes and serum NfL levels[60]. No significant association was noted between depressive episodes and serum NfL levels[60]. Patients having had BD for over 3 years had higher serum NfL levels than HCs and those having had it for a relatively shorter period[60]. Another study reported that plasma NfL levels were slightly elevated in patients with BD relative to HCs, with longer duration correlating with higher NfL[61].

Studies have also explored the relationship between age and NfL levels in patients with BD. In the only study that investigated pediatric patients with BD, adolescents aged 13-17 years experiencing manic episodes showed higher serum NfL levels than HCs[62]. In adult patients with BD, two studies reported a positive correlation between age and NfL levels[58,63]. The authors argued that the normal age-related rise in NfL levels is amplified in BD, possibly because of an accelerated ageing process linked to immune, neuroendocrine, and circadian dysregulation[58]. However, another study including BD patients aged ≤ 53 years indicated an attenuated increase of NfL with increasing age[64].

Increased NfL levels were also found to be associated with cognitive performance decline in patients with BD. In a model including CSF biomarkers of neurodegeneration and cognition, higher concentrations of CSF NfL were shown to be the strongest predictor of worse memory performance[65]. Both elevated CSF NfL and serum NfL levels are reportedly correlated with poor working memory[44,65], and elevated CSF NfL is linked with verbal performance decline[65]. Moreover, one study reported on the effect of the interaction between vitamin D and NfL on cognitive performance and found that the direction of this interaction differed by age[63]. In younger patients with BD (aged 20-45 years), co-occurrence of high NfL levels and low vitamin D levels was associated with poor composite cognition, verbal fluency, and processing speed, whereas in older patients (aged 46-65 years), this combination was associated with better verbal fluency[63].

NFL AND SZ

The results regarding peripheral NfL levels in patients with SZ were inconsistent, with more studies reporting no significant elevation compared to HCs. Among studies with negative findings, some specifically compared peripheral NfL levels between patients with SZ and HCs[43,66,67], while others investigated NfL across a range of neurological and psychiatric disorders, including SZ[56,68]. Studies found no significant differences even in patients with treatment-resistant SZ and their first-degree relatives[66,67]. However, heterogeneity was present. Although group-level comparisons between SZ and HCs showed negative findings, one study reported a higher proportion of NfL levels above age-specific cut-off values in SZ than in HCs[43]. Another study found that the relationship between brain regional thickness reduction and plasma NfL was observed only in patients with SZ, not in the normal population[67].

Several studies have reported elevated NfL levels in patients with SZ, with some indicating that the increase is limited to specific subgroups[62,64,69,70]. A 2020 study found that elevated peripheral NfL levels in patients with SZ were restricted to clozapine-treated individuals with multiple psychotic episodes and treatment resistance, whereas untreated first-episode patients and partial responders to other antipsychotics showed no significant changes in NfL levels[69]. A 2023 study reported significantly higher serum NfL levels in early-onset SZ patients aged 13-17 years, independent of clinical symptom scores[62]. However, a 2024 study revealed that young patients aged ≤ 36 years had lower NfL levels than HCs, whereas those aged ≥ 50 years showed substantially elevated NfL levels[64]. A 2023 longitudinal study involving 98 acutely ill patients with SZ and 132 HCs found that approximately 25% of patients with SZ had increased NfL levels, without describing their clinical characteristics[70]. Using NfL and associated biological factors could effectively predict 5-year disease relapse[70].

NFL AND SUBSTANCE USE DISORDER

Studies investigating NfL in substance use disorder are predominantly focused on alcohol dependence and alcohol use disorder (AUD). Two studies compared NfL levels between patients with alcohol dependence and HCs[71,72]. In one study, which recruited 147 patients with alcohol dependence and 114 age- and sex-matched HCs, blood NfL levels were found to be higher in patients with alcohol dependence than in HCs at baseline, and this difference persisted even after withdrawal treatment for 1 week and 2 weeks[71]. The other study also showed elevated serum NfL in patients with alcohol dependence compared with controls having no history of drinking[72]. Meanwhile, Montreal Cognitive Assessment, Pittsburgh Sleep Quality Index, Generalized Anxiety Disorder Scale-7, and PHQ-9 were used to assess cognitive function and psychological state, and magnetic resonance imaging analysis was used to measure the severity of white matter lesions in patients with alcohol dependence[72]. Montreal Cognitive Assessment scores and white matter volume were negatively correlated with NfL levels, whereas Pittsburgh Sleep Quality Index scores, PHQ-9 scores, and white matter lesion severity were positively correlated with NfL levels[72].

Some studies investigated the dynamic changes in NfL levels in patients with alcohol dependence during and after withdrawal[71,73,74]. One such study revealed significantly elevated plasma NfL levels in patients with severe AUD on the first day of hospitalization for alcohol cessation relative to the long-term abstinent group[73]. One study measured plasma NfL at three time points during inpatient alcohol withdrawal: Day 1 after admission (T1), day 3 or 4 (T2) of alcohol withdrawal, and day 13, 14, or 15 (T3) of alcohol withdrawal[74]. Statistical analyses showed that plasma NfL levels significantly increased from T1 to T2 but not from T1 to T3[74]. Another study reported a significant reduction of NfL levels after 1 and 2 weeks of alcohol withdrawal treatment[71]. In addition, researchers found that individuals carrying the rs671 GA genotype of aldehyde dehydrogenase 2 had significantly higher peripheral NfL levels than those with the GG genotype at baseline and after 1 and 2 weeks of alcohol withdrawal[71].

Studies also reported that NfL levels may act as a predictive factor of the severity of alcohol withdrawal and treatment efficacy. One study showed that higher admission plasma NfL levels in patients with AUD predicted the subsequent development of delirium tremens, with a cut-off level of 27.2 pg/mL[75]. One study explored the relationship of serum NfL and the repetitive transcranial magnetic stimulation (rTMS) intervention in patients with alcohol dependence[76]. The magnitude of NfL reduction was significantly greater in patients receiving rTMS than in those undergoing sham stimulation, and the efficacy of rTMS was positively correlated with the decline in NfL levels[76].

Patients with ketamine dependence reportedly have elevated serum NfL relative to HCs, and those comorbid with MDD or persistent psychosis have higher serum NfL levels than those with ketamine dependence only[49,68,77]. Participants with chronic cocaine use and a current abstinence duration of < 6 months were found to have higher plasma NfL levels than HCs at baseline[78]. Longitudinal changes in plasma NfL levels showed a directionally concordant pattern with hair cocaine concentrations, wherein increases in hair cocaine levels were associated with corresponding increases in NfL, and decreases showed the opposite trend[78]. A case report described that a 24-year-old man with subacute myelopathy following several months of recreational N₂O use showed markedly elevated serum NfL levels (51.3 pg/mL; reference range: 0-10.7 pg/mL)[79]. The author argued that this finding was described as “indicating significant neuronal damage”[79].

One study reported no difference in serum NfL levels between participants with chronic 3,4-methylenedioxymethamphetamine (MDMA) use and MDMA-naïve HCs[80]. In this study, NfL levels were quantified after at least 3 days of abstinence from illicit substances; the average time since last MDMA use was 22.56 ± 18.54 days[80]. To our knowledge, this was the only study identified in our literature search that reported no significant difference in peripheral NfL levels between substance users and HCs.

NFL AND ANXIETY

Studies on NfL in anxiety disorders are extremely scarce. Only one study aimed at investigating the role of NfL in differentiating frontotemporal dementia from primary psychiatric disorders reported serum NfL levels in patients with anxiety disorder[81]. In this study, the mean NfL level in the anxiety group (n = 142) was 12.6 ± 0.707 pg/mL (mean log: 1.0 ± 0.020 pg/mL, median: 9.8 pg/mL), whereas the mean NfL level in HCs (n = 69) was 13.9 ± 0.314 pg/mL (mean log: 1.0 ± 0.029 pg/mL, median: 10.1 pg/mL). However, the authors did not draw statistical comparisons[81].

NFL AND ECT

We identified four studies investigating changes in NfL levels after ECT[82-85]. The earliest study, which was published in 2000, measured CSF NfL levels before and after six ECT sessions in the sample set (n = 9) using an enzyme-linked immunosorbent assay[82]. The results showed that CSF NfL levels did not significantly change after ECT treatment[82]. The three subsequent studies, conducted between 2020 and 2025, used ultrasensitive Simoa technology to investigate NfL dynamics across the ECT treatment period[83-85]. These investigations covered the acute phase following a single ECT session, the cumulative exposure phase over multiple ECT sessions, and the post-treatment phase, 7 days after ECT course completion[83-85]. These three studies consistently showed that serum NfL levels remained stable throughout the ECT treatment period[83-85]. No correlations were observed between NfL and symptom resolution or cognitive decline[83-85]. Studies showed no significant changes in serum NfL levels, even in patients with marked transient cognitive adverse effects[84]. These findings provide no biomarker evidence that ECT induces measurable neuroaxonal injury, as reflected by NfL, within the investigated time periods.

IMPLICATIONS AND FUTURE RESEARCH

The limitations of using NfL should not be neglected. NfL is not a disease-specific biomarker and is elevated in several brain-related diseases. Additionally, blood NfL is influenced not only by the disease but also by age, body mass index, and kidney function[9]. Although still in the early stages of investigation, NfL shows promise as a potential biomarker in mental disorders. Important potential applications of NfL include differentiating psychiatric symptoms between neurological diseases and primary psychiatric disorders, assessing disease severity, reflecting treatment response, and estimating relapse risk. Findings summarized in this minireview indicate that NfL levels remain heterogeneous and inconsistent within the same diagnostic category. Given the sensitive and dynamic nature of NfL, such heterogeneity may be attributable to sample size, different disease stages, symptom profiles, age, comorbidities, and treatment status, and may help identify biologically distinct subgroups within a given mental health disorder. Future research on NfL and mental disorders requires further validation in large samples and across different subgroups of mental disorders. Longitudinal studies are also needed to track the dynamic changes in NfL. Meanwhile, standardization of assay methods and establishment of reference ranges are necessary to improve comparability across studies. Further in-depth investigations should focus on the neuropathological mechanisms underlying mental disorders and clarify the role of NfL in these processes. Finally, novel research paradigms, such as multimodal approaches and artificial intelligence, can be integrated into future investigations.

CONCLUSION

This minireview provides a brief introduction to the structure and function of NfL and comprehensively summarizes current findings on its involvement in five mental disorders and ECT. Current evidence remains heterogeneous across studies. Findings on NfL and ECT are consistent, showing no significant changes in CSF or serum NfL levels following ECT treatment. This variability is observed both within and across diagnostic categories, limiting its direct clinical utility. These findings highlight the need for further in-depth studies to better understand the role of NfL in mental disorders.