Letter to the Editor: From discovery to application: Serum 5-hydroxytryptamine for early screening of Parkinson’s complications still faces key challenges

Abstract

Based on 70 patients with Parkinson’s disease, this study by Chen et al, published in the recent issue of the World Journal of Psychiatry, aimed to proposes that serum 5-hydroxytryptamine (5-HT) may simultaneously indicate two key complications: Levodopa-induced dyskinesia and depression. The results showed that serum 5-HT levels were significantly reduced in both groups and remained independent predictors in multivariate analyses, with receiver operating characteristic analyses suggesting a certain degree of discriminative ability. This concept aligns with the clinical need to explain motor and non-motor complications through a shared pathway. However, before it can be incorporated into routine clinical management, external validation, longitudinal studies, standardized measurement, and clearly defined clinical thresholds are still required. Serum 5-HT may serve as one component of risk stratification, but it should not be regarded as a single decisive biomarker.

Key Words: Parkinson‘s disease; 5-hydroxytryptamine; Biomarker; Motor dysfunction; Depression

Core Tip: Reduced serum 5-hydroxytryptamine levels may indicate an increased risk of both dyskinesia and depression in patients with Parkinson’s disease, suggesting its potential role as a unified screening marker for these complications. However, due to limited validation, as well as the absence of robust longitudinal data and standardized assessment protocols, its clinical applicability remains constrained. Therefore, it should be considered only as an adjunctive biomarker rather than a definitive diagnostic or prognostic indicator at the present stage.

TO THE EDITOR

Parkinson’s disease affects approximately 1%-2% of the population and ranks as the second most prevalent neurodegenerative disorder[1]. Parkinson’s disease presents with a broad spectrum of manifestations, including motor features such as bradykinesia, altered muscle tone, postural instability, and resting tremor, as well as non-motor symptoms like impaired olfaction, sleep disorders, autonomic dysfunction of the urinary and gastrointestinal systems, and depression[2,3]. What truly draws patients and their families into long-term attrition are often two categories of complications: On the one hand, levodopa-induced motor fluctuations and dyskinesia; on the other hand, non-motor symptoms such as depression[4]. While one erodes function and the other undermines motivation, together they ultimately depress quality of life. What clinicians most urgently need are tools that can provide risk warning before complications emerge and guide intervention before symptoms worsen - ideally, peripheral indicators that are convenient, low-cost, and repeatable.

The study “Serum 5-hydroxytryptamine levels as biomarkers for motor dysfunction and depression in Parkinson’s disease patients” by Chen et al[5] in the recent issue of the World Journal of Psychiatry turns its attention to serum serotonin [5-hydroxytryptamine (5-HT)] and poses an intriguing question: Can a single peripheral biomarker simultaneously signal the risk of motor complications (dyskinesia) and non-motor complications (depression) in Parkinson’s disease? The results offer a relatively consistent signal. Patients with dyskinesia exhibit lower serum 5-HT; patients with depression also show lower serum 5-HT; when both complications coexist, 5-HT levels are lowest. After adjusting for age at onset, disease duration, medication use, and other variables, 5-HT remains independently associated with these complications, and ROC analyses indicate a certain degree of discriminative ability. In a field long lacking a “simple and unified indicator”, such findings merit serious consideration. In view of this, for serum 5-HT to assume a role in early screening or risk stratification, at least four thresholds must be crossed.

First threshold: External validation and reproducibility

A single-center study with 70 participants - further divided into four subgroups -represents a reasonable starting point for exploratory research, but it is insufficient to support changes in routine practice[5]. Are thresholds stable across regions, populations, medication patterns, and comorbidity profiles? Will the area under the curve hold up in real-world settings? These questions require multicenter studies with larger samples for external validation. Without reproducibility, the notion of a “unified biomarker” remains confined to the page.

Second threshold: Longitudinal prediction rather than cross-sectional association

The study demonstrates associations between current 5-HT levels and current complication status[5]. What clinicians truly need to know is whether 5-HT can provide advance risk signals before complications develop, and whether it can predict their onset and progression during follow-up. If 5-HT primarily reflects the burden of established disease rather than serving as an antecedent signal, its value shifts from an “early warning tool” to a mere “status indicator” - a distinction with major practical implications.

Third threshold: Assay standardization and management of confounders

Serum 5-HT levels are influenced by multiple factors, including diet, stress, sleep, inflammatory status, platelet release, blood collection and processing procedures, and a wide range of medications (some excluded in this study, but far more prevalent in real-world practice)[6]. Without standardized timing of blood sampling, harmonized processing protocols, validated assay methods, and rigorous quality control, thresholds will be difficult to generalize across institutions. In clinical translation, standardization is often more challenging than achieving statistical significance.

Fourth threshold: Translating cut-offs into actionable pathways

Although the study reports cut-off values with corresponding sensitivity and specificity, clinicians are primarily concerned with “what to do next”. If a Parkinson’s disease patient’s serum 5-HT falls below a threshold, should levodopa regimens be adjusted, peak-dose exposure minimized, or dyskinesia risk education and monitoring initiated earlier? For depression risk, should screening be intensified, psychiatric referral prioritized, or antidepressant selection approached with greater caution and interaction monitoring? In other words, a biomarker must be embedded within an executable management pathway - who to test, when to test, how often to retest, what interventions to trigger, and how to evaluate benefits and risks. Without such pathways, an indicator remains merely “data”.

Nevertheless, the significance of this study should not be underestimated. Its value lies at least in two aspects[5]. First, it translates the pathological insight that the serotonergic system influences both dyskinesia and depression into a potentially measurable peripheral signal. Second, it offers testable hypotheses for future stratified management - for example, whether low 5-HT defines a “high-risk complication phenotype,” thereby informing individualized trade-offs between motor control and mental health management. More importantly, this work reminds us that the management of Parkinson’s disease complications should no longer be fragmented between “motor” and “emotional” domains. Viewing dyskinesia and depression within a shared biological pathway framework encourages a shift from piecemeal, symptom-by-symptom treatment toward systemic risk governance. This is precisely the direction modern management of neurodegenerative diseases should take[5].

A more restrained and pragmatic conclusion is therefore warranted: Serum 5-HT holds promise as a candidate tool for risk stratification of Parkinson’s disease complications, particularly as an initial screening indicator in resource-limited settings; however, until the evidence chain is complete, it should be regarded as an adjunctive signal rather than a decisive diagnostic marker. What is truly worth anticipating is the next step - multicenter longitudinal cohorts, standardized assays, and studies linking biomarkers to clinical intervention pathways[5]. Only when “what we measure” enables us to “do better” will a biomarker have truly completed the final mile from paper to patient. In addition, regarding external validation, future confirmatory studies should particularly focus on subgroup analyses of different races, different levodopa equivalent daily doses, and whether other drugs that affect the 5-HT system (such as selective serotonin reuptake inhibitors) are used in combination, in order to explore the universality of thresholds and application values. And in future studies, a unified and standardized operating procedure should be reported and established, including fasting requirements; blood sampling time (with consideration of circadian rhythms); blood processing procedures (centrifugation speed and duration, measures to prevent platelet activation); and the analytical methods used (e.g., high performance liquid chromatography-tandem mass spectrometry vs enzyme-linked immunosorbent assay), along with their limits of detection and precision.

CONCLUSION

Serum 5-HT may serve as a shared peripheral indicator for both levodopa-induced dyskinesia and depression in Parkinson’s disease, offering a potential tool for early risk stratification of motor and non-motor complications. Although reduced serum 5-HT shows independent associations with these complications, its clinical application is limited by the lack of external validation, longitudinal evidence, assay standardization, and clear management pathways. Thus, serum 5-HT should currently be viewed as an adjunctive screening marker rather than a definitive biomarker.