Identification of cerebrospinal fluid and serum metabolomic biomarkers in first episode psychosis patients

Abstract

Psychotic disorders are currently diagnosed by examining the patient’s mental state and medical history. Identifying reliable diagnostic, monitoring, predictive, or prognostic biomarkers would be useful in clinical settings and help to understand the pathophysiology of schizophrenia. Here, we performed an untargeted metabolomics analysis using ultra-high pressure liquid chromatography coupled with time-of-flight mass spectroscopy on cerebrospinal fluid (CSF) and serum samples of 25 patients at their first-episode psychosis (FEP) manifestation (baseline) and after 18 months (follow-up). CSF and serum samples of 21 healthy control (HC) subjects were also analyzed. By comparing FEP and HC groups at baseline, we found eight CSF and 32 serum psychosis-associated metabolites with non-redundant identifications. Most remarkable was the finding of increased CSF serotonin (5-HT) levels. Most metabolites identified at baseline did not differ between groups at 18-month follow-up with significant improvement of positive symptoms and cognitive functions. Comparing FEP patients at baseline and 18-month follow-up, we identified 20 CSF metabolites and 90 serum metabolites that changed at follow-up. We further utilized Ingenuity Pathway Analysis (IPA) and identified candidate signaling pathways involved in psychosis pathogenesis and progression. In an extended cohort, we validated that CSF 5-HT levels were higher in FEP patients than in HC at baseline by reversed-phase high-pressure liquid chromatography. To conclude, these findings provide insights into the pathophysiology of psychosis and identify potential psychosis-associated biomarkers.

The Importance of Cerebrospinal Fluid Investigation in First-episode Psychosis

“…Five of the 29 reviewed studies employed comprehensive analyses rendering immunological, metabolomic, or proteomic biomarker profiles. While targeted analyses could provide valuable isolated data, evolving methodologies will allow for more broad, untargeted analyses which will provide comprehensive profiles, such as those reported by Shang et al [28]. These will allow a simultaneous standardized analysis of a large number of target biomarkers which will facilitate the process of obtaining reliable data.…”

“…To answer the second question, multiple studies [26][27][28] indicate that the biomarker profile changes during the different stages of psychosis. It is unclear whether neuronal alterations in chronic stages develop with illness progression or appear as a long-term medication effect [30].…”

“…Moreover, it is the biomarker class most consistently and significantly modified. Three studies [28,46,47] analyzed the global metabolic profile of CSF samples from pFEP patients and healthy controls. All three studies found a highly significant differential distribution of metabolites in samples from patients.…”

“…Moreover, Holmes et al [46] showed that antipsychotic treatment resulted in a normalization of the CSF metabolic signature in 50% of FES patients. Adding to proof pointing to altered serotonergic and dopaminergic transmission [28,48], Orhan et al [49] found significantly lower γ-aminobutyric acid (GABA) levels in patients. In addition, GABA levels were associated with the scores of Positive and Negative Syndrome Scale -total score and general psychopathology subscales (PANSS-T & -GP), Clinical Global Impression (CGI), and Global Assessment of Functioning.…”

Ependymocytes control cerebrospinal fluid flow to the peripheral organs through periaxonal pathway

“…To test for serotonergic input we injected 5-HT at 8.8 ng/ml diluted in ACSF into CIM of rat, or 0.88 ng/ml into CIM of mice that corresponds to a final concentration of 5-HT in CSF ~ 100 pmol/ml, which is within the physiological range of 1-100 pmol/ml 22,23 . The T2-weighted MRI images were acquired from the brain and cervical spinal cord segments (Fig.…”