Introducing neurofilament light chain measure in psychiatry: current evidence, opportunities, and pitfalls.

The recent introduction of new-generation immunoassay methods allows the reliable quantification of structural brain markers in peripheral matrices. Neurofilament light chain (NfL), a neuron-specific cytoskeletal component released in extracellular matrices after neuroaxonal impairment, is considered a promising blood marker of active brain pathology. Given its sensitivity to a wide range of neuropathological alterations, NfL has been suggested for the use in clinical practice as a highly sensitive, but unspecific tool to quantify active brain pathology. While large efforts have been put in characterizing its clinical profile in many neurological conditions, NfL has received far less attention as a potential biomarker in major psychiatric disorders. Therefore, we briefly introduce NfL as a marker of neuroaxonal injury, systematically review recent findings on cerebrospinal fluid and blood NfL levels in patients with primary psychiatric conditions and highlight the opportunities and pitfalls. Current evidence suggests an elevation of blood NfL levels in patients with major depression, bipolar disorder, psychotic disorders, anorexia nervosa, and substance use disorders compared to physiological states. However, blood NfL levels strongly vary across diagnostic entities, clinical stage, and patient subgroups, and are influenced by several demographic, clinical, and analytical factors, which require accurate characterization. Potential clinical applications of NfL measure in psychiatry are seen in diagnostic and prognostic algorithms, to exclude neurodegenerative disease, in the assessment of brain toxicity for different pharmacological compounds, and in the longitudinal monitoring of treatment response. The high inter-individual variability of NfL levels and the lack of neurobiological understanding of its release are some of the main current limitations. Overall, this primer aims to introduce researchers and clinicians to NfL measure in the psychiatric field and to provide a conceptual framework for future research directions.

Oral sodium oxybate does not alter plasma kisspeptin levels in healthy male volunteers.

Gamma-hydroxybutyrate (GHB, clinically administrated as sodium oxybate) is a GABA-B/GHB receptor agonist inducing prosexual effects and progesterone secretion in humans. As the neuropeptide kisspeptin has well-established roles in regulating sexual behavior and as it was also associated with GABA-B receptor and progesterone function, we investigated the effect of two GHB doses (20 and 35 mg/kg p.o.) on plasma kisspeptin levels in 30 healthy male volunteers, using a double-blind, randomized, placebo-controlled cross-over design. We found no significant alterations of kisspeptin levels after GHB administration compared to placebo. In conclusion, plasma kisspeptin levels are not related to the prosexual effects of GHB.

Urinary concentrations of GHB and its novel amino acid and carnitine conjugates following controlled GHB administration to humans.

Gamma-hydroxybutyrate (GHB) remains a challenging clinical/forensic toxicology drug. Its rapid elimination to endogenous levels mainly causes this. Especially in drug-facilitated sexual assaults, sample collection often occurs later than the detection window for GHB. We aimed to investigate new GHB conjugates with amino acids (AA), fatty acids, and its organic acid metabolites for their suitability as ingestion/application markers in urine following controlled GHB administration to humans. We used LC-MS/MS for validated quantification of human urine samples collected within two randomized, double-blinded, placebo-controlled crossover studies (GHB 50 mg/kg, 79 participants) at approximately 4.5, 8, 11, and 28 h after intake. We found significant differences (placebo vs. GHB) for all but two analytes at 4.5 h. Eleven hours post GHB administration, GHB, GHB-AAs, 3,4-dihydroxybutyric acid, and glycolic acid still showed significantly higher concentrations; at 28 h only GHB-glycine. Three different discrimination strategies were evaluated: (a) GHB-glycine cut-off concentration (1 µg/mL), (b) metabolite ratios of GHB-glycine/GHB (2.5), and (c) elevation threshold between two urine samples (> 5). Sensitivities were 0.1, 0.3, or 0.5, respectively. Only GHB-glycine showed prolonged detection over GHB, mainly when compared to a second time- and subject-matched urine sample (strategy c).

A novel bedtime pulsatile-release caffeine formula ameliorates sleep inertia symptoms immediately upon awakening.

Sleep inertia is a disabling state of grogginess and impaired vigilance immediately upon awakening. The adenosine receptor antagonist, caffeine, is widely used to reduce sleep inertia symptoms, yet the initial, most severe impairments are hardly alleviated by post-awakening caffeine intake. To ameliorate this disabling state more potently, we developed an innovative, delayed, pulsatile-release caffeine formulation targeting an efficacious dose briefly before planned awakening. We comprehensively tested this formulation in two separate studies. First, we established the in vivo caffeine release profile in 10 young men. Subsequently, we investigated in placebo-controlled, double-blind, cross-over fashion the formulation's ability to improve sleep inertia in 22 sleep-restricted volunteers. Following oral administration of 160 mg caffeine at 22:30, we kept volunteers awake until 03:00, to increase sleep inertia symptoms upon scheduled awakening at 07:00. Immediately upon awakening, we quantified subjective state, psychomotor vigilance, cognitive performance, and followed the evolution of the cortisol awakening response. We also recorded standard polysomnography during nocturnal sleep and a 1-h nap opportunity at 08:00. Compared to placebo, the engineered caffeine formula accelerated the reaction time on the psychomotor vigilance task, increased positive and reduced negative affect scores, improved sleep inertia ratings, prolonged the cortisol awakening response, and delayed nap sleep latency one hour after scheduled awakening. Based on these findings, we conclude that this novel, pulsatile-release caffeine formulation facilitates the sleep-to-wake transition in sleep-restricted healthy adults. We propose that individuals suffering from disabling sleep inertia may benefit from this innovative approach.Trials registration: NCT04975360.