A literature on symptomatology, treatment and prevention of schizophrenia in the developmental age is scarce. Children and adolescents morbidity rates are estimated at 1 per 40,000 for children below the 13 years of life and 1 per 10,000 for adolescents between 13 and 18 years (1). Early-onset schizophrenia is believed to have strong biological correlates such as higher genetic and neurodevelopmental burden (2). Particular attention in research on adolescents’ brain is paid for dynamic changes in the structure and functioning of the central nervous system (3). Biological data on brain maturation underline the effect of neural network shaping, synaptic pruning and development of the prefrontal cortex (4, 5). These phenomena find reflection in behavioural concerns in adolescents, like higher levels of impulsivity, poorer decision-making and suicidality (5, 6). Adolescence links also with social development, identity shaping, group identification and setting the goals for future life in adulthood. Both biological and societal phenomena determine adolescent population as highly prone for the risk of psychiatric morbidity.
Recent endeavour focuses on early recognition of psychotic symptoms among adolescents as well as identifying at risk mental state groups (ARMS) (7), who may benefit from early intervention and targeted prophylaxis (8). Among ARMS patients, general division is made on three different subpopulations: attenuated psychotic symptoms (APS), genetic risk and deterioration syndrome (GRD) and brief limited intermitted psychotic symptoms (BLIPS) (for definitions, see supplementary material: box 1.) (7). Identification of at risk clinical groups enables development of evidence-based early intervention strategies, like omega-3 fatty acids supplementation (9), psychotherapy (10) and pharmacological management (11). Reliable multi-centred data on effectivity in wider populations are still lacking, but the clear evidence support usefulness of early-intervention to minimalize the duration of untreated psychosis (DUP). As it was shown that higher DUP links with poorer prognosis and functioning level both in adult and adolescents with diagnosis of schizophrenia (12, 13).
Proper diagnosis of psychotic symptoms in developmental age is challenging. Current consensus in schizophrenia diagnostics is based on subjective, symptomatic description. Regarding the youngest population, highly transient psychotic symptomatology hampers establishing of proper diagnosis. One of possible routes to precise the early assessment of schizophrenic patients is finding of a reliable biomarker for confirmation of the disease and monitoring its course (14, 15). The term biomarker is understood as a measurable parameter that can be used as a clinical indicator (16), giving an confirmation of suspected diagnosis, drug-response or serve as prognostic parameter (14). Biomarker studies in children population may also enrich pathology description at the moment of disease onset and may serve as covariates in behavioural assessment, like impulsivity and suicidal risk. Potential candidates for biomarkers derive from genetic, immunological or neurodevelopmental theory of schizophrenia (17). One of the most thoroughly studied protein in the field of schizophrenia is the brain-derived neurotrophic factor (BDNF). BDNF belongs to neurotrophins family and serves as the modulator of synaptic plasticity, neuronal growth and resilience (18). Expression of BDNF is widely present throughout the central nervous system, particularly in the hippocampus. BDNF is encoded on 11th chromosome (11p14.1). This genetic region is associated with neurodevelopmental disorders such as autism-spectrum or attention deficits (19). The process of BDNF biosynthesis occurs in neuronal and glial cells and consists of three stages: pre-proBDNF, proBDNF and mature BDNF (20). BDNF mature protein is then stored in high-density vesicles, localized mainly in the presynaptic part of the neuron (20).
ProBDNF and mature protein reveal opposite effects regarding synaptic plasticity and neuronal survival. Interaction of mature protein with the tropomyosin-related kinase B (TrkB) receptors promotes neuronal branching and facilitates processes of long-term potentiation (21). proBDNF binds to p75 low affinity nerve growth factor receptor (p75NTR) and leads to dampening of synaptic activity and promotion of apoptosis (18). Activation of the receptors leads to recruitment of different cellular pathways. TrkB ligand binding leads to phosphorylation of the receptor and internalization of the receptor-ligand complex. Further steps include activation of three pathways: phospholipase C-γ, ras mitogen activated protein kinase and phosphatidylinositol 3 kinase (21). Whereas pathways activated by p75NTR include mainly pro-apoptotic molecules like caspases and c-Jun. p75NTR signalling, however, is not completely understood (18). Possibly, the proper balance between promotion and supression of synaptic plasticity is crucial for maintaining the brain homeostasis. Increased activity of p75NTR has been indicated as potential neurodegenerative mechanism in animal models of Alzheimer and Huntington Disease (22, 23).
Studies on BDNF pathway are particularly important for understanding schizophrenia (24) due to synaptic plasticity deficits (25). Involvement of BDNF in schizophrenia pathology was revealed in different stages of the disease regarding genetic and proteomic analyses (26).
Most of studies were based on peripheral concentration of BDNF among patients. Potential clinical utility of BDNF is seen in correlation between peripheral and cerebrospinal fluid concentration (27). It is interpreted as reflecting changed pattern of BDNF activity in CNS (18).
Another suggested biomarker in psychiatry is S100B protein, associated with the blood-brain barrier (BBB) damage. S100B is calcium-binding protein perceived as the marker of neuronal distress and indicator of traumatic neural injuries, neurodegenerative disorders and psychoses (28). S100B is detectable in peripheral blood, hence the interest about its biomarker value. Case-control studies showed higher concentration of the protein in schizophrenia patients than in healthy control groups (29, 30) with no relation to disease severity and cognitive functionning (30). Concentrations of S100B in schizophrenia population may also be affected by seasonal and day/night patterns of activity (31, 32). Contemporary data on peripheral blood levels of BDNF and S100B suggest these proteins as dynamically changing damage-associated molecular patterns (28) rather than stable parameter.
Due to Weickert’s suggest (16), well-established biomarker should be reliable and valid in diagnosis prediction. Moreover need to offer the replicability and access to commercial use in medicine. BDNF and related proteins as well as S100B seem to be widely accessible and easy applicable due to its peripheral expression, relevance to CNS state and low expense. These biomarkers rather appear as the state-dependent (reflecting current psychotic state) not trait-dependent (reflecting schizophrenia as a diagnosis). These proteins might not be exceptionally relevant to schizophrenia-spectrum, but potentially enrich wider symptomatology and behavioural assessment.
1.2 Aims of the study
We performed a case-control comparison between early-onset schizophrenia adolescents and sex and age matched healthy subjects regarding plasma concentrations of BDNF, proBDNF, p75NTR and S100B. Putative biological markers were also complied with symptomatic assessment and executive functions measurement. The main hypothesis was (i) existence of significant differences in peripheral blood plasma concentrations of BDNF, proBDNF, p75NTR and S100B between SCH and HC, secondary (ii) its relationship with the exhibited symptoms of schizophrenia-spectrum and suicidal parameters and tertiary (iii), link with behavioural executive tests results the impulsivity and decision-making style in adolescent population.