Brain-Derived Neurotrophic Factor (BDNF) and IL-1beta in Pediatric and Adolescent' Depressive Disorders: a look towards precision psychiatry

Introduction. Depression is one of the main and most debilitating mood disorders, as for personal functioning and social costs (Masi and Brovedani, 2011). It is estimated that depression affects more than 15% of the population lifetime (Kessler et al., 2003), with percentages in pediatric age that reach about 1-2% in prepuberal age and 4-6% in adolescence (Kessler et al., 2001). Although the early-onset depression usually tends to improve over time and resolve in a part of the cases, the functional impact of the disease is more difficult to recover, with consequences that tend to take a chronic trend and finally predispose to a high rate of recurrence of disease, a high risk of psychopathology in the future, as well as increase risk of suicide attempts and completed suicides (Masi and Brovedani, 2011). Studies on neuroanatomy, post-mortem brain observations and in vivo neuroimaging suggest that the impairment of neuroplasticity in specific neuronal networks may be involved in the pathogenesis of mood disorders (Biggio, 2011). In particular, recent studies have emphasized the role of the neurotrophic factor called Brain Derived Neurotrophic Factor (BDNF) whose depletion is associated with a reduction in neurogenesis and in the volume of important brain areas including the hippocampus, the prefrontal cortex and the amygdala (Biggio, 2011). Other researches found reduced BDNF concentrations in the blood of depressed patients, which increased after undergoing treatment with psychopharmacological therapy (Brunoni et al., 2008; Sen et al., 2008; Bocchio-Chiavetto et al., 2010; Molendijk et al. al., 2014). Scientific studies also found that the neuroinflammation process could contribute to the origin of some psychiatric conditions, especially depression (Dantzer et al. 2008; Miller et al. 2009; Kim et al. 2014; Rosenblat et al. 2014). Depressed patients often present an increase levels of proinflammatory cytokines (like IL-1beta) in blood and cerebrospinal fluid (Miller et al, 2009; Kim et al. 2014), so many authors have hypothesized their role as early clinical biomarker of pathology. Objective. The aim of the present study is to measure plasma levels of BDNF and IL-1beta in subjects affected by depression in the developmental age compared to healthy peers. Secondary aims are: a) the evaluation in the depressed subjects of the trend of plasma levels before and after psychopharmacological treatment (at 3, 6 and 12 months); b) the analysis of the relationship between plasma levels of BDNF and IL-1beta and clinical psychopatological features of depression. The last objective is to verify the usefulness of BDNF and IL-1beta dosages as peripheral biomarkers of disease or of unresponsiveness to treatment, finally to improve diagnostic characterization of depressed patients and to target the treatment in pediatric age. Methods. Thirteen subjects aged 11-17,9 years, diagnosed with depressive disorder (according to DSM-IV-TR; APA, 2002), as well as matched healthy subjects (n =12), were evaluated by trained raters and provided blood for BDNF and IL-1beta measurements. The diagnostic evaluation was conducted through free talks and the administration of a panel of structured (YSR-CBCL, CDI, MASC, CGI, C-GAS, SadPerson) and projective tests. The same panel was adminstrated to healthy subjects to explore subthereshold dimensions. Depressed subjects were treated with pharmacological therapy (Selective Serotonin Reuptake Inhibitors, mood stabilizers, SGAs) and psychotherapy. The plasma levels of BDNF and IL-1beta were measured according to definite timing (basal T0, before the start of therapy / psychotherapy, after 6 and 12 months). For depressed patients, an additional measure after 3 months of therapy was performed. Analysis of BDNF and IL-1beta levels were performed using specific ELISA kits (BDNF Emax ImmunoAssay System, Promega, Madison, U.S.A and Antigenix America, Huntington Station, NY, USA) Results. The depressed subjects, compared to the healthy peers, differ in a statistically significant way for a constant familiarity for psychiatric pathology, in particular in the maternal line, a history of events experienced as traumatic, a constant presence of conflicts within the family, scholastic and relational problems, sleep disorders and alcohol/drugs use. Compared to heathy subjects at intake, plasma BDNF concentrations are lower, while IL-1beta are higher in depressed patients, even if they do not reach a statistical significance. Regarding psychodiagnostic assessment, comparing test scores between depressed and non-depressed subjects at T0, there are significant differences in CBCL, YSR, C-GAS, CGI-S, CDI (p <0.05) and SadPerson (p <0.001) scores. No significant differences were found between the gropus in the MASC scores. Statistically significant correlations were found between BDNF levels at T0 of depressed subjects and problems of attention (r=-.695, p=.026) and school skills (r= .878, p= .004). At T6, BDNF inversely correlates to affective disorders (r=-.975, p=.005) reported at YSR T12. In depressed group, considering the presence of suicidal attempts, there are statistical significative differences for anxious-depressed (Z=-2.158, p=.031) and anxiety problems (Z=-2.669, p=.008) at YSR. The same analysis performed considering the personal history of trauma, highlighted statistical significative differences for rule break (Z=-2.384, p=.017) and conduct disorders (Z=-2.037, p=.042). Conclusions. Depressed pediatric patients present lower levels of BDNF and higher levels of IL-1beta compared to healthy peers at the moment of diagnosis, although without a statistical significant difference. At intake BDNF appears to correlate to academic competences, while after 6 months of therapy higher BDNF levels orient to a better prognosis as for depression symptomatology. The evolution from suicidal ideation to SA appear to be linked to the perception of limited social support (reduced resilience) in adolescents with reduced levels of BDNF. Depressed children with a history of trauma present more externalizing symptoms, while the dimension of anxiety appears to be somehow protective from suicidal attempts. The study supports the bio-psycho-social model of DD, highlighting the importance of a balance between neurogenesis, neuroinflammation and cerebral plasticity in the delicate period of developmental age. BDNF seems to be a symptoms or disease biomarker more than a severity index, so the integration of different instruments of evaluations, both clinical and biological (multimodal methods), as well as the integration of different voices (multi-informant approach) seems to represent the “best practice” for pediatric clinical assessment of mental health in line with precision psychiatry. Further studies are needed to explore the role of BDNF and cytokines in the response of pediatric population to SSRIs, to identify biomarkers for predicting early treatment response, to produce new drug targets, to find preventive strategies and individually target therapy.