Transcription factor AP-2 beta genotype and psychosocial adversity in relation to adolescent depressive symptomatology. Inventing biomarkers, which would be characteristic for childrens and adolescents depression, might clarify the diagnosis and improve treatment outcomes. Full-length articles of screening studies, studies in non-adolescents or with a mixed sample with the age beyond the range of 1019 years for adolescents or 2025 years for young adults, studies with only the mean age, studies without clearly identified gene expression or polymorphism, or others was excluded from the analysis. https://doi.org/10.1016/j.jad.2017.10.024, Chen J, Li X, McGue M (2012) Interacting effect of BDNF Val66Met polymorphism and stressful life events on adolescent depression. WebSome diseases are caused by genetic mutation (s) or by a permanent change in one or more specific genes. BDNF was the second most frequently studied gene in adolescents. Notably, the associations were robust to adjustments for childhood BMI. Within the promoter of the serotonin transporter gene (SLC6A4), there is a serotonin-transporter-linked polymorphic region (5-HTTLPR) with a long (l) or short (s) allele resulting in respectively higher and lower SLC6A4 gene activity [8]. https://doi.org/10.1007/s10578-021-01246-y, DOI: https://doi.org/10.1007/s10578-021-01246-y. and transmitted securely. https://doi.org/10.1016/j.neubiorev.2019.04.010, Fuchikami M, Morinobu S, Segawa M, Okamoto Y, Yamawaki S, Ozaki N et al (2011) DNA methylation profiles of the brain-derived neurotrophic factor (BDNF) gene as a potent diagnostic biomarker in major depression. Specifically, IL-6 seems promising as a biomarker of depression state and recovery since its elevated level has been shown to decrease with successful antidepressant treatment [62]. These findings have contributed to the idea of using anti-inflammatory agents in the treatment of depression, which might result in new treatment strategies [60]. This paper summarized the available studies on molecular biomarkers in child and adolescent depression, mainly focusing on the neurotransmitter, inflammatory, neurotrophic, neuroendocrine, and metabolomic factors. The end date for the search is August 29, 2015. concluded that posttreatment non-suppression of cortisol on the DST could also be utilized to predict poor outcomes in depression [27]. Studies performed on the adult population have demonstrated that BDNF circulating level is significantly lower in blood samples of depressed patients and that effective antidepressant treatment can reverse this effect [82, 83]. Although there is strong evidence proving that the expression of FKBP5 modulates the response to antidepressants in adults [46, 47], no such correlation was found in the study performed on the group of adolescent patients [21]. Numerous findings suggest that circulating miRNA levels could be used as promising biomarkers of depression state or antidepressant treatment response in adult patients [124, 125]. Eur neuropsychopharmacol 25(10):15321543. The association between the 5-HTTLPR polymorphism and a treatment outcome has been more widely investigated among adult patients. Moreover, it is postulated that by generating oxidative stress, the inflammatory cytokines impair the synthesis of nearly all monoamines known to be involved in the pathogenesis of depression [48]. In line with these notions, Spindola et al. Hilt L. M., Sander L. C., Nolen-Hoeksema S., Simen A. Science 274(5292):15271531. Depression persistence and serotonin transporter genotype in adolescents under usual care conditions. Numerous studies have reported on the roles of genetic factors in the development of depression in adolescents and young adults. Many studies have shown that minor alleles of various FKBP5 genes single nucleotide polymorphisms (SNPs) increase the risk for MDD in adults, particularly rs1360780, rs9470080, rs3800373 [43, 44]. A meta-analysis has demonstrated that the 5-HTTLPR long-allele carriers had higher probability of response than patients with short-allele homozygotes of 5-HTTLPR with heterogeneity effect (Serretti et al., 2007). Abstract Unipolar depressive disorder in adolescence is common worldwide but often unrecognised. Studies in adolescents demonstrated that depressive symptoms are not associated with gene plasticity index of the MAOA gene (Stavrakakis et al., 2013), whereas gene environment interaction of the 5-HTTLPR was further moderated by MAOA activity level (Nobile et al., 2009). Although mounting evidence implicates the potential of BDNF to be used as a biomarker in depression, the studies on BDNF peripheral level in the population of children and adolescents with depression are scarce and inconclusive. No associations between single nucleotide polymorphisms in corticoid receptor genes and heart rate and cortisol responses to a standardized social stress test in adolescents: the TRAILS study. More studies on depression involving the pediatric population seem vital to comprehend the natural course of the disease and identify features that may underlie commonly observed differences in treatment outcomes between adults and children. A B. This relation was also confirmed in the group of pediatric patients with MDD, aged 918, treated with fluoxetine [59]. https://doi.org/10.1080/15592294.2019.1700628, Kaufman J, Wymbs NF, Montalvo-Ortiz JL, Orr C, Albaugh MD, Althoff R et al (2018) Methylation in OTX2 and related genes, maltreatment, and depression in children. The BDNF Val66Met polymorphism predicts rumination and depression differently in young adolescent girls and their mothers. Only one study analyzed the association between 5-HTTLPR polymorphism and the severity of depressive symptoms. Impact of the interaction between the 5HTTLPR polymorphism and maltreatment on adolescent depression. https://doi.org/10.1037/a0018875, Katrenkov B, Vavkov M, Waczulkov I, Oravec S, Garaiova I, Nagyov Z et al (2020) Lipid profile, lipoprotein subfractions, and fluidity of membranes in children and adolescents with depressive disorder: effect of omega-3 fatty acids in a double-blind randomized controlled study. The .gov means its official. Seven genes (COMT, serotonin 2A, MAOA, estrogen receptor and , AR, glucocorticoid receptor, and adipose polyunsaturated fatty acid gene) showed no association with depression in adolescents. https://doi.org/10.1016/j.biopsych.2010.04.034, Porcelli S, Fabbri C, Serretti A (2012) Meta-analysis of serotonin transporter gene promoter polymorphism (5-HTTLPR) association with antidepressant efficacy. https://doi.org/10.1176/ajp.150.11.1618, Zobel AW, Nickel T, Sonntag A, Uhr M, Holsboer F, Ising M (2001) Cortisol response in the combined dexamethasone/CRH test as predictor of relapse in patients with remitted depression: a prospective study. For instance, a study performed on 84 adolescent patients with depression revealed significantly decreased levels of BDNF compared to the healthy control (n=64) and a significant negative correlation between BDNF level and clinical symptoms severity [85]. The authors also supported the theory of altered HGF/c-MET signaling in depression with the finding that both MET and HGF mRNA expressions were decreased in brain samples of adult depressed individuals. Monoamine oxidase A is a monoamine oxidase encoded by the MAOA gene that preferentially deaminates norepinephrine, epinephrine, serotonin, and dopamine. https://doi.org/10.1016/0140-6736(92)92105-o, Cheng Y, Li Z, He S, Tian Y, He F, Li W (2018) Elevated heat shock proteins in bipolar disorder patients with hypothalamic pituitary adrenal axis dysfunction. Some This trend was also observed among the adolescents in the study performed by Henje Blom et al., where the authors found that the unmedicated group of depressed female adolescents had higher IL-6 levels than the group which received antidepressants [62]. There was a wide variation in methods and analysis. For example, Lawford et al study demonstrated that patients with DRD2*A1/A2 genotype had significantly higher depression scores compared to those with the DRD2*A2/A2 genotype (Lawford et al., 2006). Hosang G. M., Shiles C., Tansey K. E., McGuffin P., Uher R. (2014). Transl Psychiatry 8(1):121. https://doi.org/10.1038/s41398-018-0169-8, Gardini ES, Schaub S, Neuhauser A, Ramseier E, Villiger A, Ehlert U et al (2020) Methylation of the glucocorticoid receptor promoter in children: links with parents as teachers, early life stress, and behavior problems. Research on biomarkers connected with neurotransmitters focuses mainly on the altered expression of proteins involved in the synthesis or degradation of monoamines. Furthermore, Tsuchimine et al. The initial hypothesis that the 5-HTTLPR s allele increases the risk of depression when combined with the history of life stress was presented by Caspi et al. The meta-analysis performed by D'Acunto et al. https://doi.org/10.1016/j.euroneuro.2013.01.010, Nederhof E, Bouma EM, Oldehinkel AJ, Ormel J (2010) Interaction between childhood adversity, brain-derived neurotrophic factor val/met and serotonin transporter promoter polymorphism on depression: the TRAILS study. Little K., Olsson C. A., Whittle S., Youssef G. J., Byrne M. L., Simmons J. G., et al.. (2014). Adenosine impacts brain functions by influencing neurotransmission and neuromodulation mainly through presynaptic A1 and postsynaptic A2A receptors. They found that patients carrying the combination of TPH2703G and the 5-HTTLPR l alleles were the most likely to respond to the treatment. https://doi.org/10.1038/mp.2016.82, American Psychiatric Association (1987) The dexamethasone suppression test: an overview of its current status in Psychiatry. Most studies did not provide detailed information about current medical treatment in the full study sample. https://doi.org/10.1016/s0006-3223(03)00181-1, Molendijk ML, Bus BA, Spinhoven P, Penninx BW, Kenis G, Prickaerts J et al (2011) Serum levels of brain-derived neurotrophic factor in major depressive disorder: state-trait issues, clinical features and pharmacological treatment. Peters et al. J Affect Disord 206:5567. Stavrakakis N., Oldehinkel A. J., Nederhof E., Oude Voshaar R. C., Verhulst F. C., Ormel J., et al.. (2013). Mood is affected by dozens of genes, and as our genetic endowments differ, so do our depressions. Various methodological approaches (analysis of candidate genes, genome-wide association analysis, genome-wide sequencing) have been used, and a large number of the associations between genes and different clinical DD variants and DD subphenotypes have been published. This study demonstrated that genetic polymorphism or expression of 13 genes was associated, but seven tested genes were not associated with the risk or severity of depression in early adolescence, while the polymorphism of three genes was associated with the risk of depression in late adolesence. 83.3% of studies (10/12) found positive association between BDNF Val66Met genotype and adolescent depressive symptoms. The results of these studies indicate that adenosine metabolism is altered in MDD and that antidepressants influence adenosine turnover. Frisch A., Postilnick D., Rockah R., Michaelovsky E., Postilnick S., Birman E., et al.. (1999). Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. As a library, NLM provides access to scientific literature. Eur Arch Psychiatry Clin Neurosci 268(2):119127. Considering the essential part that 5-HTT plays in pharmacotherapy, it is not surprising that 5-HTTLPR polymorphism has also been widely investigated as a potential predictor of antidepressant treatment response. This study updated the genetic findings in adolescent depression with an age range of 1019 years defined by WHO as adolescence and 2025 years as young adult. Serretti A., Kato M., De Ronchi D., Kinoshita T. (2007). Epigenetic studies in the population of children could be beneficial in clarifying the pathogenesis of depression since the potential impact of comorbidities on epigenetic modifications is greatly reduced compared to the adult population. BDNF Val 66 Met and 5-HTTLPR genotype moderate the impact of early psychosocial adversity on plasma brain-derived neurotrophic factor and depressive symptoms: a prospective study. The depressive symptoms were not associated with gene plasticity index of the BDNF gene in adolescents (Stavrakakis et al., 2013), whereas BDNF mRNA level correlated with symptom improvement in adult patients with depression (Cattaneo et al., 2010). Depress Anxiety 28(12):10741080. Depression is also the leading cause of disability in young people worldwide. There is a significant paucity of research on this subject in the population of children and adolescents, which is striking, given the fact that approximately half of MDD diagnoses among adults derive from adolescent-onset disorder. Curr Drug Metab 9(7):622627. Recently, two meta-analyses have addressed the association between increased peripheral cytokine levels and depressive symptoms among children and adolescents. J Psychiatr Res 78:6571. Some studies investigated the threeway interaction model of BDNF Val66Met polymorphism, the serotonin transporter linked promoter region (5-HTTLPR) polymorphism, and childhood adversity in predicting the development of depression. According to Xia et al. reported that adversity and peripheral OTX2 methylation profile were associated with individual differences in depression, suggesting a potential role for OTX2 in conferring risk for MDD in children [117]. https://doi.org/10.1007/s10519-009-9285-9, Benjet C, Thompson RJ, Gotlib IH (2010) 5-HTTLPR moderates the effect of relational peer victimization on depressive symptoms in adolescent girls. BDNF genotype moderates the relation between physical activity and depressive symptoms. While inosine levels were decreased in child depression, this alteration was not characteristic of adult depression. (2010) study revealed that chronic family stress at age 15 predicted higher depression scores at age 20 among females with one or two S alleles of 5-HTT gene (Table (Table44). https://doi.org/10.1111/camh.12387, Chung KH, Chiou HY, Chen YH (2017) Associations between serum homocysteine levels and anxiety and depression among children and adolescents in Taiwan. Another biomarker that could be considered a promising indicator of depression state and recovery is serum BDNF level. https://doi.org/10.1016/j.jad.2014.04.002, Wang Q, Shelton RC, Dwivedi Y (2018) Interaction between early-life stress and FKBP5 gene variants in major depressive disorder and post-traumatic stress disorder: a systematic review and meta-analysis. Although some research confirmed the combined influence of these factors on early-life depression, the results were differential, and the relation was not confirmed in a representative, population-based study of adolescents [74,75,76]. https://doi.org/10.1016/j.jpsychires.2019.03.030, DAcunto G, Nageye F, Zhang J, Masi G, Cortese S (2019) Inflammatory cytokines in children and adolescents with depressive disorders: a systematic review and meta-analysis. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. (2010). However, there have been many discrepancies between the studies. LX: data extraction, data analysis, and manuscript writing. PubMedGoogle Scholar. suggest that perturbations in the adenosine metabolic pathway might be characteristic of childrens and adolescents depression [114]. Goodyer I. M., Bacon A., Ban M., Croudace T., Herbert J. Eley T. C., Sugden K., Corsico A., Gregory A. M., Sham P., McGuffin P., et al.. (2004). investigated the blood levels of the same cytokines (TNF-, IL-1, and IL-6) in the group of treatment nave depressed adolescents and reported significantly increased IL-6 in the studied group when compared with healthy controls [55]. The abstracts of the 1334 articles were screened one by one and articles not written in English, review articles not for depression in adolescents, comments, and articles for animal or in vitro studies were excluded from this study. [98]. Risk of bias was assessed by evaluating choice of study design, selection of study population, allocation of control individuals, and quality of assay used. Regarding the youth population, the results of the recent study performed by Zhou et al. A few reviews or meta-analyses have also summarized the gene environment interaction in adolescents with depression (Frani et al., 2010; Rice, 2010; Dunn et al., 2011). A recent meta-analysis of the association between the 5-HTTLPR, stress, and the development of depression contained 81 studies with a mean age from 977 years. Reports on gene expression or polymorphisms measured in peripheral blood or postmortem studies in adolescents were eligible for review. Ciuculete et al. https://doi.org/10.1016/j.biopsych.2006.07.039, Schle C, Baghai TC, Eser D, Hfner S, Born C, Herrmann S et al (2009) The combined dexamethasone/CRH Test (DEX/CRH test) and prediction of acute treatment response in major depression. 5-HTTLPR moderates the effect of relational peer victimization on depressive symptoms in adolescent girls. Science 356(6343):11851188. Outcomes of studies on the relationship between BDNF and dopaminergic pathway and depression in adolescents. J Neurosci 25(19):48564867. A flowchart of the inclusions and exclusions of studies in the current study. Additionally, Rotberg et al. However, more studies are needed to confirm the clinical usefulness of the 5-HTTLPR polymorphism in predicting the treatment outcome in the youth population. government site. The results obtained in a recent cross-sectional study performed on the group of 89 children and adolescents with depressive disorder are in concordance with the findings mentioned above [107]. It is reflected in persistent hypercortisolemia and non-suppression in the dexamethasone suppression test (DST). The hope is that as researchers pinpoint the genes involved in mood J Psychopharmacol (Oxford, England) 19(1):5965. https://doi.org/10.1038/s41386-018-0157-y, Vernay B, Koch M, Vaccarino F, Briscoe J, Simeone A, Kageyama R et al (2005) Otx2 regulates subtype specification and neurogenesis in the midbrain. Nevertheless, studies on the adolescent population point to the significant associations between 5-HTTLPR polymorphism, environmental stress, and risk of depression. J Child Adolesc Psychopharmacol 23(4):290294. Metabolomics focuses on substrates and products of metabolism such as lipids, fatty acids, or amino acids. In contrast, Frisch et al. The authors investigated the relationship between depressive symptoms and lipid profile in a group of depressed children and adolescents and found no significant differences in TCH, LDL, and HDL levels between the patients and a control group. Chronic and acute stress, gender and serotonin transporter gene-environment interactions predicting depression symptoms in youth. Regarding the youth population Spindola et al. 1 However, the role of genetic https://doi.org/10.1038/ng1479, Ising M, Maccarrone G, Brckl T, Scheuer S, Hennings J, Holsboer F et al (2019) FKBP5 gene expression predicts antidepressant treatment outcome in depression. Int J Mol Sci 20(3):485. https://doi.org/10.3390/ijms20030485, Neurauter G, Schrcksnadel K, Scholl-Brgi S, Sperner-Unterweger B, Schubert C, Ledochowski M et al (2008) Chronic immune stimulation correlates with reduced phenylalanine turnover. The hypofunction of the mesolimbic dopaminergic pathway has been linked to anhedonia, one of the major symptoms of depression (Leggio et al., 2013). Biomarkers in Child and Adolescent Depression - PMC Regarding the population of children, the genome-wide methylation study performed by Weder et al. The primary search strategy was carried out using both the keywords and test words: depression and adolescent and gene; depression and adolescent and polymorphism; depression and adolescent and genetics; depression and adolescent and genetic variants; and depression and adolescent and genotype. This notion may underlie commonly observed treatment resistance among depressed adolescents. Based on 17 studies, the authors summarized that compared to control peers, depressed subjects tended to have a dysregulated response to DST with persistent hypercortisolemia. The authors did not confirm any association between TNF- level and depression, although the effect size fell short of statistical significance, which was coherent with a trend observed in the previous meta-analysis [56]. More studies on the youth population are needed to verify whether such metabolic disturbances may underlie the resistance towards antidepressant treatments, at least in some cases.