1. Introduction
Bipolar disorder (BD) is a severe mental disorder with a reported prevalence in the general population of 2.4%
[1][2][1,2]. People suffering from BD report a worsening of social functioning in terms of work-related problems, a high college drop-out rate, and interpersonal difficulties
[3][4][5][3,4,5], as well as increased comorbidity with physical disorders and mortality compared to the general population
[6][7][8][9][6,7,8,9]. In 2019, BD resulted in 8.50 million global disability-adjusted life years (DALYs), equivalent to 0.3% of DALY, contributing to 6.8% of DALYs for aggregate mental disorders
[1]. Moreover, BD is associated with a significant economic burden
[10], with an estimated total annual national economic expenditure of more than USD 195 billion in the US alone, with approximately 25% attributed to direct medical costs
[10] and the remaining to loss of productivity.
Bipolar disorder is a multifactorial disease, with a complex interaction between biological and environmental factors, both contributing to the definition of the pathophysiology of BD
[11][12][13][11,12,13]. Nevertheless, studies are still far from identifying biological mechanisms underlying the etiopathogenesis of BD and other mental disorders
[14][15][14,15].
In the past few decades, research has been focused on the correlation between BD and neuro- and systemic inflammation
[16]; in particular, the role of pro-inflammatory cytokines, immuno-modulators, and growth factors in influencing the episodic course of the disorder has been investigated
[17].
Neuroinflammation is characterized by an increased number of circulating proinflammatory cytokines, increased immune cell entry into the central nervous system through the blood–brain barrier, microglial activation, and degeneration of the encephalic tissue
[18]. Different brain insults can cause microglial activation, with the release of interleukin-1β (IL-1β) and activation of astrocytes, starting the pro-inflammatory cascade
[19].
Many studies have shown higher levels of inflammatory markers both in the bloodstream and in cerebro-spinal fluid (CSF) in BD patients
[20]. Consistent findings have been reported through the analysis of brain tissue samples of deceased BD patients
[21] and with neuroimaging studies. In a positron emission tomography (PET) study, Haarman et al. (2014)
[22] found a significantly increased binding potential, an indirect marker of neuroinflammation, in BD patients when compared with healthy controls (HC). Chronic neuroinflammation can lead to several modifications in brain tissue, particularly the reduction in circulating brain-derived neurotrophic factor (BDNF)
[23]. BDNF is a growth factor synthesized mostly in the brain in response to neuronal activity; it is produced as pro-BDNF, a precursor that can be activated in mature BDNF (m-BDNF) by extracellular metalloproteinases or intracellular endoproteases.
BDNF explicates its function mostly by the activation of the TrkB receptor. During intrauterine life, BDNF signaling guides the differentiation from progenitors into mature brain cells
[24], but it keeps its role in activating neurogenesis even in adult life
[25]. BDNF plays a key role in the regulation of neuronal transmission and synaptic plasticity, operating on both the presynaptic side, acting on the neurotransmitters’ release, and the postsynaptic side, modulating receptors’ expression
[26]. BDNF can also be found in the bloodstream, since it is also produced by other tissues and cells, such as cardiomyocytes and platelets
[27]. Many studies have reported that changes in BDNF serum levels may reflect modifications in the brain’s BDNF production and/or clearance
[28].
Recent data suggest a correlation between BDNF signaling deficits and some major brain diseases, including psychiatric disorders such as schizophrenia, major depressive disorder (MDD), and BD
[29][30][31][29,30,31]. A significant decrease in circulating BDNF levels in BD patients compared to healthy controls, especially during acute episodes of the illness, has been found
[32], suggesting its possible mediating role in affective disorders.
Moreover, a large body of literature has investigated the possible influence on BDNF activity of the rs6265 polymorphism, a single-nucleotide polymorphism (SNP) in the BDNF gene. The rs6265 polymorphism is a common functional nonsynonymous SNP, a coding mutation that changes the protein sequence, in which the amino acid valine (Val) is replaced with methionine (Met) in the BDNF protein, resulting in a less efficient BDNF secretion. Due to the important role played by BDNF in the nervous system, this SNP has been extensively studied in the pathogenesis of several psychiatric disorders, including mood disorders
[33][34][33,34].
2. Brain-Derived Neurotrophic Factor as a Bipolar Disorder Biomarker
Overall, there is a reduction in BDNF circulating levels during acute phases of BD, which increase after effective therapy. When directly compared, the levels of BDNF were significantly lower in acute phases of BD compared to euthymic patients. This finding is particularly relevant considering that BDNF induces neuronal growth and survival and synaptic long-term potentiation (LTP) [26][35][26,76], inhibits the apoptosis cascade (by activating the phospholipase C-gamma), induces its own mRNA transcription (by enhancing phosphatidylinositol 3-Phosphate, PI3K), and modulates gene regulation.
The finding that BDNF levels are reduced in BD vs. healthy controls, and that they are reduced during acute phases vs. euthymia, can potentially link the BDNF levels to the pathophysiology of BD. In fact, the relationship between BDNF, BD, and neuroinflammation is well established. Guan et al. (2006) [36][77] induced an inflammatory response by administering lipopolysaccharide (LPS) to mice. Interestingly, the authors found a reduced BDNF mRNA in the hippocampus 4 h after the administration, and decreased BDNF circulating levels 7 h after the LPS administration. Studies carried out on patients treated with interferon alpha (INF-α) showed decreased BDNF circulating levels and increased levels of pro-inflammatory cytokines, such as IL-1 and IL-2, in association with the development of depressive symptoms [37][78]. Further to this, the acute phases of BD seem to be related to neuroinflammation, with microglial activation and immune cell clusters in the brain [38][79]. During chronic inflammation, pro-inflammatory cytokines bind microglia, with the release of neurotoxic molecules and a decrease in BDNF signaling [39][37]. Nevertheless, only a few studies have investigated both BDNF levels and neuroinflammation in samples of BD [40][80]. The relationship between BDNF, neuroinflammation, and mood episodes should be further investigated in order to improve the knowledge of the pathogenesis of BD.
In fact, lower circulating BDNF mRNA levels have been found in patients compared to HC. Furthermore, Cinar RK et al. (2016) [41][45] observed a significant increase in BDNF mRNA levels during the remission period compared with the acute phase. This result can be explained by the fact that mRNA molecules store genetic information that will be decoded and translated into proteins [42][81]; therefore, decreased mRNA levels reported during acute phases of the disorder can be considered an indirect sign of BDNF levels downregulation. These findings highlight that BDNF may be a biomarker of BD and that its proteolytic conversion may be important in the pathophysiology of BD.
One study reported a significant correlation between childhood trauma and BDNF levels [43][39]. This result, although it requires further investigation, is of particular relevance, since childhood trauma has been reported as one of the most significant risk factors for the development of severe mental disorders and is associated with negative outcomes [44][45][82,83], and with a stable dysregulation of other biological pathways, including that of calcium metabolisms—which includes parathormone, vitamin D, and serum levels of calcium—and the hypothalamic–pituitary–adrenal axis [46][84].
Another relevant finding is the higher methylation in BDNF gene promoter found in BD patients
[47][48]. Since methylation is a form of epigenetic silencing
[48][85], its presence can be considered an indirect sign of BDNF downregulation.
Two studies have investigated the Val66Met mutation, also known as the rs6265 SNP. This polymorphism does not seem to alter BDNF biological activity, but it can impair activity-dependent release, resulting in reduced BDNF circulating levels
[49][86]. A correlation between the polymorphism and features that are usually associated with a worse outcome has been found, in line with the hypothesis that the downregulation of BDNF signaling can be associated with a more severe BD course.
BDNF is a promising biomarker, with possible future applications in clinical practice. In particular, in the near future, BDNF levels could be used to support the diagnosis of BD, to improve precision in the detection of early stages of BD, and to differentiate between BD and other affective disorders, such as major depressive disorders. In fact, although BD and MDD are distinct clinical entities, they share clinical features, resulting in high rates of misdiagnosis in some cases
[50][90]. As an example, the frequent occurrence of depressive episodes and the later onset of mania in BD subjects may delay a proper diagnosis for years, resulting in greater severity of symptoms, impaired psychosocial functioning, treatment resistance, and higher suicidality
[51][91]. Such a delay is also associated with a higher number of lifetime relapses and hospitalizations, with increased direct and indirect costs associated with the treatment and management of both MDD and BD
[52][92]. Despite increasing knowledge of the pathophysiology of affective disorders, clear clinical indicators and biomarkers for a reliable differential diagnosis between MDD and BD are still missing, which calls for an investigation of novel indices and biomarkers.
Encyclopedia
