Major depressive disorder (MDD) is a serious disorder that affects approximately 17% of the population at some point in life, resulting in major social and economic consequences . There is still very little known about the neurobiological alterations that underlie the pathophysiology or treatment of MDD. There is increasing evidence suggesting that brain-derived neurotrophic factor (BDNF), neurotrophin-3, and fibroblast growth factor (FGF) systems are altered in different tissue samples, including post-mortem brain tissue, cerebrospinal fluid, and blood from patients with MDD. Neurotrophins are a family of secreted growth factors that regulate survival, growth, differentiation and maintenance of neurons in both the central nervous system and the peripheral nervous system  and their reduced availability can result in increased cellular vulnerability or even cell death. It has been postulated that the enhanced and prolonged secretion of neurotrophic factors in response to antidepressant treatment could promote neuronal survival and protect neurons from the damaging effects of stress. These studies have led to the formulation of the neurotrophic hypothesis of depression, which proposes that reduced neurotrophic factors levels predispose to depression, whereas increases neurotrophic factors produce an antidepressant action.
2. Brain-Derived Neurotrophic Factor (BDNF) in Major Depressive Disorder (MDD)
BDNF has shown antidepressant-like effects in animal models of depression. For instance, in the forced swim test and learned helplessness models of depression, BDNF infusion into the midbrain alleviated depressive behavior . Moreover, a single bilateral infusion of BDNF into the dentate gyrus (DG) of the hippocampus had an antidepressant effect in both paradigms .
Various stressors can suppress
Several classes of antidepressant increase BDNF level in the healthy rodent brain with chronic treatment, and also reverse stress-induced downregulation of BDNF . Thus, regardless of their primary mechanism of action, antidepressants share the ability to rapidly activate signaling through the TrkB receptor and induce a long-lasting increase in BDNF production . However, they fail to produce any behavioral changes in transgenic mice with reduced BDNF levels or TrkB signaling, whereas wild-type mice exhibit a normal behavioral response , demonstrating that BDNF release and TrkB signaling are not only sufficient but also necessary for antidepressant-like behavioral effects.
Electroconvulsive seizures increase mRNA levels of both
Several studies of post-mortem brain samples have implicated BDNF as a factor in the pathophysiology of depressive disorders; in one report, BDNF and TrkB levels were reduced in the hippocampus of patients with depressive disorder . Given that BDNF expression is downregulated in response to stress, structural changes in the hippocampus of depressed individuals may be attributed in part to reductions in BDNF and TrkB levels . In patients with depression, a decrease in prefrontal cortical volume is correlated with decreased BDNF and TrkB levels . These findings indicate that depression affects BDNF expression in limbic regions. As observed in animal models, postmortem tissue samples from human subjects show increased BDNF levels in the hippocampus and cortex after long-term antidepressant use as compared to untreated subjects .
The Val66Met polymorphism is located in the pro-BDNF sequence, which is cleaved posttranscriptionally; while not affecting mature BDNF protein function, it has been shown to alter activity-dependent BDNF secretion in cultured cells , as well as intracellular distribution, packaging, and release of the BDNF protein in vitro . Interestingly, mutant mice carrying the Val66Met polymorphism show reduced BDNF secretion but no differences in the level of total BDNF . Moreover, hippocampal volume is reduced in mice with the BDNF Met/Met or Val/Met allele as compared to wild-type mice. Our research found that the presence of the Val66Met polymorphism was not significantly correlated with serum BDNF levels in depressive patients nor in control subjects. Postmortem analyses and imaging studies have found that depressive patients have significantly smaller hippocampal volumes compared to controls, which is reversed by antidepressant treatment ; smaller volumes were also observed in both patients and controls carrying the Met-BDNF allele as compared to individuals that were homozygous for the Val-BDNF allele. It was therefore concluded that Met-BDNF allele carriers may be susceptible to depression due to smaller hippocampal volumes . Our laboratory has also demonstrated that the Val66Met allele frequency was similar among depressed and non-depressed subjects, consistent with previous studies in Asian populations [25-26]; however, an association between the BDNF Val66Met polymorphism and depression has been reported in a geriatric Chinese population . A significant genetic association between the BDNF Val66Met polymorphism and treatment response in depressed patients was detected in a meta-analysis demonstrating that Val/Met heterozygous patients had a better response rate than Val/Val homozygous patients, especially among Asians . Moreover, Met allele carriers showed a favorable response to antidepressant treatment . However, other studies have not found any link between genetic variation in
Suicide is a major public health problem linked to depression.
BDNF is present in human blood, although it is more highly concentrated in brain tissue. It was previously reported that BDNF could cross the blood-brain barrier, and that serum and brain BDNF levels showed similar changes during aging in rats, suggesting that the former is a reflection of the latter . Serum BDNF level was markedly lower in depressed than in healthy control subjects and was negatively correlated with depression severity, an effect that was more pronounced in females . Similar findings were reported in another study, which also found greater changes in serum BDNF protein level in female but not in male patients treated with antidepressants during a 4-week period . Some studies report that serum BDNF level is negatively correlated with depression severity [37-38]. Other investigators have found that plasma BDNF level is positively correlated with scores on the Hamilton Depression Rating Scale , although our own research did not substantiate these findings . Serum BDNF level is determined by at least eight independent factors: time of blood withdrawal, time of storage, food intake before sampling, urbanicity, age, sex, smoking status, and drinking behavior . However, the conflicting data from various studies suggest that other factors are likely to modulate BDNF level in depression.
3. Glial cell line-Derived Neurotrophic Factor (GDNF) in MDD
Glial pathology in depressive disorder is well-documented by a number of quantitative studies on postmortem fronto-limbic brain regions. The density of astrocyte cell bodies immunoreactive for glial fibrillary acidic protein (GFAP) is consistently reduced in brain tissue specimens from depressed individuals, as is the expression of astrocyte proteins such as GFAP, GDNF, connexins, glutamate transporters, and glutamine synthetase . Astrocytes play essential roles in maintaining brain homeostasis and neuronal functions, and also mediate innate immunity and inflammatory responses in the brain. GDNF is a member of the transforming growth factor β superfamily that was isolated and purified from the conditioned medium of cultured rat glial cells of the B49 cell line . GDNF consists of 134 amino acids with near-identical sequence in rats and humans. The widespread distribution of GDNF and its receptors in various regions of the adult brain suggests a role in maintaining neuronal circuits in the mature central nervous system (CNS) . An increase in astrocyte GDNF synthesis and protein expression is believed to play an active role in neuronal survival and plasticity after excitotoxic damage , while experimental strategies of GDNF delivery by astrocytes have shown neuroprotective effects in vivo for dopaminergic neurons .
Animal studies have revealed that GDNF affects cognitive function, including learning and memory , while GDNF infusion increases hippocampal neurogenesis . GDNF+/− mutant mice show abnormal hippocampal synaptic transmission , and GDNF overexpression in astrocytes of the hippocampal CA1 region can improve spatial learning and memory performance in cognitively impaired aging rats by enhancing local cholinergic, dopaminergic, and serotonergic transmission .
Several different classes of antidepressant including amitriptyline, clomipramine, mianserin, fluoxetine, and paroxetine have been shown to increase
Some animal studies have reported that chronic treatment with several classes of antidepressant or mood stabilizer has no affect on
The reduction in the volume of the cortex and limbic system that is observed in depressed patients is primarily associated with a decrease in glial cell numbers and to a lesser degree with decreased neuronal density and size . In postmortem brain tissue from a small number of subjects with recurrent depression, increased GDNF level was detected in the parietal cortex relative to controls, and it was postulated that a loss of neurons and glia leads to an upregulation of GDNF as a compensatory response, which has also been reported in brain injury and animal models .
Electroacupuncture (EA) stimulation has been used for several decades to treat various mood disorders. A recent meta-analysis of 20 clinical trials found that acupuncture monotherapy was as effective as antidepressant treatment in terms of treatment response and alleviating the severity of symptoms . Serum GDNF was increased by treatment with EA or fluoxetine in depressed patients and was associated with decreased Hamilton Depression Rating Scale scores in depressed patients . In rats with transection of the medial forebrain bundle, EA upregulated
As in the case of antidepressants, the therapeutic effects of electroconvulsive therapy (ECT) involve stimulation of proliferation in neural progenitors via upregulation of specific signal transduction pathways . ECT stimulates glial cell proliferation in the prefrontal cortex of rats by causing a reduction in the expression of
Adult mice heterozygous for a null mutation at the
A recent study evaluated the effect of 21 single nucleotide polymorphisms in the
The neuroprotective effects of GDNF may be due in part to its ability to protect neurons from oxidative stress. Postmortem studies indicate that patients with recurrent depressive disorder have increased oxidative stress in some brain regions, such as the frontal cortex, thalamus, and putamen . Subchronic infusion of recombinant human GDNF increased superoxide dismutase, catalase, and glutathione peroxidase activities in rat striatum, suggesting that GDNF may have antioxidant properties . GDNF also protected human mesencephalic neuron-derived cells from oxidative injury .
We found that serum GDNF level was decreased in antidepressant-free patients with MDD and was not correlated with depression severity. We also found that decreased serum GDNF level in naive patients recovered to normal levels after treatment with antidepressants . Reduced
4. Insulin-like Growth Factor (IGF) in MDD
There is increasing evidence that IGF-1 plays an important role in diseases affecting the CNS. IGF-1 increases the synthesis and activity of BDNF , and both are required for neuronal survival and synaptic plasticity in the brain . IGF-1 also enhances proliferation, survival, differentiation, and maturation of all CNS cells and has demonstrated neurotrophic, neurogenic, and neuroprotective functions . IGF-1 is the only neurotrophic factor known to be regulated by the immune system, the dysregulation of which is implicated in the pathogenesis of depression.
Individuals with depression have reduced hippocampal volume as compared to controls. Post mortem and brain imaging studies have revealed atrophy in the hippocampus of depressed patients, which may be reversed by antidepressant treatment . Peripheral infusion of IGF-1 induced neurogenesis in adult rat hippocampus, and IGF-1 stimulates proliferation in adult rat hippocampal progenitor cells , while in vitro studies found that IGF-1 increased the total number of progenitor cells and promoted the specification of a neuronal lineage from precursors . Transgenic mice lacking IGF-1 or IGF-1R show severe delays in brain development ; mice overexpressing IGF-1 in the brain exhibit an increased numbers of neurons and synapses in the dentate gyrus, while IGF-1 knockout mice have a decreased number of granule cells in this region [83-84].
In animal models of depression, the specificity of the models used, the immune status of the tested animals, or animals’ age and gender can influence the levels of growth factors including that of IGF-1. In one study using the Cre-loxP system to knock out the
Early adverse experiences contribute to the development of vulnerability to stress and increase the risk of stress-related psychiatric disorders in adulthood. For instance, maternal separation during critical periods of brain development can lead to learning disabilities, behavioral anomalies, or psychiatric disorders in later life . Repeated maternal separation of neonatal rats caused prolonged and abnormal fluctuations in the expression of BDNF and IGF-1 and their respective receptors TrkB and IGF-1R in the cerebral cortex . Another study found that maternal separation alone or in combination with a single episode of restraint stress decreased the mRNA expression of
The potential antidepressant activity of IGF-1 has been examined in various animal models of depression in which behavioral tests such as forced swimming and tail suspension were used to evaluate antidepressant effects. These studies have consistently shown that IGF-1 treatment has antidepressant-like effects and normalizes behavioral disturbances in depressive animals [88-90]. In addition, repeated administration of fluoxetine induced the upregulation of IGF-1 and its receptor in the frontal cortex but a downregulation in the hippocampus . IGF-1 level was also upregulated in the adult rat hippocampus after chronic administration of venlafaxine 
Increased IGF-1 level in the blood of depressed patients has been observed in clinical studies [93-94], while others have reported decreased peripheral IGF-1 concentration in patients, possibly due to overactivation of the hypothalamic-pituitary-adrenal axis. A recent study demonstrated that a low IGF-1 level in females and a high level in males can predict the incidence of depressive disorder 5 years later . IGF-1 concentration was also found to decline during antidepressant treatment in patients, albeit only in responders .
5. Vascular Growth Factor (VGF) in MDD
VGF+/− mice have no gross abnormalities in brain morphology and exhibit normal anxiety levels. However, these mice show neurological and behavioral deficits akin to depression [100-102], suggesting that a reduced VGF level may account for depression in humans. Chronic treatment with different classes of antidepressant such as imipramine, fluoxetine, and duloxetine has been shown to modulate VGF expression [100-101,103], while infusion of VGF into the midbrain or hippocampus produces antidepressant effects in the learned helplessness paradigm of depression, as well as in the tail suspension and forced swim tests, which are used to evaluate the action of antidepressants [101-102]. In one of these studies, exercise increased VGF in the hippocampus of wild-type mice and induced an antidepressant-like response in the forced swim test; the increase was less pronounced in VGF+/− mice, which also failed to show behavioral improvement resulting from exercise in the forced swim test. Moreover, the administration of VGF peptide induced a robust, dose-dependent antidepressant-like response in the forced swim and tail suspension tests. In another study, VGF-derived peptide protected primary cultures of rat cerebellar granule cells from serum and potassium deprivation-induced cell death in a dose-and time-dependent manner .
Chronic antidepressant treatment in adult rodents increases neurogenesis in the dentate gyrus of the hippocampus, which may be a common mechanism by which antidepressants induce their therapeutic effects . VGF peptide similarly enhanced neurogenesis of hippocampal cells and may favor the differentiation of proliferating progenitors into neurons over glia . Although the precise relationship between depression and neurogenesis remains to be elucidated, stimulating cell proliferation may be one way in which VGF exerts antidepressant effects.
ECT is a highly effective and rapid treatment for depressed patients who do not respond to antidepressants. While the molecular mechanisms underlying the therapeutic efficacy of ECT are not fully understood, it is thought that ECT and antidepressants increase the expression of select neurotrophic factors that reverse or block the atrophy and cell loss resulting from stress and depression. ECT was shown to increase the level of VGF in the hippocampus of rats [103,106], and a decrease in
In the European Genome-based Therapeutic Drugs for Depression study, nine psychiatric centers in eight European countries recruited 811 adult outpatients suffering from unipolar depression of at least moderate severity. These patients showed significant upregulation in leukocyte
Findings from human postmortem studies of bipolar patients indicate that VGF is downregulated in the CA regions of the hippocampus and Brodmann’s area 9 of the dorsolateral prefrontal cortex . Importantly, VGF showed effects similar to those of lithium, which is used to treat bipolar disorder. However, another study found an increase in VGF23–62 peptide level in the cerebrospinal fluid of 16 patients diagnosed with MDD . The association between
6. Fibroblast Growth Factor (FGF) in MDD
FGFs and their receptors constitute an elaborate signaling system that is organized in dynamic spatial and temporal expression patterns. There are at least 23 members of the FGF family, 22 of which are distributed throughout the CNS in humans along with five FGF receptors. FGF1 and FGF2, which lack a signal sequence, are secreted and directly regulate intracellular signaling cascades in target cells. FGF ligands share a conserved central domain of about 120 amino acids that binds heparin and is required for stable FGF ligand-receptor interactions . FGFRs are tyrosine kinase receptors with three immunoglobulin-like domains (D1, D2, and D3) .
FGF signaling has been implicated in a variety of mood disorders, including MDD. The neurotrophic hypothesis of depression posits that neurogenesis and neuronal plasticity are affected by the imbalance in growth factor levels. FGF2 attenuates the reduction in hippocampal volume and promotes hippocampal neurogenesis after traumatic brain injury in mice . Post-mortem examinations have shown that the expression of FGF1, FGF2, and receptors FGFR2 and FGFR3 is decreased in the frontal cortical area in MDD relative to controls. FGF signaling is also upregulated by treatment with antidepressants . A lower serum FGF-2 level has been reported in MDD patients, which may be reversed by antidepressants . In an animal model, a single subcutaneous injection of FGF2 administered to rats on postnatal day 1 increased cell survival in the DG 3 weeks later, producing a larger hippocampus with more cells ; a similar effect was observed in the adult brain .
FGFR1 conditional knockout mice lacking
FGF2 has antidepressant-like effects when administered later in adulthood. FGF2 infusions had both antidepressant and anxiolytic effects in behavioral models of depression and anxiety . FGF activity has also been linked to the response to antidepressant medications in humans, and some studies have found a correlation between
Affymetrix microarray analyses of cortical brain regions detected a significant number of
7. Neurotropin-3 (NT3) in MDD
NT3 is a member of the neurotrophin family of proteins that supports the survival of specific types of neuron . NT3 is distributed throughout the DG and promotes hippocampal plasticity by regulating neurogenesis via binding of TrkB and TrkC tyrosine kinase neurotrophin receptors .
NT3 has been implicated in the pathogenesis of depression and the therapeutic mechanism of antidepressants. Hippocampal atrophy has been consistently demonstrated as one of the predominant pathophysiological changes in subjects with a history of MDD, and is correlated with duration of the illness . NT3 prevented the degeneration of noradrenergic neurons in the LC  that are associated with the pathophysiology of major depression . NT3 infusions cause an upregulation in the mRNA level of
NT3 antagonizes the proliferative effects of basic FGF, and enhances neuronal differentiation, while blocking NT3 function leads to a decrease in neurogenesis . In NT-3 mutant mice with brain-specific
Postmortem analyses have demonstrated altered levels of neurotrophic factor expression in the brains of patients with mood disorder. Serum NT3 levels were increased during acute mood states of bipolar depression patients as compared to euthymic patients and normal controls . In another study, serum NT3 level in drug-free and medicated patients with bipolar disorder during manic and depressive episodes was increased relative to controls, while there was no difference between medicated and drug-free patients .
8. Nerve Growth Factor (NGF) in MDD
NGF was the first identified neurotrophin in a family of structurally similar growth factors. In the CNS, NGF is involved in neuronal survival, protection of sympathetic and cholinergic neurons against neurodegeneration, and in the modulation of the immune response as well as learning and memory .
NGF has demonstrated neuroprotective effects on basal forebrain cholinergic neurons in Alzheimer’s disease patients . However, the injection of NGF antibody was shown to induce the death of sympathetic neurons in mouse, rat, cat, and rabbit models . Mouse models of anxiety, chronic stress, and depression involving learned helplessness, threatening or painful stimuli, maternal deprivation, and other factors induce a reduction in NGF in the frontal cortex, amygdala, hippocampus, and nucleus accumbens [143-145]. In MDD patients, serum NGF level is higher than in controls, and has been associated with the severity of depressive symptoms in women .
Whether alterations in NGF are state-or trait-dependent is under debate. In mood disorders, a state-related phenomenon appears and then disappears with mood state; in contrast, a trait-related phenomenon occurs regardless of variations in the clinical state. One study of in-and outpatients with mood disorders including uni-and bipolar depression and bipolar mania found no differences or changes in NGF levels in patients with depressive episodes and after 8 weeks of medical treatment , consistent with previous findings that NGF levels do not vary among depressed patients [148-150].
Nonetheless, several clinical studies have reported that serum NGF concentration is decreased relative to healthy controls in MDD patients [151-152], including those receiving duloxetine  and those experiencing depression late in life . In contrast, other studies have reported increased NGF in patients with elevated levels of stress and severe depression . The severity of washing symptoms is correlated with an upregulation in NGF in patients with obsessive-compulsive disorder , while another study found a positive correlation between plasma NGF level and disease duration in patients with bipolar mood disorders .
Various studies have investigated the effects of ECT on NGF levels in animals and humans. Electroconvulsive stimuli administered once daily for 8 days increased NGF level in the frontal cortex of adult rats . Repeated exposure to electroconvulsive stimuli also increased TrkA and NGF protein levels in the rat hippocampus , suggesting that NGF may play a role in the mechanism of action of electroconvulsive treatment. In contrast to animal studies, ECT treatment has not been found to affect NGF levels in human patients. In patients with treatment-resistant major depression  or bipolar disorder with depression , NGF levels were not significantly increased by ECT, even with concurrent administration of antidepressants and psychotherapy.
Several preclinical and clinical observations indicate that depression may be associated with the inability of neural systems to exhibit adaptive plasticity. Given the role of neurotrophic factors in neural and structural plasticity, and that depression and antidepressants exert opposite actions on neurotrophic factors expression and functions, it is apparent that neurotrophic factors signaling may be crucial in the pathophysiology of depression and in the mechanism of action of antidepressants. However, future work will be necessary to determine whether neurotrophic factors is a risk factor for initiation or maintenance or in the recovery process with respect to MDD and how its circuit-level function contributes at MDD stages. In addition, the search for more effective and applicable neurotrophic factors-based therapies is crucial.
This chapter was partially supported by Jiangsu Province Natural Science Foundation (BK2011434) and Yangzhou Municipal Key Technology Problems Foundation (YZ2010089).