Pathogenesis Of Major Depression Research Articles

53. The Anterior Hippocampus and the Pathogenesis of Major Depression

53. The Anterior Hippocampus and the Pathogenesis of Major Depression

The State of Our Understanding of the Pathophysiology and Optimal Treatment of Depression: Glass Half Full or Half Empty?

Major depressive disorder is a remarkably common and often severe psychiatric disorder associated with high levels of morbidity and mortality. Patients with major depression are prone to several comorbid psychiatric conditions, including posttraumatic stress disorder, anxiety disorders, obsessive-compulsive disorder, and substance use disorders, and medical conditions, including cardiovascular disease, diabetes, stroke, cancer, which, coupled with the risk of suicide, result in a shortened life expectancy. The goal of this review is to provide an overview of our current understanding of major depression, from pathophysiology to treatment. In spite of decades of research, relatively little is known about its pathogenesis, other than that risk is largely defined by a combination of ill-defined genetic and environmental factors. Although we know that female sex, a history of childhood maltreatment, and family history as well as more recent stressors are risk factors, precisely how these environmental influences interact with genetic vulnerability remains obscure. In recent years, considerable advances have been made in beginning to understand the genetic substrates that underlie disease vulnerability, and the interaction of genes, early-life adversity, and the epigenome in influencing gene expression is now being intensively studied. The role of inflammation and other immune system dysfunction in the pathogenesis of major depression is also being intensively investigated. Brain imaging studies have provided a firmer understanding of the circuitry involved in major depression, providing potential new therapeutic targets. Despite a broad armamentarium for major depression, including antidepressants, evidence-based psychotherapies, nonpharmacological somatic treatments, and a host of augmentation strategies, a sizable percentage of patients remain nonresponsive or poorly responsive to available treatments. Investigational agents with novel mechanisms of action are under active study. Personalized medicine in psychiatry provides the hope of escape from the current standard trial-and-error approach to treatment, moving to a more refined method that augurs a new era for patients and clinicians alike.

Discovery of Potent, Selective, and Direct Acid Sphingomyelinase Inhibitors with Antidepressant Activity.

Recent studies on sphingolipids suggest that acid sphingomyelinase (ASM), which plays a central role in the pathogenesis of major depression, is emerging to be a novel target for developing antidepressants. Herein we first described the design, synthesis, and biological evaluation of hydroxamic acid-based direct inhibitors of ASM with the effort of validating their antidepressant effects in vivo. As a result, a series of novel ASM inhibitors were developed using a structure-based approach. Our studies demonstrated that the administration of 21b improved depression-like behaviors of rats. Importantly, this positive result was relevant to the inhibition of ASM and the increasing neurogenesis in hippocampus. To the best of our knowledge, this is the first time that direct inhibitors of ASM were developed to support the possibility of ASM as a potential therapeutic target for depression.

Are brain derived neurotrophic factor, neurotrophin-3 and neurotrophin-4 gene expression changes effective in the pathogenesis of major depression?

Objective: Brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4 (NT-4) are neuro-trophins and they are critical regulators of the survival, differentiation, growth and plasticity of neuronal networks. There is plenty of evidence suggesting the involvement of altered levels of expression of neurotrophic factors in the pathophysiology of neuropsychiatric disorders. However, the relationship between neurotrophins and major depression (MD) remains unclear. In this study, we assessed the relationship between the BDNF, NT-3, NT-4 gene expression levels in blood cells and MD. Methods: In a case-control study, total RNA was obtained from blood cells, 51 MD patients (diagnosed according to the DSM-5 criteria) and 75 healthy controls. Detected with quantitative Real Time PCR, expression levels of BDNF, NT-3, NT-4 genes were compared between the groups. Results: In this study, BDNF expression levels of the patients with MD were significantly higher than the control group but no statistically significant difference between NT-3 and NT-4 expression levels. There was no differences in expression levels of BDNF, NT-3 and NT-4 genes in MD patients with family history. There was no statistically significant difference in the BDNF, NTF-3 and NTF-4 expression levels among the sex groups for the patient group and no statistically significant difference between MD patients according to antidepressant usage time. Discussion: Not only in understanding the pathogenesis of MD but also in the follow-up of treatment, expression level changes of BDNF gene in blood cells of MD patients must be considered because of the bidirectional movement of BDNF between the periphery and the brain and effect of changing serum BDNF levels.

Associations between Depressive Disorders and Inflammatory Rheumatic Diseases.

Depressive disorders, are not only common but also among the leading causes of disability worldwide. They are associated with increased incidences of various other diseases. It has been shown that in patients with autoimmune diseases, when depression coexists, the quality of life is worse and medical treatment and management is compromised. Depression-like symptoms, such as fatigue and disinterest are also common in inflammatory rheumatic diseases and often associated with poor quality of life. Medical therapy targeting inflammation results in alleviation of these symptoms in many patients. Interestingly, there is cumulating evidence suggesting potential roles of inflammatory cytokines in the pathogenesis of major depression. Effects of some of the biological agents used in rheumatic diseases have been studied on depressive disorders. Results have been controversial and further studies are needed in this area. These findings suggest associations between depression and inflammatory rheumatic diseases and raise the possibility that treatment of one of them might influence the outcome of the other. We have reviewed the current literature on associations between depression and inflammatory rheumatologic diseases, such as rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome and ankylosing spondylitis.

Neutrophil-lymphocyte Ratio and C-reactive Protein Level in Patients with Major Depressive Disorder Before and After Pharmacotherapy

Neutrophil-lymphocyte ratio (NLR) and C-reactive protein (CRP) level are useful biomarkers of inflammation. This study aimed to assess NLR and CRP level in patients with major depressive disorder before and after pharmacotherapy to determine whether NLR or CRP could be used as biomarkers of severity of major depression and whether there was any sex difference. Patients with major depression who received no pharmacotherapy 1 month prior to the study were included. Their haemoglobin, total white blood cell count, neutrophil and lymphocyte counts, NLR, and CRP levels were evaluated at baseline and 12 weeks post pharmacotherapy, as were the Montgomery Asberg Rating Scale for Depression, the Scale for Impact of Suicidality Management and Assessment and Planning of Care (SIS-MAP), and the Clinical Global Impression Scale - Severity. 24 male and 26 female patients were included. At 12 weeks after pharmacotherapy, males had a higher haemoglobin level (p = 0.025), higher total white blood cell count (p = 0.018), and lower percentage of neutrophils (p = 0.019) than females. There was no sex difference in NLR or CRP. From baseline to 12 weeks, males had no significant change in any blood parameter, but females had a significantly greater increase in the percentage of neutrophils (p = 0.0001) and decrease in the percentage of lymphocytes (p = 0.012), resulting in a significantly increased NLR (p = 0.001). Both males and females had significant improvement on all 3 scales (p < 0.001). At 12 weeks, in males, the increase in NLR positively correlated with CRP as well as the Montgomery-Asberg Depression Rating Scale and the SIS-MAP, but not the Clinical Global Impression-Severity Scale. In females, the increase in NLR did not correlate with CRP or any of the scales. In female patients, the NLR increased in response to antidepressant therapy while CRP remained unchanged. This indicated that inflammation has a role in the pathogenesis of major depression.

Pathogenesis of Major Depression by Stress Induced Hyperactivity of Hypothalmic-pituitary Adrenal Axis Mediated by Dysregulations of Neurotransmitter, Innate Immune Systems and Altered Brain micro RNA Expressions

Pathogenesis of Major Depression by Stress Induced Hyperactivity of Hypothalmic-pituitary Adrenal Axis Mediated by Dysregulations of Neurotransmitter, Innate Immune Systems and Altered Brain micro RNA Expressions

Negative cognitive style interacts with negative life events to predict first onset of a major depressive episode in adolescence via hopelessness.

The hopelessness theory of depression is a prominent account of depression that posits that individuals with a negative inferential style are more likely to become hopeless when they experience negative life events (NLEs) and that hopelessness is a proximal cause of depression. There is strong evidence supporting the role of a negative inferential style in the pathogenesis of major depression; however, substantially less is known about the proposed role played by hopelessness. The cornerstone hypothesis of hopelessness theory, that hopelessness is a proximal cause of major depression, is largely untested. A small number of studies have generated inconclusive evidence that hopelessness mediates the relationship between a negative inferential style, NLEs, and depressive symptoms. The current study tested whether hopelessness mediates the relationship between a Negative Inferential Style × NLEs interaction and (a) 1st onset of a major depressive episode (MDE) and (b) depressive symptoms in a fully prospective design. A diverse sample of 249 adolescents, ages 12-13 years, were assessed at baseline and at 2 or more follow-ups over approximately 2.5 years. Self-report as well as life event and diagnostic interviews assessed inferential style, NLEs, hopelessness, depressive symptoms, and depression diagnosis. Moderated mediation analyses indicated that hopelessness mediated the relationship between a Negative Inferential Style × NLEs interaction and (a) 1st onset of an MDE as well as (b) depressive symptoms at higher levels of multiple types of NLEs. The current study demonstrates the validity of the hopelessness theory of depression and its continued clinical relevance in predicting depression in adolescence. (PsycINFO Database Record

MicroRNA-101 in the ventrolateral orbital cortex (VLO) modulates depressive-like behaviors in rats and targets dual-specificity phosphatase 1 (DUSP1)

Long-term exposure to stress plays a key role in the pathogenesis of major depression. Recently, the ventrolateral orbital cortex (VLO) has received considerable attention for its role in the antidepressant response. However, the mechanisms underlying stress response in the VLO remain largely elusive. MiR-101 has been implicated in regulating multiple neurological processes. The present study used the chronic unpredictable mild stress (CUMS) rat model to investigate the expression of miR-101 in the VLOs of rat brains and the possible relevance of miR-101 to depression. Furthermore, an intra-VLO administration of a miR-101 mimic was performed to provide insights into the miR-101-mediated dysregulation mechanisms associated with depression. The results showed that chronic stress induced typical depressive-like behaviors in rats and decreased miR-101 levels in the VLOs of rat brains. Moreover, the dual specificity phosphatase 1 (DUSP1) protein levels were increased in the VLOs in CUMS rats, whereas the ERK phosphorylation and BDNF levels in the CUMS rats were decreased. Enhancing miR-101 expression via an intro-VLO microinjection of its mimic reversed the depressive-like behaviors in CUMS rats. Intra-VLO treatment with the miR-101 mimic also attenuated the upregulation of CUMS-induced DUSP1 expression and inhibited the downstream ERK phosphorylation and BDNF expression. These results suggest that miR-101 has functional significance in the pathophysiology of stress-induced dysfunctions in the VLO. MiR-101 may directly regulate DUSP1 expression, and the mechanism underlying the antidepressant effects of miR-101 may involve the negative regulation of DUSP1 expression, which in turn promotes downstream ERK/BDNF signaling.

An astroglial basis of major depressive disorder? An overview.

Depression is a chronic, recurring, and serious mood disorder that afflicts up to 20% of the global population. The monoamine hypothesis has dominated our understanding of the pharmacotherapy of depression for more than half a century; however, our understanding of the pathophysiology and pathogenesis of major depression has lagged far behind. Astrocytes are the most abundant and versatile cells in the brain, participating in most, if not all, of brain functions as both a passive housekeeper and an active player. Mounting evidence from clinical, preclinical and post-mortem studies has revealed a decrease in the number or density of astrocytes and morphological and functional astroglial atrophy in patients with major depressive disorder (MDD) and in animal models of depression. Furthermore, currently available antidepressant treatments at least partially exert their therapeutic effects on astrocytes. More importantly, dysfunctional astrocytes lead to depressive-like phenotypes in animals. Together, current studies point to astroglial pathology as the potential root cause of MDD. Thus, a shift from a neuron-centric to an astrocyte-centric cause of MDD has gained increasing attention during the past two decades. Here we will summarize the current evidence supporting the hypothesis that MDD is a disease of astrocyte pathology and highlight previous studies on promising strategies that directly target astrocytes for the development of novel antidepressant treatments.

EP 81. Medial prefrontal aberrations in major depressive disorder revealed by Cytoarchitectonically informed Voxel-based Morphometry

Objective The heterogeneous human frontal pole has been identified as a node in the dysfunctional network of major depressive disorder (MDD) ( Mayberg, 2003 ). The contribution of the medial (socio affective) versus lateral (cognitive) frontal pole to major depression pathogenesis is currently unclear. The authors performed morphometric comparison of the microstructurally informed subdivisions of human frontal pole ( Bludau et al., 2014 ) between depressed patients and comparison subjects using both uni- and multivariate statistics. Method Multisite voxel- and region-based morphometric MRI analysis was conducted in 73 depressed patients and 73 matched comparison subjects without psychiatric history (Gender: Controls [f/m]40/33; Patients [f/m]40/33; chi 2 :1.0, Age: Controls [mean/ SD]38.51/12.56; Patients [mean/SD]41.70/12.95; ttest (p-value): 0.13). Frontal pole volume was first compared between depressed patients and comparison subjects by subdivision-wise classical morphometric analysis. In a second approach, frontal pole volume was compared by subdivision-naive multivariate searchlight analysis based on support vector machines. Results The group comparison showed a significant decrease in volume of the left medial part of the frontal pole (left Fp2) of MDD patients compared to the controls ( Fig. 1 ) ( p r = −0.32)) and within the patients of all sites (Fp2_L ∼ BDI ( r = −0.26)). Duration as well as episodes also correlates negatively with the volume of left Fp2 within the patients (Fp2_L ∼ duration ( r = −0.35); Fp2_L ∼ episodes ( r = −0.34)). Histologically uninformed multivariate voxel-wise statistics provided converging evidence for structural aberrations specific to the microstructurally defined medial area of the frontal pole in depressed patients ( Fig. 2 ). Conclusions Across disparate methods, subregion specificity in the left medial frontal pole volume in depressed patients was demonstrated. Indeed, the frontal pole was shown to structurally and functionally connect to other key regions in major depression pathology, such as the anterior cingulate cortex and the amygdala via the uncinate fasciculus. Present and previous findings consolidate the left medial portion of the frontal pole as particularly altered in major depression.

Antidepressant-like effect of tadalafil, a phosphodiesterase type 5 inhibitor, in the forced swim test: Dose and duration of treatment dependence

Nitric oxide (NO), an intercellular messenger in central nervous system, plays an important role in the pathogenesis of major depression. Antidepressant-like effect of sildenafil, a phosphodiesterase 5 inhibitor (PDE5-I), at lower dose, but not at higher doses, was reported previously. Hence, present work was undertaken to study the effects of tadalafil (TAD), another PDE5-I, per se and in combination with L-NAME in forced swimming test (FST) in rat for 14 days. TAD (5 mg/kg, p.o.) significantly reduced immobility duration, increased swimming duration on day 1 and 14, and increased climbing frequency on day 14 as compared to normal group. Whereas, TAD (10 and 20 mg/kg, p.o.) insignificant in this regards. On day 1 and 14, L-NAME (20 mg/kg, i.p.) showed reduction in immobility duration and increase in swimming duration and climbing frequency. L-NAME (20 mg/kg) after TAD (20 mg/kg) reduced immobility duration and increased swimming duration on day 1 and 14 and increased climbing frequency on day 14 as compared to normal group. Tadlafil, at low dose but not at higher dose, has antidepressant-like effect on behavior in FST. L-NAME has antidepressant-like effect on behavior in FST. L-NAME does not interact with tadalafil (20 mg/kg) in regards of effects on behavior in FST. The results showed that, tadalafil produced dose dependent but time-independent effect on immobility and swimming whereas dose and time dependent effect on climbing was evident.

Sgk1 regulates desmoglein 1 expression levels in oligodendrocytes in the mouse corpus callosum after chronic stress exposure

Major depression, one of the most prevalent mental illnesses, is thought to be a multifactorial disease related to both genetic and environmental factors. However, the genes responsible for and the pathogenesis of major depression at the molecular level remain unclear. Recently, we reported that stressed mice with elevated plasma corticosterone levels show upregulation and activation of serum glucocorticoid-regulated kinase (Sgk1) in oligodendrocytes. Active Sgk1 causes phosphorylation of N-myc downstream-regulated gene 1 (Ndrg1), and phospho-Ndrg1 increases the expression of N-cadherin, α-catenin, and β-catenin in oligodendrocytes. This activation of the Sgk1 cascade results in morphological changes in the oligodendrocytes of nerve fiber bundles, such as those present in the corpus callosum. However, little is known about the molecular functions of the traditional and/or desmosomal cadherin superfamily in oligodendrocytes. Therefore, in this study, we aimed to elucidate the functions of the desmosomal cadherin superfamily in oligodendrocytes. Desmoglein (Dsg) 1, Dsg2, and desmocollin 1 (Dsc1) were found to be expressed in the corpus callosum of mouse brain, and the expression of a subtype of Dsg1, Dsg1c, was upregulated in oligodendrocytes after chronic stress exposure. Furthermore, Dsg1 proteins were localized around the plasma membrane regions of oligodendrocytes. A study in primary oligodendrocyte cultures also revealed that chronic upregulation of Sgk1 by dexamethasone administration is involved in upregulation of Dsg1c mRNA. These results may indicate that chronic stress induced Sgk1 activation in oligodendrocytes, which increases Dsg1 expression near the plasma membrane. Thus, Dsg1 upregulation may be implicated in the molecular mechanisms underlying the morphological changes in oligodendrocytes in response to chronic stress exposure.

A central role for the acid sphingomyelinase/ceramide system in neurogenesis and major depression.

Major depressive disorder is a severe and chronic illness with high lifetime prevalence and a high incidence of suicide as the cause of death for patients with this diagnosis. Major depressive disorder is often treated with anti-depressants. Although these drugs have been used for many years, their exact mode of action is still unknown. It has been suggested that many anti-depressants act by increasing the concentrations of serotonergic transmitters in the synaptic space. However, recent studies have examined the effects of anti-depressants on neurogenesis in the hippocampus, the restoration of hippocampal neuronal networks that may be affected by major depression, and the regulation of the hypothalamic-pituitary-adrenal axis by immature neurons in the hippocampus. Here, we present and discuss a novel hypothesis suggesting that these events are regulated by the concentrations of sphingolipids, in particular ceramide, in the hippocampus. These concepts suggest that the acid sphingomyelinase/ceramide system plays a central role in the pathogenesis of major depression and may be a novel target for anti-depressants.

Association of serum leptin and ghrelin with depressive symptoms in a Japanese working population: a cross-sectional study.

BackgroundLeptin and ghrelin have been implicated in the pathogenesis of major depression. However, evidence is lacking among apparently healthy people. This study examined the relationship of these appetite hormones to depressive symptoms in a Japanese working population.MethodsA cross-sectional study was conducted in 2009 among 497 Japanese employees (287 men and 210 women) aged 20–68 years. Fasting serum leptin and ghrelin levels were measured using a Luminex suspension bead-based multiplexed array. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression (CES-D) scale. Logistic regression analysis was performed to estimate odds ratio (OR) and 95% confidence interval (CI) for depressive symptoms with adjustment for potential confounders.ResultsThe prevalence of depressive symptoms (CES-D ≥16) was 26.5% and 33.3% among men and women, respectively. Women in the middle and highest tertiles of leptin levels showed lower odds for depressive symptoms compared with those in the lowest level, although the trend association was not statistically significant (Ptrend = 0.14). Higher ghrelin levels were associated with increased odds for depressive symptoms in women (Ptrend = 0.02). The multivariable adjusted OR (95% CI) of having depressive symptoms for the lowest through highest tertiles of ghrelin levels were 1.00 (reference), 1.71 (0.76 - 3.86), and 2.69 (1.16 - 6.28), respectively. Neither leptin nor ghrelin was associated with depressive symptoms in men.ConclusionsResults suggest that lower leptin and higher ghrelin levels may be related to higher prevalence of depressive status among Japanese women.

Insights from interferon-α-related depression for the pathogenesis of depression associated with inflammation.

Interferon-α (IFN-α) is a pleiotropic cytokine that is administered as a therapeutic in highly prevalent medical conditions such as chronic hepatitis C and B virus infection, melanoma and lymphoma. IFN-α induces, to a clinically relevant degree, concentration, memory, drive and mood disturbances in almost half of all patients. For this reason, IFN-α is increasingly being replaced by more specifically acting drugs. In the past decades, IFN-α has offered a valuable insight into the pathogenesis of major depression, particularly in settings associated with inflammation. IFN-α triggers immune responses, hypothalamo-pituitary-adrenal axis abnormalities and disturbances of brain metabolism resembling those in other depression states. IFN-α stimulates indoleamine-2,3 dioxygenase-1, activating the kynurenine pathway with reduced formation of the neurotransmitters serotonin and dopamine, excessive formation of the NMDA agonist quinolinic acid, and reduced formation of the NMDA antagonist kynurenic acid. In addition, IFN-α disturbs neurotrophic signaling and impedes neurite outgrowth, synaptic plasticity, endogenous neurogenesis and neuronal survival. Consequently, IFN-α-related depression may represent a model for the neurodegenerative changes that are noticed in late-life major depression. Indeed, the observation that brain responses in IFN-α-related depression resemble idiopathic depression is supported by the existence of common genetic signatures, among which of note, a number of neuronal survival and plasticity genes have been identified. In view of the high incidence of depressive symptoms, IFN-α-related depression is an attractive model for studying links between neuronal plasticity, neurodegeneration and depression. We predict that in the latter areas new targets for anti-depressant therapies could be identified, which may deepen our understanding of idiopathic major depression.

The influence of childhood abuse, adult stressful life events and temperaments on depressive symptoms in the nonclinical general adult population

BackgroundPrevious studies have shown the interaction between heredity and childhood stress or life events on the pathogenesis of major depression. We hypothesized that childhood abuse, affective temperaments, and adult stressful life events interact and influence depressive symptoms in the general adult population and tested this hypothesis in this study. MethodsThe 294 participants from the nonclinical general adult population were studied using the following self-administered questionnaire surveys: the Patient Health Questionnaire-9 (PHQ-9), Life Experiences Survey (LES), Temperament Evaluation of the Memphis, Pisa, Paris, and San Diego auto-questionnaire (TEMPS-A), and Child Abuse and Trauma Scale (CATS). The data were analyzed with single and multiple regressions and structural equation modeling (Amos 20.0). ResultsChildhood abuse indirectly predicted the severity of the depressive symptoms through affective temperaments measured by TEMPS-A in the structural equation modeling. Four temperaments – depressive, cyclothymic, irritable, and anxious – directly predicted the severity of depressive symptoms and the negative appraisal of life events during the past year. The negative appraisal of life events during the past year mildly, but significantly, predicted the severity of depressive symptoms. LimitationsThe subjects of this study were nonclinical. The findings might not be generalized to patients with mood disorders. ConclusionsThis study suggests that childhood abuse, especially neglect, indirectly increased depressive symptoms through increased affective temperaments, which, in turn, increase the negative appraisal of stressful life events. An important role of affective temperaments in the effect of childhood abuse and stressful life events on depressive symptoms was suggested.

The involvement of microRNAs in major depression, suicidal behavior, and related disorders: a focus on miR-185 and miR-491-3p.

Major depressive disorders are common and disabling conditions associated with significant psychosocial impairment and suicide risk. At least 3-4% of all depressive individuals die by suicide. Evidence suggests that small non-coding RNAs, in particular microRNAs (miRNAs), play a critical role in major affective disorders as well as suicide. We performed a detailed review of the current literature on miRNAs and their targets in major depression and related disorders as well as suicidal behavior, with a specific focus on miR-185 and miR-491-3p, which have been suggested to participate in the pathogenesis of major depression and/or suicide. miRNAs play a fundamental role in the development of the brain. Several miRNAs are reported to influence neuronal and circuit formation by negatively regulating gene expression. Global miRNA reduced expression was found in the prefrontal cortex of depressed suicide completers when compared to that of nonpsychiatric controls who died of other causes. One particular miRNA, miR-185, was reported to regulate TrkB-T1, which has been associated with suicidal behavior upon truncation. Furthermore, cAMP response element-binding protein-brain-derived neurotrophic factor pathways may regulate, through miRNAs, the homeostasis of neural and synaptic pathways playing a crucial role in major depression. miRNAs have gained attention as key players involved in nervous system development, physiology, and disease. Further evidence is needed to clarify the exact role that miRNAs play in major depression and related disorders and suicidal behavior.

Functional Val66Met polymorphism of Brain-derived neurotrophic factor in type 2 diabetes with depression in Han Chinese subjects

BackgroundBrain-derived neurotrophic factor (BDNF) has been implicated in the pathogenesis of major depression. Individuals with type 2 diabetes (T2DM) have a high prevalence of major depression and low levels of BDNF. We therefore explored whether the BDNF Val66Met polymorphism is associated with co-morbid depression and whether depression affects the serum levels of BDNF in a Han Chinese subjects with T2DM.MethodsA Total of 296 T2DM patients and 70 healthy volunteers (Health control, HC group) were recruited in this study. T2DM patients were divided into two subgroups: depressive diabetes group (DDM group, n = 64) and non-depressive diabetes group (NDDM group, n = 232), according to the presence or the absence of depression assessed by Center for Epidemiologic Studies Depression Scale (CES-D) and Patient Health Questionnaire-9 (PHQ-9). Val66Met polymorphism was detected by polymerase chain reaction-restriction fragment length polymorphism analysis (PCR-RFLP). Serum BDNF levels were measured by ELISA kit.ResultsIn this study, 21.6% (64/296) patients with T2DM had depression. The BDNF Val66Met genotype distributions were statistically different among the three groups (χ2 = 7.39, p < 0.05). DDM group carried the highest frequencies of Met allele (53.9%) compared to HC group (39.3%) and NDDM group (38.8%). Subjects with Met/Met had lowest serum BDNF levels (76.59 ± 5.12 pg/ml, F = 7.39, p < 0.05) compared to subjects with Val/Met (79.04 ± 5.19 pg/ml) and Val/Val (83.83 ± 3.97 pg/ml). Within T2DM group, it was also observed that the serum BDNF levels in DDM group were significantly lower than those in NDDM group (76.67 ± 5.35 vs. 79.84 ± 3.97 pg/ml, p < 0.05). In type 2 diabetes subjects, BDNF serum levels were significant correlations with genotypes (r = −0.346, p < 0.01), depression scores (r = −0.486, p < 0.01) and HbA1c (r = −0.168, p < 0.05). After adjustment for gender, HbA1c, BMI and numbers of complications, BDNF Val/Met genotype distributions (OR = 2.105, p < 0.05) and decreased serum BDNF levels (OR = 0.835, p < 0.01) were independently associated with depression in T2DM.ConclusionsThe BDNF Val66Met polymorphism might be implicated in the pathogenesis of depression in T2DM by decreasing serum BDNF levels in Han Chinese Subjects.

The progressive development of depression-like behavior in corticosterone-treated rats is paralleled by slowed granule cell maturation and decreased reelin expression in the adult dentate gyrus

We have hypothesized that the extracellular matrix protein reelin is involved in the pathogenesis of major depression. This hypothesis is based on previous work in which we showed that repeated exposure to the stress hormone corticosterone, which increases depression-like behavior in rodents, also decreases the number of reelin+ cells in specific regions of the hippocampus and decreases hippocampal neurogenesis. In addition, we have found that heterozygous reeler mice, which express approximately 50% of normal brain levels of reelin, are more susceptible to the depressogenic effects of corticosterone than their wild-type counterparts. To further understand the relationship between corticosterone, reelin, and depression, we assessed whether the effects of corticosterone on hippocampal reelin expression and neurogenesis parallel the progressive development of depression-like behavior over a 21-day period. Rats were subjected to 7, 14 or 21 days of repeated corticosterone injections (40 mg/kg, s.c.) or vehicle injections followed by behavioral testing, immunohistochemistry, and Golgi analyses. We found that corticosterone-treated rats showed gradual increases in depression-like behavior over time, which were accompanied by similarly gradual decreases in reelin expression in the dentate subgranular zone and decreases in the number and dendritic complexity of surviving immature dentate granule cells. Interestingly, corticosterone had no significant effect on dendritic complexity in mature granule cells. These results support our hypothesis that reelin plays a role in the pathogenesis of depression and suggest that reelin could be an important target for the development of novel therapeutics for the treatment of depression.