Changes in BDNF serum levels in patients with major depression disorder (MDD) after 6 months treatment with sertraline, escitalopram, or venlafaxine

Recent studies have implicated brain-derived neurotrophic factor (BDNF) in the pathophysiology of depression and the activity of antidepressant drugs. Serum BDNF levels are lower in depressed patients, and increase in response to antidepressant medication. However, how BDNF responds to different classes of antidepressant drugs is unknown. We assessed serum BDNF levels in 21 patients with major depressive episode treated with sertraline, escitalopram, or venlafaxine and 20 healthy controls. Serum samples were collected between 10 a.m. and 12 p.m. at baseline, 5 weeks, and 6 months of treatment. BDNF levels were measured via immunoassay. The severity of symptoms and response to treatment were assessed by the Hamilton rating scales for depression (HRSD). Baseline serum BDNF levels were significantly lower in depressed patients compared to controls. Sertraline increased BDNF levels after 5 weeks and 6 months of treatment. Venlafaxine increased BDNF levels only after 6 months. Escitalopram did not affect BDNF levels at either time point. A significant negative association was found between percentage increase in BDNF levels and percentage decreased in HRSD scores after 6 months of treatment. In conclusion, these results suggest that different antidepressant drugs have variable effects on serum BDNF levels. This is true even though the three different drugs were equally effective in relieving symptoms of depression and anxiety.     

抑郁症患者血清脑源性神经营养因子水平及其相关因素

目的 探讨抑郁症患者血清脑源性神经营养因子水平及其相关因素,为防治抑郁症提供重要依据.方法 采用酶联免疫吸附法和汉密尔顿抑郁量表分别测定40例抑郁症患者(患者组)的血清BDNF水平和抑郁严重程度,并与49名正常者(对照组)进行对比分析.结果 患者组治疗前血清BDNF水平明显降低,与对照组比较差异有统计学意义(P＜0.01).患者组治疗8周末血清BDNF水平明显升高,HAMD总分明显降低,与治疗前比较差异有统计学意义(P＜0.05).患者组治疗前后血清BDNF水平与性别及年龄均呈负相关,差异具有统计学意义(P＜0.05),与受教育程度、病程及HAMD总分比较无统计学意义(P＞0.05).结论 抑郁症患者存在血清BDNF水平的下降,抗抑郁治疗可改善抑郁症状,并显著提高血清BDNF水平.     

Cognitive functions and serum levels of brain-derived neurotrophic factor in patients with major depressive disorder

Objective

We assessed major cognitive domains in major depressive disorder (MDD) compared to a healthy control group using neurocognitive tests. We hypothesized that lower serum brain-derived neurotrophic factor (BDNF) levels would be associated with poorer neurocognitive performance in patients with major depression and that these associations would be shown in healthy controls as well.

Method

Executive functions, sustaining and focusing of attention, memory functions, and verbal fluency were assessed in this study using the Trail-Making Test (TMT), Stroop Color Word Interference Test-TBAG Form (SCWT), Wisconsin Card Sorting Test (WCST), Test of Variables of Attention (TOVA), Auditory Consonant Trigram test (ACTT), Digit Span subtest of the Wechsler Memory Scale (DST), Rey Auditory Verbal Learning Test (RAVLT), and Controlled Oral Word Association Test (COWAT).

Results

The MDD group showed significantly poorer performance than the control group in cognitive functions; they also had lower levels of BDNF than the control group. However, there was no correlation between cognitive performances and BDNF levels except in the TMT, Part B.

Conclusions

The current understanding of the importance of neurocognitive assessment and related biological markers in depression is improving. Further studies with larger sample sizes evaluating neurocognitive functions with molecular analyses of BDNF levels may reveal a novel marker for predicting and monitoring neurocognitive deficits in depression.     

The roles of BDNF in the pathophysiology of major depression and in antidepressant treatment

Neurotrophic factors are critical regulators of the formation and plasticity of neuronal networks. Brain-derived neurotrophic factor (BDNF) is abundant in the brain and periphery, and is found in both human serum and plasma. Animal studies have demonstrated that stress reduces BDNF expression or activity in the hippocampus and that this reduction can be prevented by treatment with antidepressant drugs. A similar change in BDNF activity occurs in the brain of patients with major depression disorder (MDD). Recently, clinical studies have indicated that serum or plasma BDNF levels are decreased in untreated MDD patients. Antidepressant treatment for at least four weeks can restore the decreased BDNF function up to the normal value. Therefore, MDD is associated with impaired neuronal plasticity. Suicidal behavior can be a consequence of severe impaired neuronal plasticity in the brain. Antidepressant treatment promotes increased BDNF activity as well as several forms of neuronal plasticity, including neurogenesis, synaptogenesis and neuronal maturation. BDNF could also play an important role in the modulation of neuronal networks. Such a neuronal plastic change can positively influence mood or recover depressed mood. These alterations of BDNF levels or neuronal plasticity in MDD patients before and after antidepressant treatment can be measured through the examination of serum or plasma BDNF concentrations. BDNF levels can therefore be useful markers for clinical response or improvement of depressive symptoms, but they are not diagnostic markers of major depression.     

A novel BDNF polymorphism affects plasma protein levels in interaction with early adversity in rhesus macaques

Early stressful events can increase vulnerability for psychopathology, although knowledge on the effectors is still limited. In this report we describe the characterization of a single nucleotide polymorphism (SNP) in rhesus macaques, which results in a Val to Met transition in the pro-BDNF domain, similar to a well described variant in the human gene. Further, we tested the hypothesis that peripheral levels of BDNF, which is involved in the response to stress and in the pathophysiology of anxiety and depression, might be differentially affected in a non-human primate model of early adverse rearing in a genotype-dependent manner. Males and females rhesus macaques reared either with their mothers (MR), in peer-only groups (PR), or in a "surrogate/peer-reared" (SPR) condition with limited peer interactions, were used as experimental subjects. BDNF levels were determined at baseline on postnatal days (PND) 14, 30 and 60 by means of specific ELISA procedure. Data indicate that BDNF levels were increased as a result of peer-rearing and that this increase was moderated by the presence of the SNP. Overall these data indicate that a SNP, which results in a Val to Met transition in the pro-BDNF domain, is present in rhesus macaques and is able to affect BDNF peripheral levels, thus making this primate model a fundamental tool to study gene by environment interactions involving the BDNF gene.     

Increased BDNF serum concentration in fibromyalgia with or without depression or antidepressants

Fibromyalgia (FM) is still often viewed as a psychosomatic disorder. However, the increased pain sensitivity to stimuli in FM patients is not an "imagined" histrionic phenomena. Pain, which is consistently felt in the musculature, is related to specific abnormalities in the CNS pain matrix. Brain-derived neurotrophic factor (BDNF) is an endogenous protein involved in neuronal survival and synaptic plasticity of the central and peripheral nervous system (CNS and PNS). Several lines of evidence converged to indicate that BDNF also participates in structural and functional plasticity of nociceptive pathways in the CNS and within the dorsal root ganglia and spinal cord. In the latter, release of BDNF appears to modulate or even mediate nociceptive sensory inputs and pain hypersensitivity. We were interested, if BDNF serum concentration may be altered in FM. The present pilot study assessed to our knowledge for the first time BDNF serum concentrations in 41 FM patients in comparison to 45 age-matched healthy controls. Mean serum levels of BDNF in FM patients (19.6 ng/ml; SD 3.1) were significantly increased as compared to healthy controls (16.8 ng/ml; SD 2.7; p<0.0001). In addition, BDNF serum concentrations in FM patients were independent from age, gender, illness duration, preexisting recurrent major depression and antidepressive medication in low doses. In conclusion, the results from our study indicate that BDNF may be involved in the pathophysiology of pain in FM. Nevertheless, how BDNF increases susceptibility to pain is still not known.     

Reduced serum BDNF levels in patients with chronic schizophrenic disorder in relapse,who were treated with typical or atypical antipsychotics

Brain-derived neurotrophic factor signals and dopaminergic function in the brain are strongly associated, and research on BDNF in schizophrenia may enhance our insights on the pathophysiological mechanisms of this disease. In the present study we aimed to investigate the possible association between serum BDNF levels and schizophrenic relapses and the possible differential effects of treatment with typical and atypical antipsychotics on serum BDNF levels in the same group of patients. We measured serum BDNF levels in 47 patients with schizophrenia during a relapse and again 6 weeks after administration of antipsychotic treatment (14 on risperidone, 18 on haloperidol, 10 on olanzapine and five on amisulpride) and in 44 healthy volunteers. Patients with schizophrenia showed reduced serum BDNF levels in relation to healthy volunteers at study entry. No significant differences were revealed in BDNF serum levels after 6 weeks of antipsychotic treatment in the patients compared to their own levels at study entry. However, serum BDNF was significantly increased in the subgroup receiving olanzapine compared to the other antipsychotics. Our findings may indicate a differential effect of olanzapine on BDNF levels compared to haloperidol, risperidone, and amisulpride.     

Effects of antipsychotics on the serum BDNF levels in schizophrenia

Brain-derived neurotrophic factor (BDNF) is active during a critical developmental period and likely influences the neuroplasticity of schizophrenia. This study longitudinally examined the effects of atypical antipsychotics on serum BDNF levels in schizophrenic patients. Specifically, this study measured serum BDNF levels in 53 patients with paranoid schizophrenia during a relapse and again 4 weeks following the administration of antipsychotic treatment (with risperidone in 32 cases, and clozapine in 21 cases). BDNF levels remained unchanged relative to study entry after 4 weeks of atypical antipsychotic treatment. However, serum BDNF was significantly increased in the subgroup receiving risperidone compared to that receiving clozapine, albeit only in the 15 male subjects and not in the 17 females. These results suggest that gender might significantly influence the antipsychotic treatment of schizophrenia from the perspective of BDNF. These findings may also indicate that the treatment with atypical antipsychotic agents differentially affects BDNF levels.     

Genetics of serum BDNF: Meta-analysis of the Val66Met and genome-wide association study

Abstract

Objectives. Lower levels of serum brain derived neurotrophic factor (BDNF) is one of the best known biomarkers of depression. To identify genetic variants associated with serum BDNF, we tested the Val66Met (rs6265) functional variant and conducted a genome-wide association scan (GWAS). Methods. In a community-based sample (N = 2054; aged 19–101, M = 51, SD = 15) from Sardinia, Italy, we measured serum BDNF concentration and conducted a GWAS. Results. We estimated the heritability of serum BDNF to be 0.48 from sib-pairs. There was no association between serum BDNF and Val66Met in the SardiNIA sample and in a meta-analysis of published studies (k = 13 studies, total n = 4727, P = 0.92). Although no genome-wide significant associations were identified, some evidence of association was found in the BDNF gene (rs11030102, P = 0.001) and at two loci (rs7170215, P = 4.8 × 10^–5 and rs11073742 P = 1.2 × 10^–5) near and within NTRK3 gene, a neurotrophic tyrosine kinase receptor. Conclusions. Our study and meta-analysis of the literature indicate that the BDNF Val66Met variant is not associated with serum BDNF, but other variants in the BDNF and NTRK3 genes might regulate the level of serum BDNF.     

Association between serum brain-derived neurotrophic factor and plasma interleukin-6 in major depressive disorder with melancholic features

Inflammatory processes as well as attenuation of brain-derived neurotrophic factor (BDNF) availability are involved in the pathophysiology of major depressive disorder (MDD). Although it is generally presumed that these two systems interact negatively in the brain, preclinical and human in vitro studies have shown synergistic rather than antagonistic interactions in the periphery. We therefore examined the association between serum levels of BDNF and plasma levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) in patients with MDD (n = 1070) and non-depressed controls (n = 379) from the Netherlands Study of Depression and Anxiety. We used multiple regression analyses with serum BDNF as the dependent variable and we specifically tested the presence of BDNF–cytokine associations in DSM-IV-assigned melancholic MDD patients, identified by the Inventory of Depressive Symptomatology. After adjustment for sociodemographics, sampling variability, lifestyle indicators, somatic diseases and medication use, BDNF levels were predicted by the interaction between MDD diagnosis and IL-6 (p-interaction = .006). Stratified analyses showed that BDNF levels are indeed positively associated with IL-6 levels in MDD patients (β = .07, p = .02), but not in non-depressed controls (β = −.07, p = .23). When further stratified for melancholic and non-melancholic MDD (p-interaction = .005), IL-6 emerged as a robust positive predictor of BDNF only in the melancholic sample (β = .21, p = .01), wherein serum BDNF levels were accordingly enhanced. Post-hoc exploratory analyses verified an accentuated positive association of BDNF levels with leucocyte counts in melancholia. No significant associations emerged between BDNF and TNF-α. Overall, our cross-sectional approach may have disclosed an allostatic, BDNF-inducing component of peripheral immunity and/or an immunotrophic function of peripheral BDNF. Both scenarios may warrant further exploration, as they could inform new research concepts towards immune-based antidepressive treatment strategies.     

Treatment with risperidone for 4 weeks increased plasma 3-methoxy-4-hydroxypnenylglycol (MHPG) levels, but did not alter plasma brain-derived neurotrophic factor (BDNF) levels in schizophrenic patients

In the present study, we investigated the effects of risperidone treatment for 4 weeks on plasma levels of 3-methoxy-4-hydroxyphenylglycol (MHPG) and brain-derived neurotrophic factor (BDNF) in 89 schizophrenic patients. We also compared the plasma levels of BDNF and MHPG between the schizophrenic group and 103 sex-and age-matched normal controls. In addition, we investigated the effects of two SNPs of the noradrenaline transporter (NAT) gene on plasma levels of MHPG, BDNF, and clinical improvement. The mean dose of risperidone was 3.8+/-1.4 mg/day. We demonstrated that treatment with risperidone increased plasma MHPG levels, and this increase was associated with an improvement of the negative symptoms of schizophrenia. In contrast, plasma BDNF did not change after 4 weeks of risperidone treatment, and the two SNPs in NAT did not influence the response to risperidone treatment or plasma MHPG and BDNF levels. These results suggest that the enhancement of noradrenergic neurons by risperidone, which occurs independently of the two SNPs of NAT, plays a role in the clinical efficacy of the drug.     

精神分裂症迟发性运动障碍患者血清脑源性神经营养因子水平研究

目的 通过比较迟发性运动障碍(TD)、非TD精神分裂症患者(TD-)和正常对照人群血清脑源性神经营养因子(BDNF)水平,探索外周BDNF浓度与TD的关系。方法 运用酶联免疫吸附法(EISIA),检测104例TD、46例TD-患者和44名正常人血清BDNF、浓度,选取46例一般状况与TD-组匹配的TD患者与TD-、正常对照组血清BDNF水平进行比较;对104例TD患者血清BDNF浓度与异常不自主运动量表(AIMS)各项分值之和进行线性回归分析。结果 46例TD和TD-患者血清BDNF水平与正常对照组比较,有显著性差异(P<0.05);TD与TD-组间无显著差异(P>0.05)。104例TD患者血清BDNF水平与AIMS各项分值之和的相关系数为0.359,相关系数显著性检验,P<0.001。结论 慢性精神分裂症患者外周BDNF浓度下降,伴发TD的患者异常运动严重程度与BDNF水平显著相关。     

Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants.

BACKGROUND: Because researchers have reported that antidepressants increase the expression of brain-derived neurotrophic factor (BDNF) in the rat hippocampus, we investigated whether serum BDNF levels may be used as a putative biological marker for major depressive disorders (MDD). METHODS: We measured serum BDNF in the following three groups: antidepressant-naive patients with MDD (n = 16), antidepressant-treated patients with MDD (n = 17), and normal control subjects (n = 50). Patients were evaluated using the Hamilton Rating Scale for Depression (HAM-D). Serum BDNF was assayed with the sandwich ELISA method. RESULTS: We found that serum BDNF was significantly lower in the antidepressant-naive group (mean, 17.6 ng/mL; SD, 9.6) than in the treated (mean, 30.6 ng/mL; SD, 12.3; p =.001) or in the control group (mean, 27.7 ng/mL; SD, 11.4; p =.002). There was a significant negative correlation (r = -.350, z = -2.003, p =.045) between serum BDNF and HAM-D scores in all patients. In a preliminary examination, reduced BDNF values of three drug-naive patients recovered to basal levels after antidepressant treatment. CONCLUSIONS: Our study suggests that low BDNF levels may play a pivotal role in the pathophysiology of MDD and that antidepressants may increase BDNF in depressed patients.     

Effects of fluoxetine and venlafaxine on serum brain derived neurotrophic factor levels in depressed patients

Background

Several studies demonstrated that depressed patients had low serum BDNF levels which correlated with the severity of their depression, and antidepressant treatment increases levels of serum BDNF in depressed patients. It was speculated that agents acting on both noradrenergic and serotonergic transporters might have a greater influence on BDNF levels. The aim of our study was to determine effects of venlafaxine vs. fluoxetine on serum BDNF levels in depressive patients.

Methods

Forty-three patients diagnosed as major depressive disorder according to DSM-IV are included in the study. Forty-three patients were randomized to take fluoxetine (22 cases) or venlafaxine (21 cases). Serum levels of BDNF were measured by ELISA at baseline and 6 weeks after the start of treatment.

Results

Baseline levels of BDNF were not significantly different between the patient group and the controls. But male patients and the male controls showed statistical differences with respect to baseline BDNF levels. BDNF levels of the patient group did not change with treatment. Yet, the increase of BDNF levels was close to statistically significant in the fluoxetine group, whereas not significant in the venlafaxine group. There were no significant differences in baseline and 6th week BDNF levels between the responders and the non-responders.

Conclusion

Further studies controlling for a wide variety of confounding variables are needed, which may help to reach a clear conclusion about the potential of BDNF as a biomarker for depression or as a predictor of antidepressant efficacy.     

The role of BDNF as a mediator of neuroplasticity in bipolar disorder

The cognitive impairment and neuroanatomical changes that takes place among patients with bipolar disorder (BD) patients has been well described. Recent data suggest that changes in neuroplasticity, cell resilience and connectivity are the main neuropathological findings in BD. Data from differential lines of research converges to the brain-derived neurotrophic factor (BDNF) as an important contributor to the neuroplasticity changes described among BD patients. BDNF serum levels have been shown to be decreased in depressive and manic episodes, returning to normal levels in euthymia. BDNF has also been shown to decrease as the disorder progresses. Moreover, factors that negatively influence the course of BD, such as life stress and trauma have been shown to be associated with a decrease in BDNF serum levels. These findings suggest that BDNF plays a central role in the progression of BD. The present review discusses the role of BDNF as a mediator of the neuroplastic changes that occur in portion with mood episodes and the potential use of serum BDNF as a biomarker in BD.     

抑郁发作自杀未遂患者脑源性神经营养因子水平及其相关因素研究

目的 探讨脑源性神经营养因子(BDNF)在抑郁发作自杀未遂者中的可能作用.方法 对抑郁发作自杀未遂患者(自杀未遂组,23例)和抑郁发作无自杀行为患者(无自杀组,24例)采用汉密尔顿抑郁量表(24项,HAMD24)、Beck绝望量表(BHS)和自杀意念自评量表(SIOSS)评定抑郁严重程度、绝望程度及自杀意图的强烈程度;采用酶联免疫吸附法测定其血清BDNF浓度,并与正常对照者(对照组,30名)比较;对自杀未遂组的血清BDNF浓度与各相关因素进行Pearson相关分析.结果 (1)自杀未遂组的HAMD24[(37.8±8.7)分]、BHS[(13.0±3.8)分]及SIOSS评分[(18.1±3.9)分]均高于无自杀组[分别为(26.0±6.0)分、(7.5±4.3)分、(12.0±4.0)分;P<0.01].(2)自杀未遂组的BDNF平均浓度[(57 ±16)ng/L]低于无自杀组[(75 ±28)ng/L;P<0.05],无自杀组的BDNF平均浓度亦低于正常对照组[(111±39)ng/L;P<0.01].(3)自杀未遂组的血清BDNF浓度与抑郁发作的病程(r=-0.541)、BHS总分(r=-0.494)、SIOSS总分(r=-0.754)呈负相关(P<0.01-0.05).结论 低水平的BDNF可能是抑郁发作自杀未遂的一个危险因素.