Blood BDNF Level Is Gender Specific in Severe Depression

Though the role of brain derived neurotrophic factor (BDNF) as a marker for major depressive disorder (MDD) and antidepressant efficacy has been widely studied, the role of BDNF in distinct groups of patients remains unclear. We evaluated the diagnostic value of BDNF as a marker of disease severity measured by HAM-D scores and antidepressants efficacy among MDD patients. Fifty-one patients who met DSM-IV criteria for MDD and were prescribed antidepressants and 38 controls participated in this study. BDNF in serum was measured at baseline, 1st, 2nd and 8th treatment weeks. Depression severity was evaluated using the Hamilton Rating Scale for Depression (HAM-D). BDNF polymorphism rs6265 (val66met) was genotyped. We found a positive correlation between blood BDNF levels and severity of depression only among untreated women with severe MDD (HAM-D>24). Serum BDNF levels were lower in untreated MDD patients compared to control group. Antidepressants increased serum BDNF levels and reduced between-group differences after two weeks of treatment. No correlations were observed between BDNF polymorphism, depression severity, duration of illness, age and BDNF serum levels. Further supporting the role of BDNF in the pathology and treatment of MDD, we suggest that it should not be used as a universal biomarker for diagnosis of MDD in the general population. However, it has diagnostic value for the assessment of disease progression and treatment efficacy in individual patients.     

Diagnostic Criteria for Depression in Type 2 Diabetes: A Data-Driven Approach

BackgroundWhile depression is a frequent psychiatric comorbid condition in diabetes and has significant clinical impact, the syndromal profile of depression and anxiety symptoms has not been examined in detail.AimsTo determine the syndromal pattern of the depression and anxiety spectrum in a large series of patients with type 2 diabetes, as determined using a data-driven approach based on latent class analysis (LCA).MethodType 2 diabetes participants from the observational community-based Fremantle Diabetes Study Phase II underwent assessment of lifetime depression using the Brief Lifetime Depression Scale, the Patient Health Questionnaire 9-item version (PHQ-9) for current depression symptoms, and the Generalized Anxiety Disorder Scale that was specifically developed and validated for this study. The main outcome measure was classes of patients with a specific syndromal profile of depression and anxiety symptoms based on LCA.ResultsLCA identified four classes that were interpreted as “major anxious depression”, “minor anxious depression”, “subclinical anxiety”, and “no anxious depression”. All nine DSM-IV/5 diagnostic criteria for major depression identified a class with a high frequency of major depression. All symptoms of anxiety had similar high probabilities as symptoms of depression for the “major depression-anxiety” class. There were significant differences between classes in terms of history of depression and anxiety, use of psychoactive medication, and diabetes-related variables.ConclusionsPatients with type 2 diabetes show specific profiles of depression and anxiety. Anxiety symptoms are an integral part of major depression in type 2 diabetes. The different classes identified here provide empirically validated phenotypes for future research.     

Is Pain Intensity Really That Important to Assess in Chronic Pain Patients? A Study Based on the Swedish Quality Registry for Pain Rehabilitation (SQRP)

Background

Incorporating the patient''s view on care and treatment has become increasingly important for health care. Patients describe the variety of consequences of their chronic pain conditions as significant pain intensity, depression, and anxiety. We hypothesised that intensities of common symptoms in chronic pain conditions carry important information that can be used to identify clinically relevant subgroups. This study has three aims: 1) to determine the importance of different symptoms with respect to participation and ill-health; 2) to identify subgroups based on data concerning important symptoms; and 3) to determine the secondary consequences for the identified subgroups with respect to participation and health factors.

Methods and Subjects

This study is based on a cohort of patients referred to a multidisciplinary pain centre at a university hospital (n = 4645, participation rate 88%) in Sweden. The patients answered a number of questionnaires concerning symptoms, participation, and health aspects as a part of the Swedish Quality Registry for Pain Rehabilitation (SQRP).

Results

Common symptoms (such as pain intensity, depression, and anxiety) in patients with chronic pain showed great variability across subjects and 60% of the cohort had normal values with respect to depressive and anxiety symptoms. Pain intensity more than psychological symptoms showed stronger relationships with participation and health. It was possible to identify subgroups based on pain intensity, depression, and anxiety. With respect to participation and health, high depressive symptomatology had greater negative consequences than high anxiety.

Conclusions

Common symptoms (such as pain intensity and depressive and anxiety symptoms) in chronic pain conditions carry important information that can be used to identify clinically relevant subgroups.     

BDNF moderates early environmental risk factors for anxiety in mouse

Anxiety is known to be influenced by both adverse childhood experiences and genetic susceptibility factors. A polymorphism in the brain‐derived neurotrophic factor (BDNF) gene modulates the association between adverse early experiences and risk for anxiety and depression in adulthood. An animal model of this gene‐by‐environment risk factor is lacking. Using two different early environmental manipulations, we found that a heterozygous null mutation in the mouse BDNF gene moderated the long‐term effect of maternal care on innate anxiety behavior. Although changes in maternal care were associated with mild changes in anxiety in wild‐type mice, this effect was magnified in heterozygous null BDNF mice with high‐ and low‐maternal care associated with low and high levels, respectively, of avoidance behavior as measured in the open field and elevated plus maze tests. These data argue for an increased sensitivity to early environmental influences of mice with reduced BDNF function and support the important role of this neurotrophic factor in the developmental plasticity of brain circuits controlling anxiety.     

DNA methylation profiles of the brain-derived neurotrophic factor (BDNF) gene as a potent diagnostic biomarker in major depression

Major depression, because of its recurring and life-threatening nature, is one of the top 10 diseases for global disease burden. Major depression is still diagnosed on the basis of clinical symptoms in patients. The search for specific biological markers is of great importance to advance the method of diagnosis for depression. We examined the methylation profile of 2 CpG islands (I and IV) at the promoters of the brain-derived neurotrophic factor (BDNF) gene, which is well known to be involved in the pathophysiology of depression. We analyzed genomic DNA from peripheral blood of 20 Japanese patients with major depression and 18 healthy controls to identify an appropriate epigenetic biomarker to aid in the establishment of an objective system for the diagnosis of depression. Methylation rates at each CpG unit was measured using a MassArray® system (SEQUENOM), and 2-dimensional hierarchical clustering analyses were undertaken to determine the validity of these methylation profiles as a diagnostic biomarker. Analyses of the dendrogram from methylation profiles of CpG I, but not IV, demonstrated that classification of healthy controls and patients at the first branch completely matched the clinical diagnosis. Despite the small number of subjects, our results indicate that classification based on the DNA methylation profiles of CpG I of the BDNF gene may be a valuable diagnostic biomarker for major depression.     

Increased Plasma Levels of Brain Derived Neurotrophic Factor (BDNF) in Patients with Fibromyalgia

Brain-derived neurotrophic factor (BDNF) is involved in neuronal survival and synaptic plasticity of the central and peripheral nervous system. BDNF appears to modulate nociceptive sensory inputs and pain hypersensitivity and has been studied in pathological situations, including chronic pain conditions and major depression. Increased serum BDNF levels have been recently reported in fibromyalgia (FM). In the present study, we assessed plasma BDNF levels in patients with FM and controls. Plasma BDNF was measured from 30 female patients with FM and 30 healthy age- and gender-matched volunteers using an enzyme immunoassay. FM patients showed higher levels of BDNF (FM = 167.1 ± 171.2 pg/mL) when compared with the control group (control = 113.8 ± 149.6 pg/mL) (P = 0.049; Mann–Whitney test). Six out of 30 controls presented superior values to the medium (15/15) of the patients with fibromyalgia (129 pg/mL) (P = 0.029, Fisher exact test). There was no correlation between plasma BDNF levels and age, disease duration, pain score, number of pain points and HAM-D score. Our results confirm previous findings of increased plasma BDNF levels in patients with FM, suggesting that BDNF may be involved in the pathophysiology of Fibromyalgia, despite high levels of depression.     

重复经颅磁刺激对卒中后抑郁的治疗效果及机制

卒中后抑郁（post-stroke depression,PSD）是并发于脑血管病的一种情感障碍疾病，发病率高，预后差。重复经颅磁刺激（repetitive transcranial magnetic stimulation,r TMS）是通过磁场变化在大脑中产生感应电流来刺激皮层的非创伤性脑刺激技术，是临床上治疗PSD的一种重要非药物治疗方法，可以显著改善PSD患者的抑郁症状。但目前rTMS的作用机制不明确。本文总结了PSD治疗中有效的rTMS刺激方案，并结合PSD的单胺类神经递质相关致病假说及PSD的临床治疗手段，探索了rTMS通过对单胺类神经递质的调控参与PSD治疗的可能机制。rTMS刺激诱导的皮层单胺类递质释放增加、葡萄糖代谢上升、皮层兴奋性增加，提高了单胺类神经递质和脑源性神经营养因子（brain-derived neurotrophic factor,BDNF）水平，进而引发前额叶抑制功能上升、与下游脑区连接改变、脑网络功能的调整，可能是rTMS治疗PSD的重要机制之一。     

Temperament Traits and Chronic Pain: The Association of Harm Avoidance and Pain-Related Anxiety

Objective

Anxiety symptoms are common in chronic pain patients. High levels of anxiety are associated with increased pain experience and disability. Proneness to anxiety has a large interindividual variation. The aim of the study was to determine whether the anxiety-related temperament trait Harm Avoidance (HA), is associated with pain-related anxiety.

Methods

One hundred chronic pain patients in a multidisciplinary pain clinic participated in the study. The patients were assessed using the HA scale of the Temperament and Character Inventory (TCI) of Cloninger and Pain Anxiety Symptoms Scale-20 (PASS-20). Both the HA total score and the four subscales of HA were analyzed. Current pain intensity was measured using the Visual Analogue Scale (VAS). The Beck Depression Inventory (BDI) was used to control for the influence of depression on the personality measurement.

Results

The HA total score was associated with PASS-20, but the association became non-significant after controlling for depression. The HA4 Fatigability subscale was associated with the PASS scales. Depression did not influence this association. Pain intensity was not correlated with HA or the PASS scales. However, the association between HA4 Fatigability and PASS was influenced by pain intensity. Higher pain intensity was associated with stronger association between the scales.

Conclusion

Harm Avoidance, representing temperament and trait-related anxiety, has relevance in pain-related anxiety. Assessing personality and temperament may deepen the clinician''s understanding of the pain experience and behavior in chronic pain patients.     

Stress and psychophysiological dysregulation in patients with fibromyalgia syndrome

Fibromyalgia syndrome (FMS) is a prevalent musculoskeletal pain disorder characterized by diffuse pain and associated psychophysiological symptoms. Despite extensive research in the past 3 decades, the etiology and pathophysiology of FMS and effective treatment approaches are yet to be delineated. Recently, it has been suggested that FMS may be related to hypofunctional stress systems, particularly in the autonomic nervous system (ANS) and the hypothalamic-pituitary-adrenal (HPA) axis. Studies have demonstrated that patients with FMS exhibit lowered sympathoadrenal reactivity to stress. These findings seem to be consistent with the large volume of research indicating the inverse relationship between pain sensitivity and sympathetic reactivity. In this paper, we discuss the role of stress in the pain experience in general, stress in patients with FMS, and review the studies evaluating the ANS and HPA functions in response to various stressors.     

Abnormality of circadian rhythm of serum melatonin and other biochemical parameters in fibromyalgia syndrome

Fibromyalgia syndrome (FMS) is a complex chronic condition causing widespread pain and variety of other symptoms. It produces pain in the soft tissues located around joints throughout the body. FMS has unknown etiology and its pathophysiology is not fully understood. However, abnormality in circadian rhythm of hormonal profiles and cytokines has been observed in this disorder. Moreover, there are reports of deficiency of serotonin, melatonin, cortisol and cytokines in FMS patients, which are fully regulated by circadian rhythm. Melatonin, the primary hormone of the pineal gland regulates the body's circadian rhythm and normally its levels begin to rise in the mid-to-late evening, remain high for most of the night, and then decrease in the early morning. FMS patients have lower melatonin secretion during the hours of darkness than the healthy subjects. This may contribute to impaired sleep at night, fatigue during the day and changed pain perception. Studies have shown blunting of normal diurnal cortisol rhythm, with elevated evening serum cortisol level in patients with FMS. Thus, due to perturbed level of cortisol secretion several symptoms of FMS may occur. Moreover, disturbed cytokine levels have also been reported in FMS patients. Therefore, circadian rhythm can be an important factor in the pathophysiology, diagnosis and treatment of FMS. This article explores the circadian pattern of abnormalities in FMS patients, as this may help in better understanding the role of variation in symptoms of FMS and its possible relationship with circadian variations of melatonin, cortisol, cytokines and serotonin levels.     

Psychopathological symptoms in patients with primary hyperaldosteronism--possible pathways

A close comorbidity between endocrine diseases and psychopathological symptoms has been described in the literature. Until now only a few studies have reported about an increased anxiety and depressive symptoms in patients with primary hyperaldosteronism (PHA). The exact pathways of psychiatric comorbidities have not been totally clarified yet, although the renin-angiotensin-aldosterone-system has gained more attention in research on anxiety and depression. There are several structures and factors, which could mediate anxiety or a depressive symptomatology. Additionally a possible influence of the standardised treatment with a mineralocorticoidreceptor (MR) antagonist or adrenalectomy should be investigated as they have been shown to affect mood. Psychiatric comorbidities are not only an additional burden in these patients, but as depression and anxiety are additional risk factors in patients with cardiovascular diseases. Possible pathomechanisms in the relation between PHA and psychiatric symptoms should be more closely investigated. For the clinical practice a regular screening for psychiatric comorbidities and an adequate treatment are required.     

Validation of the Fibromyalgia Survey Questionnaire within a cross-sectional survey

The Fibromyalgia Survey Questionnaire (FSQ) assesses the key symptoms of fibromyalgia syndrome. The FSQ can be administrated in survey research and settings where the use of interviews to evaluate the number of pain sites and extent of somatic symptom intensity and tender point examination would be difficult. We validated the FSQ in a cross-sectional survey with FMS patients. In a cross-sectional survey, participants with physician diagnosis of FMS were recruited by FMS-self help organisations and nine clinical institutions of different levels of care. Participants answered the FSQ (composed by the Widespread Pain Index [WPI] and the Somatic Severity Score [SSS]) assessing the Fibromyalgia Survey Diagnostic Criteria (FSDC) and the Patient Health Questionnaire PHQ 4. American College of Rheumatology 1990 classification criteria were assessed in a subgroup of participants. 1,651 persons diagnosed with FMS were included into analysis. The acceptance of the FSQ-items ranged between 78.9 to 98.1% completed items. The internal consistency of the items of the SSS ranged between 0.75-0.82. 85.5% of the study participants met the FSDC. The concordance rate of the FSDC and ACR 1990 criteria was 72.7% in a subsample of 128 patients. The Pearson correlation of the SSS with the PHQ 4 depression score was 0.52 (p<0.0001) and with the PHQ anxiety score was 0.51 (p<0.0001) (convergent validity). 64/202 (31.7%) of the participants not meeting the FSDC criteria and 152/1283 (11.8%) of the participants meeting the FSDC criteria reported an improvement (slightly too very much better) in their health status since FMS-diagnosis (Chi(2)?=?55, p<0.0001) (discriminant validity). The study demonstrated the feasibility of the FSQ in a cross-sectional survey with FMS-patients. The reliability, convergent and discriminant validity of the FSQ were good. Further validation studies of the FSQ in clinical and general population settings are necessary.     

Biology and therapy of fibromyalgia. Genetic aspects of fibromyalgia syndrome

Genetic and environmental factors may play a role in the etiopathology of fibromyalgia syndrome (FMS) and other related syndromes. There is a high aggregation of FMS in families of FMS patients. The mode of inheritance is unknown but it is most probably polygenic. There is evidence that polymorphisms of genes in the serotoninergic, dopaminergic and catecholaminergic systems play a role in the etiology of FMS. These polymorphisms are not specific for FMS and are associated with other functional somatic disorders and depression. Future genetic studies in the field of FMS and related conditions should be conducted in larger cohorts of patients and ethnically matched control groups.     

Anxiety and depression in children and adults: influence of serotonergic and neurotrophic genes?

There are two major hypotheses regarding the etiology of anxiety and depression: the mono‐amine hypothesis and the hypothesis of an abnormal stress response acting partly via reduced neurogenesis. Association studies have focused on genes involved in these processes, but with inconclusive results. This study investigated the effect of 45 single nucleotide polymorphisms (SNPs) in genes encoding for serotonin receptors 1A, 1D, 2A, catechol‐O‐methyltransferase (COMT), tryptophane hydroxylase type 2 (TPH2), brain derived neurotrophic factor (BDNF), PlexinA2 and regulators of G‐protein‐coupled signaling (RGS) 2, 4, 16. Anxious depression (A/D) symptoms were assessed five times in 11 years in over 11 000 adults with 1504 subjects genotyped and at age 7, 10, 12 and during adolescence in over 20 000 twins with 1078 subjects genotyped. In both cohorts, a longitudinal model with one latent factor loading on all A/D measures over time was analysed. The genetic association effect modeled at the level of this latent factor was 60% and 70% heritable in the children and adults, respectively, and explained around 50% of the total phenotypic variance. Power analyses showed that the samples contained 80% power to detect an effect explaining between 1.4% and 3.6% of the variance. However, no SNP showed a consistent effect on A/D. To conclude, this longitudinal study in children and adults found no association of SNPs in the serotonergic system or core regulators of neurogenesis with A/D. Overall, there has been no convincing evidence, so far, for a role of genetic variation in these pathways in the development of anxiety and depression.     

Morningness-eveningness and social anxiety symptoms: the influence of depression symptoms on the indirect effect through punishment sensitivity and experiential avoidance

Social anxiety has recently been linked to morningness-eveningness; however, the psychological mechanisms underlying this relationship are not well known. As such, the purpose of the current study is to propose a model by which morningness-eveningness is related to social anxiety symptoms through punishment sensitivity and experiential avoidance within an adult American, community sample recruited via Amazon’s Mechanical Turk (MTurk). It was hypothesized that experiential avoidance and punishment sensitivity would be associated with increased social anxiety symptoms and that morningness-eveningness would be negatively related to social anxiety symptoms. Furthermore, eveningness was hypothesized to be associated with increased punishment sensitivity and in turn, greater experiential avoidance. Lastly, the relationship between morningness-eveningness and social anxiety was hypothesized to be mediated by punishment sensitivity among the group with high depression levels, but not among the group with lesser depression symptoms. The results indicated that eveningness was related to social anxiety symptoms through experiential avoidance, and that depression symptoms influenced the relationship between morningness-eveningness and punishment sensitivity such that, in those high in depression symptoms, there was a significant association between eveningness and punishment sensitivity, but not among those with lower depression levels. The study findings build upon existing chronobiological research and addresses inconsistencies in previous literature.     

Association between the Val66Met polymorphism of brain-derived neurotrophic factor gene and schizophrenia in Russians

Recent studies have demonstrated a role of the brain-derived neurotrophic factor (BDNF) in schizophrenia. An association between the Val66Met BDNF polymorphism has been reported but the results of different studies are inconsistent. An aim of the present article is to study the allele and genotype distribution in patients with schizophrenia (783) and mentally healthy controls (633). No statistically significant between-group differences have been found. When the group of patients has been stratified by sex and form of schizophrenia, the higher frequency of the Val/Val genotype is observed in the subgroup of men with continuous (chronic) schizophrenia as compared to men with attack-like form (p = 0.047). Clinical symptoms assessed with the PANSS were more severe in male patients with the Val/Val genotype. The Val66Met polymorphism was not associated with forms of schizophrenia or clinical symptoms in female patients. The results obtained suggest that the association between the BDNF gene and schizophrenia may be related to sex and clinical heterogeneity of disease. The Val/Val genotype is associated with severer form of schizophrenia in men.     

Oxytocin Prevents the Development of 3-NP-Induced Anxiety and Depression in Male and Female Rats: Possible Interaction of OXTR and mGluR2

Huntington disease (HD) is a progressive neurological disorder with dominant motor symptoms. It also has psychiatric manifestations, like anxiety and depression, that can emerge themselves before motor symptoms and impose a major burden on patients. Oxytocin (OXT) is a newly emerged treatment for disorders like autism and schizophrenia and recently is using to alleviate depression and anxiety. In the current study, we investigated the behavioral and molecular effects of OXT on the development of anxiety and depression in 3-nitropropionic acid (3-NP)-induced model of HD. Anxiety- and depression-like behaviors as well as the levels of oxytocin receptor (OXTR), metabotropic glutamate receptor (mGluR) 2, mGluR5, and glutathione (GSH) were measured in striatum, hippocampus, prefrontal cortex, and amygdala. Also, we questioned if sex had any modulatory effect. We found that 3-NP increased anxiety and depression compared to controls. It also reduced the levels of OXTR and mGluR2, increased mGluR5, and reduced GSH in studied brain regions. Pretreatment with OXT before the injection of 3-NP ameliorated anxiety and depression. Additionally, it protected the brain from developing low levels of OXTR, mGluR2, and GSH and high levels of mGluR5 in studied regions. The protective effects of OXT were similar between male and female animals. These data suggest that OXTR, mGluR2, mGluR5, and GSH may contribute to psychiatric manifestations of HD. In addition, pretreatment with OXT could prevent the mood changes in male and female rats.