Increased serum IgM antibodies directed against phosphatidyl inositol (Pi) in chronic fatigue syndrome (CFS) and major depression: evidence that an IgM-mediated immune response against Pi is one factor underpinning the comorbidity between both CFS and depression

Major depression and chronic fatigue syndrome (CFS) are accompanied by signs of oxidative and nitrosative stress (O&NS) and an inflammatory response. Phosphatidyl inositol (Pi) is thought to play a role in depression. The aim of the present study is to examine whether depression and CFS are characterized by an IgM-mediated immune response directed against Pi. Toward this end, this study examines the serum IgM antibodies directed against Pi in 14 patients with major depression, 14 patients with CFS, 14 subjects with partial CFS, and in 11 normal controls. We found that the prevalence and mean value for the serum IgM levels directed against Pi were significantly greater in patients with major depression and CFS than in normal controls and patients with partial CFS. There were significant and positive correlations between serum IgM levels directed against Pi and two symptoms of the FibroFatigue Scale, i.e. fatigue and depression. The results show that an IgM-related immune response directed against Pi may occur in both depression and CFS and may play a role in the pathophysiology of the key symptom of CFS and major depression. It is suggested that the above disorders in Pi result from increased O&NS in both depression and CFS. Autoanti-Pi antibodies may have biological effects, for example, by changing inositol 1,4,5-triphosphate (IP3), phosphatidylinositol-4,5-bisphosphate (PIP2), diacylglycerol and phosphatidylinositol-3,4,5-triphosphate (PIP3) production, thus interfering with intracellular signalling processes. Future research in major depression and CFS should focus on the functional consequences of the immune responses directed against Pi.     

DNA methylation analysis of the angiotensin converting enzyme (ACE) gene in major depression

Background

The angiotensin converting enzyme (ACE) has been repeatedly discussed as susceptibility factor for major depression (MD) and the bi-directional relation between MD and cardiovascular disorders (CVD). In this context, functional polymorphisms of the ACE gene have been linked to depression, to antidepressant treatment response, to ACE serum concentrations, as well as to hypertension, myocardial infarction and CVD risk markers. The mostly investigated ACE Ins/Del polymorphism accounts for ∼40%–50% of the ACE serum concentration variance, the remaining half is probably determined by other genetic, environmental or epigenetic factors, but these are poorly understood.

Materials and Methods

The main aim of the present study was the analysis of the DNA methylation pattern in the regulatory region of the ACE gene in peripheral leukocytes of 81 MD patients and 81 healthy controls.

Results

We detected intensive DNA methylation within a recently described, functional important region of the ACE gene promoter including hypermethylation in depressed patients (p = 0.008) and a significant inverse correlation between the ACE serum concentration and ACE promoter methylation frequency in the total sample (p = 0.02). Furthermore, a significant inverse correlation between the concentrations of the inflammatory CVD risk markers ICAM-1, E-selectin and P-selectin and the degree of ACE promoter methylation in MD patients could be demonstrated (p = 0.01 - 0.04).

Conclusion

The results of the present study suggest that aberrations in ACE promoter DNA methylation may be an underlying cause of MD and probably a common pathogenic factor for the bi-directional relationship between MD and cardiovascular disorders.     

Decreased dehydroepiandrosterone sulfate but normal insulin-like growth factor in chronic fatigue syndrome (CFS): relevance for the inflammatory response in CFS

There are a few reports that chronic fatigue syndrome (CFS) may be accompanied by changes in hormones, such as dehydroepiandrosterone (DHEA) and insulin-like growth factor (IGF1). This study examines the serum concentrations of DHEA-sulfate (DHEAS), IGF1 and IGF1 binding protein-3 (IGFBP3) in 20 patients with CFS and in 12 normal controls. The IGFBP3/IGF1 ratio was computed as an index for IGF1 availability. We found significantly lower serum DHEAS concentrations in CFS, but no significant differences either in IGF1 or the IGFBP3/IGF1 ratio between CFS patients and normal controls. The decrease in serum DHEAS was highly sensitive and specific for CFS. There were significant and positive correlations between serum DHEAS and serum zinc and the mitogen-induced expression of the CD69 molecule on CD3+CD8+ T cells (an indicator of early T cell activation). There was a significant and negative correlation between serum DHEAS and the increase in the serum alpha-2 protein fraction (an inflammatory marker). Serum IGF1, but not DHEAS, was significantly and inversely correlated to age. The results show that CFS is accompanied by lowered levels of DHEAS and that the latter may play a role in the immune (defect in the early activation of T cells) and the inflammatory pathophysiology of CFS.     

Escitalopram in adolescent major depression

Escitalopram is the purified functional isomer contained in citalopram. Escitalopram is now prescribed in 26 countries. In the United States, the only US Food and Drug Administration (FDA)-approved selective serotonin reuptake inhibiter (SSRI) for adolescents is fluoxetine. However, in clinical practice all antidepressants are used in adolescents. Five patients had parents who opted for the use of escitalopram instead of other treatments. Reasons included poor response and side effects from other SSRIs. Specifically, escitalopram was considered possibly less likely to cause obesity than paroxetine. It also caused a lower frequency of akathisia than fluoxetine, more stable blood levels over years than sertraline, very low drug interactions, and a low onset of anxiety if using a 5-mg starting dose. Although studies in adolescents are very limited for escitalopram, its parent medication--citalopram--has been used in over 40 million patients. Parents and adolescent patients should be made aware of all antidepressant options, if psychopharmacology is indicated. In some patients, escitalopram may have use.     

Unravelling myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): Gender-specific changes in the microRNA expression profiling in ME/CFS

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multisystem illness characterized by medically unexplained debilitating fatigue with suggested altered immunological state. Our study aimed to explore peripheral blood mononuclear cells (PBMCs) for microRNAs (miRNAs) expression in ME/CFS subjects under an exercise challenge. The findings highlight the immune response and inflammation links to differential miRNA expression in ME/CFS. The present study is particularly important in being the first to uncover the differences that exist in miRNA expression patterns in males and females with ME/CFS in response to exercise. This provides new evidence for the understanding of differential miRNA expression patterns and post-exertional malaise in ME/CFS. We also report miRNA expression pattern differences associating with the nutritional status in individuals with ME/CFS, highlighting the effect of subjects' metabolic state on molecular changes to be considered in clinical research within the NINDS/CDC ME/CFS Common Data Elements. The identification of gender-based miRNAs importantly provides new insights into gender-specific ME/CFS susceptibility and demands exploration of sex-suited ME/CFS therapeutics.     

Acute unstable depressive syndrome (AUDS) is associated more frequently with epilepsy than major depression

Background  

Depressive disorders are frequent in epilepsy and associated with reduced seizure control. Almost 50% of interictal depressive disorders have to be classified as atypical depressions according to DSM-4 criteria. Research has mainly focused on depressive symptoms in defined populations with epilepsy (e.g., patients admitted to tertiary epilepsy centers). We have chosen the opposite approach. We hypothesized that it is possible to define by clinical means a subgroup of psychiatric patients with higher than expected prevalence of epilepsy and seizures. We hypothesized further that these patients present with an Acute Unstable Depressive Syndrome (AUDS) that does not meet DSM-IV criteria of a Major Depressive Episode (MDE). In a previous publication we have documented that AUDS patients indeed have more often a history of epileptic seizures and abnormal EEG recordings than MDE patients (Vaaler et al. 2009). This study aimed to further classify the differences of depressive symptoms at admittance and follow-up of patients with AUDS and MDE.     

Maintenance of Chronic Fatigue Syndrome (CFS) in Young CFS Patients Is Associated with the 5-HTTLPR and SNP rs25531 A > G Genotype

Earlier studies have shown that genetic variability in the SLC6A4 gene encoding the serotonin transporter (5-HTT) may be important for the re-uptake of serotonin (5-HT) in the central nervous system. In the present study we investigated how the 5-HTT genotype i.e. the short (S) versus long (L) 5-HTTLPR allele and the SNP rs25531 A > G affect the physical and psychosocial functioning in patients with chronic fatigue syndrome (CFS). All 120 patients were recruited from The Department of Paediatrics at Oslo University Hospital, Norway, a national referral center for young CFS patients (12–18 years). Main outcomes were number of steps per day obtained by an accelerometer and disability scored by the Functional Disability Inventory (FDI). Patients with the 5-HTT SS or SL_G genotype had a significantly lower number of steps per day than patients with the 5-HTT L_AL_G, SL_A or L_AL_A genotype. Patients with the 5-HTT SS or SL_G genotype also had a significantly higher FDI score than patients with the 5-HTT L_AL_G, SL_A or L_AL_A genotype. Thus, CFS patients with the 5-HTT SS or SL_G genotype had worse 30 weeks outcome than CFS patients with the 5-HTT L_AL_G, SL_A or L_AL_A genotype. The present study suggests that the 5-HTT genotype may be a factor that contributes to maintenance of CFS.     

Wolf-Hirschhorn (4p-)syndrome in a near adult with major depression; successful treatment with citalopram

The Wolf-Hirschhorn Syndrome (WHS) or 4p-deletion syndrome is characterized by mental retardation, growth retardation, microcephaly and typical facial features. In addition, a wide spectrum of somatic abnormalities can be associated that may cause comorbidity. The syndrome has been extensively described in children, but less information is available about adult patienis. In this case report a near adult female WHS patient is described who developed a major depression with atypical symptoms that was successfully treated with citalopram. Treatment for one year in the effective dose prevented recurrence of depressive symptomatology.     

Migraine headaches in Chronic Fatigue Syndrome (CFS): Comparison of two prospective cross-sectional studies

Background  

Headaches are more frequent in Chronic Fatigue Syndrome (CFS) than healthy control (HC) subjects. The 2004 International Headache Society (IHS) criteria were used to define CFS headache phenotypes.     

Low natural killer cytotoxicity in major depression

Natural killer cell cytotoxicity was significantly lower in a group of hospitalized depressed men than in matched controls. The absolute number of neutrophils was increased in the depressed group, but the numbers of other cell types did not differ between groups. These findings further demonstrate that altered immunity is a biologic concomitant of affective disorders.     

Thyroid activity in patients with major depression

Hypothalamus-pituitary-thyroid (HPT) axis dysfunction has been associated with pathophysiology of major depression. The aim of the study was to determine serum levels of total 3,5,3'-triiodothyronine (T3), total thyroxine (T4) and thyroid-stimulating-hormone (TSH) in patients with major depression and healthy controls. The study included 53 medication-free patients with depression and 49 healthy controls. Exclusion criteria for patients was: other axis-I and axis-II diagnoses, intensive psychotherapy or electroconvulsive therapy, prior clinical and/or laboratory evidence of hypo- or hyperthyroidism, alcohol or nicotine dependence, pregnancy, hormone supplement therapy, somatic illnesses (diabetes, renal or hepatic disorders), infections or autoimmune diseases, recent surgical treatment or significantly changed body weight. For controls: the presence of psychiatric disorders and/or thyroid dysfunctions. The diagnosis of major depression was made using structured clinical interview based on DSM-IV criteria. The results showed significantly lower T3 and TSH levels in patients compared to controls. There was no significant difference in T4 values between patients with depression and control subjects. The results showing altered levels of thyroid hormones in depression indicate that further research on thyroid hormone activity can contribute to the better understanding of the biological basis of depression. Based on the high frequency of the subtle neuroendocrine disorders coexisting with depression, the association of thyroid abnormalities and depression should not be underestimated. Future research should identify different behavioral endophenotypes characteristic for depression, which would greatly facilitate delineating the biological phenomena associated with this psychiatric illness.     

Neuroendocrine aspects of hypercortisolism in major depression

A consistent finding in biological psychiatry is that hypothalamic-pituitary-adrenal (HPA) axis physiology is altered in humans with major depression. These findings include hypersecretion of cortisol at baseline and on the dexamethasone suppression test. In this review, we present a process-oriented model for HPA axis regulation in major depression. Specifically, we suggest that acute depressions are characterized by hypersecretion of hypothalamic corticotropin-releasing factor, pituitary adrenocorticotropic hormone (ACTH), and adrenal cortisol. In chronic depressions, however, enhanced adrenal responsiveness to ACTH and glucocorticoid negative feedback work in complementary fashion so that cortisol levels remain elevated while ACTH levels are reduced. In considering the evidence for hypercortisolism in humans, studies of nonhuman primates are presented and their utility and limitations as comparative models of human depression are discussed.     

Treatment of major depression with steroid suppressive drugs

The hypercorticism frequently observed in major depression, unaccompanied by signs of Cushing's syndrome, is still poorly understood. One suicidal young woman, with very high cortisol levels and unusual resistance to dexamethasone suppression, is described. She was successfully treated with steroid suppressive drugs (aminoglutethimide, metyrapone), had a prompt and complete remission and has remained well for more than two years on no medication. This success prompted an on-going clinical trial of this therapy. The available drugs and a working hypothesis of their action are discussed.     

长链非编码RN在重性抑郁障碍中的作用

重性抑郁障碍(major depression disorder, MDD)是当代社会一种严重的精神性疾病,但目前并不完全明确其发生发展的分子机制。长链非编码RNA(long noncoding RNA, lncRNA)与MDD之间有着密切的联系,目前已知在健康人群与MDD患者之间存在2 000多种差异表达的lncRNAs,如TCONS00019174、ENST00000566208、NONHSAG045500、ENST00000517573、NONHSAT034045和NONHSAT142707等。上述6种lncRNAs在MDD患者外周血中的表达量均显著低于对照组,MDD患者经抗抑郁治疗后,lncRNAs表达量可恢复正常。TCONS00019174可通过激活Wnt-β-catenin途径,使入核的β-catenin蛋白质增加并与其下游分子结合促进转录,发挥抗抑郁作用;高表达的lnc RNA NONHSAG045500可以抑制MDD患者五羟色胺转运体的表达从而产生抗抑郁作用。因此,研究lncRNA在MDD中的表达及作用,将为MDD患者的诊治带来新的契机。     

Serotonergic genes modulate amygdala activity in major depression

Serotonergic genes have been implicated in the pathogenesis of depression probably via their influence on neural activity during emotion processing. This study used an imaging genomics approach to investigate amygdala activity in major depression as a function of common functional polymorphisms in the serotonin transporter gene (5-HTTLPR) and the serotonin receptor 1A gene (5-HT(1A)-1019C/G). In 27 medicated patients with major depression, amygdala responses to happy, sad and angry faces were assessed using functional magnetic resonance imaging at 3 Tesla. Patients were genotyped for the 5-HT(1A)-1019C/G and the 5-HTTLPR polymorphism, including the newly described 5-HTT-rs25531 single nucleotide polymorphism. Risk allele carriers for either gene showed significantly increased bilateral amygdala activation in response to emotional stimuli, implicating an additive effect of both genotypes. Our data suggest that the genetic susceptibility for major depression might be transported via dysfunctional neural activity in brain regions critical for emotion processing.     

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.