Maj Vinberg

Measurements of brain-derived neurotrophic factor: Methodological aspects and demographical data

Although numerous studies have dealt with changes in blood brain-derived neurotrophic factor (BDNF), methodological issues about BDNF measurements have only been incompletely resolved. We validated BDNF ELISA with respect to accuracy, reproducibility and the effect of storage and repeated freezing cycles on BDNF concentrations. Additionally, the effect of demographic characteristics in healthy subjects on BDNF was verified. Whole blood and serum was collected from 206 healthy subjects and a subgroup was genotyped for BDNF Val66Met polymorphism. The effect of age, gender, BDNF genotype and thrombocyte count on whole blood BDNF was assessed. The BDNF ELISA measurement was accurate, 91.6+/-3.0%, and showed high reproducibility, whereas inter-assay and intra-subject variations were modest, 8.4+/-5.2% and 17.5+/-14.1%, respectively. Storage of whole blood samples at 4 degrees C significantly decreased BDNF concentration, while repeated freezing cycles and storage at -20 degrees C was without any effect. Storage at -20 degrees C of serum, but not whole blood, was associated with a significant decrease in BDNF concentration. Women had significantly higher whole blood BDNF concentrations than men (18.6+/-1.3 ng/ml versus 16.5+/-1.4 ng/ml), and showed a right-skewed BDNF concentration distribution. No association between whole blood BDNF concentrations and thrombocyte count, age, or BDNF genotype was found. In conclusion, the BDNF ELISA assay determines whole blood BDNF accurately and with high reproducibility. Female gender is associated with higher whole blood BDNF concentrations whereas age, thrombocyte count and BDNF Val66Met polymorphism were un-associated.

Salivary cortisol in depressed patients versus control persons: a systematic review and meta-analysis.

The pathophysiology of depression has been associated to dysregulation of the hypothalamic-pituitary-adrenal axis and the use of salivary cortisol measures is increasingly being incorporated into research. The aim of the present study was to investigate whether salivary cortisol differs for patients with depression and control persons. We did a systematic review with sequential meta-analysis and meta-regression according to the PRISMA Statement based on comprehensive database searches for studies of depressed patients compared to control persons in whom salivary cortisol was measured. Twenty case-control studies, including 1354 patients with depression and 1052 control persons were identified. In a random-effects meta-analysis salivary cortisol was increased for depressed patients as compared to control persons on average 2.58 nmol/l (95% C.I.: 0.95-4.21) p=0.002 in the morning and on average 0.27 nmol/l (95% C.I.: 0.03-0.51) p=0.03 in the evening. In a fixed-effects model the mean difference was 0.58 nmol/l (95% C.I.). Study sequential cumulative meta-analyses suggested random error for the finding of this rather small difference between groups. The reference intervals for morning salivary cortisol in depressed patients (0-29 nmol/l) and control persons (1-23 nmol/l) showed substantial overlap suggesting lack of discriminative capacity. These results should be interpreted with caution as the heterogeneity for the morning analysis was large and a funnel plot, suggested presence of bias. Further, in meta-regression analyses higher intra-assay coefficients of variation in cortisol kits (p=0.07) and mean age (p=0.08) were associated with a higher mean difference of morning salivary cortisol between depressed and controls, while gender and depression severity were not. Based on the available studies there is not firm evidence for a difference of salivary cortisol in depressed patients and control persons and salivary cortisol is unable to discriminate between persons with and without depression.

Cytokines in bipolar disorder: A systematic review and meta-analysis

BACKGROUND Current research and hypothesis regarding the pathophysiology of bipolar disorder suggests the involvement of immune system dysfunction that is possibly related to disease activity. Our objective was to systematically review evidence of cytokine alterations in bipolar disorder according to affective state. METHODS We conducted a systemtic review of studies measuring endogenous cytokine concentrations in patients with bipolar disorder and a meta-analysis, reporting results according to the PRISMA statement. RESULTS Thirteen studies were included, comprising 556 bipolar disorder patients and 767 healthy controls, evaluating 15 different cytokines-, cytokine receptors- or cytokine antagonists. The levels of tumor necrosis factor-α (TNF-α), the soluble tumor necrosis factor receptor type 1 (sTNF-R1) and the soluble inlerleukin-2 receptor (sIL-2R) were elevated in manic patients compared with healthy control subjects (p<0.01 for each). Levels of sTNF-R1 and TNF-α were elevated in manic patients compared to euthymic patients (p=0.01 and p=0.04, respectively). sTNF-R1 levels were elevated in euthymic patients compared with healthy control subjects (p<0.01). There were no significant findings for other comparisons, including intra-individual alterations of cytokine levels. LIMITATIONS Stratification according to mood state resulted in small study numbers for some cytokines. Findings were limited by heterogeneity, small sample sizes and a lack of control for confounding factors in individual studies. CONCLUSIONS This meta-analysis found some support for immune dysregulation in bipolar disorder. Future research is warranted to elucidate the role of endogenous cytokine alterations in bipolar disorder. Clinical studies examining longitudinal changes within individuals are recommended.

Designing mobile health technology for bipolar disorder: a field trial of the monarca system

An increasing number of pervasive healthcare systems are being designed, that allow people to monitor and get feedback on their health and wellness. To address the challenges of self-management of mental illnesses, we have developed the MONARCA system - a personal monitoring system for bipolar patients. We conducted a 14 week field trial in which 12 patients used the system, and we report findings focusing on their experiences. The results were positive; compared to using paper-based forms, the adherence to self-assessment improved; the system was considered very easy to use; and the perceived usefulness of the system was high. Based on this study, the paper discusses three HCI questions related to the design of personal health technologies; how to design for disease awareness and self-treatment, how to ensure adherence to personal health technologies, and the roles of different types of technology platforms.

Validity of the diagnosis of a single depressive episode in a case register

ObjectiveTo validate the ICD-10 diagnosis of a single depressive episode as used in daily clinical psychiatric practice and as recorded in the Danish Psychiatric Central Research Register.MethodsPatients discharged with a diagnosis of a single depressive episode were consecutively sampled from the register and diagnosed according to an interview using the Schedules for Clinical Assessment in Neuropsychiatry (SCAN).ResultsA total of 75.4% of 399 patients with a register diagnosis of a single depressive episode also got this diagnosis according to the SCAN interview (82.8% for severe type of a single depression, 76.0% for moderate type of a single depression and 65.2% for mild type of a single depression).ConclusionThe ICD-10 diagnosis of a single depressive episode can be used in daily clinical practice with sufficient precision. The validity of the diagnosis is highest for severe and moderate type of depression and decreases for mild depression.

Interaction between genetic polymorphisms and stressful life events in first episode depression

BACKGROUND A polymorphism in the serotonin transporter (5-HTT) gene seems to moderate the influence of stressful life events on depression. However, the results from previous studies of gene-environment interactions in depression are inconsistent and might be confounded by the history of depression among participants. METHOD We applied a case-only design, including 290 ethnically homogeneous patients suffering exclusively from first episode depression. Psychiatric mo-morbidity, personality traits and disorders and stressful life events in a six months period preceding onset of depression were evaluated by means of interviews and questionnaires. Additionally, we genotyped nine polymorphisms in the genes encoding the serotonin transporter, brain derived neurotrophic factor, catechol-O-methyltransferase, angiotensin converting enzyme, tryptophane hydroxylase, and the serotonin receptors 1A, 2A, and 2C. RESULTS The low activity variants of the 5-HTT-linked polymorphic region in the serotonin transporter gene and the Met-allele of a single nucleotide polymorphism (Val66Met) in the gene encoding brain derived neurotrophic factor were independently associated with the presence of stressful life events prior to onset of depression, also when corrected for the effect of age, gender, marital status, personality disorder, neuroticism, and severity of depressive symptoms at the time of interview. CONCLUSION Polymorphisms in the genes encoding the serotonin transporter and the brain derived neurotrophic factor interact with recent stressful life events on depression among patients with no history of previous depressive episodes.

Hippocampal volume changes in healthy subjects at risk of unipolar depression

Unipolar depression is moderately heritable. It is unclear whether structural brain changes associated with unipolar depression are present in healthy persons at risk of the disorder. Here we investigated whether a genetic predisposition to unipolar depression is associated with structural brain changes. A priori, hippocampal volume reductions were hypothesized. Using a high-risk study design, magnetic resonance imaging brain scans were obtained from 59 healthy high-risk subjects having a co-twin with unipolar depression, and 53 healthy low-risk subjects without a first-degree family history of major psychiatric disorder. High-risk twins had smaller hippocampal volumes than low-risk twins (p<0.04). The finding was most pronounced in DZ twins. Groups did not differ on global brain tissue volumes or regional tissue volumes assessed in exploratory voxel-wise whole cerebrum analyses. In conclusion, hippocampal volume reduction may index a predisposition to develop depression and thus may be predictive of future onset of the disorder. Further studies are needed to elucidate the role of (shared) environmental and genetic factors.

Daily electronic self-monitoring of subjective and objective symptoms in bipolar disorder--the MONARCA trial protocol (MONitoring, treAtment and pRediCtion of bipolAr disorder episodes): a randomised controlled single-blind trial.

Introduction Electronic self-monitoring of affective symptoms using cell phones is suggested as a practical and inexpensive way to monitor illness activity and identify early signs of affective symptoms. It has never been tested in a randomised clinical trial whether electronic self-monitoring improves outcomes in bipolar disorder. We are conducting a trial testing the effect of using a Smartphone for self-monitoring in bipolar disorder. Methods We developed the MONARCA application for Android-based Smartphones, allowing patients suffering from bipolar disorder to do daily self-monitoring—including an interactive feedback loop between patients and clinicians through a web-based interface. The effect of the application was tested in a parallel-group, single-blind randomised controlled trial so far including 78 patients suffering from bipolar disorder in the age group 18–60 years who were given the use of a Smartphone with the MONARCA application (intervention group) or to the use of a cell phone without the application (placebo group) during a 6-month study period. The study was carried out from September 2011. The outcomes were changes in affective symptoms (primary), social functioning, perceived stress, self-rated depressive and manic symptoms, quality of life, adherence to medication, stress and cognitive functioning (secondary and tertiary). Analysis Recruitment is ongoing. Ethics Ethical permission has been obtained. Dissemination Positive, neutral and negative findings of the study will be published. Registration details The trial is approved by the Regional Ethics Committee in The Capital Region of Denmark (H-2-2011-056) and The Danish Data Protection Agency (2013-41-1710). The trial is registered at ClinicalTrials.gov as NCT01446406.

Is there an association between subjective and objective measures of cognitive function in patients with affective disorders

Background: Patients with affective disorders experience cognitive dysfunction in addition to their affective symptoms. The relationship between subjectively experienced and objectively measured cognitive function is controversial with several studies reporting no correlation between subjective and objective deficits. Aims: To investigate whether there is a correlation between subjectively reported and objectively measured cognitive function in patients with affective disorders, and whether subjective complaints predict objectively measured dysfunction. Methods: The study included 45 participants; 15 with bipolar disorder (BD), 15 with unipolar disorder (UD) and 15 healthy individuals. Participants’ subjectively experienced cognitive function and objective cognitive function were assessed with the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) and the Screen for Cognitive Impairment in Psychiatry (SCIP), respectively. Patients were rated for affective symptoms with Hamilton Depression Rating Scale (HDRS) and Young Mania Rating Scale (YMRS). Results: Patients demonstrated subjective and objective cognitive dysfunction relative to controls (P-values ≤ 0.01) but there were no differences between patient groups (P > 0.1). We found no correlation between subjectively experienced and objectively measured cognitive dysfunction in BD (P = 0.7), and a non-significant trend towards a correlation in UD (P = 0.06), which disappeared when controlling for gender (P = 0.1). Conclusion: Our results suggest that it is not necessarily patients who have cognitive complaints that are most impaired. If confirmed in a larger sample, our findings suggest that neuropsychological assessment is warranted to elucidate the potential role of cognitive dysfunction in patients’ everyday lives and to inform treatment strategies targeting these difficulties.

Peripheral blood brain-derived neurotrophic factor in bipolar disorder: a comprehensive systematic review and meta-analysis

Peripheral blood brain-derived neurotrophic factor (BDNF) has been proposed as a potential biomarker related to disease activity and neuroprogression in bipolar disorder, speculated to mirror alterations in brain expression of BDNF. The research area is rapidly evolving; however, recent investigations have yielded conflicting results with substantial variation in outcomes, highlighting the need to critically assess the state of current evidence. The aims of the study were to investigate differences in peripheral blood BDNF concentrations between bipolar disorder patients and healthy control subjects and between affective states in bipolar disorder patients, including assessment of the effect of treatment of acute episodes on BDNF levels. A systematic review of English language studies without considering publication status was conducted in PubMed (January 1950–November 2014), Embase (1974–November 2014) and PsycINFO (1806–November 2014), and 35 studies comprising a total of 3798 participants were included in the meta-analysis. The results indicated that crude peripheral blood BDNF levels may be lower in bipolar disorder patients overall (Hedges’ g=−0.28, 95% CI: −0.51 to −0.04, P=0.02) and in serum of manic (g=−0.77, 95% CI: −1.36 to −0.18, P=0.01) and depressed (g=−0.87, 95% CI: −1.42 to −0.32, P=0.002) bipolar disorder patients compared with healthy control subjects. No differences in peripheral BDNF levels were observed between affective states overall. Longer illness duration was associated with higher BDNF levels in bipolar disorder patients. Relatively low study quality, substantial unexplained between-study heterogeneity, potential bias in individual studies and indications of publication bias, was observed and studies were overall underpowered. It could thus not be excluded that identified differences between groups were due to factors not related to bipolar disorder. In conclusion, limitations in the evidence base prompt tempered conclusions regarding the role of peripheral BDNF as a biomarker in bipolar disorder and substantially improving the quality of further research is warranted.