Ania Korszun

Genome-Wide Association Study of Major Recurrent Depression in the U.K. Population

OBJECTIVE Studies of major depression in twins and families have shown moderate to high heritability, but extensive molecular studies have failed to identify susceptibility genes convincingly. To detect genetic variants contributing to major depression, the authors performed a genome-wide association study using 1,636 cases of depression ascertained in the U.K. and 1,594 comparison subjects screened negative for psychiatric disorders. METHOD Cases were collected from 1) a case-control study of recurrent depression (the Depression Case Control [DeCC] study; N=1346), 2) an affected sibling pair linkage study of recurrent depression (probands from the Depression Network [DeNT] study; N=332), and 3) a pharmacogenetic study (the Genome-Based Therapeutic Drugs for Depression [GENDEP] study; N=88). Depression cases and comparison subjects were genotyped at Centre National de Génotypage on the Illumina Human610-Quad BeadChip. After applying stringent quality control criteria for missing genotypes, departure from Hardy-Weinberg equilibrium, and low minor allele frequency, the authors tested for association to depression using logistic regression, correcting for population ancestry. RESULTS Single nucleotide polymorphisms (SNPs) in BICC1 achieved suggestive evidence for association, which strengthened after imputation of ungenotyped markers, and in analysis of female depression cases. A meta-analysis of U.K. data with previously published results from studies in Munich and Lausanne showed some evidence for association near neuroligin 1 (NLGN1) on chromosome 3, but did not support findings at BICC1. CONCLUSIONS This study identifies several signals for association worthy of further investigation but, as in previous genome-wide studies, suggests that individual gene contributions to depression are likely to have only minor effects, and very large pooled analyses will be required to identify them.

Arterial endothelial function is impaired in treated depression

Objectives: To determine whether patients with treated depression but no other risk factors for coronary heart disease (CHD) have abnormal arterial endothelial function, an abnormality that is common to other acquired risk factors for CHD. Design: Case–control study. Setting: Secondary care departments of cardiology and psychiatry in a single centre and the surrounding community. Participants: Patients with treated depression and matched healthy controls, aged 18–55 years, without conventional acquired risk factors for CHD. These were recruited from local community mental health clinics, general practices, and patient support groups, and through posters placed in public areas of the hospital. Patients had major depression as defined in the American Psychiatric Association’s Diagnostic and statistical manual of mental disorders, fourth edition. Fifteen patients and 12 controls were recruited, and 12 patients and 10 controls completed the study. Outcomes: Brachial artery flow mediated dilatation and baroreflex sensitivity. Results: Arterial endothelial function measured by flow mediated dilatation was impaired in depression (mean (SEM) −0.7% (1.7%)) compared with controls (5.7% (0.9%), p = 0.005 by non-paired t test). Baroreflex sensitivity did not differ significantly between the groups. Conclusion: Arterial endothelial function is impaired in treated depression. This abnormality may contribute to the increased risk of CHD seen in depression.

Sex, trauma, stress hormones and depression.

Although few studies dispute that there are gender differences in depression, the etiology is still unknown. In this review, we cover a number of proposed factors and the evidences for and against these factors that may account for gender differences in depression. These include the possible role of estrogens at puberty, differences in exposure to childhood trauma, differences in stress perception between men and women and the biological differences in stress response. None of these factors seem to explain gender differences in depression. Finally, we do know that when depressed, women show greater hypothalamic–pituitary–adrenal (HPA) axis activation than men and that menopause with loss of estrogens show the greatest HPA axis dysregulation. It may be the constantly changing steroid milieu that contributes to these phenomena and vulnerability to depression.

Use of actigraphy for monitoring sleep and activity levels in patients with fibromyalgia and depression.

OBJECTIVE The hallmark symptom of fibromyalgia (FM) is widespread chronic pain, but most patients are also impaired due to fatigue and sleep disturbance, and there is a strong association with depression. We compared levels of activity and sleep patterns in FM patients, with and without comorbid depression, to those of normal healthy controls and depressed patients. METHODS Actigraphy was carried out on 16 patients with uncomplicated FM, 6 FM patients with comorbid depression, 9 patients with recurrent major depression, and 28 healthy controls over a period of 5-7 days. The means of daytime activity levels, nighttime activity levels, and percentage time spent asleep during the daytime and nighttime were calculated and compared. RESULTS Controls showed high levels of activity during the day and uninterrupted periods of sleep at night. Patients with FM alone showed similar levels of daytime activity, but disturbed sleep with significantly increased levels of activity at night compared to normal controls. Patients with depression alone also showed disturbed sleep compared to normal controls. However, patients with FM and comorbid depression showed the most impairment, with significantly reduced daytime activity and significantly increased daytime sleeping compared to controls, as well as more sleep interruption and movement during the night. CONCLUSION Actigraphy is a useful means of studying activity levels and sleep patterns and demonstrated significant differences between FM patients with and without comorbid depression.

The hypothalamic-pituitary-gonadal axis in mood disorders

This article has demonstrated that stress and HPA axis activation affect the reproductive axis. Despite similarities in the HPA axis picture between women with major depression and those with hypothalamic amenorrhea and exercise or nutritional amenorrhea, no abnormalities in LH secretion have been documented in major depression. Lower estradiol in the follicular phase in depressed women and lower testosterone in depressed men however, have been observed [81, 92]. Although PMS would appear to be the best candidate for a mood disorder associated with abnormalities in reproductive hormones, no abnormalities in LH, estradiol or progesterone have been documented in PMS either [62]. Similarly, blockade of progesterone appears to be ineffective as a treatment for PMS [79]. Complete elimination of monthly cycling with leuprolide improves mood, however. No published studies have examined women with major depression to determine whether leuprolide will exacerbate or improve depressive symptoms. Some studies suggest beneficial effects of estrogen on mood in postmenopausal women, but no placebo controlled studies have explored estrogen augmentation in the treatment of major depression in either post- or premenopausal women, although estrogen is beneficial in women with perimenopause-related mood disorders [78].

Basal Circadian Cortisol Secretion in Women with Temporomandibular Disorders

Muscular temporomandibular disorder (TMD) is a common stress-related condition showing marked comorbidity with depression and fibromyalgia (FM), both of which are associated with dysregulation of cortisol secretion. We measured cortisol levels in 15 women with well-defined TMD and 15 matched controls by sampling blood at 10-minute intervals over 24 hours in a controlled environment. TMD patients showed markedly increased daytime cortisol levels 30% to 50% higher than those of controls (p = 0.0032) and a one-hour phase delay in the timing of maximum cortisol levels (p = 0.048). Increased activation of the stress hormone axis by conscious pain perception is a likely explanation, but the magnitude of the increase could indicate that pain in the facial region acts as a greater stimulus than pain elsewhere in the body.

Medical disorders in people with recurrent depression

BACKGROUND Few studies have examined the rates of physical disorders in those with recurrent depression. AIMS To examine self-reported physical disorders in people with recurrent depression compared with a psychiatrically healthy control group. METHOD As part of a genetic case-control association study, 1546 participants with recurrent depression and 884 controls were interviewed about lifetime ever treatment for 16 different physical health disorders. RESULTS The cases group had a significantly higher frequency of 14 physical disorders and more obesity than the control group. After controlling for age, gender, body mass index (BMI) and multiple testing, those in the cases group had significantly higher rates of gastric ulcer, rhinitis/hay fever, osteoarthritis, thyroid disease, hypertension and asthma. CONCLUSIONS People with recurrent depression show high rates of many common physical disorders. Although this can be partly explained by BMI, shared aetiological pathways such as dysfunction of the hypothalamic-pituitary axis may have a role.

Genomewide Association Scan of Suicidal Thoughts and Behaviour in Major Depression

Background Suicidal behaviour can be conceptualised as a continuum from suicidal ideation, to suicidal attempts to completed suicide. In this study we identify genes contributing to suicidal behaviour in the depression study RADIANT. Methodology/Principal Findings A quantitative suicidality score was composed of two items from the SCAN interview. In addition, the 251 depression cases with a history of serious suicide attempts were classified to form a discrete trait. The quantitative trait was correlated with younger onset of depression and number of episodes of depression, but not with gender. A genome-wide association study of 2,023 depression cases was performed to identify genes that may contribute to suicidal behaviour. Two Munich depression studies were used as replication cohorts to test the most strongly associated SNPs. No SNP was associated at genome-wide significance level. For the quantitative trait, evidence of association was detected at GFRA1, a receptor for the neurotrophin GDRA (p = 2e-06). For the discrete trait of suicide attempt, SNPs in KIAA1244 and RGS18 attained p-values of <5e-6. None of these SNPs showed evidence for replication in the additional cohorts tested. Candidate gene analysis provided some support for a polymorphism in NTRK2, which was previously associated with suicidality. Conclusions/Significance This study provides a genome-wide assessment of possible genetic contribution to suicidal behaviour in depression but indicates a genetic architecture of multiple genes with small effects. Large cohorts will be required to dissect this further.

Stressful life events and the brain-derived neurotrophic factor gene in bipolar disorder

BACKGROUND Gene-environment interactions may contribute to the high heritability of bipolar affective disorder. The aim of the present study was to examine the interplay between the BDNF Val(66)Met polymorphism and stressful life events (SLEs) in bipolar disorder. METHOD A total of 1085 participants were recruited, including 487 bipolar I cases and 598 psychiatrically healthy controls. All participants completed the List of Threatening Life Events Questionnaire; bipolar subjects reported the events that occurred 6 months leading up to their worst manic episode and 6 months prior to their worst depressive episode, controls recorded events experienced 6 months before interview. The sample was genotyped for the BDNF Val(66)Met polymorphism (rs6265). RESULTS Both Met carrier BDNF genotype and SLEs were significantly associated with the worst depressive episode of bipolar disorder. For the worst depressive episodes the effects of SLEs were also significantly moderated by BDNF genotype (gene x environment interaction). LIMITATIONS The use of a self report questionnaire to measure stressful life events may increase recall inaccuracies, therefore caution should be taken when interpreting these results. DISCUSSION The findings of this study highlight the importance of the interplay between genes and the environment in bipolar disorder.

PSYCHONEUROENDOCRINOLOGY OF DEPRESSION: Hypothalamic-Pituitary-Gonadal Axis

Women are more susceptible than men to depression, particularly during periods of rapid fluctuation of gonadal hormones, such as premenstrually, postpartum, and during the climacteric. This review summarizes the evidence for the association of depression with abnormalities in reproductive hormones. Although there are similarities in stress hormones changes between depressed women and women with stress-related amenorrhea, no abnormalities in LH activity have been documented in depression. Similarly no abnormalities in LH, estradiol, or progesterone have been documented in premenstrual syndrome (PMS), although complete elimination of monthly cycling with leuprolide improves mood. Some studies have suggested beneficial effects of estrogen on mood in postmenopausal women but as yet there have been no adequately controlled studies of estrogen treatment of either premenopausal or postmenopausal women.