Katja Appel

Moderation of Adult Depression by a Polymorphism in the FKBP5 Gene and Childhood Physical Abuse in the General Population

Childhood maltreatment and depressive disorders have both been associated with a dysregulation of the hypothalamic–pituitary–adrenal axis. The FKBP5 gene codes for a co-chaperone regulating the glucocorticoid-receptor sensitivity. Previous evidence suggests that subjects carrying the TT genotype of the FKBP5 gene single-nucleotide polymorphism (SNP) rs1360780 have an increased susceptibility to adverse effects of experimental stress. We therefore tested the hypothesis of an interaction of childhood abuse with rs1360780 in predicting adult depression. In all, 2157 Caucasian subjects from the Study of Health in Pomerania (German general population) completed the Beck Depression Inventory (BDI-II) and Childhood Trauma Questionnaire. The DSM-IV diagnosis of major depressive disorder (MDD) was assessed by interview. Genotypes of rs1360780 were taken from the Affymetrix Human SNP Array 6.0. Significant interaction (p=0.006) of physical abuse with the TT genotype of rs1360780 was found increasing the BDI-II score to 17.4 (95% confidence interval (CI)=12.0–22.9) compared with 10.0 (8.2–11.7) in exposed CC/CT carriers. Likewise, the adjusted odds ratio for MDD in exposed TT carriers was 8.2 (95% CI=1.9–35.0) compared with 1.3 (0.8–2.3) in exposed subjects with CC/CT genotypes. Relative excess risk due to interaction (RERI) analyses confirmed a significant additive interaction effect (RERI=6.8; 95% CI=0.64–33.7; p<0.05). In explorative analyses, the most severe degree of sexual and emotional abuse also yielded significant interaction effects (p<0.05). This study revealed interactions between physical abuse and rs1360780 of the FKBP5 gene, confirming its role in the individual susceptibility to depression. Given the large effect sizes, rs1360780 could be included into prediction models for depression in individuals exposed to childhood abuse.

Childhood maltreatment, the corticotropin-releasing hormone receptor gene and adult depression in the general population†‡

Dysregulations of the hypothalamic‐pituitary‐adrenal (HPA) axis have been implicated in the pathogenesis of depressive disorders and the corticotropin‐releasing hormone (CRH) was found to modulate emotional memory consolidation. Recently, two studies have reported an interaction between childhood abuse and the TAT–haplotype of the CRH‐Receptor Gene (CRHR1) connecting childhood adversities and genetic susceptibility to adult depression. We tested the hypothesis of an interaction of childhood maltreatment with single nucleotide polymorphisms (SNPs) and haplotypes of the CRHR1 gene not previously investigated. Caucasian subjects (n = 1,638) from the German general population (Study of Health in Pomerania, SHIP) were analyzed. As in the previous studies, childhood abuse and neglect were assessed with the Childhood Trauma Questionnaire (CTQ) and depression with the Beck Depression Inventory (BDI‐2). The CRHR1‐SNPs were genotyped on the Affymetrix Genome‐Wide Human SNP Array 6.0 platform. We identified an interaction between the TAT–haplotype and childhood physical neglect. The interaction with physical neglect showed significant (P < 0.05) results in 23 of the 28 SNPs, with rs17689882 (P = 0.0013) reaching “gene‐wide” significance. Although we did not replicate the specific interaction of abuse and the TAT–haplotype of the CRHR1 gene we confirmed the relevance of an interplay between variants within the CRHR1 gene and childhood adversities in the modulation of depression in adults. The largest effect was found for rs17689882, a SNP previously not analyzed. Relevant sample differences between this and prior studies like lower BDI‐2 scores, less childhood maltreatment and higher psychosocial functioning may account for the differences in gene–environment interaction findings.

Genetic epistasis between the brain-derived neurotrophic factor Val66Met polymorphism and the 5-HTT promoter polymorphism moderates the susceptibility to depressive disorders after childhood abuse.

BACKGROUND Based on biological interactions between the serotonergic system and the brain-derived neurotrophic factor (BDNF), BDNF is a plausible candidate for a gene-gene-environment interaction moderating the interaction between the s/l- promoter polymorphism of the serotonin transporter (5-HTTLPR) and childhood abuse. We tested the hypothesis of a three-way interaction with respect to depressive symptoms. METHODS 2035 Caucasian subjects from the Study of Health in Pomerania (German general population) completed the Beck Depression Inventory (BDI-II) and the Childhood Trauma Questionnaire. All subjects were genotyped for the BDNF Val66Met (rs6265) and the s/l 5-HTTLPR polymorphisms. RESULTS Tobit regression analyses revealed a three-way-interaction between the three genotypes of 5-HTTLPR and the BDNF genotypes and overall childhood abuse for the BDI-II score (p=0.02). Emotional abuse carried the main effect of the interaction (p=0.008). The s/s genotype of the 5-HTTLPR exerted its negative impact on mental health after childhood abuse only in the presence of the BDNF Val/Val genotype but not in the presence of the BDNF Met allele. In contrast, the l allele of the 5-HTTLPR also emerged as a genetic risk factor for depression in carriers of one or two Met alleles. CONCLUSIONS Our results point to a gene-gene-environment interaction that relevantly impacts on the role of the s/s genotype of the 5-HTTLPR in childhood abuse: Depending on the BDNF background (Val/Val versus Met allele) the s/s genotype showed either protective or risk properties with regard to depressive symptoms.

Neuroticism developmental courses - implications for depression, anxiety and everyday emotional experience; a prospective study from adolescence to young adulthood

BackgroundNeuroticism is frequently discussed as a risk factor for psychopathology. According to the maturity principle, neuroticism decreases over the course of life, but not uniformly across individuals. However, the implications of differences in personality maturation on mental health have not been well studied so far. Hence, we hypothesized that different forms of neuroticism development from adolescence to young adulthood are associated with differences in depression, anxiety and everyday emotional experience at the age of 25.MethodsA sample of 266 adolescents from the general population was examined three times over ten years (age at T0: 15, T1: 20 and T2: 25) using questionnaires, interviews and ecological momentary assessment (EMA). At all measurement points, neuroticism was assessed with the NEO inventory. At T2, diagnoses of major depression and anxiety disorders were captured with a structured clinical interview (M-CIDI). Phone-based EMA was used to assess emotional experience and affective instability over a two-week period at T2.ResultsThe best fitting model was a latent class growth analysis with two groups of neuroticism development. Most individuals (n = 205) showed moderate values whereas 61 participants were clustered into a group with elevated neuroticism levels. In both groups neuroticism significantly changed during the ten year period with a peak at the age of 20. Individuals with a higher absolute level were at 14-fold increased risk for depression and 7-fold risk for anxiety disorders at the age of 25. In EMA, increased negative affect and arousal as well as decreased positive emotions were found in this high group.ConclusionsOther than expected, personality did not mature in our sample. However, there was a significant change of neuroticism values from adolescence to young adulthood. Further, over 20% of our participants showed a neuroticism development which was associated with adverse outcomes such as negatively toned emotional experience and a heightened risk to suffer from depressive and anxiety disorders in young adulthood. These high-risk persons need to be identified early to provide interventions supporting continuous personality maturation.

Update on the 2005 paper: moderation of mental and physical distress by polymorphisms in the 5-HT transporter gene by interacting with social stressors and chronic disease burden

Update on the 2005 paper: moderation of mental and physical distress by polymorphisms in the 5-HT transporter gene by interacting with social stressors and chronic disease burden

Borderline Personality Disorder in Four Different Age Groups: A Cross-Sectional Study of Community Residents in Germany

Studies examining the natural course of borderline personality disorder (BPD) over the life span have yielded declining prevalence rates in older age groups. However, there is evidence that different BPD symptoms have different longitudinal patterns, with impulsivity decreasing with advancing age and negative affect remaining stable into late adulthood. However, since all studies dealt with treated, clinical samples of BPD patients, it is not yet known whether this represents the natural course of BPD symptoms or just mirrors difference in treatability of these symptoms. The authors addressed this issue by investigating a nonclinical population and compared prevalence of BPD, impulsivity, and depressivity in various age groups from adolescence to late adulthood (N = 2,488); all individuals were assessed by standardized clinical interviews. Syndromal and subsyndromal BPD rates sharply decreased between adolescents and young adults and remained stable thereafter. Whereas the same course was found for impulsivity, depressivity increased between young, middle-aged, and older adults. The present results support the hypothesis that age-related decreases in BPD diagnosis might be attributable to declining levels of impulsivity, whereas the persistence of a subsyndromal BPD might be attributable to an enduring negative affect.

The impact of childhood trauma on depression: does resilience matter? Population-based results from the Study of Health in Pomerania

OBJECTIVE Data suggests that traumatic experiences at early age contribute to the onset of major depressive disorder (MDD) in later life. This study aims at investigating the influence of dispositional resilience on this relationship. METHODS Two thousand and forty-six subjects aged 29-89 (SD=13.9) from a community based sample who were free of MDD during the last 12 months prior to data collection were diagnosed for Lifetime diagnosis of MDD by the Munich-Composite International Diagnostic Interview (M-CIDI) according to DSM-IV criteria. Childhood maltreatment (CM) and resilience were assessed with the Childhood Trauma Questionnaire (CTQ) and the Resilience-Scale (RS-25). RESULTS Both CM (OR=1.03, 95% CI [1.02, 1.04], P<.000) and resilience (OR=0.98, 95% CI [0.98, 0.99], P<.000) were associated with MDD later in life. The detrimental effects of low resilience on MDD were not only especially prominent in subjects with a history of CM (OR=3.18, 95% CI [1.84, 5.50], P<.000), but also effective in subjects without CM (OR=2.62, 95% CI [1.41, 4.88], P=.002). CONCLUSIONS The findings support the clinical assumption that resilient subjects may be partly protected against the detrimental long-term effects of child abuse and neglect.

Psychometric functioning, socio‐demographic variability of childhood maltreatment in the general population and its effects of depression

Maltreatment of children is a major public‐health and social‐welfare problem but socio‐demographic variability has received little attention. This work addresses such variability in a general population cohort and associations with depression. Analyses were based on the cross‐sectional SHIP‐LEGEND examination among 2265 adults (29–89 years). Childhood maltreatment was multi‐dimensionally assessed with the German 28‐item Childhood Trauma Questionnaire (CTQ): emotional neglect; emotional abuse; physical neglect; physical abuse; sexual abuse. Non‐linear associations between CTQ responses and age were assessed with fractional polynomials and cubic splines. Scale properties were analysed with confirmatory factor analyses and item response models. Associations between childhood maltreatment domains and depression [Beck Depression Inventory‐II (BDI‐II)] were assessed. The majority (58.9%) reported events indicative of at least mild levels of childhood maltreatment. CTQ subscales showed characteristically different non‐linear associations to age across the five studied domains, indicating methodological issues like recall bias and the influence of seminal events. Psychometric scale properties were acceptable to good for all subscales except for physical neglect. Associations to depression measures varied systematically across socio‐demographic strata. We conclude that socio‐demographic variability is a major issue when studying self‐reported childhood maltreatment in a community sample. This needs to be taken into account for the study of associations to psychiatric key outcomes. Copyright

A risk marker for alcohol dependence on chromosome 2q35 is related to neuroticism in the general population

A risk marker for alcohol dependence on chromosome 2q35 is related to neuroticism in the general population

Associations of leisure-time and occupational physical activity and cardiorespiratory fitness with incident and recurrent major depressive disorder, depressive symptoms, and incident anxiety in a general population

OBJECTIVE Physical activity and cardiorespiratory fitness may help prevent depression and anxiety. Previous studies have been limited by error-prone measurements. We examined whether self-reported physical activity domains and peak exercise capacity (peakVO₂) are associated with incident and recurrent major depressive disorder (MDD), depressive symptoms, and anxiety disorders. METHODS This was a prospective population-based study of 1,080 adult men and women (25-83 years) with a median follow-up of 4.5 years and measures of physical activity during leisure time, sports, and work (Baecke questionnaire); a measure of depressive symptoms (Beck Depression Inventory II); symptom-limited cycle ergometer testing (peakVO₂, oxygen uptake at anaerobic threshold [VO₂@AT], maximum power output at peak exertion); and a structured psychiatric interview (Munich Composite International Diagnostic Interview). Baseline data were collected between 2002 and 2006, and follow-up data, between 2007 and 2010. RESULTS After adjustment for age, sex, education, smoking, alcohol consumption, and waist circumference, the relative risks for incident MDD per standard deviation (SD) increase in leisure-time physical activity, physical activity during sport, physical activity at work, peakVO₂, VO₂@AT, and maximum power output were 1.002 (95% confidence interval, 0.90 to 1.12), 1.02 (0.90 to 1.15), 0.94 (0.80 to 1.10), 0.71 (0.52 to 0.98), 0.83 (0.66 to 1.04), and 0.71 (0.52 to 0.96), respectively. PeakVO₂, VO₂@AT, and maximum power output were associated with recurrent MDD, depressive symptoms, and anxiety. PeakVO₂ was more strongly related to the co-occurrence of MDD and anxiety (adjusted odds ratio [OR] = 0.45 [0.24 to 0.84]) than depression or anxiety alone (OR = 0.71 [0.53 to 0.94]). CONCLUSIONS Greater cardiorespiratory fitness but not domain-specific physical activity was associated with a lower incidence of MDD and clinical anxiety.