Harald Jürgen Freyberger

Mental and physical distress is modulated by a polymorphism in the 5-HT transporter gene interacting with social stressors and chronic disease burden

Previous studies have yielded conflicting results as to the putative role of the functional polymorphism of the promoter region of the serotonin transporter gene (SLC6A4) in the etiology of anxiety-related traits and depressive disorders. Recently, a significant gene–environment interaction was found between life stressors, the short allele of the SLC6A4 polymorphism and depression. The aim of the present study was to investigate if such a gene–environment interaction could be replicated within a different population with a different risk structure. A total of 1005 subjects from a general population sample (Study of Health in Pomerania) were genotyped. Mental and physical distress were assessed on 38 items of the modified complaint scale (BL-38). The interaction between the SLC6A4 genotype, social stressors and chronic diseases with regard to the BL-38 score was evaluated by ANOVA. There was no independent association of genotype with mental and physical distress. However, significant interactions between genotype, unemployment and chronic diseases (F=6.6; df=3, 671; P<0.001) were found in females but not in males. The genotype explained 2% of the total variance of the BL-38 score and 9.1% of the explained variance. The results partly confirm previous findings of a significant gene–environment interaction of the short allele, indicating a higher mental vulnerability to social stressors and chronic diseases. The relevance of this finding is sustained by the fact that the sample characteristics and the risk structure were highly different from previous studies.

Serotonin transporter gene (SLC6A4) promoter polymorphisms and the susceptibility to posttraumatic stress disorder in the general population.

OBJECTIVE There has been debate whether polymorphisms within the serotonin transporter-linked polymorphic region (5-HTTLPR) moderate susceptibility to posttraumatic stress disorder (PTSD). The authors investigated 5-HTTLPR genotypes and their interaction with the number of traumatic events in the prediction of PTSD in a general population sample. METHOD Analyses were based on data from 3,045 subjects who participated in the Study of Health in Pomerania. All participants were assessed with the PTSD module of the Structured Clinical Interview for DSM-IV. The short (S)/long (L) polymorphism of 5-HTTLPR (rs4795541) and the A-G polymorphism (rs25531) were genotyped. RESULTS Among the participants, 1,663 had been exposed to at least one traumatic event, and 67 (4.0%) developed PTSD. Among those who had experienced less than three traumatic events, the lifetime prevalence of PTSD was 2.6%, 3.5%, and 4.3% for those with zero, one, and two L(A) alleles, respectively, but the lifetime prevalence was 0%, 7.3%, and 19.6%, respectively, among those with three or more traumatic experiences. This finding suggests that there is an additive excess risk for frequent trauma in the L(A)/L(A) genotype, which was confirmed by the relative excess risk due to interaction (RERI). In allelic analysis, RERI was 3.3. Thus, the odds ratio for PTSD in L(A) allele carriers exposed to three or more traumas was 3.3 times higher as a result of the interaction between PTSD and the L(A) allele. CONCLUSIONS An additive gene-environment interaction with the high expression L(A) allele of 5-HTTLPR and frequent trauma in PTSD was found. The attributable proportion indicated that more than 60% of all L(A) allele carriers who were exposed to three or more traumas developed PTSD as a result of an interaction between genotype and exposure.

Prevalence, quality of life and psychosocial function in obsessive-compulsive disorder and subclinical obsessive-compulsive disorder in northern Germany.

AbstractBackground: Despite the worldwide relevance of obsessive-compulsive disorder (OCD) there are considerable differences in prevalence rates and gender ratios between the studies and a substantial lack of prevalence data on subclinical OCD. Moreover, data on quality of life and on psychosocial function of subjects with OCD and subclinical OCD in the general population are missing to date. Methods: German versions of the DMS-IV adapted Composite International Diagnostic Interview were administered to a representative sample of 4075 persons aged 18–64 years living in a northern Germany region. Specific DSM-IV based criteria for subclinical OCD were used. Results: The life-time prevalence rates for OCD and subclinical OCD were 0.5% and 2%, respectively. Twelve month prevalence rates were 0.39% and 1.6%, respectively. The gender female:male ratio was 5.7 in OCD and 1.2 in subclinical OCD. In various measures of psychosocial function and quality of life, OCD and subclinical OCD were significantly impaired. However, subclinical OCD subjects did not visit mental health professionals more often than controls. Conclusion: Due to different epidemiological characteristics subclinical OCD might represent a syndrome distinct from OCD which is also associated with significant impairments in personal and interpersonal functions and in quality of life.

The Relationship between Dimensions of Alexithymia and Dissociation

Background: The study investigated the following hypotheses: (1) Alexithymia is significantly associated with dissociation. (2) Pathological versus nonpathological dissociation is associated with alexithymic traits. Methods: Psychiatric in- and outpatients (n = 173) and nonclinical subjects (n = 38) were investigated with the Toronto Alexithymia Scale (TAS-20), the FDS (German version of Dissociation Experience Scale) and the Symptom Check List (SCL-90-R; GSI). Correlation analyses followed by MANOVA and logistic regression were performed. Results: Significant correlations and partial correlations, controlling for GSI, were observed between dissociation and alexithymia. The MANOVA demonstrated significantly higher scores for the two TAS-20 dimensions ‘difficulty identifying feelings’ and ‘difficulty expressing feelings’ in the group with pathological dissociation. On the basis of the TAS-20 subscores, logistic regression analysis correctly classified 72.5% of the cases into the pathological and the nonpathological dissociation group. Conclusions: These results support our hypothesis that pathological traits of dissociation are highly associated with alexithymia. A model is discussed in which alexithymic characteristics may contribute to the development of pathological dissociation and stress-related disorders such as posttraumatic stress disorder.

Alexithymia and the Temperament and Character Model of Personality

Objective: In our study we explored the associations between alexithymia (Toronto Alexithymia Scale 20, TAS-20) and the dimensions and subscales of Cloninger’s theoretically based and empirically validated psychobiological model of personality to further clarify the relationship between alexithymia and personality traits. Methods: Psychiatric in- and outpatients (n = 254) were investigated with the TAS-20, the Temperament and Character Inventory (TCI) and the Symptom Check List SCL-90-R to control for the severity of current psychopathology. Correlation and regression analyses were performed. Results: The regression analysis identified the TCI dimensions low self-directedness (SD), low reward dependence (RD) and to a minor degree harm avoidance (HA) as independent predictors for alexithymia. At the level of subscales, interpersonal detachment (RD3), low resourcefulness (SD3), low responsibility and blaming (SD1) and shyness with strangers (HA3) were predictors for alexithymia. The degree of explained variance of the TAS-20 scores by the TCI dimensions and subscales ranged between 43 and 45% whereas the inclusion of the general severity index into the regression models accounted for an additional 5% of the variance. Conclusions: Alexithymia is best explained by a mixture across different dimensions and subscales within Cloninger’s psychobiological model of personality. However, alexithymia is captured only partly by current concepts of personality, and additional contributing psychological and biological factors need to be identified to understand alexithymia more extensively.

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.

Neurotrophic Factor S100beta in Major Depression

Disturbances in the serotonergic system are considered to be implicated in the pathophysiology of depressive disorders. The possible role of the neurotrophic factor S100 beta, which is suspected to regulate regeneration of serotonergic synapses, has not been investigated in depressive disorders. The S100beta concentration in the cerebrospinal fluid was measured in 11 patients with the current diagnosis of mild or moderate depressive episodes (DSM-IV) and in 11 matched control patients. Using the t test for paired samples, the presence of a depressive episode was significantly associated with an elevation of the cerebrospinal fluid concentration of S100beta (t = 2.6, d.f. = 10, p = 0.024). Replications of this finding in severely depressed patients are necessary to confirm the association between neurotrophic factor S100beta and depressive disorders.

Impact of forced displacement during World War II on the present-day mental health of the elderly: a population-based study

BACKGROUND The effects of traumatization among the elderly is a neglected topic in research and clinical settings. Forced displacement of civilians is one of the main traumatic features of modern armed conflict. Roughly 12 million German people were displaced in World War II (WWII) and to our knowledge there has been no representative study investigating the mental health outcomes of such trauma in the elderly population. The survey assessed whether current depression, anxiety, resilience and life satisfaction were significantly associated with forced displacement in WWII. METHODS A nationwide representative face-to-face household survey was conducted in Germany. A representative sample of the German population aged 61 years or older (N = 1513 participants, N = 239 displaced in WWII) was approached using 258 sample points. Measurements included depressive symptoms (PHQ-2), anxiety (GAD-7), resilience (RS-11), general and domain-specific life satisfaction (FLZ(M)) and sociodemographic variables. RESULTS Forced displacement in WWII is significantly associated with higher levels of anxiety and lower levels of resilience and life satisfaction 60 years later. In regression analyses, forced displacement in WWII significantly predicted current anxiety (beta 0.07; p < 0.01), life satisfaction (beta -0.06; p < 0.05) and resilience (beta -0.07; p < 0.01). CONCLUSION To our knowledge this is the first nationwide representative survey to examine the late-life effects of forced displacement, particularly of persons displaced during WWII in Germany. Further research is needed to identify mediating variables and to evaluate psychotherapeutic interventions in elderly trauma survivors.

Life- and person-centred help in Mecklenburg-Western Pomerania, Germany (DelpHi): study protocol for a randomised controlled trial

BackgroundThe provision of appropriate medical and nursing care for people with dementia is a major challenge for the healthcare system in Germany. New models of healthcare provision need to be developed, tested and implemented on the population level. Trials in which collaborative care for dementia in the primary care setting were studied have demonstrated its effectiveness. These studies have been conducted in different healthcare systems, however, so it is unclear whether these results extend to the specific context of the German healthcare system.The objective of this population-based intervention trial in the primary care setting is to test the efficacy and efficiency of implementing a subsidiary support system on a population level for persons with dementia who live at home.Methods and study designThe study was designed to assemble a general physician-based epidemiological cohort of people above the age of 70 who live at home (DelpHi cohort). These people are screened for eligibility to participate in a trial of dementia care management (DelpHi trial). The trial is a cluster-randomised, controlled intervention trial with two arms (intervention and control) designed to test the efficacy and efficiency of implementing a subsidiary support system for persons with dementia who live at home. This subsidiary support system is initiated and coordinated by a dementia care manager: a nurse with dementia-specific qualifications who delivers the intervention according to a systematic, detailed protocol. The primary outcome is quality of life and healthcare for patients with dementia and their caregivers. This is a multidimensional outcome with a focus on four dimensions: (1) quality of life, (2) caregiver burden, (3) behavioural and psychological symptoms of dementia and (4) pharmacotherapy with an antidementia drug and prevention or suspension of potentially inappropriate medication. Secondary outcomes include the assessment of dementia syndromes, activities of daily living, social support health status, utilisation of health care resources and medication.DiscussionThe results will provide evidence for specific needs in ambulatory care for persons with dementia and will show effective ways to meet those needs. Qualification requirements will be evaluated, and the results will help to modify existing guidelines and treatment paths.Trial registrationNCT01401582