Hildegard Pfister

Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment

The stress hormone–regulating hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the causality as well as the treatment of depression. To investigate a possible association between genes regulating the HPA axis and response to antidepressants and susceptibility for depression, we genotyped single-nucleotide polymorphisms in eight of these genes in depressed individuals and matched controls. We found significant associations of response to antidepressants and the recurrence of depressive episodes with single-nucleotide polymorphisms in FKBP5, a glucocorticoid receptor–regulating cochaperone of hsp-90, in two independent samples. These single-nucleotide polymorphisms were also associated with increased intracellular FKBP5 protein expression, which triggers adaptive changes in glucocorticoid receptor and, thereby, HPA-axis regulation. Individuals carrying the associated genotypes had less HPA-axis hyperactivity during the depressive episode. We propose that the FKBP5 variant–dependent alterations in HPA-axis regulation could be related to the faster response to antidepressant drug treatment and the increased recurrence of depressive episodes observed in this subgroup of depressed individuals. These findings support a central role of genes regulating the HPA axis in the causality of depression and the mechanism of action of antidepressant drugs.

Test-retest reliability of the computerized DSM-IV version of the Munich-Composite International Diagnostic Interview (M-CIDI)

Abstract The structure and content of the Munich-Composite International Diagnostic Interview (M-CIDI) for the assessment of DSM-IV symptoms, syndromes, and diagnoses is described along with findings from a test-retest reliability study. A sample of 60 community respondents were interviewed twice independently by trained interviewers with an average time interval of 38 days between investigations. Test-retest reliability was good for almost all specific DSM-IV core symptom questions and disorders examined, with kappa values ranging from fair for two diagnoses – bulimia (kappa 0.55) and generalized anxiety disorder (kappa 0.45) – to excellent (kappa above 0.72) for all other anxiety disorders and alcohol use disorders. Test-retest reliability for age of onset and time-related questions was fairly consistently high (intra-class correlation values of 0.79 or above), with one notable exception: the assessment of disorders with onset before puberty. We concluded that the M-CIDI is acceptable for respondents, efficient in terms of time needed for and ease of administration, and reliable in terms of consistency of findings over time periods of at least 1 month.

Primary anxiety disorders and the development of subsequent alcohol use disorders : a 4-year community study of adolescents and young adults

BACKGROUND Cross-sectional findings in community surveys of adults suggest that adolescent anxiety disorders are strong predictors of the subsequent onset of alcohol use, abuse and dependence. However, prospective data that follow a sample of adolescents into adulthood are needed to confirm these associations. METHOD Baseline and 4-year follow-up data from the EDSP-Study, a prospective community survey of 3021 (2548 at follow-up) adolescents and young adults aged 14 to 24 years at baseline carried out in Munich, were used. DSM-IV anxiety disorders, alcohol use and alcohol use disorders were assessed with the Munich-Composite-International-Diagnostic-Interview (M-CIDI). Multiple logistic regression analysis, controlling for age, gender, other mental disorders, substance use disorders and antisocial behaviour was used to study the associations of baseline anxiety disorders with the subsequent onset and course of alcohol use and alcohol disorders. RESULTS Baseline social phobia significantly predicts the onsets of regular use and hazardous use and the persistence of dependence. Panic attacks significantly predict the onsets of hazardous use and abuse as well as the persistence of combined abuse/dependence. Panic disorder significantly predicts the persistence of combined abuse/dependence. Other anxiety disorders do not significantly predict any of the outcomes. CONCLUSIONS Panic and social phobia are predictors of subsequent alcohol problems among adolescents and young adults. Further studies are needed to investigate the underlying mechanisms and the potential value of targeted early treatment of primary panic and social phobia to prevent secondary alcohol use disorders.

Why do people with anxiety disorders become depressed? A prospective-longitudinal community study.

Objective: To examine the temporal relationships of anxiety and depressive disorders, their risk factors and to explore why people with anxiety develop depression.

Disabilities and quality of life in pure and comorbid generalized anxiety disorder and major depression in a national survey.

&NA; Using a nationally representative sample, this study examines the disease‐specific impairments of DSM‐IV generalized anxiety disorder (GAD) by comparing them to the impairments associated with major depressive disorder (MDD). Results are based on 4181 respondents between the ages of 18‐65 years who were interviewed with the 12‐month version of the Munich‐Composite International Diagnostic Interview as part of the German National Health Interview and Examination Survey—Mental Health Supplement (GHS). After controlling for age, gender, and other psychopathology, ‘pure’ current GAD without MDD (n = 33), pure MDD (n = 344) and comorbid GAD and MDD (n = 40) were each associated with high impairment as defined by poor self‐perceived health, at least 3 days limited or impaired in the past month, and low quality of life scores [from the Short Form‐36 Health Survey (SF‐36)]. Quality of life scores on several of the SF‐36 scales were significantly lower for respondents with pure GAD as compared to respondents with pure MDD. Overall, the results show that DSM‐IV GAD is associated with high impairment even after controlling for other psychopathology. The impairment outcomes for GAD were comparable in size to those for MDD. These findings underline the significance of this disorder from a clinical and social perspective and provide support for the independent diagnostic status of GAD. Int Clin Psychopharmacol 15:319‐328

Complex segregation analysis of restless legs syndrome provides evidence for an autosomal dominant mode of inheritance in early age at onset families

A strong familial component of restless legs syndrome (RLS) is known. The objective of this study therefore was to investigate the likely mode of inheritance of RLS. RLS patients and their first‐degree relatives were investigated and classified in RLS affected and RLS nonaffected subjects. Assessments were based on direct, personal standardized diagnostic interviews. Complex segregation analysis was performed with the families stratified according to the mean age at onset of the disease within the families. Two hundred thirty‐eight RLS patients, 537 first‐degree relatives, and 133 spouses were interviewed. Two groups of families were stratified: mean age at onset up to 30 years of age (Group A) and older than 30 years (Group B; p < 0.005). In Group A, segregation analysis strongly favored a single major gene acting autosomal dominant with a multifactorial component. Parameter estimates were 0.003 for the allele frequency, 1.0 for the penetrance, and 0.005 for the phenocopy rate. In Group B, no evidence for a major gene could be elucidated. The segregation pattern found in our families argues for an autosomal allele acting dominantly in RLS families with an early age at onset of symptoms and suggests that RLS is a causative heterogeneous disease.

Anxietas Tibiarum : depression and anxiety disorders in patients with restless legs syndrome

BackgroundSymptoms of anxiety and depression in patients with restless legs syndrome (RLS) have been observed. However, it is unclear whether rates of threshold depression and anxiety disorders according to DSM-IV criteria in such patients are also elevated.Methods238 RLS patients were assessed with a standardized diagnostic interview (Munich-Composite International Diagnostic Interview for DSM-IV) validated for subjects aged 18–65 years. Rates of anxiety and depressive disorders were compared between 130 RLS patients within this age range and 2265 community respondents from a nationally representative sample with somatic morbidity of other types.ResultsRLS patients revealed an increased risk of having 12-month anxiety and depressive disorders with particularly strong associations with panic disorder (OR=4.7; 95% CI=2.1–10.1), generalized anxiety disorder (OR=3.5; 95% CI= 1.7–7.1), and major depression (OR=2.6; 95% CI=1.5–4.4). In addition, lifetime rates of panic disorder and most depressive disorders as well as comorbid depression and anxiety disorders were considerably increased among RLS patients compared with controls.ConclusionsThe results suggest that RLS patients are at increased risk of having specific anxiety and depressive disorders. Causal attributions of patients suggest that a considerable proportion of the excess morbidity for depression and panic disorder might be due to RLS symptomatology.

Structure, Content and Reliability of the Munich-Composite International Diagnostic Interview (M-CIDI) Substance Use Sections

After reviewing currently available diagnostic assessment instruments for substance use disorders this paper describes the format and structure of the Munich-Composite International Diagnostic Interview (M-CIDI) substance disorder section. In addition, the test-retest reliability of diagnoses and criteria for nicotine, alcohol, illegal and prescription drugs, is reported. Findings obtained in community sample of adolescents and young adults indicate that the substance section is acceptable for almost all types of respondents, efficient in terms of time and ease of administration as well as reliable in terms of consistency of findings over time. The test-retest reliability over a period of an average of 1 month, as examined by two independent interviewers indicates good-to-excellent kappa values for all substance disorders assessed, with significant kappa values ranging between 0.55 for drug abuse and 0.83 for alcohol abuse. There was also fairly consistently high agreement for the assessment of single DSM-IV diagnostic criteria for abuse and dependence as well as the M-CIDI quantity-frequency and time-related questions. To conclude, although – unlike previous studies – this study was conducted in a community sample and not in patients and used considerably longer time intervals of more than a month between investigations, our M-CIDI reliability findings are at least as high as those from previous studies.

Heterogeneity of DSM-IV Major Depressive Disorder as a Consequence of Subthreshold Bipolarity

CONTEXT There is growing evidence that major depressive disorder (MDD) might be overdiagnosed at the expense of bipolar disorder (BPD). OBJECTIVES To identify a subgroup of subthreshold BPD among DSM-IV MDD, which is distinct from pure MDD regarding a range of validators of bipolarity, and to examine the pattern of these validators among different groups with affective disorders. DESIGN Ten-year prospective longitudinal and family study including 3 follow-up waves. Data were assessed with the DSM-IV Munich Composite International Diagnostic Interview. SETTING Community sample in Munich, Germany. PARTICIPANTS A total of 2210 subjects (aged 14-24 years at baseline) who completed the third follow-up. MAIN OUTCOME MEASURES Cumulative incidence of pure MDD, BPD, and subthreshold BPD (defined as fulfilling criteria for MDD plus having manic symptoms but never having met criteria for [hypo]mania). RESULTS Among 488 respondents with MDD, 286 (58.6%) had pure MDD and 202 (41.4%) had subthreshold BPD (cumulative incidence, 9.3%). Compared with respondents who had pure MDD, respondents with subthreshold BPD were found to have a significantly increased family history of mania, considerably higher rates of nicotine dependence and alcohol use disorders, rates of panic disorder that were twice as high, and a tendency toward higher rates of criminal acts. Prospective analyses showed that subthreshold BPD converted more often into BPD during follow-up, with DSM-IV criterion D (symptoms observable by others) being of critical predictive relevance. With increasing severity of the manic component, rates for diverse validators accordingly increased (eg, alcohol use disorders, parental mania) or decreased (harm avoidance). CONCLUSIONS Data suggest that MDD is a heterogeneous concept including a large group with subthreshold BPD, which is clinically significant and shares similarities with BPD. Findings might support the need for a broader concept and a more comprehensive screening of bipolarity, which could be substantial for future research and adequate treatment of patients with bipolarity.

Interaction of FKBP5 gene variants and adverse life events in predicting depression onset: results from a 10-year prospective community study.

OBJECTIVE The binding protein FKBP5 is an important modulator of the function of the glucocorticoid receptor, the main receptor of the stress hormone system. This turns the FKBP5 gene into a key candidate for gene-environment interactions, which are considered critical for pathogenesis of stress-related disorders. The authors explored gene-environment interactions between FKBP5 gene variants and adverse life events in predicting the first occurrence of a major depressive episode. METHOD The analyses were based on 884 Caucasians in a 10-year prospective community study. At baseline, they were 14-24 years old and did not fulfill criteria for a major depressive episode. The DSM-IV-based Munich Composite International Diagnostic Interview was used to assess adverse life events preceding baseline and major depressive episodes during follow-up. On the basis of previous findings, five single-nucleotide polymorphisms (SNPs) within the FKBP5 gene were selected for genotyping. RESULTS While the authors did not observe genetic main effects, they found interactions between the five SNPs and traumatic (but not separation) events, with the strongest effect for severe trauma. The effect of trauma on incident major depressive episodes was evident among subjects homozygous for the minor alleles but not subjects with other genotypes. The findings were replicated in the U.K. Environmental Risk Longitudinal Twin Study. CONCLUSIONS These hypothesis-driven results suggest that an interaction between FKBP5 genotype and trauma is involved in the onset of depression. Subjects homozygous for the minor alleles of the investigated FKBP5 SNPs seem to be particularly sensitive to effects of trauma exposure in terms of triggering depression onset.