Petra Zimmermann

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.

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.

Substance Use and Substance Use Disorders in a Community Sample of Adolescents and Young Adults: Incidence, Age Effects and Patterns of Use

Objective: We present the prevalence and incidence rates of alcohol, nicotine, and illicit substance use, abuse, and dependence in a sample of German adolescents and young adults. Patterns of onset, cohort trends, and use of various substance classes are also analyzed. Method: A prospective longitudinal epidemiological study with a representative sample of adolescents and young adults (n = 3,021; baseline age range = 14–24 years) was conducted in Munich, Germany. Participants were assessed between 1995 and 1999 with the Munich-Composite International Diagnostic Interview. Results: Cumulative lifetime incidence (up to age 28) of any substance abuse or dependence was 43.8%, and 12-month prevalence of any substance abuse or dependence was 24.4%. The lifetime incidence of nicotine dependence was most frequent (24.8%), followed by alcohol abuse (19.3%) and alcohol dependence (9.2%); 61.7% endorsed the regular use of a substance for at least one circumscribed period during their lifetime. Age-specific incidence rates and age at onset of substance use disorders differed by age cohorts. Furthermore, nicotine dependence was significantly associated with illicit substance use disorders (HR = 2.6, 95% CI 1.7–4.0). An interactive relationship between age, age at onset of nicotine dependence, and subsequent onset of illicit substance use disorders was found. Conclusions: Since the baseline investigation in 1995, high incidence rates of substance use disorders and substance use have been observed in this young German sample. Especially younger cohorts report significantly earlier ages at onset of abuse and dependence. There also seems to be a trend towards a secondary age at onset peak of nicotine dependence after the onset of illicit drug use disorders. Further investigations are needed to study these patterns in younger samples. However, results emphasize the need for a combined prevention of illicit drugs and nicotine dependence.

The interplay of familial depression liability and adverse events in predicting the first onset of depression during a 10-year follow-up

BACKGROUND The aim of the present article is to explore interaction and correlation effects between familial depression liability and selected adverse (separation and traumatic) events in predicting the first onset of a major depressive episode (MDE) in a 10-year prospective longitudinal community survey. METHODS Analyses are based on 1982 subjects (14 to 24 years at baseline) without baseline MDE who participated during the whole study period and for whom diagnostic information about psychopathology in both parents was available. The offsprings familial depression liability was determined by aggregating information on parental depressive symptoms obtained from family history data and direct interviews with parents. Data were assessed with the Munich-Composite International Diagnostic Interview according to its DSM-IV algorithms. RESULTS Adverse events predicted a substantially increased incidence of MDE among respondents with familial liability but not in those without familial liability. There was a significant interaction between familial liability and traumatic events with the strongest effect for the number of severe traumatic events (risk difference = 11.3%; 95% confidence interval = 3.55-19.15). Associations with familial liability were most pronounced for separation events. CONCLUSIONS Adverse events are particularly pathogenic in individuals with familial liability. The involvement of interactions and correlations between familial liability and adversity might depend on type, severity, and number of events. Both processes are suggested to be concomitant rather than exclusive.

FKBP5 Genotype-Dependent DNA Methylation and mRNA Regulation After Psychosocial Stress in Remitted Depression and Healthy Controls

Background: Polymorphisms in the FK506 binding protein 5 (FKBP5) gene have been shown to influence glucocorticoid receptor sensitivity, stress response regulation, and depression risk in traumatized subjects, with most consistent findings reported for the functional variant rs1360780. In the present study, we investigated whether the FKBP5 polymorphism rs1360780 and lifetime history of major depression are associated with DNA methylation and FKBP5 gene expression after psychosocial stress. Methods: A total of 116 individuals with a positive (n = 61) and negative (n = 55) lifetime history of major depression participated in the Trier Social Stress Test. We assessed plasma cortisol concentrations, FKBP5 mRNA expression, and CpG methylation of FKBP5 intron 7 in peripheral blood cells. Results: Genotype-dependent plasma cortisol response to psychosocial stress exposure was observed in healthy controls, with the highest and longest-lasting cortisol increase in subjects with the TT genotype of the FKBP5 polymorphism rs1360780, and healthy controls carrying the T risk allele responded with a blunted FKBP5 mRNA expression after psychosocial stress. No genotype effects could be found in remitted depression. Conclusions: The FKBP5 rs1360780 polymorphism is associated with plasma cortisol and FKBP5 mRNA expression after psychosocial stress in healthy controls but not in remitted depression. Preliminary results of the DNA methylation analysis suggest that epigenetic modifications could be involved.

Changes in the Hypothalamic-Pituitary-Adrenal Axis and Leptin Levels during Antidepressant Treatment

Background: In depressed patients, overstimulation of the hypothalamo-pituitary-adrenocortical (HPA) system, probably caused by glucocorticoid receptor resistance, is the most consistent neurobiological finding. Glucocorticoids themselves are reported to increase leptin synthesis and secretion in humans. Methods: We examined alterations in plasma levels of leptin as well as changes in the HPA system function using the combined dexamethasone/corticotropin-releasing hormone (dex/CRH) test on admission and at discharge in 74 depressed inpatients. Results: Mean leptin concentration did not change significantly between admission and discharge. However, changes in ACTH response and partial cortisol response to the combined dex/CRH test between admission and discharge were significantly correlated with leptin levels at discharge. Conclusions: Leptin levels at discharge rise as the HPA axis normalizes. These findings may be explained by an improvement in glucocorticoid receptor sensitivity among depressed patients during antidepressant therapy and a consecutively increased influence of glucocorticoids on leptin levels via the glucocorticoid receptor.

The role of mental disorders in the risk and speed of transition to alcohol use disorders among community youth

BACKGROUND Among adolescents and young adults with DSM-IV alcohol use disorders (AUDs), there are inter-individual differences in the speed of transition from initial alcohol use (AU) to AUD. AUDs are highly co-morbid with other mental disorders. The factors associated with rapid transition from first AU to AUD remain unknown and the role of mental disorders in rapid transitions is unclear. Given this background we examined (1) whether prior anxiety, mood, externalizing and non-alcohol substance use disorders are related to the risk and speed of transition from first AU to DSM-IV alcohol abuse (AA) and alcohol dependence (AD) and (2) whether early age of onset of prior mental disorders (PMDs) is a promoter of rapid transition. METHOD A total of 3021 community subjects (97.7% lifetime AU) aged 14-24 years at baseline were followed up prospectively for up to 10 years. AU and mental disorders were assessed with the DSM-IV/M-CIDI. RESULTS Among subjects with lifetime AU, several PMDs, such as specific phobia, bipolar disorder and nicotine dependence, were associated with an increased risk of AUD independent of externalizing disorders. Associations of PMDs with the speed of transition to AUDs were mostly weak and inconsistent. Only social phobia and externalizing disorders were associated with faster transitions to AD even after adjustment for other PMDs. Earlier age of onset of PMD was not associated with rapid transition. CONCLUSIONS Mental disorders are associated with the risk of AUD. With the possible exception of social phobia and externalizing disorders, they do not promote rapid transition, even if they occur particularly early. Future research needs to identify factors relevant to rapid transition to AUD.

Association of a 19- and a 21-kDa GTP-binding protein to pancreatic microsomal vesicles is regulated by the intravesicular pH established by a vacuolar-type H+-ATPase

SummaryEvidence suggests that certain ras-related small molecular weight GTP-binding proteins (smg-proteins) are involved in intracellular membrane trafficking and vesicle fusion. We have previously shown that intravesicular acidification due to a vacuolar-type H+-ATPase, which is Cl− dependent and highly sensitive to the specific inhibitor bafilomycin, enhances GTP-induced fusion of pancreatic microsomal vesicles (Hampe, W., Zimmermann, P., Schulz, I. 1990. FEBS Lett.271:62–66). This process may involve function of smg-proteins. The present study shows that MgATP (2 mm), but neither MgATPγS nor ATP in the absence of Mg2+, increases association of 19- and 21-kDa smg-proteins to the vesicle membrane as monitored by their [α-32P]GTP binding. The affinity of smg-proteins for [α-32P]GTP was not altered by MgATP. Bafilomycin B1 (10−8m), the protonophore CCCP (10−5m), and replacement of Cl− in the incubation buffer by CH3COO− or NO3−resulted in an almost complete inhibition of the MgATP-dependent association of the 19- and 21-kDa smg-proteins to the vesicle membranes. Furthermore, the MgATP effect on both smg-proteins was found to be due to the intravesicular pH and not to the H+ gradient over the vesicle membrane. We conclude that association of a 19-kDa (immunologically identified as the ADP-ribosylation factor, arf) and a yet unidentified 21-kDa GTP-binding protein to vesicle membranes is regulated by the intravesicular pH established by a vacuolar-type H+-ATPase.

Anxious and non-anxious forms of major depression: familial, personality and symptom characteristics.

BACKGROUND Earlier clinical studies have suggested consistent differences between anxious and non-anxious depression. The aim of this study was to compare parental pathology, personality and symptom characteristics in three groups of probands from the general population: depression with and without generalized anxiety disorder (GAD) and with other anxiety disorders. Because patients without GAD may have experienced anxious symptoms for up to 5 months, we also considered GAD with a duration of only 1 month to produce a group of depressions largely unaffected by anxiety. METHOD Depressive and anxiety disorders were assessed in a 10-year prospective longitudinal community and family study using the DSM-IV/M-CIDI. Regression analyses were used to reveal associations between these variables and with personality using two durations of GAD: 6 months (GAD-6) and 1 month (GAD-1). RESULTS Non-anxious depressives had fewer and less severe depressive symptoms, and higher odds for parents with depression alone, whereas those with anxious depression were associated with higher harm avoidance and had parents with a wider range of disorders, including mania. CONCLUSIONS Anxious depression is a more severe form of depression than the non-anxious form; this is true even when the symptoms required for an anxiety diagnosis are ignored. Patients with non-anxious depression are different from those with anxious depression in terms of illness severity, family pathology and personality. The association between major depression and bipolar disorder is seen only in anxious forms of depression. Improved knowledge on different forms of depression may provide clues to their differential aetiology, and guide research into the types of treatment that are best suited to each form.