P. Zimmermann, T. Brückl, Agnes Nocon, A. Heck, H. Pfister, E. Binder, M. Uhr, R. Lieb, F. Holsboer, M. Ising
Interaction of FKBP5 gene variants and adverse life events in predicting depression onset: Results from a 10-year prospective community study
American Journal of Psychiatry, vol. 168, no. 10, pp. 1107-1116
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.
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.
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.
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.
P. Zimmermann, T. Brückl, H. Pfister, R. Lieb, H.-U. Wittchen, F. Holsboer, M. Ising, E. Binder, M. Uhr, Agnes Nocon
The interplay of variations in the FKBP5 gene and adverse life events in predicting the first onset of depression during a ten-year follow-up
[Congress Abstract; 26th Symposium of the AGNP; Munich; October, 7-10, 2009]
Pharmacopsychiatry, vol. 42, no. 5
P. Zimmermann, T. Brückl, Agnes Nocon, H. Pfister, R. Lieb, H.-U. Wittchen, F. Holsboer, J. Angst
Heterogeneity of DSM-IV Major Depressive Disorder as a Consequence of Subthreshold Bipolarity
Archives of General Psychiatry, vol. 66, no. 12, pp. 1341-1352
Agnes Nocon, T. Brückl, P. Zimmermann, J. Rehm, H. Irving, H. Pfister, M. Höfler, R. Lieb, H.-U. Wittchen
Pathways into panic and phobias
The International Journal of Neuropsychopharmacology, vol. 11, no. Suppl. 1
H.-U. Wittchen, Agnes Nocon, K. Beesdo, D. Pine, M. Hoefler, R. Lieb, A. Gloster
Agoraphobia and Panic: Prospective-longitudinal Relations Suggest a Rethinking of Diagnostic Concepts
Psychotherapy and Psychosomatics, vol. 77, no. 3, pp. 147-157
Background: The relationship of panic attacks (PA), panic disorder (PD) and agoraphobia (AG) is controversial. The aim of the current study is to prospectively examine the 10-year natural course of PA, PD and AG in the first three decades of life, their stability and their reciprocal transitions. Methods: DSM-IV syndromes were assessed via Composite International Diagnostic Interview – Munich version in a 10-year prospective-longitudinal community study of 3,021 subjects aged 14–24 years at baseline. Results: (1) Incidence patterns for PA (9.4%), PD (with and without AG: 3.4%) and AG (5.3%) revealed differences in age of onset, incidence risk and gender differentiation. (2) Temporally primary PA and PD revealed only a moderately increased risk for subsequent onset of AG, and primary AG had an even lower risk for subsequent PA and PD. (3) In strictly prospective analyses, all baseline groups (PA, PD, AG) had low remission rates (0–23%). Baseline PD with AG or AG with PA were more likely to have follow-up AG, PA and other anxiety disorders and more frequent complications (impairment, disability, help-seeking, comorbidity) as compared to PD without AG and AG without PA. Conclusions: Differences in incidence patterns, syndrome progression and outcome, and syndrome stability over time indicate that AG exists as a clinically significant phobic condition independent of PD. The majority of agoraphobic subjects in this community sample never experienced PA, calling into question the current pathogenic assumptions underlying the classification of AG as merely a consequence of panic. The findings point to the necessity of rethinking diagnostic concepts and DSM diagnostic hierarchies.
P. Zimmermann, T. Brückl, R. Lieb, Agnes Nocon, M. Ising, K. Beesdo, H.-U. Wittchen
The interplay of familial depression liability and adverse events in predicting the first onset of depression during a 10-year follow-up
Biological Psychiatry, vol. 63, no. 4, pp. 406-414
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.
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 offspring's 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.
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.
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.
Agnes Nocon, H.-U. Wittchen, K. Beesdo, T. Brückl, M. Höfler, M. Pfister, P. Zimmermann, R. Lieb
Differential familial liability of panic disorder and agoraphobia
Depression and Anxiety, vol. 25, no. 5, pp. 422-434
To examine the familial liability of panic disorder (PD) and agoraphobia (AG) in a community sample, namely the effect of parental PD and AG on the offspring's risk to develop either or both conditions in adolescence or adulthood. A representative community sample of N=3,021 adolescents and young adults aged 14-24 years at baseline was followed up over a period of 10 years in up to four waves. Family information was assessed by either direct interviews with at least one parent or by using subjects' family history information at either wave (N=3,014). Diagnoses and selected symptoms were assessed in both, parents and subjects, by using a standardized diagnostic interview (DSM-IV M-CIDI) with its respective family history module. (1) Parental panic attacks (PA), PD, and AG were all shown to be associated with an increased risk of offspring to also develop PA, PD, and AG. (2) Associations of parental PD were present irrespective of parental AG, whereas parental AG without PD was not associated with an increased offspring risk. (3) Outcome risk was particularly elevated in offspring of parents with PD+AG. (4) Parental PD or AG was not associated with an earlier age of onset of any syndrome in the offspring. We confirmed and expanded previous results from clinical samples that comorbid PD and AG aggregate in families. AG without PD is not familial, but it might enhance the familial transmission of PD.
Agnes Nocon, T. Brückl, P. Zimmermann, R. Lieb, H.-U. Wittchen
Specific vulnerability and risk factors for the onset of panic disorder, agoraphobia and other phobias
[Congress Abstract; 25th Symposium of the AGNP; Munich; October, 3-6, 2007]
Pharmacopsychiatry, vol. 40, no. 5
Background: On the background of the ongoing debate whether agoraphobia is a conditioned reaction to biologically elicited panic attacks as proposed by Donald Klein, or whether agoraphobia is accompanied by panic attacks just like other phobias as suggested by Isaac Marks, we aim to study the common and the specific nature of vulnerability/risk factors of panic disorder [PD], agoraphobia [AG], social [SOC] and specific phobia [SPE]. Method: Analyses are based on 3021 participants from a 10-year prospective-longitudinal community survey (14-24 years old at baseline). Lifetime DSM-IV diagnoses and syndromes were assessed via standardized M-CIDI interview. Vulnerabilities in three domains (socio-demographic, family and behavioral-emotional) were assessed. Results: (1) Subjects with PD, SOC and SP were at higher risk for AG, and subjects with AG and SP were at higher risk for panic attacks/disorder. 2) All syndromes were associated with behavioral inhibition (fear). 3) Only phobias, but not PD, were associated with temperament (harm avoidance), behavioral inhibition (social), gender, parental mood disorder, and separation from parents. 4) Parenting style (rejection) was associated to SOC and SP, but not to AG or PD. Discussion: There is some evidence that phobias (particularly AG and SP) are similar with respect to anxiety comorbidity patterns and associations with socio-demographic, family and behavioral-emotional factors, and that these associations are not accounted for by anxiety comorbidity. Risk factors for PD might be rather unspecific and accounted for by comorbid phobias.
Agnes Nocon, H.-U. Wittchen, H. Pfister, P. Zimmermann, R. Lieb
Dependence symptoms in young cannabis users? A prospective epidemiological study
Journal of Psychiatric Research, vol. 40, no. 5, pp. 394-403
To examine prospectively over a period of 4 years the profile of cannabis dependence and the risk of specific dependence criteria in a community sample of adolescents.
A representative community sample of 2446 young adults aged 14-24 years at baseline was followed up over a period of 4 years. Frequency of use measures and of criteria for DSM-IV dependence were assessed by standardized diagnostic interview measures (CIDI). To explore the nature of this association, frequency of use and concomitant use of other psychoactive substances was considered.
30% of the sample were cannabis users. Among all users 35% met at least one dependence criterion. Most frequently reported dependence criteria among all users were withdrawal (17%), tolerance (15%), loss of control (14%) and continued use despite a health problem (13%). Even without concomitant use of other illicit drugs, 22% of low frequency users and 81% of high frequency users met at least one dependence criterion. Symptom patterns were similar in high and low frequency users. The occurrence of a dependence syndrome or of specific dependence criteria could not be attributed to the use of other illicit drugs or to comorbid nicotine and alcohol dependence.
Regular cannabis use in adolescence is associated with the development of a dependence syndrome. This association cannot be explained by the concomitant use of other illicit substances or by comorbid nicotine and alcohol dependence.