Publications (51) View all
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Article: Meta-analysis argues for a female-specific role of MAOA-uVNTR in panic disorder in four European populations.
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ABSTRACT: Panic disorder (PD) is a common mental disorder, ranking highest among the anxiety disorders in terms of disease burden. The pathogenesis of PD is multifactorial with significant heritability, however only a few convincing risk genes have been reported thus far. One of the most promising candidates is the gene encoding monoamine oxidase A (MAOA), due to its key role in monoaminergic neurotransmission, established validity of animal models, and the efficacy of MAO inhibitors in the treatment of PD. A promoter repeat polymorphism in MAOA (MAOA-uVNTR) impacts on gene expression; high-expression alleles have been reported to increase the risk for PD. To further scrutinize the role of this polymorphism, we performed a formal meta-analysis on MAOA-uVNTR and PD using original data from four published European (Estonian, German, Italian, and Polish) samples and genotypes from three hitherto unpublished German PD samples, resulting in the largest (n = 1,115 patients and n = 1,260 controls) genetic study on PD reported to date. In the unpublished samples, evidence for association of MAOA-uVNTR with PD was obtained in one of the three samples. Results of the meta-analysis revealed a significant and female-specific association when calculating an allelic model (OR = 1.23, P = 0.006). This sex-specific effect might be explained by a gene-dose effect causing higher MAOA expression in females. Taken together, our meta-analysis therefore argues that high-expression MAOA-uVNTR alleles significantly increase the risk towards PD in women. However, epigenetic mechanisms might obfuscate the genetic association, calling for ascertainment in larger samples as well as assessment of the MAOA promoter methylation status therein. © 2012 Wiley Periodicals, Inc.American Journal of Medical Genetics Part B Neuropsychiatric Genetics 08/2012; 159B(7):786-93. · 3.70 Impact Factor -
Article: Multimodale Therapie der Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung im Erwachsenenalter
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ABSTRACT: Die Behandlungsindikation für die Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung im Erwachsenenalter (adulte ADHS) ergibt sich nicht allein aus der Diagnose, sondern resultiert aus Symptomausprägungen, komorbiden Störungen, geringer psychosozialer Adaptation sowie eingeschränkten Ressourcen. Grundlage der Therapie ist Psychoedukation mit Vermittlung von Kenntnissen zu Symptomen, Störungsmodellen und Behandlungsoptionen. Die Kombination von Psychopharmako- und Psychotherapie wird empfohlen. Methylphenidat, das aufgrund hoher Effektstärken und geringen Nebenwirkungen die Medikation der ersten Wahl ist, ist in Deutschland nicht zugelassen („off-label use“). Atomoxetin ist zugelassen für die Weiterbehandlung im Erwachsenenalter und indiziert bei unzureichender Wirkung oder Nebenwirkungen von Methylphenidat sowie komorbidem Substanzkonsum. Verschiedene psychotherapeutische Interventionen unter Nutzung vorhandener Ressourcen zeigen positive Effekte. Psychosoziale Beratung und Selbsthilfegruppen ergänzen das Behandlungskonzept. Das Fortbestehen der Behandlungsindikation ist in regelmäßigen Abständen zu überprüfen. Eine störungsspezifische multimodale Therapie entspricht der komplexen überwiegend neurobiologischen Ätiologie und den psychosozialen Folgen der adulten ADHS. The indication for treatment of adult attention-deficit hyperactivity disorder (adult ADHD) is derived not from the diagnosis itself but results from the severity of symptoms, comorbidities, psychosocial consequences, and a lack of defined resources for ADHD. The basis of therapy is psychoeducation that includes teaching about symptoms, models of the disorder, and options for treatment. The combination of pharmacotherapy and psychotherapy is recommended. Methylphenidate is considered the first-line therapy, because of its strong effect and modest side effects, but is not authorized in Germany (“off-label use”). Atomoxetine, which is authorized for continuing treatment into adulthood, is indicated if methylphenidate is insufficient or has unacceptable side effects and in case of comorbid substance use. Various psychotherapeutic interventions using available ADHD-typical resources have demonstrated positive effects. Psychosocial support and self-help groups complete the treatment concept. Persistence of the treatment indication has to be reevaluated at regular intervals. Disorder-specific multimodal therapy of adult ADHD conforms to the complex, primarily neurobiologic etiology and the psychosocial consequences.Der Nervenarzt 04/2012; 79(7):801-808. · 0.68 Impact Factor -
Article: Komorbidität von Suchterkrankungen und Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung
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ABSTRACT: Störungen des Substanzkonsums (Substanzabhängigkeit und Substanzmissbrauch) sind ebenso wie adulte Aufmerksamkeitsdefizit-/Hyperaktivitätsstörungen (adulte ADHS) häufige psychische Störungen mit hoher individueller und gesellschaftlicher Relevanz. Beide Erkrankungen weisen eine relativ hohe Heridität auf, wobei die Suszeptibilität durch Interaktionen von multiplen gemeinsamen und divergenten Kandidatengenen mit Umweltfaktoren vermittelt wird. Störungen des Substanzkonsums und adulte ADHS weisen beide ein erhöhtes Risiko für weitere Achse-I-Störungen auf. Die Studien zur Komorbidität von adulter ADHS mit Störungen des Substanzkonsums sind inkonsistent. Verschiedene Komorbiditätshypothesen werden diskutiert. Ein standardisiertes diagnostisches Prozedere ist unbedingt zu beachten. Das Übersehen der Komorbidität von Störungen des Substanzkonsums mit ADHS führt dazu, dass relevante spezifische Therapien nicht erfolgen oder Stimulanzien bei Störungen des Substanzkonsums zu leichtfertig verordnet werden. Multimodale, integrierte Behandlungskonzepte für komorbide bestehende Störungen des Substanzkonsums und adulter ADHS müssen noch entwickelt werden. Substance use disorders (e.g. substance addiction, substance abuse) and adult attention-deficit hyperactivity disorders (adult ADHD) are frequent psychiatric disorders with a high individual and social relevance. Complex interactions of common and divergent susceptibility genes and environmental factors are important for both disorders which have a relatively high heritability. Substance use disorders and adult ADHD are both associated with an increased risk for additional axis I disorders. The results of studies with respect to the comorbidity of adult ADHD and substance use disorders are inconsistent. Different hypotheses with respect to comorbidity are under discussion. A standardised diagnostic procedure has to be followed. The consequence of misdiagnosing adult ADHD with comorbid substance use disorder is that relevant specific therapeutic procedures will not be followed or stimulants will be prescribed too easily for individuals with substance use disorders. Multimodal integrated therapeutic concepts for the comorbidity of substance use disorders and adult ADHD have yet to be developed.Der Nervenarzt 04/2012; 80(9):1015-1021. · 0.68 Impact Factor -
Article: DIRAS2 is Associated with Adult ADHD, Related Traits, and Co-Morbid Disorders
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ABSTRACT: Several linkage analyses implicated the chromosome 9q22 region in attention deficit/hyperactivity disorder (ADHD), a neurodevelopmental disease with remarkable persistence into adulthood. This locus contains the brain-expressed GTP-binding RAS-like 2 gene (DIRAS2) thought to regulate neurogenesis. As DIRAS2 is a positional and functional ADHD candidate gene, we conducted an association study in 600 patients suffering from adult ADHD (aADHD) and 420 controls. Replication samples consisted of 1035 aADHD patients and 1381 controls, as well as 166 families with a child affected from childhood ADHD. Given the high degree of co-morbidity with ADHD, we also investigated patients suffering from bipolar disorder (BD) (n=336) or personality disorders (PDs) (n=622). Twelve single-nucleotide polymorphisms (SNPs) covering the structural gene and the transcriptional control region of DIRAS2 were analyzed. Four SNPs and two haplotype blocks showed evidence of association with ADHD, with nominal p-values ranging from p=0.006 to p=0.05. In the adult replication samples, we obtained a consistent effect of rs1412005 and of a risk haplotype containing the promoter region (p=0.026). Meta-analysis resulted in a significant common OR of 1.12 (p=0.04) for rs1412005 and confirmed association with the promoter risk haplotype (OR=1.45, p=0.0003). Subsequent analysis in nuclear families with childhood ADHD again showed an association of the promoter haplotype block (p=0.02). rs1412005 also increased risk toward BD (p=0.026) and cluster B PD (p=0.031). Additional SNPs showed association with personality scores (p=0.008–0.048). Converging lines of evidence implicate genetic variance in the promoter region of DIRAS2 in the etiology of ADHD and co-morbid impulsive disorders.Keywords: adult ADHD; linkage; genome-wide association; ras pathway; association study; bipolar disorderNeuropsychopharmacology 07/2011; 36(11):2318-2327. · 7.99 Impact Factor -
Article: Cross-Disorder Analysis of Bipolar Risk Genes: Further Evidence of DGKH as a Risk Gene for Bipolar Disorder, but also Unipolar Depression and Adult ADHD
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ABSTRACT: Recently, several genome-wide association studies (GWAS) on bipolar disorder (BPD) suggested novel risk genes. However, only few of them were followed up and further, the specificity of these genes is even more elusive. To address these issues, we genotyped SNPs in ANK3, CACNA1C, CMTM8, DGKH, EGFR, and NPAS3, which were significantly associated with BPD in previous GWAS, in a sample of 380 BPD patients. Replicated SNPs were then followed up in patients suffering from unipolar depression (UPD; n=387) or adult attention-deficit/hyperactivity disorder (aADHD; n=535). While we could not confirm an association of ANK3, CACNA1C, and EGFR with BPD, 10 SNPs in DGKH, CMTM8, and NPAS3 were nominally associated with disease, with two DGKH markers surviving correction for multiple testing. When these were followed up in UPD and aADHD, seven DGKH SNPs were also associated with UPD, while one SNP each in NPAS3 and CMTM8 and four in DGKH were linked to aADHD. Furthermore, a DGKH haplotype consisting of rs994856/rs9525580/rs9525584 GAT was associated with all disorders tested, while the complementary AGC haplotype was protective. The corresponding haploblock spans a 27-kb region covering exons coding for amino acids 65–243, and thus might include functional variants yet to be identified. We demonstrate an association of DGKH with BPD, UPD, and aADHD by applying a two-stage design. These disorders share the feature of mood instability, so that this phenotype might be associated with genetic variation in DGKH.Keywords: association; bipolar disorder; depression; adult ADHD; NPAS3; CMTM8Neuropsychopharmacology 06/2011; 36(10):2076-2085. · 7.99 Impact Factor
