RGS2 ggenetic variation: association analysis with panic disorder and dimensional as well as intermediate phenotypes of anxiety.

Accumulating evidence from mouse models points to the G protein-coupled receptor RGS2 (regulator of G-protein signaling 2) as a promising candidate gene for anxiety in humans. Recently, RGS2 polymorphisms were found to be associated with various anxiety disorders, e.g., rs4606 with panic disorder (PD), but other findings have been negative or inconsistent concerning the respective risk allele. To further examine the role of RGS2 polymorphisms in the pathogenesis of PD, we genotyped rs4606 and five additional RGS2 tag single nucleotide polymorphisms (SNPs; rs16834831, rs10801153, rs16829458, rs1342809, rs1890397) in two independent PD samples, comprising 531 matched case/control pairs. The functional SNP rs4606 was nominally associated with PD when both samples were combined. The upstream SNP rs10801153 displayed a Bonferroni-resistant significant association with PD in the second and the combined sample (P = 0.006 and P = 0.017). We furthermore investigated the effect of rs10801153 on dimensional anxiety traits, a behavioral avoidance test (BAT), and an index for emotional processing in the respective subsets of the total sample. In line with categorical results, homozygous risk (G) allele carriers displayed higher scores on the Agoraphobic Cognitions Questionnaire (ACQ; P = 0.015) and showed significantly more defensive behavior during fear provoking situations (P = 0.001). Furthermore, significant effects on brain activation in response to angry (P = 0.013), happy (P = 0.042) and neutral faces (P = 0.032) were detected. Taken together, these findings provide further evidence for the potential role of RGS2 as a candidate gene for PD.

Use of health care services by people with mental illness: secondary data from three statutory health insurers and the German Statutory Pension Insurance Scheme.

BACKGROUND: A discipline- and sector-specific analysis of health-care utilization by persons with mental illness in Germany is an indispensable aid to planning for the provision of adequate basic care. METHOD: Secondary data from three statutory health insurers and the German Statutory Pension Insurance Scheme for the period 2005-2007 were evaluated to identify insurees with mental illness (ICD-10 diagnosis groups F0-F5). RESULTS: In the period 2005-2007, 3.28 million (33%) of 9.92 million insurees had at least one contact with the health-care system in which a mental disorder was diagnosed. 50.4% (1,651,367) of these insurees had at least two mental disorders. Nearly all (98.8%) of the insurees with a psychiatric index diagnosis had at least one somatic diagnosis coded as well. 95.7% of treatments were provided in the outpatient setting. Somatic medical specialties provided the majority of treatments both in ambulatory care and in the hospital. For example, 77.5% of persons with severe depression were treated with five kinds of treatment that were provided exclusively by primary care physicians and other specialists in somatic medicine in private practice, sometimes in combination with psychiatric treatment or psychotherapy. CONCLUSION: There was a high degree of comorbidity of mental and somatic illness. The fact that the vast majority of treatment was provided in the outpatient setting implies that cooperation across health-care sectors and disciplines should be reinforced, and that measures should be taken to ensure the adequate delivery of basic psychiatric care by primary care physicians.

Gender differences in associations of glutamate decarboxylase 1 gene (GAD1) variants with panic disorder.

BACKGROUND: Panic disorder is common (5% prevalence) and females are twice as likely to be affected as males. The heritable component of panic disorder is estimated at 48%. Glutamic acid dehydrogenase GAD1, the key enzyme for the synthesis of the inhibitory and anxiolytic neurotransmitter GABA, is supposed to influence various mental disorders, including mood and anxiety disorders. In a recent association study in depression, which is highly comorbid with panic disorder, GAD1 risk allele associations were restricted to females. METHODOLOGY/PRINCIPAL FINDINGS: Nineteen single nucleotide polymorphisms (SNPs) tagging the common variation in GAD1 were genotyped in two independent gender and age matched case-control samples (discovery sample n = 478; replication sample n = 584). Thirteen SNPs passed quality control and were examined for gender-specific enrichment of risk alleles associated with panic disorder by using logistic regression including a genotype×gender interaction term. The latter was found to be nominally significant for four SNPs (rs1978340, rs3762555, rs3749034, rs2241165) in the discovery sample; of note, the respective minor/risk alleles were associated with panic disorder only in females. These findings were not confirmed in the replication sample; however, the genotype×gender interaction of rs3749034 remained significant in the combined sample. Furthermore, this polymorphism showed a nominally significant association with the Agoraphobic Cognitions Questionnaire sum score. CONCLUSIONS/SIGNIFICANCE: The present study represents the first systematic evaluation of gender-specific enrichment of risk alleles of the common SNP variation in the panic disorder candidate gene GAD1. Our tentative results provide a possible explanation for the higher susceptibility of females to panic disorder.

Adenosine A(2A) receptor gene: evidence for association of risk variants with panic disorder and anxious personality.

Adenosine A(2A) receptors are suggested to play an important role in different brain circuits and pathways involved in anxiety reactions. A variant within the corresponding ADORA2A gene (rs5751876) increased the risk for panic disorder (PD), for elevated anxiety during challenge tests in healthy probands and for anxiety-related arousal in blood-injury phobia. These multiple effects may mirror a more general effect of the SNP on basic personality traits. In the present study we therefore aimed to replicate the original finding in a large PD sample and extend it by investigating an additional proband sample characterized for different anxiety-related personality scores. In addition, as rs5751876 is assumed not to be the disease variant itself but to be in linkage disequilibrium (LD) with the true functional polymorphism other SNPs of potentially functional relevance were identified by re-sequencing the whole gene including several newly identified regions of putative regulatory potential and analysed for their impact on PD and anxious personality. We were indeed able to replicate rs5751876 as risk factor for PD, particularly PD with agoraphobia. Rs5751876 and several other variants in high LD (rs5751862, rs2298383 and rs3761422) as well as the corresponding haplotypes were also associated with different anxiety-related personality scores (Bonferroni corrected P(all) < 0.05). Of these variants, rs2298383 shows functional potential based on in silico analyses and might therefore represent the true underlying causal variant. Our data provide further support for an important role of ADORA2A variants in the pathogenesis of anxiety disorders and anxious personality reflecting their potential as basic susceptibility factors.

Association analysis of Rgs7 variants with panic disorder.

Following our recent finding of Rgs2 playing a role in the development of human panic disorder (PD), we examine another positional and functional candidate from the functionally interwoven Rgs (regulator of G-protein signaling) family, Rgs7, in the pathogenesis of PD. A German PD sample (N = 224) was compared with matched controls (N = 224) for seven SNPs within and flanking the gene. The intronic SNP3 (rs11805657) and its corresponding haplotypes were found to be associated with PD, particularly PD with comorbid agoraphobia (PDAgP), with the effect originating from the female subgroup (P values 0.008-0.047). The rare A-allele was underrepresented in patients, suggesting a protective effect with carriers possessing an about 2-fold lower risk for developing the disorder compared to G/G homozygotes. Our results argue against a major role of Rgs7 gene variants in the pathogenesis of PD, but are consistent with a minor gender-specific effect on PD, particularly PDAgP.

Drug development in neuropsychopharmacology.

Personalized medicine is still in its infancy concerning drug development in neuropsychopharmacology. Adequate biomarkers with clinical relevance to drug response and/or tolerability and safety largely remain to be identified. Possibly, this kind of personalized medicine will first gain clinical relevance in the dementias. The clinical relevance of the genotyping of drug-metabolizing enzymes as suggested by drug licensing authorities for the pharmacokinetic evaluation of medicinal products needs to be proven in sound clinical trials.

Combined effects of exonic polymorphisms in CRHR1 and AVPR1B genes in a case/control study for panic disorder.

Accumulating evidence from animal studies suggests that the corticotropin releasing hormone (CRH) and arginine vasopressin (AVP) neuropeptide systems, contribute to anxiety behavior. To investigate whether polymorphisms in the genes regulating these two systems may alter susceptibility to anxiety disorders in humans, we genotyped 71 single nucleotide polymorphisms (SNPs) in CRH, CRHR1, CRHR2, AVP, AVPR1A, AVPR1B in a German sample from Munich with patients suffering from panic disorder and matched healthy controls (n = 186/n = 299). Significant associations were then replicated in a second German sample with 173 patients with panic disorder and 495 controls. In both samples separately and the combined sample, SNPs within CHRH1 and AVPR1B were nominally associated with panic disorder. We then tested two locus multiplicative and interaction effects of polymorphisms of these two genes on panic disorder. Fifteen SNP pairs showed significant multiplicative effects in both samples. The SNP pair with the most significant association in the combined sample (P = 0.00057), which withstood correction for multiple testing, was rs878886 in CRHR1 and rs28632197 in AVPR1B. Both SNPs are of potential functional relevance as rs878886 is located in the 3' untranslated region of the CRHR1 and rs28632197 leads to an arginine to histidine amino acid exchange at position 364 of AVPR1B which is located in the intracellular C-terminal domain of the receptor. These data suggest that polymorphisms in the AVPR1B and the CRHR1 genes alter the susceptibility to panic disorder.

Chromosome 4q31-34 panic disorder risk locus: association of neuropeptide Y Y5 receptor variants.

There is strong evidence for a genetic contribution to the pathogenesis of panic disorder, with a recent linkage study pointing toward a risk locus on chromosome 4q31-q34 [Kaabi et al., 2006]. Since the neuropeptide Y (NPY) system has been reported to be involved in the pathophysiology of anxiety and in particular panic disorder and the genes coding for NPY Y1, Y2, and Y5 receptors are located in the suggested risk region (4q31-q32), variants in the NPY, NPY Y1, Y2, and Y5 genes were investigated for association with panic disorder in a sample of 230 German patients with panic disorder and matched healthy controls. A synonymous (Gly-426-Gly) NPY Y5 coding variant (rs11946004) as well as haplotypes including rs11946004 and an intronic NPY Y5 variant (rs11724320) were significantly associated with panic disorder (P = 0.027), with the effect originating from the subgroup of female patients (P = 0.030), particularly with concurrent agoraphobia (P = 0.002-0.019). No association was observed for any variants located in the genes coding for NPY, NPY Y1, or Y2. The present results provide preliminary support for an influence of NPY Y5 receptor variants on the etiology of panic disorder in a potentially gender-specific manner further strengthening the evidence for a risk locus on chromosome 4q31-q34 in anxiety disorders. However, in order to allow for conclusive evaluation of the present finding and to exclude a false positive result, further studies in larger, independent, preferably family based samples are warranted.

[Cost and quality aspects in the treatment of Parkinson's disease]. / Kosten- und Qualitäts- aspekte in der Therapie des Morbus Parkinson.

There is a debate on the control of direct costs in Parkinson's disease (PD). The aim of the present review is to discuss the results of recent pharmacoeconomic trials on the cost effectiveness of the therapy of PD patients. Levodopa preparations appear to be cheaper as compared to dopamine agonists in the short term, but in the long run a treatment without dopamine agonists causes earlier onset of motor complications yielding an increase of direct and indirect costs and worse quality of life. However, these long-term aspects which include social aspects, have only partially been considered. In the end, medical and not financial aspects are essential. The Parkinsonian patient should benefit from the scientific progress in the treatment of PD. This will improve quality of life and at least decrease the indirect costs of PD on the long term.

Recent life events and suicide: a case-control study in Tallinn and Frankfurt.

The purpose of this study was to analyze the differences in the disposition and frequency of recent life events preceding suicide in two cities with different socio-political backgrounds: Tallinn in Estonia and Frankfurt/Main in Germany. The information about 156 suicidents in Tallinn and 163 suicidents in Frankfurt was compiled using the psychological autopsy technique [Shneidman, E. S. (1981). The psychological autopsy. Suicide and Life-Threatening Behavior, 11, 325-340; Jacobs, D., & Klein-Benheim, M. (1995). The psychological autopsy: A useful tool for determining proximate causation in suicide cases. Bulletin of American Academy of Psychiatry Law, 23(2), 165-182]. General population controls were matched by age and sex. The occurrence of recent life events was similar among suicidents in Tallinn (81%) and Frankfurt (77%). However, in both sites only male suicides had higher risk of occurrence of any life event than controls (Tallinn: OR'=1.9; 95% CI=1.1-3.7; Frankfurt: OR'=2.0; 95% CI=1.0-4.1) and the mean number of life events was significantly higher among male suicidents in Tallinn in comparison with controls. This may indicate that males are more sensitive to the rapid changes in a society undergoing transition. It seems that it is not the number of life events, but rather their meaning and disposition that creates the risk of suicide. Family discord (weighted OR=4.5; 95% CI=2.5-8.1), loss of job (weighted OR=2.6; 95% CI=1.0-6.4) and financial deterioration (weighted OR=2.2; 95% CI=1.3-3.8) were more prevalent among suicides in Tallinn in comparison with those in Frankfurt. The most significant differences between suicides and controls were family discord, separation and loss of job in Tallinn and somatic illness in Frankfurt. These differences between the two societies, post-Soviet Estonia and Germany, could be explained by the different positions of Estonia and Germany on the survival/self-expression dimensions recorded by the World Value Survey. People in Estonia tend to emphasize economic and physical security above all other goals, and feel threatened by the changes taking place in society. In Germany, good health is considered a necessity for a consumer and self-expressive style of life, and poor health is perceived as a serious threat to the quality of life in a post-materialistic value system.

The novel brain-specific tryptophan hydroxylase-2 gene in panic disorder.

Panic disorder is a common psychiatric disorder characterized by recurrent anxiety attacks and anticipatory anxiety. Due to the severity of the symptoms of the panic attacks and the frequent additional occurrence of agoraphobia, panic disorder is an often debilitating disease. Elevation of central serotonin levels by drugs such as clomipramine represents one of the most effective treatment options for panic disorder. This points to an important role of dysregulation of the serotonergic system in the genetic etiology of panic disorder. The novel brain-specific 5-HT synthesizing enzyme, tryptophan hydroxylase-2 (TPH2), which represents the rate-limiting enzyme of 5-HT production in the brain, may therefore be of particular importance in panic disorder. We focused on the putative transcriptional control region of TPH2 and identified two novel common single nucleotide polymorphisms (SNPs) of TPH2 in and close to this region. Moreover, a recently described loss-of-function mutation of TPH2 which results in an 80% reduction of serotonin production, was assessed. In an analysis of the putative transcriptional control region SNPs in a sample of panic disorder patients and controls no association of the disorder with the TPH2 SNPs or haplotypes was found. Moreover, the loss-of-function R441H mutation of TPH2 was not present in the panic disorder patients. The results of this first study of TPH2 in panic disorder argue against an importance of allelic variation of TPH2 in the pathogenesis of panic disorder with or without agoraphobia.

Axis I disorders and personality disorders as risk factors for suicide.

There is a lack of psychological autopsy studies assessing the influence of axis I disorders on axis II disorders as risk factors for suicide. Therefore, we investigated the association between personality disorders, axis I disorders, and suicide. Psychiatric disorders were evaluated by a semi-structured interview including the Structured Clinical Interview for DSM-IV Axis I (SCID-I) and Personality Disorders (SCID-II) in 163 completed suicides (mean age 49.6 +/- 19.3 years; 64.4% men) and by personal interview in 396 population-based control persons (mean age 51.6 +/- 17.0 years; 55.8% men). In both genders, suicides significantly more often had personality disorders of all clusters than controls, also after adjustment for axis I disorders (p < 0.001, each). In addition, alcohol-related disorders, major depression, and co-occurrence of personality disorders of more than one cluster (men: OR = 16.13; women: OR = 20.43) remained independent predictors for suicide in both genders, "pure" cluster B personality disorders only in women and "pure" cluster C personality disorders only in men. In both genders, co-occurrence of personality disorders of more than one cluster contributed to risk of completed suicide after control for axis I psychiatric disorders and has to be considered as an independent risk factor for suicide.

[Age and gender: confounders for axis I disorders as risk factors for suicide]. / Achse-I-Störungen als Risikofaktoren für Suizid in Abhängigkeit von Alter und Geschlecht.

OBJECTIVES AND METHODS: Aim of the study was to identify and estimate psychiatric axis I disorders as risk factors for suicide in different age groups using a psychological autopsy study with case-control design. 163 suicides and 396 population-based control persons were assessed with a standardized semi-structured interview including SCID-I (for DSM-IV). RESULTS: Logistic regression analyses revealed significantly elevated odds ratios for alcohol-related disorders in men aged 31 to 45, 46 to 60, and 61 to 75 years (OR = 9.0, OR = 7.5, and OR = 10.7, respectively) and for Major Depression, single episode, in men and women aged 61 to 75 years (OR = 42.7 and OR = 15.9). In males aged 31 to 45 years polysubstance-related disorders (OR = 9.5) and in females aged 61 to 75 years cognitive and mental disorders due to a general medical condition (OR = 12.2) were significantly and independently associated with suicide. CONCLUSIONS: Alcohol-related disorders and Major Depression differently contribute to male and female suicide risk in special age groups. These findings imply differentiated prevention strategies.