Anxiety Disorders: Smoller JW

Smoller JW. · No affiliation provided · Am J Psychiatry. · Pubmed #17974923 links to  free full text

This publication has no abstract.

Smoller JW, Gardner-Schuster E, Covino J. · Harvard Medical School, Psychiatric Genetics Program in Mood and Anxiety Disorders, Massachusetts General Hospital, Boston, MA, USA. · Am J Med Genet C Semin Med Genet. · Pubmed #18412108 No free full text.

Abstract: Panic disorder and phobic anxiety disorders are common disorders that are often chronic and disabling. Genetic epidemiologic studies have documented that these disorders are familial and moderately heritable. Linkage studies have implicated several chromosomal regions that may harbor susceptibility genes; however, candidate gene association studies have not established a role for any specific loci to date. Increasing evidence from family and genetic studies suggests that genes underlying these disorders overlap and transcend diagnostic boundaries. Heritable forms of anxious temperament, anxiety-related personality traits and neuroimaging assays of fear circuitry may represent intermediate phenotypes that predispose to panic and phobic disorders. The identification of specific susceptibility variants will likely require much larger sample sizes and the integration of insights from genetic analyses of animal models and intermediate phenotypes.

Finn CT, Smoller JW. · Harvard Medical School, Department of Psychiatry and Psychiatric Genetics Program in Mood and Anxiety Disorders, Massachusetts General Hospital, Boston, MA, USA. · Harv Rev Psychiatry. · Pubmed #16603476 No free full text.

Abstract: While psychiatrists may commonly discuss family history in clinical practice, there has been little systematic research documenting the role and effectiveness of genetic counseling for psychiatric disorders. In the coming years, the expected identification of susceptibility genes for psychiatric disorders may bring new opportunities and expectations from patients and families for the clinical translation of research findings in psychiatric genetics. We review evidence for possible increasing demand for genetic counseling, particularly if specific genes related to psychiatric disorders are identified. We then explore both the potential role of genetic counseling for psychiatric disorders and the issues involved in conveying genetic information in the clinical setting. Further research regarding the effectiveness of counseling interventions, as well as additional efforts directed at genetics education for clinicians, will be needed if emerging advances in genetic research are to be incorporated into clinical practice.

Finn CT, Smoller JW. · Department of Psychiatry, Massachusetts General Hospital, 15 Parkman Street, WACC-812, Boston, MA 02114, USA. · Curr Psychiatry Rep. · Pubmed #11276408 No free full text.

Abstract: Of the anxiety disorders, panic disorder (PD) has been the most extensively studied from a genetic standpoint. Results of family studies have consistently demonstrated that PD runs in families, and twin studies indicate that genes contribute to this familiality. However, phenotypic and genetic complexity has made finding the specific genes involved in PD a challenge. There is still uncertainty about how best to define the phenotype for genetic studies and whether it is the clinical phenotype of PD or more latent psychologic and biologic traits that are inherited. To date, molecular genetic studies have suggested some chromosomal regions and genes that may contribute to risk, but none of these have been established. We review the genetic epidemiology of PD as well as recent molecular genetic studies of the disorder, and conclude with a discussion of promising strategies that attempt to uncover specific genetic loci involved in the etiology of PD.

Smoller JW, Simon NM, Pollack MH, Kradin R, Stern T. · Departments of Psychiatry and Pulmonary Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. · Semin Clin Neuropsychiatry. · Pubmed #10378952 No free full text.

Abstract: Anxiety is a common and sometimes disabling symptom among patients with respiratory disease. Anxiety disorders appear to be the most prevalent psychiatric disorders in clinical samples of patients with pulmonary disease. Recognition that the differential diagnosis of dyspnea and anxiety includes both pulmonary and psychiatric conditions can be crucial to appropriate medical management and minimizing iatrogenic harm. This article reviews the epidemiology, comorbidity, diagnosis, and treatment of anxiety syndromes in patients with pulmonary disease. Successful treatment of anxiety disorders can substantially improve quality of life and a variety of treatment options are available. Safe and effective pharmacotherapy requires attention to potential adverse drug effects on pulmonary function and drug-to-drug interactions. Nonpharmacological treatments such as cognitive/behavioral therapies offer effective treatment without the risk of medication side effects.

Koenen KC, Saxe G, Purcell S, Smoller JW, Bartholomew D, Miller A, Hall E, Kaplow J, Bosquet M, Moulton S, Baldwin C. · No affiliation provided · Mol Psychiatry. · Pubmed #16088328 No free full text.

This publication has no abstract.

Koenen KC, DeVivo I, Rich-Edwards J, Smoller JW, Wright RJ, Purcell SM. · Department of Society, Human Development and Health, Harvard School of Public Health, Boston, MA 02115, USA. · BMC Psychiatry. · Pubmed #19480706 links to  free full text

Abstract: BACKGROUND: One in nine American women will meet criteria for the diagnosis of posttraumatic stress disorder (PTSD) in their lifetime. Although twin studies suggest genetic influences account for substantial variance in PTSD risk, little progress has been made in identifying variants in specific genes that influence liability to this common, debilitating disorder. METHODS AND DESIGN: We are using the unique resource of the Nurses Health Study II, a prospective epidemiologic cohort of 68,518 women, to conduct what promises to be the largest candidate gene association study of PTSD to date. The entire cohort will be screened for trauma exposure and PTSD; 3,000 women will be selected for PTSD diagnostic interviews based on the screening data. Our nested case-control study will genotype 1000 women who developed PTSD following a history of trauma exposure; 1000 controls will be selected from women who experienced similar traumas but did not develop PTSD.The primary aim of this study is to detect genetic variants that predict the development of PTSD following trauma. We posit inherited vulnerability to PTSD is mediated by genetic variation in three specific neurobiological systems whose alterations are implicated in PTSD etiology: the hypothalamic-pituitary-adrenal axis, the locus coeruleus/noradrenergic system, and the limbic-frontal neuro-circuitry of fear. The secondary, exploratory aim of this study is to dissect genetic influences on PTSD in the broader genetic and environmental context for the candidate genes that show significant association with PTSD in detection analyses. This will involve: conducting conditional tests to identify the causal genetic variant among multiple correlated signals; testing whether the effect of PTSD genetic risk variants is moderated by age of first trauma, trauma type, and trauma severity; and exploring gene-gene interactions using a novel gene-based statistical approach. DISCUSSION: Identification of liability genes for PTSD would represent a major advance in understanding the pathophysiology of the disorder. Such understanding could advance the development of new pharmacological agents for PTSD treatment and prevention. Moreover, the addition of PTSD assessment data will make the NHSII cohort an unparalleled resource for future genetic studies of PTSD as well as provide the unique opportunity for the prospective examination of PTSD-disease associations.

Blaya C, Moorjani P, Salum GA, Gonçalves L, Weiss LA, Leistner-Segal S, Manfro GG, Smoller JW. · Anxiety Disorders Program, Hospital de Clínicas de Porto Alegre, Post-Graduate Program in Medical Sciences: Psychiatry, Federal University of Rio Grande do Sul, Department of Psychiatry, Luiz Manoel Gonzaga 630/11, 90470-280 Porto Alegre, RS, Brazil. · Neurosci Lett. · Pubmed #19429002 No free full text.

Abstract: Genetic variation at the EF-hand domain containing 2 gene (EFHC2) locus has been associated with fear recognition in Turner syndrome. The aim of this study was to examine whether EFHC2 variants are associated with non-syndromic anxiety-related traits [harm avoidance (HA) and behavioral inhibition (BI)] and with panic disorder (PD). Our sample comprised 127 PD patients and 132 controls without psychiatric disorder. We genotyped nine SNPs within the EFHC2 locus and used PLINK to perform association analyses. An intronic SNP (rs1562875) was associated with HA (permuted p=0.031) accounting alone for over 3% of variance in this trait. This same SNP was nominally, but not empirically, associated with BI (r(2)=0.022; nominal p=0.022) and PD (OR=2.64; nominal p=0.009). The same association was found in a subsample of only females. In sum, we observed evidence of association between a variant in EFHC2, a gene previously associated with the processing of fear and social threat, and HA. Larger studies are warranted to confirm this association.

Smoller JW, Gardner-Schuster E, Misiaszek M. · Department of Psychiatry, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. · Depress Anxiety. · Pubmed #18412063 No free full text.

Abstract: The nosology of anxiety disorders has undergone substantial evolution over the past several decades. The modern classification of these disorders dates to the publication of Diagnostic and Statistical Manual-III (DSM-III) in 1980, but the validity of the current diagnostic categories has been the subject of controversy. Genetic research can help clarify the boundaries of diagnostic categories by examining the etiologic relationships among them. The question posed in the title of this article asks to what degree the DSM-IV definitions of the anxiety disorders are supported by the evolving body of research on the genetic basis of pathologic anxiety. With DSM-V on the horizon, there is a renewed imperative to examine the structure of these disorders. In this article, we address this issue by, first, providing a brief update about the current status of genetic research on anxiety disorders and then considering whether the evidence suggests that genetic influences conform to or transcend DSM definitions. Finally, we discuss future directions for the genetic dissection of anxiety disorders.

Smoller JW, Paulus MP, Fagerness JA, Purcell S, Yamaki LH, Hirshfeld-Becker D, Biederman J, Rosenbaum JF, Gelernter J, Stein MB. · Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. · Arch Gen Psychiatry. · Pubmed #18316676 links to  free full text

Abstract: CONTEXT: Although anxiety disorders are heritable, their genetic and phenotypic complexity has made the identification of susceptibility genes difficult. Well-validated animal models and intermediate phenotypes provide crucial tools for genetic dissection of anxiety. The gene encoding regulator of G protein signaling 2 (Rgs2) is a quantitative trait gene that influences mouse anxiety behavior, making its human ortholog (RGS2) a compelling candidate gene for human anxiety phenotypes. OBJECTIVE: To examine whether variation in RGS2 is associated with intermediate phenotypes for human anxiety disorders. DESIGN: Family-based and case-control association analysis of single-nucleotide polymorphisms at the RGS2 locus in 3 independent samples. SETTING: Massachusetts General Hospital, University of California, San Diego, and San Diego State University. PARTICIPANTS: Study participants included a family-based sample (n = 119 families) of children who underwent laboratory-based assessments of temperament (behavioral inhibition), a sample of 744 unrelated adults who completed assessments of extraversion and introversion, and 55 unrelated adults who underwent functional magnetic resonance imaging measures of response to emotional faces. MAIN OUTCOME MEASURES: Laboratory-based behavioral measures of childhood temperament, self-report measure of personality, and functional magnetic resonance imaging response to emotion processing. RESULTS: Markers spanning RGS2 were associated with childhood behavioral inhibition, a temperamental precursor of social anxiety disorder (haplotype P = 3 x 10(-5); odds ratio, 2.99 in complete trios). In independent samples, RGS2 markers, including rs4606, which has previously been associated with RGS2 expression, were also associated with introversion (a core personality trait in social anxiety disorder) and with increased limbic activation (insular cortex and amygdala) during emotion processing (brain phenotypes correlated with social anxiety). The genotype at rs4606 explained 10% to 15% of the variance in amygdala and insular cortex activation to emotional faces. CONCLUSIONS: These results provide the first evidence that a gene that influences anxiety in mice is associated with intermediate phenotypes for human anxiety disorders across multiple levels of assessment, including childhood temperament, adult personality, and brain function. This translational research suggests that some genetic influences on anxiety are evolutionarily conserved and that pharmacologic modulation of RGS2 function may provide a novel therapeutic approach for anxiety disorders.

Smoller JW, Pollack MH, Wassertheil-Smoller S, Jackson RD, Oberman A, Wong ND, Sheps D. · Department of Psychiatry, Massachusetts General Hospital, Simches Research Building, 185 Cambridge Street, Boston, MA 02114, USA. · Arch Gen Psychiatry. · Pubmed #17909127 links to  free full text

Abstract: CONTEXT: Previous studies have documented an association of depression and phobic anxiety with cardiovascular morbidity and mortality, but little is known about the cardiovascular sequelae of panic anxiety. OBJECTIVE: To determine whether panic attacks are associated with risk of cardiovascular morbidity and mortality in postmenopausal women. DESIGN: Prospective cohort survey. SETTING: Ten clinical centers of the 40-center Women's Health Initiative. PARTICIPANTS: A total of 3369 community-dwelling, generally healthy postmenopausal women (aged 51-83 years) enrolled between 1997 and 2000 in the Myocardial Ischemia and Migraine Study who completed a questionnaire about occurrence of panic attacks in the previous 6 months. MAIN OUTCOME MEASURES: Cardiovascular/cerebrovascular outcomes (fatal and nonfatal myocardial infarction and stroke) and all-cause mortality were ascertained after a mean of 5.3 years of follow-up. RESULTS: A 6-month history of full-blown panic attacks, endorsed by 10% of postmenopausal women in this cohort, was associated with both coronary heart disease (hazard ratio, 4.20; 95% confidence interval, 1.76-9.99) and the combined end point of coronary heart disease or stroke (hazard ratio, 3.08; 95% confidence interval, 1.60-5.94) after controlling for multiple potential confounders. The hazard ratio for all-cause mortality, excluding those with a history of cardiovascular/cerebrovascular events, was 1.75 (95% confidence interval, 1.04-2.94). CONCLUSION: Panic attacks are relatively common among postmenopausal women and appear to be an independent risk factor for cardiovascular morbidity and mortality in older women.

Stewart SE, Fagerness JA, Platko J, Smoller JW, Scharf JM, Illmann C, Jenike E, Chabane N, Leboyer M, Delorme R, Jenike MA, Pauls DL. · Psychiatric Neurodevelopmental and Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA. · Am J Med Genet B Neuropsychiatr Genet. · Pubmed #17894418 No free full text.

Abstract: CONTEXT: Obsessive-Compulsive Disorder (OCD) is a debilitating illness with putative glutamatergic abnormalities. Two separate proximal haplotypes in the glutamate transporter gene, SLC1A1, were recently reported to be associated with OCD among males, but replication is required. OBJECTIVES: This study examines SLC1A1 as a candidate gene for OCD and explores gender influences. It was hypothesized that a significant association between SLC1A1 and OCD would be replicated in an independent sample of males but not females. DESIGN: Family-based association candidate gene study. SETTING: Participants were recruited from tertiary care OCD specialty clinics. PARTICIPANTS: OCD probands and their first degree relatives. MAIN OUTCOMES MEASURES: Association of OCD with genotypes of single nucleotide polymorphism (SNP) markers and related haplotypes. RESULTS: Association between OCD and the three-marker haplotype rs12682807/ rs2072657/ rs301430, with overtransmission of A/T/T, was observed in both genders combined (global P = 0.0015) and in males (global P = 0.0031). Single-marker associations with OCD in the region (rs3780412 and rs2228622) demonstrated modest significance (permuted P = 0.045). CONCLUSIONS: This study identifies a significant association between the SLC1A1 glutamate transporter gene and OCD in a haplotype overlapping with that recently reported.

Stewart SE, Platko J, Fagerness J, Birns J, Jenike E, Smoller JW, Perlis R, Leboyer M, Delorme R, Chabane N, Rauch SL, Jenike MA, Pauls DL. · Psychiatric Neuroscience Research Division, and Obsessive-Compulsive Disorder Clinic, Harvard Medical School, Massachusetts General Hospital, Boston, MA 02114, USA. · Arch Gen Psychiatry. · Pubmed #17283288 links to  free full text

Abstract: CONTEXT: Obsessive-compulsive disorder (OCD) is a debilitating familial psychiatric illness with associated brain abnormalities in the white matter. The gene for oligodendrocyte lineage transcription factor 2 (OLIG2) is an essential regulator in the development of cells that produce white matter (myelin). The OLIG2 gene is also highly expressed in brain regions implicated in OCD. OBJECTIVES: To examine OLIG2 as a candidate gene for OCD susceptibility and to explore whether comorbidity subtypes of OCD have distinct associations with OLIG2 and the functionally related OLIG1 gene. It was hypothesized a priori that OLIG2 and OLIG1 were associated with OCD regardless of the presence of comorbid Tourette disorder (TD), but not with TD alone. DESIGN: Family-based association candidate gene study. SETTING: Participants and their family members were recruited from tertiary care OCD and TD specialty clinics. PARTICIPANTS: Families of 66 probands with OCD with and without TD and 31 probands with TD without OCD. MAIN OUTCOME MEASURES: Genotypes of single nucleotide polymorphism markers and related haplotypes. RESULTS: The following 3 single nucleotide polymorphism markers on OLIG2 were associated with the OCD without TD phenotype: rs762178 (minor allele frequency, 35%; P<.001), rs1059004 (minor allele frequency, 44%; P = .005), and rs9653711 (minor allele frequency, 44%; P = .004). A 5-marker haplotype (A/C/T/T/G) constituting these single nucleotide polymorphisms and exonic single nucleotide polymorphisms rs6517137 and rs13046814 was undertransmitted (frequency, 32%; permuted P=.004), whereas the G/A/T/T/C haplotype (frequency, 22%; permuted P=.02) was overtransmitted to probands with OCD alone, with a significant global P value (permuted P=.008). CONCLUSIONS: This is the first study reporting an association between OLIG2 and OCD, specifically when TD comorbidity is absent. The findings support a role for white matter abnormalities in the etiology of the disorder.

Simon NM, Weiss AM, Kradin R, Evans KC, Reese HE, Otto MW, Oppenheimer JE, Smoller JW, Zalta A, Worthington JJ, Pollack MH. · Massachusetts General Hospital, Boston, Massachusetts 02114, USA. · J Nerv Ment Dis. · Pubmed #17164635 No free full text.

Abstract: Little is known about factors that mediate the relationship between anxiety and respiratory-related distress and disability. We hypothesized that elevations in anxiety sensitivity would be associated with greater severity of dyspnea, greater dyspnea-related avoidance, and poorer subjective assessment of health in patients with dyspnea referred for pulmonary function testing, regardless of objective evidence of pulmonary dysfunction. A total of 182 consecutive patients receiving pulmonary function tests to evaluate dyspnea were screened with a patient-rated Primary Care Evaluation of Mental Disorders and completed the Anxiety Sensitivity Index and questionnaires assessing symptom severity and avoidance. Anxiety Sensitivity Index score predicted more severe subjective dyspnea and greater dyspnea-related avoidance, even after adjustment for anxiety disorders and pulmonary dysfunction. Despite some limitations, these data provide preliminary support that strategies to identify, measure, and address high levels of anxiety sensitivity should be examined to reduce subjective distress and improve functioning for patients with dyspnea.

Smoller JW, Pollack MH, Wassertheil-Smoller S, Brunner R, Curb D, Torner J, Oberman A, Hendrix SL, Hsia J, Sheps DS. · Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts, USA. · Psychosom Med. · Pubmed #17101813 links to  free full text

Abstract: BACKGROUND: Chest pain is a common symptom of panic attacks, but little is known about the relationship in older women among panic attacks, chest pain, and daily life ischemia. METHODS: The authors conducted a cross-sectional survey of 3063 community-dwelling, generally healthy postmenopausal women enrolled between 1997 and 2000 in the Myocardial Ischemia and Migraine Study in 10 clinical centers of the 40-center Women's Health Initiative. Participants, ages 50 to 79 years, completed a questionnaire about occurrence of panic attacks in the previous 6 months and underwent 24-hour ambulatory electrocardiogram monitoring (AECG); 2705 women had valid AECG recordings and panic attack questionnaires. ST depression on AECG, heart rate variability (HRV), and chest pain episodes were compared among women with and without a 6-month history of panic attack. RESULTS: There was no difference in overall prevalence of ischemic episodes during AECG between women with and without panic attacks. Women with a recent history of panic were more likely to experience chest pain during AECG after controlling for potential confounders (odds ratio [OR] = 2.01; 95% confidence interval [CI] = 1.40-2.88), including both nonischemic (OR = 1.83; 95% CI = 1.26-2.65) and ischemic chest pain (OR = 4.94; 95% CI = 1.41-17.30). Although mean HRV was lower in those with panic attacks (p = .017), this was not significant after controlling for confounders. CONCLUSIONS: Postmenopausal women with a recent history of panic attacks do not appear to have more daily life ischemia as measured by occurrence of ST depression during 24-hour monitoring, but do have more chest pain and possibly lower HRV, suggesting that even sporadic panic attacks may be related to cardiovascular risk.

Simon NM, Smoller JW, McNamara KL, Maser RS, Zalta AK, Pollack MH, Nierenberg AA, Fava M, Wong KK. · Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. · Biol Psychiatry. · Pubmed #16581033 No free full text.

Abstract: BACKGROUND: Little is known about the biological mechanisms underlying the excess medical morbidity and mortality associated with mood disorders. Substantial evidence supports abnormalities in stress-related biological systems in depression. Accelerated telomere shortening may reflect stress-related oxidative damage to cells and accelerated aging, and severe psychosocial stress has been linked to telomere shortening. We propose that chronic stress associated with mood disorders may contribute to excess vulnerability for diseases of aging such as cardiovascular disease and possibly some cancers through accelerated organismal aging. METHODS: Telomere length was measured by Southern Analysis in 44 individuals with chronic mood disorders and 44 nonpsychiatrically ill age-matched control subjects. RESULTS: Telomere length was significantly shorter in those with mood disorders, representing as much as 10 years of accelerated aging. CONCLUSIONS: These results provide preliminary evidence that mood disorders are associated with accelerated aging and may suggest a novel mechanism for mood disorder-associated morbidity and mortality.

Finn CT, Wilcox MA, Korf BR, Blacker D, Racette SR, Sklar P, Smoller JW. · Department of Psychiatry, the Psychiatric Genetics Program in Mood and Anxiety Disorders, Massachusetts General Hospital, Boston, Mass. 02115, USA. · J Clin Psychiatry. · Pubmed #16013896 No free full text.

Abstract: OBJECTIVE: Knowledge about the genetic basis of psychiatric illness is growing rapidly, and psychiatrists may be called upon to incorporate this information into clinical practice. The goal of this study was to assess psychiatrists' familiarity with and attitudes toward genetic information. METHOD: We surveyed 844 participants, the majority of whom were psychiatrists, attending a continuing medical education course in the fall of 2002 and measured knowledge, opinions, and current practice patterns in regard to psychiatric genetics. RESULTS: Responses were received from 352 psychiatrists (54% of those surveyed). Most psychiatrists correctly answered fewer than half of survey items assessing general and psychiatric genetic knowledge. While 83% considered it their role to discuss genetic information with patients and families, fewer than 25% felt prepared or competent to do so. In response to hypothetical questions regarding genetic testing, a substantial proportion of psychiatrists indicated willingness to use such tests for diagnostic clarification, as well as presymptomatic and even prenatal risk prediction. The majority of respondents expressed interest in further genetics education. CONCLUSIONS: Our results suggest that psychiatrists view genetic information as clinically relevant, but have limitations in knowledge that may impact the incorporation of psychiatric genetics into clinical practice.

Smoller JW, Yamaki LH, Fagerness JA, Biederman J, Racette S, Laird NM, Kagan J, Snidman N, Faraone SV, Hirshfeld-Becker D, Tsuang MT, Slaugenhaupt SA, Rosenbaum JF, Sklar PB. · Department of Psychiatry, Massachusetts General Hospital, Boston 02114, USA. · Biol Psychiatry. · Pubmed #15953484 No free full text.

Abstract: BACKGROUND: Behavioral inhibition to the unfamiliar (BI) is a heritable temperamental phenotype involving the tendency to display fearful, avoidant, or shy behavior in novel situations. BI is a familial and developmental risk factor for panic and phobic anxiety disorders. We previously observed an association between BI and a microsatellite marker linked to the corticotropin releasing hormone (CRH) gene in children at risk for panic disorder. To evaluate this further, we genotyped additional families for this marker and a panel of markers encompassing the CRH locus. METHODS: Sixty-two families that included parents with panic disorder and children who underwent laboratory-based behavioral observations were studied. Family-based association tests and haplotype analysis were used to evaluate the association between BI and polymorphisms spanning the CRH locus. RESULTS: We examined a set of markers which we found to reside in a block of strong linkage disequilibrium encompassing the CRH locus. The BI phenotype was associated with the microsatellite marker (p=.0016) and three single nucleotide polymorphisms (SNPs), including a SNP in the coding sequence of the gene (p=.023). Haplotype-specific tests revealed association with a haplotype comprising all of the markers (p=.015). CONCLUSIONS: These results suggest that the CRH gene influences inhibited temperament, a risk factor for panic and phobic anxiety disorders. Genetic studies of anxiety-related temperament represent an important strategy for identifying the genetic basis of anxiety disorders.

Simon NM, Otto MW, Fischmann D, Racette S, Nierenberg AA, Pollack MH, Smoller JW. · Massachusetts General Hospital, WACC 815, 15 Parkman Street, Boston, Massachusetts 02114, United States. · J Affect Disord. · Pubmed #15894380 No free full text.

Abstract: BACKGROUND: Panic disorder (PD) occurs at high rates in bipolar disorder and more commonly than in unipolar depression. Reports of PD onset during hypomania and depressive mania (i.e., mixed states) raise questions about whether the affective disturbances of bipolar disorder play a specific role in the exacerbation or onset of PD. Anxiety sensitivity (AS), a risk factor for PD appears greater in bipolar disorder compared to unipolar depression, although the association of specific mood states with AS remains unknown. METHODS: We examined the association of current mood state (i.e., mixed state, mania or hypomania, bipolar depression, unipolar depression, and euthymia) with Anxiety Sensitivity Index (ASI) scores in 202 individuals with bipolar disorder (n=110) or major depressive disorder (n=92). RESULTS: Current mood state was significantly associated with ASI score (Chi-square=21.2, df=4, p=0.0003). In multiple regression analyses, including covariates for comorbid anxiety disorders, current mania or hypomania was a significant predictor of ASI scores (p<0.04). Current mixed state tended toward a similar association (p<0.10). LIMITATIONS: Conclusions are limited by the study's cross-sectional nature and relatively small sample size. CONCLUSIONS: These findings of elevated AS during manic states, independent of comorbid anxiety disorders, provide preliminary support for the hypothesis that manic states contribute to risk for the development or exacerbation of PD, and that AS may contribute to the high prevalence and severity of PD comorbid with bipolar disorder.

Smoller JW, Rosenbaum JF, Biederman J, Kennedy J, Dai D, Racette SR, Laird NM, Kagan J, Snidman N, Hirshfeld-Becker D, Tsuang MT, Sklar PB, Slaugenhaupt SA. · Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. · Biol Psychiatry. · Pubmed #14675801 No free full text.

Abstract: BACKGROUND: Behavioral inhibition to the unfamiliar (BI), a heritable temperamental profile involving an avoidant response to novel situations, may be an intermediate phenotype in the development of anxiety disorders. Corticotropin-releasing hormone (CRH) is a key mediator of the stress response through its effects on the hypothalamic-pituitary-adrenal axis and limbic brain systems. Transgenic mice overexpressing CRH exhibit BI-like behaviors, implicating this gene in the development of the phenotype. METHODS: We genotyped a marker tightly linked to the CRH locus in 85 families of children who underwent laboratory-based behavioral assessments of BI and performed family-based association analyses. RESULTS: We observed an association between an allele of the CRH-linked locus and BI (p =.015). Among offspring of parents with panic disorder, this association was particularly marked (p =.0009). We further demonstrate linkage disequilibrium between this marker and single nucleotide polymorphisms encompassing the CRH gene. CONCLUSIONS: These results are consistent with the possibility that variants in the CRH gene are associated with anxiety proneness.

Smoller JW, Pollack MH, Wassertheil-Smoller S, Barton B, Hendrix SL, Jackson RD, Dicken T, Oberman A, Sheps DS, Anonymous00372. · Department of Psychiatry, Massachusetts General Hospital, Boston, MA 02114, USA. · Arch Intern Med. · Pubmed #14504117 links to  free full text

Abstract: BACKGROUND: Panic attacks are known to be more common in women than in men, but the prevalence and correlates of panic in the postmenopausal period have not been well defined. METHODS: Cross-sectional survey of 3369 community-dwelling postmenopausal women enrolled between December 1, 1997, and November 30, 2000, in the Myocardial Ischemia and Migraine Study, a 10-center ancillary study of the 40-center Women's Health Initiative. Participants, aged 50 to 79 years and predominantly white (73%), completed questionnaires about the occurrence of panic attacks in the previous 6 months and about migraine headaches and underwent 24-hour ambulatory electrocardiographic monitoring. The 6-month prevalences of full-blown and limited-symptom panic attacks were calculated, and their associations with other sociodemographic and clinical variables were examined in multivariate analyses. RESULTS: One of the panic attack types was reported by 17.9% (95% confidence interval, 16.6%-19.2%) of women (full-blown attacks, 9.8%; limited-symptom attacks, 8.1%). Adjusting for age and race or ethnicity, full-blown panic attacks were more common in women with a history of migraine, emphysema, cardiovascular disease, chest pain during ambulatory electrocardiography, and symptoms of depression. Full-blown panic attacks were associated in a dose-response manner with negative life events during the past year. Panic attacks were associated with functional impairment even after adjusting for comorbid medical conditions and depression. There was no significant association with self-reported use of hormone replacement therapy. CONCLUSIONS: Panic attacks may be relatively common among postmenopausal women and seem to be associated with stressful life events, medical comorbidity, and functional impairment.

Simon NM, Smoller JW, Fava M, Sachs G, Racette SR, Perlis R, Sonawalla S, Rosenbaum JF. · WACC 815, Massachusetts General Hospital, 15 Parkman Street, Boston, MA 02114, USA. · J Psychiatr Res. · Pubmed #12650739 No free full text.

Abstract: The frequent comorbidity of anxiety disorders and mood disorders has been documented in previous studies. However, it remains unclear whether specific anxiety traits or disorders are more closely associated with unipolar major depression (MDD) or bipolar disorder (BPD). We sought to examine whether MDD and BPD can be distinguished by their association with specific types of anxiety comorbidity. Individuals with a primary lifetime diagnosis of either bipolar disorder (N=122) or major depressive disorder (N=114) received diagnostic assessments of anxiety disorder comorbidity, and completed questionnaires assessing anxiety sensitivity and neuroticism. The differential association of these anxiety phenotypes with MDD versus BPD was examined with multivariate modeling. Panic disorder and generalized anxiety disorder (GAD) specifically emerged amongst all the anxiety disorders as significantly more common in patients with BPD than MDD. After controlling for current mood state, anxiety sensitivity and neuroticism did not differ by mood disorder type. This study supports prior research suggesting a specific panic disorder-bipolar disorder connection, and suggests GAD may also be differentially associated with BPD. Further research is needed to clarify the etiologic basis of anxiety disorder/BPD comorbidity and to optimize treatment strategies for patients with these co-occurring disorders.

Otto MW, Pollack MH, Maki KM, Gould RA, Worthington JJ, Smoller JW, Rosenbaum JF. · Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. · Depress Anxiety. · Pubmed #11754127 No free full text.

Abstract: We examined the rates and correlates of a childhood history of anxiety disorders in 100 adults with a primary diagnosis of social phobia (social anxiety disorder). Adulthood and childhood disorders were assessed by experienced clinicians with structured clinical interviews. Rates of childhood anxiety disorders were evaluated to diagnostic comorbidity and a comparison group of patients with panic disorder. Onset of social phobia occurred before age 18 in 80% of the sample. Over half of the sample (54%) met criteria for one or more childhood anxiety disorders other than social phobia: 47% for overanxious disorder, 25% for avoidant disorder, 13% for separation anxiety disorder, and 1% for childhood agoraphobia. A history of childhood anxiety was associated with an early age of onset of social phobia, greater severity of fear and avoidance of social situations, greater fears of negative evaluation, and greater anxiety and depression morbidity. Rates of childhood social phobia, overanxious disorder, and avoidant disorder were significantly higher in patients with social phobia relative to our panic-disordered comparison group. We found approximately equal rates of a childhood history of separation anxiety disorder in patients with social phobia and panic disorder, providing further evidence against a unique relationship between separation anxiety disorder and panic disorder.

Smoller JW, Rosenbaum JF, Biederman J, Susswein LS, Kennedy J, Kagan J, Snidman N, Laird N, Tsuang MT, Faraone SV, Schwarz A, Slaugenhaupt SA. · Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. · Am J Med Genet. · Pubmed #11353440 No free full text.

Abstract: Genes influence the development of anxiety disorders, but the specific loci involved are not known. Genetic association studies of anxiety disorders are complicated by the complexity of the phenotypes and the difficulty in identifying appropriate candidate loci. We have begun to examine the genetics of behavioral inhibition to the unfamiliar (BI), a heritable temperamental predisposition that is a developmental and familial risk factor for panic and phobic disorders. Specific loci associated with homologous phenotypes in mouse models provide compelling candidate genes for human BI. We conducted family-based association analyses of BI using four genes derived from genetic studies of mouse models with features of behavioral inhibition. The sample included families of 72 children classified as inhibited by structured behavioral assessments. We observed modest evidence of association (P = 0.05) between BI and the glutamic acid decarboxylase gene (65 kDA isoform), which encodes an enzyme involved in GABA synthesis. No significant evidence of association was observed for the genes encoding the adenosine A(1A) receptor, the adenosine A(2A) receptor, or preproenkephalin. This study illustrates the potential utility of using candidate genes derived from mouse models to dissect the genetic basis of BI, a possible intermediate phenotype for panic and phobic disorders.

Smoller JW, Acierno JS, Rosenbaum JF, Biederman J, Pollack MH, Meminger S, Pava JA, Chadwick LH, White C, Bulzacchelli M, Slaugenhaupt SA. · Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts, USA. · Am J Med Genet. · Pubmed #11304837 No free full text.

Abstract: Family and twin studies have indicated that genes influence susceptibility to panic and phobic anxiety disorders, but the location of the genes involved remains unknown. Animal models can simplify gene-mapping efforts by overcoming problems that complicate human pedigree studies including genetic heterogeneity and high phenocopy rates. Homology between rodent and human genomes can be exploited to map human genes underlying complex traits. We used regions identified by quantitative trait locus (QTL)-mapping of anxiety phenotypes in mice to guide a linkage analysis of a large multiplex pedigree (99 members, 75 genotyped) segregating panic disorder/agoraphobia. Two phenotypes were studied: panic disorder/agoraphobia and a phenotype ("D-type") designed to capture early-onset susceptibility to anxiety disorders. A total of 99 markers across 11 chromosomal regions were typed. Parametric lod score analysis provided suggestive evidence of linkage (lod = 2.38) to a locus on chromosome 10q under a dominant model with reduced penetrance for the anxiety-proneness (D-type) phenotype. Nonparametric (NPL) analysis provided evidence of linkage for panic disorder/agoraphobia to a locus on chromosome 12q13 (NPL = 4.96, P = 0.006). Modest evidence of linkage by NPL analysis was also found for the D-type phenotype to a region of chromosome 1q (peak NPL = 2.05, P = 0.035). While these linkage results are merely suggestive, this study illustrates the potential advantages of using mouse gene-mapping results and exploring alternative phenotype definitions in linkage studies of anxiety disorder.