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Specificity of familial transmission of anxiety and comorbid disorders
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JOURNAL OF PSYCHIATRIC RESEARCH
Journal of Psychiatric Research 42 (2008) 596–604
www.elsevier.com/locate/jpsychires
Specificity of familial transmission of anxiety and comorbid disorders Nancy C.P. Low
a,b,*
, Lihong Cui b, Kathleen R. Merikangas
b
a Department of Psychiatry, McGill University, Montreal, Quebec, Canada Section on Developmental Genetic Epidemiology, Mood and Anxiety Disorders Program, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, 35 Convent Drive (MSC 3720), Bethesda, MD 20892-3720, USA b
Received 18 December 2006; accepted 2 July 2007
Abstract This study examines the specificity and impact of comorbid disorders in probands on the familial transmission of panic and social anxiety disorders. It employs a contemporary family study design with 225 probands (with and without panic and social anxiety disorders) sampled from outpatient clinics and the local community. Their 1053 adult first-degree relatives were assessed for lifetime disorders, based on best estimate diagnoses derived from semi-structured psychiatric diagnostic interviews (Schedule for Affective Disorders and Schizophrenia), multi-informant family history information, and medical records. Generalized estimating equations were used to examine the familial aggregation of panic and social anxiety disorders, and the contributions of comorbid disorders. Results show specificity of familial aggregation of both panic disorder and social anxiety in probands and relatives (i.e., panic odds ratio = 3.7, 95%CI 1.5–9.3; social anxiety odds ratio = 1.8, 95%CI 1.1–2.9) after controlling for comorbid disorders. There was no contribution of common comorbid disorders (depression, alcoholism, generalized anxiety disorder and agoraphobia) in probands on the familial aggregation of either disorder. These findings confirm prior studies of specificity of familial transmission of panic and social anxiety disorders, and demonstrate that the association between these disorders in probands is not attributable to comorbid mood, anxiety or substance use disorders. Therefore, despite the high magnitude of co-occurrence of panic disorder and social anxiety, there may be distinct etiologic factors underlying each disorder. These findings have implications for studies of the etiology, genetics, and treatment of these disorders. Ó 2007 Elsevier Ltd. All rights reserved. Keywords: Familial aggregation/transmission; Specificity of transmission; Anxiety disorders; Panic disorder; Social anxiety/phobia; Comorbidity
1. Introduction Anxiety disorders are the most prevalent form of psychopathology in the general population (Kessler et al., 2005). Among them, panic and social anxiety disorders have among the greatest associated impairment in several domains of functioning, in addition to significant negative effects on quality of life (Simon et al., 2002). This is in part due to their early onset (often in adolescence), chronic lifelong course, and high comorbidity. The lifetime and 1-year prevalence of DSM-IV-defined (APA, 1994) panic disorder * Corresponding author. Address: Department of Psychiatry, McGill University, 1033 Pine Avenue West, Room 104, Montreal, Quebec, H3A 1A1, Canada. Tel.: +1 514 465 9033; fax: +1 514 398 4370. E-mail address: [email protected] (N.C.P. Low).
0022-3956/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.jpsychires.2007.07.002
range from 2.1% to 5.1% and 0.8% to 2.8%, respectively (Alonso et al., 2004; Grant et al., 2006; Kessler et al., 2006), and the corresponding ranges for social anxiety disorder rates are 1.9–12.1% and 1.2–6.8%, respectively (Lampe et al., 2003; Alonso et al., 2004; Grant et al., 2005; Kessler et al., 2005). There is considerable evidence from both clinical and community samples regarding the overlap among the DSM-IV anxiety disorders, as well as, between affective, alcohol and substance abuse disorders (Regier et al., 1990; Kessler et al., 2005). The most recent community surveys of the United States reveal that the majority of those with lifetime panic disorder or social anxiety disorder have at least one other Axis I anxiety disorder subtype as well as other Axis I disorders. For example, the National Comorbidity Survey – Replication (NCS-R) found the following
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proportions of comorbid disorders among participants with lifetime panic disorder: 83% with any disorder, 66% with another anxiety disorder, 50% with a mood disorder and 27% with a substance use disorder (Kessler et al., 2006). Likewise, data from the National Epidemiologic Survey of Alcohol and Related Conditions (NESARC) indicated that persons with social anxiety disorder had high frequencies of other anxiety disorders (54%), mood disorders (56%,) and alcohol use disorders (48%) (Grant et al., 2005). The family study design provides a powerful method to investigate sources of comorbidity (Merikangas, 1990; Klein and Riso, 1993). Evidence for differential diatheses underlying familial transmission of comorbid compared to non-comorbid disorders has implications for identifying sources of phenotypic heterogeneity, identifying etiologic factors, and designing therapeutic interventions. Previous family studies examining the specificity of transmission of anxiety disorders have dealt with comorbidity among probands in three different ways. First, some studies have selected ‘‘pure’’ diagnostic groups of probands, that is, those with only the anxiety disorder of interest (Kendler, 1990). However, these studies were inconsistent in excluding other psychiatric disorders, such as depression or alcohol dependence (Harris et al., 1983; Noyes et al., 1986; Maier et al., 1993; Mendlewicz et al., 1993; Fyer et al., 1995). A second, and less common, method of addressing comorbidity between anxiety disorders is to permit comorbid anxiety (and possibly other psychiatric disorders) in probands (Stein et al., 1998) and adjust for the possible effects of comorbidity in the analyses. A third set of family studies actually incorporates comorbidity into the study design by selecting proband groups with and without comorbid disorders (Weissman et al., 1993; Merikangas et al., 1994; Merikangas et al., 1998). There are advantages and disadvantages to each of these approaches. ‘‘Pure’’ diagnostic groups allow study findings to be attributed specifically to the disorder since there are no comorbid disorders. ‘‘Proof of concept’’ studies and other specific biological hypotheses can be tested in these groups. However, samples of probands without comorbidity are not representative of both general population and clinical samples of individuals with these conditions. Therefore, the major advantage of selecting probands with comorbid disorders is that they are more representative – for example, allowing mood and substance use disorders along with panic or social anxiety disorder would examine a more generalizable group, as comorbidity is the rule rather than the exception. These studies, however, will also require larger sample sizes in order to test the potential mediating effects of comorbid disorders. The use of representative samples will take on increasing importance with the growing shift to large-scale collaborative case-control association studies to identify susceptibility genes for complex disorders. The representativeness of a sample to its disease base population is not only important when the sample is being used to estimate disease prevalence or
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attributable risk, but in genetic studies, systematic sampling is crucial because biased ascertainment can compromise both the validity of estimates of genetic parameters in statistical studies, and the identification of genetic markers in linkage and association studies (Cavalli-Sforza and Bodmer, 1971; Cardon and Bell, 2001; Little et al., 2002; Colhoun et al., 2003; Newton-Cheh and Hirschhorn, 2005). Progress has been slow in identifying and replicating genes underlying anxiety disorders (Arnold et al., 2004; Merikangas and Low, 2005) in part because of the selection and criteria for cases and controls. Finally given advances in statistical approaches (Zeger and Liang, 1986; Zeger et al., 1988), even with selection of probands with comorbid disorders, one can examine of the independent contribution of other factors on familial aggregation and on other outcomes of interest. In the present study, we selected probands with anxiety disorders with comorbid major depression and/or alcohol abuse/dependence from both community and clinic sources in order to examine their role in the specificity of transmission of anxiety disorders. The two chief objectives were: (1) to examine the specificity of transmission of panic disorder and social anxiety disorder, and (2) to investigate the effect of comorbid anxiety disorders, major depression, and alcohol abuse/dependence, on the familial aggregation of panic disorder and social anxiety disorder. 2. Methods and materials 2.1. Sample and measures 2.1.1. Probands Two-hundred twenty-five probands participated in the study. Probands were originally selected with the goal to examine the familial aggregation of anxiety and alcohol use disorders. The patients were recruited from outpatient clinics for anxiety and alcohol use disorders at the Connecticut Mental Health Center in New Haven, Connecticut. All patients treated at the clinics over a 3-year period were screened for eligibility in the study, and those who met the appropriate diagnostic criteria were invited to participate. All probands were assigned to one of four lifetime diagnostic groups: (1) panic disorder and/or social anxiety disorder without a lifetime history of alcohol abuse/dependence (N = 67); (2) alcohol abuse/dependence with panic disorder and/or social anxiety disorder (N = 45); (3) alcohol abuse/dependence without a lifetime history of panic or social anxiety disorders (N = 54); and (4) controls (no Axis I disorders) (N = 59). All of the controls and 33.9% of the anxiety probands were recruited from the population of the greater New Haven area through a random digit dialing procedure. The rationale for including a combination of probands from the clinic and community was to minimize Berkson’s bias (treatment-seeking bias) and obtain a more representative sample for examination. The diagnostic interview for adults was the semi-structured Schedule for Affective Dis-
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orders and Schizophrenia (SADS) (Endicott and Spitzer, 1978), current and lifetime versions, which was modified to incorporate DSM-III and DSM-III-R criteria and to include more detailed information on anxiety disorders and substance use patterns. Probands were excluded if they had evidence of schizophrenia, schizoaffective disorder, mental retardation, opioid and cocaine use disorders, or a significant medical disorder causing their psychiatric symptoms. Probands with comorbid affective, other anxiety disorders, and substance (that is, marijuana and sedatives/hypnotics – as long as they were not the primary substance of abuse/dependence) use disorders were included. To address the goals of this examination of the specificity of transmission of panic and social anxiety disorder, the above mentioned four proband groups were reclassified into five hierarchal, mutually exclusive anxiety disorder proband groups. These new anxiety disorder proband groups were developed using a hierarchy whereby panic and/or social anxiety supercede other adult anxiety disorders (generalized anxiety disorder, agoraphobia, specific phobia) and other comorbid disorders (such as, alcohol use and affective disorders). The final anxiety disorder proband groups used this analysis were as follows: (1) both panic disorder and social anxiety disorder (N = 26); (2) panic disorder alone (panic disorder without a lifetime history of social anxiety disorder) (N = 40); (3) social anxiety disorder alone (social anxiety disorder without a lifetime history of panic disorder) (N = 46); (4) other anxiety disorders (anxiety disorders other than panic disorder and social anxiety disorder – mainly generalized anxiety disorder and agoraphobia) (N = 32); and (5) no anxiety disorders (no Axis I anxiety disorders) (N = 81).
2.1.2. Relatives There were a total of 1053 first-degree relatives included in this sample: 113 from families of panic and social anxiety probands, 186 from families of panic disorder alone probands, 240 from families of social anxiety disorder alone probands, 148 from families of ‘‘other anxiety’’ probands, and 366 from families of ‘‘no anxiety’’ probands. The relatives were composed of siblings (48.5%), parents (41.0%), and adult offspring (10.5%). Diagnostic information on all first-degree relatives was obtained by direct interview and by a structured family history interview. Family history information was obtained using a modified version of the Family History-Research Diagnostic Criteria developed by Andreasen et al. (Andreasen et al., 1977) to collect diagnostic spectrum information and to obtain both DSMIII and DSM-III-R diagnoses in adults and children. All eligible relatives were asked to participate in the study. Inclusion criteria required that permission be obtained first
from probands to contact living relatives, of whom 57% were interviewed directly, either in person or by telephone. The interview rates did not differ significantly between the anxiety proband groups and are in accordance with previous family studies of substance abuse. All analyses controlled for the effect of interview status. 2.2. Family procedures Complete pedigrees on first degree relatives including children over age 18 were obtained. Both direct (either face-to-face or by telephone) and indirect (family history by relatives) assessments of first degree relatives including parents, siblings and offspring over age 18 were conducted by clinically experienced interviewers who were blind to the diagnostic status of the proband. Offspring under age 18 were evaluated in a high risk study of children of parents with anxiety disorders and alcohol use disorders. Information on relatives who were deceased, refused to participate or were geographically distant was obtained blinded to proband diagnoses from multiple relatives and best estimate diagnostic assessments were made by a panel of experienced clinicians based on all available information. Treatment records were requested for all probands and relatives who had received treatment for these conditions. 2.3. Interview procedures All procedures complied with strict ethical standards in the treatment of human subjects and were approved by the Yale University School of Medicine Institutional Review Board. After complete description of the study to the subjects, written informed consent was obtained. Probands were directly interviewed with a structured interview on health, behavior, mental disorders and substance use disorders. In order to avoid bias, blindness to the proband diagnosis was built into both the direct interviews and best estimate procedures for diagnoses of relatives. There was also an attempt to maintain blindness to proband diagnoses in the collection of family history information by using two independent interviewers. However, in many cases this became practically unfeasible because of increased subject burden. All adult first-degree relatives were approached for direct interview by an independent interviewer blinded to the proband diagnoses. The proband and interviewed first-degree relatives provided family history data on all their first-degree relatives. Interviewers with experience in clinical psychiatry were chosen to interview and an extensive effort was made to establish reliability. Kappas derived from joint ratings of individual interviews were generally higher for substance abuse (0.72–0.94) than for anxiety or affective disorders (0.54–0.78) across the first three series of training sessions. Although kappas for each of the subtypes of anxiety disorders alone were not recorded, the reliability for the subtypes of panic and social anxiety fell in the upper range of the kappas cited for anxiety and affective disorders,
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whereas specific phobias and hypomania tended to be less reliable. Comparison of diagnoses obtained through direct face-to-face interview versus telephone interview showed high levels of agreement across all diagnostic categories. 2.4. Best estimate diagnostic procedures Diagnoses of anxiety and substance use disorders were based upon all available information, including the diagnostic interview, family history reports, and medical records using the best estimate method of diagnoses (Leckman et al., 1982). Each substance of abuse was characterized by: age at onset, quantity, frequency, chronicity, substance of choice, number of symptoms, and severity. Best estimate diagnoses were made by clinicians with extensive experience in either the evaluation and treatment of anxiety, substance use or mood and disorders. Specific diagnostic algorithms were not included for the best estimate diagnostic process because of the variability in the information as well as the descriptive nature of the narrative summaries provided in the family history interviews. Clinicians were blinded to the diagnostic status of the probands when making best estimates of the relatives. Direct interview information was prioritized among all the available diagnostic data because of the well-established under-estimation of diagnoses in non-interviewed relatives. When direct assessment was unavailable, family history information from multiple informants was used. Direct interviews and family history are far more concordant for observable disorders such as drug abuse and behavior disorders than for less readily observable disorders such as anxiety and mood disorders (Orvaschel et al., 1982; Thompson et al., 1982). The study design involved attempts to collect family history information from all interviewed probands, spouses
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and relatives. In order to distinguish between true negatives and negatives emanating from a lack of knowledge or information about the index subject of the family history, the amount of direct contact and indirect information available to the informant when collecting the family history information about each index case was rated. This rating was used in establishing composite diagnostic ratings from multiple family history reports. Most disagreements in family history reports in this study and others are comprised of false negatives (one informant reports a positive diagnoses and the other reports no diagnosis), rather than discordance between informants regarding specific diagnoses. 2.5. Statistical analyses Chi-square tests were used to test the associations between proband sex and anxiety proband groups. Wilcoxon Rank Sum tests were conducted to compare the ages of onset of disorders among proband groups and corresponding relative groups. Kruskal–Wallis tests were used to test differences between proband global assessment of functioning scores and number of anxiety disorders among proband groups and corresponding relative groups. If significant overall differences were observed, pair-wise comparisons were made using Wilcoxon Rank Sum Tests, and Bonferroni correction of significance levels was applied. Generalized estimating equations were conducted for two models investigating the outcomes of specific anxiety disorders (that is, panic and social anxiety disorders) in relatives. The main effects examined were: (1) specific anxiety disorders in probands; and (2) comorbid major depression, alcohol abuse/dependence and anxiety disorders in probands. The covariates considered in the models were: (1) sex of proband and relative; (2) presence of comorbid dis-
Table 1 Sociodemographic characteristics of probands Characteristic
Anxiety proband groupsa (1) Panic and social anxiety (N = 26)
(2) Panic (N = 40)
(3) Social anxiety (N = 46)
(4) Other anxiety (N = 32)
(5) No anxiety (N = 81)
39.0 (5.9, 26–51) 26.9a 38.3 (11–72)
39.5 (5.2, 29–51) 20.1a 33.9 (11–73)
40.8 (6.3, 29–56) 58.7b 39.7 (11–80)
40.4 (6.2, 24–53) 37.5a 40.4 (11–72)
41.0 (6.3, 28–55) 67.9b 34.3 (11–72)
69.2 69.2
85.0 85.0
82.2 73.9
75.0 81.3
86.1 88.9
Household income (in thousands of dollars) (%): 629 34.6 30–59 46.2 60+ 19.2
25.0 50.0 25.0
37.0 39.1 23.9
36.7 30.0 33.3
16.0 51.9 32.1
Education (%): Partial high school and lower High school Partial university and higher
2.5 32.5 65.0
15.2 34.8 50.0
12.5 28.1 59.4
9.9 24.7 65.4
Age (in years) (mean, SD, range) Male (%) Socioeconomic status (x/100) (mean, range) Percent employed (%) Married (%)
0.0 36.0 64.0
Between a and b: groups 1, 2 and 4 are statistically different from groups 3 and 5. a No statistical difference. b No statistical difference.
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orders in relatives (anxiety disorders, major depression and alcohol abuse/dependence); (3) age of relative (continuous); and (4) interview status of relative (direct interview versus family history information). The models were run using GENMOD procedure in SAS 9.1 (SAS Institute Inc., Cary, NC).
(which ranged between 56% and 85%) was high in all anxiety disorder proband groups. Lastly, the ‘‘no anxiety’’ proband group had a higher global assessment of functioning scores compared to the anxiety proband groups.
3. Results
Anxiety, affective and alcohol use disorder rates among the relatives of anxiety proband groups are presented in Table 3. Overall, rates of most anxiety disorders are highest among relatives of panic probands. The relatives of probands with panic disorder (regardless if the panic disorder is comorbid with social anxiety) have higher rates of panic compared to relatives of ‘‘social anxiety’’, ‘‘other anxiety’’ and ‘‘no anxiety’’ probands (8.9% and 11.8% versus 1.7%, 1.4%, 1.6%, respectively). Therefore, the transmission of panic disorder seems unaffected by the presence of social anxiety in these probands. Relatives with panic disorder also have a significantly greater number of anxiety disorders compared to all other anxiety groups. Relatives of probands with both social anxiety and panic disorder have the highest rate of social anxiety (19.5%), followed by relatives of probands with social anxiety disorder alone and panic disorder alone (12.1% and 13.4%, respectively), then the remaining relatives of probands with other anxiety disorders and no anxiety (5.4% and 7.4%, respectively).
3.1. Clinical profile of probands Sociodemographic characteristics of the anxiety disorder proband groups are presented in Table 1. No differences were observed except for a female preponderance among the proband anxiety groups with panic disorder. All participants were Caucasian and of note, highly educated. Table 2 contrasts the clinical characteristics of the probands with panic disorder and social anxiety disorder. Social anxiety disorder proband groups, with or without comorbid panic, had the highest rates of agoraphobia. Panic disorder proband groups had the highest rates of generalized anxiety. There were no statistical differences in the ages of onset of panic or social anxiety between the anxiety disorder proband groups. With respect to other psychiatric comorbidity, rates of affective disorders were elevated in all of the proband groups with anxiety disorders compared to the ‘no anxiety’ group. The prevalence of major depression
3.2. Clinical profile of relatives
Table 2 Clinical profile of proband groups Characteristic
Anxiety proband groupsa (1) Panic and social anxiety (N = 26)
(2) Panic (N = 40)
(3) Social anxiety (N = 46)
(4) Other anxiety (N = 32)
Other anxiety disorders (%): Agoraphobia Generalized anxiety Specific phobia
15.4 50.0 53.9
7.5 52.5 35.0
19.6 28.3 56.5
9.4 40.6 65.6
Age of onset (in years) (mean, SD, range): Panic disorder Social anxiety disorder No. of anxiety disorders (mean, SD, range) Current anxiety disorder (%)
21.9 (9.0, 5–38)b 13.4 (7.7, 5–35)c 3.3 (0.9, 2–5) 80.8
26.1 (9.4, 6–41)b na 2.0 (0.8, 1–4) 67.5
na 11.9 (5.6, 5–26)c 2.0 (0.8, 1–4) 69.6
na na 1.2 (0.5, 0–2) 18.8
na na na 0.0
84.6d
72.5d
63.0d
56.3d
24.7d
57.7 26.9 46.2
65.0 7.5 27.5
56.5 6.5 47.8
53.1 3.1 59.4
17.3 7.4 43.2
63.8 (7.9, 45–75)e
68.6 (7.8, 55–90)e 69.3 (11.4, 50–90)e 69.5 (12.6, 45–85)e 74.9 (12.5, 45–90)f
Lifetime psychiatric comorbidity (%): Any affective disorder (major depression, bipolar disorder) Major depression Bipolar Alcohol abuse/dependence Global assessment of functioning (lifetime GAF) (x/100) (mean, SD, range)
(5) No anxiety (N = 81) 0.0 0.0 0.0
na = not applicable. a Overall difference between all five groups was tested first. If a significant overall difference was observed, then pair-wise comparisons were made using Wilcoxon Rank Sum Tests and Bonferroni correction of significance levels was applied. b No statistical difference. c No statistical difference. d All groups statistically different from each other. e No statistical difference. f Between e and f: group 5 is statistically different from groups 1, 2, 3, and 4.
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Table 3 Clinical profiles of relatives of anxiety proband groups Characteristic
Relatives by anxiety proband groupsa (1) ‘‘Panic and social anxiety’’ relatives (N = 113 )
(2) ‘‘Panic’’ relatives (N = 186)
(3) ‘‘Social anxiety’’ relatives (N = 240)
(4) ‘‘Other anxiety’’ relatives (N = 148)
(5) ‘‘No anxiety’’ relatives (N = 366)
Any anxiety disorder (%) All panic disorder (%) All social anxiety disorder (%) Panic disorder without social anxiety (%) Social anxiety disorder without panic (%) Panic and social anxiety disorders (%)
39.8 8.9 19.5 18.2 18.0 27.3
39.8 11.8 13.4 40.9 13.5 59.1
24.6 1.7 12.1 13.6 31.5 4.6
21.0 1.4 5.4 4.6 7.8 4.6
23.5 1.6 7.4 22.7 29.2 4.6
Other anxiety disorders (%): Generalized anxiety Agoraphobia Specific phobia
21.4 3.5 17.7
22.6 8.6 15.6
8.8 2.5 7.5
9.5 0.7 9.5
7.7 1.9 10.7
Age of onset (in years) (mean, SD, range): Social anxiety disorder 13.0 (12.9, 5–63)b No. of anxiety disorders (mean, SD, 0.7 (1.0, 1–4)c range) Psychiatric comorbidity (%): Major depression Alcohol abuse/dependence Global assessment of functioning (lifetime GAF) (x/100) (mean, SD, range)
12.8 (8.1, 4–35)b 0.7 (1.1, 0–5)c
13.0 (8.9, 2–43)b 0.3 (0.7, 0–5)d
32.7e 31.0g
29.0e 31.2g
19.6f 24.6g
71.1 (10.4, 18–85)h
69.8 (11.4, 21–90)h 72.9 (10.6, 25–90)h
9.4 (6.7, 3–20)b 0.3 (0.6, 0–4)d
9.3 (3.7, 4–18)b 0.3 (0.6, 0–3)d
18.9f 25.0g
17.5f 23.0g
72.4 (9.5, 25–95)h
73.1 (11.3, 20–95)h
a Overall difference between all five groups was tested first. If a significant overall difference was observed, then pair-wise comparisons were made using Wilcoxon Rank Sum Tests and Bonferroni correction of significance levels was applied. b No statistical difference. c No statistical difference. d No statistical difference. Between c and d groups 1 and 2 are statistically different from Groups 3, 4, and 5. e No statistical difference. f No statistical difference. Between e and f Groups 1 and 2 are statistically different from Groups 3, 4, and 5. g No statistical difference. h No statistical difference.
Table 4 Association between proband and relative panic and social anxiety disorders Outcomes: disorder in relativesa Panic disorder
Social anxiety disorder
Odds ratio
95% CIb
p-value
Odds ratio
95% CIb
p-value
Main effects: disorders in probands Panic Social anxiety
3.7 0.8
1.5–9.3 0.3–1.8
0.0045 ns
1.2 1.8
0.7–2.0 1.1–2.9
ns 0.0143
Comorbid disorders in probands: Generalized anxiety Agoraphobia Major depression Alcohol abuse/dependence
1.3 0.3 1.3 1.1
0.5–3.3 0.05–1.4 0.5–3.0 0.4–3.0
ns ns ns ns
1.1 1.2 0.8 1.4
0.6–1.8 0.6–2.5 0.5–1.3 0.9–2.3
ns ns ns ns
Covariates: Proband sex (0 = male, 1 = female)
1.5
0.8–8.3
ns
1.6
1.0–2.8
ns
Relatives’ disorders/characteristics: Panic Social anxiety Sex (0 = male, 1 = female) Age Direct interview
4.9
2.3–10.7
<0.0001
4.6 6.5 0.9 1.6
2.1–10.3 2.1–19.8 0.8–1.1 0.6–4.4
0.0002 0.001 ns ns
1.3 1.1 2.6
0.8–2.1 0.9–1.1 1.7–4.0
ns ns <0.0001
a b
Controlled for major depression and alcohol abuse/dependence in relatives (see Results text for details). CI = confidence interval.
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Rates of major depression were elevated in relatives of probands with panic disorder. No differences were seen in rates of alcohol use disorders in the relatives. 3.3. Multivariate modeling In order to examine the specificity of transmission of the anxiety disorder and the effect of comorbid disorders in probands while controlling for potential confounders, three generalized estimating equations were used to test the following outcomes in relatives: (1) panic disorder and (2) social anxiety disorder (see Table 4). 3.3.1. Panic disorder There was a strong and specific association between proband panic disorder and panic disorder in relatives (OR = 3.7, 95%CI 1.5, 9.3, p = 0.0045), even after controlling for other comorbid anxiety disorders (e.g. social anxiety, generalized anxiety, agoraphobia) in the probands. None of the other anxiety disorders were associated with panic disorder in the relatives. Likewise, major depression and alcoholism in the proband were not associated with panic disorder in the relatives. Among the disorders in relatives, there was significant comorbidity of panic disorder with social anxiety disorder (OR = 4.6, 95%CI 2.1, 10.3, p = 0.0002), major depression (OR = 2.3, 95%CI 1.2, 4.4, p = 0.0151) and alcoholism (OR = 2.5, 95%CI 1.0, 5.9, p = 0.0399). Finally, the rates of panic disorder were elevated among female compared to male relatives. 3.3.2. Social anxiety disorder Similar to the findings for panic disorder, familial transmission of social anxiety disorder was highly specific (OR = 1.8, 95%CI 1.1, 2.9, p = 0.0143). Comorbid major depression, other anxiety disorders and alcoholism in the proband did not predict social anxiety in relatives. Among the relatives, there was evidence of significant comorbidity of social anxiety disorder with panic disorder (OR = 4.9, 95%CI 2.3, 10.7, p < 0.0001) and major depression (OR = 2.4 95%CI 1.6, 3.5, p < 0.0001), but not alcoholism. There was no sex difference among relatives with social anxiety disorder. In order to test whether our findings differed among anxiety disorder probands with and without comorbid alcohol abuse/dependence, we ran the same analyses among the probands with anxiety disorders alone (that is in the original proband group selected for panic disorder and/or social anxiety disorder without a lifetime history of alcohol abuse/dependence) and controls (no Axis I disorders). This anxiety disorder alone sample analyses produced in similar results as the overall sample. 4. Discussion This study contributes to the current literature by extending the evidence regarding the specificity of familial transmission of anxiety disorders to a partially non-clinical
sample, and incorporating the co-occurrence of mood and alcohol use disorders in the proband into statistical models. The observation of a strong and specific association between panic disorder in probands and relatives confirms the magnitude of familial transmission of panic disorder found in previous family studies which range from about 3 to 20 depending on differences in sampling, inclusion criteria, and control groups (Noyes et al., 1986; Maier et al., 1993; Mendlewicz et al., 1993; Fyer et al., 1995; Horwath et al., 1995). In the present study, there was a four-fold increased risk of panic disorder among relatives of probands with panic disorder after adjusting for the effects of all comorbid disorders among probands. Likewise, we also found specificity of familial transmission of social anxiety disorder but the magnitude (odds ratio = 1.8, 95%CI 1.1–2.9) was lower than that of panic disorder. This falls on the lower end of prior estimates which range from 2 to 13 (Fyer et al., 1993; Fyer et al., 1995; Stein et al., 1998). However, prior studies investigated probands without comorbid disorders, or did not adjust for comorbid disorders in deriving estimates of familial aggregation. Studies of children under age 18 of parents with panic and social anxiety have become an increasingly important source of information on premorbid risk factors and early forms of expression of anxiety. Similar to our findings in adults, studies of children also demonstrate specificity of expression of parental and child anxiety (Lieb et al., 2000; Merikangas et al., 2003; Biederman et al., 2006). The lack of mediation of familial transmission of anxiety disorders by comorbid depression and substance use disorders has important implications for both etiologic and intervention studies. In terms studies of pathogenesis, the independence of familial factors underlying panic and social anxiety disorders (and the lack of contribution of major depression, other anxiety and substance use disorders) suggest that future studies could attempt to identify specific biologic, genetic and environmental risk factors that may lead each disorder to these patterns of comorbidity. These investigations are already underway. As an example, Grillon has discriminated two subtypes of anxiety based on psychophysiologic response to fear-potentiated startle; one manifested by contextual fear consistent with the panic-generalized anxiety disorder spectrum; and the other by cue-related fear (specific and social phobias) that may underlie these phobic states (Grillon et al., 1998). Similar findings have emerged from psychophysiologic studies conducted with children of parents with anxiety disorders as well, suggesting that these may be vulnerability factors rather than consequences of anxiety states (Grillon et al., 1998). The fact that high risk youth also manifest these difference in startle, suggests that the biologic and genetic factors underlying these conditions are transmitted vertically in families. With respect to the treatment, since these comorbid disorders may not represent manifestations of the same diatheses underlying anxiety disorders, they may be consequences of anxiety disorders. Based upon the results of
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prospective studies, family and twin studies (Kushner et al., 2000; McGue et al., 2001; Zimmermann et al., 2003) that have shown that alcoholism is likely to result from selfmedication of social anxiety disorders, Kessler and Frank (Kessler et al., 1996) proposed interventions aimed at primary prevention of secondary disorders. Even though aggregate evidence from large therapeutic trials do not support differential response of social anxiety and panic disorder to medications (mainly selective serotonin reuptake inhibitors and tricyclics) (Otto et al., 2001; Hedges et al., 2006) or psychotherapy (predominantly cognitivebehavioral therapy) (Rodebaugh et al., 2004; Mitte, 2005), in light of the demonstration of specificity of transmission, more focused development of treatment interventions for target symptoms of each disorder may be considered. Finally, interpretation of the findings should be considered with these limitations. First, all of the relatives were not interviewed directly so we had to rely on family history information provided by other family members. However, the effect of interview status was controlled in the analyses where it was observed that direct interview status was associated two-fold with social anxiety disorder in the relatives, but unrelated to panic disorder. This use of family history information may have led to an under-detection, diagnosis and therefore, estimation of the social anxiety disorder among relatives. Supporting this assumption is literature that reports the family history method is more reliable as a surrogate of direct interviews for substance use versus mood and anxiety disorders (Orvaschel et al., 1982; Thompson et al., 1982; Kosten et al., 1992; Heun and Muller, 1998). Second, the sample was based on probands with panic disorder and social anxiety disorders, and did not include the full range of anxiety disorders. Thirdly, as a result of combining anxiety probands from the local community and clinics to reduce clinical ascertainment bias (Berkson’s bias), there may be concern that these cases may differ with respect to their clinical profile (such as, severity, comorbidity, age of onset, etc.) or in other ways that would preclude their combination. Analyses of this selection bias among these panic and social anxiety disorder probands was associated with an elevated risk among relatives of panic probands for panic disorder from the clinic, but not social anxiety relatives. However, the sample size was small and the study may be limited by low power. In general, the effect of clinic sampling is likely attributable to the greater severity of clinic cases which may also be associated with increased familial morbidity. Lastly, all our participants were Caucasian and therefore our results cannot be extended to other ethnic/racial groups. References Alonso J, Angermeyer MC, Bernert S, Bruffaerts R, Brugha TS, Bryson H, et al. Prevalence of mental disorders in Europe: results from the European Study of the Epidemiology of Mental Disorders (ESEMeD) project. Acta Psychiatrica Scandinavica Supplement 2004:21–7.
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Mitte K. A meta-analysis of the efficacy of psycho- and pharmacotherapy in panic disorder with and without agoraphobia. Journal of Affective Disorders 2005;88:27–45. Newton-Cheh C, Hirschhorn JN. Genetic association studies of complex traits: design and analysis issues. Mutation Research 2005;5731– 5732:54–69. Noyes Jr R, Crowe RR, Harris EL, Hamra BJ, McChesney CM, Chaudhry DR. Relationship between panic disorder and agoraphobia. A family study. Archives of General Psychiatry 1986;43: 227–32. Orvaschel H, Thompson WD, Belanger A, Prusoff BA, Kidd KK. Comparison of the family history method to direct interview. Factors affecting the diagnosis of depression. Journal of Affective Disorders 1982;4:49–59. Otto MW, Tuby KS, Gould RA, McLean RY, Pollack MH. An effect-size analysis of the relative efficacy and tolerability of serotonin selective reuptake inhibitors for panic disorder. American Journal of Psychiatry 2001;158:1989–92. Regier DA, Farmer ME, Rae DS, Locke BZ, Keith SJ, Judd LL, et al. Comorbidity of mental disorders with alcohol and other drug abuse. Results from the Epidemiologic Catchment Area (ECA) Study. Jama 1990;264:2511–8. Rodebaugh TL, Holaway RM, Heimberg RG. The treatment of social anxiety disorder. Clinical Psychology Review 2004;24:883–908. Simon NM, Otto MW, Korbly NB, Peters PM, Nicolaou DC, Pollack MH. Quality of life in social anxiety disorder compared with panic disorder and the general population. Psychiatric Services 2002;53:714–8. Stein MB, Chartier MJ, Hazen AL, Kozak MV, Tancer ME, Lander S, et al. A direct-interview family study of generalized social phobia. American Journal of Psychiatry 1998;155:90–7. Thompson WD, Orvaschel H, Prusoff BA, Kidd KK. An evaluation of the family history method for ascertaining psychiatric disorders. Archives of General Psychiatry 1982;39:53–8. Weissman MM, Wickramaratne P, Adams PB, Lish JD, Horwath E, Charney D, et al. The relationship between panic disorder and major depression. A new family study. Archives of General Psychiatry 1993;50:767–80. Zeger S, Liang K. Longitudinal data analysis for discrete and continuous outcomes. Biometrics 1986;421:121–30. Zeger S, Liang K, Albert P. Models for longitudinal data: a generalized estimating equation approach. Biometrics 1988;444:1049–60. Erratum in: Biometrics 1989;45(1):347. Zimmermann P, Wittchen HU, Hofler M, Pfister H, Kessler RC, Lieb R. Primary anxiety disorders and the development of subsequent alcohol use disorders: a 4-year community study of adolescents and young adults. Psychological Medicine 2003;33: 1211–22.
JOURNAL OF PSYCHIATRIC RESEARCH
Journal of Psychiatric Research 42 (2008) 596–604
www.elsevier.com/locate/jpsychires
Specificity of familial transmission of anxiety and comorbid disorders Nancy C.P. Low
a,b,*
, Lihong Cui b, Kathleen R. Merikangas
b
a Department of Psychiatry, McGill University, Montreal, Quebec, Canada Section on Developmental Genetic Epidemiology, Mood and Anxiety Disorders Program, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, 35 Convent Drive (MSC 3720), Bethesda, MD 20892-3720, USA b
Received 18 December 2006; accepted 2 July 2007
Abstract This study examines the specificity and impact of comorbid disorders in probands on the familial transmission of panic and social anxiety disorders. It employs a contemporary family study design with 225 probands (with and without panic and social anxiety disorders) sampled from outpatient clinics and the local community. Their 1053 adult first-degree relatives were assessed for lifetime disorders, based on best estimate diagnoses derived from semi-structured psychiatric diagnostic interviews (Schedule for Affective Disorders and Schizophrenia), multi-informant family history information, and medical records. Generalized estimating equations were used to examine the familial aggregation of panic and social anxiety disorders, and the contributions of comorbid disorders. Results show specificity of familial aggregation of both panic disorder and social anxiety in probands and relatives (i.e., panic odds ratio = 3.7, 95%CI 1.5–9.3; social anxiety odds ratio = 1.8, 95%CI 1.1–2.9) after controlling for comorbid disorders. There was no contribution of common comorbid disorders (depression, alcoholism, generalized anxiety disorder and agoraphobia) in probands on the familial aggregation of either disorder. These findings confirm prior studies of specificity of familial transmission of panic and social anxiety disorders, and demonstrate that the association between these disorders in probands is not attributable to comorbid mood, anxiety or substance use disorders. Therefore, despite the high magnitude of co-occurrence of panic disorder and social anxiety, there may be distinct etiologic factors underlying each disorder. These findings have implications for studies of the etiology, genetics, and treatment of these disorders. Ó 2007 Elsevier Ltd. All rights reserved. Keywords: Familial aggregation/transmission; Specificity of transmission; Anxiety disorders; Panic disorder; Social anxiety/phobia; Comorbidity
1. Introduction Anxiety disorders are the most prevalent form of psychopathology in the general population (Kessler et al., 2005). Among them, panic and social anxiety disorders have among the greatest associated impairment in several domains of functioning, in addition to significant negative effects on quality of life (Simon et al., 2002). This is in part due to their early onset (often in adolescence), chronic lifelong course, and high comorbidity. The lifetime and 1-year prevalence of DSM-IV-defined (APA, 1994) panic disorder * Corresponding author. Address: Department of Psychiatry, McGill University, 1033 Pine Avenue West, Room 104, Montreal, Quebec, H3A 1A1, Canada. Tel.: +1 514 465 9033; fax: +1 514 398 4370. E-mail address: [email protected] (N.C.P. Low).
0022-3956/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.jpsychires.2007.07.002
range from 2.1% to 5.1% and 0.8% to 2.8%, respectively (Alonso et al., 2004; Grant et al., 2006; Kessler et al., 2006), and the corresponding ranges for social anxiety disorder rates are 1.9–12.1% and 1.2–6.8%, respectively (Lampe et al., 2003; Alonso et al., 2004; Grant et al., 2005; Kessler et al., 2005). There is considerable evidence from both clinical and community samples regarding the overlap among the DSM-IV anxiety disorders, as well as, between affective, alcohol and substance abuse disorders (Regier et al., 1990; Kessler et al., 2005). The most recent community surveys of the United States reveal that the majority of those with lifetime panic disorder or social anxiety disorder have at least one other Axis I anxiety disorder subtype as well as other Axis I disorders. For example, the National Comorbidity Survey – Replication (NCS-R) found the following
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proportions of comorbid disorders among participants with lifetime panic disorder: 83% with any disorder, 66% with another anxiety disorder, 50% with a mood disorder and 27% with a substance use disorder (Kessler et al., 2006). Likewise, data from the National Epidemiologic Survey of Alcohol and Related Conditions (NESARC) indicated that persons with social anxiety disorder had high frequencies of other anxiety disorders (54%), mood disorders (56%,) and alcohol use disorders (48%) (Grant et al., 2005). The family study design provides a powerful method to investigate sources of comorbidity (Merikangas, 1990; Klein and Riso, 1993). Evidence for differential diatheses underlying familial transmission of comorbid compared to non-comorbid disorders has implications for identifying sources of phenotypic heterogeneity, identifying etiologic factors, and designing therapeutic interventions. Previous family studies examining the specificity of transmission of anxiety disorders have dealt with comorbidity among probands in three different ways. First, some studies have selected ‘‘pure’’ diagnostic groups of probands, that is, those with only the anxiety disorder of interest (Kendler, 1990). However, these studies were inconsistent in excluding other psychiatric disorders, such as depression or alcohol dependence (Harris et al., 1983; Noyes et al., 1986; Maier et al., 1993; Mendlewicz et al., 1993; Fyer et al., 1995). A second, and less common, method of addressing comorbidity between anxiety disorders is to permit comorbid anxiety (and possibly other psychiatric disorders) in probands (Stein et al., 1998) and adjust for the possible effects of comorbidity in the analyses. A third set of family studies actually incorporates comorbidity into the study design by selecting proband groups with and without comorbid disorders (Weissman et al., 1993; Merikangas et al., 1994; Merikangas et al., 1998). There are advantages and disadvantages to each of these approaches. ‘‘Pure’’ diagnostic groups allow study findings to be attributed specifically to the disorder since there are no comorbid disorders. ‘‘Proof of concept’’ studies and other specific biological hypotheses can be tested in these groups. However, samples of probands without comorbidity are not representative of both general population and clinical samples of individuals with these conditions. Therefore, the major advantage of selecting probands with comorbid disorders is that they are more representative – for example, allowing mood and substance use disorders along with panic or social anxiety disorder would examine a more generalizable group, as comorbidity is the rule rather than the exception. These studies, however, will also require larger sample sizes in order to test the potential mediating effects of comorbid disorders. The use of representative samples will take on increasing importance with the growing shift to large-scale collaborative case-control association studies to identify susceptibility genes for complex disorders. The representativeness of a sample to its disease base population is not only important when the sample is being used to estimate disease prevalence or
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attributable risk, but in genetic studies, systematic sampling is crucial because biased ascertainment can compromise both the validity of estimates of genetic parameters in statistical studies, and the identification of genetic markers in linkage and association studies (Cavalli-Sforza and Bodmer, 1971; Cardon and Bell, 2001; Little et al., 2002; Colhoun et al., 2003; Newton-Cheh and Hirschhorn, 2005). Progress has been slow in identifying and replicating genes underlying anxiety disorders (Arnold et al., 2004; Merikangas and Low, 2005) in part because of the selection and criteria for cases and controls. Finally given advances in statistical approaches (Zeger and Liang, 1986; Zeger et al., 1988), even with selection of probands with comorbid disorders, one can examine of the independent contribution of other factors on familial aggregation and on other outcomes of interest. In the present study, we selected probands with anxiety disorders with comorbid major depression and/or alcohol abuse/dependence from both community and clinic sources in order to examine their role in the specificity of transmission of anxiety disorders. The two chief objectives were: (1) to examine the specificity of transmission of panic disorder and social anxiety disorder, and (2) to investigate the effect of comorbid anxiety disorders, major depression, and alcohol abuse/dependence, on the familial aggregation of panic disorder and social anxiety disorder. 2. Methods and materials 2.1. Sample and measures 2.1.1. Probands Two-hundred twenty-five probands participated in the study. Probands were originally selected with the goal to examine the familial aggregation of anxiety and alcohol use disorders. The patients were recruited from outpatient clinics for anxiety and alcohol use disorders at the Connecticut Mental Health Center in New Haven, Connecticut. All patients treated at the clinics over a 3-year period were screened for eligibility in the study, and those who met the appropriate diagnostic criteria were invited to participate. All probands were assigned to one of four lifetime diagnostic groups: (1) panic disorder and/or social anxiety disorder without a lifetime history of alcohol abuse/dependence (N = 67); (2) alcohol abuse/dependence with panic disorder and/or social anxiety disorder (N = 45); (3) alcohol abuse/dependence without a lifetime history of panic or social anxiety disorders (N = 54); and (4) controls (no Axis I disorders) (N = 59). All of the controls and 33.9% of the anxiety probands were recruited from the population of the greater New Haven area through a random digit dialing procedure. The rationale for including a combination of probands from the clinic and community was to minimize Berkson’s bias (treatment-seeking bias) and obtain a more representative sample for examination. The diagnostic interview for adults was the semi-structured Schedule for Affective Dis-
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orders and Schizophrenia (SADS) (Endicott and Spitzer, 1978), current and lifetime versions, which was modified to incorporate DSM-III and DSM-III-R criteria and to include more detailed information on anxiety disorders and substance use patterns. Probands were excluded if they had evidence of schizophrenia, schizoaffective disorder, mental retardation, opioid and cocaine use disorders, or a significant medical disorder causing their psychiatric symptoms. Probands with comorbid affective, other anxiety disorders, and substance (that is, marijuana and sedatives/hypnotics – as long as they were not the primary substance of abuse/dependence) use disorders were included. To address the goals of this examination of the specificity of transmission of panic and social anxiety disorder, the above mentioned four proband groups were reclassified into five hierarchal, mutually exclusive anxiety disorder proband groups. These new anxiety disorder proband groups were developed using a hierarchy whereby panic and/or social anxiety supercede other adult anxiety disorders (generalized anxiety disorder, agoraphobia, specific phobia) and other comorbid disorders (such as, alcohol use and affective disorders). The final anxiety disorder proband groups used this analysis were as follows: (1) both panic disorder and social anxiety disorder (N = 26); (2) panic disorder alone (panic disorder without a lifetime history of social anxiety disorder) (N = 40); (3) social anxiety disorder alone (social anxiety disorder without a lifetime history of panic disorder) (N = 46); (4) other anxiety disorders (anxiety disorders other than panic disorder and social anxiety disorder – mainly generalized anxiety disorder and agoraphobia) (N = 32); and (5) no anxiety disorders (no Axis I anxiety disorders) (N = 81).
2.1.2. Relatives There were a total of 1053 first-degree relatives included in this sample: 113 from families of panic and social anxiety probands, 186 from families of panic disorder alone probands, 240 from families of social anxiety disorder alone probands, 148 from families of ‘‘other anxiety’’ probands, and 366 from families of ‘‘no anxiety’’ probands. The relatives were composed of siblings (48.5%), parents (41.0%), and adult offspring (10.5%). Diagnostic information on all first-degree relatives was obtained by direct interview and by a structured family history interview. Family history information was obtained using a modified version of the Family History-Research Diagnostic Criteria developed by Andreasen et al. (Andreasen et al., 1977) to collect diagnostic spectrum information and to obtain both DSMIII and DSM-III-R diagnoses in adults and children. All eligible relatives were asked to participate in the study. Inclusion criteria required that permission be obtained first
from probands to contact living relatives, of whom 57% were interviewed directly, either in person or by telephone. The interview rates did not differ significantly between the anxiety proband groups and are in accordance with previous family studies of substance abuse. All analyses controlled for the effect of interview status. 2.2. Family procedures Complete pedigrees on first degree relatives including children over age 18 were obtained. Both direct (either face-to-face or by telephone) and indirect (family history by relatives) assessments of first degree relatives including parents, siblings and offspring over age 18 were conducted by clinically experienced interviewers who were blind to the diagnostic status of the proband. Offspring under age 18 were evaluated in a high risk study of children of parents with anxiety disorders and alcohol use disorders. Information on relatives who were deceased, refused to participate or were geographically distant was obtained blinded to proband diagnoses from multiple relatives and best estimate diagnostic assessments were made by a panel of experienced clinicians based on all available information. Treatment records were requested for all probands and relatives who had received treatment for these conditions. 2.3. Interview procedures All procedures complied with strict ethical standards in the treatment of human subjects and were approved by the Yale University School of Medicine Institutional Review Board. After complete description of the study to the subjects, written informed consent was obtained. Probands were directly interviewed with a structured interview on health, behavior, mental disorders and substance use disorders. In order to avoid bias, blindness to the proband diagnosis was built into both the direct interviews and best estimate procedures for diagnoses of relatives. There was also an attempt to maintain blindness to proband diagnoses in the collection of family history information by using two independent interviewers. However, in many cases this became practically unfeasible because of increased subject burden. All adult first-degree relatives were approached for direct interview by an independent interviewer blinded to the proband diagnoses. The proband and interviewed first-degree relatives provided family history data on all their first-degree relatives. Interviewers with experience in clinical psychiatry were chosen to interview and an extensive effort was made to establish reliability. Kappas derived from joint ratings of individual interviews were generally higher for substance abuse (0.72–0.94) than for anxiety or affective disorders (0.54–0.78) across the first three series of training sessions. Although kappas for each of the subtypes of anxiety disorders alone were not recorded, the reliability for the subtypes of panic and social anxiety fell in the upper range of the kappas cited for anxiety and affective disorders,
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whereas specific phobias and hypomania tended to be less reliable. Comparison of diagnoses obtained through direct face-to-face interview versus telephone interview showed high levels of agreement across all diagnostic categories. 2.4. Best estimate diagnostic procedures Diagnoses of anxiety and substance use disorders were based upon all available information, including the diagnostic interview, family history reports, and medical records using the best estimate method of diagnoses (Leckman et al., 1982). Each substance of abuse was characterized by: age at onset, quantity, frequency, chronicity, substance of choice, number of symptoms, and severity. Best estimate diagnoses were made by clinicians with extensive experience in either the evaluation and treatment of anxiety, substance use or mood and disorders. Specific diagnostic algorithms were not included for the best estimate diagnostic process because of the variability in the information as well as the descriptive nature of the narrative summaries provided in the family history interviews. Clinicians were blinded to the diagnostic status of the probands when making best estimates of the relatives. Direct interview information was prioritized among all the available diagnostic data because of the well-established under-estimation of diagnoses in non-interviewed relatives. When direct assessment was unavailable, family history information from multiple informants was used. Direct interviews and family history are far more concordant for observable disorders such as drug abuse and behavior disorders than for less readily observable disorders such as anxiety and mood disorders (Orvaschel et al., 1982; Thompson et al., 1982). The study design involved attempts to collect family history information from all interviewed probands, spouses
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and relatives. In order to distinguish between true negatives and negatives emanating from a lack of knowledge or information about the index subject of the family history, the amount of direct contact and indirect information available to the informant when collecting the family history information about each index case was rated. This rating was used in establishing composite diagnostic ratings from multiple family history reports. Most disagreements in family history reports in this study and others are comprised of false negatives (one informant reports a positive diagnoses and the other reports no diagnosis), rather than discordance between informants regarding specific diagnoses. 2.5. Statistical analyses Chi-square tests were used to test the associations between proband sex and anxiety proband groups. Wilcoxon Rank Sum tests were conducted to compare the ages of onset of disorders among proband groups and corresponding relative groups. Kruskal–Wallis tests were used to test differences between proband global assessment of functioning scores and number of anxiety disorders among proband groups and corresponding relative groups. If significant overall differences were observed, pair-wise comparisons were made using Wilcoxon Rank Sum Tests, and Bonferroni correction of significance levels was applied. Generalized estimating equations were conducted for two models investigating the outcomes of specific anxiety disorders (that is, panic and social anxiety disorders) in relatives. The main effects examined were: (1) specific anxiety disorders in probands; and (2) comorbid major depression, alcohol abuse/dependence and anxiety disorders in probands. The covariates considered in the models were: (1) sex of proband and relative; (2) presence of comorbid dis-
Table 1 Sociodemographic characteristics of probands Characteristic
Anxiety proband groupsa (1) Panic and social anxiety (N = 26)
(2) Panic (N = 40)
(3) Social anxiety (N = 46)
(4) Other anxiety (N = 32)
(5) No anxiety (N = 81)
39.0 (5.9, 26–51) 26.9a 38.3 (11–72)
39.5 (5.2, 29–51) 20.1a 33.9 (11–73)
40.8 (6.3, 29–56) 58.7b 39.7 (11–80)
40.4 (6.2, 24–53) 37.5a 40.4 (11–72)
41.0 (6.3, 28–55) 67.9b 34.3 (11–72)
69.2 69.2
85.0 85.0
82.2 73.9
75.0 81.3
86.1 88.9
Household income (in thousands of dollars) (%): 629 34.6 30–59 46.2 60+ 19.2
25.0 50.0 25.0
37.0 39.1 23.9
36.7 30.0 33.3
16.0 51.9 32.1
Education (%): Partial high school and lower High school Partial university and higher
2.5 32.5 65.0
15.2 34.8 50.0
12.5 28.1 59.4
9.9 24.7 65.4
Age (in years) (mean, SD, range) Male (%) Socioeconomic status (x/100) (mean, range) Percent employed (%) Married (%)
0.0 36.0 64.0
Between a and b: groups 1, 2 and 4 are statistically different from groups 3 and 5. a No statistical difference. b No statistical difference.
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orders in relatives (anxiety disorders, major depression and alcohol abuse/dependence); (3) age of relative (continuous); and (4) interview status of relative (direct interview versus family history information). The models were run using GENMOD procedure in SAS 9.1 (SAS Institute Inc., Cary, NC).
(which ranged between 56% and 85%) was high in all anxiety disorder proband groups. Lastly, the ‘‘no anxiety’’ proband group had a higher global assessment of functioning scores compared to the anxiety proband groups.
3. Results
Anxiety, affective and alcohol use disorder rates among the relatives of anxiety proband groups are presented in Table 3. Overall, rates of most anxiety disorders are highest among relatives of panic probands. The relatives of probands with panic disorder (regardless if the panic disorder is comorbid with social anxiety) have higher rates of panic compared to relatives of ‘‘social anxiety’’, ‘‘other anxiety’’ and ‘‘no anxiety’’ probands (8.9% and 11.8% versus 1.7%, 1.4%, 1.6%, respectively). Therefore, the transmission of panic disorder seems unaffected by the presence of social anxiety in these probands. Relatives with panic disorder also have a significantly greater number of anxiety disorders compared to all other anxiety groups. Relatives of probands with both social anxiety and panic disorder have the highest rate of social anxiety (19.5%), followed by relatives of probands with social anxiety disorder alone and panic disorder alone (12.1% and 13.4%, respectively), then the remaining relatives of probands with other anxiety disorders and no anxiety (5.4% and 7.4%, respectively).
3.1. Clinical profile of probands Sociodemographic characteristics of the anxiety disorder proband groups are presented in Table 1. No differences were observed except for a female preponderance among the proband anxiety groups with panic disorder. All participants were Caucasian and of note, highly educated. Table 2 contrasts the clinical characteristics of the probands with panic disorder and social anxiety disorder. Social anxiety disorder proband groups, with or without comorbid panic, had the highest rates of agoraphobia. Panic disorder proband groups had the highest rates of generalized anxiety. There were no statistical differences in the ages of onset of panic or social anxiety between the anxiety disorder proband groups. With respect to other psychiatric comorbidity, rates of affective disorders were elevated in all of the proband groups with anxiety disorders compared to the ‘no anxiety’ group. The prevalence of major depression
3.2. Clinical profile of relatives
Table 2 Clinical profile of proband groups Characteristic
Anxiety proband groupsa (1) Panic and social anxiety (N = 26)
(2) Panic (N = 40)
(3) Social anxiety (N = 46)
(4) Other anxiety (N = 32)
Other anxiety disorders (%): Agoraphobia Generalized anxiety Specific phobia
15.4 50.0 53.9
7.5 52.5 35.0
19.6 28.3 56.5
9.4 40.6 65.6
Age of onset (in years) (mean, SD, range): Panic disorder Social anxiety disorder No. of anxiety disorders (mean, SD, range) Current anxiety disorder (%)
21.9 (9.0, 5–38)b 13.4 (7.7, 5–35)c 3.3 (0.9, 2–5) 80.8
26.1 (9.4, 6–41)b na 2.0 (0.8, 1–4) 67.5
na 11.9 (5.6, 5–26)c 2.0 (0.8, 1–4) 69.6
na na 1.2 (0.5, 0–2) 18.8
na na na 0.0
84.6d
72.5d
63.0d
56.3d
24.7d
57.7 26.9 46.2
65.0 7.5 27.5
56.5 6.5 47.8
53.1 3.1 59.4
17.3 7.4 43.2
63.8 (7.9, 45–75)e
68.6 (7.8, 55–90)e 69.3 (11.4, 50–90)e 69.5 (12.6, 45–85)e 74.9 (12.5, 45–90)f
Lifetime psychiatric comorbidity (%): Any affective disorder (major depression, bipolar disorder) Major depression Bipolar Alcohol abuse/dependence Global assessment of functioning (lifetime GAF) (x/100) (mean, SD, range)
(5) No anxiety (N = 81) 0.0 0.0 0.0
na = not applicable. a Overall difference between all five groups was tested first. If a significant overall difference was observed, then pair-wise comparisons were made using Wilcoxon Rank Sum Tests and Bonferroni correction of significance levels was applied. b No statistical difference. c No statistical difference. d All groups statistically different from each other. e No statistical difference. f Between e and f: group 5 is statistically different from groups 1, 2, 3, and 4.
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Table 3 Clinical profiles of relatives of anxiety proband groups Characteristic
Relatives by anxiety proband groupsa (1) ‘‘Panic and social anxiety’’ relatives (N = 113 )
(2) ‘‘Panic’’ relatives (N = 186)
(3) ‘‘Social anxiety’’ relatives (N = 240)
(4) ‘‘Other anxiety’’ relatives (N = 148)
(5) ‘‘No anxiety’’ relatives (N = 366)
Any anxiety disorder (%) All panic disorder (%) All social anxiety disorder (%) Panic disorder without social anxiety (%) Social anxiety disorder without panic (%) Panic and social anxiety disorders (%)
39.8 8.9 19.5 18.2 18.0 27.3
39.8 11.8 13.4 40.9 13.5 59.1
24.6 1.7 12.1 13.6 31.5 4.6
21.0 1.4 5.4 4.6 7.8 4.6
23.5 1.6 7.4 22.7 29.2 4.6
Other anxiety disorders (%): Generalized anxiety Agoraphobia Specific phobia
21.4 3.5 17.7
22.6 8.6 15.6
8.8 2.5 7.5
9.5 0.7 9.5
7.7 1.9 10.7
Age of onset (in years) (mean, SD, range): Social anxiety disorder 13.0 (12.9, 5–63)b No. of anxiety disorders (mean, SD, 0.7 (1.0, 1–4)c range) Psychiatric comorbidity (%): Major depression Alcohol abuse/dependence Global assessment of functioning (lifetime GAF) (x/100) (mean, SD, range)
12.8 (8.1, 4–35)b 0.7 (1.1, 0–5)c
13.0 (8.9, 2–43)b 0.3 (0.7, 0–5)d
32.7e 31.0g
29.0e 31.2g
19.6f 24.6g
71.1 (10.4, 18–85)h
69.8 (11.4, 21–90)h 72.9 (10.6, 25–90)h
9.4 (6.7, 3–20)b 0.3 (0.6, 0–4)d
9.3 (3.7, 4–18)b 0.3 (0.6, 0–3)d
18.9f 25.0g
17.5f 23.0g
72.4 (9.5, 25–95)h
73.1 (11.3, 20–95)h
a Overall difference between all five groups was tested first. If a significant overall difference was observed, then pair-wise comparisons were made using Wilcoxon Rank Sum Tests and Bonferroni correction of significance levels was applied. b No statistical difference. c No statistical difference. d No statistical difference. Between c and d groups 1 and 2 are statistically different from Groups 3, 4, and 5. e No statistical difference. f No statistical difference. Between e and f Groups 1 and 2 are statistically different from Groups 3, 4, and 5. g No statistical difference. h No statistical difference.
Table 4 Association between proband and relative panic and social anxiety disorders Outcomes: disorder in relativesa Panic disorder
Social anxiety disorder
Odds ratio
95% CIb
p-value
Odds ratio
95% CIb
p-value
Main effects: disorders in probands Panic Social anxiety
3.7 0.8
1.5–9.3 0.3–1.8
0.0045 ns
1.2 1.8
0.7–2.0 1.1–2.9
ns 0.0143
Comorbid disorders in probands: Generalized anxiety Agoraphobia Major depression Alcohol abuse/dependence
1.3 0.3 1.3 1.1
0.5–3.3 0.05–1.4 0.5–3.0 0.4–3.0
ns ns ns ns
1.1 1.2 0.8 1.4
0.6–1.8 0.6–2.5 0.5–1.3 0.9–2.3
ns ns ns ns
Covariates: Proband sex (0 = male, 1 = female)
1.5
0.8–8.3
ns
1.6
1.0–2.8
ns
Relatives’ disorders/characteristics: Panic Social anxiety Sex (0 = male, 1 = female) Age Direct interview
4.9
2.3–10.7
<0.0001
4.6 6.5 0.9 1.6
2.1–10.3 2.1–19.8 0.8–1.1 0.6–4.4
0.0002 0.001 ns ns
1.3 1.1 2.6
0.8–2.1 0.9–1.1 1.7–4.0
ns ns <0.0001
a b
Controlled for major depression and alcohol abuse/dependence in relatives (see Results text for details). CI = confidence interval.
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Rates of major depression were elevated in relatives of probands with panic disorder. No differences were seen in rates of alcohol use disorders in the relatives. 3.3. Multivariate modeling In order to examine the specificity of transmission of the anxiety disorder and the effect of comorbid disorders in probands while controlling for potential confounders, three generalized estimating equations were used to test the following outcomes in relatives: (1) panic disorder and (2) social anxiety disorder (see Table 4). 3.3.1. Panic disorder There was a strong and specific association between proband panic disorder and panic disorder in relatives (OR = 3.7, 95%CI 1.5, 9.3, p = 0.0045), even after controlling for other comorbid anxiety disorders (e.g. social anxiety, generalized anxiety, agoraphobia) in the probands. None of the other anxiety disorders were associated with panic disorder in the relatives. Likewise, major depression and alcoholism in the proband were not associated with panic disorder in the relatives. Among the disorders in relatives, there was significant comorbidity of panic disorder with social anxiety disorder (OR = 4.6, 95%CI 2.1, 10.3, p = 0.0002), major depression (OR = 2.3, 95%CI 1.2, 4.4, p = 0.0151) and alcoholism (OR = 2.5, 95%CI 1.0, 5.9, p = 0.0399). Finally, the rates of panic disorder were elevated among female compared to male relatives. 3.3.2. Social anxiety disorder Similar to the findings for panic disorder, familial transmission of social anxiety disorder was highly specific (OR = 1.8, 95%CI 1.1, 2.9, p = 0.0143). Comorbid major depression, other anxiety disorders and alcoholism in the proband did not predict social anxiety in relatives. Among the relatives, there was evidence of significant comorbidity of social anxiety disorder with panic disorder (OR = 4.9, 95%CI 2.3, 10.7, p < 0.0001) and major depression (OR = 2.4 95%CI 1.6, 3.5, p < 0.0001), but not alcoholism. There was no sex difference among relatives with social anxiety disorder. In order to test whether our findings differed among anxiety disorder probands with and without comorbid alcohol abuse/dependence, we ran the same analyses among the probands with anxiety disorders alone (that is in the original proband group selected for panic disorder and/or social anxiety disorder without a lifetime history of alcohol abuse/dependence) and controls (no Axis I disorders). This anxiety disorder alone sample analyses produced in similar results as the overall sample. 4. Discussion This study contributes to the current literature by extending the evidence regarding the specificity of familial transmission of anxiety disorders to a partially non-clinical
sample, and incorporating the co-occurrence of mood and alcohol use disorders in the proband into statistical models. The observation of a strong and specific association between panic disorder in probands and relatives confirms the magnitude of familial transmission of panic disorder found in previous family studies which range from about 3 to 20 depending on differences in sampling, inclusion criteria, and control groups (Noyes et al., 1986; Maier et al., 1993; Mendlewicz et al., 1993; Fyer et al., 1995; Horwath et al., 1995). In the present study, there was a four-fold increased risk of panic disorder among relatives of probands with panic disorder after adjusting for the effects of all comorbid disorders among probands. Likewise, we also found specificity of familial transmission of social anxiety disorder but the magnitude (odds ratio = 1.8, 95%CI 1.1–2.9) was lower than that of panic disorder. This falls on the lower end of prior estimates which range from 2 to 13 (Fyer et al., 1993; Fyer et al., 1995; Stein et al., 1998). However, prior studies investigated probands without comorbid disorders, or did not adjust for comorbid disorders in deriving estimates of familial aggregation. Studies of children under age 18 of parents with panic and social anxiety have become an increasingly important source of information on premorbid risk factors and early forms of expression of anxiety. Similar to our findings in adults, studies of children also demonstrate specificity of expression of parental and child anxiety (Lieb et al., 2000; Merikangas et al., 2003; Biederman et al., 2006). The lack of mediation of familial transmission of anxiety disorders by comorbid depression and substance use disorders has important implications for both etiologic and intervention studies. In terms studies of pathogenesis, the independence of familial factors underlying panic and social anxiety disorders (and the lack of contribution of major depression, other anxiety and substance use disorders) suggest that future studies could attempt to identify specific biologic, genetic and environmental risk factors that may lead each disorder to these patterns of comorbidity. These investigations are already underway. As an example, Grillon has discriminated two subtypes of anxiety based on psychophysiologic response to fear-potentiated startle; one manifested by contextual fear consistent with the panic-generalized anxiety disorder spectrum; and the other by cue-related fear (specific and social phobias) that may underlie these phobic states (Grillon et al., 1998). Similar findings have emerged from psychophysiologic studies conducted with children of parents with anxiety disorders as well, suggesting that these may be vulnerability factors rather than consequences of anxiety states (Grillon et al., 1998). The fact that high risk youth also manifest these difference in startle, suggests that the biologic and genetic factors underlying these conditions are transmitted vertically in families. With respect to the treatment, since these comorbid disorders may not represent manifestations of the same diatheses underlying anxiety disorders, they may be consequences of anxiety disorders. Based upon the results of
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prospective studies, family and twin studies (Kushner et al., 2000; McGue et al., 2001; Zimmermann et al., 2003) that have shown that alcoholism is likely to result from selfmedication of social anxiety disorders, Kessler and Frank (Kessler et al., 1996) proposed interventions aimed at primary prevention of secondary disorders. Even though aggregate evidence from large therapeutic trials do not support differential response of social anxiety and panic disorder to medications (mainly selective serotonin reuptake inhibitors and tricyclics) (Otto et al., 2001; Hedges et al., 2006) or psychotherapy (predominantly cognitivebehavioral therapy) (Rodebaugh et al., 2004; Mitte, 2005), in light of the demonstration of specificity of transmission, more focused development of treatment interventions for target symptoms of each disorder may be considered. Finally, interpretation of the findings should be considered with these limitations. First, all of the relatives were not interviewed directly so we had to rely on family history information provided by other family members. However, the effect of interview status was controlled in the analyses where it was observed that direct interview status was associated two-fold with social anxiety disorder in the relatives, but unrelated to panic disorder. This use of family history information may have led to an under-detection, diagnosis and therefore, estimation of the social anxiety disorder among relatives. Supporting this assumption is literature that reports the family history method is more reliable as a surrogate of direct interviews for substance use versus mood and anxiety disorders (Orvaschel et al., 1982; Thompson et al., 1982; Kosten et al., 1992; Heun and Muller, 1998). Second, the sample was based on probands with panic disorder and social anxiety disorders, and did not include the full range of anxiety disorders. Thirdly, as a result of combining anxiety probands from the local community and clinics to reduce clinical ascertainment bias (Berkson’s bias), there may be concern that these cases may differ with respect to their clinical profile (such as, severity, comorbidity, age of onset, etc.) or in other ways that would preclude their combination. Analyses of this selection bias among these panic and social anxiety disorder probands was associated with an elevated risk among relatives of panic probands for panic disorder from the clinic, but not social anxiety relatives. However, the sample size was small and the study may be limited by low power. In general, the effect of clinic sampling is likely attributable to the greater severity of clinic cases which may also be associated with increased familial morbidity. Lastly, all our participants were Caucasian and therefore our results cannot be extended to other ethnic/racial groups. References Alonso J, Angermeyer MC, Bernert S, Bruffaerts R, Brugha TS, Bryson H, et al. Prevalence of mental disorders in Europe: results from the European Study of the Epidemiology of Mental Disorders (ESEMeD) project. Acta Psychiatrica Scandinavica Supplement 2004:21–7.
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