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Familial analysis of panic disorder and agoraphobia
Journal of Affective Elsevier
1
Disorders, 17 (1989) 1-8
JAD 00614
Familial analysis of panic disorder and agoraphobia Gruppo
Italian0
Disturbi
d’Ansia
*
(Rkceived 16 February 1988) (Revision received 7 July 1988) (Accepted 7 September 1988)
Summary In this paper we studied the distribution of age at onset in 144 patients with panic disorder (PD) and/or agoraphobia (according to DSM-III criteria). We also investigated the incidences in their first-degree relatives of PD, agoraphobia, affective disorders. other anxiety disorders and alcoholism. Our aim was to detect the existence of a specific susceptibility system in these families, considering a wide spectrum of disorders. We found an earlier onset of PD and agoraphobia in the subgroup of our probands who previously met criteria for a separation anxiety disorder in childhood. The presence of both separation anxiety disorder and agoraphobia in the probands increased the familial risk for PD and agoraphobia. Nevertheless, the main finding appeared to be the specific familial concentration of agoraphobia, a disorder exclusively clustered in families of agoraphobic patients.
Key words: Agoraphobia;
Panic disorder;
Familial
Introduction The potential role of the presence of panic disorders (PD) in the reclassification of anxiety disorders can be supported by familial studies.
* The Gruppo Italiano Disturbi d’Ansia is a multicenter group consisting of the Chair of Clinical Psychiatry III, University of Milan (E. Smeraldi, A. Orsini, M. Gasperini, G. Sciuto and M. Battaglia); the Chair of Clinical Psychiatry II, University of Pisa (G.B. Cassano, G. Perugi and W. Mignani); the Chair of Clinical Psychiatry, University of Florence (C. Faravelli and S. Pallanti); and the Chair of Clinical Psychiatry V. University of Rome (G. Bressa). Address for correspondence: Prof. E. Smeraldi, H. San Raffaele 1, Dipartimento di Scienze e Tecnologie Bioinediche, Via Luigi Prinetti 29, 20127 Milan, Italy. 0165-0327/89/$03.50
6 1989 Elsevier Science Publishers
clustering
The specific familial concentration of both PD and agoraphobia has been known for some time (Cohen et al., 1951). However, most of the previous studies did not include sufficient operational diagnostic criteria in their protocols and investigated heterogeneous groups of anxiety disorders, in which the separate forms could not be definitely distinguished. More recently, studies with better operational diagnostic criteria have demonstrated a higher morbidity for PD and agoraphobia in first-degree relatives of patients with PD than in relatives of control subjects (Crowe et al., 1983; Harris et al., 1983; Noyes et al., 1986). The risk for agoraphobia was found to be higher for the relatives of patients with the same disorder (11.6%). while for the relatives of patients with PD
B.V. (Biomedical
Division)
it was nearly equivalent to that of the general population (1.9%) (Noyes et al., 1986). Another important result of that study was the observation that agoraphobia appears at an earlier age than PD. This, together with a more complex and disabling symptomatology, a higher frequency of complications (depression and alcoholism) and a poorer outcome, suggests that agoraphobia might be considered to be a more severe form of PD. Studies in twins showed the frequency of anxiety disorders and PD to be five times greater in monozygotic twins (MZ) than in dizygotic twins (DZ) (Torgersen. 1983). with a higher concordance for phobic disorders in MZ than in DZ twins (Carey and Gottesman, 1981). There are no data as yet about the specific concordance for agoraphobia and the cross-concordance for the two disorders. In addition to the co-existence of PD and agoraphobia within the same family, it was observed that both disorders are frequently associated with separation anxiety disorder during childhood (Klein, 1981). This disorder is also more frequent in the offspring of patients with PD and/or agoraphobia (Berg, 1975; Weissman et al., 1984a) than in the general population and seems to respond to imipramine, a drug that is also able to block panic attacks (Gittelman-Klein and Klein. 1971). These observations led Klein (1981) to hypothesize that common pathogenetic mechanisms underlie the two disorders. both reflecting an increased sensitivity to separation throughout life. From a genetic point of view, such an association could be the phenotypic manifestation in different periods of life of a common susceptibility to illness. Alternatively, it could be the expression and the evolution of learned phobic avoidant behavior as a reaction to stress (Klein, 1964). Reports in the literature about the familial concentration of generalized anxiety disorder (GAD) and its relationship to PD and agoraphobia are somewhat controversial (Slater and Shields, 1969; Solyom et al., 1974; Burns and Thorpe, 1977; Carey and Gottesman, 1981; Crowe et al., 1983; Harris et al., 1983; Leckman et al., 1983a,b; Torgersen. 1983; Moran and Andrews, 1985). Twin studies led Torgersen (1983) to hypothesize that PD has a specific genetic nature and is independent of anticipatory (generalized) anxiety, while
Raskin et al. (1982) did not find different risks for PD and GAD in families of patients with the same disorders. The data of Leckman et al. (1983b) do not support the hypothesis of an independent familial transmission of PD and GAD either. The efficacy of tricyclic antidepressants and monoamine oxidase inhibitors in blocking both spontaneous and lactate-induced panic attacks in susceptible subjects (Tyrer et al., 1980: Rifkin et al.. 1981) and the common finding of a major affective disorder (MAD), either primary (Bowen and Kohout, 1979; Munjack and Moss, 1981) or secondary (Cloninger et al., 1981) in patients with PD raised the question of a possible relationship between PD and mood disorders. Familial epidemiological studies showed a lower incidence of MAD for first-degree relatives of patients with PD (Noyes et al., 1978, 1986; Weissman et al., 1984b) than for first-degree relatives of patients with multiple diagnoses (depression and anxiety disorder) (Leckman et al., 1983a; Pauls and Di Benedetto, 1987). Therefore, we studied the distribution of age at onset in patients with PD and/or agoraphobia. We also evaluated the risks for PD and agoraphobia for the first-degree relatives of our patients. Finally, we investigated the incidences in these families of other psychiatric disorders which may be related to PD and agoraphobia, such as affective disorders, other anxiety disorders and alcoholism. Materials
and methods
One hundred and forty-four consecutive outpatients meeting DSM-III criteria (American Psychiatric Association, 1980) for panic disorder (PD) (28 men, 32 women) and agoraphobia (AGO) with or without panic attacks (29 men, 55 women) who came to the Institutes of Clinical Psychiatry of the Universities of Florence, Milan, Pisa and Rome were investigated. Whether or not there had been a separation anxiety disorder in childhood and/or adolescence was investigated by interviewing both patients and close relatives. Fifty-three patients, 23 in the PD group and 30 in the AGO group, had had this disorder. The existence of an affective disorder in the proband was evaluated, and this constituted an exclusion criterion. The probands
3
all had a diagnosis of PD, without any other possibly related disorders which could interfere with evaluating the nosographic autonomy of PD and its relationship to other disorders within the families. Distribution of age at onset The age at onset of the illness was the time when the patient first met the DSM-III criteria for PD or AGO. The distribution of age at onset was studied by the Cox method (1972). Survival analysis was performed, the dependent variable being the age at onset, on which we evaluated the statistical significance of the following independent variables: type of diagnosis (0 = PD; 1 = AGO); presence or absence of a separation anxiety disorder in the patient’s history (0 = absent; 1= present); sex of proband (0 = male; 1 = female); and presence or absence of a homotypic disorder in at least one of the parents (0 = unaffected; 1 = affected). Familial risk for psychiatric disorder Since the more recent contributions in the literature indicate that anxiety disorders, affective disorders, alcohol abuse and alcohol dependence disorder are more frequent among relatives of patients with PD and/or agoraphobia than in the general population (Leckman et al., 1983b; Noyes et al., 1986) we investigated the existence of such disorders in the 502 first-degree relatives of our patients. At least one relative in each family was directly interviewed by a senior psychiatrist. All relatives of 13 probands from the Psychiatry Clinic of Pisa were given self-administered personal questionnaires before being interviewed. Information about relatives who were not interviewed was collected through anamnestic reports by the probands and the other available relatives. Although data about the offspring of our patients were also collected, they were not included in our analysis because the children were few and young, which tends to exclude them from the risk for most of the disorders that were considered. The anxiety disorders group included all anxiety and somatoform disorders except PD and agoraphobia (with and without panic attacks), which constituted a separate diagnostic group. In a sec-
ond step, we studied the frequency of generalized anxiety disorders (GAD). GAD was isolated from the other anxiety disorders included in our analysis for two reasons. First, we agree with other investigators that the question of a genetic relationship between acute and chronic anxiety (PD. agoraphobia and the other anxiety disorders) is more important than the question of the relationship between PD, agoraphobia and GAD. Second, GAD was more concentrated in the families of our probands than other anxiety disorders and somatoform disorders, which had prevalences similar to those observed in the general population. Consequently the inclusion of these latter disorders in a spectrum common to PD and agoraphobia would be unjustified. The affective disorders group included not only major depression (both single and recurrent episode) and bipolar disorder, but also dysthymic disorder, cyclothymic disorder and atypical depression. Another diagnostic category included alcohol dependence and alcohol abuse: data in the literature indicate a higher frequency of these disorders in the families of patients with PD and/or agoraphobia than in the general population (Noyes et al., 1986). We analyzed the prevalences of these disorders in our families. The frequencies of each diagnostic category (PD and/or AGO, anxiety disorders, GAD, affective disorders, alcoholism) were listed in contingency tables and analyzed using the Glimod program (Cox, 1970). The independent variables were proband’s diagnosis (PD, AGO), existence in the proband of a separation anxiety disorder (absent, present), sex of the proband, sex of the relative and type of relationship (parents, siblings). No age correction,*was applied to unaffected subjects still at risk for developing the disorders. Each disorder, in fact, has a specific distribution of age at onset that cannot be applied to other disorders. All analyses were performed on the Sperry/ Univac 1100/90 computer of the University of Milan. Results
In our sample there was an excess of female probands (60.4%): 53% of the probands with PD
4
and 65.5% of those with agoraphobia were women. The frequency in the personal history of a separation anxiety disorder according to DSM-III criteria was also higher for female (39.1%) than for male (33.3%) probands. We were also interested in the distribution of the separation anxiety disorder in our sample. The incidence of a separation anxiety disorder was 38.3% for probands with PD and 35.7% for probands with agoraphobia. Fifty-seven percent of the patients with a positive history of separation anxiety disorder in early life had agoraphobia later in their lives. Age at onset The range of ages at onset in our patients (12-60 years) was wide, with a mean age of 26. However, the highest frequency of onsets was concentrated in a narrower range: only 10% of the onsets occurred before age 16 and 90% before age 39. We investigated the statistical significance on the distribution of age at onset of the following independent variables: proband sex, type of diagnosis. positive or negative history of separation anxiety disorder in childhood, presence or absence of a homotypic disorder in proband’s parents. When all these variables were considered together, the statistical analysis indicated that none of them is able to significantly affect the age at onset distribution. The only variable that seems to play a role in advancing the age of onset is a positive history for separation anxiety disorder, but this effect was not statistically significant (I = 1.6987; P = 0.09). The mean ages at onset in patients with and without a history of separation anxiety disorder were 25.2 and 26.5 years. Fumilial risk for psychiatric disorders The global frequencies of PD and AGO among the relatives of our patients were compared with those found in a community survey (Faravelli, to be published) for diagnoses comparable to those of the patient sample. The risk was 1.46%’ for the general population. 10.1% for the relatives of patients with AGO and 4.4% for the relatives of patients with PD (see Table l), showing a greater risk for these disorders in the relatives of panic patients than in the general population. The dif-
TABLE
1
PERCENTAGES OF PANIC DISORDERS (PD), AGORAPHOBIA (AGO), ANXIETY DISORDERS, GAD, AFFECTIVE DISORDERS (AFF) AND ALCOHOLISM (ALC) IN FIRST-DEGREE RELATIVES OF PATIENTS WITH PD AND AGORAPHOBIA PD
Agoraphobia
1.7 0 11.7 10 10 3.3 60
3.7 6.2 2.5 0 6.2 4.9 81
x.3 0 15 x.3 15 0 60
4.x x.4 14.5 10.X 15.7 1.2 x3
PD AGO ANXIETY GAD AFF ALC Total
4.3 0 x.5 4.3 0 2.1 47
2.4 3.5 4.8 1.2 3.5 1.2 x5
s/s len PD AGO ANXIETY GAD AFF ALC Total
2.6 0 7.7 7.7 12.x 0 39
6.4 6.4 x.5 x.5 2.1 2.1 47
Frrthm
PD AGO ANXIETY GAD AFF ALC Total Mothers
PD AGO ANXIETY GAD AFF ALC Total Brothen
ference in risk for the two disorders was statistically significant (z = - 2.26. P = 0.02 for the variable ‘presence/absence of agoraphobia’), as can be seen from Table 2, which lists the significances for all the main effects. None of the other variables (proband’s sex, relative’s sex, presence/absence of separation anxiety disorder in proband’s history, type of relationship) and none of the two-way interactions which were tested proved to significantly affect the risk for PD and agoraphobia in the relatives.
5 TABLE
2
LOGISTIC ANALYSIS OF THE FREQUENCY OF PANIC DISORDER AND AGORAPHOBIA IN FIRST-DEGREE RELATIVES Regression Mean frequency Proband sex Presence/absence of a separation anxiety disorder Presence/absence of agoraphobia Sex of relative Type of relationship
weight (P )
Statistical significance
- 2.61 - 0.02
-12.44 -0.10
(2)
**
-0.18
-1.04
- 0.45 -0.27 0.18
-2.26 * -1.56 1 .Ol
* * P = 0.001. * P = 0.02.
The presence of a separation anxiety disorder, although not statistically significant, implies a higher risk for PD and agoraphobia in the relatives of patients with agoraphobia (11.8%) than in the relatives of patients with PD (7.1%) while the relatives of probands without a separation anxiety disorder had risks of 9.3% and 2.9% (Table 3).
TABLE
Finally, a study of the separate incidences of the two disorders in the relatives showed a more uniform distribution of PD, without statistically significant effects of any of the variables that we selected (with a global incidence of 4.2%). The distribution of agoraphobia is very interesting. It is concentrated exclusively in the first-degree relatives of agoraphobic patients, with a frequency of 6.1%, independent of the presence or absence of separation anxiety disorder in childhood (8.8% vs. 4.6%) the proband’s sex (male 5.4%, female 6.4%) or relative’s sex (male 4.8%, female 7.7%) (Tables 1, 3). Our analyses of the familial risk for anxiety disorders (except PD and agoraphobia) indicated statistically significant effects of the variables ‘presence or absence of a separation anxiety disorder’ (z = - 2.45, P = 0.015) and ‘relative’s sex’ (z = - 2.23, P = 0.016). Female relatives had a higher risk for disease than males (12.2% vs. 6.2%) reflecting the trend of a higher risk for anxiety disorders in women in the general population. The risk for anxiety disorders is higher in the families of probands without agoraphobia (11.2%) than in those with agoraphobia (7.4%). This does not agree
3
PERCENTAGES OF PANIC DISORDERS (PD), AGORAPHOBIA DISORDERS (AFF) AND ALCOHOLISM (ALC) IN FIRST-DEGREE ENCE OF SEPARATION ANXIETY DISORDER (SAD) PD Without
(AGO), ANXIETY DISORDERS, GAD, AFFECTIVE RELATIVES ACCORDING TO THE ABSENCE/PRES-
AGO SAD
With SAD
Without
SAD
With SAD
M
F
M
F
M
F
M
F
PD AGO ANXIETY GAD AFF ALC Total
2.9 0 5.9 5.9 14.7 2.9 34
1.5 0 15 1.5 2.5 2.5 40
4.5 0 13.6 13.6 18.2 0 22
4.2 0 20.8 12.5 20.8 0 24
7.1 2.4 4.8 2.4 14.3 2.4 42
3.1 6 9.4 6.3 3.1 3.1 64
0 12.5 18.8 18.8 18.8 6.3 16
4.8 11.9 7.1 2.4 16.7 2.4 42
Siblings PD AGO ANXIETY GAD AFF ALC Total
0 0 0 0 4.8 0 21
0 0 7.3 4.9 2.4 0 41
14.3 0 14.3 14.3 21.4 0 14
10 0 20 10 0 0 10
3.8 3.8 3.8 3.8 1.1 0 26
4.8 4.8 3.2 1.6 1.6 3.2 62
11.1 11.1 11.1 11.1 0 0 9
0 2.9 11.4 5.7 2.9 0 35
Parents
6
with the hypothesis that ‘pure PD’ and anxiety disorders are definitely separate disorders. The higher frequency of anxiety disorders in the families of patients with PD without agoraphobia is not easy to understand: perhaps the subdivision of probands according to the presence or absence of agoraphobia is not definitive, since non-agoraphobic patients may develop agoraphobia later. In our sample the mean duration of illness was also shorter for patients with pure PD than for those with agoraphobia (5.6 vs. 7.5 years). This indicates that the symptomatology of the first group of patients might evolve towards agoraphobia. The presence of a separation anxiety disorder in probands systematically doubles the risk for anxiety disorders in the families of probands both with (from 8.1% to 17.1%) and without (from 5.7% to 10.8%) agoraphobia. The frequency of generalized anxiety disorder (GAD) proved to be more uniformly distributed in first-degree relatives of our patients, with an overall incidence of 6%. Statistical analyses showed that the variables with significant effects are: the sex of the relative (z = - 2.56, P = 0.003), with the male relatives having a GAD incidence of 3.9% and the females of 7.7%; and the presence or absence of a separation anxiety disorder (z = - 2.22, P = 0.006). The relatives of probands with a positive history for this disorder had a risk for GAD of 9.3% while relatives of probands without a separation anxiety disorder had a risk of 4.2%. whereas for the general population it is 5.8%. Significant factors for the risk for affective disorders in the relatives of our patients (Table 4) include sex of proband, sex of relative, type of relationship and the presence or absence of a separation anxiety disorder. The frequency of illness varied according to the sex of the proband (z = 2.58, P = 0.015) and the sex of the relative (Z = -2.52, P = 0.015) with the relatives of male probands having a much higher risk for affective disorders than those of female probands (13% vs. 6.6%). Moreover, affective disorders are clustered in female relatives, with the mothers and sisters more frequently affected than the fathers and brothers (12.2% vs. 5.1%). The risk for affective disorders also differed according to the type of
TABLE
4
LOGISTIC ANALYSIS FECTIVE DISORDERS
Mean frequency Proband sex Presence/absence of a separation anxiety disorder Presence/absence of agoraphobia Sex of relative Type of relationship
OF THE FREQUENCY OF AFIN FIRST-DEGREE RELATIVES Regression weight (p)
Statistical significance
- 2.50 0.40
-12.28 *** 2.58 * *
- 0.48
- 2.84 * *
0.05 - 0.44 0.48
0.31 ~ 2.52 * * 2.43 *
(1)
* * * P = 0.001, * * P = 0.015, * P = 0.016.
relationship (z = 2.43, P = 0.016). The presence of a separation anxiety disorder in the proband enhances the risk for affective disorders in the relatives of probands with PD (from 5.9% to 17.1%) to a greater extent than in those of agoraphobic probands (from 5.7% to 10.8%). This contradicts previous observations (Deltito et al., 1986) reporting the absence of a history of separation anxiety disorder in patients with PD and a positive familiality for affective disorders. We found quite a low risk for alcoholism (2%) in the relatives of our probands, regardless of the diagnosis of PD or agoraphobia (1.5% vs. 2.4%). This does disagree with previous reports in the literature (Noyes et al., 1986). We also failed to find any relationship between the risk for alcoholism and the presence or absence of a separation anxiety disorder. The variables ‘sex of relative’ (z = 1.63, P = 0.09) and ‘type of relationship’ (z = 1.10, P = 0.25) were the only ones to affect the distribution of risk of illness. Male relatives had a higher incidence than females (2.9% vs. 0.9%) and the parents were twice as often affected as the siblings. Comments
We observed higher frequencies of PD. agoraphobia and separation anxiety disorder in women than in men, which agrees with previous reports (Marks and Lader, 1973; Weissman, 1983). The frequency of separation anxiety disorder in childhood for patients with both PD and
agoraphobia differed from that found by Deltito et al. in a previous study (1986) of 39 Italian probands. In that study, the probands with PD and without avoidant behavior had no history of separation anxiety disorder, while 60% of probands with agoraphobia met the criteria for having had that disorder in their childhood. However, because of the different ascertainment criteria we used, it cannot a priori be ruled out that the probands with a positive history for separation anxiety disorder who only met the criteria for PD at the time of our investigation might also develop agoraphobia at a later time. The trend toward an advancing effect of separation anxiety disorder on the age of onset of PD and agoraphobia, even though it requires further support, could be interpreted as indicating greater genetic severity or might serve as a predictive factor for the susceptibility to these disorders. The presence of separation anxiety disorder actually doubles the familial risk for anxiety disorders in the groups of both agoraphobic and non-agoraphobic patients. This suggests that separation anxiety disorder could identify a clinically more severe form of PD, also characterized by a familial susceptibility to anxiety disorders. Nevertheless, we must emphasize the difficulty of assessing the anamnestic presence of a separation anxiety disorder according to DSM-III criteria. In fact, less dramatic conditions of separation anxiety that are not reported in the anamnesis or are not sufficient per se to be identified as a definite disorder could indicate different thresholds of susceptibility in the PD group. Another consideration emerging from our study is that the current DSM-III criteria for agoraphobia seem to be too restrictive. Less severe phobic avoidant behaviors are excluded from diagnostic criteria: these, even though not completely disabling for the patient, could well characterize probands susceptible to a later development of the complete picture of agoraphobia. In conclusion, in addition to separation anxiety disorder, agoraphobia appears to be very important in increasing the familial risk for PD and agoraphobia. The specific familial concentration of agoraphobia, a disorder exclusively found in the relatives of agoraphobic patients, is noteworthy.
A purely genetic interpretation of our results cannot be exhaustive, because cultural factors may well influence the occurrence of alcoholism, as may the other disorders we took into account, in different cohorts, generations and sexes. Our analysis, even though preliminary and exploratory, suggests that the structure of the familial segregation of PD, agoraphobia and the other psychiatric disorders we analyzed needs more specific clarification. That would give us a clearer view of the relationships in the wide spectrum of disorders clustered in the families of these patients, also taking into account second- and third-degree relatives. References American Psychiatric Association (1980) Diagnostic and Statistical Manual, 3rd edn. American Psychiatric Association, Washington, DC. American Psychiatric Association (1986) DSM-III-R in Development - Second Draft. American Psychiatric Association, Washington, DC. Berg, I. (1976) School phobia in the children of agoraphobic women. Br. J. Psychiatry 128, 86-89. Bowen, R.C. and Kohout, J. (1979) The relationship between agoraphobia and primary affective disorders. Can. Psychiatr. Ass. 24, 317-322. Burns, L.E. and Thorpe, G.L. (1977) Fears and clinical phobias: epidemiological aspects and the National Survey of Agoraphobics. J. Int. Med. Res. 5, 132-139. Carey, G. and Gottesman, 1.1. (1981) Twin and family studies of anxiety, phobia and obsessive disorders. In: D.F. Klein and J.G. Rabkin (Eds.), Anxiety - New Research and Changing Concepts. Raven Press, New York, NY. pp. 117-335. Cloninger, C.R., Martin, E.L., Clayton, P. and Guze. S.B. (1981) A blind follow-up and family study of anxiety neurosis: preliminary analysis of the St. Louis 500. In: D.F. Klein and J.G. Rabkin (Eds.), Anxiety - New Research and Changing Concepts. Raven Press, New York. NY, pp. 137-148. Cohen, M.E., Badal, D., Kilpatrick, A., Reed, E.W. and White, P.D. (1951) The high familial prevalence of neurocirculatory asthenia (anxiety neurosis, effort syndrome). Am. J. Hum. Genet. 3, 126-158. Cox, D.R. (1970) Analysis of Binary Data. Chapman and Hall, New York, NY. Cox, D.R. (1972) Regression models and life tables (with discussion). J.R. Stat. Sot. B. 34. 1877220. Crowe, R.R., Noyes, R., Pauls. D.L. and Stymen, D. (1983) A family study of panic disorder. Arch. Gen. Psychiatry 40, 1065-1069. Deltito, J.A., Perugi, G., Maremmani, I., Mignani, V. and Cassano, G.B. (1986) The importance of separation anxiety
in the differentiation of panic disorders from agoraphobia. Psychiatr. Dev. 3, 227-236. Gittelman-Klein. R. and Klein, D.F. (1971) Controlled imipramine treatment of school phobia. Arch. Gen. Psychiatry 25, 204-207. Harris, E.L.. Noyes, R., Crowe, R.R. and Chaudhry, D.R. (1983) Family study of agoraphobia. Report of a pilot study. Arch. Gen. Psychiatry 40, 1061-1064. Klein, D.F. (1964) Delineation of two drug-responsive anxiety syndromes. Psychopharmacologia 5, 397-408. Klein, D.F. (1981) Anxiety reconceptualized. In: D.F. Klein and J.G. Rabkin (Eds.), Anxiety - New Research and Changing Concepts. Raven Press, New York, NY. pp. 235-262. Leckman, J.F., Merikangas, K.R.. Pauls. D.L. Prusoff. B.A. and Weissmann, M.M. (1983a) Anxiety disorders and depression: contradictions between family study data and DSM-III conventions. Am. J. Psychiatry 40, 880-882. Leckman, J.F.. Weissman, M.M., Merikangas. K.R., Pauls, D.L. and Prusoff, B.A. (1983b) Panic disorder and major depression. Arch. Gen. Psychiatry 40, 1055-1060. Marks. I. and Lader. M. (1973) Anxiety states (anxiety neurosis): a review. J. Nerv. Ment. Dis. 156, 3-18. Moran, C. and Andrews, G. (1985) The familial occurrence of agoraphobia. Br. J. Psychiatry 146, 262-267. Munjack. M. and Moss, H.B. (1981) Affective disorders and alcoholism in families of agoraphobics. Arch. Gen. Psychiatry 38, 869-871. Noyes, R.J.. Clancy, J., Crowe, R.. Hoenk, P.R. and Slymen, D.J. (1978) The familial prevalence of anxiety neurosis. Arch. Gen. Psychiatry 35. 1057-1074. Noyes, R.J.. Crowe. R.R., Harris, E.L.. Hamra, B.J., McChesney, C.M. and Chaudhry, D.R. (1986) Relationship between panic disorder and agoraphobia. A family study. Arch. Gen. Psychiatry 43, 227-232.
Pauls. D.L. and Di Benedetto. A.M. (1987) The familial relationship between panic disorder and major depressive disorder. In: G. Racagni and E. Smeraldi (Eds.). Anxious Depression: Assessment and Treatment. Raven Press, New York, NY. Raskin, M.. Pecke. H.V.S.. Dickman, W. and Pinsker, H. (1982) Panic and generalized anxiety disorder. Arch. Gen. Psychiatry 39, 687-689. Rifkin, A., Klein, D.F., Dillon. E. et al. (1981) Blockade by imipramine or desimipramine of pamc induced by sodium lactate. Am. J. Psychiatry 138. 676-677. Slater. E. and Shields, J. (1969) Genetical aspects of anxiety. In: M.H. Lader (Eds.). Studies of Anxiety. Readly, London. Solyom, L.. Beck. P., Solyom, C. and Hugel, R. (1974) Some etiological factors in phobic neurosis. Can. Psychiatry. Ass. J. 19, 69-78. Torgersen. S. (1983) Genetic factors in anxiety disorders. Arch. Gen. Psychiatry 40, 1083-1089. Tyrer. P.. Lee, I. and Alexander. J. (1980) Awareness of cardiac function in anxious. phobic and hypochondriacal patients. Psychol. Med. 10, 171-174. Weissman, M.M. (1983) The epidemiology of anxiety disorders: rates, risks. familial patterns. Presented at the NIMH Conference “Anxiety and Anxiety Disorders”. Tuxedo. NY, September 12-14. Weissman, M.M.. Prusoff. B.A.. Gammon. G.D., Merikangaa. K.R.. Leckman, J. and Kidd, K.K. (1984a) Psychopathology in the children (ages 6-18) of depressed and normal parents. J. Am. Acad. Child Psychiatry 23, 78-84. Weissman, M.M.. Leckman. J.F.. Merikangas, K.R.. Gammon. G.D. and Prusoff, B.A. (1984b) Depression and anxiety disorders in parents and children: results from the Yale family study. Arch. Gen. Psychiatry 41. 845-852.
1
Disorders, 17 (1989) 1-8
JAD 00614
Familial analysis of panic disorder and agoraphobia Gruppo
Italian0
Disturbi
d’Ansia
*
(Rkceived 16 February 1988) (Revision received 7 July 1988) (Accepted 7 September 1988)
Summary In this paper we studied the distribution of age at onset in 144 patients with panic disorder (PD) and/or agoraphobia (according to DSM-III criteria). We also investigated the incidences in their first-degree relatives of PD, agoraphobia, affective disorders. other anxiety disorders and alcoholism. Our aim was to detect the existence of a specific susceptibility system in these families, considering a wide spectrum of disorders. We found an earlier onset of PD and agoraphobia in the subgroup of our probands who previously met criteria for a separation anxiety disorder in childhood. The presence of both separation anxiety disorder and agoraphobia in the probands increased the familial risk for PD and agoraphobia. Nevertheless, the main finding appeared to be the specific familial concentration of agoraphobia, a disorder exclusively clustered in families of agoraphobic patients.
Key words: Agoraphobia;
Panic disorder;
Familial
Introduction The potential role of the presence of panic disorders (PD) in the reclassification of anxiety disorders can be supported by familial studies.
* The Gruppo Italiano Disturbi d’Ansia is a multicenter group consisting of the Chair of Clinical Psychiatry III, University of Milan (E. Smeraldi, A. Orsini, M. Gasperini, G. Sciuto and M. Battaglia); the Chair of Clinical Psychiatry II, University of Pisa (G.B. Cassano, G. Perugi and W. Mignani); the Chair of Clinical Psychiatry, University of Florence (C. Faravelli and S. Pallanti); and the Chair of Clinical Psychiatry V. University of Rome (G. Bressa). Address for correspondence: Prof. E. Smeraldi, H. San Raffaele 1, Dipartimento di Scienze e Tecnologie Bioinediche, Via Luigi Prinetti 29, 20127 Milan, Italy. 0165-0327/89/$03.50
6 1989 Elsevier Science Publishers
clustering
The specific familial concentration of both PD and agoraphobia has been known for some time (Cohen et al., 1951). However, most of the previous studies did not include sufficient operational diagnostic criteria in their protocols and investigated heterogeneous groups of anxiety disorders, in which the separate forms could not be definitely distinguished. More recently, studies with better operational diagnostic criteria have demonstrated a higher morbidity for PD and agoraphobia in first-degree relatives of patients with PD than in relatives of control subjects (Crowe et al., 1983; Harris et al., 1983; Noyes et al., 1986). The risk for agoraphobia was found to be higher for the relatives of patients with the same disorder (11.6%). while for the relatives of patients with PD
B.V. (Biomedical
Division)
it was nearly equivalent to that of the general population (1.9%) (Noyes et al., 1986). Another important result of that study was the observation that agoraphobia appears at an earlier age than PD. This, together with a more complex and disabling symptomatology, a higher frequency of complications (depression and alcoholism) and a poorer outcome, suggests that agoraphobia might be considered to be a more severe form of PD. Studies in twins showed the frequency of anxiety disorders and PD to be five times greater in monozygotic twins (MZ) than in dizygotic twins (DZ) (Torgersen. 1983). with a higher concordance for phobic disorders in MZ than in DZ twins (Carey and Gottesman, 1981). There are no data as yet about the specific concordance for agoraphobia and the cross-concordance for the two disorders. In addition to the co-existence of PD and agoraphobia within the same family, it was observed that both disorders are frequently associated with separation anxiety disorder during childhood (Klein, 1981). This disorder is also more frequent in the offspring of patients with PD and/or agoraphobia (Berg, 1975; Weissman et al., 1984a) than in the general population and seems to respond to imipramine, a drug that is also able to block panic attacks (Gittelman-Klein and Klein. 1971). These observations led Klein (1981) to hypothesize that common pathogenetic mechanisms underlie the two disorders. both reflecting an increased sensitivity to separation throughout life. From a genetic point of view, such an association could be the phenotypic manifestation in different periods of life of a common susceptibility to illness. Alternatively, it could be the expression and the evolution of learned phobic avoidant behavior as a reaction to stress (Klein, 1964). Reports in the literature about the familial concentration of generalized anxiety disorder (GAD) and its relationship to PD and agoraphobia are somewhat controversial (Slater and Shields, 1969; Solyom et al., 1974; Burns and Thorpe, 1977; Carey and Gottesman, 1981; Crowe et al., 1983; Harris et al., 1983; Leckman et al., 1983a,b; Torgersen. 1983; Moran and Andrews, 1985). Twin studies led Torgersen (1983) to hypothesize that PD has a specific genetic nature and is independent of anticipatory (generalized) anxiety, while
Raskin et al. (1982) did not find different risks for PD and GAD in families of patients with the same disorders. The data of Leckman et al. (1983b) do not support the hypothesis of an independent familial transmission of PD and GAD either. The efficacy of tricyclic antidepressants and monoamine oxidase inhibitors in blocking both spontaneous and lactate-induced panic attacks in susceptible subjects (Tyrer et al., 1980: Rifkin et al.. 1981) and the common finding of a major affective disorder (MAD), either primary (Bowen and Kohout, 1979; Munjack and Moss, 1981) or secondary (Cloninger et al., 1981) in patients with PD raised the question of a possible relationship between PD and mood disorders. Familial epidemiological studies showed a lower incidence of MAD for first-degree relatives of patients with PD (Noyes et al., 1978, 1986; Weissman et al., 1984b) than for first-degree relatives of patients with multiple diagnoses (depression and anxiety disorder) (Leckman et al., 1983a; Pauls and Di Benedetto, 1987). Therefore, we studied the distribution of age at onset in patients with PD and/or agoraphobia. We also evaluated the risks for PD and agoraphobia for the first-degree relatives of our patients. Finally, we investigated the incidences in these families of other psychiatric disorders which may be related to PD and agoraphobia, such as affective disorders, other anxiety disorders and alcoholism. Materials
and methods
One hundred and forty-four consecutive outpatients meeting DSM-III criteria (American Psychiatric Association, 1980) for panic disorder (PD) (28 men, 32 women) and agoraphobia (AGO) with or without panic attacks (29 men, 55 women) who came to the Institutes of Clinical Psychiatry of the Universities of Florence, Milan, Pisa and Rome were investigated. Whether or not there had been a separation anxiety disorder in childhood and/or adolescence was investigated by interviewing both patients and close relatives. Fifty-three patients, 23 in the PD group and 30 in the AGO group, had had this disorder. The existence of an affective disorder in the proband was evaluated, and this constituted an exclusion criterion. The probands
3
all had a diagnosis of PD, without any other possibly related disorders which could interfere with evaluating the nosographic autonomy of PD and its relationship to other disorders within the families. Distribution of age at onset The age at onset of the illness was the time when the patient first met the DSM-III criteria for PD or AGO. The distribution of age at onset was studied by the Cox method (1972). Survival analysis was performed, the dependent variable being the age at onset, on which we evaluated the statistical significance of the following independent variables: type of diagnosis (0 = PD; 1 = AGO); presence or absence of a separation anxiety disorder in the patient’s history (0 = absent; 1= present); sex of proband (0 = male; 1 = female); and presence or absence of a homotypic disorder in at least one of the parents (0 = unaffected; 1 = affected). Familial risk for psychiatric disorder Since the more recent contributions in the literature indicate that anxiety disorders, affective disorders, alcohol abuse and alcohol dependence disorder are more frequent among relatives of patients with PD and/or agoraphobia than in the general population (Leckman et al., 1983b; Noyes et al., 1986) we investigated the existence of such disorders in the 502 first-degree relatives of our patients. At least one relative in each family was directly interviewed by a senior psychiatrist. All relatives of 13 probands from the Psychiatry Clinic of Pisa were given self-administered personal questionnaires before being interviewed. Information about relatives who were not interviewed was collected through anamnestic reports by the probands and the other available relatives. Although data about the offspring of our patients were also collected, they were not included in our analysis because the children were few and young, which tends to exclude them from the risk for most of the disorders that were considered. The anxiety disorders group included all anxiety and somatoform disorders except PD and agoraphobia (with and without panic attacks), which constituted a separate diagnostic group. In a sec-
ond step, we studied the frequency of generalized anxiety disorders (GAD). GAD was isolated from the other anxiety disorders included in our analysis for two reasons. First, we agree with other investigators that the question of a genetic relationship between acute and chronic anxiety (PD. agoraphobia and the other anxiety disorders) is more important than the question of the relationship between PD, agoraphobia and GAD. Second, GAD was more concentrated in the families of our probands than other anxiety disorders and somatoform disorders, which had prevalences similar to those observed in the general population. Consequently the inclusion of these latter disorders in a spectrum common to PD and agoraphobia would be unjustified. The affective disorders group included not only major depression (both single and recurrent episode) and bipolar disorder, but also dysthymic disorder, cyclothymic disorder and atypical depression. Another diagnostic category included alcohol dependence and alcohol abuse: data in the literature indicate a higher frequency of these disorders in the families of patients with PD and/or agoraphobia than in the general population (Noyes et al., 1986). We analyzed the prevalences of these disorders in our families. The frequencies of each diagnostic category (PD and/or AGO, anxiety disorders, GAD, affective disorders, alcoholism) were listed in contingency tables and analyzed using the Glimod program (Cox, 1970). The independent variables were proband’s diagnosis (PD, AGO), existence in the proband of a separation anxiety disorder (absent, present), sex of the proband, sex of the relative and type of relationship (parents, siblings). No age correction,*was applied to unaffected subjects still at risk for developing the disorders. Each disorder, in fact, has a specific distribution of age at onset that cannot be applied to other disorders. All analyses were performed on the Sperry/ Univac 1100/90 computer of the University of Milan. Results
In our sample there was an excess of female probands (60.4%): 53% of the probands with PD
4
and 65.5% of those with agoraphobia were women. The frequency in the personal history of a separation anxiety disorder according to DSM-III criteria was also higher for female (39.1%) than for male (33.3%) probands. We were also interested in the distribution of the separation anxiety disorder in our sample. The incidence of a separation anxiety disorder was 38.3% for probands with PD and 35.7% for probands with agoraphobia. Fifty-seven percent of the patients with a positive history of separation anxiety disorder in early life had agoraphobia later in their lives. Age at onset The range of ages at onset in our patients (12-60 years) was wide, with a mean age of 26. However, the highest frequency of onsets was concentrated in a narrower range: only 10% of the onsets occurred before age 16 and 90% before age 39. We investigated the statistical significance on the distribution of age at onset of the following independent variables: proband sex, type of diagnosis. positive or negative history of separation anxiety disorder in childhood, presence or absence of a homotypic disorder in proband’s parents. When all these variables were considered together, the statistical analysis indicated that none of them is able to significantly affect the age at onset distribution. The only variable that seems to play a role in advancing the age of onset is a positive history for separation anxiety disorder, but this effect was not statistically significant (I = 1.6987; P = 0.09). The mean ages at onset in patients with and without a history of separation anxiety disorder were 25.2 and 26.5 years. Fumilial risk for psychiatric disorders The global frequencies of PD and AGO among the relatives of our patients were compared with those found in a community survey (Faravelli, to be published) for diagnoses comparable to those of the patient sample. The risk was 1.46%’ for the general population. 10.1% for the relatives of patients with AGO and 4.4% for the relatives of patients with PD (see Table l), showing a greater risk for these disorders in the relatives of panic patients than in the general population. The dif-
TABLE
1
PERCENTAGES OF PANIC DISORDERS (PD), AGORAPHOBIA (AGO), ANXIETY DISORDERS, GAD, AFFECTIVE DISORDERS (AFF) AND ALCOHOLISM (ALC) IN FIRST-DEGREE RELATIVES OF PATIENTS WITH PD AND AGORAPHOBIA PD
Agoraphobia
1.7 0 11.7 10 10 3.3 60
3.7 6.2 2.5 0 6.2 4.9 81
x.3 0 15 x.3 15 0 60
4.x x.4 14.5 10.X 15.7 1.2 x3
PD AGO ANXIETY GAD AFF ALC Total
4.3 0 x.5 4.3 0 2.1 47
2.4 3.5 4.8 1.2 3.5 1.2 x5
s/s len PD AGO ANXIETY GAD AFF ALC Total
2.6 0 7.7 7.7 12.x 0 39
6.4 6.4 x.5 x.5 2.1 2.1 47
Frrthm
PD AGO ANXIETY GAD AFF ALC Total Mothers
PD AGO ANXIETY GAD AFF ALC Total Brothen
ference in risk for the two disorders was statistically significant (z = - 2.26. P = 0.02 for the variable ‘presence/absence of agoraphobia’), as can be seen from Table 2, which lists the significances for all the main effects. None of the other variables (proband’s sex, relative’s sex, presence/absence of separation anxiety disorder in proband’s history, type of relationship) and none of the two-way interactions which were tested proved to significantly affect the risk for PD and agoraphobia in the relatives.
5 TABLE
2
LOGISTIC ANALYSIS OF THE FREQUENCY OF PANIC DISORDER AND AGORAPHOBIA IN FIRST-DEGREE RELATIVES Regression Mean frequency Proband sex Presence/absence of a separation anxiety disorder Presence/absence of agoraphobia Sex of relative Type of relationship
weight (P )
Statistical significance
- 2.61 - 0.02
-12.44 -0.10
(2)
**
-0.18
-1.04
- 0.45 -0.27 0.18
-2.26 * -1.56 1 .Ol
* * P = 0.001. * P = 0.02.
The presence of a separation anxiety disorder, although not statistically significant, implies a higher risk for PD and agoraphobia in the relatives of patients with agoraphobia (11.8%) than in the relatives of patients with PD (7.1%) while the relatives of probands without a separation anxiety disorder had risks of 9.3% and 2.9% (Table 3).
TABLE
Finally, a study of the separate incidences of the two disorders in the relatives showed a more uniform distribution of PD, without statistically significant effects of any of the variables that we selected (with a global incidence of 4.2%). The distribution of agoraphobia is very interesting. It is concentrated exclusively in the first-degree relatives of agoraphobic patients, with a frequency of 6.1%, independent of the presence or absence of separation anxiety disorder in childhood (8.8% vs. 4.6%) the proband’s sex (male 5.4%, female 6.4%) or relative’s sex (male 4.8%, female 7.7%) (Tables 1, 3). Our analyses of the familial risk for anxiety disorders (except PD and agoraphobia) indicated statistically significant effects of the variables ‘presence or absence of a separation anxiety disorder’ (z = - 2.45, P = 0.015) and ‘relative’s sex’ (z = - 2.23, P = 0.016). Female relatives had a higher risk for disease than males (12.2% vs. 6.2%) reflecting the trend of a higher risk for anxiety disorders in women in the general population. The risk for anxiety disorders is higher in the families of probands without agoraphobia (11.2%) than in those with agoraphobia (7.4%). This does not agree
3
PERCENTAGES OF PANIC DISORDERS (PD), AGORAPHOBIA DISORDERS (AFF) AND ALCOHOLISM (ALC) IN FIRST-DEGREE ENCE OF SEPARATION ANXIETY DISORDER (SAD) PD Without
(AGO), ANXIETY DISORDERS, GAD, AFFECTIVE RELATIVES ACCORDING TO THE ABSENCE/PRES-
AGO SAD
With SAD
Without
SAD
With SAD
M
F
M
F
M
F
M
F
PD AGO ANXIETY GAD AFF ALC Total
2.9 0 5.9 5.9 14.7 2.9 34
1.5 0 15 1.5 2.5 2.5 40
4.5 0 13.6 13.6 18.2 0 22
4.2 0 20.8 12.5 20.8 0 24
7.1 2.4 4.8 2.4 14.3 2.4 42
3.1 6 9.4 6.3 3.1 3.1 64
0 12.5 18.8 18.8 18.8 6.3 16
4.8 11.9 7.1 2.4 16.7 2.4 42
Siblings PD AGO ANXIETY GAD AFF ALC Total
0 0 0 0 4.8 0 21
0 0 7.3 4.9 2.4 0 41
14.3 0 14.3 14.3 21.4 0 14
10 0 20 10 0 0 10
3.8 3.8 3.8 3.8 1.1 0 26
4.8 4.8 3.2 1.6 1.6 3.2 62
11.1 11.1 11.1 11.1 0 0 9
0 2.9 11.4 5.7 2.9 0 35
Parents
6
with the hypothesis that ‘pure PD’ and anxiety disorders are definitely separate disorders. The higher frequency of anxiety disorders in the families of patients with PD without agoraphobia is not easy to understand: perhaps the subdivision of probands according to the presence or absence of agoraphobia is not definitive, since non-agoraphobic patients may develop agoraphobia later. In our sample the mean duration of illness was also shorter for patients with pure PD than for those with agoraphobia (5.6 vs. 7.5 years). This indicates that the symptomatology of the first group of patients might evolve towards agoraphobia. The presence of a separation anxiety disorder in probands systematically doubles the risk for anxiety disorders in the families of probands both with (from 8.1% to 17.1%) and without (from 5.7% to 10.8%) agoraphobia. The frequency of generalized anxiety disorder (GAD) proved to be more uniformly distributed in first-degree relatives of our patients, with an overall incidence of 6%. Statistical analyses showed that the variables with significant effects are: the sex of the relative (z = - 2.56, P = 0.003), with the male relatives having a GAD incidence of 3.9% and the females of 7.7%; and the presence or absence of a separation anxiety disorder (z = - 2.22, P = 0.006). The relatives of probands with a positive history for this disorder had a risk for GAD of 9.3% while relatives of probands without a separation anxiety disorder had a risk of 4.2%. whereas for the general population it is 5.8%. Significant factors for the risk for affective disorders in the relatives of our patients (Table 4) include sex of proband, sex of relative, type of relationship and the presence or absence of a separation anxiety disorder. The frequency of illness varied according to the sex of the proband (z = 2.58, P = 0.015) and the sex of the relative (Z = -2.52, P = 0.015) with the relatives of male probands having a much higher risk for affective disorders than those of female probands (13% vs. 6.6%). Moreover, affective disorders are clustered in female relatives, with the mothers and sisters more frequently affected than the fathers and brothers (12.2% vs. 5.1%). The risk for affective disorders also differed according to the type of
TABLE
4
LOGISTIC ANALYSIS FECTIVE DISORDERS
Mean frequency Proband sex Presence/absence of a separation anxiety disorder Presence/absence of agoraphobia Sex of relative Type of relationship
OF THE FREQUENCY OF AFIN FIRST-DEGREE RELATIVES Regression weight (p)
Statistical significance
- 2.50 0.40
-12.28 *** 2.58 * *
- 0.48
- 2.84 * *
0.05 - 0.44 0.48
0.31 ~ 2.52 * * 2.43 *
(1)
* * * P = 0.001, * * P = 0.015, * P = 0.016.
relationship (z = 2.43, P = 0.016). The presence of a separation anxiety disorder in the proband enhances the risk for affective disorders in the relatives of probands with PD (from 5.9% to 17.1%) to a greater extent than in those of agoraphobic probands (from 5.7% to 10.8%). This contradicts previous observations (Deltito et al., 1986) reporting the absence of a history of separation anxiety disorder in patients with PD and a positive familiality for affective disorders. We found quite a low risk for alcoholism (2%) in the relatives of our probands, regardless of the diagnosis of PD or agoraphobia (1.5% vs. 2.4%). This does disagree with previous reports in the literature (Noyes et al., 1986). We also failed to find any relationship between the risk for alcoholism and the presence or absence of a separation anxiety disorder. The variables ‘sex of relative’ (z = 1.63, P = 0.09) and ‘type of relationship’ (z = 1.10, P = 0.25) were the only ones to affect the distribution of risk of illness. Male relatives had a higher incidence than females (2.9% vs. 0.9%) and the parents were twice as often affected as the siblings. Comments
We observed higher frequencies of PD. agoraphobia and separation anxiety disorder in women than in men, which agrees with previous reports (Marks and Lader, 1973; Weissman, 1983). The frequency of separation anxiety disorder in childhood for patients with both PD and
agoraphobia differed from that found by Deltito et al. in a previous study (1986) of 39 Italian probands. In that study, the probands with PD and without avoidant behavior had no history of separation anxiety disorder, while 60% of probands with agoraphobia met the criteria for having had that disorder in their childhood. However, because of the different ascertainment criteria we used, it cannot a priori be ruled out that the probands with a positive history for separation anxiety disorder who only met the criteria for PD at the time of our investigation might also develop agoraphobia at a later time. The trend toward an advancing effect of separation anxiety disorder on the age of onset of PD and agoraphobia, even though it requires further support, could be interpreted as indicating greater genetic severity or might serve as a predictive factor for the susceptibility to these disorders. The presence of separation anxiety disorder actually doubles the familial risk for anxiety disorders in the groups of both agoraphobic and non-agoraphobic patients. This suggests that separation anxiety disorder could identify a clinically more severe form of PD, also characterized by a familial susceptibility to anxiety disorders. Nevertheless, we must emphasize the difficulty of assessing the anamnestic presence of a separation anxiety disorder according to DSM-III criteria. In fact, less dramatic conditions of separation anxiety that are not reported in the anamnesis or are not sufficient per se to be identified as a definite disorder could indicate different thresholds of susceptibility in the PD group. Another consideration emerging from our study is that the current DSM-III criteria for agoraphobia seem to be too restrictive. Less severe phobic avoidant behaviors are excluded from diagnostic criteria: these, even though not completely disabling for the patient, could well characterize probands susceptible to a later development of the complete picture of agoraphobia. In conclusion, in addition to separation anxiety disorder, agoraphobia appears to be very important in increasing the familial risk for PD and agoraphobia. The specific familial concentration of agoraphobia, a disorder exclusively found in the relatives of agoraphobic patients, is noteworthy.
A purely genetic interpretation of our results cannot be exhaustive, because cultural factors may well influence the occurrence of alcoholism, as may the other disorders we took into account, in different cohorts, generations and sexes. Our analysis, even though preliminary and exploratory, suggests that the structure of the familial segregation of PD, agoraphobia and the other psychiatric disorders we analyzed needs more specific clarification. That would give us a clearer view of the relationships in the wide spectrum of disorders clustered in the families of these patients, also taking into account second- and third-degree relatives. References American Psychiatric Association (1980) Diagnostic and Statistical Manual, 3rd edn. American Psychiatric Association, Washington, DC. American Psychiatric Association (1986) DSM-III-R in Development - Second Draft. American Psychiatric Association, Washington, DC. Berg, I. (1976) School phobia in the children of agoraphobic women. Br. J. Psychiatry 128, 86-89. Bowen, R.C. and Kohout, J. (1979) The relationship between agoraphobia and primary affective disorders. Can. Psychiatr. Ass. 24, 317-322. Burns, L.E. and Thorpe, G.L. (1977) Fears and clinical phobias: epidemiological aspects and the National Survey of Agoraphobics. J. Int. Med. Res. 5, 132-139. Carey, G. and Gottesman, 1.1. (1981) Twin and family studies of anxiety, phobia and obsessive disorders. In: D.F. Klein and J.G. Rabkin (Eds.), Anxiety - New Research and Changing Concepts. Raven Press, New York, NY. pp. 117-335. Cloninger, C.R., Martin, E.L., Clayton, P. and Guze. S.B. (1981) A blind follow-up and family study of anxiety neurosis: preliminary analysis of the St. Louis 500. In: D.F. Klein and J.G. Rabkin (Eds.), Anxiety - New Research and Changing Concepts. Raven Press, New York. NY, pp. 137-148. Cohen, M.E., Badal, D., Kilpatrick, A., Reed, E.W. and White, P.D. (1951) The high familial prevalence of neurocirculatory asthenia (anxiety neurosis, effort syndrome). Am. J. Hum. Genet. 3, 126-158. Cox, D.R. (1970) Analysis of Binary Data. Chapman and Hall, New York, NY. Cox, D.R. (1972) Regression models and life tables (with discussion). J.R. Stat. Sot. B. 34. 1877220. Crowe, R.R., Noyes, R., Pauls. D.L. and Stymen, D. (1983) A family study of panic disorder. Arch. Gen. Psychiatry 40, 1065-1069. Deltito, J.A., Perugi, G., Maremmani, I., Mignani, V. and Cassano, G.B. (1986) The importance of separation anxiety
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Pauls. D.L. and Di Benedetto. A.M. (1987) The familial relationship between panic disorder and major depressive disorder. In: G. Racagni and E. Smeraldi (Eds.). Anxious Depression: Assessment and Treatment. Raven Press, New York, NY. Raskin, M.. Pecke. H.V.S.. Dickman, W. and Pinsker, H. (1982) Panic and generalized anxiety disorder. Arch. Gen. Psychiatry 39, 687-689. Rifkin, A., Klein, D.F., Dillon. E. et al. (1981) Blockade by imipramine or desimipramine of pamc induced by sodium lactate. Am. J. Psychiatry 138. 676-677. Slater. E. and Shields, J. (1969) Genetical aspects of anxiety. In: M.H. Lader (Eds.). Studies of Anxiety. Readly, London. Solyom, L.. Beck. P., Solyom, C. and Hugel, R. (1974) Some etiological factors in phobic neurosis. Can. Psychiatry. Ass. J. 19, 69-78. Torgersen. S. (1983) Genetic factors in anxiety disorders. Arch. Gen. Psychiatry 40, 1083-1089. Tyrer. P.. Lee, I. and Alexander. J. (1980) Awareness of cardiac function in anxious. phobic and hypochondriacal patients. Psychol. Med. 10, 171-174. Weissman, M.M. (1983) The epidemiology of anxiety disorders: rates, risks. familial patterns. Presented at the NIMH Conference “Anxiety and Anxiety Disorders”. Tuxedo. NY, September 12-14. Weissman, M.M.. Prusoff. B.A.. Gammon. G.D., Merikangaa. K.R.. Leckman, J. and Kidd, K.K. (1984a) Psychopathology in the children (ages 6-18) of depressed and normal parents. J. Am. Acad. Child Psychiatry 23, 78-84. Weissman, M.M.. Leckman. J.F.. Merikangas, K.R.. Gammon. G.D. and Prusoff, B.A. (1984b) Depression and anxiety disorders in parents and children: results from the Yale family study. Arch. Gen. Psychiatry 41. 845-852.