Comorbidity of anxiety disorders in a multicenter anxiety study

Comorbidity of Anxiety Disorders in a Multicenter Anxiety Study Robert M. Goisman, Idell Goldenberg, Russell G. Vasile, and Martin B. Keller From 11 sites in New England and Missouri, 711 patients with _> one of five index anxiety disorders were recruited onto a longitudinal study in which they were interviewed every 6 months regarding symptoms, course, and treatments received. Of the five disorders studied, panic disorder without agoraphobia was the disorder most often found as a sole diagnosis and generalized anxiety disorder (GAD} was least often found alone, both as lifetime diagnoses or when restricted to cases active at intake. Panic disorder with agoraphobia and agoraphobia without history of panic disorder (AWOPD) had three specific diagnoses with

which they were frequently comorbid: social phobia, simple phobia, and GAD. AWOPD, social phobia, and GAD were frequently found in the presence of each other. It is possible that the experience of anxiety due to any syndromal cause may decrease the threshold for an individual to experience other anxiety syruptoms or disorders. Clinicians should be aware of these patterns of comorbidity in order to formulate accurate differential diagnoses and prescribe treatments in a rational manner.

HE SUBJECT of the comorbidity of anxiety disorders is a relatively neglected one. Among reports that do address it, many investigations have tended to categorize subjects into mutually exclusive diagnostic categories ~,2 or to focus on a selected or "primary" diagnosis.3-7 An alternative approach is to describe what often happens in clinical practice, i.e., a patient presents with a chief complaint referable to one diagnosis but on careful evaluation reveals symptoms consistent with a second or third illness. By thus not preselecting any one disorder as primary, one might obtain a closer approximation of the actual rates at which criteria for multiple anxiety disorders are met. Here we report on comorbid anxiety disorders observed in the Harvard/Brown Anxiety Disorders Research Program (HARP), a longitudinal follow-up study of 711 subjects with > one of five DSM-III-R anxiety diagnoses from 11 sites in Massachusetts, Rhode Island, and Missouri. We describe findings on both current and lifetime comorbidity, relate them to the severity of symptoms as experienced by the study subjects, and discuss them in terms of possible implications for the etiology and treatment of anxiety. A number of organizing principles appear in the comorbidity literature that may help focus our presentation and discussion. Comorbidity can be analyzed in clinical samples or in epidemiologic ones, and can be referred to with regard to lifetime occurrence or current status. In a patient with two anxiety diagnoses, either one (or neither) might be designated as the primary diagnosis and the other as the second-

ary diagnosis; among other possibilities, primary might mean etiologically responsible, temporally earlier, or the diagnosis dominating the presentation. This primary-secondary distinction is also found in the affective disorders literature, s,9 Patients can additionally be separated by degree of social impairment or by response to treatment. A complication is that despite the attempt at standardization of diagnostic criteria exemplified by DSM-III-R, 1° the actual criteria for a given diagnosis used in one study may not match those used in another study,.so that meaningful discussion of comorbidity across studies becomes difficult, e.g., in a discussion of comorbidity of social phobia with other anxiety disorders. 3 Another related problem is that, to some extent, what is considered comorbidity and what is considered simply epiphenomenal is a matter of convention. In the hierarchy system of diagnosis used in DSM-III, 11,12in the presence of some diagnoses certain symptoms were assumed a priori to be only an outgrowth of an underlying disorder, so that at times two diagnoses could not exist simultaneously simply by definition.

T

Copyright © 1995 by W.B. Saunders Company

From the Department of Psychiatry, Harvard Medical School, Boston; Massachusetts Mental Health Center, Boston; Department of Psychiatry, New England Deaconess Hospital, Boston, MA; and Department of Psychiatry and Human Behavior, Brown University School of Medicine, Providence, RL Supported by the Upjohn Company. Address reprint requests to Robert M. Goisman, M.D., Massachusetts Mental Health Center, 74 Fenwood Rd, Boston, MA 02115. Copyright © 1995 by W.B. Saunders Company 0010-440X/95/3604-0008503. 00/0

ComprehensivePsychiatry, Vol. 36, No. 4 (July/August), 1995: pp 303-311

303

304

GOISMAN ET AL

Indeed, some investigators 13(although not all 14) have criticized DSM-III-R for implicitly assigning agoraphobia the role of generally only being an outgrowth of panic disorder. Thus, assumptions made about what constitutes a legitimate psychiatric diagnosis and what represents simply a symptomatic outgrowth of a diagnosis will influence what is reported as comorbidity rather than as associated symptomatology. Our aim in this study was simply to describe patterns of comorbidity observed in a large sample of anxiety-disordered patients, using the current diagnostic nomenclature and with minimal theoretic preconceptions regarding the interpretation of these patterns. Our belief was that in doing so, patterns useful to clinicians and of possible theoretic significance will have the greatest likelihood of emerging. METHOD The H A R P study is a prospective, naturalistic, longitudinal, multicenter study of 711 patients with > one of the following current or past DSM-III-R index anxiety diagnoses: panic disorder (with or without agoraphobia), agoraphobia without a history of panic disorder (AWOPD), generalized anxiety disorder (GAD), or social phobia. Insufficient for inclusion but frequently seen as comorbid conditions are DSM-III-R diagnoses of simple phobia, posttraumatic stress disorder, obsessive-compulsive disorder, or anxiety disorder NOS. The one exception to these criteria is the inclusion of a small number (n = 19) of subjects with obsessive-compulsive disorder without other past or present index diagnoses. Subjects are > 18 years of age, are willing to participate voluntarily in the study, and sign a written consent form. Exclusion criteria are the presence of an organic brain syndrome, a history of schizophrenia, or current psychosis. Subjects are entered onto this study from over 30 clinicians' practices at 11 different clinical treatment facilities. The specific sites, methods of subject recruitment and interviewer training, and instruments used at intake and follow-up assessments are described in detail elsewhere.13,15,16 The initial comprehensive evaluation assesses lifetime history using the following: selected items from the Personal History of Depressive Disordersl7; the Structured Clinical Interview for DSM-III-R Non-Affective Disorders-Patient Versionl8; and the Research Diagnostic Criteria Schedule for Affective Disorders and Schizophrenia-Lifetime.19 Items of the last two instruments were combined to create the SCALUP, an intake instrument. 2° We examined the association among anxiety disorders in our entire study group for lifetime comorbidity and comorbidity active at intake. We considered the five disorders necessary for entry to the study to be index diagnoses without specifying which diagnosis in a subject with comorbid illnesses would be considered primary. We first asked how many additional diagnoses were observed with each

index disorder, both those currently active at intake and those reported across the subject's lifetime. Second, we asked specifically the frequency with which each anxiety disorder was observed to be comorbid with each index disorder currently and over a lifetime. Since our study required one of five index diagnoses for inclusion, we could not examine rates of comorbidity for nonindex anxiety disorders. Since a subject could have more than one of these five disorders, we could not make statistical comparisons that assumed diagnoses to be mutually exclusive. These data were analyzed using SAS. 21 RESULTS

For purposes of clarity, we will briefly describe each table and then discuss our findings in detail by index diagnosis. Consistent with DSM-III-R, we will discuss our findings for current and lifetime diagnoses without the imposition of diagnostic hierarchies. By structuring our data in this manner, we seek to present a closer approximation of the actual rates at which criteria for multiple anxiety disorders are met. The current study group consists of 711 subjects entered into HARP at intake. Sex, age, marital status, educational level, and age of onset distributions are listed in Table 1. Tables 2 and 3 list the number of additional Table 1. Sociodemographic Data Variable

No.

%

Mean -+ SD, Years

Sex Male

240

34

Female Age, years Marital status

471

66

Married

368

52

197 39 95 12

28 6 13 1

2 108 167 207 172 43 9 3

.5 15 24 29 24 6 1 .5

Single Cohabitating Separated/divorced Widowed Educational level Unknown Graduate College/university Partial college HS Partial HS Junior HS < 7 years Age of onset Uncomplicated panic Panic with agoraphobia AWOPD Social phobia GAD Abbreviation: HS, high school.

40.6 - 12.6

127 417 44 199 211

31.8 27.5 25.9 14.4 22.2

± 12.2 ± 19.6 ± 14.4 ± 8.4 --. 14.9

COMORBIDITY OF ANXIETY DISORDERS

305

Table 2. Number of Additional Anxiety Disorders-Lifetime 0 Index Diagnosis

1

2

3

4

No.

%

No.

%

No.

%

No.

%

No.

%

54

43

44

35

21

17

8

6

0

0

167

40

155

37

58

14

32

8

5

1

AWOPD

14

32

11

25

11

25

7

16

1

2

Social phobia

34

17

80

40

44

22

35

18

6

3

GAD

23

11

96

46

49

23

37

18

6

3

Uncomplicated panic Panic with agoraphobia

diagnoses for each index disorder by lifetime and active-intake diagnoses, respectively. The purpose of these tables is to examine the degree to which having a given anxiety diagnosis increases the likelihood of having > one additional anxiety diagnoses, and also to evaluate whether this likelihood differs when lifetime diagnoses are considered as compared with when only disorders active at study intake are considered. Tables 4 and 5 list the rates at which specific anxiety diagnoses were observed to accompany each index disorder; as stated earlier, these are presented separately for lifetime diagnoses and for active-intake diagnoses. Previous studies have focused on one or two mutually exclusive anxiety disorders and reported on observed rates of comorbidity, but we chose instead to report on the relative frequencies of multiple anxiety diagnoses. Even though our index diagnoses are not mutually exclusive groups, we believe that the relative frequencies provide interesting and informative patterns of comorbidity to compare with studies that applied exclusionary or hierarchic diagnostic criteria.

comorbid diagnosis (19% lifetime and intake). Uncomplicated panic occurred less frequently with simple phobia (9% lifetime, 8% intake). Panic With Agoraphobia Panic with agoraphobia was also relatively frequently seen as a sole diagnosis (40% lifetime, 47% intake) and infrequently found with > two diagnoses. Subjects with panic with agoraphobia were observed to have the following comorbid diagnoses at similar rates: social phobia (20% lifetime, 18% intake), GAD (25%, 21%), and simple phobia (20% lifetime and intake). A WOPD Subjects with AWOPD were observed to have at least two additional diagnoses at almost twice the frequency of subjects with uncomplicated panic disorder (lifetime 43% v 23%, intake 30% v 15%), although as a sole diagnosis AWOPD is fairly frequent (lifetime 32%, intake 50%). GAD was the disorder most frequently comorbid with AWOPD (lifetime 34%, intake 27%), followed by social phobia (lifetime 30%, intake 17%) and simple phobia (20% lifetime and intake). Half of the subjects with AWOPD active at intake had this disorder as the sole diagnosis.

Uncomplicated Panic Uncomplicated panic was the disorder most often seen as a sole diagnosis (43% lifetime, 55% intake). Conversely, it was the least-often found with >__ two diagnoses. GAD was the most frequent comorbid diagnosis (24% lifetime, 23% intake) for subjects with panic disorder. Social phobia was the next most frequently

Social Phobia Less than 25% of social phobia subjects had social phobia as the sole diagnosis either life-

Table 3. Number of Additional Anxiety Disorders-Active at Intake 0 Index Diagnosis

1

2

3

4

No.

%

No.

%

No.

%

No.

%

No.

%

44

55

24

30

9

11

3

4

0

0

169

47

124

35

43

12

18

5

3

1

AWOPD

15

50

6

20

7

23

2

7

0

0

Socialphobia

41

23

73

42

36

21

23

13

3

2

GAD

33

18

82

46

38

21

24

13

3

2

Uncomplicated panic Panic with agoraphobia

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GOISMAN ET AL

Table 4. Specific Additional Anxiety Disorder Diagnoses-Lifetime Index Diagnosis Uncomplicated

Panic Additional Diagnosis

No.

%

Panic With Agoraphobia

Social Phobia

AWOPD

GAD

No.

%

No.

%

No.

%

No.

%

17

4

1 8

2 18

24 84

12 42

30 102

14 48

13

7

15 70

7 33

Uncomplicated panic Panic with agoraphobia

17

13

AWOPD Social phobia

1 24

1 19

8 84

2 20

13

30

GAD OCD

30 16

24 13

102 54

25 13

15 6

34 14

70 36

35 18

41

19

PTSD Simple phobia

10 12

8 9

37 85

9 20

4 11

9 25

29 41

15 21

27 44

13 21

Total

127

417

44

199

211

Abbreviations: OCD, obsessive-compulsive disorder; PTSD, posttraumatic stress disorder.

time or at intake. Of those with lifetime social phobia, 42% were also diagnosed with panic with agoraphobia, 35% with GAD, and 21% with simple phobia. Similarly, of subjects with active social phobia at intake, 36% also had active panic with agoraphobia, 34% active GAD, and 21% active simple phobia. GAD

Of those with lifetime GAD, 48% had an additional diagnosis of panic with agoraphobia, 33% social phobia, and 21% simple phobia. Of subjects with active GAD at intake, 42% also had active panic with agoraphobia and 33% active social phobia. GAD was the diagnosis most frequently accompanied by at least one other comorbid anxiety disorder, with almost 90% having a lifetime history of at least one other anxiety disorder. Overall, the diagnostic picture of comorbidity remains fairly consistent whether one considers

any diagnosis over the subject's lifetime or only what the individual presents with currently. Uncomplicated panic disorder appears to have the lowest percentage of specific comorbidities among the anxiety disorders investigated. Panic with agoraphobia and AWOPD have common specific comorbid disorders: social phobia, simple phobia, and GAD. AWOPD, social phobia, and GAD were frequently (lifetime 22% to 25%, intake 21% to 23%) comorbid with at least two other diagnoses in the study group (Tables 2 and 3). These last three disorders are most frequently found in the presence of each other in both lifetime and current comparisons. DISCUSSION

As we did earlier, we will discuss our findings by diagnosis. The recent literature on comorbidity of each of our index diagnoses with other anxiety disorders will be cited for purposes of comparison. These studies are listed in Table 6.

Table 5. Specific Additional Anxiety Disorder Diagnoses-Active at Intake Index Diagnosis Uncomplicated Panic

Additional Diagnosis

No.

Uncomplicated panic Panic with agoraphobia AWOPD Social phobia GAD OCD PTSD Simple phobia

0 0 15 18 8 4 6

Total

80

%

0 0 19 23 10 5 8

Social

Panic With Agoraphobia

AWOPD

Phobia

GAD

%

No.

%

No.

%

No.

%

0

0

0 0

0 0

0 64 76 38 28 72

0 18 21 11 8 20

15 64 5

9 36 3

5

17 27 13 7 23

18 76 8 59

10 42 4 33

59 28 19 36

34 33 14 34

18 8 19

No.

357

8 4 2 7 30

176

16 11 21

180

307

COMORBIDITY OF ANXIETY DISORDERS

Table 6. Comorbidity Studies Cited in Discussion Author Noyes et al?

Sample Size

Study Design/Source

112

Cross-sectional/clinical

Joyce et al. 2 Klerman et al. 4

1,498 18,571

Cross-sectional/community Cross-sectional/community

Johnson et al. s

18,011

Cross-sectional/community

Sanderson et al? ~

130

Cross-sectional/clinical

Schwalberg et al. 22

82

Cross-sectional/clinical

Van Ameringen et al. 23

57

Cross-sectional/clinical

Turner et al. z4

71

Cross-sectional/clinical

Schneier et al. 25 Sanderson and Barlow 2s

13,537 22

Cross-sectional/community Cross-sectional/clinical

Major Findings GAD frequently comorbid with simple phobia, PD frequently comorbid with agoraphobia PDA more often comorbid with GAD than was PD PD and panic attacks frequently comorbid with agoraphobia and seldom found alone Uncomplicated PD less prevalent than PD comorbid with other diagnoses Social phobia more commonly comorbid with GAD than with PDA or OCD, simple phobia commonly comorbid GAD most common comorbid anxiety disorder in PD and social phobia PD, PDA, and GAD most common comorbid diagnoses in social phobia GAD most common comorbid anxiety diagnosis in social phobia Simple phobia and agoraphobia most common comorbid anxiety diagnoses in social phobia GAD most frequently comorbid with social phobia

NOTE. Reports by Mannuzza et al. 3 and Cassano et al. 1~are not included, since they are primarily reviews rather than presentations of new data. Abbreviations: PD, panic disorder; PDA, PD with agoraphobia.

Panic Disorder and A WOPD Our findings for lifetime uncomplicated panic and panic with agoraphobia are roughly consistent with those reported by previous investigators whose methods were comparable to our own. We found lifetime panic with and without agoraphobia to coexist with at least one other anxiety disorder 37% of the time. Klerman et al. 4 found 33% of 254 subjects with DSM-III panic disorder to have comorbid agoraphobia and 72% of these 254 to have comorbid agoraphobia, major depression, alcohol abuse, or drug abuse. Johnson et al. 5 found more than two thirds of Epidemiologic Catchment Area subjects with lifetime panic disorder to meet criteria for > one of 10 other axis I diagnoses. Similarly, our findings regarding current panic with and without agoraphobia concur with previously reported data. We found 45% of subjects with current uncomplicated panic and 53 % of those with current panic with agoraphobia to have at least one comorbid anxiety diagnosis. Of 20 patients with current DSM-III-R panic disorder at the State University of New York at Albany anxiety disorders center, 65% had at least one other lifetime anxiety diagnosis. 22 Cassano et al. 1~ found 70% of 302 patients with current DSM-III-R panic disorder to also have at least one of seven additional current syn-

dromes (most commonly GAD); these syndromes would qualify as additional diagnoses except for the hierarchy of diagnoses dictated by DSM-III nosology. Sanderson et al. ~2 found 38 of 55 patients with current DSM-III-R panic and agoraphobia to have at least one additional current axis I diagnosis, with 25% of these 55 having > two such diagnoses. In agreement with Cassano et al., 11we found GAD to be the diagnosis most often found to coexist with current panic disorder of either type. We could find no references to the comorbidity of AWOPD in the recent literature with which to compare our findings, other than a report that the incidence of social phobia among agoraphobics varied from 0% to 55% in various reports. 3 Social Phobia We found 83% of subjects with lifetime social phobia and 77% of subjects with current social phobia to have at least one comorbid anxiety diagnosis, most commonly GAD. Van Ameringen et al. 23 found 70% of 57 current DSM-III-R social phobics to have had at least one other lifetime anxiety diagnosis, most commonly panic of either type or GAD. In a literature review, Mannuzza et al. 3 summarized five current and lifetime studies of various anxiety-disordered

308

populations and found the reported incidence of agoraphobia among social phobics to vary from 0% to 60% and of panic among social phobics to vary from 0% to 30%. Schwalberg et al. 22 found 45% of 20 current social phobics to have at least one other lifetime DSM-III-R anxiety diagnosis, most commonly GAD. Others have also found a typical anxiety disorder comorbidity of > 33% with the index diagnosis of social phobia. Sanderson et al. 12 found 58% of 24 current social phobics to have >__ one current DSM-III-R anxiety diagnoses, most commonly simple phobia. Turner et al. 24found one third of current social phobics to have current GAD and 11% to have current simple phobias. In analyzing Epidemiologic Catchment Area data, Schneier et al. 25 found 45% of 361 lifetime social phobics to have had lifetime DSM-III agoraphobia with or without panic and 59% to have had simple phobia. The finding of approximately 35% to 45% of active social phobia patients having a current or lifetime comorbid diagnosis of panic with agoraphobia or GAD s e e m s typical. 3,22,24,25 We found only 21% of our lifetime social phobics to have comorbid simple phobia, which contrasts with the 59% reported by Schneier et alY but could be lower due to our having excluded simple phobia as an index diagnosis in the HARP study. The younger mean age of onset we found with our social phobic subjects appears striking, but others have reported mean ages of onset of social phobia of 10 to 19 years,27 15 to 20 years, 2s and 15.5 yearsY Fyer29 has reviewed literature on shyness and behavioral inhibition, two descriptors of childhood temperament that could be seen as predisposing to an earlier vulnerability to clinical social phobic symptoms than to other anxiety disorders. GAD

GAD was slightly more likely to be found with lifetime panic and agoraphobia than with lifetime uncomplicated panic. Similarly, Joyce et al. 2 found lifetime DSM-III GAD to be more frequently found in subjects with a history of panic attacks with "moderate phobic avoidance" (p. 309) than in those with a history of panic attacks alone. Sanderson and Barlow26 studied 22 consecutive patients receiving a current DSM-III-R GAD diagnosis and found that

GOISMAN ET AL

59% also met criteria for current social phobia and 27% for current panic disorder. Regarding comorbidity with phobias, Noyes et al. 1found 32% of 41 current GAD patients to have had current or past simple phobias, a figure roughly comparable to our 21% (lifetime) and 19% (current) of GAD subjects with simple phobias. This group also found 17% of these 41 to have current or lifetime social phobia, as compared with our 33% of GAD subjects meeting current or lifetime criteria for social phobia; the lower prevalence in their study may be due to accepting GAD but not social phobia as an inclusion criterion, whereas HARP included both GAD and social phobic patients. General Comments

Allowing subjects to meet criteria for multiple diagnoses revealed an interestingly consistent picture of comorbid combinations possible among these disorders. Uncomplicated panic is the most likely of these five disorders to exist independently, but even this disorder is found alone less than 50% of the time. Social phobia, simple phobia, and GAD are commonly seen together, even considering an additional comorbid disorder. It would thus seem prudent to question routinely any patient with one of these disorders by lifetime or current status as to the possible presence of the other two. Our findings are consistent with a number of possible explanations. One is that the reliability of DSM-III-R diagnostic subdivisions may be questionable, so that what appears to be frequent comorbidity is really a function of the vagueness of our diagnostic criteria or our inability to observe naturally occurring patterns accurately. Although this explanation cannot be definitively ruled out, a recent study of 267 outpatients with DSM-III-R anxiety disorders receiving two separate structured interviews found good or excellent reliability for many of these categories,3°making this explanation somewhat less than compelling. This, in turn, argues in favor of retention of much of the current system of diagnostic subdivisions within the anxiety disorders, at least until more basic etiologic mechanisms that may reveal deep structural commonalities are discovered. Another possibility is that these disorders may share some common etiologic pathways. As noted by Barlow,3x the experience of some

COMORBIDITY OF ANXIETY DISORDERS

symptoms of anxiety may lead to an anticipation of more anxiety; this anticipation is then itself anxiety-provoking, leading to a vicious circle of ever-increasing expectation, pattern recognition, and further expectation. If this is the case, then it is reasonable that having one anxiety diagnosis should decrease the threshold for having a second. Schneier et al. 25 have recently speculated in a similar fashion regarding social phobia as a primary diagnosis. The prevalence of GAD as a lifetime comorbid anxiety diagnosis in our study may reflect a general tendency for patients initially having one anxiety disorder to develop secondarily additional nonspecific anxiety responses in a classical conditioning phenomenon. This hypothesis could be tested in part by determining what percentage of patients with GAD had it as the initial anxiety diagnosis; we found 46% of our GAD subjects to have the onset of GAD before the onset of other anxiety disorder symptoms. Taken to its extreme, this argument could lead to a call to abolish GAD as a separate entity and regard it only as a somewhat inevitable nonspecific by-product of having any of a number of chronic anxiety disorders. Of course, the most significant aspect of these findings is the possible implication for clinical practice. Beyond the obvious caveat that the presence of one anxiety disorder should impel the clinician to scrupulously rule in or out other likely comorbid conditions when assessing a new patient, the sequencing of various therapy interventions may be affected by comorbidity. For example, a patient with comorbid social phobia and panic might be best served by choosing a monoamine oxidase inhibitor rather than a tricyclic antidepressant, due to the putative specific efficacy of the former for social phobia, as well as its general usefulness in panic. 32 Similarly, a patient with GAD and panic might benefit from extended practice in learning a relaxation method before working on interoceptive exposure. HARP data not otherwise presented here additionally indicated that 47% to 63% of subjects with each of our index diagnoses met criteria for an affective disorder during their lifetime and 40% to 55% at intake. Data from family and twin studies have suggested that anxiety and depressive disorders are present in pure forms in the relatives of probands, but that

309

some degree of overlap in the transmission of these disorders occurs as well; these data are inconclusive as to whether one condition predisposes to another or whether there is a common etiology.33,34 Some studies35,36 (but not others 37,38) have suggested a pronounced familial loading for panic disorder and depression. At least one study has found first-degree relatives of patients dually diagnosed with major depression and panic disorder to have a markedly increased morbidity risk for depression, panic, phobias, and alcoholism?9 Likelihood of familial loading may vary depending on whether panic attacks occur only in depressive episodes or in euthymic states as well. 4°,4~ Thus, the effect of comorbid depression on the treatment of anxiety needs to be considered as well. This might lead the clinician, for example, to assess carefully a patient for depression and to treat vigorously any depression present before recommending that the patient go through a rigorous and demanding series of cognitive-behavioral exercises. To address these issues in depth, a separate report investigating the comorbidities of anxiety with affective disorders is being prepared. Although we have not yet pursued this, a similar argument could be made for the role of concomitant substance abuse.9, 39

The consistency of comorbidity patterns shown by both lifetime and current-status comparisons argues that the clinical phenomena that diagnostic categories attempt to describe are robust. The question remains as to what criteria should be applied to these clinical descriptions. Perhaps even the tendency to designate one illness as primary may get in the way of rigorous thinking and obscure coexisting illnesses; we found that among our five index diagnoses, only 46% to 68% of subjects with a given diagnosis had that condition as the initial anxiety disorder. This suggests that applying the labels of primary to a given diagnosis may imply temporal primacy when this is not the case half the time. There are limitations inherent in the design of a study such as HARP that must be kept in mind when analyzing these data. Foremost among these is that this is a clinical sample, even if a large one; thus, patterns observed among patients who have presented for treatment can be generalized to those that might be

310

GOISMAN ET AL

found in a community-based, partially nontreated sample only with care. Similarly, this is a relatively well-educated and middle-class sample, which again may or may not generalize to other populations. Another limitation is our specification of some but not all anxiety disorders as inclusion criteria. Strengths of this study include the large sample size, multicenter recruitment, length of follow-up study, and degree of operationalization of study variables with reliable assessment instruments. Although much previous research has emphasized the assessment, course, and treatment of single diagnoses, this report has attempted to point out the perils of trying to make diagnosis overly parsimonious. Determination of the etiologic underpinnings of these disorders and their comorbidities must be left for future research. But the complex relationships we have detailed here argue strongly that the clinician must attend to all diagnostic possibilities to provide the most effective treatment. ACKNOWLEDGMENT The HARP is conducted with the participation of the following investigators: P. Alexander, M.D., A. Gordon,

M.D., M.B. Keller, M.D. (Chairperson), S. Rasmussen, M.D., R. Stout, Ph.D. (Butler Hospital-Brown University School of Medicine); M.G. Warshaw, M.S.S., M.A. (Brown University School of Medicine); J. Curran, Ph.D., K. White, M.D. (Veterans Administration Hospital, ProvidenceBrown University School of Medicine); J. Cole, M.D., G. Mallya, M.D. (McLean Hospital-Harvard Medical School); E. Fierman, M.D. (Beth Israel Hospital-Harvard Medical School); F. Rodriguez-Villa, M.D. (Cambridge HospitalHarvard Medical School); M.P. Rogers, M.D. (Brigham and Women's Hospital-Harvard Medical School); R.M. Goisman, M.D., N. Weinshenker, M.D. (Massachusetts Mental Health Center-Harvard Medical School); R.G. Vasile, M.D. (New England Deaconess Hospital-Harvard Medical School); J. Ellison, M.D.; A.O. Massion, M.D. (University of Massachusetts Medical School); G. Steketee, Ph.D. (Boston University School of Social Work); and K. Yonkers, M.D. (University of Texas Southwestern Medical Center). Additional contributions came from R.M.A. Hirschfeld, M.D. (University of Texas, Galveston); J. Hooley, D.Phil (Harvard University); P.W. Lavori, Ph.D. (Stanford University); J.C. Perry, M.D., M.P.H. (Jewish General Hospital-McGill University School of Medicine, Montreal); L.G. Peterson, M.D. (Veterans Administration Medical Center, Togus, ME); J. Reich, M.D., M.P.H.; J. Rice, Ph.D. (Renard Hospital-Washington University School of Medicine, St Louis); H. Samuelson, M.A. (Brigham and Women's Hospital); and M. Weissman, Ph.D. (Columbia University). The manuscript was reviewed by the Publications Committee of the HARP and has its endorsement. The Quintiles Corporation provided valuable consultation services to this project.

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