Delimitation of generalized anxiety disorder: Clinical comparisons with panic and major depressive disorders

Delimitation of Generalized Anxiety Disorder: Clinical Comparisons With Panic and Major Depressive Disorders Crisitiana Nisita, Albert0 Petracca, Hagop S. Akiskal, Letizia Galli, Isabella Gepponi, and Giovanni B. Cassano We compared 40 outpatients with “pure” generalized anxiety disorder (GAD) with 152 panic disordered patients with varying degrees of phobic avoidance, and 24 1 primary major depressives with single and recurrent episodic patterns. Despite sociodemographic and symptomatologic overlaps with these comparison groups, GAD emerged as a relatively distinct disorder, characterized by chronic low-grade symptomatology with observed anxiety at interview, as well as nausea, headache, tension, and insomnia. These anxious “traits,” which appear to be part of the habitual self of the patient, are subject to fluctuation over time, and may form the temperamental substrate or precursor of panic and other anxiety and depressive disorders. 0 1990 by W. 6. Saunders Company.

S

INCE ITS INCLUSION in DSM-III,’ generalized anxiety disorder (GAD) has received increasing attention in clinical and research settings. However, its reliability and validity have been much debated.2s3 The symptomatologic profile does not appear to be sufficiently unique to permit the establishment of clear boundaries with other anxiety disorders, particularly panic disorder (PD) without phobic avoidance, and with adjustment and mood disorders, particularly major depressive disorder (MDD). As generalized anxiety is often seen concomitantly with other psychiatric and medical diagnoses, it has been suggested that GAD should be conceptualized as a separate anxiety category to be diagnosed in addition to other anxiety or mood disorders.4 This position derives in part from Klein’s contributions that distinguish PD from GAD.’ GAD has also been considered as a mild type of PD,6 as a residual phase of chronic depression,’ or as anxious personality or temperament.8’g This report presents clinical comparisons between GAD and PD, and between GAD and MDD, that are relevant to these relationships. METHODS The study group comprised 40 largely self-referred outpatients who met DSM-III-R”’ criteria for GAD. They were compared with other DSM-III-R diagnostic groups consisting of (1) PD (n = 37); (2) PD with limited (mild to moderate) phobic avoidance (n = 30); (3) PD with severe phobic avoidance or agoraphobia (n = 85); (4) recurrent major depression (n = 154); and (5) major depression, single episode (n = 87). These comparison groups consisted of self-referred and physician-referred outpatients, except for about half the sample of depressives that had been hospitalized during prior episodes. Patients in all groups represented consecutive admissions-meeting the DSM-III-R criteria under consideration-to the Institute of Clinical Psychiatry at the University of Pisa and affiliated clinical facilities during a 2-year period.

From the Institute of Clinical Psychiatry, University of Piss. Italy; and the Section of Affective Disorders, University of Tennessee, Memphis. TN. Address reprint requests to Giovanni B. Cassano. M.D.. Institute of Clinical Psychiatry, University of Piss. 56100 Pisa, Via Roma, 67. Italy. ~‘11990 by W.B. Saunders Company. 0010-440x/90/31 05-001 I $03.00/0

Comprehensive

Psychiatry,

Vol. 3 1, No. 5 (September/October),

1990: pp 409-415

409

410

NISITA ET AL

The present report derives from a larger research project that represents ongoing collaboration between the Institute of Clinical Psychiatry at the University of Pisa, Italy and the Section of Affective Disorders at the University of Tennessee, Memphis. The aims of the project are to examine the relationship between various anxiety and mood disorders and to characterize their long term course. To this end, we have constructed two semistructured interview schedules that take into account the familial, developmental, temperamental, and phenomenologic subtleties of these disorders: (1) the schedule on anxiety disorders” has been extensively used in cross-national research on panic and related disorders; (2) the semistructured interview for depression I2 is modified from the University of Tennessee Mood Clinic Data Questionnaire” to incorporate DSM-III-R criteria. Diagnostic evaluation of patients is conducted by two experienced psychiatrists who then present all the clinical data to the senior Italian author (G.B.C.); final consensus diagnoses are assigned by this author, who, after reviewing all the available information gathered through the above methods, clarifies all unresolved clinical issues in a brief face-to-face interview. In the PD groups, DSM-III-R criteria were employed without the restraint of any hierarchical diagnostic schema; comorbidity with other anxiety and depressive disorders did not constitute exclusion criteria. Data from the following rating scales were compared between GAD and PD groups: Adult Personal Data Inventory (APDI)14 for demographic, clinical, personal and family history; Sheehan Clinician Anxiety Rating Scale (SCRAS), except items about panic features, which by definition were absent in the GAD group; and the Sheehan Disability Scale (DISS). The latter two anxiety scales have been widely used in the World-Wide Panic Disorder Study.15 We then compared GAD with the recurrent and single episode major depressive groups. These two depressive groups represented primary mood disorders in that we excluded those depressives with preexisting major psychiatric disorders such as mental retardation, dementia, schizophrenia, anorexia nervosa, somatization hysteria, alcoholism, and other clinically significant substance use disorders, and panic, agoraphobic, social phobic, and obsessive-compulsive disorders. The comparisons between GAD and the two depressive groups were made on demographic and symptomatologic variables, the Hamilton Depression Scale (Ham-D)16 and the Hopkins Symptom Checklist (HSCL-90).” As for statistical comparisons, we used the chi-square test for categorical variables and analysis of variance followed by Scheffe for continuous variables.

RESULTS Comparison of GAD With PD

The sex ratio in all anxiety categories showed female preponderance (Table 1). The index age for GAD (mean, 48.9) was significantly older than that for the three PD groups (mean, 38.3). Despite similar age of onset for all the anxiety groups (=30 years), the age of first treatment for the GAD group was significantly older than that in the three PD groups. These findings reflect the common clinical observation that the more symptomatic acute picture in PD leads to earlier and higher rates of treatment. This Table 1. Age Parameters in GAD Compared With PD, Panic Disorder With Limited Avoidance (PD-LIM), and Panic Disorder With Agoraphobia (PD-AGO) Mean (k SD) Age (vr) Index age Age at onset Age at first treatment*

GAD (n = 40)

(n LD37)

(npELYO)

PD-AGO (n = 85)

48.9 (10.2) 30.2 (12.3)

34.7 (9.8) 29.7 (8.7)

36.2 (11.6) 29.8 (11.9)

40.6 (11.9) 27.9 (10.5)

12.31 0.72

41.0 (13.2)

24.7 (14.4)

26.4 (14.3)

27.9 (15.5)

7.89

F (df =

3)

P .OOlT NS .05t

*As not all patients had sought treatment previously, the respective numbers were (in the order of the table) 29, 37,29, and 84. TScheffi test, GAD > all PD groups.

CLINICAL DELIMITATION

Table 2. Significant

OF GAD

411

items In the Sheehan Clinician Anxiety Rating Scale (SCRASS) GAD Compared With P D. PD-LIM. and PD-AGO

in

Meall GAD (n = 40)

(n

PD = 37)

PD-LIM (n = 30)

PD-AGO In = 85)

F Idf

=

3)

P

Scheffe

Unsteady feelings Na&Xla Headache Derealization Depersonalization

0.7 1.1 1.7 0.0 0.0

0.8 0.5 0.8 0.2 0.2

1.4 0.8 1.5 0.5 0.4

1.5 0.7 1.1 0.4 0.4

7.31 3.13 6.90 4.24 3.13

.OOl ,027 ,002 .006 ,027

GAD GAD GAD GAD GAD

< > > < <

Hypochondriasis Fear going crazy Fear of dying Dependence on others Early insomnia

0.6 0.1 0.1 0.2 1.0

1.4 0.5 1.6 0.2 0.4

1.3 1.1 1.6 1.3 0.5

1.3 1.2 1.8 2.8 0.3

5.21 8.75 19.16 123.79 6.43

,002 .OOl ,001 .OOl ,001

GAD GAD GAD GAD GAD

-C all < LIM, AGO < all < LIM. AGO < PD. AGO

Late insomnia Phobias

1.2 0.2

0.5 0.3

0.4 1.7

0.4 3.0

9.05 173.97

,001 ,001

GAD > all GAD < LIM. AGO

Tension AfXWy at interview

2.9

2.3

2.0

2.2

6.37

,001

GAD > LIM, AGO

1.2

0.6

0.5

0.7

6.23

.OO 1

GAD > all

AGO PD PD. AGO LIM, AGO AGO

was further supported by the significantly higher symptomatic picture in PD, contributed by seven of the 35 SCRAS items listed in Table 2; however, six items (anxiety at interview, nausea, headache, tension, early insomnia, late insomnia) were significantly higher in GAD. Life events linked by the patients to the onset of symptomatology were observed in 30% of GAD patients compared with 10% or less in the other groups (x2 = 15.30, df = 3, P < .Ol). On the DES measure (Table 3), work, social, family areas, and global disability did not discriminate GAD from PD, but both GAD and PD were significantly less impaired than PD with limited avoidance and agoraphobia. Comparison of GAD With Depression

Female preponderance in GAD (70%) and in recurrent and single depressive groups (79% and 66% respectively) were comparable. The same was true for index age; yet, as shown in Table 4, the age of onset was youngest in GAD and age of first treatment oldest in single episode depressives; recurrent depression was intermedi-

Table 3. Work and Social Adjustment in GAD Compared and PD-AGO

With Various PD. PD-LIM,

Mean (* SD)

Work impairment Social leisure impairment Family-home impairment Work/social disability ‘Scheffi tscheffi

GAD (n = 40)

(n pD37)

(npEL’!fO)

(R”=^“,“,)

2.8 (2.6)

3.1 (2.7)

4.5 (2.9)

5.7 (3.1)

11.86

,001”

2.7 (2.6)

3.1 (2.5)

4.8 (2.7)

6.3 (2.6)

23.55

.OOlf

2.5 (2.0

2.4 (1.9)

2.3 (1.9)

4.0 (2.7)

7.79

,001’

2.6 (1.2)

2.4 (0.9)

3.2 (0.8)

4.0 (0.8)

36.79

.001t

test: AGO > GAD. test: LIM, AGO > GAD.

F (df

=

3)

P

412

NISITA ET AL

Table 4. Age Parameters

in GAD Compared

With Major Depressive

Groups

Mean (SD)

Age (vr) Index age Age at onset Age at first treatment

GAD (n=40) 48.9 (10.2) 30.2 (12.3) 41 .O (13.2)

Recurrent Depression (n= 154)

Single-Episode Depression (n = 87)

52.3 (13.3) 36.8 (13.7) 38.2 (I 3.4)

49.6 (15.2) 47.9 (15.4) 49.1 (15.1)

F (df

=

2)

1.69 26.88 15.63

P NS .OOlT .OOl$

*Because not all patients had previously sought treatment, the respective numbers (in the order of the table) were 29, 148, and 77. TScheffi test: both depressive groups Y GAD. $Scheffi test: single-episode depression groups > GAD.

ate in these respects, but not significantly different from GAD, nor from singleepisode depressives. On Ham-D factors, except for sleep disturbance, GAD was significantly less symptomatic (anxiety-somatization, F = 9.56, df = 2, P -c .OOl; weight, F = 6.15, df = 2, P -c .OOl; cognitive disturbances, F = 16.90, df = 2, P < .OOl; diurnal variation, F = 4.57, df = 2, P < .Ol; retardation, F = 77.97, df = 2, P < .OOl). Table 5 summarizes those Ham-D items that contributed to this significance; almost all symptoms had higher values in depressed groups, but agitation, psychic, and somatic anxiety were selectively higher in GAD. On the HSCL-90 factors, only interpersonal sensitivity and anger-hostility were significantly higher in GAD, whereas depression was more common in the depressive groups (interpersonal sensitivity, F = 15.10; df = 2; P c; .OOl; depression, F = 20.89, df = 2, P c .OOl; anger-hostility, F = 19.42, df = 2, P < .OOl).

Table 5. Significant

Items on Ham-d in GAD Compared

With Major Depressive

Groups

Mean

Depressed mood Guilt Suicide Insomnia late Work Retardation Agitation Anxiety psychic Anxiety somatic Genital symptoms Weight history Derealization Paranoid Obsessive/compulsive Total

GAD (n = 40)

Recurrent Depression (n = 154)

Single Episode (n = 87)

0.7 0.0 0.0 0.5 0.5 0.0 1.3 2.9 2.6 0.9 0.1 0.0 0.0 0.1 14.8

2.4 0.9 0.9 1.1 2.5 1 .o 0.6 1.9 1.7 1.3 0.6 0.5 0.2 0.4 22.3

2.2 0.6 0.8 0.9 2.5 0.9 0.5 1.8 1.6 1.2 0.6 0.6 0.2 0.3 20.8

F (df

=

65.74 22.70 15.18 9.04 75.09 23.20 18.20 23.09 23.37 4.28 6.14 8.74 3.44 7.23 26.51

2)

P ,001 .oo1 ,001 .OOl .OOl ,001 ,001 .001+ .001* .Ol .002 .OOl .003t ,001 .OOl

*Significance for GAD > both groups of depressives;T significance for only GAD < recurrent depression; for all other comparisons GAD < both groups of depressives.

CLINICAL DELIMITATION

413

OF GAD

DISCUSSION The predominantly self-referred pattern in GAD versus the other groups and the predominantly outpatient setting of the anxiety and mood disorders represent current clinical realities. This is felicitous from a methodologic standpoint, because any differences between anxious and depressive groups are unlikely to be due to the greater clinical severity of the latter (i.e., inpatient melancholic episodes). The demographic and clinical data reported provide support for the distinction between GAD and PD. Age, time interval from onset of symptomatology to psychiatric consultation, and associated symptomatologic features were different in the two disorders. GAD showed a more protracted course with a longer time from onset of symptoms to psychiatric intervention. That GAD represents a chronic in disorder has been commented upon previously. 4.8~17First psychiatric consultation GAD is probably deferred because of the milder degree of symptoms that minimally interfered with social and work functioning. In symptomatologic comparisons, we confirmed the report of Hoehn-Saric and McLeod” in the higher prevalence of somatic symptoms such as gastrointestinal and muscular complaints in GAD; this difference was in part definitional. Panic-agoraphobic patients had a more florid symptomatologic picture, which was particularly striking in cognitive symptomatology. We also noted in GAD the absence of such symptoms as depersonalization and derealization-the presence of which is believed to reflect temporal lobe dysfunction2’-though again this was in part definitional. Life events, at onset of illness, were significantly more often reported by GAD patients. Our clinical impression is that individuals suffering from GAD tend to overestimate work difficulties and interpersonal losses to “explain” onset of symptoms. Sometimes they tend to connect the onset of their disturbances to psychosocial stress which occurred many years before onset. The causal relationship is difficult to assess because of the low-grade nature of GAD symptoms. Noyes et al.*’ suggested that personality vulnerability was an important factor in GAD compared with PD and agoraphobia, a position with which we concur. They further suggested that GAD could not be easily distinguished from an adjustment disorder. We favor an alternative interpretation according to which GAD patients have always been anxious individuals who become more symptomatic at stressful periods in their lives. As the anxious traits are part of the habitual self, they are not perceived as illness; suffering is experienced with symptomatic exacerbation of this habitual pattern and, therefore, they date the onset of their illness to such periods of exacerbation. This interpretation supports Akiskal’s8*9 conceptualization of GAD as an “anxious temperament,” and is in line with that of Barlow et al., who characterized GAD as one of chronic “apprehensive expectation” or chronic worrying. The relationship between GAD and Depression is more complex. Reviewing studies of anxiety neurosis and depressive illness, Breier et aI.” suggested that PD can be validly separated from depression, while symptoms of GAD contribute to the overlap between the two disorders. However, our data show that GAD is not characterized by core symptoms of depression such as guilt, suicidal ideation, psychomotor retardation, and loss of interest. Furthermore, in the absence of

414

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superimposed depression, impairment of work and loss of interest are generally mild. The finding of greater self-reported interpersonal sensitivity and anger-hostility in GAD versus depressive groups tends to support the suggestion that GAD is best conceptualized as a “trait” temperamental disorder. This trait nature of GAD may represent its core identity, providing partial validity; indeed, previous research by Breslau and Davis2’3 based on DSM-III definitions-or minor modifications thereof-that stipulated duration measured in months had shown considerable comoribidity and thereby had failed to establish validity. The distinctive clinical profile of GAD as reported here may be considered an artifact of selection in that patients with the disorder were included only if criteria for other disorders were not met. However, as the aim of the study was to examine the nature of GAD, this method is justified because dilution of GAD with adjacent disorders would not have led to meaningful comparisons with these adjacent disorders. In conclusion, our findings do support the existence of GAD in a relatively “pure” and “trait” form and its clinical differentiation from both depressive and panicagoraphobic disorders. In a more general way, our data tend to support the clinical differentiation of anxiety and depressive disorders.23*24This investigation undertaken on cross-sectional symptomatologic comparisons of GAD with panic and major depressive disorders is largely limited to the clinical distinction between these disorders, It is compatible with the position that significant overlap can exist between some anxiety and depressive disorders from a familial and follow-up standpoint. Thus, in many instances, GAD could represent the “milder” temperamental substrate or precursor of either panic or major depressive disorders.25 The pure GAD disorder will not typically occasion clinical consultation, unless superimposed by panic or depressive disorders. As conceptualized here, GAD is to PD what cyclothymia is to bipolar disorder.24 We are prospectively following up our GAD sample and will be in a position to test this hypothesis by observing longitudinal overlap with other anxiety and depressive disorders. ACKNOWLEDGMENT We thank Francesco Mengali for assistance in statistical analyses.

REFERENCES 1. American Psychiatric Association: Task Force on Nomenclature and Statistics: Diagnostic and Statistical Manual of Mental Disorders (ed 3). Washington, DC, American Psychiatric Association, 1980 2. Breslau N, Davis CC: Further evidence on the doubtful validity of generalized anxiety disorder. Psychiatry Res 16:177-179,1985 3. Breslau N, Davis CC: DSM-III generalized anxiety disorder: An empirical investigation of more stringent criteria. Psychiatry Res 15:231-238, 1985 4. Barlow DH, Blanchard EB, Vermilyea JA, et al: Generalized anxiety disorder: Description and reconceptualization. Am J Psychiatry 143:40-44, 1986 5. Klein DF: Anxiety reconceptualized, in Klein DF, Rabkin J (eds): Anxiety-New Research and Changing Concepts. New York, NY, Raven, 1981 6. Sheehan DV: The Anxiety Disease. New York, NY, Bantam, 1986 7. Cassano GB, Maggini C, Akiskal HS: Short-term, subchronic, and chronic sequelae of affective disorders, in Diagnosis and Treatment of Affective Disorders. Psychiatr Clin North Am Philadelphia, PA, Saunders, March, 1983

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8. Akiskal HS: Anxiety: Definition, relationship to depression and proposal for an integrative model, in Tuma AH, Maser JD (eds): Anxiety and Anxiety Disorders. New Jersey, Erlbaum, 1985 9. Akiskal HS: Personality in anxiety disorders. Psychiatr Psychobiol (in press) 10. American Psychiatric Association: Work Group to Revise DSM-III: Diagnostic and Statistical Manual of Mental Disorders (ed 3, revised). Washington, DC, American Psychiatric Association, 1987 I 1. Petracca A, Peru@ G, Cassano GB: Questionario per il Disturb0 da Attacchi di Panico. Istituto di Clinica Psichiatrica, Universita di Pisa, Italy, 1983 12. Cassano GB, Musetti L, Peru@ G, et al: Major depression subcategories: Their potentiality for clinical research, in Biziere S (ed): Diagnostic et Traitement de la Depression. Montpellier, France, Quo Vadis Symposium, 1987 13. Akiskal HS, Bitar AH, Puzantian VR, et al: The nosological status of neurotic depression: A prospective three-to-four year examination in light of the primary-secondary and unipolar-bipolar dichotomies. Arch Gen Psychiatry 35:756-755, 1978 14. ECDEU Assessment Manual. Washington, DC, US Department of Health, Education and Welfare, 1976 15. Klerman GL, Coleman JH, Purpura RP: The design and conduct of the Upjohn Cross-National Collaborative Panic Study. Psychopharmacol Bull 22:59-64,1987 16. Hamilton M: Development of a rating scale for primary depressive illness. Br J Sot Clin Psycho1 6:278-296, 1967 17. Anderson DJ, Noyes R Jr, Crowe RR: A comparison of panic disorder and generalized anxiety disorder. Am J Psychiatry 141:572-575, 1984 18. Derogatis LR, Lipman RS, Rickels K, et al: The Hopkins Symptom Checklist (HSCL): A self report symptom inventory. Behav Sci 19:1- 15, 1974 19. Hoehn-Sric R, McLeod D: Generalized anxiety disorder. Psychiatr Clin North Am 873-88, 1985 20. Cassano GB, Petracca A, Peru@ G, et al: Derealization and panic attacks: A clinical evaluation on 150 patients with panic disorder/agoraphobia. (in press) 21. Noyes R, Clarkson C, Crowe RR, et al: A family study of generalized anxiety disorder. Am J Psychiatry 144:1019-1024, 1987 22. Brier A, Charney DS, Henninger GR: The diagnostic validity of anxiety disorders and their relationship to depressive illness. Am J Psychiatry 142:787-797, 1985 23. Gurney C, Roth M, Garside RF, et al: Studies in the classification of affective disorders: The relationship between anxiety states and depressive illness. II. Br J Psychiatry 12 1:162- 166, 1972 24. Roth M, Gurney C, Garside RF, et al: Studies in the classification of affective disorders: The relationship between anxiety states and depressive illness. I. Br J Psychiatry 12 1:147- 161, 1972 25. Akiskal HS: Personality in anxiety disorders. Psychiatr Psychobiol 3:161s-166s 1988 26. Akiskal HS, Djenderedjian AH, Rosenthal RH, et al: Cyclothymic disorder: Validating criteria for inclusion in the bipolar affective group. Am J Psychiatry 134:1227-1233, 1977