- Email: [email protected]
Major depression in patients with panic disorder: factors associated with course and recurrence
Journal of Affective Disorders, 19 (1990) 287-296
287
Elsevier JAD 00732
Major depression in patients with panic disorder: factors associated with course and recurrence Murray B. Stein, Manuel E. Tancer and Thomas W. Uhde Section on Anxiety and Affective Disorders, Biological Psychiatry Branch, National Institute of Mental Health, Bethesda, MD, U.S.A.
(Received 3 November 1989) (Accepted 23 March 1990)
Summary The relationship between anxiety and depressive disorders has been the subject of considerable interest and controversy. In this study, the occurrence and course of affective illness was systematically examined in 63 patients meeting D S M - I I I - R criteria for panic disorder. Forty (63%) of the patients had experienced at least one major depressive episode. Of these, 13 (32.5%) experienced their first depressive episode prior to the onset of panic disorder, 15 (37.5%) experienced their first depressive episode after the onset of panic disorder, and in 12 (30.0%) the onset of the disorders was concurrent. Patients with agoraphobia had comparable rates of depression (68%) to patients without agoraphobia (53%, P = NS), and they had similar temporal patterns of depressive illness. Comorbidity with social phobia was associated with an increased longitudinal likelihood of major depression compared to patients without this comorbid diagnosis ( P < 0.05). Patients with longer duration of illness, early onset depression, melancholic depression, or family histories of anxiety or depression had an increased likelihood of having experienced recurrent depression. These findings are discussed in the context of c u r r e n t theories regarding the development of affective illness in patients with anxiety disorders.
K e y words." Depression; Panic disorder; Longitudinal; Phenomenology; Recurrence
Introduction Panic disorder is a common (Regier et al., 1988), frequently disabling (Markowitz et al., 1989) illness that has recently been shown to be associ-
Address for correspondence: Thomas W. Uhde, M.D., Chief, Section on Anxiety and Affective Disorders, Biological Psychiatry Branch, NIMH, 9000 RockvillePike, Bethesda, MD 20892, U.S.A.
ated with an increased risk for suicidal ideation and suicide attempts (Weissman et al., 1989). Clinicians have long been aware that depression occurs in patients with anxiety states (Mapother, 1926; Lewis, 1934; Roth, 1959), and the past decade has seen a large amount of research directed at further documenting and understanding the occurrence, course, and consequences of affective illness in patients with anxiety neurosis or panic disorder. Despite the existence of a substantial body of data that documents a longitudinal
0165-0327/90/$03.50 © 1990 Elsevier Science Publishers B.V. (Biomedical Division)
288
relationship between anxiety and depressive states, the precise nature of this relationship remains controversial. There is little doubt that clinically relevant depressions occur in patients with panic disorder. Beginning with the study of patients with "anxiety neurosis" (a group comprised of patients with generalized anxiety disorder and panic disorder) (Clancy et al., 1978; Cloninger et al., 1981; Schapira et al., 1972; Woodruff et al., 1972) and moving on to the study of patients with panic disorder a n d / o r agoraphobia (Aronson and Logue, 1987; Bowen and Kohout, 1979; Breier et al., 1984, 1985; Buller et al., 1986; Charney et al., 1986; Dealy et al., 1981; Lesser et al., 1988; Munjack and Moss, 1981; Nutzinger and Zapotoczky, 1985; Raskin et al., 1982; Van Valkenburg et al., 1984; Uhde et al., 1985), there appears to have emerged the general consensus that major depression occurs in anywhere from 35 to 91% of patients with panic disorder (Stein and Uhde, 1988), with a mean of around 50%. Differences in methodology, particularly in the choice of an index population (e.g., whether patients with primary or current major depression are to be included) may account for some of this large variance. Furthermore, little is known about factors that may be associated with various courses of affective illness, such as the relevance of primary versus secondary depressions in patients with panic disorder. Some investigators have suggested that panic disorder patients with secondary depression may be at greater risk for depressive chronicity and poor outcome than are panic patients with primary depression (Nutzinger and Kapotczky, 1985; Buller et al., 1986) while other investigators found few, if any, differences between these two subgroups (Breier et al., 1984, 1985). Still other investigators excluded patients with primary depression (e.g., Lesser et al., 1988), such that nothing could be said about that distinction. In this study, we systematically examined the prior occurrence and course of affective illness in a clinical sample of 63 patients with panic disorder. In addition to documenting the overall rate of depression in these patients, we examined a number of clinical characteristics that might be associated with depressive liability, as well as parameters that might be associated preferentially
with primary versus secondary depression, and recurrent versus nonrecurrent depression. We discuss our findings in the context of previous investigations on this topic, with special emphasis accorded the specific methodological constraints of our study.
Subjects and methods
Subjects Subjects were recruited through newspaper advertisements or through ongoing contacts with local mental health referral sources. Subjects were initially screened with written questionnaires, and then all were contacted by telephone. Those subjects who appeared, on the basis of this telephone contact, to be likely candidates for our studies were invited to come to the National Institute of Mental Health for a diagnostic interview by an experienced research psychiatrist using a modified version of the Schedule for Affective Disorders and Schizophrenia - Lifetime Version, Modified for the the Study of Anxiety Disorders (SADS-LA) (Fyer et al., 1985; Mannuzza et al., 1986); DSMIII-R diagnoses were applied. Exclusion criteria included the presence of any significant medical disorder, or the current presence of a major depressive episode. Therefore, the data presented in this report derive from consecutively evaluated individuals who presented for diagnostic interviews in our clinic between September 1987 and July 1989, who met current criteria for panic disorder (PD), but not for current major depression. Thirty-five of the 63 subjects in this study were included in our previous report investigating social anxiety in patients with panic disorder (Stein et al., 1989). In the current study, we investigated the occurrence and timing of lifetime episodes of major depression (MDE), according to DSM-III-R criteria. At the time of diagnostic interview, a battery of self-report data was collected. These measures included the Fear Questionnaire (FQ, Marks and Mathews, 1979), the Self-Rated Zung Anxiety Questionnaire (ZAS, Zung, 1971), the Social Avoidance and Distress Scale (SAD, Watson and Friend, 1969), and the Fear of Negative Evaluation Scale (FNE, Watson and Friend, 1969). In addition, the interviewer rated each subject's over-
289 all level of functional impairment from their psychiatric disorder on a five-point scale (1---no symptoms and normal activity; 2 = some symptoms are present, but they are not interfering with normal work or social activities; 3 = symptoms are interfering with normal work or social activities in minor ways; 4 = normal work or social activities interfered with markedly but not prevented or radically changed; 5 = normal work or social activities either radically changed or prevented) (Cooper, 1963). All patients in this study rated at least a " 2 " on this scale. Panic disorder patients also had their degree of phobic avoidance categorized as either being with agoraphobia (PDA, n = 43) or without agoraphobia (PDU, i.e., "uncomplicated", n = 20). In addition, the presence or absence of a concurrent diagnosis of social phobia was ascertained for each panic disorder patient, as described elsewhere (Stein et al., 1989). Concurrent diagnoses of obsessive-compulsive disorder and dysthymia were also determined, according to D S M - I I I - R criteria. Family histories of psychiatric illness were obtained by asking each subject about first-degree relatives with histories of depression, anxiety, or substance abuse. Since relatives were not directly interviewed, we attempted to increase our diagnostic precision by using a reported history of treatment as a criterion for determining a positive family history for depression or anxiety. For the diagnosis of a family history of substance abuse, however, a history of reported abuse and resultant psychosocial impairment was considered sufficient. In general, then, our insistence on a history of treatment in order to record a positive first-degree family history likely results in greater specificity and homogeneity of diagnosis, but at the cost of underestimating these rates (Andreason et al., 1977, 1986; Z i m m e r m a n et al., 1988). Major depressive episodes (MDE) occurring at any time during the patient's lifetime were diagnosed according to D S M - I I I - R criteria. If a patient had at least one episode of melancholia (according to Research Diagnostic Criteria (RDC, Spitzer et al., 1978) as elicited by the SADS-LA), then this was recorded. Patients who had greater than one lifetime episode of M D E were designated as having recurrent depression. Depressive episodes were classified as occurring prior to the
onset of PD if they occurred more than 6 months prior, concurrent if they occurred within 6 months before or after the onset of PD, and after the onset of PD if they occurred more than 6 months after. The 6 month interval was selected in an effort to diminish problems with recall about the sequence of events. Age of onset for PD was determined as the age at wlfich full diagnostic criteria were met. We did not feel that our diagnostic interview was sufficiently detailed to pinpoint the precise age of onset of PD when this occurred in childhood. Therefore, when onset was determined to be earlier than adolescence, this was arbitrarily recorded as age 12 for these analyses; this occurred in only three cases.
Statistical analysis Chi-square or Fisher's Exact Test were used to compare categorical data. Student's t-tests (twotailed) were used to compare normally distributed data between two groups; M a n n - W h i t n e y U-tests were alternatively used when a non-parametric test was more appropriate. Logistic regression analyses were also undertaken to identify factors associated with the occurrence of MDE, primary versus secondary depression, as well as the occurrence of recurrent depression. The analyses utilized an algorithm that enters or removes variables one at a time from this list of potential predictors (BMDP Statistical Software Package P2R, University of California Press, 1985). The criterion to enter a variable into the model was set at P < 0.1000, and to remove a variable was set at P < 0.1500. The characteristics entered into each analysis are described in the Results section. In all cases, data are reported as mean + standard deviation (SD). All P values greater than or equal to 0.10 are reported as " N S " whereas P values less than 0.10 are specifically reported. Sample sizes may vary for different analyses due to missing data. Results
Characteristics of the total sample The mean age of the 63 patients in the sample was 35.7 _ 8.4 (range: 20-59) years. The mean age
290 at onset of P D for the total s a m p l e was 27.2 _+ 9.9 (range: 1 2 - 5 2 ) years a n d the m e a n d u r a t i o n of illness was 8.4 + 7.8 (range: 1 - 4 2 ) years. F o r t y (63%) of the p a t i e n t s were female a n d 23 (37%) were male. F o r t y - t h r e e p a t i e n t s (68%) h a d P D A a n d 20 (32%) h a d P D U . T h i r t y - f o u r (77%) of the P D A p a t i e n t s were women, c o m p a r e d to six (30%) of the P D U p a t i e n t s (X 2 = 16.2, df= 1, P < 0.0005); i.e., w o m e n were m u c h m o r e likely t h a n men to be a g o r a p h o b i c . F o r t y - f o u r (70%) of the 63 p a t i e n t s h a d b e e n m a r r i e d , w h e r e a s 19 (30%) h a d never b e e n m a r r i e d ; P D A a n d P D U d i d not differ in this respect. T w e n t y - t h r e e (37%) of the p a t i e n t s h a d a global f u n c t i o n a l i m p a i r m e n t r a t i n g of 2 or 3, a n d 40 (63%) h a d a g l o b a l functional i m p a i r m e n t rating of 4 or 5; P D A p a t i e n t s were m o r e i m p a i r e d t h a n P D U p a t i e n t s (X 2 = 11.95, df= 1, P < 0.001). N i n e (14%) of the p a t i e n t s also met criteria for d y s t h y m i a , three (5%) m e t criteria for obsessivec o m p u l s i v e disorder, a n d 19 (30%) met criteria for social p h o b i a . Of the 19 p a t i e n t s w h o also m e t criteria for social p h o b i a , in 1 4 / 1 9 (74%) the social p h o b i a t e m p o r a l l y p r e c e d e d the onset of p a n i c disorder, a n d in 5 / 1 9 (26%) the reverse sequence was r e p o r t e d . F a m i l y history d a t a in first-degree relatives were available for 58 patients. Seventeen (29%) of the
p a t i e n t s gave f a m i l y histories of depression, 11 (19%) gave family histories of anxiety, a n d 20 (34%) gave f a m i l y histories of s u b s t a n c e abuse. P D A a n d P D U d i d n o t differ in these rates.
Rates and course of major depression in the total sample F o r t y (63%) of 63 P D p a t i e n t s h a d e x p e r i e n c e d at least one lifetime e p i s o d e of m a j o r d e p r e s s i o n (MDE). The chronological relationships between P D a n d M D E in the v a r i o u s s u b g r o u p s are detailed in T a b l e 1. F o u r t e e n (35%) of the p a t i e n t s with M D E h a d r e c u r r e n t d e p r e s s i o n , a n d 26 (65%) h a d non-recurrent depression. D a t a on the p r e s e n c e or absence of m e l a n c h o l i a were available in a subset of 26 p a t i e n t s with M D E ; of these, 17 (65%) h a d experienced at least one e p i s o d e of m e l a n c h o l i c depression a n d nine (35%) h a d not.
Comparison of PD patients with versus without a history of MDE E a c h of the p a r a m e t e r s listed in T a b l e 2 was c o m p a r e d for those p a t i e n t s with (n = 40) versus those w i t h o u t (n = 23) a lifetime history of m a j o r depression. T h e s e two s u b g r o u p s were c o m p a r a b l e in c u r r e n t age, age of onset, d u r a t i o n of illness, a n d global, a g o r a p h o b i a a n d b l o o d - i n j u r y subscale
TABLE 1 TEMPORAL RELATIONSHIP BETWEEN ONSET OF PANIC DISORDER AND ONSET OF FIRST EPISODE OF MAJOR DEPRESSION IN PATIENTS WITH PANIC DISORDER (n = 40)
N (% of total) Current age (years) Range Age at onset of PD (years) Range Duration of PD (years) Range Age at onset of major depression (years) Range Interval between onset of PD and onset of major depression (years) Range
First depressive episode prior to onset of PD
First depressive episode concurrent with onset of PD
First depressive episode after onset of PD
13 (32.5%) 37.4 + 11.3 20-59 28.8 +_11.9 16-52 8.5 ± 11.9 1-42
12 (30.0%) 34.2 + 9.5 22-50 27.8 ± 10.3 18-48 6.4 5:6.8 1-22
15 (37.5%) 35.5 _+7.3 23-49 23.7 + 9.4 12-43 11.8 + 7.6 1-26
23.6 + 12.6 12-48
27.8 ± 10.3 18-48
28.1 + 7.2 18-44
- 7.0 + 7.1 - 23- - 1
0 -
+ 5.4 + 4.4 1-12
291 TABLE 2 COMPARISON OF PANIC DISORDER PATIENTS WITH (n = 40) AND WITHOUT (n = 23) PAST MAJOR DEPRESSION
Current age (years) Age at PD onset (years) Duration of PD (years) Degree of global functional impairment (2-3) (4-5) Social Avoidance and Distress Fear of Negative Evaluation Fear Questionnaire (global) Fear Questionnaire (agoraphobia) Fear Questionnaire (social phobia) Fear Questionnaire (depression) Zung Anxiety
Without past MDE
With past MDE
35.7 ± 6.8 28.3 ± 8.5 7.3 ± 5.2
35.7___ 9.5 26.6 ± 10.5 9.1 ± 9.1
11/23 (48%) 12/23 (52%) 8.0± 7.4 12.6± 8.4 4.5 ± 1.9 13.9± 11.7 9.0± 6.7 2.9 ± 2.8 48.1 ± 10.5
12/40 (30%)] 28/40 (70%)-~ 12.5 ± 9.2 19.9± 8.4 4.7 ± 2.2 12.7± 9.7 12.2± 6.4 4.0 ± 2.2 56.0 ± 10.0
t
0.03 0.66 0.99 X2 = 2.00 1.91 3.06 0.06 0.40 1.80 N = 54 ~ 2.64
df
P<
61 61 61
NS NS NS
53 52 53 53 53
NS 0.07 0.004 NS NS 0.08 0.08 0.02
47
a Mann-Whitney U-test used.
scores on the F Q ( P = NS). H o w e v e r , the P D patients with a history of depression t e n d e d to score higher than P D patients w i t h o u t a history of depression on each of the measures p e r t a i n i n g to social and evaluative fear a n d anxiety: the S A D , F N E , and the social p h o b i a subscale of the F Q . T h e P D patients with a history of depression also
TABLE 3 VARIABLES CONSIDERED IN STEPWlSE LOGISTIC REGRESSION ANALYSES Categorical variables 1. Gender 2. Marital status 3. Presenceor absence of agoraphobia 4. Presence or absence of social phobia 5. Presenceor absence of dysthymia 6. Presenceor absence of obsessive-compulsive disorder 7. Family history of depression 8. Family history of anxiety 9. Family history of either depression or anxiety 10. Family history of substance abuse 11. Global functional impairment a 12. Primary or secondary depression 13. Recurrent or nonrecurrent depression 14. Melancholic or nonrnelancholic depression Continuous variables 15. Age at onset of panic disorder 16. Duration ill with panic disorder 17. Age at onset of first major depressive episode
a Dichotomized as "2 or 3" vs. "4 or 5".
scored h i g h e r on a m o r e global m e a s u r e of anxiety, the Z A S , an d t e n d e d to score higher on the depression subscale of the F Q . Characteristics that were entered into the stepwise logistic regression to identify factors associated with the o c c u r r e n c e of M D E i n c l u d e d variables 1 - 1 1 an d 1 5 - 1 6 as listed in T a b l e 3. Th e logistic regression revealed that the presence of c o m o r b i d social p h o b i a was the only variable associated with an increased rate of M D E (goodness of fit X 2 = 71.7, P < 0.07); 16 of 19 patients (84%) with c o m o r b i d social p h o b i a h ad e x p e r i e n c e d an M D E c o m p a r e d to 24 of 44 patients (55%) w i t h o u t this c o m o r b i d diagnosis. This association held eq u al l y true for patients whose social p h o b i a t e m p o r a l l y p r e c e d e d their p a n i c diso r d e r as for those w h o f o l l o w e d the reverse sequence.
P r i m a r y versus s e c o n d a r y d e p r e s s i o n T w e n t y - f i v e o f 40 (62.5%) patients h ad p r i m a r y depressions (which, for p u r p o s e s of this analysis, i n c l u d e d those patients w h o se first m a j o r depressive episode was p r i o r to or c o n c u r r e n t with the onset of p a n i c disorder) an d 15 (37.5%) had seco n d a r y depressions. In the p r i m a r y depressives the m e a n interval b e t w e e n the first M D E an d the onset of P D was 3.3 ___6.0 years (range: 0 - 2 3 ) whereas in the s e c o n d a r y depressives the m e a n
292 interval b e t w e e n the onset of P D a n d the first M D E was 5.4 + 4.4 years (range: 1 - 1 2 ) . W h e n p a t i e n t s having h a d p r i m a r y versus seco n d a r y d e p r e s s i o n were c o m p a r e d along all the p a r a m e t e r s used in T a b l e 2, the two g r o u p s were n o t f o u n d to significantly differ on a n y variable. Because we were a w a r e that our p r i m a r y c a t e g o r y was different f r o m the t r a d i t i o n a l (i.e., F e i g h n e r ) c o n c e p t a n d m a y have influenced our findings, we also c o m p a r e d all three groups (i.e., d e p r e s s i o n p r i o r to p a n i c onset, c o n c u r r e n t onset, a n d d e p r e s sion following p a n i c onset) separately. T h e three g r o u p s still were f o u n d to b e i n d i s t i n g u i s h a b l e a l o n g each of the d i m e n s i o n s e x a m i n e d . T h e stepwise logistic regression for i d e n t i f y i n g characteristics a s s o c i a t e d with p r i m a r y versus seco n d a r y d e p r e s s i o n s utilized all of the variables listed in T a b l e 3 (except for n u m b e r 12, the varia b l e u n d e r c o n s i d e r a t i o n ) . O n l y the severity of f u n c t i o n a l i m p a i r m e n t e m e r g e d as a relevant term, b u t even this h a d negligible classificatory value ( g o o d n e s s of fit X 2 = 49.49, P < 0.10); two of 12 p a t i e n t s (17%) w i t h low f u n c t i o n a l i m p a i r m e n t (i.e., scoring 2 or 3) h a d s e c o n d a r y depressions, c o m p a r e d to 13 of 28 p a t i e n t s (46%) with high functional i m p a i r m e n t (i.e., scoring 4 or 5). N o
o t h e r v a r i a b l e s were p r e f e r e n t i a l l y a s s o c i a t e d with p r i m a r y versus s e c o n d a r y depression. R e c u r r e n t versus nonrecurrent depressions
T a b l e 4 c o m p a r e s p a t i e n t s with a n d w i t h o u t r e c u r r e n t d e p r e s s i o n a l o n g a n u m b e r of b e h a v i o r a l d i m e n s i o n s . P a t i e n t s with r e c u r r e n t d e p r e s s i o n t e n d e d to have h a d an earlier age at onset of PD, to have b e e n ill with P D for a longer d u r a t i o n , a n d to have h a d their first depressive e p i s o d e at an earlier age. I n a d d i t i o n , a l t h o u g h the two subg r o u p s d i d n o t differ in their F Q a g o r a p h o b i a or g l o b a l subscale scores, n o r in Z A S scores, the r e c u r r e n t depressives scored m a r k e d l y higher on two of three m e a s u r e s of social a n d evaluative anxiety a n d a v o i d a n c e (i.e., the S A D a n d F Q social p h o b i a subscale, b u t n o t the F N E ) . C h a r a c t e r i s t i c s e n t e r e d into the logistic regression analysis i n c l u d e all those listed in T a b l e 3 ( e x c l u d i n g n u m b e r 13, the v a r i a b l e u n d e r consideration), a n d the results are s u m m a r i z e d in T a b l e s 5 A a n d 5B. T a b l e 5 A i n c l u d e d a history of m e l a n c h o l i a as a p o t e n t i a l p r e d i c t o r ; for this analysis d a t a were a v a i l a b l e for o n l y a subset (n = 24) of patients. T a b l e 5B e x c l u d e d a h i s t o r y of m e l a n c h o l i a as a p o t e n t i a l p r e d i c t o r , a n d conse-
TABLE 4 COMPARISON OF PANIC DISORDER PATIENTS WITH RECURRENT (n =14) VERSUS NONRECURRENT (n = 26) DEPRESSIONS
Current age (years) Age at PD onset (years) Duration of PD (years) Age at first MDE onset (years) Degree of global functional impairment (2-3) (4-5) Social Avoidance and Distress Feart of Negative Evaluation Fear Questionnaire (global) Fear Questionnaire (agoraphobia) Fear Questionnaire (social phobia) Fear Questionnaire (depression) Zung Anxiety
With Recurrent MDE
With Nonrecurrent MDE
t
df
P<
35.9± 9.8 22.8 _ 9.8 13.1 ± 10.6
35.7± 9.1 28.7 ± 10.4 7.0+ 7.5
0.07 1.73 2.10
38 38 38
NS 0.10 0.05
21.7 ± 10.0
29.0 ± 9.3
2.21
34
0.04
4/14 (29%) 10/14 (71%) 20.4_ 5.2 22,8_+ 8.2 4.5 ± 1.8 14.6+ 8.9 17.7 ± 4.8 4.7 + 1.8 59.4± 9.2
8/26 (31%)~ 18/26 (69%)1 9.0 ± 8.4 18.5_+ 8.4 4.6 ± 2.3 11.8±10.1 9.6 ± 5.4 3.7 + 2.3 54.3 ± 10.2
Fisher's Exact (two-tailed) 4.15 33 1.42 32 0.03 32 0.80 32 4.29 32 1.29 31 1.35 28
NS 0.0002 NS NS NS 0.0002 NS NS
293 T A B L E 5A S U M M A R Y O F STEPWISE LOGISTIC R E G R E S S I O N R E S U L T S F O R R E C U R R E N T D E P R E S S I O N a Step
term entered
number 1 2 3
Goodness
P
Correctly classified
of fit X2 Duration of illness Age at onset first M D E History of melancholia
21.03 9.74 0.00
0.52 0.98 1.00
Recurrent
Nonrecurrent
Total
44.4 77.8 88.9
86.7 93.3 93.3
70.8 87.5 91.7
Terms entered include all of 1-17 as shown in Table 3.
T A B L E 5B S U M M A R Y O F STEPWISE LOGISTIC R E G R E S S I O N RESULTS F O R R E C U R R E N T D E P R E S S I O N ~ Step number
Term entered
Goodness of fit X 2
P
Recurrent
Nonrecurrent
Total
1 2
Age at onset first M D E First degree family history of either anxiety or depression Duration of illness
32.56
0.3
54.5
91.3
79.4
25.33 20.54
0.75 0.90
54.5 72.7
87.0 82.6
76.5 79.4
3
,% Correctly classified
a Terms entered exclude melancholia (Table 3, item 14) from the analysis.
quently included the larger patient sample. These analyses, taken together, confirm the expected finding that duration of illness is associated with recurrence, as are early onset of depression, history of melancholia, and a first=degree family history of either depression or anxiety. Discussion
We found that 63% of the patients with panic disorder experienced at least one episode of major depression at some time during their course of illness to date. This rate would appear to be consistent with most studies in the literature, and serves as a reminder that depressive illness will ultimately occur in the majority of patients with panic disorder. Clinicians who treat patients with panic disorder would be well-advised to remain alert to the development of major depression in their patients. Our findings echo those of Weissman et al. (1989), who, in a much larger sample of subjects with panic disorder in the community, found that these individuals are at high risk for suicidal ideation and suicide attempts. Interest-
ingly, in that study (Weissman et al., 1989), the increased risk for suicidal ideation and attempts could not be explained on the basis of comorbidity with major depression. We will discuss this further when we come to the issue of depressive recurrences. In interpreting the rate of depression in our sample, it is important to note that we excluded subjects who currently met criteria for major depression. Prior studies of major depression in patients with panic disorder have each employed their own unique selection criteria, and this large variability in subject selection across studies renders much of the relevant literature on this topic difficult to interpret. In terms of our own data, it would be reasonable to expect that our exclusion of currently depressed individuals might result in an underestimation of the overall rates of depression, as well as the rates for recurrent depression. Consequently, our ~decision to exclude currently depressed individuals was not necessarily "good" or " b a d " , but must nonetheless be recognized as a characteristic of our study. Optimally, it would have been useful to have had a cohort of currently
294
depressed PD patients as a comparison group, and we~do intend to utilize this strategy in our upcoming studies. Another methodologic element that must be considered in the interpretation of our study and other studies in this field is the the question of when one defines the "onset" of illness. We chose to define onset of illness for PD as the time at which full diagnostic criteria were met. Obviously, then, this influenced our determination of depressive episodes as being either temporally primary or secondary. Several recent studies have suggested that patients with panic disorder may actually experience symptoms of their illness many years prior to their meeting full diagnostic criteria. Generalized anxiety (Garvey et al., 1988; Fava et al., 1988), phobic symptoms (Fava et al., 1988; Lelliott et al., 1989; Thompson et al., 1989), and childhood anxiety disorders such as overanxious disorder or separation anxiety disorder (Gittelman, 1986; Aronson and Logue, 1987) have all been reported to precede the onset of full-blown panic disorder. Thus, it could be argued that what we are designating as primary depression in relation to the onset of panic disorder, may not actually be primary in relation to the onset of these subsyndromal characteristics. A recent study, however, has shown that the retrospective determination of "subdisorder" anxiety symptoms (particularly generalized anxiety or " n e a r " panic attack symptoms) may be unreliable (Fyer et al., 1989). Therefore, while we would concur that the further study of subsyndromal symptoms as a prelude to panic a n d / o r depression is a worthwhile endeavor, we feel that our current demarcation of "onset of illness" is the most reliable estimate available given the current state of the an of retrospective psychiatric diagnosis. In this study, we were able to examine a number of clinical characteristics associated with depressive occurrence and subtypes (i.e., primary versus secondary, recurrent versus nonrecurrent). Of all the parameters examined in relation to the lifetime occurrence of major depression, only the comorbid presence of social phobia was associated with an increased rate. These findings in an expanded sample size continue to support our earlier observations (Stein et al., 1989). Factors such as severity of illness, degree of agoraphobic avoid-
ance, and duration of illness - all of which might reasonably be thought to increase the liability for depression if depression was a natural consequence of or a reaction to the demoralizing effects of chronic anxiety - seemed to carry little weight in determining why and when some patients with panic disorder become depressed. Other factors which we examined, such as gender or family history, did not serve to enlighten us in this respect. The impact of life events (Roy-Byrne et al., 1986), which this study was not designed to assess, clearly merits further prospective study, as does the continued examination of factors reported to be associated with poorer outcome (particularly with respect to more frequent or severe depressive episodes) such as personality disorders (Reich, 1988) or obsessive-compulsive features (Mellman and Uhde, 1987). When we examined the issue of primary versus secondary depressions, like Buller et al. (1986) we failed to find significant distinguishing characteristics on a cross-sectional basis. Similarly, Van Valkenburg et al. (1984), in a naturalistic outcome study, found that PD patients with primary or secondary depression both did equally poorly (compared to PD patients without a history of depression). Several investigators have, however, found that patients with secondary depression have a higher incidence of depressive episodes at follow-up (Buller et al., 1986) or are more likely to exhibit chronic depressions and generally poorer outcome (Nutzinger and Zapotczky, 1985). Therefore, the primary vs. secondary distinction may indeed have prognostic implications, and should be further studied despite our predominantly negative findings here. In contrast to our inability to discriminate between primary and secondary depressives, we found that several variables seemed to distinguish between those patients who did and did not experience recurrent depressive episodes. For the PD patients with recurrent depressive episodes, many of the factors that one might logically assume to cluster with a more severe variant of illness (or, perhaps, with a biological predisposition), such as positive family history or presence of melancholia, were found in the patients with recurrent depression. In fact, while 10 of 17 patients with histories of melancholia experienced recurrent depressive
295 episodes, none of the p a t i e n t s w i t h o u t histories of m e l a n c h o l i a h a d recurrences. This finding suggests that it m a y be r e a s o n a b l e for clinicians to r o u t i n e l y d e t e r m i n e whether or n o t their P D p a t i e n t s have h a d melancholia, as this may, if c o n f i r m e d in p r o s p e c t i v e studies, have clinical utility in p r e d i c t ing a greater l i k e l i h o o d of depressive recurrence(s). S o m e w h a t unexpectedly, we f o u n d that the recurrent depressives scored a b o u t twice as high on two i n d e p e n d e n t measures of social anxiety a n d a v o i d a n c e (i.e., the S A D a n d the F Q social p h o b i a subscale; T a b l e 5). This suggests either that those p a r t i c u l a r traits (i.e., social anxiety a n d a v o i d a n c e ) p r e d i s p o s e to recurrent depression, or, alternatively, that these r e p r e s e n t the outcome of recurrent depressive episodes a n d / o r longer d u r a t i o n of p a n i c illness. W h i l e this association w o u l d seem to be of c o n s i d e r a b l e interest, o u r d a t a d o not allow us to infer a n y n o t i o n of causality; this is, however, deserving of further study. In addition, n o t surprisingly, recurrent depression was associated with longer d u r a t i o n of illness a n d earlier age at onset of first depressive episode. This latter o b s e r v a t i o n is of p a r t i c u l a r interest, since earlier age at onset (of p a n i c disorder, in this case) was a s s o c i a t e d with increased risk for suicidal i d e a t i o n a n d a t t e m p t s in the s t u d y b y W e i s s m a n et al. (1989). W h i l e those a u t h o r s were able to c o n t r o l for the o c c u r r e n c e of m a j o r d e p r e s s i o n as a risk factor, they d i d not c o n t r o l for recurrent depressive episodes n o r d i d they e x a m i n e the possible effect of early versus late onset depressions. Thus, it is possible that the increased risk for suicidal i d e a t i o n a n d a t t e m p t s seen in p a t i e n t s with early onset p a n i c d i s o r d e r m a y be m e d i a t e d t h r o u g h an i n c r e a s e d likelihood of r e c u r r e n t or early onset depressive episodes. This hypothesis r e m a i n s to be tested in future studies. In a d d i t i o n to the c o m m e n t s we have m a d e above, a n u m b e r of other m e t h o d o l o g i c a l issues related to our c u r r e n t s t u d y a n d previous investigations in this a r e a deserve attention. First, o u r subjects r e p r e s e n t e d a clinical p o p u l a t i o n seeking treatment, a n d we would, therefore, expect o u r p a t i e n t s to be m o r e severely ill t h a n those individuals with P D in the c o m m u n i t y who d o n o t seek treatment. F o r this reason, conclusions r e a c h e d here m a y n o t be a p p l i c a b l e to the total p o p u l a t i o n
of i n d i v i d u a l s with PD. Second, while we a n d o t h e r a u t h o r s refer to the lifetime o c c u r r e n c e of depressive illness, it s h o u l d be u n d e r s c o r e d that we are a c t u a l l y referring to a t r u n c a t e d p e r i o d of o b s e r v a t i o n . T h a t is, m o s t of the p a t i e n t s s t u d i e d are in their third t h r o u g h fifth d e c a d e s of life, a n d have yet to p a s s t h r o u g h the entire p e r i o d of risk for depressive disorders. So, while our observations can i l l u m i n a t e s o m e of the factors that m a y b e a s s o c i a t e d with the l o n g i t u d i n a l o c c u r r e n c e of affective illness in these relatively y o u n g patients, further studies that follow a c o h o r t of P D p a t i e n t s prospectively over an e x t e n d e d p e r i o d of time are needed and would constitute a major improvem e n t over the m e t h o d o l o g y e m p l o y e d here.
Acknowledgement The a u t h o r s wish to a c k n o w l e d g e the statistical c o n s u l t a t i o n of J o h n Bartko, Ph.D.
References Andreason, N.C., Endicott, J., Spitzer, R.L. and Winokur, G. (1977) The family history method using diagnostic criteria. Arch. Gen. Psychiatry 34, 1229-1235. Andreason, N.C., Rice, J., Endicott, J. et al. (1986) The family history approach to diagnosis: how useful is it? Arch. Gen. Psychiatry 43, 421-429. Aronson, T.A. and Logne, C.M. (1987) On the longitudinal course of panic disorder: developmental history and predictors of phobic complications. Compr. Psychiatry 28, 344355. Breier, A., Charney, D.S. and Heninger, G.R. (1984) Major depression in patients with agoraphobia and panic disorder. Arch. Gen. Psychiatry 41, 1129-1135. Breier, A., Charney, D.S. and Heninger, G.R. (1985) The diagnostic validity of anxiety disorders and their relationship to depressive illness. Am. J. Psychiatry 142, 787-797. Bowen, R.C. and Kohout, J. (1979) The relationship between agoraphobia and primary affective disorders. Can. J. Psychiatry 24, 317-321. Buller, R., Maier, W. and Benkert, O. (1986) Clinical subtypes in panic disorder: their descriptive and prospective validity. J. Affect. Disord. 11,105-114. Charney, D.S., Heninger, G.R., Price, L.H. and Breier, A. (1986) Major depression and panic disorder: diagnostic and neurobiological relationship. Psychopharmacol. Bull. 22, 503-511. Clancy, J., Noyes, R., Hoenk, P.R. and Slymen, D.J. (1978) Secondary depression in anxiety neurosis. J. Nerv. Ment. Dis. 166, 846-850. Clayton, P.J. (1983) The prevalence and course of the affective disorders. In: J.M. Davis and J.W. Maas (Eds.), The Affective Disorders. American Psychiatric Press, Washington, DC, pp. 193-201.
296 Cloninger, C.R., Martin, R.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: Anxiety: New Research and Changing Concepts, pp. 137148. Cooper, J.E. (1963) A study of behaviour therapy in 30 psychiatric patients. Lancet i, 411-415. Dealy, R.S., Ishiki, D,M., Avery, D.H., Wilson, L.G. and Dunner, D.L. (1981) Secondary depression in anxiety disorders. Compr. Psychiatry 22, 612-618. Endicott, J. and Spitzer, R.L. (1978) A diagnostic interview: the Schedule for Affective Disorders and Schizophrenia. Arch. Gen. Psychiatry 35, 837-844. Fava, G.A., Grandi, S. and Canestrari, R. (1988) Prodromal symptoms in panic disorder with agoraphobia. Am. J. Psychiatry 145, 1564-1567. Fyer, A.J., Endicott, J., Mannuzza, S. and Klein, D.F. (1985) Schedule for Affective Disorders and Schizophrenia: Lifetime Version. (Modified for the study of anxiety disorders.) Anxiety Disorders Clinic, New York State Psychiatric Institute, New York, NY. Fyer, A.J., Mannuzza, S., Martin, L.Y., Gallops, M.S., Endicott, J., Schleyer, B., Gorman, J.M., Liebowitz, M.R. and Klein, D.F. (1989) Reliability of anxiety assessment. II. Symptom agreement. Arch. Gen. Psychiatry 46, 1102-1110. Garvey, M.J., Cook, B. and Noyes, R. Jr. (1988) The occurrence of a prodrome of generalized anxiety in panic disorder. Compr. Psychiatry 29, 445-449. Gittelman, R. (1986) Childhood anxiety disorders: correlates and outcome. In: R. Gittelman (Ed.), Anxiety Disorders of Childhood. Guilford, New York, NY, pp. 101-125. Lelliott, P., Marks, I.M., McNamee, G. and Tobena, A. (1989) Onset of panic disorder with agoraphobia. Arch. Gen. Psychiatry 46, 1000-1004. Lesser, I.M., Rubin, R.T., Pecknold, J.C., Rifldn, A., Swinson, R.P., Lydiard, R.B., Burrows, G.D., Noyes, R. and DuPont, R.L. Jr. (1988) Secondary depression in panic disorder and agoraphobia. I. Frequency, severity, and response to treatment. Arch. Gen. Psychiatry 45, 437-443. Lewis, A.J. (1934) Melancholia - A clinical survey of depressive states. J. Ment. Sci. 80, 277-378. Mannuzza, S., Fyer, A.J., Klein, D.F. and Endicott, J. (1986) Schedule for Affective Disorders and Schizophrenia - Lifetime version (modified for the study of anxiety disorders): rationale and conceptual development. J. Psychiatr. Res. 20, 317-325. Mapother, E. (1926) DiscuSsion on manic-depressive psychosis. Br. Med. J. I, 225-227. Markowitz, J.S., Weissman, M.M., Ouellette, R., Lish, J.D. and Klerman G.L, (1989) Quality of life in panic disorder. Arch. Gen. Psychiatry 46, 984-992. Marks, I.M. and Mathews, A.M. (1979) Brief standard self-rating for phobic patients. Behav. Res. Ther. 17, 263-267. Mellman, T.A. and Uhde, T.W. (1987) Obsessive-compulsive symptoms in panic disorder. Am. J. Psychiatry 144, 15731576. Munjack, D.J. and Moss, H.B. (1981) Affective disorder and alcoholism in families of agoraphobics. Arch. Gen. Psychiatry 38, 869-871.
Nutzinger, D.O. and Zapotoczky, H,G. (1985) The influence of depression on the outcome of cardiac phobia (panic disorder). Psychopathology 18, 155-162. Raskin, M., Peeke, H.V.S., Dickman, W. and Pinsker, H. (1982) Panic and generalized anxiety disorders: developmental antecedents and precipitants. Arch. Gen. Psychiatry 39, 687-689. Regier, D.A., Boyd, J.H., Burke, J.D. Jr., Rae, D.S., Myers, J.K., Kramer, M., Robins, L.N., George, L.K., Karno, M. and Locke, B.Z. (1988) One month prevalence of mental disorders in the United States. Arch. Gen. Psychiatry 45, 977-986. Reich, J.H. (1988) DSM-II1 personality disorders and the outcome of treated panic disorder. Am. J. Psychiatry 145, 1149-1152. Roth, M. (1959) The phobic anxiety-depersonalization syndrome. Proc. R. Soc. Med. 52, 587-595. Roy-Byrne, P.P., Geraci, M. and Uhde, T.W. (1986) Life events and course of illness in patients with panic disorder. Am. J. Psychiatry 143, 1033-1035. Schapira, K., Roth, M., Kerr, T.A. and Gurney, C. (1972) The prognosis of affective disorders: the differentiation of anxiety states from depressive illnesses. Br. J. Psychiatry 121,175-181. Spitzer, R.L., Endicott, J. and Robins, E. (1978) Research Diagnostic Criteria: rationale and reliability. Arch. Gen. Psychiatry 35, 773-782. Stein, M.B. and Uhde, T.W. (1988) Panic disorder and major depression: a tale of two syndromes. Psychiatr. Clin. N. Am. 11,441-461. Stein, M.B., Shea, C.A. and Uhde, T.W. (1989) Social phobic symptoms in patients with panic disorder: clinical and theoretical imphcations. Am. J. Psychiatry 146, 235-238. Thompson, A.H., Bland, R.C. and Orn, H.T. (1989) Relationship and chronology of depression, agoraphobia, and panic disorder in the general population. J. Nerv. Ment. Dis. 177, 456-463. Uhde, T.W., Boulenger, J.-P., Roy-Byrne, P.P., Vittone, B.J. and Post, R.M. (1985) Longitudinal course of panic disorder: clinical and biological considerations. Prog. Neuropsychopharmacol. Biol. Psychiatry 9, 39-51. Van Valkenburg, C., Akiskal, H.S., Puzantian, V. and Rosenthal, T. (1984) Anxious depressions: clinical, family history, and naturalistic outcome. Comparisons with panic and major depressive disorders. J. Affect. Disord. 6, 67-82 Watson, D. and Friend, R. (1969) Measurement of socialevaluative anxiety. J. Consult. Clin. Psychol. 33, 448-457. Weissman, M.M., Klerman, G.L., Markowitz, J.S. and Ouellette, R. (1989) Suicidal ideation and suicide attempts in panic disorder and panic attacks. N. Engl. J. Med. 321, 1209-1214. Woodruff, R.A., Guze, S.B. and Clayton, P.J. (1972) Anxiety neurosis among psychiatric outpatients. Compr. Psychiatry 13, 165-170. Zirnmerman, M., Coryell, W., Pfohl, B. and Stangl, D. (1988) The reliability of the family history method for psychiatric diagnoses. Arch. Gen, Psychiatry 45, 320-322. Zung, W.W.K. (1971) A rating instrument for anxiety disorders. Psychosomatics 12, 371-379.
287
Elsevier JAD 00732
Major depression in patients with panic disorder: factors associated with course and recurrence Murray B. Stein, Manuel E. Tancer and Thomas W. Uhde Section on Anxiety and Affective Disorders, Biological Psychiatry Branch, National Institute of Mental Health, Bethesda, MD, U.S.A.
(Received 3 November 1989) (Accepted 23 March 1990)
Summary The relationship between anxiety and depressive disorders has been the subject of considerable interest and controversy. In this study, the occurrence and course of affective illness was systematically examined in 63 patients meeting D S M - I I I - R criteria for panic disorder. Forty (63%) of the patients had experienced at least one major depressive episode. Of these, 13 (32.5%) experienced their first depressive episode prior to the onset of panic disorder, 15 (37.5%) experienced their first depressive episode after the onset of panic disorder, and in 12 (30.0%) the onset of the disorders was concurrent. Patients with agoraphobia had comparable rates of depression (68%) to patients without agoraphobia (53%, P = NS), and they had similar temporal patterns of depressive illness. Comorbidity with social phobia was associated with an increased longitudinal likelihood of major depression compared to patients without this comorbid diagnosis ( P < 0.05). Patients with longer duration of illness, early onset depression, melancholic depression, or family histories of anxiety or depression had an increased likelihood of having experienced recurrent depression. These findings are discussed in the context of c u r r e n t theories regarding the development of affective illness in patients with anxiety disorders.
K e y words." Depression; Panic disorder; Longitudinal; Phenomenology; Recurrence
Introduction Panic disorder is a common (Regier et al., 1988), frequently disabling (Markowitz et al., 1989) illness that has recently been shown to be associ-
Address for correspondence: Thomas W. Uhde, M.D., Chief, Section on Anxiety and Affective Disorders, Biological Psychiatry Branch, NIMH, 9000 RockvillePike, Bethesda, MD 20892, U.S.A.
ated with an increased risk for suicidal ideation and suicide attempts (Weissman et al., 1989). Clinicians have long been aware that depression occurs in patients with anxiety states (Mapother, 1926; Lewis, 1934; Roth, 1959), and the past decade has seen a large amount of research directed at further documenting and understanding the occurrence, course, and consequences of affective illness in patients with anxiety neurosis or panic disorder. Despite the existence of a substantial body of data that documents a longitudinal
0165-0327/90/$03.50 © 1990 Elsevier Science Publishers B.V. (Biomedical Division)
288
relationship between anxiety and depressive states, the precise nature of this relationship remains controversial. There is little doubt that clinically relevant depressions occur in patients with panic disorder. Beginning with the study of patients with "anxiety neurosis" (a group comprised of patients with generalized anxiety disorder and panic disorder) (Clancy et al., 1978; Cloninger et al., 1981; Schapira et al., 1972; Woodruff et al., 1972) and moving on to the study of patients with panic disorder a n d / o r agoraphobia (Aronson and Logue, 1987; Bowen and Kohout, 1979; Breier et al., 1984, 1985; Buller et al., 1986; Charney et al., 1986; Dealy et al., 1981; Lesser et al., 1988; Munjack and Moss, 1981; Nutzinger and Zapotoczky, 1985; Raskin et al., 1982; Van Valkenburg et al., 1984; Uhde et al., 1985), there appears to have emerged the general consensus that major depression occurs in anywhere from 35 to 91% of patients with panic disorder (Stein and Uhde, 1988), with a mean of around 50%. Differences in methodology, particularly in the choice of an index population (e.g., whether patients with primary or current major depression are to be included) may account for some of this large variance. Furthermore, little is known about factors that may be associated with various courses of affective illness, such as the relevance of primary versus secondary depressions in patients with panic disorder. Some investigators have suggested that panic disorder patients with secondary depression may be at greater risk for depressive chronicity and poor outcome than are panic patients with primary depression (Nutzinger and Kapotczky, 1985; Buller et al., 1986) while other investigators found few, if any, differences between these two subgroups (Breier et al., 1984, 1985). Still other investigators excluded patients with primary depression (e.g., Lesser et al., 1988), such that nothing could be said about that distinction. In this study, we systematically examined the prior occurrence and course of affective illness in a clinical sample of 63 patients with panic disorder. In addition to documenting the overall rate of depression in these patients, we examined a number of clinical characteristics that might be associated with depressive liability, as well as parameters that might be associated preferentially
with primary versus secondary depression, and recurrent versus nonrecurrent depression. We discuss our findings in the context of previous investigations on this topic, with special emphasis accorded the specific methodological constraints of our study.
Subjects and methods
Subjects Subjects were recruited through newspaper advertisements or through ongoing contacts with local mental health referral sources. Subjects were initially screened with written questionnaires, and then all were contacted by telephone. Those subjects who appeared, on the basis of this telephone contact, to be likely candidates for our studies were invited to come to the National Institute of Mental Health for a diagnostic interview by an experienced research psychiatrist using a modified version of the Schedule for Affective Disorders and Schizophrenia - Lifetime Version, Modified for the the Study of Anxiety Disorders (SADS-LA) (Fyer et al., 1985; Mannuzza et al., 1986); DSMIII-R diagnoses were applied. Exclusion criteria included the presence of any significant medical disorder, or the current presence of a major depressive episode. Therefore, the data presented in this report derive from consecutively evaluated individuals who presented for diagnostic interviews in our clinic between September 1987 and July 1989, who met current criteria for panic disorder (PD), but not for current major depression. Thirty-five of the 63 subjects in this study were included in our previous report investigating social anxiety in patients with panic disorder (Stein et al., 1989). In the current study, we investigated the occurrence and timing of lifetime episodes of major depression (MDE), according to DSM-III-R criteria. At the time of diagnostic interview, a battery of self-report data was collected. These measures included the Fear Questionnaire (FQ, Marks and Mathews, 1979), the Self-Rated Zung Anxiety Questionnaire (ZAS, Zung, 1971), the Social Avoidance and Distress Scale (SAD, Watson and Friend, 1969), and the Fear of Negative Evaluation Scale (FNE, Watson and Friend, 1969). In addition, the interviewer rated each subject's over-
289 all level of functional impairment from their psychiatric disorder on a five-point scale (1---no symptoms and normal activity; 2 = some symptoms are present, but they are not interfering with normal work or social activities; 3 = symptoms are interfering with normal work or social activities in minor ways; 4 = normal work or social activities interfered with markedly but not prevented or radically changed; 5 = normal work or social activities either radically changed or prevented) (Cooper, 1963). All patients in this study rated at least a " 2 " on this scale. Panic disorder patients also had their degree of phobic avoidance categorized as either being with agoraphobia (PDA, n = 43) or without agoraphobia (PDU, i.e., "uncomplicated", n = 20). In addition, the presence or absence of a concurrent diagnosis of social phobia was ascertained for each panic disorder patient, as described elsewhere (Stein et al., 1989). Concurrent diagnoses of obsessive-compulsive disorder and dysthymia were also determined, according to D S M - I I I - R criteria. Family histories of psychiatric illness were obtained by asking each subject about first-degree relatives with histories of depression, anxiety, or substance abuse. Since relatives were not directly interviewed, we attempted to increase our diagnostic precision by using a reported history of treatment as a criterion for determining a positive family history for depression or anxiety. For the diagnosis of a family history of substance abuse, however, a history of reported abuse and resultant psychosocial impairment was considered sufficient. In general, then, our insistence on a history of treatment in order to record a positive first-degree family history likely results in greater specificity and homogeneity of diagnosis, but at the cost of underestimating these rates (Andreason et al., 1977, 1986; Z i m m e r m a n et al., 1988). Major depressive episodes (MDE) occurring at any time during the patient's lifetime were diagnosed according to D S M - I I I - R criteria. If a patient had at least one episode of melancholia (according to Research Diagnostic Criteria (RDC, Spitzer et al., 1978) as elicited by the SADS-LA), then this was recorded. Patients who had greater than one lifetime episode of M D E were designated as having recurrent depression. Depressive episodes were classified as occurring prior to the
onset of PD if they occurred more than 6 months prior, concurrent if they occurred within 6 months before or after the onset of PD, and after the onset of PD if they occurred more than 6 months after. The 6 month interval was selected in an effort to diminish problems with recall about the sequence of events. Age of onset for PD was determined as the age at wlfich full diagnostic criteria were met. We did not feel that our diagnostic interview was sufficiently detailed to pinpoint the precise age of onset of PD when this occurred in childhood. Therefore, when onset was determined to be earlier than adolescence, this was arbitrarily recorded as age 12 for these analyses; this occurred in only three cases.
Statistical analysis Chi-square or Fisher's Exact Test were used to compare categorical data. Student's t-tests (twotailed) were used to compare normally distributed data between two groups; M a n n - W h i t n e y U-tests were alternatively used when a non-parametric test was more appropriate. Logistic regression analyses were also undertaken to identify factors associated with the occurrence of MDE, primary versus secondary depression, as well as the occurrence of recurrent depression. The analyses utilized an algorithm that enters or removes variables one at a time from this list of potential predictors (BMDP Statistical Software Package P2R, University of California Press, 1985). The criterion to enter a variable into the model was set at P < 0.1000, and to remove a variable was set at P < 0.1500. The characteristics entered into each analysis are described in the Results section. In all cases, data are reported as mean + standard deviation (SD). All P values greater than or equal to 0.10 are reported as " N S " whereas P values less than 0.10 are specifically reported. Sample sizes may vary for different analyses due to missing data. Results
Characteristics of the total sample The mean age of the 63 patients in the sample was 35.7 _ 8.4 (range: 20-59) years. The mean age
290 at onset of P D for the total s a m p l e was 27.2 _+ 9.9 (range: 1 2 - 5 2 ) years a n d the m e a n d u r a t i o n of illness was 8.4 + 7.8 (range: 1 - 4 2 ) years. F o r t y (63%) of the p a t i e n t s were female a n d 23 (37%) were male. F o r t y - t h r e e p a t i e n t s (68%) h a d P D A a n d 20 (32%) h a d P D U . T h i r t y - f o u r (77%) of the P D A p a t i e n t s were women, c o m p a r e d to six (30%) of the P D U p a t i e n t s (X 2 = 16.2, df= 1, P < 0.0005); i.e., w o m e n were m u c h m o r e likely t h a n men to be a g o r a p h o b i c . F o r t y - f o u r (70%) of the 63 p a t i e n t s h a d b e e n m a r r i e d , w h e r e a s 19 (30%) h a d never b e e n m a r r i e d ; P D A a n d P D U d i d not differ in this respect. T w e n t y - t h r e e (37%) of the p a t i e n t s h a d a global f u n c t i o n a l i m p a i r m e n t r a t i n g of 2 or 3, a n d 40 (63%) h a d a g l o b a l functional i m p a i r m e n t rating of 4 or 5; P D A p a t i e n t s were m o r e i m p a i r e d t h a n P D U p a t i e n t s (X 2 = 11.95, df= 1, P < 0.001). N i n e (14%) of the p a t i e n t s also met criteria for d y s t h y m i a , three (5%) m e t criteria for obsessivec o m p u l s i v e disorder, a n d 19 (30%) met criteria for social p h o b i a . Of the 19 p a t i e n t s w h o also m e t criteria for social p h o b i a , in 1 4 / 1 9 (74%) the social p h o b i a t e m p o r a l l y p r e c e d e d the onset of p a n i c disorder, a n d in 5 / 1 9 (26%) the reverse sequence was r e p o r t e d . F a m i l y history d a t a in first-degree relatives were available for 58 patients. Seventeen (29%) of the
p a t i e n t s gave f a m i l y histories of depression, 11 (19%) gave family histories of anxiety, a n d 20 (34%) gave f a m i l y histories of s u b s t a n c e abuse. P D A a n d P D U d i d n o t differ in these rates.
Rates and course of major depression in the total sample F o r t y (63%) of 63 P D p a t i e n t s h a d e x p e r i e n c e d at least one lifetime e p i s o d e of m a j o r d e p r e s s i o n (MDE). The chronological relationships between P D a n d M D E in the v a r i o u s s u b g r o u p s are detailed in T a b l e 1. F o u r t e e n (35%) of the p a t i e n t s with M D E h a d r e c u r r e n t d e p r e s s i o n , a n d 26 (65%) h a d non-recurrent depression. D a t a on the p r e s e n c e or absence of m e l a n c h o l i a were available in a subset of 26 p a t i e n t s with M D E ; of these, 17 (65%) h a d experienced at least one e p i s o d e of m e l a n c h o l i c depression a n d nine (35%) h a d not.
Comparison of PD patients with versus without a history of MDE E a c h of the p a r a m e t e r s listed in T a b l e 2 was c o m p a r e d for those p a t i e n t s with (n = 40) versus those w i t h o u t (n = 23) a lifetime history of m a j o r depression. T h e s e two s u b g r o u p s were c o m p a r a b l e in c u r r e n t age, age of onset, d u r a t i o n of illness, a n d global, a g o r a p h o b i a a n d b l o o d - i n j u r y subscale
TABLE 1 TEMPORAL RELATIONSHIP BETWEEN ONSET OF PANIC DISORDER AND ONSET OF FIRST EPISODE OF MAJOR DEPRESSION IN PATIENTS WITH PANIC DISORDER (n = 40)
N (% of total) Current age (years) Range Age at onset of PD (years) Range Duration of PD (years) Range Age at onset of major depression (years) Range Interval between onset of PD and onset of major depression (years) Range
First depressive episode prior to onset of PD
First depressive episode concurrent with onset of PD
First depressive episode after onset of PD
13 (32.5%) 37.4 + 11.3 20-59 28.8 +_11.9 16-52 8.5 ± 11.9 1-42
12 (30.0%) 34.2 + 9.5 22-50 27.8 ± 10.3 18-48 6.4 5:6.8 1-22
15 (37.5%) 35.5 _+7.3 23-49 23.7 + 9.4 12-43 11.8 + 7.6 1-26
23.6 + 12.6 12-48
27.8 ± 10.3 18-48
28.1 + 7.2 18-44
- 7.0 + 7.1 - 23- - 1
0 -
+ 5.4 + 4.4 1-12
291 TABLE 2 COMPARISON OF PANIC DISORDER PATIENTS WITH (n = 40) AND WITHOUT (n = 23) PAST MAJOR DEPRESSION
Current age (years) Age at PD onset (years) Duration of PD (years) Degree of global functional impairment (2-3) (4-5) Social Avoidance and Distress Fear of Negative Evaluation Fear Questionnaire (global) Fear Questionnaire (agoraphobia) Fear Questionnaire (social phobia) Fear Questionnaire (depression) Zung Anxiety
Without past MDE
With past MDE
35.7 ± 6.8 28.3 ± 8.5 7.3 ± 5.2
35.7___ 9.5 26.6 ± 10.5 9.1 ± 9.1
11/23 (48%) 12/23 (52%) 8.0± 7.4 12.6± 8.4 4.5 ± 1.9 13.9± 11.7 9.0± 6.7 2.9 ± 2.8 48.1 ± 10.5
12/40 (30%)] 28/40 (70%)-~ 12.5 ± 9.2 19.9± 8.4 4.7 ± 2.2 12.7± 9.7 12.2± 6.4 4.0 ± 2.2 56.0 ± 10.0
t
0.03 0.66 0.99 X2 = 2.00 1.91 3.06 0.06 0.40 1.80 N = 54 ~ 2.64
df
P<
61 61 61
NS NS NS
53 52 53 53 53
NS 0.07 0.004 NS NS 0.08 0.08 0.02
47
a Mann-Whitney U-test used.
scores on the F Q ( P = NS). H o w e v e r , the P D patients with a history of depression t e n d e d to score higher than P D patients w i t h o u t a history of depression on each of the measures p e r t a i n i n g to social and evaluative fear a n d anxiety: the S A D , F N E , and the social p h o b i a subscale of the F Q . T h e P D patients with a history of depression also
TABLE 3 VARIABLES CONSIDERED IN STEPWlSE LOGISTIC REGRESSION ANALYSES Categorical variables 1. Gender 2. Marital status 3. Presenceor absence of agoraphobia 4. Presence or absence of social phobia 5. Presenceor absence of dysthymia 6. Presenceor absence of obsessive-compulsive disorder 7. Family history of depression 8. Family history of anxiety 9. Family history of either depression or anxiety 10. Family history of substance abuse 11. Global functional impairment a 12. Primary or secondary depression 13. Recurrent or nonrecurrent depression 14. Melancholic or nonrnelancholic depression Continuous variables 15. Age at onset of panic disorder 16. Duration ill with panic disorder 17. Age at onset of first major depressive episode
a Dichotomized as "2 or 3" vs. "4 or 5".
scored h i g h e r on a m o r e global m e a s u r e of anxiety, the Z A S , an d t e n d e d to score higher on the depression subscale of the F Q . Characteristics that were entered into the stepwise logistic regression to identify factors associated with the o c c u r r e n c e of M D E i n c l u d e d variables 1 - 1 1 an d 1 5 - 1 6 as listed in T a b l e 3. Th e logistic regression revealed that the presence of c o m o r b i d social p h o b i a was the only variable associated with an increased rate of M D E (goodness of fit X 2 = 71.7, P < 0.07); 16 of 19 patients (84%) with c o m o r b i d social p h o b i a h ad e x p e r i e n c e d an M D E c o m p a r e d to 24 of 44 patients (55%) w i t h o u t this c o m o r b i d diagnosis. This association held eq u al l y true for patients whose social p h o b i a t e m p o r a l l y p r e c e d e d their p a n i c diso r d e r as for those w h o f o l l o w e d the reverse sequence.
P r i m a r y versus s e c o n d a r y d e p r e s s i o n T w e n t y - f i v e o f 40 (62.5%) patients h ad p r i m a r y depressions (which, for p u r p o s e s of this analysis, i n c l u d e d those patients w h o se first m a j o r depressive episode was p r i o r to or c o n c u r r e n t with the onset of p a n i c disorder) an d 15 (37.5%) had seco n d a r y depressions. In the p r i m a r y depressives the m e a n interval b e t w e e n the first M D E an d the onset of P D was 3.3 ___6.0 years (range: 0 - 2 3 ) whereas in the s e c o n d a r y depressives the m e a n
292 interval b e t w e e n the onset of P D a n d the first M D E was 5.4 + 4.4 years (range: 1 - 1 2 ) . W h e n p a t i e n t s having h a d p r i m a r y versus seco n d a r y d e p r e s s i o n were c o m p a r e d along all the p a r a m e t e r s used in T a b l e 2, the two g r o u p s were n o t f o u n d to significantly differ on a n y variable. Because we were a w a r e that our p r i m a r y c a t e g o r y was different f r o m the t r a d i t i o n a l (i.e., F e i g h n e r ) c o n c e p t a n d m a y have influenced our findings, we also c o m p a r e d all three groups (i.e., d e p r e s s i o n p r i o r to p a n i c onset, c o n c u r r e n t onset, a n d d e p r e s sion following p a n i c onset) separately. T h e three g r o u p s still were f o u n d to b e i n d i s t i n g u i s h a b l e a l o n g each of the d i m e n s i o n s e x a m i n e d . T h e stepwise logistic regression for i d e n t i f y i n g characteristics a s s o c i a t e d with p r i m a r y versus seco n d a r y d e p r e s s i o n s utilized all of the variables listed in T a b l e 3 (except for n u m b e r 12, the varia b l e u n d e r c o n s i d e r a t i o n ) . O n l y the severity of f u n c t i o n a l i m p a i r m e n t e m e r g e d as a relevant term, b u t even this h a d negligible classificatory value ( g o o d n e s s of fit X 2 = 49.49, P < 0.10); two of 12 p a t i e n t s (17%) w i t h low f u n c t i o n a l i m p a i r m e n t (i.e., scoring 2 or 3) h a d s e c o n d a r y depressions, c o m p a r e d to 13 of 28 p a t i e n t s (46%) with high functional i m p a i r m e n t (i.e., scoring 4 or 5). N o
o t h e r v a r i a b l e s were p r e f e r e n t i a l l y a s s o c i a t e d with p r i m a r y versus s e c o n d a r y depression. R e c u r r e n t versus nonrecurrent depressions
T a b l e 4 c o m p a r e s p a t i e n t s with a n d w i t h o u t r e c u r r e n t d e p r e s s i o n a l o n g a n u m b e r of b e h a v i o r a l d i m e n s i o n s . P a t i e n t s with r e c u r r e n t d e p r e s s i o n t e n d e d to have h a d an earlier age at onset of PD, to have b e e n ill with P D for a longer d u r a t i o n , a n d to have h a d their first depressive e p i s o d e at an earlier age. I n a d d i t i o n , a l t h o u g h the two subg r o u p s d i d n o t differ in their F Q a g o r a p h o b i a or g l o b a l subscale scores, n o r in Z A S scores, the r e c u r r e n t depressives scored m a r k e d l y higher on two of three m e a s u r e s of social a n d evaluative anxiety a n d a v o i d a n c e (i.e., the S A D a n d F Q social p h o b i a subscale, b u t n o t the F N E ) . C h a r a c t e r i s t i c s e n t e r e d into the logistic regression analysis i n c l u d e all those listed in T a b l e 3 ( e x c l u d i n g n u m b e r 13, the v a r i a b l e u n d e r consideration), a n d the results are s u m m a r i z e d in T a b l e s 5 A a n d 5B. T a b l e 5 A i n c l u d e d a history of m e l a n c h o l i a as a p o t e n t i a l p r e d i c t o r ; for this analysis d a t a were a v a i l a b l e for o n l y a subset (n = 24) of patients. T a b l e 5B e x c l u d e d a h i s t o r y of m e l a n c h o l i a as a p o t e n t i a l p r e d i c t o r , a n d conse-
TABLE 4 COMPARISON OF PANIC DISORDER PATIENTS WITH RECURRENT (n =14) VERSUS NONRECURRENT (n = 26) DEPRESSIONS
Current age (years) Age at PD onset (years) Duration of PD (years) Age at first MDE onset (years) Degree of global functional impairment (2-3) (4-5) Social Avoidance and Distress Feart of Negative Evaluation Fear Questionnaire (global) Fear Questionnaire (agoraphobia) Fear Questionnaire (social phobia) Fear Questionnaire (depression) Zung Anxiety
With Recurrent MDE
With Nonrecurrent MDE
t
df
P<
35.9± 9.8 22.8 _ 9.8 13.1 ± 10.6
35.7± 9.1 28.7 ± 10.4 7.0+ 7.5
0.07 1.73 2.10
38 38 38
NS 0.10 0.05
21.7 ± 10.0
29.0 ± 9.3
2.21
34
0.04
4/14 (29%) 10/14 (71%) 20.4_ 5.2 22,8_+ 8.2 4.5 ± 1.8 14.6+ 8.9 17.7 ± 4.8 4.7 + 1.8 59.4± 9.2
8/26 (31%)~ 18/26 (69%)1 9.0 ± 8.4 18.5_+ 8.4 4.6 ± 2.3 11.8±10.1 9.6 ± 5.4 3.7 + 2.3 54.3 ± 10.2
Fisher's Exact (two-tailed) 4.15 33 1.42 32 0.03 32 0.80 32 4.29 32 1.29 31 1.35 28
NS 0.0002 NS NS NS 0.0002 NS NS
293 T A B L E 5A S U M M A R Y O F STEPWISE LOGISTIC R E G R E S S I O N R E S U L T S F O R R E C U R R E N T D E P R E S S I O N a Step
term entered
number 1 2 3
Goodness
P
Correctly classified
of fit X2 Duration of illness Age at onset first M D E History of melancholia
21.03 9.74 0.00
0.52 0.98 1.00
Recurrent
Nonrecurrent
Total
44.4 77.8 88.9
86.7 93.3 93.3
70.8 87.5 91.7
Terms entered include all of 1-17 as shown in Table 3.
T A B L E 5B S U M M A R Y O F STEPWISE LOGISTIC R E G R E S S I O N RESULTS F O R R E C U R R E N T D E P R E S S I O N ~ Step number
Term entered
Goodness of fit X 2
P
Recurrent
Nonrecurrent
Total
1 2
Age at onset first M D E First degree family history of either anxiety or depression Duration of illness
32.56
0.3
54.5
91.3
79.4
25.33 20.54
0.75 0.90
54.5 72.7
87.0 82.6
76.5 79.4
3
,% Correctly classified
a Terms entered exclude melancholia (Table 3, item 14) from the analysis.
quently included the larger patient sample. These analyses, taken together, confirm the expected finding that duration of illness is associated with recurrence, as are early onset of depression, history of melancholia, and a first=degree family history of either depression or anxiety. Discussion
We found that 63% of the patients with panic disorder experienced at least one episode of major depression at some time during their course of illness to date. This rate would appear to be consistent with most studies in the literature, and serves as a reminder that depressive illness will ultimately occur in the majority of patients with panic disorder. Clinicians who treat patients with panic disorder would be well-advised to remain alert to the development of major depression in their patients. Our findings echo those of Weissman et al. (1989), who, in a much larger sample of subjects with panic disorder in the community, found that these individuals are at high risk for suicidal ideation and suicide attempts. Interest-
ingly, in that study (Weissman et al., 1989), the increased risk for suicidal ideation and attempts could not be explained on the basis of comorbidity with major depression. We will discuss this further when we come to the issue of depressive recurrences. In interpreting the rate of depression in our sample, it is important to note that we excluded subjects who currently met criteria for major depression. Prior studies of major depression in patients with panic disorder have each employed their own unique selection criteria, and this large variability in subject selection across studies renders much of the relevant literature on this topic difficult to interpret. In terms of our own data, it would be reasonable to expect that our exclusion of currently depressed individuals might result in an underestimation of the overall rates of depression, as well as the rates for recurrent depression. Consequently, our ~decision to exclude currently depressed individuals was not necessarily "good" or " b a d " , but must nonetheless be recognized as a characteristic of our study. Optimally, it would have been useful to have had a cohort of currently
294
depressed PD patients as a comparison group, and we~do intend to utilize this strategy in our upcoming studies. Another methodologic element that must be considered in the interpretation of our study and other studies in this field is the the question of when one defines the "onset" of illness. We chose to define onset of illness for PD as the time at which full diagnostic criteria were met. Obviously, then, this influenced our determination of depressive episodes as being either temporally primary or secondary. Several recent studies have suggested that patients with panic disorder may actually experience symptoms of their illness many years prior to their meeting full diagnostic criteria. Generalized anxiety (Garvey et al., 1988; Fava et al., 1988), phobic symptoms (Fava et al., 1988; Lelliott et al., 1989; Thompson et al., 1989), and childhood anxiety disorders such as overanxious disorder or separation anxiety disorder (Gittelman, 1986; Aronson and Logue, 1987) have all been reported to precede the onset of full-blown panic disorder. Thus, it could be argued that what we are designating as primary depression in relation to the onset of panic disorder, may not actually be primary in relation to the onset of these subsyndromal characteristics. A recent study, however, has shown that the retrospective determination of "subdisorder" anxiety symptoms (particularly generalized anxiety or " n e a r " panic attack symptoms) may be unreliable (Fyer et al., 1989). Therefore, while we would concur that the further study of subsyndromal symptoms as a prelude to panic a n d / o r depression is a worthwhile endeavor, we feel that our current demarcation of "onset of illness" is the most reliable estimate available given the current state of the an of retrospective psychiatric diagnosis. In this study, we were able to examine a number of clinical characteristics associated with depressive occurrence and subtypes (i.e., primary versus secondary, recurrent versus nonrecurrent). Of all the parameters examined in relation to the lifetime occurrence of major depression, only the comorbid presence of social phobia was associated with an increased rate. These findings in an expanded sample size continue to support our earlier observations (Stein et al., 1989). Factors such as severity of illness, degree of agoraphobic avoid-
ance, and duration of illness - all of which might reasonably be thought to increase the liability for depression if depression was a natural consequence of or a reaction to the demoralizing effects of chronic anxiety - seemed to carry little weight in determining why and when some patients with panic disorder become depressed. Other factors which we examined, such as gender or family history, did not serve to enlighten us in this respect. The impact of life events (Roy-Byrne et al., 1986), which this study was not designed to assess, clearly merits further prospective study, as does the continued examination of factors reported to be associated with poorer outcome (particularly with respect to more frequent or severe depressive episodes) such as personality disorders (Reich, 1988) or obsessive-compulsive features (Mellman and Uhde, 1987). When we examined the issue of primary versus secondary depressions, like Buller et al. (1986) we failed to find significant distinguishing characteristics on a cross-sectional basis. Similarly, Van Valkenburg et al. (1984), in a naturalistic outcome study, found that PD patients with primary or secondary depression both did equally poorly (compared to PD patients without a history of depression). Several investigators have, however, found that patients with secondary depression have a higher incidence of depressive episodes at follow-up (Buller et al., 1986) or are more likely to exhibit chronic depressions and generally poorer outcome (Nutzinger and Zapotczky, 1985). Therefore, the primary vs. secondary distinction may indeed have prognostic implications, and should be further studied despite our predominantly negative findings here. In contrast to our inability to discriminate between primary and secondary depressives, we found that several variables seemed to distinguish between those patients who did and did not experience recurrent depressive episodes. For the PD patients with recurrent depressive episodes, many of the factors that one might logically assume to cluster with a more severe variant of illness (or, perhaps, with a biological predisposition), such as positive family history or presence of melancholia, were found in the patients with recurrent depression. In fact, while 10 of 17 patients with histories of melancholia experienced recurrent depressive
295 episodes, none of the p a t i e n t s w i t h o u t histories of m e l a n c h o l i a h a d recurrences. This finding suggests that it m a y be r e a s o n a b l e for clinicians to r o u t i n e l y d e t e r m i n e whether or n o t their P D p a t i e n t s have h a d melancholia, as this may, if c o n f i r m e d in p r o s p e c t i v e studies, have clinical utility in p r e d i c t ing a greater l i k e l i h o o d of depressive recurrence(s). S o m e w h a t unexpectedly, we f o u n d that the recurrent depressives scored a b o u t twice as high on two i n d e p e n d e n t measures of social anxiety a n d a v o i d a n c e (i.e., the S A D a n d the F Q social p h o b i a subscale; T a b l e 5). This suggests either that those p a r t i c u l a r traits (i.e., social anxiety a n d a v o i d a n c e ) p r e d i s p o s e to recurrent depression, or, alternatively, that these r e p r e s e n t the outcome of recurrent depressive episodes a n d / o r longer d u r a t i o n of p a n i c illness. W h i l e this association w o u l d seem to be of c o n s i d e r a b l e interest, o u r d a t a d o not allow us to infer a n y n o t i o n of causality; this is, however, deserving of further study. In addition, n o t surprisingly, recurrent depression was associated with longer d u r a t i o n of illness a n d earlier age at onset of first depressive episode. This latter o b s e r v a t i o n is of p a r t i c u l a r interest, since earlier age at onset (of p a n i c disorder, in this case) was a s s o c i a t e d with increased risk for suicidal i d e a t i o n a n d a t t e m p t s in the s t u d y b y W e i s s m a n et al. (1989). W h i l e those a u t h o r s were able to c o n t r o l for the o c c u r r e n c e of m a j o r d e p r e s s i o n as a risk factor, they d i d not c o n t r o l for recurrent depressive episodes n o r d i d they e x a m i n e the possible effect of early versus late onset depressions. Thus, it is possible that the increased risk for suicidal i d e a t i o n a n d a t t e m p t s seen in p a t i e n t s with early onset p a n i c d i s o r d e r m a y be m e d i a t e d t h r o u g h an i n c r e a s e d likelihood of r e c u r r e n t or early onset depressive episodes. This hypothesis r e m a i n s to be tested in future studies. In a d d i t i o n to the c o m m e n t s we have m a d e above, a n u m b e r of other m e t h o d o l o g i c a l issues related to our c u r r e n t s t u d y a n d previous investigations in this a r e a deserve attention. First, o u r subjects r e p r e s e n t e d a clinical p o p u l a t i o n seeking treatment, a n d we would, therefore, expect o u r p a t i e n t s to be m o r e severely ill t h a n those individuals with P D in the c o m m u n i t y who d o n o t seek treatment. F o r this reason, conclusions r e a c h e d here m a y n o t be a p p l i c a b l e to the total p o p u l a t i o n
of i n d i v i d u a l s with PD. Second, while we a n d o t h e r a u t h o r s refer to the lifetime o c c u r r e n c e of depressive illness, it s h o u l d be u n d e r s c o r e d that we are a c t u a l l y referring to a t r u n c a t e d p e r i o d of o b s e r v a t i o n . T h a t is, m o s t of the p a t i e n t s s t u d i e d are in their third t h r o u g h fifth d e c a d e s of life, a n d have yet to p a s s t h r o u g h the entire p e r i o d of risk for depressive disorders. So, while our observations can i l l u m i n a t e s o m e of the factors that m a y b e a s s o c i a t e d with the l o n g i t u d i n a l o c c u r r e n c e of affective illness in these relatively y o u n g patients, further studies that follow a c o h o r t of P D p a t i e n t s prospectively over an e x t e n d e d p e r i o d of time are needed and would constitute a major improvem e n t over the m e t h o d o l o g y e m p l o y e d here.
Acknowledgement The a u t h o r s wish to a c k n o w l e d g e the statistical c o n s u l t a t i o n of J o h n Bartko, Ph.D.
References Andreason, N.C., Endicott, J., Spitzer, R.L. and Winokur, G. (1977) The family history method using diagnostic criteria. Arch. Gen. Psychiatry 34, 1229-1235. Andreason, N.C., Rice, J., Endicott, J. et al. (1986) The family history approach to diagnosis: how useful is it? Arch. Gen. Psychiatry 43, 421-429. Aronson, T.A. and Logne, C.M. (1987) On the longitudinal course of panic disorder: developmental history and predictors of phobic complications. Compr. Psychiatry 28, 344355. Breier, A., Charney, D.S. and Heninger, G.R. (1984) Major depression in patients with agoraphobia and panic disorder. Arch. Gen. Psychiatry 41, 1129-1135. Breier, A., Charney, D.S. and Heninger, G.R. (1985) The diagnostic validity of anxiety disorders and their relationship to depressive illness. Am. J. Psychiatry 142, 787-797. Bowen, R.C. and Kohout, J. (1979) The relationship between agoraphobia and primary affective disorders. Can. J. Psychiatry 24, 317-321. Buller, R., Maier, W. and Benkert, O. (1986) Clinical subtypes in panic disorder: their descriptive and prospective validity. J. Affect. Disord. 11,105-114. Charney, D.S., Heninger, G.R., Price, L.H. and Breier, A. (1986) Major depression and panic disorder: diagnostic and neurobiological relationship. Psychopharmacol. Bull. 22, 503-511. Clancy, J., Noyes, R., Hoenk, P.R. and Slymen, D.J. (1978) Secondary depression in anxiety neurosis. J. Nerv. Ment. Dis. 166, 846-850. Clayton, P.J. (1983) The prevalence and course of the affective disorders. In: J.M. Davis and J.W. Maas (Eds.), The Affective Disorders. American Psychiatric Press, Washington, DC, pp. 193-201.
296 Cloninger, C.R., Martin, R.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: Anxiety: New Research and Changing Concepts, pp. 137148. Cooper, J.E. (1963) A study of behaviour therapy in 30 psychiatric patients. Lancet i, 411-415. Dealy, R.S., Ishiki, D,M., Avery, D.H., Wilson, L.G. and Dunner, D.L. (1981) Secondary depression in anxiety disorders. Compr. Psychiatry 22, 612-618. Endicott, J. and Spitzer, R.L. (1978) A diagnostic interview: the Schedule for Affective Disorders and Schizophrenia. Arch. Gen. Psychiatry 35, 837-844. Fava, G.A., Grandi, S. and Canestrari, R. (1988) Prodromal symptoms in panic disorder with agoraphobia. Am. J. Psychiatry 145, 1564-1567. Fyer, A.J., Endicott, J., Mannuzza, S. and Klein, D.F. (1985) Schedule for Affective Disorders and Schizophrenia: Lifetime Version. (Modified for the study of anxiety disorders.) Anxiety Disorders Clinic, New York State Psychiatric Institute, New York, NY. Fyer, A.J., Mannuzza, S., Martin, L.Y., Gallops, M.S., Endicott, J., Schleyer, B., Gorman, J.M., Liebowitz, M.R. and Klein, D.F. (1989) Reliability of anxiety assessment. II. Symptom agreement. Arch. Gen. Psychiatry 46, 1102-1110. Garvey, M.J., Cook, B. and Noyes, R. Jr. (1988) The occurrence of a prodrome of generalized anxiety in panic disorder. Compr. Psychiatry 29, 445-449. Gittelman, R. (1986) Childhood anxiety disorders: correlates and outcome. In: R. Gittelman (Ed.), Anxiety Disorders of Childhood. Guilford, New York, NY, pp. 101-125. Lelliott, P., Marks, I.M., McNamee, G. and Tobena, A. (1989) Onset of panic disorder with agoraphobia. Arch. Gen. Psychiatry 46, 1000-1004. Lesser, I.M., Rubin, R.T., Pecknold, J.C., Rifldn, A., Swinson, R.P., Lydiard, R.B., Burrows, G.D., Noyes, R. and DuPont, R.L. Jr. (1988) Secondary depression in panic disorder and agoraphobia. I. Frequency, severity, and response to treatment. Arch. Gen. Psychiatry 45, 437-443. Lewis, A.J. (1934) Melancholia - A clinical survey of depressive states. J. Ment. Sci. 80, 277-378. Mannuzza, S., Fyer, A.J., Klein, D.F. and Endicott, J. (1986) Schedule for Affective Disorders and Schizophrenia - Lifetime version (modified for the study of anxiety disorders): rationale and conceptual development. J. Psychiatr. Res. 20, 317-325. Mapother, E. (1926) DiscuSsion on manic-depressive psychosis. Br. Med. J. I, 225-227. Markowitz, J.S., Weissman, M.M., Ouellette, R., Lish, J.D. and Klerman G.L, (1989) Quality of life in panic disorder. Arch. Gen. Psychiatry 46, 984-992. Marks, I.M. and Mathews, A.M. (1979) Brief standard self-rating for phobic patients. Behav. Res. Ther. 17, 263-267. Mellman, T.A. and Uhde, T.W. (1987) Obsessive-compulsive symptoms in panic disorder. Am. J. Psychiatry 144, 15731576. Munjack, D.J. and Moss, H.B. (1981) Affective disorder and alcoholism in families of agoraphobics. Arch. Gen. Psychiatry 38, 869-871.
Nutzinger, D.O. and Zapotoczky, H,G. (1985) The influence of depression on the outcome of cardiac phobia (panic disorder). Psychopathology 18, 155-162. Raskin, M., Peeke, H.V.S., Dickman, W. and Pinsker, H. (1982) Panic and generalized anxiety disorders: developmental antecedents and precipitants. Arch. Gen. Psychiatry 39, 687-689. Regier, D.A., Boyd, J.H., Burke, J.D. Jr., Rae, D.S., Myers, J.K., Kramer, M., Robins, L.N., George, L.K., Karno, M. and Locke, B.Z. (1988) One month prevalence of mental disorders in the United States. Arch. Gen. Psychiatry 45, 977-986. Reich, J.H. (1988) DSM-II1 personality disorders and the outcome of treated panic disorder. Am. J. Psychiatry 145, 1149-1152. Roth, M. (1959) The phobic anxiety-depersonalization syndrome. Proc. R. Soc. Med. 52, 587-595. Roy-Byrne, P.P., Geraci, M. and Uhde, T.W. (1986) Life events and course of illness in patients with panic disorder. Am. J. Psychiatry 143, 1033-1035. Schapira, K., Roth, M., Kerr, T.A. and Gurney, C. (1972) The prognosis of affective disorders: the differentiation of anxiety states from depressive illnesses. Br. J. Psychiatry 121,175-181. Spitzer, R.L., Endicott, J. and Robins, E. (1978) Research Diagnostic Criteria: rationale and reliability. Arch. Gen. Psychiatry 35, 773-782. Stein, M.B. and Uhde, T.W. (1988) Panic disorder and major depression: a tale of two syndromes. Psychiatr. Clin. N. Am. 11,441-461. Stein, M.B., Shea, C.A. and Uhde, T.W. (1989) Social phobic symptoms in patients with panic disorder: clinical and theoretical imphcations. Am. J. Psychiatry 146, 235-238. Thompson, A.H., Bland, R.C. and Orn, H.T. (1989) Relationship and chronology of depression, agoraphobia, and panic disorder in the general population. J. Nerv. Ment. Dis. 177, 456-463. Uhde, T.W., Boulenger, J.-P., Roy-Byrne, P.P., Vittone, B.J. and Post, R.M. (1985) Longitudinal course of panic disorder: clinical and biological considerations. Prog. Neuropsychopharmacol. Biol. Psychiatry 9, 39-51. Van Valkenburg, C., Akiskal, H.S., Puzantian, V. and Rosenthal, T. (1984) Anxious depressions: clinical, family history, and naturalistic outcome. Comparisons with panic and major depressive disorders. J. Affect. Disord. 6, 67-82 Watson, D. and Friend, R. (1969) Measurement of socialevaluative anxiety. J. Consult. Clin. Psychol. 33, 448-457. Weissman, M.M., Klerman, G.L., Markowitz, J.S. and Ouellette, R. (1989) Suicidal ideation and suicide attempts in panic disorder and panic attacks. N. Engl. J. Med. 321, 1209-1214. Woodruff, R.A., Guze, S.B. and Clayton, P.J. (1972) Anxiety neurosis among psychiatric outpatients. Compr. Psychiatry 13, 165-170. Zirnmerman, M., Coryell, W., Pfohl, B. and Stangl, D. (1988) The reliability of the family history method for psychiatric diagnoses. Arch. Gen, Psychiatry 45, 320-322. Zung, W.W.K. (1971) A rating instrument for anxiety disorders. Psychosomatics 12, 371-379.