Child Study Center, Yale University School of Medicine, New Haven, Connecticut 06510
The occurrence of anxiety symptoms with episodes of major depression is veil documented (2,8-11,16). When individuals with either an anxiety disorder or major depression are followed over time, a particularly strong association has been observed between panic anxiety and depression. Dealy et al. (8) compared patients who had anxiety neurosis alone with patients who had anxiety neurosis with major depression. They found a significantly elevated rate of panic attacks among patients with depression. Other studies have suggested that when the two disorders co-occur in the same individual, they may be temporally independent. Raskin et al. (17) reported that 14 of 17 patients with panic disorder had expe­rienced major depression that did not coincide with an episode of panic disorder. Bowen and Kohout (1) found that 91% of patients with agoraphobia and panic attacks had had an episode of major depression that did not coincide with episodes of panic, whereas Munjack and Moss (14) found that 41% of agoraphobic patients with panic attacks had had previous episodes of depression. Results from other studies have also suggested an association between panic disorder and depression. However, none of these studies specifically addressed whether the two disorders occurred together or separately. Cloninger et al. (4) noted that 75% of patients who experienced panic attacks later developed depres­sion and Crowe et al. (6) found that 13 of 41 patients with panic disorder had chronologically secondary depression. In a follow-up study of 29 patients with "cardiac phobia," Nutzinger and Zapotoczky (16) found that 82.8% showed depression in addition to suffering from anxiety symptoms. While it is clear that the onset of depression came after the onset of anxiety in these studies, the investigators did not report whether the episodes of depression occurred inde­pendently of the episodes of panic disorder experienced by the patients. In examining patients with major depression, Leckman et al. (12) found that 81 of 133 patients had anxiety disorders in addition to being depressed. Twenty­two of the 81 individuals with both anxiety and depression had panic disorder. of the total 133 depressed subjects, 16.5% experienced panic attacks with suf ficient frequency and severity to satisfy criteria for a diagnosis of probable or definite panic disorder. This frequency is higher than expected by chance alone. These results, taken with the data from studies of panic disorder patients, suggest that panic disorder (PD) and major depressive disorder (MDD) may share some etiological factors. Treatment studies have also provided data that support the hypothesis of a potential relationship between PD and MDD. It is well known that tricyclic antidepressants and monoamine oxidase inhibitors are effective in the treatment of MDD (7). Evidence from controlled studies indicates that these agents also are effective in the reduction of the frequency of panic attacks (3). This antipanic effect appears to be independent of clinical manifestations of depression (18,22) suggesting that there may be some common underlying etiological factors for both panic and major depressive disorders. Although results from the above studies imply that PD and MDD are strongly associated and may have common factors involved in their etiology, additional data are needed to examine more carefully the relationship between the two illnesses. Since both disorders have been shown to be familial, family data can be quite useful in elucidating whether they share etiological factors. If PD and MDD are etiologically related, then increased rates of one disorder should be observed in the relatives of patients with the other illness. Family data have given apparently contradictory results. Several studies (1,12,14,19) have suggested that there is a familial relationship between PD and MDD since an increased rate of depression was observed among the relatives of probands with either MDD and PD (MDD + PD) or with PD alone. However, other studies (6,15) did not find an increased rate of primary depression in the relatives of probands with PD or agoraphobia with panic attacks (Ag/PD). The discrepancy between these family study results may be accounted for by meth­odological differences (5,13). The purpose of the study reported here was to reexamine the reports of Leckman et al. (12), Crowe et al. (6), and Noyes et al. (15) to determine if methodological differences could account for the apparent discrepant findings. Methodological differences between the studies focused on the procedures used in assigning diagnoses. In the Crowe et al. and Noyes et al. studies, DSM- III convention was used in that a diagnosis of a specific psychiatric condition was precluded when it could have been secondary to another mental disorder. For example, a diagnosis of primary major depression would not have been made if it occurred after the onset of panic disorder. Thus, the morbid risk figures reported in these two studies reflect the rates of chronologically primary disorders. These rates, in effect, represent the frequency of ill individuals among the relatives since no one would be included more than once. On the other hand, Leckman and co-workers did not use the primary/secondary distinction in re­porting diagnoses. If an individual had sufficient symptoms to meet DSM- Ш criteria for a specific diagnosis, that diagnosis was assigned and reported. An individual could, and often did, receive several diagnoses. Therefore, the rates reported by Leckman et al. were rates of diagnoses and not rates of ill individuals, дп individual was included in the computation of rates as many times as that person received a diagnosis. Because of this difference in how rates of illness were reported, it is difficult to compare the results of the studies.

This work was supported in part by an NIMH Research Scientist Development Award (MH-00508) to Dr. Pauls.
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Data from three published reports (6,12,15) were retabulated to allow a direct comparison of the studies. Since Crowe et al. (6) and Noyes et al. (15) reported rates of secondary depression among relatives, it was possible to retabulate their data so that frequencies of diagnoses were obtained. These frequencies could then be compared to the results reported by Leckman et al. (12). For this chapter, the data presented in Crowe et al. (6) and Noyes et al. (15) were retabulated to obtain rates of the following diagnoses: major depressive disorder (MDD), panic disorder and/or generalized anxiety disorder (PD/GAD), and any anxiety disorder that included PD/GAD. The retabulation was accomplished by simply summing the rates for primary diagnoses and all secondary diagnoses for a specific mental disorder. For instance, the rate of MDD is equal to the rate of primary MDD plus all rates of secondary MDD. The data from the Leckman et al. study were retabulated to obtain similar diagnostic groupings for relatives of probands with MDD alone (MDD) and for relatives of probands with MDD and PD (MDD + PD). In addition, because the data from the Crowe et al. and Noyes et al. studies included families of probands with chronologically primary panic disorder or agoraphobia regardless of whether they had secondary depression, we combined the families from the Leckman et al. study in which the probands had major depression without anxiety and the families where the proband had primary major depression and secondary panic disorder. This combination allowed a comparison of rates of diagnoses among relatives of probands with primary major depression with and without panic disorder (MDD ± PD), primary panic disorder with and without major depression (PD ± MDD), and primary ago­raphobia with panic attacks with and without depression (Ag/PD ± MDD). Since some forms of MDD are familial, this retabulation of the Leckman et al. data could introduce a bias. For instance, if the rate of MDD is not elevated in the relatives of probands with PD or agoraphobia alone, then the rate of MDD among relatives in the MDD ± PD families should be higher than the rate of MDD among relatives in the PD ± MDD families. A more appropriate com­parison would be to contrast the rates of illness among the relatives of probands with chronologically primary MDD and secondary PD (MDD + PD) with the rates of illness among the relatives of probands with chronologically primary PD with secondary MDD (PD + MDD). Although the data for the MDD + PD probands were reported by Leckman and co-workers, it was not possible to extract the data for PD + MDD from the published reports of Crowe and Noyes. or this report, the control relatives collected by Leckman et al. were chosen for comparison because the probands were persons with no history of psychiatric illness. The control samples reported by Crowe et al. and Noyes et al. included probands with MDD.

Table 1 presents the retabulated data from all three studies. It is important to note that the rates of MDD (primary plus secondary) among relatives of probands with MDD without anxiety (MDD), panic disorder with or without depression (PD ± MDD), and agoraphobia with or without depression (Ag/PD ± MDD) were not significantly different from each other and all were significantly greater than the rate observed among relatives of controls (Table 2). The rate of MDD among relatives of MDD probands with chronologically secondary panic disorder (MDD + PD) was higher than the rates of MDD among relatives of other types of probands. The rate of MDD among relatives of panic disorder and agoraphobic probands could be lower because of the fact that it represents an average rate from families of panic disorder and/or agoraphobic probands with and without depression. It is important to note that the rates of MDD among relatives of MDD probands with or without panic (MDD ± PD) is not significantly elevated when compared to the rates of MDD among relatives of PD ± MDD and Ag/ PD ± MDD probands. If the pattern is similar to that observed among relatives of MDD probands, then there could be a significantly elevated rate among rel­atives of anxious probands with chronologically secondary depression when compared to the rates among relatives of anxious-only probands. Unfortunately, the published data do not allow the separation of anxious probands into those groups. Nevertheless, these results demonstrate that when overall rates of diagnoses
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The analyses reported here demonstrate that methodological approaches are critical to our eventual understanding of a possible relationship between MDD and PD. The two approaches taken by Crowe et al. (6), Noyes et al. (15), and Leckman et al. (12) differ in their use of the primary/secondary distinction. From the work of Crowe, and Noyes and colleagues, it is clear that there is not an elevated risk of chronologically primary MDD in families of probands with chronologically primary PD. However, from the work of Leckman et al. and others (12,19) and from the results reported here it is clear that the rate of MDD (without regard to whether it is primary or secondary) is significantly elevated in families of both MDD and PD probands. What is not clear from the data presented here is whether that increased rate of MDD is among all relatives of PD or agoraphobic probands or whether it occurs only in those families where the proband had a diagnosis of MDD. Leckman et al. (12) reported that there was a significant difference between relatives of MDD versus MDD + PD pro­bands. Crowe et al. (6) and Noyes et al. (15) also reported that the rate of secondary depression was elevated among relatives of PD probands with secondary depres­sion, but the data do not allow a direct comparison to the results of Leckman et al. (12). Nevertheless, it appears that the co-occurrence of MDD and PD within the same individual is an important predictive factor for MDD among the relatives regardless of whether PD or MDD is the chronologically primary disorder. Clinical studies have examined patients with both MDD and PD and have shown differences when compared to patients with MDD alone. Van Valkenburg et al. (20) showed such patients to have the poorest outcome on follow-up. They were also the patients who responded least favorably to tricyclic antidepressant intervention. Nutzinger and Zapotoczky (16) also demonstrated that individuals with "cardiac phobia" who had a secondary depression were more likely to be ill at follow-up. Phenomenological studies have suggested that the episodes of depression that occur together with panic disorder may be somewhat unique. Vitone and Uhde (21) found that patients with both panic and depression were more likely to have episodes of severe depression with melancholic features. However, the episodes of depression tended to be shorter, with only 24% of patients having depressive episodes lasting more than 2 weeks. Given these findings and the data reported in this study, it appears that in­dividuals with both PD and MDD may have a unique syndrome when compared to individuals with only MDD or PD. In order to determine if this is the case, additional phenomenological, biolog­ical, and pharmacological studies are needed in which patients with MDD alone, PD alone, PD + MDD, and MDD + PD are studied together with their families. It must be emphasized that in future studies particular attention needs to be paid to how diagnostic assessments are made and reported. Reporting only pri­mary diagnoses can obscure important information. On the other hand, reporting only rates of diagnosis can also be misleading. All relevant diagnoses of each individual need to be reported in such a way so that it is possible to determine whether relatives have the same diagnostic profile as the probands.