Psychiatry Research 126 (2004) 143–149 Moderating effects of major depression on patterns of comorbidity in patients with panic disorder Joseph Biederman*, Carter Petty, Stephen V. Faraone, Dina Hirshfeld-Becker, Mark H. Pollack, Aude Henin, Jennifer Gilbert, Jerrold F. Rosenbaum Clinical Research Program in Pediatric Psychopharmacology, Massachusetts General Hospital, and Harvard Medical School, WACC 725, 15 Parkman Street, Boston, MA 02114, USA Received 10 October 2003; received in revised form 2 February 2004; accepted 2 February 2004 Abstract Given the high rate of co-occurring major depression in patients with panic disorder, it is unclear whether patterns of comorbidity in individuals with panic disorder reported in the literature are associated with panic disorder or with the presence of major depression. Subjects were 231 adult subjects with panic disorder and major depression (ns 102), panic disorder without comorbid major depression (ns29), major depression without comorbid panic disorder (ns39), and neither panic disorder nor major depression (ns61). Subjects were comprehensively assessed with structured diagnostic interviews that examined psychopathology across the life cycle. Panic disorder, independently of comorbidity with major depression, was significantly associated with comorbid separation anxiety disorder, simple phobia, obsessive–compulsive disorder, generalized anxiety disorder, and agoraphobia. Major depression, independently of comorbidity with panic disorder, was significantly associated with comorbidity with psychoactive substance use disorders and childhood disruptive behavior disorders. Overanxious disorder was associated with both panic disorder and major depression. Major depression has important moderating effects on patterns of comorbidity of panic disorder in referred adults. 䊚 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Panic disorder; Depression; Adult; Comorbidity 1. Introduction Panic disorder is a relatively common disorder estimated to affect between 1 and 3% of the general population (Brown and Barlow, 1992; Frank et al., 2002; Kaufman and Charney, 2000). Although studies have shown that panic disorder *Corresponding author. Tel.: q1-617-726-1731; fax: q1617-724-1540. E-mail address: jbiederman@partners.org (J. Biederman). is associated with significant morbidity, there is considerable variability in outcome (Goodwin et al., 2002b). While some individuals experience isolated panic attacks, others go on to develop panic disorder, agoraphobia, and severe functional disability. The reasons for these differences remain unclear, but at least some of this variability may be due to psychiatric comorbidity. Individuals with panic disorder have high rates of psychiatric comorbidity, estimated at 74–90% 0165-1781/04/$ - see front matter 䊚 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.psychres.2004.02.001 144 J. Biederman et al. / Psychiatry Research 126 (2004) 143–149 (Kaufman and Charney, 2000) with somewhat similar patterns in both clinical and epidemiological studies (Gittelman and Klein, 1984; Goodwin et al., 2001). For example, using data from the National Comorbidity Survey, Goodwin et al. (2002b) documented that panic is associated with increased risk for anxiety and non-anxiety comorbidity. Likewise, in a clinical sample, Goodwin et al. (2002c) reported significant associations between panic attacks and social phobia, specific phobias, and OCD. Major depression has been identified as the most common comorbidity in panic disorder, both on a current and lifetime basis (Gorman and Coplan, 1996; Iketani et al., 2002). Epidemiological studies estimate that 56–73% of individuals with panic disorder have had a lifetime diagnosis of major depression and the rate is even higher in referred samples. Thus, given the frequent co-occurrence of major depression in patients with panic disorder, it is not clear whether reported patterns of comorbidity are attributable to the panic disorder itself or to the presence of major depression (Caron and Rutter, 1991). For example, both clinical and epidemiological studies identified important associations in adults between panic disorder and substance use disorders (Goodwin et al., 2002b,c), but this association has been found to be moderated by major depression (Goodwin and Olfson, 2001). Also, most studies in the extant literature limited the assessment of psychiatric comorbidity to disorders of adulthood, with inadequate attention to the assessment of childhood disorders such as childhood anxiety and disruptive behavior disorders. This shortcoming of the literature to date precludes a developmental understanding of the unfolding of psychopathology in individuals with panic disorder. For example, early age of onset of panic disorder has been associated with comorbidity with other anxiety disorders, in particular agoraphobia (Breier et al., 1986; Goldstein et al., 1997; Goodwin et al., 2001), childhood separation anxiety disorder, and OCD (Goodwin et al., 2001). These findings underscore the importance of examining childhood disorders in studies of comorbidity of panic disorder. An improved understanding of patterns of comorbidity across the life cycle has potentially important implications. Clinically, individuals with specific patterns of comorbidity may require different treatment approaches. Scientifically, identifying patterns of comorbidity can help recognize distinct subgroups of panic disorder subjects with different etiology, course, and treatment response. From the public health perspective, a developmental perspective on the unfolding of psychopathology in subjects with panic disorder can aid in the development of preventive and early intervention programs for individuals at risk for panic disorder. In light of these considerations, this study’s main goal was to evaluate whether patterns of comorbidity in patients with panic disorder are independent of the presence of comorbid major depression. Based on the extant literature, we hypothesized that patterns of comorbidity would differ in patients with and without major depression. 2. Methods 2.1. Subjects Details about the study’s methodology have been presented elsewhere (Rosenbaum et al., 2000). Briefly, three groups of adult probands were recruited for a study of behavioral inhibition in their offspring. These individuals were recruited from clinic referrals or in response to advertisements calling for adults in treatment for panic disorder or major depression. These included patients in the following categories: (1) adults treated for panic disorder (ns131); (2) adults treated for major depression who had no history of either panic disorder or agoraphobia (ns39); and (3) comparison adults with neither major anxiety nor mood disorders (ns61). All subjects had at least one child between the ages of 2 and 6 years. The subjects’ ages ranged from 24 to 52 years. Only patients who received a positive lifetime DSM-III-R diagnosis of panic disorder or major depression by structured psychiatric interview and who had been treated for these disorders were included. The comparison group of adults was free of major anxiety disorders (panic disorder, 145 J. Biederman et al. / Psychiatry Research 126 (2004) 143–149 Table 1 Demographics Demographic characteristics PDqMD ns102 PD ns29 MD ns39 Controls ns61 Test statistic P-value Age Males—n (%) SES 38.2"5.2 12 (12) 2.5"1.0 40.5"5.6 5 (17) 2.0"0.9 38.3"5.2 8 (21) 2.3"1.1 38.3"5.1 11 (18) 1.9"1.0 F(3,195)s1.3 x2(3)s2.2 x2(3)s15.8 0.27 0.53 0.001 agoraphobia, social phobia, generalized anxiety disorder, or obsessive–compulsive disorder) or mood disorders (major depression, bipolar disorder, or dysthymia). Comparison subjects were recruited through advertisements to hospital personnel and in community newspapers. The study was approved by the institutional review board, and all participants provided written informed consent. judgment by the two senior investigators (J.B. and J.F.R.). Psychiatric interviewers of parents were unaware of the ascertainment status of the parent (e.g. panic disorder patient, major depression patient, comparison subject), and the final diagnoses for all subjects were made by clinicians who were blind to the subjects’ original recruitment group, to all non-psychiatric data collected from the individual being diagnosed, and to all information about other family members. 2.2. Procedures 2.3. Statistical analyses We conducted direct psychiatric assessments with each subject using the Structured Clinical Interview for DSM-III-R (SCID) (Spitzer et al., 1990) for lifetime adult diagnoses, and supplements from the Kiddie Schedule for Affective Disorders and Schizophrenia modules (KSADS-E) for child disorders, disruptive behavior disorders and childhood anxiety disorders (Orvaschel, 1994). We assessed socioeconomic status (SES) with the Hollingshead Four-Factor Index (Hollingshead, 1975), which includes information about subjects’ educational levels and occupations. Interviews were conducted by highly selected, trained, and supervised raters with a bachelor’s degree in psychology. All raters were supervised by two senior clinical investigators (J.F.R. and J.B.). Raters underwent a comprehensive training program in which they were required to (1) master the diagnostic instruments; (2) learn about DSMIII-R criteria; (3) watch training tapes; (4) participate in interviews performed by experienced raters; and (5) rate several subjects under the supervision of the experienced raters. Raters received ongoing supervision of their assessments from senior project staff, and all interviews were audiotaped for quality control. Diagnoses for all subjects were made on the basis of a consensus We first compared subjects from the diagnostic groups for potentially confounding demographic variables (age, gender, and socioeconomic status). Then we examined differences in psychopathology between subjects using logistic regression and controlling for potential demographic confounds. Fisher’s exact test was used for comparing rates of disorders when one or more cells had a zero frequency. All tests were two-tailed with alpha set at a 0.05 level. 3. Results Analyses were made using the following four groups: (1) adults with both panic disorder and major depression (PDqMD; ns102); (2) adults with panic disorder without comorbid major depression (PD; ns29); (3) adults with major depression without comorbid panic disorder (MD; ns39); and (4) adults with neither panic disorder nor major depression and without agoraphobia, social phobia, generalized anxiety disorder, obsessive–compulsive disorder, or mania (controls; ns 61). For outcome disorders excluded in the controls (agoraphobia, social phobia, generalized anxiety disorder, obsessive–compulsive disorder, and 146 J. Biederman et al. / Psychiatry Research 126 (2004) 143–149 Fig. 1. Rates of disorders in subjects with panic disorder and major depression. (a) Comparisons including controls (for disorders not excluded in controls). (b) Comparisons excluding controls (for disorders excluded in controls). mania), analyses were limited to the three groups with major depression or panic disorder. As shown in Table 1, the MD, PD, PDqMD, and control groups differed significantly in socioeconomic status (SES) but not in age or gender. Therefore, all analyses were statistically corrected for SES. As shown in Fig. 1, significant differences between groups were found for overanxious disorder (P-0.001), separation anxiety disorder (P0.001), psychoactive substance use disorders (Ps 0.003), disruptive behavior disorders (Ps0.02), generalized anxiety disorder (Ps0.01), and agoraphobia (P-0.001). Follow-up pairwise compar- J. Biederman et al. / Psychiatry Research 126 (2004) 143–149 147 Fig. 2. Risk of comorbid disorders given major depression or panic disorder controlling for other disorder. isons revealed that all three psychopathological groups had significantly higher rates of overanxious disorder and separation anxiety disorder compared with controls. In addition, the PDqMD group had a significantly higher rate of overanxious disorder compared with the MD group. Both PD groups (with and without MD) had significantly higher rates of simple phobia than the controls, while both MD groups (with and without PD) had significantly higher rates of psychoactive substance use disorders and disruptive behavior disorders than the control group. The rate of antisocial personality disorder was significantly higher in the MD group than in the PD group (Fig. 1a). Both PD groups had higher rates of agoraphobia than the MD group, while the PDq MD group had significantly higher rates of generalized anxiety disorder and obsessive– compulsive disorder than the MD group. Rates of mania were elevated in the two MD groups, but the difference attained statistical significance only for the PDqMD group (Fig. 1b). In order to better determine which comorbidities were associated with PD and MD, comorbidities were used as dependent variables in logistic regres- sion models where PD status and MD status were used as independent variables. These models therefore assessed the association of PD and MD, independently of the status of the other with each comorbid disorder. This analysis indicated that PD, independent of MD, was significantly associated with separation anxiety disorder (Ps0.007), simple phobia (Ps0.02), obsessive–compulsive disorder (Ps0.04), generalized anxiety disorder (Ps 0.005), and agoraphobia (P-0.001), while MD, independent of PD, was significantly associated with comorbidity with psychoactive substance use disorders (Ps0.002) and disruptive behavior disorders (Ps0.003). Both PD and MD were associated with overanxious disorder (PD: P-0.001; MD: Ps0.003). Fig. 2 presents odds ratios for these significant relationships. 4. Discussion The results showed divergent patterns of comorbidity for panic disorder and major depression. While panic disorder was associated with other comorbid child and adult anxiety disorders independently of major depression status, major 148 J. Biederman et al. / Psychiatry Research 126 (2004) 143–149 depression was associated with childhood disruptive behavior disorders and substance use disorders independently of panic disorder status. These results show that major depression has important moderating effects on patterns of comorbidity in referred adults with panic disorder worthy of further consideration in clinical and scientific studies of panic disorder. With the exception of childhood overanxious disorder which was associated with major depression and panic disorder other comorbid anxiety disorders including agoraphobia, obsessive–compulsive disorder, simple phobia, and childhood separation anxiety disorder were selectively associated with panic disorder. In contrast, major depression was selectively associated with comorbid childhood disruptive behavior disorders and psychoactive substance use disorders. These results stress the importance of major depression in identifying differential patterns of comorbidity in patients with panic disorder across the life cycle. Our results confirm the association between panic disorder and substance use disorders (Goodwin and Hamilton, 2002a; Goodwin et al., 2002b,c; Merikangas et al., 1998; Regier et al., 1998; RoyByrne et al., 2000)) but suggest that these associations may be accounted for by the presence of major depression. Consistent with our results are those of Goodwin and Olfson (2001), who also found that the association between panic disorder and substance use disorder may be accounted for by major depression. These findings are not surprising considering that panic disorder comorbid with major depression is the most common presentation of panic disorder in referred and nonreferred samples. The association between major depression and comorbidity with childhood disruptive behavior disorders is consistent with an emerging body of literature that documents a high degree of syndromatic overlap and familial co-aggregation between disruptive behavior and depressive disorders (Biederman et al., 2001, 1987; Faraone and Biederman, 1997; Fendrich et al., 1990; Orvaschel et al., 1988; Puig-Antich and Rabinovich, 1986). The divergent patterns of comorbidity for panic disorder and major depression observed in this sample of referred adult probands are consistent with prior work examining patterns of psychopathology in high-risk children of adults with panic disorder and major depression (Biederman et al., 2001). This work documented significant diagnostic specificity in patterns of transmission between parents with panic disorder and parents with major depression and their offspring, in which parental panic disorder selectively increased the risk for anxiety disorders in the offspring, while parental major depression selectively increased the risk for mood and disruptive behavior disorders in offspring, independently of the other disorder in the parent (Biederman et al., 2001). Our findings should be viewed in the context of some methodological limitations. The numbers of adults with major depression without comorbid panic disorder and with panic disorder without comorbid major depression were relatively small. Since subjects were clinically referred and selected by having young offspring, findings may not generalize to other populations of patients with panic disorder. However, patterns of comorbidity identified in this sample are highly consistent with others reported in the literature, suggesting that these ascertainment issues may not have been critical. Since findings are retrospective, they could have been influenced by recall bias. Despite these considerations, this study documents divergent patterns of comorbidity for panic disorder and major depression in which panic disorder was associated primarily with other anxiety disorders while major depression was associated with childhood disruptive behavior disorders and psychoactive substance use disorder, irrespective of the comorbidity with the other disorder. 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