Comorbidity in Generalized Anxiety Disorder

GENERALIZED ANXIETY DISORDER

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COMORBIDITY IN GENERALIZED ANXIETY DISORDER Russell Noyes, Jr, MD

Comorbidity in generalized anxiety disorder (GAD) is a subject of increasing theoretic and practical importance. Because comorbid disorders are especially common among persons with GAD, some investigators have questioned whether this is an independent disorder or a prodrome, residual, or severity marker for other anxiety or depressive disorders.l4?36 Pure GAD exists in a significant minority of persons, however, so there is a basis for retaining the category. Rates of comorbidity are especially high for other anxiety disorders, such as panic disorder, and depressive disorders, such as dysthymia and major depressive disorder (MDD).75Such a pattern suggests that these co-occurring disorders are somehow related to GAD and that understanding these relationships may increase clinicians’ knowledge of cause and cla~sification.4~ Also, because patients with comorbidity seem to respond less well to treatment and have a worse outcome, treatment planning must take coexisting disorders into account.12This article reviews data concerning these issues, but first, several comments about the definition and meaning of cornorbidity are needed. Feinsteinzl first used the term cornorbidity to refer to patients with co-occurring medical illness. Since the removal of hierarchical rules from the DSM-111-R, extensive comorbidity among psychiatric disorders has been d ~ c u m e n t e dAmong .~~ psychiatric patients, half have more than one current diagnosis, and among persons in the general population, half of those with a lifetime disorder have another diagnosis as well.37 Such comorbidity has research and clinical implications. To begin with, high rates of co-occurrence may mean that diagnostic categories are

From the Department of Psychiatry, University of Iowa College of Medicine, Iowa City, Iowa

THE PSYCHIATRIC CLINICS OF NORTH AMERICA VOLUME 24 * NUMBER 1 * MARCH 2001

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poorly defined.4 Also, relationships between categories and other variables may be caused by comorbidity which then must be taken into account. Also, extensive comorbidity may provide clues to causal relationships, and, finally, comorbid conditions may influence treatment response and The classification system influences rates of comorbidity in several ways. For instance, the splitting rather than lumping of disorders tends to increase rates of comorbidity." Thus, dividing anxiety neurosis (DSM11) into panic disorder and GAD (DSM-111) results in many patients with both disorders. Diagnostic thresholds also influence comorbidity rates. As thresholds are lowered, the prevalence of a disorder increases and the rates of comorbidity decrease. For example, Breslau and Davis9 observed that, when stricter criteria were applied, the prevalence of GAD in a sample of women decreased from 45% to 9%, and the prevalence of coexisting depression increased. Eliminating hierarchical exclusionary rules dramatically increases c~morbidity.~ In the DSM-111, GAD was a residual category, but in the DSM-111-R, the disorder achieved independent status, making it one of the most prevalent of all disorders. There are several reasons why two or more disorders may occur in one individual, and these must be kept in mind in evaluating studies. Klein and Riso identified 11 possible explanations*: Explanations based on sampling and base rates 1. Comorbidity due to chance 2. Comorbidity due to sampling bias 3. Comorbidity due to population stratification Explanations based on artifacts of diagnostic criteria 4. Comorbidity due to overlapping criteria 5. Comorbidity due to one disorder encompassing the other Explanations based on drawing boundaries in the wrong places 6 . Multiformity 7. Heterogeneity of the comorbid condition 8. The comorbid condition is a third, independent disorder 9. The pure and comorbid conditions are different phases or alternative expressions of the same disorder Explanations based on etiological relationships 10. One disorder is a risk factor for the other 11. The two disorders arise from overlapping etiologic processes Several of these explanations are especially relevant to GAD. For instance, symptoms that overlap with dysthymia and MDD, such as worry, poor concentration, and sleep difficulty, contribute to artifactual comorbidity (model 4). Also, GAD may be a secondary manifestation of a more pervasive condition in the context of panic disorder (model 5). According to model 9, pure and comorbid conditions are merely differ*From Klein DN, Riso LP: Psychiatric disorders: Problems of boundaries and comorbidity. In Costello CG (ed): Basic Issues in Psychopathology. New York, Guilford, 1994, pp 19-66; with permission.

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ent phases of the same disorder. Evidence that GAD may be a prodromal or residual form of panic disorder in some instances fits this The final explanatory models are based on causal relationships. Thus, one disorder might be a risk factor for another. Some investigators have suggested, for example, that GAD is a personality vulnerability for other disorder~.'~,An alternative model views comorbid conditions as having a common cause. For instance, evidence shows that GAD and MDD have a shared genetic d i a t h e ~ i s . ~ ~ PREVALENCE AND PAlTERN OF COMORBIDITY Clinical Populations

Studies of comorbidity in patients with GAD have shown considerable variation (Table 1). Some of this variation reflects differing populations. Early studies examined patients receiving psychological therapies,65 whereas later studies involved symptomatic volunteerss and patients receiving drug therapy.&,70 Some studies excluded patients with current panic disorder, MDD, or both. Also, GAD was variously defined as the primary or principal diagnosis (i.e., which came first or which was p r e d ~ m i n a n t )Despite . ~ ~ these differences, the overall rates of comorbidity, as shown in Table 1, were high (45-98%), and in one virtually all patients with GAD had other lifetime disorders.2 Such high rates-perhaps the highest among the anxiety disorders-have caused some investigators to question whether GAD is a separate disorder', 48; however, Brawman-Mintzer et als reported that, for 26% of subjects, GAD was the only diagnosis. MDD was the most prevalent comorbid disorder, and had studies included patients with current MDD (excluded in many), lifetime rates would likely have exceeded 50% (Table 1). With respect to anxiety disorders, social phobia was the most prevalent (16-59%), followed by specific phobia (1646%). Rates for panic disorder (3-27%) were reduced by the exclusion of patients with this disorder form drug study protocols. According to Massion et a1,48 nearly half of psychiatric patients with GAD had lifetime panic disorder with or without agoraphobia. Similarly, Cassano et all5 reported that 63% of patients with panic disorder had GAD. Consequently, panic disorder may be the most prevalent comorbid anxiety disorder. Specific patterns of comorbidity, when found, strengthen the validity of diagnostic categories, and, because the distinction between panic disorder and GAD has remained contro~ersial,4~ investigators have compared such patterns in these d i s ~ r d e r s . ~ , ~ ~results , 70 ~The have been inconsistent and have been interpreted variously. For example, Noyes et a156 found more depersonalization and agoraphobia associated with panic disorder than with GAD, but these may be associated features instead of separate disorders. GAD commonly co-occurs with other anxiety and depressive disor-

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Data from Massion AO, Warshaw MG, Keller M B Quality of life and psychiatric morbidity in panic disorder and generalized anxiety disorder. Am J Psychiatry

disorder

Dysthymia Substance-use disorders Alcohol abuse Drug abuse Any comorbid

Anxiety disorders Panic disorder Agoraphobia Social phobia Specific phobia Posttraumatic stress disorder Obsessivecompulsive disorder Depressive disorders Major depression

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ders. Rates seem especially high in panic disorder and MDD. For example, Brown and Barlow12found that 32% of patients with panic disorder had GAD and that 9% had subthreshold GAD. Similarly, Starcevic et a172 found GAD among 52% of patients with panic disorder but found a higher rate among those with agoraphobia (68%) than among those without (32%). With respect to depressive disorders, Sanderson et aF6 found GAD to be the most common comorbid disorder among patients with dysthymia (22%) and MDD (20%). Likewise, Pini et a158observed generalized anxiety in 65% of patients with dysthymia and 37% of those with unipolar depression. Despite the extensive overlap, Riskind et a161 concluded that dysthymia and GAD are probably separate conditions. Studies examining temporal relationships have shown that the onset of GAD usually is earlier than that of other anxiety and depressive disorders.12 Typically, such patients have lifelong and chronic anxiety, apprehension, and somatic arousaP5; however, results have been inconsistent and have, for the most part, been based on retrospective recall. Brawman-Mintzer et als found that the onset of GAD was earlier than those of dysthymia and panic disorder but later than those of simple and social phobia. In their series, a first episode of MDD often occurred shortly after the onset of anxiety. Massion et a148reported that the onset of GAD was earlier than that of other anxiety disorders in 46% of patients. Their findings support those of others, who have observed GAD in some patients years before the onset of panic disorder.20 Findings among children and adolescents tend to support those in adults.16GAD-and its forerunner, overanxious disorder (DSM-111-R)-is one of the most common anxiety disorders among children. Like GAD in adulthood, the rate of comorbidity is perhaps the highest among the anxiety disorders in children. For example, Last et a141found that 96% of patients with overanxious disorder had at least one other lifetime anxiety disorder, and Masi et a147 identified comorbidity in 87% of children and adolescents with GAD. Similar to as in adults, the most common comorbid conditions were separation anxiety disorder, social anxiety, and depressive disorders (especially among adolescents). Also, community surveys have shown that most children and adolescents with overanxious disorder also have other anxiety depressive disorders.29,52 Among Results among the elderly also are like those in elderly persons, the prevalence of anxiety disorders decreases relative to the adult population, with the possible exception of GAD. At a 12month rate of 7% to 9%, GAD may be the most prevalent anxiety disorder in persons more than 65 years of age40; however, most persons with GAD have comorbid conditions. For instance, Lindesay et a142 found that 91% of elderly persons with GAD in the community also had depression. Similarly, Manela et a143reported that 70% of elderly community residents with GAD had depression and that 36% had a phobic disorder. These authors found that only 18% had pure GAD. Two longitudinal studies concluded that anxiety usually occurs secondary to d e p r e ~ s i o nFor . ~ ~example, Blazer et a16 found that 32% of middle-aged

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and elderly patients who had been hospitalized for depression suffered from anxiety afterward. General Population

Persons with coexisting disorders are more likely to seek treatment and so are over-represented in clinical samples. Nevertheless, rates of comorbidity among persons with GAD in the general population seem to be as high as those in clinical populations. The National Comorbidity Survey, which ignored DSM-111-R diagnostic hierarchy rules, found that 90% of respondents with lifetime GAD had one or more other lifetime disorders.75Of those with current (past 30 days) GAD, 66% had at least one other current disorder. Table 2 shows percentages and odds ratios for individual disorders. The strongest comorbidities were depressive disorders, panic disorder, and (for current only) agoraphobia. In the National Comorbidity Survey, 58% of those with 12-month GAD also had 12-month MDD, and in the Midlife Development in the United States Survey, the 12-month rate was 70?’0.~~ Also, the percentages of those with MDD who also had GAD were 18% and 16% in these studies. Despite the high rate of comorbidity, 10% of individuals with GAD had only this lifetime disorder, and an additional 12% had an onset of GAD before that of any other disorder.” Taken together, approximately 20% of cases could be considered primary. Also, as shown in Table 3,82% of respondents with GAD met at least one severity criterion. Comorbidity increased the proportion of those whose disorder interfered significantly with their lives and activities, who ever sought professional help, or who

Table 2. COMORBIDITY OF 30-DAY AND LIFETIME DSM-Ill-R GENERALIZED ANXIETY DISORDER WITHOUT HIERARCHY 30-Day Generalized Anxiety Disorder Comorbid Disorder

Mania Major depression Dysthymia Panic disorder Agoraphobia Simple phobia Social phobia Alcohol Drug Any of the above

Lifetime Generalized Anxiety Disorder

%

SE

OR

%

SE

OR

12.1 38.6 22.1 22.6 26.7 24.5 23.2 11.2 5.1 66.3

4.1 6.0 5.3 5.7 6.8 6.2 4.6 3.1 2.1 6.9

19.64 13.86 24.78 26.08 19.21 5.91 6.87 1.68 1.99 10.18

10.5 62.4 39.5 23.5 25.7 35.1 34.4 37.6 27.6 90.4

2.0 4.2 3.6 2.2 2.8 3.5 3.4 3.7 2.6 1.6

9.91 9.72 13.52 12.32 5.80 4.88 3.77 2.04 3.08 11.56

OR = odds ratio; SE = standard error. Modified from Wittchen HU,Zhao S, Kessler RC, et al: DSM-111-R generalized anxiety disorder in the National Comorbidity Survey Arch Gen Psychiatry 51:355-364, 1994; reprinted with permission from the American Medical Association.

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Table 3. LIFETIME GENERALIZED ANXIETY DISORDER: INTERFERENCE, HELP SEEKING, AND USE OF MEDICATION Interference

Pure GAD Comorbid GAD Total

Help Seeking

Medication

Any of the Three

%*

SE

%'

SE

%*

SE

%"

SE

28.1 51.2 49.0

0.08 0.04 0.04

48.2

0.10 0.04 0.03

24.1 46.2 44.0

0.08 0.04 0.04

59.2 84.4 82.0

0.10 0.03 0.02

67.9 66.0

*Data from Wittchen HU, Zhao S, Kessler RC, et al: DSM-11-R generalized anxiety disorder in the National Comorbidity Survey. Arch Gen Psychiatry 51:355-364,1994. SE = standard error; GAD = generalized anxiety disorder.

ever took medication for the disorder. Nevertheless, even in its pure form, GAD was associated with significant impairment and treatment seeking, so clearly GAD occurs in pure form and is associated with substantial life impairment. These community data suggest that GAD is an independent disorder but that it has a close relationship to depression. Personality Comorbidity

Studies have shown that personality disorders are common among patients with psychiatric conditions, including GAD. Investigations focusing on clinical populations have found personality disturbances in 31% to 46% of patients with GAD.=,49-51, ffi,71 This range is higher than the 10% to 18?'0~~cited for the general population but is comparable to rates observed in patients with other anxiety disorders.49,51 Not only have the rates of personality disorders been similar to those for other anxiety and depressive disorders, but also the pattern has appeared indistinguishable. Thus, patients with GAD were shown to have personality disorders belonging to Cluster C, although Cluster B disorders were also represented. Several investigator^^^,^^, 65 have found avoidant personality disorder to be common, occurring in 19% to 29% of samples; however, observing similar patterns in panic disorder, obsessive-compulsive disorder, and recurrent depression, Mauri et a149and Mavissakalian et a151concluded that the relationship between GAD and personality is probably not specific. These investigators speculated that the observed abnormalities might represent a personality predisposition to anxiety or an effect of an anxiety disorder on personality. Several investigators, beginning with Gasperini et al,25 reported interpersonal sensitivity, mistrust, and hostility that seemed unique to patients with GAD. According to these investigators, patients with GAD showed more hypervigilance, tendency to be easily slighted, suspiciousriess, and dependence than did normal controls. Also, Mavissakalian et a151 reported that they differed from other neurotic groups in traits of suspiciousness; mistrust; and intense, uncontrollable anger. Similarly,

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Blashfield et a15 found that patients with GAD were more hostile and mistrustful of their interpersonal environment than were matched patients with panic disorder, and Mavissakalian et a150found that interpersonal sensitivity was a strong correlate of abnormal personality in these patients. Taken together, these findings suggest that GAD is associated with more avoidance, interpersonal sensitivity, and perhaps greater personality abnormality than other anxiety disorders. Alternatively, such features may be characteristic of GAD itself. MORBIDITY ASSOCIATED WITH COMORBIDITY

The literature indicates that, in general, comorbidity is associated with greater severity! more impairment, more help seeking, and worse outcome of the primary disorder. Does this apply to GAD and, if so, to what extent? Data from the National Comorbidity Survey (NCS) examining this question are shown in Table 3. More patients with comorbidity experienced interference with daily activities than did patients with pure GAD (51.2%v 24.1%).Kessler et a136examined data on impairment from both the NCS and the Midlife Development in the United States Survey. Using measures of perceived work role and social role impairment, they compared respondents with GAD alone, MDD alone, and those with both disorders. They found that (1) respondents with either disorder were more impaired than those with neither (2) persons with these disorders had comparable impairment, and (3) even after adjusting for other diagnoses and sociodemographic differences, those with both disorders were more impaired than were persons with just one. Likewise, Brown et all1 found that depressed patients with GAD had more severe symptoms but that those with comorbid panic disorder had greater severity of disease. Comorbidity increases help seeking among persons with GAD. Data from the NCS show that lifetime comorbidity is associated with greater professional treatment seeking and medication taking.” As is shown in Table 3, fewer people with pure GAD sought help than did people with comorbidity. Also, fewer people with pure GAD received medication for anxiety than did people with comorbidity. Similarly, Bland et aP observed help seeking in 43% of people with comorbidity versus 26% of people with pure GAD. Also, persons with comorbid GAD were more likely to have sought help for anxiety in the specialty mental health sector. Also, a study examining costs associated with GAD showed greater health care utilization among patients with ~omorbidity.~~ These patients underwent more laboratory tests, saw more specialists, took more medication, and were more often hospitalized than were those without comorbid symptoms. Comorbidity also is associated with worse outcome for GAD. This was shown by Judd et a128who looked at ”seek&g psychiatric treatment” and ”serious conflict with others’’ among persons with GAD alone versus with lifetime MDD. More of those with MDD sought treatment

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(31%v 16%)and reported conflict (46% v 30%). As a comorbid condition, GAD also is associated with a worse outcome. For instance, in a study of depressed outpatients, Sherbourne and Wells68found that those with GAD had more depressive symptoms initially and less often remitted than did those without. Also, they more commonly developed new depressive episodes in the first year compared with noncomorbid cases. Similar findings have been reported for patients with panic disorder and comorbid GAD.44 RELATIONSHIPS BETWEEN COMORBID DISORDERS

The high rate of comorbidity between GAD and MDD has created interest in the relationship between these disorders.53To determine this, Kendler et a132,33 examined data from the Virginia Twin Registry. In this large epidemiologic sample of women, they found strong evidence for comorbidity; the odds ratio for GAD (1month) in the presence of MDD was 8.9. Using bivariate twin analysis, they examined the contribution of genetic, familial environmental, and individual specific environmental factors to observed comorbidity. They found that the genetic correlation between GAD and MDD could not be distmguished from unity, suggesting that genes contributing to GAD also contribute to MDD. They found no etiologic role for familial environment in either disorder, but the correlation between individual specific environment for GAD and MDD was 0.51, which suggested that, although some environmental factors contribute to both disorders, others are relatively specific for one or the other. Neale and Kendler55examined possible models for the relationship between these disorders. Based on their analysis, they rejected several models, including comorbidity caused by chance; alternative forms of GAD; a third independent disorder; and GAD as a cause of MDD. They found that factors that cause GAD-genetic and environmental-increase the risk for MDD and vice versa. According to their best-fitting model, MDD is a cause of GAD. Using questionnaire assessment of subjects in the Swedish Twin Registry, Roy et a P extended these findings across genders. Like the Virginia Twin Study, this investigation showed that GAD and MDD share the same genetic vulnerability. Also, environmental determinants seemed relatively distinct. Their findings are consistent with studies pointing to differences in life events associated with these disorders. For instance, Finlay-Jones and Brownz showed that depression is associated with loss events (e.g., death of a loved one) and anxiety, with danger events (e.g., threat of death from illness). Another replication by Kendler31extended Virginia Twin Registry findings to l-year GAD by means of a follow-up interview. Because the same results have been found in several studies, they seem robust. Still, they are dependent on the reliability and validity of a diagnosis-GAD-that continues to be questioned.

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TREATMENT IMPLICATIONS OF COMORBIDITY

Comorbidity among the anxiety disorders contributes to greater severity and worse outcome of the primary disorder. The treatment implications are First, coexisting disorders may affect response to treatment and outcome. Second, treatment for the primary disorder may or may not lead to improvement of coexisting disorders. Third, treatment that takes comorbidity into account may be more effective than treatment that does not. Fourth, effective early treatment may prevent comorbid disturbances that are prone to develop later. All of these considerations seem important for GAD because of the high rate of comorbidity; however, until recently, the influence of such comorbidity on treatment was ignored. In fact, commonly co-occurring disorders, such as depression and substance-abuse disorder, were often the basis for excluding patients from treatment protocols. To examine the effects of psychological therapy (i.e., nondirective therapy, applied relaxation, self-control desensitization, and brief cognitive therapy) on comorbid conditions, Borkovec et a17separated patients with GAD into successful and failed outcome groups 12 months after treatment. They found that successful treatment led to a substantial decrease in comorbidity. Only 3 of 23 patients in the successful outcome group still had additional diagnoses, and only 3 of 35 coexisting conditions remained. The investigators offered three possible explanations. First, if anxiety disorders share overlapping features, then improvement of the primary condition might affect related disorders. Second, treatment generalization might eliminate comorbid and primary disorders. Third, if some pathologic processes, such as worry, underlie many psychiatric conditions, then eliminating them might allow for adaptive learning. Durham et all9 examined predictors of response to psychological therapy (i.e., cognitive therapy, analytic psychotherapy, and anxietymanagement training) in a large group of patients with GAD. They used logistic regression analyses to examine predictors of improvement and relapse over a 12-month period. The most powerful predictors, apart from the type of treatment received, were marital status and psychiatric comorbidity. Axis I comorbidity was strongly predictive of improvement and relapse, although severity of anxiety symptoms was not. The investigators concluded that the complexity of a patient’s clinical presentation, more than overall severity, makes therapy difficult. Other studies have examined the treatment response and outcome of patients with panic disorder and MDD who also have comorbid GAD. In their review, Roy-Byrne and C o ~ l e yfound ~ ~ two studies in which symptoms of GAD were predictive of outcome and two others in which other predictors were more important. In several studies, symptoms of GAD appeared more resistant to treatment than those of panic disorder, which is consistent with the observation of residual generalized anxiety symptoms following the abatement of pan? attacks. It is also consistent with the observation of Pollack et a159that patients with panic disorder

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with comorbid anxiety disorders are less likely to achieve remission. On the other hand, Nagy et a154observed comparable change in generalized anxiety and other symptoms among patients receiving imipramine. Most of these studies involved drug treatment. To examine the impact of comorbidity on the response to cognitive-behavioral therapy of panic disorder, Brown et all3 assessed a large group of patients for 24 months after treatment. Fifty-one percent had at least one additional diagnosis, the most common being GAD, social phobia, and depressive disorder. Surprisingly, this comorbidity did not predict premature termination of treatment or worse outcome of panic disorder. A significant decrease in the percentage of patients with coexisting disorders-specially GAD-was observed after treatment; although 26% had this disorder before treatment, only 9% warranted the diagnosis afterward. On the other hand, patients with persisting comorbidity were more likely to seek additional treatment during the follow-up period. Similar findings were reported by Tsao et alY3 who treated patients with panic disorder with cognitive-behavioral therapy. Nearly two thirds had comorbid disorders, the most common being social phobia (36%) and GAD (30%). These investigators found therapy for panic disorder effective in reducing the frequency and severity of comorbid conditions, although they were not the focus of treatment. The percentage with comorbid disorders decreased from 64% before treatment to 27% after treatment. Decreases in comorbid diagnoses were greatest for social phobia (75%) and GAD (70%). In this study, pretreatment comorbidity was not associated with greater severity of panic disorder. On the other hand, there was a trend for comorbidity to predict less favorable treatment response, which is consistent with findings from other psychological and pharmacologic treatment studies.30,6o Comorbid anxiety disorders seem to have a similar influence on the treatment response of patients with depression. Antidepressant treatment studies have, with few exceptions, shown that depressed psychiatric patients with coexisting anxiety disorders have a poorer outcome than do those with depression These findings were extended to depressed primary care patients by Brown et all0 who compared the response to psychological and pharmacological therapy in patients with and without lifetime anxiety disorders, including GAD (71%).Depressed patients with comorbid anxiety had more severe depression at baseline, dropped out at a higher rate, responded less rapidly, and showed less improvement over the 8-month trial. Treatment was effective for patients with MDD with and without generalized anxiety, but the former took longer to recover than did the latter. SUMMARY

GAD has rates of comorbidity that equal or exceed those of other anxiety disorders, and it is one of the most common comorbid conditions with other disorders. Depressive disorders, especially MDD, and other

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anxiety disorders, especially panic disorder, most commonly co-occur. The pattern of comorbidity is consistent in community and clinical populations and in children and elderly people. Comorbidity is associated with greater impairment, more treatment seeking, and worse outcome among persons with GAD compared with pure GAD. Likewise, patients with panic disorder and MDD who have coexisting GAD tend to have more severe symptoms and less favorable outcome. The relationship between GAD and MDD seems especially close, and data from twin studies suggest that these conditions share a genetic diathesis. Patients with GAD and coexisting conditions respond less well to psychological and pharmacologic treatment, but, for those who do respond, treatment for the primary disorder often also produces improvement in comorbid conditions. Thus, research continues to show that GAD is important as a primary and a comorbid disturbance. References 1. Andrews G: Panic and generalized anxiety disorders. Curr Opinion Psychiatry, 6:191194, 1993 2. Barlow DH, Blanchard EB, Vermilyea JA, et a1 Generalized anxiety and generalized anxiety disorder: Description and reconceptualization. Am J Psychiatry 143:4044,1986 3. Bland RC, Newman SC, Om H: Help-seeking for psychiatric disorders. Can J Psychiatry 42935-942, 1997 4. Blashfield RK: Comorbidity and classification.In Maser JD, Cloninger CR (eds): Comorbidity of Mood and Anxiety Disorders. Washington, DC, American Psychiatric Press, 1990, pp 61-82 5. Blashfield RK, Noyes R, Reich J, et a1 Personality disorder traits in generalized anxiety and panic disorder patients. Compr Psychiatry 35:329-334, 1994 6. Blazer D, Hughes DC, Fowler N Anxiety as an outcome symptom of depression in elderly and middle-aged adults. Int J Geriatr Psychiatry 4:273-278, 1989 7. Borkovec TD, Abel JL, Newman H: Effects of psychotherapy on comorbid conditions in generalized anxiety disorder. J Consult Clin Psychol 63:479-483, 1995 8. Brawman-Mintzer 0, Lydiard RB, Emmanuel N, et al: Psychiatric comorbidity in patients with generalized anxiety disorder. Am J Psychiatry 150:1216-1218, 1993 9. Breslau N, Davis GC: DSM-I11 generalized anxiety disorder: An empirical investigation of more stringent criteria. Psychiatry Res 15:231-238, 1985 10. Brown C, Schulberg HC, Madonia MJ, et al: Treatment outcomes for primary care patients with major depression and lifetime anxiety disorders. Am J Psychiatry 153:1293-1300, 1996 11. Brown C, Schulberg HC, Shear MK Phenomenology and severity of major depression and comorbid lifetime anxiety disorders in primary medical care practice, Anxiety 2:210-218, 1996 12. Brown TA, Barlow D H Comorbidity among anxiety disorders: Implications for treatment and DSM-IV. J Consult Clin Psychol 60:835-844, 1992 13. Brown TA, Antony MM, Barlow D H Diagnostic comorbidity in panic disorder: Effect on treatment outcome and course of comorbid diagnoses following treatment. J Consult Clin Psychol 63:40&418, 1995 14. Brown TA, Barlow DH, Liebowitz MR The empirical basis of generalized anxiety disorder. Am J Psychiatry 151:1272-1280, 1994 15. Cassano GB, Perugi G, Masetti L: Co-morbidity in panic disorder. Psychiatr Ann 20517-521, 1990 16. Curry JF, Murphy LB: Comorbidity in anxiety disorders. In March JS (ed): Anxiety Disorders in Children and Adolescents. New York, Guilford Press, 1995, pp 301-307

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