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Bipolar disorder often co-occurs with other axis I disorders, but little is known about the relationships between the clinical features of bipolar illness and these comorbid conditions. Authors evaluated 288 outpatients with bipolar I or II disorder, using structured diagnostic interviews and clinicianadministered and self-rated question-naires.
Bipolar disorder often co-occurs with other axis I disorders, but little is known about the relationships between the clinical features of bipolar illness and these comorbid conditions. Authors evaluated 288 outpatients with bipolar I or II disorder, using structured diagnostic interviews and clinicianadministered and self-rated question-naires.
Bipolar disorder often co-occurs with other axis I disorders, but little is known about the relationships between the clinical features of bipolar illness and these comorbid conditions. Authors evaluated 288 outpatients with bipolar I or II disorder, using structured diagnostic interviews and clinicianadministered and self-rated question-naires.
Axis I Psychiatric Comorbidity and Its Relationship to Historical Illness Variables in 288 Patients With Bipolar Disorder Susan L. McElroy, M.D. Lori L. Altshuler, M.D. Trisha Suppes, M.D., Ph.D. Paul E. Keck, Jr., M.D. Mark A. Frye, M.D. Kirk D. Denicoff, M.D. Willem A. Nolen, M.D., Ph.D. Ralph W. Kupka, M.D. Gabriele S. Leverich, L.C.S.W.-C. Jennifer R. Rochussen A. John Rush, M.D. Robert M. Post, M.D. Objective: Bipolar disorder often co-oc- curs with other axis I disorders, but little is known about the relationships be- tween the clinical features of bipolar ill- ness and these comorbid conditions. Therefore, the authors assessed comor- bid lifetime and current axis I disorders in 288 patients with bipolar disorder and the relationships of these comorbid dis- orders to selected demographic and his- torical illness variables. Method: They evaluated 288 outpatients with bipolar I or II disorder, using struc- tured diagnostic interviews and clinician- administered and self-rated question- naires to determine the diagnosis of bipo- lar disorder, comorbid axis I disorder di- agnoses, and demographic and historical illness characteristics. Results: One hundred eighty-seven (65%) of the patients with bipolar disorder also met DSM-IV criteria for at least one co- morbid lifetime axis I disorder. More pa- tients had comorbid anxiety disorders (N=78, 42%) and substance use disorders (N=78, 42%) than had eating disorders (N=9, 5%). There were no differences in comorbidity between patients with bipo- lar I and bipolar II disorder. Both lifetime axis I comorbidity and current axis I co- morbidity were associated with earlier age at onset of affective symptoms and syndromal bipolar disorder. Current axis I comorbidity was associated with a history of development of both cycle accelera- tion and more severe episodes over time. Conclusions: Patients with bipolar disor- der often have comorbid anxiety, sub- stance use, and, to a lesser extent, eating disorders. Moreover, axis I comorbidity, especially current comorbidity, may be associated with an earlier age at onset and worsening course of bipolar illness. Further research into the prognostic and treatment response implications of axis I comorbidity in bipolar disorder is impor- tant and is in progress. (Am J Psychi a t r y 2 0 0 1 ; 1 5 8 : 4 2 0 4 2 6 ) Epidemiologic data indicate that the rates of sub- stance use and anxiety disorders in persons with bipolar disorder are significantly higher than the rates of sub- stance use and anxiety disorders in the general population (112). Clinical data suggest that bipolar disorder may also commonly co-occur with eating disorders (6, 1316). Con- versely, patients with substance use, anxiety, and eating disorders often have bipolar disorder (4, 5, 1722). Al- though major depressive disorder is also associated with elevated rates of most of these axis I disorders, epidemio- logic studies comparing the psychiatric comorbidity of the depressive and bipolar disorders have often found higher rates of substance use (3, 9), panic (7), and obsessive-com- pulsive (8) disorders in bipolar patients than in depressive patients. Little is known about the relationships between bipolar disorder and the axis I psychiatric conditions with which it often co-occurs. For example, few studies have systemati- cally examined rates of comorbid axis I disorders across different diagnostic subtypes of bipolar disorder (e.g., bi- polar I versus bipolar II disorder) or the effects of axis I psychiatric comorbidity on the phenomenology, course, outcome, and treatment response of bipolar disorder. Pre- liminary data have suggested that axis I psychiatric co- morbidity (e.g., the presence of a substance use or anxiety disorder) may be associated with more severe subtypes of bipolar disorder (i.e., bipolar I versus bipolar II disorder) (3), earlier age at onset of bipolar disorder (22), mixed or dysphoric rather than pure mania (15, 22, 23), higher rates of suicidality (7), poorer overall outcome (2430), and less favorable response to lithium (22, 28, 30, 31). Other stud- ies, however, describe findings inconsistent with these (7). The Stanley Foundation Bipolar Treatment Outcome Network was established to advance the understanding of the long-term course and treatment of bipolar disorder (32). Toward this goal, we used DSM-IV criteria to assess systematically the comorbid lifetime and current axis I psychiatric disorders in the first 288 patients with bipolar I or II disorder who entered the Stanley Foundation Bipolar Treatment Outcome Network. We hypothesized that non- bipolar axis I disorders would be highly prevalent in these Am JPsychiatry 158:3, March 2001 421 MCELROY, ALTSHULER, SUPPES, ET AL. patients and that the presence of these disorders would be associated with negative effects on the presentation and course of their bipolar disorder, as assessed by historical ill- ness variables. Method The methods of the Stanley Foundation Bipolar Treatment Outcome Network (32), along with the demographic and clini- cal features of the first 261 patients (33), are described in greater detail elsewhere. Patients with any type of bipolar disorder were recruited from private, academic, and community mental health clinic outpatient settings by referral and advertisement. These patients entered into the Stanley Foundation Bipolar Treatment Outcome Network if they met the following inclu- sion criteria: 1) age at least 18 years; 2) DSM-IV diagnosis of bi- polar I disorder, bipolar II disorder, bipolar disorder not other- wise specified, or schizoaffective disorder, bipolar type; 3) willingness and ability to perform prospective daily mood charting and attend monthly evaluation appointments; 4) will- ingness to be in some form of ongoing treatment with a psychi- atrist and to consider possible entry into future clinical trials; and 5) provision of written informed consent after the study procedures had been fully explained. Patients were not paid for their participation. The Stanley Foundation Bipolar Treatment Outcome Network protocol included an extensive baseline evaluation (32). This evaluation was typically conducted over several visits and in- cluded completion of the Structured Clinical Interview for DSM- IV, Patient Edition (SCID-P) (34) to establish the diagnosis of bi- polar disorder, illness characteristics (e.g., bipolar disorder sub- type and age at onset), and comorbid axis I disorder diagnoses. The evaluation also included completion of structured patient- rated and clinician-administered questionnaires to determine demographic (e.g., current annual income, current level of occu- pational functioning) and historical illness (e.g., age at onset of affective symptoms; history of dysphoric mania, psychosis, rapid cycling, and suicide attempts; course of illness; and family his- tory of psychiatric illness) variables. The SCID-P and question- naires were administered by highly trained clinical research as- sistants at the individual sites. All had received SCID-P training at their own sites as well as extensive training in the SCID-P and the other instruments at the NIMH site (32). This training was su- pervised by one of the investigators (G.S.L.). As part of their SCID-P training, every clinical research assistant viewed and rated four tapes of SCID-P interviews. Excellent interrater reli- ability was achieved for the diagnosis of bipolar disorder with an overall kappa score of 0.92. In completing the SCID-P and questionnaires, the researchers obtained information from all sources available in addition to the patient interview, including medical records and interviews with family members and treating clinicians. Age at onset of bipolar and comorbid disorders was defined as the first time the patient met full DSM-IV criteria for the disorder. For this study, only patients with bipolar I or II disorder were included in the analysis. In addition, only core DSM-IV sub- stance use, anxiety, and eating disorders were considered as co- morbid axis I disorders. DSM-IV not otherwise specified disorders and impulse control disorders not elsewhere classified, although assessed, were not included in the analysis. All statistical analyses were performed with SPSS, version 8.0 (SPSS, Inc., Chicago, 1997). Categorical variables were compared by using chi-square tests. Continuous variables were compared by using independent-sample or paired-sample t tests as appro- priate. A Bonferroni inequality correction was applied to all vari- ables significant at the p<0.05 level by chi-square or t test. To ex- amine which historical illness variables were associated with lifetime and current comorbidity, a stepwise logistic regression was performed. An alpha of 0.2 was selected as the cutoff for in- clusion in the regression. Results Two hundred eighty-eight patients with bipolar I or bipo- lar II disorder completed the SCID-P and the patient and cli- nician questionnaires. All patients were outpatients re- cruited from the community. One hundred twenty-six (44%) of the patients were men, the mean current age was 42.8 TABLE 1. Number of Lifetime and Current Comorbid Axis I Disorders Among 288 Patients With Bipolar I and Bipolar II Disorder Lifetime or Current Comorbid Diagnosis Number of Comorbid Axis I Disorders Comparison of Bipolar I and Bipolar II All Patients With Bipolar Diagnosis (N=288) Bipolar I (N=239) Bipolar II (N=49) Mean SD Mean SD Mean SD t (df=286) p Lifetime 1.7 2.1 1.8 2.2 1.2 1.4 1.73 <0.09 Current 0.5 1.0 0.6 1.0 0.4 0.7 1.39 <0.17 TABLE 2. Lifetime and Current Comorbid Axis I Disorders Among Patients With Bipolar I and Bipolar II Disorder Number of Current or Lifetime Comorbid Axis I Disorders All Patients With Bipolar Disorder (N=288) Bipolar I (N=239) Bipolar II (N=49) Comparison of Bipolar I and Bipolar II N % N % N % 2 (df=1) p None Lifetime 101 35 80 33 21 43 1.57 0.25 Current 192 67 155 65 37 76 2.08 0.19 One or more Lifetime 187 65 159 67 28 57 1.57 0.25 Current 96 33 84 35 12 24 2.08 0.19 Two or more Lifetime 120 42 102 43 18 37 0.59 0.53 Current 37 13 32 13 5 10 0.37 0.65 Three or more Lifetime 68 24 60 25 8 16 1.73 0.27 Current 16 6 15 6 1 2 1.39 0.33 422 Am JPsychiatry 158:3, March 2001 COMORBIDITY WITH BIPOLAR DISORDER years (SD=11.3, range=19.181.9), the mean age at onset of illness was 22.3 (SD=10.4, range=157), and the mean dura- tion of illness was 20.6 years (SD=12.2, range=0.154.8). One hundred sixteen (40%) of the patients reported limitation of occupational functioning by their bipolar illness, 205 (71%) reported one or more psychiatric hospitalizations, and 160 (56%) had a first-degree relative with a mood disorder. These features were highly similar to those of the first 261 Stanley Foundation Bipolar Treatment Outcome Network patients described in greater detail elsewhere (33). Table 1 shows that the lifetime DSM-IV axis I psychiatric comorbidity in this group of bipolar patients was high; pa- TABLE 3. Lifetime and Current Comorbid Axis I Disorders of Patients With Bipolar I and Bipolar II Disorder Current or Lifetime Comorbid Axis I Disorder All Patients With Bipolar Diagnosis (N=288) Bipolar I (N=239) Bipolar II (N=49) Comparison of Bipolar I and Bipolar II a N % N % N % 2 (df=1) p Substance use disorders Lifetime 122 42 107 45 15 31 3.33 1.00 Current 12 4 9 4 3 6 0.57 1.00 Alcohol Lifetime 96 33 85 36 11 22 3.14 1.00 Current 7 2 4 2 3 6 3.40 1.00 Stimulant Lifetime 25 9 22 9 3 6 0.49 1.00 Current 1 0 1 0 0 0 0.21 1.00 Sedative Lifetime 24 8 23 10 1 2 3.06 1.00 Current 1 0 1 0 0 0 0.21 1.00 Cocaine Lifetime 27 9 25 10 2 4 1.95 1.00 Current 2 1 2 1 0 0 0.41 1.00 Opiate Lifetime 20 7 20 8 0 0 4.41 0.59 Current 1 0 1 0 0 0 0.21 1.00 Marijuana Lifetime 45 16 40 17 5 10 1.32 1.00 Current 4 1 4 2 0 0 0.83 1.00 Hallucinogen Lifetime 18 6 17 7 1 2 1.78 1.00 Current 1 0 1 0 0 0 0.21 1.00 Anxiety disorders Lifetime 122 42 100 42 22 45 0.16 1.00 Current 86 30 76 32 10 20 2.52 1.00 Panic disorder/agoraphobia Lifetime 58 20 48 20 10 20 0.00 1.00 Current 27 9 25 10 2 4 1.95 1.00 Social phobia Lifetime 47 16 41 17 6 12 0.72 1.00 Current 36 13 33 14 3 6 2.20 1.00 Simple phobia Lifetime 30 10 26 11 4 8 0.32 1.00 Current 24 8 21 9 3 6 0.38 1.00 Generalized anxiety disorder Lifetime 8 3 7 3 1 2 0.12 1.00 Current 8 3 7 3 1 2 0.12 1.00 PTSD Lifetime 19 7 17 7 2 4 0.61 1.00 Current 12 4 11 5 1 2 0.67 1.00 OCD Lifetime 27 9 22 9 5 10 0.05 1.00 Current 22 8 19 8 3 6 0.19 1.00 Other anxiety disorders Lifetime 8 3 6 3 2 4 0.37 1.00 Current 6 2 5 2 1 2 0.00 1.00 Eating disorders Lifetime 17 6 11 5 6 12 4.28 0.59 Current 4 1 3 1 1 2 0.18 1.00 Anorexia nervosa Lifetime 6 2 4 2 2 4 6.34 0.95 Current 0 0 0 0 0 0 Bulimia nervosa Lifetime 11 4 8 3 3 6 0.85 1.00 Current 4 1 3 1 1 2 0.18 1.00 a There were no significant differences by chi-square between bipolar I comorbidity and bipolar II comorbidity (df=1). Probability multiplied by 19 to correct for multiple comparisons (Bonferronis inequality correction). Am JPsychiatry 158:3, March 2001 423 MCELROY, ALTSHULER, SUPPES, ET AL. tients met criteria for a mean of 1.7 (SD=2.1) lifetime non- bipolar axis I disorders. Current comorbidity was lower; patients met criteria for a mean of 0.5 (SD=1.0) current nonbipolar axis I disorders. Patients with bipolar I disor- der did not differ from those with bipolar II disorder in their mean number of comorbid lifetime or current axis I disorders. As shown in Table 2, 187 (65%) of the patients met DSM-IV criteria for at least one lifetime comorbid dis- order, and 96 (33%) met criteria for at least one current co- morbid disorder. Sixty-eight (24%) patients had three or more lifetime disorders. Again, bipolar I and bipolar II pa- tients showed no differences regarding rates of lifetime or current comorbid disorders. Table 3 displays the rates of specific comorbid lifetime and current axis I disorders in the entire group of patients and by bipolar subtype. Anxiety and substance use disor- ders were the most common comorbid lifetime disorders, followed by eating disorders, in all patients as well as in the bipolar I and II patients as separate groups. In addition, both as families of disorders and individually, substance use, anxiety, and eating disorders were equally common in patients with bipolar I and bipolar II disorders. Alcohol was the most commonly abused substance, and mari- juana was the most commonly abused drug, followed by noncocaine stimulants, cocaine, and sedatives. Panic dis- order/agoraphobia and social phobia were the two most common anxiety disorders. Bulimia nervosa was the most common eating disorder. Table 4 shows the relationships between the presence and absence of at least one lifetime or current axis I disor- der and selected demographic and historical illness vari- ables. Lifetime axis I comorbidity was associated with early age at onset of first affective symptoms and bipolar disorder, development of more severe episodes over time, and family history of alcoholism and drug abuse. Current axis I comorbidity was associated with early age at onset of first affective symptoms and illness, limited occupational functioning, history of rapid cycling, and history of devel- opment of both cycle acceleration and more severe epi- sodes over time. Appendix 1 lists the demographic and historical illness indicators associated with one or more lifetime or current comorbid axis I disorders entered into the regression analysis. As shown in Table 5, significant in- dicators for lifetime comorbidity by stepwise logistic re- gression were early onset of bipolar disorder, early onset of affective symptoms, and family history of drug abuse. Sig- nificant indicators for current comorbidity were again early onset of bipolar disorder and affective symptoms, as well as development of more severe episodes over time and cycle acceleration. TABLE 4. Demographic and Historical Illness Measures for 288 Bipolar Patients With and Without Lifetime and Current Comorbid Axis I Disorders Number of Lifetime Comorbid Axis I Disorders Number of Current Comorbid Axis I Disorders Variable None (N=101) One or More (N=187) Analysis a None (N=192) One or More (N=96) Analysis a M ea n SD M ea n SD t d f p M ea n SD M ea n SD t d f p Age (years) Current 44.8 12.0 41.7 11.2 2.32 286 0.47 43.8 11.6 41.0 10.5 1.92 286 1.00 At onset of bipolar disorder b 26.0 10.6 20.3 9.7 4.53 267 0.0002 24.0 10.3 19.0 9.6 3.84 267 0.003 At onset of first affective symptoms 23.8 11.8 17.2 9.2 5.22 282 0.000007 21.3 10.4 16.0 10.0 4.06 282 0.001 At first treatment 30.9 11.3 29.4 11.0 1.16 277 1.00 30.1 11.4 29.5 10.6 0.46 277 1.00 At first hospitalization 30.0 10.9 29.3 10.9 0.43 203 1.00 29.8 10.9 28.9 11.0 0.57 203 1.00 N % N % 2 d f p N % N % 2 d f p Bipolar disorder diagnosis I or II b : bipolar I 80 79 159 85 1.57 1 1.00 155 81 84 88 2.08 1 1.00 Income <$20,000/year 66 65 107 57 2.10 1 1.00 121 63 52 54 2.25 1 1.00 Limited occupational functioning 35 35 81 43 2.05 1 1.00 64 33 52 54 11.55 1 0.03 Suicide attempts (one or more) 23 23 64 34 4.08 1 0.99 53 28 34 35 1.85 1 1.00 History Rapid cycling b,c 48 48 105 56 2.10 1 1.00 89 46 64 67 10.34 1 0.05 Psychosis b 59 58 113 60 0.13 1 1.00 105 55 67 70 6.37 1 0.29 Dysphoric mania b 49 49 123 66 8.12 1 0.14 106 55 66 69 4.88 1 0.69 Psychiatric hospitalization 76 75 129 69 1.25 1 1.00 140 73 65 68 0.85 1 1.00 Cycle acceleration 38 38 98 52 5.75 1 0.42 77 40 59 61 11.71 1 0.03 More severe episodes 51 50 134 72 12.78 1 0.02 108 56 77 80 16.00 1 0.001 Psychiatric history in first-degree relatives Unipolar disorder 54 53 106 57 0.27 1 1.00 106 55 54 56 0.03 1 1.00 Bipolar disorder 34 34 89 48 5.20 1 0.55 81 42 42 44 0.06 1 1.00 Any mood disorder 62 61 128 68 1.46 1 1.00 127 66 63 66 0.01 1 1.00 Suicide 16 16 39 21 1.07 1 1.00 33 17 22 23 1.36 1 1.00 Alcoholism 26 26 88 47 12.46 1 0.009 68 35 46 48 4.18 1 1.00 Drug abuse 18 18 70 37 11.89 1 0.02 55 29 33 34 0.99 1 1.00 a Probability multiplied by 22 to correct for multiple comparisons (Bonferronis inequality correction). b Clinician report (Clinician Questionnaire or Structured Clinical Interview for DSM-IV, Patient Edition); all others based on patient report. c Rapid cyclingfour or more episodes per year. 424 Am JPsychiatry 158:3, March 2001 COMORBIDITY WITH BIPOLAR DISORDER Discussion Our findings of high rates of lifetime and current sub- stance use, anxiety, and, possibly, eating disorders in out- patients with bipolar disorders are consistent with existing data from community (112) and clinical (46, 1316, 22, 23, 2830, 3537) samples, suggesting that these disorders co-occur with bipolar disorder more often than expected by chance alone. Indeed, in our group, bipolar disorder was twice as likely to be accompanied by another lifetime axis I psychiatric disorder (N=187, 65%) than to exist by it- self (N=101, 35%). Moreover, consistent with other find- ings, axis I comorbidity was associated with a more ad- verse onset and course of bipolar disorder (with earlier age at onset of affective symptoms and the bipolar disorder syndrome and higher rates of development of cycle accel- eration and more severe episodes over time) (7, 14, 2231). These findings, however, must be considered in view of several methodological limitations. First, this study in- cluded only patients with bipolar disorder and lacked di- rect comparisons with a normal control group, another psychiatrically ill group, or an epidemiologic sample. Also, interviewers were not blind to the patients established di- agnoses of bipolar disorder. The rates of comorbid axis I disorders found in our group might therefore be falsely el- evated because of Berksons bias (38) or interviewer bias. In addition, historical illness variables reported here were obtained retrospectively, sometimes by self-report, and it is possible that patients with comorbid disorders were bi- ased toward overreporting earlier age at onset and more severe course of their bipolar symptoms. A second limitation is that our group of bipolar patients may not be representative of the disorder because of the inclusion criteria of the Stanley Foundation Bipolar Treat- ment Outcome Network. Specifically, only outpatients willing to participate in research and to be compliant with treatment were included. Our results, therefore, might not be generalizable to other bipolar populations, including those who are hospitalized or those who are not in treat- ment. However, comparison of the Stanley Foundation Bi- polar Treatment Outcome Network bipolar patients with other clinical populations, including those of Winokur (39), the NIMH Collaborative Study (40), and the National Depressive and Manic-Depressive Association (41), re- veals many similarities (33). Another potential limitation is that there is considerable phenomenologic overlap among the manic, depressive, and mixed symptoms and episodes of bipolar disorder and other axis I disorders. Rates of certain axis I disorders might be falsely elevated because of misattribution of af- fective symptoms to these other disorders. Indeed, an im- portant complication of studies of comorbidity in general is that as the number of recognized psychiatric diagnoses increases, rates of comorbidity increase as well (6). Despite these limitations, our study has several strengths. First, to our knowledge, this is the largest cohort of indi- viduals with bipolar disorder to have their comorbid axis I disorders systematically assessed with structured inter- views. Epidemiologic studies assessing axis I comorbidity of patients with bipolar disorder have evaluated cohorts of 168 (3, 7, 8), 29 (10), and 99 (11) subjects, respectively. The largest clinical study assessing axis I comorbidity in bipo- lar patients (29) assessed comorbid substance abuse in 134 hospitalized bipolar I patients with a manic or mixed episode and found that 33% met criteria for an alcohol use disorder and 34% met criteria for a drug use disorder. Sec- ond, this is the first study to use DSM-IV criteria to diag- nose both bipolar and comorbid axis I disorders. Third, patients were drawn from five different sites that were geographically diverse, including four sites in the United States and one site in Europe. Fourth, relationships among comorbidity and demographic and historical illness vari- ables were systematically evaluated. Our findings of high rates of substance use, anxiety, and, to a lesser degree, eating disorders in patients with bipolar disorder have several important clinical implications. The first is that a comprehensive evaluation of patients with bipolar disorder should include a systematic search for and assessment of these and other comorbid disorders. Also, patients with uncomplicated bipolar disorder, espe- cially children, adolescents, and young adults, need to be observed carefully for the development of other axis I dis- orders and educated about their risk for developing them. Conversely, patients presenting with multiple axis I disor- ders should be carefully evaluated for the development of mood disorders, especially bipolar disorder. Second, in young people with a family history of bipolar disorder, the emergence of an early-onset anxiety, substance use, or eating disorder should trigger consideration of a prodro- mal mood disorder, including a bipolar disorder. Third, our findings that axis I psychiatric comorbidity may be as- sociated with earlier age at onset and development of cy- cle acceleration and more severe episodes over time clinical features of bipolar disorder that themselves have been associated with more severe illness or poorer out- comesuggest that bipolar disorder with a comorbid axis I disorder should be carefully and ultimately perhaps dif- ferentially managed. TABLE 5. Significant Indicators of Lifetime and Current Co- morbid Axis I Disorders in Patients With Bipolar Disorders According to Logistic Regression Indicator p Patients with one or more lifetime axis I disorders Early onset of bipolar disorder 0.002 Early onset of affective symptoms 0.03 Family history of drug abuse 0.002 Patients with one or more current axis I disorders Early onset of bipolar disorder 0.03 Early onset of affective symptoms 0.0002 More severe episodes 0.005 Cycle acceleration 0.02 Am JPsychiatry 158:3, March 2001 425 MCELROY, ALTSHULER, SUPPES, ET AL. Our data, however, do not permit conclusions regarding the comparative treatment of bipolar patients with and without various comorbid axis I disorders. To our knowl- edge, no large, prospective, controlled studies have as- sessed the effects of treating different comorbid disorders on the outcome of bipolar disorder or compared the effi- cacy of different mood-stabilizing agents in bipolar pa- tients with selected comorbid disorders. Such prospective data are necessary to determine whether differential treat- ment based on comorbidity improves the outcome of bi- polar disorder. Nonetheless, consideration of axis I co- morbidity in bipolar disorder might represent yet another clinically useful way of characterizing or subtyping the ill- ness. Furthermore, greater attention should be focused on the efficacy of agents with antimanic or mood-stabilizing properties in the treatment of pathological substance use, anxiety, and eating syndromes. How might the extensive overlap of bipolar disorder with these other axis I disorders be explained? One possibility is that these disorders are in fact distinct but unrelated dis- ease entities, representing either risk factors for each other or the sharing of similar end states from different etiologic mechanisms. This possibility is supported in part by the findings of high rates of substance use disorders in the families of patients with comorbid substance use disorder, suggesting the inheritance of two (or more) illnesses in some patients. Another possibility, however, is that bipolar disorder is related to substance use, anxiety, and eating dis- orders (or at least some forms of these disorders) and, by extension, that all of these disorders may be related to one another and share a common underlying pathophysiologic etiology (8). This possibility is supported by three large- scale epidemiologic studies indicating that mood, anxiety, and substance use disorders are highly comorbid with one another (3, 9, 11, 42). It is also supported by a growing body of research suggesting that substance use, anxiety, and eat- ing disorders may be associated with elevated familial rates of mood disorders and may respond to agents with thymo- leptic (antidepressant and/or mood-stabilizing) properties (21, 43). Indeed, preliminary research indicates that dys- regulation in several common neurotransmitter systems including the dopaminergic, serotonergic, noradrenergic, and -aminobutyric-acid-ergicmay be important in the pathophysiology of all of these disorders (4, 44, 45). Further research examining the overlap of these disorders would therefore appear to be just as important as further research into their differences. In sum, our findings are consistent with others suggest- ing that bipolar disorder is more often than not accompa- nied by other axis I disorders. Moreover, axis I comorbidity may be associated with clinical features that themselves have been associated with greater severity and/or poorer outcome of bipolar disorder. In subsequent work, we will extend these observations to the impact of axis I comor- bidity on the prospectively evaluated course of illness and differential response to treatment of bipolar disorder. Received June 15, 1998; revisions received Dec. 23, 1999, and March 2, 2000; accepted March 24, 2000. From the Stanley Founda- tion Bipolar Treatment Outcome Network, including the Biological Psychiatry Program, Department of Psychiatry, University of Cincin- nati College of Medicine; the University of California, Los Angeles, Neuropsychiatric Institute and the West Los Angeles Veterans Affairs Medical Center, Los Angeles; the Southwest Medical Center at Dallas; the Biological Psychiatry Branch, NIMH, Bethesda, Md.; and the HC Rmke Group, Willem Arntsz Huis and Academic Hospital, Utrecht, the Netherlands. 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Bipolar disorder diagnosis (bipolar I versus bipolar II) Income (<$20,000) Limited occupational functioning a Suicide attempts (one or more) b History of rapid cycling c History of dysphoric mania b History of psychosis History of psychiatric hospitalization Cycle acceleration over time c More severe episodes over time a Family history of a depressive disorder Family history of bipolar disorder Family history of any mood disorder Family history of schizophrenia Family history of suicide Family history of alcoholism b Family history of drug abuse b a This variable was included in the logistic regression for zero versus one or more lifetime and current axis I disorders. b This variable was included in the logistic regression for zero versus one or more lifetime axis I disorders. c This variable was included in the logistic regression for zero versus one or more current axis I disorders. 426 Am JPsychiatry 158:3, March 2001 COMORBIDITY WITH BIPOLAR DISORDER 6. 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