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Bipolar II
Journal of Af_ectiue Disorders, 8 (1985) 17-28 Elsevier
17
JAD 00255
Bipolar II Combine or Keep Separate?
Jean Endicott,
John Nee, Nancy Andreasen, Paula Clayton, Coryell
Martin Keller and William
NIMH Clinical Research Branch Collaborative Program on the Psychobiology of Depression: Clinical Studies, with partrcipation of the following: R.M.A. Hirschfeld, M.D. (Project Director and Co -Chairperson) and B. H. Lurkin, B.A. (NIMH, Bethesda); G. L. Klermnn, M.D. (Chairperson, Boston); M.B. Keller, M.D. and P. Lauori. Ph.D. (Boston); J.A. Fawcett, M.D. and W.A. Scheftner, M.D. (Chicago), N. C. Andreasen, M.D., W. Cotyell, M.D., G. Winokur, M.D. and P. Wasek, B.A. (Iowa dity); J. Endicott, Ph.D. and P. McDonald-Scott, M.A. (New York); S. Gure, M.D., T. Reich, M.D. and J. Rice, Ph.D. (St. Louis). Other contributors include: P.J. Clayton, M.D., J. Croughan, M.D., M. M. Katz, Ph.D., E. Robins, M.D., R. Shapiro, M.D. and R. Spitrer, M.D. (Received 27 February, 1984) (Accepted 9 May, 1984)
Summary Data on prior course, characteristics of index episode, and familial aggregation of patients with bipolar II disorder is discussed. The data supports the separation of this condition from both bipolar I and recurrent unipolar disorder.
Key words:
Bipolar I disorder - Bipolar II disorder - Recurrent unipolar disorder
Introduction Initially, use of the term bipolar disorder was limited to patients who had had both major depressive and manic episodes (Leonard 1962; Perris 1966, 1968; Dunner et al. 1976). More recently Supported in part by New York State Department of Mental Hygiene, NIMH Grant MH123664 and NIMH Grant MH30906. The paper was reviewed by the publications committee of the collaborative depression study and has its endorsement. Reprint requests: Jean Endicott, Ph.D., Research Assessment and Training Unit, New York State Psychiatric Institute, 722 West 168th Street, New York, NY 10032, U.S.A. 0165-0327/85/$03.30
0 1985 Elsevier Science Publishers
patients who have major depressive and hypomanic (but not manic) episodes have also been considered to have a form of bipolar disorder, first referred to as bipolar II by Dunner et al. (1970). Although the categories of bipolar I, bipolar II and unipolar (or monopolar) affective disorder are widely used, the criteria vary. Even the criteria used to separate (1) manic from hypomanic episodes and (2) hypomanic episodes from increased energy and activity still differ somewhat from one investigator or clinician to another. For instance, some investigators require hospitalization of the patient for a diagnosis of a manic episode (Perris 1968; Dunner et al. 1970) while others do not
B.V. (Biomedical
Division)
18
(Feighner et al. 1972; Spitzer et al. 1978; Krauthammer and Klerman 1979; DSM-III 1980; Akiskal 1981). Similarly, criteria for hypomanic periods vary with some investigators requiring a manic syndrome without treatment or hospitalization (Dunner et al. 1970) while others include periods of greater than usual energy, activity, and less need for sleep, etc., even if there is no evidence of impairment, poor judgment or loss of control (Spitzer et al. 1978). The best way to characterize other patients who have affective lability or mood swings without well delineated and episodic periods of hypomania (e.g., labile personality, cyclothymic disorder, or chronic hypomania). is even less clear (Spitzer et al. 1978; DSM-III 1980: Akiskal 1981). Some investigators limit their bipolar samples to patients who have had manic episodes and include patients with hypomanic episodes in their nonbipolar sample. Even if one considers hypomanic periods evidence of ‘bipolarity’ and excludes them from the nonbipolar sample, there is controversy as to the best way to study or classify patients who have such episodes in the absence of manic periods. Should they be combined with those who have bipolar I disorder into a general bipolar category or be kept separate? This paper reports findings from the clinical studies portion of the NIMH Clinical Research Branch Collaborative Project on the Psychobiology of Depression which support the separation of bipolar II disorder from both bipolar I and recurrent unipolar disorders. Two traditional ways of deciding whether conditions are worthy of separation is to compare their course and/or degree of familial aggregation (Feighner et al. 1972). For example, differences in age at onset, periodicity and severity, between groups of patients are usually considered suggestive of etiological heterogeneity. In addition, although differences in familial rates of particular disorders between groups are not proof of different genetic transmission, they are highly supportive of the hypothesis. The analyses reported in this paper are focused on: (1) the degree to which the prior course of patients in the 3 diagnostic groups is similar or different, including the degree to which the patients with bipolar II disorder resemble those with
bipolar I disorder or those with recurrent unipolar disorder; and (2) the evidence for differential familial association of various kinds of affective disorders for the 3 groups. Methods Subjects This paper compares patients who were diagnosed using the Research Diagnostic Criteria (RDC) (Spitzer et al. 1978). By these criteria a definite manic disorder requires a period with a persistent syndrome of elated mood and 3 associated symptoms (e.g., less need for sleep, increased activity), or irritable mood and 4 associated symptoms. The syndrome must either (1) lead to hospitalization, (2) last at least 1 week and result in serious impairment in functioning socially, at work, at home, at school, or with the family, or (3) be so severe that meaningful conversation is impossible. The criteria for hypomanic disorder requires a period with a persistent syndrome of elevated mood and 2 symptoms or irritable mood and 3 symptoms that last at least 2 days. There are no criteria for impairment. These criteria were used to select 3 groups: (I) bipolar I patients who had had at least 1 episode which met criteria for mania and 1 for major depressive disorder (n = 122); (2) bipolar II patients who had had at least 1 episode of major depressive disorder and at least 1 that met criteria for hypomanic disorder but who had never had an episode of mania (n = 66); (3) recurrent unipolar depressive patients who had had at least 2 episodes of major depressive disorder (and never met criteria for manic or hypomanic disorder) (n = 104). Patients who had ever met criteria for schizophrenia, schizoaffective disorder, or unspecified functional psychosis were excluded from all 3 groups. In addition, patients who met criteria for cyclothymic or labile personality were excluded from the recurrent unipolar group. All index subjects were admitted as inpatients or outpatients to 1 of the 5 participating centers in the collaborative depression project. This project is described in detail elsewhere (Katz et al. 1978). These analyses included subjects and relatives on the master file in the spring of 1983. The index subjects were evaluated during the
19
intake episode with a number of procedures, including the Schedule for Affective Disorders and Schizophrenia (SADS) (Endicott and Spitzer 1978) and the RDC. The diagnostic evaluations were based on all sources of information available and were updated at discharge or 2 months after admission. The information included chart review, discussions with therapists and spouses, and observations during the intake episode. The procedures used for first degree relatives included a direct interview with the Schedule for Affective Disorders and Schizophrenia lifetime version (SADS-L) whenever possible. This was conducted by a professional rater blind to proband diagnosis. In addition, each index subject and 1 other family member were interviewed using the Family History Research Diagnostic Criteria (FHRDC) (Andreasen et al. 1977) interview guide, and a consensus FH-RDC was constructed using information from the 2 informants for subjects who had not been interviewed directly. The family analyses reported here are based on direct SADS-L interviews of the first degree relatives. It is unlikely that a history of hypomanic episodes would be TABLE
described by family members unless they are carefully questioned regarding such periods (and the FH-RDC does not include such questions). Results
with Discussion
Some of the results in this section are discussed as they are described for the purpose of clarity and to avoid redundancy in the conclusions section. Statistically significant differences are noted in the tables. When the data are presented by sex of subjects, all comparisons are made within sex and between groups. Males and females were not compared for statistical purposes. Because of the large number of contrasts and the exploratory nature of the analyses, the indications of statistical significance should be considered descriptive rather than hypotheses testing. The P-values are given at the less than 0.05 level only since they were not adjusted for multiple comparisons. Comments such as ‘somewhat higher’ are indicative of trends only. Characteristics of index subjects and relatives Table 1 shows the number of index subjects
1
CHARACTERISTICS
OF INDEX
PATIENTS Diagnoses
AND RELATIVES of index patients
Bipolar II
Bipolar I Male
for intake episode
Female
Recurrent
Male
Female
Male
unipolar Female
Total number of index patients
52
70
21
35
68
136
Age of index patients Mean Median
35 33
41 40
35 30
38 34
42 39
43 40
Status of index patients % Inpatient % Outpatient
96 4
94 6
69 31
60 40
83 17
77 23
Total number of index patients in family study
44
53
9
21
38
83
167
222
39
52
197
247
40 38
43 43
40 38
49 41
45 45
43 43
Total number of relatives interviewed Age of interviewed Mean Median
relatives
20
available, the number of family units in the family studies portion of the analyses, and the number of first degree relatives who were interviewed directly. There were no significant differences in the distributions of the ages of the index patients or of
TABLE
the directly interviewed relatives for the 3 groups. All of the index patients with bipolar II and recurrent unipolar major depressive disorder were in an episode of major depressive disorder when they were admitted to the study. The index pa-
2
AGE AT ONSET
AND
PRIOR
TREATMENT
OF INDEX
Bipolar I
PATIENTS Bipolar
II
Recurrent
unipolar
Male (n = 35)
Female (n = 70)
Male (n = 21)
Female (n = 35)
Male (n = 6X)
Female (n = 136)
Age first significant affective symptoms Mean Median % Under 19 8 Over age 30
24 ‘I 20 3x 27
25 19 33 29
24 21 34 24
23 ’ 19 34 23 ’
2’) ‘J 24 22 44
2x ‘ 24 26 42 t
Age first prior outpatient treatment Mean (if ever) Median (if ever) ‘R Under 19
25 il 20 35
26 24 32
22 h 19 4x d
24 ’ 21 34
31 &h 26 22 .’
30 L 27 24
27 a
17 c.d
26 a 22
30 29
52 a 30 27
34 C 30 31
37 34 d 31
31 d 33 30
Age at first major depressive episode Mean Median
24 a 22
27 25
26 23
25 22
32 d 2x
29 26
Age at first manic episode * Mean Median
29 27
33 30
Age first prior psychiatric hospitalization % Never Mean (if ever) Median (if ever)
Age first hypomanic episode * Mean Median Median number prior major depressive episodes ‘JW.~ The same * Patients inquired
2
4
_ -.
_
29 24
27 27
_ _
_
2
4
2
2
values with the same superscript letter are significantly different from each other (P i 0.05). All comparisons were for sex only: a, b for males; c, d for females. may have had hypomanic episodes prior to manic eposides but If there had been 2 or more manic episodes they were not about. Therefore they are not noted here.
21
tients with bipolar I disorder may have been admitted with an episode of either major depressive, mania, mixed or cycled between depression and mania. Prior course of index patients Age at onset Table 2 summarizes the data on the age at first clinically significant affective symptoms, first outpatient treatment, first hospitalization and first major depressive, manic, or (for bipolar II subjects) hypomanic episode. On inspection, the bipolar II patients can be seen to be more similar to the bipolar I patients than to the recurrent unipolar patients whenever the bipolar I and recurrent unipolar patients differed. This was true for both males and females. In every comparison shown, the average age of the patients in the 2 bipolar groups was somewhat lower than that for the unipolar patients, with some of the within sex differences reaching statistically significant levels (see Table 2). There were no significant differences between the 2 groups of bipolar patients on any of the measures. The bipolar I patients were more likely to have been hospitalized prior to the index episode with a trend for the average age at first hospitalization for both bipolar groups to be earlier than that of the unipolar group. (The greater likelihood of hospitalization of bipolar I patients may be accounted for, in part, by the RDC criteria which allows hospitalization to count as the severity criteria for mania if severe impairment cannot be established on the basis of the more clinical criteria.) Other characteristics of episodes of affective disorder All of the index subjects had had at least 1 episode of major depressive disorder and most were in such an episode at the time of admission to the study. Table 3 shows some of the characteristics of these episodes. The bipolar patients were more likely to have had (currently or in the past) an episode of major depressive disorder characterized by delusions and/or hallucinations (i.e., psychotic subtype). The first episode of major depressive disorder in all 3 groups of patients was
more often classified as primary rather than secondary (i.e., not preceded by one or more specified mental disorders). With the exception of the bipolar I females being somewhat higher, there are no large differences in the percentage of first episodes being primary in the 3 groups of patients. The same was true for the intake episode as well, although fewer subjects met criteria for primary major depressive disorder at that time (having had other types of disorders since the first depressive episode). Both groups of bipolar patients had significantly (P < 0.05) larger percentages of patients who had made at least 1 suicide attempt rated as indicating ‘at least moderate intent to die’. A large percentage of both bipolar I and bipolar II patients cycled during the intake episode. By definition the bipolar II patients would have cycled into a hypomanic period only while the bipolar I patients could have cycled into a period of manic or hypomanic symptoms. The tendency to have cycling or mixed episodes was also shown in the past by both groups of bipolar patients. The mean Global Assessment Scale (GAS) (Endicott et al. 1976) level of severity for the index episode was similar for the 3 groups with that of the bipolar I patients indicating somewhat more severe psychopathology and more impaired functioning (in keeping with the larger percentage of hospitalized patients in the bipolar I group). There were no differences in the percentages of the three groups who met criteria for the RDC endogenous subtype of major depressive disorder during the index episode. Many of the patients in all 3 groups also had had a chronic ‘minor’ affective disorder that preceded the major affective episode that led to admission to the study. When both chronic depressive disorders (intermittent depressive disorder or chronic minor depressive disorder) and cyclothymic personality are added together, the rate of chronic affective symptoms was higher in the bipolar II and recurrent unipolar patients than in the bipolar I patients (significantly so, for the males). (Since only 6 recurrent unipolar patients had been excluded because they had also met criteria for cyclothymic personality, this exclusion did not greatly affect their percentage with a chronic affective disorder.)
22 TABLE
3
OTHER
CHARACTERISTICS
OF AFFECTIVE
DISORDER
IN INDEX Bipolar
Bipolar I
PATIENTS II
Recurrent
Female (n = 70)
Male (n = 21)
Female (n = 35)
($)
(SE)
(%)
(F)
21
34 ‘
24
23
10
16’
60
84
62
71
66
77
13 ‘&I 13
10 19
29 6
2x il *
25 d *
10 a.h
26
29 a
35
2x
Lifetime suicide attempt with at least moderate intent to die
21
27 ’
24
29 ’
12
Intake episode included major depressive period Psychotic ** Endogenous ** Primary * *
56 a,h 21 62 47
61
100 a 24 67 57
100 c 14 63 51 c
Intake episode involved cycling
40
54
52
31
Mean Global Assessment Scale score at intake
30
31
35
32
Lifetime diagnosis Psychotic major depression First episode of major depression was primary Chronic depressive disorder Cyclothymic disorder Either chronic depressive or cyclothymic disorder
4” 6
u.h’c’d The values with the same superscript same sex only: a, b for males; c, d for * Patients with cyclothymic disorder were ** Percentage based on subjects who had a
cd
23 ’ 5x 79’
‘
letter are significantly different from each other females. excluded (n = 6). major depressive period during intake episode.
Characteristics of episodes of nonaffective disorders Table 4 indicates that the patients in all 3 groups had met RDC criteria for a number of other mental disorders, particularly alcoholism in the males. It is noteworthy that the rate of alcoholism in the bipolar II females approaches that of the males and is significantly higher (P < 0.05) than that for the other 2 groups of females. There were no trends for differences in the rates for various anxiety disorders, Briquet’s disorder, or drug abuse. However, a larger percentage of bipolar II males and females had also met criteria for schizotypal features (14%). More bipolar II males had met criteria for antisocial personality as
Male (n = 6X) (%)
unipolar
Male (n = 52)
h
Female (n =136) @)
25
13
65 56
100” 12‘ 66 66
35
35
10
cd
(P < 0.05). All comparisons
were for
well, while more bipolar II females reported premenstrual dysphoria. Both groups of bipolar males were more likely to have been hyperactive as children and there was a tendency for both groups of bipolar females to report more childhood hyperactivity as well (as compared with the recurrent unipolar females). The bipolar I patients had a lower percentage of ‘other psychiatric disorders’. The ‘other disorders’ were usually conditions which meet DSM-III criteria for a personality disorder not included in the RDC. As noted in Table 4 and above, the bipolar II patients had more frequently met criteria for one or more nonaffective mental disorders. The num-
23 TABLE
4
PERCENTAGE
OF INDEX
PATIENTS
WHO HAD EVER MET CRITERIA
Bipolar I
Alcoholism Drug abuse Panic disorder General anxiety disorder Phobic disorder Obsessive-compulsive disorder Briquet’s disorder Antisocial personality Schizotypal features Other psychiatric disorders Hyperactivity as a child Premenstrual dysphoria
Bipolar II
Recurrent
DISORDERS
unipolar
Female (n = 70)
Male (n = 21)
Female (n = 35)
Male (n = 68)
Female (n = 136)
(%)
(S)
(S)
(W)
13 ‘ 4 6 3
33
(8) 29 c.d
(%)
40 4 2 10 2 2 0 0” 12 12 a 29
32 10 0 7 7 4 0 3h 7 31 a 18
16d 6 4 5
5 0
5 0
0 1 0 4 16’ 20 44’
0 0
14 a.h 14 29 30 _ different
6 6 6 6 9 6 3 14 37 c 14 7I c.d
1 4 2 6 24 10 42 d
from each other (P < 0.05). All comparisons
were for same
5
PERCENTAGE OF INDEX PATIENTS WITH SPECIFIC RDC AFFECTIVE DISORDERS
AT LEAST
Diagnoses
Fumi!v posrtruafor: * ** Mania/hypomania Bipolar I Bipolar II Manic only Hypomanic only (never manic) Unipolar major depressive disorder (never manic or hypomanic) Other affective disorders (minor, intermittent, labile, cyclothymic and never manic, hypomanic or major depressive) Any affective disorder Schizoaffective, manic Schizoaffective, depr. * ** *** a.h
NONAFFECTIVE
Male (n = 52)
a.b.r.d The values with the same superscript letter are significantly sex only: a, b for males: c, d for females.
TABLE
FOR SPECIFIC
ONE
FIRST
of index patients
DEGREE
RELATIVE
WHO
*
Bipolar I (n = 97)
Bipolar II (n = 30)
Recurrent (n = 121)
(W)
(%)
(S)
31 a g a& 11= 3 a.h
27 3a 23 a,b Oa
15 a 3h 10 h Oh
g a.h
0”
3b
39
31
52
5 75 3 a.h
7 70 0” 0
7 74 Oh 1
2
MET CRITERIA
unipolar
**
All index patients with a lifetime diagnosis of schizophrenia or schizoaffective disorder were excluded from the sample Index patients with a lifetime diagnosis of cyclothymic or labile personality were also excluded. Unless noted, diagnoses are not mutually exclusive. The values with the same superscript letter are significantly different from each other at at least P < 0.05 level.
FOR
24
ber and nature of the other disorders would often be associated with a lack of clarity in their lifetime diagnosis and lead to problems of reliability of descriptions of past episodes. In addition, the additional disorders are apt to be associated with chronic symptoms and impairment. This is particularly true for the female bipolar II patients. In addition to other mental disorders, there was a trend for the bipolar II patients to never marry and, for those who had done so, to more frequently be separated or divorced. Given the confusing clinical picture and chronic nature of the problems seen in many of the bipolar II patients, it is not surprising that they were often noted to have a ‘clinical’ diagnosis (made by past therapists or by the cohort rater) of ‘borderline personality’. Probably another major reason for frequent use of this clinical diagnosis is that more of the bipolar II patients (both male and female) had met criteria for schizotypal features (14%). Furthermore, 57%
TABLE
Familial aggregation Rutes of specific disorders in first degree relatives of the three groups of patients Tables 5-7 present the familial lifetime rates of various disorders for the subset of patients in-
6
LIFETIME Relatives
of both male and female bipolar II patients had been scored positive for at least 1 schizotypal item (a percentage much higher than that for the other 2 groups). The types of schizotypal items on which the bipolar II patients scored more frequently tended to fall under the general clinical category of ‘sense of reality’ (e.g., depersonalization, illusions, magical thinking, and ideas of reference). Furthermore, the failure to recognize that patients with bipolar II disorder had an affective disorder, much less a bipolar affective disorder, is indicated by a less frequent use of antidepressants or lithium, even during the index episode.
DIAGNOSES diagnoses
OF AFFECTIVE Diagnoses
DISORDERS
IN INTERVIEWED
OF INDEX
PATIENTS
of index patients Recurrent (n = 121)
Bipolar II (n = 30)
Bipolar I (n = 97)
Ever manic/hypomanic * Major depressive only Minor, intermittent only Labile, cyclothymic only Any affective disorder Subtypes of Major Aff. Dis. Bipolar I Bipolar II Unipolar depression Recurrent unipolar depr. Primary depr. ** Secondary depr. * * * Psychotic depr. Incapacitating depr. Schizoaffective, manic Schizoaffective. depr.
RELATIVES
&polar
Male (n = 167)
Female (n = 222)
Male (n = 39)
Female (n = 52)
Male (n = 197)
Female (n = 247)
(%)
(S)
(%)
(%)
(S)
(S)
12.0 il 18.6 1.8 il.h 2.4 34.7
7.7 24.3 ’ 9.4 1.4 42.X
10.3 h 12.x 7.7 L1 0.0 30.X
11.5 21.2 d 5.x 1.9 40.4
3.0 u.h 20.3 6.6 h 0.5 30,s
5.3 36.4 c.d 6.9 2.0 50.2
3.0 4.x B 18.6 7.8 20.4 7.2 0.6 3.0 0.6 0.6
1.X 3.2 ’ 24.3 ‘ X.6 ‘ 26.1 ‘ 4.5 0.9 4.1 0.9 0.5
0 10.3 h 12.x 7.7 15.4 5.1 0.0 2.6 0 0
1.9 9.6 21.2 9.6 26.9 5.x 1.9 9.6 1.9 0
1 .o 1.o n.h 20.3 5.6 13.7 9.1 0.0 4.1 0 0
0.4 4.0 36.4 15.4 34.8 7.3 2.0 4.5 0.0 4
‘ d ’
L
* Includes relatives with unipolar and bipolar manic or hypomanic disorders. ** Includes relatives with both unipolar and bipolar disorders who ever met criteria for primary depressive disorder. *** Includes relatives who have ever had a secondary major depressive disorder. a.h.c.d The values with the same superscript letter are significantly different from each other (P -C0.05). All comparisons same sex only: a, b for males; c. d for females.
‘.’ r L.d
c
were for
25
family units with unipolar major depressive disorder only (Tables 5 and 6). However, in spite of the similarity in total indices of familial ‘bipolarity’, the rates of the 2 types of bipolar disorder in the families differ somewhat for the bipolar I and II patients (Tables 5 and 6). The subtypes of bipolar disorder in the family units and individual relatives are more similar to that of the patients (i.e., bipolar I patients have more bipolar I relatives, while bipolar II patients have more bipolar II relatives). The relative risk for bipolar I disorder in the family units of bipolar I probands was 3.1 (that of the family units of bipolar II probands was less than 1.0). On the other hand, the relative risk of bipolar II disorder in the family units of bipolar II probands was 2.2 while that in the family units of bipolar I probands was less than 1.0. These findings suggest some specificity of association between subtypes of bipolar disorders in index patients and relatives. Furthermore, using the multiple threshold method of genetic analysis indicated that the unitary hy-
volved in the family studies portion of the project. The diagnoses are based upon direct clinical interviews and are presented in 2 forms: (1) the percentage of patients who have a positive family history (i.e., at least 1 first degree relative has had a specific disorder) (Table 5); and (2) the percentage of first degree relatives who have had the disorder (Table 6). The percentages in these tables have not been adjusted for age, since the ages in relatives of the 3 groups of patients had similar means and distributions. The rates for both types of bipolar disorder are higher in the relatives and for the family units of both bipolar groups. If one combines the rates for the 2 types of bipolar disorder in the family units (Table 5) 31% of the bipolar I patients and 26.6% of the bipolar II patients have families positive for manic or hypomanic periods, while only 14.9% of the recurrent unipolar patients have at least 1 relative who has had manic or hypomanic episodes. On the other hand, the recurrent unipolar patients are more apt to have more relatives and
TABLE
7
LIFETIME Relatives
DIAGNOSIS diagnoses
OF NONAFFECTIVE Diagnoses
DISORDERS
OF INDEX
PATIENTS
of index patients
Bipolar I (n = 97)
Alcoholism Drug abuse Panic disorder Generalized anxiety disorder Phobia Obsessive-compulsive disorder Schizophrenia Unspecified psychosis At least 1 schizotypal feature Other psychiatric disorder Never mentally ill
IN RELATIVES
Bipolar II (n = 30)
Recurrent (n = 12)
unipolar
Male (n = 167)
Female (n = 222)
Male (n = 39)
Female (n = 52)
Male (n = 197)
Female (n = 247)
(%)
(%)
(%)
(%)
(S)
(%)
23.1 4.8 0.6
5.0 2.7 1.8
23.1 2.6 0
3.8 1.9 0
21.3 5.1 2.0
5.3 2.8 1.2 11.3 3.6
6.0 1.2
1.7 0.9 c
5.1 0
5.8 5.8 c
6.1 2.0
6 1.8
Or 0.5
0 0
1.9 c 0
0 0
0.8 0
0.6
0
0
0
0
0
1.8
2.7
5.1
0
2.5
2.4
10.2
12.6
1.7
11.5
14.2
13.8
41.3
44.6
53.8
42.3
51.8
38.9
’ The values with the same superscript
letter are significantly
different
from each other (P i 0.05).
26
pothesis of continuity could be rejected for bipolar I and bipolar II disorders (Theodore Reich, personal communication). None of the differences for other types of affective disorders among the 3 groups of relatives are statistically significant. For example, if one adds the rates for mania and major depression only to calculate the rates for any type of major affective disorder, 51.6% of family units of bipolar I patients, 40.0% of bipolar II patients, and 54.6% of recurrent unipolar patients met criteria for some type of major affective disorder (Table 5). If the families with hypomania only are then added, the rates are 70.0%, 63.3% and 67%, and when the rates for all other affective disorders (i.e., the ‘minor’ affective disorders) are added, the rates are 75.4%, 70% and 73.6%. Similarly, if one looks at the rates for a major (or any) affective disorder in the relatives of the 3 groups, the 3 groups of relatives do not differ significantly (Table 6). The 3 groups of relatives also differed little, if at all, in the rates of RDC nonaffective disorders. The female relatives of the bipolar II patients had a higher frequency of phobic disorder and obsessive-compulsive disorder (Table 7). The percentage of relatives judged to have met criteria for never mentally ill was also similar for the 3 groups, averaging approximately 45%. Conclusions The title of the article, ‘Bipolar II - Combine or Keep Separate?’ calls for some recommendations based on the data we have presented. There are no firm criteria that are used in medicine by which one decides that differential course or family data indicate that 2 groups are essentially the same or different enough to warrant continued separation in future analyses. However, one can assess the possible effects on research studies of such differences when making recommendations to either combine samples into 1 group or to continue to separate them. In the authors’ opinion, the data on prior course, characteristics of the index episode, and familial aggregation of the 2 types of bipolar disorder are sufficiently different to support the separation of both bipolar I and bipolar II disorders from recur-
rent unipolar disorder. Furthermore, the data are in keeping with those of others and indicate that bipolar II disorder is closer to bipolar I than to unipolar depressive disorder (Dunner et al. 1970; Gershon et al. 1982; Dunner 1983). There is less evidence supportive of the continued separation of bipolar I and bipolar II disorders. The 2 groups are similar in many ways (i.e., age at onset, increased tendency to cycle within episodes, increased risk for psychotic depressive episodes, and similarity in the percentage of family units and individual relatives characterized by either manic or hypomanic episodes). However, in spite of these similarities, there are a number of ways in which the 2 bipolar groups differ and these differences are potentially of great importance to both clinicians and investigators. A larger proportion of the bipolar II patients have a prior history that is complicated by other mental disorders. Their prior history is also more often characterized by the types of chronic symptoms that have been found to be predictive of a less satisfactory response to the usual treatments for major affective episodes (Akiskall981; Stone 1981; Gaviria et al. 1982). If this is the case, in the future the bipolar II patients are also likely to be found to have different biological features as well as other non-familial correlates. For instance, a recent study found more Raynaud’s phenomena, migraine headache, and symptoms referred to in the literature as ‘migraine equivalents’ in patients with bipolar II disorder than in those with either bipolar I or unipolar depressive disorder (Endicott 1984). The higher degree of comorbidity of other mental disorders as well as other medical disorders in the bipolar II patients is apt to complicate the interpretation of treatment and biological studies of patients with affective disorder if patients with bipolar I and bipolar II disorders are not tagged so that analyses may take this into account. Other evidence supportive of continued separation of bipolar II disorder from bipolar I disorder is found in the family data. Although the percentage of relatives who report ever having been either manic or hypomanic in both bipolar groups is higher than that for the recurrent unipolar group, there is also a higher percentage of both relatives and family units of the bipolar II patients who are characterized as bipolar II dis-
27
order as compared with the other 2 groups. In spite of the relative unreliability of the judgment of past episodes of hypomania (Andreasen et al. 1977) (which is apt to work against finding consistent group differences), the findings reported here of an increased rate of bipolar II disorders in the relatives of bipolar II patients are consistent with other studies which used somewhat different procedures (Dunner et al. 1983; Gershon et al. 1982). Both of these studies also found a somewhat higher rate of bipolar II disorder in the relatives of bipolar II patients. Furthermore, when the analyses of data in the current project were limited to more homogeneous groups of both patients and relatives (i.e., those whose most recent depressive episode had been classified as primary by RDC criteria) the findings were similar (Coryell 1984). Although the specific rates varied slightly, the bipolar II patients also had the highest rate of bipolar II relatives when the more pure samples of both relatives and index subjects were studied. Both relative risk and multiple threshold genetic analysis support a rejection of the hypothesis that bipolar II disorder is simply a less severe form of bipolar I disorder. The results reported here, as well as those of others, suggest that bipolar II patients and relatives are heterogeneous as to genotype and include some individuals who are at risk to ‘switch’ to bipolar I disorder at some time in the future (Dunner et al. 1976; Akiskal et al. 1977, 1978, 1983; Klerman 1980). These individuals may indeed be displaying a less severe manifestation of bipolar I disorder. At the same time, there is sufficient data to suggest that other bipolar II patients may have a type of bipolar disorder that ‘breeds true’ and not simply a less severe manifestation of bipolar I disorder. At the present time we cannot identify the 2 (or more) hypothesized ‘types’ of bipolar II patients and relatives. Followup studies and more sophisticated genetic analyses with larger samples may help determine the degree to which the assumption of at least 2 types of bipolar II disorder holds. In view of our results as well as those of others which identify similarities and differences for the 3 conditions in prior course, phenomenology, and familial rates of disorder, the authors recommend that bipolar II patients be categorized separately
from both unipolar and bipolar I patients. This recommendation is consistent with that noted recently by Kupfer and Rush (1983) when they conveyed the recommendations of a conference on the origins of depression held in Berlin in 1982. References Akiskal, H.S., Subaffective disorders Dysthymic, cyclothymic, and bipolar II disorders in the ‘borderline’ realm, Psychiat. Clin. N. Amer., 4 (1981) 25-46. Akiskal, H.S., Bitar, A.H., Puzantian, V.R., Rosenthal, T.H. and Walter, P.W., The nosological status of neurotic depression - A prospective three or four year follow-up examination in light of the primary-secondary and unipolar-bipolar dichotomies, Arch. Gen. Psychiat. (Chic.), 35 (1978) 756-766. Akiskal, H.S., Djenderedjian, A.H., Rosenthal, R.H. and Khani, M.K.. Cyclothymic disorder - Validating criteria for inclusion in the bipolar affective group, Amer. J. Psychiat., 134 (1977) 1227-1233. Akiskal, H.S., Walker, P.W., Puzantian, V.R., King, D.. Rosenthal, T.L. and Dranon, M., Bipolar outcome in the course of depressive illness, J. Affect. Dis., 5 (1983) 115-128. Andreasen, N.C., Endicott, J., Spitzer, R.L. and Winokur, G., The family history method using diagnostic criteria, Arch. Gen. Psychiat. (Chic.), 34 (1977) 1229-1235. Angst, J., Frey, R., Lohmeyer, B. and Zerbin-Rudin, E., Bipolar manic-depressive psychosis - Results of genetic investigation, Hum. Genet., 55 (1966) 2377254. Coryell, W., Endicott, J., Reich, T., Andreasen, N. and Keller, M., A family study of bipolar II disorder, Brit. J. Psychiat., In press. Diagnostic and Statistical Manual (DSM-III). 3rd edition, American Psychiatric Association, Washington, DC, 1980. Dunner, D.L., Subtypes of bipolar affective disorder with particular regard to bipolar II, Psychiat. Develop., 1 (1983) 75-86. Dunner, D.L., Fleiss, J.L. and Fieve, R.R., The course of development of mania in patients with recurrent depression. Amer. J. Psychiat., 133 (1976) 905-908. Dunner, D.L., Gershon, E.S. and Goodwin, F.K., Heritable factors in the severity of affective disorders, Sci. Proc. Amer. Psychiat. Ass., 123 (1970) 187-188. Endicott. J. and Spitzer, R.L.. A diagnostic interview - The schedule for affective disorders and schizophrenia, Arch. Gen. Psychiat. (Chic.), 35 (1978) 837-844. Endicott, J., Spitzer, R.L., Fleiss, J.L. and Cohen, J., Global assessment scale A procedure for measuring overall severity of psychiatric disturbance, Arch. Gen. Psychiat. (Chic.), 33 (1976) 766-771. Endicott, N.A., Psychosocial and behavioral factors in myocardial infarction and sudden death. In: S. Chanin (Ed.), Introduction to Psychosomatic Medicine, Norton, New York, NY., 1984, In press. Feighner, J.R., Robins, E., Guze, S.B., Woodruff, R.A., Winokur, G. and Munoz, R., Diagnostic criteria for use in
28 psychiatric research, Arch. Gen. Psychiat. (Chic.), 26 (1972) 57-63. Gaviria, M.. Flaherty, .I. and Val, E., A comparison of bipolar patients with and without borderline personality disorder, Psychiat. .I., 7 (1982) 190-195. Gershon, E.S., Hamovit, J., Guroff, J.J., Dibble, E., Lackman. J.F., Sceery, W., Targun, S.D., Nurenberger, J.L.. Goldin, R.R. and Bunney, W.E., A family study of schizoaffective. bipolar I, bipolar II, unipolar, and normal control probands, Arch. Gen. Psychiat. (Chic.), 39 (1982) 1157-1167. Katz, M.M., Secunda, SK., Hirschfeld, R.M.A. and Koslow, S.H., NIMH clinical research branch collaborative program on the psychobiology of depression, Arch. Gen. Psychiat. (Chic.), 36 (1978) 765-771. Klerman. G.L., Long-term outcomes of neurotic depressions. In: S. Sells, R. Crandall, M. Roff, J.S. Strauss and W. Pollin (Eds.), Human Functioning in Longitudinal Perspective. Williams and Wilkins, Baltimore, MD, 1980. pp. 58-70. Krauthammer, C. and Klerman, G.L., The epidemiology of
mania. In: B. Shopsin (Ed.), Manic Illness, Raven Press, New York. NY, 1979, pp. 11-28. Kupfer, D.J. and Rush, J., Recommendations for depression publications (Letter to the editor), Arch. Gen. Psychiat. (Chic.), 40 (1983) 1931. Leonhard. K., Korff, I. and Shulz. H.. Die Temperamente in den Familien der monopolaren und bipolaren phasischen Psychosen. Psychiat. Neurol.. 143 (1962) 416-434. Perris, C., A study of bipolar (manic depressive) and unipolar recurrent depressive psychosis, Part 1 (Genetic investigations), Acta Psychiat. Stand., Suppl. 194 (1966) 15544. Perris, C., The course of depressive psychosis, Acta Psychiat. Stand., 44 (1968) 238-248. Spitzer, R.L., Endicott, J. and Robins, E., Research diagnostic criteria ~ Rationale and reliability, Arch. Gen. Psychiat. (Chic.), 35 (1978) 773-782. Stone, M., Borderline syndromes A consideration of subtypes and an overview, directions for research, Psychiat. Clin. N. Amer., 4 (1981) 3-24.
17
JAD 00255
Bipolar II Combine or Keep Separate?
Jean Endicott,
John Nee, Nancy Andreasen, Paula Clayton, Coryell
Martin Keller and William
NIMH Clinical Research Branch Collaborative Program on the Psychobiology of Depression: Clinical Studies, with partrcipation of the following: R.M.A. Hirschfeld, M.D. (Project Director and Co -Chairperson) and B. H. Lurkin, B.A. (NIMH, Bethesda); G. L. Klermnn, M.D. (Chairperson, Boston); M.B. Keller, M.D. and P. Lauori. Ph.D. (Boston); J.A. Fawcett, M.D. and W.A. Scheftner, M.D. (Chicago), N. C. Andreasen, M.D., W. Cotyell, M.D., G. Winokur, M.D. and P. Wasek, B.A. (Iowa dity); J. Endicott, Ph.D. and P. McDonald-Scott, M.A. (New York); S. Gure, M.D., T. Reich, M.D. and J. Rice, Ph.D. (St. Louis). Other contributors include: P.J. Clayton, M.D., J. Croughan, M.D., M. M. Katz, Ph.D., E. Robins, M.D., R. Shapiro, M.D. and R. Spitrer, M.D. (Received 27 February, 1984) (Accepted 9 May, 1984)
Summary Data on prior course, characteristics of index episode, and familial aggregation of patients with bipolar II disorder is discussed. The data supports the separation of this condition from both bipolar I and recurrent unipolar disorder.
Key words:
Bipolar I disorder - Bipolar II disorder - Recurrent unipolar disorder
Introduction Initially, use of the term bipolar disorder was limited to patients who had had both major depressive and manic episodes (Leonard 1962; Perris 1966, 1968; Dunner et al. 1976). More recently Supported in part by New York State Department of Mental Hygiene, NIMH Grant MH123664 and NIMH Grant MH30906. The paper was reviewed by the publications committee of the collaborative depression study and has its endorsement. Reprint requests: Jean Endicott, Ph.D., Research Assessment and Training Unit, New York State Psychiatric Institute, 722 West 168th Street, New York, NY 10032, U.S.A. 0165-0327/85/$03.30
0 1985 Elsevier Science Publishers
patients who have major depressive and hypomanic (but not manic) episodes have also been considered to have a form of bipolar disorder, first referred to as bipolar II by Dunner et al. (1970). Although the categories of bipolar I, bipolar II and unipolar (or monopolar) affective disorder are widely used, the criteria vary. Even the criteria used to separate (1) manic from hypomanic episodes and (2) hypomanic episodes from increased energy and activity still differ somewhat from one investigator or clinician to another. For instance, some investigators require hospitalization of the patient for a diagnosis of a manic episode (Perris 1968; Dunner et al. 1970) while others do not
B.V. (Biomedical
Division)
18
(Feighner et al. 1972; Spitzer et al. 1978; Krauthammer and Klerman 1979; DSM-III 1980; Akiskal 1981). Similarly, criteria for hypomanic periods vary with some investigators requiring a manic syndrome without treatment or hospitalization (Dunner et al. 1970) while others include periods of greater than usual energy, activity, and less need for sleep, etc., even if there is no evidence of impairment, poor judgment or loss of control (Spitzer et al. 1978). The best way to characterize other patients who have affective lability or mood swings without well delineated and episodic periods of hypomania (e.g., labile personality, cyclothymic disorder, or chronic hypomania). is even less clear (Spitzer et al. 1978; DSM-III 1980: Akiskal 1981). Some investigators limit their bipolar samples to patients who have had manic episodes and include patients with hypomanic episodes in their nonbipolar sample. Even if one considers hypomanic periods evidence of ‘bipolarity’ and excludes them from the nonbipolar sample, there is controversy as to the best way to study or classify patients who have such episodes in the absence of manic periods. Should they be combined with those who have bipolar I disorder into a general bipolar category or be kept separate? This paper reports findings from the clinical studies portion of the NIMH Clinical Research Branch Collaborative Project on the Psychobiology of Depression which support the separation of bipolar II disorder from both bipolar I and recurrent unipolar disorders. Two traditional ways of deciding whether conditions are worthy of separation is to compare their course and/or degree of familial aggregation (Feighner et al. 1972). For example, differences in age at onset, periodicity and severity, between groups of patients are usually considered suggestive of etiological heterogeneity. In addition, although differences in familial rates of particular disorders between groups are not proof of different genetic transmission, they are highly supportive of the hypothesis. The analyses reported in this paper are focused on: (1) the degree to which the prior course of patients in the 3 diagnostic groups is similar or different, including the degree to which the patients with bipolar II disorder resemble those with
bipolar I disorder or those with recurrent unipolar disorder; and (2) the evidence for differential familial association of various kinds of affective disorders for the 3 groups. Methods Subjects This paper compares patients who were diagnosed using the Research Diagnostic Criteria (RDC) (Spitzer et al. 1978). By these criteria a definite manic disorder requires a period with a persistent syndrome of elated mood and 3 associated symptoms (e.g., less need for sleep, increased activity), or irritable mood and 4 associated symptoms. The syndrome must either (1) lead to hospitalization, (2) last at least 1 week and result in serious impairment in functioning socially, at work, at home, at school, or with the family, or (3) be so severe that meaningful conversation is impossible. The criteria for hypomanic disorder requires a period with a persistent syndrome of elevated mood and 2 symptoms or irritable mood and 3 symptoms that last at least 2 days. There are no criteria for impairment. These criteria were used to select 3 groups: (I) bipolar I patients who had had at least 1 episode which met criteria for mania and 1 for major depressive disorder (n = 122); (2) bipolar II patients who had had at least 1 episode of major depressive disorder and at least 1 that met criteria for hypomanic disorder but who had never had an episode of mania (n = 66); (3) recurrent unipolar depressive patients who had had at least 2 episodes of major depressive disorder (and never met criteria for manic or hypomanic disorder) (n = 104). Patients who had ever met criteria for schizophrenia, schizoaffective disorder, or unspecified functional psychosis were excluded from all 3 groups. In addition, patients who met criteria for cyclothymic or labile personality were excluded from the recurrent unipolar group. All index subjects were admitted as inpatients or outpatients to 1 of the 5 participating centers in the collaborative depression project. This project is described in detail elsewhere (Katz et al. 1978). These analyses included subjects and relatives on the master file in the spring of 1983. The index subjects were evaluated during the
19
intake episode with a number of procedures, including the Schedule for Affective Disorders and Schizophrenia (SADS) (Endicott and Spitzer 1978) and the RDC. The diagnostic evaluations were based on all sources of information available and were updated at discharge or 2 months after admission. The information included chart review, discussions with therapists and spouses, and observations during the intake episode. The procedures used for first degree relatives included a direct interview with the Schedule for Affective Disorders and Schizophrenia lifetime version (SADS-L) whenever possible. This was conducted by a professional rater blind to proband diagnosis. In addition, each index subject and 1 other family member were interviewed using the Family History Research Diagnostic Criteria (FHRDC) (Andreasen et al. 1977) interview guide, and a consensus FH-RDC was constructed using information from the 2 informants for subjects who had not been interviewed directly. The family analyses reported here are based on direct SADS-L interviews of the first degree relatives. It is unlikely that a history of hypomanic episodes would be TABLE
described by family members unless they are carefully questioned regarding such periods (and the FH-RDC does not include such questions). Results
with Discussion
Some of the results in this section are discussed as they are described for the purpose of clarity and to avoid redundancy in the conclusions section. Statistically significant differences are noted in the tables. When the data are presented by sex of subjects, all comparisons are made within sex and between groups. Males and females were not compared for statistical purposes. Because of the large number of contrasts and the exploratory nature of the analyses, the indications of statistical significance should be considered descriptive rather than hypotheses testing. The P-values are given at the less than 0.05 level only since they were not adjusted for multiple comparisons. Comments such as ‘somewhat higher’ are indicative of trends only. Characteristics of index subjects and relatives Table 1 shows the number of index subjects
1
CHARACTERISTICS
OF INDEX
PATIENTS Diagnoses
AND RELATIVES of index patients
Bipolar II
Bipolar I Male
for intake episode
Female
Recurrent
Male
Female
Male
unipolar Female
Total number of index patients
52
70
21
35
68
136
Age of index patients Mean Median
35 33
41 40
35 30
38 34
42 39
43 40
Status of index patients % Inpatient % Outpatient
96 4
94 6
69 31
60 40
83 17
77 23
Total number of index patients in family study
44
53
9
21
38
83
167
222
39
52
197
247
40 38
43 43
40 38
49 41
45 45
43 43
Total number of relatives interviewed Age of interviewed Mean Median
relatives
20
available, the number of family units in the family studies portion of the analyses, and the number of first degree relatives who were interviewed directly. There were no significant differences in the distributions of the ages of the index patients or of
TABLE
the directly interviewed relatives for the 3 groups. All of the index patients with bipolar II and recurrent unipolar major depressive disorder were in an episode of major depressive disorder when they were admitted to the study. The index pa-
2
AGE AT ONSET
AND
PRIOR
TREATMENT
OF INDEX
Bipolar I
PATIENTS Bipolar
II
Recurrent
unipolar
Male (n = 35)
Female (n = 70)
Male (n = 21)
Female (n = 35)
Male (n = 6X)
Female (n = 136)
Age first significant affective symptoms Mean Median % Under 19 8 Over age 30
24 ‘I 20 3x 27
25 19 33 29
24 21 34 24
23 ’ 19 34 23 ’
2’) ‘J 24 22 44
2x ‘ 24 26 42 t
Age first prior outpatient treatment Mean (if ever) Median (if ever) ‘R Under 19
25 il 20 35
26 24 32
22 h 19 4x d
24 ’ 21 34
31 &h 26 22 .’
30 L 27 24
27 a
17 c.d
26 a 22
30 29
52 a 30 27
34 C 30 31
37 34 d 31
31 d 33 30
Age at first major depressive episode Mean Median
24 a 22
27 25
26 23
25 22
32 d 2x
29 26
Age at first manic episode * Mean Median
29 27
33 30
Age first prior psychiatric hospitalization % Never Mean (if ever) Median (if ever)
Age first hypomanic episode * Mean Median Median number prior major depressive episodes ‘JW.~ The same * Patients inquired
2
4
_ -.
_
29 24
27 27
_ _
_
2
4
2
2
values with the same superscript letter are significantly different from each other (P i 0.05). All comparisons were for sex only: a, b for males; c, d for females. may have had hypomanic episodes prior to manic eposides but If there had been 2 or more manic episodes they were not about. Therefore they are not noted here.
21
tients with bipolar I disorder may have been admitted with an episode of either major depressive, mania, mixed or cycled between depression and mania. Prior course of index patients Age at onset Table 2 summarizes the data on the age at first clinically significant affective symptoms, first outpatient treatment, first hospitalization and first major depressive, manic, or (for bipolar II subjects) hypomanic episode. On inspection, the bipolar II patients can be seen to be more similar to the bipolar I patients than to the recurrent unipolar patients whenever the bipolar I and recurrent unipolar patients differed. This was true for both males and females. In every comparison shown, the average age of the patients in the 2 bipolar groups was somewhat lower than that for the unipolar patients, with some of the within sex differences reaching statistically significant levels (see Table 2). There were no significant differences between the 2 groups of bipolar patients on any of the measures. The bipolar I patients were more likely to have been hospitalized prior to the index episode with a trend for the average age at first hospitalization for both bipolar groups to be earlier than that of the unipolar group. (The greater likelihood of hospitalization of bipolar I patients may be accounted for, in part, by the RDC criteria which allows hospitalization to count as the severity criteria for mania if severe impairment cannot be established on the basis of the more clinical criteria.) Other characteristics of episodes of affective disorder All of the index subjects had had at least 1 episode of major depressive disorder and most were in such an episode at the time of admission to the study. Table 3 shows some of the characteristics of these episodes. The bipolar patients were more likely to have had (currently or in the past) an episode of major depressive disorder characterized by delusions and/or hallucinations (i.e., psychotic subtype). The first episode of major depressive disorder in all 3 groups of patients was
more often classified as primary rather than secondary (i.e., not preceded by one or more specified mental disorders). With the exception of the bipolar I females being somewhat higher, there are no large differences in the percentage of first episodes being primary in the 3 groups of patients. The same was true for the intake episode as well, although fewer subjects met criteria for primary major depressive disorder at that time (having had other types of disorders since the first depressive episode). Both groups of bipolar patients had significantly (P < 0.05) larger percentages of patients who had made at least 1 suicide attempt rated as indicating ‘at least moderate intent to die’. A large percentage of both bipolar I and bipolar II patients cycled during the intake episode. By definition the bipolar II patients would have cycled into a hypomanic period only while the bipolar I patients could have cycled into a period of manic or hypomanic symptoms. The tendency to have cycling or mixed episodes was also shown in the past by both groups of bipolar patients. The mean Global Assessment Scale (GAS) (Endicott et al. 1976) level of severity for the index episode was similar for the 3 groups with that of the bipolar I patients indicating somewhat more severe psychopathology and more impaired functioning (in keeping with the larger percentage of hospitalized patients in the bipolar I group). There were no differences in the percentages of the three groups who met criteria for the RDC endogenous subtype of major depressive disorder during the index episode. Many of the patients in all 3 groups also had had a chronic ‘minor’ affective disorder that preceded the major affective episode that led to admission to the study. When both chronic depressive disorders (intermittent depressive disorder or chronic minor depressive disorder) and cyclothymic personality are added together, the rate of chronic affective symptoms was higher in the bipolar II and recurrent unipolar patients than in the bipolar I patients (significantly so, for the males). (Since only 6 recurrent unipolar patients had been excluded because they had also met criteria for cyclothymic personality, this exclusion did not greatly affect their percentage with a chronic affective disorder.)
22 TABLE
3
OTHER
CHARACTERISTICS
OF AFFECTIVE
DISORDER
IN INDEX Bipolar
Bipolar I
PATIENTS II
Recurrent
Female (n = 70)
Male (n = 21)
Female (n = 35)
($)
(SE)
(%)
(F)
21
34 ‘
24
23
10
16’
60
84
62
71
66
77
13 ‘&I 13
10 19
29 6
2x il *
25 d *
10 a.h
26
29 a
35
2x
Lifetime suicide attempt with at least moderate intent to die
21
27 ’
24
29 ’
12
Intake episode included major depressive period Psychotic ** Endogenous ** Primary * *
56 a,h 21 62 47
61
100 a 24 67 57
100 c 14 63 51 c
Intake episode involved cycling
40
54
52
31
Mean Global Assessment Scale score at intake
30
31
35
32
Lifetime diagnosis Psychotic major depression First episode of major depression was primary Chronic depressive disorder Cyclothymic disorder Either chronic depressive or cyclothymic disorder
4” 6
u.h’c’d The values with the same superscript same sex only: a, b for males; c, d for * Patients with cyclothymic disorder were ** Percentage based on subjects who had a
cd
23 ’ 5x 79’
‘
letter are significantly different from each other females. excluded (n = 6). major depressive period during intake episode.
Characteristics of episodes of nonaffective disorders Table 4 indicates that the patients in all 3 groups had met RDC criteria for a number of other mental disorders, particularly alcoholism in the males. It is noteworthy that the rate of alcoholism in the bipolar II females approaches that of the males and is significantly higher (P < 0.05) than that for the other 2 groups of females. There were no trends for differences in the rates for various anxiety disorders, Briquet’s disorder, or drug abuse. However, a larger percentage of bipolar II males and females had also met criteria for schizotypal features (14%). More bipolar II males had met criteria for antisocial personality as
Male (n = 6X) (%)
unipolar
Male (n = 52)
h
Female (n =136) @)
25
13
65 56
100” 12‘ 66 66
35
35
10
cd
(P < 0.05). All comparisons
were for
well, while more bipolar II females reported premenstrual dysphoria. Both groups of bipolar males were more likely to have been hyperactive as children and there was a tendency for both groups of bipolar females to report more childhood hyperactivity as well (as compared with the recurrent unipolar females). The bipolar I patients had a lower percentage of ‘other psychiatric disorders’. The ‘other disorders’ were usually conditions which meet DSM-III criteria for a personality disorder not included in the RDC. As noted in Table 4 and above, the bipolar II patients had more frequently met criteria for one or more nonaffective mental disorders. The num-
23 TABLE
4
PERCENTAGE
OF INDEX
PATIENTS
WHO HAD EVER MET CRITERIA
Bipolar I
Alcoholism Drug abuse Panic disorder General anxiety disorder Phobic disorder Obsessive-compulsive disorder Briquet’s disorder Antisocial personality Schizotypal features Other psychiatric disorders Hyperactivity as a child Premenstrual dysphoria
Bipolar II
Recurrent
DISORDERS
unipolar
Female (n = 70)
Male (n = 21)
Female (n = 35)
Male (n = 68)
Female (n = 136)
(%)
(S)
(S)
(W)
13 ‘ 4 6 3
33
(8) 29 c.d
(%)
40 4 2 10 2 2 0 0” 12 12 a 29
32 10 0 7 7 4 0 3h 7 31 a 18
16d 6 4 5
5 0
5 0
0 1 0 4 16’ 20 44’
0 0
14 a.h 14 29 30 _ different
6 6 6 6 9 6 3 14 37 c 14 7I c.d
1 4 2 6 24 10 42 d
from each other (P < 0.05). All comparisons
were for same
5
PERCENTAGE OF INDEX PATIENTS WITH SPECIFIC RDC AFFECTIVE DISORDERS
AT LEAST
Diagnoses
Fumi!v posrtruafor: * ** Mania/hypomania Bipolar I Bipolar II Manic only Hypomanic only (never manic) Unipolar major depressive disorder (never manic or hypomanic) Other affective disorders (minor, intermittent, labile, cyclothymic and never manic, hypomanic or major depressive) Any affective disorder Schizoaffective, manic Schizoaffective, depr. * ** *** a.h
NONAFFECTIVE
Male (n = 52)
a.b.r.d The values with the same superscript letter are significantly sex only: a, b for males: c, d for females.
TABLE
FOR SPECIFIC
ONE
FIRST
of index patients
DEGREE
RELATIVE
WHO
*
Bipolar I (n = 97)
Bipolar II (n = 30)
Recurrent (n = 121)
(W)
(%)
(S)
31 a g a& 11= 3 a.h
27 3a 23 a,b Oa
15 a 3h 10 h Oh
g a.h
0”
3b
39
31
52
5 75 3 a.h
7 70 0” 0
7 74 Oh 1
2
MET CRITERIA
unipolar
**
All index patients with a lifetime diagnosis of schizophrenia or schizoaffective disorder were excluded from the sample Index patients with a lifetime diagnosis of cyclothymic or labile personality were also excluded. Unless noted, diagnoses are not mutually exclusive. The values with the same superscript letter are significantly different from each other at at least P < 0.05 level.
FOR
24
ber and nature of the other disorders would often be associated with a lack of clarity in their lifetime diagnosis and lead to problems of reliability of descriptions of past episodes. In addition, the additional disorders are apt to be associated with chronic symptoms and impairment. This is particularly true for the female bipolar II patients. In addition to other mental disorders, there was a trend for the bipolar II patients to never marry and, for those who had done so, to more frequently be separated or divorced. Given the confusing clinical picture and chronic nature of the problems seen in many of the bipolar II patients, it is not surprising that they were often noted to have a ‘clinical’ diagnosis (made by past therapists or by the cohort rater) of ‘borderline personality’. Probably another major reason for frequent use of this clinical diagnosis is that more of the bipolar II patients (both male and female) had met criteria for schizotypal features (14%). Furthermore, 57%
TABLE
Familial aggregation Rutes of specific disorders in first degree relatives of the three groups of patients Tables 5-7 present the familial lifetime rates of various disorders for the subset of patients in-
6
LIFETIME Relatives
of both male and female bipolar II patients had been scored positive for at least 1 schizotypal item (a percentage much higher than that for the other 2 groups). The types of schizotypal items on which the bipolar II patients scored more frequently tended to fall under the general clinical category of ‘sense of reality’ (e.g., depersonalization, illusions, magical thinking, and ideas of reference). Furthermore, the failure to recognize that patients with bipolar II disorder had an affective disorder, much less a bipolar affective disorder, is indicated by a less frequent use of antidepressants or lithium, even during the index episode.
DIAGNOSES diagnoses
OF AFFECTIVE Diagnoses
DISORDERS
IN INTERVIEWED
OF INDEX
PATIENTS
of index patients Recurrent (n = 121)
Bipolar II (n = 30)
Bipolar I (n = 97)
Ever manic/hypomanic * Major depressive only Minor, intermittent only Labile, cyclothymic only Any affective disorder Subtypes of Major Aff. Dis. Bipolar I Bipolar II Unipolar depression Recurrent unipolar depr. Primary depr. ** Secondary depr. * * * Psychotic depr. Incapacitating depr. Schizoaffective, manic Schizoaffective. depr.
RELATIVES
&polar
Male (n = 167)
Female (n = 222)
Male (n = 39)
Female (n = 52)
Male (n = 197)
Female (n = 247)
(%)
(S)
(%)
(%)
(S)
(S)
12.0 il 18.6 1.8 il.h 2.4 34.7
7.7 24.3 ’ 9.4 1.4 42.X
10.3 h 12.x 7.7 L1 0.0 30.X
11.5 21.2 d 5.x 1.9 40.4
3.0 u.h 20.3 6.6 h 0.5 30,s
5.3 36.4 c.d 6.9 2.0 50.2
3.0 4.x B 18.6 7.8 20.4 7.2 0.6 3.0 0.6 0.6
1.X 3.2 ’ 24.3 ‘ X.6 ‘ 26.1 ‘ 4.5 0.9 4.1 0.9 0.5
0 10.3 h 12.x 7.7 15.4 5.1 0.0 2.6 0 0
1.9 9.6 21.2 9.6 26.9 5.x 1.9 9.6 1.9 0
1 .o 1.o n.h 20.3 5.6 13.7 9.1 0.0 4.1 0 0
0.4 4.0 36.4 15.4 34.8 7.3 2.0 4.5 0.0 4
‘ d ’
L
* Includes relatives with unipolar and bipolar manic or hypomanic disorders. ** Includes relatives with both unipolar and bipolar disorders who ever met criteria for primary depressive disorder. *** Includes relatives who have ever had a secondary major depressive disorder. a.h.c.d The values with the same superscript letter are significantly different from each other (P -C0.05). All comparisons same sex only: a, b for males; c. d for females.
‘.’ r L.d
c
were for
25
family units with unipolar major depressive disorder only (Tables 5 and 6). However, in spite of the similarity in total indices of familial ‘bipolarity’, the rates of the 2 types of bipolar disorder in the families differ somewhat for the bipolar I and II patients (Tables 5 and 6). The subtypes of bipolar disorder in the family units and individual relatives are more similar to that of the patients (i.e., bipolar I patients have more bipolar I relatives, while bipolar II patients have more bipolar II relatives). The relative risk for bipolar I disorder in the family units of bipolar I probands was 3.1 (that of the family units of bipolar II probands was less than 1.0). On the other hand, the relative risk of bipolar II disorder in the family units of bipolar II probands was 2.2 while that in the family units of bipolar I probands was less than 1.0. These findings suggest some specificity of association between subtypes of bipolar disorders in index patients and relatives. Furthermore, using the multiple threshold method of genetic analysis indicated that the unitary hy-
volved in the family studies portion of the project. The diagnoses are based upon direct clinical interviews and are presented in 2 forms: (1) the percentage of patients who have a positive family history (i.e., at least 1 first degree relative has had a specific disorder) (Table 5); and (2) the percentage of first degree relatives who have had the disorder (Table 6). The percentages in these tables have not been adjusted for age, since the ages in relatives of the 3 groups of patients had similar means and distributions. The rates for both types of bipolar disorder are higher in the relatives and for the family units of both bipolar groups. If one combines the rates for the 2 types of bipolar disorder in the family units (Table 5) 31% of the bipolar I patients and 26.6% of the bipolar II patients have families positive for manic or hypomanic periods, while only 14.9% of the recurrent unipolar patients have at least 1 relative who has had manic or hypomanic episodes. On the other hand, the recurrent unipolar patients are more apt to have more relatives and
TABLE
7
LIFETIME Relatives
DIAGNOSIS diagnoses
OF NONAFFECTIVE Diagnoses
DISORDERS
OF INDEX
PATIENTS
of index patients
Bipolar I (n = 97)
Alcoholism Drug abuse Panic disorder Generalized anxiety disorder Phobia Obsessive-compulsive disorder Schizophrenia Unspecified psychosis At least 1 schizotypal feature Other psychiatric disorder Never mentally ill
IN RELATIVES
Bipolar II (n = 30)
Recurrent (n = 12)
unipolar
Male (n = 167)
Female (n = 222)
Male (n = 39)
Female (n = 52)
Male (n = 197)
Female (n = 247)
(%)
(%)
(%)
(%)
(S)
(%)
23.1 4.8 0.6
5.0 2.7 1.8
23.1 2.6 0
3.8 1.9 0
21.3 5.1 2.0
5.3 2.8 1.2 11.3 3.6
6.0 1.2
1.7 0.9 c
5.1 0
5.8 5.8 c
6.1 2.0
6 1.8
Or 0.5
0 0
1.9 c 0
0 0
0.8 0
0.6
0
0
0
0
0
1.8
2.7
5.1
0
2.5
2.4
10.2
12.6
1.7
11.5
14.2
13.8
41.3
44.6
53.8
42.3
51.8
38.9
’ The values with the same superscript
letter are significantly
different
from each other (P i 0.05).
26
pothesis of continuity could be rejected for bipolar I and bipolar II disorders (Theodore Reich, personal communication). None of the differences for other types of affective disorders among the 3 groups of relatives are statistically significant. For example, if one adds the rates for mania and major depression only to calculate the rates for any type of major affective disorder, 51.6% of family units of bipolar I patients, 40.0% of bipolar II patients, and 54.6% of recurrent unipolar patients met criteria for some type of major affective disorder (Table 5). If the families with hypomania only are then added, the rates are 70.0%, 63.3% and 67%, and when the rates for all other affective disorders (i.e., the ‘minor’ affective disorders) are added, the rates are 75.4%, 70% and 73.6%. Similarly, if one looks at the rates for a major (or any) affective disorder in the relatives of the 3 groups, the 3 groups of relatives do not differ significantly (Table 6). The 3 groups of relatives also differed little, if at all, in the rates of RDC nonaffective disorders. The female relatives of the bipolar II patients had a higher frequency of phobic disorder and obsessive-compulsive disorder (Table 7). The percentage of relatives judged to have met criteria for never mentally ill was also similar for the 3 groups, averaging approximately 45%. Conclusions The title of the article, ‘Bipolar II - Combine or Keep Separate?’ calls for some recommendations based on the data we have presented. There are no firm criteria that are used in medicine by which one decides that differential course or family data indicate that 2 groups are essentially the same or different enough to warrant continued separation in future analyses. However, one can assess the possible effects on research studies of such differences when making recommendations to either combine samples into 1 group or to continue to separate them. In the authors’ opinion, the data on prior course, characteristics of the index episode, and familial aggregation of the 2 types of bipolar disorder are sufficiently different to support the separation of both bipolar I and bipolar II disorders from recur-
rent unipolar disorder. Furthermore, the data are in keeping with those of others and indicate that bipolar II disorder is closer to bipolar I than to unipolar depressive disorder (Dunner et al. 1970; Gershon et al. 1982; Dunner 1983). There is less evidence supportive of the continued separation of bipolar I and bipolar II disorders. The 2 groups are similar in many ways (i.e., age at onset, increased tendency to cycle within episodes, increased risk for psychotic depressive episodes, and similarity in the percentage of family units and individual relatives characterized by either manic or hypomanic episodes). However, in spite of these similarities, there are a number of ways in which the 2 bipolar groups differ and these differences are potentially of great importance to both clinicians and investigators. A larger proportion of the bipolar II patients have a prior history that is complicated by other mental disorders. Their prior history is also more often characterized by the types of chronic symptoms that have been found to be predictive of a less satisfactory response to the usual treatments for major affective episodes (Akiskall981; Stone 1981; Gaviria et al. 1982). If this is the case, in the future the bipolar II patients are also likely to be found to have different biological features as well as other non-familial correlates. For instance, a recent study found more Raynaud’s phenomena, migraine headache, and symptoms referred to in the literature as ‘migraine equivalents’ in patients with bipolar II disorder than in those with either bipolar I or unipolar depressive disorder (Endicott 1984). The higher degree of comorbidity of other mental disorders as well as other medical disorders in the bipolar II patients is apt to complicate the interpretation of treatment and biological studies of patients with affective disorder if patients with bipolar I and bipolar II disorders are not tagged so that analyses may take this into account. Other evidence supportive of continued separation of bipolar II disorder from bipolar I disorder is found in the family data. Although the percentage of relatives who report ever having been either manic or hypomanic in both bipolar groups is higher than that for the recurrent unipolar group, there is also a higher percentage of both relatives and family units of the bipolar II patients who are characterized as bipolar II dis-
27
order as compared with the other 2 groups. In spite of the relative unreliability of the judgment of past episodes of hypomania (Andreasen et al. 1977) (which is apt to work against finding consistent group differences), the findings reported here of an increased rate of bipolar II disorders in the relatives of bipolar II patients are consistent with other studies which used somewhat different procedures (Dunner et al. 1983; Gershon et al. 1982). Both of these studies also found a somewhat higher rate of bipolar II disorder in the relatives of bipolar II patients. Furthermore, when the analyses of data in the current project were limited to more homogeneous groups of both patients and relatives (i.e., those whose most recent depressive episode had been classified as primary by RDC criteria) the findings were similar (Coryell 1984). Although the specific rates varied slightly, the bipolar II patients also had the highest rate of bipolar II relatives when the more pure samples of both relatives and index subjects were studied. Both relative risk and multiple threshold genetic analysis support a rejection of the hypothesis that bipolar II disorder is simply a less severe form of bipolar I disorder. The results reported here, as well as those of others, suggest that bipolar II patients and relatives are heterogeneous as to genotype and include some individuals who are at risk to ‘switch’ to bipolar I disorder at some time in the future (Dunner et al. 1976; Akiskal et al. 1977, 1978, 1983; Klerman 1980). These individuals may indeed be displaying a less severe manifestation of bipolar I disorder. At the same time, there is sufficient data to suggest that other bipolar II patients may have a type of bipolar disorder that ‘breeds true’ and not simply a less severe manifestation of bipolar I disorder. At the present time we cannot identify the 2 (or more) hypothesized ‘types’ of bipolar II patients and relatives. Followup studies and more sophisticated genetic analyses with larger samples may help determine the degree to which the assumption of at least 2 types of bipolar II disorder holds. In view of our results as well as those of others which identify similarities and differences for the 3 conditions in prior course, phenomenology, and familial rates of disorder, the authors recommend that bipolar II patients be categorized separately
from both unipolar and bipolar I patients. This recommendation is consistent with that noted recently by Kupfer and Rush (1983) when they conveyed the recommendations of a conference on the origins of depression held in Berlin in 1982. References Akiskal, H.S., Subaffective disorders Dysthymic, cyclothymic, and bipolar II disorders in the ‘borderline’ realm, Psychiat. Clin. N. Amer., 4 (1981) 25-46. Akiskal, H.S., Bitar, A.H., Puzantian, V.R., Rosenthal, T.H. and Walter, P.W., The nosological status of neurotic depression - A prospective three or four year follow-up examination in light of the primary-secondary and unipolar-bipolar dichotomies, Arch. Gen. Psychiat. (Chic.), 35 (1978) 756-766. Akiskal, H.S., Djenderedjian, A.H., Rosenthal, R.H. and Khani, M.K.. Cyclothymic disorder - Validating criteria for inclusion in the bipolar affective group, Amer. J. Psychiat., 134 (1977) 1227-1233. Akiskal, H.S., Walker, P.W., Puzantian, V.R., King, D.. Rosenthal, T.L. and Dranon, M., Bipolar outcome in the course of depressive illness, J. Affect. Dis., 5 (1983) 115-128. Andreasen, N.C., Endicott, J., Spitzer, R.L. and Winokur, G., The family history method using diagnostic criteria, Arch. Gen. Psychiat. (Chic.), 34 (1977) 1229-1235. Angst, J., Frey, R., Lohmeyer, B. and Zerbin-Rudin, E., Bipolar manic-depressive psychosis - Results of genetic investigation, Hum. Genet., 55 (1966) 2377254. Coryell, W., Endicott, J., Reich, T., Andreasen, N. and Keller, M., A family study of bipolar II disorder, Brit. J. Psychiat., In press. Diagnostic and Statistical Manual (DSM-III). 3rd edition, American Psychiatric Association, Washington, DC, 1980. Dunner, D.L., Subtypes of bipolar affective disorder with particular regard to bipolar II, Psychiat. Develop., 1 (1983) 75-86. Dunner, D.L., Fleiss, J.L. and Fieve, R.R., The course of development of mania in patients with recurrent depression. Amer. J. Psychiat., 133 (1976) 905-908. Dunner, D.L., Gershon, E.S. and Goodwin, F.K., Heritable factors in the severity of affective disorders, Sci. Proc. Amer. Psychiat. Ass., 123 (1970) 187-188. Endicott. J. and Spitzer, R.L.. A diagnostic interview - The schedule for affective disorders and schizophrenia, Arch. Gen. Psychiat. (Chic.), 35 (1978) 837-844. Endicott, J., Spitzer, R.L., Fleiss, J.L. and Cohen, J., Global assessment scale A procedure for measuring overall severity of psychiatric disturbance, Arch. Gen. Psychiat. (Chic.), 33 (1976) 766-771. Endicott, N.A., Psychosocial and behavioral factors in myocardial infarction and sudden death. In: S. Chanin (Ed.), Introduction to Psychosomatic Medicine, Norton, New York, NY., 1984, In press. Feighner, J.R., Robins, E., Guze, S.B., Woodruff, R.A., Winokur, G. and Munoz, R., Diagnostic criteria for use in
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