Bipolar II with and without cyclothymic temperament: “dark” and “sunny” expressions of soft bipolarity

Journal of Affective Disorders 73 (2003) 49–57 www.elsevier.com / locate / jad

Research report

Bipolar II with and without cyclothymic temperament: ‘‘dark’’ and ‘‘sunny’’ expressions of soft bipolarity a, b b Hagop S. Akiskal *, Elie G. Hantouche , Jean Franc¸ois Allilaire a

International Mood Center, UCSD Department of Psychiatry, 9500 Gilman Drive, La Jolla, San Diego, CA 92093 -0603, USA b ´ ˆ ` Hospital, Paris, France Mood Center, Psychiatry Department, Pitie-Salpetriere Received 7 January 2002; accepted 10 May 2002

Abstract Background: In the present report deriving from the French national multi-site EPIDEP study, we focus on the characteristics of Bipolar II (BP-II), divided on the basis of cyclothymic temperament (CT). In our companion article (Hantouche et al., 2003, this issue), we found that this temperament in its self-rated version correlated significantly with hypomanic behavior of a risk-taking nature. Our aim in the present analyses is to further test the hypothesis that such patients—assigned to CT on the basis of clinical interview—represent a more ‘‘unstable’’ variant of BP-II. Methods: From a total major depressive population of 537 psychiatric patients, 493 were re-examined on average a month later; after excluding 256 DSM-IV MDD and 41 with history of mania, the remaining 196 were placed in the BP-II spectrum. As mounting international evidence indicates that hypomania associated with antidepressants belongs to this spectrum, such association per se did not constitute a ground for exclusion. CT was assessed by clinicians using a semi-structured interview based on Akiskal and Mallya (1987) in its French version; as two files did not contain full interview data on CT, the critical clinical variable in the present analyses, this left us with an analysis sample of 194 BP-II. Socio-demographic, psychometric, clinical, familial and historical parameters were compared between BP-II subdivided by CT. Psychometric measures included self-rated CT and hypomania scales, as well as Hamilton and Rosenthal scales for depression. Results: BP-II cases categorically assigned to CT (n 5 74) versus those without CT (n 5 120), were differentiated as follows: (1) younger age at onset (P 5 0.005) and age at seeking help (P 5 0.05); (2) higher scores on HAM-D (P 5 0.03) and Rosenthal (atypical depressive) scale (P 5 0.007); (3) longer delay between onset of illness and recognition of bipolarity (P 5 0.0002); (4) higher rate of psychiatric comorbidity (P 5 0.04); (5) different profiles on axis II (i.e., more histrionic, passive-aggressive and less obsessive-compulsive personality disorders). Family history for depressive and bipolar disorders did not significantly distinguish the two groups; however, chronic affective syndromes were significantly higher in BP-II with CT. Finally, cyclothymic BP-II scored significantly much higher on irritable-risk-taking than ‘‘classic’’ driven-euphoric items of hypomania. Conclusion: Depressions arising from a cyclothymic temperament—even when meeting full criteria for hypomania—are likely to be misdiagnosed as personality disorders. Their high familial load for affective disorders (including that for bipolar disorder) validate the bipolar nature of these ‘‘cyclothymic depressions.’’ Our data support their inclusion as a more ‘‘unstable’’ variant of BP-II, which we have elsewhere termed ‘‘BP-II 1 / 2.’’ These patients can best be *Corresponding author. VA Psychiatry Service (116-A), 3350 La Jolla Village Drive, San Diego, CA 92161, USA. Tel.: 1 1-619-5528585x2226; fax: 1 1-619-534-8598. E-mail address: [email protected] (H.S. Akiskal). 0165-0327 / 02 / $ – see front matter  2002 Elsevier Science B.V. All rights reserved. PII: S0165-0327( 02 )00320-8

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characterized as the ‘‘darker’’ expression of the more prototypical ‘‘sunny’’ BP-II phenotype. Coupled with the data from our companion paper (Hantouche et al., 2003, this issue), the present findings indicate that screening for cyclothymia in major depressive patients represents a viable approach for detecting a bipolar subtype that could otherwise be mistaken for an erratic personality disorder. Overall, our findings support recent international consensus in favoring the diagnosis of cyclothymic and bipolar II disorders over erratic and borderline personality disorders when criteria for both sets of disorders are concurrently met.  2002 Elsevier Science B.V. All rights reserved.

1. Introduction It is generally accepted that the cyclothymic temperament (CT) is the precursor of bipolar, especially bipolar II (BP-II) disorder (Akiskal et al., 1977; Depue et al., 1981, Akiskal, 2001). However, in a review article, Howland and Thase (1993) opined that only some forms of cyclothymia are associated with bipolar disorder, and that the condition is clinically heterogeneous. Historically, Kraepelin (1921 [English translation]) was among the first to suggest that CT—which he actually termed ‘‘predisposition’’ rather than ‘‘temperament’’—represents a subclinical condition preceding the more severe circular states of mania and melancholia. Kretschmer (1936), too, used the term ‘‘cyclothymia’’ as the constitutional basis for periodic depression and hypomania. The classical paper on cyclothymia as an ambulatory form of manic-depression was written by the German psychiatrist Hecker (see English translation in this issue (Koukopoulos, 2003); he was a disciple of Kahlbaum who had coined the term ‘‘cyclothymia’’ (‘‘zyklothymie’’, Kahlbum, 1882). A rich French literature (see, for instance, Ritti, 1880; Khan, 1909)—insufficiently appreciated today by anglophone and germanophone psychiatrists—has documented the short-lived repeated excitement in the lives of these ambulatory depressives, thereby justifying their inclusion within the larger sphere of manic-depressive psychosis as the more classical illness was called in those days. Given the lifelong nature of the subthreshold affective instability, CT is often misdiagnosed as an erratic personality disorder (Akiskal et al., 1977, 1979). As a result, major depressive episodes with a cyclothymic base might be erroneously assigned to the realm of borderline

personality disorder (Akiskal, 1981; Levitt et al., 1990). To avoid such diagnostic pitfalls, one of us (Akiskal, 1994) has suggested the rubric of ‘‘cyclothymic depression’’ to highlight the bipolar nature of these patients. In contemporary times, the link of CT to bipolar disorder was validated by the author’s team (Akiskal et al., 1977) in a clinical population, and Depue et al. (1981) in a college population. Epidemiologic research has demonstrated a population prevalence of 6.3% (Placidi et al., 1998) with excellent discriminating validity from other temperament constructs (Akiskal et al., 1998). Despite the classical tradition and contemporary research, CT is rarely used today as a diagnostic rubric by clinicians and researchers (Brieger and Marneros, 1997). In order to further clarify the question of a ‘‘cyclothymic–BP-II continuum’’ (Akiskal et al., 1979), we report herein data from the French multicenter EPIDEP study. We focus on a systematic comparison between BP-II with and without CT.

2. Methods

2.1. EPIDEP global methodology Our methods are documented in previous reports (Hantouche et al., 1998; Allilaire et al., 2001). Briefly, the study involved 48 specially trained French psychiatrists in 15 sites. It was based on a common protocol including: The DSM-IV criteria with Semi-Structured Interview for Major Depression and Hypomania, the HAM-D (21 items) and Rosenthal Atypical De-

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pression Scale (eight additive items), and the GAF scale (from DSM-IV). Expanded criteria for Soft Bipolarity (see most updated version, Akiskal and Pinto, 1999), as well as criteria modified from the work of Angst (1992) (Hypomania Checklist). The Affective Temperament assessment via SemiStructured Interview for CT in its French version (Hantouche and Akiskal, 1997), based on Akiskal and Mallya (1987) criteria (see Appendix A). Family history for mental disorders according to the Research Diagnostic Criteria family history version (Andreasen et al., 1977).

2.2. EPIDEP global data To place the current analyses in context, we provide a description of previous findings in the EPIDEP study. From a total of 537 patients included at visit 1, 493 returned to visit 2 scheduled approximately a month later (Allilaire et al., 2001); the 44 lost to follow-up and the 493 retained in the study were essentially similar in demographic and baseline clinical characteristics. Based on systematic clinical search for past hypomania, the BP-II rate was found to be 39.8%. This rate is based on all hypomanias recorded in past psychiatric records, or obtained by history during visit 2. Although DSM-IV diagnostic algorithms bar from the BP-II rubric those hypomanic episodes which are solely associated with pharmacotherapy, their distinction from spontaneously occurring hypomanias is not easily made in clinical practice. Nor is it valid: a converging transatlantic literature (Akiskal et al., 2000) indicates that antidepressant-associated hypomanias belong to the bipolar sphere as judged by family history and prospective follow-up (see also Akiskal et al., 2003, this issue). When compared with the remainder of major depressive ‘‘unipolar’’ patients (Allilaire et al., 2001), BP-II was characterized by a relatively distinct clinical presentation at index depressive episode despite uniformity in global intensity of depression: over-representation of ‘‘suicidal thoughts’’, ‘‘guilt feeling’’, ‘‘depersonalization’’, ‘‘hypersomnia’’ and ‘‘weight gain.’’ Other differences were obtained on the course of illness: younger age at onset of first depression, higher rate of suicidal attempts, recurrence and hospitalizations. Although family history

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was significantly higher in BP-II, they encountered greater difficulties for being recognized as bipolar by previous physicians. Finally, complex temperamental traits—mixture of cyclothymic, hyperthymic and irritable—were more significantly represented in the BP-II group. Other data from a previous report in midstream (Hantouche et al., 1998) showed that 88% of patients recognized by clinicians as cyclothymic were BP-II; however, not all patients with BP-II were cyclothymic.

2.3. Patient selection for the present analyses For the purpose of the present analyses, 196 BP-II patients—minus two patients whose clinical files did not contain full record of CT interview data—were divided into two subgroups according to the presence of cyclothymic temperament. This diagnosis was based on the Akiskal and Mallya criteria obtained by clinical interview using a semi-structured format (Appendix A): 74 patients were thereby classified in the ‘‘BP-II with CT’’ subgroup, and 120 patients in the ‘‘BP-II without CT.’’

2.4. Statistical methods For inter-group comparative analyses, we used chi-square, Student’s, and Fisher’s tests for sociodemographic, historical and clinical data, as well as psychometric measures that were recorded in both sub-groups at inclusion during acute depression and after its resolution. For hypomania we used the mean score on Angst’s Checklist, as well as the scores on its two-factor structure (Hantouche et al., 2003, this issue).

3. Results

3.1. Socio-demographic and historical characteristics Table 1, which summarizes these comparisons, showed that the rate of index hospitalization for resistant depression was significantly higher in the non-cyclothymic BP-II group. Other significant differences were observed on age at illness onset and type of onset (e.g., irritable, flamboyant behavior,

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Table 1 Inter-group comparison between BP-II with cyclothymic temperament (CT) versus BP-II without CT: patient characteristics and historical data

Female (%) Current age (years) Marital status (%) Married Divorced Current hospitalization (%) For suicide risk For resistant depression Age at disorder onset (years) Rate of disorder onset before 18 year (%) Symptoms present before 18 year (%) Irritable / flamboyant behavior Substance abuse Premature sexuality Age at seeking help (years) Age at first hospitalization (years) Prior multiple hospitalizations (%) Number of prior hospitalizations Delay from onset of symptoms (years) Recurrence rate Total episodes Total hypomanic episodes Total major depressive episodes Polarity of first episode (%) Hypomanic Depressive Mixed Inter-episodic quality (%) Free-interval Mixed symptoms Suicide attempts (lifetime) Psychiatric co-morbidity (last 6 months) (%) GAF (DSM-IV)

substance abuse) before age of 18, and on ages of first seeking medical help and first hospitalization (all of which were younger in cyclothymic BP-II). As for the recurrence rate, there was a tendency, not statistically significant, for higher rate of prior depressive episodes in the cyclothymic BP-II subgroup. Significantly higher rates with mixed residual symptoms between major episodes were recorded in the cyclothymic BP-II; this was also true for comorbidity with other psychiatric problems. No difference was obtained on the polarity of first episode, which was in the majority of cases depressive in nature. History for suicidal behavior was very high in both

BP-II with CT (n 5 74)

BP-II without CT (n 5 120)

P

80 44 (613)

69 47 (613)

NS NS

55 23 43 61 48 25 33

58 25 38 50 80 32 21

NS NS NS 0.005 0.005 0.007

44 10 12 32 35 37 2.5 11

25 0.8 5 36 40 35 2.6 7

0.007 0.01 0.06 0.05 0.02 NS NS 0.004

12 5.7 5.9

9 4.3 4.5

0.08 NS 0.07

5 81 14

8 86 6

NS

31 31 49 77 61 (613)

42 11 38 63 61 (614)

0.009 NS 0.04 NS

BP-II sub-groups. Finally, GAF mean score during the last year was in the low sixties in both subgroups, indicating a moderate level of impairment.

3.2. Baseline depressive measures and response to current treatment Psychometric measures of depression at visit 1 (Table 2) showed significant differences with higher levels on global intensity and on Rosenthal scale among the cyclothymic BP-II. However, the mean reduction from baseline (rate of global improvement and delay to remission) after current antidepressant

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Table 2 Inter-group comparison between BP-II with cyclothymic temperament (CT) versus BP-II without CT: psychometric measures before and after resolution of acute depressive episode BP-II with CT (n 5 74)

BP-II without CT (n 5 120)

P

Depression assessment (at inclusion) Total HAM-D 29 items HAM-D 21 score Rosenthal-8 score

37.4 (67.0) 28 (65.9) 9.5 (64.3)

34.3 (66.2) 26 (65.4) 8.1 (2.7)

0.001 0.03 0.007

Response to current antidepressant treatment Reduction of HAM-D 29 items (%) CGI-I (score 1 or 2) (%) Delay to remission (days) Mood switching rate (%)

66 76 31 35

62 76 27 26

NS NS NS NS

Hypomania assessment* (lifetime) F-1 (driven-euphoric) F-2 (irritable-risk-taking)

9.6 (62.6) 3.9 (61.7)

8.5 (63.3) 2.6 (61.9)

0.01 0.001

* See companion article (Hantouche et al., 2003, this issue).

treatment, was equivalent in both sub-groups. The mood-switch rate was higher, albeit nonsignificantly, in BP-II with cyclothymia. Psychometric measures of hypomania in cyclothmic BP-II revealed higher intensity on both factors (Table 3): When individual hypomanic item scores were compared in the BP-II sub-groups, significant differences were obtained on four items (from the list of 12 items of the first factor) and on six items (from the list of eight items of the second factor). In particular, BP-II patients with CT were characterized by irritable risk-taking features.

3.3. Delay in diagnosis, axis II problems and family history Correct diagnosis and treatment were significantly delayed in the cyclothymic BP-II sub-group (Table 4). This would appear to be accounted for by significantly higher rates of axis II diagnoses, i.e., cluster ‘‘B’’ (especially histrionic) and ‘‘passive-aggressive’’ personality in cyclothymic BP-II and significantly higher rates of cluster ‘‘C’’ (especially OCPD) in the non-cyclothymic BP-II sub-group. Finally, family history showed equivalent rates of mood disorders in both sub-groups; it is noteworthy that BP-II with and without cyclothymia had the same rates for familial bipolar disorder. However,

chronic syndromes (P 5 0.05) and suicidality (nonsignificantly) were recorded more frequently in the families of BP-II with cyclothymia.

4. Discussion

4.1. Overall findings These data deriving from EPIDEP support the continuum between hypomania and cyclothymia. When BP-II is associated with CT, it is a more unstable bipolar spectrum disorder by comparison to non-cyclothymic BP-II with its classic ‘‘sunny’’ driven-euphoric features. Key characteristics are represented by younger age at onset, higher intensity on both polarities of the illness (depression and hypomania), higher level on the irritable risk-taking component of hypomania (which means more negative consequences), higher rate of comorbidity, more interepisodic mixed features and instability and, as a consequence, the malfortune of being diagnosed as an erratic personality disorder. Based on both crosssectional and long-term traits, we would therefore propose a contrast between the latter ‘‘darker’’ cyclothymic variant of BP-II and the ‘‘sunnier’’ BPII without cyclothymia.

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Table 3 Individual hypomanic items in diagnostic subtypes BP-II with CT (n 5 72)

BP-II without CT (n 5 119)

P

Factor 1* (%) Less sleep More drive and energy More self-confident Increased work motivation Increased social activity Increased physical activity More plans and ideas Less shy, less inhibited More talkative than usual Extremely happy mood, over-euphoric More laughing Faster thinking, more puns and jokes

83 89 86 85 79 72 89 86 76 69 72 72

66 84 81 75 72 72 75 76 75 55 55 63

0.008 NS NS NS NS NS 0.02 NS NS 0.04 0.01 NS

Factor 2* (%) More traveling, imprudent driving Excessive shopping and spending Foolish behavior in business More irritable, impatient Attention easily distractible Increased sex drive and interest in sex Increased consumption of coffee, cigarettes Increased consumption of alcohol

56 54 15 71 74 54 42 29

35 31 10 51 51 38 26 19

0.004 0.002 NS 0.008 0.002 0.03 0.03 NS

* See companion article (Hantouche et al., 2003, this issue).

Table 4 Inter-group comparison between BP-II with cyclothymic temperament (CT) versus BP-II without CT: course of illness, axis II problems, and family history BP-II with CT (n 5 74)

BP-II without CT (n 5 120)

P

Delay to correct diagnosis ( . 10 years) (%) Delay to receive mood-stabilizers ( . 5 years) (%) Axis II (%) Total Cluster ‘‘A’’ Cluster ‘‘B’’ Histrionic Cluster ‘‘C’’ OCPD Passive-aggressive

56 73

31 59

0.0002 0.08

70 1 42 21 19 1 12

53 4 24 11 27 9 4

0.02 NS 0.05 0.06 NS 0.06 0.03

Family history (%) Total with psychiatric problems Chronic affective syndromes Suicide attempts Bipolar disorder Unipolar disorder

63 34 22 14 49

53 21 13 13 40

NS 0.05 NS NS NS

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4.2. Clinical implications In our companion article (Hantouche et al., 2003, this issue), the factor analysis of Angst’s Hypomania Checklist suggested the presence of two major components of hypomania. The second factor (with risk-taking behavior), was more discriminatory between soft bipolar subtypes. The strongest link was observed between ‘‘irritable risk-taking’’ hypomania and CT. This observation is confirmed in the present report by showing the specific items that are more frequently represented in the ‘‘BP-II with CT’’ (nearly all the items of the ‘‘irritable risk-taking’’ component of hypomania). The main problem in psychiatric practice is to recognize the bipolar nature of this ‘‘darker’’ irritable risk-taking expression of bipolar II. Over half (56%) of cyclothymic depressives had waited more than 10 years in order to receive a correct diagnosis for their mood disorder. We submit that the presence of CT may have acted as a source of misdiagnosis (oriented toward pathologic personality, especially histrionic and passive-aggressive types). The younger age at onset with course characterized by mixed residual inter-episodic symptomatology and comorbidity appear to have further compromised the diagnostic process. Analyses over a prospective observation period of 11 years in the NIMH collaborative depression study (Akiskal et al., 1995) have shown that early onset depressions pursuing a course characterized by social instability, comorbidity, and mood-labile, energetic-active, and daydreaming traits are most likely to switch to bipolar II; these patients had many of the stigmata of borderline personality. Although a recent study concurred that mood lability was shared by both bipolar II and borderline personality disorders (Henry et al., 2001), they nonetheless concluded that the two disorders were distinct. The findings of the present study indicate that cyclothymic bipolar II are often indistinguishable from depressed patients with borderline features. This accords well with recent international consensus (Akiskal et al., 2000) to the effect that when patients meet criteria for both sets of disorders, a bipolar diagnosis should be the preferred diagnosis. Although Howland and Thase (1993) suggested that cyclothymia by itself could cover a clinically heterogeneous condition, CT has actually been val-

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idated by both familial and prospective data (Akiskal et al., 1977; Akiskal et al., 1979; Depue et al., 1981). Moreover, one could consider cyclothymia as a mixture of brief recurrent subthreshold bipolar episodes. In the Zurich epidemiologic cohort, this form was firmly supported by higher comorbidity with depression (dysthymia, major depressive episodes), and higher rate of seeking professional help and divorce (Angst, 1998). Even quality of life was more disturbed in brief recurrent hypomania when compared with classic BP-II according to DSM-IV (Angst, 1992, 1998). Our EPIDEP data showed more severity and intensity on all psychometric measures in the sub-group BP-II with CT. It would appear that CT acts as an amplifier of depressive and hypomanic swings. The data of Kwapil et al. (2000) showed that subjects with hypomanic personality traits reported more bipolar disorder in a 13-year follow-up. Also, such patients with elevated scores on the impulsivenonconformity scale (Chapman et al., 1984) experienced greater rates of bipolar disorder, poorer overall adjustment, and higher rates of arrest than the remaining individuals with hypomanic traits and controls. In sum, impulsivity and nonconformity can be integral to CT. Measuring CT appears to be a viable clinical method to search for soft bipolarity, even in recurrent depressions without clearcut hypomania. In patients presenting BP-II with CT, in the present study, a significant association with the darker side of hypomania emerged. In fact, rapid swings in mood, behavior and cognition along bipolar lines seem to facilitate the appearance of less favorable features of hypomania, such as risk-taking and imprudent behaviors, as well as substance abuse. An Italian study actually showed that CT is prevalent in subjects with HIV seropositivity (Perretta et al., 1998). To conclude, we found evidence consistent with the validity of a subtype of soft bipolarity (BP-II spectrum) characterized by the presence of cyclothymic temperament. Special clinical attention should be devoted to this cyclothymic depressive or ‘‘BP-II 1 / 2’’ prototype of bipolarity, because of major risks of suicide, depressive recurrence and non-recognition of the affective nature of the illness, which begins early in life. In pedopsychiatric practice, such patients are considered to be in the borderline realm (Brent et al., 1993). The bipolar

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characterization of these patients—with the use of our cyclothymic measures—is of utmost public health interest. This can be accomplished by clinical interview (Akiskal and Mallya, 1987), as in the present study; or, as demonstrated in our companion paper (Hantouche et al., 2003, this issue), by selfassessment (Hantouche and Akiskal, 1997, representing the French version of TEMPS-A, Akiskal et al., 2003).

(b) Introverted self-absorption alternating with uninhibited people seeking. (c) Decreased verbal output alternating with talkativeness. (d) Unexplained tearfulness alternating with excessive punning and jocularity. (e) Marked unevenness in quantity and quality of productivity-associated with unusual working hours. B—Indeterminate onset, before age of 21 years.

Acknowledgements The authors thank J.M. Azorin, M.L. Bourgeois and D. Sechter (Besanc¸on), and all other EPIDEP Group Investigators. The study was supported by an unrestricted grant from Sanofi-Synthelabo France ˆ ˆ and active collaboration of Dr. L. Chatenet-Duchene. Sylvie Lancrenon conducted the statistical analyses.

Appendix A. Interview Version of Cyclothymic Temperament Questionnaire (CT-CQ) as used in EPIDEP study in its French version (Hantouche and Akiskal, 1997)1 Evidence of biphasic dysregulation characterized by abrupt shifts from one phase to the other, each phase lasting for days at a time, with infrequent euthymia: A1—Subjective manifestations (at least two): (a) Lethargy alternating with eutonia. (b) Pessimistic brooding alternating with optimism and carefree attitudes. (c) Mental confusion alternating with sharpened and creative thinking. (d) Shaky self-esteem. A2—Behavioral manifestations (at least two): (a) Hypersomnia alternating with decreased need for sleep. 1

Adapted from Akiskal et al. (1979) and Akiskal and Mallya (1987).

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