Letters to the Editor
Clinical and Family History Markers of Bipolar II Disorder
This letter provides my comments with respect to the important and useful paper by Ghaemi and others (1). Bipolar spectrum disorder (BSD) is placed between unipolar disorder and bipolar disorders I and II (BD I, BD II). In their paper, they propose a definition: at least 1 major depressive episode (MDE), no spontaneous manic or hypomanic episodes, and signs of bipolarity. Of these signs, the most important are antidepressant- induced mania or hypomania and a family history of BD, with other criteria being > 3 MDEs, atypical features, and onset of first MDE at age < 25 years.
In recent studies, I have tested whether unipolar MDE that shows some of these features is linked to BD II, supporting this BSD definition. One study compared patients with unipolar disorder—both highly recurrent (HRUP) (> 4 MDEs) (n = 57) and low recurrent (LRUP) MDE (< 5 MDEs) (n = 32)—with patients having BD II MDE (n = 151) (2). Patients with HRUP did not differ significantly from those with BD II with respect to first MDE onset, but compared with LRUP patients, they had a significantly lower age of onset, more atypical features, and a family history of BD II. This suggests that HRUP could be midway between unipolar disorder and BD II, supporting Goodwin and Jamison’s view that recurrence can be as important as polarity in mood disorders (3).
A second study (4) compared persons with atypical features of unipolar disorder (n = 38), early-onset unipolar disorder (age < 21 years) (n = 39), and BD II MDE (n = 234). Compared with BD II patients, those with atypical features did not differ significantly in onset-age, in MDE recurrences, or in family history of BD II. However, compared with patients having nonatypical unipolar disorder, they had a significantly lower onset-age. Compared with BD II patients, those with early-onset unipolar disorder did not differ significantly in atypical features, in recurrences, or in family history of BD II. However, compared with patients having non–early-onset unipolar disorder, they had significantly more atypical features and recurrences. These findings suggest a link between atypical unipolar disorder and BD II, as well as a link between early-onset unipolar disorder and BD II, supporting Ghaemi and others’ BSD definition.
Ghaemi and others’ signs of bipolarity could also be useful in reducing the underdiagnosis of BD II (1). BD II underdiagnosis relates to many factors, including hypomania that patients do not view as a disorder (often, it has improved functioning). Other signs include difficulty in remembering positive events owing to depression-associated negative cognitive bias (BD II patients usually present for MDE), clinician skills, use of structured vs semistructured (better) interviews, and lack of information from family members (5,6).
I have tested some of the Ghaemi and others’ bipolarity signs to find out whether, during MDE assessment, these signs could be useful to induce clinicians to carefully assess past hypomania, thus reducing BD II underdiagnosis and mistreatment (1).
I describe the study methods in detail in previous reports (2,4,7–9). I interviewed a consecutive sample of 260 outpatients with BD II and 173 drug-free outpatients with unipolar disorder who presented for MDE treatment in a private clinic in Italy. These samples are more representative of mood disorders, which are usually treated in clinical practice vs tertiary care centres (10,11). I used the Structured Clinical Interview for DSM-IV (12). Systematic assessment of past hypomania was improved by more probing for overactivity and for information from family members; it resulted in increased BD II diagnoses (13,14). I assessed hypomania symptoms during MDE. The BD II group comprised 68.4% women, with a mean (SD) age of 41.7 (14.0) years. Of these patients, 81.1% presented with > 3 MDEs, with a mean (SD) MDE onset-age of 22.9 (10.8) years; 53% had atypical features; 59.2% showed depressive mixed state (DMX) (that is, MDE and > 2 concurrent hypomania symptoms, recently found to be very common in BD II [2,4,7]); and 54.1% a family history of BD I and II (assessed by structured interview) (15). Of the unipolar disorder group, 60.6% were women; the mean (SD) age was 47.0 (15.6) years; 58.9% had > 3 MDEs, with a mean (SD) onset-age of 32.0 (14.5) years; 25.4% had atypical features; 29.4% showed DMX; and 21.2% had a family history of BD. Sensitivity (SE) and specificity (SP) for predicting BD II were calculated by logistic regression for some signs of bipolarity (1). The results are as follows: > 3 MDEs (SE = 81.1%, SP = 41.0%), onset < 25 years (SE = 66.9%, SP = 64.1%), atypical features (SE = 53.0%, SP = 74.5%), DMX (SE = 59.2%, SP = 70.5%), and family history of BD (SE = 54.1%, SP = 78.7%). Family history of BD had the highest specificity (that is, few false positives). Family history, however, can be difficult to assess (3). Conversely, 2 cross-sectional bipolarity signs that are not memory dependent—atypical features and DMX—also had high specificity and were not difficult to assess during MDE assessment (7,8). In a busy clinical practice, these 2 cross-sectional markers of BD II can induce clinicians to carefully probe for past hypomania. Results not only support Ghaemi and others’ BSD but also suggest some clinical and family history markers to reduce BD II underdiagnosis.
1. Ghaemi SN, Ko JY, Goodwin FK. “Cade’s disease” and beyond: misdiagnosis, antidepressant use, and a proposed definition for bipolar spectrum disorder. Can J Psychiatry 2002;47:125–34.
2. Benazzi F. Highly recurrent unipolar may related to bipolar II. Compr Psychiatry 2002;43:263–8.
3. Goodwin FK, Jamison KR. Manic-depressive illness. New York: Oxford University Press; 1990.
4. Benazzi F. Is there a link between atypical and early onset “unipolar” depression and bipolar II disorder? Compr Psychiatry (forthcoming).
5. Benazzi F. High prevalence of bipolar spectrum disorders. J Clin Psychiatry 2001;62:735–6.
6. Akiskal HS, Bourgeois ML, Angst J, Post R, Moller H-J, Hirschfeld R. Re-evaluating the prevalence and diagnostic composition within the broad clinical spectrum of bipolar disorders. J Affect Disord 2000;59 (Suppl 1):S5–S30.
7. Benazzi F, Akiskal HS. Delineating bipolar II mixed states in the Ravenna-San Diego collaborative study: the relative prevalence and diagnostic significance of hypomanic features during major depressive episodes. J Affect Disord 2001;67:115–22.
8. Benazzi F. Sensitivity and specificity of clinical markers for the diagnosis of bipolar II disorder. Compr Psychiatry 2001;42:461–5.
9. Benazzi F. Bipolar II depression in late life: prevalence and clinical features in 525 depressed outpatients. J Affect Disord 2001;66:13–8.
10. Akiskal HS, Pinto O. The evolving bipolar spectrum: prototypes I, II, III, and IV. In: Akiskal HS, editor. Bipolarity: beyond classic mania. Psychiatr Clin North Am 1999;22:517–34.
11. Ghaemi SN. Dr Ghaemi replies. High prevalence of bipolar spectrum disorders, by Benazzi F. J Clin Psychiatry 2001;62:735–6.
12. First MB, Spitzer RL, Gibbon M, Williams JBW. Structured clinical interview for DSM-IV axis I disorders-clinician version (SCID-CV). Washington (DC): American Psychiatric Press; 1997.
13. Benazzi F, Akiskal HS. Refining the evaluation of bipolar II: beyond the strict SCID-CV guidelines for hypomania. J Affect Disord 2003;73:33–8.
14. Angst J, Gamma A, Benazzi F, Ajdacic V, Eich D, Rossler W. Toward a re-definition of subthreshold bipolarity: epidemiology and proposed criteria for bipolar-II, minor bipolar disorders and hypomania. J Affect Disord 2003;73:133–46.
15. Weissman MM, Wickramaratne P, Adams P, Wolk S, Verdeli H, Olfson M. Brief screening for family psychiatric history. The family history screen. Arch Gen Psychiatry 2000;57:675–82.
Franco Benazzi, MD