- Email: [email protected]
Bipolar II disorder family history using the family history screen: findings and clinical implications
COMPREHENSIVE PSYCHIATRY (Official Journal of the American Psychopathological Association)
VOL. 45, NO. 2
MARCH/APRIL 2004
Bipolar II Disorder Family History Using the Family History Screen: Findings and Clinical Implications Franco Benazzi Psychiatric family history of bipolar II disorder is understudied. The aims of the current study were to find the psychiatric family history of bipolar II patients using a new structured interview, the Family History Screen by Weissman et al (2000), and to find bipolar disorders family history predicting power for the diagnosis of bipolar II. One hundred sixty-four consecutive unipolar major depressive disorder (MDD) and 241 consecutive bipolar II major depressive episode (MDE) outpatients were interviewed with the Structured Clinical Interview for DSM-IV (SCID). The Family History Screen was used. Sensitivity and specificity of predictors of the diagnosis of bipolar II (bipolar [type I and II] family history, bipolar II family history, atypical depression, depressive mixed state, many MDE recurrences, early onset) were studied. Bipolar II subjects
had significantly more bipolar I, more bipolar II (50.7%), more MDE, and more social phobia in firstdegree relatives than did unipolar subjects. Bipolar II subjects had many more first-degree relatives with bipolar II than with bipolar I. Among the predictors of the diagnosis of bipolar II, bipolar II family history had the highest specificity (82.8%), while early onset had the highest sensitivity. Discriminant analysis of predictor variables found that bipolar II family history and early onset were highly significant predictors. In conclusion, bipolar II family history was common in bipolar II patients, and it had high specificity for predicting bipolar II. If detected, it could reduce bipolar II misdiagnosis by inducing careful probing for a history of hypomania. © 2004 Elsevier Inc. All rights reserved.
T
of patients) and family study method (direct interview of relatives) reporting on bipolar II family history of bipolar II patients. These studies showed that first-degree relatives of bipolar II patients often had more bipolar II than unipolar and bipolar I. The family study method is thought to be more accurate than the family history method.2 However, the family history method was shown to be useful and to have respectable sensitivity for major diagnoses when compared to the family study method.10 Coryell’s review2 of family studies (only five studies included between 1982 and 1993) found that morbid risks in relatives of bipolar II patients were 4.2% to 40.4% for bipolar II, 0.7% to
HE PSYCHIATRIC FAMILY HISTORY of bipolar II disorder is understudied, probably because the diagnosis of bipolar II by the family history method may be difficult.1,2 This problem is linked to the problem of the diagnosis of bipolar II in patients, a diagnosis which may have low reliability because it is often based on history of hypomania and not on observation of hypomania (bipolar II patients usually present for depression and not for hypomania).3-5 As hypomanic episodes are often pleasant periods of improved functioning not seen as a disorder by patients, and depressed patients may have a negative cognitive bias for past positive events,4 the diagnosis of bipolar II is often missed.3-7 Family members and close friends are needed to supplement clinical information.4,8 To increase reliability, the interviewer should be a clinician trained in the diagnosis of bipolar II disorder, using semistructured interviews based on clinical evaluation.5,6,9 The diagnosis of bipolar II by the family history method has the same problems at a higher level. Goodwin and Jamison’s 1990 review1 found few studies using the family history method (interview
From the Outpatient Psychiatry Center, University of California at San Diego (USA) Collaborating Center, Ravenna, Italy; and the Department of Psychiatry, National Health Service, Forli, Italy. Address reprint requests to Franco Benazzi, M.D., Via Pozzetto 17, 48010 Castiglione di Cervia RA, Italy. © 2004 Elsevier Inc. All rights reserved. 0010-440X/04/4502-0003$30.00/0 doi:10.1016/j.comppsych.2003.12.003
Comprehensive Psychiatry, Vol. 45, No. 2 (March/April), 2004: pp 77-82
77
78
FRANCO BENAZZI
3.5% for bipolar I, and 18.5% to 42.5% for depression (bipolar and unipolar), while morbid risks in relatives of unipolar patients were 0.3% to 2.6% for bipolar II, 0.2% to 1.5% for bipolar I, and 10.2% to 32.2% for depression. Recent family history studies11-18 found that bipolar II patients had 29% of first-degree relatives with bipolar II (only in one study17), 8.3% to 51.0% with bipolar (I ⫹ II), and 39.4% to 56.1% with unipolar depression; unipolar patients had 3.0% to 3.4% of firstdegree relatives with bipolar (I ⫹ II), and 33.3% to 68% with unipolar depression; bipolar (I ⫹ II) patients had 22.9% to 54.0% of first-degree relatives with bipolar (I ⫹ II), and 29.7% to 55.0% with unipolar depression. The aims of the present study were to find the psychiatric family history of bipolar II patients using a new validated structured interview, the Family History Screen by Weissman et al,19 and to find the power of bipolar disorders family history for predicting the diagnosis of bipolar II. The Family History Screen can distinguish mania from hypomania, while the often-used family history interview by Andreasen et al.20 does not. The study of bipolar II is important for clinical practice, because bipolar II was found to be common (up to 60%) among depressed outpatients,4,6,14,21-25 and because of possible negative effects of antidepressants,7,26-28 high suicide risk,29 high anxiety disorders and substance abuse (related to the setting) comorbidity,30,31 and high frequency of residual depressive symptoms (increasing relapse risk).32 METHOD The study was conducted by a senior clinical and mood disorder research psychiatrist of the Department of Psychiatry, National Health Service of Forli, in his outpatient psychiatry private center (based in Ravenna and Forli, Emilia-Romagna region), which is a University of California at San Diego (USA) Collaborating Center. Private practice was chosen because it is more representative of mood disorder patients spontaneously seeking psychiatric treatment in Italy (mood disorder patients in private practice may be more representative also in the United States33). In Italy, private practice is the first (or the second, after family doctors) line of treatment of mood disorders, and national psychiatric health services and university centers usually treat the most severe mood patients. Most persons can be visited by a private psychiatrist (reducing a possible selection bias related to income). Many researchers believe that mood disorder patients in tertiary-care academic centers are not representative of the usual patients treated in clinical practice.7,34-36 A total of 164 consecutive unipolar (major depressive disorder [MDD], MDD superimposed on dysthymic disorder) and 241 consecutive bipolar II outpatients (informed consent ob-
tained), presenting spontaneously for major depressive episode (MDE) treatment, were included in the last 2 years. MDD and MDD superimposed on dysthymic disorder were combined in one group, following previous reports.37,38 Patients had not received psychopharmacotherapy for the index MDE before evaluation. However, some patients on low-dose benzodiazepines (no more than 0.75 mg per day of alprazolam or equivalents) were included in both groups. Current substance abuse and severe personality disorder patients were not included, because these characteristics may confound the diagnosis of bipolar II and mixed states.4 In the present study setting, the prevalence of bipolar II and unipolar patients with severe personality disorder was found to be very low using structured interviewing.39 Clinically significant general medical illness and dementia patients were not included. All patients were interviewed by the author during the first visit (a cross-sectional assessment) with the Structured Clinical Interview for DSM-IV Axis I Disorders–Clinician Version (SCID-CV) (inter-rater reliability kappas ranging from 0.70 to 1.00),40 and the Global Assessment of Functioning (GAF) scale.8 The SCID-CV is partly semistructured, and based on clinical evaluation (not on simple yes/no answers to structured questions). In the diagnosis of bipolar II disorder, clinical evaluation by clinicians trained on bipolar II diagnosis led to more correct diagnoses than strict structured interviewing.5,9 All patients were systematically SCID-CV–interviewed for history of manic/hypomanic episodes, and for the presence of hypomanic symptoms during the index MDE. The SCID-CV skip-out instruction of the question about past periods of elevated or irritable mood was not followed, because it was shown6 that systematic assessment of the history of all past hypomanic symptoms increased the frequency of bipolar II diagnoses. History of mania/hypomania was always investigated soon after having made the diagnosis of MDE before the assessment of other variables, in order to avoid a possible bias related to the knowledge of indicators of bipolarity. Psychiatric family history was investigated with the Family History Screen,19 a new validated structured interview for collecting lifetime psychiatric history on first-degree relatives (median sensitivity, 67.6%; specificity, 87.6%). The patient and often also a first-degree relative were interviewed. The power of a positive bipolar family history for predicting the diagnosis of bipolar II disorder was tested against variables reported to predict bipolar II diagnosis (DSM-IV atypical features specifier, depressive mixed state, many recurrences [more than four MDEs], and early onset [continuous variable] of the first MDE).1,3,4,41-44 Depressive mixed state was defined as a MDE plus three or more (DMX3) concurrent hypomanic symptoms, following the definition of Akiskal and Benazzi.44 The DSM-IV 4-day minimum duration of hypomania for bipolar II diagnosis (a cut-off not based on data45) was not followed. Instead, at least 2 days of hypomania were required for bipolar II diagnosis, on the basis of previous studies supporting this cut-off.3,4,14,15,46-48 Most bipolar II patients in the present study had a history of more than one hypomania (increasing diagnosis reliability).4 Often, family members or close friends supplemented clinical information during the interview (increasing diagnosis reliability).4 Sample features are presented in Table 1. The sample had the typical features reported to distinguish bipolar II from unipolar MDD (lower age of onset, more recurrences, more atypical features, and more DMX3).1,3,4,22,41-44
BIPOLAR II FAMILY HISTORY
79
Table 1. Sample Features: Bipolar II Versus Unipolar Variables: mean (SD), %
Bipolar II (n ⫽ 241)
Unipolar (n ⫽ 164)
t/z
Female gender Age (yr) Age of onset first MDE (yr) Duration of illness (yr) GAF score MDE symptoms ⬎ 2 yr Axis I comorbidity ⬎ 4 MDEs Psychotic features Melancholic features Atypical features DMX3
67.2% 41.9(14.1) 22.9(10.8) 19.1(13.6) 50.4(9.0) 44.3% 55.1% 80.9% 8.7% 13.6% 53.5% 59.3%
60.3% 47.1(15.5) 32.1(14.5) 14.9(12.7) 50.8(9.2) 33.5% 46.9% 59.7% 7.9% 18.2% 23.7% 26.8%
1.4 ⫺3.4 ⫺7.3 3.1 ⫺0.4 2.1 1.6 4.6 0.2 ⫺1.2 5.9 6.4
df
403 403 403 403
P
.1546 .0005 .0000 .0019 .6637 .0294 .1050 .0000 .7754 .2088 .0000 .0000
Abbreviations: MDE, major depressive episode; GAF, Global Assessment of Functioning scale; DMX3, depressive mixed state, defined according to Akiskal and Benazzl, 2003.44
Statistics Means were compared with the t test, and proportions were compared with the two-sample test of proportion. Univariate logistic regression was used to study sensitivity and specificity. Maximum-likelihood logit estimation was used for discriminant analysis. STATA Statistical Software, Release 7 (Stata Corp, College Station, TX) was used. P values were two-tailed, and alpha level was set at 0.05.
RESULTS
Comparison of psychiatric family history between bipolar II and unipolar subjects (Table 2) found that bipolar II subjects had significantly more bipolar I, more bipolar II, more MDE, and more social phobia in first-degree relatives. Bipolar II subjects had many more first-degree relatives with bipolar II than with bipolar I. Unipolar subjects had many more first-degree relatives with MDE than with bipolar disorders. Both bipolar II and unipolar subjects had a high frequency of MDE in first-degree relatives, and MDE was the most common mood disorder in the first-degree relatives of bipolar II patients. The frequency of
MDE in first-degree relatives of bipolar II subjects was significantly higher than in unipolar patients. Table 3 shows the sensitivity and specificity of predictors of the diagnosis of bipolar II disorder, i.e., family history of bipolar (type I and II) disorders, family history of bipolar II disorder, atypical features, DMX3, many MDE recurrences, and early onset. A family history of bipolar II disorder had the highest specificity, while early onset had the highest sensitivity. Table 4 shows the results of the discriminant analysis of the above bipolar predictors of bipolar II. While all of the predictors resulted in significant or nearly significant bipolar II disorder occurrence, positive family history and early onset were highly significant. DISCUSSION
Results showed that differences in family history of mood disorder between bipolar II and unipolar patients were in line with the trends reported in previous studies,1,2,11-18 supporting the
Table 2. Comparison of Psychiatric Family History Between Bipolar II and Unipolar Patients Variables: %
Bipolar II (n ⫽ 241)
Unipolar (n ⫽ 164)
z
P
Bipolar I disorder Bipolar II disorder MDE Panic disorder Social phobia Obsessive compulsive disorder Psychosis Substance abuse Suicide attempts Suicide
9.5 50.7 88.2 34.5 25.0 27.2 15.4 16.1 8.0 1.4
3.0 17.1 74.7 32.3 11.1 20.2 13.1 12.1 4.0 3.0
2.5 6.8 3.5 0.4 3.4 1.6 0.6 1.1 1.6 ⫺1.1
.0111 .0000 .0004 .6455 .0005 .1072 .5184 .2615 .1059 .2644
80
FRANCO BENAZZI
Table 3. Sensitivity and Specificity of Family History of Bipolar (I ⴙ II) Disorders, Family History of Bipolar II Disorder, Early Onset of First MDE, Many MDE Recurrences (>4), MDE With Atypical Features Specifier, and MDE With Three or More Concurrent Hypomanic Symptoms (DMX3), for Predicting Bipolar II Diagnosis, by Logistic Regression Variable: %
Sensitivity
Specificity
Bipolar (I ⫹ II) family history Bipolar II family history Atypical features DMX3 ⬎4 MDEs Early onset
56.6 50.7 53.5 59.3 80.9 86.2
79.8 82.8 76.2 73.1 40.2 39.0
validity of the Family History Screen19 in the study of mood disorder family history in bipolar II patients. The figures for mood disorders were in the range or higher than the figures reported in previous studies,1,2,11-18 findings which may be related to different sample features, type of interview, and methods (family history v family study) used in different studies. Bipolar II patients had significantly more bipolar I and bipolar II in first-degree relatives than unipolar patients, and many more first-degree relatives with bipolar II than with bipolar I. Both bipolar II and unipolar patients had a high frequency of MDE in first-degree relatives, and MDE was the most common mood disorder in the first-degree relatives of bipolar II patients. The frequency of MDE in first-degree relatives of bipolar II patients was significantly higher than in unipolar patients, a finding that can be related to the sum of bipolar and unipolar MDEs, as bipolar disorders were significantly more common in firstdegree relatives of bipolar II patients. Family history of social phobia was significantly more common in bipolar II patients than in unipolar patients. This finding supports the close association reported between bipolar II disorder and social phobia.49-51 Family history of suicidal behavior was not significantly more common in bipolar II than in unipolar patients, differently from previous reports30 on suicidal behavior in bipolar II subjects (reported to be higher in bipolar II than in unipolar patients). The finding may be related to the setting, the country of the study, and to the sample features of the present study (substance abuse and borderline personality disorder patients were not included). In the present study setting, bipolar II could be less severe than the bipolar II studied in other settings (which included many
patients with unstable personality23). An important feature of the Family History Screen in the study of bipolar II is its ability to make a diagnosis of bipolar II (not only of bipolar disorders), which led to the finding of a bipolar II family history in 50.7% of bipolar II patients, which could have been missed by using interviews with no bipolar I/bipolar II differences in the questions. The comparison of the sensitivity and specificity of the predictors of bipolar II disorder (i.e., family history of bipolar (type I and II) disorders, family history of bipolar II disorder, atypical features, DMX3, many MDE recurrences, and early onset) found that a family history of bipolar II disorder had the highest specificity (meaning few falsepositives), while early onset had the highest sensitivity (meaning few false-negatives). The discriminant analysis of the predictors of bipolar II found that, while all were significant or nearly significant, bipolar II family history and early onset were highly significant. However, bipolar II family history had the highest specificity for predicting the diagnosis of bipolar II disorder. The results suggest that a positive family history for bipolar II disorder may be the most useful predictor of a diagnosis of bipolar II disorder, in line with a previous report.4 These results support the need to probe for a family history of bipolar II disorder during the cross-sectional assessment of a MDE patient, as a positive bipolar II family history could suggest a bipolar II diagnosis. However, as it may not be easy to get the history of hypomania by a bipolar II depressed patients (because hypomanic episodes are usually pleasant periods of improved functioning not seen as a disorder by patients, and the negative cognitive bias of depression may make it difficult to remember past positive periods),52 it may be even more difficult to get from the patient a history of hypomania about relatives. As a result, while for a clinician trained in the diagnosis of bipolar II it may Table 4. Discriminant Analysis of Positive Family History of Bipolar II Disorders, Early Onset of First MDE, Many MDE Recurrences (>4), MDE With Atypical Features Specifier, and MDE With Three or More Concurrent Hypomanic Symptoms (DMX3), for Predicting Bipolar II Diagnosis Variable
Coefficient
Z
P
Bipolar II family history Atypical features DMX3 ⬎4 MDEs Early onset
1.1 0.6 0.6 0.6 ⫺0.0
3.1 1.9 2.0 1.8 ⫺3.9
.002 .055 .042 .069 .000
BIPOLAR II FAMILY HISTORY
81
not be too difficult to get a history of hypomania from the patient about her/himself, and her/his relatives, this task might be too difficult for clinicians in usual clinical practice. As reported in Table 2, the frequency of the family history of bipolar I disorder was very low compared to that of bipolar II disorder in bipolar II patients. While family history of mania may be easier to get from a patient because mania leads to marked impairment of functioning, hospital admission, or psychosis (according to DSM-IV criteria)—events/symptoms that are easier to remember—the family history of mania was very low compared to the family history of bipolar II disorder in bipolar II patients. Therefore, a clinician could find it more useful (i.e., easier and less time-consuming) to rely on some cross-sectional clinical markers of bipolar II disorder such as atypical features and DMX341,44 during MDE assessment. These two bipolar II markers are much less dependent on memory than family history, and are not difficult to identify during a cross-sectional assessment of a MDE patient. These two clinical markers had a high specificity for the diagnosis of bipolar II disorder, which was not much lower than the specificity of bipolar II disorder family history. Finding these clinical markers during the cross-sectional evaluation of a depressed patient should indicate suspicion that the patient may have a bipolar II disorder, and should induce a careful probing for the history of hypomania.
influenced probing when using the Family History Screen. However, the Family History Screen is a structured interview, and this should have much reduced unintentional bias by the interviewer. The Family History Screen findings were in line with previous reports using different interviews. Sample features were in line with the reported typical features distinguishing bipolar and unipolar,1,4,21,22,43 supporting the validity of the interview, and suggesting that a skillful interview during a MDE (when the MDE is not too severe as in most present study patients, whose median GAF was 50) may still give valid clinical information. The interview was conducted by a clinician studying and treating mood disorders for a long time, using validated structured interviews, information from key informants, and systematically interviewing about history of hypomania and current hypomanic symptoms with the partly semistructured SCID-CV.5 Semistructured interviews by trained clinicians led to more correct diagnoses of bipolar II and had high inter-rater reliability than fully structured diagnostic interviews.5,9 These study features may have reduced the study limitations.1,4 It would be important to replicate the study, with skilled interviewers independently conducting the diagnostic evaluation of the probands and the Family History Screen evaluations.
Limitations
Only outpatients, with no concurrent psychopharmacotherapy and no substance abuse disorders were studied in a large sample of bipolar II in a nontertiary setting.
Single-interviewer and cross-sectional assessment limited the validity of the findings. This fact may have
Advantages
REFERENCES 1. Goodwin FK, Jamison KR. Manic-Depressive Illness. New York, NY: Oxford University Press, 1990. 2. Coryell W. Bipolar II disorder: the importance of hypomania. Bipolar Disorders. Clinical Course and Outcome. In: Goldberg JF, Harrow M. Washington, DC: American Psychiatric Press, 1999:219-236. 3. Akiskal HS. The prevalent clinical spectrum of bipolar disorders: beyond DSM-IV. J Clin Psychopharmacol 1996; 16(Suppl 1):4S-14S. 4. Akiskal HS. Classification, diagnosis and boundaries of bipolar disorders: a review. In: Maj M, Akiskal HS, Lopez-Ibor JJ (eds). Bipolar Disorder., Sartorius N. Chichester, UK: Wiley, 2002:1-52. 5. Dunner DL, Tay KL. Diagnostic reliability of the history of hypomania in bipolar II patients and patients with major depression. Compr Psychiatry 1993;34:303-307. 6. Benazzi F, Akiskal HS. Refining the evaluation of bipolar II: beyond the strict SCID-CV guidelines for hypomania. J Affect Disord 2003;73:33-38. 7. Ghaemi SN, Boiman EE, Goodwin FK. Diagnosing bi-
polar disorder and the effect of antidepressants: a naturalistic study. J Clin Psychiatry 2000;61:804-808. 8. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Ed. 4. Washington, DC: American Psychiatric Association, 1994. 9. Simpson SG, McMahon FJ, McInnis MG, MacKinnon DF, Edwin D, Folstein SE, et al. Diagnostic reliability of bipolar II diagnosis. Arch Gen Psychiatry 2002;59:736-740. 10. Andreasen NC, Rice J, Endicott J, Reich T, Coryell W. The family history approach to diagnosis. How useful is it? Arch Gen Psychiatry 1986;43:421-429. 11. Kupfer DJ, Frank E, Grochocinski VJ, Cluss PA, Kouck PR, Stapf DA. Demographic and clinical characteristics of individuals in a bipolar disorder case registry. J Clin Psychiatry 2002;63:120-125. 12. Tondo L, Baldessarini RJ, Floris G. Long-term clinical effectiveness of lithium maintenance treatment in types I and II bipolar disorders. Br J Psychiatry 2001;178(suppl):s184-s190. 13. Angst J, Merikangas KR. Multi-dimensional criteria for the diagnosis of depression. J Affect Disord 2001;62:7-15.
82
14. Cassano GB, Akiskal HS, Savino M, Musetti L, Perugi G, Soriani A. Proposed subtypes of bipolar II and related disorders: with hypomanic episodes (or cyclothymia) and with hyperthymic temperament. J Affect Disord 1992;26:127-140. 15. Angst J. The emerging epidemiology of hypomania and bipolar II disorder. J Affect Disord 1998;50:143-151. 16. Allilaire JF, Hantouche EG, Sechter D, Bourgeois ML, Azorin JM, Lancrenon S, et al. Frequence et aspects cliniques du trouble bipolaire II dans une etude multicentrique: EPIDEP. L’Encephale 2001;27:149-158. 17. Judd LL. Longitudinal studies of bipolar disorders: is there a spectrum? In: Bipolar Spectrum Disorders: U.S. and European Perspectives. Symposium Book of Abstacts and Slides. New Orleans, LA: American Psychiatric Association annual meeting, 2001. 18. Suppes T, Leverich GS, Keck PE, Nolen WA, Denicoff KD, Altshuler LL, et al. The Stanley Foundation bipolar treatment outcome network II. Demographics and illness characteristics of the first 261 patients. J Affect Disord 2001;67:45-59. 19. 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; 57:675-682. 20. Andreasen NC, Endicott J, Spitzer RL, Winokur G. The family history method using diagnostic criteria. Reliability and validity. Arch Gen Psychiatry 1977;34:1229-1235. 21. Benazzi F. Prevalence of bipolar II disorder in outpatient depression: a 203-case study in private practice. J Affect Disord 1997;43:163-166. 22. Benazzi F. Bipolar II depression in late life: prevalence and clinical features in 525 depressed outpatients. J Affect Disord 2001;66:13-18. 23. Hantouche EG, Akiskal HS, Lencrenon S, Allilaire J-F, Sechter D, Azorin J-M, et al. Systematic clinical methodology for validating bipolar-II disorder: data in mid-stream from a French national multi-site study (EPIDEP). J Affect Disord 1998;50:163-173. 24. Perugi G, Akiskal HS, Lattanzi L, Cecconi D, Mastrocinque C, Patronelli A, et al. The high prevalence of “soft” bipolar (II) features in atypical depression. Compr Psychiatry 1998;39:63-71. 25. Angst J. Comorbidity of mood disorders: a longitudinal prospective study. Br J Psychiatry 1996;168(Suppl 30):31-37. 26. Benazzi F. Antidepressant-associated hypomania in outpatient depression: a 203-case study in private practice. J Affect Disord 1997;46:73-76. 27. Altshuler LL, Post RM, Leverich GS, Mikalauskas K, Rosoff A, Ackerman L. Antidepressant-induced mania and cycle acceleration: a controversy revisited. Am J Psychiatry 1995; 152:1130-1138. 28. Kilzieh N, Akiskal HS. Rapid-cycling bipolar disorder. Psychiatr Clin North Am 1999;22:585-607. 29. Rihmer Z, Pestality P. Bipolar II disorder and suicidal behavior. Psychiatr Clin North Am 1999;22:667-673. 30. Perugi G, Toni C, Akiskal HS. Anxious-bipolar comorbidity. Psychiatr Clin North Am 1999;22:565-583. 31. Sonne SC, Brady KT. Substance abuse and bipolar comorbidity. Psychiatr Clin North Am 1999;22:609-627. 32. Benazzi F. Prevalence and clinical correlates of residual depressive symptoms in bipolar II disorder. Psychother Psychosom 2001;70:232-238. 33. Ghaemi SN. Dr. Ghaemi replies. High prevalence of
FRANCO BENAZZI
bipolar spectrum disorders, by Benazzi F. J Clin Psychiatry 2001;62:735-736. 34. Goldberg JF, Kocsis JH. Depression in the course of bipolar disorder. In: Goldberg JF, Harrow M (eds). Bipolar Disorders. Clinical Course and Outcome. Washington, DC: American Psychiatric Press, 1999:129-147. 35. Akiskal HS, Pinto O. The evolving bipolar spectrum: prototypes I, II, III, and IV. Psychiatr Clin North Am 1999;22: 517-534. 36. Post RM, Nolen WA, Kupka RW, Denicoff KD, Leverich GS, Keck PE, et al. The Stanley Foundation Bipolar Network. 1. Rationale and methods. Br J Psychiatry 2001;178(suppl): s169-s176. 37. Angst J, Sellaro R, Merikangas KR. Depressive spectrum diagnoses. Compr Psychiatry 2000;41(Suppl 2):39-47. 38. Judd LL, Akiskal HS. Delineating the longitudinal structure of depressive illness: beyond clinical subtypes and duration thresholds. Pharmacopsychiatry 2000;33:3-7. 39. Benazzi F. Borderline personality disorder and bipolar II disorder in private practice depressed outpatients. Compr Psychiatry 2000;41:106-110. 40. 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. 41. Benazzi F. Sensitivity and specificity of clinical markers for the diagnosis of bipolar II disorder. Compr Psychiatry 2001; 42:461-465. 42. McMahon FJ, Stine OC, Chase GA, Meyers DA, Simpson SG, DePaulo JR. Influence of clinical subtype, sex, and lineality on age at onset of major affective disorder in a family sample. Am J Psychiatry 1994;151:210-215. 43. Baldessarini RJ. A plea for integrity of the bipolar disorder concept. Bipolar Disord 2000;2:3-7. 44. Akiskal HS, Benazzi F. Family history validation of the bipolar nature of depressive mixed states. J Affect Disord 2003; 73:113-122. 45. Dunner DL. Diagnostic revisions for DSM-IV. In: Goodnick PL (eds). Mania. Clinical and Research Perspectives. Washington, DC: American Psychiatric Press, 1998:3-10. 46. Benazzi F. Is 4 days the minimum duration of hypomania in bipolar II disorder? Eur Arch Psychiatry Clin Neurosci 2001; 251:32-34. 47. Akiskal HS, Djenderedjian AH, Rosenthal RH, Khani MK. Cyclothymic disorder: validating criteria for inclusion in the bipolar affective group. Am J Psychiatry 1977;134:1227-1233. 48. Coryell W, Endicott J, Maser JD, Keller MB, Leon AC, Akiskal HS. Long-term stability of polarity distinctions in the affective disorders. Am J Psychiatry 1995;152:385-390. 49. Perugi G, Frare F, Madaro D, Maremmani I, Akiskal HS. Alcohol abuse in social phobic patients: is there a bipolar connection? J Affect Disord 2002;68:33-39. 50. Perugi G, Frare F, Toni C, Mata B, Akiskal HS. Bipolar II and unipolar comorbidity in 153 outpatients with social phobia. Compr Psychiatry 2001;42:375-381. 51. Perugi G, Akiskal HS, Ramacciotti S, Nassini S, Toni C, Milanfranchi A, et al. Depressive comorbidity of panic, social phobic, and obsessive-compulsive disorders re-examined: is there a bipolar II connection? J Psychiatr Res 1999;33:53-61. 52. Benazzi F. High prevalence of bipolar spectrum disorders. J Clin Psychiatry 2001;62:735-736.
VOL. 45, NO. 2
MARCH/APRIL 2004
Bipolar II Disorder Family History Using the Family History Screen: Findings and Clinical Implications Franco Benazzi Psychiatric family history of bipolar II disorder is understudied. The aims of the current study were to find the psychiatric family history of bipolar II patients using a new structured interview, the Family History Screen by Weissman et al (2000), and to find bipolar disorders family history predicting power for the diagnosis of bipolar II. One hundred sixty-four consecutive unipolar major depressive disorder (MDD) and 241 consecutive bipolar II major depressive episode (MDE) outpatients were interviewed with the Structured Clinical Interview for DSM-IV (SCID). The Family History Screen was used. Sensitivity and specificity of predictors of the diagnosis of bipolar II (bipolar [type I and II] family history, bipolar II family history, atypical depression, depressive mixed state, many MDE recurrences, early onset) were studied. Bipolar II subjects
had significantly more bipolar I, more bipolar II (50.7%), more MDE, and more social phobia in firstdegree relatives than did unipolar subjects. Bipolar II subjects had many more first-degree relatives with bipolar II than with bipolar I. Among the predictors of the diagnosis of bipolar II, bipolar II family history had the highest specificity (82.8%), while early onset had the highest sensitivity. Discriminant analysis of predictor variables found that bipolar II family history and early onset were highly significant predictors. In conclusion, bipolar II family history was common in bipolar II patients, and it had high specificity for predicting bipolar II. If detected, it could reduce bipolar II misdiagnosis by inducing careful probing for a history of hypomania. © 2004 Elsevier Inc. All rights reserved.
T
of patients) and family study method (direct interview of relatives) reporting on bipolar II family history of bipolar II patients. These studies showed that first-degree relatives of bipolar II patients often had more bipolar II than unipolar and bipolar I. The family study method is thought to be more accurate than the family history method.2 However, the family history method was shown to be useful and to have respectable sensitivity for major diagnoses when compared to the family study method.10 Coryell’s review2 of family studies (only five studies included between 1982 and 1993) found that morbid risks in relatives of bipolar II patients were 4.2% to 40.4% for bipolar II, 0.7% to
HE PSYCHIATRIC FAMILY HISTORY of bipolar II disorder is understudied, probably because the diagnosis of bipolar II by the family history method may be difficult.1,2 This problem is linked to the problem of the diagnosis of bipolar II in patients, a diagnosis which may have low reliability because it is often based on history of hypomania and not on observation of hypomania (bipolar II patients usually present for depression and not for hypomania).3-5 As hypomanic episodes are often pleasant periods of improved functioning not seen as a disorder by patients, and depressed patients may have a negative cognitive bias for past positive events,4 the diagnosis of bipolar II is often missed.3-7 Family members and close friends are needed to supplement clinical information.4,8 To increase reliability, the interviewer should be a clinician trained in the diagnosis of bipolar II disorder, using semistructured interviews based on clinical evaluation.5,6,9 The diagnosis of bipolar II by the family history method has the same problems at a higher level. Goodwin and Jamison’s 1990 review1 found few studies using the family history method (interview
From the Outpatient Psychiatry Center, University of California at San Diego (USA) Collaborating Center, Ravenna, Italy; and the Department of Psychiatry, National Health Service, Forli, Italy. Address reprint requests to Franco Benazzi, M.D., Via Pozzetto 17, 48010 Castiglione di Cervia RA, Italy. © 2004 Elsevier Inc. All rights reserved. 0010-440X/04/4502-0003$30.00/0 doi:10.1016/j.comppsych.2003.12.003
Comprehensive Psychiatry, Vol. 45, No. 2 (March/April), 2004: pp 77-82
77
78
FRANCO BENAZZI
3.5% for bipolar I, and 18.5% to 42.5% for depression (bipolar and unipolar), while morbid risks in relatives of unipolar patients were 0.3% to 2.6% for bipolar II, 0.2% to 1.5% for bipolar I, and 10.2% to 32.2% for depression. Recent family history studies11-18 found that bipolar II patients had 29% of first-degree relatives with bipolar II (only in one study17), 8.3% to 51.0% with bipolar (I ⫹ II), and 39.4% to 56.1% with unipolar depression; unipolar patients had 3.0% to 3.4% of firstdegree relatives with bipolar (I ⫹ II), and 33.3% to 68% with unipolar depression; bipolar (I ⫹ II) patients had 22.9% to 54.0% of first-degree relatives with bipolar (I ⫹ II), and 29.7% to 55.0% with unipolar depression. The aims of the present study were to find the psychiatric family history of bipolar II patients using a new validated structured interview, the Family History Screen by Weissman et al,19 and to find the power of bipolar disorders family history for predicting the diagnosis of bipolar II. The Family History Screen can distinguish mania from hypomania, while the often-used family history interview by Andreasen et al.20 does not. The study of bipolar II is important for clinical practice, because bipolar II was found to be common (up to 60%) among depressed outpatients,4,6,14,21-25 and because of possible negative effects of antidepressants,7,26-28 high suicide risk,29 high anxiety disorders and substance abuse (related to the setting) comorbidity,30,31 and high frequency of residual depressive symptoms (increasing relapse risk).32 METHOD The study was conducted by a senior clinical and mood disorder research psychiatrist of the Department of Psychiatry, National Health Service of Forli, in his outpatient psychiatry private center (based in Ravenna and Forli, Emilia-Romagna region), which is a University of California at San Diego (USA) Collaborating Center. Private practice was chosen because it is more representative of mood disorder patients spontaneously seeking psychiatric treatment in Italy (mood disorder patients in private practice may be more representative also in the United States33). In Italy, private practice is the first (or the second, after family doctors) line of treatment of mood disorders, and national psychiatric health services and university centers usually treat the most severe mood patients. Most persons can be visited by a private psychiatrist (reducing a possible selection bias related to income). Many researchers believe that mood disorder patients in tertiary-care academic centers are not representative of the usual patients treated in clinical practice.7,34-36 A total of 164 consecutive unipolar (major depressive disorder [MDD], MDD superimposed on dysthymic disorder) and 241 consecutive bipolar II outpatients (informed consent ob-
tained), presenting spontaneously for major depressive episode (MDE) treatment, were included in the last 2 years. MDD and MDD superimposed on dysthymic disorder were combined in one group, following previous reports.37,38 Patients had not received psychopharmacotherapy for the index MDE before evaluation. However, some patients on low-dose benzodiazepines (no more than 0.75 mg per day of alprazolam or equivalents) were included in both groups. Current substance abuse and severe personality disorder patients were not included, because these characteristics may confound the diagnosis of bipolar II and mixed states.4 In the present study setting, the prevalence of bipolar II and unipolar patients with severe personality disorder was found to be very low using structured interviewing.39 Clinically significant general medical illness and dementia patients were not included. All patients were interviewed by the author during the first visit (a cross-sectional assessment) with the Structured Clinical Interview for DSM-IV Axis I Disorders–Clinician Version (SCID-CV) (inter-rater reliability kappas ranging from 0.70 to 1.00),40 and the Global Assessment of Functioning (GAF) scale.8 The SCID-CV is partly semistructured, and based on clinical evaluation (not on simple yes/no answers to structured questions). In the diagnosis of bipolar II disorder, clinical evaluation by clinicians trained on bipolar II diagnosis led to more correct diagnoses than strict structured interviewing.5,9 All patients were systematically SCID-CV–interviewed for history of manic/hypomanic episodes, and for the presence of hypomanic symptoms during the index MDE. The SCID-CV skip-out instruction of the question about past periods of elevated or irritable mood was not followed, because it was shown6 that systematic assessment of the history of all past hypomanic symptoms increased the frequency of bipolar II diagnoses. History of mania/hypomania was always investigated soon after having made the diagnosis of MDE before the assessment of other variables, in order to avoid a possible bias related to the knowledge of indicators of bipolarity. Psychiatric family history was investigated with the Family History Screen,19 a new validated structured interview for collecting lifetime psychiatric history on first-degree relatives (median sensitivity, 67.6%; specificity, 87.6%). The patient and often also a first-degree relative were interviewed. The power of a positive bipolar family history for predicting the diagnosis of bipolar II disorder was tested against variables reported to predict bipolar II diagnosis (DSM-IV atypical features specifier, depressive mixed state, many recurrences [more than four MDEs], and early onset [continuous variable] of the first MDE).1,3,4,41-44 Depressive mixed state was defined as a MDE plus three or more (DMX3) concurrent hypomanic symptoms, following the definition of Akiskal and Benazzi.44 The DSM-IV 4-day minimum duration of hypomania for bipolar II diagnosis (a cut-off not based on data45) was not followed. Instead, at least 2 days of hypomania were required for bipolar II diagnosis, on the basis of previous studies supporting this cut-off.3,4,14,15,46-48 Most bipolar II patients in the present study had a history of more than one hypomania (increasing diagnosis reliability).4 Often, family members or close friends supplemented clinical information during the interview (increasing diagnosis reliability).4 Sample features are presented in Table 1. The sample had the typical features reported to distinguish bipolar II from unipolar MDD (lower age of onset, more recurrences, more atypical features, and more DMX3).1,3,4,22,41-44
BIPOLAR II FAMILY HISTORY
79
Table 1. Sample Features: Bipolar II Versus Unipolar Variables: mean (SD), %
Bipolar II (n ⫽ 241)
Unipolar (n ⫽ 164)
t/z
Female gender Age (yr) Age of onset first MDE (yr) Duration of illness (yr) GAF score MDE symptoms ⬎ 2 yr Axis I comorbidity ⬎ 4 MDEs Psychotic features Melancholic features Atypical features DMX3
67.2% 41.9(14.1) 22.9(10.8) 19.1(13.6) 50.4(9.0) 44.3% 55.1% 80.9% 8.7% 13.6% 53.5% 59.3%
60.3% 47.1(15.5) 32.1(14.5) 14.9(12.7) 50.8(9.2) 33.5% 46.9% 59.7% 7.9% 18.2% 23.7% 26.8%
1.4 ⫺3.4 ⫺7.3 3.1 ⫺0.4 2.1 1.6 4.6 0.2 ⫺1.2 5.9 6.4
df
403 403 403 403
P
.1546 .0005 .0000 .0019 .6637 .0294 .1050 .0000 .7754 .2088 .0000 .0000
Abbreviations: MDE, major depressive episode; GAF, Global Assessment of Functioning scale; DMX3, depressive mixed state, defined according to Akiskal and Benazzl, 2003.44
Statistics Means were compared with the t test, and proportions were compared with the two-sample test of proportion. Univariate logistic regression was used to study sensitivity and specificity. Maximum-likelihood logit estimation was used for discriminant analysis. STATA Statistical Software, Release 7 (Stata Corp, College Station, TX) was used. P values were two-tailed, and alpha level was set at 0.05.
RESULTS
Comparison of psychiatric family history between bipolar II and unipolar subjects (Table 2) found that bipolar II subjects had significantly more bipolar I, more bipolar II, more MDE, and more social phobia in first-degree relatives. Bipolar II subjects had many more first-degree relatives with bipolar II than with bipolar I. Unipolar subjects had many more first-degree relatives with MDE than with bipolar disorders. Both bipolar II and unipolar subjects had a high frequency of MDE in first-degree relatives, and MDE was the most common mood disorder in the first-degree relatives of bipolar II patients. The frequency of
MDE in first-degree relatives of bipolar II subjects was significantly higher than in unipolar patients. Table 3 shows the sensitivity and specificity of predictors of the diagnosis of bipolar II disorder, i.e., family history of bipolar (type I and II) disorders, family history of bipolar II disorder, atypical features, DMX3, many MDE recurrences, and early onset. A family history of bipolar II disorder had the highest specificity, while early onset had the highest sensitivity. Table 4 shows the results of the discriminant analysis of the above bipolar predictors of bipolar II. While all of the predictors resulted in significant or nearly significant bipolar II disorder occurrence, positive family history and early onset were highly significant. DISCUSSION
Results showed that differences in family history of mood disorder between bipolar II and unipolar patients were in line with the trends reported in previous studies,1,2,11-18 supporting the
Table 2. Comparison of Psychiatric Family History Between Bipolar II and Unipolar Patients Variables: %
Bipolar II (n ⫽ 241)
Unipolar (n ⫽ 164)
z
P
Bipolar I disorder Bipolar II disorder MDE Panic disorder Social phobia Obsessive compulsive disorder Psychosis Substance abuse Suicide attempts Suicide
9.5 50.7 88.2 34.5 25.0 27.2 15.4 16.1 8.0 1.4
3.0 17.1 74.7 32.3 11.1 20.2 13.1 12.1 4.0 3.0
2.5 6.8 3.5 0.4 3.4 1.6 0.6 1.1 1.6 ⫺1.1
.0111 .0000 .0004 .6455 .0005 .1072 .5184 .2615 .1059 .2644
80
FRANCO BENAZZI
Table 3. Sensitivity and Specificity of Family History of Bipolar (I ⴙ II) Disorders, Family History of Bipolar II Disorder, Early Onset of First MDE, Many MDE Recurrences (>4), MDE With Atypical Features Specifier, and MDE With Three or More Concurrent Hypomanic Symptoms (DMX3), for Predicting Bipolar II Diagnosis, by Logistic Regression Variable: %
Sensitivity
Specificity
Bipolar (I ⫹ II) family history Bipolar II family history Atypical features DMX3 ⬎4 MDEs Early onset
56.6 50.7 53.5 59.3 80.9 86.2
79.8 82.8 76.2 73.1 40.2 39.0
validity of the Family History Screen19 in the study of mood disorder family history in bipolar II patients. The figures for mood disorders were in the range or higher than the figures reported in previous studies,1,2,11-18 findings which may be related to different sample features, type of interview, and methods (family history v family study) used in different studies. Bipolar II patients had significantly more bipolar I and bipolar II in first-degree relatives than unipolar patients, and many more first-degree relatives with bipolar II than with bipolar I. Both bipolar II and unipolar patients had a high frequency of MDE in first-degree relatives, and MDE was the most common mood disorder in the first-degree relatives of bipolar II patients. The frequency of MDE in first-degree relatives of bipolar II patients was significantly higher than in unipolar patients, a finding that can be related to the sum of bipolar and unipolar MDEs, as bipolar disorders were significantly more common in firstdegree relatives of bipolar II patients. Family history of social phobia was significantly more common in bipolar II patients than in unipolar patients. This finding supports the close association reported between bipolar II disorder and social phobia.49-51 Family history of suicidal behavior was not significantly more common in bipolar II than in unipolar patients, differently from previous reports30 on suicidal behavior in bipolar II subjects (reported to be higher in bipolar II than in unipolar patients). The finding may be related to the setting, the country of the study, and to the sample features of the present study (substance abuse and borderline personality disorder patients were not included). In the present study setting, bipolar II could be less severe than the bipolar II studied in other settings (which included many
patients with unstable personality23). An important feature of the Family History Screen in the study of bipolar II is its ability to make a diagnosis of bipolar II (not only of bipolar disorders), which led to the finding of a bipolar II family history in 50.7% of bipolar II patients, which could have been missed by using interviews with no bipolar I/bipolar II differences in the questions. The comparison of the sensitivity and specificity of the predictors of bipolar II disorder (i.e., family history of bipolar (type I and II) disorders, family history of bipolar II disorder, atypical features, DMX3, many MDE recurrences, and early onset) found that a family history of bipolar II disorder had the highest specificity (meaning few falsepositives), while early onset had the highest sensitivity (meaning few false-negatives). The discriminant analysis of the predictors of bipolar II found that, while all were significant or nearly significant, bipolar II family history and early onset were highly significant. However, bipolar II family history had the highest specificity for predicting the diagnosis of bipolar II disorder. The results suggest that a positive family history for bipolar II disorder may be the most useful predictor of a diagnosis of bipolar II disorder, in line with a previous report.4 These results support the need to probe for a family history of bipolar II disorder during the cross-sectional assessment of a MDE patient, as a positive bipolar II family history could suggest a bipolar II diagnosis. However, as it may not be easy to get the history of hypomania by a bipolar II depressed patients (because hypomanic episodes are usually pleasant periods of improved functioning not seen as a disorder by patients, and the negative cognitive bias of depression may make it difficult to remember past positive periods),52 it may be even more difficult to get from the patient a history of hypomania about relatives. As a result, while for a clinician trained in the diagnosis of bipolar II it may Table 4. Discriminant Analysis of Positive Family History of Bipolar II Disorders, Early Onset of First MDE, Many MDE Recurrences (>4), MDE With Atypical Features Specifier, and MDE With Three or More Concurrent Hypomanic Symptoms (DMX3), for Predicting Bipolar II Diagnosis Variable
Coefficient
Z
P
Bipolar II family history Atypical features DMX3 ⬎4 MDEs Early onset
1.1 0.6 0.6 0.6 ⫺0.0
3.1 1.9 2.0 1.8 ⫺3.9
.002 .055 .042 .069 .000
BIPOLAR II FAMILY HISTORY
81
not be too difficult to get a history of hypomania from the patient about her/himself, and her/his relatives, this task might be too difficult for clinicians in usual clinical practice. As reported in Table 2, the frequency of the family history of bipolar I disorder was very low compared to that of bipolar II disorder in bipolar II patients. While family history of mania may be easier to get from a patient because mania leads to marked impairment of functioning, hospital admission, or psychosis (according to DSM-IV criteria)—events/symptoms that are easier to remember—the family history of mania was very low compared to the family history of bipolar II disorder in bipolar II patients. Therefore, a clinician could find it more useful (i.e., easier and less time-consuming) to rely on some cross-sectional clinical markers of bipolar II disorder such as atypical features and DMX341,44 during MDE assessment. These two bipolar II markers are much less dependent on memory than family history, and are not difficult to identify during a cross-sectional assessment of a MDE patient. These two clinical markers had a high specificity for the diagnosis of bipolar II disorder, which was not much lower than the specificity of bipolar II disorder family history. Finding these clinical markers during the cross-sectional evaluation of a depressed patient should indicate suspicion that the patient may have a bipolar II disorder, and should induce a careful probing for the history of hypomania.
influenced probing when using the Family History Screen. However, the Family History Screen is a structured interview, and this should have much reduced unintentional bias by the interviewer. The Family History Screen findings were in line with previous reports using different interviews. Sample features were in line with the reported typical features distinguishing bipolar and unipolar,1,4,21,22,43 supporting the validity of the interview, and suggesting that a skillful interview during a MDE (when the MDE is not too severe as in most present study patients, whose median GAF was 50) may still give valid clinical information. The interview was conducted by a clinician studying and treating mood disorders for a long time, using validated structured interviews, information from key informants, and systematically interviewing about history of hypomania and current hypomanic symptoms with the partly semistructured SCID-CV.5 Semistructured interviews by trained clinicians led to more correct diagnoses of bipolar II and had high inter-rater reliability than fully structured diagnostic interviews.5,9 These study features may have reduced the study limitations.1,4 It would be important to replicate the study, with skilled interviewers independently conducting the diagnostic evaluation of the probands and the Family History Screen evaluations.
Limitations
Only outpatients, with no concurrent psychopharmacotherapy and no substance abuse disorders were studied in a large sample of bipolar II in a nontertiary setting.
Single-interviewer and cross-sectional assessment limited the validity of the findings. This fact may have
Advantages
REFERENCES 1. Goodwin FK, Jamison KR. Manic-Depressive Illness. New York, NY: Oxford University Press, 1990. 2. Coryell W. Bipolar II disorder: the importance of hypomania. Bipolar Disorders. Clinical Course and Outcome. In: Goldberg JF, Harrow M. Washington, DC: American Psychiatric Press, 1999:219-236. 3. Akiskal HS. The prevalent clinical spectrum of bipolar disorders: beyond DSM-IV. J Clin Psychopharmacol 1996; 16(Suppl 1):4S-14S. 4. Akiskal HS. Classification, diagnosis and boundaries of bipolar disorders: a review. In: Maj M, Akiskal HS, Lopez-Ibor JJ (eds). Bipolar Disorder., Sartorius N. Chichester, UK: Wiley, 2002:1-52. 5. Dunner DL, Tay KL. Diagnostic reliability of the history of hypomania in bipolar II patients and patients with major depression. Compr Psychiatry 1993;34:303-307. 6. Benazzi F, Akiskal HS. Refining the evaluation of bipolar II: beyond the strict SCID-CV guidelines for hypomania. J Affect Disord 2003;73:33-38. 7. Ghaemi SN, Boiman EE, Goodwin FK. Diagnosing bi-
polar disorder and the effect of antidepressants: a naturalistic study. J Clin Psychiatry 2000;61:804-808. 8. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Ed. 4. Washington, DC: American Psychiatric Association, 1994. 9. Simpson SG, McMahon FJ, McInnis MG, MacKinnon DF, Edwin D, Folstein SE, et al. Diagnostic reliability of bipolar II diagnosis. Arch Gen Psychiatry 2002;59:736-740. 10. Andreasen NC, Rice J, Endicott J, Reich T, Coryell W. The family history approach to diagnosis. How useful is it? Arch Gen Psychiatry 1986;43:421-429. 11. Kupfer DJ, Frank E, Grochocinski VJ, Cluss PA, Kouck PR, Stapf DA. Demographic and clinical characteristics of individuals in a bipolar disorder case registry. J Clin Psychiatry 2002;63:120-125. 12. Tondo L, Baldessarini RJ, Floris G. Long-term clinical effectiveness of lithium maintenance treatment in types I and II bipolar disorders. Br J Psychiatry 2001;178(suppl):s184-s190. 13. Angst J, Merikangas KR. Multi-dimensional criteria for the diagnosis of depression. J Affect Disord 2001;62:7-15.
82
14. Cassano GB, Akiskal HS, Savino M, Musetti L, Perugi G, Soriani A. Proposed subtypes of bipolar II and related disorders: with hypomanic episodes (or cyclothymia) and with hyperthymic temperament. J Affect Disord 1992;26:127-140. 15. Angst J. The emerging epidemiology of hypomania and bipolar II disorder. J Affect Disord 1998;50:143-151. 16. Allilaire JF, Hantouche EG, Sechter D, Bourgeois ML, Azorin JM, Lancrenon S, et al. Frequence et aspects cliniques du trouble bipolaire II dans une etude multicentrique: EPIDEP. L’Encephale 2001;27:149-158. 17. Judd LL. Longitudinal studies of bipolar disorders: is there a spectrum? In: Bipolar Spectrum Disorders: U.S. and European Perspectives. Symposium Book of Abstacts and Slides. New Orleans, LA: American Psychiatric Association annual meeting, 2001. 18. Suppes T, Leverich GS, Keck PE, Nolen WA, Denicoff KD, Altshuler LL, et al. The Stanley Foundation bipolar treatment outcome network II. Demographics and illness characteristics of the first 261 patients. J Affect Disord 2001;67:45-59. 19. 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; 57:675-682. 20. Andreasen NC, Endicott J, Spitzer RL, Winokur G. The family history method using diagnostic criteria. Reliability and validity. Arch Gen Psychiatry 1977;34:1229-1235. 21. Benazzi F. Prevalence of bipolar II disorder in outpatient depression: a 203-case study in private practice. J Affect Disord 1997;43:163-166. 22. Benazzi F. Bipolar II depression in late life: prevalence and clinical features in 525 depressed outpatients. J Affect Disord 2001;66:13-18. 23. Hantouche EG, Akiskal HS, Lencrenon S, Allilaire J-F, Sechter D, Azorin J-M, et al. Systematic clinical methodology for validating bipolar-II disorder: data in mid-stream from a French national multi-site study (EPIDEP). J Affect Disord 1998;50:163-173. 24. Perugi G, Akiskal HS, Lattanzi L, Cecconi D, Mastrocinque C, Patronelli A, et al. The high prevalence of “soft” bipolar (II) features in atypical depression. Compr Psychiatry 1998;39:63-71. 25. Angst J. Comorbidity of mood disorders: a longitudinal prospective study. Br J Psychiatry 1996;168(Suppl 30):31-37. 26. Benazzi F. Antidepressant-associated hypomania in outpatient depression: a 203-case study in private practice. J Affect Disord 1997;46:73-76. 27. Altshuler LL, Post RM, Leverich GS, Mikalauskas K, Rosoff A, Ackerman L. Antidepressant-induced mania and cycle acceleration: a controversy revisited. Am J Psychiatry 1995; 152:1130-1138. 28. Kilzieh N, Akiskal HS. Rapid-cycling bipolar disorder. Psychiatr Clin North Am 1999;22:585-607. 29. Rihmer Z, Pestality P. Bipolar II disorder and suicidal behavior. Psychiatr Clin North Am 1999;22:667-673. 30. Perugi G, Toni C, Akiskal HS. Anxious-bipolar comorbidity. Psychiatr Clin North Am 1999;22:565-583. 31. Sonne SC, Brady KT. Substance abuse and bipolar comorbidity. Psychiatr Clin North Am 1999;22:609-627. 32. Benazzi F. Prevalence and clinical correlates of residual depressive symptoms in bipolar II disorder. Psychother Psychosom 2001;70:232-238. 33. Ghaemi SN. Dr. Ghaemi replies. High prevalence of
FRANCO BENAZZI
bipolar spectrum disorders, by Benazzi F. J Clin Psychiatry 2001;62:735-736. 34. Goldberg JF, Kocsis JH. Depression in the course of bipolar disorder. In: Goldberg JF, Harrow M (eds). Bipolar Disorders. Clinical Course and Outcome. Washington, DC: American Psychiatric Press, 1999:129-147. 35. Akiskal HS, Pinto O. The evolving bipolar spectrum: prototypes I, II, III, and IV. Psychiatr Clin North Am 1999;22: 517-534. 36. Post RM, Nolen WA, Kupka RW, Denicoff KD, Leverich GS, Keck PE, et al. The Stanley Foundation Bipolar Network. 1. Rationale and methods. Br J Psychiatry 2001;178(suppl): s169-s176. 37. Angst J, Sellaro R, Merikangas KR. Depressive spectrum diagnoses. Compr Psychiatry 2000;41(Suppl 2):39-47. 38. Judd LL, Akiskal HS. Delineating the longitudinal structure of depressive illness: beyond clinical subtypes and duration thresholds. Pharmacopsychiatry 2000;33:3-7. 39. Benazzi F. Borderline personality disorder and bipolar II disorder in private practice depressed outpatients. Compr Psychiatry 2000;41:106-110. 40. 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. 41. Benazzi F. Sensitivity and specificity of clinical markers for the diagnosis of bipolar II disorder. Compr Psychiatry 2001; 42:461-465. 42. McMahon FJ, Stine OC, Chase GA, Meyers DA, Simpson SG, DePaulo JR. Influence of clinical subtype, sex, and lineality on age at onset of major affective disorder in a family sample. Am J Psychiatry 1994;151:210-215. 43. Baldessarini RJ. A plea for integrity of the bipolar disorder concept. Bipolar Disord 2000;2:3-7. 44. Akiskal HS, Benazzi F. Family history validation of the bipolar nature of depressive mixed states. J Affect Disord 2003; 73:113-122. 45. Dunner DL. Diagnostic revisions for DSM-IV. In: Goodnick PL (eds). Mania. Clinical and Research Perspectives. Washington, DC: American Psychiatric Press, 1998:3-10. 46. Benazzi F. Is 4 days the minimum duration of hypomania in bipolar II disorder? Eur Arch Psychiatry Clin Neurosci 2001; 251:32-34. 47. Akiskal HS, Djenderedjian AH, Rosenthal RH, Khani MK. Cyclothymic disorder: validating criteria for inclusion in the bipolar affective group. Am J Psychiatry 1977;134:1227-1233. 48. Coryell W, Endicott J, Maser JD, Keller MB, Leon AC, Akiskal HS. Long-term stability of polarity distinctions in the affective disorders. Am J Psychiatry 1995;152:385-390. 49. Perugi G, Frare F, Madaro D, Maremmani I, Akiskal HS. Alcohol abuse in social phobic patients: is there a bipolar connection? J Affect Disord 2002;68:33-39. 50. Perugi G, Frare F, Toni C, Mata B, Akiskal HS. Bipolar II and unipolar comorbidity in 153 outpatients with social phobia. Compr Psychiatry 2001;42:375-381. 51. Perugi G, Akiskal HS, Ramacciotti S, Nassini S, Toni C, Milanfranchi A, et al. Depressive comorbidity of panic, social phobic, and obsessive-compulsive disorders re-examined: is there a bipolar II connection? J Psychiatr Res 1999;33:53-61. 52. Benazzi F. High prevalence of bipolar spectrum disorders. J Clin Psychiatry 2001;62:735-736.