Hong Kong J Psychiatry 2007;17:139-44

REVIEW ARTICLE

Dr Arthur DP Mak, MBChB, MRCPsych, Department of Psychiatry, Tai Po
Hospital, Hong Kong, China.

Address for correspondence: Dr Arthur DP Mak, Department of Psychiatry, Tai Po Hospital, Tai Po, New Territories, Hong Kong, China.
Tel: (852) 9301 3429; Fax: (852) 2667 6353; E-mail: arthurmak@mac.com

Submitted: 21 May 2007; Accepted: 20 August 2007

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Background

The last decade saw an awakening to the Kraepelinian continuum between manic and depressive states¹ in affective disorder research. Based on clinical observations, longitudinal follow-up, and family history, Kraepelin was able to identify patients who had mania and depression, others with depression who only had hypomania but never manic episodes, and yet others pursuing a cyclical course with temperamental manic-depressive features. These observations supported Kraepelin’s unitary view of manic- depressive illness. The latter was conceived to be a single morbid process with various clinical expressions, linked by common temperamental and genetic factors.

Recent epidemiological evidence and clinical observations have revived the bipolar spectrum concept.² Community prevalence of bipolar spectrum disorders of 5 to 8.3% have been reported.³ This constituted a large increase (1.2-1.6%) for studies reporting narrowly defined bipolar disorders, as in the Epidemiologic Catchment Area study,⁴ and the National Comorbidity Survey.⁵ The screening module of the World Health Organization Composite International Diagnostic Interview for bipolar disorder and sub-threshold bipolar conditions was validated by blind reappraisal with the non-patient version of the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders– 4th edition (DSM-IV) [SCID]. Using that screening module, the National Comorbidity Survey Replication Study yielded a 6.6% lifetime prevalence for bipolar spectrum disorder.⁶ The increased recognition of bipolar disorder translates into treatment needs which must be qualified in terms of clinical phenomenology, illness outcome, and health risks. Between bipolar I and the rest of the soft bipolar spectrum, bipolar II disorder has been the only diagnostic category recognised in the DSM-IV.⁷

What follows is a selected literature review with the aim of examining the clinical validity of bipolar II disorder from the perspectives of psychopathology, prevalence and outcome, and their significance with respect to nosology. Articles were retrieved from a MEDLINE search under the Medical Subject Heading of ‘bipolar disorder ’, published from 1966 to January 2007. Articles concerning the psychopathology, prevalence, clinical correlates, and outcome of bipolar II disorder were then selected for review. Since the focus of this review was on clinical diagnostic and nosological conceptual issues, genetic, neuroimaging, and treatment studies were not reviewed, which may represent a shortcoming worthy of focus in another review.

Beyond Bipolar I — Psychopathology of Bipolar II Disorder

Bipolar II disorder has been defined as the occurrence of spontaneous hypomania in patients with clinical depression. The distinction between bipolar I and II was first made by Fieve and Dunner⁸ in their seminal article, which distinguished hypomania from mania by the latter’s need for hospitalisation. Despite initial controversy about its nosologic status, subsequent epidemiological and clinical studies have provided a solid foundation for regarding bipolar II as a prevalent and phenomenologically distinct disorder. A family epidemiological study found bipolar II to be the commonest bipolar phenotype among 266 first-degree relatives of bipolar I and II probands, suggesting that it may be the commonest form of bipolar spectrum disorder,⁹ and longitudinal follow-up studies yielded strong diagnostic stability.^10,11 In a 10-year follow-up study of bipolar I, II, and unipolar depressed patients, only 7.5% of bipolar II subjects defined at entry developed full-blown mania over a 10-year follow-up.¹² This provided support for bipolar II as a phenomenologically stable diagnosis, rather than a transitory state between bipolar I and unipolar depression.

Based on longitudinal follow-up data on 163 patients with primary affective disorders, Dunner et al¹³ found patients with both history of hypomanic episodes and clinical depression to have a distinctly stormy and variable course with high suicidality. This was at variance with patients with full-blown manic episodes (bipolar I), while sharing the genetic risk of family bipolarity with bipolar I subjects. Genetic risk of family bipolarity in unipolar depressives was considerably less. Further evidence supported a close association between bipolar II disorder and atypical depression. Initial attempts to characterise bipolar depression involved mainly bipolar I subjects, which found more frequent psychomotor retardation than with unipolar depression.^14-16 Studies involving bipolar II samples more commonly noted patients with anxious, agitated, irritable, impulsive, and mixed symptoms, as well as atypical features such as reverse vegetative symptoms, which distinguished it from unipolar depression.^17,18 This suggests that bipolar II depression is phenomenologically distinct from depression in bipolar I disorder. In the French EPIDEP study, principal component analysis entailed scoring according to the Hamilton Depression Rating Scale and Rosenthal (8-item) scale for atypical features, as well as the Multi-Visual Analog Scale of Bipolarity on unipolar versus bipolar II depressives.¹⁹ This study found that bipolar II depressives had scores that were significantly higher for ‘hypersomnia’, and lower for ‘psychomotor retardation’, ‘loss of interest’, and ‘insomnia’.

Bipolar depression, especially bipolar II, has been associated with a broad spectrum of psychiatric co- morbidities. Bipolar II patients in the community have a high rate of anxiety disorders, especially social phobia, panic disorder / agoraphobia and obsessive-compulsive disorder,^20,21 bulimia nervosa and body dysmorphic disorder, alcohol and substance abuse disorders.^21-23 Very often, the stormy affective course may lend resemblance to axis-II cluster B personality disorders, and borderline personality disorder has also been described as a co-morbidity.^18,24,25 The occurrence of complex co-morbidities in bipolar II both underscore a stormy and complex clinical picture which could lead to diagnostic confusion, treatment delay, and high treatment needs.

The Hypomanic Swing

The presence of hypomania elicited from history has high specificity for bipolarity,²⁶ but its apparent absence does not rule out bipolar II disorder. Indeed, as mentioned above, one of the obstacles to identifying bipolar II patients in clinical settings has been the difficulty in picking up hypomania. Most patients do not present to clinicians with hypomanic episodes, which are often felt to be ego-syntonic. Many would experience these with little subjective distress, but present to clinics when they experience clinical depression. In the same vein, clinicians may not be able to recognise hypomanic psychopathology, due to the comparative lack of functional impairment and ego-syntonicity.²⁰ When patients present with clinical depression, on the other hand, state-dependent memory would hinder the subject’s ability to recall past hypomanic experiences, which appear to have less coherence with the current depressive state.²⁷ This significantly hinders the reliability of a bipolar II diagnosis. Apart from this subject-related factor, a series of other technical issues surround the evaluation of bipolar II, most importantly, hypomanic affective symptoms.^25,28

Duration Criteria

The minimum time required for a diagnosis of hypomania has changed over the past decades. The Research Diagnostic Criteria (RDC) required 2 days for a diagnosis of hypomania,²⁹ while DSM-III and DSM-III-R did not specify the period. The DSM-IV proposed 4 days, but without adequate evidence according to experts on bipolar disorders; so currently a 2-day duration is favoured.²⁸ Using the RDC 2-day duration criterion for hypomania, bipolar II disorder thus defined was diagnostically stable, when followed up over 10 years, and followed a different clinical course from the bipolar I entity.¹² In the Zurich study, a modal duration of 1 to 3 days for hypomania was found in a population- based 28- to 30-year cohort.³⁰ In a large-scale Italian clinical study on bipolar II patients using a specified duration of hypomania of 2 days,¹¹ bipolar II patients thus defined had rates of family history statistically indistinguishable from that of bipolar I disorder, both of which were significantly higher than those of unipolar depressives. There is now an international consensus, based on the aforementioned evidence, that the modal duration of hypomania should be 2 days.²⁸

The Semi-structured Interview

One reason for the lack of reliability in diagnosing bipolar II disorder is due to the interview format. It has been reported that inter-rater reliability of a bipolar II diagnosis based on structured interviews has been low.^26,31 Structured interviews may also lack validity, since clinical evaluation is not involved.³² Dunner and Tay³³ found that trained clinicians using a semi-structured interview, as opposed to non-clinicians using a structured interview, more often made the bipolar II diagnosis, and had a higher degree of diagnostic agreement.

The Structured Clinical Interview for DSM-IV Axis I Disorders — Clinician Version (SCID-CV³⁴) is one of the commonest semi-structured diagnostic interviews used in research settings for assessing DSM psychiatric diagnoses. It consists of structured questions, but diagnoses are rated based on clinical evaluation. If the screening question about past hypomanic episodes (one of the moods) was answered negatively, the whole past hypomania section would be skipped. In the revision of the SCID-CV made by Benazzi and Akiskal¹⁷ to improve evaluation of hypomania, enquiry for all DSM-IV non-mood manic / hypomanic symptoms was comprehensive. Thus, irrespective of negative answers to the screening question on mood, exploration of behavioural symptoms was not skipped, before going on to the assessment of dysthymic disorders. If hypomanic behaviour was recalled, a hypomanic episode would be coded if the subject or informant was then able to endorse hypomanic mood. This design was to avoid the pitfall of missing out subjects with past hypomanic episodes, where mild euphoria or irritability could be harder to recall than hypomanic behaviour.

To ensure systematic assessment of all hypomanic symptoms, Benazzi and Akiskal’s consecutive series¹⁷ of patients presenting to a psychiatric outpatient clinic with major depression were assessed systematically by a revised SCID-CV, which ignored the skip-out instruction in hypomania and entailed a 2-day criterion; by this form of testing 61.5% of depressed patients had bipolar II disorder. These patients had a clear pattern of ‘bipolar validators’ (familial bipolarity, age of onset, recurrences, and atypical depressive features) associated with bipolarity, but less commonly found in unipolar depressives. With bipolar II patients identified using the unmodified SCID in the author’s previous series,²⁴ a much lower prevalence of 45% was encountered.

In all of the above studies on bipolar spectrum disorders, the diagnosis of hypomania was made after supplementation by corroborative information from the patient’s significant others and clinicians’ observations. This was considered necessary due to the difficulty in recalling hypomania both by virtue of state-dependent memory and the subjectively indistinct quality of past hypomanic affectivity, compared to observed hypomanic symptoms more apparent to family members or significant others. Thus, there is now an international consensus that evaluation of bipolar II disorder be based on collateral information from the subject’s family or significant others.²⁸

The Screening Instrument

A common strategy to increase sensitivity in detecting mental disorders in a particular target population has been to apply a screening instrument. The Mood Disorders Questionnaire (MDQ), a self-rated instrument consisting of 13 yes / no items derived from DSM-IV criteria, coupled with exploration of clinical experience concerning manic or hypomanic symptoms, and additional items on concurrence of the endorsed symptoms and functional impairment. Thus far, it stands alone as the only instrument shown to have robust psychometric properties, which is also practical and easy to use in clinical population screening for bipolar spectrum disorders. When validated against the bipolar I, II and bipolar disorder ‘not-otherwise-specified’ categories of SCID-I applied to psychiatric outpatients, its psychometric properties appeared promising, showing good sensitivity (0.73) and specificity (0.90).³⁵ Currently however, it is increasingly used for identification of bipolar spectrum disorders in clinical service settings, where resource limitations constrain recourse to in-depth, multi-informant and semi-structured diagnostic interviews by a trained psychiatrist. Although not feasible in routine practice, it does not replace careful clinical enquiry and the diagnostic interview itself, especially as a means of avoiding the false negatives that interfere with the identification of bipolarity. In addition, the gold standard used in the validation study was SCID-I, and included the skip-out instructions in the hypomania section. It therefore lacked sensitivity to hypomanic states that subjects may not immediately associate with hypomanic mood. The psychometric properties of the MDQ therefore need reappraisal, in the light of recent advances in diagnostic interviews for bipolar spectrum disorders.

A High Suicidality

Bipolar outcome among depressive patients has been associated with an earlier age of onset than unipolar depressives, and commonly they endure more than 3 major depressive episodes, apart from post-partal onset.^28,36,37 In particular, longitudinal data show that the age of onset for bipolar I and II patients was similar, but the latter had more frequent episodes of depression, with increased chronicity¹² compared to the former. Psychosocial disability, at least in the depressive phase, was comparable to that of bipolar I disorder.^12,38 Notably, psychosocial disability appeared to be predicted more significantly by depressive than manic episodes, given that the main definitional difference between bipolar I and II was greater severity of manic symptoms in the former.

Since its original conception, bipolar II disorder has been associated with elevated risk of suicidal thoughts, suicidal behaviour, and completed suicide.¹³ The association of suicidality and bipolar II disorder has been summarised in a review by Rihmer and Pestality,³⁹ which combined the results of 6 studies that separately analysed bipolar I, bipolar II, and unipolar depressed patients.^{11,13,23,40-42} This review inferred that 24% of bipolar II patients experienced a suicide attempt in their lifetime, compared with 17% of bipolar I patients. In unipolar depressives, a significantly lower proportion (12%) had a lifetime history of suicide attempts.³⁹ Among depressed patients who attempted suicide, a higher percentage (19%) could be re-diagnosed with bipolar II disorder than among those who did not (9%).⁴³ Thus, in bipolar II disorder, suicide must be considered an especially common, serious, and preventable complication, and the need for suicide precautions appear even more compelling than in patients with unipolar depression.

Clinic Prevalence

In the psychiatric outpatient setting, the prevalence of bipolar II disorder among patients with depression has not been comprehensively studied. The failure to recognise sub- threshold expression of mania may be largely to blame for under-diagnosis of this entity.^20,25 A series of recent clinical studies using refined methods of symptom elicitation and evidence-based diagnostic criteria for hypomania, support a high prevalence of bipolar II disorder in various clinic settings. Among patients clinically diagnosed with unipolar depression in a primary psychiatric care setting, trained clinicians using systematic diagnostic interviews yielded a 60% prevalence of bipolar spectrum disorders.⁴⁴ Such a high prevalence was also borne out in studies conducted in tertiary referral psychiatric centres using systematic diagnostic interviews; the frequency of hypomania recognised among patients with a diagnosis of depression was comparable, ranging from 30 to 55%.^{3,15,17,45-47} The most compelling data for a high prevalence of bipolar II disorder among patients with major depression came from the French EPIDEP study.⁴⁷ Based on semi-structured assessment, clinical observation, and collateral information, it was suggested that bipolar II disorder comprised 40% of patients with major depression recruited from a broad variety of clinical samples across France. Compared to the originally estimated figure of 22%, the much higher prevalence actually encountered shows that collateral information and clinical observation are useful adjuncts to the semi-structured interview by trained interviewers. In assessing hypomania, the substantial methodological advantages these research techniques offer appear to augment the proper identification of hypomania.

The Bipolar Course

In a prospective study, Akiskal et al³⁶ found a set of features with high specificity but moderate sensitivity in predicting bipolar outcome among subjects with major depression, which were later supported by the preponderance of evidence. Thus, a family history of bipolar disorder was associated with 100% specificity for bipolar outcome in the research subjects with depressive illness, while sensitivity was moderate, at 58%. In the same prospective study,³⁶ loaded pedigrees had 95% specificity but 32% sensitivity, whilst 88% of the patients with hypersomnic-retarded depression switched to bipolar disorder upon follow-up. Further prospective evidence has demonstrated that atypical depressions more often than not progress to bipolar spectrum disorders,⁴⁸ affirming the close relationship between atypical depression and bipolarity. High recurrence rate and early age of onset were also associated with bipolarity among clinically depressed patients.³⁶ As mentioned previously, complex co-morbidities, including anxiety disorders, especially social phobia, panic disorder / agoraphobia and obsessive-compulsive disorder,^20,21 bulimia nervosa and body dysmorphic disorder, alcohol and substance abuse disorders are more commonly associated with a bipolar illness.^21-23 While suicidality may not be considered a validator of bipolarity per se, suicide ideation, attempts and completed suicide were found to be over-represented in bipolar II compared with bipolar I and unipolar depression.^{11,13,23,40-42} A higher proportion of depressive patients with a history of suicide attempts could be re-diagnosed with bipolar disorder compared to those without such a history.

Discussion

All these considerations indicate the phenomenon that bipolar II disorder has been under-diagnosed in clinic service settings. Systematic interviewing performed by trained clinicians, with appropriate collateral information, unravels a high prevalence that is diagnostically stable, phenomenologically distinct from bipolar I and unipolar depression, and shares genetic risks with bipolar I disorder. Reliance on a 4-day duration criteria as in the DSM-IV was also shown to be a source of underestimation of bipolar phenomenology. Under-recognition of hypomania and depressive features associated with bipolar II depression is of particular clinical significance, in view of the high risk of suicidality.

So far, there has been no clinical study on bipolar spectrum disorders among ethnic Chinese subjects that addresses the clinical phenomenology and nosology, community and clinic prevalence, and the course of this illness. In particular, it is not known whether bipolar II disorder is prominent in the Chinese depressive population attending clinics, as has been reported in Caucasians. The impact of excessive reliance on enquiring subjective experience of mood in eliciting affective syndromes may be especially obfuscating in the local population, where the idiom of distress is more commonly somatic. The potential public health consequence of under-diagnosing bipolar spectrum disorders (particularly bipolar II that was responsible for the majority reported in the West) could be very important. Since it is associated with a high risk of suicidality, it is vital that the clinic prevalence of bipolar II, predictors, and corresponding outcome be explored, so as to facilitate a better clinical service to Chinese populations across the globe.

References

1. Kraepelin E. Manic-depressive insanity and paranoia. Edinburgh: ES Livingstone; 1921.
2. Goodwin FK. Manic-depressive illness. New York: Oxford University Press; 1990.
3. Angst J. The emerging epidemiology of hypomania and bipolar II disorder. J Affect Disord 1998;50:143-51.
4. Regier DA, Boyd JH, Burke JD Jr, Rae DS, Myers JK, Kramer M, et al. One-month prevalence of mental disorders in the United States. Based on five Epidemiologic Catchment Area sites. Arch Gen Psychiatry 1988;45:977-86.
5. Kessler RC, McGonagle KA, Zhao S, Nelson CB, Hughes M, Eshleman S, et al. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey. Arch Gen Psychiatry 1994;51:8-19.
6. Kessler RC, Akiskal HS, Angst J, Guyer M, Hirschfeld RM, Merikangas KR, et al. Validity of the assessment of bipolar spectrum disorders in the WHO CIDI 3.0. J Affect Disord 2006;96:259-69.
7. Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision (DSM-IV-TR). Washington, DC: American Psychiatric Association; 2000.
8. Fieve RR, Dunner DL. Unipolar and bipolar affective states. In: Flach FF, Draghi SS, editors. The nature and treatment of depression. New York: John Wiley & Sons; 1975:145-60.
9. Simpson SG, Folstein SE, Meyers DA, McMahon FJ, Brusco DM, DePaulo JR Jr. Bipolar II: the most common bipolar phenotype? Am J Psychiatry 1993;150:901-3.
10. Akiskal HS. The prevalent clinical spectrum of bipolar disorders: beyond DSM-IV. J Clin Psychopharmacol 1996;16(2 Suppl 1):S4-14.
11. 1 Cassano GB, Akiskal HS, Savino M, Musetti L, Perugi G. Proposed subtypes of bipolar II and related disorders: with hypomanic episodes (or cyclothymia) and with hyperthymic temperament. J Affect Disord 1992;26:127-40.
12. 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;152:385-90.
13. Dunner DL, Gershon ES, Goodwin FK. Heritable factors in the severity of affective illness. Biol Psychiatry 1976;11:31-42.
14. Akiskal HS. Subaffective disorders: dysthymic, cyclothymic and bipolar II disorders in the “borderline” realm. Psychiatr Clin North Am 1981;4:25-46.
15. Akiskal HS, Mallya G. Criteria for the “soft” bipolar spectrum: treatment implications. Psychopharmacol Bull 1987;23:68-73.
16. Mitchell PB, Wilhelm K, Parker G, Austin MP, Rutgers P, Malhi GS. The clinical features of bipolar depression: a comparison with matched major depressive disorder patients. J Clin Psychiatry 2001;62:212-6.
17. 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.
18. Perugi G, Toni C, Akiskal HS. Anxious-bipolar comorbidity. Diagnostic and treatment challenges. Psychiatr Clin North Am 1999;22:565-83.
19. Hantouche EG, Akiskal HS. Bipolar II vs. unipolar depression: psychopathologic differentiation by dimensional measures. J Affect Disord 2005;84:127-32.
20. Cassano GB, Dell’Osso L, Frank E, Miniati M, Fagiolini A, Shear K, et al. The bipolar spectrum: a clinical reality in search of diagnostic criteria and an assessment methodology. J Affect Disord 1999;54:319- 28.
21. Young LT, Cooke RG, Robb JC, Levitt AJ, Joffe RT. Anxious and non- anxious bipolar disorder. J Affect Disord 1993;29:49-52.
22. Angst J, Angst F, Stassen HH. Suicide risk in patients with major depressive disorder. J Clin Psychiatry 1999;60 Suppl 2:S57-62.
23. Endicott J, Nee J, Andreasen N, Clayton P, Keller M, Coryell W. Bipolar II. Combine or keep separate? J Affect Disord 1985;8:17-28.
24. Benazzi F. Prevalence of bipolar II disorder in outpatient depression: a 203-case study in private practice. J Affect Disord 1997;43:163-6.
25. Perugi G, Akiskal HS. The soft bipolar spectrum redefined: focus on the cyclothymic, anxious-sensitive, impulse-dyscontrol, and binge- eating connection in bipolar II and related conditions. Psychiatr Clin North Am 2002;25:713-37.
26. Rice JP, McDonald-Scott P, Endicott J, Coryell W, Grove WM, Keller MB, et al. The stability of diagnosis with an application to bipolar II disorder. Psychiatry Res 1986;19:285-96.
27. Akiskal HS, Pinto O. The evolving bipolar spectrum. Prototypes I, II, III, and IV. Psychiatr Clin North Am 1999;22:517-34.
28. Akiskal HS, Bourgeois ML, Angst J, Post R, Moller H, Hirschfeld R. Re-evaluating the prevalence of and diagnostic composition within the broad clinical spectrum of bipolar disorders. J Affect Disord 2000;59 (Suppl 1):S5-30.
29. Spitzer RL, Endicott J, Robins E. Research diagnostic criteria: rationale and reliability. Arch Gen Psychiatry 1978;35:773-82.
30. Wicki W, Angst J. The Zurich Study. X. Hypomania in a 28- to 30- year-old cohort. Eur Arch Psychiatry Clin Neurosci 1991;240:339-48.
31. Dunner DL. Bipolar depression with hypomania (bipolar II). In: Widiger TA, Frances AJ, Pincus HA, Ross R, First MB, Davis WW, editors. DSM-IV Sourcebook, v. 2. Washington, DC: American Psychiatric Association; 1996:3-10.
32. Brugha TS, Bebbington PE, Jenkins R. A difference that matters: comparisons of structured and semi-structured psychiatric diagnostic interviews in the general population. Psychol Med 1999;29:1013-20.
33. Dunner DL, Tay LK. Diagnostic reliability of the history of hypomania in bipolar II patients and patients with major depression. Compr Psychiatry 1993;34:303-7.
34. First MB, Gibbon M, Williams JB. Structured Clinical Interview For DSM-IV Axis 1 Disorders — Clinician Version. Washington, DC: American Psychiatric Press; 1997.
35. Hirschfeld RM, Williams JB, Spitzer RL, Calabrese JR, Flynn L, Keck PE Jr, et al. Development and validation of a screening instrument for bipolar spectrum disorder: the Mood Disorder Questionnaire. Am J Psychiatry 2000;157:1873-5.
36. Akiskal HS, Walker P, Puzantian VR, King D, Rosenthal TL, Dranon M. Bipolar outcome in the course of depressive illness. Phenomenologic, familial, and pharmacologic predictors. J Affect Disord 1983;5:115- 28.
37. 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.
38. Judd LL, Akiskal HS, Zeller PJ, Paulus M, Leon AC, Maser JD, et al. Psychosocial disability during the long-term course of unipolar major depressive disorder. Arch Gen Psychiatry 2000;57:375-80.
39. Rihmer Z, Pestality P. Bipolar II disorder and suicidal behavior. Psychiatr Clin North Am 1999;22:667-73.
40. Coryell W, Andreasen NC, Endicott J, Keller M. The significance of past mania or hypomania in the course and outcome of major depression. Am J Psychiatry 1987;144:309-15.
41. Tondo L, Baldessarini RJ, Hennen J, Minnai GP, Salis P, Scamonatti L, et al. Suicide attempts in major affective disorder patients with comorbid substance use disorders. J Clin Psychiatry 1999;60 (Suppl 2):63-9.
42. Vieta E, Benabarre A, Colom F, Gasto C, Nieto E, Otero A, et al. Suicidal behavior in bipolar I and bipolar II disorder. J Nerv Ment Dis 1997;185:407-9.
43. Bulik CM, Carpenter LL, Kupfer DJ, Frank E. Features associated with suicide attempts in recurrent major depression. J Affect Disord 1990;18:29-37.
44. Ghaemi SN, Boiman EE, Goodwin FK. Diagnosing bipolar disorder and the effect of antidepressants: a naturalistic study. J Clin Psychiatry 2000;61:804-8.
45. Benazzi F. Prevalence of bipolar II disorder in outpatient depression: a 203-case study in private practice. J Affect Disord 1997;43:163-6.
46. Benazzi F. Frequency of bipolar spectrum in 111 private practice depression outpatients. Eur Arch Psychiatry Clin Neurosci 2003;253:203-8.
47. Hantouche EG, Akiskal HS, Lancrenon S, Allilaire JF, Sechter D, Azorin JM, 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;50:163-73.
48. Ebert DB, Kalb R, Ott G. Atypical depression as a bipolar spectrum disease: evidence from a longitudinal study: the early course of atypical depression. Psychiatria Danubina 1993;5:133-6.