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Three issues of current concern in bipolar II disorder include: diagnostic criteria for hypomania, diagnosis of mixed depression, and management of mixed depression.
August 2006, Vol. XXIII, No. 9
According to DSM-IV,1, diagnosis of bipolar disorder (BP) II requires the presence of major depressive and hypomanic episodes. DSM-IV further characterizes hypomania as requiring (a) periods of elevated or irritable mood (mood changes), which must always be present and must last at least 4 days, different from the usual mood; (b) 3 of the following 8 symptoms if mood is elevated, 4 if mood is irritable: inflated self-esteem, decreased need for sleep, more talkativeness, racing thoughts, distractibility, increased goaldirected activity, psychomotor agitation, and excessive involvement in risky activities; (c) change in functioning; (d) observable mood and functioning change; (e) no marked impairment of functioning, no psychotic symptoms; and (f) symptoms must not be caused by substances, drugs (including antidepressants), or medical disorders.
This article will focus on 3 issues of current concern: diagnostic criteria for hypomania, diagnosis of mixed depression, and management of mixed depression.
A recent series of studies has found that BP II is much more common than the 0.5% community prevalence reported by DSM-IV: the current estimate of community prevalence is about 5%.2-4 However, clinical studies in different settings have found a much higher prevalence of BP II among depressed outpatients, reporting an equal number with major depressive disorder (MDD) in a ratio of 1:1.5-13
In comparison to previous studies, 4,8,10-15 the much higher prevalence of BP II found in these studies is related to the following methodologic advances:
The use of fully structured interviews by lay interviewers, which used yes/no questions and did not provide for clinical evaluation, often led to underdiagnosis of BP II or misdiagnosis of BP II as MDD. The use of semistructured interviews by trained clinicians provides a clearer diagnostic perspective and consequently, a smaller margin of error.
Using the criteria of a minimum duration of hypomania of 2 or more days rather than the DSM-IV 4-day cutoff may increase accurate diagnosis. Unlike the 4-day cutoff, the 2-day cutoff is based on data that show no difference on bipolar measures such as family history, age at onset, and number of recurrences. When DSM-IV criteria are strictly followed, BP II is often (at least 30% of the time) misdiagnosed as MDD.
Because the DSM-IV stem question requires remembering periods of elevated or irritable mood, the response to this question by patients with BP II is frequently no, since these periods may be seen as normal mood fluctuations. If the wording of the question includes much more than usual, this may be perceived as a sign of a severe mental disorder, and is often denied. Bypassing the stem question of DSM-IV to assess the history of hypomania can provide a more accurate diagnosis.
Overactivity (increased goal-directed activities) is an observable behavior, easier to remember than the mood state required by DSM-IV. During the initial interview, relatives and friends can report on mood changes that are more easily recalled after remembering a period of overactivity. Overactivity has been found to be the core feature of hypomania, and it can have at least the same priority as mood changes for the diagnosis of BP II.4,11,13,16
Factor analysis studies and clinical studies have supported the upgrading of overactivity. Factor analysis studies have shown that activation is the core feature of hypomania. Many DSM-IV symptoms of hypomania (7 of 9) could be considered to be the result of an activation/excitement state of the brain: increased goal-directed activity, psychomotor agitation, decreased need for sleep, more talkativeness, racing thoughts, distractibility, and excessive involvement in risky activities.
In 1913, Kraepelin17 described 3 basic domains of mania/hypomania and depression: excitement or inhibition of mood, thinking, and behavior. He did not set any priority among them, but stated that increased busyness, ie, overactivity, was the most striking feature of hypomania. His predecessors, Falret (1854) and Hecker (1898) noted the diagnostic utility of behavioral activation for the diagnosis of disorders similar to BP II, ie, cyclothymia and circular insanity.18,19 Actually, in Kraepelin's view, there could be a manic state even without an elevated mood, as in the mixed state depressive or anxious mania. According to DSM-IV, elevated mood is the prototypical symptom of hypomania. This may mislead clinicians into believing that the basic feature of hypomania is elevated mood and that the other symptoms are secondary and less important.
The major depressive episodes of BP II, and not uncommonly those of MDD, may have concurrent hypomanic symptoms but cannot include elevated mood and the related inflated self-esteem. These mixed depressions thus become missed depressions. Mixed depression misdiagnosis impacts negatively on the treatment of depression. Clinical studies have shown that BP II diagnosed by setting overactivity, and not mood changes, as the priority symptom of hypomania is similar on diagnostic measures to DSM-IV BP II, which requires mood changes for the diagnosis of hypomania. Diagnosing hypomania by requiring overactivity does not lead to overdiagnosis of BP II, and most DSM-IV BP II (approximately 80%) is included.
The Structured Clinical Interview for DSM-IV (SCID)20 has the disadvantage of having the stem question for hypomania based on mood changes, if the response is negative, assessment must move to nonbipolar disorders. Another important disadvantage of the SCID is that it does not assess hypomania/hypomanic symptoms in a major depressive episode, leading to missing mixed depressions, especially in outpatients.
Two recent studies have reported on mixed hypomania, which is a combination of hypomania and depressive symptoms or a major depressive episode. 21,22 This diagnosis also will be missed by the SCID. Patients with BP II may not seek treatment for hypomania, because it is frequently seen as a period of improved functioning. Impairment in hypomania, when it occurs, is mild, and is seen more often by relatives and friends than by patients with hypomanic BP II.
The basic data supporting a distinction between BP I and BP II23,24 are presented in the Table. In comparison to BP I, there are many fewer studies of BP II and there is little evidence to support the treatment guidelines. Compared with BP I, patients with BP II are more prone to episodes of depression, higher Axis I comorbidity (especially panic disorder), a higher suicide risk, and a high incidence of substance abuse.9,25-28
|Characteristic||BP I||BP II|
|Bipolar family history||More BP I relatives than BP II relatives||More BP II relatives than BP I relatives|
|Prevalence||Equal in men and women||Higher in women than men|
|Depression||More likely psychomotor retardation||More likely psychomotor agitation|
|Rapid cycling||Less common||More common|
|Risk of suicidality||Lower||Higher|
Patients with BP II plus concurrent cyclothymic temperament (high instability of mood, thinking, and behavior) are more common in tertiary care settings (around 50% of these patients), have more Axis I comorbidity, and are at higher risk for suicide and substance abuse. Because of the negative impact that this concurrent temperament has on the course of BP II, this subgroup is referred to as dark; without the concurrent condition the subgroup is called sunny, because there are often periods of improved functioning.29
The DSM-IV boundary between hypomania and mania is based on marked impairment of functioning in mania, but its definition is unclear and may lead to misdiagnosis. However, it helps that hypomanic episodes often have improved functioning, especially in nontertiary-care settings.30-32 It is unknown whether mood-stabilizing agents should be given long-term to patients with BP II. The risk of switching to hypomania with antidepressants is lower in BP II than in BP I,33,34 but because BP II is highly recurrent (especially depression), understanding how to prevent future episodes of depression is imperative. Depression associated with BP II is often mixed and atypical; and its treatment needs to be the focus of future studies.35
Many episodes of depression (major depressive episodes) in BP II are mixed. Mixed depression (depressive mixed state) has been defined as the combination of depression and hypomanic symptoms (usually not reaching the minimum number required by DSM-IV for the diagnosis of hypomania).17,21,22,36-43 Hypomanic symptoms start during the depression (ie, these are not the tail of a recent hypomanic episode), and are not induced by antidepressants (ie, have a spontaneous onset), although antidepressants can induce and worsen these symptoms.
Very few studies have included samples of untreated BP II that would allow the study of spontaneous-onset intradepression hypomanic symptoms. Several definitions of mixed depression have been suggested and tested. Some require 2 or 3 hypomanic symptoms, others require 3 specific symptoms such as psychomotor agitation. The most validated definition to date requires a cutoff of 3 hypomanic symptoms. Its validation is based on stronger associations with bipolar validators, such as family history, age at onset, and BP II. This mixed depression has a positive predictive value of more than 70% for BP II.
The diagnostic validity of agitated depression has been tested in outpatients.44 Most agitated depressions are mixed (they have many intradepression hypomanic symptoms), and most are related to BP II. Inpatients with agitated depressions often have many severe manic symptoms, including psychosis (uncommon in outpatients with agitated depression). In a BP II and MDD sample, agitated depression was different on bipolar validators from nonagitated depression only when it was mixed (it was often mixed). This finding suggests that it is not psychomotor agitation alone that makes agitated depression different from nonagitated depression, which brings into question the diagnostic validity of agitated depression.
The frequency of mixed depression in BP II has ranged between 20% and 70%. Its frequency is related to the setting (eg, tertiary care vs nontertiary care, inpatients vs outpatients), the interview methods, the BP I and BP II ratio versus MDD, the study of treated samples (as mood-stabilizing treatment suppresses manic/hypomanic symptoms), and the definition used. It is more common in BP I and BP II than in MDD, but it is not uncommon in MDD (around 30% in outpatients). Mixed depression in MDD has been found to be closer to that of BP I and BP II, on bipolar family history and age at onset, than to that of nonmixed MDD.
The most common symptoms of mixed depression, which are more severe in BP I than BP II, are irritability, racing thoughts and distractibility (mental activation), psychomotor agitation (which is mild in outpatients), and talkativeness (behavioral activation). Factor analysis of these symptoms has found 2 factors: a mental activation and a behavioral activation factor. These factors closely match the factors found in the hypomania occurring outside the depression, supporting the hypomanic nature of these symptoms. In outpatients, symptoms such as irritability and racing (crowded) thoughts are often not spontaneously reported, and should be systematically assessed and psychomotor agitation is mild. Atypical depression is common in BP4,9,45 and studies have found that atypical depression is more likely than typical depression to be mixed. In this case, it is the mental activation of mixed depression that is present in atypical depression, making the combination of the 2 states possible.46
The bipolar nature of mixed depression is supported by several lines of evidence:
Two lines of evidence question the categoric definition of mixed depression,55 as reported above: (1) the distribution of the intradepression hypomanic symptoms between BP II and MDD is not bimodal, as it should have been in a categoric disorder54; and (2) the doseresponse relationship between number of intradepression hypomanic symptoms and bipolar family history loading, ie, the higher the number of symptoms, the higher the bipolar family history loading. A discontinuity, ie, no dose-response relationship, should have been found if mixed depression were a categoric disorder.42,55 The nonbimodal distribution of the cross-sectional intradepression hypomanic symptoms is complemented by a similar lack of bimodality in the lifetime manic/hypomanic symptoms in patients with BP I and MDD.56
From a clinical practice point of view, there are several important considerations regarding mixed depression. Depressed patients should be systematically assessed for concurrent hypomanic symptoms, which, if present, should lead to a careful probing for a history of hypomania, supplemented by information from key informants. Antidepressants should be used with care in the treatment of mixed depression, since antidepressants alone (ie, without protection by mood-stabilizing agents) could worsen the concurrent hypomanic symptoms, sometimes leading to suicidal behavior.36 Irritability, psychomotor agitation, and bipolarity are possible precursors to suicidality that may be related to the effects of antidepressants.57
Studies of mixed depression have shown that cross-sectionally assessed psychomotor agitation and racing/ crowded thoughts are independent predictors of suicidal ideas,58,59 and that mixed depression is often present before suicide attempts.60 It would thus appear that it is not antidepressants that induce suicidality, but their incorrect use.58-60 In mixed depression it seems logical to first control the hypomanic symptoms with mood-stabilizing drugs and then to add an antidepressant.35 Sometimes, when a patient with mixed depression has concurrent full hypomania (ie, irritability and at least 4 symptoms), quickly treating the hypomania also resolves the depression.
Controlled studies are needed, but, because of the FDA warning, cannot be undertaken. The FDA does not allow studies on antidepressants in subjects with depression who have symptoms/features (such as psychomotor agitation, irritability, hypomanic symptoms, impulsivity, bipolar depression, and bipolar family history) that may be precursors to suicidality. Therefore, retrospective studies and naturalistic studies are the only source of information about the treatment of mixed depression.
Diagnostic criteria for hypomania, mixed depression, and the treatment of mixed depression, are the current hot topics in connection with BP II. All 3 of these may have an important impact on the treatment of BP II disorder.
Franco Benazzi, MD, PhD, is director of the Hecker Psychiatry Research Center at Forli, Italy, a University of California at San Diego (USA) Collaborating Center. The focus of his research is bipolar II disorder, atypical depression, and mixed depression. He has published numerous articles on these subjects in international peer-reviewed journals. He reports that he has no conflicts of interest concerning the subject matter of this article.
1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR). Washington, DC: American Psychiatric Association; 2000.
2. Rihmer Z, Angst J. Mood disorders: epidemiology. In: Sadock BJ, Sadock VA, eds. Kaplan & Sadock's Comprehensive Textbook of Psychiatry. Philadelphia: Lippincott Williams & Wilkins; 2005:1575-1582.
3. Kessler RC, Berglund P, Demler O, et al. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62:593-602.
4. Angst J, Gamma A, Benazzi F, et al. Toward a redefinition of subthreshold bipolarity: epidemiology and proposed criteria for bipolar-II, minor bipolar disorders and hypomania. J Affect Disord. 2003; 73:133-146.
5. Benazzi F. Prevalence of bipolar II disorder in outpatient depression: a 203-case study in private practice. J Affect Disord. 1997;43:163-166.
6. Benazzi F. High frequency of bipolar spectrum in outpatients with depression. Can J Psychiatry. 2004; 49:279-280.
7. Hantouche EG, Akiskal HS, Lencrenon S, 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.
8. Angst J, Adolfsson R, Benazzi F, et al. The HCL- 32: towards a self-assessment tool for hypomanic symptoms in outpatients. J Affect Disord. 2005; 88:217-233.
9. Perugi G, Toni C, Travierso MC, et al. The role of cyclothymia in atypical depression: toward a databased reconceptualization of the borderline-bipolar II connection. J Affect Disord. 2003;73:87-98.
10. 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.
11. Benazzi F. Diagnosis of bipolar II disorder: a comparison of structured versus semistructured interviews. Prog Neuropsychopharmacol Biol Psychiatry. 2003;27:985-991.
12. Simpson SG, McMahon FJ, McInnis MG, et al. Diagnostic reliability of bipolar II diagnosis. Arch Gen Psychiatry. 2002;59:736-740.
13. Akiskal HS, Benazzi F. Optimizing the detection of bipolar II disorder in outpatient private practice: toward a systematization of clinical diagnostic wisdom. J Clin Psychiatry. 2005;66:914-921.
14. Judd LL, Akiskal HS, Schettler PJ, et al. A prospective investigation of the natural history of the longterm weekly symptomatic status of bipolar II disorder. Arch Gen Psychiatry. 2003;60:261-269.
15. Benazzi F, Akiskal H. The duration of hypomania in bipolar-II disorder in private practice: methodology and validation. J Affect Disord. 2006, Jan 18; [Epub ahead of print].
16. Hantouche EG, Angst J, Akiskal HS. Factor structure of hypomania: interrelationships with cyclothymia and the soft bipolar spectrum. J Affect Disord. 2003;73:39-47.
17. Kraepelin E. Manic-depressive Insanity and Paranoia. Edinburgh: Livingstone E & S; 1921.
18. Sedler MJ. Falret's discovery: the origin of the concept of bipolar affective illness. Am J Psychiatry. 1983;140:1127-1133.
19. Koukopoulos A. Ewald Hecker's description of cyclothymia as a cyclical mood disorder: its relevance to the modern concept of bipolar II. J Affect Disord. 2003;73:199-205.
20. First MB, Spitzer RL, Gibbon M, et al. Structured Clinical Interview for DSM-IV Axis I Disorders-- Clinician Version (SCID-CV). Washington, DC: American Psychiatric Press; 1997.
21. Suppes T, McElroy SL, Altshuler LL, et al. Mixed hypomania in 908 patients with bipolar disorder evaluated prospectively in the Stanley Bipolar Treatment Network: a sex-specific phenomenon. Arch Gen Psychiatry. 2005;62:1089-1096.
22. Akiskal HS, Benazzi F. Toward a clinical delineation of dysphoric hypomania: operational and conceptual dilemmas. Bipolar Disord. 2005;7:456-464.
23. Benazzi F. Mood patterns and classification in bipolar disorder. Curr Opin Psychiatry. 2006;19:1-8.
24. Coryell W. Bipolar II disorder: the importance of hypomania. In: Goldberg JF, Harrow M, eds. Bipolar Disorders. Clinical Course and Outcome. Washington, DC: American Psychiatric Press; 1999:219-236.
25. Benazzi F. Mixed depression: a clinical marker of bipolar-II disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2005;29:267-274.
26. Rihmer Z, Pestality P. Bipolar II disorder and suicidal behavior. Psychiatr Clin North Am. 1999; 22:667-673.
27. Vieta E, Colom F, Corbella B, et al. Clinical correlates of psychiatric comorbidity in bipolar I patients. Bipolar Disord. 2001;3:253-258.
28. Judd LL, Akiskal HS, Schettler PJ, et al. The longterm natural history of the weekly symptomatic status of bipolar I disorder. Arch Gen Psychiatry. 2002;59:530-537.
29. Akiskal HS, Hantouche EG, Allilaire JF. Bipolar II with and without cyclothymic temperament: "dark" and "sunny" expressions of soft bipolarity. J Affect Disord. 2003;73:49-57.
30. Benazzi F. Borderline personality disorder and bipolar II disorder in private practice depressed outpatients. Compr Psychiatry. 2000;41:106-110.
31. Dunner DL. Clinical consequences of under-recognized bipolar spectrum disorder. Bipolar Disord. 2003;5:456-463.
32. Benazzi F. Level of functioning in hypomania of bipolar II disorder. Can J Psychiatry. 2004;49: 214-215.
33. Benazzi F. Antidepressant-associated hypomania in outpatient depression: a 203-case study in private practice. J Affect Disord. 1997;46:73-77.
34. Altshuler LL, Suppes T, Black DO, et al. Lower switch rate in depressed patients with bipolar II than bipolar I disorder treated adjunctively with secondgeneration antidepressants. Am J Psychiatry. 2006;163:313-315.
35. Benazzi F. The problem of the treatment of bipolar-II depression. Bipolar Disord. 2004;6:440-441.
36. Koukopoulos A, Albert MJ, Sani G, et al. Mixed depressive states: nosologic and therapeutic issues. Int Rev Psychiatry. 2005;17:21-37.
37. Perugi G, Akiskal HS, Micheli C, et al. Clinical characterization of depressive mixed state in bipolar- I patients: Pisa-San Diego collaboration. J Affect Disord. 2001;67:105-114.
38. Maj M, Pirozzi R, Magliano L, et al. Agitated depression in bipolar I disorder: prevalence, phenomenology, and outcome. Am J Psychiatry. 2003; 160:2134-2140.
39. Maj M, Pirozzi R, Magliano L, et al. Agitated “unipolar” major depression: prevalence, phenomenology, and outcome. J Clin Psychiatry. 2006; 67: 712-719.
40. Akiskal HS, Benazzi F. Family history validation of the bipolar nature of depressive mixed states. J Affect Disord. 2003;73:113-122.
41. Sato T, Bottlender R, Schroter A, et al. Frequency of manic symptoms during a depressive episode and unipolar “depressive mixed state” as bipolar spectrum. Acta Psychiatr Scand. 2003;107:268-274.
42. Benazzi F. Family history validation of a definition of mixed depression. Compr Psychiatry. 2005;46:159-166.
43. Bauer MS, Simon GE, Ludman E, et al. “Bipolarity” in bipolar disorder: distribution of manic and depressive symptoms in a treated population. Br J Psychiatry. 2005;187:87-88.
44. Benazzi F. Agitated depression: a valid depression subtype? Prog Neuropsychopharmacol Biol Psychiatry. 2004;28:1279-1285.
45. Benazzi F. Testing atypical depression definitions. Int J Methods Psychiatr Res. 2005;14:82-91.
46. Benazzi F. Atypical depression with hypomanic symptoms. J Affect Disord. 2001;65:179-183.
47. Benazzi F. Factor structure of recalled DSM-IV hypomanic symptoms of bipolar II disorder. Compr Psychiatry. 2004;45:441-446.
48. Angst J, Sellaro R, Stassen HH, et al. Diagnostic conversion from depression to bipolar disorders: results of a long-term prospective study of hospital admissions. J Affect Disord. 2005;84:149-157.
49. Goldberg JF, Harrow M, Whiteside JE. Risk for bipolar illness in patients initially hospitalized for unipolar depression. Am J Psychiatry. 2001; 158:1265-1270.
50. Sato T, Bottlender R, Sievers M, et al. Evaluating the inter-episode stability of depressive mixed states. J Affect Disord. 2004;81:103-113.
51. Bottlender R, Sato T, Kleindienst N, et al. Mixed depressive features predict maniform switch during treatment of depression in bipolar I disorder. J Affect Disord. 2004;78:149-152.
52. Goldberg JF, Truman CJ, Fordis J, et al. Antidepressant use during mixed states: naturalistic outcome data from the STEP-1000. Neuropsychopharmacology. 2004;29:S144.
53. Frye MA, McElroy SL, Hellemann G, et al. Clinical correlates associated with antidepressant-related mania. In: Program and abstracts of the American Psychiatric Association Annual Meeting; 2006; Toronto. Abstract NR215.
54. Benazzi F. Bipolar II disorder and major depressive disorder: continuity or discontinuity? World J Biol Psychiatry. 2003;4:166-171.
55. Akiskal HS, Benazzi F. The DSM-IV and ICD-10 categories of recurrent [major] depressive and bipolar II disorders: evidence that they lie on a dimensional spectrum. J Affect Disord. 2006;92:45-54.
56. Cassano GB, Frank E, Miniati M, et al. Conceptual underpinnings and empirical support for the mood spectrum. Psychiatr Clin North Am. 2002;25: 699-712.
57. Food and Drug Administration. Available at: http://www.fda.gov/cder/drug/advisory/SSRI20007.htm. Accessed April 28, 2006.
58. Akiskal HS, Benazzi F, Perugi G, et al. Agitated "unipolar" depression re-conceptualized as a depressive mixed state: implications for the antidepressantsuicide controversy. J Affect Disord. 2005; 85: 245-258.
59. Benazzi F. Suicidal ideation and depressive mixed states. Psychother Psychosom. 2005;74:61-62.
60. Balazs J, Benazzi F, Rihmer Z, et al. The close link between suicide attempts and mixed (bipolar) depression: Implications for suicide prevention. J Affect Disord. 2006;91:133-138.