CNS Drugs

, Volume 21, Issue 9, pp 727–740 | Cite as

Bipolar II Disorder

Epidemiology, Diagnosis and Management
Therapy In Practice


Bipolar II disorder (BP-II) is defined, by DSM-IV, as recurrent episodes of depression and hypomania. Hypomania, according to DSM-IV, requires elevated (euphoric) and/or irritable mood, plus at least three of the following symptoms (four if mood is only irritable): grandiosity, decreased need for sleep, increased talking, racing thoughts, distractibility, overactivity (an increase in goal-directed activity), psychomotor agitation and excessive involvement in risky activities. This observable change in functioning should not be severe enough to cause marked impairment of social or occupational functioning, or to require hospitalisation. The distinction between BP-II and bipolar I disorder (BP-I) is not clearcut. The symptoms of mania (defining BP-I) and hypomania (defining BP-II) are the same, apart from the presence of psychosis in mania, and the distinction is based on the presence of marked impairment associated with mania, i.e. mania is more severe and may require hospitalisation. This is an unclear boundary that can lead to misclassification; however, the fact that hypomania often increases functioning makes the distinction between mania and hypomania clearer.

BP-II depression can be syndromal and subsyndromal, and it is the prominent feature of BP-II. It is often a mixed depression, i.e. it has concurrent, usually subsyndromal, hypomanic symptoms. It is the depression that usually leads the patient to seek treatment.

DSM-IV bipolar disorders (BP-I, BP-II, cyclothymic disorder and bipolar disorder not otherwise classified, which includes very rapid cycling and recurrent hypomania) are now considered to be part of the ‘bipolar spectrum’. This is not included in DSM-IV, but is thought to also include antidepressant/substance-associated hypomania, cyclothymic temperament (a trait of highly unstable mood, thinking and behaviour), unipolar mixed depression and highly recurrent unipolar depression.

BP-II is underdiagnosed in clinical practice, and its pharmacological treatment is understudied. Underdiagnosis is demonstrated by recent epidemiological studies. While, in DSM-IV, BP-II is reported to have a lifetime community prevalence of 0.5%, epidemiological studies have instead found that it has a lifetime community prevalence (including the bipolar spectrum) of around 5%. In depressed outpatients, one in two may have BP-II. The recent increased diagnosing of BP-II in research settings is related to several factors, including the introduction of the use of semi-structured interviews by trained research clinicians, a relaxation of diagnostic criteria such that the minimum duration of hypomania is now less than the 4 days stipulated by DSM-IV, and a probing for a history of hypomania focused more on overactivity (increased goal-directed activity) than on mood change (although this is still required for a diagnosis of hypomania).

Guidelines on the treatment of BP-II are mainly consensus based and tend to follow those for the treatment of BP-I, because there have been few controlled studies of the treatment of BP-II. The current, limited evidence supports the following lines of treatment for BP-II. Hypomania is likely to respond to the same agents useful for mania, i.e. mood-stabilising agents such as lithium and valproate, and the second-generation antipsychotics (i.e. olanzapine, quetiapine, risperidone, ziprasidone, aripiprazole). Hypomania should be treated even if associated with overfunctioning, because a depression often soon follows hypomania (the hypomania-depression cycle). For the treatment of acute BP-II depression, two controlled studies of quetiapine have not found clearcut positive effects. Naturalistic studies, although open to several biases, have found antidepressants in acute BP-II depression to be as effective as in unipolar depression; however, one recent large controlled study (mainly in patients with BP-I) has found antidepressants to be no more effective than placebo. Results from naturalistic studies and clinical observations on mixed depression, while in need of replication in controlled studies, indicate that antidepressants may worsen the concurrent intradepression hypomanic symptoms. The only preventive treatment for both depression and hypomania that is supported by several, albeit older, controlled studies is lithium. Lamotrigine has shown some efficacy in delaying depression recurrences, but there have also been several negative unpublished studies of the drug in this indication.


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  1. 1.
    Angst J. The bipolar spectrum. Br J Psychiatry 2007; 190: 189–91PubMedCrossRefGoogle Scholar
  2. 2.
    Judd LL, Akiskal HS, Schettler PJ, et al. The long-term natural history of the weekly symptomatic status of bipolar I disorder. Arch Gen Psychiatry 2002; 59: 530–7PubMedCrossRefGoogle Scholar
  3. 3.
    Judd LL, Akiskal HS, Schettler PJ, et al. A prospective investigation of the natural history of the long-term weekly symptomatic status of bipolar II disorder. Arch Gen Psychiatry 2003; 60: 261–9PubMedCrossRefGoogle Scholar
  4. 4.
    Judd LL, Schettler PJ, Akiskal HS, et al. Long-term symptomatic status of bipolar I vs bipolar II disorders. Int J Neuropsychopharmacol 2003; 6: 127–37PubMedCrossRefGoogle Scholar
  5. 5.
    Judd LL, Akiskal HS, Schettler PJ, et al. The comparative clinical phenotype and long term longitudinal episode course of bipolar I and II: a clinical spectrum or distinct disorders? J Affect Disord 2003; 73: 19–32PubMedCrossRefGoogle Scholar
  6. 6.
    Judd LL, Akiskal HS, Schettler PJ, et al. Psychosocial disability in the course of bipolar I and II disorders: a prospective, comparative, longitudinal study. Arch Gen Psychiatry 2005; 62: 1322–30PubMedCrossRefGoogle Scholar
  7. 7.
    Ostacher MJ. The evidence for antidepressant use in bipolar depression. J Clin Psychiatry 2006; 67Suppl. 11: 18–21PubMedGoogle Scholar
  8. 8.
    Kraepelin E. Manic-depressive insanity and paranoia. Edinburgh: Livingstone E & S, 1921Google Scholar
  9. 9.
    American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th ed., text rev. Washington (DC): American Psychiatric Association, 2000Google Scholar
  10. 10.
    World Health Organization. The ICD-10 classification of mental and behavioural disorders. Geneva: World Health Organization, 1992Google Scholar
  11. 11.
    Angst J, Gamma A, Benazzi F, et al. Toward a re-definition of subthreshold bipolarity: epidemiology and proposed criteria for bipolar-II, minor bipolar disorders and hypomania. J Affect Disord 2003; 73: 133–46PubMedCrossRefGoogle Scholar
  12. 12.
    Akiskal HS, Azorin JM, Hantouche EG. Proposed multidimensional structure of mania: beyond the euphoric-dysphoric dichotomy. J Affect Disord 2003; 73: 7–18PubMedCrossRefGoogle Scholar
  13. 13.
    Benazzi F. Factor structure of recalled DSM-IV hypomanic symptoms of bipolar II disorder. Compr Psychiatry 2004; 45: 441–6PubMedCrossRefGoogle Scholar
  14. 14.
    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: 199–205PubMedCrossRefGoogle Scholar
  15. 15.
    Sedler MJ. Falret’s discovery: the origin of the concept of bipolar affective illness. Am J Psychiatry 1983; 140: 1127–33PubMedGoogle Scholar
  16. 16.
    Benazzi F. Is there a continuity between bipolar and depressive disorders? Psychother Psychosom 2007; 76: 70–6PubMedCrossRefGoogle Scholar
  17. 17.
    Ghaemi SN, Baldessarini RJ. The manic-depressive spectrum and mood stabilization: Kraepelin’s ghost. Psychother Psychosom 2007; 76: 65–9PubMedCrossRefGoogle Scholar
  18. 18.
    Robins E, Guze SB. Establishment of diagnostic validity in psychiatric illness: its application to schizophrenia. Am J Psychiatry 1970; 126: 983–7PubMedGoogle Scholar
  19. 19.
    Hantouche EG, Angst J, Akiskal HS. Factor structure of hypomania: interrelationships with cyclothymia and the soft bipolar spectrum. J Affect Disord 2003; 73: 39–47PubMedCrossRefGoogle Scholar
  20. 20.
    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: 217–33PubMedCrossRefGoogle Scholar
  21. 21.
    Cassidy F, Forest K, Murry E, et al. A factor analysis of the signs and symptoms of mania. Arch Gen Psychiatry 1998; 55: 27–32PubMedCrossRefGoogle Scholar
  22. 22.
    Bauer MS, Crits-Christoph P, Ball WA, et al. Independent assessment of manic and depressive symptoms by self-rating: scale characteristics and implications for the study of mania. Arch Gen Psychiatry 1991; 48: 807–12PubMedCrossRefGoogle Scholar
  23. 23.
    Dilsaver SC, Chen YR, Shoaib AM, et al. Phenomenology of mania: evidence for distinct depressed, dysphoric, and euphoric presentations. Am J Psychiatry 1999; 156: 426–30PubMedGoogle Scholar
  24. 24.
    Swann AC, Janicak PL, Calabrese JR, et al. Structure of mania: depressive, irritable, and psychotic clusters with different retrospectively-assessed course patterns of illness in randomized clinical trial participants. J Affect Disord 2001; 67: 123–32PubMedCrossRefGoogle Scholar
  25. 25.
    Coryell W, Endicott J, Maser JD, et al. Long-term stability of polarity distinctions in the affective disorders. Am J Psychiatry 1995; 152: 385–90PubMedGoogle Scholar
  26. 26.
    Akiskal HS, Maser JD, Zeller PJ, et al. Switching from ‘unipolar’ to bipolar II: an 11-year prospective study of clinical and temperamental predictors in 559 patients. Arch Gen Psychiatry 1995; 52: 114–23PubMedCrossRefGoogle Scholar
  27. 27.
    Duffy A, Grof P, Robertson C, et al. The implications of genetics studies of major mood disorders for clinical practice. J Clin Psychiatry 2000; 61: 630–7PubMedCrossRefGoogle Scholar
  28. 28.
    Joyce PR, Doughty CJ, Wells JE, et al. Affective disorders in the first-degree relatives of bipolar probands: results from the South Island Bipolar Study. Compr Psychiatry 2004; 45: 168–74PubMedCrossRefGoogle Scholar
  29. 29.
    Benazzi F. Bipolar II disorder family history using the family history screen: findings and clinical implications. Compr Psychiatry 2004; 45: 77–82PubMedCrossRefGoogle Scholar
  30. 30.
    Gershon ES, Hamovit J, Guroff JJ, et al. A family study of schizoaffective, bipolar I, bipolar II, unipolar, and normal control probands. Arch Gen Psychiatry 1982; 39: 1157–67PubMedCrossRefGoogle Scholar
  31. 31.
    Heun R, Maier W. The distinction of bipolar II disorder from bipolar I and recurrent unipolar depression: results of a controlled family study. Acta Psychiatr Scand 1993; 87: 279–84PubMedCrossRefGoogle Scholar
  32. 32.
    Akiskal HS, Akiskal KK, Haykal RF, et al. TEMPS-A: progress towards validation of a self-rated clinical version of the Temperament Evaluation of the Memphis, Pisa, Paris, and San Diego Autoquestionnaire. J Affect Disord 2005; 85: 3–16PubMedCrossRefGoogle Scholar
  33. 33.
    Akiskal HS, Akiskal KK, Lancrenon S, et al. Validating the bipolar spectrum in the French national epidep study: overview of phenomenology and relative prevalence of its clinical prototypes. J Affect Disord 2006; 96: 197–205PubMedCrossRefGoogle Scholar
  34. 34.
    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: 45–54PubMedCrossRefGoogle Scholar
  35. 35.
    Benazzi F. Challenging the unipolar-bipolar division: does mixed depression bridge the gap? Prog Neuropsychopharmacol Biol Psychiatry 2007; 31: 97–103PubMedCrossRefGoogle Scholar
  36. 36.
    Cassano GB, Frank E, Miniati M, et al. Conceptual underpinnings and empirical support for the mood spectrum. Psychiatr Clin North Am 2002; 25(4): 699–712PubMedCrossRefGoogle Scholar
  37. 37.
    Cassano GB, Rucci P, Frank E, et al. The mood spectrum in unipolar and bipolar disorder: arguments for a unitary approach. Am J Psychiatry 2004; 161(7): 1264–9PubMedCrossRefGoogle Scholar
  38. 38.
    McElroy SL, Keck Jr PE, Pope Jr HG, et al. Clinical and research implications of the diagnosis of dysphoric or mixed mania or hypomania. Am J Psychiatry 1992; 149: 1633–44PubMedGoogle Scholar
  39. 39.
    Benazzi F. Bipolar disorder: focus on bipolar II disorder and mixed depression. Lancet 2007; 369: 935–45PubMedCrossRefGoogle Scholar
  40. 40.
    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: 87–8PubMedCrossRefGoogle Scholar
  41. 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: 268–74PubMedCrossRefGoogle Scholar
  42. 42.
    Akiskal HS, Benazzi F. Family history validation of the bipolar nature of depressive mixed states. J Affect Disord 2003; 73: 113–22PubMedCrossRefGoogle Scholar
  43. 43.
    Maj M, Pirozzi R, Magliano L, et al. Agitated ‘unipolar’ major depression: prevalence, phenomenology, and outcome. J Clin Psychiatry 2006; 67: 712–9PubMedCrossRefGoogle Scholar
  44. 44.
    Koukopoulos K, Sani G, Albert MJ, et al. Agitated depression: spontaneous and induced. In: Marneros A, Goodwin F, editors. Bipolar disorders. Cambridge: Cambridge University Press, 2005: 157–86CrossRefGoogle Scholar
  45. 45.
    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: 105–14PubMedCrossRefGoogle Scholar
  46. 46.
    Maj M, Pirozzi R, Magliano L, et al. Agitated depression in bipolar I disorder: prevalence, phenomenology, and outcome. Am J Psychiatry 2003; 160: 2134–40PubMedCrossRefGoogle Scholar
  47. 47.
    Benazzi F. Mixed states in bipolar II disorder: should full hypomania always be required? Psychiatry Res 2004; 127: 247–57PubMedCrossRefGoogle Scholar
  48. 48.
    Biondi M, Picardi A, Pasquini M, et al. Dimensional psychopathology of depression: detection of an ‘activation’ dimension in unipolar depressed outpatients. J Affect Disord 2005; 84: 133–9PubMedCrossRefGoogle Scholar
  49. 49.
    Serretti A, Olgiati P. Profiles of “manic” symptoms in bipolar I, bipolar II and major depressive disorders. J Affect Disord 2005; 84: 159–66PubMedCrossRefGoogle Scholar
  50. 50.
    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 gender-specific phenomenon. Arch Gen Psychiatry 2005; 62: 1089–96PubMedCrossRefGoogle Scholar
  51. 51.
    Akiskal HS, Benazzi F. Toward a clinical delineation of dysphoric hypomania: operational and conceptual dilemmas. Bipolar Disord 2005; 7: 456–64PubMedCrossRefGoogle Scholar
  52. 52.
    Sato T, Bottlender R, Kleindienst N, et al. Irritable psychomotor elation in depressed inpatients: a factor validation of mixed depression. J Affect Disord 2005; 84: 187–96PubMedCrossRefGoogle Scholar
  53. 53.
    Benazzi F. Bipolar II disorder and major depressive disorder: continuity or discontinuity? World J Biol Psychiatry 2003; 4: 166–71PubMedCrossRefGoogle Scholar
  54. 54.
    Dikeos DG, Wickham H, McDonald C, et al. Distribution of symptom dimensions across Kraepelinian divisions. Br J Psychiatry 2006; 189: 346–53PubMedCrossRefGoogle Scholar
  55. 55.
    Benazzi F. Does age at onset support a dimensional relationship between bipolar II disorder and major depressive disorder? World J Biol Psychiatry 2007; 31: 944–51Google Scholar
  56. 56.
    Benazzi F. Does temperamental instability support a continuity between bipolar II disorder and major depressive disorder? Eur Psychiatry 2006; 21: 274–9PubMedCrossRefGoogle Scholar
  57. 57.
    Benazzi F. A continuity between bipolar II depression and major depressive disorder? Prog Neuropsychopharmacol Biol Psychiatry 2006; 30: 1043–50PubMedCrossRefGoogle Scholar
  58. 58.
    Benazzi F, Akiskal HS. A downscaled practical measure of mood lability as a screening tool for bipolar II. J Affect Disord 2005; 84: 225–32PubMedCrossRefGoogle Scholar
  59. 59.
    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: 49–57PubMedCrossRefGoogle Scholar
  60. 60.
    Benazzi F. Borderline personality-bipolar spectrum relationship. Prog Neuropsychopharmacol Biol Psychiatry 2006; 30: 68–74PubMedCrossRefGoogle Scholar
  61. 61.
    Akiskal HS. Demystifying borderline personality: critique of the concept and unorthodox reflections on its natural kinship with the bipolar spectrum. Acta Psychiatr Scand 2004; 110: 401–7PubMedCrossRefGoogle Scholar
  62. 62.
    Hantouche EG, Akiskal HS. Toward a definition of a cyclothymic behavioral endophenotype: which traits tap the familial diathesis for bipolar II disorder? J Affect Disord 2006; 96: 233–7PubMedCrossRefGoogle Scholar
  63. 63.
    Akiskal HS, Hantouche EG, Allilaire JF, et al. Validating antidepressant-associated hypomania (bipolar III): a systematic comparison with spontaneous hypomania (bipolar II). J Affect Disord 2003; 73: 65–74PubMedCrossRefGoogle Scholar
  64. 64.
    Gijsman HJ, Geddes JR, Rendell JM, et al. Antidepressants for bipolar depression: a systematic review of randomized, controlled trials. Am J Psychiatry 2004; 161: 1537–47PubMedCrossRefGoogle Scholar
  65. 65.
    Moller HJ, Grunze H, Broich K. Do recent efficacy data on the drug treatment of acute bipolar depression support the position that drugs other than antidepressants are the treatment of choice? A conceptual review. Eur Arch Psychiatry Clin Neurosci 2006; 256: 1–16PubMedCrossRefGoogle Scholar
  66. 66.
    Ghaemi SN, Hsu DJ, Soldani F, et al. Antidepressants in bipolar disorder: the case for caution. Bipolar Disord 2003; 5: 421–33PubMedCrossRefGoogle Scholar
  67. 67.
    Benazzi F, Akiskal HS. Biphasic course in bipolar II outpatients: prevalence and clinical correlates of a cyclic pattern described by Baillarger and Falret in hospitalised patients in 1854. J Affect Disord 2006; 96: 183–7PubMedCrossRefGoogle Scholar
  68. 68.
    Perugi G, Toni C, Travierso MC, et al. The role of cyclothymia in atypical depression: toward a data-based reconceptualization of the borderline-bipolar II connection. J Affect Disord 2003; 73: 87–98PubMedCrossRefGoogle Scholar
  69. 69.
    Ghaemi SN, Ko JY, Goodwin FK. “Cade’s disease” and beyond: misdiagnosis, antidepressant use, and a proposed definition for bipolar spectrum disorder. Can J Psychiatry 2002; 47: 125–34PubMedGoogle Scholar
  70. 70.
    Benazzi F. Family history validation of a definition of mixed depression. Compr Psychiatry 2005; 46: 159–66PubMedCrossRefGoogle Scholar
  71. 71.
    Regeer EJ, Krabbendam L, de Graaf R, et al. A prospective study of the transition rates of subthreshold (hypo)mania and depression in the general population. Psychol Med 2006; 36: 619–27PubMedCrossRefGoogle Scholar
  72. 72.
    Weissman MM, Leaf PJ, Tischler GL, et al. Affective disorders in five United States communities. Psychol Med 1988; 18: 141–53PubMedCrossRefGoogle Scholar
  73. 73.
    Kessler RC, McGonagle KA, Zhao 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: 8–19PubMedCrossRefGoogle Scholar
  74. 74.
    Regeer EJ, ten Have M, Rosso ML, et al. Prevalence of bipolar disorder in the general population: a reappraisal study of the Netherlands Mental Health Survey and Incidence Study. Acta Psychiatr Scand 2004; 110: 374–82PubMedCrossRefGoogle Scholar
  75. 75.
    Goldney RD, Fisher LJ, Grande ED, et al. Bipolar I and II disorders in a random and representative Australian population. Aust N Z J Psychiatry 2005; 39: 726–9PubMedCrossRefGoogle Scholar
  76. 76.
    Jacobi F, Wittchen HU, Holting C, et al. Prevalence, co-morbidity and correlates of mental disorders in the general population: results from the German Health Interview and Examination Survey (GHS). Psychol Med 2004; 34: 597–611PubMedCrossRefGoogle Scholar
  77. 77.
    Schaffer A, Cairney J, Cheung A, et al. Community survey of bipolar disorder in Canada: lifetime prevalence and illness characteristics. Can J Psychiatry 2006; 51: 9–16PubMedGoogle Scholar
  78. 78.
    ten Have M, Vollebergh W, Bijl R, et al. Bipolar disorder in the general population in The Netherlands (prevalence, consequences and care utilisation): results from The Netherlands Mental Health Survey and Incidence Study (NEMESIS). J Affect Disord 2002; 68: 203–13PubMedCrossRefGoogle Scholar
  79. 79.
    Kessler RC, Akiskal HS, Angst J, et al. Validity of the assessment of bipolar spectrum disorders in the WHO CIDI 3. 0. J Affect Disord 2006; 69: 259–69CrossRefGoogle Scholar
  80. 80.
    Szadoczky E, Papp Z, Vitrai J, et al. The prevalence of major depressive and bipolar disorders in Hungary: results from a national epidemiologic survey. J Affect Disord 1998; 50: 153–62PubMedCrossRefGoogle Scholar
  81. 81.
    Kessler RC, Berglund P, Dernier 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: 593–602PubMedCrossRefGoogle Scholar
  82. 82.
    Faravelli C, Rosi S, Alessandra Scarpato M, et al. Threshold and subthreshold bipolar disorders in the Sesto Fiorentino Study. J Affect Disord 2006; 94: 111–9PubMedCrossRefGoogle Scholar
  83. 83.
    Judd LL, Akiskal HS. The prevalence and disability of bipolar spectrum disorders in the US population: re-analysis of the ECA database taking into account subthreshold cases. J Affect Disord 2003; 73: 123–31PubMedCrossRefGoogle Scholar
  84. 84.
    Goldberg JF, Harrow M, Whiteside JE. Risk for bipolar illness in patients initially hospitalized for unipolar depression. Am J Psychiatry 2001; 158: 1265–70PubMedCrossRefGoogle Scholar
  85. 85.
    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: 149–57PubMedCrossRefGoogle Scholar
  86. 86.
    Hirschfeld RM, Williams JB, Spitzer RL, et al. Development and validation of a screening instrument for bipolar spectrum disorder: the Mood Disorder Questionnaire. Am J Psychiatry 2000; 157: 1873–5PubMedCrossRefGoogle Scholar
  87. 87.
    Angst J, Dobler-Mikola A, Binder J. The Zurich study: a prospective epidemiological study of depressive, neurotic and psychosomatic syndromes: I. Problem, methodology. Em-Arch Psychiatry Neurol Sci 1984; 234: 13–20CrossRefGoogle Scholar
  88. 88.
    Benazzi F. Prevalence of bipolar II disorder in outpatient depression: a 203-case study in private practice. J Affect Disord 1997; 43: 163–6PubMedCrossRefGoogle Scholar
  89. 89.
    Smith DJ, Harrison N, Muir W, et al. The high prevalence of bipolar spectrum disorders in young adults with recurrent depression: toward an innovative diagnostic framework. J Affect Disord 2005; 84: 167–78PubMedCrossRefGoogle Scholar
  90. 90.
    Rybakowski JK, Suwalska A, Lojko D, et al. Bipolar mood disorders among Polish psychiatric outpatients treated for major depression. J Affect Disord 2005; 84: 141–7PubMedCrossRefGoogle Scholar
  91. 91.
    Benazzi F, Akiskal H. The duration of hypomania in bipolar-II disorder in private practice: methodology and validation. J Affect Disord 2006; 69: 189–96CrossRefGoogle Scholar
  92. 92.
    Benazzi F. Diagnosis of bipolar II disorder: a comparison of structured versus semistructured interviews. Prog Neuropsychopharmacol Biol Psychiatry 2003; 27: 985–91PubMedCrossRefGoogle Scholar
  93. 93.
    Simpson SG, McMahon FJ, McInnis MG, et al. Diagnostic reliability of bipolar II diagnosis. Arch Gen Psychiatry 2002; 59: 736–40PubMedCrossRefGoogle Scholar
  94. 94.
    Benazzi F, Akiskal HS. Refining the evaluation of bipolar II: beyond the strict SCID-CV guidelines for hypomania. J Affect Disord 2003; 73: 33–8PubMedCrossRefGoogle Scholar
  95. 95.
    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: 914–21PubMedCrossRefGoogle Scholar
  96. 96.
    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, 1997Google Scholar
  97. 97.
    Benazzi F. Challenging DSM-IV criteria for hypomania: diagnosing based on number of no-priority symptoms. Eur Psychiatry 2007; 22: 99–103PubMedCrossRefGoogle Scholar
  98. 98.
    Benazzi F. Is overactivity the core feature of hypomania in bipolar II disorder? Psychopathology 2007; 40: 54–60PubMedCrossRefGoogle Scholar
  99. 99.
    Faedda GL, Baldessarini RJ, Glovinsky IP, et al. Pediatric bipolar disorder: phenomenology and course of illness. Bipolar Disord 2004; 6: 305–13PubMedCrossRefGoogle Scholar
  100. 100.
    Birmaher B, Axelson D, Strober M, et al. Clinical course of children and adolescents with bipolar spectrum disorders. Arch Gen Psychiatry 2006; 63: 175–83PubMedCrossRefGoogle Scholar
  101. 101.
    Geller B, Tillman R, Bolhofner K, et al. Controlled, blindly rated, direct-interview family study of a prepubertal and early-adolescent bipolar I disorder phenotype: morbid risk, age at onset, and comorbidity. Arch Gen Psychiatry 2006; 63: 1130–8PubMedCrossRefGoogle Scholar
  102. 102.
    Axelson D, Birmaher B, Strober M, et al. Phenomenology of children and adolescents with bipolar spectrum disorders. Arch Gen Psychiatry 2006; 63: 1139–48PubMedCrossRefGoogle Scholar
  103. 103.
    Dilsaver SC, Benazzi F, Akiskal HS. Mixed states: the most common outpatient presentation of bipolar depressed adolescents? Psychopathology 2005; 38: 268–72PubMedCrossRefGoogle Scholar
  104. 104.
    Lewinsohn PM, Klein DN, Seeley JR. Bipolar disorder during adolescence and young adulthood in a community sample. Bipolar Disord 2000; 2 (3 Pt 2): 281–93PubMedCrossRefGoogle Scholar
  105. 105.
    Verhulst FC, van der Ende J, Ferdinand RF, et al. The prevalence of DSM-III-R diagnoses in a national sample of Dutch adolescents. Arch Gen Psychiatry 1997; 54: 329–36PubMedCrossRefGoogle Scholar
  106. 106.
    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: 149–52PubMedCrossRefGoogle Scholar
  107. 107.
    Goldberg JF, Truman CJ, Fordis J, et al. Antidepressant use during mixed states: naturalistic outcome data from the STEP-1000 [abstract]. Neuropsychopharmacology 2004; 29: S144Google Scholar
  108. 108.
    Benazzi F. Which could be a clinically useful definition of depressive mixed state? Prog Neuropsychopharmacol Biol Psychiatry 2002; 26: 1105–11PubMedCrossRefGoogle Scholar
  109. 109.
    Benazzi F. Bipolar II depressive mixed state: finding a useful definition. Compr Psychiatry 2003; 44: 21–7PubMedCrossRefGoogle Scholar
  110. 110.
    Benazzi F. Bipolar family history of the hypomanic symptoms and dimensions of mixed depression. Compr Psychiatry 2005; 46: 399–404PubMedCrossRefGoogle Scholar
  111. 111.
    Benazzi F. Agitated depression: a valid depression subtype? Prog Neuropsychopharmacol Biol Psychiatry 2004; 28: 1279–85PubMedCrossRefGoogle Scholar
  112. 112.
    Akiskal HS, Benazzi F, Perugi G, et al. Agitated “unipolar” depression re-conceptualized as a depressive mixed state: implications for the antidepressant-suicide controversy. J Affect Disord 2005; 85: 245–58PubMedCrossRefGoogle Scholar
  113. 113.
    Krabbendam L, Myin-Germeys I, De Graaf R, et al. Dimensions of depression, mania and psychosis in the general population. Psychol Med 2004; 34: 1–10CrossRefGoogle Scholar
  114. 114.
    Benazzi F. Unipolar depression with racing thoughts: a bipolar spectrum disorder? Psychiatry Clin Neurosci 2005; 59: 570–5PubMedCrossRefGoogle Scholar
  115. 115.
    Frye MA, McElroy SL, Hellemann G, et al. Clinical correlates associated with antidepressant-related mania [abstract NR215]. Programme and abstracts of the American Psychiatric Association Annual Meeting; 2006 May 20–25; Toronto (ON)Google Scholar
  116. 116.
    Ghaemi SN. Re-evaluating concepts of depression: the bipolar spectrum [abstract]. New vistas in treatment-resistant depression: symposium of the American Psychiatric Association Annual Meeting. 2006 May 20–25, Toronto (ON)Google Scholar
  117. 117.
    Kendell R, Jablensky A. Distinguishing between the validity and utility of psychiatric diagnoses. Am J Psychiatry 2003; 160: 4–12PubMedCrossRefGoogle Scholar
  118. 118.
    US Food and Drug Administration Center for Drug Evaluation and Research. Labeling change request letter for antidepressant medication [online]. Available from URL: [Accessed 2007 Feb 13]
  119. 119.
    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: 133–8PubMedCrossRefGoogle Scholar
  120. 120.
    Benazzi F. Suicidal ideation and depressive mixed states. Psychother Psychosom 2005; 74: 61–2PubMedCrossRefGoogle Scholar
  121. 121.
    MacKinnon DF, Potash JB, McMahon FJ, et al. Rapid mood switching and suicidality in familial bipolar disorder. Bipolar Disord 2005; 7: 441–8PubMedCrossRefGoogle Scholar
  122. 122.
    Hawton K, Sutton L, Haw C, et al. Suicide and attempted suicide in bipolar disorder: a systematic review of risk factors. J Clin Psychiatry 2005; 66: 693–704PubMedCrossRefGoogle Scholar
  123. 123.
    Bauer MS, Wisniewski SR, Marangell LB, et al. Are antidepressants associated with new-onset suicidality in bipolar disorder? A prospective study of participants in the systematic treatment enhancement program for bipolar disorder (STEP-BD). J Clin Psychiatry 2006; 67: 8–55CrossRefGoogle Scholar
  124. 124.
    Benazzi F. Antidepressant-induced or clinician-induced suicidality in depression [letter]? Am J Psychiatry 2006; 163: 1644PubMedCrossRefGoogle Scholar
  125. 125.
    Baldessarini R, Pompili M, Tondo L. Suicidal risk in antidepressant drug trial. Arch Gen Psychiatry 2006; 63: 246–8PubMedCrossRefGoogle Scholar
  126. 126.
    McElroy SL, Kotwal R, Kaneria R, et al. Antidepressants and suicidal behavior in bipolar disorder. Bipolar Disord 2006; 8: 596–617PubMedCrossRefGoogle Scholar
  127. 127.
    Perlis RH, Beasley Jr CM, Wines Jr JD, et al. Treatment-associated suicidal ideation and adverse effects in an open, multicenter trial of fluoxetine for major depressive episodes. Psychother Psychosom 2007; 76: 40–6PubMedCrossRefGoogle Scholar
  128. 128.
    Arvilommi P, Suominen KS, Mantere OK, et al. Adequacy of treatment received by diagnosed and undiagnosed patients with bipolar I and II disorders. J Clin Psychiatry 2007; 68: 102–10PubMedCrossRefGoogle Scholar
  129. 129.
    Benazzi F. Antidepressant-associated hypomania in outpatient depression: a 203-case study in private practice. J Affect Disord 1997; 46: 73–7PubMedCrossRefGoogle Scholar
  130. 130.
    Altshuler LL, Suppes T, Black DO, et al. Lower switch rate in depressed patients with bipolar II than bipolar I disorder treated adjunctively with second-generation antidepressants. Am J Psychiatry 2006; 163: 313–5PubMedCrossRefGoogle Scholar
  131. 131.
    Leverich GS, Altshuler LL, Frye MA, et al. Risk of switch in mood polarity to hypomania or mania in patients with bipolar depression during acute and continuation trials of venlafaxine, sertraline, and bupropion as adjuncts to mood stabilizers. Am J Psychiatry 2006; 163: 232–9PubMedCrossRefGoogle Scholar
  132. 132.
    Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longerterm outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry 2006; 163: 1905–17PubMedCrossRefGoogle Scholar
  133. 133.
    Amsterdam JD, Garcia-Espana F, Fawcett J, et al. Efficacy and safety of fluoxetine in treating bipolar II major depressive episode. J Clin Psychopharmacol 1998; 18: 435–40PubMedCrossRefGoogle Scholar
  134. 134.
    Amsterdam JD, Garcia-Espana F. Venlafaxine monotherapy in women with bipolar II and unipolar major depression. J Affect Disord 2000; 59: 225–9PubMedCrossRefGoogle Scholar
  135. 135.
    Amsterdam J. Efficacy and safety of venlafaxine in the treatment of bipolar II major depressive episode. J Clin Psychopharmacol 1998; 18: 414–7PubMedCrossRefGoogle Scholar
  136. 136.
    Parker G, Tully L, Olley A, et al. SSRIs as mood stabilizers for bipolar II disorder? A proof of concept study. J Affect Disord 2006; 92: 205–14PubMedCrossRefGoogle Scholar
  137. 137.
    Post RM, Altshuler LL, Leverich GS, et al. Mood switch in bipolar depression: comparison of adjunctive venlafaxine, bupropion and sertraline. Br J Psychiatry 2006; 189: 124–31PubMedCrossRefGoogle Scholar
  138. 138.
    Sachs GS, Nierenberg AA, Calabrese JR, et al. Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med 2007; 356: 1711–22PubMedCrossRefGoogle Scholar
  139. 139.
    Zarate Jr CA, Payne JL, Singh J, et al. Pramipexole for bipolar II depression: a placebo-controlled proof of concept study. Biol Psychiatry 2004; 56: 54–60PubMedCrossRefGoogle Scholar
  140. 140.
    Himmelhoch JM, Thase ME, Mallinger AG, et al. Tranyl-cypromine versus imipramine in anergic bipolar depression. Am J Psychiatry 1991; 148: 910–6PubMedGoogle Scholar
  141. 141.
    Calabrese JR, Keck Jr PE, MacFadden W, et al. A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression. Am J Psychiatry 2005; 162: 1351–60PubMedCrossRefGoogle Scholar
  142. 142.
    Hirschfeld RM, Weisler RH, Raines SR, et al. Quetiapine in the treatment of anxiety in patients with bipolar I or II depression: a secondary analysis from a randomized, double-blind, placebo-controlled study. J Clin Psychiatry 2006; 67: 355–62PubMedCrossRefGoogle Scholar
  143. 143.
    Cookson J, Keck Jr PE, Ketter TA, et al. Number needed to treat and time to response/remission for quetiapine monotherapy efficacy in acute bipolar depression: evidence from a large, randomized, placebo-controlled study. Int Clin Psychopharmacol 2007; 22: 93–100PubMedCrossRefGoogle Scholar
  144. 144.
    Thase ME, MacFadden W, Weisler RH, et al. Efficacy of quetiapine monotherapy in bipolar I and II depression: a double-blind, placebo-controlled study (the BOLDER II study). J Clin Psychopharmacol 2006; 26: 600–9PubMedCrossRefGoogle Scholar
  145. 145.
    Calabrese JR, Bowden CL, Sachs GS, et al. A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. Lamictal 602 Study Group. J Clin Psychiatry 1999; 60: 79–88CrossRefGoogle Scholar
  146. 146.
    Nierenberg AA, Ostacher MJ, Calabrese JR, et al. Treatment-resistant bipolar depression: a STEP-BD equipoise randomized effectiveness trial of antidepressant augmentation with lamotrigine, inositol, or risperidone. Am J Psychiatry 2006; 163: 210–6PubMedCrossRefGoogle Scholar
  147. 147.
    Brown EB, McElroy SL, Keck Jr PE, et al. A 7-week, randomized, double-blind trial of olanzapine/fluoxetine combination versus lamotrigine in the treatment of bipolar I depression. J Clin Psychiatry 2006; 67: 1025–33PubMedCrossRefGoogle Scholar
  148. 148.
    Manning JS, Haykal RF, Connor PD, et al. Sustained remission with lamotrigine augmentation or monotherapy in female resistant depressives with mixed cyclothymic-dysthymic temperament. J Affect Disord 2005; 84: 259–66PubMedCrossRefGoogle Scholar
  149. 149.
    Barbosa L, Berk M, Vorster M. A double-blind, randomized, placebo-controlled trial of augmentation with lamotrigine or placebo in patients concomitantly treated with fluoxetine for resistant major depressive episodes. J Clin Psychiatry 2003; 64: 403–7PubMedCrossRefGoogle Scholar
  150. 150.
    GlaxoSmithKline clinical trial register: lamotrigine studies [online]. Available from URL: [Accessed 2007 Jul 18]
  151. 151.
    Benazzi F. The problem of the treatment of bipolar-II depression. Bipolar Disord 2004; 6: 440–1PubMedCrossRefGoogle Scholar
  152. 152.
    Mammen OK, Pilkonis PA, Chengappa KN, et al. Anger attacks in bipolar depression: predictors and response to citalopram added to mood stabilizers. J Clin Psychiatry 2004; 65: 627–33PubMedCrossRefGoogle Scholar
  153. 153.
    Brown EB, McElroy SL, Keck Jr PE, et al. A 7-week, randomized, double-blind trial of olanzapine/fluoxetine combination versus lamotrigine in the treatment of bipolar I depression. J Clin Psychiatry 2006; 67: 1025–33PubMedCrossRefGoogle Scholar
  154. 154.
    Houston JP, Ahl J, Meyers AL, et al. Reduced suicidal ideation in bipolar I disorder mixed-episode patients in a placebo-controlled trial of olanzapine combined with lithium or valproate. J Clin Psychiatry 2006; 67: 1246–52PubMedCrossRefGoogle Scholar
  155. 155.
    Koukopoulos A. The primacy of mania. In: Akiskal HS, Tohen M, editors. Bipolar psychopharmacology. Chichester: John Wiley and Sons, 2006: 169–92CrossRefGoogle Scholar
  156. 156.
    Maj M. Clinical prediction of response to lithium prophylaxis in bipolar patients: the importance of the previous pattern of course of the illness. Clin Neuropharmacol 1990; 13Suppl. 1: S66–70PubMedCrossRefGoogle Scholar
  157. 157.
    Ketter TA, Wang PO, Nowakowska C, et al. Treatment of acute mania in bipolar disorder. In: Ketter TA, editor. Advances in the treatment of bipolar disorder. Washington, DC: American Psychiatric Publishing, 2005: 11–55Google Scholar
  158. 158.
    Vieta E, Gasto C, Colom F, et al. Role of risperidone in bipolar II: an open 6-month study. J Affect Disord 2001; 67: 213–9PubMedCrossRefGoogle Scholar
  159. 159.
    Fieve RR, Dunner DL, Kumbaraci T, et al. Lithium carbonate prophylaxis of depression in three subtypes in primary affective disorder. Pharmakopsychiatr Neuropsychopharmakol 1976; 9: 100–7PubMedGoogle Scholar
  160. 160.
    Dunner DL, Stallone F, Fieve RR. Lithium carbonate and affective disorders: V. A double-blind study of prophylaxis of depression in bipolar illness. Arch Gen Psychiatry 1976; 33: 117–20Google Scholar
  161. 161.
    Dunner DL, Stallone F, Fieve RR. Prophylaxis with lithium carbonate: an update. Arch Gen Psychiatry 1982; 39: 1344–5PubMedGoogle Scholar
  162. 162.
    Quitkin F, Rifkin A, Kane J, et al. Prophylactic effect of lithium and imipramine in unipolar and bipolar II patients: a preliminary report. Am J Psychiatry 1978; 135: 570–2PubMedGoogle Scholar
  163. 163.
    Peselow ED, Dunner DL, Fieve RR, et al. Lithium prophylaxis of depression in unipolar, bipolar II, and cyclothymic patients. Am J Psychiatry 1982; 139: 747–52PubMedGoogle Scholar
  164. 164.
    Prien RF, Kupfer DJ, Mansky PA, et al. Drug therapy in the prevention of recurrences in unipolar and bipolar affective disorders: report of the NIMH Collaborative Study Group comparing lithium carbonate, imipramine, and a lithium carbonate-imipramine combination. Arch Gen Psychiatry 1984; 41: 1096–104PubMedCrossRefGoogle Scholar
  165. 165.
    Tondo L, Baldessarini RJ, Hennen J, et al. Lithium maintenance treatment of depression and mania in bipolar I and bipolar II disorders. Am J Psychiatry 1998; 155: 638–45PubMedGoogle Scholar
  166. 166.
    Greil W, Kleindienst N. Lithium versus carbamazepine in the maintenance treatment of bipolar II disorder and bipolar disorder not otherwise specified. Int Clin Psychopharmacol 1999; 14: 283–5PubMedGoogle Scholar
  167. 167.
    Kane JM, Quitkin FM, Rifkin A, et al. Lithium carbonate and imipramine in the prophylaxis of unipolar and bipolar II illness: a prospective, placebo-controlled comparison. Arch Gen Psychiatry 1982; 39: 1065–9PubMedCrossRefGoogle Scholar
  168. 168.
    Bowden CL, Calabrese JR, Sachs G, et al. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder. Arch Gen Psychiatry 2003; 60: 392–400PubMedCrossRefGoogle Scholar
  169. 169.
    Calabrese JR, Suppes T, Bowden CL, et al. A double-blind, placebo-controlled, prophylaxis study of lamotrigine in rapid-cycling bipolar disorder. J Clin Psychiatry 2000; 61: 841–50PubMedCrossRefGoogle Scholar
  170. 170.
    Goodwin GM, Bowden CL, Calabrese JR, et al. A pooled analysis of 2 placebo-controlled 18-month trials of lamotrigine and lithium maintenance in bipolar I disorder. J Clin Psychiatry 2004; 65: 432–41PubMedCrossRefGoogle Scholar
  171. 171.
    Calabrese JR, Bowden CL, Sachs G, et al. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar I disorder. J Clin Psychiatry 2003; 64: 1013–24PubMedCrossRefGoogle Scholar
  172. 172.
    Tohen M, Ketter TA, Zarate CA, et al. Olanzapine versus divalproex sodium for the treatment of acute mania and maintenance of remission: a 47-week study. Am J Psychiatry 2003; 160: 1263–71PubMedCrossRefGoogle Scholar
  173. 173.
    Coryell W, Solomon D, Turvey C, et al. The long-term course of rapid-cycling bipolar disorder. Arch Gen Psychiatry 2003; 60: 914–20PubMedCrossRefGoogle Scholar
  174. 174.
    Tondo L, Hennen J, Baldessarini RJ. Rapid-cycling bipolar disorder: effects of long-term treatments. Acta Psychiatr Scand 2003; 108: 4–14PubMedCrossRefGoogle Scholar
  175. 175.
    Calabrese JR, Shelton MD, Rapport DJ, et al. A 20-month, double-blind, maintenance trial of lithium versus divalproex in rapid-cycling bipolar disorder. Am J Psychiatry 2005; 162: 2152–61PubMedCrossRefGoogle Scholar
  176. 176.
    Gyulai L, Bowden CL, McElroy SL, et al. Maintenance efficacy of divalproex in the prevention of bipolar depression. Neuropsychopharmacology 2003; 28: 1374–82PubMedCrossRefGoogle Scholar
  177. 177.
    Wehr TA, Sack DA, Rosenthal NE, et al. Rapid cycling affective disorder: contributing factors and treatment responses in 51 patients. Am J Psychiatry 1988; 145: 179–84PubMedGoogle Scholar

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© Adis Data Information BV 2007

Authors and Affiliations

  1. 1.Hecker Psychiatry Research Center, a University of California at San Diego (USA) Collaborating Center at ForliForliItaly
  2. 2.Department of PsychiatryUniversity of SzegedSzegedHungary
  3. 3.Department of PsychiatryNational Health ServiceForliItaly
  4. 4.Castiglione Cervia RAItaly

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