Mixed Forms in Bipolar Disorder and Relation to Gender

  • Ana González-PintoEmail author
  • Maddi Laborde Zufiaurre
  • Beatriz González Hernández
  • Purificación López Peña
  • Ana Isabel Cano
  • Saioa López-Zurbano


Mixed states describe the simultaneous presence of manic and depressive symptoms in the same patient. This phenomenon is more prevalent in women. Activation, thinking, and mood are combined in a strange form, being possible that some of these three dimensions are increased from the euthymic period, while others are decreased. It is quite common presentation of irritable mood, with rapid thinking, suicidal ideas, anxiety, helplessness, and sexual disinhibition. Sometimes there are variations in the clinical presentation in the same day.

There are some depressive symptoms present in the mixed states that are more relevant for the diagnosis: depressed mood, guilt, suicidal ideation, anhedonia, and fatigue. Irritable mood and psychotic symptoms are also frequently present in mixed states.

One aspect that is relevant for the prognosis of mixed states is the earlier age at onset. The younger age at onset and the delay in the diagnosis explain partially, but not all the differences in prognosis of this severe disease. These patients are also in higher risk of drug and alcohol abuse.

Actually DSM-V has included partially this aspect and has considered the diagnosis of mixed symptoms as specifier of mania, hypomania, bipolar depression, and moreover, unipolar depression. The special follow-up of those patients with unipolar major depression and three manic symptoms is actually diagnosed as major depression with mixed symptoms. A careful follow-up should be done in those patients in order to consider a bipolar disorder in the future.


Age at onset Gender Mixed forms Prognosis 


  1. 1.
    Perez J, Baldessarini RJ, Cruz N, Salvatore P, Vieta E. Andres Piquer-Arrufat [1711–1772]: contributions of an eighteenth-century Spanish physician to the concept of manic-depressive illness. Harv Rev Psychiatry. 2011;19(2):68–77.PubMedCrossRefGoogle Scholar
  2. 2.
    Gonzalez-Pinto A, Aldama A, Mosquera F, Gonzalez GC. Epidemiology, diagnosis and management of mixed mania. CNS Drugs. 2007;21(8):611–26.PubMedCrossRefGoogle Scholar
  3. 3.
    Heinroth JCA. Lehrbuch der Störungen des Seelenlebens Oder der Seelenstörungen und Ihre Behandlung vRSaE. Germany: Leipzig**; 1918.Google Scholar
  4. 4.
    Marneros A. Origin and development of concepts of bipolar mixed states. J Affect Disord. 2001;67(1):229–40.PubMedCrossRefGoogle Scholar
  5. 5.
    Kraepelin E. Psychiatrie. Ein Lehrbuch für Studierende und Ärzte, Klinische Psychiatrie. Leipzig: Verlag von Johann Ambrsius Barth; 1899.Google Scholar
  6. 6.
    Kraepelin E. Manic depressive insanity and paranoia. J Nerv Ment Dis. 1921;53(4):350.CrossRefGoogle Scholar
  7. 7.
    Spitzer RL, Endicott J, Robins E. Research diagnostic criteria: rationale and reliability. Arch Gen Psychiatry. 1978;35(6):773.PubMedCrossRefGoogle Scholar
  8. 8.
    Association AP. Diagnostic and statistical manual of mental disorders: DSM-IV-TR®: American Psychiatric Pub; 2000.Google Scholar
  9. 9.
    World Health Organization. The ICD-10 classification of mental and behavioural disorders: clinical descriptions and diagnostic guidelines. Geneva: World Health Organization; 1992.Google Scholar
  10. 10.
    Cassidy F, Carroll BJ. The clinical epidemiology of pure and mixed manic episodes. Bipolar Disord. 2001;3(1):35–40.PubMedCrossRefGoogle Scholar
  11. 11.
    Gonzalez-Pinto A, Aldama A, Pinto AG, Mosquera F, Perez de Heredia JL, Ballesteros J, et al. Dimensions of mania: differences between mixed and pure episodes. Eur Psychiatry. 2004;19(5):307–10.PubMedCrossRefGoogle Scholar
  12. 12.
    Bauer MS, Whybrow PC. Rapid cycling bipolar affective disorder. II. Treatment of refractory rapid cycling with high-dose levothyroxine: a preliminary study. Arch Gen Psychiatry. 1990;47(5):435–40.PubMedCrossRefGoogle Scholar
  13. 13.
    McElroy SL, Strakowski SM, Keck PE Jr, Tugrul KL, West SA, Lonczak HS. Differences and similarities in mixed and pure mania. Compr Psychiatry. 1995;36(3):187–94.PubMedCrossRefGoogle Scholar
  14. 14.
    McElroy SL, Keck PE Jr, Pope HG Jr, Hudson JI, Faedda GL, Swann AC. Clinical and research implications of the diagnosis of dysphoric or mixed mania or hypomania. Am J Psychiatry. 1992;149(12):1633–44.PubMedCrossRefGoogle Scholar
  15. 15.
    Akiskal HS, Benazzi F. Toward a clinical delineation of dysphoric hypomania - operational and conceptual dilemmas. Bipolar Disord. 2005;7(5):456–64.PubMedCrossRefGoogle Scholar
  16. 16.
    Hantouche EG, Akiskal HS, Azorin JM, Chatenet-Duchene L, Lancrenon S. Clinical and psychometric characterization of depression in mixed mania: a report from the French National Cohort of 1090 manic patients. J Affect Disord. 2006;96(3):225–32.PubMedCrossRefGoogle Scholar
  17. 17.
    Perugi G, Micheli C, Akiskal HS, Madaro D, Socci C, Quilici C, et al. Polarity of the first episode, clinical characteristics, and course of manic depressive illness: a systematic retrospective investigation of 320 bipolar I patients. Compr Psychiatry. 2000.;41[1;41:13–8.PubMedCrossRefGoogle Scholar
  18. 18.
    Cassidy F, Murry E, Forest K, Carroll BJ. Signs and symptoms of mania in pure and mixed episodes. J Affect Disord. 1998;50.[2-3:187–201.PubMedCrossRefGoogle Scholar
  19. 19.
    Sato T, Bottlender R, Kleindienst N, Moller HJ. Syndromes and phenomenological subtypes underlying acute mania: a factor analytic study of 576 manic patients. Am J Psychiatry. 2002;159(6):968–74.PubMedCrossRefGoogle Scholar
  20. 20.
    Gonzalez-Pinto A, Ballesteros J, Aldama A, Perez de Heredia JL, Gutierrez M, Mosquera F, et al. Principal components of mania. J Affect Disord. 2003;76(1–3):95–102.PubMedCrossRefGoogle Scholar
  21. 21.
    Dilsaver SC, Chen YR, Shoaib AM, Swann AC. Phenomenology of mania: evidence for distinct depressed, dysphoric, and euphoric presentations. Am J Psychiatry. 1999;156(3):426–30.PubMedGoogle Scholar
  22. 22.
    Swann AC, Janicak PL, Calabrese JR, Bowden CL, Dilsaver SC, Morris DD, 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.[1-3:123–32.PubMedCrossRefGoogle Scholar
  23. 23.
    Rossi A, Daneluzzo E, Arduini L, Di Domenico M, Pollice R, Petruzzi C. A factor analysis of signs and symptoms of the manic episode with Bech-Rafaelsen Mania and Melancholia Scales. J Affect Disord. 2001;64.[2-3:267–70.PubMedCrossRefGoogle Scholar
  24. 24.
    Hantouche EG, Allilaire JP, Bourgeois ML, Azorin JM, Sechter D, Chatenet-Duchene L, et al. The feasibility of self-assessment of dysphoric mania in the French national EPIMAN study. J Affect Disord. 2001;67.[1-3:97–103.PubMedCrossRefGoogle Scholar
  25. 25.
    Akiskal HS, Azorin JM, Hantouche EG. Proposed multidimensional structure of mania: beyond the euphoric-dysphoric dichotomy. J Affect Disord. 2003;73(1–2):7–18.PubMedCrossRefGoogle Scholar
  26. 26.
    Murphy DL, Beigel A, Weingartner H, Bunney WE Jr. The quantitation of manic behavior. Mod Probl Pharmacopsychiatry. 1974;7:203–20.PubMedCrossRefGoogle Scholar
  27. 27.
    Double DB. The factor structure of manic rating scales. J Affect Disord. 1990;18(2):113–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Serretti A, Rietschel M, Lattuada E, Krauss H, Held T, Nothen MM, et al. Factor analysis of mania. Arch Gen Psychiatry. 1999;56(7):671–2.PubMedCrossRefGoogle Scholar
  29. 29.
    American Psychiatry Association. Mixed features specifier. wDo.
  30. 30.
    Vieta E. Bipolar mixed states and their treatment. 2007.Google Scholar
  31. 31.
    Muralidharan K, Ali M, Silveira LE, Bond DJ, Fountoulakis KN, Lam RW, et al. Efficacy of second generation antipsychotics in treating acute mixed episodes in bipolar disorder: a meta-analysis of placebo-controlled trials. J Affect Disord. 2013;150(2):408–14.PubMedCrossRefGoogle Scholar
  32. 32.
    Hirschfeld RM. Bipolar spectrum disorder: improving its recognition and diagnosis. J Clin Psychiatry. 2001;62(Suppl 14):5–9.PubMedGoogle Scholar
  33. 33.
    Kawa I, Carter JD, Joyce PR, Doughty CJ, Frampton CM, Wells JE, et al. Gender differences in bipolar disorder: age of onset, course, comorbidity, and symptom presentation. Bipolar Disord. 2005;7(2):119–25.PubMedCrossRefGoogle Scholar
  34. 34.
    Dell’Osso L, Placidi GF, Nassi R, Freer P, Cassano GB, Akiskal HS. The manic-depressive mixed state: familial, temperamental and psychopathologic characteristics in 108 female inpatients. Eur Arch Psychiatry Clin Neurosci. 1991;240(4–5):234–9.PubMedCrossRefGoogle Scholar
  35. 35.
    Gonzalez-Pinto A, Barbeito S, Alonso M, Alberich S, Haidar MK, Vieta E, et al. Poor long-term prognosis in mixed bipolar patients: 10-year outcomes in the Vitoria prospective naturalistic study in Spain. J Clin Psychiatry. 2011.;72[5;72:671–6.PubMedCrossRefGoogle Scholar
  36. 36.
    Diflorio A, Jones I. Is sex important? Gender differences in bipolar disorder. Int Rev Psychiatry. 2010;22(5):437–52.PubMedCrossRefGoogle Scholar
  37. 37.
    Nivoli AM, Pacchiarotti I, Rosa AR, Popovic D, Murru A, Valenti M, et al. Gender differences in a cohort study of 604 bipolar patients: the role of predominant polarity. J Affect Disord. 2011;133(3):443–9.PubMedCrossRefGoogle Scholar
  38. 38.
    Cassidy F, Yatham LN, Berk M, Grof P. Pure and mixed manic subtypes: a review of diagnostic classification and validation. Bipolar Disord. 2008;10.[1 Pt 2:131–43.PubMedCrossRefGoogle Scholar
  39. 39.
    Azorin JM, Belzeaux R, Kaladjian A, Adida M, Hantouche E, Lancrenon S, et al. Risks associated with gender differences in bipolar I disorder. J Affect Disord. 2013;151(3):1033–40.PubMedCrossRefGoogle Scholar
  40. 40.
    Payne JL. The role of estrogen in mood disorders in women. Int Rev Psychiatry. 2003;15(3):280–90.PubMedCrossRefGoogle Scholar
  41. 41.
    Teatero ML, Mazmanian D, Sharma V. Effects of the menstrual cycle on bipolar disorder. Bipolar Disord. 2014;16(1):22–36.PubMedCrossRefGoogle Scholar
  42. 42.
    Vliegen N, Casalin S, Luyten P. The course of postpartum depression: a review of longitudinal studies. Harv Rev Psychiatry. 2014;22(1):1–22.PubMedCrossRefGoogle Scholar
  43. 43.
    Gupta N, O’Brien R, Jacobsen LJ, Davis A, Zuckerman A, Supran S, et al. Mood changes in adolescents using depot-medroxyprogesterone acetate for contraception: a prospective study. J Pediatr Adolesc Gynecol. 2001;14(2):71–6.PubMedCrossRefGoogle Scholar
  44. 44.
    Gibbs Z, Lee S, Kulkarni J. Factors associated with depression during the perimenopausal transition. Women’s Health Issues. 2013;23(5):e301–7.PubMedCrossRefGoogle Scholar
  45. 45.
    Freeman MP, Gelenberg AJ. Bipolar disorder in women: reproductive events and treatment considerations. Acta Psychiatr Scand. 2005;112(2):88–96.PubMedCrossRefGoogle Scholar
  46. 46.
    Di Florio A, Forty L, Gordon-Smith K, Heron J, Jones L, Craddock N, et al. Perinatal episodes across the mood disorder spectrum. JAMA Psychiat. 2013;70(2):168–75.CrossRefGoogle Scholar
  47. 47.
    Vesga-Lopez O, Blanco C, Keyes K, Olfson M, Grant BF, Hasin DS. Psychiatric disorders in pregnant and postpartum women in the United States. Arch Gen Psychiatry. 2008;65(7):805–15.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Freeman MP, Smith KW, Freeman SA, McElroy SL, Kmetz GE, Wright R, et al. The impact of reproductive events on the course of bipolar disorder in women. J Clin Psychiatry. 2002;63(4):284–7.PubMedCrossRefGoogle Scholar
  49. 49.
    Gottschalk A, Bauer MS, Whybrow PC. Evidence of chaotic mood variation in bipolar disorder. Arch Gen Psychiatry. 1995;52(11):947–59.PubMedCrossRefGoogle Scholar
  50. 50.
    van de Ven AC, Muntjewerff JW, Netea-Maier RT, de Vegt F, Ross HA, Sweep FC, et al. Association between thyroid function, thyroid autoimmunity, and state and trait factors of depression. Acta Psychiatr Scand. 2012;126(5):377–84.PubMedCrossRefGoogle Scholar
  51. 51.
    Ibach B, Poljansky S, Marienhagen J, Sommer M, Manner P, Hajak G. Contrasting metabolic impairment in frontotemporal degeneration and early onset Alzheimer’s disease. NeuroImage. 2004;23(2):739–43.PubMedCrossRefGoogle Scholar
  52. 52.
    MacKinnon DF, Zandi PP, Cooper J, Potash JB, Simpson SG, Gershon E, et al. Comorbid bipolar disorder and panic disorder in families with a high prevalence of bipolar disorder. Am J Psychiatry. 2002;159(1):30–5.PubMedCrossRefGoogle Scholar
  53. 53.
    Saunders EF, Fitzgerald KD, Zhang P, McInnis MG. Clinical features of bipolar disorder comorbid with anxiety disorders differ between men and women. Depress Anxiety. 2012;29(8):739–46.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Hawton K, Sutton L, Haw C, Sinclair J, Harriss L. Suicide and attempted suicide in bipolar disorder: a systematic review of risk factors. J Clin Psychiatry. 2005;66(6):693–704.PubMedCrossRefGoogle Scholar
  55. 55.
    Lopez P, Mosquera F, de Leon J, Gutierrez M, Ezcurra J, Ramirez F, et al. Suicide attempts in bipolar patients. J Clin Psychiatry. 2001;62(12):963–6.PubMedCrossRefGoogle Scholar
  56. 56.
    Rotondo A, Mazzanti C, Dell’Osso L, Rucci P, Sullivan P, Bouanani S, et al. Catechol o-methyltransferase, serotonin transporter, and tryptophan hydroxylase gene polymorphisms in bipolar disorder patients with and without comorbid panic disorder. Am J Psychiatry. 2002;159(1):23–9.PubMedCrossRefGoogle Scholar
  57. 57.
    Akiskal HS. The distinctive mixed states of bipolar I, II, and III. Clin Neuropharmacol. 1992;15(Suppl 1 Pt A):632A–3A.PubMedCrossRefGoogle Scholar
  58. 58.
    Akiskal HS, Mallya G. Criteria for the “soft” bipolar spectrum: treatment implications. Psychopharmacol Bull. 1987;23(1):68–73.PubMedGoogle Scholar
  59. 59.
    Akiskal HS, Hantouche EG, Bourgeois ML, Azorin JM, Sechter D, Allilaire JF, et al. Gender, temperament, and the clinical picture in dysphoric mixed mania: findings from a French national study [EPIMAN]. J Affect Disord. 1998;50(2–3):175–86.PubMedCrossRefGoogle Scholar
  60. 60.
    Altshuler LL, Kupka RW, Hellemann G, Frye MA, Sugar CA, McElroy SL, et al. Gender and depressive symptoms in 711 patients with bipolar disorder evaluated prospectively in the Stanley Foundation bipolar treatment outcome network. Am J Psychiatry. 2010;167(6):708–15.PubMedCrossRefGoogle Scholar
  61. 61.
    Kendler KS, Gardner CO. Sex differences in the pathways to major depression: a study of opposite-sex twin pairs. Am J Psychiatry. 2014;171:426.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Egeland JA. Bipolarity: the iceberg of affective disorders? Compr Psychiatry. 1983;24(4):337–44.PubMedCrossRefGoogle Scholar
  63. 63.
    Rutz W, Walinder J, von Knorring L, Pihlgren H, Rihmer Z. [Is depression in men under-treated? High frequency of sudden, unexpected suicides]. Lakartidningen. 1995;92(42):3893–4, 9–900.Google Scholar
  64. 64.
    Hasin D, Carpenter KM, McCloud S, Smith M, Grant BF. The alcohol use disorder and associated disabilities interview schedule [AUDADIS]: reliability of alcohol and drug modules in a clinical sample. Drug Alcohol Depend. 1997;44(2–3):133–41.PubMedCrossRefGoogle Scholar
  65. 65.
    Miller S, Suppes T, Mintz J, Helleman G, Frye MA. Mixed depression in bipolar disorder: prevalence rate and clinical correlates during naturalistic follow-up in the Stanley bipolar network. Am J Psychiatry. 2016;173(10):1015–23.PubMedCrossRefGoogle Scholar
  66. 66.
    Fellinger M, Waldhor T, Blüml V, Williams N, Vyssoki B. Influence of gender on inpatient treatment for bipolar disorder: an analysis of 60,607 hospitalisations. J Affect Disord. 2018;225:104–7.PubMedCrossRefGoogle Scholar
  67. 67.
    Reinares M, Bonnín Cdel M, Hidalgo-Mazzei D, Undurraga J, Mur M, Nieto E, Sáez C, Vieta E. Making sense of DSM-5 mania with depressive features. Aust N Z J Psychiatry. 2015;49(6):540–9.PubMedCrossRefGoogle Scholar
  68. 68.
    Suppes T, Mintz J, McElroy SL, et al. Mixed hypomania in 908 patients with bipolar disorder evaluated prospectively in the Stanley Foundation bipolar treatment network: a sex-specific phenomenon. Arch Gen Psychiatry. 2005;62:1089–96.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Ana González-Pinto
    • 1
    • 2
    • 3
    Email author
  • Maddi Laborde Zufiaurre
    • 2
  • Beatriz González Hernández
    • 2
  • Purificación López Peña
    • 1
    • 2
  • Ana Isabel Cano
    • 2
  • Saioa López-Zurbano
    • 1
    • 2
  1. 1.University of the Basque Country UPV/EHULeioaSpain
  2. 2.Alava University Hospital-SantiagoVitoriaSpain
  3. 3.CIBERSAMBarcelonaSpain

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