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Diagnosis, Epidemiology and Management of Mixed States in Bipolar Disorder

Abstract

Approximately 40 % of patients with bipolar disorder experience mixed episodes, defined as a manic state with depressive features, or manic symptoms in a patient with bipolar depression. Compared with bipolar patients without mixed features, patients with bipolar mixed states generally have more severe symptomatology, more lifetime episodes of illness, worse clinical outcomes and higher rates of comorbidities, and thus present a significant clinical challenge. Most clinical trials have investigated second-generation neuroleptic monotherapy, monotherapy with anticonvulsants or lithium, combination therapy, and electroconvulsive therapy (ECT). Neuroleptic drugs are often used alone or in combination with anticonvulsants or lithium for preventive treatment, and ECT is an effective treatment for mixed manic episodes in situations where medication fails or cannot be used. Common antidepressants have been shown to worsen mania symptoms during mixed episodes without necessarily improving depressive symptoms; thus, they are not recommended during mixed episodes. A greater understanding of pathophysiological processes in bipolar disorder is now required to provide a more accurate diagnosis and new personalised treatment approaches. Targeted, specific treatments developed through a greater understanding of bipolar disorder pathophysiology, capable of affecting the underlying disease processes, could well prove to be more effective, faster acting, and better tolerated than existing therapies, therefore providing better outcomes for individuals affected by bipolar disorder. Until such time as targeted agents are available, second-generation neuroleptics are emerging as the treatment of choice in the management of mixed states in bipolar disorder.

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References

  1. 1.

    Castle DJ. Bipolar mixed states: still mixed up? Curr Opin Psychiatry. 2014;27(1):38–42.

    Article  PubMed  Google Scholar 

  2. 2.

    Berk M, Dodd S, Malhi GS. ‘Bipolar missed states’: the diagnosis and clinical salience of bipolar mixed states. Aust N Z J Psychiatry. 2005;39(4):215–21.

    PubMed  Google Scholar 

  3. 3.

    American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Washington, DC: American Psychiatric Association; 2000.

    Google Scholar 

  4. 4.

    Benazzi F, Akiskal HS. Delineating bipolar II mixed states in the Ravenna-San Diego collaborative study: the relative prevalence and diagnostic significance of hypomanic features during major depressive episodes. J Affect Disord. 2001;67(1–3):115–22.

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Angst J, Azorin JM, Bowden CL, Perugi G, Vieta E, Gamma A, et al. Prevalence and characteristics of undiagnosed bipolar disorders in patients with a major depressive episode: the BRIDGE study. Arch Gen Psychiatry. 2011;68(8):791–8.

    Article  PubMed  Google Scholar 

  6. 6.

    American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed. Arlington: American Psychiatric Association; 2013.

    Google Scholar 

  7. 7.

    Perugi G, Angst J, Azorin JM, Bowden CL, Mosolov S, Reis J, et al. Mixed features in patients with a major depressive episode: the BRIDGE-II-MIX study. J Clin Psychiatry. 2015;76(3):e351–8.

    Article  PubMed  Google Scholar 

  8. 8.

    Shim IH, Woo YS, Bahk WM. Prevalence rates and clinical implications of bipolar disorder “with mixed features” as defined by DSM-5. J Affect Disord. 2015;173:120–5.

    Article  PubMed  Google Scholar 

  9. 9.

    Dunner DL. Atypical antipsychotics: efficacy across bipolar disorder subpopulations. J Clin Psychiatry. 2005;66(Suppl 3):20–7.

    CAS  PubMed  Google Scholar 

  10. 10.

    Himmelhoch JM, Mulla D, Neil JF, Detre TP, Kupfer DJ. Incidence and significance of mixed affective states in a bipolar population. Arch Gen Psychiatry. 1976;33(9):1062–6.

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Kessing LV. The prevalence of mixed episodes during the course of illness in bipolar disorder. Acta Psychiatr Scand. 2008;117(3):216–24.

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Secunda SK, Swann A, Katz MM, Koslow SH, Croughan J, Chang S. Diagnosis and treatment of mixed mania. Am J Psychiatry. 1987;144(1):96–8.

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Malhi GS. Diagnosis of bipolar disorder: who is in a mixed state? Lancet. 2013;381(9878):1599–600.

    Article  PubMed  Google Scholar 

  14. 14.

    Swann AC, Lafer B, Perugi G, Frye MA, Bauer M, Bahk WM, et al. Bipolar mixed states: an international society for bipolar disorders task force report of symptom structure, course of illness, and diagnosis. Am J Psychiatry. 2013;170(1):31–42.

    Article  PubMed  Google Scholar 

  15. 15.

    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.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Swann AC, Secunda SK, Katz MM, Croughan J, Bowden CL, Koslow SH, et al. Specificity of mixed affective states: clinical comparison of dysphoric mania and agitated depression. J Affect Disord. 1993;28(2):81–9.

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Malhi GS, Lampe L, Coulston CM, Tanious M, Bargh DM, Curran G, et al. Mixed state discrimination: a DSM problem that wont go away? J Affect Disord. 2014;158:8–10.

    Article  PubMed  Google Scholar 

  18. 18.

    González-Pinto A, Aldama A, Mosquera F, Gómez CG. Epidemiology, diagnosis and management of mixed mania. CNS Drugs. 2007;21(8):611–26.

    Article  PubMed  Google Scholar 

  19. 19.

    Vieta E, Grunze H, Azorin JM, Fagiolini A. Phenomenology of manic episodes according to the presence or absence of depressive features as defined in DSM-5: results from the IMPACT self-reported online survey. J Affect Disord. 2014;156:206–13.

    Article  PubMed  Google Scholar 

  20. 20.

    Henry C, M’Bailara K, Poinsot R, Casteret AA, Sorbara F, Leboyer M, et al. Evidence for two types of bipolar depression using a dimensional approach. Psychother Psychosom. 2007;76(6):325–31.

    Article  PubMed  Google Scholar 

  21. 21.

    Akiskal HS, Benazzi F, Perugi G, Rihmer Z. Agitated, “unipolar” depression re-conceptualized as a depressive mixed state: implications for the antidepressant-suicide controversy. J Affect Disord. 2005;85(3):245–58.

    Article  PubMed  Google Scholar 

  22. 22.

    Benazzi F, Akiskal HS. Psychometric delineation of the most discriminant symptoms of depressive mixed states. Psychiatry Res. 2006;141(1):81–8.

    Article  PubMed  Google Scholar 

  23. 23.

    Faedda GL, Marangoni C, Reginaldi D. Depressive mixed states: a reappraisal of Koukopoulos’ criteria. J Affect Disord. 2015;176:18–23.

    Article  PubMed  Google Scholar 

  24. 24.

    Sani G, Napoletano F, Vohringer PA, Sullivan M, Simonetti A, Koukopoulos A, et al. Mixed depression: clinical features and predictors of its onset associated with antidepressant use. Psychother Psychosom. 2014;83(4):213–21.

    Article  PubMed  Google Scholar 

  25. 25.

    Koukopoulos A, Sani G. DSM-5 criteria for depression with mixed features: a farewell to mixed depression. Acta Psychiatr Scand. 2014;129(1):4–16.

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Cavanagh J, Schwannauer M, Power M, Goodwin GM. A novel scale for measuring mixed states in bipolar disorder. Clin Psychol Psychother. 2009;16(6):497–509.

    Article  PubMed  Google Scholar 

  27. 27.

    Henry C, M’Bailara K, Lepine JP, Lajnef M, Leboyer M. Defining bipolar mood states with quantitative measurement of inhibition/activation and emotional reactivity. J Affect Disord. 2010;127(1–3):300–4.

    Article  PubMed  Google Scholar 

  28. 28.

    Baldessarini RJ, Bolzani L, Cruz N, Jones PB, Lai M, Lepri B, et al. Onset-age of bipolar disorders at six international sites. J Affect Disord. 2010;121(1–2):143–6.

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Shim IH, Woo YS, Jun TY, Bahk WM. Mixed-state bipolar I and II depression: time to remission and clinical characteristics. J Affect Disord. 2014;152–154:340–6.

    Article  PubMed  Google Scholar 

  30. 30.

    Undurraga J, Baldessarini RJ, Valenti M, Pacchiarotti I, Vieta E. Suicidal risk factors in bipolar I and II disorder patients. J Clin Psychiatry. 2012;73(6):778–82.

    Article  PubMed  Google Scholar 

  31. 31.

    Fagiolini A, Forgione R, Maccari M, Cuomo A, Morana B, Dell’Osso MC, et al. Prevalence, chronicity, burden and borders of bipolar disorder. J Affect Disord. 2013;148(2–3):161–9.

    Article  PubMed  Google Scholar 

  32. 32.

    Malhi GS, Tanious M, Fritz K, Coulston CM, Bargh DM, Phan KL, et al. Differential engagement of the fronto-limbic network during emotion processing distinguishes bipolar and borderline personality disorder. Mol Psychiatry. 2013;18(12):1247–8.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  33. 33.

    Bowden CL, Collins MA, McElroy SL, Calabrese JR, Swann AC, Weisler RH, et al. Relationship of mania symptomatology to maintenance treatment response with divalproex, lithium, or placebo. Neuropsychopharmacology. 2005;30(10):1932–9.

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    McIntyre RS, Cohen M, Zhao J, Alphs L, Macek TA, Panagides J. Asenapine for long-term treatment of bipolar disorder: a double-blind 40-week extension study. J Affect Disord. 2010;126(3):358–65.

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Suppes T, Vieta E, Liu S, Brecher M, Paulsson B. Maintenance treatment for patients with bipolar I disorder: results from a North American study of quetiapine in combination with lithium or divalproex (trial 127). Am J Psychiatry. 2009;166(4):476–88.

    Article  PubMed  Google Scholar 

  36. 36.

    Tohen M, Calabrese JR, Sachs GS, Banov MD, Detke HC, Risser R, et al. Randomized, placebo-controlled trial of olanzapine as maintenance therapy in patients with bipolar I disorder responding to acute treatment with olanzapine. Am J Psychiatry. 2006;163(2):247–56.

    Article  PubMed  Google Scholar 

  37. 37.

    Tohen M, Sutton VK, Calabrese JR, Sachs GS, Bowden CL. Maintenance of response following stabilization of mixed index episodes with olanzapine monotherapy in a randomized, double-blind, placebo-controlled study of bipolar 1 disorder. J Affect Disord. 2009;116(1–2):43–50.

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Vieta E, Suppes T, Eggens I, Persson I, Paulsson B, Brecher M. Efficacy and safety of quetiapine in combination with lithium or divalproex for maintenance of patients with bipolar I disorder (international trial 126). J Affect Disord. 2008;109(3):251–63.

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Patkar A, Gilmer W, Pae CU, Vohringer PA, Ziffra M, Pirok E, et al. A 6 week randomized double-blind placebo-controlled trial of ziprasidone for the acute depressive mixed state. PLoS One. 2012;7(4):e34757.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  40. 40.

    Szegedi A, Zhao J, van Willigenburg A, Nations KR, Mackle M, Panagides J. Effects of asenapine on depressive symptoms in patients with bipolar I disorder experiencing acute manic or mixed episodes: a post hoc analysis of two 3-week clinical trials. BMC Psychiatry. 2011;11:101.

    PubMed Central  CAS  Article  PubMed  Google Scholar 

  41. 41.

    Baker RW, Tohen M, Fawcett J, Risser RC, Schuh LM, Brown E, et al. Acute dysphoric mania: treatment response to olanzapine versus placebo. J Clin Psychopharmacol. 2003;23(2):132–7.

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    Baldessarini RJ, Hennen J, Wilson M, Calabrese J, Chengappa R, Keck PE Jr, et al. Olanzapine versus placebo in acute mania: treatment responses in subgroups. J Clin Psychopharmacol. 2003;23(4):370–6.

    CAS  Article  PubMed  Google Scholar 

  43. 43.

    Tohen M, Jacobs TG, Grundy SL, McElroy SL, Banov MC, Janicak PG, et al. Efficacy of olanzapine in acute bipolar mania: a double-blind, placebo-controlled study. The Olanzapine HGGW Study Group. Arch Gen Psychiatry. 2000;57(9):841–9.

    CAS  Article  PubMed  Google Scholar 

  44. 44.

    Tohen M, Sanger TM, McElroy SL, Tollefson GD, Chengappa KN, Daniel DG, et al. Olanzapine versus placebo in the treatment of acute mania. Olanzapine HGEH Study Group. Am J Psychiatry. 1999;156(5):702–9.

    CAS  PubMed  Google Scholar 

  45. 45.

    Shi L, Schuh LM, Trzepacz PT, Huang LX, Namjoshi MA, Tohen M. Improvement of Positive and Negative Syndrome Scale cognitive score associated with olanzapine treatment of acute mania. Curr Med Res Opin. 2004;20(9):1371–6.

    Article  PubMed  Google Scholar 

  46. 46.

    Keck PE Jr, Marcus R, Tourkodimitris S, Ali M, Liebeskind A, Saha A, et al. A placebo-controlled, double-blind study of the efficacy and safety of aripiprazole in patients with acute bipolar mania. Am J Psychiatry. 2003;160(9):1651–8.

    Article  PubMed  Google Scholar 

  47. 47.

    McIntyre RS, Cohen M, Zhao J, Alphs L, Macek TA, Panagides J. A 3-week, randomized, placebo-controlled trial of asenapine in the treatment of acute mania in bipolar mania and mixed states. Bipolar Disord. 2009;11(7):673–86.

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    Sachs G, Sanchez R, Marcus R, Stock E, McQuade R, Carson W, et al. Aripiprazole in the treatment of acute manic or mixed episodes in patients with bipolar I disorder: a 3-week placebo-controlled study. J Psychopharmacol. 2006;20(4):536–46.

    CAS  Article  PubMed  Google Scholar 

  49. 49.

    Suppes T, Eudicone J, McQuade R, Pikalov A 3rd, Carlson B. Efficacy and safety of aripiprazole in subpopulations with acute manic or mixed episodes of bipolar I disorder. J Affect Disord. 2008;107(1–3):145–54.

    CAS  Article  PubMed  Google Scholar 

  50. 50.

    Berwaerts J, Xu H, Nuamah I, Lim P, Hough D. Evaluation of the efficacy and safety of paliperidone extended-release in the treatment of acute mania: a randomized, double-blind, dose-response study. J Affect Disord. 2012;136(1–2):e51–60.

    CAS  Article  PubMed  Google Scholar 

  51. 51.

    Keck PE Jr, Versiani M, Potkin S, West SA, Giller E, Ice K. Ziprasidone in the treatment of acute bipolar mania: a three-week, placebo-controlled, double-blind, randomized trial. Am J Psychiatry. 2003;160(4):741–8.

    Article  PubMed  Google Scholar 

  52. 52.

    Khanna S, Vieta E, Lyons B, Grossman F, Eerdekens M, Kramer M. Risperidone in the treatment of acute mania: double-blind, placebo-controlled study. Br J Psychiatry. 2005;187:229–34.

    Article  PubMed  Google Scholar 

  53. 53.

    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.

    CAS  Article  PubMed  Google Scholar 

  54. 54.

    Potkin SG, Keck PE Jr, Segal S, Ice K, English P. Ziprasidone in acute bipolar mania: a 21-day randomized, double-blind, placebo-controlled replication trial. J Clin Psychopharmacol. 2005;25(4):301–10.

    CAS  Article  PubMed  Google Scholar 

  55. 55.

    Stahl S, Lombardo I, Loebel A, Mandel FS. Efficacy of ziprasidone in dysphoric mania: pooled analysis of two double-blind studies. J Affect Disord. 2010;122(1–2):39–45.

    CAS  Article  PubMed  Google Scholar 

  56. 56.

    Vieta E, Nuamah IF, Lim P, Yuen EC, Palumbo JM, Hough DW, et al. A randomized, placebo- and active-controlled study of paliperidone extended release for the treatment of acute manic and mixed episodes of bipolar I disorder. Bipolar Disord. 2010;12(3):230–43.

    CAS  Article  PubMed  Google Scholar 

  57. 57.

    Bowden CL, Brugger AM, Swann AC, Calabrese JR, Janicak PG, Petty F, et al. Efficacy of divalproex vs lithium and placebo in the treatment of mania. The Depakote Mania Study Group. JAMA. 1994;271(12):918–24.

    CAS  Article  PubMed  Google Scholar 

  58. 58.

    Swann AC, Bowden CL, Calabrese JR, Dilsaver SC, Morris DD. Mania: differential effects of previous depressive and manic episodes on response to treatment. Acta Psychiatr Scand. 2000;101(6):444–51.

    CAS  Article  PubMed  Google Scholar 

  59. 59.

    Weisler RH, Hirschfeld R, Cutler AJ, Gazda T, Ketter TA, Keck PE, et al. Extended-release carbamazepine capsules as monotherapy in bipolar disorder : pooled results from two randomised, double-blind, placebo-controlled trials. CNS Drugs. 2006;20(3):219–31.

    CAS  Article  PubMed  Google Scholar 

  60. 60.

    Weisler RH, Kalali AH, Ketter TA. A multicenter, randomized, double-blind, placebo-controlled trial of extended-release carbamazepine capsules as monotherapy for bipolar disorder patients with manic or mixed episodes. J Clin Psychiatry. 2004;65(4):478–84.

    CAS  Article  PubMed  Google Scholar 

  61. 61.

    Weisler RH, Keck PE Jr, Swann AC, Cutler AJ, Ketter TA, Kalali AH. Extended-release carbamazepine capsules as monotherapy for acute mania in bipolar disorder: a multicenter, randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2005;66(3):323–30.

    CAS  Article  PubMed  Google Scholar 

  62. 62.

    Bowden CL, Swann AC, Calabrese JR, Rubenfaer LM, Wozniak PJ, Collins MA, et al. A randomized, placebo-controlled, multicenter study of divalproex sodium extended release in the treatment of acute mania. J Clin Psychiatry. 2006;67(10):1501–10.

    CAS  Article  PubMed  Google Scholar 

  63. 63.

    Freeman TW, Clothier JL, Pazzaglia P, Lesem MD, Swann AC. A double-blind comparison of valproate and lithium in the treatment of acute mania. Am J Psychiatry. 1992;149(1):108–11.

    CAS  Article  PubMed  Google Scholar 

  64. 64.

    Ghaemi SN, Gilmer WS, Goldberg JF, Zablotsky B, Kemp DE, Kelley ME, et al. Divalproex in the treatment of acute bipolar depression: a preliminary double-blind, randomized, placebo-controlled pilot study. J Clin Psychiatry. 2007;68(12):1840–4.

    CAS  Article  PubMed  Google Scholar 

  65. 65.

    Baker RW, Brown E, Akiskal HS, Calabrese JR, Ketter TA, Schuh LM, et al. Efficacy of olanzapine combined with valproate or lithium in the treatment of dysphoric mania. Br J Psychiatry. 2004;185:472–8.

    Article  PubMed  Google Scholar 

  66. 66.

    Houston JP, Ahl J, Meyers AL, Kaiser CJ, Tohen M, Baldessarini RJ. Reduced suicidal ideation in bipolar I disorder mixed-episode patients in a placebo-controlled trial of olanzapine combined with lithium or divalproex. J Clin Psychiatry. 2006;67(8):1246–52.

    CAS  Article  PubMed  Google Scholar 

  67. 67.

    Houston JP, Ketter TA, Case M, Bowden C, Degenhardt EK, Jamal HH, et al. Early symptom change and prediction of subsequent remission with olanzapine augmentation in divalproex-resistant bipolar mixed episodes. J Psychiatr Res. 2011;45(2):169–73.

    Article  PubMed  Google Scholar 

  68. 68.

    Sachs GS, Grossman F, Ghaemi SN, Okamoto A, Bowden CL. Combination of a mood stabilizer with risperidone or haloperidol for treatment of acute mania: a double-blind, placebo-controlled comparison of efficacy and safety. Am J Psychiatry. 2002;159(7):1146–54.

    Article  PubMed  Google Scholar 

  69. 69.

    Tohen M, Chengappa KN, Suppes T, Zarate CA Jr, Calabrese JR, Bowden CL, et al. Efficacy of olanzapine in combination with valproate or lithium in the treatment of mania in patients partially nonresponsive to valproate or lithium monotherapy. Arch Gen Psychiatry. 2002;59(1):62–9.

    CAS  Article  PubMed  Google Scholar 

  70. 70.

    Houston JP, Tohen M, Degenhardt EK, Jamal HH, Liu LL, Ketter TA. Olanzapine-divalproex combination versus divalproex monotherapy in the treatment of bipolar mixed episodes: a double-blind, placebo-controlled study. J Clin Psychiatry. 2009;70(11):1540–7.

    CAS  Article  PubMed  Google Scholar 

  71. 71.

    Benazzi F, Berk M, Frye MA, Wang W, Barraco A, Tohen M. Olanzapine/fluoxetine combination for the treatment of mixed depression in bipolar I disorder: a post hoc analysis. J Clin Psychiatry. 2009;70(10):1424–31.

    CAS  Article  PubMed  Google Scholar 

  72. 72.

    Tohen M, Vieta E, Calabrese J, Ketter TA, Sachs G, Bowden C, et al. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry. 2003;60(11):1079–88.

    CAS  Article  PubMed  Google Scholar 

  73. 73.

    Medda P, Perugi G, Zanello S, Ciuffa M, Rizzato S, Cassano GB. Comparative response to electroconvulsive therapy in medication-resistant bipolar I patients with depression and mixed state. J ECT. 2010;26(2):82–6.

    CAS  Article  PubMed  Google Scholar 

  74. 74.

    Valenti M, Benabarre A, Garcia-Amador M, Molina O, Bernardo M, Vieta E. Electroconvulsive therapy in the treatment of mixed states in bipolar disorder. Eur Psychiatry. 2008;23(1):53–6.

    Article  PubMed  Google Scholar 

  75. 75.

    Gruber NP, Dilsaver SC, Shoaib AM, Swann AC. ECT in mixed affective states: a case series. J ECT. 2000;16(2):183–8.

    CAS  Article  PubMed  Google Scholar 

  76. 76.

    Devanand DP, Polanco P, Cruz R, Shah S, Paykina N, Singh K, et al. The efficacy of ECT in mixed affective states. J ECT. 2000;16(1):32–7.

    CAS  Article  PubMed  Google Scholar 

  77. 77.

    Fountoulakis KN, Kontis D, Gonda X, Siamouli M, Yatham LN. Treatment of mixed bipolar states. Int J Neuropsychopharmacol. 2012;15(7):1015–26.

    CAS  Article  PubMed  Google Scholar 

  78. 78.

    Goodwin GM. Evidence-based guidelines for treating bipolar disorder: revised second edition: recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 2009;23(4):346–88.

    CAS  Article  PubMed  Google Scholar 

  79. 79.

    Yatham LN, Kennedy SH, O’Donovan C, Parikh S, MacQueen G, McIntyre R, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines for the management of patients with bipolar disorder: consensus and controversies. Bipolar Disord. 2005;7(Suppl 3):5–69.

    Article  PubMed  Google Scholar 

  80. 80.

    Goldberg JF, Perlis RH, Bowden CL, Thase ME, Miklowitz DJ, Marangell LB, et al. Manic symptoms during depressive episodes in 1380 patients with bipolar disorder: findings from the STEP-BD. Am J Psychiatry. 2009;166(2):173–81.

    Article  PubMed  Google Scholar 

  81. 81.

    McIntyre RS, Cohen M, Zhao J, Alphs L, Macek TA, Panagides J. Asenapine in the treatment of acute mania in bipolar I disorder: a randomized, double-blind, placebo-controlled trial. J Affect Disord. 2010;122(1–2):27–38.

    CAS  Article  PubMed  Google Scholar 

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Acknowledgments

The authors would like to thank Sheridan Henness, PhD, of Springer Healthcare Communications, for medical writing assistance, including drafting of the manuscript, English editing of the ‘Expert Opinion and Practical Guidance’ section, and assistance with post-submission revisions. This assistance was funded by Lundbeck, Italy.

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Correspondence to Andrea Fagiolini.

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Medical writing assistance was funded by Lundbeck, Italy.

Conflicts of interest

The authors declare the following conflicts of interest. Andrea Fagiolini received research grants and/or honoraria as a consultant to and/or participant on advisory boards from Angelini, Astra Zeneca, Bristol-Myers Squibb, Eli Lilly, Janssen, Lundbeck, Novartis, Otsuka, Pfizer, Boehringer Ingelheim, Takeda and Roche.

Allan H. Young is employed by King’s College London, is an Honorary Consultant to the South London and Maudsley NHS Foundation Trust (SLaM), has received fees for paid lectures and advisory boards for all major pharmaceutical companies with drugs used in affective and related disorders, and has no share holdings in pharmaceutical companies. He is a Lead Investigator for the Embolden Study (Astra-Zeneca), the BCI Neuroplasticity Study and the Aripiprazole Mania Study, and is involved in investigator-initiated studies from Astra-Zeneca, Eli Lilly, Lundbeck, and Wyeth. In addition, he has received grant funding (past and present) from the National Institute of Mental Health (NIMH, USA), Canadian Institutes of Health Research (CIHR, Canada), National Alliance for Research on Schizophrenia and Depression (NARSAD, USA), Stanley Medical Research Institute (USA), Medical Research Council (MRC, UK), Wellcome Trust (UK), Royal College of Physicians (Edinburgh), British Medical Association (BMA, UK), UBC-VGH Foundation (Canada), Western Economic Diversification Canada (WEDC, Canada), CCS Depression Research Fund (Canada), Michael Smith Foundation for Health Research (MSFHR, Canada), and the National Institute for Health Research (NIHR, UK).

Giuseppe Maina received grant funding, consulting fees and reimbursements from Lundbeck Italia, Otsuka, Pfizer Italia, Janssen Cilag, and Astra Zeneca.

Anna Coluccia, Alessandro Cuomo, Arianna Goracci, and Rocco N. Forgione declare they have no conflicts of interest.

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Fagiolini, A., Coluccia, A., Maina, G. et al. Diagnosis, Epidemiology and Management of Mixed States in Bipolar Disorder. CNS Drugs 29, 725–740 (2015). https://doi.org/10.1007/s40263-015-0275-6

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Keywords

  • Bipolar Disorder
  • Olanzapine
  • Valproate
  • Quetiapine
  • Mixed State