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Mixed States: Modelling and Management


Our current conceptualisation of mixed states, defined as co-occurring manic and depressive symptoms, is unlikely to advance our knowledge or inform clinical practice. Episodes of mixed states can no longer be coded in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), and the ‘mixed features specifier’ fails to capture the most common mixed state presentations. This reflects a lack of understanding of both the importance of mixed states and their underlying pathophysiology. Indeed, research into the nature of mixed states is scarce and uninformative, and most clinical practice guidelines fail to provide advice regarding their management. In this paper, we proffer a reconceptualisation of mixed states that provides a framework for informing clinical practice and research. It is based on the ACE model, which deconstructs mood disorders into three domains of symptoms: activity, cognition, and emotion. Symptoms within each domain vary independently over time and in different directions (towards either excitation or inhibition). By deconstructing mood disorders into component domains, mixed states can be explained as the product of different domains varying ‘out of sync’. In most cases, the aetiology of mixed states is unknown. Alongside such idiopathic mixed states, we describe three potential causes of mixed states that are important to consider when formulating management: transitions, ultradian cycling, and treatment-emergent affective switches. In addition to providing guidance on the identification of various kinds of mixed states, we discuss practical strategies for their management, including the monitoring of ACE domains and functioning, to inform the use of psychoeducation and lifestyle changes, psychotherapy, pharmacology, and electroconvulsive therapy.

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  1. 1.

    Kraepelin E. Manic-depressive insanity and paranoia. (M Barclay, trans). Chicago: Chicago Medical Book Company; 1921.

  2. 2.

    Vieta E, Valentí M. Mixed states in DSM-5: implications for clinical care, education, and research. J Affect Disord. 2013;148(1):28–36.

  3. 3.

    Goldberg JF, Perlis RH, Bowden CL, Thase ME, Miklowitz DJ, Marangell LB, et al. Manic symptoms during depressive episodes in 1,380 patients with bipolar disorder: findings from the STEP-BD. Am J Psychiatry. 2009;166(2):173–81.

  4. 4.

    McIntyre RS, Soczynska JK, Cha DS, Woldeyohannes HO, Dale RS, Alsuwaidan MT, et al. The prevalence and illness characteristics of DSM-5-defined “mixed feature specifier” in adults with major depressive disorder and bipolar disorder: results from the International Mood Disorders Collaborative Project. J Affect Disord. 2015;172:259–64.

  5. 5.

    McIntyre RS, Ng-Mak D, Chuang C-C, Halpern R, Patel PA, Rajagopalan K, et al. Major depressive disorder with subthreshold hypomanic (mixed) features: a real-world assessment of treatment patterns and economic burden. J Affect Disord. 2017;210:332–7.

  6. 6.

    Perugi G, Angst J, Azorin J-M, 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.

  7. 7.

    González-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):671–6.

  8. 8.

    Yildiz A, Vieta E, Tohen M, Baldessarini RJ. Factors modifying drug and placebo responses in randomized trials for bipolar mania. Int J Neuropsychopharmacol. 2011;14(7):863–75.

  9. 9.

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

  10. 10.

    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.

  11. 11.

    Malhi GS, Fritz K, Allwang C, Burston N, Cocks C, Devlin J, et al. Are manic symptoms that ‘dip’ into depression the essence of mixed features? J Affect Disord. 2016;192:104–8.

  12. 12.

    Tondo L, Vázquez G, Baldessarini R. Mania associated with antidepressant treatment: comprehensive meta-analytic review. Acta Psychiatr Scand. 2010;121(6):404–14.

  13. 13.

    Morrissette DA. Do no harm: a paradigm shift in the unchecked use of antidepressants. CNS Spectr. 2017;22(2):118–9.

  14. 14.

    Sani G, Napoletano F, Vöhringer 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.

  15. 15.

    Goikolea J, Colom F, Torres I, Capapey J, Valentí M, Undurraga J, et al. Lower rate of depressive switch following antimanic treatment with second-generation antipsychotics versus haloperidol. J Affect Disord. 2013;144(3):191–8.

  16. 16.

    Carvalho AF, Sharma MS, Brunoni AR, Vieta E, Fava GA. The safety, tolerability and risks associated with the use of newer generation antidepressant drugs: a critical review of the literature. Psychother Psychosom. 2016;85(5):270–88.

  17. 17.

    Fabrazzo M, Tortorella A. Safety and tolerability of mood stabilisers. Pharmacovigilance in Psychiatry. New York: Springer; 2016. p. 209–32.

  18. 18.

    Hirsch L, Patten SB, Bresee L, Jette N, Pringsheim T. Second-generation antipsychotics and metabolic side-effects: Canadian population-based study. BJPsych open. 2018;4(4):256–61.

  19. 19.

    Salvatore P, Baldessarini RJ, Centorrino F, Egli S, Albert M, Gerhard A, et al. Weygandt’s on the mixed states of manic-depressive insanity: a translation and commentary on its significance in the evolution of the concept of bipolar disorder. Harvard Rev Psychiatry. 2002;10(5):255–75.

  20. 20.

    Kraepelin E. Manic depressive insanity and paranoia. J Nerv Ment Dis. 1921;53(4):350.

  21. 21.

    Malhi GS, Irwin L, Hamilton A, Morris G, Boyce P, Mulder R, et al. Modelling mood disorders: an ACE solution? Bipolar Disord. 2018;20:4–16.

  22. 22.

    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.

  23. 23.

    Baier PC, Brzozka MM, Shahmoradi A, Reinecke L, Kroos C, Wichert SP, et al. Mice lacking the circadian modulators SHARP1 and SHARP2 display altered sleep and mixed state endophenotypes of psychiatric disorders. PLoS One. 2014;9(10):e110310.

  24. 24.

    Lee H-J, Son G-H, Geum D. Circadian rhythm hypotheses of mixed features, antidepressant treatment resistance, and manic switching in bipolar disorder. Psychiatry Investig. 2013;10(3):225–32.

  25. 25.

    Chang KD, Keck PE, Stanton SP, McElroy SL, Strakowski SM, Geracioti TD. Differences in thyroid function between bipolar manic and mixed states. Biol Psychiatry. 1998;43(10):730–3.

  26. 26.

    Petri E, Bacci O, Barbuti M, Pacchiarotti I, Azorin JM, Angst J, et al. Obesity in patients with major depression is related to bipolarity and mixed features: evidence from the BRIDGE-II-Mix study. Bipolar Disord. 2017;19(6):458–64.

  27. 27.

    Suppes T, Eberhard J, Lemming O, Young AH, McIntyre RS. Anxiety, irritability, and agitation as indicators of bipolar mania with depressive symptoms: a post hoc analysis of two clinical trials. Int J Bipolar Disord. 2017;5(1):36.

  28. 28.

    Gonzalez-Pinto A, Ballesteros J, Aldama A, De Heredia JP, Gutierrez M, Mosquera F. Principal components of mania. J Affect Disord. 2003;76(1–3):95–102.

  29. 29.

    Angst J. Switch from depression to mania, or from mania to depression. J Psychopharmacol. 1987;1(1):13–9.

  30. 30.

    Perlis RH, Ostacher MJ, Goldberg JF, Miklowitz DJ, Friedman E, Calabrese J, et al. Transition to mania during treatment of bipolar depression. Neuropsychopharmacology. 2010;35(13):2545.

  31. 31.

    Koukopoulos A, Albert MJ, Sani G, Koukopoulos AE, Girardi P. Mixed depressive states: nosologic and therapeutic issues. Int Rev Psychiatry. 2005;17(1):21–37.

  32. 32.

    Kramlinger KG, Post RM. Ultra-rapid and ultradian cycling in bipolar affective illness. Br J Psychiatry. 1996;168(3):314–23.

  33. 33.

    Maggini C, Salvatore P, Gerhard A, Migone P. Psychopathology of stable and unstable mixed states: a historical view. Compr Psychiatry. 2000;41(2):77–82.

  34. 34.

    Frye MA, Helleman G, McElroy SL, Altshuler LL, Black DO, Keck M Jr, Paul E, et al. Correlates of treatment-emergent mania associated with antidepressant treatment in bipolar depression. Am J Psychiatry. 2009;166(2):164–72.

  35. 35.

    El-Mallakh RS, Vöhringer PA, Ostacher MM, Baldassano CF, Holtzman NS, Whitham EA, et al. Antidepressants worsen rapid-cycling course in bipolar depression: a STEP-BD randomized clinical trial. J Affect Disord. 2015;184:318–21.

  36. 36.

    Radua J, Grunze H, Amann BL. Meta-analysis of the risk of subsequent mood episodes in bipolar disorder. Psychother Psychosom. 2017;86(2):90–8.

  37. 37.

    Schneck CD, Miklowitz DJ, Miyahara S, Araga M, Wisniewski S, Gyulai L, et al. The prospective course of rapid-cycling bipolar disorder: findings from the STEP-BD. Am J Psychiatry. 2008;165(3):370–7.

  38. 38.

    Koukopoulos A, Sani G, Koukopoulos A, Minnai G, Girardi P, Pani L, et al. Duration and stability of the rapid-cycling course: a long-term personal follow-up of 109 patients. J Affect Disord. 2003;73(1–2):75–85.

  39. 39.

    Zimmerman M, Chelminski I, Young D, Dalrymple K, Martinez JH. A clinically useful self-report measure of the DSM-5 mixed features specifier of major depressive disorder. J Affect Disord. 2014;168:357–62.

  40. 40.

    Sani G, Vöhringer PA, Barroilhet SA, Koukopoulos AE, Ghaemi SN. The Koukopoulos Mixed Depression Rating Scale (KMDRS): an International Mood Network (IMN) validation study of a new mixed mood rating scale. J Affect Disord. 2018;232:9–16.

  41. 41.

    Malhi GS, Porter R, Irwin L, Hamilton A, Morris G, Bassett D, et al. Defining a mood stabiliser: novel framework for research and clinical practice. BJPsych Open. 2018;4(4):278–81.

  42. 42.

    Goldberg JF, Truman CJ. Antidepressant-induced mania: an overview of current controversies. Bipolar Disord. 2003;5(6):407–20.

  43. 43.

    Altshuler LL, Post RM, Leverich GS, Mikalauskas K. Antidepressant-induced mania and cycle acceleration: a controversy revisited. Am J Psychiatry. 1995;152(8):1130.

  44. 44.

    Boerlin HL, Gitlin MJ, Zoellner LA, Hammen CL. Bipolar depression and antidepressant-induced mania: a naturalistic study. J Clin Psychiatry. 1998;59:374–9.

  45. 45.

    Stahl SM, Morrissette DA, Faedda G, Fava M, Goldberg JF, Keck PE, et al. Guidelines for the recognition and management of mixed depression. CNS Spectr. 2017;22(2):203–19.

  46. 46.

    Patel R, Reiss P, Shetty H, Broadbent M, Stewart R, McGuire P, et al. Do antidepressants increase the risk of mania and bipolar disorder in people with depression? A retrospective electronic case register cohort study. BMJ Open. 2015;5(12):e008341.

  47. 47.

    Malhi GS, Bassett D, Boyce P, Bryant R, Fitzgerald PB, Fritz K, et al. Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders. Aust N Z J Psychiatry. 2015;49(12):1087–206.

  48. 48.

    Agalawatta N, Kaufmann C, Byrow Y, Burston N, Lyndon W, Malhi GS. Are antidepressants a double-edged sword? Treatment emergent affective switch or antidepressant discontinuation syndrome. Aust N Z J Psychiatry. 2017;51(4):405–6.

  49. 49.

    Grunze H, Vieta E, Goodwin GM, Bowden C, Licht RW, Azorin J-M, et al. The World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Biological Treatment of Bipolar Disorders: acute and long-term treatment of mixed states in bipolar disorder. World J Biol Psychiatry. 2018;19(1):2–58.

  50. 50.

    Cuomo A, Nikolova VL, Yalin N, Arnone D, Fagiolini A, Young AH. Pharmacological treatment of mixed states. CNS Spectr. 2017;22(2):186–95.

  51. 51.

    Verdolini N, Hidalgo-Mazzei D, Murru A, Pacchiarotti I, Samalin L, Young A, et al. Mixed states in bipolar and major depressive disorders: systematic review and quality appraisal of guidelines. Acta Psychiatr Scand. 2018;138:196–222.

  52. 52.

    Goldberg JF, Perlis RH, Ghaemi SN, Calabrese JR, Bowden CL, Wisniewski S, et al. Adjunctive antidepressant use and symptomatic recovery among bipolar depressed patients with concomitant manic symptoms: findings from the STEP-BD. Am J Psychiatry. 2007;164(9):1348–55.

  53. 53.

    González-Pinto A, López-Peña P, Bermúdez-Ampudia C, Vieta E, Martinez-Cengotitabengoa M. Can lithium salts prevent depressive episodes in the real world? Eur Neuropsychopharmacol. 2018;28(12):1351–9.

  54. 54.

    Butler AC, Chapman JE, Forman EM, Beck AT. The empirical status of cognitive-behavioral therapy: a review of meta-analyses. Clin Psychol Rev. 2006;26(1):17–31.

  55. 55.

    Fava GA, Ruini C, Rafanelli C, Finos L, Conti S, Grandi S. Six-year outcome of cognitive behavior therapy for prevention of recurrent depression. Am J Psychiatry. 2004;161(10):1872–6.

  56. 56.

    Miklowitz DJ. Adjunctive psychotherapy for bipolar disorder: state of the evidence. Am J Psychiatry. 2008;165(11):1408–19.

  57. 57.

    Geddes JR, Miklowitz DJ. Treatment of bipolar disorder. Lancet. 2013;381(9878):1672–82.

  58. 58.

    MacDonald L, Chapman S, Syrett M, Bowskill R, Horne R. Improving medication adherence in bipolar disorder: a systematic review and meta-analysis of 30 years of intervention trials. J Affect Disord. 2016;194:202–21. https://doi.org/10.1016/j.jad.2016.01.002.

  59. 59.

    Crowe M, Porter R, Inder M, Lacey C, Carlyle D, Wilson L. Effectiveness of interventions to improve medication adherence in bipolar disorder. Aust N Z J Psychiatry. 2012;46(4):317–26. https://doi.org/10.1177/0004867411428101.

  60. 60.

    Colom F, Vieta E, Martinez-Aran A, Reinares M, Goikolea JM, Benabarre A, et al. A randomized trial on the efficacy of group psychoeducation in the prophylaxis of recurrences in bipolar patients whose disease is in remission. Arch Gen Psychiatry. 2003;60(4):402–7.

  61. 61.

    Yatham LN, Kennedy SH, Parikh SV, Schaffer A, Bond DJ, Frey BN, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord. 2018;20(2):97–170. https://doi.org/10.1111/bdi.12609.

  62. 62.

    Valentí M, Benabarre A, García-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.

  63. 63.

    Malhi GS, Hamilton A, Morris G, Mannie Z, Das P, Outhred T. The promise of digital mood tracking technologies: are we heading on the right track? Evid Based Ment Health. 2017;20(4):102–7.

  64. 64.

    Malhi GS, Byrow Y, Outhred T, Fritz K. Exclusion of overlapping symptoms in DSM-5 mixed features specifier: heuristic diagnostic and treatment implications. CNS Spectr. 2017;22(2):126–33.

  65. 65.

    Malhi GS, Byrow Y, Fritz K. Mixed mood states: time to adopt a 3D perspective?. London: Sage Publications; 2016.

  66. 66.

    Krüger S, Trevor Young L, Bräunig P. Pharmacotherapy of bipolar mixed states. Bipolar Disord. 2005;7(3):205–15.

  67. 67.

    Goldberg JF, Kurita K, Hoblyn J, Ghaemi S, Perlis R, Miklowitz D, et al. Depressive illness burden associated with complex polypharmacy in patients with bipolar disorder: findings from the STEP-BD. J Clin Psychiatry. 2009;70(2):155–62.

  68. 68.

    Goldberg J, Ketter T, Miklowitz D, Calabrese J, Bowden C, Thase M. Safety and tolerability associated with second-generation antipsychotic polytherapy in bipolar disorder: findings from the Systematic Treatment Enhancement Program for Bipolar Disorder. J Clin Psychiatry. 2011;72(2):240–7.

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Correspondence to Gin S. Malhi.

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GSM has received grant or research support from National Health and Medical Research Council, Australian Rotary Health, NSW Health, American Foundation for Suicide Prevention, Ramsay Research and Teaching Fund, Elsevier, AstraZeneca and Servier; has been a speaker for AstraZeneca, Janssen-Cilag, Lundbeck, Otsuka and Servier; and has been a consultant for AstraZeneca, Janssen Cilag, Lundbeck, Otsuka and Servier. KF, PE, and LI have no conflicts of interest that are directly relevant to the content of this article.


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Malhi, G.S., Fritz, K., Elangovan, P. et al. Mixed States: Modelling and Management. CNS Drugs 33, 301–313 (2019). https://doi.org/10.1007/s40263-019-00609-3

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