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Mixed features: evolution of the concept, past and current definitions, and future prospects

  • Alan C. Swann (a1)

Abstract

Mixed states address the relationships between episodes and the course of an illness, presenting significant clinical challenges. Recurrent affective disorders were described thousands of years ago as dimensional disturbances of the basic elements of behavior, combining the characteristics of what we would now consider manic and depressive episodes. It was recognized from the beginning that combinations of depressive and manic features are associated with a severe illness course, including increased suicide risk. Early descriptions of affective disorders formulated them as systemic illnesses, a concept supported by more recent data. Descriptions of affective disorders and their course, including mixed states, became more systematic during the 19th century. Structured criteria achieved importance with evidence that, in addition to early onset, frequent recurrence, and comorbid problems, mixed states had worse treatment outcomes than other episodes. In contrast to 2000 years of literature on recurrent affective episodes and mixed states, the unipolar–bipolar disorder distinction was formalized in the mid-20th century. Mixed-state criteria, initially developed for bipolar disorder, ranged from fully combined depression and mania to the DSM–5 criteria, no longer limited to bipolar disorder, of a primary depressive or manic episode with at least three symptoms of the other episode type. The challenges involved in understanding and identifying mixed states center largely on what drives them, including (1) their formulation as either categorical or dimensional constructs, (2) the specificity of their relationships to depressive or manic episodes, and (3) specificity for bipolar versus major depressive disorder. Their existence challenges the distinction between bipolar and major depressive disorders. The challenges involved in identifying the underlying physiological mechanisms go to the heart of these questions.

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Corresponding author

*Address correspondence to: Alan C. Swann, Baylor College of Medicine, Department of Psychiatry, 1977 Butler Boulevard, Suite E4.400, Houston, Texas 7030, USA. (Email: acswann@bcm.edu)

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Support was provided by the Mental Health Care Line at the Michael E. DeBakey Veterans Affairs Medical Center.

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References

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1. Aretaeus. On the Causes and Symptoms of Chronic Disease. Boston: Milford House; 1972.
2. Gelder, M, Gath, D, Mayou, R, Cowen, P. Oxford Textbook of Psychiatry, 3rd ed. Oxford: Oxford University Press; 1998.
3. Mathews, M. How Did Pre-Twentieth Century Theories of the Aetiology of Depression Develop? Brighton: Priory Lodge Education; 2004.
4. Alexander, FG, Selesnick, ST. The History of Psychiatry: An Evaluation of Psychiatric Thought and Practice from Prehistoric Times to the Present. New York: Harper & Row; 1966.
5. Hippocrates. The Genuine Works of Hippocrates. New York: Dover; 1868.
6. Ackerknecht, EH. A Short History of Psychiatry [in German]. Trans S Wolff New York: Hafner; 1959.
7. Johnstone, EC, Freeman, CPL, Zealey, AK. eds. Companion to Psychiatric Studies, 6th ed. Edinburgh: Churchill Livingstone; 1998.
8. Angst, J, Marneros, A. Bipolarity from ancient to modern times: conception, birth and rebirth. J Affect Disord. 2001; 67(1–3): 319.
9. Kraepelin, E. Manic-Depressive Illness and Paranoia. Edinburgh: Livingstone; 1921.
10. Weygandt, W. Uber die Mischzustande des Manisch-Depressiven Irreseins [in German]. Munich: Verlag von J.F. Lehmann; 1899.
11. Galen. On the Natural Faculties. Cambridge: Harvard University Press; 1916.
12. Berk, M, Kapczinski, F, Andreazza, AC, et al. Pathways underlying neuroprogression in bipolar disorder: focus on inflammation, oxidative stress and neurotrophic factors. Neurosci Biobehav Rev. 2011; 35(3): 804817.
13. Luo, Y, He, H, Zhang, M, Huang, X, Fan, N. Altered serum levels of TNF-α, IL-6 and IL-18 in manic, depressive, mixed state of bipolar disorder patients. Psychiatry Res. 2016; 244: 1923. Epub ahead of print Jul 18.
14. Aretaeus. On the Causes and Symptoms of Acute Disease. Boston: Milford House; 1972.
15. Iasevoli, F, Valchera, A, Di Giovambattista, E, et al. Affective temperaments are associated with specific clusters of symptoms and psychopathology: a cross-sectional study on bipolar disorder inpatients in acute manic, mixed, or depressive relapse. J Affect Disord. 2013; 151(2): 540550. Epub ahead of print Jul 12.
16. Mazzarini, L, Pacchiarotti, I, Colom, F, et al. Predominant polarity and temperament in bipolar and unipolar affective disorders. J Affect Disord. 2009; 119(1–3): 2833. Epub ahead of print Apr 5.
17. Perugi, G, Micheli, C, Akiskal, HS, 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): 1318.
18. Schneider, K. Klinische Psychopathologie [in German], 5th ed. Stuttgart: Thieme; 1959.
19. Secunda, SK, Katz, MM, Swann, A, et al. Mania: diagnosis, state measurement and prediction of treatment response. J Affect Disord. 1985; 8(2): 113121.
20. Himmelhoch, JM, Mulla, D, Neil, JF, Detre, TP, Kupfer, DJ. Incidence and severity of mixed affective states in a bipolar population. Arch Gen Psychiatry. 1976; 33(9): 10621066.
21. Himmelhoch, JM, Garfinkel, ME. Sources of lithium resistance in mixed mania. Psychopharmacol Bull. 1986; 22(3): 613620.
22. Leonhard, K. On monopolar and bipolar endogenous psychoses [in German]. Nervenarzt. 1968; 39(3): 104106.
23. Benazzi, F, Akiskal, HS. How best to identify a bipolar-related subtype among major depressive patients without spontaneous hypomania: superiority of age at onset criterion over recurrence and polarity? J Affect Disord. 2008; 107(1–3): 7788. Epub ahead of print Sep 12, 2007.
24. 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. 1994; 52(2): 114123.
25. Winokur, G, Wesner, R. From unipolar depression to bipolar illness: 29 who changed. Acta Psychiatr Scand. 1987; 76(1): 5963.
26. Benazzi, F. Classifying mood disorders by age-at-onset instead of polarity. Prog Neuropsychopharmacol Biol Psychiatry. 2009; 33(1): 8693.
27. Bowden, CL, Lecrubier, Y, Bauer, M, et al. Maintenance therapies for classic and other forms of bipolar disorder. J Affect Disord. 2000; 59(Suppl 1): S57S67.
28. Akiskal, HS, Benazzi, F. Family history validation of the bipolar nature of depressive mixed states. J Affect Disord. 2003; 73(1–2): 113122.
29. Zimmermann, P, Bruckl, T, Nocon, A, et al. Heterogeneity of DSM–IV major depressive disorder as a consequence of subthreshold bipolarity. Arch Gen Psychiatry. 2009; 66(12): 13411352. http://jamanetwork.com/journals/jamapsychiatry/fullarticle/210481.
30. 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): 115122.
31. Azorin, JM, Aubrun, E, Bertsch, J, Reed, C, Gerard, S, Lukasiewicz, M. Mixed states vs. pure mania in the French sample of the EMBLEM study: results at baseline and 24 months. European mania in bipolar longitudinal evaluation of medication. BMC Psychiatry. 2009; 9: 33. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2701946/pdf/1471-244X-9-33.pdf.
32. Benazzi, F. Challenging the unipolar–bipolar division: does mixed depression bridge the gap? Prog Neuropsychopharmacol Biol Psychiatry. 2007; 31(1): 97103. Epub ahead of print Sep 15.
33. Agosti, V, Stewart, JW. Hypomania with and without dysphoria: comparison of comorbidity and clinical characteristics of respondents from a national community sample. J Affect Disord. 2008; 108(1–2): 177182. Epub ahead of print Oct 25, 2007.
34. 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): 245258.
35. Benazzi, F. The continuum/spectrum concept of mood disorders: is mixed depression the basic link? Eur Arch Psychiatry Clin Neurosci. 2006; 256(8): 512515.
36. Biondi, M, Picardi, A, Pasquini, M, Gaetano, P, Pancheri, P. Dimensional psychopathology of depression: detection of an “activation” dimension in unipolar depressed outpatients. J Affect Disord. 2005; 84(2–3): 133139.
37. Fiedorowicz, JG, Endicott, J, Solomon, DA, Keller, MB, Coryell, WH. Course of illness following prospectively observed mania or hypomania in individuals presenting with unipolar depression. Bipolar Disord. 2012; 14(6): 664671. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3432672/pdf/nihms386648.pdf.
38. Swann, AC, Moeller, FG, Steinberg, JL, Schneider, L, Barratt, ES, Dougherty, DM. Manic symptoms and impulsivity during bipolar depressive episodes. Bipolar Disord. 2007; 9(3): 206212. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2723749/pdf/nihms128564.pdf.
39. Benazzi, F. Mixed states in bipolar II disorder: should full hypomania always be required? Psychiatry Res. 2004; 127(3): 247257.
40. Swann, AC, Bowden, CL, Morris, D, et al. Depression during mania: treatment response to lithium or divalproex. Arch Gen Psychiatry. 1997; 54(1): 3742.
41. Swann, AC, Steinberg, JL, Lijffijt, M, Moeller, FG. Continuum of depressive and manic mixed states in patients with bipolar disorder: quantitative measurement and clinical features. World Psychiatry. 2009; 8(3): 166172. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2758583/pdf/wpa030166.pdf.
42. Pacchiarotti, I, Nivoli, AM, Mazzarini, L, et al. The symptom structure of bipolar acute episodes: in search for the mixing link. J Affect Disord. 2013; 149(1–3): 5666. Epub ahead of print Feb 7.
43. Baldessarini, RJ, Salvatore, P, Khalsa, HM, Tohen, M. Dissimilar morbidity following initial mania versus mixed-states in type-I bipolar disorder. J Affect Disord. 2010; 126(1–2): 299302. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2925064/pdf/nihms202298.pdf.
44. Sato, T, Bottlender, R, Sievers, M, Schröter, A, Kleindienst, N, Möller, HJ. Evaluating the inter-episode stability of depressive mixed states. J Affect Disord. 2004; 81(2): 103113.
45. Swann, AC, Stokes, PE, Casper, R, Chang, S, Katz, MM, Garver, D. Hypothalamic–pituitary–adrenocortical function in mixed and pure mania. Acta Psychiatr Scand. 1992; 85(4): 270274.
46. Swann, AC, Stokes, PE, Secunda, S, et al. Depressive mania versus agitated depression: biogenic amine and hypothalamic–pituitary–adrenocortical function. Biol Psychiatry. 1994; 35(10): 803813.
47. Henry, C, M’Bailara, K, Desage, A, Gard, S, Misdrahi, D, Vieta, E. Towards a reconceptualization of mixed states, based on an emotional-reactivity dimensional model. J Affect Disord. 2007; 101(1–3): 3541.
48. Koukopoulos, A, Sani, G, Ghaemi, SN. Mixed features of depression: why DSM–5 is wrong (and so was DSM–IV). Br J Psychiatry. 2013; 203(1): 35. http://bjp.rcpsych.org/content/203/1/3.long.
49. Janzarik, W. Dynamische Grundkonstellationen in Endogenen Psychosen [Dynamic Basic Constellations in Endogenous Psychoses] [in German]. Berlin–Göttingen–Heidelberg: Springer; 1959.
50. Berner, P, Gabriel, E, Katschnig, H, et al. Diagnostic Criteria for Schizophrenia and Affective Psychoses. Washington, DC: World Psychiatric Association/American Psychiatric Association; 1983.
51. Swann, AC, Secunda, SK, Katz, MM, et al. Lithium treatment of mania: clinical characteristics, specificity of symptom change, and outcome. Psychiatry Res. 1986; 18(2): 127141.
52. 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: 16331644.
53. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC: American Psychiatric Association; 1995.
54. Cassidy, F, Murry, E, Forest, K, Carroll, BJ. The performance of DSM–III–R major depression criteria in the diagnosis of bipolar mixed states. J Affect Disord. 1997; 46(1): 7981.
55. 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(10): 10891096. http://jamanetwork.com/journals/jamapsychiatry/fullarticle/208953.
56. Goodwin, FK, Jamison, KR. Manic-Depressive Illness. New York: Oxford University Press; 1990.
57. American Psychiatric Association. Diagnostic and Statistical Manual, 5th ed. Washington, DC: American Psychiatric Association; 2013.
58. Katz, MM, Wetzler, S, Cloitre, M, et al. Expressive characteristics of anxiety in depressed men and women. J Affect Disord. 1993; 28(4): 267277.
59. Swann, AC, Secunda, SK, Katz, MM, et al. Specificity of mixed affective states: clinical comparison of mixed mania and agitated depression. J Affect Disord. 1993; 28(2): 8189.
60. Koukopoulos, A, Sani, G. DSM–5 criteria for depression with mixed features: a farewell to mixed depression. Acta Psychiatr Scand. 2014; 129(1): 416. Epub ahead of print Apr 19, 2013.
61. Perugi, G, Angst, J, Azorin, JM, et al. Mixed features in patients with a major depressive episode: the BRIDGE–II–MIX study. J Clin Psychiatry. 2015; 76(3): e351e358.
62. Verdolini, N, Agius, M, Ferranti, L, Moretti, P, Piselli, M, Quartesan, R. The state of the art of the DSM–5 “with mixed features” specifier. Scientific World Journal. 2015; 2015: 757258. Epub ahead of print Aug 25. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562096/pdf/TSWJ2015-757258.pdf.
63. Goldberg, D. Plato versus Aristotle: categorical and dimensional models for common mental disorders. Compr Psychiatry. 2000; 41(2 Suppl 1): 813.
64. Quitkin, FM, Rabkin, JG, Prien, RF. Bipolar disorder: are there manic-prone and depressive-prone forms? J Clin Psychopharmacol. 1986; 6(3): 167172.
65. Swann, AC, Lafer, B, Perugi, G, 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): 3142. http://ajp.psychiatryonline.org/doi/pdf/10.1176/appi.ajp.2012.12030301.
66. Perugi, G, Medda, P, Swann, AC, Reis, J, Rizzato, S, Mauri, M. Phenomenological subtypes of severe bipolar mixed states: a factor analytic study. Compr Psychiatry. 2014; 55(4): 799806. Epub ahead of print Jan 29.
67. Ghaemi, SN. Why antidepressants are not antidepressants: STEP–BD, STAR*D, and the return of neurotic depression. Bipolar Disord. 2008; 10(8): 957968.
68. Ghaemi, SN, Rosenquist, KJ, Ko, JY, Baldassano, CF, Kontos, NJ, Baldessarini, RJ. Antidepressant treatment in bipolar versus unipolar depression. Am J Psychiatry. 2004; 161(1): 163165. http://ajp.psychiatryonline.org/doi/pdf/10.1176/appi.ajp.161.1.163.
69. Goldberg, JF, Perlis, RH, Ghaemi, SN, 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): 13481355. http://ajp.psychiatryonline.org/doi/pdf/10.1176/appi.ajp.2007.05122032.
70. Ghaemi, SN, Lenox, MS, Baldessarini, RJ. Effectiveness and safety of long-term antidepressant treatment in bipolar disorder. J Clin Psychiatry. 2001; 62(7): 565569.
71. Ghaemi, SN, Wingo, AP, Filkowski, MA, Baldessarini, RJ. Long-term antidepressant treatment in bipolar disorder: meta-analyses of benefits and risks. Acta Psychiatr Scand. 2008; 118(5): 347356. Epub ahead of print Aug 24. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2718794/pdf/nihms109410.pdf.
72. Sani, G, Napoletano, F, Vohringer, PA, et al. Mixed depression: clinical features and predictors of its onset associated with antidepressant use. Psychother Psychosom. 2014; 83(4): 213221.
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