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Exclusion of overlapping symptoms in DSM-5 mixed features specifier: heuristic diagnostic and treatment implications

  • Gin S Malhi (a1) (a2) (a3), Yulisha Byrow (a1) (a2) (a3), Tim Outhred (a1) (a2) (a3) and Kristina Fritz (a1) (a2) (a3)


This article focuses on the controversial decision to exclude the overlapping symptoms of distractibility, irritability, and psychomotor agitation (DIP) with the introduction of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) mixed features specifier. In order to understand the placement of mixed states within the current classification system, we first review the evolution of mixed states. Then, using Kraepelin’s original classification of mixed states, we compare and contrast his conceptualization with modern day definitions. The DSM-5 workgroup excluded DIP symptoms, arguing that they lack the ability to differentiate between manic and depressive states; however, accumulating evidence suggests that DIP symptoms may be core features of mixed states. We suggest a return to a Kraepelinian approach to classification—with mood, ideation, and activity as key axes—and reintegration of DIP symptoms as features that are expressed across presentations. An inclusive definition of mixed states is urgently needed to resolve confusion in clinical practice and to redirect future research efforts.


Corresponding author

*Address for correspondence, Professor Gin S. Malhi, Academic Department of Psychiatry, Kolling Institute, Northern Sydney Local Health District, St Leonards, NSW 2065 Australia. (Email:


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1. Kraepelin, E. Clinical psychiatry: a text-book for students and physicians, New York: Macmillan; 1904.
2. Diefendorf, RA. IX. Manic-depressive insanity. In: Clinical Psychiatry: A Textbook for Students and Physicians, Abstracted and Adapted from the 7th German Edition of Kraepelin’s Lehrbuch Der Psychiatrie. 7th ed. New York: Macmillan & Co.; 1907: 381422.
3. Maina, G, Bertetto, N, Boccolini, FD, Di Salvo, G, Rosso, G, Bogetto, F. The concept of mixed state in bipolar disorder: from Kraepelin to DSM-5. Journal of Psychopathology. 2013; 19: 287295.
4. Trede, K, Salvatore, P, Baethge, C, Gerhard, A, Maggini, C, Baldessarini, RJ. Manic-depressive illness: evolution in Kraepelin’s Textbook, 1883–1926. Harv Rev Psychiatry. 2005; 13(3): 155178.
5. Marneros, A. Origin and development of concepts of bipolar mixed states. J Affect Disord. 2001; 67(1–3): 229240.
6. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 3rd ed. Washington, DC: American Psychiatric Association; 1980.
7. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 3rd ed rev. Washington, DC: American Psychiatric Association; 1987.
8. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.
9. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed rev. Washington, DC: American Psychiatric Association; 2000.
10. Faedda, GL, Marangoni, C, Reginaldi, D. Depressive mixed states: a reappraisal of Koukopoulos’criteria. J Affect Disord. 2015; 176: 1823.
11. Akiskal, HS, Hantouche, EG, Bourgeois, ML, 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): 175186.
12. Perugi, G, Akiskal, HS, Micheli, C, et al. Clinical subtypes of bipolar mixed states. J Affect Disord. 1997; 43(3): 169180.
13. Benazzi, F. Age at onset of bipolar II depressive mixed state. Psychiatry Res. 2001; 103(2–3): 229235.
14. Koukopoulos, A, Koukopoulos, A. Agitated depression as a mixed state and the problem of melancholia. Psychiatr Clin North Am. 1999; 22(3): 547564.
15. 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.
16. Koukopoulos, A, Sani, G. DSM-5 criteria for depression with mixed features: a farewell to mixed depression. Acta Psychiatr Scand. 2014; 129(1): 416.
17. Koukopoulos, A, Sani, G, Koukopoulos, A, Manfredi, G, Pacchiarotti, I, Girardi, P. Melancholia agitata and mixed depression. Acta Psychiatr Scand Suppl. 2007;(433): 5057.
18. McIntyre, RS, Soczynska, JK, Cha, DS, 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: 259264.
19. Harrison, PJ, Cipriani, A, Harmer, CJ, et al. Innovative approaches to bipolar disorder and its treatment. Ann N Y Acad Sci. 2016; 1366(1): 7689.
20. 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): 131143.
21. Perugi, G, Angst, J, Azorin, J-M, et al. Mixed features in patients with a major depressive episode: the BRIDGE-II-MIX study. J Clin Psychiatry. 2015; 76(3): e351e358.
22. Judd, LL, Schettler, PJ, Akiskal, H, et al. Prevalence and clinical significance of subsyndromal manic symptoms, including irritability and psychomotor agitation, during bipolar major depressive episodes. J Affect Disord. 2012; 138(3): 440448.
23. Pae, CU, Vohringer, PA, Holtzman, NS, et al. Mixed depression: a study of its phenomenology and relation to treatment response. J Affect Disord. 2012; 136(3): 10591061.
24. Targum, SD, Suppes, T, Pendergrass, JC, et al. Major depressive disorder with subthreshold hypomania (mixed features): clinical characteristics of patients entered in a multiregional, placebo-controlled study. Prog Neuropsychopharmacol Biol Psychiatry. 2016; 68: 914.
25. Miller, S, Suppes, T, Mintz, J, et al. Mixed depression in bipolar disorder: prevalence rate and clinical correlates during naturalistic follow-up in the Stanley Bipolar Network. Am J Psychiatry. In press. doi:10.1176/appi.ajp.2016.15091119.
26. Malhi, GS, Fritz, K, Allwang, C, et al. Agitation for recognition by DSM-5 mixed features specifier signals fatigue? Aust N Z J Psychiatry. 2015; 49(6): 499501.
27. Cassidy, F, Ahearn, E, Carroll, BJ. Concordance of self-rated and observer-rated dysphoric symptoms in mania. J Affect Disord. 2009; 114(1–3): 294298.
28. Cassidy, F. Anxiety as a symptom of mixed mania: implications for DSM-5. Bipolar Disord. 2010; 12(4): 437439.
29. Swann, AC, Steinberg, JL, Lijffijt, M, Moeller, GF. Continuum of depressive and manic mixed states in patients with bipolar disorder: quantitative measurement and clinical features. World Psychiatry. 2009; 8(3): 166172.
30. Sato, T, Bottlender, R, Kleindienst, N, Möller, HJ. Syndromes and phenomenological subtypes underlying acute mania: a factor analytic study of 576 manic patients. Am J Psychiatry. 2002; 159(6): 968974.
31. Malhi, GS, Fritz, K, Allwang, C, et al. Are manic symptoms that “dip” into depression the essence of mixed features? J Affect Disord. 2016; 192: 104108.
32. Malhi, GS, Masson, M, Bellivier, F. Teasing apart bipolar III: the causes and consequences of a treatment-emergent affective switch (TEAS) into mania. Aust N Z J Psychiatry. 2015; 49(10): 866868.
33. Perugi, G, Medda, P, Reis, J, Rizzato, S, Giorgi Mariani, M, Mauri, M. Clinical subtypes of severe bipolar mixed states. J Affect Disord. 2013; 151(3): 10761082.
34. 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.
35. Fornaro, M, Stubbs, B, De Berardis, D, et al. Atypical antipsychotics in the treatment of acute bipolar depression with mixed features: a systematic review and exploratory meta-analysis of placebo-controlled clinical trials. Int J Mol Sci. 2016; 17(2): 241.
36. McIntyre, RS, Cucchiaro, J, Pikalov, A, Kroger, H, Loebel, A. Lurasidone in the treatment of bipolar depression with mixed (subsyndromal hypomanic) features. J Clin Psychiatry. 2015; 76(4): 398405.
37. Medda, P, Toni, C, Mariana, MG, De Simone, L, Mauri, M, Perugi, G. Electroconvulsive therapy in 197 patients with a severe, drug-resistant bipolar mixed state: treatment outcome and predictors of response. J Clin Psychiatry. 2015; 76(9): 11681173.
38. Tohen, M, McIntyre, RS, Kanba, S, Fujikoshi, S, Katagiri, H. Efficacy of olanzapine in the treatment of bipolar mania with mixed features defined by DSM-5. J Affect Disord. 2014; 168: 136141.
39. National Institute for Health and Care Excellence. Bipolar disorder: assessment and management. Clinical Guideline [CG185]. London: National Institute for Health and Care Excellence; 2014.
40. Ostacher, MJ, Tandon, R, Suppes, T. Florida Best Practice Psychotherapeutic Medication Guidelines for Adults with Bipolar Disorder: a novel, practical, patient-centered guide for clinicians. J Clin Psychiatry. 2016; 77(7): 920926.
41. Malhi, GS, Bassett, D, Boyce, P, et al. Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders. Aust N Z J Psychiatry. 2015; 49(12): 10871206.
42. 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): 14241431.
43. Fountoulakis, KN, Kontis, D, Gonda, X, Siamouli, M, Yatham, LN. Treatment of mixed bipolar states. Int J Neuropsychopharmacol. 2012; 15(7): 10151026.
44. Muralidharan, K, Ali, M, Silveira, LE, 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): 408414.
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