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Mixed features in major depressive disorder: diagnoses and treatments

  • Trisha Suppes (a1) (a2) and Michael Ostacher (a1) (a2)


For the first time in 20 years, the American Psychiatric Association (APA) updated the psychiatric diagnostic system for mood disorders in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Perhaps one of the most notable changes in the DSM-5 was the recognition of the possibility of mixed symptoms in major depression and related disorders (MDD). While MDD and bipolar and related disorders are now represented by 2 distinct chapters, the addition of a mixed features specifier to MDD represents a structural bridge between bipolar and major depression disorders, and formally recognizes the possibility of a mix of hypomania and depressive symptoms in someone who has never experienced discrete episodes of hypomania or mania. This article reviews historical perspectives on “mixed states” and the recent literature, which proposes a range of approaches to understanding “mixity.” We discuss which symptoms were considered for inclusion in the mixed features specifier and which symptoms were excluded. The assumption that mixed symptoms in MDD necessarily predict a future bipolar course in patients with MDD is reviewed. Treatment for patients in a MDD episode with mixed features is critically considered, as are suggestions for future study. Finally, the premise that mood disorders are necessarily a spectrum or a gradient of severity progressing in a linear manner is argued.


Corresponding author

*Address for correspondence: Trisha Suppes, MD, PhD, VA Palo Alto Health Care System, 3801 Miranda Ave. 151T, Palo Alto, CA 94304, USA. (Email:


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1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th ed. Arlington, VA: American Psychiatric Publishing; 2013.
2. Marneros, A. Origin and development of concepts of bipolar mixed states. J Affect Disord. 2001; 67(1–3): 229240.
3. Angst, J, Marneros, A. Bipolarity from ancient to modern times: conception, birth and rebirth. J Affect Disord. 2001; 67(1–3): 319.
4. 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): 10621066.
5. Akiskal, HS, Rosenthal, RH, Rosenthal, TL, Kashgarian, M, Khani, MK, Puzantian, VR. Differentiation of primary affective illness from situational, symptomatic, and secondary depressions. Arch Gen Psychiatry. 1979; 36(6): 635643.
6. McElroy, SL, Keck, PE, Pope, HG, Hudson, JI, Faedda, GL, Swann, AC. Clinical and research implication of the diagnosis of dysphoric or mixed mania or hypomania. Am J Psychiatry. 1992; 149(12): 16331644.
7. Faedda, GL, Marangoni, C, Rginaldi, D. Depressive mixed states: a reappraisal of Koukopoulos’ criteria. J Affect Disord. 2015; 176: 1823.
8. 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.
9. Perugi, G, Angst, J, Azorin, J, et al. Mixed features in patients with a major depressive episode: the BRIDGE-II-MIX study. J Clin Psychiatry. 2015; 76(3): e351e358.
10. Angst, J, Cui, L, Swendsen, J, et al. Major depressive disorder with subthreshold bipolarity in the National Comorbidity Survey Replication. Am J Psychiatry. 2010; 167(10): 11941201.
11. Kukopulos, A, Caliari, B, Tundo, A, et al. Rapid cyclers, temperament, and antidepressants. Compr Psychiatry. 1983; 24(3): 249258.
12. Benazzi, F, Akiskal, HS. Psychometric delineation of the most discriminant symptoms of depressive mixed states. Psychiatry Res. 2006; 141(1): 8188.
13. Akiskal, HS, Benazzi, F, Perugi, G, Rihmer, . Agitated “unipolar” depression re-conceptualized as a depressive mixed state: implications for the antidepressant-suicide controversy. J Affect Disord. 2005; 85(3): 245258.
14. Suppes, T, Mintz, J, McElroy, SL, et al. Mixed hypomania in 908 patients with bipolar disorder evaluated prospectively in the Stanley Bipolar Treatment Network: a sex-specific phenomenon. Arch Gen Psychiatry. 2005; 62(10): 10891096.
15. Goldberg, JF, Perlis, RH, Bowden, CL, et al. Manic symptoms during depressive episodes in 1380 patients with bipolar disorder: findings from the STEP-BD. Am J Psychiatry. 2009; 166(2): 173181.
16. 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. 2016; 173(10): 10151023.
17. Angst, J, Azorin, J, Bowden, C, et al. Prevalence and characteristics of undiagnosed bipolar disorders in patients with major depressive episode. Arch Gen Psychiatry. 2011; 68(8): 791799.
18. Fiedorowicz, J, Endicott, J, Leon, A, Solomon, D, Keller, M, Coryell, W. Subthreshold hypomanic symptoms in progression form unipolar major depression to bipolar disorder. Am J Psychiatry. 2011; 168(1): 4048.
19. Zimmermann, P, Brückl, 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.
20. Liu, X, Jiang, K. Should major depressive disorder with mixed features be classified as bipolar disorder? Shanghai Arch of Psychiatry. 2014; 26(5): 294296.
21. Perlis, R, Uher, R, Ostacher, M, et al. Association between bipolar spectrum features and treatment outcomes in outpatients with major depressive disorder. Arch Gen Psychiatry. 2011; 68(4): 351360.
22. Serra, G, Koukopoulos, A, De Chiara, L, et al. Features preceding diagnosis of bipolar versus major depressive disorders. J Affect Disord. 2015; 173: 134142.
23. Perlis, R, Cusin, C, Fava, M. Proposed DSM-5 mixed features are associated with greater likelihood of remission in out-patients with major depressive disorder. Psychol Med. 2014; 44(7): 13611367.
24. McIntyre, R, Soczynska, J, Cha, D, 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.
25. Smith, D, Forty, L, Russell, E, et al. Sub-threshold manic symptoms in recurrent major depressive disorder are a marker for poor outcome. Acta Psychiatr Scand. 2009; 119(4): 325329.
26. Balázs, J, Benazzi, F, Rihmer, Z, Rihmer, A, Akiskal, KK, Akiskal, HS. The close link between suicide attempts and mixed (bipolar) depression: implications for suicide prevention. J Affect Disord. 2006; 91(2–3): 133138.
27. Swann, A, Lafer, B, Perugi, G, et al. Bipolar mixes 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.
28. Koukopoulos, A, Sani, G. DSM-5 criteria for depression with mixed features: a farewell to mixed depression. Acta Psychiatr Scand. 2014; 129(1): 416.
29. Suppes, T, Silva, R, Cucchiaro, J, et al. Lurasidone for the treatment of major depressive disorder with mixed features: a randomized, double-blind, placebo-controlled study. Am J Psychiatry. 2016; 173(4): 400407.
30. Benazzi, F, Koukopoulous, , Akiskal, H. Toward a validation of a new definition of agitated depression as a mixed state (mixed depression). Eur Psychiatry. 2004; 19(2): 8590.
31. Benazzi, F. Reviewing the diagnostic validity and utility of mixed depression (depressive mixed states). European Psychiatry. 2008; 23(1): 4048.
32. Benazzi, F, Akiskal, H. 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.
33. Clementz, B, Sweeney, J, Hamm, J, et al. Identification of distinct psychosis biotypes using brain-based biomarkers. Am J Psychiatry. 2015; 173(4): 373384.
34. Williams, L. Precision psychiatry: a neural circuit taxonomy for depression and anxiety. Lancet Psychiatry. 2016; 3(5): 472480.
35. Altshuler, L, Sugar, C, McElroy, S, et al. Switch rates during lithium monotherapy, sertraline monotherapy and lithium/sertraline combination therapy for the acute treatment of bipolar II depression: a randomized double-blind comparison. Am J Psychiatry. 2017; 174(3): 266276.
36. Amsterdam, J, Shults, J. Efficacy and safety of long-term fluoxetine versus lithium monotherapy of bipolar II disorder: a randomized, double-blind, placebo-substitution study. Am J Psychiatry. 2010; 167(7): 792800.
37. Suppes, T. Is there a role for antidepressants in the treatment of bipolar II depression? Am J Psychiatry. 2010; 167(7): 738740.


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Mixed features in major depressive disorder: diagnoses and treatments

  • Trisha Suppes (a1) (a2) and Michael Ostacher (a1) (a2)


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