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What is the role of conventional antidepressants in the treatment of major depressive episodes with Mixed Features Specifier?

  • Gianni L. Faedda (a1) and Ciro Marangoni (a2)


The newly introduced Mixed Features Specifier of Major Depressive Episode and Disorder (MDE/MDD) is especially challenging in terms of pharmacological management. Prior to the publication of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, the symptoms of the mixed features specifier were intradepressive hypomanic symptoms, always and only associated with bipolar disorder (BD).

Intradepressive hypomanic symptoms, mostly referred to as depressive mixed states (DMX), have been poorly characterized, and their treatment offers significant challenges. To understand the diagnostic context of DMX, we trace the nosological changes and collocation of intradepressive hypomanic symptoms, and examine diagnostic and prognostic implications of such mixed features.

One of the reasons so little is known about the treatment of DMX is that depressed patients with rapid cycling, substance abuse disorder, and suicidal ideation/attempts are routinely excluded from clinical trials of antidepressants. The exclusion of DMX patients from clinical trials has prevented an assessment of the safety and tolerability of short- and long-term use of antidepressants. Therefore, the generalization of data obtained in clinical trials for unipolar depression to patients with intradepressive hypomanic features is inappropriate and methodologically flawed.

A selective review of the literature shows that antidepressants alone have limited efficacy in DMX, but they have the potential to induce, maintain, or worsen mixed features during depressive episodes in BD. On the other hand, preliminary evidence supports the effective use of some atypical antipsychotics in the treatment of DMX.


Corresponding author

*Address for correspondence: Gianni L. Faedda, Lucio Bini Mood Disorders Center, 245 E. 50th St., New York, NY 10022, USA. (Email:


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1. Koukopoulos, A, Sani, G, Koukopoulos, AE, Manfredi, G, Pacchiarotti, I, Girardi, P. Melancholia agitata and mixed depression. Acta Psychiatr Scand Suppl. 2007; 433: 5057.
2. Spitzer, RL, Endicott, J, Robins, E. Research diagnostic criteria: rationale and reliability. Arch Gen Psychiatry. 1978; 35(6): 773782.
3. 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.
4. Koukopoulos, A, Faedda, G, Proietti, R, D’Amico, S, de Pisa, E, Simonetto, C. Mixed depressive syndrome. Encephale. 1992; 18(1): 1921.
5. Sani, G, Vöhringer, P, Napoletano, F, et al. Koukopoulos’ diagnostic criteria for mixed depression: a validation study. J Affect Disord. 2014; 164: 1418.
6. 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.
7. Smith, DJ, 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.
8. 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.
9. 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.
10. Nusslock, R, Frank, E. Subthreshold bipolarity: diagnostic issues and challenges. Bipolar Disord. 2011; 13(7–8): 587603.
11. 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.
12. 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.
13. Koukopoulos, A, Sani, G. DSM-5 criteria for depression with mixed features: a farewell to mixed depression. Acta Psychiatr Scand. 2014; 129(1): 416.
14. Faedda, GL, Marangoni, C, Serra, G, et al. Precursors of bipolar disorders: a systematic literature review of prospective studies. J Clin Psychiatry. 2015; 76(5): 614624.
15. Perlis, RH, Ostacher, MJ, Goldberg, JF, et al. Transition to mania during treatment of bipolar depression. Neuropsychopharmacology. 2010; 35(13): 25452552.
16. Frye, MA, Helleman, G, McElroy, SL, et al. Correlates of treatment-emergent mania associated with antidepressant treatment in bipolar depression. Am J Psychiatry. 2009; 166(2): 164172.
17. 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.
18. 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.
19. Fornaro, M, Martino, M, De Pasquale, C, Moussaoui, D. The argument of antidepressant drugs in the treatment of bipolar depression: mixed evidence or mixed states? Expert Opin Pharmacother. 2012; 13(14): 20372051.
20. Sani, G, Napoletano, F, Vöhringer, PA, et al. Mixed depression: clinical features and predictors of its onset associated with antidepressant use. Psychother Psychosom. 2014; 83(4): 213221.
21. Perlis, RH, 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.
22. Pacchiarotti, I, Bond, DJ, Baldessarini, RJ, et al. The International Society for Bipolar Disorders (ISBD) task force report on antidepressant use in bipolar disorders. Am J Psychiatry. 2013; 170(11): 12491262.
23. 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.
24. Sachs, GS, Nierenberg, AA, Calabrese, JR, et al. Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med. 2007; 356(17): 17111722.
25. 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.
26. Michaux, L, Saulnier, M, Bureau, G. A propos des Etats Mixtes. Sem Hop Paris. 1950; 83: 42754286.
27. Campbell, JD. Mixed and manic phases of manic-depressive psychosis. In. Manic Depressive Disease. Philadelphia: Lippincott; 1953.
28. Glassman, AH. Depression, delusions, and drug response. Am J Psychiatry. 1975; 132(7): 716719.
29. Wehr, TA, Goodwin, FK. Rapid cycling in manic-depressives induced by tricyclic antidepressants. Arch Gen Psychiatry. 1979; 36: 555559.
30. Kukopulos, A, Reginaldi, D, Laddomada, P, Floris, G, Serra, G, Tondo, L. Course of the manic-depressive cycle and changes caused by treatment. Pharmakopsychiatr Neuropsychopharmakol. 1980; 13(4): 156167.
31. Tondo, L, Laddomada, P, Serra, G, Minnai, G, Kukopulos, A. Rapid cyclers and antidepressants. Int Pharmacopsychiatry. 1981; 16(2): 119123.
32. Akiskal, HS, Mallya, G. Criteria for the “soft” bipolar spectrum: treatment implications. Psychopharmacol Bull. 1987; 23(1): 6873.
33. Faedda, GL, Marangoni, C, Reginaldi, D. Depressive mixed states: a reappraisal of Koukopoulos’ criteria. J Affect Disord. 2015; 176: 1823.
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CNS Spectrums
  • ISSN: 1092-8529
  • EISSN: 2165-6509
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