Stefano Pini Accursio Raia Giulia Amatori Benedetta Nardi Barbara Carpita Antonio Tundo Liliana Dell'Osso


Mixed depressive states are defined by the co-presence of depressive and manic symptoms. They represent extremely variable conditions from the point of view of clinical expressiveness and are difficult to recognize, ranging from clear schizophrenic-like psychoses and pseudodemented pictures to subsyndromal psychopathology. At the basis of the extreme variability of depressive pictures with mixed features are the different combinations that depressive and manic symptoms can assume. Furthermore, the intensity of depressive symptoms and manic symptoms, combined, can be variable, a factor that contributes to making the picture even more variable. Each form of mixed depressive state therefore presents its own specific symptomatic characteristics and specific difficulties in differential diagnosis and each form requires a different therapeutic strategy. In this work we have distinguished four possible specific subtypes of mixed depressive states, describing their specific clinical presentation and the therapeutic options most supported by the literature with the aim of contributing to a better recognition of mixed depressive states, to avoid incorrect diagnoses at patient and treatments that are useless if not worsening.



mood disorder, depression, bipolar disorder, bipolar mixed states, depressive mixed states, mixed states

1. American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). [ available at 4/21/2024]
2. American Psychiatric Association. (2022). Diagnostic and statistical manual of mental disorders (5th ed., text rev.). [ available at 4/21/2024]
3. Himmelhoch JM, Coble P, Kupfer KJ, Ingenito J. Agitated psychotic depression associated with severe hypomanic episodes: a rare syndrome. Am J Psychiatry. 1976 Jul;133(7):765-71. doi: 10.1176/ajp.133.7.765. PMID: 937566.
4. Keller MB, Lavori PW, Coryell W, et al. Differential outcome of pure manic, mixed/cycling, and pure depressive episodes in patients with bipolar illness. JAMA. 1986 Jun 13;255(22):3138-42. PMID: 3702024.
5. Cohen S, Khan A, Robison J. Significance of mixed features in acute mania. Compr Psychiatry. 1988 Jul-Aug;29(4):421-6. doi: 10.1016/0010-440x(88)90023-5. PMID: 2900713.
6. Tondo L, Vazquez GH, Baldessarini RJ. Suicidal Behavior Associated with Mixed Features in Major Mood Disorders. Psychiatr Clin North Am. 2020 Mar;43(1):83-93. doi: 10.1016/j.psc.2019.10.008. PMID: 32008690.
7. Rothschild AJ. Challenges in the treatment of depression with psychotic features. Biol Psychiatry. 2003 Apr 15;53(8):680-90. doi: 10.1016/s0006-3223(02)01747-x. PMID: 12706954.
8. Ohayon MM, Schatzberg AF. Prevalence of depressive episodes with psychotic features in the general population. Am J Psychiatry. 2002 Nov;159(11):1855-61. doi: 10.1176/appi.ajp.159.11.1855. PMID: 12411219.
9. Solé E, Garriga M, Valentí M, Vieta E. Mixed features in bipolar disorder. CNS Spectr. 2017 Apr;22(2):134-140. doi: 10.1017/S1092852916000869. PMID: 28031070.
10. Pacchiarotti I, Kotzalidis GD, Murru A, et al. Mixed Features in Depression: The Unmet Needs of Diagnostic and Statistical Manual of Mental Disorders Fifth Edition. Psychiatr Clin North Am. 2020;43(1):59-68. doi: 10.1016/j.psc.2019.10.006. PMID: 32008688. doi:10.1016/j.psc.2019.10.006
11. Himmelhoch JM. Major mood disorders related to epileptic changes. In: Bluner D, ed. Psychiatric Aspects of Epilepsy. Washington, DC: American Psychiatric Press; 1984:271-294.
12. Akiskal HS, Mallya G. Criteria for the "soft" bipolar spectrum: treatment implications. Psychopharmacol Bull. 1987;23(1):68-73. PMID: 3602332.
13. Parial S. Bipolar disorder in women. Indian J Psychiatry. 2015 Jul;57(Suppl 2):S252-63. doi: 10.4103/0019-5545.161488. PMID: 26330643; PMCID: PMC4539870.
14. Vázquez GH, Tondo L, Mazzarini L, Gonda X. Affective temperaments in general population: a review and combined analysis from national studies. J Affect Disord. 2012 Jun;139(1):18-22. doi: 10.1016/j.jad.2011.06.032, PMID: 21774989.
15. Dell'Osso L, Placidi GF, Nassi R, et al. The manic-depressive mixed state: familial, temperamental and psychopathologic characteristics in 108 female inpatients. Eur Arch Psychiatry Clin Neurosci. 1991;240(4-5):234-9. doi: 10.1007/BF02189532. PMID: 1828997.
16. Himmelhoch JM, Garfinkel ME. Sources of lithium resistance in mixed mania. Psychopharmacol Bull. 1986;22(3):613-20. PMID: 3797567.
17. Di Nicola M, Pepe M, Modica M, et al. Mixed States in Patients with Substance and Behavioral Addictions. Psychiatr Clin North Am. 2020 Mar;43(1):127-137. doi: 10.1016/j.psc.2019.10.012. PMID: 32008679.
18. Kanner AM. Mood disorder and epilepsy: a neurobiologic perspective of their relationship. Dialogues Clin Neurosci. 2008;10(1):39-45. doi: 10.31887/DCNS.2008.10.1/amkanner. PMID: 18472483; PMCID: PMC3181864.
19. Kraepelin E. Manic-Depressive Insanity and Paranoia. Edinburgh, Scotland: E&S Livingston; 1921.
20. Suppes T, McElroy SL, Gilbert J, Dessain EC, Cole JO. Clozapine in the treatment of dysphoric mania. Biol Psychiatry. 1992 Aug 1;32(3):270-80. doi: 10.1016/0006-3223(92)90108-c. PMID: 1420643.
21. Delgado A, Velosa J, Zhang J, et al. Clozapine in bipolar disorder: A systematic review and meta-analysis. J Psychiatr Res. 2020 Jun;125:21-27. doi: 10.1016/j.jpsychires.2020.02.026. PMID: 32182485.
22. Falret JP. Des Maladies mentales et des asiles daliénés. Paris: J.B. Baillière et fils, 1864
23. Dell'Osso L, Pini S, Tundo A, et al. Clinical characteristics of mania, mixed mania, and bipolar depression with psychotic features. Compr Psychiatry. 2000 Jul-Aug;41(4):242-7. doi: 10.1053/comp.2000.7432. PMID: 10929790.
24. Winokur G, Clayton P, Reich T, eds. Manic-Depressive Illness. St. Louis, Mo: Mosby Company; 1969.
25. Palma M, Ferreira B, Borja-Santos N, et al. Efficacy of Electroconvulsive Therapy in Bipolar Disorder with Mixed Features. Depress Res Treat. 2016;2016:8306071. doi: 10.1155/2016/8306071. PMID: 26881069; PMCID: PMC4736372.
26. Kramlinger KG, Post RM. The addition of lithium to carbamazepine. Antidepressant efficacy in treatment-resistant depression. Arch Gen Psychiatry. 1989 Sep;46(9):794-800. doi: 10.1001/archpsyc.1989.01810090036007. PMID: 2505730.
27. Rakofsky JJ, Lucido MJ, Dunlop BW. Lithium in the treatment of acute bipolar depression: A systematic review and meta-analysis. J Affect Disord. 2022 Jul 1;308:268-280. doi: 10.1016/j.jad.2022.04.058. PMID: 35429528.
How to Cite
Pini, S., Raia, A., Amatori, G., Nardi, B., Carpita, B., Tundo, A., & Dell'Osso, L. (2024). A reevaluation of mixed depressive states from the DSM-5- TR perspective: a series of prototypical cases. Archive of Clinical Cases, 11(1), 22-28.
Case Reports

How to Cite

Pini, S., Raia, A., Amatori, G., Nardi, B., Carpita, B., Tundo, A., & Dell'Osso, L. (2024). A reevaluation of mixed depressive states from the DSM-5- TR perspective: a series of prototypical cases. Archive of Clinical Cases, 11(1), 22-28.