Background: Mixed depression (MxD) is narrowly defined in the DSM-IV and somewhat broader in the DSM-5, although both exclude psychomotor agitation as a diagnostic criterion. This article proposes a clinical description for defining MxD, which emphasizes psychomotor excitation. Methods: Two hundred and nineteen consecutive outpatients were diagnosed with an MxD episode using criteria proposed by Koukopoulos et al. [Acta Psychiatr Scand 2007;115(suppl 433):50-57]; we here report their clinical features and antidepressant-related effects. Results: The most frequent MxD symptoms were: psychic agitation or inner tension (97%), absence of retardation (82%), dramatic description of suffering or weeping spells (53%), talkativeness (49%), and racing or crowded thoughts (48%). MxD was associated with antidepressants in 50.7% of patients, with similar frequency for tricyclic antidepressants (45%) versus selective serotonin reuptake inhibitors (38.5%). Positive predictors of antidepressant-associated MxD were bipolar disorder type II diagnosis, higher index depression severity, and higher age at index episode. Antipsychotic or no treatment was protective against antidepressant-associated MxD. Conclusions: MxD, defined as depression with excitatory symptoms, can be clinically identified, is common, occurs in both unipolar depression and bipolar disorder, and is frequently associated with antidepressant use. If replicated, this view of MxD could be considered a valid alternative to the DSM-5 criteria for depression with mixed features.

1.
American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, ed 4, text revision. Washington, American Psychiatric Association, 2000.
2.
American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, ed 5 (DSM-5). Arlington, American Psychiatric Association, 2013.
3.
Koukopoulos A, Sani G: DSM-5 criteria for depression with mixed features: a farewell to mixed depression. Acta Psychiatr Scand 2014;129:4-16.
4.
Koukopoulos A, Sani G, Ghaemi SN: Mixed features of depression: why DSM-5 is wrong (and so was DSM-IV). Br J Psychiatry 2013;203:3-5.
5.
Uher R, Payne JL, Pavlova B, Perlis RH: Major depressive disorder in DSM-5: implications for clinical practice and research of changes from DSM-IV. Depress Anxiety 2013, Epub ahead of print. DOI: 10.1002/da.22217.
6.
Koukopoulos A, Sani G, Koukopoulos AE, Manfredi G, Pacchiarotti I, Girardi P: Melancholia agitata and mixed depression. Acta Psychiatr Scand 2007;115(suppl 433):50-57.
7.
Koukopoulos A, Faedda G, Proietti R, D'Amico S, de Pisa E, Simonetto C: Un syndrome depressif mixte. Encephale 1992;1:19-21.
8.
Benazzi F: Depressive mixed state frequency: age/gender effects. Psychiatry Clin Neurosci 2002;56:537-543.
9.
Maj M, Pirozzi R, Magliano L, Bartoli L: Agitated depression in bipolar I disorder: prevalence, phenomenology, and outcome. Am J Psychiatry 2003;160:2134-2140.
10.
Kraepelin E: Manic-Depressive Insanity and Paranoia. Edinburgh, Livingstone, 1921.
11.
Benazzi F: Age at onset of bipolar II depressive mixed state. Psychiatry Res 2001;103:229-235.
12.
Akiskal HS, Benazzi F: Family history validation of the bipolar nature of depressive mixed states. J Affect Disord 2003;73:113-122.
13.
Ducrey S, Gex-Fabry M, Dayer A, Pardos ER, Roth L, Aubry JM, Bertschy G: Retrospective comparison of inpatients with mixed and non-mixed depression. Psychopathology 2003;36:292-298.
14.
Sato TB, Schroter A, Moller HJ: Frequency of manic symptoms during a depressive episode and unipolar ‘depressive mixed state' as bipolar spectrum. Acta Psychiatr Scand 2003;107:268-274.
15.
Benazzi F: The role of gender in depressive mixed state. Psychopathology 2003;36:213-217.
16.
Akiskal HS: The distinctive mixed states of bipolar I, II, and III. Clin Neuropharmacol 1992;15:632-633.
17.
Akiskal HS: The prevalent clinical spectrum of bipolar disorders: beyond DSM-IV. J Clin Psychopharmacol 1996;16:4-14.
18.
Akiskal HS, Hantouche EG, Bourgeois ML, Azorin JM, Sechter D, Allilaire JF, Lancrenon S, Fraud JP, Châtenet-Duchêne L: Gender, temperament, and the clinical picture in dysphoric mixed mania: findings from a French national study (EPIMAN). J Affect Disord 1998;50:175-186.
19.
Hantouche EG, Akiskal HS: Toward a definition of a cyclothymic behavioral endophenotype: which traits tap the familial diathesis for bipolar II disorder? J Affect Disord 2006;96:233-237.
20.
Benazzi F: Impact of temperamental mood lability on depressive mixed state. Psychopathology 2005;39:19-24.
21.
Dell'Osso L, Placidi GF, Nassi R, Freer P, Cassano GB, Akiskal HS: The manic-depressive mixed state: familial, temperamental and psychopathologic characteristics in 108 female inpatients. Eur Arch Psychiatry Clin Neurosci 1991;240:234-239.
22.
Benazzi F: Family history validation of a definition of mixed depression. Compr Psychiatry 2005;46:159-166.
23.
Maj M, Pirozzi R, Magliano L: Agitated ‘unipolar' major depression: prevalence, phenomenology, and outcome. J Clin Psychiatry 2006;67:712-719.
24.
Bowden CL: Predictors of response to divalproex and lithium. J Clin Psychiatry 1995;56(suppl 3):25-30.
25.
Pacchiarotti I, Mazzarini L, Kotzalidis GD, Valentí M, Nivoli AM, Sani G, Torrent C, Murru A, Sanchez-Moreno J, Patrizi B, Girardi P, Vieta E, Colom F: Mania and depression. Mixed, not stirred. J Affect Disord 2011;133:105-113.
26.
Swann AC, Bowden CL, Morris D, Calabrese JR, Petty F, Small J, Dilsaver SC, Davis JM: Depression during mania. Treatment response to lithium or divalproex. Arch Gen Psychiatry 1997;54:37-42.
27.
American Psychiatric Association: Practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry 2002;159:1-50.
28.
Suppes T, Mintz J, McElroy SL, Altshuler LL, Kupka RW, Frye MA, Keck PE Jr, Nolen WA, Leverich GS, Grunze H, Rush AJ, Post RM: 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;62:1089-1096.
29.
Bauer MS, Callahan AM, Jampala C, Petty F, Sajatovic M, Schaefer V, Wittlin B, Powell BJ: Clinical practice guidelines for bipolar disorder from the Department of Veterans Affairs. J Clin Psychiatry 1999;60:9-21.
30.
Sachs G, Printz D, Kahn D, Carpenter D, Docherty JP: The Expert Consensus Guideline Series: Medication Treatment of Bipolar Disorder 2000. Postgrad Med 2000(special number):1-104.
31.
Vieta E, Valentí M: Mixed states in DSM-5: implications for clinical care, education, and research. J Affect Disord 2013;148:28-36.
32.
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 2012;15:1-7.
33.
Akiskal HS, Mallya G: Criteria for the ‘soft' bipolar spectrum: treatment implications. Psychopharmacol Bull 1987;23:68-73.
34.
Koukopoulos A, Koukopoulos A: Agitated depression as a mixed state and the problem of melancholia. Psychiatr Clin North Am 1999;22:547-564.
35.
Kruger S, Trevor Young L, Braunig P: Pharmacotherapy of bipolar mixed states. Bipolar Disord 2005;7:205-215.
36.
Goldberg JF, Perlis RH, Ghaemi SN, Calabrese JR, Bowden CL, Wisniewski S, Miklowitz DJ, Sachs GS, Thase ME: Adjunctive antidepressant use and symptomatic recovery among bipolar depressed patients with concomitant manic symptoms: findings from the STEP-BD. Am J Psychiatry 2007;164:1348-1355.
37.
Perlis RH, Ostacher MJ, Goldberg JF, Miklowitz DJ, Friedman E, Calabrese J, Thase ME, Sachs GS: Transition to mania during treatment of bipolar depression. Neuropsychopharmacology 2010;35:2545-2552.
38.
Serretti A, Artioli P, Zanardi R, Rossini D: Clinical features of antidepressant associated manic and hypomanic switches in bipolar disorder. Prog Neuropsychopharmacol Biol Psychiatry 2003;27:751-757.
39.
Bond DJ, Noronha MM, Kauer-Sant'anna M, Lam RW, Yatham LN: Antidepressant-associated mood elevations in bipolar II disorder compared with bipolar I disorder and major depressive disorder: a systematic review and meta-analysis. J Clin Psychiatry 2008;69:1589-1601.
40.
Frye MA, Helleman G, McElroy SL, Altshuler LL, Black DO, Keck PE Jr, Nolen WA, Kupka R, Leverich GS, Grunze H, Mintz J, Post RM, Suppes T: Correlates of treatment-emergent mania associated with antidepressant treatment in bipolar depression. Am J Psychiatry 2009;166:164-172.
41.
Tamada RS, Issler CK, Amaral JA, Sachs GS, Lafer B: Treatment emergent affective switch: a controlled study. Bipolar Disord 2004;6:333-337.
42.
Valentí M, Pacchiarotti I, Rosa AR, Bonnín CM, Popovic D, Nivoli AM, Murru A, Grande I, Colom F, Vieta E: Bipolar mixed episodes and antidepressants: a cohort study of bipolar I disorder patients. Bipolar Disord 2011;13:145-154.
43.
Spitzer RL, Endicott J, Robins E: Research diagnostic criteria: rationale and reliability. Arch Gen Psychiatry 1978;35:773-782.
44.
Rothman KJ, Greenland S, Lash TL: Modern Epidemiology, ed 3. Philadelphia, Lippincott, Williams & Wilkins, 2008.
45.
Koukopoulos A, Ghaemi SN: The primacy of mania: a reconsideration of mood disorders. Eur Psychiatry 2009;24:125-134.
46.
Cassano GB, Rucci P, Benvenuti A, Miniati M, Calugi S, Maggi L, Pini S, Kupfer DJ, Maj M, Fagiolini A, Frank E: The role of psychomotor activation in discriminating unipolar from bipolar disorders: a classification-tree analysis. J Clin Psychiatry 2012;73:22-28.
47.
Offidani E, Fava GA, Tomba E, Baldessarini RJ: Excessive mood elevation and behavioral activation with antidepressant treatment of juvenile depressive and anxiety disorders: a systematic review. Psychother Psychosom 2013;82:132-141.
48.
Offidani E, Guidi J, Tomba E, Fava GA: Efficacy and tolerability of benzodiazepines versus antidepressants in anxiety disorders: a systematic review and meta-analysis. Psychother Psychosom 2013;82:355-362.
49.
Goodwin FK, Jamison KR: Manic-Depressive Illness: Bipolar Disorders and Recurrent Depression. New York, Oxford University Press, 2007.
50.
Koukopoulos K, Sani G, Albert MJ, Minnai GP, Koukopoulos A: Agitated depression: spontaneous and induced; in Marneros A (ed): Bipolar Disorders. Cambridge, Cambridge University Press, 2005, pp 157-186.
51.
Serretti A, Olgiati P: Profiles of ‘manic' symptoms in bipolar I, bipolar II and major depressive disorders. J Affect Disord 2005;84:159-166.
52.
Akiskal HS, Akiskal KK, Haykal RF, Manning JS, Connor PD: TEMPS-A: progress towards validation of a self-rated clinical version of the Temperament Evaluation of the Memphis, Pisa, Paris, and San Diego Autoquestionnaire. J Affect Disord 2005;85:3-16.
53.
Akiskal HS, Mendlowicz MV, Jean-Louis G, Rapaport MH, Kelsoe JR, Gillin JC, Smith TL: TEMPS-A: validation of a short version of a self-rated instrument designed to measure variations in temperament. J Affect Disord 2005;85:45-52.
54.
Akiskal HS, Kilzieh N, Maser JD, Clayton PJ, Schettler PJ, Traci Shea M, Endicott J, Scheftner W, Hirschfeld RM, Keller MB: The distinct temperament profiles of bipolar I, bipolar II and unipolar patients. J Affect Disord 2006;92:19-33.
55.
Mazzarini L, Pacchiarotti I, Colom F, Sani G, Kotzalidis GD, Rosa AR, Sanna L, De Rossi P, Girardi N, Bonnin CM, Sanchez-Moreno J, Vazquez GH, Gasto C: Predominant polarity and temperament in bipolar and unipolar affective disorders. J Affect Disord 2009;119:28-33.
56.
Fava GA: Do antidepressant and antianxiety drugs increase chronicity in affective disorders? Psychother Psychosom 1994;61:125-131.
57.
Fava GA: Can long-term treatment with antidepressant drugs worsen the course of depression? J Clin Psychiatry 2003;64:123-133.
58.
Pacchiarotti I, Bond DJ, Baldessarini RJ, Nolen WA, Grunze H, Licht RW, Post RM, Berk M, Goodwin GM, Sachs GS, Tondo L, Findling RL, Youngstrom EA, Tohen M, Undurraga J, González-Pinto A, Goldberg JF, Yildiz A, Altshuler LL, Calabrese JR, Mitchell PB, Thase ME, Koukopoulos A, Colom F, Frye MA, Malhi GS, Fountoulakis KN, Vázquez G, Perlis RH, Ketter TA, Cassidy F, Akiskal H, Azorin JM, Valentí M, Mazzei DH, Lafer B, Kato T, Mazzarini L, Martínez-Aran A, Parker G, Souery D, Ozerdem A, McElroy SL, Girardi P, Bauer M, Yatham LN, Zarate CA, Nierenberg AA, Birmaher B, Kanba S, El-Mallakh RS, Serretti A, Rihmer Z, Young AH, Kotzalidis GD, MacQueen GM, Bowden CL, Ghaemi SN, Lopez-Jaramillo C, Rybakowski J, Ha K, Perugi G, Kasper S, Amsterdam JD, Hirschfeld RM, Kapczinski F, Vieta E: The International Society for Bipolar Disorders (ISBD) task force report on antidepressant use in bipolar disorders. Am J Psychiatry 2013;170:1249-1262.
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