Abstract
Purpose of Review
Mixed presentations in bipolar disorder have long posed clinical and nosological challenges. The DSM-5 mixed features specifier was developed to provide a more flexible and clinically relevant definition of mixed presentations compared with narrowly defined DSM-IV mixed episodes. However, there is little guidance on treating such presentations. Here, we summarize the evidence for biological treatments of DSM-5 and similarly defined mixed features (MFs).
Recent Findings
The literature on treating MFs is almost exclusively based on post hoc analyses. Within this limited evidence base is preliminary positive data for aripiprazole, asenapine, cariprazine, olanzapine, risperidone, and ziprasidone in treating acute mania with MFs, and cariprazine, lurasidone, olanzapine, and ziprasidone for depressive symptoms in depression with MFs. Divalproex may also be efficacious for acute mania with MFs. The few extant maintenance studies suggest that divalproex and olanzapine may have long-term efficacy in those with index MFs or for the prevention of MFs, respectively.
Summary
The existing evidence suggests that clinicians consider atypical antipsychotics and divalproex for treating acute mixed presentations. However, adequately powered treatment trials—and studies of maintenance and neurostimulation therapies—are needed. Additionally, data-driven techniques to identify relevant symptom clusters may help improve our conceptualization of mixed presentations.
Similar content being viewed by others
References
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Verdolini N, Agius M, Ferranti L, Moretti P, Piselli M, Quartesan R. The state of the art of the DSM-5 “with mixed features” specifier. ScientificWorldJournal. 2015;2015:757258. https://doi.org/10.1155/2015/757258.
Vieta E, Valenti M. Mixed states in DSM-5: implications for clinical care, education, and research. J Affect Disord. 2013;148(1):28–36. https://doi.org/10.1016/j.jad.2013.03.007.
Salvatore P, Baldessarini RJ, Centorrino F, Egli S, Albert M, Gerhard A, et al. Weygandt’s on the mixed states of manic-depressive insanity: a translation and commentary on its significance in the evolution of the concept of bipolar disorder. Harv Rev Psychiatry. 2002;10(5):255–75.
Ghaemi SN. Bipolar spectrum: a review of the concept and a vision for the future. Psychiatry Investig. 2013;10(3):218–24. https://doi.org/10.4306/pi.2013.10.3.218.
Mason BL, Brown ES, Croarkin PE. Historical underpinnings of bipolar disorder diagnostic criteria. Behav Sci (Basel). 2016;6(3). doi:https://doi.org/10.3390/bs6030014.
Frye MA, Helleman G, McElroy SL, Altshuler LL, Black DO, Keck PE Jr, et al. Correlates of treatment-emergent mania associated with antidepressant treatment in bipolar depression. Am J Psychiatry. 2009;166(2):164–72. https://doi.org/10.1176/appi.ajp.2008.08030322.
Goldberg JF, Perlis RH, Bowden CL, Thase ME, Miklowitz DJ, Marangell LB, et al. Manic symptoms during depressive episodes in 1,380 patients with bipolar disorder: findings from the STEP-BD. Am J Psychiatry. 2009;166(2):173–81. https://doi.org/10.1176/appi.ajp.2008.08050746.
American Psychiatric Association. Diagnostic and statistical manual of mental disorders (5th ed.). Arlington. VA: American Psychiatric Publishing; 2013.
McElroy SL, Keck PE Jr, Pope HG Jr, Hudson JI, Faedda GL, Swann AC. Clinical and research implications of the diagnosis of dysphoric or mixed mania or hypomania. Am J Psychiatry. 1992;149(12):1633–44. https://doi.org/10.1176/ajp.149.12.1633.
Koukopoulos A, Sani G. DSM-5 criteria for depression with mixed features: a farewell to mixed depression. Acta Psychiatr Scand. 2014;129(1):4–16. https://doi.org/10.1111/acps.12140.
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):131–43. https://doi.org/10.1111/j.1399-5618.2007.00558.x.
•• Vazquez GH, Lolich M, Cabrera C, Jokic R, Kolar D, Tondo L et al. Mixed symptoms in major depressive and bipolar disorders: a systematic review. J Affect Disord. 2018;225:756–60. doi:https://doi.org/10.1016/j.jad.2017.09.006. (a comprehensive meta-analysis of the prevalence of DSM-5-defined mixed features in bipolar disorder).
Swann AC, Lafer B, Perugi G, Frye MA, Bauer M, Bahk WM, 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):31–42. https://doi.org/10.1176/appi.ajp.2012.12030301.
McIntyre RS, Soczynska JK, Cha DS, Woldeyohannes HO, Dale RS, Alsuwaidan MT, 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;172:259–64. https://doi.org/10.1016/j.jad.2014.09.026.
Tohen M, Gold AK, Sylvia LG, Montana RE, McElroy SL, Thase ME, et al. Bipolar mixed features - results from the comparative effectiveness for bipolar disorder (Bipolar CHOICE) study. J Affect Disord. 2017;217:183–9. https://doi.org/10.1016/j.jad.2017.03.070.
Shim IH, Woo YS, Bahk WM. Prevalence rates and clinical implications of bipolar disorder “with mixed features” as defined by DSM-5. J Affect Disord. 2015;173:120–5. https://doi.org/10.1016/j.jad.2014.10.061.
Seo HJ, Wang HR, Jun TY, Woo YS, Bahk WM. Factors related to suicidal behavior in patients with bipolar disorder: the effect of mixed features on suicidality. Gen Hosp Psychiatry. 2016;39:91–6. https://doi.org/10.1016/j.genhosppsych.2015.12.005.
Vieta E, Grunze H, Azorin JM, Fagiolini A. Phenomenology of manic episodes according to the presence or absence of depressive features as defined in DSM-5: results from the impact self-reported online survey. J Affect Disord. 2014;156:206–13. https://doi.org/10.1016/j.jad.2013.12.031.
• Miller S, Suppes T, Mintz J, Hellemann G, Frye MA, McElroy SL 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):1015–23. https://doi.org/10.1176/appi.ajp.2016.15091119. (a large prospective study examining the naturalistic course of patients with DSM-5-defined mixed features)
Muralidharan K, Ali M, Silveira LE, Bond DJ, Fountoulakis KN, Lam RW, 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):408–14. https://doi.org/10.1016/j.jad.2013.04.032.
•• Cuomo A, Nikolova VL, Yalin N, Arnone D, Fagiolini A, Young AH. Pharmacological treatment of mixed states. CNS Spectr. 2017;22(2):186–95. https://doi.org/10.1017/s1092852917000013. (a rigorous and comprehensive systematic review of the evidence for pharmacological treatment of variously defined mixed presentations).
Grunze H, Vieta E, Goodwin GM, Bowden C, Licht RW, Azorin JM, et al. The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of bipolar disorders: acute and long-term treatment of mixed states in bipolar disorder. World J Biol Psychiatry. 2018;19(1):2–58. https://doi.org/10.1080/15622975.2017.1384850.
Fornaro M, Stubbs B, De Berardis D, Perna G, Valchera A, Veronese N, 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. https://doi.org/10.3390/ijms17020241.
McIntyre RS, Tohen M, Berk M, Zhao J, Weiller E. DSM-5 mixed specifier for manic episodes: evaluating the effect of depressive features on severity and treatment outcome using asenapine clinical trial data. J Affect Disord. 2013;150(2):378–83. https://doi.org/10.1016/j.jad.2013.04.025.
McIntyre RS, Cohen M, Zhao J, Alphs L, Macek TA, Panagides J. A 3-week, randomized, placebo-controlled trial of asenapine in the treatment of acute mania in bipolar mania and mixed states. Bipolar Disord. 2009;11(7):673–86. https://doi.org/10.1111/j.1399-5618.2009.00748.x.
Azorin JM, Sapin C, Weiller E. Effect of asenapine on manic and depressive symptoms in bipolar I patients with mixed episodes: results from post hoc analyses. J Affect Disord. 2013;145(1):62–9. https://doi.org/10.1016/j.jad.2012.07.013.
Berk M, Tiller JW, Zhao J, Yatham LN, Malhi GS, Weiller E. Effects of asenapine in bipolar I patients meeting proxy criteria for moderate-to-severe mixed major depressive episodes: a post hoc analysis. J Clin Psychiatry. 2015;76(6):728–34. https://doi.org/10.4088/JCP.13m08827.
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;168:136–41. https://doi.org/10.1016/j.jad.2014.06.039.
McIntyre RS, Masand PS, Earley W, Patel M. Cariprazine for the treatment of bipolar mania with mixed features: a post hoc pooled analysis of 3 trials. J Affect Disord. 2019;257:600–6. https://doi.org/10.1016/j.jad.2019.07.020.
Suppes T, Eudicone J, McQuade R, Pikalov A 3rd, Carlson B. Efficacy and safety of aripiprazole in subpopulations with acute manic or mixed episodes of bipolar i disorder. J Affect Disord. 2008;107(1–3):145–54. https://doi.org/10.1016/j.jad.2007.08.015.
Woo YS, Bahk WM, Jon DI, Chung SK, Lee SY, Ahn YM, et al. Risperidone in the treatment of mixed state bipolar patients: results from a 24-week, multicenter, open-label study in Korea. Psychiatry Clin Neurosci. 2010;64(1):28–37. https://doi.org/10.1111/j.1440-1819.2009.02026.x.
Stahl S, Lombardo I, Loebel A, Mandel FS. Efficacy of ziprasidone in dysphoric mania: pooled analysis of two double-blind studies. J Affect Disord. 2010;122(1–2):39–45. https://doi.org/10.1016/j.jad.2009.06.023.
Swann AC, Bowden CL, Morris D, Calabrese JR, Petty F, Small J, et al. Depression during mania. Treatment response to lithium or divalproex. Arch Gen Psychiatry. 1997;54(1):37–42. https://doi.org/10.1001/archpsyc.1997.01830130041008.
Suppes T, Ketter TA, Gwizdowski IS, Dennehy EB, Hill SJ, Fischer EG, et al. First controlled treatment trial of bipolar II hypomania with mixed symptoms: quetiapine versus placebo. J Affect Disord. 2013;150(1):37–43. https://doi.org/10.1016/j.jad.2013.02.031.
Tohen M, Kanba S, McIntyre RS, Fujikoshi S, Katagiri H. Efficacy of olanzapine monotherapy in the treatment of bipolar depression with mixed features. J Affect Disord. 2014;164:57–62. https://doi.org/10.1016/j.jad.2014.04.003.
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):1424–31. https://doi.org/10.4088/JCP.08m04772gre.
McIntyre RS, Cucchiaro J, Pikalov A, Kroger H, Loebel A. Lurasidone in the treatment of bipolar depression with mixed (subsyndromal hypomanic) features: post hoc analysis of a randomized placebo-controlled trial. J Clin Psychiatry. 2015;76(4):398–405. https://doi.org/10.4088/JCP.14m09410.
McIntyre RS, Suppes T, Earley W, Patel M, Stahl SM. Cariprazine efficacy in bipolar I depression with and without concurrent manic symptoms: post hoc analysis of 3 randomized, placebo-controlled studies. CNS Spectr. 2019:1–9. https://doi.org/10.1017/s1092852919001287.
Patkar A, Gilmer W, Pae CU, Vohringer PA, Ziffra M, Pirok E, et al. A 6 week randomized double-blind placebo-controlled trial of ziprasidone for the acute depressive mixed state. PLoS One. 2012;7(4):e34757. https://doi.org/10.1371/journal.pone.0034757.
Goldberg JF, Perlis RH, Ghaemi SN, Calabrese JR, Bowden CL, Wisniewski S, 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):1348–55. https://doi.org/10.1176/appi.ajp.2007.05122032.
Bowden CL, Collins MA, McElroy SL, Calabrese JR, Swann AC, Weisler RH, et al. Relationship of mania symptomatology to maintenance treatment response with divalproex, lithium, or placebo. Neuropsychopharmacology. 2005;30(10):1932–9. https://doi.org/10.1038/sj.npp.1300788.
Tohen M, Mintz J, Bowden CL. Analysis of bipolar maintenance treatment with lithium versus olanzapine utilizing multi-state outcome analysis of treatments (MOAT). Bipolar Disord. 2016;18(3):282–7. https://doi.org/10.1111/bdi.12383.
Valenti M, Benabarre A, Garcia-Amador M, Molina O, Bernardo M, Vieta E. Electroconvulsive therapy in the treatment of mixed states in bipolar disorder. Eur Psychiatry. 2008;23(1):53–6. https://doi.org/10.1016/j.eurpsy.2007.10.011.
Medda P, Toni C, Mariani 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):1168–73. https://doi.org/10.4088/JCP.14m09181.
Palma M, Ferreira B, Borja-Santos N, Trancas B, Monteiro C, Cardoso G. Efficacy of electroconvulsive therapy in bipolar disorder with mixed features. Depress Res Treat. 2016;2016:8306071. https://doi.org/10.1155/2016/8306071.
Kim W, Kim H, Citrome L, Akiskal HS, Goffin KC, Miller S, et al. More inclusive bipolar mixed depression definitions by requiring fewer non-overlapping mood elevation symptoms. Acta Psychiatr Scand. 2016;134(3):189–98. https://doi.org/10.1111/acps.12563.
Judd LL, Schettler PJ, Akiskal H, Coryell W, Fawcett J, Fiedorowicz JG, 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):440–8. https://doi.org/10.1016/j.jad.2011.12.046.
Suppes T, Eberhard J, Lemming O, Young AH, McIntyre RS. Anxiety, irritability, and agitation as indicators of bipolar mania with depressive symptoms: a post hoc analysis of two clinical trials. Int J Bipolar Disord. 2017;5(1):36. https://doi.org/10.1186/s40345-017-0103-7.
Houston JP, Tohen M, Degenhardt EK, Jamal HH, Liu LL, Ketter TA. Olanzapine-divalproex combination versus divalproex monotherapy in the treatment of bipolar mixed episodes: a double-blind, placebo-controlled study. J Clin Psychiatry. 2009;70(11):1540–7. https://doi.org/10.4088/JCP.08m04895yel.
Yatham LN, Fountoulakis KN, Rahman Z, Ammerman D, Fyans P, Marler SV, et al. Efficacy of aripiprazole versus placebo as adjuncts to lithium or valproate in relapse prevention of manic or mixed episodes in bipolar I patients stratified by index manic or mixed episode. J Affect Disord. 2013;147(1–3):365–72. https://doi.org/10.1016/j.jad.2012.11.042.
Colom F, Vieta E, Sanchez-Moreno J, Palomino-Otiniano R, Reinares M, Goikolea JM, et al. Group psychoeducation for stabilised bipolar disorders: 5-year outcome of a randomised clinical trial. Br J Psychiatry. 2009;194(3):260–5. https://doi.org/10.1192/bjp.bp.107.040485.
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):799–806. https://doi.org/10.1016/j.comppsych.2014.01.012.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
Trisha Chakrabarty and Kamyar Keramatian each declare no potential conflicts of interest.
Lakshmi N. Yatham has received research support from or served as a consultant or speaker for Alkermes, Allergan, CANMAT, CIHR, Dainippon Sumitomo, Janssen, Lundbeck, Otsuka, Sanofi, Sunovion, Teva, and Valeant.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
This article is part of the Topical Collection on Topical Collection on Bipolar Disorders
Rights and permissions
About this article
Cite this article
Chakrabarty, T., Keramatian, K. & Yatham, L.N. Treatment of Mixed Features in Bipolar Disorder: an Updated View. Curr Psychiatry Rep 22, 15 (2020). https://doi.org/10.1007/s11920-020-1137-6
Published:
DOI: https://doi.org/10.1007/s11920-020-1137-6