Skip to main content

Treatment of Mixed Features in Bipolar Disorder: an Updated View

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.

This is a preview of subscription content, access via your institution.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  2. 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.

    Article  PubMed  Google Scholar 

  3. 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.

    Article  Google Scholar 

  4. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  5. 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.

    Article  Google Scholar 

  6. 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.

    Article  PubMed  Google Scholar 

  7. 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.

    Article  PubMed  Google Scholar 

  8. American Psychiatric Association. Diagnostic and statistical manual of mental disorders (5th ed.). Arlington. VA: American Psychiatric Publishing; 2013.

  9. 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.

    CAS  Article  PubMed  Google Scholar 

  10. 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.

    CAS  Article  PubMed  Google Scholar 

  11. 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.

    Article  PubMed  Google Scholar 

  12. •• 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).

    Article  Google Scholar 

  13. 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.

    Article  PubMed  Google Scholar 

  14. 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.

    Article  PubMed  Google Scholar 

  15. 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.

    Article  PubMed  Google Scholar 

  16. 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.

    Article  PubMed  Google Scholar 

  17. 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.

    Article  PubMed  Google Scholar 

  18. 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.

    Article  PubMed  Google Scholar 

  19. • 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)

    Article  Google Scholar 

  20. 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.

    CAS  Article  PubMed  Google Scholar 

  21. •• 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).

    Article  Google Scholar 

  22. 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.

    Article  PubMed  Google Scholar 

  23. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  24. 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.

    CAS  Article  PubMed  Google Scholar 

  25. 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.

    CAS  Article  PubMed  Google Scholar 

  26. 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.

    CAS  Article  PubMed  Google Scholar 

  27. 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.

    Article  PubMed  Google Scholar 

  28. 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.

    CAS  Article  PubMed  Google Scholar 

  29. 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.

    CAS  Article  PubMed  Google Scholar 

  30. 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.

    CAS  Article  PubMed  Google Scholar 

  31. 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.

    CAS  Article  PubMed  Google Scholar 

  32. 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.

    CAS  Article  PubMed  Google Scholar 

  33. 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.

    CAS  Article  PubMed  Google Scholar 

  34. 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.

    CAS  Article  PubMed  Google Scholar 

  35. 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.

    CAS  Article  PubMed  Google Scholar 

  36. 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.

    CAS  Article  PubMed  Google Scholar 

  37. 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.

    Article  PubMed  Google Scholar 

  38. 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.

  39. 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.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. 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.

    Article  PubMed  Google Scholar 

  41. 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.

    CAS  Article  PubMed  Google Scholar 

  42. 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.

    CAS  Article  PubMed  Google Scholar 

  43. 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.

    Article  PubMed  Google Scholar 

  44. 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.

    Article  PubMed  Google Scholar 

  45. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  46. 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.

    CAS  Article  PubMed  Google Scholar 

  47. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  48. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  49. 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.

    CAS  Article  PubMed  Google Scholar 

  50. 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.

    CAS  Article  PubMed  Google Scholar 

  51. 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.

    CAS  Article  PubMed  Google Scholar 

  52. 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.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Lakshmi N. Yatham.

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

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

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

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11920-020-1137-6

Keywords

  • Mixed features
  • Mixed episodes
  • Bipolar disorder
  • DSM-5
  • Mood stabilizer
  • Antipsychotic