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Treating mixed mania/hypomania: a review and synthesis of the evidence

Published online by Cambridge University Press:  22 December 2016

Minoru Takeshima
Minoru Takeshima*
Affiliation:
J Clinic, Kanazawa City, Japan
*
*Address for correspondence: Minoru Takeshima, J Clinic, 3-30-10 Sainen, Kanazawa City 920-0024, Japan. (Email: min-take@p2.tcnet.ne.jp)
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Abstract

The DSM–5 incorporates a broad concept of mixed states and captured ≥3 nonoverlapping symptoms of the opposite polarity using a “with mixed features” specifier to be applied to manic/hypomanic and major depressive episodes. Pharmacotherapy of mixed states is challenging because of the necessity to treat both manic/hypomanic and depressive symptoms concurrently. High-potency antipsychotics used to treat manic symptoms and antidepressants can potentially deteriorate symptoms of the opposite polarity. This review aimed to provide a synthesis of the current evidence for pharmacotherapy of mixed states with an emphasis on mixed mania/hypomania. A PubMed search was conducted for randomized controlled trials (RCTs) that were at least moderately sized, included a placebo arm, and contained information on acute-phase and maintenance treatments of adult patients with mixed episodes or mania/hypomania with significant depressive symptoms. Most studies were post-hoc subgroup and pooled analyses of the data from RCTs for acute manic and mixed episodes of bipolar I disorder; only two prospectively examined efficacy for mixed mania/hypomania specifically. Aripiprazole, asenapine, carbamazepine, olanzapine, and ziprasidone showed the strongest evidence of efficacy in acute-phase treatment. Quetiapine and divalproex/valproate were also efficacious. Combination therapies with these atypical antipsychotics and mood stabilizers can be considered in severe cases. Olanzapine and quetiapine (alone or in combination with lithium/divalproex) showed the strongest evidence of efficacy in maintenance treatment. Lithium and lamotrigine may be beneficial given their preventive effects on suicide and depressive relapse. Further prospective studies primarily focusing on mixed states are needed.

Keywords

Maniamixed episodesmixed maniamixed hypomaniamixed specifiermixed featuresmixed statesdysphoric maniabipolar disorderpharmacotherapy
Type
Review Articles
Information
CNS Spectrums , Volume 22 , Issue 2: Theme: Mixed features in major depressive episodes , April 2017 , pp. 177 - 185
Copyright
© Cambridge University Press 2016 

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Footnotes

The author would like to thank Editage (www.editage.jp) for the English-language editing. However, the author is solely responsible for the scientific content of the paper.

References

1. Marneros, A. Origin and development of concepts of bipolar mixed states. J Affect Disord. 2001; 67(1–3): 229–240.CrossRefGoogle ScholarPubMed
2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision. Washington, DC: American Psychiatric Association; 2000.Google Scholar
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): 31–42. http://ajp.psychiatryonline.org/doi/pdf/10.1176/appi.ajp.2012.12030301.CrossRefGoogle ScholarPubMed
4. Vieta, E, Valenti, M. Mixed states in DSM–5: implications for clinical care, education, and research. J Affect Disord. 2013; 148(1): 28–36. Epub ahead of print Apr 2. http://www.jad-journal.com/article/S0165-0327(13)00232-2/pdf.Google Scholar
5. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th ed. Arlington, VA: American Psychiatric Association; 2013.Google Scholar
6. 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): 1249–1262. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4091043/pdf/nihms596538.pdf.Google Scholar
7. Sachs, G, Sanchez, R, Marcus, R, et al. Aripiprazole in the treatment of acute manic or mixed episodes in patients with bipolar I disorder: a 3-week placebo-controlled study. J Psychopharmacol. 2006; 20(4): 536–546. Epub ahead of print Jan 9.Google Scholar
8. Keck, PE Jr, Marcus, R, Tourkodimitris, S, et al. A placebo-controlled, double-blind study of the efficacy and safety of aripiprazole in patients with acute bipolar mania. Am J Psychiatry. 2003; 160(9): 1651–1658. http://ajp.psychiatryonline.org/doi/pdf/10.1176/appi.ajp.160.9.1651.Google Scholar
9. 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): 145–154.CrossRefGoogle ScholarPubMed
10. 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): 673–686.Google Scholar
11. McIntyre, RS, Cohen, M, Zhao, J, Alphs, L, Macek, TA, Panagides, J. Asenapine versus olanzapine in acute mania: a double-blind extension study. Bipolar Disord. 2009; 11(8): 815–826. Epub ahead of print Oct 14. Erratum in Bipolar Disord. 2010; 12(1): 112.Google Scholar
12. Szegedi, A, Zhao, J, van Willigenburg, A, Nations, KR, Mackle, M, Panagides, J. Effects of asenapine on depressive symptoms in patients with bipolar I disorder experiencing acute manic or mixed episodes: a post-hoc analysis of two 3-week clinical trials. BMC Psychiatry. 2011; 11: 101. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3152513/pdf/1471-244X-11-101.pdf.Google Scholar
13. 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): 62–69. Epub ahead of print Aug 4, 2012.CrossRefGoogle ScholarPubMed
14. 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): 378–383. Epub ahead of print May 25.Google Scholar
15. Tohen, M, Jacobs, TG, Grundy, SL, et al. Efficacy of olanzapine in acute bipolar mania: a double-blind, placebo-controlled study. The Olanzipine HGGW Study Group. Arch Gen Psychiatry. 2000; 57(9): 841–849. Erratum in Arch Gen Psychiatry. 2002; 59(1): 91. http://jamanetwork.com/journals/jamapsychiatry/fullarticle/205739.CrossRefGoogle Scholar
16. Tohen, M, Sanger, TM, McElroy, SL, et al. Olanzapine versus placebo in the treatment of acute mania: Olanzapine HGEH Study Group. Am J Psychiatry. 1999; 156(5): 702–709. http://ajp.psychiatryonline.org/doi/pdf/10.1176/ajp.156.5.702.CrossRefGoogle ScholarPubMed
17. Baker, RW, Tohen, M, Fawcett, J, et al. Acute dysphoric mania: treatment response to olanzapine versus placebo. J Clin Psychopharmacol. 2003; 23(2): 132–137.Google Scholar
18. Baldessarini, RJ, Hennen, J, Wilson, M, et al. Olanzapine versus placebo in acute mania: treatment responses in subgroups. J Clin Psychopharmacol. 2003; 23(4): 370–376.Google Scholar
19. 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: 136–141. Epub ahead of print Jul 3.Google Scholar
20. Katagiri, H, Takita, Y, Tohen, M, Higuchi, T, Kanba, S, Takahashi, M. Efficacy and safety of olanzapine in the treatment of Japanese patients with bipolar I disorder in a current manic or mixed episode: a randomized, double-blind, placebo- and haloperidol-controlled study. J Affect Disord. 2012; 136(3): 476–484. Epub ahead of print Nov 30, 2011.CrossRefGoogle ScholarPubMed
21. Vieta, E, Nuamah, IF, Lim, P, et al. A randomized, placebo- and active-controlled study of paliperidone extended release for the treatment of acute manic and mixed episodes of bipolar I disorder. Bipolar Disord. 2010; 12(3): 230–243.CrossRefGoogle ScholarPubMed
22. Berwaerts, J, Xu, H, Nuamah, I, Lim, P, Hough, D. Evaluation of the efficacy and safety of paliperidone extended-release in the treatment of acute mania: a randomized, double-blind, dose-response study. J Affect Disord. 2012; 136(1–2): e51–e60. Epub ahead of print Jul 10, 2010.CrossRefGoogle Scholar
23. Cutler, AJ, Datto, C, Nordenhem, A, Minkwitz, M, Acevedo, L, Darko, D. Extended-release quetiapine as monotherapy for the treatment of adults with acute mania: a randomized, double-blind, 3-week trial. Clin Ther. 2011; 33(11): 1643–1658. Epub ahead of print Nov 4.Google Scholar
24. Keck, PE Jr., Versiani, M, Potkin, S, West, SA, Giller, E, Ice, K. Ziprasidone in the treatment of acute bipolar mania: a three-week, placebo-controlled, double-blind, randomized trial. Am J Psychiatry. 2003; 160(4): 741–748. http://ajp.psychiatryonline.org/doi/pdf/10.1176/appi.ajp.160.4.741.CrossRefGoogle Scholar
25. Potkin, SG, Keck, PE Jr., Segal, S, Ice, K, English, P. Ziprasidone in acute bipolar mania: a 21-day randomized, double-blind, placebo-controlled replication trial. J Clin Psychopharmacol. 2005; 25(4): 301–310.CrossRefGoogle Scholar
26. 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. Epub ahead of print Jul 17, 2009.Google Scholar
27. Weisler, RH, Kalali, AH, Ketter, TA. A multicenter, randomized, double-blind, placebo-controlled trial of extended-release carbamazepine capsules as monotherapy for bipolar disorder patients with manic or mixed episodes. J Clin Psychiatry. 2004; 65(4): 478–484.Google Scholar
28. Weisler, RH, Keck, PE Jr., Swann, AC, Cutler, AJ, Ketter, TA, Kalali, AH. Extended-release carbamazepine capsules as monotherapy for acute mania in bipolar disorder: a multicenter, randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2005; 66(3): 323–330.Google Scholar
29. Weisler, RH, Hirschfeld, R, Cutler, AJ, et al. Extended-release carbamazepine capsules as monotherapy in bipolar disorder: pooled results from two randomised, double-blind, placebo-controlled trials. CNS Drugs. 2006; 20(3): 219–231.Google Scholar
30. Bowden, CL, Brugger, AM, Swann, AC, et al. Efficacy of divalproex vs lithium and placebo in the treatment of mania: The Depakote Mania Study Group. JAMA. 1994; 271(12): 918–924.Google Scholar
31. Swann, AC, Bowden, CL, Morris, D, et al. Depression during mania: treatment response to lithium or divalproex. Arch Gen Psychiatry. 1997; 54(1): 37–42.Google Scholar
32. Bowden, CL, Swann, AC, Calabrese, JR, et al. A randomized, placebo-controlled, multicenter study of divalproex sodium extended release in the treatment of acute mania. J Clin Psychiatry. 2006; 67(10): 1501–1510.CrossRefGoogle ScholarPubMed
33. Tohen, M, Chengappa, KN, Suppes, T, et al. Efficacy of olanzapine in combination with valproate or lithium in the treatment of mania in patients partially nonresponsive to valproate or lithium monotherapy. Arch Gen Psychiatry. 2002; 59(1): 62–69. http://jamanetwork.com/journals/jamapsychiatry/fullarticle/205956.Google Scholar
34. Baker, RW, Brown, E, Akiskal, HS, et al. Efficacy of olanzapine combined with valproate or lithium in the treatment of dysphoric mania. Br J Psychiatry. 2004; 185: 472–478. http://bjp.rcpsych.org/content/185/6/472.long.Google Scholar
35. 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): 1540–1547. Epub ahead of print Sep 22.CrossRefGoogle ScholarPubMed
36. Tohen, M, Calabrese, JR, Sachs, GS, et al. Randomized, placebo-controlled trial of olanzapine as maintenance therapy in patients with bipolar I disorder responding to acute treatment with olanzapine. Am J Psychiatry. 2006; 163(2): 247–256. http://ajp.psychiatryonline.org/doi/pdf/10.1176/appi.ajp.163.2.247.CrossRefGoogle ScholarPubMed
37. Tohen, M, Sutton, VK, Calabrese, JR, Sachs, GS, Bowden, CL. Maintenance of response following stabilization of mixed-index episodes with olanzapine monotherapy in a randomized, double-blind, placebo-controlled study of bipolar 1 disorder. J Affect Disord. 2009; 116(1–2): 43–50. Epub ahead of print Dec 2, 2008.Google Scholar
38. Weisler, RH, Nolen, WA, Neijber, A, Hellqvist, A, Paulsson, B. Continuation of quetiapine versus switching to placebo or lithium for maintenance treatment of bipolar I disorder (trial 144: a randomized controlled study). J Clin Psychiatry. 2011; 72(11): 1452–1464.Google Scholar
39. Bowden, CL, Collins, MA, McElroy, SL, et al. Relationship of mania symptomatology to maintenance treatment response with divalproex, lithium, or placebo. Neuropsychopharmacology. 2005; 30(10): 1932–1939. http://www.nature.com/npp/journal/v30/n10/pdf/1300788a.pdf.Google Scholar
40. Bowden, CL, Calabrese, JR, McElroy, SL, et al. A randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder: Divalproex Maintenance Study Group. Arch Gen Psychiatry. 2000; 57(5): 481–489. http://jamanetwork.com/journals/jamapsychiatry/fullarticle/481596.Google Scholar
41. Carlson, BX, Ketter, TA, Sun, W, et al. Aripiprazole in combination with lamotrigine for the long-term treatment of patients with bipolar I disorder (manic or mixed): a randomized, multicenter, double-blind study (CN138-392). Bipolar Disord. 2012; 14(1): 41–53.CrossRefGoogle ScholarPubMed
42. Marcus, R, Khan, A, Rollin, L, et al. Efficacy of aripiprazole adjunctive to lithium or valproate in the long-term treatment of patients with bipolar I disorder with an inadequate response to lithium or valproate monotherapy: a multicenter, double-blind, randomized study. Bipolar Disord. 2011; 13(2): 133–144.CrossRefGoogle ScholarPubMed
43. Yatham, LN, Fountoulakis, KN, Rahman, Z, 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): 365–372. Epub ahead of print Jan 3.Google Scholar
44. Suppes, T, Vieta, E, Liu, S, Brecher, M, Paulsson, B. Maintenance treatment for patients with bipolar I disorder: results from a North American study of quetiapine in combination with lithium or divalproex (trial 127). Am J Psychiatry. 2009; 166(4): 476–488. Epub ahead of print Mar 16. http://ajp.psychiatryonline.org/doi/pdf/10.1176/appi.ajp.2008.08020189.Google Scholar
45. Vieta, E, Suppes, T, Eggens, I, Persson, I, Paulsson, B, Brecher, M. Efficacy and safety of quetiapine in combination with lithium or divalproex for maintenance of patients with bipolar I disorder (international trial 126). J Affect Disord. 2008; 109(3): 251–263. Epub ahead of print Jun 24.Google Scholar
46. Vieta, E, Suppes, T, Ekholm, B, Udd, M, Gustafsson, U. Long-term efficacy of quetiapine in combination with lithium or divalproex on mixed symptoms in bipolar I disorder. J Affect Disord. 2012; 142(1–3): 36–44. Epub ahead of print Oct 9.Google Scholar
47. Suppes, T, Ketter, TA, Gwizdowski, IS, et al. First controlled treatment trial of bipolar II hypomania with mixed symptoms: quetiapine versus placebo. J Affect Disord. 2013; 150(1): 37–43. Epub ahead of print Mar 19.Google Scholar
48. Muralidharan, K, Ali, M, Silveira, LE, 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): 408–414. Epub ahead of print Jun 2.Google Scholar
49. McIntyre, RS, Yoon, J. Efficacy of antimanic treatments in mixed states. Bipolar Disord. 2012; 14(Suppl 2): 22–36.Google Scholar
50. Fountoulakis, KN, Kontis, D, Gonda, X, Siamouli, M, Yatham, LN. Treatment of mixed bipolar states. Int J Neuropsychopharmacol. 2012; 15(7): 1015–1026. Epub ahead of print Jan 5.CrossRefGoogle ScholarPubMed
51. Grunze, H, Azorin, JM. Clinical decision making in the treatment of mixed states. World J Biol Psychiatry. 2014; 15(5): 355–368. Epub ahead of print May 14.CrossRefGoogle ScholarPubMed
52. Bowden, CL, Grunze, H, Mullen, J, et al. A randomized, double-blind, placebo-controlled efficacy and safety study of quetiapine or lithium as monotherapy for mania in bipolar disorder. J Clin Psychiatry. 2005; 66(1): 111–121.Google Scholar
53. Calabrese, JR, Keck, PE Jr., Macfadden, W, et al. A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression. Am J Psychiatry. 2005; 162(7): 1351–1360. http://ajp.psychiatryonline.org/doi/pdf/10.1176/appi.ajp.162.7.1351.Google Scholar
54. Ghaemi, SN, Gilmer, WS, Goldberg, JF, et al. Divalproex in the treatment of acute bipolar depression: a preliminary double-blind, randomized, placebo-controlled pilot study. J Clin Psychiatry. 2007; 68(12): 1840–1844.Google Scholar
55. Muzina, DJ, Gao, K, Kemp, DE, et al. Acute efficacy of divalproex sodium versus placebo in mood stabilizer-naive bipolar I or II depression: a double-blind, randomized, placebo-controlled trial. J Clin Psychiatry. 2011; 72(6): 813–819. Epub ahead of print Aug 24, 2010.Google Scholar
56. Cipriani, A, Hawton, K, Stockton, S, Geddes, JR. Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis. BMJ. 2013; 346: f3646. http://www.bmj.com/content/346/bmj.f3646.long.Google Scholar
57. Tohen, M, Zarate, CA Jr., Hennen, J, et al. The Mclean–Harvard first-episode mania study: prediction of recovery and first recurrence. Am J Psychiatry. 2003; 160(12): 2099–2107. http://ajp.psychiatryonline.org/doi/pdf/10.1176/appi.ajp.160.12.2099.Google Scholar
58. Goodwin, GM, Bowden, CL, Calabrese, JR, et al. A pooled analysis of 2 placebo-controlled 18-month trials of lamotrigine and lithium maintenance in bipolar I disorder. J Clin Psychiatry. 2004; 65(3): 432–441.Google Scholar