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Pharmacological treatment of mixed states

Published online by Cambridge University Press:  18 April 2017

Alessandro Cuomo ,
Viktoriya L. Nikolova ,
Nefize Yalin ,
Danilo Arnone ,
Andrea Fagiolini  and
Allan H. Young
Alessandro Cuomo
Affiliation:
General Psychiatry Residency Training Program, University of Siena School of Medicine, Siena, Italy
Viktoriya L. Nikolova
Affiliation:
Centre for Affective Disorders, Department of Psychological Medicine, Institute of Psychiatry, Psychology & Neuroscience, King’s College, London
Nefize Yalin
Affiliation:
Centre for Affective Disorders, Department of Psychological Medicine, Institute of Psychiatry, Psychology & Neuroscience, King’s College, London
Danilo Arnone
Affiliation:
Centre for Affective Disorders, Department of Psychological Medicine, Institute of Psychiatry, Psychology & Neuroscience, King’s College, London
Andrea Fagiolini
Affiliation:
Department of Medical Sciences, Surgery and Neurosciences, University of Siena School of Medicine, Siena, Italy
Allan H. Young*
Affiliation:
Centre for Affective Disorders, Department of Psychological Medicine, Institute of Psychiatry, Psychology & Neuroscience, King’s College, London
*
*Address for correspondence: Professor Allan H. Young, Centre for Affective Disorders, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, PO72 De Crespigny Park, London SE5 8AF, United Kingdom. Email: (Allan.Young@kcl.ac.uk)
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Abstract

Mixed states in bipolar disorder have been neglected, and the data concerning treatment of these conditions have been relatively obscure. To address this, we systematically reviewed published pharmacological treatment data for “mixed states/episodes” in mood disorders, including “with mixed features” in DSM–5. We searched PubMed, MEDLINE, The Cochrane Library, clinicaltrials.gov, and controlled-trials.com (with different combinations of the following keywords: “mixed states/features,” “bipolar,” “depressive symptoms/bipolar depression,” “manic symptoms,” “treatment,” “DSM–5”) through to October 2016. We applied a quality-of-evidence approach: first-degree evidence=randomized placebo-controlled studies of pharmacological interventions used as monotherapy; second-degree evidence=a similar design in the absence of a placebo or of a combination therapy as a comparative group; third-degree evidence=case reports, case series, and reviews of published studies. We found very few primary double-blind, placebo-controlled studies on the treatment of mixed states: the preponderance of available data derives from subgroup analysis performed on studies that originally involved manic patients. Future research should study the effects of treatments in mixed states defined using current criteria.

Keywords

Mixed states/episodesmood disordersDSM–5depressive symptomsmanic symptomstreatmentpharmacological interventionspharmacotherapies
Type
Review Articles
Information
CNS Spectrums , Volume 22 , Issue 2: Theme: Mixed features in major depressive episodes , April 2017 , pp. 186 - 195
Copyright
© Cambridge University Press 2017 

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Footnotes

We thank Ms. Caroline Loveland for her help in preparing this manuscript. Dr. Danilo Arnone is supported by the Academy of Medical Sciences (AMS-SGCL8).

This paper represents independent research funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London, the Maudsley NHS Foundation Trust, and King’s College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health.

References

1. 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. Accessed January 8, 2017.CrossRefGoogle ScholarPubMed
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. Epub ahead of print Apr 2. http://www.jad-journal.com/article/S0165-0327(13)00232-2/pdf. Accessed January 8, 2017.Google Scholar
3. Castle, DJ. Bipolar mixed states: still mixed up? Curr Opin Psychiatry. 2014; 27(1): 38–42.Google Scholar
4. Houston, JP, Ahl, J, Meyers, AL, Kaiser, CJ, Tohen, M, Baldessarini, RJ. Reduced suicidal ideation in bipolar I disorder mixed-episode patients in a placebo-controlled trial of olanzapine combined with lithium or divalproex. J Clin Psychiatry. 2006; 67(8): 1246–1252.Google Scholar
5. Liberati, A, Altman, DG, Tetzlaff, J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Ann Intern Med. 2009; 151(4): W65–W94. Epub ahead of print Jul 20.Google Scholar
6. 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. Accessed January 8, 2017.Google Scholar
7. 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. http://jamanetwork.com/journals/jamapsychiatry/fullarticle/205739. Accessed January 8, 2017.Google Scholar
8. Novick, D, Reed, C, Haro, JM, et al. Comparison of olanzapine and risperidone in the EMBLEM Study: translation of randomized controlled trial findings into clinical practice. Int Clin Psychopharmacol. 2010; 25(5): 257–263.Google Scholar
9. Perlis, RH, Baker, RW, Zarate, CA Jr, et al. Olanzapine versus risperidone in the treatment of manic or mixed states in bipolar I disorder: a randomized, double-blind trial. J Clin Psychiatry. 2006; 67(11): 1747–1753.Google Scholar
10. Tohen, M, Goldberg, JF, Gonzalez-Pinto Arrillaga, AM, et al. A 12-week, double-blind comparison of olanzapine vs. haloperidol in the treatment of acute mania. Arch Gen Psychiatry. 2003; 60(12): 1218–1226. http://jamanetwork.com/journals/jamapsychiatry/fullarticle/208076. Accessed January 8, 2017.CrossRefGoogle ScholarPubMed
11. Tohen, M, Greil, W, Calabrese, JR, et al. Olanzapine versus lithium in the maintenance treatment of bipolar disorder: a 12-month, randomized, double-blind, controlled clinical trial. Am J Psychiatry. 2005; 162(7): 1281–1290. http://ajp.psychiatryonline.org/doi/pdf/10.1176/appi.ajp.162.7.1281. Accessed January 8, 2017.CrossRefGoogle ScholarPubMed
12. 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.CrossRefGoogle Scholar
13. Tohen, M, Ketter, TA, Zarate, CA, et al. Olanzapine versus divalproex sodium for the treatment of acute mania and maintenance of remission: a 47-week study. Am J Psychiatry. 2003; 160(7): 1263–1271. http://ajp.psychiatryonline.org/doi/pdf/10.1176/appi.ajp.160.7.1263. Accessed January 8, 2017.Google Scholar
14. Tohen, M, Chengappa, KN, Suppes, T, et al. Relapse prevention in bipolar I disorder: 18-month comparison of olanzapine plus mood stabiliser v. mood stabiliser alone. Br J Psychiatry. 2004; 184: 337–345. http://bjp.rcpsych.org/content/184/4/337.long. Accessed January 8, 2017.Google Scholar
15. 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
16. 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
17. 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/pdfplus/10.1176/appi.ajp.2008.08020189. Accessed January 8, 2017.Google Scholar
18. 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. Accessed January 8, 2017.CrossRefGoogle ScholarPubMed
19. Keck, PE, Orsulak, PJ, Cutler, AJ, et al. Aripiprazole monotherapy in the treatment of acute bipolar I mania: a randomized, double-blind, placebo- and lithium-controlled study. J Affect Disord. 2009; 112(1–3): 36–49. Epub ahead of print Oct 2, 2008.CrossRefGoogle Scholar
20. Young, AH, Oren, DA, Lowy, A, et al. Aripiprazole monotherapy in acute mania: 12-week randomised placebo- and haloperidol-controlled study. Br J Psychiatry. 2008, 194(1): 40–48. http://bjp.rcpsych.org/content/194/1/40.long. Accessed January 8, 2017.Google Scholar
21. Keck, PE Jr, Calabrese, JR, McIntyre, RS, et al. Aripiprazole monotherapy for maintenance therapy in bipolar I disorder: a 100-week, double-blind study versus placebo. J Clin Psychiatry. 2007; 68(10): 1480–1491.Google Scholar
22. Findling, RL, Nyilas, M, Forbes, RA, et al. Acute treatment of pediatric bipolar I disorder, manic or mixed episode, with aripiprazole: a randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2009; 70(10): 1441–1451.Google Scholar
23. Vieta, E, Bourin, M, Sanchez, R, et al. Effectiveness of aripiprazole v. haloperidol in acute bipolar mania: double-blind, randomised, comparative 12-week trial. Br J Psychiatry. 2005; 187: 235–242. http://bjp.rcpsych.org/content/187/3/235.long. Accessed January 8, 2017.Google Scholar
24. Vieta, E, T’Joen, C, McQuade, RD, et al. Efficacy of adjunctive aripiprazole to either valproate or lithium in bipolar mania patients partially nonresponsive to valproate/lithium monotherapy: a placebo-controlled study. Am J Psychiatry. 2008; 165(10): 1316–1325. http://ajp.psychiatryonline.org/doi/pdf/10.1176/appi.ajp.2008.07101560. Accessed January 8, 2017.Google Scholar
25. 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.Google Scholar
26. Vieta, E, Owen, R, Baudelet, C, McQuade, RD, Sanchez, R, Marcus, RN. Assessment of safety, tolerability and effectiveness of adjunctive aripiprazole to lithium/valproate in bipolar mania: a 46-week, open-label extension following a 6-week double-blind study. Curr Med Res Opin. 2010; 26(6): 1485–1496.CrossRefGoogle Scholar
27. McIntyre, RS, Cohen, M, Zhao, J, Alphs, L, Macek, TA, Panagides, J. Asenapine for long-term treatment of bipolar disorder: a double-blind 40-week extension study. J Affect Disord. 2010; 126(3): 358–365.Google Scholar
28. McIntyre, RS, Cohen, M, Zhao, J, Alphs, L, Macek, TA, Panagides, J. Asenapine in the treatment of acute mania in bipolar I disorder: a randomized, double-blind, placebo-controlled trial. J Affect Disord. 2010; 122(1–2): 27–38.Google Scholar
29. Bowden, CL, Vieta, E, Ice, KS, Schwartz, JH, Wang, PP, Versavel, M. Ziprasidone plus a mood stabilizer in subjects with bipolar I disorder: a 6-month, randomized, placebo-controlled, double-blind trial. J Clin Psychiatry. 2010; 71(2): 130–137.Google Scholar
30. 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. Accessed January 8, 2017.Google Scholar
31. 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.Google Scholar
32. 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.Google Scholar
33. 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.Google Scholar
34. Khanna, S, Vieta, E, Lyons, B, Grossman, F, Eerdekens, M, Kramer, M. Risperidone in the treatment of acute mania: double-blind, placebo-controlled study. Br J Psychiatry. 2005; 187: 229–234. http://bjp.rcpsych.org/content/187/3/229.long. Accessed January 8, 2017.CrossRefGoogle ScholarPubMed
35. Sachs, GS, Greenberg, WM, Starace, A, et al. Cariprazine in the treatment of acute mania in bipolar I disorder: a double-blind, placebo-controlled, phase III trial. J Affect Disorders. 2015; 174: 296–302. Epub ahead of print Nov 24, 2014. http://www.jad-journal.com/article/S0165-0327(14)00728-9/pdf. Accessed January 8, 2017.Google Scholar
36. Durgam, S, Starace, A, Li, D, et al. The efficacy and tolerability of cariprazine in acute mania associated with bipolar I disorder: a phase II trial. Bipolar Disord. 2015; 17(1): 63–75. Epub ahead of print Jul 24, 2014.Google Scholar
37. Calabrese, JR, Keck, PE Jr, Starace, A, et al. Efficacy and safety of low- and high-dose cariprazine in acute and mixed mania associated with bipolar I disorder: a double-blind, placebo-controlled study. J Clin Psychiatry. 2015; 76(3): 284–292.Google Scholar
38. 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.Google Scholar
39. Freeman, TW, Clothier, JL, Pazzaglia, P, Lesem, MD, Swann, AC. A double-blind comparison of valproate and lithium in the treatment of acute mania. Am J Psychiatry. 1992; 149(1): 108–111.Google Scholar
40. Bowden, CL, Calabrese, JR, Sachs, G, et al. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently manic or hypomanic patients with bipolar I disorder. Arch Gen Psychiatry. 2003; 60(4): 392–400. http://jamanetwork.com/journals/jamapsychiatry/fullarticle/207328. Accessed January 8, 2017.Google Scholar
41. Calabrese, JR, Bowden, CL, Sachs, G, et al. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar I disorder. J Clin Psychiatry. 2003; 64(9): 1013–1024.Google Scholar
42. Perugi, G, Toni, C, Ruffolo, G, Sartini, S, Simonini, E, Akiskal, H. Clinical experience using adjunctive gabapentin in treatment-resistant bipolar mixed states. Pharmacopsychiatry. 1999; 32(4): 136–141.Google Scholar
43. 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. Epub ahead of print Sep 27, 2007.Google Scholar
44. 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. http://journals.sagepub.com/doi/pdf/10.1177/0269881106059693. Accessed January 8, 2017.Google Scholar
45. 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
46. Suppes, T, Silva, R, Cucchiaro, J, et al. Lurasidone for the treatment of major depressive disorder with mixed features: a randomized, double-blind, placebo-controlled study. Am J Psychiatry. 2016; 173(4): 400–407. Epub ahead of print Nov 10, 2015.Google Scholar
47. Patkar, A, Gilmer, W, Pae, CU, 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. Epub ahead of print Apr 24. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3335844/. Accessed January 8, 2017.Google Scholar
48. 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
49. Suppes, T, McElroy, SL, Gilbert, J, Dessain, EC, Cole, JO. Clozapine in the treatment of dysphoric mania. Biol Psychiatry. 1992; 32(3): 270–280.Google Scholar
50. 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
51. 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
52. 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
53. 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
54. 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.Google Scholar
55. 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. Accessed January 8, 2017.Google Scholar
56. 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): 1424–1431.Google Scholar
57. 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
58. 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. Accessed January 8, 2017.CrossRefGoogle ScholarPubMed
59. 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
60. 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. Accessed January 8, 2017.Google Scholar
61. Ketter, TA, Kalali, AH, Weisler, RH. A 6-month, multicenter, open-label evaluation of beaded, extended-release carbamazepine capsule monotherapy in bipolar disorder patients with manic or mixed episodes. J Clin Psychiatry. 2004; 65(5): 668–673.Google Scholar
62. 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.Google Scholar
63. Woo, YS, Bahk, WM, Jon, DI, 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. Epub ahead of print Nov 4, 2009.Google Scholar