Bipolar disorder is the sixth leading cause of medical disability worldwide for persons aged 15 to 44 years.1 People with bipolar disorder work 14 years less than the average population,2 and unemployment often exceeds 60%, even among patients with a college education.3,4 The social consequences are also high. More than 65% of patients have difficulty in maintaining long-term relationships and 60% have troubled relationships with their children.3 Bipolar disorder is further associated with an extreme danger to oneself. Up to 50% of patients with bipolar disorder will attempt suicide and as many as 20% will complete suicide.5 Given these serious consequences, it is important to implement a treatment plan that treats bipolar episodes rapidly and effectively.
After the resolution of an acute episode, maintenance therapy can be used to reduce future relapses. Without treatment, more than 90% of patients will experience subsequent manic or depressive episodes.6 Even with treatment, relapse rates range from 40% to 60%.7,8 Each additional mood episode worsens a patient’s long-term prognosis and increases the risk of future relapses. Therefore, it is crucial that a prophylactic treatment plan be implemented.9,10
While effective treatments for acute mania and bipolar prophylaxis are available, they are not without risk. Many medication regimens are associated with significant adverse effects. As a result, side effect mitigation has become an important part of the treatment plan.
This article examines the latest research on treating acute manic episodes and reducing the risk of future episodes, including optimal dosing and titration schedules. It also discusses common medication side effects and mitigation strategies.
Treatment of acute manic episodes
The treatment of acute mania initially centered on mood stabilizers and typical antipsychotics including lithium, valproate/divalproex, carbamazepine, and chlorpromazine. More recently, second-generation antipsychotics (SGAs) have been found to reduce the duration of manic episodes while minimizing extrapyramidal symptoms (EPS) often associated with typical antipsychotics. Trials studying the efficacy of pharmacologic agents in acute mania have used several approaches. These include the analysis of individual medications versus placebo, active comparator trials, and combination therapy studies. Each type of trial provides clinically relevant information that can be used to improve the treatment of acute mania.
Monotherapy versus placebo
In studies of individual medications versus placebo, 9 agents have shown efficacy and received an FDA indication for the treatment of acute mania. Once efficacy has been established, it is important to evaluate the time to onset of symptom reduction given the high rates of morbidity and mortality associated with mania. Among FDA-approved agents, onset varies from 3 to 21 days.11 Medication dosing and rate of titration can significantly affect clinical response and may increase the risk of side effects.12,13
Early studies demonstrated the benefits of lithium, valproate/divalproex, carbamazepine, and chlorpromazine in the treatment of acute mania. Later trials found that SGAs are also efficacious in reducing the duration of manic episodes. It has been hypothesized that SGAs decrease dopamine transmission through blockade or partial agonism of dopamine D2 receptors. This may explain their antimanic effect, since mania is reportedly associated with dopaminergic hyperactivity.14
All 5 SGAs (olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole) have been examined in at least 2 placebo-controlled, double-blind trials for the treatment of acute mania. The primary measure of efficacy in the majority of studies was the change from baseline to end point based on the Young Mania Rating Scale (YMRS). Ziprasidone studies evaluated changes based on Mania Rating Scale scores of the Schedule for Affective Disorders and Schizophrenia (MRS-SADS). Most studies lasted 3 weeks, with the exception of olanzapine (4 weeks) and quetiapine (12 weeks). Given the similarity of these trials, it is possible to directly compare important parameters including starting dose relative to onset of action, response rates, completion rates, use of concomitant medications, and statistically significant differences in side effects. The design and results of these studies are summarized in Table 1.
Drugs Mentioned in This Article
Carbamazepine (Carbatrol, Tegretol, others)
Chloral hydrate (Aquachloral)
Chlorpromazine (Largactil, Thorazine)
Divalproex (Epival, Depakote)
Lithium (Eskalith, Lithane, Lithobid)
Valproate/Valproic acid (Depakote, others)
Zolpidem tartrate (Ambien)
Calabrese JR, Vieta E, Shelton MD. Latest maintenance data on lamotrigine in bipolar disorder. Eur Neuropsychopharmacol. 2003;2:S57-S66.
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;162:1282-1290.
1. Murray CJ, Lopez AD. Global mortality, disability, and the contribution of risk factors: Global Burden of Disease Study. Lancet. 1997;349:1436-1442.
2. Albanese MJ, Pies R. The bipolar patient with comorbid substance use disorder: recognition and management. CNS Drugs. 2004;18:585-596.
3. Kupfer DJ, Frank E, Grochocinski VJ, et al. Demographic and clinical characteristics of individuals in a bipolar disorder case registry. J Clin Psychiatry. 2002;63:120-125.
4. Hirschfeld MA, Lewis L, Vornik LA. Perceptions and impact of bipolar disorder: how far have we really come? Results of the national depressive and manic-depressive association 2000 survey of individuals with bipolar disorder. J Clin Psychiatry. 2003;64:161-174.
5. Baldessarini RJ, Tondo L, Hennen J. Effects of lithium treatment and its discontinuation on suicidal behavior in bipolar manic-depressive disorders. J Clin Psychiatry. 1999;60(suppl 2):77-84.
6. Solomon DA, Keitner GI, Miller IW, et al. Course of illness and maintenance treatments for patients with bipolar disorder. J Clin Psychiatry. 1995;56:5-13.
7. Geddes JR, Burgess S, Hawton K, et al. Long-term lithium therapy for bipolar disorder: systematic review and meta-analysis of randomized controlled trials. Am J Psychiatry. 2004;161:217-222.
8. Bowden CL, Calabrese JR, McElroy SL, et al, for the Divalproex Maintenance Study Group. A randomized placebo-controlled 12-month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder. Arch Gen Psychiatry. 2000;57:481-489.
9. Cusin C, Serretti A, Lattuada E, et al. Impact of clinical variables on illness time course in mood disorders. Psychiatry Res. 2000;97:217-227.
10. Kessing LV, Andersen PK, Mortensen PB, Bolwig TG. Recurrence in affective disorder, I: case register study. Br J Psychiatry. 1998;172:23-28.
11. Yatham LN. Atypical antipsychotics for bipolar disorder. Psychiatr Clin North Am. 2005;28:325-347.
12. Allen MH, Hirschfeld RM, Wozniak PJ, et al. Linear relationship of valproate serum concentration to response and optimal serum levels for acute mania. Am J Psychiatry. 2006;163:272-275.
13. Hirschfeld RM, Baker JD, Wozniak PJ, et al. The safety and early efficacy of oral-loaded divalproex versus standard-titration divalproex, lithium, olanzapine, and placebo in the treatment of acute mania associated with bipolar disorder. J Clin Psychiatry. 2003;64:841-846.
14. Yatham LN. Brain imaging investigations of dopaminergic pathways in mood disorders. In: Soares JC, ed. Brain Imaging in Affective Disorders. New York: Marcel Dekker; 2003.
15. Tohen M, Sanger TM, McElroy SL, et al, for the Olanzapine HGEH Study Group. Olanzapine versus placebo in the treatment of acute mania. Am J Psychiatry. 1999;156:702-709.
16. Tohen M, Jacobs TG, Grundy SL, et al, for the Olanzapine HGGW Study Group. Efficacy of olanzapine in acute bipolar mania: a double-blind, placebo-controlled study. Arch Gen Psychiatry. 2000;57:841-849.
17. Hirschfeld RM, Keck PE Jr, Kramer M, et al. Rapid antimanic effect of risperidone monotherapy: a 3-week multicenter, double-blind, placebo-controlled trial. Am J Psychiatry. 2004;161:1057-1065.
18. Khanna S, Vieta E, Lyons B, et al. Risperidone in the treatment of acute mania: double-blind, placebo-controlled study. Br J Psychiatry. 2005;187: 227-234.
19. 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;66:111-121.
20. McIntyre RS, Brecher M, Paulsson B, et al. Quetiapine or haloperidol as monotherapy for bipolar mania—a 12 week, double-blind, randomised, parallel-group, placebo-controlled trial. Eur Neuropsychopharmacol. 2005;15: 573-585.
21. Keck PE Jr, Versiani M, Potkin S, et al. Ziprasidone in the treatment of acute bipolar mania: a three-week, placebo-controlled, double-blind, randomized trial. Am J Psychiatry. 2003;160:741-748.
22. Potkin SG, Keck PE Jr, Segal S, et al. Ziprasidone in acute bipolar mania: a 21-day randomized, double-blind, placebo-controlled replication trial. J Clin Psychopharmacol. 2005;25:301-310.
23. 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;160:1651-1658.
24. 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;20:536-546.
25. Hirschfeld RM, Allen MH, McEvoy JP, et al. Safety and tolerability of oral loading valproate in acutely manic bipolar patients. J Clin Psychiatry. 1999;60:815-818.
26. McElroy SL, Keck PE Jr, Tugrul KC, Bennett JA. Valproate as a loading treatment in acute mania. Neuropsychobiology. 1993;27:146-149.
27. Keck PE Jr, McElroy SL, Tugrul KC, Bennett JA. Valproate oral loading in the treatment of acute mania. J Clin Psychiatry. 1993;54:305-308.
28. McElroy SL, Keck PE Jr, Stanton SP, et al. A randomized comparison of divalproex oral loading versus haloperidol in the initial treatment of psychotic mania. J Clin Psychiatry. 1996;57:142-146.
29. Pope HG Jr, McElroy SL, Keck PE Jr, Hudson JI. Valproate in the treatment of acute mania: a placebo-controlled study. Arch Gen Psychiatry. 1991;48:62-68.
30. Bowden CL, Brugger AM, Swann AC, et al, for the Depakote Mania Study Group. Efficacy of divalproex vs lithium and placebo in the treatment of mania. JAMA. 1994;271:918-924.
31. American Psychiatric Association. Practice guideline for the treatment of patients with bipolar disorder. 2nd ed. Available at: http://www.psych.org/ psych_pract/treatg/pg/bipolar_revisebook_index.cfm. Accessed November 15, 2006.
32. Vasudev K, Goswami U, Kohli K. Carbamazepine and valproate: feasibility, relative safety and efficacy, and therapeutic drug monitoring in manic disorder. Psychopharmacology (Berl). 2000;150:15-23.
33. Goldberg JF, Garno JL, Leon AC, et al. Rapid titration of mood stabilizers predicts remission from mixed or pure mania in bipolar patients. J Clin Psychiatry. 1998;59:151-158.
34. McCoy L, Votolato NA, Schwarzkopf SB, Nasrallah HA. Clinical correlates of valproate augmentation in refractory bipolar disorder. Ann Clin Psychiatry. 1993;5:29-33.
35. Tohen M, Baker RW, Altshuler LL, et al. Olanzapine versus divalproex in the treatment of acute mania. Am J Psychiatry. 2002;159:1011-1017.
36. Zajecka JM, Weisler R, Sachs G, et al. A comparison of the efficacy, safety, and tolerability of divalproex sodium and olanzapine in the treatment of bipolar disorder. J Clin Psychiatry. 2002;63:1148-1155.
37. 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;160:1263-1271.
38. Baker R, Zarate C Jr, Brown E, et al. A three-week comparison of olanzapine versus risperidone in the treatment of bipolar mania: improvement in manic and depressive symptoms and treatment adherence. Presented at: 156th Annual Meeting of the American Psychiatric Association; May 17-22, 2003; San Francisco. Abstract 15.
39. Tohen M, Chengappa KNR, 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;59:62-69.
40. Sachs GS, Grossman F, Ghaemi SN, et al. Combination of a mood stabilizer with risperidone or haloperidol for treatment of acute mania: a double-blind, placebo-controlled comparison of efficacy and safety. Am J Psychiatry. 2002;159:1146-1154.
41. Yatham LN, Grossman F, Augustyns I, et al. Mood stabilizer plus risperidone or placebo in the treatment of acute mania: international, double-blind, randomized, controlled trial. Br J Psychiatry. 2003;182:141-147.
42. Sachs G, Chengappa KN, Suppes T, et al. Quetiapine with lithium or divalproex for the treatment of bipolar mania: a randomized, double-blind, placebo-controlled trial. Bipolar Disord. 2004;6:213-223.
43. Yatham LN, Paulsson B, Mullen J, Vagero AM. Quetiapine versus placebo in combination with lithium or divalproex for the treatment of bipolar mania. J Clin Psychopharmacol. 2004;24:599-606.
44. 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: 392-400.
45. Calabrese JR, Bowden CL, Sachs GS, et al, for the Lamictal 602 Study Group. A double-blind, placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. J Clin Psychiatry. 1999;60:79-88.
46. Baldessarini R, Tondo L, Hennen J. Lithium treatment and suicide risk in major affective disorders: update and new findings. J Clin Psychiatry. 2003;64(suppl 5):44-52.
47. Baldessarini RJ, Tondo L, Hennen J. Treating the suicidal patient with bipolar disorder: reducing suicide risk with lithium. Ann NY Acad Sci. 2001;932:24-38.
48. Tondo L, Hennen J, Baldessarini RJ. Lower suicide risk with long-term lithium treatment in major affective illness: a meta-analysis. Acta Psychiatr Scand. 2001;104:163-172.
49. Baldessarini RJ, Tondo L, Hennen J, Viguera AC. Is lithium still worth using? An update of selected recent research. Harv Rev Psychiatry. 2002;10:59-75.
50. Calabrese JR, Vieta E, Shelton MD. Latest maintenance data on lamotrigine in bipolar disorder. Eur Neuropsychopharmacol. 2003;2:S57-S66.
51. Keck PE, Bowden CL, Meinhold JM, et al. Relationship between serum valproate and lithium levels and efficacy and tolerability in bipolar maintenance therapy. Int J Psychiatry Clin Pract. 2005;9:271-277.
52. Tohen M, Calabrese JR, Sachs G, 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;163:247-256.
53. Keck PE, Calabrese JR, McQuade RD, et al. A randomized, double-blind, placebo-controlled 26 week trial of aripiprazole in recently manic patients with bipolar I disorder. J Clin Psychiatry. 2006;67:627-637.
54. 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;162:1282-1290.
55. Tohen M, Chengappa KN, Suppes T, et al. Relapse prevention in bipolar I disorder: 18-month comparison of olanzapine plus mood stabilizer versus mood stabilizer alone. Br J Psychiatry. 2004;184:337-345.
56. Kinon BJ, Gilmore JA. Long-term olanzapine treatment: weight change and weight-related health factors in schizophrenia. J Clin Psychiatry. 2001;62:92-100.
57. Beasley CM Jr, Tollefson GD, Tran PV, et al. Olanzapine versus placebo and haloperidol: acute phase results of the North American double-blind olanzapine trial. Neuropsychopharmacology. 1996;14:111-123.
58. Ertugrul A, Meltzer HY. Antipsychotic drugs in bipolar disorder. Int J Neuropsychopharmacol. 2003;6:277-284.
59. Bowden CL, Asnia GM, Ginsberg LD, et al. Safety and tolerability of lamotrigine for bipolar disorder. Drug Saf. 2004;27:173-184.
60. Ketter TA, Wang PW, Chander RA, et al. Dermatology precautions and slower titration yield low incidence of lamotrigine treatment-emergent rash. J Clin Psychiatry. 2005;66:642-645.
61. Nguyen C, Jensen B, Franklin D, et al. The difference of a diet: a retrospective study assessing weight and BMI changes among hospitalized patients taking olanzapine before and after implementation of behavioral modifications. Presented at: American Psychiatric Association Annual Meeting; May 20-25, 2006; Toronto.
62. Nguyen CT, Yu B, Maguire G. Update on atypicals: preemptive tactics to reduce weight gain. Curr Psychiatry Online. 2003. Available at: http://www.currentpsychiatry.com/article_pages.asp?AID=614&UID=31489. Accessed November 21, 2006.
63. Kwon SJ, Choi JS, Bahk WM, et al. Weight management program for treatment-emergent weight gain in olanzapine-treated patients with schizophrenia or schizoaffective disorder: a 12-week randomized controlled clinical trial. J Clin Psychiatry. 2006;67:547-553.
64. Ball PM, Coons VB, Buchanan RW. A program for treating olanzapinerelated weight gain. Psychiatr Serv. 2001;52:967-969.
65. Centorrino F, Wurtman JJ, Duca KA, et al. Weight loss in overweight patients maintained on atypical antipsychotic agents. Int J Obes (Lond). 2006;30:1011-1016.
66. Knox JM. A study of weight reducing diets in psychiatric in-patients. Br J Psychiatry. 1980;136:287-289.