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Atypical Antipsychotics in Bipolar Disorder



Data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), a large NIMH-sponsored multicenter study designed to determine optimal acute and chronic pharmacologic and behavioral interventions for the treatment of bipolar disorder, has started to become publicly available. After enrollment in the study, patients received evaluations every 3 months during their first year and then every 6 months thereafter. As this study first started enrolling patients in 1998, the usage pattern of the agents, in particular the newer anticonvulsants and/or second generation antipsychotics, may have subsequently changed. The most commonly prescribed class of medications at study entry, the standard mood stabilizers like lithium, valproate, or carbamazepine, were taken by 72% of patients. The newer anticonvulsants (lamotrigine, gabapentin, and topiramate) were taken by 32% of patients. Nearly 41% of patients were treated with antidepressants, and 27% were taking second-generation atypical antipsychotics. Only 11% of patients were treated with mood stabilizer monotherapy.[30]

STEP-BD was designed as a hybrid to include patients in both naturalistic long-term follow-up along with those in randomized, placebo-controlled clinical trials. The overall study included patients with bipolar disorder of all subtypes, severity, and demographic groups. All study clinicians received a minimum of 20 hours of treatment-related study in the management of bipolar disorder[31] based on expert opinion consensus guidelines.[32] They were encouraged to offer patients treatments from "Menus of Reasonable Choices" and were not forced to adhere to a formal treatment algorithm within the naturalistic part of the study. The study designers intended for STEP-BD to serve well-characterized bipolar subjects who could enter both clinical trials and randomized pathways for acute depression, refractory depression, and relapse prevention. The randomized care pathways generally had more rigorous inclusion criteria than did the naturalistic arm of the study and were primarily designed to compare one of several psychotropic medication regimens considered first-line treatment options.[32]

The significant relapse rates seen in the STEP-BD population further highlight the need for newer and better behavioral and pharmacologic interventions. Of interest, over a 24-month follow-up of 1469 patients who were symptomatic at study entry, only 58% achieved recovery, defined as 2 or fewer syndromal features of mania, hypomania, or depression for at least 8 weeks. However, 49% of these patients had a recurrence of symptoms after being free of symptoms for 8 or more weeks: 35% of patients relapsed into a depression, and 14% of patients relapsed into a mania.[33] Data from this study are available at

Despite the advances in the management of acute mania, the treatment of bipolar depression remains a formidable challenge. There is increasing evidence that the largest part of the disability of bipolar disorder stems from the depressive phase of the illness. A long-term longitudinal study of patients with bipolar I disorder followed over a 12-year period is of interest.[34] Patients were symptomatically ill approximately 47% of the time over the 12-year period they were followed, spending nearly 3-fold more time experiencing syndromal or subsyndromal depressive symptoms as compared with manic or hypomanic symptoms. Currently, a clear demonstration of the efficacy of the atypical antipsychotics, with the exception of quetiapine and the olanzapine/fluoxetine combination, in the treatment of bipolar depression is still lacking. There is evidence that lamotrigine,[35] quetiapine,[18,36] olanzapine, and the fluoxetine-olanzapine combination[37] are effective in the treatment of bipolar depression, as are various antidepressants and electroconvulsive therapy, though a number of failed trials have been reported.[38] Of note, lamotrigine, which was approved by the FDA for the prevention of recurring episodes of bipolar disorder, is not effective in the treatment of acute mania. Other monotherapy trials with anticonvulsants, including gabapentin, oxcarbazepine, and topiramate, also have failed to document efficacy for the management of acute mania.[39,40]

A review of the literature highlights the significant unmet needs in the treatment of bipolar disorder. Even in the most recent studies described above, clinical remission rates are suboptimal. Although this is in part related to the relatively brief observation period of 21 days for the majority of acute mania, long-term maintenance studies have also demonstrated a high rate of relapse within the 6- to 18-month observation period usual in many of these studies. Although monotherapy would be ideal, it is not realistic for a sizeable percentage of bipolar patients. Like cancer and hypertension, bipolar disorder requires considerable pharmacologic management coupled with psychotherapeutic intervention to achieve the highest rates of remission. Until we obtain a better understanding of the pathophysiology of bipolar disorder, we must be guided by evidence of the best current treatment of this devastating disorder.

Supported by an independent educational grant from GlaxoSmithKline.



  1. Robins LN, Reiger DA. Psychiatric Disorders in America: The Epidemiologic Catchment Area Study. New York, NY: Free Press; 1991.
  2. Kessler RC, McGonagle KA, Zhao S, et al. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Arch Gen Psychiatry. 1994;51:8-19. Abstract
  3. Valtonen H, Suominen K, Mantere O, Leppamaki S, Arvilommi P, Isometsa ET. Suicidal ideation and attempts in bipolar I and II disorders. J Clin Psychiatry. 2005;66:1456-1462. Abstract
  4. Strakowski SM, McElroy SL, Keck PE Jr, West SA. Suicidality among patients with mixed and manic bipolar disorder. Am J Psychiatry. 1996;153:674-676. Abstract
  5. Cipriani A, Rendell JM, Geddes JR. Haloperidol alone or in combination for acute mania. Cochrane Database Syst Rev.2006;3:CD004362.
  6. 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;57:841-849. Abstract
  7. Tohen M, Baker RW, Altshuler LL, et al. Olanzapine versus divalproex in the treatment of acute mania. Am J Psychiatry. 2002;159:1011-1017. Abstract
  8. Zajecka, JM, Weisler R, Sachs G, Swann AC, Wozniak P, Sommerville KW. 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. Abstract
  9. 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;59:62-69. Abstract
  10. 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. Abstract
  11. 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. Abstract
  12. 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;271:918-924. Abstract
  13. 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. Abstract
  14. McIntyre RS, Brecher M, Paulsson B, Huizar K, Mullen J. 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. Abstract
  15. Vieta E, Mullen J, Brecher M, Paulsson B, Jones M. Quetiapine monotherapy for mania associated with bipolar disorder: combined analysis of two international, double-blind, randomised, placebo-controlled studies. Curr Med Res Opin. 2005;21:923-934. Abstract
  16. 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. Abstract
  17. 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. Abstract
  18. 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;162:1351-1360. Abstract
  19. Thase ME, Macfadden W, Weisler RH, et al; BOLDER II Study Group. Efficacy of quetiapine monotherapy in bipolar I and II depression: a double-blind, placebo-controlled study (the BOLDER II study). J Clin Psychopharmacol. 2006;26:600-609. Abstract
  20. 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. Abstract
  21. Khanna SE, 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. Abstract
  22. 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. Abstract
  23. Bahk WM, Yoon JS, Kim YH, et al. Risperidone in combination with mood stabilizers for acute mania: a multicentre, open study. Int Clin Psychopharmacol. 2004;19:299-303. Abstract
  24. Keck PE Jr, Versiani M, Potkin S, West SA, Giller E, Ice K; Ziprasidone in Mania Study Group. Ziprasidone in the treatment of acute bipolar mania: a three-week, placebo-controlled, double-blind, randomized trial. Am J Psychiatry. 2003;160:741-748. Abstract
  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;25:301.
  26. Nicolson S, Nemeroff CB. Geodon in the treatment of mania. Neuropsychiatr Dis Treat. In press.
  27. 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. Abstract
  28. Sachs G, Sanchez R, Marcus R, et al; Aripiprazole Study Group. 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. Abstract
  29. Keck PE Jr, 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;67:626-637. Abstract
  30. Ghaemi, SN, Hsu DJ, Thase ME, et al. Pharmacological treatment patterns at study entry for the first 500 STEP-BD participants. Psychiatr Serv. 2006;57:660-665. Abstract
  31. Sachs GS, Thase ME, Otto MW, et al. Rationale, design, and methods of the systematic treatment enhancement program for bipolar disorder (STEP-BD). Biol Psychiatry. 2003;53:1028-1042. Abstract
  32. Sachs GS, Printz DJ, Kahn DA, Carpenter D, Docherty JP. The Expert Consensus Guideline Series: Medication Treatment of Bipolar Disorder 2000. Postgrad Med, 2000;Spec No:1-104.
  33. Perlis RH, Ostacher MJ, Patel JK, et al. Predictors of recurrence in bipolar disorder: primary outcomes from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Am J Psychiatry, 2006;163:217-224.
  34. Judd LL, Akiskal HS, Schettler PJ, et al. The long-term natural history of the weekly symptomatic status of bipolar I disorder. Arch Gen Psychiatry. 2002;59:530-537. Abstract
  35. Calabrese JR, Bowden CL, Sachs GS, Ascher JA, Monaghan R, Rudd GD. A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. Lamictal 602 Study Group. J Clin Psychiatry. 1999;60:79-88. Abstract
  36. Vieta E, Goikolea JM. Atypical antipsychotics: newer options for mania and maintenance therapy. Bipolar Disord. 2005;7(suppl 4):21-33. Abstract
  37. Tohen M, Vieta E, Calabrese J, et al. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry. 2003;60:1079-1188. Abstract
  38. Gitlin M. Treatment-resistant bipolar disorder. Mol Psychiatry. 2006;11:227-240. Abstract
  39. Goodnick PJ. Anticonvulsants in the treatment of bipolar mania. Expert Opin Pharmacother. 2006;7:401-410. Abstract
  40. Kushner SF, Khan A, Lane R, Olson WH. Topiramate monotherapy in the management of acute mania: results of four double-blind placebo-controlled trials. Bipolar Disord. 2006;8:15-27. Abstract