CNS Drugs

, Volume 20, Issue 1, pp 29–42 | Cite as

Polytherapy in Bipolar Disorder

  • Daniel Lin
  • Hiram Mok
  • Lakshmi N. Yatham
Therapy In Practice


Bipolar disorder is a life-long condition that is associated with frequent recurrence/relapse of symptoms. Although putative mood stabilisers, such as lithium, are considered to improve the natural course of bipolar disorder, complete long-term remission is rarely achieved. In order to effectively control mood symptoms and to reduce relapse, clinicians often use polypharmacy to treat patients with bipolar disorder. In this article, we examine the recent literature on treatment strategies in bipolar disorder to determine if combination treatments provide additional benefit over monotherapy for the management of various phases of bipolar disorder.

The evidence suggests that for acute mania a combination of lithium or valproate and an atypical antipsychotic is the most effective approach, with approximately 20% more patients responding to the combination than to monotherapy with any antimanic agent. Few studies have examined the use of combination therapy in comparison to monotherapy for bipolar depression. The limited evidence suggests that lithium plus an antidepressant appears to be more effective than lithium alone in those with lower serum lithium concentrations. Similarly, the combination of olanzapine plus fluoxetine is more effective than olanzapine alone. There is consensus that antidepressant monotherapy is not appropriate because of concerns of a manic switch, but monotherapy with lithium or lamotrigine may be adequate for mild to moderate bipolar depression.

For maintenance treatment, commonly used agents, such as lithium, valproate or olanzapine appear to be most effective in preventing manic relapses, whereas lamotrigine is more effective in preventing depressive relapses. As a result of these findings, it makes intuitive sense to combine lamotrigine with lithium, valproate or an atypical antipsychotic to achieve better mood stability. However, the efficacy and safety of such combinations have not been systematically compared with monotherapy. Preliminary studies suggest that lithium plus valproate may be more effective than lithium alone in preventing affective relapses. Similarly, the combination of lithium or valproate plus olanzapine seems to be more effective than monotherapy with a mood stabiliser in preventing manic episodes.


Bipolar Disorder Carbamazepine Risperidone Olanzapine Paroxetine 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Dr Yatham has been a consultant/speaker and received grant funding from Eli Lilly, AstraZeneca, Janssen, Bristol Myers Squibb, and GlaxoSmithKline. Dr Mok has been a consultant and speaker for Lundbeck, Wyeth, Eli Lilly, Janssen and AstraZeneca. No sources of funding were used to assist in the preparation of this review.


  1. 1.
    Goldberg JF, Harrow M, Grossman LS. Course and outcome in bipolar affective disorder: a longitudinal follow-up study. Am J Psychiatry 1995; 152(3): 379–84PubMedGoogle Scholar
  2. 2.
    Hirschfeld RM, 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(2): 161–74PubMedCrossRefGoogle Scholar
  3. 3.
    Dalton EJ, Cate-Carter TD, Mundo E, et al. Suicide risk in bipolar patients: the role of co-morbid substance use disorders. Bipolar Disord 2003; 5(1): 58–61PubMedCrossRefGoogle Scholar
  4. 4.
    Tondo L, Isacsson G, Baldessarini R. Suicidal behaviour in bipolar disorder: risk and prevention. CNS Drugs 2003; 17(7): 491–511PubMedCrossRefGoogle Scholar
  5. 5.
    Sachs GS, Rush AJ. Response, remission, and recovery in bipolar disorders: what are the realistic treatment goals? J Clin Psychiatry 2003; 64Suppl. 6: 18–22PubMedGoogle Scholar
  6. 6.
    Post RM, Denicoff KD, Leverich GS, et al. Morbidity in 258 bipolar outpatients followed for 1 year with daily prospective ratings on the NIMH life chart method. J Clin Psychiatry 2003; 64(6): 680–90PubMedCrossRefGoogle Scholar
  7. 7.
    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(2): 120–5PubMedCrossRefGoogle Scholar
  8. 8.
    Frye MA, Ketter TA, Leverich GS, et al. The increasing use of polypharmacotherapy for refractory mood disorders: 22 years of study. J Clin Psychiatry 2000; 61(1): 9–15PubMedCrossRefGoogle Scholar
  9. 9.
    Freeman MP, Stoll AL. Mood stabilizer combinations: a review of safety and efficacy. Am J Psychiatry 1998; 155(1): 12–21PubMedGoogle Scholar
  10. 10.
    Practice guidelines for the treatment of patients with bipolar disorder (revision). Am J Psychiatry 2002; 159 (4 Suppl.): 1-50Google Scholar
  11. 11.
    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): 918–24Google Scholar
  12. 12.
    McElroy SL, Keck PE, Stanton SP, et al. A randomized comparison of divalproex oral loading versus haloperidol in the initial treatment of acute psychotic mania. J Clin Psychiatry 1996; 57(4): 142–6PubMedGoogle Scholar
  13. 13.
    Oluboka OJ, Bird DC, Kutcher S, et al. A pilot study of loading versus titration of valproate in the treatment of acute mania. Bipolar Disord 2002; 4(5): 341–5PubMedCrossRefGoogle Scholar
  14. 14.
    Post RM, Frye MA, Denicoff KD, et al. Beyond lithium in the treatment of bipolar illness. Neuropsychopharmacology 1998; 19(3): 206–19PubMedCrossRefGoogle Scholar
  15. 15.
    Chou JC. Recent advances in treatment of acute mania. J Clin Psychopharmacol 1991; 11(1): 3–21PubMedGoogle Scholar
  16. 16.
    Leucht S, Pitschel-Walz G, Abraham D, et al. Efficacy and extrapyramidal side-effects of the new antipsychotics olanzapine, quetiapine, risperidone, and sertindole compared to conventional antipsychotics and placebo: a meta-analysis of randomized controlled trials. Schizophr Res 1999; 35(1): 51–68PubMedCrossRefGoogle Scholar
  17. 17.
    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): 702–9Google Scholar
  18. 18.
    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): 841–9CrossRefGoogle Scholar
  19. 19.
    Keck Jr PE, 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(4): 741–8PubMedCrossRefGoogle Scholar
  20. 20.
    Hirschfeld RM, Keck Jr PE, Kramer M, et al. Rapid antimanic effect of risperidone monotherapy: a 3-week multicenter, double-blind, placebo-controlled trial. Am J Psychiatry 2004; 161(6): 1057–65PubMedCrossRefGoogle Scholar
  21. 21.
    Smulevich AB, Khanna S, Eerdekens M, et al. Acute and continuation risperidone monotherapy in bipolar mania: a 3-week placebo-controlled trial followed by a 9-week double-blind trial of risperidone and haloperidol. Eur Neuropsychopharmacol 2005; 15(1): 75–84PubMedCrossRefGoogle Scholar
  22. 22.
    Khanna S, Vieta E, Lyons B, et al. Risperidone in the treatment of acute bipolar mania: a double-blind, placebo-controlled study of 290 patients. Eur Neuropsychopharmacol 2003; 13: S314–5CrossRefGoogle Scholar
  23. 23.
    McIntyre RS, Brecher M, Paulsson B. Quetiapine or haloperidol as monotherapy for bipolar mania: a 12-week, double blind, randomised, parallel group, placebo-controlled trial. Eur Neuropsychopharmacol 2005; 15(5): 573–85PubMedCrossRefGoogle Scholar
  24. 24.
    Segal S, Riesenberg RA, Ice K, et al. Ziprasidone in mania: a 21-day randomized, double-blind, placebo controlled trial. Eur Neuropsychopharmacol 2003; 13: S345–6CrossRefGoogle Scholar
  25. 25.
    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: 229–34PubMedCrossRefGoogle Scholar
  26. 26.
    Jones M, Huizar K. Quetiapine monotherapy for acute mania associated with bipolar disorder (STAMP 1 and STAMP 2) [abstract no. NR432]. 156th APA Annual Meeting; 2003 May 17–22; San Francisco (CA)Google Scholar
  27. 27.
    Berk M, Ichim L, Brook S. Olanzapine compared to lithium in mania: a double-blind randomized controlled trial. Int Clin Psychopharmacol 1999; 14(6): 339–43PubMedCrossRefGoogle Scholar
  28. 28.
    Segal J, Berk M, Brook S. Risperidone compared with both lithium and haloperidol in mania: a double-blind randomized controlled trial. Clin Neuropharmacol 1998; 21(3): 176–80PubMedGoogle Scholar
  29. 29.
    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): 1218–26PubMedCrossRefGoogle Scholar
  30. 30.
    Shi L, Namjoshi MA, Zhang F, et al. Olanzapine versus haloperidol in the treatment of acute mania: clinical outcomes, health-related quality of life and work status. Int Clin Psychopharmacol 2002; 17(5): 227–37PubMedCrossRefGoogle Scholar
  31. 31.
    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(12): 1148–55PubMedCrossRefGoogle Scholar
  32. 32.
    Tohen M, Baker RW, Altshuler LL, et al. Olanzapine versus divalproex in the treatment of acute mania. Am J Psychiatry 2002; 159(6): 1011–7PubMedCrossRefGoogle Scholar
  33. 33.
    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): 111–21PubMedCrossRefGoogle Scholar
  34. 34.
    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): 62–9PubMedCrossRefGoogle Scholar
  35. 35.
    Yatham LN, Grossman F, Augustyns I, et al. Mood stabilisers plus risperidone or placebo in the treatment of acute mania. International, double-blind, randomised controlled trial. Br J Psychiatry 2003; 182: 141–7Google Scholar
  36. 36.
    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(7): 1146–54PubMedCrossRefGoogle Scholar
  37. 37.
    Delbello MP, Schwiers ML, Rosenberg HL, et al. A double-blind, randomized, placebo-controlled study of quetiapine as adjunctive treatment for adolescent mania. J Am Acad Child Adolesc Psychiatry 2002; 41(10): 1216–23PubMedCrossRefGoogle Scholar
  38. 38.
    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 study. Bipolar Disord 2004; 6(3): 213–23PubMedCrossRefGoogle Scholar
  39. 39.
    Sharma V, Persad E, Mazmanian D, et al. Treatment of rapid cycling bipolar disorder with combination therapy of valproate and lithium. Can J Psychiatry 1993; 38(2): 137–9PubMedGoogle Scholar
  40. 40.
    Reischies FM, Hartikainen J, Berghofer A. Initial lithium and valproate combination therapy in acute mania. Neuropsychobiology 2002; 46Suppl. 1: 22–7PubMedCrossRefGoogle Scholar
  41. 41.
    Granneman GR, Schneck DW, Cavanaugh JH, et al. Pharmacokinetic interactions and side effects resulting from concomitant administration of lithium and divalproex sodium. J Clin Psychiatry 1996; 57(5): 204–6PubMedGoogle Scholar
  42. 42.
    Small JG, Klapper MH, Marhenke JD, et al. Lithium combined with carbamazepine or haloperidol in the treatment of mania. Psychopharmacol Bull 1995; 31(2): 265–72PubMedGoogle Scholar
  43. 43.
    Tohen M, Castillo J, Pope Jr HG, et al. Concomitant use of valproate and carbamazepine in bipolar and schizoaffective disorders. J Clin Psychopharmacol 1994; 14(1): 67–70PubMedCrossRefGoogle Scholar
  44. 44.
    Schaff MR, Fawcett J, Zajecka JM. Divalproex sodium in the treatment of refractory affective disorders. J Clin Psychiatry 1993; 54(10): 380–4PubMedGoogle Scholar
  45. 45.
    Ketter TA, Pazzaglia PJ, Post RM. Synergy of carbamazepine and valproic acid in affective illness: case report and review of the literature. J Clin Psychopharmacol 1992; 12(4): 276–81PubMedCrossRefGoogle Scholar
  46. 46.
    Keck Jr PE, McElroy SL, Nemeroff CB. Anticonvulsants in the treatment of bipolar disorder. J Neuropsychiatry Clin Neurosci 1992; 4(4): 395–405PubMedGoogle Scholar
  47. 47.
    Bowden CL. Novel treatments for bipolar disorder. Expert Opin Investig Drugs 2001; 10(4): 661–71PubMedCrossRefGoogle Scholar
  48. 48.
    Chaudhry RP, Waters BG. Lithium and carbamazepine interaction: possible neurotoxicity. J Clin Psychiatry 1983; 44(1): 30–1PubMedGoogle Scholar
  49. 49.
    Shukla S, Godwin CD, Long LE, et al. Lithium-carbamazepine neurotoxicity and risk factors. Am J Psychiatry 1984; 141(12): 1604–6PubMedGoogle Scholar
  50. 50.
    Onady AA, Calabrese JR. Carbamazepine auto- and heteroinduction complicating clinical care. J Clin Psychopharmacol 1989; 9(5): 387–8PubMedGoogle Scholar
  51. 51.
    Sovner R. A clinically significant interaction between carbamazepine and valproic acid. J Clin Psychopharmacol 1988; 8(6): 448–9PubMedCrossRefGoogle Scholar
  52. 52.
    Srisurapanont M, Yatham LN, Zis AP. Treatment of acute bipolar depression: a review of the literature. Can J Psychiatry 1995; 40(9): 533–44PubMedGoogle Scholar
  53. 53.
    Calabrese JR, Bowden CL, Sachs GS, et al. A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. Lamictal 602 Study Group. J Clin Psychiatry 1999; 60(2): 79–88CrossRefGoogle Scholar
  54. 54.
    Frye MA, Ketter TA, Kimbrell TA, et al. A placebo-controlled study of lamotrigine and gabapentin monotherapy in refractory mood disorders. J Clin Psychopharmacol 2000; 20(6): 607–14PubMedCrossRefGoogle Scholar
  55. 55.
    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): 1013–24PubMedCrossRefGoogle Scholar
  56. 56.
    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): 392–400PubMedCrossRefGoogle Scholar
  57. 57.
    Burgess S, Geddes J, Hawton K, et al. Lithium for maintenance treatment of mood disorders. Cochrane Database Syst Rev 2001; (3): CD003013Google Scholar
  58. 58.
    Yatham LN, Calabrese JR, Kusumakar V. Bipolar depression: criteria for treatment selection, definition of refractoriness, and treatment options. Bipolar Disord 2003; 5(2): 85–97PubMedCrossRefGoogle Scholar
  59. 59.
    Peet M. Induction of mania with selective serotonin re-uptake inhibitors and tricyclic antidepressants. Br J Psychiatry 1994; 164(4): 549–50PubMedCrossRefGoogle Scholar
  60. 60.
    Himmelhoch JM, Thase ME, Mallinger AG, et al. Tranylcypromine versus imipramine in anergic bipolar depression. Am J Psychiatry 1991; 148(7): 910–6PubMedGoogle Scholar
  61. 61.
    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(11): 1079–88PubMedCrossRefGoogle Scholar
  62. 62.
    Calabrese JR, Keck Jr PE, 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 Jul; 162(7): 1351–60PubMedCrossRefGoogle Scholar
  63. 63.
    Nemeroff CB, Evans DL, Gyulai L, et al. Double-blind, placebo-controlled comparison of imipramine and paroxetine in the treatment of bipolar depression. Am J Psychiatry 2001; 158(6): 906–12PubMedCrossRefGoogle Scholar
  64. 64.
    Sachs GS, Lafer B, Stoll AL, et al. A double-blind trial of bupropion versus desipramine for bipolar depression. J Clin Psychiatry 1994; 55(9): 391–3PubMedGoogle Scholar
  65. 65.
    Post RM, Altshuler LL, Frye MA, et al. Rate of switch in bipolar patients prospectively treated with second-generation antidepressants as augmentation to mood stabilizers. Bipolar Disord 2001; 3(5): 259–65PubMedCrossRefGoogle Scholar
  66. 66.
    Vieta E, Martinez-Aran A, Goikolea JM, et al. A randomized trial comparing paroxetine and venlafaxine in the treatment of bipolar depressed patients taking mood stabilizers. J Clin Psychiatry 2002; 63(6): 508–12PubMedCrossRefGoogle Scholar
  67. 67.
    Post RM, Altshuler LL, Leverich GS, et al. Higher swtich rates on venlafaxine than bupropion or sertraline in bipolar depression. Br J Psychiatry. In pressGoogle Scholar
  68. 68.
    Young LT, Joffe RT, Robb JC, et al. Double-blind comparison of addition of a second mood stabilizer versus an antidepressant to an initial mood stabilizer for treatment of patients with bipolar depression. Am J Psychiatry 2000; 157(1): 124–6PubMedGoogle Scholar
  69. 69.
    Shelton RC, Stahl SM. Risperidone and paroxetine given singly and in combination for bipolar depression. J Clin Psychiatry 2004; 65(12): 1715–9PubMedCrossRefGoogle Scholar
  70. 70.
    Kusumakar V, Yatham LN. An open study of lamotrigine in refractory bipolar depression. Psychiatry Res 1997; 72(2): 145–8PubMedCrossRefGoogle Scholar
  71. 71.
    Faught E, Morris G, Jacobson M, et al. Adding lamotrignine to valproate: incidence of rash and other adverse effects: Postmarketing Antiepileptic Drug Survey (PADS) group. Epilepsia 1999; 40(8): 1135–40PubMedCrossRefGoogle Scholar
  72. 72.
    Kramlinger KG, Post RM. The addition of lithium to carbamazepine: antidepressant efficacy in treatment-resistant depression. Arch Gen Psychiatry 1989; 46(9): 794–800PubMedCrossRefGoogle Scholar
  73. 73.
    Small JG. Anticonvulsants in affective disorders. Psychopharmacol Bull 1990; 26(1): 25–36PubMedGoogle Scholar
  74. 74.
    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; 60Suppl. 2: 77–84PubMedGoogle Scholar
  75. 75.
    Gelenberg AJ, Kane JM, Keller MB, et al. Comparison of standard and low serum levels of lithium for maintenance treatment of bipolar disorder. N Engl J Med 1989; 321(22): 1489–93PubMedCrossRefGoogle Scholar
  76. 76.
    Maj M, Pirozzi R, Magliano L, et al. Long-term outcome of lithium prophylaxis in bipolar disorder: a 5-year prospective study of 402 patients at a lithium clinic. Am J Psychiatry 1998; 155(1): 30–5PubMedGoogle Scholar
  77. 77.
    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): 481–9Google Scholar
  78. 78.
    Macritchie KA, Geddes JR, Scott J, et al. Valproic acid, valproate and divalproex in the maintenance treatment of bipolar disorder. Cochrane Database Syst Rev 2001; (3): CD003196Google Scholar
  79. 79.
    Calabrese JR, Suppes T, Bowden CL, et al. A double-blind, placebo-controlled, prophylaxis study of lamotrigine in rapid-cycling bipolar disorder. Lamictal 614 Study Group. J Clin Psychiatry 2000; 61(11): 841–50CrossRefGoogle Scholar
  80. 80.
    Dardennes R, Even C, Bange F, et al. Comparison of carbamazepine and lithium in the prophylaxis of bipolar disorders: a meta-analysis. Br J Psychiatry 1995; 166(3): 378–81PubMedCrossRefGoogle Scholar
  81. 81.
    Kleindienst N, Greil W. Differential efficacy of lithium and carbamazepine in the prophylaxis of bipolar disorder: results of the MAP study. Neuropsychobiology 2000; 42Suppl. 1: 2–10PubMedCrossRefGoogle Scholar
  82. 82.
    Greil W, Ludwig-Mayerhofer W, Erazo N, et al. Lithium versus carbamazepine in the maintenance treatment of bipolar disorders: a randomised study. J Affect Disord 1997; 43(2): 151–61PubMedCrossRefGoogle Scholar
  83. 83.
    Greil W, Kleindienst N. The comparative prophylactic efficacy of lithium and carbamazepine in patients with bipolar I disorder. Int Clin Psychopharmacol 1999; 14(5): 277–81PubMedGoogle Scholar
  84. 84.
    Greil W, Kleindienst N. Lithium versus carbamazepine in the maintenance treatment of bipolar II disorder and bipolar disorder not otherwise specified. Int Clin Psychopharmacol 1999; 14(5): 283–5PubMedGoogle Scholar
  85. 85.
    Yatham LN. Acute and maintenance treatment of bipolar mania: the role of atypical antipsychotics. Bipolar Disord 2003; 5Suppl. 2: 7–19PubMedCrossRefGoogle Scholar
  86. 86.
    Tohen MT, Bowden C, Calabrese J, et al. Olanzapine versus placebo for relapse prevention in bipolar disorder. Arch Gen Psychiatry. In pressGoogle Scholar
  87. 87.
    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): 1281–90PubMedCrossRefGoogle Scholar
  88. 88.
    American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. Washington, DC: American Psychiatric Association, 1994Google Scholar
  89. 89.
    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: 337–45CrossRefGoogle Scholar
  90. 90.
    Solomon DA, Ryan CE, Keitner GI, et al. A pilot study of lithium carbonate plus divalproex sodium for the continuation and maintenance treatment of patients with bipolar I disorder. J Clin Psychiatry 1997; 58(3): 95–9PubMedCrossRefGoogle Scholar
  91. 91.
    Denicoff KD, Smith-Jackson EE, Disney ER, et al. Comparative prophylactic efficacy of lithium, carbamazepine, and the combination in bipolar disorder. J Clin Psychiatry 1997; 58(11): 470–8PubMedCrossRefGoogle Scholar
  92. 92.
    Denicoff KD, Smith-Jackson EE, Bryan AL, et al. Valproate prophylaxis in a prospective clinical trial of refractory bipolar disorder. Am J Psychiatry 1997; 154(10): 1456–8PubMedGoogle Scholar
  93. 93.
    Kusumakar V, Yatham LN, Haslam DR, et al. The foundations of effective management of bipolar disorder. Can J Psychiatry 1997; 42Suppl. 2: 69S-73SGoogle Scholar
  94. 94.
    Yatham LN, Kusumakar V, Parikh SV, et al. Bipolar depression: treatment options. Can J Psychiatry 1997; 42Suppl. 2: 87S–91SPubMedGoogle Scholar
  95. 95.
    Colom F, Vieta E, Martinez-Aran A, et al. A randomized trial on the efficacy of group psychoeducation in the prophylaxis of recurrences in bipolar patients whose disease is in remission. Arch Gen Psychiatry 2003; 60(4): 402–7PubMedCrossRefGoogle Scholar
  96. 96.
    Perry A, Tarder N, Morriss R, et al. Randomised controlled trial of efficacy of teaching patients with bipolar disorder to identify early symptoms of relapse and obtain treatment. BMJ 1999; 318(7177): 149–53PubMedCrossRefGoogle Scholar
  97. 97.
    Lam DH, Watkins ER, Hayward P, et al. A randomized controlled study of cognitive therapy for relapse prevention for bipolar affective disorder: outcome of the first year. Arch Gen Psychiatry 2003; 60(2): 145–52PubMedCrossRefGoogle Scholar
  98. 98.
    Miklowitz DJ, Simoneau TL, George EL, et al. Family-focused treatment of bipolar disorder: 1-year effects of a psychoeducational program in conjunction with pharmacotherapy. Biol Psychiatry 2000; 48(6): 582-92PubMedCrossRefGoogle Scholar

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© Adis Data Information BV 2006

Authors and Affiliations

  1. 1.Department of PsychiatryUniversity of British ColumbiaVancouverCanada
  2. 2.Department of Psychiatry, Mood Disorders CentreUniversity of British ColumbiaVancouverCanada

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