Skip to main content
SpringerLink
Log in

Evidence Based Combination Therapy for Bipolar Disorder

  • Chapter
  • First Online:
Polypharmacy in Psychiatry Practice, Volume II

Abstract

The treatment of bipolar illness is complex and full of caveats for the clinician, and it seems that at least some aspects of the disorder are rather refractory to treatment. While some agents are efficacious as monotherapy, the overall outcome is unsatisfactory. However, only specific combinations have solid evidence supporting their efficacy. Antidepressants should only be used in combination with an antimanic agent, because they can induce switching to mania/hypomania/mixed states/or rapid cycling when utilized as monotherapy however only fluoxetine in combination with olanzapine has data supporting its usefulness for the treatment of bipolar depression. Adding an antipsychotic to acutely manic patients who are partial responders to lithium/valproate/carbamazepine is a reasonable choice. The combination with best data in acute bipolar depression is lithium plus lamotrigine. Patients stabilized on combination treatment might do worse if shifted to monotherapy during maintenance, and patients refractory to monotherapy could benefit with add on treatment with olanzapine, valproate, an antidepressant or lamotrigine, depending on the index acute phase. Combination therapy may improve treatment outcome but it also carries more side-effect burden. Further research is necessary as well as the development of better guidelines and algorithms for the step-by-step rational treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

BD:

Bipolar Disorder

ECT:

Electroconvulsive Therapy

HDRS-21:

Hamilton Depression Rating Scale-21

Li:

Lithium

MADRS:

Montgomery-Asberg Depression Rating Scale

OFC:

Olanzapine-fluoxetine combination

RCT:

Randomised Controlled Studies

YMRS:

Young Mania Rating Scale

References

  1. Ng B, Camacho A, Lara DR et al (2007) A case series on the hypothesized connection between dementia and bipolar spectrum disorders: bipolar type VI? J Affect Disord 107:307–315

    Article  PubMed  Google Scholar 

  2. Akiskal HS (1996) The prevalent clinical spectrum of bipolar disorders: beyond DSM-IV. J Clin Psychopharmacol 16(2 Suppl 1):4S–14S

    Article  PubMed  CAS  Google Scholar 

  3. Akiskal HS, Pinto O (1999) The evolving bipolar spectrum prototypes I, II, III, and IV. Psychiatr Clin North Am 22(3):517–534, vii

    Article  PubMed  CAS  Google Scholar 

  4. Akiskal HS, Benazzi F (2004) Validating Kraepelin’s two types of depressive mixed states: “depression with flight of ideas” and “excited depression”. World J Biol Psychiatry 5(2):107–113

    Article  PubMed  Google Scholar 

  5. Winokur G, Turvey C, Akiskal H et al (1998) Alcoholism and drug abuse in three groups—bipolar I, unipolars and their acquaintances. J Affect Disord 50(2–3):81–89

    Article  PubMed  CAS  Google Scholar 

  6. Goldberg JF, Harrow M, Grossman LS (1995) Course and outcome in bipolar affective disorder: a longitudinal follow-up study. Am J Psychiatry 152(3):379–384

    PubMed  CAS  Google Scholar 

  7. Goldberg JF, Harrow M, Grossman LS (1995) Recurrent affective syndromes in bipolar and unipolar mood disorders at follow-up. Br J Psychiatry 166(3):382–385

    Article  PubMed  CAS  Google Scholar 

  8. Keck PE Jr, McElroy SL, Strakowski SM et al (1998) 12-month outcome of patients with bipolar disorder following hospitalization for a manic or mixed episode. Am J Psychiatry 155(5):646–652

    PubMed  Google Scholar 

  9. Strakowski SM, Keck PE Jr, McElroy SL et al (1998) Twelve-month outcome after a first hospitalization for affective psychosis. Arch Gen Psychiatry 55(1):49–55

    Article  PubMed  CAS  Google Scholar 

  10. Martinez-Aran A, Vieta E, Torrent C et al (2007) Functional outcome in bipolar disorder: the role of clinical and cognitive factors. Bipolar Disord 9(1–2):103–113

    Article  PubMed  CAS  Google Scholar 

  11. Mur M, Portella MJ, Martinez-Aran A et al (2007) Persistent neuropsychological deficit in euthymic bipolar patients: executive function as a core deficit. J Clin Psychiatry 68(7):1078–1086

    Article  PubMed  Google Scholar 

  12. Daban C, Martinez-Aran A, Torrent C et al (2006) Specificity of cognitive deficits in bipolar disorder versus schizophrenia a systematic review. Psychother Psychosom 75(2):72–84

    Article  PubMed  Google Scholar 

  13. Kraepelin E (1921) Manic-depressive insanity and paranoia. Robertson GM, Barclay RM (translator, ed), Livingstone, Edinburgh

    Google Scholar 

  14. Tohen M, Waternaux CM, Tsuang MT (1990) Outcome in mania. A 4-year prospective follow-up of 75 patients utilizing survival analysis. Arch Gen Psychiatry 47(12):1106–1111

    Article  PubMed  CAS  Google Scholar 

  15. Angst J (1998) The emerging epidemiology of hypomania and bipolar II disorder. J Affect Disord 50:143–151

    Article  PubMed  CAS  Google Scholar 

  16. Judd LL, Akiskal HS (2003) The prevalence and disability of bipolar spectrum disorders in the US population: re-analysis of the ECA database taking into account subthreshold cases. J Affect Disord 73(1–2):123–131

    Article  PubMed  Google Scholar 

  17. Acorn S (1993) Mental and physical health of homeless persons who use emergency shelters in Vancouver. Hosp Community Psychiatry 44(9):854–857

    PubMed  CAS  Google Scholar 

  18. Angst J, Azorin JM, Bowden CL et al (2011) Prevalence and characteristics of undiagnosed bipolar disorders in patients with a major depressive episode: the BRIDGE study. Arch Gen Psychiatry 68(8):791–798

    Article  PubMed  Google Scholar 

  19. Angst J, Gamma A, Bowden CL et al (2011) Diagnostic criteria for bipolarity based on an international sample of 5,635 patients with DSM-IV major depressive episodes. Eur Arch Psychiatry Clin Neurosci

    Google Scholar 

  20. World Health Organization (2003) The world health report 2003—shaping the future. WHO, Geneva

    Google Scholar 

  21. Fountoulakis KN, Grunze H, Panagiotidis P et al (2008) Treatment of bipolar depression: an update. J Affect Disord 109(1–2):21–34

    Article  PubMed  Google Scholar 

  22. Fountoulakis KN, Vieta E, Sanchez-Moreno J et al (2005) Treatment guidelines for bipolar disorder: a critical review. J Affect Disord 86(1):1–10

    Article  PubMed  CAS  Google Scholar 

  23. Fountoulakis KN, Vieta E, Siamouli M et al (2007) Treatment of bipolar disorder: a complex treatment for a multi-faceted disorder. Ann Gen Psychiatry 6:27

    Article  PubMed  Google Scholar 

  24. Garfinkel PE, Stancer HC, Persad E (1980) A comparison of haloperidol, lithium carbonate and their combination in the treatment of mania. J Affect Disord 2(4):279–288

    Article  PubMed  CAS  Google Scholar 

  25. Sachs GS, Grossman F, Ghaemi SN et al (2002) 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 159(7):1146–1154

    Article  PubMed  Google Scholar 

  26. Chou JC, Czobor P, Charles O et al (1999) Acute mania: haloperidol dose and augmentation with lithium or lorazepam. J Clin Psychopharmacol 19(6):500–505

    Article  PubMed  CAS  Google Scholar 

  27. Lenox RH, Newhouse PA, Creelman WL et al (1992) Adjunctive treatment of manic ­agitation with lorazepam versus haloperidol: a double-blind study. J Clin Psychiatry 53(2):47–52

    PubMed  CAS  Google Scholar 

  28. Small JG, Klapper MH, Marhenke JD et al (1995) Lithium combined with carbamazepine or haloperidol in the treatment of mania. Psychopharmacol Bull 31(2):265–272

    PubMed  CAS  Google Scholar 

  29. Klein E, Bental E, Lerer B et al (1984) Carbamazepine and haloperidol v placebo and ­haloperidol in excited psychoses a controlled study. Arch Gen Psychiatry 41(2):165–170

    Article  PubMed  CAS  Google Scholar 

  30. Tohen M, Bowden CL, Smulevich AB et al (2008) Olanzapine plus carbamazepine v. ­carbamazepine alone in treating manic episodes. Br J Psychiatry 192(2):135–143

    Article  PubMed  Google Scholar 

  31. Amrollahi Z, Rezaei F, Salehi B, et al (2010) Double-blind, randomized, placebo-controlled 6-week study on the efficacy and safety of the tamoxifen adjunctive to lithium in acute ­bipolar mania. J Affect Disord (in press)

    Google Scholar 

  32. Pande AC, Crockatt JG, Janney CA et al (2000) Gabapentin in bipolar disorder: a placebo-controlled trial of adjunctive therapy gabapentin bipolar disorder study group. Bipolar Disord 2(3 Pt 2):249–255

    Article  PubMed  CAS  Google Scholar 

  33. Mishory A, Yaroslavsky Y, Bersudsky Y et al (2000) Phenytoin as an antimanic anticonvulsant: a controlled study. Am J Psychiatry 157(3):463–465

    Article  PubMed  CAS  Google Scholar 

  34. Yatham LN, Grossman F, Augustyns I et al (2003) Mood stabilisers plus risperidone or ­placebo in the treatment of acute mania. International, double-blind, randomised controlled trial. Br J Psychiatry 182:141–147

    Article  PubMed  Google Scholar 

  35. Juruena MF, Ottoni GL, Machado-Vieira R et al (2009) Bipolar I and II disorder residual symptoms: oxcarbazepine and carbamazepine as add-on treatment to lithium in a double-blind, randomized trial. Prog Neuropsychopharmacol Biol Psychiatry 33(1):94–99

    Article  PubMed  CAS  Google Scholar 

  36. Tohen M, Chengappa KN, Suppes T et al (2002) 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 59(1):62–69

    Article  PubMed  CAS  Google Scholar 

  37. Houston JP, Ahl J, Meyers AL et al (2006) 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 67(8):1246–1252

    Article  PubMed  CAS  Google Scholar 

  38. Sachs G, Chengappa KN, Suppes T et al (2004) Quetiapine with lithium or divalproex for the treatment of bipolar mania: a randomized, double-blind, placebo-controlled study. Bipolar Disord 6(3):213–223

    Article  PubMed  CAS  Google Scholar 

  39. Yatham LN, Paulsson B, Mullen J et al (2004) Quetiapine versus placebo in combination with lithium or divalproex for the treatment of bipolar mania. J Clin Psychopharmacol 24(6):599–606

    Article  PubMed  CAS  Google Scholar 

  40. Yatham LN, Vieta E, Young AH et al (2007) A double blind, randomized, placebo-controlled trial of quetiapine as an add-on therapy to lithium or divalproex for the treatment of bipolar mania. Int Clin Psychopharmacol 22(4):212–220

    Article  PubMed  Google Scholar 

  41. Vieta E, T’Joen C, McQuade RD et al (2008) 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 165(10):1316–1325

    Article  PubMed  Google Scholar 

  42. Muller-Oerlinghausen B, Retzow A, Henn FA et al (2000) Valproate as an adjunct to ­neuroleptic medication for the treatment of acute episodes of mania: a prospective, ­randomized, double-blind, placebo-controlled, multicenter study European Valproate Mania Study Group. J Clin Psychopharmacol 20(2):195–203

    Article  PubMed  CAS  Google Scholar 

  43. Weisler R, Dunn J, English P (2003) Adjunctive Ziprasidone for acute bipolar mania: ­randomized, placebo-controlled trial. 4th international forum on mood and anxiety disorders, November 19–21, Monte Carlo, Monaco 2003

    Google Scholar 

  44. unpublished A three-week, double-blind, multicenter, placebo-controlled study evaluating the efficacy and safety of add-on oral ziprasidone in subjects with acute mania treated with lithium or divalproex 2011 [September 5th, 2011]. Available from: http://www.clinicalstudyresults.org/documents/company-study_9884_0.pdf

  45. Roy Chengappa KN, Schwarzman LK, Hulihan JF et al (2006) Adjunctive topiramate ­therapy in patients receiving a mood stabilizer for bipolar I disorder: a randomized, placebo-­controlled trial. J Clin Psychiatry 67(11):1698–1706

    Article  PubMed  CAS  Google Scholar 

  46. Berwaerts J, Lane R, Nuamah IF, et al (2010) Paliperidone extended-release as adjunctive therapy to lithium or valproate in the treatment of acute mania: a randomized, placebo-­controlled study. J Affect Disord (in press)

    Google Scholar 

  47. Machado-Vieira R, Soares JC, Lara DR et al (2008) A double-blind, randomized, placebo-controlled 4-week study on the efficacy and safety of the purinergic agents allopurinol and dipyridamole adjunctive to lithium in acute bipolar mania. J Clin Psychiatry 69(8):1237–1245

    Article  PubMed  CAS  Google Scholar 

  48. Nery FG, Monkul ES, Hatch JP et al (2008) Celecoxib as an adjunct in the treatment of depressive or mixed episodes of bipolar disorder: a double-blind, randomized, placebo-controlled study. Hum Psychopharmacol 23(2):87–94

    Article  PubMed  CAS  Google Scholar 

  49. Behzadi AH, Omrani Z, Chalian M et al (2009) Folic acid efficacy as an alternative drug added to sodium valproate in the treatment of acute phase of mania in bipolar disorder: a double-blind randomized controlled trial. Acta Psychiatr Scand 120(6):441–445

    Article  PubMed  CAS  Google Scholar 

  50. Bersudsky Y, Applebaum J, Gaiduk Y et al (2010) Valnoctamide as a valproate substitute with low teratogenic potential in mania: a double-blind, controlled, add-on clinical trial. Bipolar Disord 12(4):376–382

    Article  PubMed  CAS  Google Scholar 

  51. McElroy SL, Winstanley EL, Martens B et al (2010) A randomized, placebo-controlled study of adjunctive ramelteon in ambulatory bipolar I disorder with manic symptoms and sleep disturbance. Int Clin Psychopharmacol 26(1):48–53

    Article  Google Scholar 

  52. Prien RF, Kupfer DJ, Mansky PA et al (1984) Drug therapy in the prevention of recurrences in unipolar and bipolar affective disorders. Report of the NIMH Collaborative Study Group comparing lithium carbonate, imipramine, and a lithium carbonate-imipramine combination. Arch Gen Psychiatry 41(11):1096–1104

    Article  PubMed  CAS  Google Scholar 

  53. Prien RF, Klett CJ, Caffey EM Jr (1973) Lithium carbonate and imipramine in prevention of affective episodes. A comparison in recurrent affective illness. Arch Gen Psychiatry 29(3):420–425

    Article  PubMed  CAS  Google Scholar 

  54. Kane JM, Quitkin FM, Rifkin A et al (1982) Lithium carbonate and imipramine in the ­prophylaxis of unipolar and bipolar II illness: a prospective, placebo-controlled comparison. Arch Gen Psychiatry 39(9):1065–1069

    Article  PubMed  CAS  Google Scholar 

  55. Nemeroff CB, Evans DL, Gyulai L et al (2001) Double-blind, placebo-controlled comparison of imipramine and paroxetine in the treatment of bipolar depression. Am J Psychiatry 158(6):906–912

    Article  PubMed  CAS  Google Scholar 

  56. Sachs GS, Lafer B, Stoll AL et al (1994) A double-blind trial of bupropion versus desipramine for bipolar depression. J Clin Psychiatry 55(9):391–393

    PubMed  CAS  Google Scholar 

  57. Post RM, Altshuler LL, Frye MA et al (2001) Rate of switch in bipolar patients prospectively treated with second-generation antidepressants as augmentation to mood stabilizers. Bipolar Disord 3(5):259–265

    Article  PubMed  CAS  Google Scholar 

  58. Post RM, Altshuler LL, Leverich GS et al (2006) Mood switch in bipolar depression: comparison of adjunctive venlafaxine, bupropion and sertraline. Br J Psychiatry 189:124–131

    Article  PubMed  CAS  Google Scholar 

  59. Altshuler LL, Post RM, Hellemann G et al (2009) Impact of antidepressant continuation after acute positive or partial treatment response for bipolar depression: a blinded, randomized study. J Clin Psychiatry 70(4):450–457

    Article  PubMed  CAS  Google Scholar 

  60. Schaffer A, Zuker P, Levitt A (2006) Randomized, double-blind pilot trial comparing lamotrigine versus citalopram for the treatment of bipolar depression. J Affect Disord 96(1–2):95–99

    Article  PubMed  CAS  Google Scholar 

  61. Pilhatsch M, Wolf R, Winter C et al (2010) Comparison of paroxetine and amitriptyline as adjunct to lithium maintenance therapy in bipolar depression: a reanalysis of a randomized, double-blind study. J Affect Disord 126(3):453–457

    Article  PubMed  CAS  Google Scholar 

  62. Tohen M, Vieta E, Calabrese J et al (2003) Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry 60(11):1079–1088

    Article  PubMed  CAS  Google Scholar 

  63. Brown EB, McElroy SL, Keck PE Jr et al (2006) A 7-week, randomized, double-blind trial of olanzapine/fluoxetine combination versus lamotrigine in the treatment of bipolar I depression. J Clin Psychiatry 67(7):1025–1033

    Article  PubMed  CAS  Google Scholar 

  64. Sachs GS, Nierenberg AA, Calabrese JR et al (2007) Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med 356(17):1711–1722

    Article  PubMed  CAS  Google Scholar 

  65. Young LT, Joffe RT, Robb JC et al (2000) 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 157(1):124–126

    PubMed  CAS  Google Scholar 

  66. Bocchetta A, Bernardi F, Burrai C et al (1993) A double-blind study of L-sulpiride versus amitriptyline in lithium-maintained bipolar depressives. Acta Psychiatr Scand 88(6):434–439

    Article  PubMed  CAS  Google Scholar 

  67. Shelton RC, Stahl SM (2004) Risperidone and paroxetine given singly and in combination for bipolar depression. J Clin Psychiatry 65(12):1715–1719

    Article  PubMed  CAS  Google Scholar 

  68. McElroy SL, Weisler RH, Chang W et al (2010) A double-blind, placebo-controlled study of quetiapine and paroxetine as monotherapy in adults with bipolar depression (EMBOLDEN II). J Clin Psychiatry 71(2):163–174

    Article  PubMed  CAS  Google Scholar 

  69. van der Loos ML, Mulder PG, Hartong EG et al (2009) Efficacy and safety of lamotrigine as add-on treatment to lithium in bipolar depression: a multicenter, double-blind, placebo-­controlled trial. J Clin Psychiatry 70(2):223–231

    Article  PubMed  Google Scholar 

  70. van der Loos ML, Mulder P, Hartong EG et al (2011) Long-term outcome of bipolar depressed patients receiving lamotrigine as add-on to lithium with the possibility of the addition of paroxetine in nonresponders: a randomized, placebo-controlled trial with a novel design. Bipolar Disord 13(1):111–117

    Article  PubMed  CAS  Google Scholar 

  71. van der Loos ML, Mulder P, Hartong EG et al (2010) Efficacy and safety of two treatment algorithms in bipolar depression consisting of a combination of lithium, lamotrigine or ­placebo and paroxetine. Acta Psychiatr Scand 122(3):246–254

    Article  PubMed  CAS  Google Scholar 

  72. Quante A, Zeugmann S, Luborzewski A et al (2010) Aripiprazole as adjunct to a mood ­stabilizer and citalopram in bipolar depression: a randomized placebo-controlled pilot study. Hum Psychopharmacol 25(2):126–132

    Article  PubMed  CAS  Google Scholar 

  73. Sachs GS, Ice KS, Chappell PB et al (2011) Efficacy and safety of adjunctive oral ziprasidone for acute treatment of depression in patients with bipolar I disorder: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 72:1413

    Article  PubMed  CAS  Google Scholar 

  74. Saricicek A, Maloney K, Muralidharan A et al (2010) Lvetiracetam in the management of bipolar depression: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 72:744–750

    Article  PubMed  CAS  Google Scholar 

  75. Diazgranados N, Ibrahim L, Brutsche NE et al (2010) A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry 67(8):793–802

    Article  PubMed  CAS  Google Scholar 

  76. Denicoff KD, Smith-Jackson EE, Disney ER et al (1997) Comparative prophylactic efficacy of lithium, carbamazepine, and the combination in bipolar disorder. J Clin Psychiatry 58(11):470–478

    Article  PubMed  CAS  Google Scholar 

  77. Zarate CA Jr, Tohen M (2004) Double-blind comparison of the continued use of antipsychotic treatment versus its discontinuation in remitted manic patients. Am J Psychiatry 161(1):169–171

    Article  PubMed  Google Scholar 

  78. Brown E, Dunner DL, McElroy SL et al (2009) Olanzapine/fluoxetine combination vs. lamotrigine in the 6-month treatment of bipolar I depression. Int J Neuropsychopharmacol 12(6):773–782

    Article  PubMed  CAS  Google Scholar 

  79. Vieta E, Suppes T, Eggens I et al (2008) 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 109(3):251–263

    Article  PubMed  CAS  Google Scholar 

  80. Suppes T, Vieta E, Liu S et al (2009) 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 166(4):476–488

    Article  PubMed  Google Scholar 

  81. Vieta E, Manuel Goikolea J, Martinez-Aran A et al (2006) A double-blind, randomized, placebo-controlled, prophylaxis study of adjunctive gabapentin for bipolar disorder. J Clin Psychiatry 67(3):473–477

    Article  PubMed  CAS  Google Scholar 

  82. Mishory A, Winokur M, Bersudsky Y (2003) Prophylactic effect of phenytoin in bipolar disorder: a controlled study. Bipolar Disord 5(6):464–467

    Article  PubMed  CAS  Google Scholar 

  83. Vieta E, Cruz N, Garcia-Campayo J et al (2008) A double-blind, randomized, placebo-­controlled prophylaxis trial of oxcarbazepine as adjunctive treatment to lithium in the long-term treatment of bipolar I and II disorder. Int J Neuropsychopharmacol 11(4):445–452

    Article  PubMed  CAS  Google Scholar 

  84. Tohen M, Chengappa KN, Suppes T et al (2004) Relapse prevention in bipolar I disorder: 18-month comparison of olanzapine plus mood stabiliser v. mood stabiliser alone. Br J Psychiatry 184:337–345

    Article  PubMed  Google Scholar 

  85. Bowden CL, Vieta E, Ice KS et al (2010) Ziprasidone plus a mood stabilizer in subjects with bipolar I disorder: a 6-month, randomized, placebo-controlled, double-blind trial. J Clin Psychiatry 71(2):130–137

    Article  PubMed  CAS  Google Scholar 

  86. Citrome L (2010) Ziprasidone HCl capsules for the adjunctive maintenance treatment of bipolar disorder in adults. Expert Rev Neurother 10(7):1031–1037

    Article  PubMed  CAS  Google Scholar 

  87. Marcus R, Khan A, Rollin L et al (2011) 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 13(2):133–144

    Article  PubMed  CAS  Google Scholar 

  88. Geddes JR, Goodwin GM, Rendell J et al (2010) Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial. Lancet 375(9712):385–395

    Article  PubMed  CAS  Google Scholar 

  89. Fountoulakis KN (2010) The BALANCE trial. Lancet 375(9723):1343–1344, author reply 1344

    Article  PubMed  Google Scholar 

  90. Suppes T, Webb A, Paul B et al (1999) Clinical outcome in a randomized 1-year trial of ­clozapine versus treatment as usual for patients with treatment-resistant illness and a history of mania. Am J Psychiatry 156(8):1164–1169

    PubMed  CAS  Google Scholar 

  91. Gyulai L, Bowden CL, McElroy SL et al (2003) Maintenance efficacy of divalproex in the prevention of bipolar depression. Neuropsychopharmacology 28(7):1374–1382

    Article  PubMed  CAS  Google Scholar 

  92. Macfadden W, Alphs L, Haskins JT et al (2009) A randomized, double-blind, placebo-controlled study of maintenance treatment with adjunctive risperidone long-acting therapy in patients with bipolar I disorder who relapse frequently. Bipolar Disord 11(8):827–839

    Article  PubMed  CAS  Google Scholar 

  93. Houston JP, Tohen M, Degenhardt EK et al (2009) Olanzapine-divalproex combination ­versus divalproex monotherapy in the treatment of bipolar mixed episodes: a double-blind, placebo-controlled study. J Clin Psychiatry 70(11):1540–1547

    Article  PubMed  CAS  Google Scholar 

  94. Houston JP, Ketter TA, Case M et al (2011) Early symptom change and prediction of subsequent remission with olanzapine augmentation in divalproex-resistant bipolar mixed ­episodes. J Psychiatr Res 45(2):169–173

    Article  PubMed  Google Scholar 

  95. Benazzi F, Berk M, Frye MA et al (2009) Olanzapine/fluoxetine combination for the treatment of mixed depression in bipolar I disorder: a post hoc analysis. J Clin Psychiatry 70(10):1424–1431

    Article  PubMed  CAS  Google Scholar 

  96. Kemp DE, Gao K, Ganocy SJ et al (2009) A 6-month, double-blind, maintenance trial of lithium monotherapy versus the combination of lithium and divalproex for rapid-cycling bipolar disorder and co-occurring substance abuse or dependence. J Clin Psychiatry 70(1):113–121

    Article  PubMed  CAS  Google Scholar 

  97. Wang Z, Gao K, Kemp DE et al (2010) Lamotrigine adjunctive therapy to lithium and divalproex in depressed patients with rapid cycling bipolar disorder and a recent substance use disorder: a 12-week, double-blind, placebo-controlled pilot study. Psychopharmacol Bull 43(4):5–21

    PubMed  Google Scholar 

  98. Calabrese JR, Suppes T, Bowden CL et al (2000) A double-blind, placebo-controlled, prophylaxis study of lamotrigine in rapid-cycling bipolar disorder. Lamictal 614 study group. J Clin Psychiatry 61(11):841–850

    Article  PubMed  CAS  Google Scholar 

  99. Schneck CD, Miklowitz DJ, Miyahara S et al (2008) The prospective course of rapid-cycling bipolar disorder: findings from the STEP-BD. Am J Psychiatry 165:370–377

    Article  PubMed  Google Scholar 

  100. Geller B, Cooper TB, Sun K et al (1998) Double-blind and placebo-controlled study of lithium for adolescent bipolar disorders with secondary substance dependency. J Am Acad Child Adolesc Psychiatry 37(2):171–178

    Article  PubMed  CAS  Google Scholar 

  101. Geller B, Cooper TB, Watts HE et al (1992) Early findings from a pharmacokinetically designed double-blind and placebo-controlled study of lithium for adolescents comorbid with bipolar and substance dependency disorders. Prog Neuropsychopharmacol Biol Psychiatry 16(3):281–299

    Article  PubMed  CAS  Google Scholar 

  102. Brown ES, Garza M, Carmody TJ (2008) A randomized, double-blind, placebo-­controlled add-on trial of quetiapine in outpatients with bipolar disorder and alcohol use disorders. J Clin Psychiatry 69(5):701–705

    Article  PubMed  CAS  Google Scholar 

  103. Lydiard RB, Culpepper L, Schioler H et al (2009) Quetiapine monotherapy as treatment for anxiety symptoms in patients with bipolar depression: a pooled analysis of results from 2 double-blind, randomized, placebo-controlled studies. Prim Care Companion J Clin Psychiatry 11(5):215–225

    Article  PubMed  Google Scholar 

  104. Nejtek VA, Avila M, Chen LA et al (2008) Do atypical antipsychotics effectively treat co-occurring bipolar disorder and stimulant dependence? A randomized, double-blind trial. J Clin Psychiatry 69(8):1257–1266

    Article  PubMed  CAS  Google Scholar 

  105. Sheehan DV, McElroy SL, Harnett-Sheehan K et al (2009) Randomized, placebo-controlled trial of risperidone for acute treatment of bipolar anxiety. J Affect Disord 115(3):376–385

    Article  PubMed  CAS  Google Scholar 

  106. Arnone D (2005) Review of the use of Topiramate for treatment of psychiatric disorders. Ann Gen Psychiatry 4(1):5

    Article  PubMed  Google Scholar 

  107. Sherwood Brown E, Carmody TJ, Schmitz JM et al (2009) A randomized, double-blind, placebo-controlled pilot study of naltrexone in outpatients with bipolar disorder and alcohol dependence. Alcohol Clin Exp Res 33(11):1863–1869

    Article  PubMed  CAS  Google Scholar 

  108. Zarate CA Jr, Payne JL, Singh J et al (2004) Pramipexole for bipolar II depression: a placebo-controlled proof of concept study. Biol Psychiatry 56(1):54–60

    Article  PubMed  CAS  Google Scholar 

  109. Eden Evins A, Demopulos C, Yovel I et al (2006) Inositol augmentation of lithium or valproate for bipolar depression. Bipolar Disord 8(2):168–174

    Article  PubMed  CAS  Google Scholar 

  110. Berk M, Copolov DL, Dean O et al (2008) N-acetyl cysteine for depressive symptoms in bipolar disorder—a double-blind randomized placebo-controlled trial. Biol Psychiatry 64(6):468–475

    Article  PubMed  CAS  Google Scholar 

  111. Magalhaes PV, Dean OM, Bush AI et al (2011) N-acetyl cysteine add-on treatment for ­bipolar II disorder: a subgroup analysis of a randomized placebo-controlled trial. J Affect Disord 129(1–3):317–320

    Article  PubMed  CAS  Google Scholar 

  112. Frye MA, Grunze H, Suppes T et al (2007) A placebo-controlled evaluation of adjunctive modafinil in the treatment of bipolar depression. Am J Psychiatry 164(8):1242–1249

    Article  PubMed  Google Scholar 

  113. Fountoulakis KN, Siamouli M, Panagiotidis P et al (2008) Ultra short manic-like episodes after antidepressant augmentation with modafinil. Prog Neuropsychopharmacol Biol Psychiatry 32(3):891–892

    Article  PubMed  CAS  Google Scholar 

  114. Calabrese JR, Ketter TA, Youakim JM et al (2010) Adjunctive armodafinil for major depressive episodes associated with bipolar I disorder: a randomized, multicenter, double-blind, placebo-controlled, proof-of-concept study. J Clin Psychiatry 71(10):1363–1370

    Article  PubMed  CAS  Google Scholar 

  115. Hiremani RM, Thirthalli J, Tharayil BS et al (2008) Double-blind randomized controlled study comparing short-term efficacy of bifrontal and bitemporal electroconvulsive therapy in acute mania. Bipolar Disord 10(6):701–707

    Article  PubMed  Google Scholar 

  116. Loo C, Katalinic N, Mitchell PB et al (2010) Physical treatments for bipolar disorder: a review of electroconvulsive therapy, stereotactic surgery and other brain stimulation techniques. J Affect Disord 132:1–13

    Article  PubMed  Google Scholar 

  117. Kessler U, Vaaler AE, Schoyen H et al (2010) The study protocol of the Norwegian randomized controlled trial of electroconvulsive therapy in treatment resistant depression in bipolar disorder. BMC Psychiatry 10(1):16

    Article  PubMed  Google Scholar 

  118. Dell’Osso B, Mundo E, D’Urso N et al (2009) Augmentative repetitive navigated transcranial magnetic stimulation (rTMS) in drug-resistant bipolar depression. Bipolar Disord 11(1):76–81

    Article  PubMed  Google Scholar 

  119. Wu JC, Kelsoe JR, Schachat C et al (2009) Rapid and sustained antidepressant response with sleep deprivation and chronotherapy in bipolar disorder. Biol Psychiatry 66(3):298–301

    Article  PubMed  CAS  Google Scholar 

  120. Sarris J, Mischoulon D, Schweitzer I (2011) Omega-3 for bipolar disorder: meta-analyses of use in mania and bipolar depression. J Clin Psychiatry 73:81–86

    Article  PubMed  CAS  Google Scholar 

  121. Frangou S, Lewis M, McCrone P (2006) Efficacy of ethyl-eicosapentaenoic acid in bipolar depression: randomised double-blind placebo-controlled study. Br J Psychiatry 188:46–50

    Article  PubMed  Google Scholar 

  122. Frangou S, Lewis M, Wollard J et al (2007) Preliminary in vivo evidence of increased N-acetyl-aspartate following eicosapentanoic acid treatment in patients with bipolar disorder. J Psychopharmacol 21(4):435–439

    Article  PubMed  CAS  Google Scholar 

  123. Keck PE Jr, Mintz J, McElroy SL et al (2006) Double-blind, randomized, placebo-controlled trials of ethyl-eicosapentanoate in the treatment of bipolar depression and rapid cycling bipolar disorder. Biol Psychiatry 60(9):1020–1022

    Article  PubMed  CAS  Google Scholar 

  124. Chiu CC, Huang SY, Chen CC et al (2005) Omega-3 fatty acids are more beneficial in the depressive phase than in the manic phase in patients with bipolar I disorder. J Clin Psychiatry 66(12):1613–1614

    Article  PubMed  Google Scholar 

  125. Stoll AL, Severus WE, Freeman MP et al (1999) Omega 3 fatty acids in bipolar disorder: a preliminary double-blind, placebo-controlled trial. Arch Gen Psychiatry 56(5):407–412

    Article  PubMed  CAS  Google Scholar 

  126. Lange F (1894) De vigtigste sindssygdomme (The most important pychiatric disorders). Gyldendal, Copenhagen

    Google Scholar 

  127. Cade J (1949) Lithium salts in the treatment of psychotic excitement. Med J Aust 36:349–352

    Google Scholar 

  128. Cade J (1970) The story of lithium. In: Ayd F, Blackwell B (eds) Discoveries in biological psychiatry. Lippincott, Philadelphia

    Google Scholar 

  129. Bech P (2006) The full story of lithium. A tribute to Mogens Schou (1918–2005). Psychother Psychosom 75(5):265–269

    Article  PubMed  CAS  Google Scholar 

  130. Schou M, Juel-Nielsen N, Stromgren E et al (1954) The treatment of manic psychosis by the administration of lithium salts. J Neurol Neurosurg Psychiatry 17:250–260

    Article  PubMed  CAS  Google Scholar 

  131. Schou M (1997) Forty years of lithium treatment. Arch Gen Psychiatry 54:9

    Article  PubMed  CAS  Google Scholar 

  132. Baastrup P (1964) The use of lithium in manic-depressive psychosis. Compr Psychiatry 5:396–408

    Article  PubMed  CAS  Google Scholar 

  133. Baastrup PC, Schou M (1967) Lithium as a prophylactic agents its effect against recurrent depressions and manic-depressive psychosis. Arch Gen Psychiatry 16(2):162–172

    Article  PubMed  CAS  Google Scholar 

  134. Schou M, Baastrup PC (1967) Lithium treatment of manic-depressive disorder dosage and control. JAMA 201(9):696–698

    Article  PubMed  CAS  Google Scholar 

  135. Baastrup PC, Poulsen JC, Schou M et al (1970) Prophylactic lithium: double blind discontinuation in manic-depressive and recurrent-depressive disorders. Lancet 2(7668):326–330

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. 3rd Department of Psychiatry, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece

    Stamatia Magiria, Melina Siamouli, Apostolos Iacovides & Konstantinos N. Fountoulakis M.D., Ph.D.

  2. Department of Clinical and Theoretical Mental Health, Faculty of Medicine, Semmelweis University, Budapest, Hungary

    Xenia Gonda

Authors
  1. Stamatia Magiria
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Melina Siamouli
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xenia Gonda
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Apostolos Iacovides
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Konstantinos N. Fountoulakis M.D., Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Konstantinos N. Fountoulakis M.D., Ph.D. .

Editor information

Editors and Affiliations

  1. Sha'ar Menashe Mental Health Center, Hadera, 38814, Israel

    Michael S. Ritsner

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media Dordrecht

About this chapter

Cite this chapter

Magiria, S., Siamouli, M., Gonda, X., Iacovides, A., Fountoulakis, K.N. (2013). Evidence Based Combination Therapy for Bipolar Disorder. In: Ritsner, M. (eds) Polypharmacy in Psychiatry Practice, Volume II. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-5799-8_9

Download citation

Publish with us

Policies and ethics

Search

Navigation