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Bipolar disorder in adults: Choosing maintenance treatment

Robert M Post, MD
Section Editor
Paul Keck, MD
Deputy Editor
David Solomon, MD


Following remission of a bipolar mood episode, patients generally require maintenance treatment to delay or prevent another episode. Standard maintenance treatment consists of pharmacotherapy plus adjunctive psychotherapy. However, if psychotherapy is not available or is declined, pharmacotherapy alone is reasonable.

Selecting maintenance treatment for bipolar disorder is reviewed here. The use of adjunctive psychotherapy for maintenance treatment of bipolar disorder; management of poor adherence to maintenance pharmacotherapy; pharmacotherapy for acute bipolar mood episodes; teratogenic risks and neonatal issues involved in pharmacotherapy; and the epidemiology, clinical manifestations, and diagnosis of bipolar disorder are discussed separately:

(See "Bipolar disorder in adults: Psychoeducation and other adjunctive maintenance psychotherapies".)

(See "Bipolar disorder in adults: Managing poor adherence to maintenance pharmacotherapy".)

(See "Bipolar disorder in adults: Choosing pharmacotherapy for acute mania and hypomania".)

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Literature review current through: Nov 2017. | This topic last updated: Nov 02, 2017.
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  1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), American Psychiatric Association, Arlington, VA 2013.
  2. 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.
  3. Gignac A, McGirr A, Lam RW, Yatham LN. Recovery and recurrence following a first episode of mania: a systematic review and meta-analysis of prospectively characterized cohorts. J Clin Psychiatry 2015; 76:1241.
  4. Gitlin M, Frye MA. Maintenance therapies in bipolar disorders. Bipolar Disord 2012; 14 Suppl 2:51.
  5. Leverich GS, Altshuler LL, Frye MA, et al. Factors associated with suicide attempts in 648 patients with bipolar disorder in the Stanley Foundation Bipolar Network. J Clin Psychiatry 2003; 64:506.
  6. Oquendo MA, Mann JJ. Identifying and managing suicide risk in bipolar patients. J Clin Psychiatry 2001; 62 Suppl 25:31.
  7. Rucci P, Frank E, Kostelnik B, et al. Suicide attempts in patients with bipolar I disorder during acute and maintenance phases of intensive treatment with pharmacotherapy and adjunctive psychotherapy. Am J Psychiatry 2002; 159:1160.
  8. Slama F, Bellivier F, Henry C, et al. Bipolar patients with suicidal behavior: toward the identification of a clinical subgroup. J Clin Psychiatry 2004; 65:1035.
  9. Fagiolini A, Kupfer DJ, Rucci P, et al. Suicide attempts and ideation in patients with bipolar I disorder. J Clin Psychiatry 2004; 65:509.
  10. Nolen WA, Luckenbaugh DA, Altshuler LL, et al. Correlates of 1-year prospective outcome in bipolar disorder: results from the Stanley Foundation Bipolar Network. Am J Psychiatry 2004; 161:1447.
  11. Yurgelun-Todd D, Sneider J. Neurocognitive deficits in bipolar disorder. Clinical Approaches in Bipolar Disorder 2006; 5:51.
  12. Post RM. Mechanisms of illness progression in the recurrent affective disorders. Neurotox Res 2010; 18:256.
  13. Post RM, Altshuler LL, Frye MA, et al. Complexity of pharmacologic treatment required for sustained improvement in outpatients with bipolar disorder. J Clin Psychiatry 2010; 71:1176.
  14. Kessing LV, Vradi E, Andersen PK. Starting lithium prophylaxis early v. late in bipolar disorder. Br J Psychiatry 2014; 205:214.
  15. Yatham LN, Kennedy SH, Parikh SV, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2013. Bipolar Disord 2013; 15:1.
  16. Grunze H, Vieta E, Goodwin GM, et al. The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of bipolar disorders: update 2012 on the long-term treatment of bipolar disorder. World J Biol Psychiatry 2013; 14:154.
  17. United Kingdom National Institute for Health and Care Excellence (NICE). Bipolar disorder: The assessment and management of bipolar disorder in adults, children and young people in primary and secondary care. NICE Clinical Guideline 185, September 2014. http://www.nice.org.uk/guidance/cg185 (Accessed on September 01, 2015).
  18. Goodwin GM, Haddad PM, Ferrier IN, et al. Evidence-based guidelines for treating bipolar disorder: Revised third edition recommendations from the British Association for Psychopharmacology. J Psychopharmacol 2016; 30:495.
  19. Judd LL, Akiskal HS, Schettler PJ, et al. A prospective investigation of the natural history of the long-term weekly symptomatic status of bipolar II disorder. Arch Gen Psychiatry 2003; 60:261.
  20. Merikangas KR, Jin R, He JP, et al. Prevalence and correlates of bipolar spectrum disorder in the world mental health survey initiative. Arch Gen Psychiatry 2011; 68:241.
  21. Smith DJ, Griffiths E, Kelly M, et al. Unrecognised bipolar disorder in primary care patients with depression. Br J Psychiatry 2011; 199:49.
  22. Angst F, Stassen HH, Clayton PJ, Angst J. Mortality of patients with mood disorders: follow-up over 34-38 years. J Affect Disord 2002; 68:167.
  23. Fazel S, Zetterqvist J, Larsson H, et al. Antipsychotics, mood stabilisers, and risk of violent crime. Lancet 2014; 384:1206.
  24. Malhi GS, Adams D, Cahill CM, et al. The management of individuals with bipolar disorder: a review of the evidence and its integration into clinical practice. Drugs 2009; 69:2063.
  25. McElroy SL, Bowden CL, Collins MA, et al. Relationship of open acute mania treatment to blinded maintenance outcome in bipolar I disorder. J Affect Disord 2008; 107:127.
  26. Weisler RH, Nolen WA, Neijber A, et al. Continuation of quetiapine versus switching to placebo or lithium for maintenance treatment of bipolar I disorder (Trial 144: a randomized controlled study). J Clin Psychiatry 2011; 72:1452.
  27. Vancampfort D, Vansteelandt K, Correll CU, et al. Metabolic syndrome and metabolic abnormalities in bipolar disorder: a meta-analysis of prevalence rates and moderators. Am J Psychiatry 2013; 170:265.
  28. Ostacher MJ, Tandon R, Suppes T. Florida Best Practice Psychotherapeutic Medication Guidelines for Adults With Bipolar Disorder: A Novel, Practical, Patient-Centered Guide for Clinicians. J Clin Psychiatry 2016; 77:920.
  29. Malhi GS, Gessler D, Outhred T. The use of lithium for the treatment of bipolar disorder: Recommendations from clinical practice guidelines. J Affect Disord 2017; 217:266.
  30. National Institute for Health and Care Excellence (NICE). Antenatal and postnatal mental health: clinical management and service guidance. NICE clinical guideline 192. December 2014. http://www.nice.org.uk/guidance/cg192 (Accessed on May 16, 2016).
  31. Briggs GG, Freeman RK. Valproic acid. In: Drugs in pregnancy and lactation: A reference guide to fetal and neonatal risk, Tenth Edition, Wolters Kluwer, Philadelphia 2015. p.1449.
  32. Zhang L, Li H, Li S, Zou X. Reproductive and metabolic abnormalities in women taking valproate for bipolar disorder: a meta-analysis. Eur J Obstet Gynecol Reprod Biol 2016; 202:26.
  33. Smith LA, Cornelius V, Warnock A, et al. Effectiveness of mood stabilizers and antipsychotics in the maintenance phase of bipolar disorder: a systematic review of randomized controlled trials. Bipolar Disord 2007; 9:394.
  34. Baldessarini RJ, Tondo L, Davis P, et al. Decreased risk of suicides and attempts during long-term lithium treatment: a meta-analytic review. Bipolar Disord 2006; 8:625.
  35. Hayes JF, Pitman A, Marston L, et al. Self-harm, Unintentional Injury, and Suicide in Bipolar Disorder During Maintenance Mood Stabilizer Treatment: A UK Population-Based Electronic Health Records Study. JAMA Psychiatry 2016; 73:630.
  36. Cipriani A, Reid K, Young AH, et al. Valproic acid, valproate and divalproex in the maintenance treatment of bipolar disorder. Cochrane Database Syst Rev 2013; :CD003196.
  37. Young AH, McElroy SL, Olausson B, et al. A randomised, placebo-controlled 52-week trial of continued quetiapine treatment in recently depressed patients with bipolar I and bipolar II disorder. World J Biol Psychiatry 2014; 15:96.
  38. Licht RW, Nielsen JN, Gram LF, et al. Lamotrigine versus lithium as maintenance treatment in bipolar I disorder: an open, randomized effectiveness study mimicking clinical practice. The 6th trial of the Danish University Antidepressant Group (DUAG-6). Bipolar Disord 2010; 12:483.
  39. Keck PE Jr, Calabrese JR, McIntyre RS, et al. Aripiprazole monotherapy for maintenance therapy in bipolar I disorder: a 100-week, double-blind study versus placebo. J Clin Psychiatry 2007; 68:1480.
  40. Velligan DI, Weiden PJ, Sajatovic M, et al. Strategies for addressing adherence problems in patients with serious and persistent mental illness: recommendations from the expert consensus guidelines. J Psychiatr Pract 2010; 16:306.
  41. Calabrese JR, Sanchez R, Jin N, et al. Efficacy and Safety of Aripiprazole Once-Monthly in the Maintenance Treatment of Bipolar I Disorder: A Double-Blind, Placebo-Controlled, 52-Week Randomized Withdrawal Study. J Clin Psychiatry 2017; 78:324.
  42. Cipriani A, Rendell JM, Geddes J. Olanzapine in long-term treatment for bipolar disorder. Cochrane Database Syst Rev 2009; :CD004367.
  43. Cipriani A, Rendell J, Geddes JR. Olanzapine in the long-term treatment of bipolar disorder: a systematic review and meta-analysis. J Psychopharmacol 2010; 24:1729.
  44. Leslie DL, Rosenheck RA. Incidence of newly diagnosed diabetes attributable to atypical antipsychotic medications. Am J Psychiatry 2004; 161:1709.
  45. Fernandez-Egea E, Miller B, Garcia-Rizo C, et al. Metabolic effects of olanzapine in patients with newly diagnosed psychosis. J Clin Psychopharmacol 2011; 31:154.
  46. Raedler TJ. Cardiovascular aspects of antipsychotics. Curr Opin Psychiatry 2010; 23:574.
  47. Tohen M, Calabrese JR, Sachs GS, et al. Randomized, placebo-controlled trial of olanzapine as maintenance therapy in patients with bipolar I disorder responding to acute treatment with olanzapine. Am J Psychiatry 2006; 163:247.
  48. Quiroz JA, Yatham LN, Palumbo JM, et al. Risperidone long-acting injectable monotherapy in the maintenance treatment of bipolar I disorder. Biol Psychiatry 2010; 68:156.
  49. Vieta E, Montgomery S, Sulaiman AH, et al. A randomized, double-blind, placebo-controlled trial to assess prevention of mood episodes with risperidone long-acting injectable in patients with bipolar I disorder. Eur Neuropsychopharmacol 2012; 22:825.
  50. McIntyre RS, Cohen M, Zhao J, et al. Asenapine for long-term treatment of bipolar disorder: a double-blind 40-week extension study. J Affect Disord 2010; 126:358.
  51. Ceron-Litvoc D, Soares BG, Geddes J, et al. Comparison of carbamazepine and lithium in treatment of bipolar disorder: a systematic review of randomized controlled trials. Hum Psychopharmacol 2009; 24:19.
  52. Vasudev A, Macritchie K, Watson S, et al. Oxcarbazepine in the maintenance treatment of bipolar disorder. Cochrane Database Syst Rev 2008; :CD005171.
  53. Pratoomsri W, Yatham LN, Bond DJ, et al. Oxcarbazepine in the treatment of bipolar disorder: a review. Can J Psychiatry 2006; 51:540.
  54. Popova E, Leighton C, Bernabarre A, et al. Oxcarbazepine in the treatment of bipolar and schizoaffective disorders. Expert Rev Neurother 2007; 7:617.
  55. Mazza M, Di Nicola M, Martinotti G, et al. Oxcarbazepine in bipolar disorder: a critical review of the literature. Expert Opin Pharmacother 2007; 8:649.
  56. Berwaerts J, Melkote R, Nuamah I, Lim P. A randomized, placebo- and active-controlled study of paliperidone extended-release as maintenance treatment in patients with bipolar I disorder after an acute manic or mixed episode. J Affect Disord 2012; 138:247.
  57. Buoli M, Serati M, Altamura AC. Is the combination of a mood stabilizer plus an antipsychotic more effective than mono-therapies in long-term treatment of bipolar disorder? A systematic review. J Affect Disord 2014; 152-154:12.
  58. Goldberg JF, Brooks JO 3rd, Kurita K, et al. Depressive illness burden associated with complex polypharmacy in patients with bipolar disorder: findings from the STEP-BD. J Clin Psychiatry 2009; 70:155.
  59. Blanco C, Laje G, Olfson M, et al. Trends in the treatment of bipolar disorder by outpatient psychiatrists. Am J Psychiatry 2002; 159:1005.
  60. Wolfsperger M, Greil W, Rössler W, Grohmann R. Pharmacological treatment of acute mania in psychiatric in-patients between 1994 and 2004. J Affect Disord 2007; 99:9.
  61. Grunze H, Vieta E, Goodwin GM, et al. The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of bipolar disorders: update 2009 on the treatment of acute mania. World J Biol Psychiatry 2009; 10:85.
  62. Suppes T, Vieta E, Liu S, et al. Maintenance treatment for patients with bipolar I disorder: results from a north american study of quetiapine in combination with lithium or divalproex (trial 127). Am J Psychiatry 2009; 166:476.
  63. Vieta E, Suppes T, Eggens I, et al. Efficacy and safety of quetiapine in combination with lithium or divalproex for maintenance of patients with bipolar I disorder (international trial 126). J Affect Disord 2008; 109:251.
  64. Macfadden W, Alphs L, Haskins JT, et al. 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 2009; 11:827.
  65. 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.
  66. Bowden CL, Vieta E, Ice KS, et al. Ziprasidone plus a mood stabilizer in subjects with bipolar I disorder: a 6-month, randomized, placebo-controlled, double-blind trial. J Clin Psychiatry 2010; 71:130.
  67. Preskorn SH, Lacey RL. Polypharmacy: when is it rational? J Psychiatr Pract 2007; 13:97.
  68. Vieta E, Suppes T, Ekholm B, et al. Long-term efficacy of quetiapine in combination with lithium or divalproex on mixed symptoms in bipolar I disorder. J Affect Disord 2012.
  69. Marcus R, Khan A, Rollin L, et al. Efficacy of aripiprazole adjunctive to lithium or valproate in the long-term treatment of patients with bipolar I disorder with an inadequate response to lithium or valproate monotherapy: a multicenter, double-blind, randomized study. Bipolar Disord 2011; 13:133.
  70. Woo YS, Bahk WM, Chung MY, et al. Aripiprazole plus divalproex for recently manic or mixed patients with bipolar I disorder: a 6-month, randomized, placebo-controlled, double-blind maintenance trial. Hum Psychopharmacol 2011; 26:543.
  71. Suppes T, Webb A, Paul B, et al. 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 1999; 156:1164.
  72. Ciapparelli A, Dell'Osso L, Bandettini di Poggio A, et al. Clozapine in treatment-resistant patients with schizophrenia, schizoaffective disorder, or psychotic bipolar disorder: a naturalistic 48-month follow-up study. J Clin Psychiatry 2003; 64:451.
  73. Chang JS, Ha KS, Young Lee K, et al. The effects of long-term clozapine add-on therapy on the rehospitalization rate and the mood polarity patterns in bipolar disorders. J Clin Psychiatry 2006; 67:461.
  74. Yatham LN, Beaulieu S, Schaffer A, et al. Optimal duration of risperidone or olanzapine adjunctive therapy to mood stabilizer following remission of a manic episode: A CANMAT randomized double-blind trial. Mol Psychiatry 2016; 21:1050.
  75. Denicoff KD, Smith-Jackson EE, Bryan AL, et al. Valproate prophylaxis in a prospective clinical trial of refractory bipolar disorder. Am J Psychiatry 1997; 154:1456.
  76. Bocchetta A, Chillotti C, Severino G, et al. Carbamazepine augmentation in lithium-refractory bipolar patients: a prospective study on long-term prophlyactic effectiveness. J Clin Psychopharmacol 1997; 17:92.
  77. Baethge C, Baldessarini RJ, Mathiske-Schmidt K, et al. Long-term combination therapy versus monotherapy with lithium and carbamazepine in 46 bipolar I patients. J Clin Psychiatry 2005; 66:174.
  78. BALANCE investigators and collaborators, Geddes JR, Goodwin GM, et al. Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial. Lancet 2010; 375:385.
  79. 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; 58:470.
  80. van der Loos ML, Mulder P, Hartong EG, et al. 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 2011; 13:111.
  81. Vieta E, Cruz N, García-Campayo J, et al. 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 2008; 11:445.
  82. Carlson BX, Ketter TA, Sun W, et al. Aripiprazole in combination with lamotrigine for the long-term treatment of patients with bipolar I disorder (manic or mixed): a randomized, multicenter, double-blind study (CN138-392). Bipolar Disord 2012; 14:41.
  83. Perlis RH, Ostacher MJ, Miklowitz DJ, et al. Benzodiazepine use and risk of recurrence in bipolar disorder: a STEP-BD report. J Clin Psychiatry 2010; 71:194.
  84. Handbook of Psychiatric Measures, Second Edition, Rush Jr AJ, First MB, Blacker D (Eds), American Psychiatric Publishing, Inc, Washington, DC.
  85. Born C, Amann BL, Grunze H, et al. Saving time and money: a validation of the self ratings on the prospective NIMH Life-Chart Method (NIMH-LCM). BMC Psychiatry 2014; 14:130.
  86. Denicoff KD, Smith-Jackson EE, Disney ER, et al. Preliminary evidence of the reliability and validity of the prospective life-chart methodology (LCM-p). J Psychiatr Res 1997; 31:593.
  87. Denicoff KD, Leverich GS, Nolen WA, et al. Validation of the prospective NIMH-Life-Chart Method (NIMH-LCM-p) for longitudinal assessment of bipolar illness. Psychol Med 2000; 30:1391.
  88. Ketter TA. Strategies for monitoring outcomes in patients with bipolar disorder. Prim Care Companion J Clin Psychiatry 2010; 12:10.
  89. Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med 2001; 16:606.
  90. Bauer MS, Crits-Christoph P, Ball WA, et al. Independent assessment of manic and depressive symptoms by self-rating. Scale characteristics and implications for the study of mania. Arch Gen Psychiatry 1991; 48:807.
  91. Gaynes BN, DeVeaugh-Geiss J, Weir S, et al. Feasibility and diagnostic validity of the M-3 checklist: a brief, self-rated screen for depressive, bipolar, anxiety, and post-traumatic stress disorders in primary care. Ann Fam Med 2010; 8:160.
  92. Malhi GS, McAulay C, Das P, Fritz K. Maintaining mood stability in bipolar disorder: a clinical perspective on pharmacotherapy. Evid Based Ment Health 2015; 18:1.
  93. Suppes T, Baldessarini RJ, Faedda GL, Tohen M. Risk of recurrence following discontinuation of lithium treatment in bipolar disorder. Arch Gen Psychiatry 1991; 48:1082.
  94. Yazici O, Kora K, Polat A, Saylan M. Controlled lithium discontinuation in bipolar patients with good response to long-term lithium prophylaxis. J Affect Disord 2004; 80:269.
  95. Baldessarini RJ, Tondo L, Floris G, Rudas N. Reduced morbidity after gradual discontinuation of lithium treatment for bipolar I and II disorders: a replication study. Am J Psychiatry 1997; 154:551.
  96. Faedda GL, Tondo L, Baldessarini RJ, et al. Outcome after rapid vs gradual discontinuation of lithium treatment in bipolar disorders. Arch Gen Psychiatry 1993; 50:448.
  97. Scott J, Colom F, Vieta E. A meta-analysis of relapse rates with adjunctive psychological therapies compared to usual psychiatric treatment for bipolar disorders. Int J Neuropsychopharmacol 2007; 10:123.
  98. Malhi GS, Adams D, Lampe L, et al. Clinical practice recommendations for bipolar disorder. Acta Psychiatr Scand Suppl 2009; :27.
  99. Frank E, Swartz HA, Mallinger AG, et al. Adjunctive psychotherapy for bipolar disorder: effects of changing treatment modality. J Abnorm Psychol 1999; 108:579.
  100. Zisselman MH, Rosenquist PB, Curlik SM. Long-term weekly continuation electroconvulsive therapy: a case series. J ECT 2007; 23:274.
  101. Yero SA, McKinney T, Petrides G, et al. Successful use of electroconvulsive therapy in 2 cases of persistent sexual arousal syndrome and bipolar disorder. J ECT 2006; 22:274.
  102. Sienaert P, Peuskens J. Electroconvulsive therapy: an effective therapy of medication-resistant bipolar disorder. Bipolar Disord 2006; 8:304.
  103. Nascimento AL, Appolinario JC, Segenreich D, et al. Maintenance electroconvulsive therapy for recurrent refractory mania. Bipolar Disord 2006; 8:301.
  104. Tsao CI, Jain S, Gibson RH, et al. Maintenance ECT for recurrent medication-refractory mania. J ECT 2004; 20:118.
  105. Vaidya NA, Mahableshwarkar AR, Shahid R. Continuation and maintenance ECT in treatment-resistant bipolar disorder. J ECT 2003; 19:10.
  106. Russell JC, Rasmussen KG, O'Connor MK, et al. Long-term maintenance ECT: a retrospective review of efficacy and cognitive outcome. J ECT 2003; 19:4.
  107. Vanelle JM, Loo H, Galinowski A, et al. Maintenance ECT in intractable manic-depressive disorders. Convuls Ther 1994; 10:195.
  108. Bonds C, Frye MA, Coudreaut MF, et al. Cost reduction with maintenance ECT in refractory bipolar disorder. J ECT 1998; 14:36.
  109. Michalak EE, Suto MJ, Barnes SJ, et al. Effective self-management strategies for bipolar disorder: A community-engaged Delphi Consensus Consultation study. J Affect Disord 2016; 206:77.