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Bipolar disorder in adults: Treating major depression with antidepressants

William V Bobo, MD, MPH
Richard C Shelton, MD
Section Editor
Paul Keck, MD
Deputy Editor
David Solomon, MD


The use of antidepressants for acute and maintenance treatment of bipolar depression is controversial because of concerns that these drugs are not effective and may harm patients by causing switches from depression to mania as well as rapid cycling [1-3]. Nevertheless, antidepressants (table 1) are the most commonly prescribed drugs for bipolar depression. Studies of bipolar patients in the United States (n = 7760) [4] and Europe (n = 2231) [5] found that an antidepressant had been prescribed for 50 and 81 percent; this may be due in part to the limited efficacy and tolerability of other treatments [6].

This topic reviews the efficacy of antidepressants for patients with bipolar major depression and the risk of these drugs causing a switch in polarity; the risk of rapid cycling is discussed separately. Choosing a medication regimen to treat bipolar major depression, mania, and hypomania is also discussed separately, as is maintenance treatment of bipolar disorder.

(See "Rapid cycling bipolar disorder: Epidemiology, pathogenesis, clinical features, and diagnosis", section on 'Antidepressants'.)

(See "Bipolar disorder in adults: Pharmacotherapy for acute depression".)

(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: Jul 13, 2016.
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  1. Fountoulakis KN. An update of evidence-based treatment of bipolar depression: where do we stand? Curr Opin Psychiatry 2010; 23:19.
  2. Licht RW, Gijsman H, Nolen WA, Angst J. Are antidepressants safe in the treatment of bipolar depression? A critical evaluation of their potential risk to induce switch into mania or cycle acceleration. Acta Psychiatr Scand 2008; 118:337.
  3. Salvi V, Fagiolini A, Swartz HA, et al. The use of antidepressants in bipolar disorder. J Clin Psychiatry 2008; 69:1307.
  4. Baldessarini RJ, Leahy L, Arcona S, et al. Patterns of psychotropic drug prescription for U.S. patients with diagnoses of bipolar disorders. Psychiatr Serv 2007; 58:85.
  5. Greil W, Häberle A, Haueis P, et al. Pharmacotherapeutic trends in 2231 psychiatric inpatients with bipolar depression from the International AMSP Project between 1994 and 2009. J Affect Disord 2012; 136:534.
  6. Fountoulakis KN, Grunze H, Panagiotidis P, Kaprinis G. Treatment of bipolar depression: an update. J Affect Disord 2008; 109:21.
  7. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), American Psychiatric Association, Arlington, VA 2013.
  8. Ghaemi SN. Treatment of rapid-cycling bipolar disorder: are antidepressants mood destabilizers? Am J Psychiatry 2008; 165:300.
  9. Yerevanian BI, Koek RJ, Mintz J, Akiskal HS. Bipolar pharmacotherapy and suicidal behavior Part 2. The impact of antidepressants. J Affect Disord 2007; 103:13.
  10. Goodwin FK, Jamison KR. Medical treatment of depression. In: Manic-Depressive Illness: Bipolar Disorders and Recurrent Depression, Second Edition, Oxford University Press, Oxford 2007. p.747.
  11. Wang PW, Ketter TA. Management of acute major depressive episodes in bipolar disorders. In: Handbook of Diagnosis and Treatment of Bipolar Disorders, Ketter TA (Ed), American Psychiatric Publishing, Inc., Washington, DC 2010. p.165.
  12. Swartz HA, Thase ME. Pharmacotherapy for the treatment of acute bipolar II depression: current evidence. J Clin Psychiatry 2011; 72:356.
  13. Frye MA, Ha K, Kanba S, et al. International consensus group on depression prevention in bipolar disorder. J Clin Psychiatry 2011; 72:1295.
  14. International Consensus Group on the evidence-based pharmacologic treatment of bipolar I and II depression. J Clin Psychiatry 2008; 69:1632.
  15. Goodwin GM, Consensus Group of the British Association for Psychopharmacology. Evidence-based guidelines for treating bipolar disorder: revised second edition--recommendations from the British Association for Psychopharmacology. J Psychopharmacol 2009; 23:346.
  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 2010 on the treatment of acute bipolar depression. World J Biol Psychiatry 2010; 11:81.
  17. Pacchiarotti I, Bond DJ, Baldessarini RJ, et al. The International Society for Bipolar Disorders (ISBD) task force report on antidepressant use in bipolar disorders. Am J Psychiatry 2013; 170:1249.
  18. 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.
  19. Thase ME. Antidepressants and rapid-cycling bipolar II disorder: dogma, definitions and deconstructing discrepant data. Br J Psychiatry 2013; 202:251.
  20. Goldberg JF, Perlis RH, Ghaemi SN, et al. Adjunctive antidepressant use and symptomatic recovery among bipolar depressed patients with concomitant manic symptoms: findings from the STEP-BD. Am J Psychiatry 2007; 164:1348.
  21. Perlis RH, Ostacher MJ, Goldberg JF, et al. Transition to mania during treatment of bipolar depression. Neuropsychopharmacology 2010; 35:2545.
  22. Goldberg JF, Truman CJ. Antidepressant-induced mania: an overview of current controversies. Bipolar Disord 2003; 5:407.
  23. Frye MA, Helleman G, McElroy SL, et al. Correlates of treatment-emergent mania associated with antidepressant treatment in bipolar depression. Am J Psychiatry 2009; 166:164.
  24. Post RM, Leverich GS, Nolen WA, et al. A re-evaluation of the role of antidepressants in the treatment of bipolar depression: data from the Stanley Foundation Bipolar Network. Bipolar Disord 2003; 5:396.
  25. Valentí M, Pacchiarotti I, Bonnín CM, et al. Risk factors for antidepressant-related switch to mania. J Clin Psychiatry 2012; 73:e271.
  26. Sachs GS, Dupuy JM, Wittmann CW. The pharmacologic treatment of bipolar disorder. J Clin Psychiatry 2011; 72:704.
  27. Bottlender R, Rudolf D, Strauss A, Möller HJ. Mood-stabilisers reduce the risk of developing antidepressant-induced maniform states in acute treatment of bipolar I depressed patients. J Affect Disord 2001; 63:79.
  28. Rouillon F, LeJoyeux M, Filteau MJ. Unwanted effects of long-term treatment. In: Long-Term Treatment of Depression, Montgomery SA, Rouillon F (Eds), John Wiley & Sons, Chichester 1992. p.81.
  29. Sachs GS, Nierenberg AA, Calabrese JR, et al. Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med 2007; 356:1711.
  30. Viktorin A, Lichtenstein P, Thase ME, et al. The risk of switch to mania in patients with bipolar disorder during treatment with an antidepressant alone and in combination with a mood stabilizer. Am J Psychiatry 2014; 171:1067.
  31. 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.
  32. Tamayo JM, Sutton VK, Mattei MA, et al. Effectiveness and safety of the combination of fluoxetine and olanzapine in outpatients with bipolar depression: an open-label, randomized, flexible-dose study in Puerto Rico. J Clin Psychopharmacol 2009; 29:358.
  33. Malhi GS, Adams D, Lampe L, et al. Clinical practice recommendations for bipolar disorder. Acta Psychiatr Scand Suppl 2009; :27.
  34. Amsterdam JD, Shults J. Comparison of fluoxetine, olanzapine, and combined fluoxetine plus olanzapine initial therapy of bipolar type I and type II major depression--lack of manic induction. J Affect Disord 2005; 87:121.
  35. Himmelhoch JM, Thase ME, Mallinger AG, Houck P. Tranylcypromine versus imipramine in anergic bipolar depression. Am J Psychiatry 1991; 148:910.
  36. Amsterdam JD, Shults J. Comparison of short-term venlafaxine versus lithium monotherapy for bipolar II major depressive episode: a randomized open-label study. J Clin Psychopharmacol 2008; 28:171.
  37. Cohn JB, Collins G, Ashbrook E, Wernicke JF. A comparison of fluoxetine imipramine and placebo in patients with bipolar depressive disorder. Int Clin Psychopharmacol 1989; 4:313.
  38. Amsterdam JD, Lorenzo-Luaces L, Soeller I, et al. Safety and effectiveness of continuation antidepressant versus mood stabilizer monotherapy for relapse-prevention of bipolar II depression: A randomized, double-blind, parallel-group, prospective study. J Affect Disord 2015; 185:31.
  39. Amsterdam JD, Lorenzo-Luaces L, Soeller I, et al. Short-term venlafaxine v. lithium monotherapy for bipolar type II major depressive episodes: effectiveness and mood conversion rate. Br J Psychiatry 2016; 208:359.
  40. McElroy SL, Weisler RH, Chang W, et al. A double-blind, placebo-controlled study of quetiapine and paroxetine as monotherapy in adults with bipolar depression (EMBOLDEN II). J Clin Psychiatry 2010; 71:163.
  41. El-Mallakh RS, Vöhringer PA, Ostacher MM, et al. Antidepressants worsen rapid-cycling course in bipolar depression: A STEP-BD randomized clinical trial. J Affect Disord 2015; 184:318.
  42. Chessick CA, Dimidjian S. Screening for bipolar disorder during pregnancy and the postpartum period. Arch Womens Ment Health 2010; 13:233.
  43. Hirschfeld RM, Williams JB, Spitzer RL, et al. Development and validation of a screening instrument for bipolar spectrum disorder: the Mood Disorder Questionnaire. Am J Psychiatry 2000; 157:1873.
  44. Hirschfeld RM. The mood disorder questionnaire: its impact on the field [corrected]. Depress Anxiety 2010; 27:627.
  45. Hirschfeld RM, Cass AR, Holt DC, Carlson CA. Screening for bipolar disorder in patients treated for depression in a family medicine clinic. J Am Board Fam Pract 2005; 18:233.
  46. Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med 2001; 16:606.
  47. Baldessarini RJ, Tondo L, Ghiani C, Lepri B. Illness risk following rapid versus gradual discontinuation of antidepressants. Am J Psychiatry 2010; 167:934.
  48. Sidor MM, Macqueen GM. Antidepressants for the acute treatment of bipolar depression: a systematic review and meta-analysis. J Clin Psychiatry 2011; 72:156.
  49. Vázquez GH, Tondo L, Undurraga J, Baldessarini RJ. Overview of antidepressant treatment of bipolar depression. Int J Neuropsychopharmacol 2013; 16:1673.
  50. 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; 158:906.
  51. Yatham LN, Vieta E, Goodwin GM, et al. Agomelatine or placebo as adjunctive therapy to a mood stabiliser in bipolar I depression: randomised double-blind placebo-controlled trial. Br J Psychiatry 2016; 208:78.
  52. Brown EB, McElroy SL, Keck PE Jr, et al. A 7-week, randomized, double-blind trial of olanzapine/fluoxetine combination versus lamotrigine in the treatment of bipolar I depression. J Clin Psychiatry 2006; 67:1025.
  53. Tohen M, Calabrese J, Vieta E, et al. Effect of comorbid anxiety on treatment response in bipolar depression. J Affect Disord 2007; 104:137.
  54. Pacchiarotti I, Valentí M, Bonnin CM, et al. Factors associated with initial treatment response with antidepressants in bipolar disorder. Eur Neuropsychopharmacol 2011; 21:362.
  55. Ghaemi SN, Ostacher MM, El-Mallakh RS, et al. Antidepressant discontinuation in bipolar depression: a Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) randomized clinical trial of long-term effectiveness and safety. J Clin Psychiatry 2010; 71:372.
  56. Ghaemi SN, Wingo AP, Filkowski MA, Baldessarini RJ. Long-term antidepressant treatment in bipolar disorder: meta-analyses of benefits and risks. Acta Psychiatr Scand 2008; 118:347.
  57. Amsterdam JD, Shults J. Efficacy and safety of long-term fluoxetine versus lithium monotherapy of bipolar II disorder: a randomized, double-blind, placebo-substitution study. Am J Psychiatry 2010; 167:792.
  58. Tohen M, Frank E, Bowden CL, et al. The International Society for Bipolar Disorders (ISBD) Task Force report on the nomenclature of course and outcome in bipolar disorders. Bipolar Disord 2009; 11:453.
  59. Tondo L, Vázquez G, Baldessarini RJ. Mania associated with antidepressant treatment: comprehensive meta-analytic review. Acta Psychiatr Scand 2010; 121:404.
  60. Daray FM, Thommi SB, Ghaemi SN. The pharmacogenetics of antidepressant-induced mania: a systematic review and meta-analysis. Bipolar Disord 2010; 12:702.
  61. Gijsman HJ, Geddes JR, Rendell JM, et al. Antidepressants for bipolar depression: a systematic review of randomized, controlled trials. Am J Psychiatry 2004; 161:1537.
  62. McElroy SL, Altshuler LL, Suppes T, et al. Axis I psychiatric comorbidity and its relationship to historical illness variables in 288 patients with bipolar disorder. Am J Psychiatry 2001; 158:420.
  63. Thompson WK, Kupfer DJ, Fagiolini A, et al. Prevalence and clinical correlates of medical comorbidities in patients with bipolar I disorder: analysis of acute-phase data from a randomized controlled trial. J Clin Psychiatry 2006; 67:783.
  64. Andrade C. Antidepressant-withdrawal mania:a critical review and synthesis of the literature. J Clin Psychiatry 2004; 65:987.
  65. Post RM, Altshuler LL, Leverich GS, et al. Mood switch in bipolar depression: comparison of adjunctive venlafaxine, bupropion and sertraline. Br J Psychiatry 2006; 189:124.
  66. Vieta E, Martinez-Arán 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; 63:508.
  67. Peet M. Induction of mania with selective serotonin re-uptake inhibitors and tricyclic antidepressants. Br J Psychiatry 1994; 164:549.
  68. Bond DJ, Noronha MM, Kauer-Sant'Anna M, et al. Antidepressant-associated mood elevations in bipolar II disorder compared with bipolar I disorder and major depressive disorder: a systematic review and meta-analysis. J Clin Psychiatry 2008; 69:1589.
  69. Frye MA, McElroy SL, Prieto ML, et al. Clinical risk factors and serotonin transporter gene variants associated with antidepressant-induced mania. J Clin Psychiatry 2015; 76:174.