Advertisement

Current Psychiatry Reports

, 16:431 | Cite as

Options for Pharmacological Treatment of Refractory Bipolar Depression

  • Leonardo Tondo
  • Gustavo H. Vázquez
  • Ross J. Baldessarini
Bipolar Disorders (WH Coryell, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Bipolar Disorders

Abstract

Bipolar disorders of types I and II, even when treated by currently standard options, show a marked excess of depressive morbidity. Treated, type I patients in mid-course or from the onset of illness are ill, overall, 50 % of weeks of follow-up, and 75 % of that unresolved morbidity is depressive. Currently widely held impressions are that bipolar depression typically is poorly responsive to antidepressants, that treatment-resistant depression (TRD) is characteristic of the disorder, and that risk of mania with antidepressant treatment is very high. However, none of these views is supported consistently by available research. TRD may be more prevalent in bipolar than unipolar mood disorders. Relatively intense research attention is directed toward characteristics and treatments of TRD in unipolar depression, but studies of bipolar TRD are uncommon. We found only five controlled trials, plus 10 uncontrolled trials, providing data on a total of 13 drug treatments, all of which involved one or two trials, in 87 % as add-ons to complex, uncontrolled regimens. In two controlled trials, ketamine was superior to placebo but it is short-acting and not orally active; pramipexole was weakly superior to placebo in one controlled trial; three other drugs failed to outperform controls. Other pharmacotherapies are inadequately evaluated and nonpharmacological options are virtually untested in bipolar TRD. The available research supports the view that antidepressants may be effective in bipolar depression provided that currently agitated patients are excluded, that risk of mania with antidepressants is only moderately greater than risk of spontaneous mania, and that bipolar TRD is not necessarily resistant to all treatments.

Keywords

Amphetamine Aripiprazole Bipolar disorder Bupropion Creatine Depression Inositol Ketamine Ketoconazole Lamotrigine Methylphenidate Modafinil N-acetylcysteine Pramipexole Quetiapine Risperidone, Stimulants Treatment resistance Tri-iodothyronine 

Notes

Acknowledgments

Supported by an award from the Aretæus Association of Rome (to L. Tondo), and a grant from the Bruce J. Anderson Foundation and by the McLean Private Donors Research Fund (to R.J. Baldessarini).

Compliance with Ethics Guidelines

Conflict of Interest

Leonardo Tondo, Gustavo H. Vázquez, and Ross J. Baldessarini declare that they have no potential bases of apparent conflict of interest in the material presented here.

Human and Animal Rights and Informed Consent

This article contains observational data from a study by Tondo and Baldessarini (2013) in patients providing informed consent for anonymous and aggregate use of data arising from their treatment (cited in footnote 2). No animal studies were involved.

References

Recently published papers of particular interest have been highlighted as: • Of importance •• Of major importance

  1. 1.
    • Baldessarini RJ, Vieta E, Calabrese JR, et al. Bipolar depression: overview and commentary. Harv Rev Psychiatry. 2010;18(3):143–57. Overview on bipolar depression.PubMedCrossRefGoogle Scholar
  2. 2.
    Judd LL, Akiskal HS, Schettler PJ, et al. Long-term natural history of the weekly symptomatic status of bipolar I disorder. Arch Gen Psychiatry. 2002;59(6):530–7.PubMedCrossRefGoogle Scholar
  3. 3.
    Post RM, Denicoff KD, Leverich GS, et al. Morbidity in 258 bipolar outpatients followed for 1year with daily prospective ratings on the NIMH life chart method. J Clin Psychiatry. 2003;64(6):680–90.PubMedCrossRefGoogle Scholar
  4. 4.
    Joffe RT, MacQueen GM, Marriott M, et al. Prospective, longitudinal study of percentage of time spent ill in patients with bipolar I or bipolar II disorders. Bipolar Disord. 2004;6(1):62–6.PubMedCrossRefGoogle Scholar
  5. 5.
    Paykel ES, Abbott R, Morriss R, et al. Sub-syndromal and syndromal symptoms in the longitudinal course of bipolar disorder. Br J Psychiatry. 2006;189(8):118–23.PubMedCrossRefGoogle Scholar
  6. 6.
    Baldessarini RJ, Salvatore P, Khalsa H-MK, et al. Morbidity in 303 first-episode bipolar I disorder patients. Bipolar Disord. 2010;12(3):264–70.PubMedCrossRefGoogle Scholar
  7. 7.
    •• Vergunst FK, Fekadu A, Wooderson SC, et al. Longitudinal course of symptom severity and fluctuation in patients with treatment-resistant unipolar and bipolar depression. Psychiatry Res. 2013;207(3):143–9. Describes longitudinal course and severity of treatment-resistant unipolar and bipolar depression.PubMedCrossRefGoogle Scholar
  8. 8.
    Baldessarini RJ, Tondo L, Visioli C. First-episode types in bipolar disorder: predictive associations with later illness. Acta Psychiatr Scand. 2013; in press.Google Scholar
  9. 9.
    Ösby U, Brandt L, Correia N, et al. Excess mortality in bipolar and unipolar disorder in Sweden. Arch Gen Psychiatry. 2001;58(9):844–50.PubMedCrossRefGoogle Scholar
  10. 10.
    Kessler U, Schoeyen HK, Andreassen OA, et al. Neurocognitive profiles in treatment-resistant bipolar I and bipolar II disorder depression. BMC Psychiatry. 2013;13(4):105.PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Whiteford HA, Degenhardt L, Rehm J, et al. Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010. Lancet. 2013; [Epub ahead of print (28 Aug)].Google Scholar
  12. 12.
    Novick DM, Swartz HA, Frank E. Suicide attempts in bipolar I and bipolar II disorder: review and meta-analysis of the evidence. Bipolar Disord. 2010;12(1):1–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Colom F, Vieta E, Daban C, et al. Clinical and therapeutic implications of predominant polarity in bipolar disorder. J Affect Disord. 2006;93(1–3):13–7.PubMedCrossRefGoogle Scholar
  14. 14.
    Baldessarini RJ, Undurraga J, Vázquez GH, et al. Predominant recurrence polarity among 928 adult international bipolar I disorder patients. Acta Psychiatr Scand. 2012;125(4):293–302.PubMedCrossRefGoogle Scholar
  15. 15.
    Pacchiarotti I, Mazzarini L, Colom F, et al. Treatment-resistant bipolar depression: towards a new definition. Acta Psychiatr Scand. 2009;120(6):429–40.PubMedCrossRefGoogle Scholar
  16. 16.
    Sachs GS. Treatment-resistant bipolar depression. Psychiatr Clin North Am. 1996;19(2):215–36.PubMedCrossRefGoogle Scholar
  17. 17.
    • Schosser A, Serretti A, Souery D, et al. European Group for the Study of Resistant Depression (GSRD)—where have we gone so far: review of clinical and genetics findings. Eur Neuropsychopharmacol. 2012;22(7):453–68. Reviews many aspects of treatment-resistant depression.PubMedCrossRefGoogle Scholar
  18. 18.
    •• Li C-T, Bai Y-M, Huang Y-L, et al. Association between antidepressant resistance in unipolar depression and subsequent bipolar depression: cohort study. Br J Psychiatry. 2012;200(1):45–51. Rare study directly comparing unipolar and bipolar treatment-resistant depression.PubMedCrossRefGoogle Scholar
  19. 19.
    Vázquez GH, Tondo L, Baldessarini RJ. Comparison of antidepressant responses in patients with bipolar vs. unipolar depression: meta-analytic review. Pharmacopsychiatry. 2011;44(1):21–6.PubMedGoogle Scholar
  20. 20.
    • Tondo L, Baldessarini RJ, Vázquez GH, et al. Clinical responses to antidepressants among 1036 acutely depressed patients with bipolar or unipolar major affective disorders. Acta Psychiatr Scand. 2013;127(5):355–64. Found that there is no difference in response in bipolar versus unipolar depression, provided that patients with agitation and dysphoric depression are not included.PubMedCrossRefGoogle Scholar
  21. 21.
    Vázquez GH, Tondo L, Undurraga J, et al. Overview of antidepressant treatment in bipolar depression: critical commentary. Intl J Neuropsychopharmacol. 2013;16(7):1673–85.CrossRefGoogle Scholar
  22. 22.
    Vázquez GH, Tondo L, Undurraga J, et al. Pharmacological treatment for bipolar depression. Adv Psychiatr Treatment. 2013; in press.Google Scholar
  23. 23.
    Goodwin GM, Consensus Group. Evidence-based guidelines for treating bipolar disorder: revised, second edition—recommendations of the British Association of Psychopharmacology. J Psychopharmacol. 2009;23(4):346–88.PubMedCrossRefGoogle Scholar
  24. 24.
    • 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 guidelines for management of patients with bipolar disorder. Bipolar Disord. 2013;15(1):1–44. Guidelines for treatment of bipolar depression.PubMedCrossRefGoogle Scholar
  25. 25.
    • Pacchiarotti I, Bond DJ, Baldessarini RJ, et al. International Society for Bipolar Disorders (ISBD) task-force report on antidepressant use in bipolar disorders. Am J Psychiatry 2013; in press. Major review of research on the treatment of bipolar depression Google Scholar
  26. 26.
    Goodwin GM. Bipolar depression and treatment with antidepressants. Br J Psychiatry. 2012;200(1):5–6.PubMedCrossRefGoogle Scholar
  27. 27.
    Goldberg JF, Burdick KE, Endick CJ. Preliminary randomized, double-blind, placebo-controlled trial of pramipexole added to mood stabilizers for treatment-resistant bipolar depression. Am J Psychiatry. 2004;161(3):564–6.PubMedCrossRefGoogle Scholar
  28. 28.
    Nierenberg AA, Ostacher MJ, Calabrese JR, et al. Treatment-resistant bipolar depression: a STEP-BD equipoise randomized effectiveness trial of antidepressant augmentation with lamotrigine, inositol, or risperidone. Am J Psychiatry. 2006;163(2):210–6.PubMedCrossRefGoogle Scholar
  29. 29.
    Frye MA, Grunze H, Suppes T, et al. A placebo-controlled evaluation of adjunctive modafinil in the treatment of bipolar depression. Am J Psychiatry. 2007;164(8):1242–9.PubMedCrossRefGoogle Scholar
  30. 30.
    Diazgranados N, Ibrahim L, Brutsche NE, et al. Randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry. 2010;67(8):793–802.PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Zarate Jr CA, Brutsche NE, Ibrahim L, et al. Replication of ketamine’s antidepressant efficacy in bipolar depression: randomized controlled add-on trial. Biol Psychiatry. 2012;71(5):939–46.PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Sienaert P, Lambrichts L, Dols A, et al. Evidence-based treatment strategies for treatment-resistant bipolar depression: systematic review. Bipolar Disord. 2013;15(1):61–9.PubMedCrossRefGoogle Scholar
  33. 33.
    Brown ES, Bobadilla L, Rush AJ. Ketoconazole in bipolar patients with depressive symptoms: case series and literature review. Bipolar Disord. 2001;3(1):23–9.PubMedCrossRefGoogle Scholar
  34. 34.
    Erfurth A, Michael N, Stadtland C, Arolt V. Bupropion as add-on strategy in difficult-to-treat bipolar depressive patients. Neuropsychobiology. 2002;45 Suppl 1:33–6.PubMedCrossRefGoogle Scholar
  35. 35.
    Cassano P, Lattanzi L, Soldani F, et al. Pramipexole in treatment-resistant depression: an extended follow-up. Depress Anxiety. 2004;20(3):131–8.PubMedCrossRefGoogle Scholar
  36. 36.
    Ketter TA, Wang PW, Chandler RA, et al. Adjunctive aripiprazole in treatment-resistant bipolar depression. Ann Clin Psychiatry. 2006;18(3):169–72.PubMedCrossRefGoogle Scholar
  37. 37.
    Roitman S, Green T, Osher Y, et al. Creatine monohydrate in resistant depression: preliminary study. Bipolar Disord. 2007;9(7):754–8.PubMedCrossRefGoogle Scholar
  38. 38.
    Nierenberg AA. Low-dose buspirone, melatonin and low-dose bupropion added to mood stabilizers for severe treatment-resistant bipolar depression. Psychother Psychosom. 2009;78(6):391–3.PubMedCrossRefGoogle Scholar
  39. 39.
    Kelly T, Lieberman DZ. The use of triiodothyronine as an augmentation agent in treatment-resistant bipolar II and bipolar disorder NOS. J Affect Disord. 2009;116(3):222–6.PubMedCrossRefGoogle Scholar
  40. 40.
    Parker G, Brotchie H. Do the old psychostimulant drugs have a role in managing treatment-resistant depression? Acta Psychiatr Scand. 2010;121(4):308–14.PubMedCrossRefGoogle Scholar
  41. 41.
    Ahn YM, Nam JY, Culver JL, et al. Lamotrigine plus quetiapine combination therapy in treatment-resistant bipolar depression. Ann Clin Psychiatry. 2011;23(1):17–24.PubMedGoogle Scholar
  42. 42.
    Schaffer LC, Schaffer CB, Miller AR, et al. Open trial of pregabalin as an acute and maintenance adjunctive treatment for outpatients with treatment-resistant bipolar disorder. J Affect Disord. 2013;147(1–3):407–10.PubMedCrossRefGoogle Scholar
  43. 43.
    Thase ME, Jonas A, Khan A. Aripiprazole monotherapy in non-psychotic bipolar I depression: results of 2 randomized, placebo-controlled studies. J Clin Psychophrmacol. 2008;28(1):13–20.CrossRefGoogle Scholar
  44. 44.
    Selle V, Schalkwijk S, Vázquez GH, Baldessarini RJ. Treatments for acute bipolar depression: meta-analyses of placebo-controlled trials of mood-stabilizers and second-generation antipsychotics. Pharmacopsychiatry 2013; in press.Google Scholar
  45. 45.
    Swartz HA, Thase ME. Pharmacotherapy for the treatment of acute bipolar II depression: current evidence. Psychiatry. 2011;72(3):356–66.Google Scholar
  46. 46.
    Lorenzo LS, Vázquez GH, Zaratiegui RM, et al. Characteristics of bipolar disorder patients given antidepressants. Hum Psychopharmacol. 2012;27(5):486–91.PubMedCrossRefGoogle Scholar
  47. 47.
    Undurraga J, Baldessarini RJ, Valenti M, et al. Bipolar depression: clinical correlates of receiving antidepressants. J Affect Disord. 2012;139(1):89–93.PubMedCrossRefGoogle Scholar
  48. 48.
    • Tondo L, Vázquez GH, Baldessarini RJ. Mania associated with antidepressant-treatment: comprehensive meta-analytic review. Acta Psychiatr Scand. 2010;121(6):404–14. Meta-analyis of more than 100 studies on the risk of switch in bipolar and unipolar patients, with and without mood-stabilizers.PubMedCrossRefGoogle Scholar
  49. 49.
    Kessler U, Vaaler AE, Schøyen H, et al. Study protocol of the Norwegian randomized controlled trial of electroconvulsive therapy in treatment resistant depression in bipolar disorder. BMC Psychiatry. 2010;10(2):16.PubMedCentralPubMedCrossRefGoogle Scholar
  50. 50.
    Baldessarini RJ. Chemotherapy in Psychiatry. 3rd ed. New York: Springer Press; 2013.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Leonardo Tondo
    • 1
    • 3
    • 5
  • Gustavo H. Vázquez
    • 1
    • 4
  • Ross J. Baldessarini
    • 1
    • 2
  1. 1.International Consortium for Bipolar and Psychotic Disorder ResearchMcLean HospitalBelmontUSA
  2. 2.Department of PsychiatryHarvard Medical SchoolBostonUSA
  3. 3.Lucio Bini Mood Disorder CentersCagliari & RomeItaly
  4. 4.Department of NeurosciencePalermo UniversityBuenos AiresArgentina
  5. 5.Mailman Research CenterMcLean HospitalBelmontUSA

Personalised recommendations