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Pharmacological Treatment of Bipolar Depression: Qualitative Systematic Review of Double-Blind Randomized Clinical Trials

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Abstract

Randomized clinical trial (RCT) is the best study design for treatment-related issues, yet these studies may present a number of biases and limitations. The objective of this study is to carry out a qualitative analysis of RCT methodology in the treatment of bipolar depression (BD). A systematic review covering the last 20 years was performed on PubMed selecting double-blind RCTs for BD. The identification items of the articles, their design, methodology, outcome and grant-related issues were all analyzed. Thirty articles were included, all of which had been published in journals with an impact factor >3. While almost half studies (46.7%) used less than 50 patients as a sample, 70% did not describe or did not perform sample size calculation. The Last Observation Carried Forward (LOCF) method was used in 2/3 of the articles and 53.4% of the studies had high sample losses (>20%). Almost half the items were sponsored by the pharmaceutical industry and 33.3% were sponsored by institutions or research foundations. Articles on the pharmacological treatment of BD have several limitations which hinder the extrapolation of the data to clinical practice. Methodological errors and biases are common and statistical simplifications compromise the consistency of the findings.

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References

  1. Belmaker RH: Bipolar disorder. New England Journal of Medicine 351(5):476–486, 2004

    Article  PubMed  CAS  Google Scholar 

  2. Judd LL, et al.: The long-term natural history of the weekly symptomatic status of bipolar I disorder. Archives of General Psychiatry 59(6):530–537, 2002

    Article  PubMed  Google Scholar 

  3. Goodwin FK, Jamison KR, Ghaemi SN: Manic-Depressive Illness: Bipolar Disorders and Recurrent Depression, 2nd edn, New York, NY, Oxford University Press, 2007

  4. Kupka RW, et al.: Three times more days depressed than manic or hypomanic in both bipolar I and bipolar II disorder. Bipolar Disorders 9(5):531–535, 2007

    Article  PubMed  Google Scholar 

  5. Sachs GS, Rush AJ: Response, remission, and recovery in bipolar disorders: What are the realistic treatment goals? Journal of Clinical Psychiatry 64:18–22, 2003

    PubMed  CAS  Google Scholar 

  6. Rihmer Z: Prediction and prevention of suicide in bipolar disorders. Clinical Neuropsychiatry 2(1):48–54, 2005

    Google Scholar 

  7. Grunze H, 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 Journal of Biological Psychiatry 11(2):81–109, 2010

    Article  PubMed  Google Scholar 

  8. Sachs GS, et al.: Effectiveness of adjunctive antidepressant treatment for bipolar depression. New England Journal of Medicine 356(17):1711–1722, 2007

    Article  PubMed  CAS  Google Scholar 

  9. Ioannidis J: Some main problems eroding the credibility and relevance of randomized trials. Bulletin of the NYU Hospital for Joint Diseases 66(2):135–139, 2008

    PubMed  Google Scholar 

  10. Van Lieshout RJ, MacQueen GM: Efficacy and acceptability of mood stabilisers in the treatment of acute bipolar depression: Systematic review. British Journal of Psychiatry 196:266–273, 2010

    Article  PubMed  Google Scholar 

  11. Moher D, et al.: CONSORT 2010 explanation and elaboration: Updated guidelines for reporting parallel group randomised trials. BMJ 340:c869, 2010

    Article  PubMed  Google Scholar 

  12. Moher D, et al.: CONSORT 2010 explanation and elaboration: Updated guidelines for reporting parallel group randomised trials. Journal of Clinical Epidemiology 63(8):e1–e37, 2010

    Article  PubMed  Google Scholar 

  13. Young AH, et al.: A double-blind, placebo-controlled study of quetiapine and lithium monotherapy in adults in the acute phase of bipolar depression (EMBOLDEN I). Journal of Clinical Psychiatry 71(2):150–162, 2010

    Article  PubMed  CAS  Google Scholar 

  14. McElroy SL, et al.: A double-blind, placebo-controlled study of quetiapine and paroxetine as monotherapy in adults with bipolar depression (EMBOLDEN II). Journal of Clinical Psychiatry 71(2):163–174, 2010

    Article  PubMed  CAS  Google Scholar 

  15. Suppes T, et al.: Effectiveness of the extended release formulation of quetiapine as monotherapy for the treatment of acute bipolar depression. Journal of Affective Disorders 121(1–2):106–115, 2010

    Article  PubMed  CAS  Google Scholar 

  16. van der Loos MLM, et al.: Efficacy and safety of lamotrigine as add-on treatment to lithium in bipolar depression: A multicenter, double-blind, placebo-controlled trial. Journal of Clinical Psychiatry 70(2):223–231, 2009

    Article  PubMed  Google Scholar 

  17. Yoon SJ, et al.: Decreased glutamate/glutamine levels may mediate cytidine’s efficacy in treating bipolar depression: A longitudinal proton magnetic resonance spectroscopy study. Neuropsychopharmacology 34(7):1810–1818, 2009

    Article  PubMed  CAS  Google Scholar 

  18. Frye MA, et al.: A placebo-controlled evaluation of adjunctive modafinil in the treatment of bipolar depression. American Journal of Psychiatry 164(8):1242–1249, 2007

    Article  PubMed  Google Scholar 

  19. Thase ME, et al.: Efficacy of quetiapine monotherapy in bipolar I and II depression: A double-blind, placebo-controlled study (the BOLDER II study). Journal of Clinical Psychopharmacology 26(6):600–609, 2006

    Article  PubMed  CAS  Google Scholar 

  20. Brown EB, et al.: A 7-week, randomized, double-blind trial of olanzapine/fluoxetine combination versus lamotrigine in the treatment of bipolar I depression. Journal of Clinical Psychiatry 67(7):1025–1033, 2006

    Article  PubMed  CAS  Google Scholar 

  21. Post RM, et al.: Mood switch in bipolar depression: Comparison of adjunctive venlafaxine, bupropion and sertraline. British Journal of Psychiatry 189:124–131, 2006

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  23. Eden Evins A, et al.: Inositol augmentation of lithium or valproate for bipolar depression. Bipolar Disorder 8(2):168–174, 2006

    Article  PubMed  CAS  Google Scholar 

  24. Frangou S, Lewis M, McCrone P: Efficacy of ethyl-eicosapentaenoic acid in bipolar depression: Randomised double-blind placebo-controlled study. British Journal of Psychiatry 188:46–50, 2006

    Article  PubMed  Google Scholar 

  25. Calabrese JR, et al.: A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression. American Journal of Psychiatry 162(7):1351–1360, 2005

    Article  PubMed  Google Scholar 

  26. 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. Journal of Affective Disorders 87(1):121–130, 2005

    Article  PubMed  CAS  Google Scholar 

  27. Davis LL, Bartolucci A, Petty F: Divalproex in the treatment of bipolar depression: A placebo-controlled study. Journal of Affective Disorders 85(3):259–266, 2005

    Article  PubMed  CAS  Google Scholar 

  28. Shelton RC, Stahl SM: Risperidone and paroxetine given singly and in combination for bipolar depression. Journal of Clinical Psychiatry 65(12):1715–1719, 2004

    Article  PubMed  CAS  Google Scholar 

  29. Zarate CA Jr, et al.: Pramipexole for bipolar II depression: a placebo-controlled proof of concept study. Biological Psychiatry 56(1):54–60, 2004

    Article  PubMed  CAS  Google Scholar 

  30. Goldberg JF, Burdick KE, Endick CJ: Preliminary randomized, double-blind, placebo-controlled trial of pramipexole added to mood stabilizers for treatment-resistant bipolar depression. American Journal of Psychiatry 161(3):564–566, 2004

    Article  PubMed  Google Scholar 

  31. Tohen M, et al.: Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Archives of General Psychiatry 60(11):1079–1088, 2003

    Article  PubMed  CAS  Google Scholar 

  32. Silverstone T: Moclobemide vs. imipramine in bipolar depression: A multicentre double-blind clinical trial. Acta Psychiatrica Scandinavica 104(2):104–109, 2001

    Article  PubMed  CAS  Google Scholar 

  33. Nemeroff CB, et al.: Double-blind, placebo-controlled comparison of imipramine and paroxetine in the treatment of bipolar depression. American Journal of Psychiatry 158(6):906–912, 2001

    Article  PubMed  CAS  Google Scholar 

  34. Chengappa KN, et al.: Inositol as an add-on treatment for bipolar depression. Bipolar Disorder 2(1):47–55, 2000

    Article  PubMed  CAS  Google Scholar 

  35. Young LT, 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. American Journal of Psychiatry 157(1):124–126, 2000

    PubMed  CAS  Google Scholar 

  36. Grossman F, et al.: A double-blind study comparing idazoxan and bupropion in bipolar depressed patients. Journal of Affective Disorders 56(2–3):237–243, 1999

    Article  PubMed  CAS  Google Scholar 

  37. Calabrese JR, et al.: A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. Lamictal 602 Study Group. Journal of Clinical Psychiatry 60(2):79–88, 1999

    Article  PubMed  CAS  Google Scholar 

  38. Ebert D, et al.: Initial lithium augmentation improves the antidepressant effects of standard TCA treatment in non-resistant depressed patients. Psychopharmacology (Berlin) 118(2):223–225, 1995

    Article  CAS  Google Scholar 

  39. Sachs GS, et al.: A double-blind trial of bupropion versus desipramine for bipolar depression. Journal of Clinical Psychiatry 55(9):391–393, 1994

    PubMed  CAS  Google Scholar 

  40. Bocchetta A, et al.: A double-blind study of L-sulpiride versus amitriptyline in lithium-maintained bipolar depressives. Acta Psychiatrica Scandinavica 88(6):434–439, 1993

    Article  PubMed  CAS  Google Scholar 

  41. Himmelhoch JM, et al.: Tranylcypromine versus imipramine in anergic bipolar depression. American Journal of Psychiatry 148(7):910–916, 1991

    PubMed  CAS  Google Scholar 

  42. Ghaemi N.: Clinician’s Guide to Statistics and Epidemiology in Mental Health: Measuring Truth and Uncertainty, 1st edn. New York, Cambridge University Press, 2009

  43. Ramirez Basco M, et al.: Methods to improve diagnostic accuracy in a community mental health setting. American Journal of Psychiatry 157(10):1599–1605, 2000

    Article  PubMed  CAS  Google Scholar 

  44. Leverich GS, et al.: Risk of switch in mood polarity to hypomania or mania in patients with bipolar depression during acute and continuation trials of venlafaxine, sertraline, and bupropion as adjuncts to mood stabilizers. American Journal of Psychiatry 163(2):232–239, 2006

    Article  PubMed  Google Scholar 

  45. Fournier JC, et al.: Antidepressant drug effects and depression severity: A patient-level meta-analysis. JAMA 303(1):47–53, 2010

    Article  PubMed  CAS  Google Scholar 

  46. Khan A, et al.: Severity of depression and response to antidepressants and placebo: An analysis of the Food and Drug Administration database. Journal of Clinical Psychopharmacology 22(1):40–45, 2002

    Article  PubMed  Google Scholar 

  47. Kirsch I, et al.: Initial severity and antidepressant benefits: A meta-analysis of data submitted to the Food and Drug Administration. PLoS Medicine 5(2):e45, 2008

    Article  PubMed  Google Scholar 

  48. Gazalle FK, et al.: Bipolar depression: The importance of being on remission. Revista Brasileira De Psiquiatria 28(2):93–96, 2006

    Article  PubMed  Google Scholar 

  49. Martinez-Aran A, et al.: Reporting outcomes in clinical trials for bipolar disorder: A commentary and suggestions for change. Bipolar Disorder 10(5):566–579, 2008

    Article  Google Scholar 

  50. Streiner DL: Missing data and the trouble with LOCF. Evidence-Based Mental Health 11(1):3–5, 2008

    Article  PubMed  Google Scholar 

  51. Harris AH, Reeder R, Hyun JK: Common statistical and research design problems in manuscripts submitted to high-impact psychiatry journals: What editors and reviewers want authors to know. Journal of Psychiatric Research 43(15):1231–1234, 2009

    Article  PubMed  Google Scholar 

  52. Phillips B, et al.: Levels of Evidence—Centre for Evidence Based Medicine. 2009. http://www.cebm.net/index.aspx?o=1025. Accessed 10 December 2010

  53. Als-Nielsen B, et al.: Association of funding and conclusions in randomized drug trials: A reflection of treatment effect or adverse events? JAMA 290(7):921–928, 2003

    Article  PubMed  Google Scholar 

  54. Schunemann HJ, et al.: An official ATS statement: Grading the quality of evidence and strength of recommendations in ATS guidelines and recommendations. American Journal of Respiratory and Critical Care Medicine 174(5):605–614, 2006

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Post-Graduation Program in Psychiatry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil

    Lucas Spanemberg, Raffael Massuda, Lucas Lovato, Leonardo Paim, Edgar Arrua Vares, Neusa Sica da Rocha & Keila Maria Mendes Ceresér

  2. Department of Psychiatry, Hospital São Lucas—Pontifícia Universidade Católica do Rio Grande do Sul (HSL/PUCRS), 6° andar Sul—Internação Psiquiátrica Av. Ipiranga, 6690, Porto Alegre, RS, CEP 90160-090, Brazil

    Lucas Spanemberg

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  1. Lucas Spanemberg
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  2. Raffael Massuda
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Correspondence to Lucas Spanemberg.

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Spanemberg, L., Massuda, R., Lovato, L. et al. Pharmacological Treatment of Bipolar Depression: Qualitative Systematic Review of Double-Blind Randomized Clinical Trials. Psychiatr Q 83, 161–175 (2012). https://doi.org/10.1007/s11126-011-9191-1

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  • DOI: https://doi.org/10.1007/s11126-011-9191-1

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