CNS Drugs

, Volume 16, Issue 11, pp 721–729 | Cite as

Treatment Research in Bipolar Disorder

Issues and Recommendations
  • Ross J. Baldessarini
Current Opinion


Bipolar (manic-depressive) disorder is one of the most common of the severe mental illnesses. Officially recognised forms comprise type I (with mania), type II (with hypomania), cyclothymia and a rapid-cycling subtype. International lifetime prevalence estimates are 1 to 5% of the general population, and bipolar disorder accounts disproportionately for idiopathic psychoses. Psychiatric and substance-abuse comorbidities are common complications, and mortality rates are increased as a result of high suicidal risks, accidents, complications of substance abuse and increased fatality of stress-sensitive medical illnesses. Complex and labile symptomatic presentations, a tendency for patients to deny illness and reject treatment, and diagnostic heterogeneity severely complicate the design, conduct and interpretation of experimental treatment trials in bipolar disorder.

Progress in the short-term treatment of mania with certain antiepileptic drugs and atypical antipsychotic agents has advanced greatly in recent years; however, long-term treatment trials other than with lithium remain rare, as are studies of type II disorder, bipolar depression and mixed states, and there is limited information on treatment effectiveness against comorbidity, dysfunction and mortality. There is a growing realisation that bipolar disorder represents a major, largely unmet, international public health challenge and that innovative methods for carrying out reliable and generalisable long-term pharmacological treatment trials, alone and in combination with cost-effective psychosocial and rehabilitative interventions, are urgently required.


Bipolar Disorder Olanzapine Bipolar Depression Placebo Condition Divalproex Sodium 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Dr Baldessarini was supported in part by an award from the Bruce J. Anderson Foundation and by the McLean Private Donors Neuropsychopharmacology Research Fund. Rita Burke provided valuable bibliographic assistance. The author has been a consultant or investigator for corporations that produce drugs used to treat patients with bipolar disorder, including Alkermes, GlaxoSmithKline, Janssen, Eli Lilly, Pfizer, Protarga and Solvay.


  1. 1.
    Goodwin FK, Jamison KR. Manic depressive illness. New York: Oxford University Press, 1990Google Scholar
  2. 2.
    Baldessarini RJ. A plea for integrity of the bipolar disorder concept. Bipolar Disord 2000; 2: 3–7PubMedCrossRefGoogle Scholar
  3. 3.
    Tohen M, Angst J. Epidemiology of bipolar disorder. In: Tsuang MT, Tohen M, editors. Textbook in psychiatric epidemiology. 2nd ed. New York: John Wiley & Sons, 1995Google Scholar
  4. 4.
    American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed., text revision. Washington, DC: American Psychiatric Association, 2000Google Scholar
  5. 5.
    Akiskal HS, Bourgeois ML, Angst J, et al. Re-evaluating the prevalence of and diagnostic composition within the broad clinical spectrum of bipolar disorders. J Affect Disord 2000; 59: S5–30PubMedCrossRefGoogle Scholar
  6. 6.
    Baldessarini RJ, Tondo L, Hennen J. Reduced suicide risk during long-term treatment with lithium. Ann N Y Acad Sci 2001; 932: 24–43PubMedCrossRefGoogle Scholar
  7. 7.
    Tondo L, Hennen J, Baldessarini RJ. Reduced suicide risk with long-term lithium treatment in major affective illness: a meta-analysis. Acta Psychiatr Scand 2001; 104: 163–72PubMedCrossRefGoogle Scholar
  8. 8.
    Tondo L, Baldessarini RJ, Floris G. Long-term effectiveness of lithium maintenance treatment in types I and II bipolar disorders. Br J Psychiatry 2001; 178Suppl. 40: S184–90PubMedCrossRefGoogle Scholar
  9. 9.
    Baldessarini RJ, Tarazi FI. Drugs and the treatment of psychiatric disorders: antipsychotic and antimanic agents. In: Hardman JG, Limbird LE, Gilman AG, editors. Goodman and Gilman’s the pharmacological basis of therapeutics. 10th ed. New York: McGraw-Hill Press, 2001: 485–520Google Scholar
  10. 10.
    Baldessarini RJ. Drugs and the treatment of psychiatric disorders: antidepressant and antianxiety agents. In: Hardman JG, Limbird LE, Gilman AG, editors. Goodman and Gilman’s the pharmacological basis of therapeutics. 10th ed. New York: McGraw-Hill Press, 2001: 447–83Google Scholar
  11. 11.
    Brambilla P, Barale F, Soares JC. Perspectives on the use of anticon vulsants in the treatment of bipolar disorder. Int J Neuro-psychopharmacol 2001; 4: 421–46Google Scholar
  12. 12.
    Strakowski SM, Del Bello MP, Adler CM. Comparative efficacy and tolerability of drug treatments for bipolar disorder. CNS Drugs 2001; 15:701–18PubMedCrossRefGoogle Scholar
  13. 13.
    Ghaemi SN, Lenox MS, Baldessarini RJ. Effectiveness and safety of long-term antidepressant treatment in bipolar disorder. J Clin Psychiatry 2001; 62: 565–9PubMedCrossRefGoogle Scholar
  14. 14.
    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: 906–12PubMedGoogle Scholar
  15. 15.
    Baldessarini RJ, Tondo L, Hennen J. Effects of rapid cycling on response to lithium maintenance treatment in 360 bipolar I and II disorder patients. J Affect Disord 2000; 61: 13–22PubMedCrossRefGoogle Scholar
  16. 16.
    Baldessarini RJ, Tondo L, Hennen J. Latency and episodes before treatment: effects on pretreatment morbidity but not response to maintenance treatment in bipolar I and II disorders. Bipolar Disord 2002. In pressGoogle Scholar
  17. 17.
    Kukopulos A, Reginaldi D, Laddomada P, et al. Course of the manic-depressive cycle and changes caused by treatments. Pharmakopsychiatr Neuropsychopharmakol 1980; 13: 156–67PubMedGoogle Scholar
  18. 18.
    Kupfer DJ, Carpenter LL, Frank E. Possible role of antidepressants in precipitating mania and hypomania in recurrent depression. Am J Psychiatry 1988; 145: 804–8PubMedGoogle Scholar
  19. 19.
    Stoll AL, Mayer PV, Kolbrener M, et al. Antidepressant-associated mania: a controlled comparison with spontaneous mania. Am J Psychiatry 1994; 151: 1642–5PubMedGoogle Scholar
  20. 20.
    Baldessarini RJ, Tondo L, Hennen J, et al. Is lithium still worth using? An update of selected recent research. Harv Rev Psychiatry 2002; 10: 59–75PubMedGoogle Scholar
  21. 21.
    Kruger S, Braunig P, Cooke RG. Comorbidity of obsessive-compulsive disorder in recovered inpatients with bipolar disorder. Bipolar Disord 2000; 2: 71–4PubMedCrossRefGoogle Scholar
  22. 22.
    Cassidy F, Ahearn EP, Carroll BJ. Substance abuse in bipolar disorder. Bipolar Disord 2001; 3: 181–8PubMedCrossRefGoogle Scholar
  23. 23.
    MacKinnon DF, Zandi PP, Cooper J, et al. Comorbid bipolar disorder and panic disorder in families with a high prevalence of bipolar disorder. Am J Psychiatry 2002; 15: 30–5CrossRefGoogle Scholar
  24. 24.
    Ghaemi SN, Pope Jr HG. Lack of insight in psychotic and affective disorders: a review of empirical studies. Harv Rev Psychiatry 1994; 2: 22–33PubMedCrossRefGoogle Scholar
  25. 25.
    Osby U, Brandt L, Correia N, et al. Excess mortality in bipolar and unipolar disorder in Sweden. Arch Gen Psychiatry 2001; 58: 844–50PubMedCrossRefGoogle Scholar
  26. 26.
    Bowden CL, Brugger A, Swann AC, et al. Efficacy of divalproex vs. lithium and placebo in the treatment of mania. JAMA 1994; 271: 918–24Google Scholar
  27. 27.
    Tohen M, Sanger TM, McElroy SL, et al. Olanzapine versus placebo in the treatment of acute mania: the Olanzapine HGEH Study Group. Am J Psychiatry 1999; 156: 702–9PubMedGoogle Scholar
  28. 28.
    Tohen M, Jacobs TG, Grundy SL, et al. Efficacy of olanzapine in acute bipolar mania: a double-blind, placebo-controlled study: the Olanzapine HGGW Study Group. Arch Gen Psychiatry 2000; 57: 841–9PubMedCrossRefGoogle Scholar
  29. 29.
    Cade JFJ. Lithium salts in the treatment of psychotic excitement. Med J Aust 1949; 2: 349–52PubMedGoogle Scholar
  30. 30.
    Prien RF, Kupfer DJ, Mansky PA, et al. Drug therapy in the prevention of recurrences in unipolar and bipolar affective disorders. Arch Gen Psychiatry 1984; 41: 1096–104PubMedCrossRefGoogle Scholar
  31. 31.
    Bowden CL, Calabrese JR, McElroy SL, et al. A randomized, placebo-controlled, 12-month trial of divalproex and lithium in treatment of outpatients with bipolar I disorder: the Divalproex Maintenance Study Group. Arch Gen Psychiatry 2000; 57: 481–9PubMedCrossRefGoogle Scholar
  32. 32.
    Baldessarini RJ, Tohen M, Tondo L. Maintenance treatment in bipolar disorder. Arch Gen Psychiatry 2000; 57: 490–2PubMedCrossRefGoogle Scholar
  33. 33.
    Kupfer DJ, Frank E, Grochocinski VJ, et al. Demographic and clinical characteristics of individuals in a bipolar disorder case registry. J Clin Psychiatry 2002; 63: 120–5PubMedCrossRefGoogle Scholar
  34. 34.
    Keller MB, Lavori PW, Klerman G, et al. Low levels and lack of predictors of somatotherapy and psychotherapy received by depressed patients. Arch Gen Psychiatry 1986; 43: 458–66PubMedCrossRefGoogle Scholar
  35. 35.
    Harman JS, Mulsant BH, Kelleher KJ, et al. Narrowing the gap in treatment of depression. Int J Psychiatry Med 2001; 31: 239–53PubMedCrossRefGoogle Scholar
  36. 36.
    Bowden CL, Swann AC, Calabrese JR, et al. Maintenance clinical trials in bipolar disorder: design implications of the divalproex-lithium-placebo study. Psychopharmacol Bull 1997; 33: 693–9PubMedGoogle Scholar
  37. 37.
    Gelenberg AJ, Frank E, Keller MB, et al. Evaluating pharmacologic treatments for bipolar disorder. In: Prien RF, Robison DS, editors. Clinical evaluation of psychotropic drugs: principles and guidelines. New York: Raven Press, 1994: 327–44Google Scholar
  38. 38.
    Prien RF, Robison DS, editors. Clinical evaluation of psychotropic drugs: principles and guidelines. New York: Raven Press, 1994: 728Google Scholar
  39. 39.
    Prien RF, Rush AJ. National Institute of Mental Health workshop report on the treatment of bipolar disorder. Biol Psychiatry 1996; 40: 215–20PubMedCrossRefGoogle Scholar
  40. 40.
    Calabrese JR, Rapport DJ. Mood stabilizers and the evolution of maintenance study designs in bipolar I disorder. J Clin Psychiatry 1999; 60 Suppl. 5: 5–13Google Scholar
  41. 41.
    Lavori PW. Placebo control groups in randomized treatment trials: a statistician’s perspective. Biol Psychiatry 2000; 47: 717–23PubMedCrossRefGoogle Scholar
  42. 42.
    Post RM, Denicoff KD, Leverich GS. Special issues in trial design and use of placebo in bipolar illness. Biol Psychiatry 2000; 47: 727–32PubMedCrossRefGoogle Scholar
  43. 43.
    Rush AJ, Post RM, Nolen WA, et al. Methodological issues in development new acute treatment for patients with bipolar illness. Biol Psychiatry 2000; 46: 615–24CrossRefGoogle Scholar
  44. 44.
    Calabrese JR, Rapport DJ, Shelton MD, et al. Evolving methodologies in bipolar disorder maintenance research. Br J Psychiatry 2001; 178Suppl. 41: s157–63PubMedCrossRefGoogle Scholar
  45. 45.
    Geddes J, Goodwin G. Bipolar disorder: clinical uncertainty, evidence-based medicine and large-scale randomized trials.Br J Psychiatry 2001; 178Suppl. 4: sl91–4Google Scholar
  46. 46.
    Post RM, Keck Jr PE, Rush AJ. New designs for studies of the prophylaxis of bipolar disorder. J Clin Psychopharmacol 2002; 22: 1–3PubMedCrossRefGoogle Scholar
  47. 47.
    Baldessarini RJ, Tondo L, Viguera AC. Effects of discontinuing lithium maintenance treatment. Bipolar Disord 1999; 1: 17–24PubMedCrossRefGoogle Scholar
  48. 48.
    Hennen J. Methods of design and analysis of experimental treatment trials in bipolar disorder. Bipolar Disord. In pressGoogle Scholar
  49. 49.
    Coppen A, Montgomery SA, Gupta RK, et al. A double-blind comparison of lithium carbonate and maprotiline in the prophylaxis of the affective disorders. Br J Psychiatry 1976; 128: 479–85PubMedCrossRefGoogle Scholar
  50. 50.
    Huxley NA, Parikh SV, Baldessarini RJ. Effectiveness of psychosocial treatments in bipolar disorder: state of the evidence. Harv Rev Psychiatry 2000; 8: 126–40PubMedGoogle Scholar
  51. 51.
    Klein DF. Improvement of phase III psychotropic drug trials by intensive phase II work. Neuropsychopharmacology 1991; 4: 251–8PubMedGoogle Scholar
  52. 52.
    Centorrino F, Hernán MA, Drago-Ferrante G, et al. Noncompliance with psychiatric outpatient visits: associated factors. Psychiatr Serv 2001; 52: 378–80PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 2002

Authors and Affiliations

  1. 1.Department of Psychiatry and Neuroscience ProgramHarvard Medical SchoolBostonUSA
  2. 2.Bipolar & Psychotic Disorders Program and International Consortium for Bipolar Disorder ResearchMcLean Division of Massachusetts General HospitalBelmontUSA

Personalised recommendations