Skip to main content
SpringerLink
Log in

Aripiprazole in Acute Mania and Long-Term Treatment of Bipolar Disorder

A Critical Review by an Italian Working Group

  • Review Article
  • Published:
Clinical Drug Investigation Aims and scope Submit manuscript

Abstract

Bipolar disorder (BD) is a chronic illness that is characterized by recurrent episodes of mania, depression or mixed symptoms. BD has a prevalence of approximately 2–4% in the general population and is associated with a substantial burden in terms of morbidity and mortality. Mania is one of the most difficult to treat manifestations of BD and antipsychotic drugs play a major therapeutic role in this respect. Acting mainly at dopamine receptors, first-generation antipsychotics are effective in controlling symptoms of BD; however, these drugs cause troublesome extrapyramidal symptoms (EPS) and hyperprolactinaemia. The more recently developed second-generation antipsychotics, which act at other receptors, provide a broader spectrum of clinical efficacy and have a more favourable tolerability profile than first-generation antipsychotics. Some second-generation antipsychotics are, however, associated with adverse effects such as weight gain and metabolic disorders, which may be cause for concern. Aripiprazole, a recently introduced second-generation antipsychotic, has a unique receptor-binding profile and mechanism of action, which are thought to account for its low propensity for weight gain, metabolic disturbances and sedation. Aripiprazole is approved in the US and in Europe for the acute management and maintenance of manic and mixed episodes associated with bipolar I disorder. In both the acute and long-term maintenance settings, clinical trials have shown aripiprazole to be clinically effective in terms of response rates, remission rates and prevention of relapse. The lack of a sedative effect does not affect the efficacy of aripiprazole in controlling mania and agitation. With both short- and long-term aripiprazole treatment, adverse event rates were similar to placebo and significantly lower than seen with comparators; one exception to this is the occurrence of EPS, which was observed more frequently in aripiprazole recipients than in patients receiving placebo, but less frequently than in patients treated with haloperidol. Aripiprazole is likely to promote treatment adherence because of its favourable tolerability profile, but more specifically focused studies are required to confirm this hypothesis. The efficacy and favourable metabolic profile of aripiprazole make it a good option in the management of acute mania and maintenance treatment, especially in an outpatient setting. Thus, aripiprazole provides clinicians with a valuable additional therapeutic option for BD. Cognizant of the lack of standardized strategies for aripiprazole dosing, switching, and prevention and management of adverse effects, an expert consensus meeting was held in Italy with the aim of producing guidelines for the use of aripiprazole in acute and long-term management of BD mania. The resulting dosage, administration and switching recommendations outlined in this report are based on empirical results from well designed aripiprazole clinical trials and clinical experience, and are in accord with the manufacturer’s prescribing information. However, careful evaluation of the individual patient and a thorough risk/benefit assessment should be made prior to initiating any treatment plan.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Table I
Table II

Similar content being viewed by others

References

  1. McIntyre RS, Konarski JZ. Bipolar disorder: a national health concern. CNS Spectr 2004 Nov; 9(11 Suppl. 12): 6–15

    Article  PubMed  Google Scholar 

  2. WHO. Mental health: new understanding, new hope. Geneva: WHO, 2001

    Google Scholar 

  3. Peele PB, Xu Y, Kupfer DJ. Insurance expenditures on bipolar disorder: clinical and parity implications. Am J Psychiatry 2003 Jul; 160(7): 1286–90

    Article  PubMed  Google Scholar 

  4. 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 Feb; 163(2): 217–24

    Article  PubMed  Google Scholar 

  5. Yatham LN, Kennedy SH, O’Donovan C, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines for the management of patients with bipolar disorder: consensus and controversies. Bipolar Disord 2005; 7Suppl. 3: 5–69

    Article  PubMed  Google Scholar 

  6. McIntyre RS, Konarski JZ. Tolerability profiles of atypical antipsychotics in the treatment of bipolar disorder. J Clin Psychiatry 2005; 66Suppl. 3: 28–36

    CAS  PubMed  Google Scholar 

  7. Burris KD, Molski TF, Xu C, et al. Aripiprazole, a novel antipsychotic, is a high-affinity partial agonist at human dopamine D2 receptors. J Pharmacol Exp Ther 2002 Jul; 302(1): 381–9

    Article  CAS  PubMed  Google Scholar 

  8. Hirose T, Uwahodo Y, Yamada S, et al. Mechanism of action of aripiprazole predicts clinical efficacy and a favourable side-effect profile. J Psychopharmacol 2004 Sep; 18(3): 375–83

    Article  CAS  PubMed  Google Scholar 

  9. Jordan S, Koprivica V, Dunn R, et al. In vivo effects of aripiprazole on cortical and striatal dopaminergic and serotonergic function. Eur J Pharmacol 2004 Jan 1; 483(1): 45–53

    Article  CAS  PubMed  Google Scholar 

  10. US Food and Drug Administration. Aripiprazole (Abilify®): prescribing information; 2008 [online]. Available from URL: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021436s026,021729s012,021713s019,021866s013lbl.pdf [Accessed 2009 9 Jun]

  11. European Medicines Agency. Aripiprazole (Abilify®): summary of product characteristics; 2008 [online]. Available from URL: http://www.emea.europa.eu/humandocs/PDFs/EPAR/abilify/emea-combined-h471en.pdf [Accessed 2009 9 Jun]

  12. Aitchison K, Bienroth M, Cookson J, et al. A UK consensus on the administration of aripiprazole for the treatment of mania. J Psychopharmacol 2009 May; 23(3): 231–40

    Article  CAS  PubMed  Google Scholar 

  13. McIntyre RS, Soczynska JK, Woldeyohannes HO, et al. Aripiprazole: pharmacology and evidence in bipolar disorder. Expert Opin Pharmacother 2007 May; 8(7): 1001–9

    Article  CAS  PubMed  Google Scholar 

  14. Gajwani P, Kemp DE, Muzina DJ, et al. Acute treatment of mania: an update on new medications. Curr Psychiatry Rep 2006 Dec; 8(6): 504–9

    Article  PubMed  Google Scholar 

  15. Sharif ZA. Overview of safety and tolerability of atypical antipsychotics used in primary care. Primary Care Companion. J Clin Psychiatry 2003; 5Suppl. 3: 14–21

    Google Scholar 

  16. Sachs GS, Gaulin BD, Gutierrez-Esteinou R, et al. Antimanic response to aripiprazole in bipolar I disorder patients is independent of the agitation level at baseline. J Clin Psychiatry 2007 Sep; 68(9): 1377–83

    Article  CAS  PubMed  Google Scholar 

  17. Fagiolini A, Maina G. Aripiprazole: a discussion on its clinical use in mania associated with bipolar I disorder. Drugs Ther Perspectives 2008; 24(7): 1–4

    Article  Google Scholar 

  18. Citrome L, Josiassen R, Bark N, et al. Pharmacokinetics of aripiprazole and concomitant lithium and valproate. J Clin Pharmacol 2005 Jan; 45(1): 89–93

    Article  CAS  PubMed  Google Scholar 

  19. Schieber FC, Boulton DW, Balch AH, et al. A non-randomized study to investigate the effects of the atypical antipsychotic aripiprazole on the steady-state pharmacokinetics of lamotrigine in patients with bipolar I disorder. Hum Psychopharmacol 2009 Mar; 24(2): 145–52

    Article  CAS  PubMed  Google Scholar 

  20. Nakamura A, Mihara K, Nagai G, et al. Pharmacokinetic and pharmacodynamic interactions between carbamazepine and aripiprazole in patients with schizophrenia. Ther Drug Monit 2009 Oct; 31(5): 575–8

    Article  CAS  PubMed  Google Scholar 

  21. Zimbroff DL, Marcus RN, Manos G, et al. Management of acute agitation in patients with bipolar disorder: efficacy and safety of intramuscular aripiprazole. J Clin Psychopharmacol 2007 Apr; 27(2): 171–6

    Article  CAS  PubMed  Google Scholar 

  22. KeckJr PE, Marcus R, Tourkodimitris S, et al. A placebo-controlled, double-blind study of the efficacy and safety of aripiprazole in patients with acute bipolar mania. Am J Psychiatry 2003 Sep; 160(9): 1651–8

    Article  PubMed  Google Scholar 

  23. Sachs G, Sanchez R, Marcus R, et al. Aripiprazole in the treatment of acute manic or mixed episodes in patients with bipolar I disorder: a 3-week placebo-controlled study. J Psychopharmacol 2006 Jul; 20(4): 536–46

    Article  CAS  PubMed  Google Scholar 

  24. Vieta E, Bourin M, Sanchez R, et al. Effectiveness of aripiprazole v. haloperidol in acute bipolar mania: double-blind, randomised, comparative 12-week trial. Br J Psychiatry 2005 Sep; 187: 235–42

    Article  PubMed  Google Scholar 

  25. Keck PE, Orsulak PJ, Cutler AJ, et al. Aripiprazole monotherapy in the treatment of acute bipolar I mania: a randomized, double-blind, placebo- and lithium-controlled study. J Affect Disord 2009 Jan; 112(1–3): 36–49

    Article  CAS  PubMed  Google Scholar 

  26. Young AH, Oren DA, Lowy A, et al. Aripiprazole monotherapy in acute mania: 12-week randomised placebo- and haloperidol-controlled study. Br J Psychiatry 2009 Jan; 194(1): 40–8

    Article  PubMed  Google Scholar 

  27. Potkin SG, Saha AR, Kujawa MJ, et al. Aripiprazole, an antipsychotic with a novel mechanism of action, and risperidone vs placebo in patients with schizophrenia and schizoaffective disorder. Arch Gen Psychiatry 2003 Jul; 60(7): 681–90

    Article  CAS  PubMed  Google Scholar 

  28. Bauer M, Glenn T, Grof P, et al. Frequency of subsyndromal symptoms and employment status in patients with bipolar disorder. Soc Psychiatry Psychiatr Epidemiol 2009 Jul; 44(7): 515–22

    Article  PubMed  Google Scholar 

  29. Marangell LB, Dennehy EB, Miyahara S, et al. The functional impact of subsyndromal depressive symptoms in bipolar disorder: data from STEP-BD. J Affect Disord 2009 Apr; 114(1–3): 58–67

    Article  PubMed  Google Scholar 

  30. Rosa AR, Reinares M, Franco C, et al. Clinical predictors of functional outcome of bipolar patients in remission. Bipolar Disord 2009 Jun; 11(4): 401–9

    Article  PubMed  Google Scholar 

  31. McIntyre RS, Woldeyohannes HO, Yasgur BS, et al. Maintenance treatment in bipolar disorder: a focus on aripiprazole. Expert Rev Neurother 2007 Aug; 7(8): 919–25

    Article  CAS  PubMed  Google Scholar 

  32. Yatham LN, Kennedy SH, Schaffer A, 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 2009. Bipolar Disord 2009 May; 11(3): 225–55

    Article  CAS  PubMed  Google Scholar 

  33. Grunze H, Kasper S, Goodwin G, et al. The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of bipolar disorders, part III: maintenance treatment. World J Biol Psychiatry 2004 Jul; 5(3): 120–35

    Article  PubMed  Google Scholar 

  34. Vieta E, Sanchez-Moreno J. Acute and long-term treatment of mania. Dialogues Clin Neurosci 2008; 10(2): 165–79

    PubMed  PubMed Central  Google Scholar 

  35. Ravindran AV, Al-Subaie A, Abraham G. Quetiapine: novel uses in the treatment of depressive and anxiety disorders. Expert Opin Investig Drugs. Epub 2010 Aug 27

  36. Geddes JR, Goodwin GM, Rendell J, et al., BALANCE investigators and collaborators. Lithium plus valproate combination therapy versus monotherapy for relapse prevention in bipolar I disorder (BALANCE): a randomised open-label trial. Lancet 2010 Jan 30; 375(9712): 385–95

    Article  PubMed  Google Scholar 

  37. KeckJr PE, Calabrese JR, McQuade RD, et al. A randomized, double-blind, placebo-controlled 26-week trial of aripiprazole in recently manic patients with bipolar I disorder. J Clin Psychiatry 2006 Apr; 67(4): 626–37

    Article  CAS  PubMed  Google Scholar 

  38. KeckJr PE, 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 Oct; 68(10): 1480–91

    Article  CAS  PubMed  Google Scholar 

  39. Woods SW, Morgenstern H, Saksa JR, et al. Incidence of tardive dyskinesia with atypical versus conventional antipsychotic medications: a prospective cohort study. J Clin Psychiatry 2010 Apr; 71(4): 463–74

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Hall DA, Agarwal P, Griffith A, et al. Movement disorders associated with aripiprazole use: a case series. Int J Neuro-sci 2009; 119(12): 2274–9

    Article  CAS  Google Scholar 

  41. Correll CU, Schenk EM. Tardive dyskinesia and new anti-psychotics. Curr Opin Psychiatry 2008 Mar; 21(2): 151–6

    Article  PubMed  Google Scholar 

  42. Gao K, Kemp DE, Ganocy SJ, et al. Antipsychotic-induced extrapyramidal side effects in bipolar disorder and schizophrenia: a systematic review. J Clin Psychopharmacol 2008 Apr; 28(2): 203–9

    Article  PubMed  PubMed Central  Google Scholar 

  43. Vieta E, T’Joen C, McQuade RD, et al. Efficacy of adjunctive aripiprazole to either valproate or lithium in bipolar mania patients partially nonresponsive to valproate/lithium monotherapy: a placebo-controlled study. Am J Psychiatry 2008 Oct; 165(10): 1316–25

    Article  PubMed  Google Scholar 

  44. Suppes T, Eudicone J, McQuade R, et al. Efficacy and safety of aripiprazole in subpopulations with acute manic or mixed episodes of bipolar I disorder. J Affect Disord 2008 Apr; 107(1–3): 145–54

    Article  CAS  PubMed  Google Scholar 

  45. Ley P. Doctor-patient communication: some quantitative estimates of the role of cognitive factors in non-compliance. J Hypertens Suppl. 1985 Apr; 3(1): S51–5

    CAS  PubMed  Google Scholar 

  46. Ross AP. Tolerability, adherence, and patient outcomes. Neurology 2008 Dec 9; 71(24 Suppl. 3): S21–3

    Article  PubMed  Google Scholar 

  47. Bachmann S, Bottmer C, Schroder J, et al. Compliance with medication but not structural MRI measures predict functional outcome in first-episode schizophrenia patients. Schizophr Res 2007 Feb; 90(1–3): 355–6

    Article  PubMed  Google Scholar 

  48. El-Mallakh RS. Medication adherence and the use of long-acting antipsychotics in bipolar disorder. J Psychiatr Pract 2007 Mar; 13(2): 79–85

    Article  PubMed  Google Scholar 

  49. Gianfrancesco FD, Sajatovic M, Rajagopalan K, et al. The association between treatment adherence and antipsychotic dose among individuals with bipolar disorder. Int Clin Psychopharmacol 2008 Nov; 23(6): 305–16

    Article  PubMed  Google Scholar 

  50. Scott J, Pope M. Self-reported adherence to treatment with mood stabilizers, plasma levels, and psychiatric hospitalization. Am J Psychiatry 2002 Nov; 159(11): 1927–9

    Article  PubMed  Google Scholar 

  51. Gianfrancesco FD, Rajagopalan K, Sajatovic M, et al. Treatment adherence among patients with bipolar or manic disorder taking atypical and typical antipsychotics. J Clin Psychiatry 2006 Feb; 67(2): 222–32

    Article  CAS  PubMed  Google Scholar 

  52. Ulfvarson J, Bardage C, Wredling RA, et al. Adherence to drug treatment in association with how the patient perceives care and information on drugs. J Clin Nurs 2007 Jan; 16(1): 141–8

    Article  PubMed  Google Scholar 

  53. Cotrell V, Wild K, Bader T. Medication management and adherence among cognitively impaired older adults. J Gerontol Soc Work 2006; 47(3–4): 31–46

    Article  PubMed  Google Scholar 

  54. Johnson FR, Ozdemir S, Manjunath R, et al. Factors that affect adherence to bipolar disorder treatments: a stated-preference approach. Med Care 2007 Jun; 45(6): 545–52

    Article  PubMed  Google Scholar 

  55. Young SD, Oppenheimer DM. Different methods of presenting risk information and their influence on medication compliance intentions: results of three studies. Clin Ther 2006 Jan; 28(1): 129–39

    Article  PubMed  Google Scholar 

  56. Colom F, Vieta E, Tacchi MJ, et al. Identifying and improving non-adherence in bipolar disorders. Bipolar Disord 2005; 7Suppl. 5: 24–31

    Article  PubMed  Google Scholar 

  57. Kasper S, Lerman MN, McQuade RD, et al. Efficacy and safety of aripiprazole vs. haloperidol for long-term maintenance treatment following acute relapse of schizophrenia. Int J Neuropsychopharmacol 2003 Dec; 6(4): 325–37

    Article  CAS  PubMed  Google Scholar 

  58. Thomas P. The stable patient with schizophrenia: from antipsychotic effectiveness to adherence. Eur Neuropsychopharmacol 2007 Mar; 17Suppl. 2: S115–22

    Article  CAS  PubMed  Google Scholar 

  59. Christensen AF, Poulsen J, Nielsen CT, et al. Patients with schizophrenia treated with aripiprazole, a multicentre naturalistic study. Acta Psychiatr Scand 2006 Feb; 113(2): 148–53

    Article  CAS  PubMed  Google Scholar 

  60. El-Sayeh HG, Morganti C, Adams CE. Aripiprazole for schizophrenia: systematic review. Br J Psychiatry 2006 Aug; 189: 102–8

    Article  CAS  PubMed  Google Scholar 

  61. Citrome L, Volavka J. The promise of atypical antipsychotics: fewer side effects mean enhanced compliance and improved functioning. Postgrad Med 2004 Oct; 116(4): 49–51, 55-9, 63

    Article  PubMed  Google Scholar 

  62. Nasrallah HA. Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles. Mol Psychiatry 2008 Jan; 13(1): 27–35

    Article  CAS  PubMed  Google Scholar 

  63. Bettinger TL, Shuler G, Jones DR, et al. Schizophrenia: multi-attribute utility theory approach to selection of atypical antipsychotics. Ann Pharmacother 2007 Feb; 41(2): 201–7

    Article  CAS  PubMed  Google Scholar 

  64. Stroup TS, Lieberman JA, McEvoy JP, et al. Results of phase 3 of the CATIE schizophrenia trial. Schizophr Res 2009 Jan; 107(1): 1–12

    Article  PubMed  Google Scholar 

  65. Casey DE, Carson WH, Saha AR, et al. Switching patients to aripiprazole from other antipsychotic agents: a multi-center randomized study. Psychopharmacology (Berl) 2003 Apr; 166(4): 391–9

    Article  CAS  Google Scholar 

  66. Manning JS, McElroy SL. Treating bipolar disorder in the primary care setting: the role of aripiprazole. Prim Care Companion J Clin Psychiatry 2009; 11: 245–57

    Article  PubMed  PubMed Central  Google Scholar 

  67. Canas F, Sanchez R. Aripiprazole in schizophrenia: dosing and switching in clinical practice [abstract]. European Psychiatry 2007; 22Suppl. 1: S107

    Article  Google Scholar 

  68. Fagiolini A. Practical guidance for prescribing with aripiprazole in bipolar disorder. Curr Med Res Opin 2008 Sep; 24(9): 2691–702

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Editorial assistance with the preparation of this manuscript was provided by Stephanie Blick of inScience Communications and funded by Bristol-Myers Squibb. Paolo Girardi has previously received research support from Lilly and Janssen and honoraria from Lilly and Organon, and has also participated on advisory boards for Lilly, Organon, Pfizer and Schering. Giuseppe Maina has participated on advisory boards for Bristol-Myers Squibb (BMS), Eli Lilly and AstraZeneca, and has received research financial support from Eli Lilly, BMS, GlaxoSmithKline, AstraZeneca and Pfizer. Mauro Mauri has participated on advisory boards for BMS, Eli Lilly, Pfizer, Sanofi, Servier, Stroder and Lundbeck. Palmiero Monteleone has received honoraria from BMS and Pfizer. Giulio Perugi has previously received honoraria as a speaker from Lilly, BMS, AstraZeneca, Sanofi, Janssen and Lundbeck, and has also received honoraria for consultancy services from Lilly, BMS, AstraZeneca, Sanofi, Janssen, Lundbeck, Boehringer Ingelheim, Stroder, Servier, Pfizer and Recordati. The other authors have no conflicts of interest that are directly relevant to the content of this review.

Author information

Authors and Affiliations

  1. Clinical Psychiatry, University ‘Magna Graecia’ of Catanzaro, Catanzaro, Italy

    Pasquale De Fazio

  2. Department of Psychiatry, Sant’Andrea Hospital, 2nd Medical School, Sapienza University, Rome, Italy

    Paolo Girardi

  3. Department of Neurosciences, Mood and Anxiety Disorders Unit, University of Turin, Turin, Italy

    Giuseppe Maina

  4. Clinical Psychiatry, Clinical Neuropsychopharmacology Unit, IRCCS, Ospedale Maggiore Policlinico, Milan, Italy

    Massimo Carlo Mauri

  5. Department of Psychiatry, Neurobiology, Pharmacology and Biotechnologies, University of Pisa, Pisa, Italy

    Mauro Mauri & Giulio Perugi

  6. Department of Psychiatry, University of Naples, Naples, Italy

    Palmiero Monteleone

  7. Department of Neuroscience, University of Padova, Padova, Italy

    Giulia Ida Perini

  8. Department of Mental Health, Pieve di Soligo, Treviso, Italy

    Giulia Ida Perini

  9. Department of Neuroscience, Institute of Clinical Research, Villa Serena (Città S.Angelo-PE), Pescara, Italy

    Alessandro Rossi

  10. Department of Experimental Medicine, University of L’Aquila, L’Aquila, Italy

    Alessandro Rossi

Authors
  1. Pasquale De Fazio
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Paolo Girardi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Giuseppe Maina
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Massimo Carlo Mauri
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mauro Mauri
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Palmiero Monteleone
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Giulia Ida Perini
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Giulio Perugi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Alessandro Rossi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alessandro Rossi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

De Fazio, P., Girardi, P., Maina, G. et al. Aripiprazole in Acute Mania and Long-Term Treatment of Bipolar Disorder. Clin. Drug Investig. 30, 827–841 (2010). https://doi.org/10.2165/11584270-000000000-00000

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/11584270-000000000-00000

Keywords

Search

Navigation