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Therapeutics
Aripiprazole is effective against the symptoms of schizophrenia and schizoaffective disorder
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  1. James P Kelleher, MD
  1. The Zucker Hillside Hospital, Glen Oaks, NY, USA

https://doi.org/10.1136/ebmh.7.1.13

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    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;60:681–90.OpenUrlCrossRefPubMedWeb of Science

    Q Is aripiprazole effective in people with schizophrenia or schizoaffective disorder?

    METHODS

    Embedded Image  Design:

    Randomised controlled trial.

    Embedded Image  Allocation:

    Unclear.

    Embedded Image  Blinding:

    Double blind (participants and assessors).

    Embedded Image  Follow up period:

    Four weeks.

    Embedded Image  Setting:

    Forty medical centres in the USA; September 1997 to October 1998.

    Embedded Image  Patients:

    404 people hospitalised with acute relapse of schizophrenia (n = 289) or schizoaffective disorder (n = 115), scoring ⩾60 on the Positive and Negative Syndrome Scale (PANSS), and responsive to antipsychotics. Participants taking long acting neuroleptics were included if they were deteriorating clinically. Exclusions: other psychiatric disorder requiring pharmacotherapy; recent history of suicidal tendencies/attempts; violence; substance abuse; neurological abnormality (not tardive dyskinesia or extrapyramidal symptoms); treatment with investigational drug in the month preceding the washout phase; and acute or unstable medical comorbidity.

    Embedded Image  Intervention:

    Four weeks of: 20 mg/day aripiprazole (n = 101), 30 mg/day aripiprazole (n = 101), 6 mg/day risperidone (n = 99), or placebo (n = 103). Participants were hospitalised for the entire study period.

    Embedded Image  Outcomes:

    Changes in PANSS scores from baseline, change in Clinical Global Impression-Severity of Illness (CGI-S) subscale score.

    Embedded Image  Patient follow up:

    Dropout rates: 50% with placebo v 40% with 20 mg/d aripiprazole v 34% with 30 mg/d aripiprazole v 37% with risperidone. Dropouts were due to worsening symptoms or lack of clinical improvement (10%), adverse effects (11%), or other reasons (19%).

    MAIN RESULTS

    Aripiprazole significantly improved overall PANSS score and CGI-S score compared with placebo (see web extra table 1⇓).

    View this table:
    Table 1

    Mean change in score from baseline

    CONCLUSIONS

    Aripiprazole is the first non-dopamine D2 receptor antagonist shown to be effective against the positive and negative symptoms in schizophrenia and schizoaffective disorder.

    Commentary

    Aripiprazole, as a partial agonist at D2 dopamine receptors, presents an intriguing new treatment approach for psychotic illness. Theoretical mechanisms of action of other antipsychotics have involved high D2 dopamine receptor blockade (for conventional agents) and high 5HT2A serotonin: D2 dopamine blockade or fast dissociation from D2 dopamine receptors (for earlier atypical agents).1

    This important, large study provides the first substantial evidence that compared with a leading atypical antipsychotic, aripiprazole has similar efficacy and greater tolerability. Trials by Kane et al2 and Daniel et al3 (reported in Kelleher et al4) of aripiprazole or haloperidol versus placebo provide related evidence. In those studies, aripiprazole had comparable efficacy and was at least as fast in onset as the conventional agent. It was also associated with less severe side effects.

    The maximum dose5 of risperidone used in this trial is not typical of today’s US practice, and titration may have been too rapid for some subjects. These factors may have influenced the results in aripiprazole’s favour. Dosing of aripiprazole may have also been high. Doses over 15 mg/day have not generally been associated with increased efficacy.6 Finally, these data remind us that risperidone can cause QTc prolongation.

    Evidence from a variety of studies suggests that aripiprazole can be recommended as a safe and effective treatment for schizophrenia. In addition to these findings, in preliminary studies aripiprazole has been beneficial for up to one year,7 and even at doses greater than 30 mg/day.8,9 Further comparisons with atypical antipsychotics, additional long term trials, and reports on use in combination with other psychotropics will ultimately define its best role. Aripiprazole is also a promising agent for the treatment of acute mania10 and possibly other illnesses. Its success could lead to the development of a new generation of antipsychotics.

    References

    1. ↵
      Kapur S, Seeman P. Does fast dissociation from the dopamine D2 receptor explain the action of atypical antipsychotics? A new hypothesis. Am J Psychiatry 2001;158:360–9.
      OpenUrlCrossRefPubMedWeb of Science
    2. ↵
      Kane JM, Carson WH, Saha AR, et al. Efficacy and safety of aripiprazole and haloperidol versus placebo in patients with schizophrenia and schizoaffective disorder. J Clin Psychiatry 2002;63:763–71.
      OpenUrlCrossRefPubMedWeb of Science
    3. ↵
      Daniel DG, Saha AG, Ingenito G, et al. Aripiprazole, a novel antipsychotic: overview of a phase II study result [abstract S157]. 22nd Annual Meeting, International Congress of Neuropsychopharmacology (CINP). Brussels, 9–13 July 2000.
    4. ↵
      Kelleher JP, Centorrino F, Albert MJ, et al. Advances in atypical antipsychotics for the treatment of schizophrenia: new formulations and new agents. CNS Drugs 200216:249–61.
      OpenUrlCrossRefPubMedWeb of Science
    5. ↵
      Citrome L, Volavka J. Optimal dosing of atypical antipsychotics in adults: a review of the current evidence. Harv Rev Psychiatry 2002;10:280–91.
      OpenUrlCrossRefPubMedWeb of Science
    6. ↵
      Physicians’ Desk Reference, 57th edition, Montvale, NJ: Medical Economics, 2003.
    7. ↵
      Kujawa M, Saha AR, Ingenito G, et al. Aripiprazole for long-term maintenance treatment of schizophrenia. Int J Neurpsychopharmacol 2002;5(Suppl 1):S186.
      OpenUrl
    8. ↵
      Saha AR, Ali MW, Ingenito GG, et al. Safety and tolerability of aripiprazole at doses higher than 30 mg. Int J Neuropsychopharmacol 2002;5(Suppl 1):S185.
      OpenUrl
    9. ↵
      Kelleher JP. New developments in atypical antipsychotic medication. In: den Boer JA, ter Horst GJ, George MS (eds). Current and future developments in psychopharmacology. Benecke NI: Amsterdam (in press).
    10. ↵
      Keck PE Jr, 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;160:1651–8.
      OpenUrlCrossRefPubMedWeb of Science

    Supplementary materials

    • Web-only Table

      Table 1 Mean changes in PANSS and CGI-S scores from baseline (analysed in a last observation carried forward basis)

      The table is available as a downloadable PDF (printer friendly file).

      If you do not have Adobe Reader installed on your computer,
      you can download this free-of-charge, please Click here

       

      Files in this Data Supplement:

      • [View PDF] - Aripiprazole significantly improved overall PANSS score and CGI-S score compared with placebo

    Footnotes

    • For correspondence: Steven Potkin, Brain Imaging Center, University of California, Irvine Hall, Irvine, California; sgpotkinuci.edu

    • Sources of funding: Bristol-Myers Squibb and Otsuka Pharmaceuticals.