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Acutely agitated patients with schizophrenia experience great personal distress and may present a danger to themselves or others (1). Such patients are frequently treated with intramuscular (IM) antipsychotic agents or benzodiazepines, or both, when rapid alleviation of agitation is necessary (2,3). IM typical antipsychotics may also reduce both positive symptoms and general psychopathology (4); however, they can cause extrapyramidal symptoms (EPS), which in turn reduces compliance with antipsychotic maintenance therapy and increases the risk of relapse (5,6). Also, IM typical antipsychotics must often be coadministered with benzodiazapines (7), which further increases the risk of adverse events. We recently reported that IM olanzapine 10.0 mg had efficacy comparable to IM haloperidol 7.5 mg for reducing acute agitation in patients with schizophrenia and that IM olanzapine had a more rapid onset of action (8). Further, treatment with IM olanzapine was not associated with acute dystonia, whereas 7.1% of patients treated with IM haloperidol experienced this distressing adverse event. We now report additional data from the same study on the antipsychotic efficacy and extra- pyramidal safety of IM olanzapine and IM haloperidol during the first 24 hours of treatment of acute schizophrenia. MethodsPatient Population Study Design The screening period (a minimum of 2 hours) included physical examinations and collection of standard histories and baseline measurements; no antipsychotics or sedatives were administered. Following screening, patients were randomly allocated by the assignment of treatment kits to double-blind treatment with IM olanzapine 10.0 mg, IM haloperidol 7.5 mg, or IM placebo (2:2:1 ratio; 1 to 3 injections over 24 hours, with the second injection more than 2 hours after the first, and the third injection more than 4 hours after the second, given on the basis of clinical need). The randomization ratio limited placebo exposure. IM haloperidol was chosen as a comparator because it is the IM antipsychotic agent most frequently used for treating acutely agitated schizophrenia patients (4,9). One benzodiazepine dose (up to 20 mg diazepam equivalents) was allowed 1 hour or more after the second IM injection of the study drug, and a second dose was allowed 1 hour or more after the third injection. Anticholinergic medications were only permitted for the control of EPS adverse events occurring during the study. Other concomitant medications with primarily central nervous system activity were prohibited. Assessments Extrapyramidal Safety. The incidences of treatment- emergent parkinsonism (that is, the proportion of patients with a Simpson–Angus Scale total score of more than 3, out of those with a total score 3 or less at baseline [10]) and treatment-emergent akathisia (that is, the proportion of patients with a Barnes Akathisia Scale global score [item 4] of 2 or more, out of those with a score less than 2 at baseline [11]) were evaluated for the 24-hour IM period. Mean changes on these EPS scales were also derived from baseline to the 24-hour endpoint. Statistical Methods ResultsPatient Characteristics
Patient Disposition Mean Changes in Positive Symptoms and General Psychopathology
As previously reported, significantly more patients given IM placebo (38.9%) received benzodiazepines during the study, compared with patients receiving IM olanzapine (16.0%; Fisher’s exact test, P = 0.002) or IM haloperidol (19.8%; Fisher’s exact test, P = 0.009) (8). Mean daily benzodiazepine dosages did not differ significantly among the groups (IM olanzapine mean 3.8, SD 4.2 mg; IM haloperidol mean 3.5, SD 2.8 mg; and IM placebo mean 3.1, SD 2.1 mg). Categorical Incidences of Parkinsonism and Akathisia Patients receiving IM olanzapine experienced significantly fewer incidences of treatment-emergent parkinsonism (4.3% with IM olanzapine vs 13.3% with IM haloperidol; Fisher’s exact test, P = 0.036) but not akathisia (1.1% with IM olanzapine vs 6.5% with IM haloperidol; Fisher’s exact test, P = 0.065), compared with patients receiving IM haloperidol, and no more incidences of either parkinsonism or akathisia than patients given IM placebo (parkinsonism 3.1% and akathisia 2.8%). Mean Changes in EPS Measures At 24 hours after the first injection, mean scores on EPS rating scales were significantly reduced during IM olanzapine treatment, compared with an increase during IM haloperidol treatment (Simpson–Angus Scale t276 = 3.6, P < 0.001; Barnes Akathisia Scale t276 = 3.1, P = 0.002) (Table 3). IM olanzapine and IM placebo cohorts were comparable for both EPS measures.
Concomitant Anticholinergic Use DiscussionWe recently reported that IM olanzapine 10.0 mg had efficacy comparable to IM haloperidol 7.5 mg for reducing acute agitation in patients with schizophrenia (8). IM olanzapine had a more rapid onset of action, and no incidence of acute dystonia was reported during IM olanzapine treatment (compared with an incidence of 7.1% for IM haloperidol). These additional data from the same study show that IM olanzapine and IM haloperidol have comparable efficacy in reducing positive symptoms and general psychopathology during the first 24 hours after the first injection. IM olanzapine also demonstrated a more favourable EPS safety profile than did IM haloperidol, with no reports of acute dystonia and significantly fewer reports of treatment-emergent parkinsonism. Efficacy in reducing positive symptoms and general psycho- pathology are important during the treatment of patients with acute schizophrenia, not only to reduce subjective distress but also because these symptoms have been correlated with violence (12,13). In this study, IM olanzapine was comparable to IM haloperidol for reducing positive symptom and general psychopathology scores as early as 2 hours after an injection (with the first measurement taken at 2 hours) and for at least 24 hours. Oral olanzapine has demonstrated superiority over oral haloperidol in improving overall psychopathology (14). Parkinsonism and akathisia can be extremely distressing, and patients can be understandably reluctant to continue antipsychotic maintenance therapy after experiencing these adverse events (5). Medication noncompliance in general is the leading cause of relapse in schizophrenia (6). The overall favourable EPS safety profile of IM olanzapine could potentially enhance patients’ adherence to antipsychotic maintenance therapy, but this requires further research. The findings of significantly less acute dystonia and treatment-emergent parkinsonism and significantly improved scores on EPS rating scales during IM olanzapine treatment, compared with IM haloperidol treatment, are consistent with oral olanzapine clinical trial literature (14–16). This study has some important limitations. First, the applicability of our results to more severely ill patients treated in routine clinical practice needs to be determined, since ethical considerations prevent their recruitment to clinical trials. Nonetheless, we took care to include patients who were ill enough for any effect of active treatment on their symptoms to be evident but not so ill that they were unable to provide informed consent or cooperate with the clinical trial requirements. The suitability of the enrolled patients is attested to by their response to IM haloperidol, which is known to effectively reduce symptoms of schizophrenia. Second, future studies are needed to investigate a range of IM medication dosages (for example, a lower dosage of IM haloperidol). Third, we did not investigate potential synergies and inter-actions between IM olanzapine and other drugs used for treating acute schizophrenia (for example, benzodiazepines). Finally, further research is required to test the hypothesis that the efficacy and EPS safety advantages of IM olanzapine can reduce subjective distress and the risk of violence in patients with schizophrenia, leading to enhanced compliance with antipsychotic maintenance therapy and prevention of relapse. In summary, IM olanzapine and IM haloperidol were comparable in reducing the symptoms of acute schizophrenia during the first 24 hours of treatment, their efficacy being evident within 2 hours after the first injection. Generally more EPS were observed during treatment with IM haloperidol than with IM olanzapine. Overall, the data from this clinical trial suggest that IM olanzapine is an efficacious, yet safer, alternative to IM haloperidol for the treatment of both acute agitation and psychotic symptomatology in patients with schizophrenia. Further, because it has been suggested that early clinical improvement predicts a more favourable eventual outcome (17), the rapid alleviation of agitation and early reduction of positive symptoms during treatment with IM olanzapine could improve the prognosis of some patients with schizophrenia. Funding and SupportThis study was sponsored by Eli Lilly and Company. References1. Pilowsky LS, Ring H, Shine PJ, Battersby M, Lader M. Rapid tranquilization. A survey of emergency prescribing in a general psychiatric hospital. Br J Psychiatry 1992;160:831–5. 2. Battaglia J, Moss S, Rush J, Kang J, Mendoza R, Leedom L, and others. Haloperidol, lorazepam, or both for psychotic agitation? A multicenter, prospective, double-blind, emergency department study. Am J Emerg Med 1997;15:335–40. 3. Ellison JM, Hughes DH, White KA. An emergency psychiatry update. Hospital and Community Psychiatry 1989;40:250–60. 4. Milton GV, Jann MW. Emergency treatment of psychotic symptoms. Pharmacokinetic considerations for antipsychotic drugs. Clin Pharmacokinet 1995;28:494–504. 5. Weiden PJ, Shaw E, Mann JJ. Causes of neuroleptic noncompliance. Psychiatr Ann 1986;16:571–5. 6. Ayuso-Gutierrez JL, del Rio Vega JM. Factors influencing relapse in the long-term course of schizophrenia. Schizophr Res 1997;28:199–206. 7. Stimmel GL. Benzodiazepines in schizophrenia. Pharmacotherapy 1996;16:148S–51S. Discussion 166S–8S. 8. Wright P, Birkett MA, David SR, Meehan K, Ferchland I, Alaka KJ, and others. Double-blind, placebo-controlled comparison of intramuscular olanzapine and intramuscular haloperidol in the treatment of acute agitation in schizophrenia. Am J Psychiatry 2001;158:1149–51. 9. Allen MH. Managing the agitated psychotic patient: a reappraisal of the evidence. J Clin Psychiatry 2000;61(Suppl 14):11–20. 10. Simpson GM, Angus JWS. A rating scale for extrapyramidal side effects. Acta Psychiatr Scand Suppl 1970;212:11–9. 11. Barnes TRE. A rating scale for drug-induced akathisia. Br J Psychiatry 1989;154:672–6. 12. McNiel DE, Binder RL. Correlates of accuracy in the assessment of psychiatric inpatients’ risk of violence. Am J Psychiatry 1995;152:901–6. 13. Noble P, Rodger S. Violence by psychiatric in-patients. Br J Psychiatry 1989;155:384–90. 14. Tollefson GD, Beasley CM Jr, Tran P, Street JS, Krueger JA, Tamura RN, and others. Olanzapine versus haloperidol in the treatment of schizophrenia and schizoaffective and schizophreniform disorders: results of an international collaborative trial. Am J Psychiatry 1997;154:457–65. 15. Beasley CM Jr, Tollefson G, Tran P, Satterlee W, Sanger T, Hamilton S. Olanzapine versus placebo and haloperidol: acute phase results of the North American double-blind olanzapine trial. Neuropsychopharmacology 1996;14:111–23. 16. Beasley CM Jr, Hamilton SH, Crawford AM, Dellva MA, Tollefson GD, Tran PV, and others. Olanzapine versus haloperidol: acute-phase results of the international double-blind olanzapine trial. Eur Neuropsychopharmacol 1997;7:125–37. 17. Harrigan SM, McGorry PD, Krstev H. Does treatment delay in first-episode psychosis really matter? Psychol Med 2003;33:97–110. AuthorsManuscript received January 2003, revised, and accepted February 2003. 1. Leader, Clinical Neuroscience, Lilly Research Centre, Eli Lilly and Company, Surrey, UK; Honorary Senior Lecturer, Institute of Psychiatry, University of London, London, UK. 2. Research Scientist, Statistical and Mathematical Sciences, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana. 3. Clinical Operations Manager, Lilly UK, Basingstoke, Hampshire, UK. 4. Specialist Registrar, Maudsley Hospital, London, UK. 5. Senior Clinical Research Physician, Eli Lilly Canada, Toronto, Ontario. 6. Senior Scientific Communications Associate, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana. 7. Clinical Research Team Leader, Lilly Research Centre, Eli Lilly and Company, Surrey, UK. 8. Clinical Research Team Leader, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana. 9. Associate Scientific Communications Consultant, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana. 10. Senior Regulatory Research Scientist, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana. 11. Associate Professor of Psychiatry, University of Wisconsin Medical School, Madison, Wisconsin. 12. Professor of Psychiatry, Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest, Hungary. 13. Professor of Psychiatry, University of Montreal and McGill University, Louis-H Lafontaine Hospital, Montreal, Quebec; Director, Clinical Psychopharmacology Unit, McGill University Health Centre, Montreal, Quebec. 14. Professor, Department of Psychiatry, University of Queensland, Brisbane, Australia. 15. Vice President of Medical and Chief Medical Officer, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana. Address for correspondence: Dr A Breier, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center DC 2128, Indianapolis, IN 46285 e-mail: Breier_Alan@lilly.com
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