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Rapid acute treatment of agitation in individuals with schizophrenia: multicentre, randomised, placebo-controlled study of inhaled loxapine

  • Michael D. Lesem (a1), Tram K. Tran-Johnson (a2), Robert A. Riesenberg (a3), David Feifel (a4), Michael H. Allen (a5), Robert Fishman (a6), Daniel A. Spyker (a6), John H. Kehne (a7) and James V. Cassella (a8)...
Abstract
Background

There is a need for a rapid-acting, non-injection, acute treatment for agitation.

Aims

To evaluate inhaled loxapine for acute treatment of agitation in schizophrenia.

Method

This phase III, randomised, double-blind, placebo-controlled, parallel-group study (ClinicalTrials.gov number NCT00628589) enrolled 344 individuals who received one, two or three doses of inhaled loxapine (5 or 10 mg) or a placebo. Lorazepam rescue was permitted after dose two. The primary efficacy end-point was change from baseline in Positive and Negative Syndrome Scale–Excited Component (PANSS–EC) 2 h after dose one. The key secondary end-point was Clinical Global Impression–Improvement scale (CGI–I) score 2 h after dose one.

Results

Inhaled loxapine (5 and 10 mg) significantly reduced agitation compared with placebo as assessed by primary and key secondary end-points. Reduced PANSS–EC score was evident 10 min after dose one with both 5 and 10mg doses. Inhaled loxapine was well tolerated, and the most common adverse events were known effects of loxapine or minor oral effects common with inhaled medications.

Conclusions

Inhaled loxapine provided a rapid, well-tolerated acute treatment for agitation in people with schizophrenia.

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Copyright
This is an Open Access article, distributed under the terms of the Creative Commons Attribution-NonCommercial licence (http://creativecommons.org/licenses/by-nc/4.0/), which permits noncommercial re-use, distribution, and reproduction in any medium, provided the original work is unaltered and is properly cited. The written permission of Cambridge University Press must be obtained for commercial re-use or in order to create a derivative work.
Corresponding author
Michael D. Lesem, MD, Claghorn-Lesem Research Clinic Ltd, 1010 Waverly Street, Houston, Texas 77008, USA. Email: mlesem@claghorn-lesem.com
Footnotes
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A portion of the data from this study was presented at the 2009 Annual Meeting of the American Psychiatric Association, San Francisco, USA.

The study was sponsored by Alexza Pharmaceuticals.

Declaration of interest

The study was sponsored by Alexza Pharmaceuticals. M.D.L., T.K.T-J, R.A.R. and D.F. were investigators. M.H.A., R.F., D.A.S., J.H.K. and J.V.C. were consultants to or employees of Alexza Pharmaceuticals during study design, execution and/or analysis.

Footnotes
References
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Rapid acute treatment of agitation in individuals with schizophrenia: multicentre, randomised, placebo-controlled study of inhaled loxapine

  • Michael D. Lesem (a1), Tram K. Tran-Johnson (a2), Robert A. Riesenberg (a3), David Feifel (a4), Michael H. Allen (a5), Robert Fishman (a6), Daniel A. Spyker (a6), John H. Kehne (a7) and James V. Cassella (a8)...
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eLetters

A Clinician's concerns

Sahoo Saddichha, Senior Resident
02 November 2011

I congratulate the authors of this article [1] on having brought forth another new weapon to add to the armament of clinicians in order to manage acute psychotic episodes, in which agitation is the chief concern. The study is a well designed and evaluated study. However, as a clinician,I would have two primary concerns. The first would be that of time-how long does the effect of inhaled loxapine last? A corollary to the same question would be "how long does one need to wait till it is safe to repeat the drug?" The second most pertinent question would be on the mode of administration. As I understand it, this is an inhaled drug that is self-administered. Now, how does one convince an acutely agitated patient to inhale the drug, when it is so difficult to make him agree to an injection in the current scenario? As I see it, the problem remains- "How to bell the cat?"

References:

1)Lesem MD, Tran-Johnson TK, Riesenberg RA. Rapid acute treatment of agitation in individuals with schizophrenia: multicentre, randomised, placebo-controlled study of inhaled loxapine. Br J Psychiatry 2011; 198:51-58.

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Conflict of interest: None declared

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Inclusion of an active control arm?

Andy R Shepherd, CT1 Trainee
24 January 2011

The authors highlight the importance of rapid and safe treatment of agitation. Indicating the delay in efficacy associated with intramuscular injection. They make no reference to the time from oral medication administration to efficacy. However, the combination of oral atypical antipsychotics, with or without benzodiazepine, is well described.1 Small trials have compared the efficacy of oral atypical antipsychotics to intramuscular typicals and produced mean changes in rating-scales similar to those in this paper, along similar timescales.2

When alternative treatments exist, placebo controlled trials are appropriate if the target condition is characterized by a high placebo response rate, relapsing, remitting or high spontaneous resolution rate, existing therapies are partially effective or have high side-effect rates.3 Inclusion of an active control arm to the trial would have added to the number of patients required in each arm, but would have also provided some valuable information on the

tolerability and clinical effectiveness of the inhaled, or oral medication.

1. Yildiz A, Sachs G, Turgay A. Pharmacological management of agitation in emergency settings. Emergency Medical Journal. 2003;20(4):339.

2 Lim HK, Kim JJ, Pae CU, et al. Comparison of risperidone orodispersible tablet and intramuscular haloperidol in the treatment of acute psychotic agitation: a randomized open, prospective study. Neuropsychobiology. 2010;62(2):81-6.

3 Emanuel EJ, Miller FG. The Ethics of Placebo Controlled Trials - A Middle Ground. New England Journal of Medicine. 2001;345(12):915.
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Conflict of interest: None Declared

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