Elsevier

Journal of Psychiatric Research

Volume 68, September 2015, Pages 198-209
Journal of Psychiatric Research

Intramuscular olanzapine for agitated patients: A systematic review and meta-analysis of randomized controlled trials

https://doi.org/10.1016/j.jpsychires.2015.07.005Get rights and content

Highlights

  • A systematic review and meta-analysis of intramuscular-olanzapine in agitated patients.

  • Intramuscular-olanzapine is preferable to intramuscular-haloperidol for agitated patients.

  • Intramuscular-olanzapine is well tolerated.

Abstract

We performed an updated systematic review and meta-analysis of randomized controlled trials (RCTs) of intramuscular (IM)-olanzapine (OLA-IM) versus controls in agitated patients. The risk ratio, number-needed-to-treat/harm, and standardized mean difference based on a random effects model were calculated. We identified 13 RCTs (19 comparisons) as follows: 7 comparisons with 1059 patients for OLA-IM versus placebo; 5 comparisons with 613 patients for OLA-IM versus haloperidol (HAL)-IM; 2 comparisons with 108 patients for OLA-IM versus ziprasidone (ZIP)-IM; 2 comparisons with 110 patients for OLA-IM versus HAL-IM plus midazolam; and 3 comparisons with 412 patients for OLA-IM versus HAL-IM plus promethazine, 2 comparisons with 355 patients for OLA-IM versus lorazepam-IM (LOR-IM); and 1 comparison with 67 patients for OLA-IM versus HAL-IM plus LOR-IM. OLA-IM was superior to placebo in both Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) and Agitation–Calmness Evaluation Scale (ACES) scores 2 h after first injection, and had a comparable side effect profile, including over sedation, extrapyramidal symptoms, akathisia, and anticholinergic use. While there was no significant difference in PANSS-EC scores after 2 h between OLA-IM and HAL-IM, OLA-IM outperformed HAL-IM in ACES after 2 h. Compared with HAL-IM, OLA-IM was associated with fewer side effects, including anticholinergic use, akathisia, extrapyramidal symptoms, and dystonia, and marginally less QT prolongation compared with HAL-IM. Based on our findings, OLA-IM is preferable to HAL-IM for the treatment of agitated patients. However, comparator data for ZIP-IM, LOR-IM and HAL-IM combination therapy were insufficient.

Introduction

Agitation is a transnosological syndrome; it presents as a cluster of pathological behaviors in a variety of psychiatric diseases, including schizophrenia, manic or mixed episodes of bipolar disorder, and dementia. In patients with these conditions, agitation can increase the likelihood of violent behavior and attempted suicide or homicide (Rueve and Welton, 2008). Therefore, it is crucial that agitated patients are treated appropriately to manage their condition and keep staff safe.

Rapid-acting medication is used to calm severely agitated patients, decrease dangerous behavior, and allow symptomatic treatment. Intramuscular (IM) injections of antipsychotics or benzodiazepines have been used to manage agitation in these patients. To this end, chlorpromazine, aripiprazole, droperidol, haloperidol (HAL), olanzapine (OLA), perphenazine, thiothixene, ziprasidone (ZIP), diazepam, lorazepam (LOR), and midazolam have all been used. Rapidly acting agents also include inhaled loxapine, approved in the United States of America and Europe, and off-label use of sublingual asenapine of which a published clinical trial exists (Pratts et al., 2014).

Powney and colleagues reported that, while HAL-IM achieved sleep by 2 h after the first injection when compared with placebo (risk ratio [RR] = 0.88, 2 randomized controlled trials [RCTs], n = 220), it was associated with a higher incidence of dystonia (RR = 7.49, 2 RCTs, n = 207) (Powney et al., 2012). ZIP-IM and HAL-IM were also reported to increase the QTc interval on electrocardiogram in a dose-dependent manner (Miceli et al., 2010). Although treatment duration with IM antipsychotics is short, it is important to select the agent with the lowest rate of acute side effects (especially, extrapyramidal symptoms (EPS), severe sedation, cardiac arrhythmia, and torsade de pointes) for agitated patients.

In fact, Satterthwaite and colleagues reported that SGAs-IM (olanzapine and ziprasidone) have a significantly lower risk of acute EPS compared with haloperidol alone (dystonia: RR = 0.19, 7 RCTs, n = 2032, akathisia: RR = 0.25, 5 RCTs, n = 1415, anticholinergic use: RR = 0.19, 2 RCTs, n = 434) (Satterthwaite et al., 2008). Moreover, although Belgamwar and Fenton did not report a comprehensive meta-analysis of ZIP-IM because of insufficient data, OLA-IM produced more responders than placebo (RR = 0.49, number-needed-to-treat [NNT] = 4, 4 RCTs, n = 769) and there was no significant difference in the discontinuation rate between OLA-IM and placebo (Belgamwar and Fenton, 2005). However, while OLA-IM involves less anticholinergic use compared with HAL-IM (RR = 0.20, number-needed-to-harm [NNH] = 8, 2 RCTs, n = 432), there were no significant differences in either the response rate or need for repeat IM injections between OLA-IM and HAL-IM (Belgamwar and Fenton, 2005). However, the number of studies and sample sizes in their study were limited (OLA-IM versus placebo: 4 RCTs, n = 769; OLA-IM versus HAL-IM: 2 RCTs, n = 482) (Belgamwar and Fenton, 2005); and since then, a number of additional RCTs regarding OLA-IM have been published. Therefore, the current study aimed to update the evidence for the efficacy and tolerability of OLA-IM in agitated patients (OLA-IM versus placebo: 7 RCTs, n = 1058; OLA-IM versus HAL-IM: 5 RCTs, n = 613; OLA-IM versus ZIP-IM: 2 RCTs, n = 108; OLA-IM versus HAL-IM plus midazolam): 2 RCTs, n = 110; and OLA-IM versus HAL-IM plus promethazine (promethazine is not available in the United States of America): 3 RCTs, n = 412, OLA-IM versus LOR-IM: 2 comparisons, n = 110, and OLA-IM versus HAL-IM plus LOR-IM: 1 comparison, n = 67.

Section snippets

Methods

This meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Moher et al., 2009).

Study characteristics

The computerized search initially yielded 59 results after duplicates were removed. We excluded a further 43 studies following a review of the titles and abstract, and 5 additional articles after full-text review (these were review articles). Two additional studies (Katagiri et al., 2012, Ono et al., 2009) were identified from the Katagiri et al. (2013) paper (Fig. 1). In total, we identified 13 studies, as follows: 7 comparisons with 1059 patients for OLA-IM versus placebo: (Breier et al., 2002

Discussion

We conducted a comprehensive meta-analysis on the efficacy, effectiveness, and side effects of OLA-IM for the treatment of agitated patients. We included sufficient patients in the meta-analyses of OLA-IM versus placebo (7 comparisons, n = 1059) and OLA-IM versus HAL-IM (5 comparisons, n = 613). However, the number of studies was too few for the comparisons of OLA-IM versus ZIP-IM (2 comparisons, n = 108), OLA-IM versus HAL-IM plus midazolam (2 comparisons, n = 110), OLA-IM versus HAL-IM plus

Role of the funding source

No funding sources were received for this study.

Contributors

Dr Kishi had full access to all study data and has responsibility for the integrity of the data and the accuracy of any data analysis. Dr Kishi was responsible for the study concept, design, and statistical analyses. Drs. Kishi and Matsunaga were responsible for the acquisition of data, the data analysis, and the data interpretation. Drs. Kishi, Matsunaga, and Iwata drafted the final manuscript. Dr Iwata supervised the study.

Conflicts of interest

Dr Kishi has received speaker's honoraria from Abbott, Astellas, Daiichi Sankyo, Dainippon Sumitomo, Eisai, Eli Lilly, GlaxoSmithKline, Janssen, Yoshitomi, Otsuka, Meiji, Shionogi, Tanabe-Mitsubishi, Tsumura, Novartis, and Pfizer. Dr Matsunaga has received speaker's honoraria from Eisai, Janssen, Novartis, Daiichi Sankyo, Ono, Eli Lilly, Takeda, and Otsuka. Dr Iwata has received speaker's honoraria from Astellas, Dainippon Sumitomo, Eli Lilly, GlaxoSmithKline, Janssen, Yoshitomi, Otsuka, Meiji,

Acknowledgments

We thank Dr. Leonardo Baldaçara, Dr. Marsal Sanches, Dr. Hung-Yu Chan, Dr. Ying-Sheue Chen, Eli Lilly and Company Limited for providing information necessary for the study.

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