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

Journal of Psychiatric Research 68 (2015) 198e209

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Intramuscular olanzapine for agitated patients: A systematic review and meta-analysis of randomized controlled trials Taro Kishi*, Shinji Matsunaga, Nakao Iwata Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan

a r t i c l e i n f o

a b s t r a c t

Article history: Received 1 April 2015 Received in revised form 2 July 2015 Accepted 3 July 2015

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, numberneeded-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 eCalmness 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. © 2015 Elsevier Ltd. All rights reserved.

Keywords: Olanzapine intramuscular injection Agitated patients Efficacy Safety Meta-analysis

1. 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

* Corresponding author. E-mail address: [email protected] (T. Kishi). http://dx.doi.org/10.1016/j.jpsychires.2015.07.005 0022-3956/© 2015 Elsevier Ltd. All rights reserved.

(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] ¼ 0.88, 2 randomized controlled trials [RCTs], n ¼ 220), it was associated with a higher incidence of dystonia (RR ¼ 7.49, 2 RCTs, n ¼ 207) (Powney et al., 2012). ZIP-IM and HALIM 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.

T. Kishi et al. / Journal of Psychiatric Research 68 (2015) 198e209

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 ¼ 0.19, 7 RCTs, n ¼ 2032, akathisia: RR ¼ 0.25, 5 RCTs, n ¼ 1415, anticholinergic use: RR ¼ 0.19, 2 RCTs, n ¼ 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 ¼ 0.49, number-needed-to-treat [NNT] ¼ 4, 4 RCTs, n ¼ 769) and there was no significant difference in the discontinuation rate between OLAIM and placebo (Belgamwar and Fenton, 2005). However, while OLA-IM involves less anticholinergic use compared with HAL-IM (RR ¼ 0.20, number-needed-to-harm [NNH] ¼ 8, 2 RCTs, n ¼ 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 ¼ 769; OLA-IM versus HAL-IM: 2 RCTs, n ¼ 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 ¼ 1058; OLA-IM versus HAL-IM: 5 RCTs, n ¼ 613; OLA-IM versus ZIP-IM: 2 RCTs, n ¼ 108; OLA-IM versus HAL-IM plus midazolam): 2 RCTs, n ¼ 110; and OLA-IM versus HAL-IM plus promethazine (promethazine is not available in the United States of America): 3 RCTs, n ¼ 412, OLA-IM versus LOR-IM: 2 comparisons, n ¼ 110, and OLA-IM versus HAL-IM plus LOR-IM: 1 comparison, n ¼ 67. 2. Methods This meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Moher et al., 2009). 2.1. Inclusion criteria, search strategy, data extraction, and outcomes We selected double-blind, rater-blinded, or open-label RCTs of OLA-IM compared with placebo or other psychotropic drug-IM (antipsychotic and anxiolytic) for agitated or violent patients as a result of mental illness. Relevant studies were identified through searches of PubMed, the databases of the Cochrane Library and PsycINFO, and clinicaltrials.gov (https://clinicaltrials. gov/) citations up to May 16, 2015. We used the following English key words: “intramuscular” AND “olanzapine” AND “randomized,” “random,” or “randomly” without language restriction. In addition, we used the Japanese drug package insert for OLA-IM. Two authors (T.K. and S.M.) checked the inclusion and exclusion criteria of the studies identified. When data required for the current meta-analysis were missing, the first or corresponding authors and Eli Lilly and Company Limited were contacted for additional information. Eli Lilly and Company Limited also provided unpublished data for the current study (Fig. 1 and Table 1). Two authors (T.K. and S.M.) independently extracted, checked, and entered the data into the Review Manager software (Version 5.3 for Windows, Cochrane Collaboration, http://tech.cochrane. org/Revman). 2.2. Data synthesis and statistical analysis We included the outcomes of this meta-analysis, which could include at least two studies per outcome (Table 2). The primary outcome for measuring efficacy was a reduction in either the

199

Positive and Negative Syndrome Scale-Excited Component (PANSSEC) (Kay et al., 1987) or AgitationeCalmness Evaluation Scale (ACES) scores (Ono, 2007; Wright et al., 2001) scores at 2 h after first injection. The secondary outcomes, measured after the first injection, were as follows: PANSS-EC and ACES scores after 24 h; agitation scale scores, total symptoms, and positive symptoms after at 2 and 24 h; Clinical Global Impressions-Severity of Illness (CGI-S) (Guy and Bonato, 1970) and Clinical Global ImpressionImprovement scale (CGI-I) (Guy and Bonato, 1970) scores after 24 h; response rate; additional injections; and all-cause discontinuation. We also evaluated individual side effects. We based our analyses on intention-to-treat (ITT) or modified ITT data (ie, at least one dose or at least one follow-up assessment) and no observed case data were allowed. The metaanalysis was performed using Review Manager. Since lower numbers provide worse ACES scores in the meta-analytic program, we reversed the algebraic sign of the outcomes where higher numbers were more sedative. Thus, for the ACES score, 1 ¼ marked agitation, 2 ¼ agitation, 3 ¼ mild agitation, 4 ¼ normal, 5 ¼ mild calmness, 6 ¼ moderate calmness, 7 ¼ marked calmness, 8 ¼ deep sleep, and 9 ¼ unarousable. We assessed the methodological qualities of the articles included in the meta-analysis based on the Cochrane risk of bias criteria (Cochrane Collaboration, http://www.cochrane.org/). To combine studies, we used the conservative random effects model by DerSimonian and Laird (DerSimonian and Laird, 1986) because of the possibility that the underlying effect differed across studies and populations that are usually heterogeneous. For continuous data, standardized mean difference (SMD) was used by combining the effect size (Hedges’ g) data. When there were several OLA-IM treatment groups with different OLA-IM doses, we selected data from the maximum OLA-IM dose for continuous data (Table 2). For dichotomous data, the RR was estimated along with its 95% confidence interval (95% CI). When there were several OLA-IM treatment groups with different OLA-IM doses, we used the combined data from all OLA-IM treatment doses for dichotomous data (Table 2). In this study, when the random effects model showed significant between-group differences, NNT/NNH was calculated. Then, NNT/NNH values were derived from the risk differences (RD) using the formula NNT/NNH ¼ 1/RD, where the 95% CIs of NNT/ NNH being the inverse of the upper and lower limits of the 95% CI of RD. We explored study heterogeneity using the I2 statistic, considering values of 50% to reflect considerable heterogeneity (Higgins et al., 2003). In cases of I2 values 50% for the primary outcomes, we planned to conduct sensitivity analyses to determine the reasons for the heterogeneity. Funnel plots were visually inspected to assess the possibility of publication bias. 3. Results 3.1. 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; Katagiri et al., 2013; Katagiri et al., 2012; Meehan et al., 2001, 2002; Ono et al., 2009; Wright et al., 2001); 5 comparisons with 613 patients for OLA-IM versus HALIM (Baldacara et al., 2011; Breier et al., 2002; Chan et al., 2014; Hsu et al., 2010; Wright et al., 2001); 2 comparisons with 108

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T. Kishi et al. / Journal of Psychiatric Research 68 (2015) 198e209

Fig. 1. PRISMA flow diagram.

patients for OLA-IM versus ZIP-IM (Baldacara et al., 2011; Mantovani et al., 2013); 2 comparisons with 110 patients for OLAIM versus HAL-IM plus midazolam (Baldacara et al., 2011; Mantovani et al., 2013); 3 comparisons with 412 patients for OLAIM versus HAL-IM plus promethazine (Baldacara et al., 2011; Mantovani et al., 2013; Raveendran et al., 2007); 2 comparisons with 355 patients for OLA-IM versus LOR-IM (Meehan et al., 2001; Meehan et al., 2002); and 1 comparison with 67 patients for OLAIM versus HAL-IM plus LOR-IM (Huang et al., 2015). Nine studies were double-blind RCTs that mentioned the required study design details, three other studies (Hsu et al., 2010; Mantovani et al., 2013; Raveendran et al., 2007) were rater-blinded RCTs, and the remaining one study was an openlabel RCT (Huang et al., 2015). All studies used ITT or modified ITT data. Eleven of these studies were published in English, and two were published in Japanese (Katagiri et al., 2012; Ono et al., 2009). Seven studies included only patients with schizophreniarelated disorders, while four others included both patients with schizophrenia-related disorders and bipolar disorder (Baldacara et al., 2011; Hsu et al., 2010; Mantovani et al., 2013; Raveendran et al., 2007). Of the remaining studies, one included dementia patients (Meehan et al., 2002) and the other included only patients with bipolar disorder (Meehan et al., 2001). The study duration was 24 h in 10 studies, and 1.5 h, 12 h, and 14 days in the remaining studies. Treatment arms had sample sizes of 11e150 participants. In the meta-analysis of OLA-IM versus placebo, none received any antipsychotics other than the assigned injection. Two studies (Breier et al., 2002; Wright et al., 2001) that compared HAL-IM included the patients who did not receive any antipsychotics other than the assigned injection, while the other three (Baldacara et al., 2011; Chan et al., 2014; Hsu et al., 2010) did not provide sufficient information. Other characteristics of the studies are summarized in Table 1. We did not perform a metaanalysis of OLA-IM versus HAL-IM plus LOR-IM because there was only one RCT (Huang et al., 2015). In summary, their study found no significant differences in PANSS-EC or ACES scores at 2 h following the first injection between the two groups. The frequencies of adverse events including akathisia and EPS showed no significant differences between the groups.

3.1.1. OLA-IM versus placebo: primary outcomes OLA-IM was superior to placebo after 2 h for both PANSS-EC scores (SMD ¼ 0.77, 95% CI ¼ 1.07 to 0.46, p < 0.00001, I2 ¼ 73, 7 RCTs, n ¼ 740) and ACES scores (SMD ¼ 1.71, 95% CI ¼ 2.85 to 0.58, p ¼ 0.003, I2 ¼ 98, 7 RCTs, n ¼ 740) (Table 3). Visual inspection of the funnel plots for primary outcomes in both treatment groups suggested no publication bias (data not shown). Since we found significant heterogeneity in these two outcomes between treatment groups, we conducted sensitivity analyses (Table 3). All studies were double-blind RCTs. The significant heterogeneity did not disappear in any subgroup for PANSS-EC scores after 2 h and we found no significant subgroup differences when we divided by schizophrenia related or other disorders, OLA-IM dose (10 mg or 5 mg), sample size (n  100 or n < 100), and country (Japan or other) (Table 4). In term of ACES scores after 2 h, only when excluding country other than Japan did the significant heterogeneity disappear (I2 ¼ 18) (Table 4). Moreover, OLA-IM remained superior to placebo in this sensitivity analysis (SMD ¼ 0.73, 95% CI ¼ 1.06 to 0.39, p < 0.0001, 3 studies, n ¼ 183) (Table 4). In addition, we found no significant subgroup differences when we divided by schizophrenia related or other disorders, OLA-IM dose (10 mg or 5 mg), inclusion criteria (PANSSEC total scores  14 and at least 1 item scores  4 or other), and patients (in patients or other) (Table 4). 3.1.2. OLA-IM versus placebo: secondary outcomes OLA-IM was superior to placebo in PANSS-EC (SMD ¼ 0.39) and ACES (SMD ¼ 0.36) scores at 24 h, agitation scales at 2 (SMD ¼ 1.93) and 24 h (SMD ¼ 0.50), total symptoms at 2 (SMD ¼ 0.95) and 24 h (SMD ¼ 0.47), positive symptoms at 2 (SMD ¼ 0.56) and 24 h (SMD ¼ 0.33), CGI-I at 24 h (SMD ¼ 0.46), response rate (RR ¼ 0.59, NNT ¼ 4), additional injections (RR ¼ 0.55, NNT ¼ 5) and all-cause discontinuation (RR ¼ 0.46, NNH ¼ not significant) (Tables 3 and 5). 3.1.3. OLA-IM versus placebo: individual side effects When compared with placebo, OLA-IM was associated with less benzodiazepine use (RR ¼ 0.53, NNH ¼ not significant) (Table 5). OLA-IM also had a lower incidence of QT prolongation compared

Table 1 Study, patient and treatment characteristics of included randomized controlled trials. Total n

Patients (%)

Diagnosis

Duration (hours)

Age (mean ± SD)

Male (%)

Race (%)

Drug

Baldacara et al., 2011 (Brazil), DB, Non-industry

150

Bipolar (maniac or mixed episode) (59.3) or psychotic disorder (60.6). Inpatients (100). OASS  20 and OAS positive items  4.

DSM-IV-TR

12

OLA10mg: 30.4 ± 9.1, HAL5mg: 31.3 ± 5.2, HAL5mg þ MID15mg: 32.0 ± 7.2, HAL5mg þ PRO50mg: 34.6 ± 9.3, ZIP20mg: 33.1 ± 6.4

OLA10mg: 60.0, HAL5mg: 66.7, HAL5mg þ MID15mg: 60.0, HAL5mg þ PRO50mg: 63.3, ZIP20mg: 53.3

NR

OLA10mg HAL5mg HAL5mg þ MID15mg HAL5mg þ PRO50mg ZIP20mg

30 30 30 30 30

Breier et al., 2002 (Croatia, Italy, Romania and South Africa), DB, Industry

270

Schizophrenia, schizophreniform disorder, or schizoaffective disorder. Recently hospitalized patients (100). PANSS-EC total scores  14 and at least 1 item scores  4.

DSM-IV

24

OLA2.5mg: 36.2 ± 10.5, OLA5mg: 35.1 ± 10.1, OLA7.5mg: 35.9 ± 11.3, OLA10mg: 36.7 ± 12.1, HAL7.5mg: 37.4 ± 10.6, PLA: 36.7 ± 10.3

OLA2.5mg: 64.6, OLA5mg: 60.0, OLA7.5mg: 56.5, OLA10mg: 56.5, HAL7.5mg: 55.0, PLA: 51.1

White (65.9), African (24.1), Western Asian (1.5), Other (8.5)

OLA2.5mg

48

OLA5mg

45

OLA7.5mg

46

OLA10mg

46

HAL7.5mg

40

PLA OLA10mg HAL7.5mg

45 25 24

Chan et al., 2014 (Taiwan), DB, Non-industry

49

Hsu et al., 2010 (Taiwan), RB, Non-industry

22

Huang et al., 2015 (Taiwan), Open, Non-industry

67

Schizophrenia (100). Inpatients due to acute relapse (100). PANSSEC total scores  14 and at least 1 item scores  4. Schizophrenia (48%), bipolar I disorder (43%), schizoaffective disorder (2%), or other psychotic disorders (7%). Inpatients (100). PANSS-EC total scores  14 and at least 1 item scores  4. Schizophrenia or schizoaffective disorder (100). Recently hospitalized patients

n

Outcomes (1e2 h(s) after The first injection) OLA10mg had better results for agitation control. ZIP20mg had better results for controlling aggressive behavior, followed by HAL5mg þ PRO50mg. HAL5mg þ MID15mg showed the worst results in all the parameters observed. PANSS-EC, BPRS total, BPRS positive, ABS: OLA2.5mg > PLA, ACES: OLA2.5mg ¼ PLA PANSS-EC, BPRS total, BPRS positive, ABS, ACES: OLA5mg > PLA, PANSS-EC, BPRS total, BPRS positive, ABS, ACES: OLA7.5mg > PLA, PANSS-EC, BPRS total, BPRS positive, ABS, ACES: OLA10mg > PLA, PANSS-EC, BPRS total, ABS, ACES: HAL7.5mg > PLA, BPRS positive: HAL7.5mg ¼ PLA

DSM-IV

24

OLA10mg: 33.9 ± 7.9, HAL7.5mg: 38.2 ± 10.9

OLA10mg: 80.0, HAL7.5mg: 62.5

NR

DSM-IV-TR

24

OLA10mg: 37.6 ± 11.7, HAL7.5mg: 36.4 ± 12.4

OLA10mg: 54.5, HAL7.5mg: 45.5

NR

OLA10mg HAL7.5mg

11 11

PANSS-EC, ACES: OLA10mg ¼ HAL7.5mg

DSM-IV

24

OLA10mg: 37.1 ± 10.8, HAL5mg þ LOR2mg: 41.3 ± 11.3

OLA10mg: 59.5, HAL5mg þ LOR2mg: 63.3

NR

OLA10mg HAL5mg þ LOR2mg

37 30

PANSS-EC, ACES: OLA10mg ¼ HAL5mg þ LOR2mg

PANSS-EC, BPRS total, BPRS positive, ACES: OLA10mg ¼ HAL7.5mg

T. Kishi et al. / Journal of Psychiatric Research 68 (2015) 198e209

Study

(continued on next page)

201

Study

202

Table 1 (continued ) Total n

34

Katagiri et al., 2013 (Japan), DB, Industry

91

Mantovani et al., 2013 (Brazil), RB, Non-industry

100

Meehan et al., 2001 (United States and Romania), DB, Industry

201

Meehan et al., 2002 (United States, Russia and Romania), DB, Industry

272

Ono et al., 2009 (Japan), DB, Industry

164

(100). PANSS-EC total scores  14 and at least 1 item scores  4. Schizophrenia (100). Inpatients (100). PANSS-EC total scores  20 and ACES score ¼ 1 or 2. Schizophrenia (100). Outpatients or inpatients (NR). ACES score ¼ 1 or 2. Patients whose agitation occurred or worsened within the prior 2 weeks, patients who were considered to require rapid tranquilization, or patients who needed careful consideration for examination or treatment. Psychotic/manic disorder (57.0). Emergency settings. Patients presented with an acute agitation state requiring medication for rapid tranquilization. Previous use of medication (67.0). Bipolar disorder, manic or mixed (100). Inpatients (100). PANSS-EC total scores  14 and at least 1 item scores  4. Current treatment: Li (NR), VAL (NR).

Alzheimer's disease, vascular dementia, or mixed dementia. Inpatients (100). PANSS-EC total scores>14 and at least 1 item scores>4. Schizophrenia (100). Inpatients (100). PANSS-EC total

Diagnosis

Duration (hours)

Age (mean ± SD)

Male (%)

Race (%)

Drug

DSM-IV-TR

24

OLA10mg: 47.4 ± 12.4, PLA: 45.9 ± 11.5

OLA10mg: 52.9, PLA: 62.5

Japanese (100)

OLA10mg

17

PLA

17

OLA10mg

45

PLA

45

OLA10mg HAL5mg þ MID15mg HAL5mg þ PRO50mg ZIP10mg

25 25

23

OLA10mg

99

LOR2mg

51

PLA OLA2.5mg

51 71

OLA5mg

66

LOR1mg

68

PLA OLA2.5mg

68 34

OLA5mg

32

DSM-IV-TR

NR

DSM- III-R

NINCDSADRDA or DSM-IV

DSM-IV-TR

24

1.5

24

24

24

OLA10mg: 46.4 ± 11.7, PLA: 47.0 ± 12.1

OLA10mg: 46.7, PLA: 51.1

OLA10mg: 29.5 ± 10.2, HAL5mg þ MID15mg: 32.9 ± 10.5, HAL5mg þ PRO50mg: 31.8 ± 9.3, ZIP10mg: 29.0 ± 9.7

OLA10mg: 52.0, HAL5mg þ MID15mg: 44.0, HAL5mg þ PRO50mg: 48.1, ZIP10mg: 41.5

OLA10mg: 40.2 ± 12.4, LOR2mg: 39.0 ± 9.7, PLA: 40.5 ± 10.5

OLA10mg: 57.6, LOR2mg: 41.2, PLA: 56.9

77.6 ± 9.7

OLA2.5mg: 43.6 ± 12.6, OLA5mg: 41.6 ± 12.5, OLA7.5mg: 47.4 ± 11.2,

39.0

OLA2.5mg: 47.1, OLA5mg: 67.7, OLA7.5mg: 52.9,

Japanese (100)

NR

White (72.6), Black (15.9), Other (11.5)

Caucasian (92.3)

Japanese (100)

n

27

Outcomes (1e2 h(s) after The first injection)

PANSS-EC, ACES: OLA10mg ¼ PLA

PANSS-EC, ACES: OLA10mg > PLA

PANSS-EC, ACES: OLA10mg ¼ HAL5mg þ MID15mg ¼ HAL5mg þ PRO50mg ¼ ZIP10mg: 29.0 ± 9.7

PANSS-EC, PANSSderived BPRS total, PANSS-derived BPRS positive, ABS, ACES: OLA-10 > PLA ABS, ACES: LOR2mg > PLA, PANSSEC, PANSS-derived BPRS total, PANSSderived BPRS positive: LOR2mg ¼ PLA PANSS-EC, ACES: OLA2.5mg > PLA PANSS-EC, ACES: OLA5mg > PLA PANSS-EC, ACES: LOR1mg > PLA PANSS-EC: OLA2.5mg ¼ PLA PANSS-EC: OLA5mg ¼ PLA

T. Kishi et al. / Journal of Psychiatric Research 68 (2015) 198e209

Katagiri et al., 2012 (Japan), DB, Industry

Patients (%)

scores  14 and at least 1 item scores  4.

300

Wright et al., 2001 (Australia, Austria, Belgium, Canada, the Czech Republic, France, Greece, Hungary, Israel, the Republic of South Africa, Spain, the United Kingdom, and the United States), DB, Industry

311

Schizophrenia (8.3), Mania (62.7), Depression (10.3), Acute psychosis (10.0), Mental retardation with psychosis (1.0), Substance induced psychosis (6.7). Emergency settings. Agitation, aggression, or violent behavior. Current treatment: AP (26.3), Li (4.7), AC (3.0), BEN (3.7), ACh (13.3), AD (3.7) Schizophrenia, schizophreniform disorder, or schizoaffective disorder. Inpatients (100). PANSS-EC total scores>14 and at least 1 item scores>4

OLA10mg: 65.6, PLA: 46.9

ICD-10

14 days

OLA5mg or 10mg: 30.6 ± 10.5, HAL5mg þ PRO25mg or HAL10mg þ PRO50mg: 30.4 ± 9.5

OLA5mg or 10mg: 60.7, HAL5mg þ PRO25mg or HAL10mg þ PRO50mg: 64.7

NR

DSM-IV

24

OLA10mg: 38.2 ± 12.2, HAL7.5mg: 38.5 ± 11.1, PLA: 37.6

OLA10mg: 64.9, HAL7.5mg: 68.3, PLA: 61.1

European (72.7), African (19.0), Asian, Latin American, other (8.4)

OLA7.5mg

34

OLA10mg

32

PLA OLA5mg or 10mg HAL5mg þ PRO25mg or HAL10mg þ PRO50mg

32 150 150

OLA10mg

131

HAL7.5mg

126

PLA

PANSS-EC: OLA7.5mg ¼ PLA PANSS-EC: OLA10mg ¼ PLA Patients given HAL5mg þ PRO25mg or HAL10mg þ PRO50mg required less medical attention or additional drugs in 4 h after intervention than those given OLA5mg or 10mg.

PANSS-EC, BPRS total, BPRS positive, ABS, ACES: OLA10mg > PLA, PANSS-EC, BPRS total, BPRS positive, ABS, ACES: HAL7.5mg > PLA,

54

ABS: Agitated Behavior Scale, AC: anticonvulsant, ACES: Agitation-Calmness Evaluation Scale, ACh: anticholinergic, AD: antidepressant, AP: antipsychotic, BEN: benzodiazepine, BPRS: Brief Psychiatric Rating Scale, DB: doubleblind, DSM-IV(-TR): Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (Text Revision), HAL: haloperidol, Li: lithium, MID: midazolam, n: number of patients, NINCDS-ADRDA: National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer's Disease and Related Disorders Association, NR: not report, OAS: Overt Aggression Scale, OASS: Overt Agitation Severity Scale, OLA: olanzapine, PANSS-EC: Positive and Negative Syndrome Scale-Excited Component, PLA: Placebo, PRO: promethazine, RB: rater-blind, VAL: valproate, ZIP: ziprasidone.

T. Kishi et al. / Journal of Psychiatric Research 68 (2015) 198e209

Raveendran et al., 2007 (India), RB, Non-industry

OLA10mg: 44.0 ± 13.7, PLA: 45.8 ± 11.6

203

Olanzapine vs Placebo

204

Table 2 Data synthesis. Breier et al., 2002

Katagiri et al., 2012

Katagiri et al., 2013

Meehan et al., 2001

Meehan et al., 2002

Ono et al., 2009

Wright et al., 2001

Change scores OLA-IM 10mg Change scores OLA-IM 10mg Change scores OLA-IM 10mg Change scores OLA-IM 10mg

Change scores OLA-IM 10mg Change scores OLA-IM 10mg Change scores OLA-IM 10mg Change scores OLA-IM 10mg

Change scores of OLA-IM 10mg Change scores of OLA-IM 10mg Change scores of OLA-IM 10mg Change scores of OLA-IM 10mg Change ABS scores of OLA-IM10mg

Change scores of OLA-IM 10mg Change scores of OLA-IM 10mg Change scores of OLA-IM 10mg Change scores of OLA-IM 10mg Change ABS scores of OLA-IM10mg

Agitation scales at 24 h

Change ABS scores of OLA-IM10mg

Change ABS scores of OLA-IM10mg

Change scores of OLA-IM 5mg Change scores of OLA-IM 5mg Change scores of OLA-IM 5mg Change scores of OLA-IM 5mg Change CMAI scores of OLA-IM 5mg Change CMAI scores of OLA-IM 5mg

Change scores OLA-IM 10mg Change scores OLA-IM 10mg Change scores OLA-IM 10mg Change scores OLA-IM 10mg

Agitation scales at 2h

Change scores of OLA-IM 10mg Change scores of OLA-IM 10mg Change scores of OLA-IM 10mg Change scores of OLA-IM 10mg Change ABS scores of OLA-IM10mg

Total symptoms at 2h

Change BPRS scores of OLA-IM10mg

Total symptoms at 24 h

Change BPRS scores of OLA-IM10mg

Positive symptoms at 2 h

Change BPRS scores of OLA-IM10mg

Positive symptoms at 24 h

Change BPRS scores of OLA-IM10mg

Change PANSSd scores of OLAIM10mg Change PANSSd scores of OLAIM10mg Change PANSSd scores of OLAIM10mg Change PANSSd scores of OLAIM10mg

PANSS-EC at 2 h PANSS-EC at 24 h ACES at 2 h ACES at 24 h

of of of of

of of of of

Baldacara et al., 2011 Olanzapine vs Haloperidol

PANSS-EC at 2 h PANSS-EC at 24 h ACES at 2 h ACES at 24 h Agitation scales at 2 h Agitation scales at 24 h Total symptoms at 2 h Total symptoms at 24 h Positive symptoms at 2 h Positive symptoms at 24 h CGI-I at 24 h Response rate

OASS endpoint scores of OLA-IM10mg

40% PANSS-EC at 3 min of OLAIM10mg

40% PANSS-EC at 2 h of OLA-IM10mg

Change scores of OLA-IM 10mg 40% PANSS-EC at 2 h of OLA-IM10mg

of

Change ABS scores of OLA-IM10mg

Change BPRS scores of OLA-IM5mg

Change BPRS scores of OLA-IM10mg Change BPRS scores of OLA-IM10mg

Change BPRS scores of OLA-IM5mg

Change scores of OLA-IM5mg 40% PANSS-EC at hours of OLAIM2.5þ5mg

Breier et al., 2002

Chan et al., 2014

Change Change Change Change Change

scores of OLA-IM 10mg scores of OLA-IM 10mg scores of OLA-IM 10mg scores of OLA-IM 10mg ABS scores of OLA-IM10mg

Change scores of OLA-IM 10mg

Change Change Change Change Change

ABS scores of OLA-IM10mg BPRS scores of OLA-IM10mg BPRS scores of OLA-IM10mg BPRS scores of OLA-IM10mg BPRS scores of OLA-IM10mg

40% PANSS-EC 2 h of OLA-IM2.5 þ 5þ10mg

of

Change scores of OLA-IM 10mg

Change BPRS scores of OLA-IM10mg Change BPRS scores of OLA-IM10mg Endpoint scores of OLA-IM10mg 40% PANSS-EC 2 h of OLA-IM10mg

Change BPRS scores of OLA-IM10mg Change scores of OLA-IM 10mg Change scores of OLA-IM 10mg 40% PANSS-EC at 30 min of OLAIM2.5 þ 5þ10mg

Hsu et al., 2010

Change scores of OLA-IM 10mg

40% PANSS-EC at hours of OLAIM10mg

Wright et al., 2001 Change Change Change Change Change

scores of OLA-IM 10mg scores of OLA-IM 10mg scores of OLA-IM 10mg scores of OLA-IM 10mg ABS scores of OLA-IM10mg

Change ABS scores of OLA-IM10mg Change BPRS scores of OLA-IM10mg Change BPRS scores of OLA-IM10mg Change BPRS scores of OLA-IM10mg Change BPRS scores of OLA-IM10mg Change scores of OLA-IM5mg 40% PANSS-EC 2 h of OLA-IM2.5 þ 5þ10mg

ABS: Agitated Behavior Scale, ACES: Agitation-Calmness Evaluation Scale, BPRS: Brief Psychiatric Rating Scale, OASS: Overt Agitation Severity Scale, OLA-IM: intramuscular olanzapine, PANSS-EC: Positive and Negative Syndrome Scale-Excited Component.

T. Kishi et al. / Journal of Psychiatric Research 68 (2015) 198e209

Response rate

Change scores of OLA-IM 10mg 40% PANSS-EC at hours of OLAIM2.5 þ 5þ10mg

of

Change BPRS scores of OLA-IM10mg

CGI-I at 24 h CGI-S at 24 h

of

T. Kishi et al. / Journal of Psychiatric Research 68 (2015) 198e209

205

Table 3 Efficacy outcomes. Intervention

Outcome

N

n

I2

SMD or RR

95% CI

p value

Olanzapine vs Placebo

PANSS-EC at 2 h PANSS-EC at 24 h ACES at 2 h ACES at 24 h Agitation scales at 2 h Agitation scales at 24 h Total symptoms at 2 h Total symptoms at 24 h Positive symptoms at 2 h Positive symptoms at 24 h CGI-I at 24 h CGI-S at 24 h Response rate Use of additional injection

7 7 7 7 4 4 3 4 3 4 2 4 7 7

740 740 740 740 557 557 417 554 417 554 232 411 1051 1056

73 45 98 6 98 20 72 70 0 58 0 11 86 7

0.77 0.39 1.71 0.36 1.93 0.50 0.95 0.47 0.56 0.33 0.46 0.09 0.59 0.55

1.07 to 0.46 0.60 to 0.18 2.85 to 0.58 0.52 to 0.21 3.54 to 0.31 0.70 to 0.30 1.36 to 0.54 0.80 to 0.14 0.77 to 0.36 0.60 to 0.06 0.74 to 0.18 0.31 to 0.13 0.43e0.81 0.47e0.66

<0.00001 0.0002 0.003 <0.00001 0.02 <0.00001 <0.00001 0.005 <0.00001 0.02 0.001 0.42 0.001* <0.00001**

Olanzapine vs Haloperidol

PANSS-EC at 2 h PANSS-EC at 24 h ACES at 2 h ACES at 24 h Agitation scales at 2 h Agitation scales at 24 h Total symptoms at 2 h Total symptoms at 24 h Positive symptoms at 2 h Positive symptoms at 24 h CGI-I at 24 h Response rate Use of additional injection

3 2 3 2 3 2 3 2 3 2 2 3 3

389 343 389 343 402 343 385 340 385 340 289 527 542

0 45 78 65 96 68 11 0 0 0 0 0 81

0.11 0.08 0.60 0.13 1.22 0.15 0.16 0.05 0.07 0.10 0.02 0.86 0.76

0.31 to 0.09 0.40 to 0.24 1.10 to 0.10 0.28 to 0.53 2.52 to 0.08 0.58 to 0.28 0.38 to 0.07 0.26 to 0.17 0.27 to 0.13 0.11 to 0.31 0.21 to 0.25 0.66e1.13 0.38e1.51

0.26 0.62 0.02 0.54 0.07 0.49 0.17 0.66 0.52 0.36 0.88 0.28 0.43

Olanzapine vs Lorazepam

PANSS-EC at 2 h PANSS-EC at 24 h ACES at 2 h ACES at 24 h Agitation scales at 2 h Agitation scales at 24 h Total symptoms at 24 h Positive symptoms at 24 h CGI-S at 24 h Response rate Use of additional injection

2 2 2 2 2 2 2 2 2 2 2

283 283 283 283 283 283 283 283 281 355 355

80 0 89 0 78 0 0 0 0 82 76

0.30 0.06 0.20 0.07 0.21 0.09 0.13 0.12 0.08 0.85 0.70

0.84 to 0.24 0.29 to 0.18 0.92 to 0.52 0.31 to 0.17 0.72 to 0.31 0.33 to 0.15 0.37 to 0.11 0.36 to 0.12 0.32 to 0.16 0.37e1.96 0.34e1.43

0.27 0.65 0.59 0.56 0.43 0.48 0.28 0.33 0.50 0.70 0.33

Olanzapine vs Haloperidol þ midazolam

Use of additional injection

2

110

0

0.49

0.29e0.83

0.008****

Olanzapine vs Haloperidol þ promethazine

Use of additional injection Use of mechanical seclusion and restraint

3 2

412 360

93 72

0.85 0.72

0.22e3.33 0.10e5.36

0.82 0.75

Olanzapine vs Ziprasidone

Use of additional injection

2

108

0

0.56

0.32e0.97

0.04*****

* Number needed to treat (NNT) ¼ 4, I2 ¼ 74, p < 0.0001. **NNT ¼ 5, I2 ¼ 86, p ¼ 0.01. ***NNT ¼ not significant. ****NNT ¼ 5, I2 ¼ 0, p ¼ 0.03. ACES: Agitation-Calmness Evaluation Scale, CGI-I(S): Clinical Global Impression e Improvement (Severity) scale), N: number of studies, n: number of patients, PANSS-EC: Positive and Negative Syndrome Scale-Excited Component, RR: risk ratio, SMD: Standardized Mean Difference, 95% CI: 95% Confidence interval. Underlining indicates risk ratio.

with placebo (RR ¼ 0.34, NNH ¼ not significant) (Table 5). There were no statistically significant differences in serious side effects, at least one side effect, EPS, orthostatic hypotension/dizziness, or over sedation (ACES score ¼ 8 or 9) between OLA-IM and placebo (Table 5). 3.1.4. OLA-IM versus HAL-IM: primary outcomes While there was no significant difference in PANSS-EC scores after 2 h between OLA-IM and HAL-IM (SMD ¼ 0.11, 95% CI ¼ 0.31 to 0.09, p ¼ 0.26, I2 ¼ 0; 3 RCTs, n ¼ 389), OLA-IM outperformed HAL-IM in ACES scores after 2 h (SMD ¼ 0.60, 95% CI ¼ 1.10 to 0.10, p ¼ 0.02, I2 ¼ 78; 3 RCTs, n ¼ 389) (Table 3). Visual inspection of the funnel plots for primary outcomes in both treatment groups suggested no publication bias (data not shown). We detected significant heterogeneity in ACES scores after 2 h between the OLA-IM and HAL-IM treatment groups (I2 ¼ 78). All

studies were double-blind RCTs. The three studies included in the meta-analysis had similar inclusion criteria (PANSS-EC total scores  14 and at least 1 item score  4), doses (10 mg OLA-IM and 7.5 mg HAL-IM), and patient characteristic (inpatients with schizophrenia related disorders) (Table 1). However, only the study by Chan (19) was not industry-sponsored and was conducted in one country (Taiwan) (Table 1). However, the significant heterogeneity remained after excluding the Chan study (I2 ¼ 76). On the other hand, the significant heterogeneity disappeared after excluding large samples (n  100) (I2 ¼ 0), and the OLA-IM remained superior (SMD ¼ 0.37, 95% CI ¼ 0.71 to 0.02, p ¼ 0.04; 2 RCTs, n ¼ 132). 3.1.5. OLA-IM versus HAL-IM: secondary outcomes Agitation scales with OLA-IM were marginally superior to HALIM after 2 h (SMD ¼ 1.22, p ¼ 0.07). However, there were no significant differences in either PANSS-EC, ACES, CGI-I, or the

206

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Table 4 Sensitivity analysis. Outcome

Variable

Subgroup

N n

I2 RR

95% CI

p value

Schizophrenia related disorders 5 459 77 0.77 1.20 to 0.33 0.0006 Other 2 281 76 0.74 1.25 to 0.24 0.004 Inclusion criteria PANSS-EC total scores  14 and at least 1 item scores  4. 6 651 71 0.69 1.01 to 0.37 <0.0001 Other 1 89 na 1.25 1.71 to 0.79 <0.00001 Patients Inpatients 6 651 71 0.69 1.01 to 0.37 <0.0001 Other 1 89 na 1.25 1.71 to 0.79 <0.00001 Olanzapine dose 10mg 6 607 73 0.82 1.16 to 0.47 <0.00001 5mg 1 133 na 0.49 0.83 to 0.14 0.006 Sample size Total n  100 3 466 52 0.73 1.01 to 0.44 <0.00001 Total n < 100 4 274 82 0.77 1.38 to 0.16 0.01 Country Japanese 3 183 82 0.56 1.31 to 0.18 0.14 Other 4 557 70 0.86 1.20 to 0.52 <0.00001

PANSS-EC 2 h Diagnosis

ACES 2 h

Schizophrenia related disorders 5 459 98 2.08 3.91 to 0.26 0.03 Other 2 281 89 0.85 1.60 to 0.11 0.03 Inclusion criteria PANSS-EC total scores  14 and at least 1 item scores  4. 6 651 98 1.84 3.20 to 0.48 0.008 Other 1 89 na 0.98 1.42 to 0.54 <0.0001 Patients Inpatients 6 651 98 1.84 3.20 to 0.48 0.008 Other 1 89 na 0.98 1.42 to 0.54 <0.0001 Olanzapine dose 10mg 6 607 98 1.93 3.31 to 0.56 0.006 5mg 1 133 na 0.47 0.82 to 0.13 0.007 Sample size Total n  100 3 466 99 2.96 5.75 to 0.18 0.04 Total n < 100 4 274 51 0.86 1.23 to 0.50 <0.00001 Country Japanese 3 183 18 0.73 1.06 to 0.39 <0.0001 Other 4 557 99 2.53 4.47 to 0.59 0.01

Diagnosis

Test for subgroup differences p ¼ 0.95, I2 ¼ 0% p ¼ 0.05, I2 ¼ 74% p ¼ 0.05, I2 ¼ 74% p ¼ 0.19, I2 ¼ 42% p ¼ 0.90, I2 ¼ 0% p ¼ 0.48, I2 ¼ 0% p ¼ 0.22, I2 ¼ 33% p ¼ 0.23, I2 ¼ 29% p ¼ 0.23, I2 ¼ 29% p ¼ 0.04, I2 ¼ 75% p ¼ 0.14, I2 ¼ 54% p ¼ 0.07, I2 ¼ 69%

ACES: Agitation-Calmness Evaluation Scale, N: number of studies, n: number of patients, na: not applicable, PANSS-EC: Positive and Negative Syndrome Scale-Excited Component, SMD: standardized mean difference, 95% CI: 95% confidence interval.

agitation scale after 24 h, the total symptoms or positive symptoms after 2 and 24 h, or the response rate or all-cause discontinuation (Tables 3 and 5). 3.1.6. OLA-IM versus HAL-IM: individual side effects Compared with HAL-IM, OLA-IM required less anticholinergic use of (RR ¼ 0.18, NNH ¼ 8) and had lower rates of akathisia (RR ¼ 0.16, NNH ¼ 17), EPS (RR ¼ 0.21, NNH ¼ 10) and dystonia (RR ¼ 0.06, NNH ¼ 14) (Table 5). OLA-IM also had a marginally lower incidence of QT prolongation compared with HAL-IM (RR ¼ 0.37, p ¼ 0.06) (Table 5). 3.1.7. OLA-IM versus LOR-IM: primary outcomes There were no statistically significant differences in the primary outcomes between OLA-IM and LOR-IM (Table 3). We found significant heterogeneity in these two outcomes between treatment groups (Table 3). However, because the total number of studies included in the meta-analysis was 2, we did not perform a sensitivity analysis. 3.1.8. OLA-IM versus LOR-IM: secondary outcomes There were no statistically significant differences in the secondary outcomes between OLA-IM and LOR-IM (Tables 3 and 5). 3.1.9. OLA-IM versus LOR-IM: individual side effects There were no statistically significant differences in individual side effects between OLA-IM and LOR-IM (Table 5). 3.2. OLA-IM versus other comparators OLA-IM involved fewer additional injections (RR ¼ 0.49, NNT ¼ not significant) (Table 3) and had lower rates of orthostatic hypotension/dizziness (RR ¼ 0.18, NNH ¼ 8) compared with HALIM plus midazolam (Table 5). In addition, compared with ZIP-IM, OLA-IM required fewer additional injections (RR ¼ 0.56, NNT ¼ 5) (Table 3).

4. 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 metaanalyses of OLA-IM versus placebo (7 comparisons, n ¼ 1059) and OLA-IM versus HAL-IM (5 comparisons, n ¼ 613). However, the number of studies was too few for the comparisons of OLA-IM versus ZIP-IM (2 comparisons, n ¼ 108), OLA-IM versus HAL-IM plus midazolam (2 comparisons, n ¼ 110), OLA-IM versus HAL-IM plus promethazine (3 comparisons, n ¼ 412), OLA-IM versus LORIM (2 comparisons, n ¼ 110), and OLA-IM versus HAL-IM plus LOR-IM (1 comparison, n ¼ 67). Therefore, we could not conclude whether OLA-IM was superior to ZIP-IM, LOR-IM, HAL-IM plus midazolam, or HAL-IM plus promethazine in agitated patients. Compared with placebo, OLA-IM significantly improved PANSSEC scores 2 h after the first injection in agitated patients and had a measurable tranquilizing effect. Moreover, OLA-IM had similar incidence of individual side effects as that of placebo, including over sedation (ACES score ¼ 9), EPS, akathisia, and anticholinergic use. A previous meta-analysis reported that HAL-IM was superior to placebo with regard to improvement in PANSS-EC scores after 2 h (mean difference [MD] ¼ 2.97, 95% CI ¼ 4.76 to 1.18, p < 0.000001, I2 ¼ 17; 2 RCTs, n ¼ 357) with a higher incidence of over sedation (RR ¼ 3.36, 2 RCTs, n ¼ 313), EPS (RR ¼ 7.15, 2 RCTs, n ¼ 358), and anticholinergic use (RR ¼ 5.57, 1 RCT, n ¼ 180) (Powney et al., 2012). In the current meta-analysis, although there was a significant difference between OLA-IM and placebo in PANSSEC scores after 2 h, OLA-IM had a lower incidence of EPS-related outcomes than did HAL-IM. A previous review showed that ZIPIM and aripiprazole-IM were also superior to placebo in response rate with a large effect size (NNT: ZIP-IM ¼ 3, aripiprazole-IM ¼ 5) (Citrome, 2007). This review also reported that ZIP-IM and aripiprazole-IM had higher rates of headache compared with placebo with a medium effect size (NNH: ZIP-IM ¼ 15, aripiprazoleIM ¼ 20). Our meta-analysis found that OLA-IM required fewer additional injections than ZIP-IM. However, the result of additional

T. Kishi et al. / Journal of Psychiatric Research 68 (2015) 198e209

207

Table 5 Safety outcomes. Intervention

Outcome

N

n

I2

SMD or RR

95% CI

Olanzapine vs Placebo

Discontinuation rate Use of anticholinergic drugs Use of benzodiazepine Serious side effect At least one side effect Akathisia Extrapyramidal symptoms Dystonia Dyskinesia SAS/DIEPSS BAS/DIEPSS Orthostatic hypotension/dizziness ACES ¼ 8 points ACES ¼ 9 points QT prolongation QTc interval

7 7 7 3 7 7 7 7 3 6 5 7 6 7 6 7

1057 1055 1055 287 1055 1038 1002 1055 286 627 504 1049 757 1055 869 724

7 0 73 na 18 0 0 na na 0 0 0 0 na 0 0

0.46 1.09 0.53 0.48 1.25 0.61 1.12 na 1.25 0.00 0.09 1.82 2.39 na 0.34 0.14

0.25e0.83 0.56e2.15 0.30e0.95 0.05e5.18 0.89e1.73 0.15e2.57 0.47e2.66

0.01 0.79 0.03 0.55 0.19 0.50 0.80

0.06e25.4 0.16 to 0.17 0.27 to 0.10 0.72e4.55 0.89e6.43

0.88 0.98 0.35 0.20 0.08

0.16e0.70 0.29 to 0.01

0.003 0.08

Discontinuation rate Use of anticholinergic drugs Use of benzodiazepine At least one side effect Akathisia Extrapyramidal symptoms Dystonia SAS/DIEPSS BAS/DIEPSS QT prolongation QTc interval

5 3 3 4 2 4 3 2 2 3 2

613 542 542 591 434 544 542 288 287 433 343

0 0 52 0 0 36 0 0 0 na 0

1.02 0.18 1.40 0.80 0.16 0.21 0.06 0.01 0.05 0.37 0.13

0.47e2.23 0.08e0.39 0.22e8.71 0.53e1.21 0.04e0.61 0.06e0.69 0.01e0.34 0.24 to 0.22 0.28 to 0.18 0.13e1.05 0.34 to 0.08

0.95 <0.0001 0.72 0.29 0.007 0.01 0.001 0.96 0.68 0.06 0.22

Discontinuation rate Use of anticholinergic drugs Use of benzodiazepine At least one side effect Akathisia Extrapyramidal symptoms Dystonia SAS/DIEPSS Orthostatic hypotension/dizziness ACES ¼ 8 points ACES ¼ 9 points QTc interval

2 2 2 2 2 2 2 2 2 2 2 2

355 355 355 355 355 355 355 277 355 355 355 276

0 0 na 63 na 0 na 0 0 0 na 0

0.56 3.07 na 0.86 0.52 1.48 na 0.12 0.68 1.12 0.17 0.12

0.24e1.28 0.55e17.2

0.17 0.20

0.50e1.47 0.03e8.07 0.30e7.35

0.57 0.64 0.63

0.12 to 0.37 0.30e1.54 0.46e2.73 0.01e4.18 0.36 to 0.12

0.32 0.36 0.80 0.28 0.33

Olanzapine vs Haloperidol þ midazolam

Extrapyramidal symptoms Orthostatic hypotension/dizziness

2 2

110 110

59 0

0.65 0.18

0.08e5.47 0.03e0.97

0.69 0.05

Olanzapine vs Haloperidol þ promethazine

Discontinuation rate Extrapyramidal symptoms Dystonia Orthostatic hypotension/dizziness

2 3 2 2

360 412 360 112

na 64 na 0

11.0 0.38 0.20 0.34

0.61e197.2 0.04e3.59 0.01e4.00 0.06e2.08

0.10 0.40 0.29 0.24

Olanzapine vs Ziprasidone

Extrapyramidal symptoms Orthostatic hypotension/dizziness

2 2

108 108

na 0

1.07 0.20

0.64e1.81 0.04e1.12

0.79 0.07

Olanzapine vs Haloperidol

Olanzapine vs Lorazepam

p Value

NNH

p value

ns ns

ns

8

0.0003

17 10 14

0.005 0.006 0.0002

8

0.02

5

0.03

ACES: Agitation-Calmness Evaluation Scale, BAS: Barnes Akathisia Rating Scale, DIEPSS: Drug-Induced Extrapyramidal Symptoms Scale, N: number of studies, n: number of patients, na: not applicable, NNH ¼ number needed to harm, ns: not significant, RR: risk ratio, SMD: Standardized Mean Difference, SAS: Simpson-Angus Scale, 95% CI: 95% Confidence interval. Underlining indicates risk ratio.

injections might be driven by the doses used in one of the studies (Mantovani et al., 2013) where initial ZIP-IM dose was 10 mg (Table 1). Moreover, OLA-IM also had a lower incidence of QT prolongation than placebo, and there were no statistically significant differences in serious side effects, at least one side effect, EPS, orthostatic hypotension/dizziness, or over sedation between OLAIM and placebo. There were no significant differences in response rate, change of CGI-S and PANSS-EC scores, all-cause discontinuation and individual side effects between OLA-IM and LOR-IM. Our findings were consistent with the results of previous meta-analysis (Belgamwar and Fenton, 2005). Project BETA (Wilson et al., 2012b) recommended that nonpharmacologic approaches, such as verbal de-escalation and reducing environmental stimulation (quiet room, low lighting), should be attempted, if possible, before medications are administered. It also recommended that medication should be

used to calm patients, not to induce sleep, and that if the patient is able to cooperate with taking oral medications, these are preferred over intramuscular preparations. SGAs with supportive data for their use in acute agitation are preferred over haloperidol. If the patient cannot cooperate with oral medications, ZIP-IM or OLA-IM are recommended for acute control of agitation. Although OLA-IM was associated with fewer additional injections and less benzodiazepine use compared with placebo, the reported occurrence of fatal adverse events following coadministration of olanzapine and lorazepam has prompted. Eli Lilly and Company (2004) recommends strict adherence to dosage and administration guidelines and avoidance of coadministration of OLA-IM and parenteral benzodiazepines. Recent retrospective chart review reported that OLA-IM plus benzodiazepines seemed to be safe in patients who had not ingested alcohol, but might produce

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T. Kishi et al. / Journal of Psychiatric Research 68 (2015) 198e209

potentially significant oxygen desaturations in patients who had (Wilson et al., 2012a). Chan and colleagues also reported that although intravenous olanzapine as an adjunct to midazolam was effective and decreases the time to adequate sedation compared with midazolam alone, after sedation the patient must be closely observed and monitored because of the risk of cardiorespiratory depression (Chan et al., 2013). However, there were no available data for performing a meta-analysis of this outcome. There are several limitations to the present analysis. First, we detected significant heterogeneity with respect to the primary outcomes in OLA-IM versus placebo (reduction in PANSS-EC and ACES scores after 2 h). Despite sensitivity analyses to identify the confounding factors, we did not find any reason for the heterogeneity. Additionally, although there were differences in sample size between the studies included in the meta-analysis, the weighting of each study were also similar (PANSS-EC: 10.0%e16.6%, ACES: 13.7%e14.6%). Second, all studies included in this meta-analysis had short trial durations. Since olanzapine is reported to be associated with metabolic risk, including weight gain, diabetes, and hyperlipidemia (Leucht et al., 2013), we should consider any longterm risk despite the ultra-short duration of IM use. Third, there were only a few studies comparing OLA-IM versus ZIP-IM, OLA-IM versus HAL-IM plus midazolam, OLA-IM versus HAL-IM plus promethazine, OLA-IM versus LOR-IM, and OLA-IM versus HAL-IM plus LOR-IM. There were only two studies that were performed in the emergency setting (Mantovani et al., 2013; Raveendran et al., 2007). Raveendran et al. (Raveendran et al., 2007) reported that more patients receiving OLA-IM than HAL-IM plus promethazine required additional drugs over a 4 h period (RR ¼ 2.07). However, the current meta-analysis did not show a significant difference in the use of additional injections between either treatment group (RR ¼ 0.85) (Table 5). Since significant heterogeneity was detected in this meta-analysis, the limited sample size of the available studies suggests that more research is needed to evaluate both the efficacy and tolerability of these medications. A network metaanalysis involving indirect comparisons may also be helpful in discerning potential differences. In conclusions, OLA-IM is preferred over HAL-IM based on EPS issues. However, we lacked sufficient data to make any meaningful conclusions about ZIP-IM, LOR-IM and HAL-IM combination therapy. 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, TanabeMitsubishi, 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, Shionogi, Novartis, and Pfizer and a research grant from GlaxoSmithKline and Otsuka. Acknowledgments We thank Dr. Leonardo Baldaçara, Dr. Marsal Sanches, Dr. HungYu Chan, Dr. Ying-Sheue Chen, Eli Lilly and Company Limited for providing information necessary for the study. References Baldacara, L., Sanches, M., Cordeiro, D.C., Jackoswski, A.P., 2011. Rapid tranquilization for agitated patients in emergency psychiatric rooms: a randomized trial of olanzapine, ziprasidone, haloperidol plus promethazine, haloperidol plus midazolam and haloperidol alone. Rev. Bras. Psiquiatr. 33, 30e39. Belgamwar, R.B., Fenton, M., 2005. Olanzapine IM or velotab for acutely disturbed/ agitated people with suspected serious mental illnesses. Cochrane Database Syst. Rev. CD003729. Breier, A., Meehan, K., Birkett, M., David, S., Ferchland, I., Sutton, V., et al., 2002. 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