Comparison of Intramuscular Olanzapine, Orally

Comparison of Intramuscular Olanzapine, OrallyDisintegrating Olanzapine Tablets, Oral Risperidone

Solution, and Intramuscular Haloperidol in theManagement of Acute Agitation in an Acute

Care Psychiatric Ward in TaiwanWen-Yu Hsu, MD,*Þ Si-Sheng Huang, MD,*Þþ Bo-Shyan Lee, MD,*Þ and Nan-Ying Chiu, MD*Þ§

Introduction: The purpose of this study was to compare efficacyand safety among intramuscular olanzapine, intramuscular haloperidol,orally disintegrating olanzapine tablets, and oral risperidone solution foragitated patients with psychosis during the first 24 hours of treatmentin an acute care psychiatric ward.Methods: Forty-two inpatients from an acute care psychiatric ward ofa medical center in central Taiwan were enrolled. They were randomlyassigned to 1 of the 4 treatment groups (10-mg intramuscular olanza-pine, 10-mg olanzapine oral disintegrating tablet, 3-mg oral risperidonesolution, or 7.5-mg intramuscular haloperidol). Agitation was measuredby using the excited component of the Positive and Negative Syn-drome Scale (PANSS-EC), the Agitation-Calmness Evaluation Scale,and the Clinical Global ImpressionVSeverity Scale during the first24 hours.Results: There were significant differences in the PANSS-EC totalscores for the 4 intervention groups at 15, 30, 45, 60, 75, and 90 min-utes after the initiation of treatment. More significant differences werefound early in the treatment. In the post hoc analysis, the patients whoreceived intramuscular olanzapine or orally disintegrating olanzapinetablets showed significantly greater improvement in PANSS-EC scoresthan did patients who received intramuscular haloperidol at points 15,30, 45, 60, 75, and 90 minutes after injection.Conclusions: These findings suggest that intramuscular olanzapine,orally disintegrating olanzapine tablets, and oral risperidone solution areas effective treatments as intramuscular haloperidol for patients withacute agitation. Intramuscular olanzapine and disintegrating olanzapinetablets are more effective than intramuscular haloperidol in the earlyphase of the intervention. There is no significant difference in effec-tiveness among intramuscular olanzapine, orally disintegrating olanza-pine tablets, and oral risperidone solution.

Key Words: olanzapine, haloperidol, risperidone, agitation,injection, orally

(J Clin Psychopharmacol 2010;30: 230Y234)

V iolence and aggressive behavior are common amongpatients with psychiatric disorders. Grassi et al1 reported a

7.5% prevalence rate for violence in acute psychiatric inpatientsin Italy. Violence is a complex behavioral phenomenon withmany causes.2

There are many ways to manage violent situations. Environ-mental intervention, behavior therapy, talking down, and medi-cation intervention may all be effective. Rapid tranquilization isthe assertive use of medication to calm severely agitated patientsquickly, decrease dangerous behavior, and allow treatment ofthe underlying condition.3 In the past, conventional antipsychoticagents augmented with benzodiazepines have been the stan-dard treatment;4,5 however, there are now many other choices.Haloperidol, a high-potency butyrophenone, is one of the mostfrequently used first-generation antipsychotic agents for thetreatment of acute agitation6; however, extrapyramidal symp-toms are a concern after haloperidol treatment. Several kinds ofsecond-generation antipsychotic agents have been used to man-age agitation and violence.7Y9

Olanzapine and risperidone are second-generation anti-psychotic agents, and they both have more than 1 route of de-livery. Lambert et al10 reported that intramuscular olanzapine(olanzapine IM) was effective in managing the agitation ofpsychosis. A naturalistic, open-label study showed that anolanzapine-treated group made statistically significant improve-ment over a group that received conventional treatment.11 Villariet al8 reported that risperidone, olanzapine, and quetiapine werefound to be as effective as haloperidol and better tolerated.Hatta et al12 stated that orally disintegrating olanzapine tablets(olanzapine ODT) and oral risperidone solution (risperidoneOS) produced similar improvements in acutely agitated patients.

The main purpose of this study was to compare efficacyand safety between first- and second-generation antipsychoticagents and between different methods of medication delivery.

METHODSThis was a prospective, randomized, rater-blinded study

comparing olanzapine IM, olanzapine ODT, risperidone OS, andintramuscular haloperidol (haloperidol IM) in an acute carepsychiatric unit for the first 24 hours after admission.

The study was conducted from January 2007 to January2008 in the acute care psychiatric ward of Changhua ChristianHospital. The study protocol was approved by the institutionalreview board, and all the subjects in this study provided in-formed consents. There was no commercial funding for thisstudy.

The study subjects were male and female patients in theacute care psychiatric ward who were 18 to 65 years old; had a

ORIGINAL CONTRIBUTION

230 www.psychopharmacology.com Journal of Clinical Psychopharmacology & Volume 30, Number 3, June 2010

From the *Department of Psychiatry, Lu-Tung Branch of Changhua ChristianHospital, Lukang; †Department of Psychiatry, Changhua Christian Hospital,Changhua; ‡Center of General Education, Central Taiwan University ofScience and Technology, Taichung; and §Department of Respiratory Care,Chang Jung Christian University, Tainan, Taiwan.Received September 16, 2009; accepted after revision March 1, 2010.Reprints: Nan-Ying Chiu, MD, Department of Psychiatry, Lu Tung Branch

of Changhua Christian Hospital, No. 888, Sec. 2, Lu Tung Rd, Lukang,Changhua 505, Taiwan (e-mail: [email protected]).

Copyright * 2010 by Lippincott Williams & WilkinsISSN: 0271-0749DOI: 10.1097/JCP.0b013e3181db8715

Copyright @ 20 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.10

Diagnostic and Statistical Manual, Fourth Edition, Text Revision,diagnosis of schizophrenia, bipolar I disorder, schizoaffectivedisorder, delusional disorder, or other psychotic disorders; andhad an excited component score of 14 or higher on the Positiveand Negative Syndrome Scale (PANSS-EC), with a score of 4 orhigher on at least 1 item (1- to 7-point scale). Pregnant or lactat-ing women; patients with serious medical illnesses; patients withclosed-angle glaucoma; patients with an allergic reaction to olan-zapine, risperidone, or haloperidol; or patients who had receiveda long-acting antipsychotic agent injection within 30 days wereexcluded. Patients were randomly assigned to receive 1 of 4interventions over a 24-hour period. The assigned process wasperformed by random ballot of the 4 interventions. The 4 groupswere 10-mg olanzapine IM, 10-mg olanzapine ODT, 3-mg ris-peridone OS, and 7.5-mg haloperidol IM.

To evaluate agitation, the excited component of thePANSS-EC (tension, uncooperativeness, hostility, poor impulsecontrol, and excitement) and the Agitation-Calmness EvaluationScale (ACES) were completed at 15, 30, 45, 60, 75, 90, 105, and120 minutes and 12 and 24 hours after the first intervention.The patients were also assessed with the Clinical GlobalImpressionVSeverity (CGI-S) Scale at baseline and 2, 12, and24 hours after receiving medications. Possible adverse effectswere recorded by subjective report and objective observationduring the 24 hours. The raters were blind to the treatmentgroup, and all had received rater training twice before thestudy. Rating was performed by senior nurses who have joined arater training before the study. A total of 42 patients completedthe study.

Statistical analyses were performed using the software sys-tem SPSS PC 10.0 (SPSS Inc, Chicago, Ill). Categorical datawere analyzed using the W2 test. Continuous data were analyzedusing the independent t test and repeated measures analysis ofvariance (ANOVA).

RESULTS

Demographic DataThe 42 patients were randomly assigned to receive 10-mg

olanzapine IM (n = 11), 10-mg olanzapine ODT (n = 10), 3-mgrisperidone oral solution (n = 10), or 7.5-mg haloperidol IM(n = 11). For the total patient group, the mean T SD age was37.33 T 11.61 years. At the time of entry into the study,

the patients had a total PANSS-EC score (mean T SD) of25.90 T 3.80, an ACES score of 1.62 T 0.58, and a CGI-S Scalescore of 5.10 T 0.98. The patients had a Diagnostic andStatistical Manual, Fourth Edition, Text Revision, diagnosis ofschizophrenia (n = 20), bipolar I disorder (n = 18), schizoaffec-tive disorder (n = 1), or other psychotic disorders (n = 3).Table 1lists the demographic data for all the patients in these 4 groups.

Positive and Negative Syndrome ScaleFigure 1 presents the course of change in the PANSS-EC

score from baseline to end point in the 4 groups. We found that

TABLE 1. Subjects’ Demographic Data

10-mgOlanzapine IM

(n = 11)

10-mgOlanzapine ODT

(n = 10)

3-mgRisperidone Solution

(n = 10)

7.5-mgHaloperidol IM

(n = 11) P

Age, mean T SD (range), y 37.55 T 11.69 (22Y56) 40.9 T 11.34 (26Y56) 34.6 T 11.85 (22Y62) 36.36 T 12.35 (22Y60) 0.68Sex, male/female 6/5 6/4 3/7 5/6 0.55Psychiatric diagnosisSchizophrenia 3 3 9 5Bipolar I disorder 6 5 1 6Schizoaffective disorder 1 0 0 0Others 1 2 0 0

Baseline PANSS-EC score,mean T SD

25.55 T 3.8 24.7 T 5.01 25.00 T 2.58 28.18 T 2.82 0.13

Baseline ACES score,mean T SD

1.36 T 0.50 1.60 T 0.70 2.00 T 0.47 1.55 T 0.52 0.08

Baseline CGI-S Scale score,mean T SD

4.91 T 0.54 5.20 T 1.32 5.10 T 0.74 5.18 T 1.25 0.91

FIGURE 1. Change in PANSS-EC score within 24 hours. To testfor the effects of treatment on PANSS-EC score, 10 time points’repeated-measures ANOVA was used in the 4 groups.

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there were significant differences in the PANSS-EC scoresbetween the 4 interventions at points 15, 30, 45, 60, 75, and90 minutes after injection. We found that a more significantdifference occurred in the earlier period after intervention. Thepatients who received olanzapine IM or olanzapine ODT hadsignificantly greater improvement in PANSS-EC scores thanthe patients who received haloperidol IM at points 15, 30, 45,60, 75, and 90 minutes after initiation of the treatment. However,there were no significant differences between olanzapine IMand risperidone OS, olanzapine ODT and risperidone OS, ris-peridone OS and haloperidol IM, or olanzapine IM and olan-zapine ODT at these points. After 90 minutes, we found nosignificant differences among the 4 groups. Table 2 shows thesedifferences at each point in time.

Agitation-Calmness Evaluation ScaleThe changes in ACES score in the 4 groups are shown

in Figure 2. There were no differences in the mean ACESscore changes among the groups at 15, 30, 45, 60, 75, 90, 105,120 minutes and 12 and 24 hours after the first treatment.

Clinical Global ImpressionVSeverity ScaleThe changes in the CGI-S Scale score in the 4 groups are

shown in Figure 3. No differences in the mean CGI-S Scalescores were found from baseline to 24 hours.

Adverse EffectsThe most commonly reported and observed adverse effects

related to medications were found in all the 4 groups. Drowsi-ness was most common. Olanzapine IM and olanzapine ODT

TABLE 2. Change in PANSS-EC Score From Baseline

OverallP

Comparison (Mean Difference T SE)

Olz IM vsOlz ODT

Olz IM vsRis OS

Olz IM vsHal IM

Olz ODT vsRis OS

Olz ODT vsHal IM

Ris OS vsHal IM

15 min 0.004 1.49 T 1.62 j0.76 T 1.62 j4.55 T 1.58 j2.25 T 1.66 j6.04 T 1.62 j3.79 T 1.6230 min 0.004 1.18 T 1.66 j1.09 T 1.66 j5.00 T 1.62 j2.27 T 1.70 j6.18 T 1.66 j3.91 T 1.6645 min 0.008 0.94 T 1.68 j0.96 T 1.68 j4.77 T 1.64 j1.90 T 1.71 j5.71 T 1.68 j3.81 T 1.6860 min 0.010 0.81 T 1.62 j1.05 T 1.62 j4.55 T 1.58 j1.86 T 1.65 j5.36 T 1.62 j3.50 T 1.6275 min 0.016 0.52 T 1.56 j1.06 T 1.56 j4.26 T 1.52 j1.58 T 1.59 j4.78 T 1.56 j3.20 T 1.5690 min 0.026 0.17 T 1.54 j1.10 T 1.54 j4.12 T 1.50 j1.27 T 1.57 j4.28 T 1.54 j3.01 T 1.54105 min 0.046 j0.22 T 1.50 j1.20 T 1.50 j3.88 T 1.46 j0.99 T 1.53 j3.66 T 1.50 j2.67 T 1.50120 min 0.089 j0.50 T 1.51 j1.15 T 1.51 j3.60 T 1.47 j0.66 T 1.54 j3.10 T 1.51 j2.44 T 1.5112 h 0.161 j0.63 T 1.38 j0.82 T 1.38 j2.96 T 1.35 j0.19 T 1.41 j2.33 T 1.38 j2.14 T 1.3824 h 0.157 j0.84 T 1.34 j1.06 T 1.34 j2.97 T 1.31 j0.22 T 1.37 j2.12 T 1.34 j1.91 T 1.34

P G 0.05 was regarded as statistically significant. Overall P was analyzed by repeated measures ANOVA. Overall P values in italics are statisticallysignificant. The comparison between the 4 groups tested was done using post hoc analysis. The P values in italics are less than 0.05.

Hal IM indicates haloperidol intramuscular; Olz IM, olanzapine intramuscular; Olz ODT, olanzapine orally disintegrating tablet; Ris OS, risperidoneoral solution.

FIGURE 2. Change in ACES Scale score within 24 hours. hal IMindicates haloperidol intramuscular; olz IM, olanzapineintramuscular; olz ODT, olanzapine orally disintegrating tablet;ris OS, risperidone oral solution. FIGURE 3. Change in CGI-S Scale score within 24 hours.

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produced more drowsiness than oral risperidone and haloper-idol IM, but the difference was not significant.

DISCUSSIONThe choices for the management of agitation in a psy-

chiatric ward are multiple and include behavioral intervention,pharmacological intervention, environmental intervention, andemotional management. Pharmacological interventions includebenzodiazepines and antipsychotic agents.3

Olanzapine and risperidone are both second-generationantipsychotic agents. In our study, olanzapine IM and olanza-pine ODT produced greater improvement in the PANSS-ECscores than did haloperidol IM within 90 minutes after thetreatment. There was no significant difference after 90 minutesamong the 4 groups. Wright et al reported that significant dif-ferences between olanzapine IM and haloperidol IM were ob-served at 15, 30, and 45 minutes after the first injection.13 Thisfinding is supported by our results. Olanzapine is more effectivethan haloperidol in the early phase after the intervention.

Olanzapine, a dopamine/serotonin antagonist in the thieno-benzodiazepine class, is available in tablet, oral disintegratingtablet, and intramuscular injection forms.

Castle et al7 reported that olanzapine IM provided some-what more effective control of acute agitation than did otherassessed IM antipsychotic agents. Wright et al13 reported thatolanzapine IM represented a rapid, effective, and safe treatmentof acute agitation in schizophrenia. Villari et al8 reported thatoral olanzapine was as effective as oral haloperidol and bettertolerated. A naturalistic, open-label study demonstrated that20-mg oral olanzapine was effective, rapid, and safe in patientswith severe agitation.11 The evidence from the previous studiessupported the observation that olanzapine is effective in themanagement of agitation with different ways of delivery. To thebest of our knowledge, no previous study has compared olan-zapine IM and olanzapine ODT.

Options in the pharmacotherapy for acute agitation includeparenteral administration of antipsychotic agents to facilitate theonset of drug action and quickly alleviate symptoms. We foundthat olanzapine ODT produced a better response in PANSS-ECscores than did olanzapine IM within 60 minutes after the treat-ment; however, the difference was not statistically significant.Intramuscular injectable antipsychotic agents offer advantagesover the traditional oral tablets in the emergency treatment ofschizophrenia in its acute phase. However, situations occurwherein patients have difficulty swallowing traditional oral tab-lets, patients may spit out liquid medications, or an injectableformulation is contraindicated or unacceptable.14 Intramus-cular injection is also a more aggressive treatment than oralmedication. Intramuscular injection might result in difficulty inmaintaining a therapeutic relationship. The orally disintegratingformulation has been developed as an alternative to improvemedication compliance. Olanzapine ODT dissolves rapidly oncontact with saliva in the mouth and has a more rapid onset ofaction.15,16 Olanzapine ODT could solve the problem of poorcooperation by agitated patients because it is easy to handleand convenient to use. From an economic perspective, olanza-pine ODT is cheaper than olanzapine IM and haloperidol inTaiwan. Olanzapine ODT might therefore be another choice inthe management of acute agitation.

No difference in extrapyramidal symptoms was foundamong the 4 groups in our study. Extrapyramidal symptoms dooccur after emergency intervention and might result in poor ad-herence to the same medication or cause problems in the rela-tionship between patient and physician. Avoiding medications

that easily lead to extrapyramidal symptoms is important forlater treatment. Second-generation antipsychotic agents may be abetter choice in this regard.

Our study had some limitations. First, our sample sizewas small. Second, we had no placebo group. Third, we didnot assess interrater reliability. In the future, well-designed, ran-domized, controlled studies with adequate subjects are neededto provide more evidence to support a preference for thesemedications.

CONCLUSIONSThese findings suggest that olanzapine IM, olanzapine

ODT, and risperidone OS are as effective as haloperidol IM inthe treatment of acute agitation. There were no significant dif-ferences between olanzapine IM, olanzapine ODT, and risper-idone OS. Olanzapine IM and ODT were more effective in theearly phase after intervention than haloperidol IM. OlanzapineODT was effective, convenient, and well tolerated in rapidlyreducing acute agitation. It offers clinicians a therapeuticalternative.

ACKNOWLEDGMENTSThe authors thank Mr Yi-Shin Lin and Mrs Yu-Jiun Chang

for assisting in the statistical analyses.

AUTHOR DISCLOSURE INFORMATIONThe authors have nothing to disclose.

REFERENCES

1. Grassi L, Peron L, Marangoni C, et al. Characteristics of violentbehaviour in acute psychiatric in-patients: a 5-year Italian study.Acta Psychiatr Scand. 2001;104:273Y279.

2. Lindenmayer JP. The pathophysiology of agitation. J Clin Psychiatry.2000;61(suppl 14):5Y10.

3. Battaglia J. Pharmacological management of acute agitation. Drugs.2005;65:1207Y1222.

4. Battaglia J, Moss S, Rush J, et al. Haloperidol, lorazepam, or bothfor psychotic agitation? A multicenter, prospective, double-blind,emergency department study. Am J Emerg Med. 1997;15:335Y340.

5. Salzman C, Green AI, Rodriguez-Villa F, et al. Benzodiazepinescombined with neuroleptics for management of severe disruptivebehavior. Psychosomatics. 1986;27:17Y22.

6. Buckley PF. The role of typical and atypical antipsychotic medicationsin the management of agitation and aggression. J Clin Psychiatry.1999;60(suppl 10):52Y60.

7. Castle DJ, Udristoiu T, Kim CY, et al. Intramuscular olanzapineversus short-acting typical intramuscular antipsychotics: comparisonof real-life effectiveness in the treatment of agitation. World J BiolPsychiatry. 2009;10:43Y53.

8. Villari V, Rocca P, Fonzo V, et al. Oral risperidone, olanzapine andquetiapine versus haloperidol in psychotic agitation. ProgNeuropsychopharmacol Biol Psychiatry. 2008;32:405Y413.

9. Kinon BJ, Stauffer VL, Kollack-Walker S, et al. Olanzapineversus aripiprazole for the treatment of agitation in acutely illpatients with schizophrenia. J Clin Psychopharmacol. 2008;28:601Y607.

10. Lambert M, Huber CG, Naber D, et al. Treatment of severe agitationwith olanzapine in 166 patients with schizophrenia, schizoaffective,or bipolar I disorder. Pharmacopsychiatry. 2008;41:182Y189.

Journal of Clinical Psychopharmacology & Volume 30, Number 3, June 2010 Comparison of Medications for Acute Agitation

* 2010 Lippincott Williams & Wilkins www.psychopharmacology.com 233


11. Pascual JC, Perez V, Martin JL, et al. Olanzapine orally-disintegratingtablet in severe psychotic agitation: a naturalistic study. Actas EspPsiquiatr. 2007;35:47Y51.

12. Hatta K, Kawabata T, Yoshida K, et al. Olanzapine orallydisintegrating tablet vs. risperidone oral solution in the treatmentof acutely agitated psychotic patients. Gen Hosp Psychiatry.2008;30:367Y371.

13. Wright P, Birkett M, David SR, et al. Double-blind,placebo-controlled comparison of intramuscular olanzapine andintramuscular haloperidol in the treatment of acute agitation inschizophrenia. Am J Psychiatry. 2001;158:1149Y1151.

14. Chue P, Jones B, Taylor CC, et al. Dissolution profile, tolerability,and acceptability of the orally disintegrating olanzapine tablet inpatients with schizophrenia. Can J Psychiatry. 2002;47:771Y774.

15. Reeves RR, Torres RA. Onset of action of orally disintegratingolanzapine versus conventional olanzapine. South Med J.2004;97:212.

16. Markowitz JS, DeVane CL, Malcolm RJ, et al. Pharmacokineticsof olanzapine after single-dose oral administration of standardtablet versus normal and sublingual administration of an orallydisintegrating tablet in normal volunteers. J Clin Pharmacol.2006;46:164Y171.

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Comparison of Intramuscular Olanzapine, Orally