What are the similarities and differences between olanzapine and ziprasidone administered IM for acute agitation?

Comment by InpharmD Researcher

Available evidence for intramuscular (IM) olanzapine and IM ziprasidone shows comparable efficacy for acute agitation, especially in short-term management (within 2 hours of injection), with no significant difference demonstrated across multiple meta-analyses. Distinct side effect profiles have been shown for both agents, with headaches and hypotension being more commonly associated with ziprasidone and olanzapine, respectively. However, the lack of more robust comparisons limits the ability to draw firm conclusions on comparative efficacy.
Background

A 2021 systematic review and meta-analysis (N= 10 studies, 1,964 patients) compared the efficacy of short-acting intramuscular (IM) second generation antipsychotic drugs, haloperidol, and placebo in patients with schizophrenia and schizophrenia-like disorders presenting with acute agitation. The primary outcome was the number of responders at 2 hours after the first injection. Compared to placebo, ziprasidone was associated with greater response (risk ratio [RR] 2.51, 95% confidence interval [CI] 1.50 to 4.22). However, no significant differences were found when comparing ziprasidone with olanzapine, aripiprazole, and haloperidol. Olanzapine was more effective in reducing agitation at 2 hours compared to aripiprazole, but not when compared to haloperidol or ziprasidone. Limited data were available for the secondary outcome of the number of responders at 24 hours, with olanzapine being more effective than placebo (RR 1.83, 95% CI 1.37 to 2.46); no study reported data for ziprasidone at 24 hours. Ultimately, head-to-head comparisons between aripiprazole, olanzapine, and ziprasidone only demonstrated a significant difference between olanzapine and aripiprazole. No significant difference was observed between olanzapine and ziprasidone. [1]

A 2015 systematic review and meta-analysis (N= 13 randomized trials) compared IM olanzapine and ziprasidone, based on data available from 2 comparisons across 108 patients. The primary outcome for measuring efficacy was a reduction in either Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) or Agitation-Calmness Evaluation Scale (ACES) scores at 2 hours after the first injection. Ultimately, the number of available studies comparing ziprasidone and olanzapine was concluded to be too few to provide a comparison of efficacy. [2]

A 2007 meta-analysis compared the efficacy and safety of IM ziprasidone, olanzapine, and aripiprazole in treating agitation. Utilizing data from 9 double-blinded, randomized, controlled trials, the researchers calculated the number needed to treat (NNT) for response to treatment for agitation and number needed to harm (NNH) for extrapyramidal effects. Defined as response at 2 hours after the first injection, the NNT for response vs placebo at the recommended dose of ziprasidone 10-20 mg was 3 (95% CI 2 to 4), for olanzapine 10 mg was 3 (95% CI 2 to 3), and for aripiprazole 9.75 mg was 5 (95% CI 4 to 8). Compared to the placebo, significant treatment-emergent adverse events in the aripiprazole group were headache (NNH 20, 95% CI 11 to 170) and nausea (NNH 17, 95% CI 11 to 38), in the ziprasidone group was headache (NNH 15, 95% CI 8 to 703), and in the olanzapine group was hypotension (NNH 50, 95% CI 30 to 154). While olanzapine demonstrated a more favorable extrapyramidal side effect profile compared to haloperidol, there was a lack of haloperidol treatment arm in the ziprasidone studies. Regardless, head-to-head comparative trials directly evaluating the 3 agents remained lacking. [3]

Background References: [1] Paris G, Bighelli I, Deste G, et al. Short-acting intramuscular second-generation antipsychotic drugs for acutely agitated patients with schizophrenia spectrum disorders. A systematic review and network meta-analysis. Schizophr Res. 2021;229:3-11. doi:10.1016/j.schres.2021.01.021
[2] Kishi T, Matsunaga S, Iwata N. Intramuscular olanzapine for agitated patients: A systematic review and meta-analysis of randomized controlled trials. J Psychiatr Res. 2015;68:198-209. doi:10.1016/j.jpsychires.2015.07.005
[3] Citrome L. Comparison of intramuscular ziprasidone, olanzapine, or aripiprazole for agitation: a quantitative review of efficacy and safety. J Clin Psychiatry. 2007;68(12):1876-1885. doi:10.4088/jcp.v68n1207
Relevant Prescribing Information

GEODON [4]

GEODON intramuscular is indicated for the treatment of acute agitation in schizophrenic adult patients for whom treatment with ziprasidone is appropriate and who need intramuscular antipsychotic medication for rapid control of agitation.

CLINICAL STUDIES: Acute Treatment of Agitation in Schizophrenia
The efficacy of intramuscular ziprasidone in the management of agitated schizophrenic patients was established in two short-term, double-blind trials of schizophrenic subjects who were considered by the investigators to be "acutely agitated" and in need of IM antipsychotic medication. In addition, patients were required to have a score of 3 or more on at least 3 of the following items of the PANSS: anxiety, tension, hostility and excitement. Efficacy was evaluated by analysis of the area under the curve (AUC) of the Behavioural Activity Rating Scale (BARS) and Clinical Global Impression (CGI) severity rating. The BARS is a seven point scale with scores ranging from 1 (difficult or unable to rouse) to 7 (violent, requires restraint). Patients' scores on the BARS at baseline were mostly 5 (signs of overt activity [physical or verbal], calms down with instructions) and as determined by investigators, exhibited a degree of agitation that warranted intramuscular therapy. There were few patients with a rating higher than 5 on the BARS, as the most severely agitated patients were generally unable to provide informed consent for participation in premarketing clinical trials.

Both studies compared higher doses of ziprasidone intramuscular with a 2 mg control dose. In one study, the higher dose was 20 mg, which could be given up to 4 times in the 24 hours of the study, at interdose intervals of no less than 4 hours. In the other study, the higher dose was 10 mg, which could be given up to 4 times in the 24 hours of the study, at interdose intervals of no less than 2 hours.

The results of the intramuscular ziprasidone trials follow:
In a one-day, double-blind, randomized trial (n=79) involving doses of ziprasidone intramuscular of 20 mg or 2 mg, up to QID, ziprasidone intramuscular 20 mg was statistically superior to ziprasidone intramuscular 2 mg, as assessed by AUC of the BARS at 0 to 4 hours, and by CGI severity at 4 hours and study endpoint.
In another one-day, double-blind, randomized trial (n=117) involving doses of ziprasidone intramuscular of 10 mg or 2 mg, up to QID, ziprasidone intramuscular 10 mg was statistically superior to ziprasidone intramuscular 2 mg, as assessed by AUC of the BARS at 0 to 2 hours, but not by CGI severity.

ZYPREXA [5]

ZYPREXA IntraMuscular is indicated for the treatment of acute agitation associated with schizophrenia and bipolar I mania. Efficacy was demonstrated in 3 short-term (24 hours of IM treatment) placebo-controlled trials in agitated adult inpatients with: schizophrenia or bipolar I disorder (manic or mixed episodes).

Clinical Studies: Agitation Associated with Schizophrenia and Bipolar I Mania
The efficacy of intramuscular olanzapine for injection for the treatment of agitation was established in 3 short-term (24 hours of IM treatment) placebo-controlled trials in agitated adult inpatients from 2 diagnostic groups: schizophrenia and bipolar I disorder (manic or mixed episodes). Each of the trials included a single active comparator treatment arm of either haloperidol injection (schizophrenia studies) or lorazepam injection (bipolar I mania study). Patients enrolled in the trials needed to be: (1) judged by the clinical investigators as clinically agitated and clinically appropriate candidates for treatment with intramuscular medication, and (2) exhibiting a level of agitation that met or exceeded a threshold score of ≥14 on the 5 items comprising the Positive and Negative Syndrome Scale (PANSS) Excited Component (i.e., poor impulse control, tension, hostility, uncooperativeness and excitement items) with at least 1 individual item score ≥4 using a 1-7 scoring system (1=absent, 4=moderate, 7=extreme). In the studies, the mean baseline PANSS Excited Component score was 18.4, with scores ranging from 13 to 32 (out of a maximum score of 35), thus suggesting predominantly moderate levels of agitation with some patients experiencing mild or severe levels of agitation. The primary efficacy measure used for assessing agitation signs and symptoms in these trials was the change from baseline in the PANSS Excited Component at 2 hours post-injection. Patients could receive up to 3 injections during the 24 hour IM treatment periods; however, patients could not receive the second injection until after the initial 2 hour period when the primary efficacy measure was assessed. The results of the trials follow:

(1) In a placebo-controlled trial in agitated inpatients meeting DSM-IV criteria for schizophrenia (n=270), 4 fixed intramuscular olanzapine for injection doses of 2.5 mg, 5 mg, 7.5 mg and 10 mg were evaluated. All doses were statistically superior to placebo on the PANSS Excited Component at 2 hours post-injection. However, the effect was larger and more consistent for the 3 highest doses. There were no significant pairwise differences for the 7.5 and 10 mg doses over the 5 mg dose.

(2) In a second placebo-controlled trial in agitated inpatients meeting DSM-IV criteria for schizophrenia (n=311), 1 fixed intramuscular olanzapine for injection dose of 10 mg was evaluated. Olanzapine for injection was statistically superior to placebo on the PANSS Excited Component at 2 hours post-injection.

(3) In a placebo-controlled trial in agitated inpatients meeting DSM-IV criteria for bipolar I disorder (and currently displaying an acute manic or mixed episode with or without psychotic features) (n=201), 1 fixed intramuscular olanzapine for injection dose of 10 mg was evaluated. Olanzapine for injection was statistically superior to placebo on the PANSS Excited Component at 2 hours post-injection.

Relevant Prescribing Information References: [4] Ziprasidone mesylate injection (Geodon). Prescribing information. Roerig; 2022.
[5] Olanzapine injection (Zyprexa IntraMuscular). Prescribing information. Eli Lilly and Company; 2022.
Literature Review

A search of the published medical literature revealed 5 studies investigating the researchable question:

What are the similarities and differences between olanzapine and ziprasidone administered IM for acute agitation?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-5 for your response.

 

A naturalistic Evaluation of Intramuscular Ziprasidone Versus Intramuscular Olanzapine for the Management of Acute Agitation and Aggression in Children and Adolescents

Design

Retrospective chart review

N= 100

Objective

To compare the efficacy and safety of intramuscular (IM) ziprasidone versus IM olanzapine in treating agitation and aggression in pediatric patients

Study Groups

Olanzapine (n= 50)

Ziprasidone (n= 50)

Inclusion criteria

Age < 18 years, hospitalized with any mental illness, treated with either IM ziprasidone or olanzapine for agitation or aggression during their inpatient hospital stay

Exclusion criteria

Age > 18 years old, diagnosed with moderate or greater mental retardation, received both medications during their stay

Methods

This was a retrospective chart review through a state hospital's pharmacy computer program in Texas. Pediatric patient data was compared between those who received olanzapine versus ziprasidone.

Duration

January 2003 to January 2005

Outcome Measures

 Effectiveness for the episode of agitation/aggression, number of aggressive episodes experienced, received emergency medication for acute agitation/aggression

Baseline Characteristics

  

Olanzapine (n= 50)

Ziprasidone (n= 50)

  

Age, years

≤ 12 years old

13.7 ± 2.4

15 (30%)

14.6 ± 2.1

5 (10%)

  

Female

 16 (32%) 34 (68%)  

Total doses given

163

251

  

Mean study dose given, mg

Doses given in patients aged ≤ 12 years old, mg

Doses given in patients aged 13 to 18 years old, mg

8.19 ± 2.43

5.92 ± 2.18

9.17 ± 1.77

19.07 ± 2.63

15.66 ± 4.35

19.45 ± 2.13

  

Results

  

Olanzapine (n=50)

Ziprasidone (n=50)

P-value

Effectiveness for the episode of agitation/aggression

 90.2% 84.9% 0.733

Number of aggressive episodes

 9 ± 8 14 ± 15 0.497

Received emergency medication for acute agitation/aggression

 11 ± 9 21 ± 26 0.009

Adverse Events

There were no clinically significant adverse events related to the study medications reported in either treatment group.

Study Author Conclusions

Overall, the results of this study suggest that IM ziprasidone and IM olanzapine may be equally effective in treating agitation and aggression in children and adolescents. This study suggests that the IM forms of these medications are well tolerated in the child and adolescent population; however, the possibility of poor documentation of adverse drug events and side effects prevents any definitive conclusions regarding safety.

InpharmD Researcher Critique

This was a study focused on pediatric patients < the age of 18 years. Although there are many limitations to a retrospective study, they also provide "real-world" data. Minimal exclusion criteria were used for study entry, making the results generalizable to many populations treated with atypical antipsychotic IM agents. 

A formal objective aggression rating scale was not available in the existing charts, so retrospective outcome data regarding the management of agitation and aggression were collected from standardized intervention forms.

 

 

Table 1 References:
[6] Khan SS, Mican LM. A naturalistic evaluation of intramuscular ziprasidone versus intramuscular olanzapine for the management of acute agitation and aggression in children and adolescents. J Child Adolesc Psychopharmacol. 2006 Dec;16(6):671-7.

 

Rapid Tranquilization for Agitated Patients in Emergency Psychiatric Rooms: a Randomized Trial of Olanzapine, Ziprasidone, Zaloperidol plus Promethazine, Haloperidol plus Midazolam and Haloperidol Alone

Design

Double-blind, randomized, controlled trial 

N= 150

Objective

To compare the effectiveness of intramuscular olanzapine, ziprasidone, haloperidol plus promethazine, haloperidol plus midazolam and haloperidol alone as the first medication(s) used to treat patients with agitation and aggressive behavior

Study Groups

Olanzapine 10 mg (n=30)

Ziprasidone 20 mg (n=30)

Haloperidol 5 mg plus promethazine 50 mg (n=30)

Haloperidol 5 mg plus midazolam 15 mg (n=30)

Haloperidol 5 mg (n=30)

Inclusion Criteria

Age 18 and 50 years, signs of agitation, bipolar (maniac or mixed episode) or psychotic disorder diagnosis, Overt Agitation Severity Scale Total Score (OASS) equal or greater than 20, Overt Aggressive Scale (OAS) with four or more positive items

Exclusion Criteria

Disorders due to drug abuse, organic disorder, anxiety or personality disorder, failure to agree to participate in the study, incapability of completing all steps, unstable clinical disease

Methods

Patients admitted to the emergency department (ED) of a Brazilian hospital were screened for enrollment. Patients were randomized to receive either intramuscular administration of 10mg of olanzapine, 20mg of ziprasidone, 5 mg of haloperidol, 5mg of haloperidol plus 50mg of promethazine, or 5mg of haloperidol plus 15mg of midazolam. Patients were assessed at 1 hour, 2 hours, 4 hours, 6 hours, and 12 hours after administration of study medication using the OASS, OAS, and Ramsay Sedation Scale score (RSS). Adverse effects were assessed by spontaneous notification, open-ended inquiry, full physical examination, and measurement of vital signs at each visit. When a patient displayed agitation and/or aggressive behavior within 12 hours, additional medication was administered when a verbal approach failed. If the behavior was at high risk, mechanical restriction was performed. 

Duration

12 hours

Outcome Measures

 OAS and OASS at 1 hour, 2 hours, 4 hours, 6 hours, and 12 hours after first medication administration

Baseline Characteristics

  

Olanzapine

n=30

Ziprasidone

n=30

Haloperidol plus midazolam

n=30

Haloperidol plus promethazine

n=30

Haloperidol alone

n=30

  

Age, years

  30.37±9.01 33.13±6.26   32.00±7.18 34.57±9.31  31.13±5.17   

Female

 18, 60% 16, 53% 18, 60% 19, 63%  20, 67%  

Psychotic disorder

  18, 60%  20, 61% 16, 53%   17, 57%  17, 57%  

Bipolar disorder

  12, 40% 10, 33% 14. 47%  13, 43%  13, 43%   

Baseline OASS

  29.6±4.3  32.3±4.6 31.6±4.9  33.3±4.3  27.4±5.6   

Baseline OAS

  9.5±2.1  10.5±2.4  10.7±2.3  11.1±2.5 9.0±2.5   

Results

Endpoint

Olanzapine

n=30

Ziprasidone

n=30

Haloperidol plus midazolam

n=30

Haloperidol plus promethazine

n=30

Haloperidol alone

n=30

  p-Value

OASS

     Hour 1

     Hour 2

     Hour 4

     Hour 6

     Hour 12

 

2.9±0.9

2.1±1.2

1.2±0.5

1.2±0.4

0.5±0.2

 

12.6±4.3

10.2±6.8

5.8±2.0

5.0±2.0

4.1±1.0

 

13.4±3.4

13.0±1.6

6.9±2.7

5.1±2.4

4.5±1.9

 

29.4±7.6

15.7±2.4

5.2±1.4

4.0±1.3

2.2±0.7

 

4.9±2.1

6.3±1.4

1.4±0.5

1.4±0.1

1.4±0.1 

 

< 0.001

< 0.001

0.0009

0.001

0.001

OAS

     Hour 1

     Hour 2

     Hour 4

     Hour 6

     Hour 12

 

3.4±1.0

2.8±0.5

2.8±0.5

2.7±0.4

2.8±0.5

 

4.3±1.0

2.6±0.9

2.6±0.9

1.9±0.2 

2.4±0.3

 

5.5±2.9

5.7±4.4

3.0±1.6

2.2±0.2

4.5±1.9 

 

8.8±4.6

4.0±2.2

2.3±0.1

1.5±0.5

0.8±0.3 

 

4.3±1.9

3.3±2.5

2.9±0.3

2.6±0.6

2.6±0.2 

 

< 0.001

<0.001

0.857

0.064

< 0.001 
 The OASS mean total scores at the first hour were, in decreasing order, 14.6±3.4 for the haloperidol plus midazolam group, 13.0±5.3 for the haloperidol plus promethazine group, 12.6±4.3 for the ziprasidone group, 4.9±2.1 for the haloperidol alone group and 2.9± for the olanzapine group (p < 0.001).

Adverse Events

 

Common Adverse Events: Excessive sedation was the main side effect (70% of all side effects) and was highest in the haloperidol plus midazolam group (p < 0.001), extrapyramidal side effects were present only in the groups allocated to regimens with haloperidol (14%), hypotension occurred in the olazapine group (n=3%), ziprasidone group (20%), the haloperidol plus midazolam group (17%) and in the haloperidol plus promethazine group (n=10%)

Study Author Conclusions

 

Olanzapine, ziprasidone, haloperidol plus promethazine, haloperidol plus midazolam and haloperidol were effective in controlling agitation and aggression caused by mental illness over 12 hours. Although all the drugs had advantages and disadvantages, haloperidol plus midazolam was associated with the worst results in all the observed parameters.
 InpharmD Researcher Critique

The population studied was those presenting at a psychiatric emergency room, which is more likely to have psychiatric etiologies of agitation (see demographics) and may not be generalizable to all-comers to a general emergency department setting.  The authors did not offer detailed comparisons of olanzapine versus ziprasidone. 

 

 

Table 2 References:
[7] Baldaara L, Sanches M, Cordeiro DC, et al. Rapid tranquilization for agitated patients in emergency psychiatric rooms: a randomized trial of olanzapine, ziprasidone, haloperidol plus promethazine, haloperidol plus midazolam and haloperidol alone. Braz J Psychiatry. 2011;33(1):30-39. doi:10.1590/s1516-44462011000100008

 

Are Low Doses of Antipsychotics Effective in the Management of Psychomotor Agitation? A Randomized, Rated-Blind Trial of 4 Intramuscular Interventions

Design

Randomized, rated-blind design

N= 100

Objective

To compare the efficacy and safety of 4 low-dose pharmacological interventions used to control psychomotor agitation guided by the clinical response

Study Groups

haloperidol + promethazine (HLP + PMZ) (n= 27)

haloperidol + midazolam (HLP + MID) (n= 25)

ziprasidone (ZIP) (n= 23)

olanzapine (OLP) (n= 25)

Inclusion Criteria

Age 18 to 60 years, acute agitation state requiring medication for rapid tranquilization

Exclusion Criteria

Serious general medical conditions, established diagnosis of delirium, contraindication to study medication

Methods

Patients were randomized to one of four groups to receive intramuscular administration of either monotherapy or combined therapy. These groups consist of haloperidol 2.5 mg + promethazine 25 mg, haloperidol 2.5 mg + midazolam 7.5 mg, ziprasidone 10 mg, or olanzapine 10 mg. Drug administration could be repeated 30 minutes after initial administration as needed. Trained attending psychiatrists and psychiatry residents evaluated the patient's agitation at baseline and 30, 60, and 90 minutes after the initial injection. Agitation was measured using the Calming Agitation-Evaluating Scale (ACES) which is a single item scale of agitation from 1 (marked agitation) to 9 (unarousable) and the Positive and Negative Symptoms Scaled-Excited Component (PANSS-EC) which consists of 5 items with total scores from 0 to 35. 

Duration

24 hours

Outcome Measures

Primary: reduction of the levels of psychomotor agitation, measured by changes in the ACES and PANSS-EC scores 

Secondary: the occurrence of adverse effects in the following 24 hours, the need for supplemental doses

Baseline Characteristics

  

HLP + PMZ (n= 27)

HLP + MID (n= 25)

ZIP (n= 23)

OLP (n= 25)

  

Age, years

  31.8 ± 9.3  32.9 ± 10.5  29.0 ± 9.7 29.5 ± 10.2  

Female

 51.9%  56%  58.5% 48.0%   

Psychotic/manic

 70.4%   48.0%  47.8%  60.0%  

ACES

  1.4 ± 0.6  1.8 ± 0.7 1.7 ± 0.7   1.7 ± 0.6  

Results

Endpoint

HLP + PMZ (n= 27)

HLP + MID (n= 25)

ZIP (n= 23)

OLP (n= 25)

p-Value

PANSS-EC at Baseline

 25.7 ± 6.0 24.3 ± 5.6 26.4±6.4 24.4 ± 5.9 0.538

PANSS-EC at 30 min

 10.9 ± 6.7 8.7 ± 4.1 12.6 ± 9.1  10.1 ± 6.4 0.245 

PANSS-EC at 60 min

 11.1 ± 7.6 8.8 ± 6.1 10.5± 8.0  8.0 ± 3.8  0.300 

PANSS-EC at 90 min

 10.7 ± 6.7  9.4 ± 9.4  11.2 ± 8.3  9.2 ± 5.3  0.676 

Supplemental dose required

 18.5% 20% 34.5% 16% 0.444

 All treatments reduced agitation, as measured by ACES (p < 0.001) with a trend to differences between the treatment groups (p = 0.079), independent of the time since the intervention. Those randomized to HLP + PMZ (p = 0.035) and ZIP (p =0.043) had a lower reduction in agitation as measured by ACES than randomized to HLP + MID or OLP (p = 0.604).

Adverse Events

Common Adverse Events: The occurrence of at least 1 extrapyramidal symptom within 24 hours after drug intervention was observed in 74.1% of those treated with HLP + PMZ, 56.0% of those treated with the OLP, 52.2 % of those treated with ZIP, and 44.0% of those treated with HLP + MID.

Study Author Conclusions

Low doses of haloperidol combined with midazolam can be as effective as olanzapine in reducing psychomotor agitation without increasing the risk of extrapyramidal effects. Because of the higher risk for the occurrence of extrapyramidal symptoms, the combination of haloperidol with promethazine should be considered a second-line treatment option.

InpharmD Researcher Critique

This single-center study had relatively small numbers allocated to each group (23 to 27 patients in each group), however, it was powered to detect a difference of at least 2 points in ACES (20 patients required in each group were needed for their power calculation) which the authors identified as a clinically relevant change. The study was designed to evaluate low drug doses which may not be generalizable to other doses used in the clinical setting. 



Table 3 References:
[8] Mantovani C, Labate CM, Sponholz A Jr, et al. Are low doses of antipsychotics effective in the management of psychomotor agitation? A randomized, rated-blind trial of 4 intramuscular interventions. J Clin Psychopharmacol. 2013;33(3):306-312. doi:10.1097/JCP.0b013e3182900fd6

 

Intramuscular Midazolam, Olanzapine, Ziprasidone, or Haloperidol for Treating Acute Agitation in the Emergency Department

Design

Prospective observational study

N= 737

Objective

To identify which medication (intramuscular olanzapine, haloperidol, ziprasidone, and midazolam) achieved the most effective sedation after 15 minutes

Study Groups

Haloperidol 5 mg (n= 151)

Haloperidol 10 mg (n= 151)

Midazolam (n= 127)

Olanzapine (n= 163)

Ziprasidone (n= 145)

Inclusion Criteria

Received medication to treat acute agitation in the ED during the 15-week study period

Exclusion Criteria

Younger than 18 years, prisoners, or under arrest. If a patient received a different medication (other than the protocol medication), or a medication by a different route of delivery (intravenously instead of intramuscularly)

Methods

Medications were administered according to an a priori protocol in which the initial medication given was predetermined in the following 3-week blocks: haloperidol 5 mg, ziprasidone 20 mg, olanzapine 10 mg, midazolam 5 mg, and haloperidol 10 mg.

Duration

June 2017 to October 2017

Outcome Measures

The primary outcome in this study was the patient’s Altered Mental Status Scale score at 15 minutes after medication administration, evaluated as the proportion of patients adequately sedated (defined as Altered Mental Status Scale score < 1)

Secondary outcomes included the median difference in Altered Mental Status Scale score from baseline at 15 minutes, time to adequate sedation, and adverse events

Baseline Characteristics

  

Olanzapine (n= 163)

Ziprasidone (n= 145)

Midazolam (n= 127)

Haloperidol 5 mg (n= 151)

 Haloperidol 10 mg (n= 151)

Age, median (IQR), y

 45 (28–54) 40 (30–56) 40 (29–53) 40 (28–52) 38 (28–50)

Men, No. (%)

 113 (69) 109 (75) 97 (76) 101 (67) 107 (71)

Psychiatric illness as cause of agitation 

No. (%)

 19 (12) 15 (10) 22 (17) 14 (9) 13 (9)

Results

Endpoint

Olanzapine (n= 163)

Ziprasidone (n= 145)

Midazolam (n= 127)

 Haloperidol 5 mg (n= 151)

Haloperidol 10 mg (n= 151)

AMSS score, median (IQR), 15 min

 0 (–1 to 1) 0 (–1 to 1) –1 (–3 to 1) 1 (–1 to 2) 1 (–1 to 2)

Proportion adequately sedated, No. (%), 15 min

 99 (61) 76 (52) 89 (71) 61 (40) 64 (42)

Time to adequate sedation, median (IQR), min

 14 (10–28) 17 (13–30) 12 (9–22) 20 (15–32) 19 (13–31)

At 15 minutes, midazolam resulted in a greater proportion of patients adequately sedated (Altered Mental Status Scale < 1) compared with ziprasidone (difference 18%; 95% confidence interval [CI] 6% to 29%), haloperidol 5 mg (difference 30%; 95% CI 19% to 41%), haloperidol 10 mg (difference 28%; 95% CI 17% to 39%), and olanzapine (difference 9%; 95% CI –1% to 20%).

Olanzapine resulted in a greater proportion of patients adequately sedated at 15 minutes compared with haloperidol 5 mg (difference 20%; 95% CI 10% to 31%), haloperidol 10 mg (difference 18%; 95% CI 7% to 29%), and ziprasidone (difference 8%; 95% CI –3% to 19%).  

Adverse Events

Common Adverse Events: Extrapyramidal adverse effects (2; 0.3%), hypotension (5; 0.5%), hypoxemia (10; 1%), and intubation (4; 0.5%). Events occurred at similar rates in each group.

Serious Adverse Events: N/A

Percentage that Discontinued due to Adverse Events: N/A

Study Author Conclusions

Intramuscular midazolam achieved more effective sedation in agitated ED patients at 15 minutes than haloperidol, ziprasidone, and perhaps olanzapine. Olanzapine provided more effective sedation than haloperidol. No differences in adverse events were identified.

InpharmD Researcher Critique

This study represents the first prospective comparative efficacy investigation of intramuscular olanzapine to treat acute agitation in the ED. It appears olanzapine may be more effective than haloperidol in this population. There were no significant differences between second-generation antipsychotics, olanzapine and ziprasidone. 

 

 

Table 4 References:
[9] Klein LR, Driver BE, Miner JR, et al. Intramuscular Midazolam, Olanzapine, Ziprasidone, or Haloperidol for Treating Acute Agitation in the Emergency Department. Ann Emerg Med. 2018;72(4):374-385. doi:10.1016/j.annemergmed.2018.04.027

 

Evaluation of Intramuscular Olanzapine and Ziprasidone in the Medically Ill

Design

Retrospective review

N= 100

Objective

 To characterize the use of intramuscular (IM) olanzapine and ziprasidone in the medically ill at an academic medical center

Study Groups

Olanzapine (n= 26)

Ziprasidone (n= 74)

Inclusion Criteria

 Age ≥ 18 years, admitted to a non-psychiatric unit, received parenteral short-acting olanzapine or ziprasidone

Exclusion Criteria

Received IM olanzapine or ziprasidone only in the emergency department (ED), upon transfer to a psychiatric unit, prisoners, or pregnant women

Methods

Patient data from charts with documented parenteral olanzapine or ziprasidone in non-psychiatric units were collected for analysis. None of the patients received intravenous (IV) doses, therefore IM was the only analyzed route of administration. Effectiveness was analyzed on the Richmond Agitation-Sedation Scale (RASS) (range: +4 [combative] to -5 [unarousable]) with improvements defined as a reduction in a positive score to 0 or -1 within 1 hour of drug administration.

Duration

 Enrollment period: August 1, 2015 to July 31, 2017

Outcome Measures

Primary: Indication for the use of IM olanzapine or ziprasidone

Secondary: Safety, efficacy, and prescribing patterns

Baseline Characteristics

  

All patients (N= 100)

  

Age, years

 56 ± 17.5  

Male

 70%  

White

African-American

62%

36%

  

Median baseline QTc on admission, msec

462

  

Comorbid severe mental illness

17%

  

History of substance abuse

35%

  

History of dementia

13%

  

Received IM ziprasidone

Received IM olanzapine

74%

26%

  

Total dose in 24 hours, mg (range)

Olanzapine

Ziprasidone

 

6.3 (2.5 to 20)

20 (20 to 40)

  

Total cumulative dose received, mg (range)

Olanzapine

Ziprasidone

 

8.8 (2.5 to 60)

20 (10 to 210)

  

Duration of use, days (median)

Olanzapine

Ziprasidone

 

1 to 4 (1)

1 to 17 (1)

  

Received parenteral first-generation antipsychotic prior to IM second-generation antipsychotic

40%

  

Received IM second-generation antipsychotic in the intensive care unit (ICU)

64%

  

Results

Endpoint

All patients (N= 100)

 

Indication

On-label

Off-label

Psychiatric disorder

Agitation

Delirium

Dementia-related agitation

Other

Unknown

 

5%

95%

8%

40%

33%

4%

11%

4%

  
  Olanzapine (n= 26) Ziprasidone (n= 74)

Received use when contraindicated

 7 (26.9%) 7 (9.5%)

Received use beyond the studied duration

 6 (23.08%) 10 (13.51%)

Study Author Conclusions

 This study characterizes the indications and clinical safety data of IM olanzapine and ziprasidone in the medically ill. IM SGAs are currently being used more often in the medically ill for delirium and agitation. Our findings confirm these were the most common indications for IM SGA use. This study also adds to the limited safety data of IM SGAs for these off-label indications.

InpharmD Researcher Critique

The primary purpose of this study was to characterize the patient population that received the parenteral injection of olanzapine and ziprasidone rather than a direct comparison. This was the primary investigation due to the author's belief that the literature comparing these two agents is limited.

Based on the description of the patients who received treatment, not all may be classified as having acute agitation. Forty percent had agitation from the nonpsychotic origin, for example, and patients were only enrolled if they were admitted to a non-psychiatric unit (administration in the ED was also excluded). 



Table 5 References:
[10] Patel SM, Crouse EL, Levenson JL. Evaluation of intramuscular olanzapine and ziprasidone in the medically ill. Ment Health Clin. 2021;11(1):6-11. Published 2021 Jan 8. doi:10.9740/mhc.2021.01.006