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Benefits of a Second Dose of Intramuscular (IM) Aripiprazole to Control Agitation in Patients With
Schizophrenia or Bipolar I Disorder
Leslie Citrome, MD, MPH1; Estelle Vester-Blokland, MD2; Donald Archibald, M Phil3; Robert McQuade, PhD4; Dusan Kostic, PhD5; Andre Pikalov, MD6, PhD; Dan Oren, MD3
1Nathan S Kline Institute for Psychiatric Research, Orangeburg, NY, USA; 2Bristol-Myers Squibb, Plainsboro, NJ, USA; 3Bristol-Myers Squibb, USA, Wallingford, CT, USA; 4Otsuka America Pharmaceutical, Inc., Princeton, NJ, USA;
5Bristol-Myers Squibb, Lawrenceville, NJ, USA; 6Otsuka America Pharmaceutical, Inc., Rockville, MD, USA

ABSTRACT INTRODUCTION (continued) RESULTS RESULTS

Objective: Assess efficacy of IM aripiprazole vs placebo in Another important goal is to consider a medication that treats the Table 1 The percentage of patients receiving a second injection in the
Figure 3
patients with schizophrenia or Bipolar I Disorder (requiring a underlying condition1 without producing significant side effects3 Schizophrenia Trial: Mean PEC and CGI-I Scores schizophrenia trial were: aripiprazole, 41%; haloperidol, 34%;
Prior to Each Injection Mean CGI-I Score for Schizophrenia Patients
second IM injection to control agitation). placebo, 57% (Figure 1)
For patients who do not respond adequately to initial IM treatment Following a 2nd IM Injection
Aripiprazole Haloperidol Percentages in the Bipolar I Disorder trial were: aripiprazole, 35%;
Methods: Agitation was defined as having a baseline PANSS with an atypical antipsychotic, it has been recommended to
Schizophrenia Trial 10 mg 6.5 mg Placebo 4 Aripiprazole 10 mg lorazepam, 35%; placebo, 64% (Figure 1)
Excited Component (PEC) score of 15-32. Schizophrenia administer a second injection at the same dose level1
Measure N Mean N Mean N Mean 3.5 Haloperidol 6.5 mg In the schizophrenia trial, mean changes in PEC scores from pre-
study: 448 agitated patients (18-69 years) were randomized to Other alternatives include administering a dose of lorazepam, PEC Baseline Prior to 71 19.2 62 19.1 50 19.3 3
Placebo second injection to 2 hours post-second injection were significantly

CGI-I Mean Score

receive injections of aripiprazole (10 mg), haloperidol (6.5 mg), administering a second injection at a higher dose level, or 1st Injection * * reduced by aripiprazole 10 mg (-5.9) vs placebo (-2.2, P≤0.01)
2.5
or placebo. Bipolar I Disorder study: 301 agitated patients administering a combination of antipsychotic plus lorazepam, PEC Prior to 2nd Injection 70 17.2 62 16.9 50 18.9 (Figure 2)
2 – Mean CGI-I scores were significantly improved for aripiprazole
(18-79 y) were randomized to receive injections of aripiprazole depending on the atypical antipsychotic prescribed1 CGI-I Prior to 2nd Injection 70 3.7 61 3.7 50 4.2
1.5 10 mg vs placebo (P≤0.01) (Figure 3)
(10 mg or 15 mg), lorazepam (2 mg), or placebo. Patients A single administration of IM aripiprazole (10 mg) has been shown In the Bipolar I Disorder trial, mean changes in PEC scores from pre-
received ≤3 injections within 24 hours. PEC and Clinical Global to be safe and effective at decreasing acute agitation rapidly in
Table 2 1
Bipolar Disorder Trial: Mean PEC and CGI-I Scores second injection to 2 hours post-second injection were significantly
Impression-Improvement (CGI-I) scores were assessed in all patients with schizophrenia4 or Bipolar I Disorder5 Prior to Each Injection
0.5
reduced by aripiprazole 10 mg or 15 mg (-7.7 and -6.0, respectively)
patients for whom a second injection was deemed appropriate. In both aripiprazole trials, patients who did not respond optimally to
0 vs placebo (-3.1, P≤0.05) (Figure 4)
Aripiprazole Aripiprazole Lorazepam
Mean change from baseline comparisons were analyzed using the initial IM injection (i.e., within 2 hours), were administered a Bipolar I Disorder Trial 10 mg 15 mg 2 mg Placebo – Mean CGI-I scores were significantly improved for aripiprazole
* P<0.01 compared to placebo.
an ANCOVA model controlling for treatment and baseline second IM injection4,5 10 mg or 15 mg vs placebo (P≤0.05) (Figure 5)
Measure N Mean N Mean N Mean N Mean
value. PEC Baseline Prior to
Both haloperidol 6.5 mg and lorazepam 2 mg significantly reduced
This poster presents data from patients in 2 IM aripiprazole pivotal PEC scores and improved CGI-I scores from pre-second injection to
Results: The percentage of patients receiving a second trials (schizophrenia, Bipolar I Disorder) who received a second IM 1st Injection 30 18.9 23 18.6 24 18.5 46 17.6 Figure 4
2 hours post-second injection in the schizophrenia and Bipolar I
PEC Prior to Mean Change in PEC Score for Bipolar I Disorder Patients
injection were: ([schizophrenia trial: aripiprazole, 41%; injection of study treatment at the same dose level Disorder trials respectively (P≤0.01 for all) (Figures 2-5)
2nd Injection 30 16.9 23 16.1 24 15.0 46 16.4 Following a 2nd IM Injection
haloperidol, 34%; placebo, 57%] [Bipolar I Disorder trial: CGI-I Prior to
aripiprazole, 35%; lorazepam, 35%; placebo, 64%]). In the OBJECTIVE 2nd Injection 30 3.7 23 4.1 24 3.7 46 3.9 0 Aripiprazole 10 mg
schizophrenia study, mean changes in PEC scores from pre- -1 Aripiprazole 15 mg
CONCLUSIONS
Lorazepam 2 mg
second injection to 2 hours post-second injection were To evaluate the efficacy of IM aripiprazole at decreasing agitation Figure 1 -2

PEC Mean Change

Percent of Patients Receiving a 2nd Injection Placebo
significantly reduced by aripiprazole 10 mg (-5.9) vs placebo in patients with schizophrenia or Bipolar I Disorder who received a -3 For patients with schizophrenia or Bipolar I Disorder who did not
Schizophrenia Bipolar I Disorder respond adequately within 2 hours of an initial IM aripiprazole
(-2.2, P≤0.01). In the Bipolar I Disorder study, mean changes second injection -4
100
in PEC scores were significantly reduced by aripiprazole 90
Aripiprazole -5 dose, a second IM aripiprazole injection at the same dose level
Haloperidol
10 mg or 15 mg (-7.7 and -6.0, respectively) vs placebo (-3.1, METHODS 80 Placebo
-6 was effective at decreasing acute agitation (PEC) and improving
†
P≤0.05). In the schizophrenia study, mean CGI-I scores were 70 -7 the overall clinical presentation (CGI-I)

Percent (%)
significantly improved for aripiprazole 10 mg vs placebo Data were examined from two randomized, double-blind, placebo- 60 Aripiprazole
-8 *
50 Lorazepam * Across trials, the need for second injection was similar for
(P≤0.01). In the Bipolar I Disorder study, mean CGI-I scores controlled IM aripiprazole clinical trials 40 Placebo -9
30
patients treated with aripiprazole and those treated with either
were significantly improved for aripiprazole 10 mg or 15 mg vs In the first trial, 448 acutely agitated patients (18-69 years) 20
* P<0.01 compared to placebo.
† P<0.05 compared to placebo. haloperidol or lorazepam
placebo (P≤0.05). Both haloperidol 6.5 mg and lorazepam diagnosed with schizophrenia received either IM aripiprazole 10
2 mg significantly reduced PEC scores and improved CGI-I in (10 mg), IM haloperidol (6.5 mg), or IM placebo 0 Use of multiple injections of IM aripiprazole as clinically
Patients Receiving a 2nd Injection Figure 5
appropriate appears to be an effective and safe method for
all studies (P≤0.01). In the second trial, 301 acutely agitated patients (18-79 years) Mean Change in PEC Score for Bipolar I Disorder Patients
diagnosed with Bipolar I Disorder received either IM aripiprazole treating acutely agitated patients with schizophrenia or Bipolar I
Conclusions: Aripiprazole efficaciously reduced agitation and Following a 2nd IM Injection
(10 mg or 15 mg), IM lorazepam (2 mg), or IM placebo Figure 2 Disorder
improved overall outcome in patients with schizophrenia or Mean Change in PEC Score for Schizophrenia Patients 3.5 Aripiprazole 10 mg
Bipolar I Disorder requiring a second injection. In both trials, acute agitation was defined as having a baseline Following a 2nd IM Injection
0 Aripiprazole 10 mg 3
Aripiprazole 15 mg REFERENCES
PANSS Excited Component (PEC) score of 15-32 † Lorazepam 2 mg

CGI-I Mean Change

-1 Haloperidol 6.5 mg
2.5 Placebo 1. Allen MH, Currier GW, Carpenter D, Ross RW, Docherty JP. The expert consensus guidelines series:
Patients received an initial injection following trial entry Placebo * treatment of behavioral emergencies 2005. Journal of Psychiatric Practice. 2005; 11(S1):1-112.

PEC Mean Change

-2
Those who did not respond adequately within two hours received a 2 * 2. National Institute for Health and Clinical Excellence (NICE). Clinical guideline I: schizophrenia: core
INTRODUCTION -3
second injection at the same dose level; all patients received ≤3 -4
1.5 interventions in the treatment and management of schizophrenia in primary and secondary care. London:
National Institute for Health and Clinical Excellence; December, 2002
Use of an IM atypical antipsychotic to treat acute agitation has injections within 24 hours -5
1 3. Citrome L. Atypical Antipsychotics for Acute Agitation: New Intramuscular Options Offer Advantages.
been included among the first-line treatment choices listed in PEC and Clinical Global Impression-Improvement (CGI-I) scores -6 0.5
Postgraduate Medicine. 2002;112(6):85-96.
4. Yocca F, Marcus R, Oren D, Manos G, Carson W, Iwamoto T, Stock E. Intramuscular aripiprazole in
current guidelines for the treatment of behavioral emergencies1 were assessed in all patients for whom a second injection was -7
* 0 acute schizophrenia: a pivotal phase III study. Poster presented at the American Psychiatric Association
deemed appropriate *
Experts have agreed that the goal of proper treatment is to -8
* P<0.01 compared to placebo.
conference, 2005.
5. Oren D, Iwamoto T, Marcus R, Vanveggel S, McQuade R, Stock E, Yocca F. Intramuscular aripiprazole
reduce agitation rapidly by calming the patient without Mean change from baseline comparisons were analyzed using an * P<0.01 compared to placebo. † P<0.05 compared to placebo.
vs placebo for agitation in acute mania. Poster presented at the American Psychiatric Association
producing excessive sedation1,2 ANCOVA model controlling for treatment and baseline value conference, 2005.

Supported by funding from Bristol-Myers Squibb and Otsuka Pharmaceutical Co., Ltd. American Psychiatric Association 159th Annual Meeting, Toronto, Canada, May 20-25, 2006