IM aripiprazole for acute agitation

In recent clinical trials, a new intramuscular (IM) form of the second-generation antipsychotic (SGA) aripiprazole has controlled agitation in adults with schizophrenia or bipolar mania without causing significant side effects (Table 1).^1-3

Table 1

IM aripiprazole: Fast facts

Clinical implications

Rapid intervention is critical to protecting the patient and caregivers when violent and/or destructive behavior accompanies agitation. IM aripiprazole substantially reduced agitation within 45 to 60 minutes of dosing in randomized, double-blind, placebo-controlled studies.^1-3

How it works

Whereas other SGAs have relatively little effect on D₂ (dopamine) receptors and relatively high 5-HT_2A (serotonin) receptor affinities, aripiprazole appears to work via partial D₂ receptor agonism. The medication:

• blocks D₂ receptors in brain regions where dopamine is overactive in schizophrenia, such as the mesolimbic pathway. This produces an antipsychotic effect.
• maintains or moderately boosts dopamine activity as needed in regions such as the nigrostriatal pathway. This reduces the risk of motor side effects and might improve negative and cognitive schizophrenia symptoms.

Aripiprazole is a partial 5-HT_1A receptor agonist and—like other SGAs—a 5-HT_2A receptor antagonist. These receptor subtypes have been implicated in antipsychotic action. In particular, partial 5-HT_1A receptor agonism is thought to help:

• reduce anxiety
• lessen depressive, negative, and cognitive symptoms
• decrease extrapyramidal symptom (EPS) liability.⁴

Aripiprazole also has moderate affinity for histaminic and alpha-adrenergic receptors and no appreciable effect on cholinergic muscarinic receptors.^5-8

Pharmacokinetics

IM aripiprazole’s activity has been attributed to its parent drug and to a lesser extent its major metabolite, dehydroaripiprazole. Both moieties act on D₂ receptors, and dehydroaripiprazole accounts for 40% of the parent drug’s exposure in plasma.

Mean elimination half-lives for aripiprazole and dehydroaripiprazole are approximately 75 and 94 hours, respectively, allowing for daily administration. Both active moieties reach steady-state concentration within 14 days of dosing. Because aripiprazole accumulation is predictable after a single dose and its pharmacokinetics are dose-proportional at steady state, higher doses are not always more effective and could increase side-effect risk.

Aripiprazole is metabolized mainly through the liver by cytochrome P-450 2D6 and 3A4 isozymes. This requires careful monitoring when prescribing the drug concomitantly with:

• agents that induce CYP 3A4—such as carbamazepine—which could diminish aripiprazole’s effectiveness by increasing its clearance and decreasing aripiprazole blood levels
• CYP 3A4 inhibitors such as ketoconazole or CYP 2D6 inhibitors such as quinidine, fluoxetine, or paroxetine, which can inhibit aripiprazole elimination⁹ and increase the risk of adverse events.

Similarly, aripiprazole could be efficacious at lower-than-therapeutic dosages when taken with medications that raise aripiprazole blood levels.

Efficacy

In 3 randomized, placebo-controlled, double-blind trials, IM aripiprazole reduced agitation in inpatients with schizophrenia, schizoaffective disorder, or type I bipolar disorder with manic or mixed episodes, with or without psychotic features.

In each trial, IM aripiprazole was as effective as comparable dosages of haloperidol or lorazepam IM preparations. Patients were moderately to severely agitated based on Positive and Negative Syndrome Scale Excited Component (PANSS-EC) assessments, which gauged impulse control, tension, hostility, uncooperativeness, and excitement.

Patients could receive up to 3 injections within 24 hours but had to wait ≥2 hours for the second injection so that investigators could record follow-up PANSS-EC scores. Clinical Global Impression of Improvement (CGI-I) scale scores were a key secondary measure.

Examination of population subsets in the studies showed no differential response based on age, race, or gender.

Tran-Johnson et al¹followed 357 patients with schizophreniform disorders, schizophrenia, or schizoaffective disorders.

Two hours after initial injection, mean PANSS-EC scores decreased approximately 3 points with placebo and 4 to 6.5 points among patients receiving 7.5 mg of IM haloperidol or 5.25, 9.75, or 15 mg of IM aripiprazole. Agitation improved significantly after 45 minutes among patients receiving 9.75 mg of IM aripiprazole, compared with 105 minutes in the IM haloperidol group.

Prevalence of EPS across 24 hours with haloperidol was 19.3%, compared with an average 5.2% among all IM aripiprazole groups, suggesting that IM aripiprazole carries a substantially lower EPS risk.

Andrezina et al²followed 448 patients with schizophrenia or schizoaffective disorder. Two hours after injection, patients in both treatment groups showed much greater improvement compared with placebo based on mean PANSS-EC score decreases and mean CGI-I scores (Table 2).

Prevalence of EPS was 1.7% with IM aripiprazole, 2.3% with placebo, and 12.6% with IM haloperidol. Prevalence of EPS-related adverse events was 0% with IM aripiprazole, 1.6% with placebo, and 16.5% with IM haloperidol.

Zimbroff et al³ gave IM aripiprazole, 9.75 or 15 mg; IM lorazepam, 2 mg; or placebo to 301 patients with type I bipolar disorder with manic or mixed episodes.

Two hours later, all 3 treatment groups showed significantly greater agitation improvement as shown by PANSS-EC scores, compared with placebo (Table 3).

Across 2 hours, oversedation—defined as an Agitation-Calmness Evaluation Scale score of 8 or 9—was less prevalent among patients receiving IM aripiprazole, 9.75 mg (6.7%), compared with IM aripiprazole, 15 mg (17.3%), or IM lorazepam (19.1%).

Table 2

Agitation, symptom improvement 2 hours after aripiprazole or haloperidol injection

Table 3

Agitation improvement 2 hours after aripiprazole or lorazepam injection

Safety and tolerability

IM aripiprazole was well tolerated in clinical trials and did not cause excessive sedation¹⁰ or injection-site pain.^1-3

Most frequently reported adverse events were headache (12% with IM aripiprazole vs 7% with placebo), nausea (9% vs 3%), dizziness (8% vs 5%), and somnolence (7% vs 4%).

Prevalence of akathisia or dystonia among all IM aripiprazole groups in the 3 trials was 2% and

No clinically significant ECG abnormalities were reported among the aripiprazole groups.^1-3,11

Dosing

Start at 9.75 mg every 2 hours as needed, but do not exceed 30 mg/d across 24 hours. Controlled studies have not evaluated efficacy or safety of more-frequent injections or safety of total daily doses >30 mg.

Try a lower dose (5.25 mg) for patients who are elderly or small in body size or have reacted adversely to other antipsychotics. If necessary, give another 5.25 mg in 2 hours. If the patient is still agitated 2 hours after the second dose, consider a third dose at 9.75 mg. Again, do not exceed 30 mg over 24 hours. Obtain lower doses by administering a portion of the vial.

Transitioning to oral Tx

If IM aripiprazole reduces psychotic symptoms as well as acute behaviors, switch the patient to oral aripiprazole once the risk of violence has diminished.¹² If psychosis does not improve with IM aripiprazole, weigh clinical factors before choosing an oral antipsychotic.

Only one controlled trial¹² has examined transitioning from IM aripiprazole to an oral antipsychotic. In the randomized study, 448 patients receiving IM aripiprazole, 9.75 mg; IM haloperidol, 6.5 mg; or placebo for agitation secondary to schizophrenia or schizoaffective disorder were transitioned to the oral preparation of the drug they were receiving: aripiprazole, 10 to 15 mg/d, or haloperidol, 7.5 to 10 mg/d. Placebo-group patients transitioned to oral aripiprazole.

Over 4 days, both oral treatments provided continued efficacy, suggesting that:

• patients receiving IM aripiprazole can be conveniently switched to the oral preparation
• IM and oral aripiprazole are equally safe.

Oral and IM aripiprazole doses are equivalent and the pharmacokinetics are comparable. For example, a patient receiving 20 mg/d of IM aripiprazole can take 20 mg of oral aripiprazole within 24 hours of the last injection.

Related resources

• Allen MH, Currier GW, Carpenter D, et al. Expert consensus guidelines: treatment of behavioral emergencies. J Psychiatr Pract 2005;11(suppl 1):5-108.
• Currier GW, Citrome LL, Zimbroff DL, et al. Intramuscular aripiprazole in the control of agitation. J Psychiatr Pract 2007;13:159-69.

Drug brand names

• Aripiprazole IM • Abilify
• Carbamazepine • Tegretol, others
• Fluoxetine • Prozac
• Haloperidol • Haldol
• Ketoconazole • Nizoral
• Lorazepam • Ativan
• Paroxetine • Paxil
• Quinidine • Quinaglute

Disclosure

Dr. Josiassen was principal investigator and Dr. Shaughnessy a co-investigator on a pre-approval clinical trial of IM aripiprazole. Both have conducted sponsor- and investigator-initiated studies for AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, Janssen, Novartis Pharmaceuticals Corp., Organon, Otsuka America Pharmaceuticals, Otsuka Maryland Research Institute, Pfizer, and Yamanuchi.

Acknowledgments

This article was supported in part by the Arthur P. Noyes Research Foundation.

The authors thank Margit Kacso, Cara Bendler, Dawn Filmyer, and Jon Weinstein for their technical and editorial assistance in preparing this article.

In recent clinical trials, a new intramuscular (IM) form of the second-generation antipsychotic (SGA) aripiprazole has controlled agitation in adults with schizophrenia or bipolar mania without causing significant side effects (Table 1).^1-3

Table 1

IM aripiprazole: Fast facts

Clinical implications

Rapid intervention is critical to protecting the patient and caregivers when violent and/or destructive behavior accompanies agitation. IM aripiprazole substantially reduced agitation within 45 to 60 minutes of dosing in randomized, double-blind, placebo-controlled studies.^1-3

How it works

Whereas other SGAs have relatively little effect on D₂ (dopamine) receptors and relatively high 5-HT_2A (serotonin) receptor affinities, aripiprazole appears to work via partial D₂ receptor agonism. The medication:

• blocks D₂ receptors in brain regions where dopamine is overactive in schizophrenia, such as the mesolimbic pathway. This produces an antipsychotic effect.
• maintains or moderately boosts dopamine activity as needed in regions such as the nigrostriatal pathway. This reduces the risk of motor side effects and might improve negative and cognitive schizophrenia symptoms.

Aripiprazole is a partial 5-HT_1A receptor agonist and—like other SGAs—a 5-HT_2A receptor antagonist. These receptor subtypes have been implicated in antipsychotic action. In particular, partial 5-HT_1A receptor agonism is thought to help:

• reduce anxiety
• lessen depressive, negative, and cognitive symptoms
• decrease extrapyramidal symptom (EPS) liability.⁴

Aripiprazole also has moderate affinity for histaminic and alpha-adrenergic receptors and no appreciable effect on cholinergic muscarinic receptors.^5-8

Pharmacokinetics

IM aripiprazole’s activity has been attributed to its parent drug and to a lesser extent its major metabolite, dehydroaripiprazole. Both moieties act on D₂ receptors, and dehydroaripiprazole accounts for 40% of the parent drug’s exposure in plasma.

Mean elimination half-lives for aripiprazole and dehydroaripiprazole are approximately 75 and 94 hours, respectively, allowing for daily administration. Both active moieties reach steady-state concentration within 14 days of dosing. Because aripiprazole accumulation is predictable after a single dose and its pharmacokinetics are dose-proportional at steady state, higher doses are not always more effective and could increase side-effect risk.

Aripiprazole is metabolized mainly through the liver by cytochrome P-450 2D6 and 3A4 isozymes. This requires careful monitoring when prescribing the drug concomitantly with:

• agents that induce CYP 3A4—such as carbamazepine—which could diminish aripiprazole’s effectiveness by increasing its clearance and decreasing aripiprazole blood levels
• CYP 3A4 inhibitors such as ketoconazole or CYP 2D6 inhibitors such as quinidine, fluoxetine, or paroxetine, which can inhibit aripiprazole elimination⁹ and increase the risk of adverse events.

Similarly, aripiprazole could be efficacious at lower-than-therapeutic dosages when taken with medications that raise aripiprazole blood levels.

Efficacy

In 3 randomized, placebo-controlled, double-blind trials, IM aripiprazole reduced agitation in inpatients with schizophrenia, schizoaffective disorder, or type I bipolar disorder with manic or mixed episodes, with or without psychotic features.

In each trial, IM aripiprazole was as effective as comparable dosages of haloperidol or lorazepam IM preparations. Patients were moderately to severely agitated based on Positive and Negative Syndrome Scale Excited Component (PANSS-EC) assessments, which gauged impulse control, tension, hostility, uncooperativeness, and excitement.

Patients could receive up to 3 injections within 24 hours but had to wait ≥2 hours for the second injection so that investigators could record follow-up PANSS-EC scores. Clinical Global Impression of Improvement (CGI-I) scale scores were a key secondary measure.

Examination of population subsets in the studies showed no differential response based on age, race, or gender.

Tran-Johnson et al¹followed 357 patients with schizophreniform disorders, schizophrenia, or schizoaffective disorders.

Two hours after initial injection, mean PANSS-EC scores decreased approximately 3 points with placebo and 4 to 6.5 points among patients receiving 7.5 mg of IM haloperidol or 5.25, 9.75, or 15 mg of IM aripiprazole. Agitation improved significantly after 45 minutes among patients receiving 9.75 mg of IM aripiprazole, compared with 105 minutes in the IM haloperidol group.

Prevalence of EPS across 24 hours with haloperidol was 19.3%, compared with an average 5.2% among all IM aripiprazole groups, suggesting that IM aripiprazole carries a substantially lower EPS risk.

Andrezina et al²followed 448 patients with schizophrenia or schizoaffective disorder. Two hours after injection, patients in both treatment groups showed much greater improvement compared with placebo based on mean PANSS-EC score decreases and mean CGI-I scores (Table 2).

Prevalence of EPS was 1.7% with IM aripiprazole, 2.3% with placebo, and 12.6% with IM haloperidol. Prevalence of EPS-related adverse events was 0% with IM aripiprazole, 1.6% with placebo, and 16.5% with IM haloperidol.

Zimbroff et al³ gave IM aripiprazole, 9.75 or 15 mg; IM lorazepam, 2 mg; or placebo to 301 patients with type I bipolar disorder with manic or mixed episodes.

Two hours later, all 3 treatment groups showed significantly greater agitation improvement as shown by PANSS-EC scores, compared with placebo (Table 3).

Across 2 hours, oversedation—defined as an Agitation-Calmness Evaluation Scale score of 8 or 9—was less prevalent among patients receiving IM aripiprazole, 9.75 mg (6.7%), compared with IM aripiprazole, 15 mg (17.3%), or IM lorazepam (19.1%).

Table 2

Agitation, symptom improvement 2 hours after aripiprazole or haloperidol injection

Table 3

Agitation improvement 2 hours after aripiprazole or lorazepam injection

Safety and tolerability

IM aripiprazole was well tolerated in clinical trials and did not cause excessive sedation¹⁰ or injection-site pain.^1-3

Most frequently reported adverse events were headache (12% with IM aripiprazole vs 7% with placebo), nausea (9% vs 3%), dizziness (8% vs 5%), and somnolence (7% vs 4%).

Prevalence of akathisia or dystonia among all IM aripiprazole groups in the 3 trials was 2% and

No clinically significant ECG abnormalities were reported among the aripiprazole groups.^1-3,11

Dosing

Start at 9.75 mg every 2 hours as needed, but do not exceed 30 mg/d across 24 hours. Controlled studies have not evaluated efficacy or safety of more-frequent injections or safety of total daily doses >30 mg.

Try a lower dose (5.25 mg) for patients who are elderly or small in body size or have reacted adversely to other antipsychotics. If necessary, give another 5.25 mg in 2 hours. If the patient is still agitated 2 hours after the second dose, consider a third dose at 9.75 mg. Again, do not exceed 30 mg over 24 hours. Obtain lower doses by administering a portion of the vial.

Transitioning to oral Tx

If IM aripiprazole reduces psychotic symptoms as well as acute behaviors, switch the patient to oral aripiprazole once the risk of violence has diminished.¹² If psychosis does not improve with IM aripiprazole, weigh clinical factors before choosing an oral antipsychotic.

Only one controlled trial¹² has examined transitioning from IM aripiprazole to an oral antipsychotic. In the randomized study, 448 patients receiving IM aripiprazole, 9.75 mg; IM haloperidol, 6.5 mg; or placebo for agitation secondary to schizophrenia or schizoaffective disorder were transitioned to the oral preparation of the drug they were receiving: aripiprazole, 10 to 15 mg/d, or haloperidol, 7.5 to 10 mg/d. Placebo-group patients transitioned to oral aripiprazole.

Over 4 days, both oral treatments provided continued efficacy, suggesting that:

• patients receiving IM aripiprazole can be conveniently switched to the oral preparation
• IM and oral aripiprazole are equally safe.

Oral and IM aripiprazole doses are equivalent and the pharmacokinetics are comparable. For example, a patient receiving 20 mg/d of IM aripiprazole can take 20 mg of oral aripiprazole within 24 hours of the last injection.

Related resources

• Allen MH, Currier GW, Carpenter D, et al. Expert consensus guidelines: treatment of behavioral emergencies. J Psychiatr Pract 2005;11(suppl 1):5-108.
• Currier GW, Citrome LL, Zimbroff DL, et al. Intramuscular aripiprazole in the control of agitation. J Psychiatr Pract 2007;13:159-69.

Drug brand names

• Aripiprazole IM • Abilify
• Carbamazepine • Tegretol, others
• Fluoxetine • Prozac
• Haloperidol • Haldol
• Ketoconazole • Nizoral
• Lorazepam • Ativan
• Paroxetine • Paxil
• Quinidine • Quinaglute

Disclosure

Dr. Josiassen was principal investigator and Dr. Shaughnessy a co-investigator on a pre-approval clinical trial of IM aripiprazole. Both have conducted sponsor- and investigator-initiated studies for AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, Janssen, Novartis Pharmaceuticals Corp., Organon, Otsuka America Pharmaceuticals, Otsuka Maryland Research Institute, Pfizer, and Yamanuchi.

Acknowledgments

This article was supported in part by the Arthur P. Noyes Research Foundation.

The authors thank Margit Kacso, Cara Bendler, Dawn Filmyer, and Jon Weinstein for their technical and editorial assistance in preparing this article.

In recent clinical trials, a new intramuscular (IM) form of the second-generation antipsychotic (SGA) aripiprazole has controlled agitation in adults with schizophrenia or bipolar mania without causing significant side effects (Table 1).^1-3

Table 1

IM aripiprazole: Fast facts

Clinical implications

Rapid intervention is critical to protecting the patient and caregivers when violent and/or destructive behavior accompanies agitation. IM aripiprazole substantially reduced agitation within 45 to 60 minutes of dosing in randomized, double-blind, placebo-controlled studies.^1-3

How it works

Whereas other SGAs have relatively little effect on D₂ (dopamine) receptors and relatively high 5-HT_2A (serotonin) receptor affinities, aripiprazole appears to work via partial D₂ receptor agonism. The medication:

• blocks D₂ receptors in brain regions where dopamine is overactive in schizophrenia, such as the mesolimbic pathway. This produces an antipsychotic effect.
• maintains or moderately boosts dopamine activity as needed in regions such as the nigrostriatal pathway. This reduces the risk of motor side effects and might improve negative and cognitive schizophrenia symptoms.

Aripiprazole is a partial 5-HT_1A receptor agonist and—like other SGAs—a 5-HT_2A receptor antagonist. These receptor subtypes have been implicated in antipsychotic action. In particular, partial 5-HT_1A receptor agonism is thought to help:

• reduce anxiety
• lessen depressive, negative, and cognitive symptoms
• decrease extrapyramidal symptom (EPS) liability.⁴

Aripiprazole also has moderate affinity for histaminic and alpha-adrenergic receptors and no appreciable effect on cholinergic muscarinic receptors.^5-8

Pharmacokinetics

IM aripiprazole’s activity has been attributed to its parent drug and to a lesser extent its major metabolite, dehydroaripiprazole. Both moieties act on D₂ receptors, and dehydroaripiprazole accounts for 40% of the parent drug’s exposure in plasma.

Mean elimination half-lives for aripiprazole and dehydroaripiprazole are approximately 75 and 94 hours, respectively, allowing for daily administration. Both active moieties reach steady-state concentration within 14 days of dosing. Because aripiprazole accumulation is predictable after a single dose and its pharmacokinetics are dose-proportional at steady state, higher doses are not always more effective and could increase side-effect risk.

Aripiprazole is metabolized mainly through the liver by cytochrome P-450 2D6 and 3A4 isozymes. This requires careful monitoring when prescribing the drug concomitantly with:

• agents that induce CYP 3A4—such as carbamazepine—which could diminish aripiprazole’s effectiveness by increasing its clearance and decreasing aripiprazole blood levels
• CYP 3A4 inhibitors such as ketoconazole or CYP 2D6 inhibitors such as quinidine, fluoxetine, or paroxetine, which can inhibit aripiprazole elimination⁹ and increase the risk of adverse events.

Similarly, aripiprazole could be efficacious at lower-than-therapeutic dosages when taken with medications that raise aripiprazole blood levels.

Efficacy

In 3 randomized, placebo-controlled, double-blind trials, IM aripiprazole reduced agitation in inpatients with schizophrenia, schizoaffective disorder, or type I bipolar disorder with manic or mixed episodes, with or without psychotic features.

In each trial, IM aripiprazole was as effective as comparable dosages of haloperidol or lorazepam IM preparations. Patients were moderately to severely agitated based on Positive and Negative Syndrome Scale Excited Component (PANSS-EC) assessments, which gauged impulse control, tension, hostility, uncooperativeness, and excitement.

Patients could receive up to 3 injections within 24 hours but had to wait ≥2 hours for the second injection so that investigators could record follow-up PANSS-EC scores. Clinical Global Impression of Improvement (CGI-I) scale scores were a key secondary measure.

Examination of population subsets in the studies showed no differential response based on age, race, or gender.

Tran-Johnson et al¹followed 357 patients with schizophreniform disorders, schizophrenia, or schizoaffective disorders.

Two hours after initial injection, mean PANSS-EC scores decreased approximately 3 points with placebo and 4 to 6.5 points among patients receiving 7.5 mg of IM haloperidol or 5.25, 9.75, or 15 mg of IM aripiprazole. Agitation improved significantly after 45 minutes among patients receiving 9.75 mg of IM aripiprazole, compared with 105 minutes in the IM haloperidol group.

Prevalence of EPS across 24 hours with haloperidol was 19.3%, compared with an average 5.2% among all IM aripiprazole groups, suggesting that IM aripiprazole carries a substantially lower EPS risk.

Andrezina et al²followed 448 patients with schizophrenia or schizoaffective disorder. Two hours after injection, patients in both treatment groups showed much greater improvement compared with placebo based on mean PANSS-EC score decreases and mean CGI-I scores (Table 2).

Prevalence of EPS was 1.7% with IM aripiprazole, 2.3% with placebo, and 12.6% with IM haloperidol. Prevalence of EPS-related adverse events was 0% with IM aripiprazole, 1.6% with placebo, and 16.5% with IM haloperidol.

Zimbroff et al³ gave IM aripiprazole, 9.75 or 15 mg; IM lorazepam, 2 mg; or placebo to 301 patients with type I bipolar disorder with manic or mixed episodes.

Two hours later, all 3 treatment groups showed significantly greater agitation improvement as shown by PANSS-EC scores, compared with placebo (Table 3).

Across 2 hours, oversedation—defined as an Agitation-Calmness Evaluation Scale score of 8 or 9—was less prevalent among patients receiving IM aripiprazole, 9.75 mg (6.7%), compared with IM aripiprazole, 15 mg (17.3%), or IM lorazepam (19.1%).

Table 2

Agitation, symptom improvement 2 hours after aripiprazole or haloperidol injection

Table 3

Agitation improvement 2 hours after aripiprazole or lorazepam injection

Safety and tolerability

IM aripiprazole was well tolerated in clinical trials and did not cause excessive sedation¹⁰ or injection-site pain.^1-3

Most frequently reported adverse events were headache (12% with IM aripiprazole vs 7% with placebo), nausea (9% vs 3%), dizziness (8% vs 5%), and somnolence (7% vs 4%).

Prevalence of akathisia or dystonia among all IM aripiprazole groups in the 3 trials was 2% and

No clinically significant ECG abnormalities were reported among the aripiprazole groups.^1-3,11

Dosing

Start at 9.75 mg every 2 hours as needed, but do not exceed 30 mg/d across 24 hours. Controlled studies have not evaluated efficacy or safety of more-frequent injections or safety of total daily doses >30 mg.

Try a lower dose (5.25 mg) for patients who are elderly or small in body size or have reacted adversely to other antipsychotics. If necessary, give another 5.25 mg in 2 hours. If the patient is still agitated 2 hours after the second dose, consider a third dose at 9.75 mg. Again, do not exceed 30 mg over 24 hours. Obtain lower doses by administering a portion of the vial.

Transitioning to oral Tx

If IM aripiprazole reduces psychotic symptoms as well as acute behaviors, switch the patient to oral aripiprazole once the risk of violence has diminished.¹² If psychosis does not improve with IM aripiprazole, weigh clinical factors before choosing an oral antipsychotic.

Only one controlled trial¹² has examined transitioning from IM aripiprazole to an oral antipsychotic. In the randomized study, 448 patients receiving IM aripiprazole, 9.75 mg; IM haloperidol, 6.5 mg; or placebo for agitation secondary to schizophrenia or schizoaffective disorder were transitioned to the oral preparation of the drug they were receiving: aripiprazole, 10 to 15 mg/d, or haloperidol, 7.5 to 10 mg/d. Placebo-group patients transitioned to oral aripiprazole.

Over 4 days, both oral treatments provided continued efficacy, suggesting that:

• patients receiving IM aripiprazole can be conveniently switched to the oral preparation
• IM and oral aripiprazole are equally safe.

Oral and IM aripiprazole doses are equivalent and the pharmacokinetics are comparable. For example, a patient receiving 20 mg/d of IM aripiprazole can take 20 mg of oral aripiprazole within 24 hours of the last injection.

Related resources

• Allen MH, Currier GW, Carpenter D, et al. Expert consensus guidelines: treatment of behavioral emergencies. J Psychiatr Pract 2005;11(suppl 1):5-108.
• Currier GW, Citrome LL, Zimbroff DL, et al. Intramuscular aripiprazole in the control of agitation. J Psychiatr Pract 2007;13:159-69.

Drug brand names

• Aripiprazole IM • Abilify
• Carbamazepine • Tegretol, others
• Fluoxetine • Prozac
• Haloperidol • Haldol
• Ketoconazole • Nizoral
• Lorazepam • Ativan
• Paroxetine • Paxil
• Quinidine • Quinaglute

Disclosure

Dr. Josiassen was principal investigator and Dr. Shaughnessy a co-investigator on a pre-approval clinical trial of IM aripiprazole. Both have conducted sponsor- and investigator-initiated studies for AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, Janssen, Novartis Pharmaceuticals Corp., Organon, Otsuka America Pharmaceuticals, Otsuka Maryland Research Institute, Pfizer, and Yamanuchi.

Acknowledgments

This article was supported in part by the Arthur P. Noyes Research Foundation.

The authors thank Margit Kacso, Cara Bendler, Dawn Filmyer, and Jon Weinstein for their technical and editorial assistance in preparing this article.