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Brazilian guidelines for the management of psychomotor agitation. Part 2. Pharmacological approach

Abstract

Objective:

To present the essential guidelines for pharmacological management of patients with psychomotor agitation in Brazil.

Methods:

This is a systematic review of articles retrieved from the MEDLINE (PubMed), Cochrane Database of Systematic Reviews, and SciELO databases published from 1997 to 2017. Other relevant articles in the literature were also used to develop these guidelines. The search strategy used structured questions formulated using the PICO model, as recommended by the Guidelines Project of the Brazilian Medical Association. Recommendations were summarized according to their level of evidence, which was determined using the Oxford Centre for Evidence-based Medicine system and critical appraisal tools.

Results:

Of 5,362 articles retrieved, 1,731 abstracts were selected for further reading. The final sample included 74 articles that met all inclusion criteria. The evidence shows that pharmacologic treatment is indicated only after non-pharmacologic approaches have failed. The cause of the agitation, side effects of the medications, and contraindications must guide the medication choice. The oral route should be preferred for drug administration; IV administration must be avoided. All subjects must be monitored before and after medication administration.

Conclusion:

If non-pharmacological strategies fail, medications are needed to control agitation and violent behavior. Once medicated, the patient should be monitored until a tranquil state is possible without excessive sedation.

Systematic review registry number:

CRD42017054440.

Psychomotor agitation; aggression; tranquilizing agents; emergency; mental disorders


Introduction

The proper management of agitated patients is essential for their safety and for the safety of the health care staff.11. Wilson MP, Pepper D, Currier GW, Holloman Jr GH, Feifel D. The psychopharmacology of agitation: Consensus Statement of the American Association for Emergency Psychiatry Project Beta Psychopharmacology Workgroup. West J Emerg Med. 2012;13:26-34.

2. Baldaçara L, Sanches M, Cordeiro DC, Jackoswski AP. Rapid tranquilization for agitated patients in emergency psychiatric rooms: a randomized trial of olanzapine, ziprasidone, haloperidol plus promethazine, haloperidol plus midazolam and haloperidol alone. Rev Bras Psiquiatr. 2011;33:30-9.
-33. McAllister-Williams RH, Ferrier IN. Rapid tranquillisation: time for a reappraisal of options for parenteral therapy. Br J Psychiatry. 2002;180:485-9. In most circumstances, non-pharmacological methods of behavior control, such as a verbal intervention or de-escalation, are helpful as an initial strategy to manage agitated patients11. Wilson MP, Pepper D, Currier GW, Holloman Jr GH, Feifel D. The psychopharmacology of agitation: Consensus Statement of the American Association for Emergency Psychiatry Project Beta Psychopharmacology Workgroup. West J Emerg Med. 2012;13:26-34.,44. Garriga M, Pacchiarotti I, Kasper S, Zeller SL, Allen MH, Vazquez G, et al. Assessment and management of agitation in psychiatry: Expert consensus. World J Biol Psychiatry. 2016;17:86-128.

5. Zeller SL, Rhoades RW. Systematic reviews of assessment measures and pharmacologic treatments for agitation. Clin Ther. 2010;32:403-25.

6. Mantovani C, Migon MN, Alheira FV, Del-Ben CM. Manejo de paciente agitado ou agressivo. Rev Bras Psiquiatr. 2010;32:S96-S103.
-77. Richmond JS, Berlin JS, Fishkind AB, Holloman GH, Jr., Zeller SL, Wilson MP, et al. Verbal De-escalation of the Agitated Patient: Consensus Statement of the American Association for Emergency Psychiatry Project BETA De-escalation Workgroup. West J Emerg Med. 2012;13:17-25. (see Part 1 of these Guidelines88. Baldaçara L, Ismael F, Leite V, Pereira LA, dos Santos RM, Gomes Júnior VP, et al. Brazilian guidelines for the management of psychomotor agitation. Part 1. Non-pharmacological approach. Braz J Psychiatry. 2018 Dec 6:0. doi: 10.1590/1516-4446-2018-0163. [Epub ahead of print]
doi: 10.1590/1516-4446-2018-0163...
). However, when non-pharmacological methods fail, rapid tranquilization with pharmacological agents may be indicated.

Tranquilization or “rapid tranquilization” can be understood as calming without sedation.33. McAllister-Williams RH, Ferrier IN. Rapid tranquillisation: time for a reappraisal of options for parenteral therapy. Br J Psychiatry. 2002;180:485-9. This strategy allows patients to have some participation in their own care. In the acute setting, rapid tranquilization facilitates diagnosis of the underlying cause of the agitation. Moreover, patients who are not asleep are easier to discharge from the emergency department.11. Wilson MP, Pepper D, Currier GW, Holloman Jr GH, Feifel D. The psychopharmacology of agitation: Consensus Statement of the American Association for Emergency Psychiatry Project Beta Psychopharmacology Workgroup. West J Emerg Med. 2012;13:26-34.

The pharmacological management of acute agitation has traditionally employed three classes of medications: first-generation antipsychotics (FGA), second-generation antipsychotics (SGAs), and benzodiazepines (BZDs). Administration is usually oral (PO, from the Latin per orem), including orally dispersible tablets (ODTs), sublingual tablets (SL), oral solutions (OSs), inhaled formulations (IN), as well as intramuscular (IM) and intravenous (IV) routes.11. Wilson MP, Pepper D, Currier GW, Holloman Jr GH, Feifel D. The psychopharmacology of agitation: Consensus Statement of the American Association for Emergency Psychiatry Project Beta Psychopharmacology Workgroup. West J Emerg Med. 2012;13:26-34.,22. Baldaçara L, Sanches M, Cordeiro DC, Jackoswski AP. Rapid tranquilization for agitated patients in emergency psychiatric rooms: a randomized trial of olanzapine, ziprasidone, haloperidol plus promethazine, haloperidol plus midazolam and haloperidol alone. Rev Bras Psiquiatr. 2011;33:30-9.,44. Garriga M, Pacchiarotti I, Kasper S, Zeller SL, Allen MH, Vazquez G, et al. Assessment and management of agitation in psychiatry: Expert consensus. World J Biol Psychiatry. 2016;17:86-128.

5. Zeller SL, Rhoades RW. Systematic reviews of assessment measures and pharmacologic treatments for agitation. Clin Ther. 2010;32:403-25.
-66. Mantovani C, Migon MN, Alheira FV, Del-Ben CM. Manejo de paciente agitado ou agressivo. Rev Bras Psiquiatr. 2010;32:S96-S103.,99. Citrome L, Volavka J. The psychopharmacology of violence: making sensible decisions. CNS Spectr. 2014;19:411-8.

The present article, corresponding to Part 2 of the Brazilian guidelines for the management of psychomotor agitation, focuses on the pharmacological approach to agitated patients. It should be noted that the article covers medications that are not yet available in this country as a way of considering future options and to contextualize Brazilian and non-Brazilian psychiatrists regarding the Brazilian scenario.

Method

This project involved 14 Brazilian psychiatry professionals selected by the Psychiatric Emergency Committee of the Brazilian Psychiatric Association (Associação Brasileira de Psiquiatria [ABP]), for their experience in and knowledge of psychiatry and psychiatric emergencies. This workgroup convened in 2016-2018 to recommend best practices in the use of medication to manage agitated patients in an emergency setting, focusing on the current daily practice of the Brazilian psychiatrist.

For the development of these guidelines, 85 articles were reviewed (among 5,362 initially collected and 755 abstracts on the pharmacological approach), retrieved from MEDLINE (PubMed), Cochrane Database of Systematic Reviews, Web of Science, and SciELO, published from 1997 to 2017, in the English, Portuguese, Spanish, or French languages. The search strategy used was based on questions structured according to the PICO strategy, with definition of Patient/Population of interest, Intervention/Exposure, Control/Comparison, and Outcome, as recommended by the Guidelines Project of the Brazilian Medical Association. The use of structured clinical questions was aimed at facilitating the elaboration of strategies to search for evidence. The search terms used were psychomotor agitation AND medication.

In evaluating the literature, despite the existence of many clinical trials and reviews, analysis of the results was limited by the following: evaluation of psychomotor agitation in the context of several different diagnoses, the settings in which evaluation and follow-up of agitated patients was conducted, and procedural variables such as the evaluation of medications in a small number of patients, using different instruments and differing outcome criteria. Therefore, the following inclusion criteria were standardized for study selection: 1) studies examining psychomotor agitation in adults (18 to 65 years); 2) studies using rapid tranquilization and including an evaluation of the outcome in the first 24 hours; and 3) studies with objective assessment of the response, based on a reduction of symptoms on an objective scale or on a calm state.

Exclusion criteria were as follows: 1) studies examining special groups, such as children, adolescents, the elderly, and the pregnant (even though recommendations are presented at the end of the present article, the treatment of such groups requires separate guidelines); 2) studies examining the use and abuse of substances, which was not the focus of this review, or articles for the treatment of situations that do not involve psychomotor agitation; 3) studies with a sample including fewer than 20 participants; or 4) studies including participants with clinical conditions such as delirium and dementia.

In addition, articles that have relevance in the literature were also used in the elaboration of the guidelines. Analysis of the articles followed four steps: I) review of relevant abstracts; II) reading of relevant articles in full; III) critical analysis of the evidence; and IV) extraction of the results and grading of the quality of evidence. Levels of evidence and strength of recommendations were defined according to the system proposed by the Oxford Center for Evidence-Based Medicine.1010. Centre for Evidence-based Medicine (CEBM). Oxford Centre for Evidence-based Medicine – Levels of Evidence (March 2009) Oxford: CEBM; 2009. http://www.cebm.net/oxford-centre-evidence-based-medicine-levels-evidence-march-2009/
http://www.cebm.net/oxford-centre-eviden...
In the results, levels of evidence are presented with numbers and letters (1A, 1B, 1C, 2A, 2B, 2C, 3A, 3B, 4, and 5), and strength of recommendation is presented with letters (A, B, C, or D).

Results

Despite the limitations of a slow onset of action44. Garriga M, Pacchiarotti I, Kasper S, Zeller SL, Allen MH, Vazquez G, et al. Assessment and management of agitation in psychiatry: Expert consensus. World J Biol Psychiatry. 2016;17:86-128.,1111. Citrome L. New treatments for agitation. Psychiatr Q. 2004;75:197-213.,1212. Ng AT, Zeller SL, Rhoades RW. Clinical challenges in the pharmacologic management of agitation. Prim Psychiatry. 2010;17:46-52. and the chance of non-adherence,44. Garriga M, Pacchiarotti I, Kasper S, Zeller SL, Allen MH, Vazquez G, et al. Assessment and management of agitation in psychiatry: Expert consensus. World J Biol Psychiatry. 2016;17:86-128.,1313. Zimbroff DL, Marcus RN, Manos G, Stock E, McQuade RD, Auby P, et al. Management of acute agitation in patients with bipolar disorder: efficacy and safety of intramuscular aripiprazole. J Clin Psychopharmacol. 2007;27:171-6. oral formulations are generally preferred over IM preparations as the initial treatment of agitated patients.11. Wilson MP, Pepper D, Currier GW, Holloman Jr GH, Feifel D. The psychopharmacology of agitation: Consensus Statement of the American Association for Emergency Psychiatry Project Beta Psychopharmacology Workgroup. West J Emerg Med. 2012;13:26-34.,44. Garriga M, Pacchiarotti I, Kasper S, Zeller SL, Allen MH, Vazquez G, et al. Assessment and management of agitation in psychiatry: Expert consensus. World J Biol Psychiatry. 2016;17:86-128. If the patient is well enough to agree with taking the medication, and if it is possible to wait longer for an effect to occur, the use of oral medications is preferred (D). If an oral option is not possible, the IM route is recommended (D). The IV route should be avoided because it poses a greater risk of serious side effects (D). Although the literature demonstrates the efficacy of some IV medications in psychomotor agitation, our group discourages their use and recommends that IV medications only be used in settings where cardiopulmonary resuscitation equipment and trained staff are available.

First-generation antipsychotics (FGAs)

Typical FGAs have a long history of use for treatment of agitation.11. Wilson MP, Pepper D, Currier GW, Holloman Jr GH, Feifel D. The psychopharmacology of agitation: Consensus Statement of the American Association for Emergency Psychiatry Project Beta Psychopharmacology Workgroup. West J Emerg Med. 2012;13:26-34. These agents act by inhibition of dopamine transmission in the human brain, especially through dopamine D2 receptor antagonism, which is associated with reduction of psychotic symptoms.1414. Stahl S. Stahl’s essential psychopharmacology: neuroscientific basis and practical applications. 3rd ed. New York: Cambridge University Press; 2008. In addition to the risk of extrapyramidal side effects (EPSs),1414. Stahl S. Stahl’s essential psychopharmacology: neuroscientific basis and practical applications. 3rd ed. New York: Cambridge University Press; 2008. FGAs’ potential blockade of muscarinic cholinergic, histaminic, and α-1-adrenergic receptors is related to additional adverse effects.1414. Stahl S. Stahl’s essential psychopharmacology: neuroscientific basis and practical applications. 3rd ed. New York: Cambridge University Press; 2008.

The most common FGAs used for rapid tranquilization due to agitation are chlorpromazine,1515. Ahmed U, Jones H, Adams CE. Chlorpromazine for psychosis induced aggression or agitation. Cochrane Database Syst Rev. 2010;CD007445. levomepromazine,1616. Suzuki H, Gen K, Takahashi Y. A naturalistic comparison study of the efficacy and safety of intramuscular olanzapine, intramuscular haloperidol, and intramuscular levomepromazine in acute agitated patients with schizophrenia. Hum Psychopharmacol. 2014;29:83-8. haloperidol,22. Baldaçara L, Sanches M, Cordeiro DC, Jackoswski AP. Rapid tranquilization for agitated patients in emergency psychiatric rooms: a randomized trial of olanzapine, ziprasidone, haloperidol plus promethazine, haloperidol plus midazolam and haloperidol alone. Rev Bras Psiquiatr. 2011;33:30-9. and droperidol.1717. Isbister GK, Calver LA, Page CB, Stokes B, Bryant JL, Downes MA. Randomized controlled trial of intramuscular droperidol versus midazolam for violence and acute behavioral disturbance: the DORM study. Ann Emerg Med. 2010;56:392-401.e1. Promethazine,22. Baldaçara L, Sanches M, Cordeiro DC, Jackoswski AP. Rapid tranquilization for agitated patients in emergency psychiatric rooms: a randomized trial of olanzapine, ziprasidone, haloperidol plus promethazine, haloperidol plus midazolam and haloperidol alone. Rev Bras Psiquiatr. 2011;33:30-9. primarily known as an antihistamine, but belonging to the group of phenothiazines, may also be used.1818. National Center for Biotechnology Information. Phenothiazine [Internet]. 2018 [cited 2018 May 29]. https://pubchem.ncbi.nlm.nih.gov/compound/7108
https://pubchem.ncbi.nlm.nih.gov/compoun...

Chlorpromazine

Chlorpromazine was mentioned in a study that reported a clinical trial showing no differences between chlorpromazine injection and haloperidol.1515. Ahmed U, Jones H, Adams CE. Chlorpromazine for psychosis induced aggression or agitation. Cochrane Database Syst Rev. 2010;CD007445.,1919. Man PL, Chen CH. Rapid tranquilization of acutely psychotic patients with intramuscular haloperidol and chlorpromazine. Psychosomatics. 1973;14:59-63. IM chlorpromazine is related to sudden, serious hypotension, and status epilepticus.1515. Ahmed U, Jones H, Adams CE. Chlorpromazine for psychosis induced aggression or agitation. Cochrane Database Syst Rev. 2010;CD007445. The authors conclude chlorpromazine should be avoided if other drugs, with a more positive evaluation, are available.1515. Ahmed U, Jones H, Adams CE. Chlorpromazine for psychosis induced aggression or agitation. Cochrane Database Syst Rev. 2010;CD007445. We recommend avoiding parenteral use of chlorpromazine for rapid tranquilization, including the IM route.

Levomepromazine

Levomepromazine is another phenothiazine. In an observational study, the response of levomepromazine was similar to that of olanzapine, and better than that of haloperidol. All medications were administered as an IM formulation.1616. Suzuki H, Gen K, Takahashi Y. A naturalistic comparison study of the efficacy and safety of intramuscular olanzapine, intramuscular haloperidol, and intramuscular levomepromazine in acute agitated patients with schizophrenia. Hum Psychopharmacol. 2014;29:83-8. Levomepromazine was related to EPS, hypotension, hypertension, somnolence, dizziness, paralytic ileus, and ketoacidosis (B).1616. Suzuki H, Gen K, Takahashi Y. A naturalistic comparison study of the efficacy and safety of intramuscular olanzapine, intramuscular haloperidol, and intramuscular levomepromazine in acute agitated patients with schizophrenia. Hum Psychopharmacol. 2014;29:83-8.

Haloperidol

The most commonly used medication in studies is haloperidol, via PO,2020. Walther S, Moggi F, Horn H, Moskvitin K, Abderhalden C, Maier N, et al. Rapid tranquilization of severely agitated patients with schizophrenia spectrum disorders: a naturalistic, rater-blinded, randomized, controlled study with oral haloperidol, risperidone, and olanzapine. J Clin Psychopharmacol. 2014;34:124-8.,2121. Kinon BJ, Ahl J, Rotelli MD, McMullen E. Efficacy of accelerated dose titration of olanzapine with adjunctive lorazepam to treat acute agitation in schizophrenia. Am J Emerg Med. 2004;22:181-6. IM,22. Baldaçara L, Sanches M, Cordeiro DC, Jackoswski AP. Rapid tranquilization for agitated patients in emergency psychiatric rooms: a randomized trial of olanzapine, ziprasidone, haloperidol plus promethazine, haloperidol plus midazolam and haloperidol alone. Rev Bras Psiquiatr. 2011;33:30-9.,1616. Suzuki H, Gen K, Takahashi Y. A naturalistic comparison study of the efficacy and safety of intramuscular olanzapine, intramuscular haloperidol, and intramuscular levomepromazine in acute agitated patients with schizophrenia. Hum Psychopharmacol. 2014;29:83-8.,2222. Chan HY, Ree SC, Su LW, Chen JJ, Chou SY, Chen CK, et al. A double-blind, randomized comparison study of efficacy and safety of intramuscular olanzapine and intramuscular haloperidol in patients with schizophrenia and acute agitated behavior. J Clin Psychopharmacol. 2014;34:355-8.

23. Daniel DG, Currier GW, Zimbroff DL, Allen MH, Oren D, Manos G, et al. Efficacy and safety of oral aripiprazole compared with haloperidol in patients transitioning from acute treatment with intramuscular formulations. J Psychiatr Pract. 2007;13:170-7.

24. Dorevitch A, Katz N, Zemishlany Z, Aizenberg D, Weizman A. Intramuscular flunitrazepam versus intramuscular haloperidol in the emergency treatment of aggressive psychotic behavior. Am J Psychiatry. 1999;156:142-4.

25. Fang M, Chen H, Li LH, Wu R, Li Y, Liu L, et al. Comparison of risperidone oral solution and intramuscular haloperidol with the latter shifting to oral therapy for the treatment of acute agitation in patients with schizophrenia. Int Clin Psychopharmacol. 2012;27:107-13.

26. Gillies D, Sampson S, Beck A, Rathbone J. Benzodiazepines for psychosis-induced aggression or agitation. Cochrane Database Syst Rev. 2013;9:CD003079.

27. Huf G, Alexander J, Gandhi P, Allen MH. Haloperidol plus promethazine for psychosis-induced aggression. Cochrane Database Syst Rev. 2016;11:CD005146.

28. Huf G, Coutinho ES, Adams CE, Group TC. Rapid tranquillisation in psychiatric emergency settings in Brazil: pragmatic randomised controlled trial of intramuscular haloperidol versus intramuscular haloperidol plus promethazine. BMJ. 2007;335:869.

29. Lim HK, Kim JJ, Pae CU, Lee CU, Lee C, Paik IH. Comparison of risperidone orodispersible tablet and intramuscular haloperidol in the treatment of acute psychotic agitation: a randomized open, prospective study. Neuropsychobiology. 2010;62:81-6.

30. MacDonald K, Wilson M, Minassian A, Vilke GM, Becker O, Tallian K, et al. A naturalistic study of intramuscular haloperidol versus intramuscular olanzapine for the management of acute agitation. J Clin Psychopharmacol. 2012;32:317-22.

31. MacDonald K, Wilson MP, Minassian A, Vilke GM, Perez R, Cobb P, et al. A retrospective analysis of intramuscular haloperidol and intramuscular olanzapine in the treatment of agitation in drug- and alcohol-using patients. Gen Hosp Psychiatry. 2010;32:443-5.

32. Man PL, Chen CH. Rapid tranquilization of acutely psychotic patients with intramuscular haloperidol and chlorpromazine. Psychosomatics. 1973;14:59-63.

33. Nobay F, Simon BC, Levitt MA, Dresden GM. A prospective, double-blind, randomized trial of midazolam versus haloperidol versus lorazepam in the chemical restraint of violent and severely agitated patients. Acad Emerg Med. 2004;11:744-9.

34. Preval H, Klotz SG, Southard R, Francis A. Rapid-acting IM ziprasidone in a psychiatric emergency service: a naturalistic study. Gen Hosp Psychiatry. 2005;27:140-4.

35. Resnick M, Burton BT. Droperidol vs. haloperidol in the initial management of acutely agitated patients. J Clin Psychiatry. 1984;45:298-9.

36. Tran-Johnson TK, Sack DA, Marcus RN, Auby P, McQuade RD, Oren DA. Efficacy and safety of intramuscular aripiprazole in patients with acute agitation: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2007;68:111-9.

37. Wright P, Birkett M, David SR, Meehan K, Ferchland I, Alaka KJ, et al. Double-blind, placebo-controlled comparison of intramuscular olanzapine and intramuscular haloperidol in the treatment of acute agitation in schizophrenia. Am J Psychiatry. 2001;158:1149-51.
-3838. Zhang H, Wang G, Zhao J, Xie S, Xu X, Shi J, et al. Intramuscular ziprasidone versus haloperidol for managing agitation in Chinese patients with schizophrenia. J Clin Psychopharmacol. 2013;33:178-85. and IV routes.2626. Gillies D, Sampson S, Beck A, Rathbone J. Benzodiazepines for psychosis-induced aggression or agitation. Cochrane Database Syst Rev. 2013;9:CD003079.,3939. Asadollahi S, Heidari K, Hatamabadi H, Vafaee R, Yunesian S, Azadbakht A, et al. Efficacy and safety of valproic acid versus haloperidol in patients with acute agitation: results of a randomized, double-blind, parallel-group trial. Int Clin Psychopharmacol. 2015;30:142-50. The efficacy of the first oral doses was similar to that of risperidone2020. Walther S, Moggi F, Horn H, Moskvitin K, Abderhalden C, Maier N, et al. Rapid tranquilization of severely agitated patients with schizophrenia spectrum disorders: a naturalistic, rater-blinded, randomized, controlled study with oral haloperidol, risperidone, and olanzapine. J Clin Psychopharmacol. 2014;34:124-8. and olanzapine (B).2020. Walther S, Moggi F, Horn H, Moskvitin K, Abderhalden C, Maier N, et al. Rapid tranquilization of severely agitated patients with schizophrenia spectrum disorders: a naturalistic, rater-blinded, randomized, controlled study with oral haloperidol, risperidone, and olanzapine. J Clin Psychopharmacol. 2014;34:124-8.,2121. Kinon BJ, Ahl J, Rotelli MD, McMullen E. Efficacy of accelerated dose titration of olanzapine with adjunctive lorazepam to treat acute agitation in schizophrenia. Am J Emerg Med. 2004;22:181-6. Oral haloperidol was effective in combination with lorazepam administered intramuscularly (B).2020. Walther S, Moggi F, Horn H, Moskvitin K, Abderhalden C, Maier N, et al. Rapid tranquilization of severely agitated patients with schizophrenia spectrum disorders: a naturalistic, rater-blinded, randomized, controlled study with oral haloperidol, risperidone, and olanzapine. J Clin Psychopharmacol. 2014;34:124-8. However, as will be mentioned, the use of multiple routes is not recommended by our group, since the onset of action of the medications will occur at different times.

Use of IM haloperidol is well established, either as a monotherapy (A)22. Baldaçara L, Sanches M, Cordeiro DC, Jackoswski AP. Rapid tranquilization for agitated patients in emergency psychiatric rooms: a randomized trial of olanzapine, ziprasidone, haloperidol plus promethazine, haloperidol plus midazolam and haloperidol alone. Rev Bras Psiquiatr. 2011;33:30-9.,1616. Suzuki H, Gen K, Takahashi Y. A naturalistic comparison study of the efficacy and safety of intramuscular olanzapine, intramuscular haloperidol, and intramuscular levomepromazine in acute agitated patients with schizophrenia. Hum Psychopharmacol. 2014;29:83-8.,2323. Daniel DG, Currier GW, Zimbroff DL, Allen MH, Oren D, Manos G, et al. Efficacy and safety of oral aripiprazole compared with haloperidol in patients transitioning from acute treatment with intramuscular formulations. J Psychiatr Pract. 2007;13:170-7.

24. Dorevitch A, Katz N, Zemishlany Z, Aizenberg D, Weizman A. Intramuscular flunitrazepam versus intramuscular haloperidol in the emergency treatment of aggressive psychotic behavior. Am J Psychiatry. 1999;156:142-4.
-2525. Fang M, Chen H, Li LH, Wu R, Li Y, Liu L, et al. Comparison of risperidone oral solution and intramuscular haloperidol with the latter shifting to oral therapy for the treatment of acute agitation in patients with schizophrenia. Int Clin Psychopharmacol. 2012;27:107-13.,2828. Huf G, Coutinho ES, Adams CE, Group TC. Rapid tranquillisation in psychiatric emergency settings in Brazil: pragmatic randomised controlled trial of intramuscular haloperidol versus intramuscular haloperidol plus promethazine. BMJ. 2007;335:869.

29. Lim HK, Kim JJ, Pae CU, Lee CU, Lee C, Paik IH. Comparison of risperidone orodispersible tablet and intramuscular haloperidol in the treatment of acute psychotic agitation: a randomized open, prospective study. Neuropsychobiology. 2010;62:81-6.
-3030. MacDonald K, Wilson M, Minassian A, Vilke GM, Becker O, Tallian K, et al. A naturalistic study of intramuscular haloperidol versus intramuscular olanzapine for the management of acute agitation. J Clin Psychopharmacol. 2012;32:317-22.,3535. Resnick M, Burton BT. Droperidol vs. haloperidol in the initial management of acutely agitated patients. J Clin Psychiatry. 1984;45:298-9.

36. Tran-Johnson TK, Sack DA, Marcus RN, Auby P, McQuade RD, Oren DA. Efficacy and safety of intramuscular aripiprazole in patients with acute agitation: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2007;68:111-9.

37. Wright P, Birkett M, David SR, Meehan K, Ferchland I, Alaka KJ, et al. Double-blind, placebo-controlled comparison of intramuscular olanzapine and intramuscular haloperidol in the treatment of acute agitation in schizophrenia. Am J Psychiatry. 2001;158:1149-51.
-3838. Zhang H, Wang G, Zhao J, Xie S, Xu X, Shi J, et al. Intramuscular ziprasidone versus haloperidol for managing agitation in Chinese patients with schizophrenia. J Clin Psychopharmacol. 2013;33:178-85.,4040. Breier A, Meehan K, Birkett M, David S, Ferchland I, Sutton V, et al. A double-blind, placebo-controlled dose-response comparison of intramuscular olanzapine and haloperidol in the treatment of acute agitation in schizophrenia. Arch Gen Psychiatry. 2002;59:441-8. or in combination with promethazine (A),22. Baldaçara L, Sanches M, Cordeiro DC, Jackoswski AP. Rapid tranquilization for agitated patients in emergency psychiatric rooms: a randomized trial of olanzapine, ziprasidone, haloperidol plus promethazine, haloperidol plus midazolam and haloperidol alone. Rev Bras Psiquiatr. 2011;33:30-9.,2727. Huf G, Alexander J, Gandhi P, Allen MH. Haloperidol plus promethazine for psychosis-induced aggression. Cochrane Database Syst Rev. 2016;11:CD005146.,2828. Huf G, Coutinho ES, Adams CE, Group TC. Rapid tranquillisation in psychiatric emergency settings in Brazil: pragmatic randomised controlled trial of intramuscular haloperidol versus intramuscular haloperidol plus promethazine. BMJ. 2007;335:869.,4141. Alexander J, Tharyan P, Adams C, John T, Mol C, Philip J. Rapid tranquillisation of violent or agitated patients in a psychiatric emergency setting. Pragmatic randomised trial of intramuscular lorazepam v. haloperidol plus promethazine. Br J Psychiatry. 2004;185:63-9.

42. Mantovani C, Labate CM, Sponholz A, Jr., de Azevedo Marques JM, Guapo VG, de Simone Brito dos Santos ME, 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;33:306-12.

43. Raveendran NS, Tharyan P, Alexander J, Adams CE, Group TR-IIC. Rapid tranquillisation in psychiatric emergency settings in India: pragmatic randomised controlled trial of intramuscular olanzapine versus intramuscular haloperidol plus promethazine. BMJ. 2007;335:865.
-4444. Trec Collaborative Group. Rapid tranquillisation for agitated patients in emergency psychiatric rooms: a randomised trial of midazolam versus haloperidol plus promethazine. BMJ. 2003;327:708-13. midazolam,22. Baldaçara L, Sanches M, Cordeiro DC, Jackoswski AP. Rapid tranquilization for agitated patients in emergency psychiatric rooms: a randomized trial of olanzapine, ziprasidone, haloperidol plus promethazine, haloperidol plus midazolam and haloperidol alone. Rev Bras Psiquiatr. 2011;33:30-9.,2727. Huf G, Alexander J, Gandhi P, Allen MH. Haloperidol plus promethazine for psychosis-induced aggression. Cochrane Database Syst Rev. 2016;11:CD005146.,4242. Mantovani C, Labate CM, Sponholz A, Jr., de Azevedo Marques JM, Guapo VG, de Simone Brito dos Santos ME, 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;33:306-12. or lorazepam (B).3030. MacDonald K, Wilson M, Minassian A, Vilke GM, Becker O, Tallian K, et al. A naturalistic study of intramuscular haloperidol versus intramuscular olanzapine for the management of acute agitation. J Clin Psychopharmacol. 2012;32:317-22.,4545. Bieniek SA, Ownby RL, Penalver A, Dominguez RA. A double-blind study of lorazepam versus the combination of haloperidol and lorazepam in managing agitation. Pharmacotherapy. 1998;18:57-62.

46. Currier GW, Simpson GM. Risperidone liquid concentrate and oral lorazepam versus intramuscular haloperidol and intramuscular lorazepam for treatment of psychotic agitation. J Clin Psychiatry. 2001;62:153-7.
-4747. Currier GW, Chou JC, Feifel D, Bossie CA, Turkoz I, Mahmoud RA, et al. Acute treatment of psychotic agitation: a randomized comparison of oral treatment with risperidone and lorazepam versus intramuscular treatment with haloperidol and lorazepam. J Clin Psychiatry. 2004;65:386-94. Much has been discussed with regard to the doses. Responses have been observed following administration of a first dose ranging from 2.5 up to 10 mg. It is important to note that haloperidol is associated with the same side effects as other antipsychotics, with a higher frequency of EPS.22. Baldaçara L, Sanches M, Cordeiro DC, Jackoswski AP. Rapid tranquilization for agitated patients in emergency psychiatric rooms: a randomized trial of olanzapine, ziprasidone, haloperidol plus promethazine, haloperidol plus midazolam and haloperidol alone. Rev Bras Psiquiatr. 2011;33:30-9.,1616. Suzuki H, Gen K, Takahashi Y. A naturalistic comparison study of the efficacy and safety of intramuscular olanzapine, intramuscular haloperidol, and intramuscular levomepromazine in acute agitated patients with schizophrenia. Hum Psychopharmacol. 2014;29:83-8.,2323. Daniel DG, Currier GW, Zimbroff DL, Allen MH, Oren D, Manos G, et al. Efficacy and safety of oral aripiprazole compared with haloperidol in patients transitioning from acute treatment with intramuscular formulations. J Psychiatr Pract. 2007;13:170-7.

24. Dorevitch A, Katz N, Zemishlany Z, Aizenberg D, Weizman A. Intramuscular flunitrazepam versus intramuscular haloperidol in the emergency treatment of aggressive psychotic behavior. Am J Psychiatry. 1999;156:142-4.
-2525. Fang M, Chen H, Li LH, Wu R, Li Y, Liu L, et al. Comparison of risperidone oral solution and intramuscular haloperidol with the latter shifting to oral therapy for the treatment of acute agitation in patients with schizophrenia. Int Clin Psychopharmacol. 2012;27:107-13.,2727. Huf G, Alexander J, Gandhi P, Allen MH. Haloperidol plus promethazine for psychosis-induced aggression. Cochrane Database Syst Rev. 2016;11:CD005146.

28. Huf G, Coutinho ES, Adams CE, Group TC. Rapid tranquillisation in psychiatric emergency settings in Brazil: pragmatic randomised controlled trial of intramuscular haloperidol versus intramuscular haloperidol plus promethazine. BMJ. 2007;335:869.

29. Lim HK, Kim JJ, Pae CU, Lee CU, Lee C, Paik IH. Comparison of risperidone orodispersible tablet and intramuscular haloperidol in the treatment of acute psychotic agitation: a randomized open, prospective study. Neuropsychobiology. 2010;62:81-6.
-3030. MacDonald K, Wilson M, Minassian A, Vilke GM, Becker O, Tallian K, et al. A naturalistic study of intramuscular haloperidol versus intramuscular olanzapine for the management of acute agitation. J Clin Psychopharmacol. 2012;32:317-22.,3535. Resnick M, Burton BT. Droperidol vs. haloperidol in the initial management of acutely agitated patients. J Clin Psychiatry. 1984;45:298-9.

36. Tran-Johnson TK, Sack DA, Marcus RN, Auby P, McQuade RD, Oren DA. Efficacy and safety of intramuscular aripiprazole in patients with acute agitation: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2007;68:111-9.

37. Wright P, Birkett M, David SR, Meehan K, Ferchland I, Alaka KJ, et al. Double-blind, placebo-controlled comparison of intramuscular olanzapine and intramuscular haloperidol in the treatment of acute agitation in schizophrenia. Am J Psychiatry. 2001;158:1149-51.
-3838. Zhang H, Wang G, Zhao J, Xie S, Xu X, Shi J, et al. Intramuscular ziprasidone versus haloperidol for managing agitation in Chinese patients with schizophrenia. J Clin Psychopharmacol. 2013;33:178-85.,4040. Breier A, Meehan K, Birkett M, David S, Ferchland I, Sutton V, et al. A double-blind, placebo-controlled dose-response comparison of intramuscular olanzapine and haloperidol in the treatment of acute agitation in schizophrenia. Arch Gen Psychiatry. 2002;59:441-8.

41. Alexander J, Tharyan P, Adams C, John T, Mol C, Philip J. Rapid tranquillisation of violent or agitated patients in a psychiatric emergency setting. Pragmatic randomised trial of intramuscular lorazepam v. haloperidol plus promethazine. Br J Psychiatry. 2004;185:63-9.

42. Mantovani C, Labate CM, Sponholz A, Jr., de Azevedo Marques JM, Guapo VG, de Simone Brito dos Santos ME, 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;33:306-12.

43. Raveendran NS, Tharyan P, Alexander J, Adams CE, Group TR-IIC. Rapid tranquillisation in psychiatric emergency settings in India: pragmatic randomised controlled trial of intramuscular olanzapine versus intramuscular haloperidol plus promethazine. BMJ. 2007;335:865.
-4444. Trec Collaborative Group. Rapid tranquillisation for agitated patients in emergency psychiatric rooms: a randomised trial of midazolam versus haloperidol plus promethazine. BMJ. 2003;327:708-13.

Haloperidol has also been used intravenously, with proven efficacy as compared with sodium valproate3939. Asadollahi S, Heidari K, Hatamabadi H, Vafaee R, Yunesian S, Azadbakht A, et al. Efficacy and safety of valproic acid versus haloperidol in patients with acute agitation: results of a randomized, double-blind, parallel-group trial. Int Clin Psychopharmacol. 2015;30:142-50. and BZDs2626. Gillies D, Sampson S, Beck A, Rathbone J. Benzodiazepines for psychosis-induced aggression or agitation. Cochrane Database Syst Rev. 2013;9:CD003079. (1A). However, the IV route amplifies the side effects, especially EPS and cardiotoxity.3939. Asadollahi S, Heidari K, Hatamabadi H, Vafaee R, Yunesian S, Azadbakht A, et al. Efficacy and safety of valproic acid versus haloperidol in patients with acute agitation: results of a randomized, double-blind, parallel-group trial. Int Clin Psychopharmacol. 2015;30:142-50. Therefore, we do not recommend IV use of haloperidol (D).

Droperidol

Droperidol, as well as haloperidol, is a butyrophenone whose efficacy has been demonstrated with IM1717. Isbister GK, Calver LA, Page CB, Stokes B, Bryant JL, Downes MA. Randomized controlled trial of intramuscular droperidol versus midazolam for violence and acute behavioral disturbance: the DORM study. Ann Emerg Med. 2010;56:392-401.e1. and IV administration.4848. Chan EW, Taylor DM, Knott JC, Phillips GA, Castle DJ, Kong DC. Intravenous droperidol or olanzapine as an adjunct to midazolam for the acutely agitated patient: a multicenter, randomized, double-blind, placebo-controlled clinical trial. Ann Emerg Med. 2013;61:72-81. In addition to the evidence regarding the efficacy and safety of the IM route (B),1717. Isbister GK, Calver LA, Page CB, Stokes B, Bryant JL, Downes MA. Randomized controlled trial of intramuscular droperidol versus midazolam for violence and acute behavioral disturbance: the DORM study. Ann Emerg Med. 2010;56:392-401.e1.,3535. Resnick M, Burton BT. Droperidol vs. haloperidol in the initial management of acutely agitated patients. J Clin Psychiatry. 1984;45:298-9.,4949. Martel M, Sterzinger A, Miner J, Clinton J, Biros M. Management of acute undifferentiated agitation in the emergency department: a randomized double-blind trial of droperidol, ziprasidone, and midazolam. Acad Emerg Med. 2005;12:1167-72.

50. Knott JC, Taylor DM, Castle DJ. Randomized clinical trial comparing intravenous midazolam and droperidol for sedation of the acutely agitated patient in the emergency department. Ann Emerg Med. 2006;47:61-7.
-5151. Richards JR, Derlet RW, Duncan DR. Chemical restraint for the agitated patient in the emergency department: lorazepam versus droperidol. J Emerg Med. 1998;16:567-73. studies have reported fewer respiratory side effects1717. Isbister GK, Calver LA, Page CB, Stokes B, Bryant JL, Downes MA. Randomized controlled trial of intramuscular droperidol versus midazolam for violence and acute behavioral disturbance: the DORM study. Ann Emerg Med. 2010;56:392-401.e1.,5050. Knott JC, Taylor DM, Castle DJ. Randomized clinical trial comparing intravenous midazolam and droperidol for sedation of the acutely agitated patient in the emergency department. Ann Emerg Med. 2006;47:61-7. and fewer additional medications with IM droperidol than midazolam.1717. Isbister GK, Calver LA, Page CB, Stokes B, Bryant JL, Downes MA. Randomized controlled trial of intramuscular droperidol versus midazolam for violence and acute behavioral disturbance: the DORM study. Ann Emerg Med. 2010;56:392-401.e1. One study used a combination of IM droperidol and midazolam (B).1717. Isbister GK, Calver LA, Page CB, Stokes B, Bryant JL, Downes MA. Randomized controlled trial of intramuscular droperidol versus midazolam for violence and acute behavioral disturbance: the DORM study. Ann Emerg Med. 2010;56:392-401.e1. IV droperidol has efficacy as monotherapy1717. Isbister GK, Calver LA, Page CB, Stokes B, Bryant JL, Downes MA. Randomized controlled trial of intramuscular droperidol versus midazolam for violence and acute behavioral disturbance: the DORM study. Ann Emerg Med. 2010;56:392-401.e1.,5050. Knott JC, Taylor DM, Castle DJ. Randomized clinical trial comparing intravenous midazolam and droperidol for sedation of the acutely agitated patient in the emergency department. Ann Emerg Med. 2006;47:61-7.,5252. Rosen CL, Ratliff AF, Wolfe RE, Branney SW, Roe EJ, Pons PT. The efficacy of intravenous droperidol in the prehospital setting. J Emerg Med. 1997;15:13-7.

53. Taylor DM, Yap CYL, Knott JC, Taylor SE, Phillips GA, Karro J, et al. Midazolam-Droperidol, Droperidol, or Olanzapine for Acute Agitation: A Randomized Clinical Trial. Ann Emerg Med. 2017;69:318-26.e1.
-5454. Yap CYL, Taylor DM, Knott JC, Taylor SE, Phillips GA, Karro J, et al. Intravenous midazolam-droperidol combination, droperidol or olanzapine monotherapy for methamphetamine-related acute agitation: subgroup analysis of a randomized controlled trial. Addiction. 2017;112:1262-9. or in combination with midazolam4848. Chan EW, Taylor DM, Knott JC, Phillips GA, Castle DJ, Kong DC. Intravenous droperidol or olanzapine as an adjunct to midazolam for the acutely agitated patient: a multicenter, randomized, double-blind, placebo-controlled clinical trial. Ann Emerg Med. 2013;61:72-81.,5353. Taylor DM, Yap CYL, Knott JC, Taylor SE, Phillips GA, Karro J, et al. Midazolam-Droperidol, Droperidol, or Olanzapine for Acute Agitation: A Randomized Clinical Trial. Ann Emerg Med. 2017;69:318-26.e1.,5454. Yap CYL, Taylor DM, Knott JC, Taylor SE, Phillips GA, Karro J, et al. Intravenous midazolam-droperidol combination, droperidol or olanzapine monotherapy for methamphetamine-related acute agitation: subgroup analysis of a randomized controlled trial. Addiction. 2017;112:1262-9. or lorazepam.5151. Richards JR, Derlet RW, Duncan DR. Chemical restraint for the agitated patient in the emergency department: lorazepam versus droperidol. J Emerg Med. 1998;16:567-73. Despite the high level of evidence (1B) regarding efficacy, the combination of droperidol and BZDs increases the risk of respiratory depression and the need for ventilatory support.4848. Chan EW, Taylor DM, Knott JC, Phillips GA, Castle DJ, Kong DC. Intravenous droperidol or olanzapine as an adjunct to midazolam for the acutely agitated patient: a multicenter, randomized, double-blind, placebo-controlled clinical trial. Ann Emerg Med. 2013;61:72-81. Therefore, due the risk of severe side effects such as the prolongation of the QT interval,1717. Isbister GK, Calver LA, Page CB, Stokes B, Bryant JL, Downes MA. Randomized controlled trial of intramuscular droperidol versus midazolam for violence and acute behavioral disturbance: the DORM study. Ann Emerg Med. 2010;56:392-401.e1. EPS,4949. Martel M, Sterzinger A, Miner J, Clinton J, Biros M. Management of acute undifferentiated agitation in the emergency department: a randomized double-blind trial of droperidol, ziprasidone, and midazolam. Acad Emerg Med. 2005;12:1167-72.,5252. Rosen CL, Ratliff AF, Wolfe RE, Branney SW, Roe EJ, Pons PT. The efficacy of intravenous droperidol in the prehospital setting. J Emerg Med. 1997;15:13-7. and hypotension,5151. Richards JR, Derlet RW, Duncan DR. Chemical restraint for the agitated patient in the emergency department: lorazepam versus droperidol. J Emerg Med. 1998;16:567-73. we do not recommmend IV use of droperidol (D).

Loxapine

Loxapine is classified as a typical antipsychotic; however, it has atypical characteristics. Loxapine has been used in its inhaled formulation for the control of psychomotor agitation and has proven efficacy compared to placebo in randomized trials (A).5555. Allen MH, Feifel D, Lesem MD, Zimbroff DL, Ross R, Munzar P, et al. Efficacy and safety of loxapine for inhalation in the treatment of agitation in patients with schizophrenia: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2011;72:1313-21.,5656. Kwentus J, Riesenberg RA, Marandi M, Manning RA, Allen MH, Fishman RS, et al. Rapid acute treatment of agitation in patients with bipolar I disorder: a multicenter, randomized, placebo-controlled clinical trial with inhaled loxapine. Bipolar Disord. 2012;14:31-40.

Clinicians must be aware that FGA are associated with the following side effects: sudden, serious hypotension; status epilepticus, especially with chlorpromazine; headache, dizziness, and nausea; EPS; hypotension; respiratory depression (IV administration or when associated with another sedative medications); bradycardia; dry mouth; seizure; and abnormal QT interval prolongation.

Second-generation antipsychotics (SGAs)

From a pharmacological perspective, atypical antipsychotics are serotonin and dopamine antagonists, D2 partial antagonists, or serotonin partial antagonists at 5HT1A receptors.1414. Stahl S. Stahl’s essential psychopharmacology: neuroscientific basis and practical applications. 3rd ed. New York: Cambridge University Press; 2008. With these properties, they are less likely to produce EPSs (such as parkinsonism) and tardive dyskinesia.1414. Stahl S. Stahl’s essential psychopharmacology: neuroscientific basis and practical applications. 3rd ed. New York: Cambridge University Press; 2008.

Atypical antipsychotics with efficacy for rapid tranquilization found in the literature were aripiprazole,3636. Tran-Johnson TK, Sack DA, Marcus RN, Auby P, McQuade RD, Oren DA. Efficacy and safety of intramuscular aripiprazole in patients with acute agitation: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2007;68:111-9.,5757. Andrezina R, Josiassen RC, Marcus RN, Oren DA, Manos G, Stock E, et al. Intramuscular aripiprazole for the treatment of acute agitation in patients with schizophrenia or schizoaffective disorder: a double-blind, placebo-controlled comparison with intramuscular haloperidol. Psychopharmacology (Berl). 2006;188:281-92.,5858. De Filippis S, Cuomo I, Lionetto L, Janiri D, Simmaco M, Caloro M, et al. Intramuscular aripiprazole in the acute management of psychomotor agitation. Pharmacotherapy. 2013;33:603-14. olanzapine,22. Baldaçara L, Sanches M, Cordeiro DC, Jackoswski AP. Rapid tranquilization for agitated patients in emergency psychiatric rooms: a randomized trial of olanzapine, ziprasidone, haloperidol plus promethazine, haloperidol plus midazolam and haloperidol alone. Rev Bras Psiquiatr. 2011;33:30-9.,1616. Suzuki H, Gen K, Takahashi Y. A naturalistic comparison study of the efficacy and safety of intramuscular olanzapine, intramuscular haloperidol, and intramuscular levomepromazine in acute agitated patients with schizophrenia. Hum Psychopharmacol. 2014;29:83-8.,4242. Mantovani C, Labate CM, Sponholz A, Jr., de Azevedo Marques JM, Guapo VG, de Simone Brito dos Santos ME, 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;33:306-12.,4343. Raveendran NS, Tharyan P, Alexander J, Adams CE, Group TR-IIC. Rapid tranquillisation in psychiatric emergency settings in India: pragmatic randomised controlled trial of intramuscular olanzapine versus intramuscular haloperidol plus promethazine. BMJ. 2007;335:865. risperidone,2929. Lim HK, Kim JJ, Pae CU, Lee CU, Lee C, Paik IH. Comparison of risperidone orodispersible tablet and intramuscular haloperidol in the treatment of acute psychotic agitation: a randomized open, prospective study. Neuropsychobiology. 2010;62:81-6.,4646. Currier GW, Simpson GM. Risperidone liquid concentrate and oral lorazepam versus intramuscular haloperidol and intramuscular lorazepam for treatment of psychotic agitation. J Clin Psychiatry. 2001;62:153-7.,4747. Currier GW, Chou JC, Feifel D, Bossie CA, Turkoz I, Mahmoud RA, et al. Acute treatment of psychotic agitation: a randomized comparison of oral treatment with risperidone and lorazepam versus intramuscular treatment with haloperidol and lorazepam. J Clin Psychiatry. 2004;65:386-94.,5959. Veser FH, Veser BD, McMullan JT, Zealberg J, Currier GW. Risperidone versus haloperidol, in combination with lorazepam, in the treatment of acute agitation and psychosis: a pilot, randomized, double-blind, placebo-controlled trial. J Psychiatr Pract. 2006;12:103-8. and ziprasidone.22. Baldaçara L, Sanches M, Cordeiro DC, Jackoswski AP. Rapid tranquilization for agitated patients in emergency psychiatric rooms: a randomized trial of olanzapine, ziprasidone, haloperidol plus promethazine, haloperidol plus midazolam and haloperidol alone. Rev Bras Psiquiatr. 2011;33:30-9.,4242. Mantovani C, Labate CM, Sponholz A, Jr., de Azevedo Marques JM, Guapo VG, de Simone Brito dos Santos ME, 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;33:306-12.,6060. Agid O, Kapur S, Warrington L, Loebel A, Siu C. Early onset of antipsychotic response in the treatment of acutely agitated patients with psychotic disorders. Schizophr Res. 2008;102:241-8.

Risperidone

PO, ODT, or OS risperidone were effective in the control of psychomotor agitation when administered alone (A)2929. Lim HK, Kim JJ, Pae CU, Lee CU, Lee C, Paik IH. Comparison of risperidone orodispersible tablet and intramuscular haloperidol in the treatment of acute psychotic agitation: a randomized open, prospective study. Neuropsychobiology. 2010;62:81-6.,6161. Gault TI, Gray SM, Vilke GM, Wilson MP. Are oral medications effective in the management of acute agitation? J Emerg Med. 2012;43:854-9.

62. Hsu WY, Huang SS, Lee BS, Chiu NY. Comparison of intramuscular olanzapine, orally disintegrating olanzapine tablets, oral risperidone solution, and intramuscular haloperidol in the management of acute agitation in an acute care psychiatric ward in Taiwan. J Clin Psychopharmacol. 2010;30:230-4.

63. Hatta K, Kawabata T, Yoshida K, Hamakawa H, Wakejima T, Furuta K, et al. Olanzapine orally disintegrating tablet vs. risperidone oral solution in the treatment of acutely agitated psychotic patients. Gen Hosp Psychiatry. 2008;30:367-71.
-6464. Normann C, Schmauss M, Bakri N, Gerwe M, Schreiner A. Initial treatment of severe acute psychosis with fast orally disintegrating risperidone tablets. Pharmacopsychiatry. 2006;39:209-12. or with lorazepam (B).4646. Currier GW, Simpson GM. Risperidone liquid concentrate and oral lorazepam versus intramuscular haloperidol and intramuscular lorazepam for treatment of psychotic agitation. J Clin Psychiatry. 2001;62:153-7.,4747. Currier GW, Chou JC, Feifel D, Bossie CA, Turkoz I, Mahmoud RA, et al. Acute treatment of psychotic agitation: a randomized comparison of oral treatment with risperidone and lorazepam versus intramuscular treatment with haloperidol and lorazepam. J Clin Psychiatry. 2004;65:386-94.,5959. Veser FH, Veser BD, McMullan JT, Zealberg J, Currier GW. Risperidone versus haloperidol, in combination with lorazepam, in the treatment of acute agitation and psychosis: a pilot, randomized, double-blind, placebo-controlled trial. J Psychiatr Pract. 2006;12:103-8.,6161. Gault TI, Gray SM, Vilke GM, Wilson MP. Are oral medications effective in the management of acute agitation? J Emerg Med. 2012;43:854-9. OS risperidone together with clonazepam was as effective as IM haloperidol2525. Fang M, Chen H, Li LH, Wu R, Li Y, Liu L, et al. Comparison of risperidone oral solution and intramuscular haloperidol with the latter shifting to oral therapy for the treatment of acute agitation in patients with schizophrenia. Int Clin Psychopharmacol. 2012;27:107-13. or PO risperidone in combination with PO lorazepam (B).4646. Currier GW, Simpson GM. Risperidone liquid concentrate and oral lorazepam versus intramuscular haloperidol and intramuscular lorazepam for treatment of psychotic agitation. J Clin Psychiatry. 2001;62:153-7.,4747. Currier GW, Chou JC, Feifel D, Bossie CA, Turkoz I, Mahmoud RA, et al. Acute treatment of psychotic agitation: a randomized comparison of oral treatment with risperidone and lorazepam versus intramuscular treatment with haloperidol and lorazepam. J Clin Psychiatry. 2004;65:386-94.

Aripiprazole

IM aripiprazole showed efficacy for psychomotor agitation control, and equivalence compared to IM haloperidol2323. Daniel DG, Currier GW, Zimbroff DL, Allen MH, Oren D, Manos G, et al. Efficacy and safety of oral aripiprazole compared with haloperidol in patients transitioning from acute treatment with intramuscular formulations. J Psychiatr Pract. 2007;13:170-7.,3636. Tran-Johnson TK, Sack DA, Marcus RN, Auby P, McQuade RD, Oren DA. Efficacy and safety of intramuscular aripiprazole in patients with acute agitation: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2007;68:111-9.,5757. Andrezina R, Josiassen RC, Marcus RN, Oren DA, Manos G, Stock E, et al. Intramuscular aripiprazole for the treatment of acute agitation in patients with schizophrenia or schizoaffective disorder: a double-blind, placebo-controlled comparison with intramuscular haloperidol. Psychopharmacology (Berl). 2006;188:281-92.,5858. De Filippis S, Cuomo I, Lionetto L, Janiri D, Simmaco M, Caloro M, et al. Intramuscular aripiprazole in the acute management of psychomotor agitation. Pharmacotherapy. 2013;33:603-14. and lorazepam.1313. Zimbroff DL, Marcus RN, Manos G, Stock E, McQuade RD, Auby P, et al. Management of acute agitation in patients with bipolar disorder: efficacy and safety of intramuscular aripiprazole. J Clin Psychopharmacol. 2007;27:171-6. The quality of the evidence supporting IM aripiprazole is high (A). However, it was not available in this formulation in Brazil at the time of this review.

Olanzapine

PO or ODT olanzapine may be effective for psychomotor agitation control.2121. Kinon BJ, Ahl J, Rotelli MD, McMullen E. Efficacy of accelerated dose titration of olanzapine with adjunctive lorazepam to treat acute agitation in schizophrenia. Am J Emerg Med. 2004;22:181-6.,6161. Gault TI, Gray SM, Vilke GM, Wilson MP. Are oral medications effective in the management of acute agitation? J Emerg Med. 2012;43:854-9.

62. Hsu WY, Huang SS, Lee BS, Chiu NY. Comparison of intramuscular olanzapine, orally disintegrating olanzapine tablets, oral risperidone solution, and intramuscular haloperidol in the management of acute agitation in an acute care psychiatric ward in Taiwan. J Clin Psychopharmacol. 2010;30:230-4.
-6363. Hatta K, Kawabata T, Yoshida K, Hamakawa H, Wakejima T, Furuta K, et al. Olanzapine orally disintegrating tablet vs. risperidone oral solution in the treatment of acutely agitated psychotic patients. Gen Hosp Psychiatry. 2008;30:367-71.,6565. Baker RW, Kinon BJ, Maguire GA, Liu H, Hill AL. Effectiveness of rapid initial dose escalation of up to forty milligrams per day of oral olanzapine in acute agitation. J Clin Psychopharmacol. 2003;23:342-8.,6666. Escobar R, San L, Perez V, Olivares JM, Polavieja P, Lopez-Carrero C, et al. [Effectiveness results of olanzapine in acute psychotic patients with agitation in the emergency room setting: results from NATURA study]. Actas Esp Psiquiatr. 2008;36:151-7. IM olanzapine is as effective4040. Breier A, Meehan K, Birkett M, David S, Ferchland I, Sutton V, et al. A double-blind, placebo-controlled dose-response comparison of intramuscular olanzapine and haloperidol in the treatment of acute agitation in schizophrenia. Arch Gen Psychiatry. 2002;59:441-8.,6767. Katagiri H, Fujikoshi S, Suzuki T, Fujita K, Sugiyama N, Takahashi M, et al. A randomized, double-blind, placebo-controlled study of rapid-acting intramuscular olanzapine in Japanese patients for schizophrenia with acute agitation. BMC Psychiatry. 2013;13:20. as ziprasidone,22. Baldaçara L, Sanches M, Cordeiro DC, Jackoswski AP. Rapid tranquilization for agitated patients in emergency psychiatric rooms: a randomized trial of olanzapine, ziprasidone, haloperidol plus promethazine, haloperidol plus midazolam and haloperidol alone. Rev Bras Psiquiatr. 2011;33:30-9. haloperidol,22. Baldaçara L, Sanches M, Cordeiro DC, Jackoswski AP. Rapid tranquilization for agitated patients in emergency psychiatric rooms: a randomized trial of olanzapine, ziprasidone, haloperidol plus promethazine, haloperidol plus midazolam and haloperidol alone. Rev Bras Psiquiatr. 2011;33:30-9.,2222. Chan HY, Ree SC, Su LW, Chen JJ, Chou SY, Chen CK, et al. A double-blind, randomized comparison study of efficacy and safety of intramuscular olanzapine and intramuscular haloperidol in patients with schizophrenia and acute agitated behavior. J Clin Psychopharmacol. 2014;34:355-8.,3030. MacDonald K, Wilson M, Minassian A, Vilke GM, Becker O, Tallian K, et al. A naturalistic study of intramuscular haloperidol versus intramuscular olanzapine for the management of acute agitation. J Clin Psychopharmacol. 2012;32:317-22.,3131. MacDonald K, Wilson MP, Minassian A, Vilke GM, Perez R, Cobb P, et al. A retrospective analysis of intramuscular haloperidol and intramuscular olanzapine in the treatment of agitation in drug- and alcohol-using patients. Gen Hosp Psychiatry. 2010;32:443-5.,3737. Wright P, Birkett M, David SR, Meehan K, Ferchland I, Alaka KJ, et al. Double-blind, placebo-controlled comparison of intramuscular olanzapine and intramuscular haloperidol in the treatment of acute agitation in schizophrenia. Am J Psychiatry. 2001;158:1149-51.,4040. Breier A, Meehan K, Birkett M, David S, Ferchland I, Sutton V, et al. A double-blind, placebo-controlled dose-response comparison of intramuscular olanzapine and haloperidol in the treatment of acute agitation in schizophrenia. Arch Gen Psychiatry. 2002;59:441-8.,4242. Mantovani C, Labate CM, Sponholz A, Jr., de Azevedo Marques JM, Guapo VG, de Simone Brito dos Santos ME, 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;33:306-12.,4343. Raveendran NS, Tharyan P, Alexander J, Adams CE, Group TR-IIC. Rapid tranquillisation in psychiatric emergency settings in India: pragmatic randomised controlled trial of intramuscular olanzapine versus intramuscular haloperidol plus promethazine. BMJ. 2007;335:865. and other antipsychotics.1616. Suzuki H, Gen K, Takahashi Y. A naturalistic comparison study of the efficacy and safety of intramuscular olanzapine, intramuscular haloperidol, and intramuscular levomepromazine in acute agitated patients with schizophrenia. Hum Psychopharmacol. 2014;29:83-8.,2727. Huf G, Alexander J, Gandhi P, Allen MH. Haloperidol plus promethazine for psychosis-induced aggression. Cochrane Database Syst Rev. 2016;11:CD005146.,6262. Hsu WY, Huang SS, Lee BS, Chiu NY. Comparison of intramuscular olanzapine, orally disintegrating olanzapine tablets, oral risperidone solution, and intramuscular haloperidol in the management of acute agitation in an acute care psychiatric ward in Taiwan. J Clin Psychopharmacol. 2010;30:230-4.,6868. Castle DJ, Udristoiu T, Kim CY, Sarosi A, Pidrman V, Omar AN, et al. Intramuscular olanzapine versus short-acting typical intramuscular antipsychotics: comparison of real-life effectiveness in the treatment of agitation. World J Biol Psychiatry. 2009;10:43-53.,6969. Perrin E, Anand E, Dyachkova Y, Wagner T, Frediani S, Ballerini A, et al. A prospective, observational study of the safety and effectiveness of intramuscular psychotropic treatment in acutely agitated patients with schizophrenia and bipolar mania. Eur Psychiatry. 2012;27:234-9. The combined use of IM olanzapine and BZDs is not recommended due to the possibility of dangerous effects (e.g., hypotension, bradycardia, and respiratory depression).44. Garriga M, Pacchiarotti I, Kasper S, Zeller SL, Allen MH, Vazquez G, et al. Assessment and management of agitation in psychiatry: Expert consensus. World J Biol Psychiatry. 2016;17:86-128.,3131. MacDonald K, Wilson MP, Minassian A, Vilke GM, Perez R, Cobb P, et al. A retrospective analysis of intramuscular haloperidol and intramuscular olanzapine in the treatment of agitation in drug- and alcohol-using patients. Gen Hosp Psychiatry. 2010;32:443-5. PO/ODT olanzapine (B), IM olanzapine (B), and IV olanzapine were shown to be effective (B).5353. Taylor DM, Yap CYL, Knott JC, Taylor SE, Phillips GA, Karro J, et al. Midazolam-Droperidol, Droperidol, or Olanzapine for Acute Agitation: A Randomized Clinical Trial. Ann Emerg Med. 2017;69:318-26.e1.,5454. Yap CYL, Taylor DM, Knott JC, Taylor SE, Phillips GA, Karro J, et al. Intravenous midazolam-droperidol combination, droperidol or olanzapine monotherapy for methamphetamine-related acute agitation: subgroup analysis of a randomized controlled trial. Addiction. 2017;112:1262-9. Besides, due the same reasons mentioned for haloperidol and droperidol, we do not recommend IV use of olanzapine (D).

Ziprasidone

Ziprasidone was effective at controlling psychomotor agitation.2323. Daniel DG, Currier GW, Zimbroff DL, Allen MH, Oren D, Manos G, et al. Efficacy and safety of oral aripiprazole compared with haloperidol in patients transitioning from acute treatment with intramuscular formulations. J Psychiatr Pract. 2007;13:170-7.,3838. Zhang H, Wang G, Zhao J, Xie S, Xu X, Shi J, et al. Intramuscular ziprasidone versus haloperidol for managing agitation in Chinese patients with schizophrenia. J Clin Psychopharmacol. 2013;33:178-85.,6060. Agid O, Kapur S, Warrington L, Loebel A, Siu C. Early onset of antipsychotic response in the treatment of acutely agitated patients with psychotic disorders. Schizophr Res. 2008;102:241-8.,7070. Lesem MD, Zajecka JM, Swift RH, Reeves KR, Harrigan EP. Intramuscular ziprasidone, 2 mg versus 10 mg, in the short-term management of agitated psychotic patients. J Clin Psychiatry. 2001;62:12-8.,7171. Daniel DG, Potkin SG, Reeves KR, Swift RH, Harrigan EP. Intramuscular (IM) ziprasidone 20 mg is effective in reducing acute agitation associated with psychosis: a double-blind, randomized trial. Psychopharmacology (Berl). 2001;155:128-34. Ziprasidone 20 mg IM was effective when compared with a low dose (2 mg),2323. Daniel DG, Currier GW, Zimbroff DL, Allen MH, Oren D, Manos G, et al. Efficacy and safety of oral aripiprazole compared with haloperidol in patients transitioning from acute treatment with intramuscular formulations. J Psychiatr Pract. 2007;13:170-7.,6060. Agid O, Kapur S, Warrington L, Loebel A, Siu C. Early onset of antipsychotic response in the treatment of acutely agitated patients with psychotic disorders. Schizophr Res. 2008;102:241-8.,7070. Lesem MD, Zajecka JM, Swift RH, Reeves KR, Harrigan EP. Intramuscular ziprasidone, 2 mg versus 10 mg, in the short-term management of agitated psychotic patients. J Clin Psychiatry. 2001;62:12-8.,7171. Daniel DG, Potkin SG, Reeves KR, Swift RH, Harrigan EP. Intramuscular (IM) ziprasidone 20 mg is effective in reducing acute agitation associated with psychosis: a double-blind, randomized trial. Psychopharmacology (Berl). 2001;155:128-34. and had positive results compared to haloperidol (and its combinations),22. Baldaçara L, Sanches M, Cordeiro DC, Jackoswski AP. Rapid tranquilization for agitated patients in emergency psychiatric rooms: a randomized trial of olanzapine, ziprasidone, haloperidol plus promethazine, haloperidol plus midazolam and haloperidol alone. Rev Bras Psiquiatr. 2011;33:30-9.,2727. Huf G, Alexander J, Gandhi P, Allen MH. Haloperidol plus promethazine for psychosis-induced aggression. Cochrane Database Syst Rev. 2016;11:CD005146.,3434. Preval H, Klotz SG, Southard R, Francis A. Rapid-acting IM ziprasidone in a psychiatric emergency service: a naturalistic study. Gen Hosp Psychiatry. 2005;27:140-4.,3838. Zhang H, Wang G, Zhao J, Xie S, Xu X, Shi J, et al. Intramuscular ziprasidone versus haloperidol for managing agitation in Chinese patients with schizophrenia. J Clin Psychopharmacol. 2013;33:178-85.,4242. Mantovani C, Labate CM, Sponholz A, Jr., de Azevedo Marques JM, Guapo VG, de Simone Brito dos Santos ME, 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;33:306-12. olanzapine,22. Baldaçara L, Sanches M, Cordeiro DC, Jackoswski AP. Rapid tranquilization for agitated patients in emergency psychiatric rooms: a randomized trial of olanzapine, ziprasidone, haloperidol plus promethazine, haloperidol plus midazolam and haloperidol alone. Rev Bras Psiquiatr. 2011;33:30-9.,4242. Mantovani C, Labate CM, Sponholz A, Jr., de Azevedo Marques JM, Guapo VG, de Simone Brito dos Santos ME, 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;33:306-12. droperidol,4949. Martel M, Sterzinger A, Miner J, Clinton J, Biros M. Management of acute undifferentiated agitation in the emergency department: a randomized double-blind trial of droperidol, ziprasidone, and midazolam. Acad Emerg Med. 2005;12:1167-72. midazolam,2727. Huf G, Alexander J, Gandhi P, Allen MH. Haloperidol plus promethazine for psychosis-induced aggression. Cochrane Database Syst Rev. 2016;11:CD005146. and lorazepam.2727. Huf G, Alexander J, Gandhi P, Allen MH. Haloperidol plus promethazine for psychosis-induced aggression. Cochrane Database Syst Rev. 2016;11:CD005146. IM ziprasidone is recommended as B.

Asenapine

Finally, SL asenapine was effective for psychomotor agitation control (A).7272. Pratts M, Citrome L, Grant W, Leso L, Opler LA. A single-dose, randomized, double-blind, placebo-controlled trial of sublingual asenapine for acute agitation. Acta Psychiatr Scand. 2014;130:61-8. In a study with120 subjects, participants were randomized to receive SL asenapine or placebo. The change in Excited Component of the Positive and Negative Syndrome Scale (PANSS-EC) at 2 hours was significantly greater in asenapine-treated subjects than in score in placebo-treated subjects. The number needed to treat (NNT) for a response compared to placebo was 3 (95% confidence interval [95%CI] 2-4). The side effects reported were distorted or bad taste and akathisia.7272. Pratts M, Citrome L, Grant W, Leso L, Opler LA. A single-dose, randomized, double-blind, placebo-controlled trial of sublingual asenapine for acute agitation. Acta Psychiatr Scand. 2014;130:61-8.

Clinicians must be aware of SGAs side effects, which include the following: hypotension, excessive sedation, headache, dizziness, nausea, EPS, respiratory arrest, bradycardia, dry mouth, seizure, prolongation of QTc interval, seizure, and syncope.

Benzodiazepines (BZDs)

BZDs enhance the effects of the neurotransmitter gamma-aminobutyric acid (GABA) at the GABA-A receptor, producing sedative, hypnotic (sleep-inducing), anxiolytic, anticonvulsant, and muscle relaxant effects.7373. Griffin CE, Kaye AM, Bueno FR, Kaye AD 3rd,. Benzodiazepine pharmacology and central nervous system-mediated effects. Ochsner J. 2013;13:214-23. BZD side effects include the following: oversedation, dizziness, weakness, loss of orientation, headache, confusion, irritability, paradoxical effect, memory impairment, lack of coordination, risk of falls, dry mouth, blurred vision, hypotension, ataxia, respiratory depression, and cardiorespiratory arrest.

The literature search on oral BZDs for agitation control found only limited data. A systematic review concluded that there is no strong evidence to support or refute the use of BZDs (with or without antipsychotics or in combination with other drugs).2626. Gillies D, Sampson S, Beck A, Rathbone J. Benzodiazepines for psychosis-induced aggression or agitation. Cochrane Database Syst Rev. 2013;9:CD003079. However, considering that BZDs are inexpensive, have moderate side effects, are easy to administer, and can easily be found in most emergency departments, we will discuss the evidence from existing randomized controlled trials (RCTs) and other relevant studies.

Oral risperidone plus oral lorazepam4646. Currier GW, Simpson GM. Risperidone liquid concentrate and oral lorazepam versus intramuscular haloperidol and intramuscular lorazepam for treatment of psychotic agitation. J Clin Psychiatry. 2001;62:153-7.,4747. Currier GW, Chou JC, Feifel D, Bossie CA, Turkoz I, Mahmoud RA, et al. Acute treatment of psychotic agitation: a randomized comparison of oral treatment with risperidone and lorazepam versus intramuscular treatment with haloperidol and lorazepam. J Clin Psychiatry. 2004;65:386-94.,5959. Veser FH, Veser BD, McMullan JT, Zealberg J, Currier GW. Risperidone versus haloperidol, in combination with lorazepam, in the treatment of acute agitation and psychosis: a pilot, randomized, double-blind, placebo-controlled trial. J Psychiatr Pract. 2006;12:103-8. and oral risperidone plus oral clonazepam were effective for psychomotor agitation (B).2525. Fang M, Chen H, Li LH, Wu R, Li Y, Liu L, et al. Comparison of risperidone oral solution and intramuscular haloperidol with the latter shifting to oral therapy for the treatment of acute agitation in patients with schizophrenia. Int Clin Psychopharmacol. 2012;27:107-13. We did not find clinical trials focusing on other oral BZDs. PO diazepam, PO and OS clonazepam, and PO lorazepam may be used for mild to moderate agitation induced by alcohol withdrawal and cocaine intoxication (D).

Further evidence was found for IM lorazepam monotherapy (A),1313. Zimbroff DL, Marcus RN, Manos G, Stock E, McQuade RD, Auby P, et al. Management of acute agitation in patients with bipolar disorder: efficacy and safety of intramuscular aripiprazole. J Clin Psychopharmacol. 2007;27:171-6.,2727. Huf G, Alexander J, Gandhi P, Allen MH. Haloperidol plus promethazine for psychosis-induced aggression. Cochrane Database Syst Rev. 2016;11:CD005146.,3333. Nobay F, Simon BC, Levitt MA, Dresden GM. A prospective, double-blind, randomized trial of midazolam versus haloperidol versus lorazepam in the chemical restraint of violent and severely agitated patients. Acad Emerg Med. 2004;11:744-9.,4141. Alexander J, Tharyan P, Adams C, John T, Mol C, Philip J. Rapid tranquillisation of violent or agitated patients in a psychiatric emergency setting. Pragmatic randomised trial of intramuscular lorazepam v. haloperidol plus promethazine. Br J Psychiatry. 2004;185:63-9.,4545. Bieniek SA, Ownby RL, Penalver A, Dominguez RA. A double-blind study of lorazepam versus the combination of haloperidol and lorazepam in managing agitation. Pharmacotherapy. 1998;18:57-62.,5151. Richards JR, Derlet RW, Duncan DR. Chemical restraint for the agitated patient in the emergency department: lorazepam versus droperidol. J Emerg Med. 1998;16:567-73.,5959. Veser FH, Veser BD, McMullan JT, Zealberg J, Currier GW. Risperidone versus haloperidol, in combination with lorazepam, in the treatment of acute agitation and psychosis: a pilot, randomized, double-blind, placebo-controlled trial. J Psychiatr Pract. 2006;12:103-8. lorazepam plus haloperidol (B),3030. MacDonald K, Wilson M, Minassian A, Vilke GM, Becker O, Tallian K, et al. A naturalistic study of intramuscular haloperidol versus intramuscular olanzapine for the management of acute agitation. J Clin Psychopharmacol. 2012;32:317-22.,4545. Bieniek SA, Ownby RL, Penalver A, Dominguez RA. A double-blind study of lorazepam versus the combination of haloperidol and lorazepam in managing agitation. Pharmacotherapy. 1998;18:57-62.

46. Currier GW, Simpson GM. Risperidone liquid concentrate and oral lorazepam versus intramuscular haloperidol and intramuscular lorazepam for treatment of psychotic agitation. J Clin Psychiatry. 2001;62:153-7.
-4747. Currier GW, Chou JC, Feifel D, Bossie CA, Turkoz I, Mahmoud RA, et al. Acute treatment of psychotic agitation: a randomized comparison of oral treatment with risperidone and lorazepam versus intramuscular treatment with haloperidol and lorazepam. J Clin Psychiatry. 2004;65:386-94.,5959. Veser FH, Veser BD, McMullan JT, Zealberg J, Currier GW. Risperidone versus haloperidol, in combination with lorazepam, in the treatment of acute agitation and psychosis: a pilot, randomized, double-blind, placebo-controlled trial. J Psychiatr Pract. 2006;12:103-8. lorazepam plus olanzapine (B),3030. MacDonald K, Wilson M, Minassian A, Vilke GM, Becker O, Tallian K, et al. A naturalistic study of intramuscular haloperidol versus intramuscular olanzapine for the management of acute agitation. J Clin Psychopharmacol. 2012;32:317-22. midazolam monotherapy (A),1717. Isbister GK, Calver LA, Page CB, Stokes B, Bryant JL, Downes MA. Randomized controlled trial of intramuscular droperidol versus midazolam for violence and acute behavioral disturbance: the DORM study. Ann Emerg Med. 2010;56:392-401.e1.,2727. Huf G, Alexander J, Gandhi P, Allen MH. Haloperidol plus promethazine for psychosis-induced aggression. Cochrane Database Syst Rev. 2016;11:CD005146.,3333. Nobay F, Simon BC, Levitt MA, Dresden GM. A prospective, double-blind, randomized trial of midazolam versus haloperidol versus lorazepam in the chemical restraint of violent and severely agitated patients. Acad Emerg Med. 2004;11:744-9.,4444. Trec Collaborative Group. Rapid tranquillisation for agitated patients in emergency psychiatric rooms: a randomised trial of midazolam versus haloperidol plus promethazine. BMJ. 2003;327:708-13.,4949. Martel M, Sterzinger A, Miner J, Clinton J, Biros M. Management of acute undifferentiated agitation in the emergency department: a randomized double-blind trial of droperidol, ziprasidone, and midazolam. Acad Emerg Med. 2005;12:1167-72.,5050. Knott JC, Taylor DM, Castle DJ. Randomized clinical trial comparing intravenous midazolam and droperidol for sedation of the acutely agitated patient in the emergency department. Ann Emerg Med. 2006;47:61-7. midazolam plus haloperidol (A),22. Baldaçara L, Sanches M, Cordeiro DC, Jackoswski AP. Rapid tranquilization for agitated patients in emergency psychiatric rooms: a randomized trial of olanzapine, ziprasidone, haloperidol plus promethazine, haloperidol plus midazolam and haloperidol alone. Rev Bras Psiquiatr. 2011;33:30-9.,2727. Huf G, Alexander J, Gandhi P, Allen MH. Haloperidol plus promethazine for psychosis-induced aggression. Cochrane Database Syst Rev. 2016;11:CD005146.,4242. Mantovani C, Labate CM, Sponholz A, Jr., de Azevedo Marques JM, Guapo VG, de Simone Brito dos Santos ME, 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;33:306-12. clonazepam monotherapy (C),7474. Chouinard G, Annable L, Turnier L, Holobow N, Szkrumelak N. A double-blind randomized clinical trial of rapid tranquilization with I.M. clonazepam and I.M. haloperidol in agitated psychotic patients with manic symptoms. Can J Psychiatry. 1993;38 Suppl 4:S114-21. flunitrazepam monotherapy (B),2424. Dorevitch A, Katz N, Zemishlany Z, Aizenberg D, Weizman A. Intramuscular flunitrazepam versus intramuscular haloperidol in the emergency treatment of aggressive psychotic behavior. Am J Psychiatry. 1999;156:142-4. midazolam plus droperidol (B),1717. Isbister GK, Calver LA, Page CB, Stokes B, Bryant JL, Downes MA. Randomized controlled trial of intramuscular droperidol versus midazolam for violence and acute behavioral disturbance: the DORM study. Ann Emerg Med. 2010;56:392-401.e1. and IM lorazepam plus oral risperidone (B).4747. Currier GW, Chou JC, Feifel D, Bossie CA, Turkoz I, Mahmoud RA, et al. Acute treatment of psychotic agitation: a randomized comparison of oral treatment with risperidone and lorazepam versus intramuscular treatment with haloperidol and lorazepam. J Clin Psychiatry. 2004;65:386-94.,5959. Veser FH, Veser BD, McMullan JT, Zealberg J, Currier GW. Risperidone versus haloperidol, in combination with lorazepam, in the treatment of acute agitation and psychosis: a pilot, randomized, double-blind, placebo-controlled trial. J Psychiatr Pract. 2006;12:103-8.,6161. Gault TI, Gray SM, Vilke GM, Wilson MP. Are oral medications effective in the management of acute agitation? J Emerg Med. 2012;43:854-9. Regarding the IV route, evidence was obtained for midazolam plus droperidol (1B)4848. Chan EW, Taylor DM, Knott JC, Phillips GA, Castle DJ, Kong DC. Intravenous droperidol or olanzapine as an adjunct to midazolam for the acutely agitated patient: a multicenter, randomized, double-blind, placebo-controlled clinical trial. Ann Emerg Med. 2013;61:72-81.,5353. Taylor DM, Yap CYL, Knott JC, Taylor SE, Phillips GA, Karro J, et al. Midazolam-Droperidol, Droperidol, or Olanzapine for Acute Agitation: A Randomized Clinical Trial. Ann Emerg Med. 2017;69:318-26.e1.,5454. Yap CYL, Taylor DM, Knott JC, Taylor SE, Phillips GA, Karro J, et al. Intravenous midazolam-droperidol combination, droperidol or olanzapine monotherapy for methamphetamine-related acute agitation: subgroup analysis of a randomized controlled trial. Addiction. 2017;112:1262-9. and midazolam plus olanzapine (1B).4848. Chan EW, Taylor DM, Knott JC, Phillips GA, Castle DJ, Kong DC. Intravenous droperidol or olanzapine as an adjunct to midazolam for the acutely agitated patient: a multicenter, randomized, double-blind, placebo-controlled clinical trial. Ann Emerg Med. 2013;61:72-81.

The most frequent side effects of BZDs are respiratory depression, ataxia, excessive sedation, memory impairment, and paradoxical disinhibition.2626. Gillies D, Sampson S, Beck A, Rathbone J. Benzodiazepines for psychosis-induced aggression or agitation. Cochrane Database Syst Rev. 2013;9:CD003079. These effects are stronger with the IV route, in combination with other psychotropic medications, and in individuals who have used nervous system depressant drugs (such as alcohol). Finally, a word of caution against IV diazepam use (indicated for alcohol withdrawal and cocaine intoxication): its active metabolite nordazepam has a much longer elimination half-life, so that the drug accumulates when administered repeatedly, especially in elderly patients because of the drug’s effect on oxidative drug metabolism.2626. Gillies D, Sampson S, Beck A, Rathbone J. Benzodiazepines for psychosis-induced aggression or agitation. Cochrane Database Syst Rev. 2013;9:CD003079.

Antipsychotics vs. benzodiazepines (BZDs)

Although one study concluded that there is no strong evidence to support or refute the use of BZDs for aggression and agitation,2626. Gillies D, Sampson S, Beck A, Rathbone J. Benzodiazepines for psychosis-induced aggression or agitation. Cochrane Database Syst Rev. 2013;9:CD003079. some studies report similar results with BZDs and antipsychotics.

We did not find any study to support the use of oral BZDs as monotherapy for rapid tranquilization. Meanwhile, oral treatment with risperidone and lorazepam appears to be a tolerable and comparable alternative to IM haloperidol and lorazepam for short-term treatment of agitated psychosis in patients who accept oral medications.4646. Currier GW, Simpson GM. Risperidone liquid concentrate and oral lorazepam versus intramuscular haloperidol and intramuscular lorazepam for treatment of psychotic agitation. J Clin Psychiatry. 2001;62:153-7.,4747. Currier GW, Chou JC, Feifel D, Bossie CA, Turkoz I, Mahmoud RA, et al. Acute treatment of psychotic agitation: a randomized comparison of oral treatment with risperidone and lorazepam versus intramuscular treatment with haloperidol and lorazepam. J Clin Psychiatry. 2004;65:386-94. Risperidone OS in combination with clonazepam is an effective treatment, comparable to IM haloperidol, and is well-tolerated for acute agitation in patients with schizophrenia.2525. Fang M, Chen H, Li LH, Wu R, Li Y, Liu L, et al. Comparison of risperidone oral solution and intramuscular haloperidol with the latter shifting to oral therapy for the treatment of acute agitation in patients with schizophrenia. Int Clin Psychopharmacol. 2012;27:107-13. Therefore, we recommend the use of oral BZDs for psychomotor agitation only when administered with antipsychotics (B), except if there is contraindication for antipsychotic use (D).

Similar results have been described for IM lorazepam and IM midazolam as compared to haloperidol monotherapy,2727. Huf G, Alexander J, Gandhi P, Allen MH. Haloperidol plus promethazine for psychosis-induced aggression. Cochrane Database Syst Rev. 2016;11:CD005146.,3333. Nobay F, Simon BC, Levitt MA, Dresden GM. A prospective, double-blind, randomized trial of midazolam versus haloperidol versus lorazepam in the chemical restraint of violent and severely agitated patients. Acad Emerg Med. 2004;11:744-9. haloperidol plus promethazine,2727. Huf G, Alexander J, Gandhi P, Allen MH. Haloperidol plus promethazine for psychosis-induced aggression. Cochrane Database Syst Rev. 2016;11:CD005146.,4141. Alexander J, Tharyan P, Adams C, John T, Mol C, Philip J. Rapid tranquillisation of violent or agitated patients in a psychiatric emergency setting. Pragmatic randomised trial of intramuscular lorazepam v. haloperidol plus promethazine. Br J Psychiatry. 2004;185:63-9.,4444. Trec Collaborative Group. Rapid tranquillisation for agitated patients in emergency psychiatric rooms: a randomised trial of midazolam versus haloperidol plus promethazine. BMJ. 2003;327:708-13. olanzapine,2727. Huf G, Alexander J, Gandhi P, Allen MH. Haloperidol plus promethazine for psychosis-induced aggression. Cochrane Database Syst Rev. 2016;11:CD005146. ziprasidone,2727. Huf G, Alexander J, Gandhi P, Allen MH. Haloperidol plus promethazine for psychosis-induced aggression. Cochrane Database Syst Rev. 2016;11:CD005146. and aripiprazole.1313. Zimbroff DL, Marcus RN, Manos G, Stock E, McQuade RD, Auby P, et al. Management of acute agitation in patients with bipolar disorder: efficacy and safety of intramuscular aripiprazole. J Clin Psychopharmacol. 2007;27:171-6. The results obtained with midazolam were similar to those described for droperidol, however with more oversedation.1717. Isbister GK, Calver LA, Page CB, Stokes B, Bryant JL, Downes MA. Randomized controlled trial of intramuscular droperidol versus midazolam for violence and acute behavioral disturbance: the DORM study. Ann Emerg Med. 2010;56:392-401.e1. In another study, IM lorazepam and lorazepam plus haloperidol were shown to be superior to haloperidol monotherapy and similar to olanzapine.3030. MacDonald K, Wilson M, Minassian A, Vilke GM, Becker O, Tallian K, et al. A naturalistic study of intramuscular haloperidol versus intramuscular olanzapine for the management of acute agitation. J Clin Psychopharmacol. 2012;32:317-22.

The results with midazolam plus haloperidol were similar to those obtained with haloperidol monotherapy, haloperidol plus promethazine, olanzapine, and ziprasidone in the first hours after the first administration. However, after 6 to 12 hours, poor results were measured by the Overt Agitation Severity Scale (OASS) and Overt Aggression Scale (OAS).22. Baldaçara L, Sanches M, Cordeiro DC, Jackoswski AP. Rapid tranquilization for agitated patients in emergency psychiatric rooms: a randomized trial of olanzapine, ziprasidone, haloperidol plus promethazine, haloperidol plus midazolam and haloperidol alone. Rev Bras Psiquiatr. 2011;33:30-9. In the other two studies, the results were similar to those observed with antipsychotics.2727. Huf G, Alexander J, Gandhi P, Allen MH. Haloperidol plus promethazine for psychosis-induced aggression. Cochrane Database Syst Rev. 2016;11:CD005146.,4242. Mantovani C, Labate CM, Sponholz A, Jr., de Azevedo Marques JM, Guapo VG, de Simone Brito dos Santos ME, 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;33:306-12.

IM clonazepam is effective and safe, but slower-acting as compared to IM haloperidol for the treatment of agitated psychiatric patients in need of rapid tranquilization.7474. Chouinard G, Annable L, Turnier L, Holobow N, Szkrumelak N. A double-blind randomized clinical trial of rapid tranquilization with I.M. clonazepam and I.M. haloperidol in agitated psychotic patients with manic symptoms. Can J Psychiatry. 1993;38 Suppl 4:S114-21. IM flunitrazepam was similar to haloperidol.2424. Dorevitch A, Katz N, Zemishlany Z, Aizenberg D, Weizman A. Intramuscular flunitrazepam versus intramuscular haloperidol in the emergency treatment of aggressive psychotic behavior. Am J Psychiatry. 1999;156:142-4. Interestingly, oral risperidone was similar to IM lorazepam.4646. Currier GW, Simpson GM. Risperidone liquid concentrate and oral lorazepam versus intramuscular haloperidol and intramuscular lorazepam for treatment of psychotic agitation. J Clin Psychiatry. 2001;62:153-7. IM lorazepam showed similar results to IM lorazepam plus oral haloperidol or oral risperidone.5959. Veser FH, Veser BD, McMullan JT, Zealberg J, Currier GW. Risperidone versus haloperidol, in combination with lorazepam, in the treatment of acute agitation and psychosis: a pilot, randomized, double-blind, placebo-controlled trial. J Psychiatr Pract. 2006;12:103-8.

The results described with IV midazolam are similar to those of droperidol, although there was a hypoventilation risk.5050. Knott JC, Taylor DM, Castle DJ. Randomized clinical trial comparing intravenous midazolam and droperidol for sedation of the acutely agitated patient in the emergency department. Ann Emerg Med. 2006;47:61-7. The combination of IV midazolam plus droperidol had better results than IV droperidol or IV olanzapine.5353. Taylor DM, Yap CYL, Knott JC, Taylor SE, Phillips GA, Karro J, et al. Midazolam-Droperidol, Droperidol, or Olanzapine for Acute Agitation: A Randomized Clinical Trial. Ann Emerg Med. 2017;69:318-26.e1.,5454. Yap CYL, Taylor DM, Knott JC, Taylor SE, Phillips GA, Karro J, et al. Intravenous midazolam-droperidol combination, droperidol or olanzapine monotherapy for methamphetamine-related acute agitation: subgroup analysis of a randomized controlled trial. Addiction. 2017;112:1262-9. IV lorazepam was less effective in controlling agitation than droperidol.5151. Richards JR, Derlet RW, Duncan DR. Chemical restraint for the agitated patient in the emergency department: lorazepam versus droperidol. J Emerg Med. 1998;16:567-73.

Thus, there is no clear difference between BZDs and antipsychotics regarding their effectiveness for rapid tranquilization. However, differences in side effects must be considered. BZDs can cause more oversedation and respiratory effects and thus should be avoided in patients with sedative drug abuse (i.e., alcohol and opioids), patients with the potential for paradoxical reactions, and patients with respiratory depression risk (D).

First-generation antipsychotics (FGAs) vs. second-generation antipsychotics (SGAs)

PO risperidone plus lorazepam was similar to IM haloperidol plus lorazepam.4646. Currier GW, Simpson GM. Risperidone liquid concentrate and oral lorazepam versus intramuscular haloperidol and intramuscular lorazepam for treatment of psychotic agitation. J Clin Psychiatry. 2001;62:153-7. PO risperidone5959. Veser FH, Veser BD, McMullan JT, Zealberg J, Currier GW. Risperidone versus haloperidol, in combination with lorazepam, in the treatment of acute agitation and psychosis: a pilot, randomized, double-blind, placebo-controlled trial. J Psychiatr Pract. 2006;12:103-8. and oral olanzapine2020. Walther S, Moggi F, Horn H, Moskvitin K, Abderhalden C, Maier N, et al. Rapid tranquilization of severely agitated patients with schizophrenia spectrum disorders: a naturalistic, rater-blinded, randomized, controlled study with oral haloperidol, risperidone, and olanzapine. J Clin Psychopharmacol. 2014;34:124-8. were as effective as PO haloperidol.5959. Veser FH, Veser BD, McMullan JT, Zealberg J, Currier GW. Risperidone versus haloperidol, in combination with lorazepam, in the treatment of acute agitation and psychosis: a pilot, randomized, double-blind, placebo-controlled trial. J Psychiatr Pract. 2006;12:103-8. Risperidone OS in combination with clonazepam is an effective treatment, comparable to IM haloperidol, and is well tolerated for acute agitation in patients with schizophrenia.2525. Fang M, Chen H, Li LH, Wu R, Li Y, Liu L, et al. Comparison of risperidone oral solution and intramuscular haloperidol with the latter shifting to oral therapy for the treatment of acute agitation in patients with schizophrenia. Int Clin Psychopharmacol. 2012;27:107-13. There is no significant difference in effectiveness between IM olanzapine, orally disintegrating olanzapine tablets, and oral risperidone solution compared to IM haloperidol.6262. Hsu WY, Huang SS, Lee BS, Chiu NY. Comparison of intramuscular olanzapine, orally disintegrating olanzapine tablets, oral risperidone solution, and intramuscular haloperidol in the management of acute agitation in an acute care psychiatric ward in Taiwan. J Clin Psychopharmacol. 2010;30:230-4. Oral olanzapine was similar to oral haloperidol.2727. Huf G, Alexander J, Gandhi P, Allen MH. Haloperidol plus promethazine for psychosis-induced aggression. Cochrane Database Syst Rev. 2016;11:CD005146. Risperidone ODT was as effective and tolerable as IM haloperidol.2929. Lim HK, Kim JJ, Pae CU, Lee CU, Lee C, Paik IH. Comparison of risperidone orodispersible tablet and intramuscular haloperidol in the treatment of acute psychotic agitation: a randomized open, prospective study. Neuropsychobiology. 2010;62:81-6.

IM aripiprazole was non-inferior compared to haloperidol.2323. Daniel DG, Currier GW, Zimbroff DL, Allen MH, Oren D, Manos G, et al. Efficacy and safety of oral aripiprazole compared with haloperidol in patients transitioning from acute treatment with intramuscular formulations. J Psychiatr Pract. 2007;13:170-7.,3636. Tran-Johnson TK, Sack DA, Marcus RN, Auby P, McQuade RD, Oren DA. Efficacy and safety of intramuscular aripiprazole in patients with acute agitation: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2007;68:111-9.,5757. Andrezina R, Josiassen RC, Marcus RN, Oren DA, Manos G, Stock E, et al. Intramuscular aripiprazole for the treatment of acute agitation in patients with schizophrenia or schizoaffective disorder: a double-blind, placebo-controlled comparison with intramuscular haloperidol. Psychopharmacology (Berl). 2006;188:281-92. IM olanzapine was similar to haloperidol.2222. Chan HY, Ree SC, Su LW, Chen JJ, Chou SY, Chen CK, et al. A double-blind, randomized comparison study of efficacy and safety of intramuscular olanzapine and intramuscular haloperidol in patients with schizophrenia and acute agitated behavior. J Clin Psychopharmacol. 2014;34:355-8.,4040. Breier A, Meehan K, Birkett M, David S, Ferchland I, Sutton V, et al. A double-blind, placebo-controlled dose-response comparison of intramuscular olanzapine and haloperidol in the treatment of acute agitation in schizophrenia. Arch Gen Psychiatry. 2002;59:441-8. IM olanzapine and ziprasidone had similar results to haloperidol and haloperidol plus promethazine.22. Baldaçara L, Sanches M, Cordeiro DC, Jackoswski AP. Rapid tranquilization for agitated patients in emergency psychiatric rooms: a randomized trial of olanzapine, ziprasidone, haloperidol plus promethazine, haloperidol plus midazolam and haloperidol alone. Rev Bras Psiquiatr. 2011;33:30-9.,3737. Wright P, Birkett M, David SR, Meehan K, Ferchland I, Alaka KJ, et al. Double-blind, placebo-controlled comparison of intramuscular olanzapine and intramuscular haloperidol in the treatment of acute agitation in schizophrenia. Am J Psychiatry. 2001;158:1149-51.,4343. Raveendran NS, Tharyan P, Alexander J, Adams CE, Group TR-IIC. Rapid tranquillisation in psychiatric emergency settings in India: pragmatic randomised controlled trial of intramuscular olanzapine versus intramuscular haloperidol plus promethazine. BMJ. 2007;335:865. Low doses of haloperidol combined with midazolam can be as effective as olanzapine in reducing psychomotor agitation without increasing the risk of extrapyramidal effects.4242. Mantovani C, Labate CM, Sponholz A, Jr., de Azevedo Marques JM, Guapo VG, de Simone Brito dos Santos ME, 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;33:306-12. Olanzapine and ziprasidone were reported to be similar to haloperidol, haloperidol plus promethazine, midazolam, and haloperidol plus midazolam2727. Huf G, Alexander J, Gandhi P, Allen MH. Haloperidol plus promethazine for psychosis-induced aggression. Cochrane Database Syst Rev. 2016;11:CD005146.; however, this article observed a quicker onset of activity with haloperidol plus promethazine and haloperidol plus midazolam, and therefore found no benefit in the use of haloperidol in monotherapy.2727. Huf G, Alexander J, Gandhi P, Allen MH. Haloperidol plus promethazine for psychosis-induced aggression. Cochrane Database Syst Rev. 2016;11:CD005146.

Haloperidol monotherapy was less effective, or at least required additional medication compared to olanzapine with or without a BZD or haloperidol plus a BZD.3030. MacDonald K, Wilson M, Minassian A, Vilke GM, Becker O, Tallian K, et al. A naturalistic study of intramuscular haloperidol versus intramuscular olanzapine for the management of acute agitation. J Clin Psychopharmacol. 2012;32:317-22. In addition, one study suggested the possibility that the anti-agitation effects of IM olanzapine and IM levomepromazine occur more rapidly than those of IM haloperidol.1616. Suzuki H, Gen K, Takahashi Y. A naturalistic comparison study of the efficacy and safety of intramuscular olanzapine, intramuscular haloperidol, and intramuscular levomepromazine in acute agitated patients with schizophrenia. Hum Psychopharmacol. 2014;29:83-8.

IV olanzapine plus midazolam was similar to droperidol plus midazolam.4848. Chan EW, Taylor DM, Knott JC, Phillips GA, Castle DJ, Kong DC. Intravenous droperidol or olanzapine as an adjunct to midazolam for the acutely agitated patient: a multicenter, randomized, double-blind, placebo-controlled clinical trial. Ann Emerg Med. 2013;61:72-81. In contrast, in another study, olanzapine was not superior to IV droperidol.5353. Taylor DM, Yap CYL, Knott JC, Taylor SE, Phillips GA, Karro J, et al. Midazolam-Droperidol, Droperidol, or Olanzapine for Acute Agitation: A Randomized Clinical Trial. Ann Emerg Med. 2017;69:318-26.e1.

Although small differences were observed, side effects were similar in the various studies evaluated to guide the choice in favor of atypical antipsychotics. Therefore, we recommend that the choice between FGAs and SGAs be based on the assessment and experience of the physician who attends each case (D).

Choice between routes of administration

Even though oral administration may be as effective as parenteral administration, it is not free of side effects. Nevertheless, since the oral route is a less invasive, it is the first option to be considered (D). However, it is important to remember that the options that were useful to treat psychomotor agitation were PO, OS, and ODT risperidone, PO and ODT olanzapine, and SL asenapine, as well as the combination of PO risperidone and lorazepam.

The oral route should be chosen if the patient is cooperative, is able to swallow, and is able to wait for the onset of effects, which takes than with parenteral administration. When the oral route is chosen, preference should be given to OS and ODT presentations, which facilitate swallowing, absorption, and the onset of effects (D). For additional details on oral medications recommended for rapid tranquilization, see Table 1.

Table 1
Recommended oral medications for rapid tranquilization in psychomotor agitation* * Only recommended formulations are included.

The IM route accounts for most of the studies. Its absorption and onset of effects is faster than the oral route. The IM route seems best suited for patients with more severe and violent agitation. This route requires training and rigorous monitoring. Again, there are few differences justifying the use of one medication over another. The literature also shows that monotherapy may not always be a good choice, since there are issues related to the repeated administration of medications.22. Baldaçara L, Sanches M, Cordeiro DC, Jackoswski AP. Rapid tranquilization for agitated patients in emergency psychiatric rooms: a randomized trial of olanzapine, ziprasidone, haloperidol plus promethazine, haloperidol plus midazolam and haloperidol alone. Rev Bras Psiquiatr. 2011;33:30-9.,1717. Isbister GK, Calver LA, Page CB, Stokes B, Bryant JL, Downes MA. Randomized controlled trial of intramuscular droperidol versus midazolam for violence and acute behavioral disturbance: the DORM study. Ann Emerg Med. 2010;56:392-401.e1.,2727. Huf G, Alexander J, Gandhi P, Allen MH. Haloperidol plus promethazine for psychosis-induced aggression. Cochrane Database Syst Rev. 2016;11:CD005146.,3030. MacDonald K, Wilson M, Minassian A, Vilke GM, Becker O, Tallian K, et al. A naturalistic study of intramuscular haloperidol versus intramuscular olanzapine for the management of acute agitation. J Clin Psychopharmacol. 2012;32:317-22. Despite the possibility of more side effects with combined medications44. Garriga M, Pacchiarotti I, Kasper S, Zeller SL, Allen MH, Vazquez G, et al. Assessment and management of agitation in psychiatry: Expert consensus. World J Biol Psychiatry. 2016;17:86-128.,1717. Isbister GK, Calver LA, Page CB, Stokes B, Bryant JL, Downes MA. Randomized controlled trial of intramuscular droperidol versus midazolam for violence and acute behavioral disturbance: the DORM study. Ann Emerg Med. 2010;56:392-401.e1.,2727. Huf G, Alexander J, Gandhi P, Allen MH. Haloperidol plus promethazine for psychosis-induced aggression. Cochrane Database Syst Rev. 2016;11:CD005146. (i.e., oversedation and respiratory depression), combinations should be considered in cases of severe agitation, especially associated with violent behavior (D). For additional details on IM medications recommended for rapid tranquilization, see Table 2.

Table 2
Recommended intramuscular medications for rapid tranquilization in psychomotor agitation* * Only recommended formulations are included. Vital signs and electrocardiogram (ECG) monitoring are recommended for patients with high cardiac risk or unknown history.

Table 3 describes the details of IV medications with best evidence for rapid tranquilization of agitated patients. The IV route has been proven effective but is associated with severe side effects, mainly respiratory depression. We do not recommend IV administration (D). If the clinician decides to use the IV route, it should be reserved only for severe cases, where other measures fail and only in places where monitoring of vital signs is continuous (such as with a multiparameter emergency monitor) (D).

Table 3
Best evidence for intravenous medications for rapid tranquilization in psychomotor agitation* * IV route should only be used in places with adequate equipment for cardiorespiratory support. Avoid IV administration if possible. Avoid IV administration in patients at high cardiac risk. Vital signs and electrocardiogram (ECG) monitoring are necessary for patients at high cardiac risk or whose history is unknown. (we do not recommend IV administration due to safety concerns)

At this point, special emphasis must be placed on a parameter guiding the choice of medication and the route to be used: cardiac risk. Psychotropics, especially antipsychotics, are related to the risk of events such as ventricular arrhythmia, QT prolongation (including torsade de pointes), and sudden death.7575. Chung AK, Chua SE. Effects on prolongation of Bazett’s corrected QT interval of seven second-generation antipsychotics in the treatment of schizophrenia: a meta-analysis. J Psychopharmacol. 2011;25:646-66.

76. Wahidi N, Johnson KM, Brenzel A, de Leon J. Two sudden and unexpected deaths of patients with schizophrenia associated with intramuscular injections of antipsychotics and practice guidelines to limit the use of high doses of intramuscular antipsychotics. Case Rep Psychiatry. 2016;2016:9406813.
-7777. Acciavatti T, Martinotti G, Corbo M, Cinosi E, Lupi M, Ricci F, et al. Psychotropic drugs and ventricular repolarisation: the effects on QT interval, T-peak to T-end interval and QT dispersion. J Psychopharmacol. 2017;31:453-60. The literature remains controversial, but points to greater risk with antipsychotics. Regarding the medications covered in these guidelines, risk has been described for chlorpromazine,7878. Berling I, Isbister GK. Prolonged QT risk assessment in antipsychotic overdose using the QT nomogram. Ann Emerg Med. 2015;66:154-64. droperidol,7979. Guy JM, André-Fouet X, Porte J, Bertrand M, Lamaud M, Verneyre H. [Torsades de pointes and prolongation of the duration of QT interval after injection of droperidol]. Ann Cardiol Angeiol (Paris). 1991;40:541-5.,8080. Charbit B, Alvarez JC, Dasque E, Abe E, Demolis JL, Funck-Brentano C. Droperidol and ondansetron-induced QT interval prolongation: a clinical drug interaction study. Anesthesiology. 2008;109:206-12. haloperidol,7676. Wahidi N, Johnson KM, Brenzel A, de Leon J. Two sudden and unexpected deaths of patients with schizophrenia associated with intramuscular injections of antipsychotics and practice guidelines to limit the use of high doses of intramuscular antipsychotics. Case Rep Psychiatry. 2016;2016:9406813.,8181. Vandael E, Vandenberk B, Vandenberghe J, Spriet I, Willems R, Foulon V. Development of a risk score for QTc-prolongation: the RISQ-PATH study. Int J Clin Pharm. 2017;39:424-32. levomepromazine,8282. Pressler J, Lucking M, Melter M, Gerling S. Nonsustained ventricular tachycardia in a patient with acquired long QT syndrome after levomepromazine injection. Intensive Care Med. 2014;40:133-4. olanzapine,7676. Wahidi N, Johnson KM, Brenzel A, de Leon J. Two sudden and unexpected deaths of patients with schizophrenia associated with intramuscular injections of antipsychotics and practice guidelines to limit the use of high doses of intramuscular antipsychotics. Case Rep Psychiatry. 2016;2016:9406813.,7878. Berling I, Isbister GK. Prolonged QT risk assessment in antipsychotic overdose using the QT nomogram. Ann Emerg Med. 2015;66:154-64.,8383. Hasnain M, Vieweg WV. QTc interval prolongation and torsade de pointes associated with second-generation antipsychotics and antidepressants: a comprehensive review. CNS Drugs. 2014;28:887-920. risperidone,7878. Berling I, Isbister GK. Prolonged QT risk assessment in antipsychotic overdose using the QT nomogram. Ann Emerg Med. 2015;66:154-64.,8383. Hasnain M, Vieweg WV. QTc interval prolongation and torsade de pointes associated with second-generation antipsychotics and antidepressants: a comprehensive review. CNS Drugs. 2014;28:887-920. and ziprasidone.7676. Wahidi N, Johnson KM, Brenzel A, de Leon J. Two sudden and unexpected deaths of patients with schizophrenia associated with intramuscular injections of antipsychotics and practice guidelines to limit the use of high doses of intramuscular antipsychotics. Case Rep Psychiatry. 2016;2016:9406813.,8383. Hasnain M, Vieweg WV. QTc interval prolongation and torsade de pointes associated with second-generation antipsychotics and antidepressants: a comprehensive review. CNS Drugs. 2014;28:887-920. Aripiprazole showed the lowest risk.7575. Chung AK, Chua SE. Effects on prolongation of Bazett’s corrected QT interval of seven second-generation antipsychotics in the treatment of schizophrenia: a meta-analysis. J Psychopharmacol. 2011;25:646-66.,7676. Wahidi N, Johnson KM, Brenzel A, de Leon J. Two sudden and unexpected deaths of patients with schizophrenia associated with intramuscular injections of antipsychotics and practice guidelines to limit the use of high doses of intramuscular antipsychotics. Case Rep Psychiatry. 2016;2016:9406813. However, it is necessary to pay attention to patients at high risk of cardiac alterations, such as previous cardiac disease, family history of sudden death or ventricular tachyarrhythmia, abnormalities of ventricular repolarization, and electrolyte imbalances.7777. Acciavatti T, Martinotti G, Corbo M, Cinosi E, Lupi M, Ricci F, et al. Psychotropic drugs and ventricular repolarisation: the effects on QT interval, T-peak to T-end interval and QT dispersion. J Psychopharmacol. 2017;31:453-60. When these risk factors are present, antipsychotic medications should be avoided, as should the parenteral route, especially the IV route. Regarding this last route, the risk will be high even in patients without the mentioned factors.7777. Acciavatti T, Martinotti G, Corbo M, Cinosi E, Lupi M, Ricci F, et al. Psychotropic drugs and ventricular repolarisation: the effects on QT interval, T-peak to T-end interval and QT dispersion. J Psychopharmacol. 2017;31:453-60. For patients with no data or for those known to have the risk factors mentioned, consider electrocardiogram (ECG) monitoring when administering parenteral medications, especially IV medications (D). It is also recommended that the lowest dose be used (D).

A new alternative is loxapine, shown to be efficacious compared to placebo. Loxapine has been used in its IN form for the control of psychomotor agitation (B).5555. Allen MH, Feifel D, Lesem MD, Zimbroff DL, Ross R, Munzar P, et al. Efficacy and safety of loxapine for inhalation in the treatment of agitation in patients with schizophrenia: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2011;72:1313-21.,5656. Kwentus J, Riesenberg RA, Marandi M, Manning RA, Allen MH, Fishman RS, et al. Rapid acute treatment of agitation in patients with bipolar I disorder: a multicenter, randomized, placebo-controlled clinical trial with inhaled loxapine. Bipolar Disord. 2012;14:31-40.,8484. Lesem MD, Tran-Johnson TK, Riesenberg RA, Feifel D, Allen MH, Fishman R, et al. Rapid acute treatment of agitation in individuals with schizophrenia: multicentre, randomised, placebo-controlled study of inhaled loxapine. Br J Psychiatry. 2011;198:51-8. Another alternative is transdermal (TD) nicotine replacement for patients with dependence (B).8585. Allen MH, Debanne M, Lazignac C, Adam E, Dickinson LM, Damsa C. Effect of nicotine replacement therapy on agitation in smokers with schizophrenia: a double-blind, randomized, placebo-controlled study. Am J Psychiatry. 2011;168:395-9.

How to combine medications

One of the greatest dilemmas in rapid tranquilization is whether combinations of different medications should be used. Even if there is evidence of efficacy, administration of combined medications is challenging, and side effects could be amplified. Despite the evidence of efficacy, as discussed in the present article, we do not recommend mixing different routes of administration (for example, administering PO and IM medication at the same time), because absorption and onset of effects will occur at different times and will complicate monitoring.

Regarding the oral route, oral risperidone plus oral lorazepam (B)4646. Currier GW, Simpson GM. Risperidone liquid concentrate and oral lorazepam versus intramuscular haloperidol and intramuscular lorazepam for treatment of psychotic agitation. J Clin Psychiatry. 2001;62:153-7.,4747. Currier GW, Chou JC, Feifel D, Bossie CA, Turkoz I, Mahmoud RA, et al. Acute treatment of psychotic agitation: a randomized comparison of oral treatment with risperidone and lorazepam versus intramuscular treatment with haloperidol and lorazepam. J Clin Psychiatry. 2004;65:386-94. and oral risperidone plus oral clonazepam (B)2525. Fang M, Chen H, Li LH, Wu R, Li Y, Liu L, et al. Comparison of risperidone oral solution and intramuscular haloperidol with the latter shifting to oral therapy for the treatment of acute agitation in patients with schizophrenia. Int Clin Psychopharmacol. 2012;27:107-13. were effective options compared to IM haloperidol plus IM lorazepam and IM haloperidol (Table 1).

Regarding the IM route, haloperidol was shown to be effective and safe when combined with promethazine (A),22. Baldaçara L, Sanches M, Cordeiro DC, Jackoswski AP. Rapid tranquilization for agitated patients in emergency psychiatric rooms: a randomized trial of olanzapine, ziprasidone, haloperidol plus promethazine, haloperidol plus midazolam and haloperidol alone. Rev Bras Psiquiatr. 2011;33:30-9.,2727. Huf G, Alexander J, Gandhi P, Allen MH. Haloperidol plus promethazine for psychosis-induced aggression. Cochrane Database Syst Rev. 2016;11:CD005146.,2828. Huf G, Coutinho ES, Adams CE, Group TC. Rapid tranquillisation in psychiatric emergency settings in Brazil: pragmatic randomised controlled trial of intramuscular haloperidol versus intramuscular haloperidol plus promethazine. BMJ. 2007;335:869.,4141. Alexander J, Tharyan P, Adams C, John T, Mol C, Philip J. Rapid tranquillisation of violent or agitated patients in a psychiatric emergency setting. Pragmatic randomised trial of intramuscular lorazepam v. haloperidol plus promethazine. Br J Psychiatry. 2004;185:63-9.

42. Mantovani C, Labate CM, Sponholz A, Jr., de Azevedo Marques JM, Guapo VG, de Simone Brito dos Santos ME, 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;33:306-12.

43. Raveendran NS, Tharyan P, Alexander J, Adams CE, Group TR-IIC. Rapid tranquillisation in psychiatric emergency settings in India: pragmatic randomised controlled trial of intramuscular olanzapine versus intramuscular haloperidol plus promethazine. BMJ. 2007;335:865.
-4444. Trec Collaborative Group. Rapid tranquillisation for agitated patients in emergency psychiatric rooms: a randomised trial of midazolam versus haloperidol plus promethazine. BMJ. 2003;327:708-13. midazolam,22. Baldaçara L, Sanches M, Cordeiro DC, Jackoswski AP. Rapid tranquilization for agitated patients in emergency psychiatric rooms: a randomized trial of olanzapine, ziprasidone, haloperidol plus promethazine, haloperidol plus midazolam and haloperidol alone. Rev Bras Psiquiatr. 2011;33:30-9.,2727. Huf G, Alexander J, Gandhi P, Allen MH. Haloperidol plus promethazine for psychosis-induced aggression. Cochrane Database Syst Rev. 2016;11:CD005146.,4242. Mantovani C, Labate CM, Sponholz A, Jr., de Azevedo Marques JM, Guapo VG, de Simone Brito dos Santos ME, 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;33:306-12. or lorazepam (B).3030. MacDonald K, Wilson M, Minassian A, Vilke GM, Becker O, Tallian K, et al. A naturalistic study of intramuscular haloperidol versus intramuscular olanzapine for the management of acute agitation. J Clin Psychopharmacol. 2012;32:317-22.,4545. Bieniek SA, Ownby RL, Penalver A, Dominguez RA. A double-blind study of lorazepam versus the combination of haloperidol and lorazepam in managing agitation. Pharmacotherapy. 1998;18:57-62.

46. Currier GW, Simpson GM. Risperidone liquid concentrate and oral lorazepam versus intramuscular haloperidol and intramuscular lorazepam for treatment of psychotic agitation. J Clin Psychiatry. 2001;62:153-7.
-4747. Currier GW, Chou JC, Feifel D, Bossie CA, Turkoz I, Mahmoud RA, et al. Acute treatment of psychotic agitation: a randomized comparison of oral treatment with risperidone and lorazepam versus intramuscular treatment with haloperidol and lorazepam. J Clin Psychiatry. 2004;65:386-94. Droperidol can be combined with midazolam by the IM route (B).1717. Isbister GK, Calver LA, Page CB, Stokes B, Bryant JL, Downes MA. Randomized controlled trial of intramuscular droperidol versus midazolam for violence and acute behavioral disturbance: the DORM study. Ann Emerg Med. 2010;56:392-401.e1. The combination of IM olanzapine and BZDs is not recommended based on the literature (D)44. Garriga M, Pacchiarotti I, Kasper S, Zeller SL, Allen MH, Vazquez G, et al. Assessment and management of agitation in psychiatry: Expert consensus. World J Biol Psychiatry. 2016;17:86-128.,3131. MacDonald K, Wilson MP, Minassian A, Vilke GM, Perez R, Cobb P, et al. A retrospective analysis of intramuscular haloperidol and intramuscular olanzapine in the treatment of agitation in drug- and alcohol-using patients. Gen Hosp Psychiatry. 2010;32:443-5. (Table 2).

Regarding the IV route, IV droperidol, another butyrophenone, has been studied, and efficacy has been demonstrated when combined with midazolam4848. Chan EW, Taylor DM, Knott JC, Phillips GA, Castle DJ, Kong DC. Intravenous droperidol or olanzapine as an adjunct to midazolam for the acutely agitated patient: a multicenter, randomized, double-blind, placebo-controlled clinical trial. Ann Emerg Med. 2013;61:72-81.,5353. Taylor DM, Yap CYL, Knott JC, Taylor SE, Phillips GA, Karro J, et al. Midazolam-Droperidol, Droperidol, or Olanzapine for Acute Agitation: A Randomized Clinical Trial. Ann Emerg Med. 2017;69:318-26.e1.,5454. Yap CYL, Taylor DM, Knott JC, Taylor SE, Phillips GA, Karro J, et al. Intravenous midazolam-droperidol combination, droperidol or olanzapine monotherapy for methamphetamine-related acute agitation: subgroup analysis of a randomized controlled trial. Addiction. 2017;112:1262-9. or lorazepam5151. Richards JR, Derlet RW, Duncan DR. Chemical restraint for the agitated patient in the emergency department: lorazepam versus droperidol. J Emerg Med. 1998;16:567-73. (Table 3). Despite the high level of evidence (1B), it is important to underscore that combinations with BZDs can cause respiratory depression and require the need for ventilatory support.4848. Chan EW, Taylor DM, Knott JC, Phillips GA, Castle DJ, Kong DC. Intravenous droperidol or olanzapine as an adjunct to midazolam for the acutely agitated patient: a multicenter, randomized, double-blind, placebo-controlled clinical trial. Ann Emerg Med. 2013;61:72-81. Therefore, this strategy requires extra care and should not be used in environments with inadequate emergency equipment (D).

Sequence of treatment

The decision to administer the drug repeatedly in cases of psychomotor agitation must be based on the individual characteristics of the patient, and therefore it is difficult to make a recommendation. We suggest that, if necessary, the same medication be used until its maximum daily dose is reached. Then, if additional medication is needed, a different medication is tried. Although there are no studies on the subject, nothing prevents the IM route from being used, but if the patient is calmer, the oral route can be considered for repeated administration (D).

Special situations

Special situations are outside the scope of the present guidelines. Each of these situations requires an individual review. However, we will briefly present the main measures to be taken in cases of agitation due to intoxication, psychiatric disorder, and delirium, and in cases of agitation in the elderly, pregnant women, and children.

Agitation due to intoxication

Unfavorable results have been reported in the literature regarding the safety of medications for rapid tranquilization in patients with acute substance intoxication. Therefore, new clinical trials and specific reviews on the subject are needed. In the presence of known substance abuse by the patient, whether the abuse is related to the agitation or not, special care should be taken. Following the use of drugs that cause central nervous system depression, such as alcohol, BZDs, and opioids, certain medications should be avoided because of the potential to compound the risk of respiratory depression (D).11. Wilson MP, Pepper D, Currier GW, Holloman Jr GH, Feifel D. The psychopharmacology of agitation: Consensus Statement of the American Association for Emergency Psychiatry Project Beta Psychopharmacology Workgroup. West J Emerg Med. 2012;13:26-34.,44. Garriga M, Pacchiarotti I, Kasper S, Zeller SL, Allen MH, Vazquez G, et al. Assessment and management of agitation in psychiatry: Expert consensus. World J Biol Psychiatry. 2016;17:86-128. We recommend haloperidol as having the longest track record of safety and efficacy and minimal effects on respiration (D).11. Wilson MP, Pepper D, Currier GW, Holloman Jr GH, Feifel D. The psychopharmacology of agitation: Consensus Statement of the American Association for Emergency Psychiatry Project Beta Psychopharmacology Workgroup. West J Emerg Med. 2012;13:26-34.,44. Garriga M, Pacchiarotti I, Kasper S, Zeller SL, Allen MH, Vazquez G, et al. Assessment and management of agitation in psychiatry: Expert consensus. World J Biol Psychiatry. 2016;17:86-128. SGAs, such as olanzapine, ziprasidone, and risperidone, have not been well studied in the context of alcohol intoxication, but may provide reasonable alternatives to haloperidol for agitation in this context.11. Wilson MP, Pepper D, Currier GW, Holloman Jr GH, Feifel D. The psychopharmacology of agitation: Consensus Statement of the American Association for Emergency Psychiatry Project Beta Psychopharmacology Workgroup. West J Emerg Med. 2012;13:26-34.,44. Garriga M, Pacchiarotti I, Kasper S, Zeller SL, Allen MH, Vazquez G, et al. Assessment and management of agitation in psychiatry: Expert consensus. World J Biol Psychiatry. 2016;17:86-128. Of note, it is important to distinguish agitation secondary to alcohol intoxication vs. agitation secondary to alcohol withdrawal, as BZDs are preferred over antipsychotics in cases associated with alcohol withdrawal.11. Wilson MP, Pepper D, Currier GW, Holloman Jr GH, Feifel D. The psychopharmacology of agitation: Consensus Statement of the American Association for Emergency Psychiatry Project Beta Psychopharmacology Workgroup. West J Emerg Med. 2012;13:26-34.,44. Garriga M, Pacchiarotti I, Kasper S, Zeller SL, Allen MH, Vazquez G, et al. Assessment and management of agitation in psychiatry: Expert consensus. World J Biol Psychiatry. 2016;17:86-128.

Agitation associated with delirium

Once delirium is suspected, the first measure to be considered is an evaluation of the patient, to investigate and address the underlying cause of the delirium. Treatment of the organic cause is superior to any drug intervention, and excessive sedation without appropriate treatment should be avoided since the failure to reverse the organic factor can lead to death. When delirium associated with an underlying medical abnormality (e.g., hypoglycemia, electrolyte imbalance, or hypoxia) is the likely cause of the agitation, the most important approach is correction of the underlying medical condition.11. Wilson MP, Pepper D, Currier GW, Holloman Jr GH, Feifel D. The psychopharmacology of agitation: Consensus Statement of the American Association for Emergency Psychiatry Project Beta Psychopharmacology Workgroup. West J Emerg Med. 2012;13:26-34.,44. Garriga M, Pacchiarotti I, Kasper S, Zeller SL, Allen MH, Vazquez G, et al. Assessment and management of agitation in psychiatry: Expert consensus. World J Biol Psychiatry. 2016;17:86-128. If immediate pharmacologic control of agitation is needed in a patient with delirium that is not due to alcohol, BZD withdrawal, or sleep deprivation, SGAs are the preferred agents.11. Wilson MP, Pepper D, Currier GW, Holloman Jr GH, Feifel D. The psychopharmacology of agitation: Consensus Statement of the American Association for Emergency Psychiatry Project Beta Psychopharmacology Workgroup. West J Emerg Med. 2012;13:26-34. Haloperidol and risperidone are also acceptable in low doses.11. Wilson MP, Pepper D, Currier GW, Holloman Jr GH, Feifel D. The psychopharmacology of agitation: Consensus Statement of the American Association for Emergency Psychiatry Project Beta Psychopharmacology Workgroup. West J Emerg Med. 2012;13:26-34.,44. Garriga M, Pacchiarotti I, Kasper S, Zeller SL, Allen MH, Vazquez G, et al. Assessment and management of agitation in psychiatry: Expert consensus. World J Biol Psychiatry. 2016;17:86-128. BZDs should be generally avoided because they can exacerbate delirium.11. Wilson MP, Pepper D, Currier GW, Holloman Jr GH, Feifel D. The psychopharmacology of agitation: Consensus Statement of the American Association for Emergency Psychiatry Project Beta Psychopharmacology Workgroup. West J Emerg Med. 2012;13:26-34.,44. Garriga M, Pacchiarotti I, Kasper S, Zeller SL, Allen MH, Vazquez G, et al. Assessment and management of agitation in psychiatry: Expert consensus. World J Biol Psychiatry. 2016;17:86-128.

Agitation in the elderly

In the elderly, agitation should be presumed to result from delirium until proven otherwise, especially in the presence of alterations in attention, orientation, and level of consciousness.44. Garriga M, Pacchiarotti I, Kasper S, Zeller SL, Allen MH, Vazquez G, et al. Assessment and management of agitation in psychiatry: Expert consensus. World J Biol Psychiatry. 2016;17:86-128. If a medical etiology has been excluded, clinicians should consider affective and anxiety disorders as the most prevalent psychiatric causes of agitation in the elderly.44. Garriga M, Pacchiarotti I, Kasper S, Zeller SL, Allen MH, Vazquez G, et al. Assessment and management of agitation in psychiatry: Expert consensus. World J Biol Psychiatry. 2016;17:86-128. After an adequate assessment of the possible etiology, it is recommended to initially try all non-pharmacological strategies. If necessary, proceed with pharmacological interventions and/or physical restraint, but do it judiciously and for a short-term period, with frequent review and close monitoring.44. Garriga M, Pacchiarotti I, Kasper S, Zeller SL, Allen MH, Vazquez G, et al. Assessment and management of agitation in psychiatry: Expert consensus. World J Biol Psychiatry. 2016;17:86-128. As a general principle for the pharmacological treatment of psychiatric agitation in the elderly, cautious use of antipsychotics has been recommended as follows: start with low doses and slowly titrate with small increments in dose, perform an appropriate observation of the medication effects and close-meshed monitoring of the clinical situation, the risks of falls, signs of confusion and oversedation.44. Garriga M, Pacchiarotti I, Kasper S, Zeller SL, Allen MH, Vazquez G, et al. Assessment and management of agitation in psychiatry: Expert consensus. World J Biol Psychiatry. 2016;17:86-128.

Pregnancy

There is a lack of studies assessing the management and treatment of psychiatric agitation in pregnant women, and often the cohorts are too small to detect significant differences between treatment options.44. Garriga M, Pacchiarotti I, Kasper S, Zeller SL, Allen MH, Vazquez G, et al. Assessment and management of agitation in psychiatry: Expert consensus. World J Biol Psychiatry. 2016;17:86-128. Considering the paucity of evidence on this topic, it has been suggested that clinicians should employ mainly verbal interventions in pregnant agitated patients whenever possible, and when medication is required, the minimal but effective amount of medication necessary to reduce agitation and the risk of aggression should be used.44. Garriga M, Pacchiarotti I, Kasper S, Zeller SL, Allen MH, Vazquez G, et al. Assessment and management of agitation in psychiatry: Expert consensus. World J Biol Psychiatry. 2016;17:86-128.,8686. Allen MH, Currier GW, Carpenter D, Ross RW, Docherty JP, Expert Consensus Panel for Behavioral E. The expert consensus guideline series. Treatment of behavioral emergencies 2005. J Psychiatr Pract. 2005;11Suppl 1:5-108; quiz 10-2. If medication is necessary, previous works have suggested haloperidol alone as first-line treatment and three agents as second-line: BZDs or risperidone monotherapy and, with less endorsement, a combination of a BZD and an FGA.44. Garriga M, Pacchiarotti I, Kasper S, Zeller SL, Allen MH, Vazquez G, et al. Assessment and management of agitation in psychiatry: Expert consensus. World J Biol Psychiatry. 2016;17:86-128.,8686. Allen MH, Currier GW, Carpenter D, Ross RW, Docherty JP, Expert Consensus Panel for Behavioral E. The expert consensus guideline series. Treatment of behavioral emergencies 2005. J Psychiatr Pract. 2005;11Suppl 1:5-108; quiz 10-2.

Limitations

The main limitation of the present work is the difficulty in comparing the results of selected studies due to heterogeneity. Studies on agitation use different medications, different doses, and different assessment tools, and they consider different outcomes as success. To minimize this bias, we limited the discussion to studies with an observed response, i.e., a reduction in an objective scale score or being in a quiet or calm state in the first hours to a maximum of 24 hours of administration. We propose that these guidelines should be updated in the future.

Conclusions

After reviewing the available evidence (online-only supplementary material, Table S1), the following recommendations can be made: 1) pharmacologic treatment is indicated only after non-pharmacologic approaches have failed; 2) the cause of the agitation, side effects of the medications, and contraindications must guide the medication choice; 3) the oral route should be preferred for drug administration; 4) IV administration must be avoided; and 5) all subjects must be monitored before and after medication administration. We also propose a hierarchical sequence to guide the pharmacological management of psychomotor agitation, as shown in Figure 1.

Figure 1
Flow diagram of the pharmacological management of psychomotor agitation. CNS: central nervous system; IM = intramuscular; IV = intravenous; ODT = oral disintegrating tablets; OS = oral solution; PO = from the Latin per orem; SL = sublingual.

Acknowledgements

The authors wish to thank the Brazilian Psychiatric Association (ABP) for providing physical space and time during events for team meetings.

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Publication Dates

  • Publication in this collection
    07 Mar 2019
  • Date of issue
    Jul-Aug 2019

History

  • Received
    30 May 2018
  • Accepted
    18 Sept 2018
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