Skip to main content

The psychopharmacology of violence: making sensible decisions

  • Leslie Citrome (a1) and Jan Volavka (a2)

Violent behavior associated with mental disorders is a common reason for admission to a psychiatric inpatient unit. Once hospitalized, patients may continue to be intermittently agitated and have persistent aggressive behaviors, preventing their discharge back into the community. Managing agitation quickly with effective pharmacological agents can avoid further escalation to aggression and violence. In the acute setting, this usually involves the parenteral use of antipsychotics, with or without benzodiazepines. Within the past decade, short-acting intramuscular formulations of second-generation antipsychotics have become available and provide a means to induce calm with a substantially lower risk of acute dystonia or akathisia compared with haloperidol. New alternative formulations that avoid injections include inhalation and sublingual administration. Longer-term management of persistent aggressive behavior by reducing the frequency and intensity of future episodes of agitation is more complex. In contrast to agitation associated with schizophrenia or bipolar mania, no agents have yet been approved by regulatory agencies for the treatment of persistent aggressive behavior. The strongest evidence supports the use of clozapine as an antihostility agent, followed by olanzapine. Adjunctive strategies with anticonvulsants and beta-adrenergic agents may also be worthwhile to consider.

Corresponding author
*Address for correspondence: Leslie Citrome, MD, MPH, 11 Medical Park Drive, Suite 106, Pomona, NY 10970, USA. (Email:
Hide All
1. Swift RH, Harrigan EP, Cappelleri JC, Kramer D, Chandler LP. Validation of the behavioural activity rating scale (BARS): a novel measure of activity in agitated patients. J Psychiatr Res. 2002; 36(2): 8795.
2. Lindenmayer JP, Brown E, Baker RW, etal. An excitement subscale of the Positive and Negative Syndrome Scale. Schizophr Res. 2004; 68(2–3): 331337.
3. Yudofsky SC, Silver JM, Jackson W, Endicott J, Williams D. The Overt Aggression Scale for the objective rating of verbal and physical aggression. Am J Psychiatry. 1986; 143(1): 3539.
4. Björkdahl A, Olsson D, Palmstierna T. Nurses’ short-term prediction of violence in acute psychiatric intensive care. Acta Psychiatr Scand. 2006; 113(3): 224229.
5. Kay SR, Opler LA, Fiszbein A. Positive and Negative Syndrome Scale Manual. North Tonawanda, NY: Multi-Health Systems; 2000.
6. Citrome L, Green L. The dangerous agitated patient: what to do right now. Postgrad Med. 1990; 87(2): 231236.
7. Citrome L. Agitation III: pharmacologic treatment of agitation. In: Glick RL, Berlin JS, Fishkind A, Zeller S, eds. Emergency Psychiatry: Principles and Practice. Baltimore, MD: Lippincott Williams & Wilkins, Wolters Kluwer Health; 2008: 137147.
8. Regier DA, Farmer ME, Rae DS, etal. Comorbidity of mental disorders with alcohol and other drug abuse: results from the Epidemiologic Catchment Area (ECA) Study. JAMA. 1990; 264(19): 25112518.
9. Battaglia J, Moss S, Rush J, etal. Haloperidol, lorazepam, or both for psychotic agitation? A multicenter, prospective, double-blind, emergency department study. Am J Emerg Med. 1997; 15(4): 335340.
10. Brook S, Lucey JV, Gunn KP. Intramuscular ziprasidone compared with intramuscular haloperidol in the treatment of acute psychosis: Ziprasidone I.M. Study Group. J Clin Psychiatry. 2000; 61(12): 933941.
11. Daniel DG, Zimbroff DL, Swift RH, Harrigan EP. The tolerability of intramuscular ziprasidone and haloperidol treatment and the transition to oral therapy. Int Clin Psychopharmacol. 2004; 19(1): 915.
12. Brook S, Walden J, Benattia I, Siu CO, Romano SJ. Ziprasidone and haloperidol in the treatment of acute exacerbation of schizophrenia and schizoaffective disorder: comparison of intramuscular and oral formulations in a 6-week, randomized, blinded-assessment study. Psychopharmacology (Berl). 2005; 178(4): 514523.
13. Wright P, Meehan K, Birkett M, etal. A comparison of the efficacy and safety of olanzapine versus haloperidol during transition from intramuscular to oral therapy. Clin Ther. 2003; 25(5): 14201428.
14. Andrezina R, Marcus RN, Oren DA, etal. Intramuscular aripiprazole or haloperidol and transition to oral therapy in patients with agitation associated with schizophrenia: sub-analysis of a double-blind study. Curr Med Res Opin. 2006; 22(11): 22092219.
15. 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(1): 1218.
16. 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(2): 128134.
17. Citrome L. Comparison of intramuscular ziprasidone, olanzapine, or aripiprazole for agitation: a quantitative review of efficacy and safety. J Clin Psychiatry. 2007; 68(12): 18761885.
18. Pfizer Inc. Geodon: US package insert for Geodon (ziprasidone HCl) capsules and Geodon (ziprasidone mesylate) injection for intramuscular use. September 2013. Accessed December 2, 2013.
19. Wright P, Birkett M, David SR, etal. Double-blind, placebo-controlled comparison of intramuscular olanzapine and intramuscular haloperidol in the treatment of acute agitation in schizophrenia. Am J Psychiatry. 2001; 158(7): 11491151.
20. Breier A, Meehan K, Birkett M, etal. 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(5): 441448.
21. Meehan K, Zhang F, David S, etal. A double-blind, randomized comparison of the efficacy and safety of intramuscular injections of olanzapine, lorazepam, or placebo in treating acutely agitated patients diagnosed with bipolar mania. J Clin Psychopharmacol. 2001; 21(4): 389397.
22. Meehan KM, Wang H, David SR, etal. Comparison of rapidly acting intramuscular olanzapine, lorazepam, and placebo: a double-blind, randomized study in acutely agitated patients with dementia. Neuropsychopharmacology. 2002; 26(4): 494504.
23. Andrezina R, Josiassen RC, Marcus RN, etal. 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(3): 281292.
24. Tran-Johnson TK, Sack DA, Marcus RN, etal. Efficacy and safety of intramuscular aripiprazole in patients with acute agitation: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2007; 68(1): 111119.
25. Zimbroff DL, Marcus RN, Manos G, etal. Management of acute agitation in patients with bipolar disorder: efficacy and safety of intramuscular aripiprazole. J Clin Psychopharmacol. 2007; 27(2): 171176.
26. Rappaport SA, Marcus RN, Manos G, McQuade RD, Oren DA. A randomized, double-blind, placebo-controlled tolerability study of intramuscular aripiprazole in acutely agitated patients with Alzheimer's, vascular, or mixed dementia. J Am Med Dir Assoc. 2009; 10(1): 2127.
27. Allen MH, Feifel D, Lesem MD, etal. 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(10): 13131321.
28. Lesem MD, Tran-Johnson TK, Riesenberg RA, etal. Rapid acute treatment of agitation in individuals with schizophrenia: multicentre, randomised, placebo-controlled study of inhaled loxapine. Br J Psychiatry. 2011; 198(1): 5158.
29. Kwentus J, Riesenberg RA, Marandi M, etal. 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(1): 3140.
30. Citrome L. Inhaled loxapine for agitation revisited: focus on effect sizes from 2 Phase III randomised controlled trials in persons with schizophrenia or bipolar disorder. Int J Clin Pract. 2012; 66(3): 318325.
31. Citrome L. Addressing the need for rapid treatment of agitation in schizophrenia and bipolar disorder: focus on inhaled loxapine as an alternative to injectable agents. Ther Clin Risk Manag. 2013; 9: 235245.
32. Merck & Co., Inc. Saphris: US package insert for Saphris (asenapine) sublingual tablets. March 2013. Accessed December 2, 2013.
33. Citrome L. Asenapine for schizophrenia and bipolar disorder: a review of the efficacy and safety profile for this newly approved sublingually absorbed second-generation antipsychotic. Int J Clin Pract. 2009; 63(12): 17621784.
34. 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 Psychiatrica Scand. In press.
35. Wilson MP, Pepper D, Currier GW, Holloman GH Jr, 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(1): 2634.
36. Volavka J, Citrome L. Heterogeneity of violence in schizophrenia and implications for long-term treatment. Int J Clin Pract. 2008; 62(8): 12371245.
37. Nolan KA, Volavka J, Czobor P, etal. Aggression and psychopathology in treatment-resistant inpatients with schizophrenia and schizoaffective disorder. J Psychiatr Res. 2005; 39(1): 109115.
38. Nolan KA, Volavka J, Mohr P, Czobor P. Psychopathy and violent behavior among patients with schizophrenia or schizoaffective disorder. Psychiatr Serv. 1999; 50(6): 787792.
39. Cooke DJ, Michie C. Refining the construct of psychopathy: towards a hierarchical model. Psychol Assess. 2001; 13(2): 171188.
40. Nolan KA, Czobor P, Roy BB, etal. Characteristics of assaultive behavior among psychiatric inpatients. Psychiatr Serv. 2003; 54(7): 10121016.
41. Citrome L. New second-generation long-acting injectable antipsychotics for the treatment of schizophrenia. Expert Rev Neurother. 2013; 13(7): 767783.
42. Volavka J, Zito JM, Vitrai J, Czobor P. Clozapine effects on hostility and aggression in schizophrenia. J Clin Psychopharmacol. 1993; 13(4): 287289.
43. Citrome L, Volavka J, Czobor P, etal. Effects of clozapine, olanzapine, risperidone, and haloperidol on hostility among patients with schizophrenia. Psychiatr Serv. 2001; 52(11): 15101514.
44. Volavka J, Czobor P, Nolan K, etal. Overt aggression and psychotic symptoms in patients with schizophrenia treated with clozapine, olanzapine, risperidone, or haloperidol. J Clin Psychopharmacol. 2004; 24(2): 225228.
45. Krakowski MI, Czobor P, Citrome L, Bark N, Cooper TB. Atypical antipsychotic agents in the treatment of violent patients with schizophrenia and schizoaffective disorder. Arch Gen Psychiatry. 2006; 63(6): 622629.
46. Citrome L. Clozapine for schizophrenia: life-threatening or life-saving treatment? Current Psychiatry. 2009; 8(12): 5663.
47. Volavka J, Czobor P, Derks EM, etal; EUFEST Study Group. Efficacy of antipsychotic drugs against hostility in the European First-Episode Schizophrenia Trial (EUFEST). J Clin Psychiatry. 2011; 72(7): 955961.
48. Volavka J, Czobor P, Citrome L, Van Dorn RA. Effectiveness of antipsychotic drugs against hostility in patients with schizophrenia in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study. CNS Spectr. In press. DOI:
49. Kinon BJ, Roychowdhury SM, Milton DR, Hill AL. Effective resolution with olanzapine of acute presentation of behavioral agitation and positive psychotic symptoms in schizophrenia. J Clin Psychiatry. 2001; 62(Suppl 2): 1721.
50. Citrome L, Volavka J. Pharmacological management of acute and persistent aggression in forensic psychiatry settings. CNS Drugs. 2011; 25(12): 10091021.
51. Citrome L. Adjunctive lithium and anticonvulsants for the treatment of schizophrenia: what is the evidence? Expert Rev Neurother. 2009; 9(1): 5571.
52. Citrome L, Levine J, Allingham B. Changes in use of valproate and other mood stabilizers for patients with schizophrenia from 1994 to 1998. Psychiatr Serv. 2000; 51(5): 634638.
53. Citrome L, Shope CB, Nolan KA, Czobor P, Volavka J. Risperidone alone versus risperidone plus valproate in the treatment of patients with schizophrenia and hostility. Int Clin Psychopharmacol. 2007; 22(6): 356362.
54. Huband N, Ferriter M, Nathan R, Jones H. Antiepileptics for aggression and associated impulsivity. Cochrane Database Syst Rev. 2010;(2): CD003499.
55. Ratey JJ, Sorgi P, O'Driscoll GA, etal. Nadolol to treat aggression and psychiatric symptomatology in chronic psychiatric inpatients: a double-blind, placebo-controlled study. J Clin Psychiatry. 1992; 53(2): 4146.
56. Alpert M, Allan ER, Citrome L, etal. A double-blind, placebo-controlled study of adjunctive nadolol in the management of violent psychiatric patients. Psychopharmacol Bull. 1990; 26(3): 367371.
57. Caspi N, Modai I, Barak P, etal. Pindolol augmentation in aggressive schizophrenic patients: a double-blind crossover randomized study. Int Clin Psychopharmacol. 2001; 16(2): 111115.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

CNS Spectrums
  • ISSN: 1092-8529
  • EISSN: 2165-6509
  • URL: /core/journals/cns-spectrums
Please enter your name
Please enter a valid email address
Who would you like to send this to? *



Altmetric attention score

Full text views

Total number of HTML views: 12
Total number of PDF views: 147 *
Loading metrics...

Abstract views

Total abstract views: 701 *
Loading metrics...

* Views captured on Cambridge Core between September 2016 - 25th November 2017. This data will be updated every 24 hours.