Psychopharmacology of Aggression and Violence in Mental Illness

PsychoGenerally, psychiatric patients do not express violent behavior; however, if it should occur, it is normally brief. Still, clinicians understand that treating violent behavior is challenging.[1] According to Swanson and colleagues, schizophrenia and other major mood disorders often place patients at a higher risk of expressing violent behavior.[2] Further adding to the risk are co-occurring substance use disorders and co-occurring personality disorders.2 In fact, in patients with schizophrenia, a co-occurring substance use disorder increases the chance of violent behavior drastically. An analysis by Fazel and colleagues looked at the violent criminality of 18,423 persons with schizophrenia or other psychoses. They found that the odds ratio for violent crime was 2.1 for persons without a co-occurring substance use disorder, but for persons with a co-occurring substance use disorder, the odds ratio rose to 8.9—a significant difference.[3]  Also, as the risk for substance use disorders in patients with schizophrenia is high, with a lifetime prevalence of 47 percent, an evaluation of an co-occurring disorders is especially important when assessing patients with schizophrenia.[4] Just as managing the schizophrenia is important, managing the co-occurring substance use disorder should be as well. New York University School of Medicine, Department of Psychiatry Professor Emeritus Jan Volavka, M.D., Ph.D. and New York Medical College Clinical Professor of Psychiatry and Behavioral Sciences Leslie Citrome, M.D., M.P.H. review evidence-based treatments in their article “Psychopharmacology of Aggression and Violence in Mental Illness.”

Patients are commonly transported to emergency departments for presenting signs of agitation, as it can easily escalate to aggression and violent behavior. Therefore, as nonpharmacological interventions for managing crisis situations are used, pharmacological approaches are useful approaches as well.[5] According to Volavka and Citrome, while oral medicines are effective, the rapid onset of short-acting parenteral formulations allow for the full effects of the medicine to be reached quicker.5 For example, lorazepam is a useful medicine when the cause of the agitation is unclear or due to alcohol withdrawal. Absorbed intramuscularly, with a half-life of 10 to 20 hours, the usual dosage is 1.5 to 2 mg every one to six hours.[6] However, a benzodiazepine, lorazepam should not be prescribed as a daily medicine as it poses risk for tolerance, dependence, and withdrawal.6 Intramuscular haloperidol is used in combination with intramuscular lorazepam, supported by a trial in which intramuscular haloperidol 5 mg, intramuscular lorazepam 2 mg, and a combination was compared in emergency department patients with psychotic disorders, agitation, and aggression.[7]

Interest has been sparked in three intramuscular formulations of the second-generation antipsychotics: aripiprazole, ziprasidone, and olanzapine.[8] Intramuscular aripiprazole was found to reduce agitation in patients diagnosed with schizophrenia and in patients diagnosed with bipolar disorder, manic or mixed,[9] with a recommended dose of 9.75 mg.[10] Intramuscular ziprasidone, was found to be effective when administered to patients with schizophrenia, schizoaffective disorder, bipolar disorder with psychotic features, or another psychotic disorder who showed signs of agitation or aggression.[11],[12] Volavka and Citrome state that although the product’s label recommends a dosage of 10 or 20 mg, the best dose appears to be 20 mg, as evidenced in two clinical trials.5 Intramuscular olanzapine was also found to be effective in treating agitation and aggression in patients with schizophrenia and bipolar disorder, manic or mixed.[13] While the recommended dosage is 10 mg, lower dosages of 2.5 to 5 mg may also be used.[14] However, patients with hypotension, bradycardia, tachycardia, and syncope should use olanzapine,5 and olanzapine and benzodiazepines should not be used simultaneously.[15]

According to Volavka and Citrome, most of the information about long-term treatment of aggression in patients with mental illness focuses on patients with schizophrenia.5 In fact, antipsychotics are the main long-term pharmacological treatment of aggression in schizophrenia.5 Two studies were designed to study aggression in patients with schizophrenia. The first trial, by Volavka and colleagues, compared the medicines clozapine, olanzapine, risperidone, and haloperidol in 157 patients with schizophrenia or schizoaffective disorder.[16] They found that clozapine better reduced hostility compared to risperidone and haloperidol, but not to olanzapine. The second trial, by Krakowski and colleagues, compared clozapine, olanzapine, and risperidone in 110 patients with schizophrenia or schizoaffective disorder.[17] They found that clozapine was more effective than olanzapine, and that olanzapine was more effective than risperidone.

Citrome states that although not FDA-approved, the anticonvulsant valproate is prescribed often in patients with schizophrenia as an adjunctive medicine for impulse control.[18] An analysis demonstrated that valproate was effective during week one of treatment; however, the results were unable to be replicated and empirical data is unavailable.[19] Another anticonvulsant, lamotrigine, was tested in patients with schizophrenia with contradictory results,[20] but some suggest lamotrigine may be used in cases of patients who are clozapine-resistant.[21] The mood-stabilizer lithium has been found to be effective when reducing aggressive behavior in patients with bipolar disorder[22]; however, there is not enough evidence to state the same for patients with schizophrenia.5

Overall, as several studies have reviewed the effectiveness of many medicines in the management of agitation and aggression in patients with schizophrenia and other major mood disorders, clozapine was found to be the most effective in reducing violent behavior in patients with schizophrenia. As a close second choice, olanzapine was found to be very effective as well. For patients with bipolar disorder, lithium was an effective choice; but anticonvulsants did not show any promise. In review, Volavka and Citrome state that other antipsychotics did not show any effective qualities in reducing aggressive behavior either.

[1] Volavka J. Neurobiology of Violence. 2 ed. Washington, DC: American Psychiatric Publishing, Inc; 2002.

[2] Swanson JW, Holzer CE 3rd, Ganju VK, Jono RT. Violence and psychiatric disorder in the community: evidence from the Epidemiologic Catchment Area surveys [published correction appears in Hosp Community Psychiatry 1991;42:954-955]. Hosp Community Psychiatry 1990;41:761-770.

[3] Fazel S, Gulati G, Linsell L, et al. Schizophrenia and violence: systematic review and meta-analysis. PLoS Med. 2009;6:e1000120.

[4] Regier DA, Farmer ME, Rae DS, et al. Comorbidity of mental disorders with alcohol and other drug abuse. Results from the Epidemiologic Catchment Area (ECA) Study. JAMA. 1990;264:2511-2518.

[5] Volkavka, J. and Citrome, L.L. (2012, April 2). Psychopharmacology of Aggression and Violence in Mental Illness: A Review of Evidence-Based Treatments. Psychiatric Times. Retrieved from http://www.psychiatrictimes.com/display/article/10168/2053737

[6] Greenblatt DJ, Shader RI, Franke K, et al. Pharmacokinetics and bioavailability of intravenous, intramuscular, and oral lorazepam in humans. J Pharm Sci. 1979;68:57-63.

[7] Battaglia J, Moss S, Rush J, et al. Haloperidol, lorazepam, or both for psychotic agitation? A multicenter, prospective, double-blind, emergency department study. Am J Emerg Med. 1997;15:335-340.

[8] Citrome L. Comparison of intramuscular ziprasidone, olanzapine, or aripiprazole for agitation: a quantitative review of efficacy and safety. J Clin Psychiatry. 2007;68:1876-1885.

[9]Zimbroff DL, Marcus RN, Manos G, et al. Management of acute agitation in patients with bipolar disorder: efficacy and safety of intramuscular aripiprazole. J Clin Psychopharmacol. 2007;27:171-176.

[10] Abilify (aripiprazole) product information. http://www.abilify.com/pdf. Accessed April 12, 2012.

[11] Lesem MD, Zajecka JM, Swift RH, et al. Intramuscular ziprasidone, 2 mg versus 10 mg, in the short-term management of agitated psychotic patients [published correction appears in J Clin Psychiatry. 2001;62:209]. J Clin Psychiatry. 2001;62:12-18.

[12] Daniel DG, Potkin SG, Reeves KR, et al. Intramuscular (IM) ziprasidone 20 mg is effective in reducing acute agitation associated with psychosis: a double-blind, randomized trial. Psychopharmacology (Berl). 2001;155:128-134.

[13] Breier A, Meehan K, Birkett M, 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;59:441-448.

[14] Zyprexa (olanzapine) product information. http://pi.lilly.com/us/zyprexa-pi.pdf. Accessed April 12, 2012.

[15] Marder SR, Sorsaburu S, Dunayevich E, et al. Case reports of postmarketing adverse event experiences with olanzapine intramuscular treatment in patients with agitation. J Clin Psychiatry.


[16] Volavka J, Czobor P, Sheitman B, et al. Clozapine, olanzapine, risperidone, and haloperidol in the treatment of patients with chronic schizophrenia and schizoaffective disorder [published correction appears in Am J Psychiatry. 2002;159:2132]. Am J Psychiatry. 2002;159:255-262.

[17] Krakowski MI, Czobor P, Citrome L, et al. Atypical antipsychotic agents in the treatment of violent patients with schizophrenia and schizoaffective disorder. Arch Gen Psychiatry. 2006;63:622-629.

[18] Citrome L. Adjunctive lithium and anticonvulsants for the treatment of schizophrenia: what is the evidence? Expert Rev Neurother. 2009;9:55-71.

[19] Citrome L, Casey DE, Daniel DG, et al. Adjunctive divalproex and hostility among patients with schizophrenia receiving olanzapine or risperidone. Psychiatr Serv. 2004;55:290-294.

[20] Goff DC, Keefe R, Citrome L, et al. Lamotrigine as add-on therapy in schizophrenia: results of 2 placebo-controlled trials. J Clin Psychopharmacol. 2007;27:582-589.

[21] Tiihonen J, Wahlbeck K, Kiviniemi V. The efficacy of lamotrigine in clozapine-resistant schizophrenia: a systematic review and meta-analysis. Schizophr Res. 2009;109:10-14.

[22] Müller-Oerlinghausen B, Lewitzka U. Lithium reduces pathological aggression and suicidality: a mini-review. Neuropsychobiology. 2010;62:43-49.


  • Kelli

    October 17, 2013, 8:27 am

    Spot on with this write-up, I actually believe that this amazing site needs a
    great deal more attention.

  • Wanda

    October 21, 2013, 11:53 pm

    It’s hard to find knowledgeable people on this topic, but you sound like you know what you’re talking about! Thanks

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