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Similarities and Differences in Agitation Related to Schizophrenia or Bipolar Disorder

Provider Perspective
Faculty Perspectives: Similarities and Differences in Agitation Associated with Schizophrenia and Bipolar Disorder

Patients with schizophrenia or bipolar mania can pre­sent with agitation. The behavioral manifestations of agitation are similar for both disease states and are measured in research protocols using the same scales. One of these scales is the Positive and Negative Syndrome Scale, Excited Component, often abbreviated as PANSS-EC or PEC.1 The PEC is a subset of the Positive and Negative Syndrome Scale (PANSS), a tool used as the gold standard for studies of antipsychotics for the treatment of schizophrenia. However, the 5 items included in the PEC (excitement, hostility, tension, uncooperativeness, and poor impulse control) are also characteristic of agitation seen in general, including in bipolar disorder. Each of the items in the PEC are scored from 1 (absent) to 7 (extreme); thus, the minimum PEC score would be 5 (absence of agitation), and the maximum PEC score would be 35 (extreme agitation). Studies of agents used to treat agitation usually require a patient to have a minimum PEC score of 14 or 15 to be eligible to participate in a clinical trial.

The US Food and Drug Administration has approved only 3 medications for the treatment of agitation associated with schizophrenia and bipolar mania: 2 short-acting intramuscular (IM) antipsychotics and 1 inhaled antipsychotic.2 These approvals were based on specific studies done in patients with agitation associated with both schizophrenia and bipolar mania. A question that sometimes arises is whether there are any differences in response depending on diagnosis. To answer this question, it is helpful to examine the clinical trials used to establish efficacy of these agents. The Table includes the outcomes from the pivotal studies used to establish efficacy for the purposes of regulatory approval for these 3 medication interventions.3-8 Responder rates and number needed to treat (NNT) for response versus placebo are not necessarily reported in the original study publications but can be found elsewhere.9-11


Some of the patients in these trials had PEC scores exceeding 30 at baseline, but, on average, PEC scores were in the 17-19 range at baseline. At end point, the most robust improvements were noted for interventions 1 and 3, which also had lower (ie, more robust) NNT values. Importantly, the trials demonstrated that response rates and NNT values for agitation associated with either schizophrenia or bipolar mania were similar or identical for these 2 agents.

1. Montoya A, Valladares A, Lizán L, et al. Validation of the Excited Component of the Positive and Negative Syndrome Scale (PANSS-EC) in a naturalistic sample of 278 patients with acute psychosis and agitation in a psychiatric emergency room. Health Qual Life Outcomes. 2011;9:18.
2. Citrome L, Volavka J. The psychopharmacology of violence: making sensible decisions. CNS Spectr. 2014;19:411-418.
3. Wright P, Birkett M, David SR, 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;158:1149-1151.
4. Meehan K, Zhang F, David S, et al. 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;21:389-397.
5. Andrezina R, Josiassen RC, Marcus RN, 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;188:281-292.
6. 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.
7. Lesem MD, Tran-Johnson TK, Riesenberg RA, et al. Rapid acute treatment of agitation in individuals with schizophrenia: multicentre, randomised, placebo-controlled study of inhaled loxapine. Br J Psychiatry. 2011;198:51-58.
8. Kwentus J, Riesenberg RA, Marandi M, 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.
9. 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.
10. 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;9:235-245.
11. 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;66:318-325.

Last modified: August 30, 2021