This Month in Psychopharmacology

Clozapine for Aggression and Violence

Although patients with schizophrenia are not typically aggressive or violent, there is a higher risk of aggression and violence among patients with schizophrenia compared to the general population. Clozapine, the “gold standard” for treating aggression in patients with schizophrenia, became available for use in the United States in 1989. In this systematic review, Faden and Citrome provide an account of the evidence gathered over the past 35 years indicating the use of clozapine for reducing aggressive behaviors. Their review indicates that:.

  • Clozapine has shown superiority over other antipsychotic treatments in ameliorating aggressive behaviors in patients with schizophrenia.
  • Despite universal recommendations to use clozapine in persistently aggressive patients with schizophrenia, clozapine is underutilized.
  • Clozapine may reduce aggression that is psychotic or impulsive in nature but, like virtually all pharmacological treatments, has limited utility in reducing psychopathic aggression (Figure)
  • Optimal dosing of clozapine includes achieving a plasma level of at least 350ng/mL
  • As clozapine is primarily metabolized by cytochrome P450 1A2 enzymes, clozapine dose may need to be lowered in patients with lower P450 1A2 activity (including females and those with elevated caffeine intake) and increased in patients with elevated P450 1A2 activity (including those who smoke cigarettes.
  • Clozapine’s anti-aggression effects appear to be independent of its antipsychotic effects.
  • Clozapine’s anti-aggression effects do not appear to be due to increased sedation.

The authors suggest future studies to further our understanding of clozapine for aggression including determining if the clozapine serum level necessary to have antipsychotic effects differs from the serum level necessary to ameliorate aggressive behaviors. Such studies would allow clinicians to better determine if, when, how, and for whom clozapine should be prescribed.

Types of Aggression

Figure. Types of Aggression
Impulsive, or reactive, aggression involves no planning and is usually an immediate response to an environmental stimulus. Impulsive aggression may reflect emotional hypersensitivity and exaggerated threat perception. Psychotic aggression is attributable to positive symptoms of psychosis, most commonly paranoid delusions of threat or persecution, command hallucinations, and grandiosity. Psychopathic aggression is characterized by the planning of assaults, predatory gain, and lack of remorse. Although impulsive and psychotic aggression can often be ameliorated by treatment with clozapine, no antipsychotic has shown significant efficacy for reducing psychopathic aggression.


Faden J, Citrome L. Schizophr Res 2024;S0920-9964(23)00420. Abstract

Additional Education and Resources:


Encore Presentation
Early Use of LAI Antipsychotics for Patient Adherence, Relapse Prevention, and Brain Preservation
CME/CE Credit: 1.0 | Expires: November 6, 2025


Encore Presentation
A Calming Presence: Managing Agitation in Bipolar Disorder and Schizophrenia
CME/CE Credit: 0.75 | Expires: November 6, 2025


Encore Presentation
Short Circuits? Exploring the Neurobiology Behind Violence and Aggression
CME/CE Credit: 1.0 | Expires: November 3, 2024


NEI Podcast
Episode 190 - (CME) The Neuroethics of Involuntary Treatment for Serious Mental Illness
CME/CE credits: 1.0  |  Expires: July 24, 2026


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