A systematic review of
the evidence of clozapine’s
anti-aggressive effects
Catherine Frogley1, Professor David Taylor2, 3, Professor Declan Murphy4 and Dr Marco Picchioni 1, 4

1. St Andrew’s Academic Centre, Kings College London, Institute of Psychiatry
2. King’s College London, Pharmaceutical Sciences Division
3. Pharmacy Department, South London and Maudsley NHS Foundation Trust
4. King’s College London, Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry
Table 1: Summary of evidence for randomised controlled trial studies
Outcome Measure
The increased risk of violence in individuals with Clozapine significantly reduced aggression. schizophrenia is now well established. Reducing this risk Baseline executive function predicted later of violent and aggressive behaviour in schizophrenia and other psychiatric disorders remains a clinical Clozapine most effective in reducing aggression. Clozapine was superior to olanzapine and haloperidol in reducing total physical and verbal Whilst there have been numerous studies investigating pharmacological strategies to reduce symptomology, Clozapine was superior to haloperidol reducing there is relatively little evidence regarding violent and Clozapine was the only drug to significantly reduce However, there is emerging evidence to suggest that the improved at a Weeks 10 and 14 compared to baseline. PANSS did not improve for either group.
second-generation antipsychotic, clozapine, is effective Psychomotor symptoms tension, aggression and at reducing this risk in patients with schizophrenia and excitement, improved in clozapine-treated group compared to baseline. No differences in psychotic some to suggest that it may be the best in selected RCT, Randomised Controlled Trial; MOAS, Modified Overt Aggression Scale; PANSS, Positive and Negative Symptom Scale; ESRS, Extrapyramidal Side effect Rating Scale; FGA, First Generation Antipsychotic; OAS, Overt Aggression Scale; BPRS, Brief Psychiatric Rating Scale.
Table 2: Summary of evidence for prospective studies comparing clozapine to other medication
Outcome Measure
We conducted a systematic electronic database search No differences in depression, anxiety, EPS or for studies that investigated clozapine’s efficacy at reducing aggression in mental disorders. Olanzapine and risperidone superior to clozapine We searched the following databases:
Risk of violence reduced in second generation Reductions on all outcomes higher in clozapine.
Clozapine improved response to behavioural programme and significant decrease in aggression.
Key: PANSS, Positive and Negative Symptom Scale; HAM-D, Hamilton Depression Rating Scale; HAM-A, Hamilton Anxiety Rating Scale;; OAS, Overt Aggression Scale; IS, Impulsivity Scale; CGI, Clinical Global Impression Scale; EPS, Extrapyramidal Symptoms; TR, Treatment-Resistant; TSBC, Time-Sample Behavioural Checklist.
We used a combination of the following
search terms:
Table 3: Summary of evidence for prospective studies comparing pre vs. post clozapine within-subjects
Outcome Measure
• Clozapine (also Clozaril, Azaleptin, Leponex, Fazacio, Clozapine reduced number of aggressive acts, Froidir, Denzapine, Zaponex, Klozapol and Clopine) time spent in seclusion and restraint, emergency Clozapine decreased impulsiveness (32%) and • Schizophren*, psychos* and other psychiatric Significant reductions in time spent in seclusion disorders such as borderline personality disorder, bipolar disorder, post traumatic stress disorder, Clozapine treatment significantly reduced seclusion Zero restraint after six months on clozapine. 70% The search identified:
Clozapine produced significant improvement on • Five prospective non-randomised, open-label studies Key: TR, Treatment-Resistant; ASDS, Aggression and Social Dysfunction Scale; BPRS, Brief Psychiatric Rating Scale; PANSS, Positive and Negative Symptom Scale; OAS, Overt Aggression Scale; IS, Impulsivity Scale; NOISE, Nurses Observation Scale for Inpatient Evaluation.
• Seven prospective non-randomised, open label studies comparing clozapine within-subjects resistant illness or in those who were persistently CONCLUSIONS
aggressive. Its anti-aggressive effects appeared to be ‘specific’, being to some extent greater than both its Clozapine can reduce violence and persistent • Four single-case note studies.
more general antipsychotic and sedative effects.
aggression in patients with schizophrenia, possibly more so than any other anti-psychotic.
There were significant methodological inconsistencies Clozapine’s anti-violent effects appear to be particularly in the studies we identified, particularly surrounding patient recruitment criteria and the definition and prominent in those patients who are persistently We found considerable evidence in support of measurement of violence. Data on therapeutic aggressive, chronically ill or more formally, ‘treatment- clozapine’s ability to reduce violent and aggressive The results of the randomised controlled studies are This anti-aggressive effect is also seen in patients Clozapine’s anti-aggressive effect was most commonly with other psychiatric disorders including emotionally explored in patients with schizophrenia, with less unstable borderline personality disorder, autistic The results of the prospective studies comparing evidence available for other psychiatric disorders, spectrum disorders, post traumatic stress disorder and clozapine to other medication are summarised in table 2.
including borderline personality disorder, autistic learning disability, though the breadth and quality of spectrum disorders, post traumatic stress disorder, The prospective studies looking at clozapine within- bipolar disorder and learning disability.
Larger, randomised, blinded, controlled studies In the case of schizophrenia, there was evidence to with robust characterisation of participants, and suggest that clozapine’s anti-aggressive effect was standardised measures of violence and aggression are more marked particularly in those with treatment needed to fully understand this link and explore the A charity leading innovation in mental health


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