A systematic review of
the evidence of clozapine’s
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
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
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
Table 3: Summary of evidence for prospective studies comparing pre vs. post clozapine within-subjects
• 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
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
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