The second randomized double-blind trial compared clozapine(Drug information on clozapine), olanzapine(Drug information on olanzapine), and risperidone(Drug information on risperidone) in 110 patients with schizophrenia or schizo-affective disorder who were selected for being violent.31 For reducing overt physical aggression, clozapine was more efficacious than olanzapine, which was, in turn, more efficacious than haloperidol(Drug information on haloperidol).
The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) has yielded important information about antiaggressive effects of antipsychotics.32 In the double-blind phase 1 trial, 1445 patients with chronic schizophrenia were randomly assigned to receive 1 of 5 antipsychotics: risperidone, olanzapine, quetiapine, ziprasidone(Drug information on ziprasidone), or perphenazine(Drug information on perphenazine). They were then followed up for 6 months for violent behavior.33 Violence declined with all medications. The only difference between medications was that perphenazine showed greater violence reduction than quetiapine in some analyses.
Data acquired in the context of the European First Episode Schizophrenia Trial (EUFEST) were used to compare in post hoc analyses the effects of haloperidol, amisulpride(Drug information on amisulpride), olanzapine, quetiapine(Drug information on quetiapine), and ziprasidone on hostility (assessed as a PANSS item).34,35 The results showed that at months 1 and 3, olanzapine was significantly superior to haloperidol, quetiapine, and amisulpride in reducing hostility.
Smaller studies, also summarized in the Table, have shown the superiority of risperidone, quetiapine, and aripiprazole(Drug information on aripiprazole) in comparison with placebo in terms of antiaggressive efficacy.36-38 The effects of ziprasidone could not be distinguished from those of other antipsychotics.33
Thus, randomized controlled trials as well as uncontrolled studies strongly support the superiority of clozapine over other antipsychotics in reducing violent behavior. Emerging evidence suggests that olanzapine may be a good second choice if clozapine cannot be used. However, metabolic adverse effects of these medications must be taken into account when making individual clinical decisions.
Mood stabilizers (anticonvulsants and lithium(Drug information on lithium))
Although not approved by the FDA for impulsive aggression, valproate is frequently prescribed as an adjunctive medication for patients with schizophrenia, perhaps with the expectation that impulse control will be improved.39 Satisfactory efficacy of adjunctive valproate(Drug information on valproate) in schizophrenia has been reported, and post hoc analysis of the hostility item of the PANSS has demonstrated valproate efficacy during the first week of treatment.40,41 However, these results could not be replicated; thus, the empirical data available do not support the efficacy of valproate as adjunctive treatment for violent patients with schizophrenia.
Lamotrigine has been tested as adjunctive treatment in schizophrenia, with contradictory results.42,43 Findings from a recent meta-analysis suggest that lamotrigine(Drug information on lamotrigine) may be useful in the most severely ill patients who are clozapine-resistant.44