Objective: The purpose of this study was to evaluate the clinical safety an
d efficacy of risperidone compared to haloperidol in patients with treatmen
t-refractory schizophrenia. Method: Sixty-seven medication-unresponsive sub
jects were randomly assigned to treatment with risperidone (N=34) or halope
ridol (N=33), After a 3-7 day-placebo washout period, there was a 4-week, d
ouble-blind, fixed-dose comparison trial that was followed by a 4-week, fle
xible-dose phase. Measures of clinical change were quantified by standard p
sychopathologic and neuromotor instruments. Results: Risperidone demonstrat
ed clinical efficacy superior to that of haloperidol on the total Brief Psy
chiatric Rating Scale (BPRS) after the first 4 weeks of treatment, Risperid
one did not show any advantage over haloperidol after an additional 4 weeks
. Overall improvement on the BPRS at 4 weeks was significantly better for t
he risperidone group (24%) than for the haloperidol group (11%). Risperidon
e-treated subjects were significantly less likely than haloperidol-treated
subjects to require concomitant anticholinergic medication after 4 weeks (2
0% versus 63%); they also had significantly less observable akathisia (24%
versus 53%) and significantly less severe tardive dyskinesia, Baseline char
acteristics that correlated significantly with risperidone response were po
sitive symptoms, conceptual disorganization, akathisia, and tardive dyskine
sia. Conclusions: Risperidone was better tolerated and more effective in a
subset of patients with treatment-refractory schizophrenia. Positive psycho
tic symptoms and extrapyramidal side effects at baseline appear to be power
ful predictors of subsequent response to risperidone.