A double-blind trial of risperidone and haloperidol for the treatment of delirium
Han CH and Kim YK;
Commented by , 28 Jul 2004
Background
Haloperidol, safe and efficacious in the treatment of delirium, has been the gold-standard until a recent trend towards the use of atypical antipsychotics. Favourable adverse effect profiles have driven this shift, albeit in the absence of empiric support.
Purpose
Compare the efficacy of risperidone versus haloperidol in the symptomatic treatment of delirium.
Methods
Medical inpatients referred to consultation psychiatry at a Korean tertiary care hospital were screened for delirium using the Confusion Assessment Method and Delirium Rating Scale (DRS). Diagnosis was based on the Structured Clinical Interview for DSM-III-R. Patients with comorbid dementia or other psychiatric diagnoses were excluded.
In a double-blind design, 28 patients were randomly assigned to a flexible-dose of haloperidol or risperidone, starting at 0.75 and 0.5 mg twice a day, respectively. The dose was increased as indicated over 7 days. Two patients in each group dropped out. There were no significant between group differences on age, sex or medical conditions.
Outcome was determined by scores on the Memorial Delirium Assessment Scale (MDAS), measured by a blinded psychiatrist at the same time daily for 7 days. Response was defined as an MDAS score <13. A series of parametric statistical tests at p<0.05 were used.
Results
The mean initial DRS score was 22.76, with no between group differences. At the end of the study (day 7), the mean doses of haloperidol and risperidone were 1.71 mg and 1.02 mg, respectively.
In both groups, the MDAS scores decreased significantly; however no between group differences were found and group-by-time effect was not significant. There was a trend (p=0.11) towards higher response rates in the haloperidol (75%) versus risperidone (42%) group.
None of the study completers had clinically significant adverse effects as determined by psychiatric examination.
Discussion
The generalizability of the study bears review. While the low doses of haloperidol and risperidone are noteworthy and consistent with clinical trends, lower doses in this Asian population may have been sufficient in comparison to Caucasian populations due to pharmacokinetic and pharmacodynamic differences in metabolism (ref. 1) .
The sample may have also represented a milder spectrum of delirium, judging by their baseline DRS scores, along with the exclusion of patients with dementia and substance use disorders.
The small sample size increased the chance of a type II error. Objective advese effect measures would have strengthened the findings, given the perception of improved tolerability driving the use of atypical antipsychotics in delirium. Additional objective outcome measures such as length of hospitalization would have also been of value.
Finally, with the absence of a placebo arm, it is difficult to discern to what extent these findings differ from the natural history of delirium. An outcome strength, however, was the MDAS, a useful measure capturing both hypo- and hyperactive subtypes of delirium.
Notwithstanding these limitations, the study makes an important contribution at a time when atypical antipsychotics are gaining widespread popularity for the treatment of delirium with a dearth of systematic efficacy and safety data.
In this second (ref. 2) published randomized controlled trial of an atypical antipsychotic versus the former gold-standard (haloperidol), there was no evidence of improved efficacy or tolerability with the former. In fact, a trend towards greater improvement with haloperidol was observed.
While anecdotal evidence suggests improved tolerability with atypical antipsychotics, serious adverse events in this medically vulnerable population are emerging: recent stroke warnings, risk of glucose intolerance, abnormal lipid metabolism, and hypotension. Higher powered studies with more objective safety and adverse effect data are required.
References
1. Bond WS. Ethnicity and psychotropic drugs. Clinical Pharmacy 1991:10(6):467-470
2. Skrobik YK, Bergeron N, Dumont M, Gottfried SB. Olanzapine vs haloperidol: treating delirium in a critical care setting. Intensive CareMedicine2004;30:444-449