Psychosomatics 45:297-301, August 2004
© 2004 The Academy of Psychosomatic Medicine
A Double-Blind Trial of Risperidone and Haloperidol for the Treatment of Delirium
Chang-Su Han, M.D., Ph.D., and
Yong-Ku Kim, M.D., Ph.D.
Received March 10, 2003; revision received Aug. 20, 2003; accepted Aug. 30, 2003. From the Department of Psychiatry, College of Medicine, Korea University Ansan Hospital. Address correspondence to Dr. Kim, Director and Associate Professor, Department of Psychiatry, Korea University, College of Medicine, Ansan Hospital, Ansan City, Gojan Dong, 516, Kyunggi Province, 425-020, Korea; yongku{at}korea.ac.kr (e-mail).
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ABSTRACT
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To compare the clinical efficacy of haloperidol and risperidone for the treatment of delirium, the authors performed a double-blind comparative study. Twenty-eight patients with delirium were recruited and randomly assigned to receive a flexible-dose regimen of haloperidol or risperidone over 7 days. The severity of delirium was assessed by using Memorial Delirium Assessment Scale scores. Scores for each group decreased significantly over the study period. However, no significant differences in mean Memorial Delirium Assessment Scale scores between groups were found. The group-by-time effect was not significant. In addition, there was no significant difference in the frequency of response to the drugs between the two groups. One patient in the haloperidol group experienced mild akathisia, but no other patients reported clinically significant side effects. These data show no significant difference in the efficacy or response rate between haloperidol and risperidone in the treatment of delirium.
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INTRODUCTION
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Delirium is defined as an alteration in mental status that is characterized by disturbance of conciousness and attention, cognition, and perception for a brief period of time and tends to fluctuate during the course of the day. In hospitalized elderly, the prevalence of delirium ranges from 10% to 40%.1 Some physicians have suggested that the incidence of delirium can serve as a quality marker for key aspects of hospital care for older patients.2 Prompt psychiatric treatment is generally recommended to reduce the length of the symptomatic period.3 Antipsychotic medications have been regarded as the treatment of choice for delirium, and haloperidol is most frequently used because of its effectiveness and low incidence of anticholinergic side effects.4,5 However, haloperidol is associated with significant side effects such as extrapyramidal symptoms, which are more frequent in elderly and seriously medically ill patients, who are most vulnerable to delirium.6
Recently, some physicians have reported treating clinical cases of delirium with atypical antipsychotic drugs such as risperidone,7 olanzapine,8,9 and quetiapine.10–12 Among those drugs, risperidone has a relatively high affinity to both serotonin and dopamine receptors, and the antagonistic effect of serotonin receptors can reduce dopamine antagonism related to extrapyradimal symptoms.13 Thus, risperidone has advantages in terms of side effects over the conventional antipsychotics and can be a first-line drug for the treatment of delirium.10
In this study, we compared the clinical efficacy of risperidone with haloperidol for the treatment of delirium.
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METHOD
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Subjects
This study was carried out at Korea University Medical Center, which includes four medical wards, two intensive care units, and two oncology wards. The protocol of this study was approved by the Ethics Committee of Korea University, and informed consent was obtained from the subjects (two patients) or family members (26 patients) after the nature of the study and its procedures had been explained. All patients presenting with altered mental status who were referred to the consulting psychiatry division were evaluated. Patient disease-related and demographic data were collected from their medical records. Screening and detection of delirium were conducted with the Confusion Assessment Method14 and Delirium Rating Scale.15 Diagnosis of delirium was determined with the Structured Clinical Interview for DSM-III-R (SCID)16 according to DSM-III-R criteria.17
Patients with any type of dementia or other psychiatric diagnosis determined with the SCID were excluded. Patients who had already been injected with antipsychotics or benzodiazepines in the emergency room or intensive care unit for their disturbing behavioral problems before the arrival of the consulting psychiatrist were excluded. In addition, one patient lost the ability to communicate verbally due to a tracheotomy and had to be excluded.
Study Design
Twenty-eight subjects were randomly assigned to receive a flexible-dose regimen of haloperidol or risperidone; a double-blind design was used. One of the consulting psychiatrists other than the investigators randomly assigned the patients to either the haloperidol or risperidone group without any knowledge about the patients. It was not possible to obtain identical looking tablets. However, the patients and caretakers did not know the name or effects of their drug. Moreover, the psychiatrist who rated their symptoms had no information about the drugs that the patients were prescribed.
The initial starting dose of each drug was 0.75 mg (haloperidol) or 0.5 mg (risperidone) twice a day. The dosage was increased depending on the status of delirium during the 7 days. During the study, two patients in the haloperidol group dropped out: one because of aggravation of his medical condition on the second day, and one because of severe sedation on the third day. In the risperidone group, two patients dropped out: one because of her husband's refusal to participate in the study on the second day, and one because of a tracheotomy operation on the fourth day. Thus, 24 patients, 12 in each group, completed this study. The groups did not differ significantly in terms of age, sex distribution, or medical conditions (Table 1). At the end of the study (the seventh day), the mean dose of the haloperidol group was 1.71 mg (SD=0.84, range=1.0–3.0), and the mean dose of the risperidone group was 1.02 mg (SD=0.41, range=0.5–2.0).
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TABLE 1. Demographic and Clinical Characteristics of Subjects With Delirium Randomly Assigned to 7 Days of Double-Blind Treatment With Haloperidol or Risperidone
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Delirium Assessment
The Confusion Assessment Method14 was used as a specific tool for screening the status of the patients' delirium. This assessment provides an algorithm for the identification of delirium according to five operational DSM-III-R criteria. The Delirium Rating Scale15 is a 10-item, clinician-rated symptom scale to identify delirium in the medically ill. Items are derived from DSM-III-R criteria, are scored from 0 to 3 or 0 to 4, and evaluate the temporal onset of symptoms, perceptual disturbances, hallucinations, delusions, psychomotor behavior, cognitive status, presence of an underlying organic pathology, sleep-wake disturbances, and fluctuation of symptoms.9,15 Cutoff scores of 10 and 12 have been suggested to distinguish patients with delirium from patients with other neuropsychiatric diseases.15,18 The cutoff score in this study was 13. The Delirium Rating Scale was used as a screening tool in this study. The Memorial Delirium Assessment Scale19 is a physician-rated instrument designed to measure the severity of delirium. Behavioral manifestations and cognitive deficit can be evaluated using this scale. The Memorial Delirium Assessment Scale yields a global score ranging from 0 to 30, with a suggested cutoff score of 13 for delirium.19 In this study, response was defined as having a Memorial Delirium Assessment Scale score under 13. One psychiatrist, blind to the status of treatment, measured the symptom changes at the same time every day for 7 days.
Statistical Analysis
Paired and unpaired Student's t tests, Fisher's exact test, Mann-Whitney U test, Kolomogorov-Smirnov z test, and two-way analysis of variance with repeated measures were used as appropriate. Statistical analysis was performed by using the Statistical Package for Social Science (SPSS 10.0).
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RESULTS
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The mean initial Delirium Rating Scale score for all subjects at screening was 22.76 (SD=4.30). There were no significant differences in mean Delirium Rating Scale scores between the haloperidol group (mean=21.83 [SD=4.43]) and the risperidone group (mean=23.50 [SD=4.19]) (t=–0.95, df=22, p=0.35). The Memorial Delirium Assessment Scale scores of each group decreased significantly during the study period (F=53.95, df=6, 132, p<0.05) (Figure 1). However, no significant difference in the mean Memorial Delirium Assessment Scale scores between the two groups was found (F=0.46, df=1, 22, p=0.51). The group-by-time effect was not significant (F=1.66, df=6, 132, p=0.14).
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FIGURE 1. Memorial Delirium Assessment Scale Scores Over 7 Days in Subjects With Delirium Randomly Assigned to Double-Blind Treatment With Haloperidol or Risperidone
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In addition, there was no significant difference in the frequency of response to the drugs between the two groups (haloperidol group response: 75%, N=9; risperidone group response: 42%, N=5) (p=0.11, Fisher's exact test). The average periods before response (total Memorial Delirium Assessment Scale score under 13) were 4.22 days (SD=2.48) in the haloperidol group and 4.17 days (SD=2.14) in the risperidone group. There were no significant intergroup differences (t=0.06, df=22, p=0.95), although the number of responding patients at the third day of the study period was seven (58.3%) in the haloperidol group and four (33.3%) in the risperidone group.
None of the 24 subjects who finished the study showed clinically significant side effects. One patient in the haloperidol group showed mild symptoms of akathisia but was able to tolerate this for the duration of the study.
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DISCUSSION
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In this study, the efficacy of haloperidol and risperidone for the treatment of delirium was not significantly different. Haloperidol is usually considered to be the first-line drug in the treatment of delirium. According to the American Psychiatric Association guidelines for the treatment of delirium,4 haloperidol should be started at 1–2 mg every 2–4 hours as needed. The potential advantages of haloperidol include the fact that it does not suppress the respiratory drive and is largely nonsedating.20 Moreover, haloperidol can be administered intramuscularly or intravenously. However, haloperidol is frequently associated with adverse side effects, such as extrapyramidal symptoms, sedation, and cognitive disturbances.5,21 Thus, since the development of atypical antipsychotics, many clinicians are prescribing newer antipsychotics such as risperidone, olanzapine, and quetiapine with the hope of fewer extrapyramidal symptoms and greater efficacy. Schwartz and Masand22 reviewed the role of atypical antipsychotics in the treatment of delirium and concluded that these agents have been shown to be effective and well tolerated in common psychotic disorders (e.g., schizophrenia or bipolar disorder), but few studies have evaluated them for the treatment of delirium.
Atypical antipsychotics cause less sedation and fewer extrapyramidal effects than conventional antipsychotics. There has been a report of two patients with delirium who were treated with a low dose of risperidone.7 There are also reports about delirium patients treated with quetiapine10,23,24 as well as reports about the use of olanzapine for delirium.8,9,25,26 Clinical experiences generally support the use of atypical antipsychotics as a reasonable first-line approach to the drug treatment of delirium.22
However, the advantage of using atypical antipsychotics for short-term treatment, which is typical in delirium, is unclear.27 Although the use of high-potency antipsychotic drugs like haloperidol brings an increased risk of extrapyramidal side effects, the actual incidence is low.28–30 Moreover, intravenous use of haloperidol seems to be less likely to cause extrapyramidal side effects in patients with delirium.31 Also, there has been a report that warned of a risk of delirium with risperidone treatment, especially among elderly patients and in particular those receiving other medications or having other disorders affecting the central nervous system.32 Tavcar and Dernovsek also reported a case of delirium induced by risperidone.33
This study has several limitations. First, there was uncertainty about the dosage of the antipsychotics. The initial dose of each drug was 0.75 mg (haloperidol) or 0.5 mg (risperidone) twice a day. But there is not yet a consensus as to what dosage of antipsychotic drugs is sufficient to resolve the symptoms of delirium. As for haloperidol, about 60% blockage of dopamine D2 receptor is sufficient to exert antipsychotic action, and haloperidol blocks more than 80% of D2 receptors. This means that beyond a certain dose (probably about 10 mg per day), there is only a higher risk of neurological side effects with no further improvement in psychiatric condition.34 The dosage of an antipsychotic drug is determined by the route of administration, the patient's age, the severity of agitation, the risk of developing side effects, and the therapeutic setting.27 Usually a low dose (1–10 mg/day) of haloperidol improves symptoms of delirium.28,35,36 When compared with haloperidol, the dosing strategy of risperidone for delirium is still not established because there is less experience and data on the use of risperidone for delirium. Furthermore, anecdotal data suggest that differences exist between Asian and non-Asian populations in the pharmacokinetics of psychotropic agents.37,38 Thus, the effective doses might be lower in our population than those given to Caucasian patients. However, the effective dosage of risperidone should be tested in future systematic research.
The second limitation of this study is the small number of patients. The relatively small size of this study may limit the ability to generalize our findings, and the possibility of a type II error cannot be ruled out. The small number of subjects might have caused the apparent difference in the number of patients who had recovered at the third day of the trial in our study. Further study with a larger number of subjects is strongly recommended.
The third limitation of this study is the lack of an objective rating of the side effects of the drugs. The authors checked for drug side effects but did not use any formal scale. A patient's self-report of side effects in the presence of delirium may underestimate these effects.
In this study, there were no significant differences in efficacy or response rate between haloperidol and risperidone among patients with delirium. Although a larger study might find significant differences, it can be cautiously suggested that risperidone is not superior to haloperidol for the acute treatment of delirium. Further study with a larger sample will be required to confirm these results.
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ACKNOWLEDGMENTS
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Dr. Kim is supported by the Brain Korea 21 Project of the Ministry of Education and Human Resources Development, Republic of Korea. The authors thank Dr. Jong-Woo Baek for help with the clinical assessment of the patients.
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REFERENCES
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ABSTRACT
INTRODUCTION
