An open pilot trial of olanzapine for delirium in the Korean population
Correspondence address: Chi-UnPae Department of Psychiatry, College of Medicine, The Catholic University of Korea, St. Mary's Hospital, 62 Youido-Dong, Youngdeungpo-Gu, Seoul 150–713, Korea. Email: firstname.lastname@example.org
Abstract This study was performed to assess the efficacy and safety of olanzapine for the treatment of delirium in a Korean population. An open trial of olanzapine was conducted in Korean patients with delirium caused by multiple medicosurgical conditions. All subjects were evaluated by Delirium Rating Scale (DRS), which is known to be one of the most sensitive scales for delirium. In addition, other data for profiles of side-effects were collected and analyzed. Twenty patients were treated by olanzapine with doses of 5.9 ± 1.5 mg/day. The initial dose was 4.6 ± 0.9 mg/day and maximal dose of olanzapine was 8.8 ± 2.2 mg/day. The average duration of treatment was 6.6 ± 1.7 days and the day of maximal response was 3.8 ± 1.7 treated days. The scores of DRS were significantly improved from 20.0 ± 3.6 at the time of pretreatment to 9.3 ± 4.6 at the post-treatment. All subjects showed no definite serious side-effects including anticholinergic and extrapyramidal symptoms. Olanzapine treatment for patients with delirium was effective and safe. This newer drug may be a useful alternative agent to classical antipsychotics in the treatment of delirium.
Delirium is a potentially fatal neuropsychiatric syndrome characterized by fluctuating levels of consciousness and global impairment of cognitive functioning, frequently accompanying abnormalities in mood, perception, behavior, and neurological symptoms including tremor, asterixis, and incoordination.1
Levkoff et al. reviewed studies published through 1990 and concluded that the prevalence of delirium ranged from 11% to 16% in medical inpatients, and the incidence of cases that developed in the hospital ranged from 4% to 10%.2 Studies in elderly patients with a hip fracture undergoing surgery showed a rate of postoperative delirium of 28–44%, 6.8% in a more younger patient group with cardiovascular operation and the prevalence of delirium in cancer patients is estimated to be between 20%, in ambulatory patients, and to as high as 85% in patients in the last weeks of life.3
Typical high-potency neuroleptics such as haloperidol have traditionally been used as the first line therapy in the treatment of delirium and this was replicated in the study by Someya et al., which surveyed clinical experiences with various neuroleptics for the treatment of delirium; 97% of participating facilities considered haloperidol the first choice drug.4 Although, we did not find accurate incidence of high-potency neuroleptic-induced EPS for treatment of delirium through a search of Medline, typical high-potency neuroleptics were also known to cause EPS which are vulnerable to elderly and serious medically ill patients, who are more prone to develop delirium.5 Similarly, in a recent study by Someya et al. haloperidol was thought to have troublesome EPS for the treatment of delirium; 39% of participating facilities thought haloperidol showed extrapyramidal symptom (EPS) for the treatment of delirium.4 At present, the newer, atypical antipsychotics are a growing class of agents that has the potential to replace typical neuroleptics.6 These drugs have the benefit of lower rates of EPS and akathisia. The first atypical antipsychotic drug, clozapine, had been available for a temporary period but concerns related to the need for blood count monitoring and possible risk of agranulocytosis had limited its wide usage.7 More recently, risperidone and olanzapine, providing the same or better potential efficacy as traditional antipsychotics, but safer adverse effect profile have become popularly available.8
In 1997, Sipahimalani and Masand used risperidone to treat two patients with delirium, which were the very first cases that this atypical antipsychotic was used in the treatment of this condition.9 The first use of olanzapine in the management of delirium was conducted in 1998 by the same researchers.10 They compared the response of 11 delirious hospitalized patients treated with haloperidol with the same number of patients treated with olanzapine. This open study concluded that olanzapine might be a useful alternative agent to haloperidol. Apart from those pioneering trials, there were several other studies related to the use of atypical antipsychotics in the setting of intensive care units or in geriatric patients.11–14 The use of risperidone for delirium has been suggested more often,15 while the large and systematic reports for the use of olanzapine in this acute confusional state, have until now been less well documented.
With this background, we designed this study to investigate efficacy and tolerability of olanzapine in the treatment of delirium in a larger sample.
SUBJECTS AND METHODS
Twenty Korean patients enrolled in this open label study. They had been referred to the psychiatric department from the departments of neurosurgery, neurology, and bone marrow transplantation unit due to the delirious behavior they displayed during hospitalization for multiple medico-surgical conditions. All patients met DSM-IV criteria for delirium.16 After complete description of the study to the primary relatives of subjects, written informed consent was obtained. Only subjects who had no psychiatric problems in the past and who had not been taking antipsychotics were included in the present study; therefore, olanzapine was their first experience of antipsychotics.
All subjects were treated with olanzapine, which was started and the dose adjusted as needed until maximum clinical benefit was achieved. Olanzapine was administered orally and prohibited any other oral or parenteral agents of antipsychotics or benzodiazepines. Efficacy of olanzapine was evaluated according to the Delirium Rating Scale (DRS),17 which was rated by a trained psychiatrist who was blind as to the condition of management. Full neurological evaluations were performed at the time of before starting treatment, and on the day of maximal response to olanzapine.
Descriptive statistics and paired t-tests were performed using the SPSS for Windows 9.0 (SPSS, Chicago, IL, USA). All P-values less than 0.05 were considered significant.
The subjects consisted of 15 males and five females. The age of subjects was 45.8 ± 18.3 years (range 19–74). Medical diagnoses of subjects included: leukaemia (n = 11), traumatic brain injury (n = 2), cerebrovascular attack (n = 2), postoperatve state due to orthopedic problems (n = 2), coronary heart disease (n = 1), Alzheimer's dementia (n = 1) and chronic obstructive pulmonary disease (n = 1). The reason for the high distribution of leukemia patients was that the bone marrow transplantation unit of the site where this study was performed, had regular consultation liaison meetings with the psychiatrist.
Mean dose of olanzapine was 5.9 (± 1.5) mg/day, mean maximal dose was 8.8 (± 2.2) mg/day, mean initial dose was 4.6 (± 0.9) mg/day, mean duration of administration was 6.6 (± 1.7) days, and mean day of maximal response was 3.8 (± 1.7) days.
The scores of DRS at the time of pretreatment, 20.0 ± 3.6, and after-treatment, 9.3 ± 4.6, were significantly different (t = 10.9, d.f. = 19, P < 0.01). Fourteen of 20 patients (70%) showed reductions of DRS scores, more than 50% after treatment of olanzapine. Eleven of 14 patients who showed decreased scores of DRS 50% or more were leukemia patients. Olny one patient with traumatic brain injury had an increased DRS score, from 19 to 21, after olanzapine administration; the change of DRS score was included in data analysis but the day of maximal response in this patient was not calculated. These data are shown in Table 1.
Table 1. Characteristics of subjects, medication history and changes of Delirium Rating Scale (DRS) for pretreatment and post-treatment with olanzapine
|Age|| ||45.8 ± 18.3|
|Traumatic brain injury||2|
| Chronic obstructive|
|Coronary artery disease||1|
|Mean dose (mg/day)||20||5.9 ± 1.5|
|Initial dose (mg/day)||20||4.6 ± 0.9|
|Duration of treatment (day)||20||6.6 ± 1.7|
|Maximal dose(mg/day)||20||8.8 ± 2.2|
|Day of maximal response||19||3.8 ± 1.7|
|Delirium rating scale (DRS)*||20|
|DRS of pretreatment|| ||20.0 ± 3.6|
|DRS of post-treatment|| ||9.3 ± 4.6|
All 20 patients completed the present study. No patient discontinued the drug due to serious side-effects. Only the two patients with traumatic brain injury showed mild sedation and dry mouth.
Typical high-potency antipsychotics, considered as first line therapy in the management of delirium, are frequently associated with adverse events, such as anticholinergic effects and EPS which are vulnerable to elderly and serious medically ill patients.5 Thus, it is not surprising that olanzapine, which has been reported as having definite efficacy in various psychotic conditions with minimal side-effects,18 would draw the interest of clinicians for the applicability in delirium.
In the USA, Sipahimalani and Masand first performed a small, open controlled study of olanzapine use, comparing haloperidol in 11 patients with delirium and reported that five of the 11 olanzapine patients (45%) showed significant improvement (> 50% score reduction) on the scores of DRS and no patient had side-effects.10 This is in contrast with six of the 11 haloperidol-treated subjects who showed improvement on the DRS and five had extrapyramidal symptoms or excessive sedation. They concluded that olanzapine might be a useful alternative to haloperidol in the treatment of delirium in hospitalized patients. In their study, mean dose of olanzapine was 8.2 (± 3.4) mg/day, peak response time was 6.8 (± 3.5) days, and the DRS scores between baseline and end-point was significantly different (17.9 ± 4.4 vs 10.3 ± 4.8), and mean difference of these scores was 7.6.
Our study of 20 Korean subjects found similar results but slightly more efficacy of olanzapine in delirium with lower doses. Fourteen of the 20 patients (70%) showed significant improvement (> 50% score reduction) on the scores of DRS. The mean dose of olanzapine was 5.9 (± 1.5) mg/day and mean day of maximal response was 3.8 (± 1.7) days. The score of DRS at the time of pretreatment (20.0 (± 3.6)) was significantly decreased to 9.3 (± 4.6) at post-treatment. The average change of DRS score (10.7) was also greater than that in the previous study.10
The differences between two studies might originate from the different demographic characteristics of subjects. Anecdotal reports suggest that differences exist between Asian and non-Asian populations in the pharmacokinetics of psychotropic agents.19 Accordingly, the effective doses might be lower in Korean subjects than those given to USA patients. This potential difference in the effective dose of this new drug should be tested in future systematic research. In addition, the subject's average age of the previous study was 64 years, much older than the average age of 46 years in the present study, thus there were possibilities of having more comorbid psychiatric and/or medical disorders and concomitant medicines, causing more difficult and complex management.
If pharmacotherapy is deemed necessary to manage delirium, a careful balance must be struck between the benefits of efficacy and the risks associated with most psychotropic agents in the delirious patients. Delirious patients in general, are more sensitive to medication adverse effects, including anticholinergic effects, orthostatic hypotension, sedation, parkinsonism, tardive dyskinesia and cognitive impairment than patients with general psychotic conditions.20 In this aspect of tolerability, no subject in the present study discontinued olanzapine, and there were no reported serious side-effects, and only two patients with traumatic brain injury complained of mild sedation and dry mouth, which suggests satisfactory tolerability of this drug in patients with delirium.
Since the neurotransmitter, acetylcholine has been implicated in animal and human studies of delirium,21 and significant correlations have been reported between elevated serum concentrations of anticholinergics measured by a radioreceptor assay and the development delirium.22,23 Olanzapine demonstrates a relatively high affinity for muscarinic receptors in pre-clinical in vitro binding assays using low ionic-strength buffer.24 However, in physiological binding medium, the affinity of olanzapine was greatly reduced.25 These latter data might relate with both ex vivo and in vivo studies which demonstrate that olanzapine has relatively minimal functional effects at muscarinic receptors.26,27 Our data also show that olanzapine would be able to be used without anticholinergic risks in patients with delirium.
This study has some critical drawbacks. First, although the number of subjects was 20, the sample size was still small. Second, the distribution of samples was not homogeneous in that the leukemia population was too predominant. Interestingly however, it should be noted that all 11 delirious leukemia patients had decreased scores of DRS 50% or more, suggesting that olanzapine treatment is very effective in this population. In this context, the olanzapine trial has clearly opened up new possibilities for clinical exploration and treatment of delirium in these patients. The present study assessed the prevalence of side-effect without any objective measures. Most importantly, this study was open trial and had no control group. For any new drug proposed as therapeutic, double-blind case-controlled studies are crucial.
In summary, this small open study indicates that low-dose olanzapine is effective in reducing behavioral disturbances and symptoms in delirium and is well tolerated in delirious patients. Although it is too early to tell whether olanzapine might be the treatment choice of delirium, further systematic controlled studies should be warranted. In particular, the recent study which showed that low-dose olanzapine (5 and 10 mg/day) was significantly superior to placebo and was well tolerated in treating agitation/aggression and psychosis in patients with Alzheimer's disease is provoking future research into olanzapine in the management of delirium.28