Psychosomatics 39:422-430, October 1998
© 1998 The Academy of Psychiatric Medicine
Olanzapine in the Treatment of Delirium
Anil Sipahimalani, M.D., and
Prakash S. Masand, M.D.
Received October 3, 1997; revised January 29, 1998; accepted February 11, 1997. From the Department of Psychiatry, State University of New York (SUNY) Health Science Center at Syracuse. Address reprint requests to Dr. Masand, Department of Psychiatry, SUNY Health Science Center at Syracuse, 750 East Adams Street, Syracuse, NY 13210.
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ABSTRACT
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Delirium is an organic psychiatric syndrome characterized by fluctuating consciousness and impaired cognitive functioning. Eleven delirious patients were treated with olanzapine (dosage mean ± standard deviation [SD]: 8.2 ± 3.4 mg qhs), and 11 delirious control patients were treated with haloperidol (dosage mean ± SD: 5.1 ± 3.5 mg qhs). Peak response time was similar in both groups. Five of the 11 olanzapine patients showed significant improvement (>50% score reduction) on the Delirium Rating Scale (DRS) and no patients had side effects, whereas 6 of the 11 control subjects showed improvement on the DRS and 5 had extrapyramidal symptoms or excessive sedation. Olanzapine may be a useful alternative to haloperidol in the treatment of delirium in hospitalized patients.
Key Words: Olanzapine • Delirium • cognition
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INTRODUCTION
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Delirium is an organic psychiatric syndrome characterized by fluctuating levels of consciousness and global impairment of cognitive functioning. Abnormalities of mood, perception, and behavior are frequently seen, and neurological symptoms can include tremor, asterixis, nystagmus, and incoordination.
Delirium occurs in 10% of hospitalized medical and surgical patients1 and is associated with increased mortality and longer hospital stays.2,3 Delirium can be caused by a variety of factors and usually has a sudden onset and fluctuating course. It is particularly common among the elderly, occurring in 14% to 56% of elderly hospitalized patients, with associated hospital mortality rates ranging from 10% to 65%.4
Tests of cognitive functioning like the Mini-Mental Status Exam are frequently used to assess the presence and severity of delirium. These tests are relatively insensitive, however, as the scores are influenced by other disorders in which disturbances of cognition are present, like dementia. Tests of cognitive function can also be affected by psychotic illnesses like schizophrenia.5 The Delirium Rating Scale (DRS)6 is a ten-item, clinician-rated symptom scale that is more sensitive than tests of cognitive function for delirium. Through usage of this scale, delirious subjects have been shown to score significantly higher than subjects with dementia, schizophrenia, or normal control subjects.6 The DRS differs from simple tests of cognitive functioning by factoring in items like temporal onset of symptoms, nature of perceptual disturbances, presence of a physical disorder, sleep–wake cycle, and fluctuation of symptoms; this makes it more specific in detecting and assessing the severity of delirium.
Typical high-potency neuroleptics like haloperidol have traditionally been used as first-line therapy in the treatment of delirium.7 These drugs are frequently associated with adverse effects, however, including extrapyramidal symptoms (EPS), which are more frequent in elderly and seriously medically ill patients, who are more likely to develop delirium in the hospital setting. Olanzapine is a newer atypical neuroleptic that is associated with a lower incidence of EPS8 and may be better tolerated than typical neuroleptics in this group of patients.
We have used risperidone to successfully treat delirium,9 and we have previously reported on the response to risperidone in a group of 11 delirious patients.10 In the latter study, we did not use a standardized scale to measure the severity of delirium and the response to treatment, and we did not compare the response to risperidone with either a control group or a conventional neuroleptic.
In the present study, conducted in 1997, we have compared the response of 11 delirious hospitalized patients treated with haloperidol with the same number of delirious patients treated with olanzapine, representing all patients with delirium treated with olanzapine in this consulting practice. The etiology of delirium was diverse and included infection, stroke, alcohol withdrawal, postsurgical delirium, metastatic brain cancer, encephalopathy associated with the human immunodeficiency virus (HIV), traumatic brain injury, renal failure, hypoxia, and electrolyte imbalance. To our knowledge, this is the first report of the use of olanzapine to treat delirium.
We hypothesized that 1) haloperidol would be used more often to treat the more severe delirium cases, 2) olanzapine would be better tolerated, and 3) haloperidol would have a quicker peak response time.
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METHODS
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The psychiatry consultation service sees patients at a university hospital, which is a 350-bed, tertiary-care, general hospital, and a veterans hospital. Both are teaching hospitals for the State University of New York (SUNY) at Syracuse, College of Medicine. The service is staffed by two third-year psychiatry residents and two full-time consultation-liaison psychiatrists.
Eleven patients with delirium were treated with olanzapine, which was usually started at 5 mg qhs, and titrated upward as needed until maximum clinical benefit was achieved. The highest dose of olanzapine used in the study was 15 mg/day.
Eleven delirious patients treated with haloperidol were seen during the same time frame as a comparison group. The doses of haloperidol used ranged from a total of 1.5 mg/day to 10 mg/day. Haloperidol was administered orally, except for one patient, who received intravenous haloperidol.
The patients were naturally assigned to haloperidol or olanzapine based upon the treating clinician's preference. Since olanzapine was unavailable in the Veterans Affairs formulary, random assignment was not possible.
Patients were evaluated according to the DRS. DRS scores were assessed before starting treatment and on the day of maximal response to drug. DRS scores were retrospectively assigned based on a chart review.
Two-tailed t-tests were performed with the program Statistica (Statsoft. Tulsa, Oklahoma). All P-values less than 0.05 were considered significant.
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RESULTS
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The average age of patients in both groups was similar (mean ± SD: 63.5 ± 23.2 for the olanzapine group and 64.5 ± 18.3 for the haloperidol group). The olanzapine group consisted of six men and five women, whereas the haloperidol group had 10 men and 1 woman. Comorbid psychiatric diagnoses included schizophrenia, schizoaffective disorder, bipolar disorder, major depression, alcohol dependence, and antisocial personality disorder (Table 1 and Table 2).
The mean ± SD dose of olanzapine was 8.2 ± 3.4 mg and for haloperidol was 5.1 ±3.5 mg. Peak response was assessed as the number of days the patient received the neuroleptic before achieving maximum improvement. Peak response was similar in both groups (mean ± SD: 6.8 ± 3.5 days for olanzapine and 7.2 ± 4.9 days for haloperidol, P=0.8279). One patient on olanzapine and one on haloperidol showed no improvement, and one patient on haloperidol had worsening of symptoms; peak response was not calculated for those patients. DRS scores were retrospectively assessed from chart review on the first day of treatment and on the day of maximum improvement. Mean ± SD pretreatment DRS scores were comparable in the olanzapine (17.9 ± 4.4) and the haloperidol (20.1 ± 5.2) groups (P=0.2968). Mean ± SD posttreatment DRS scores were 10.3 ± 4.8 for the olanzapine group and 11.1 ± 7.1 for the haloperidol group (P=0.7601). The mean improvement was 7.6 for the olanzapine group and 10 for the haloperidol group.
We also assessed response based on the Clinical Global Impression scale, with patients classified as having mild, moderate, or marked improvement; no improvement; or mild, moderate, or marked worsening. For the purpose of this study, mild improvement was defined as an 11% to 20% reduction in the DRS scores, moderate as a 21% to 50% reduction, and marked as a greater than 50% reduction in the DRS score. Mild worsening was defined as an 11% to 20% increase in the score. No improvement was defined as a 0% ± 10% change in the scores. None of the patients had moderate or marked worsening.
Five of the olanzapine patients and six of the haloperidol patients showed a greater than 50% reduction in their DRS scores. Average dose, time to peak response, and duration of treatment were also calculated for these patients (Table 1 and Table 2).
Three patients in the olanzapine group showed moderate improvement, two showed mild improvement, and one showed no change (Table 3). In the haloperidol group, two patients showed moderate improvement, one mild, one no change, and one mild worsening of symptoms (Table 4).
The DRS scale has a number of items that do not change, even after full resolution of delirium (see Appendix 1). These are Item 1, which addresses temporal onset of symptoms, and Item 7, which rates whether a specific lesion or physiological disturbance can be correlated with the onset of altered behavior. In addition, some items are influenced by the presence of coexisting psychiatric illnesses like dementia, schizophrenia, etc. This is the reason our patients, even after maximum improvement, still had DRS scores of from 5 to 7.
Mean ± SD duration of treatment was 23.6 ± 28.3 days for olanzapine, compared with 14.6 ± 12.8 days for haloperidol (P=0.3480). The reason for this discrepancy was that two of the patients on olanzapine had behavioral disturbances, one due to a traumatic brain injury and one due to dementia. These two outliers were treated with olanzapine in the hospital for 74 and 79 days, respectively, because the olanzapine was felt to be of help.
None of the patients on olanzapine had side effects. Three of the patients on haloperidol had EPS, and two were excessively sedated.
In the olanzapine group, three of the patients (Nos. 1, 2, and 6) were on concomitant standing doses of neuroleptics for the treatment of psychotic illnesses (Table 2), two patients were receiving haloperidol (Nos. 1 and 2), and one patient was on fluphenazine (No. 6). The doses of these neuroleptics remained the same throughout the patients' course of their treatment with olanzapine. Olanzapine was added to their standing neuroleptic because we did not want to risk side effects from higher doses of conventional neuroleptics, as the patients were all elderly and medically very ill. One of these patients (No. 1) was also on low-dose thioridazine (25 mg), which was stopped shortly after starting olanzapine to minimize the anticholinergic load.
One of the patients on olanzapine (No. 10), who improved minimally, still showed agitation; haloperidol (2 mg bid) was added to the regimen, which proved to be of some benefit. The posttreatment DRS score for this patient was assessed before the addition of haloperidol.
Two of the olanzapine patients were initially treated with haloperidol and subsequently switched to olanzapine, as they developed EPS from the haloperidol. One of the patients (No. 5) was treated with intravenous haloperidol initially and then switched to olanzapine as soon as he could take oral medication.
In the haloperidol group, one patient (No. 3) was on standing risperidone (1 mg qhs) throughout the study period for treatment of behavioral disturbances due to dementia; haloperidol was added to this patient's regimen. One of the patients (No. 9) was treated with risperidone for 3 days and then switched to haloperidol when no improvement was achieved.
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DISCUSSION
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Typically, high-potency neuroleptics like haloperidol are used as first-line treatment for delirium,7 but these drugs are frequently associated with side effects like EPS. EPS is likely to be more common in delirious patients, in part because delirium is more common in elderly and severely medically ill patients, who are more prone to EPS.11 This effect was seen in our small study, in which three of the patients in the haloperidol group had EPS, and two patients in the olanzapine group had previously been treated with haloperidol, which had to be stopped because of EPS.
Aside from EPS, haloperidol has a tolerable side-effect profile when used in seriously medically ill patients and does not cause significant hypotension.12–14 Several approaches have been used to decrease EPS associated with haloperidol. For example, the addition of lorazepam to the haloperidol regimen may lower the incidence of EPS compared with haloperidol alone.15 Adding an anticholinergic agent has also been tried. This approach is usually not a good solution because it may exacerbate EPS and may also exacerbate the delirium.
The atypical antipsychotics, such as risperidone and olanzapine, may be useful in treating delirium because of lower incidence EPS than with conventional neuroleptics. Risperidone is at least as effective as conventional neuroleptics in the treatment of psychosis, and its use is associated with a low incidence of adverse events.16–18 We have previously reported the results of treating delirious patients with risperidone.9,10 We have found risperidone to be an effective treatment for delirium in hospitalized patients, with a good side-effect profile. The availability of risperidone as a liquid may make its administration to delirious patients easier than in tablet form.
Olanzapine is a newer neuroleptic that, like risperidone, blocks 5HT2 as well as D2 receptors and has been shown to have a better side-effect profile than haloperidol in terms of EPS.
In our study, we compared the responses to haloperidol (n=11) and olanzapine (n=11) in hospitalized delirious patients. One of our hypotheses in this study was that haloperidol could be used to treat the more severe cases of delirium, since haloperidol is the gold-standard treatment of choice and can be administered parenterally, whereas olanzapine, because of its anticholinergic effects, was not expected to lessen a patient's delirium. Therefore, we expected the pretreatment DRS scores of the haloperidol group would be significantly higher than those of the olanzapine group. However, the scores of the former group were not statistically significantly higher than the latter (mean ± SD: 20.1 ± 5.2 and 17.9 ± 4.4, respectively), thus refuting our initial hypothesis.
Olanzapine was clearly better tolerated than haloperidol in this study. No side effects were reported in the olanzapine group, whereas three patients on haloperidol developed EPS and two experienced excessive sedation.
Our third hypothesis was that haloperidol would have a quicker peak response time based on our clinical impression with psychotic patients in the hospital and because olanzapine has a greater anticholinergic effect than haloperidol. However, we found peak response times to be similar between the two groups (mean ± SD: 6.8 ± 3.5 days for olanzapine [Table 2] and 7.2 ± 4.9 days for haloperidol [Table 1], P=0.8279).
The haloperidol group had a preponderance of male patients (Table 1). Acute dystonic reactions to neuroleptics have been reported to occur more frequently in young male patients.19 Thus, even though most of the patients were elderly, the gender distribution may be a factor in the higher incidence of side effects in the haloperidol group. Also, schizophrenic men are reported to have a poorer response to antipsychotic drugs than female schizophrenic patients.20 There are no data showing a poorer response to neuroleptics in male patients with delirium.
Drawbacks of our study include a small sample size and lack of randomization, and the clinical ratings were based on retrospective chart review. In addition, as detailed in the results section, some of the patients were on concomitant neuroleptics and some had previously been treated with different neuroleptics, which may have influenced the response.
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CONCLUSION
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Olanzapine may be a useful alternative to haloperidol in the treatment of delirium in hospitalized patients. The DRS is a useful means of quantifying treatment responses in delirious patients. Larger, controlled studies are warranted to further explore these preliminary findings and conclusions.
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ABSTRACT
INTRODUCTION
