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* Delirium
* Atypical Neuroleptics
Psychosomatics 43:175-182, June 2002
© 2002 The Academy of Psychosomatic Medicine

An Open Trial of Olanzapine for the Treatment of Delirium in Hospitalized Cancer Patients

William Breitbart, M.D., Annie Tremblay, M.D., and Christopher Gibson, Ph.D.

Received September 7, 2001; accepted December 7, 2001. From the Department of Psychiatry and Behavioral Sciences, Memorial Sloan-Kettering Cancer Center, New York, New York; and Department of Psychiatry, Hotel Dieu Quebec, Quebec City, Canada. Address for correspondence and reprints: Dr. William Breitbart, Chief, Psychiatry Service, Department of Psychiatry and Behavioral Sciences, Memorial Sloan-Kettering Cancer Center, 1242 Second Avenue, Box 421, New York, New York 10021. E-mail; Breitbaw{at}mskcc.org


  ABSTRACT

 
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
We conducted an open, prospective trial of olanzapine for the treatment of delirium in a sample of 79 hospitalized cancer patients. Patients all met DSM-IV criteria for a diagnosis of delirium and were rated systematically with the Memorial Delirium Assessment Scale (MDAS) as a measure of delirium severity, phenomenology, and resolution, over the course of a 7-day treatment period. Sociodemographic and medical variables and measures of physical performance status and drug-related side effects were collected. Fifty-seven patients (76%) had complete resolution of their delirium on olanzapine therapy. No patients experienced extrapyramidal side effects; however, 30% experienced sedation (usually not severe enough to interrupt treatment). Several factors were found to be significantly associated with poorer response to olanzapine treatment for delirium, including age >70 years, history of dementia, central nervous system spread of cancer and hypoxia as delirium etiologies, "hypoactive" delirium, and delirium of "severe" intensity (i.e., MDAS >23). A logistic-regression model suggests that age >70 years is the most powerful predictor of poorer response to olanzapine treatment for delirium (odds ratio, 171.5). Olanzapine appears to be a clinically efficacious and safe drug for the treatment of the symptoms of delirium in the hospitalized medically ill.

Key Words: Olanzapine • Delirium

  INTRODUCTION

 
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Delirium is a common and often serious neuropsychiatric complication in hospitalized patients with medical illness.1 Between 15% and 30% of the medically ill develop delirium during a hospitalization. 1 Delirium is highly prevalent among hospitalized cancer patients, with prevalence rates ranging from 25% to 85%, depending on the stage of disease. 4 Delirium is associated with increased morbidity, mortality, and interference with symptom (e.g., pain) assessment and control in cancer patients. 5–10 The effective treatment of delirium is therefore an important priority in the care of hospitalized cancer patients and other medically ill populations. 3

The standard approach to managing delirium in the medically ill, even in those with advanced cancer, includes a search for underlying causes, correction of those factors, and management of the symptoms of delirium. 1 The management of the symptoms of delirium involves the use of both nonpharmacological and pharmacological interventions. 1,1112 Nonpharmacological or supportive interventions alone are often not effective in controlling the symptoms of delirium, and symptomatic treatment with neuroleptics or antipsychotic medications is necessary. 112 Haloperidol, a typical high-potency neuroleptic, is the gold standard of neuroleptic drug therapy for the control of the symptoms of delirium. 1 In addition to haloperidol, other typical neuroleptic drugs (e.g., chlorpromazine and droperidol) have also been shown to be effective in the treatment of delirium in multiple case reports, uncontrolled trials, and at least one controlled trial. 1,12–20 The major disadvantage of the use of typical neuroleptics like haloperidol for the treatment of the symptoms of delirium includes the development of extrapyramidal side effects, tardive dyskinesia, and neuroleptic malignant syndrome. 1

Several new atypical neuroleptic agents (e.g., risperidone and olanzapine), with more variable dopamine D2 antagonist properties and perhaps more specific dopamine blocking effects, which results in lower incidence of extrapyramidal and related side effects, are now available and are being used clinically in the treatment of behavioral disturbances in dementia 21–26 and in the treatment of delirium in medically hospitalized patients. 2027–35 Risperidone has been demonstrated to have potential utility in the management of delirium in a series of case reports. 29,3032,34 These case reports involved only a small number of patients; however, they suggested that risperidone may be useful in the control of the symptoms of delirium, at relatively low doses (0.5–2 mg/day) and associated with less extrapyramidal side effects. Olanzapine has also been studied in a series of case reports that have examined its utility in the management of delirium. 27,28,31 These case reports also involved a small number of patients. Sipahimalani and Prakash31 compared the response of 11 delirious patients treated with haloperidol and 11 delirious patients treated with olanzapine in the course of their clinical practice. They used 5–15 mg of olanzapine/day compared with 1.5–10 mg of haloperidol/day. Patients were rated retrospectively, on the basis of chart review, with the Delirium Rating Scale (DRS). Five of the patients who took olanzapine and six of those who took haloperidol showed a >50% reduction in their DRS scores. None of the patients on olanzapine developed side effects, but three patients on haloperidol developed extrapyramidal side effects. Three of the patients who took olanzapine were simultaneously receiving typical neuroleptics such as haloperidol.

The literature on the use of atypical neuroleptics for the treatment of delirium is thus quite limited in terms of methodology and the number of patients studied. We therefore undertook to examine the clinical utility and safety of olanzapine in the treatment of delirium in a large sample of hospitalized cancer patients by use of a prospective, open-label trial design with systematic assessment of delirium treatment response (that used the Memorial Delirium Assessment Scale [MDAS]) and side effects. Our secondary goal was to examine the relationships between clinical response to olanzapine treatment and a variety of factors, including delirium phenomenology, delirium etiology, and sociodemographic and medical variables.


  METHODS

 
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects and Procedures
Subjects in this study were gathered from all referrals to the Psychiatry Service at Memorial Sloan-Kettering Cancer Center during the period ranging from July 1, 2000 through November 1, 2000. A total of 154 patients met DSM-IV criteria for delirium and were treated. Fifty-two of these patients were deemed inappropriate for olanzapine treatment because of an inability to take medication by mouth (including 38 patients who were too agitated or paranoid to use oral medications only). Twenty other patients were excluded because of the concurrent use of other neuroleptic medications. Consequently, a total of 82 patients were available for this study. All patients had been referred to the Psychiatry Service for consultation and treatment and provided verbal consent to be evaluated for the purposes of this study. Because the study procedures required very little deviation from standard clinical practice (the presence of two treating psychiatrists documenting delirium diagnosis, severity, and treatment side effects), written informed consent and institutional review board approval were not obtained.

After the diagnosis of delirium was confirmed by the two study clinician investigators (W.B. and A.T.), 82 delirious patients were rated by these investigators for delirium severity and phenomenology by use of the MDAS and started on olanzapine treatment. Patients were rated with the MDAS at the time of initial evaluation prior to olanzapine treatment (baseline [T1]), and MDAS ratings were repeated at 2–3 days (T2) and 4–7 days (T3) after the initiation of treatment. Initial olanzapine dosage and subsequent titration of dosage was based on clinical judgment, and side effects were rated at each MDAS assessment point. Data on delirium etiology, cancer diagnosis, cancer stage, physical functioning, presence of brain metastases, history of dementia, and sociodemographic data were also collected. Of the 82 patients studied, 3 were unable to be assessed at time T2 and T3, so 79 patients were used in the data analyses.

Study Measures
Sociodemographic and medical variables (including delirium etiologies) were collected at the baseline assessment and supplemented throughout the period of olanzapine treatment as they became apparent. These variables included age, sex, cancer diagnosis, stage of cancer (localized, metastatic, or terminal), history of dementia, presence of brain metastases, and delirium etiologies. In addition, the following study measures were used.

MDAS
The MDAS is a 10-item, four-point clinician-rated scale (possible range 0–30) designed and validated to accurately diagnose and rate the severity of delirium in medically ill patients, including cancer patients and other medically ill populations. 36–38 Items included in the MDAS reflect the diagnostic criteria for delirium in the DSM-IV. Scale items assess disturbance in arousal and level of consciousness, as well as several areas of cognitive functioning (memory, attention, orientation, and disturbances in thinking) and psychomotor activity. The initial validation study36 suggested a cutoff score of 13 as being sensitive and specific in identifying the presence or absence of delirium (>=13 indicative of delirium). Subsequent validation studies37,38 have suggested a score as low as 10 being a more stringent cutoff score for identifying delirium in medically ill patients. In this study, we used a MDAS score of <=10 to indicate delirium resolution (a more stringent threshold for delirium resolution than a cutoff score of 13). The MDAS allows for delirium to be classified into subtypes (i.e., hypoactive, hyperactive, or mixed) on the basis of arousal disturbance and psychomotor activity (i.e., MDAS item 9). Delirium severity can be categorized by use of MDAS scores, with "mild" delirium reflected by MDAS scores <=15, "moderate" delirium by MDAS scores of 16–22, and "severe" delirium by MDAS scores of 23–30. MDAS ratings were performed at baseline, T2 (on day 2–3), and T3 (day 4–7). The two raters (W.B. and A.T.) had adequate interrater reliability with the MDAS (kappa > 0.8).

Karnofsky Performance Status Scale
The Karnofsky Performance Status Scale (KPS) is a clinician-rated measure of physical performance ability. It is widely used to estimate overall physical functioning in medically ill populations. It ranges from 0 to 100, with low scores representing greater need for medical care and assistance in daily living activities and higher scores corresponding to more independent functioning.39 The KPS was rated at baseline only.

Clinician's Rating of Side Effects
Side effects that, according to the clinical judgment of the investigators (W.B. and A.T.), were felt to possibly be due to olanzapine were documented at each assessment point and rated for severity (baseline, T2, and T3).

Statistical Analyses
Analyses for this study were performed by use of the SPSS for Windows statistical software package. To measure the base efficacy of olanzapine, scores on the MDAS were entered into a 1 (treatment: olanzapine) x 3 (time: baseline, T2 [2–3 days], and T3 [4–7 days]) analyses of variance (ANOVA). Paired-sample t tests were then performed to determine exact differences between assessment times. The possible correlates of delirium resolution were examined by conducting Pearson product moment correlations on the continuous variables (i.e., age and KPS score) and {chi}2 analyses on dichotomous variables. {chi}2 analyses were performed to determine associations between various patient variables and treatment outcome at T2 and T3, with delirium resolution at either of these times being defined as a total MDAS score <=10. For the purpose of these analyses, age was defined as a dichotomous variable with two levels: age <70 and >70 years. From these analyses, variables that appeared to significantly interact with treatment outcome were then entered into a logistical regression analysis to determine the best predictors of delirium resolution with olanzapine.


  RESULTS

 
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Subjects
The mean age for the 79 patients was 60.6 years (SD 17.3; range, 19–89). Gender was evenly divided (40 men and 39 women). The ethnic composition included whites (75%, n = 59), blacks (14%, n = 11), Hispanics (7%, n = 6), and Asians (4%, n = 3). The mean KPS score was 37 (SD 9.9; range, 20–85). A diverse range of cancer diagnoses was encountered within this group. Cancer diagnoses included lung (21%, n = 17), gastrointestinal (18%, n = 14), lymphoma (11%, n = 9), breast (10%, n = 8), head and neck (6%, n = 5), ovarian (2%, n = 2), brain (2%, n = 2), sarcoma (2%, n = 2), and other cancers (25%, n = 20). The stage of cancer was primarily metastatic (80%, n = 63), followed by localized (15%, n = 12) and terminal (5%, n = 4) stages. A relative minority of the sample had a history of brain metastases (20%, n = 16) or a history of dementia (17%, n = 14). The causes of the delirium episode varied among patients. Multiple etiologies (70%, n = 55) were more common than single etiologies (30%, n = 24). The most common etiologies for delirium included opioid analgesics (63%, n = 50), corticosteroids (34%, n = 27), systemic infection (33%, n = 26), hypoxia (25%, n = 20), central nervous system (CNS) spread of cancer (14%, n = 11), dehydration (11%, n = 9), other medications (2.5%, n = 2), and other (unclassified) etiologies (17%, n = 13). Delirium severity, based on MDAS scores, was distributed normally, with a mean MDAS score of 19.85 (SD 3.79; range, 10–28) for the population. Approximately 17% (n = 13) of delirious patients were characterized as having a mild delirium (MDAS scores <=15), 61% (n = 48) had a moderate delirium (MDAS score 15–22), and 23% (n = 18) had a severe delirium (MDAS scores >=23). Delirium was categorized as to subtype of delirium; 46% (n = 36) had "hypoactive" delirium, whereas 54% (n = 43) had "hyperactive" delirium (based on MDAS item 9, all patients with hyperactive or mixed delirium were classified as hyperactive; patients with hypoactive delirium were classified as hypoactive).

Olanzapine Treatment
All 79 patients with delirium included in this study were treated with olanzapine in an open-label trial as part of their standard care. Olanzapine treatment was initiated immediately after baseline MDAS assessment. The mean starting dose for olanzapine at baseline was 3.0 mg (SD 0.14; range, 2.5–10). The mean dose of olanzapine at T2 was 4.6 mg (SD 0.27; range, 2.5–15). The mean dose of olanzapine at T3 or end of study was 6.3 mg (SD, 0.52; range, 2.5–20). Olanzapine was administered orally and given either as a single bedtime dose or in a divided dose regimen (i.e., twice a day, in the morning and at bedtime).

Treatment Efficacy—Improvement in MDAS Scores
Olanzapine treatment resulted in significant improvement in delirium severity, on the basis of MDAS scores, over the course of treatment (baseline, Table 2, and Table 3). A one-way within-subjects ANOVA was performed that indicated a significant treatment effect, Wilks A = 0.345, F(1, 78 = 53.1, P = 0.001. MDAS scores improved significantly from baseline to T2, from baseline to T3, and from T2 to T3. The mean baseline MDAS score (19.85, SD 3.79), was significantly lower (improved) at T2 (12.73, 6.87), t (78) = 16.9, P = 0.001, and even lower (more improved) at T3 (10.78, SD 7.31), t (78) = 17.6, P = 0.001. In addition, the mean MDAS scores between T2 and T3 were also significantly improved, t (78) = 8.6, P = 0.001. (see Figure 1)



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FIGURE 1.



Treatment Efficacy—Delirium Resolution Based on MDAS Cutoff Score
When an MDAS score <=10 was used as the definition of delirium resolution, 45% (n = 36) of patients at T2 and 76% (n = 57) of patients at T3 had resolution of their delirium with olanzapine treatment.

Correlates and Predictors of Treatment Outcome/Delirium Resolution
A series of {chi}2 analyses were performed to determine the associations between a variety of sociodemographic, medical, and delirium phenomenological variables and delirium resolution at T3 (Table 1). Resolution of delirium was defined as a total MDAS score <=10. Several variables were significantly associated with delirium resolution and olanzapine treatment efficacy at T3 (end of study, days 4–7), including age, history of dementia, subtype of delirium, delirium etiology (i.e., hypoxia or CNS cancer spread), and delirium severity. Age was found to be significant predictor of olanzapine treatment response, with patients age >70 years having a response rate of only 42% at T3 (see Figure 2), compared with individuals age <70 years, of whom 93% improved, {chi}2 (1, n = 79) = 22.8, P < 0.001. A history of dementia significantly predicted poorer olanzapine response and delirium resolution, with 46% of patients with a history of dementia achieving delirium resolution at T3, compared with 75.5% of those without a history of dementia, {chi}2 (1, n = 79) = 4.1, P < 0.05. The subtype of delirium also appears to be important in determining response to olanzapine treatment. Only 48% of patients with hypoactive delirium had resolution of their delirium at T3 on olanzapine compared with 83% of patients with hyperactive delirium, {chi}2 (1, n = 79) = 7.95, P < 0.006.


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TABLE 1.





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FIGURE 2.



Among the various delirium etiologies examined, hypoxia and CNS spread of cancer were significant predictors of olanzapine response and delirium resolution. Patients with delirium in whom hypoxia was an identified delirium etiology had a 50% rate of delirium resolution at T3 compared with 76% of those without hypoxia, {chi}2 (1, n = 79) = 3.7, P < 0.05. Patients with CNS spread as a delirium etiology had a significantly poorer response to olanzapine, with 40% achieving delirium resolution at T3 compared with 75% of those without CNS spread, {chi}2 (1, n = 79) = 4.7, P <.039. Delirium severity was categorized as either mild (MDAS score 0–15), moderate (MDAS score 15–22), or severe (MDAS score 23–30). For the purposes of analysis, we collapsed the mild and moderate delirium severity groups and compared that group with patients who had severe delirium. Comparing delirium severity groups in this manner revealed that patients with mild to moderate severity delirium were significantly more likely to respond to olanzapine treatment than patients with severe delirium, {chi}2 (1, n = 79) = 5.7, P < 0.02. Patients with mild delirium (n = 13) had a 100% response to olanzapine treatment. Thirty-five (73%) of 48 patients with moderate delirium responded to olanzapine, whereas only 9 (50%) of 18 patients with severe delirium responded to olanzapine.

A logistic-regression analysis was conducted to determine the best predictors of treatment response from among the clinical and sociodemographic variables considered in the study at T3 (Table 2). The overall model was statistically significant, {chi}2 (5, n = 79) = 52.4, P < 0.001. Age was the strongest predictor of treatment response (odds ratio [OR] = 171.5) (with patients age >70 years demonstrating significantly poorer response than patients age <70 years), followed by CNS spread as a delirium etiology (OR = 74.9). Finally, the subtype of delirium was also a significant predictor of delirium treatment outcome (OR = 11.3), with hyperactive delirium responding better to olanzapine treatment than hypoactive delirium. History of dementia, delirium severity, and hypoxia were not significant predictors of olanzapine delirium treatment response on the basis of the logistic regression model.


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TABLE 2.



Olanzapine Treatment—Related Side Effects
The clinician investigators (W.B. and A.T.) recorded all side effects, which in their clinical judgment were potentially related to olanzapine treatment, at each of the three assessment points (i.e., baseline, T2, and T3). The investigators rated the severity of these side effects on a Clinician's Rating of Side Effects checklist. Olanzapine side effects were not common, were limited in variety, and were rarely severe enough to cause a reduction in dosage or terminate treatment. The most common side effect reported was sedation, with 30% of patients reporting sedation at T2 and 30% reporting sedation at T3. Olanzapine dosage was reduced because of sedation in eight patients. In 1.3% of patients, at both T2 (n = 1) and T3 (n = 1), olanzapine appeared to worsen delirium, and olanzapine was stopped. Both of these patients were age >80 years. An additional 3.8% of patients experienced a variety of other side effects of mild severity that included rash, pruritus, nausea, stomach ache, dizziness, light headedness, blurring of vision, and headache.


  DISCUSSION

 
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In this open-label trial, with close to 80 hospitalized cancer patients with delirium, we have been able to demonstrate that olanzapine, an atypical neuroleptic, is a safe and effective agent in the symptomatic management of delirium. More than 75% of patients who received olanzapine achieved complete resolution of their delirium by the end of the study (T3, day 4–7) as defined by an MDAS score <=10. This rate of delirium resolution is significantly greater than the rate of 49% reported in a study of delirium outcome among terminally ill cancer patients treated primarily with haloperidol. 40–42 This response rate is also greater than the delirium response rate reported in previous case reports with olanzapine31 and is comparable to the response rates reported in a controlled trial of the treatment of delirium among hospitalized patients with AIDS that used haloperidol or chlorpromazine. 12 MDAS scores significantly improved from baseline to T2 (day 2–3), from T2 to T3, and from baseline to T3 with olanzapine treatment. The greatest improvement in MDAS scores occurred within the first 3 days of treatment (i.e., from baseline to T2; see Figure 1), but continued improvement took place over the next several days (to T3, end of study) in the majority of patients. This, again, is consistent with earlier reports of relatively rapid resolution of the symptoms of delirium on the initiation of neuroleptic treatment. 12

The symptoms of delirium resolved at relatively low mean dosages of olanzapine, and patients experienced relatively few and relatively mild adverse effects. The mean dose of olanzapine at T2 was 4.6 mg (range, 2.5–15), and the mean dose of olanzapine at T3 or end of study was 6.3 mg (range, 2.5–20), which suggests that a dose of ~5 mg/day is a relatively reasonable starting dosage for olanzapine therapy in delirium, which then can be modified upward or downward depending on clinical response and side effects.

Sedation was the most common side effect and was encountered in 30% of patients on olanzapine therapy. This is possibly due to the anti-histaminic effects of olanzapine. 40 Most strikingly, no patients on olanzapine therapy developed extrapyramidal side effects, a major advantage of atypical neuroleptics like olanzapine. Of note, two patients treated with olanzapine seemed to have a worsening of their delirium, and olanzapine therapy was discontinued. It is unclear exactly why these patients experienced a worsening of their delirium; there are multiple potential factors that could have played a role. One factor that does need to be considered, however, is the potential that olanzapine's muscarinic antagonist properties could theoretically play a role in worsening the delirium of some susceptible patients. 40 The patients who experienced worsening of delirium on olanzapine were both age >80 years and could have been particularly sensitive to the anti-muscarinic properties of olanzapine.

Perhaps the most interesting findings in our study are the factors that appear to predict response to olanzapine therapy for the symptoms of delirium. Several factors in a logistic regression analysis have been demonstrated in this study to strongly predict poorer response to olanzapine treatment for delirium and include age (>70 years), subtype of delirium (hypoactive delirium), and CNS spread of cancer as an etiology of delirium. Although not fitting the logistic regression model, a history of dementia, delirium severity, and hypoxia as a cause of delirium were also significantly correlated with poorer response to olanzapine treatment for delirium.

By far the most powerful predictor of poorer response to olanzapine treatment for delirium is age. Patients age >70 years had a delirium resolution rate of only 42%, compared with 93% in those age <70 years (see Figure 2). Patients with hypoactive delirium, who essentially had an arousal disturbance in their delirium that was characterized by hypoarousal, lethargy, or sleepiness were also significantly less likely to have a resolution of their delirium (43% resolved) compared with those who had hyperactive delirium patients (83% resolved). CNS spread of cancer as an etiology of delirium resulted in a 40% response rate on olanzapine compared with a 75% response rate in those without CNS cancer spread. Similarly, patients with a history of dementia responded less robustly to olanzapine, as did patients with more severe intensity delirium (MDAS scores >23). Hypoxia as a delirium etiology was also correlated with poorer treatment response.

Several of the factors noted above to be associated with poorer resolution of delirium with olanzapine treatment are in fact known to be associated with increased risk of delirium and possibly poorer response to treatment for delirium in general (e.g., not specifically with olanzapine). For instance, age, history of dementia, and preexisting brain pathology have all been demonstrated to increase the risk of delirium among elderly hospitalized medically ill. 43 In this study, however, age appears to be a unique predictor of poorer olanzapine response, independent of a history of dementia (which can be an age-related factor). Of interest, no other studies of delirium treatment have reported on the roles of age or history of dementia influencing treatment response. Lawlor et al. 42 actually reported that CNS spread of cancer and hypoxia, as delirium etiologies, were significantly predictive of poorer response to delirium treatment with "typical" neuroleptics such as haloperidol. Although it is clinically understandable that patients with more severe delirium might have a less robust response to any treatment for delirium, no other reports or controlled trials have examined that specific issue. Certainly no other delirium intervention case series or uncontrolled trials have addressed the differential response of delirium "subtypes" (i.e., hypoactive vs. hyperactive); however, Breitbart et al. 12,43 have demonstrated that, at least in one controlled trial, patients with hypoactive delirium responded equally well to haloperidol or chlorpromazine compared with those with hyperactive delirium. In this study, it is conceivable that the sedation associated with olanzapine therapy somehow interfered with the resolution of delirium in our patients with hypoactive delirium or affected the rating of MDAS items which reflect arousal and psychomotor behavior (thus artificially minimizing improvement in MDAS scores of hypoactive patients).

Although this study has several strengths (e.g., prospective, systematic evaluation of delirium severity and phenomenology, olanzapine dosage and side effects, and medical variables, in a large sample of delirious patients), there are important limitations that should be noted. First, this was an uncontrolled trial without a comparison or control group. The trial was open, and investigators were not blinded to treatment condition. Additionally, the sample was not random and in fact was biased to include only those patients whose delirium could be managed safely with a drug that was limited to the oral route of administration. Although we did have a wide, and normally distributed, range of delirium severity in our sample, the method of patient selection we used would obviously tend to exclude very agitated or combative patients who posed an immediate danger to themselves or others. Of note, we did have approximately equal numbers of hyperactive (54%) and hypoactive (46%) delirious patients.

Despite the above-noted limitations, our study is an important step in beginning to demonstrate the clinical efficacy and safety of atypical neuroleptic drugs like olanzapine for use in the management of delirium among hospitalized medically ill patients. Further research, particularly double-blind, randomized, controlled trials of olanzapine versus typical neuroleptics (e.g., haloperidol) or olanzapine versus other atypical neuroleptics in the management of delirium will be needed to confirm our findings and expand clinicians' understanding of the optimal treatment interventions for delirium.


  REFERENCES

 
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Trzepacz PT, Breitbart W:Practice guideline for the treatment of patients with delirium. Am J Psychiatry 1999; 156:11[Abstract/Free Full Text]
  2. Massie MJ, Holland J, Glass E: Delirium in terminally ill cancer patients. Am J Psychiatry 1983; 140:1048-1050[Abstract/Free Full Text]
  3. Breitbart W, Bruera E, Chochinov HW, et al: Neuropsychiatric syndromes and psychological symptoms in patients with advanced cancer. J Pain Symptom Manage 1995; 10:131-141[CrossRef][Medline]
  4. Breitbart W, Strout D: Delirirum in the terminally ill. Clin Geriatr Med 2000; 16:357-372[CrossRef][Medline]
  5. Rabins PV, Folstein MF: Delirium and dementia: diagnostic criteria and fatality rates. Br J Psychiatry 1982:140; 149-153
  6. Varsamis J, Zuchowski T, Maini KK: Survival rates and causes of death in geriatric psychiatric patients: a six-year follow-up study. Can Psychiatr Assoc J 1972; 17:17-22[Medline]
  7. Stiefel F, Holland J: Delirium in cancer patients. Int Psychogeriatr 1991; 3:333-336[CrossRef][Medline]
  8. Trzepacz PT, Teague GB, Lipowski ZJ: Delirium and other organic mental disorders in a general hospital. Gen Hosp Psychiatry 1985; 7:101-106[CrossRef][Medline]
  9. Bruera E, Fainsinger R, Miller MJ, et al: The assessment of pain intensity in patients with cognitive failure: a preliminary report. J Pain Symptom Manage; 1992 7:267-270
  10. Coyle N, Breitbart W, Weaver S, et al: Delirium as a contributing factor to "Crescendo" pain: three case reports. J Pain Symptom Manage; 1994 9:44-47
  11. Inouye B, Bogardus ST Jr, Charpentier PA, et al: A multicomponent intervention to prevent delirium in hospitalized older patients. N Engl J Med 1999; 340:669-676[Abstract/Free Full Text]
  12. Breitbart W, Marotta R, Platt M, et al: A double-blind trial of haloperidol, chlorpromazine and lorazepam in the treatment of delirium in hospitalized AIDS patients. Am J Psychiatry 1996; 153:231-237[Abstract/Free Full Text]
  13. Muskin P, Mellman L, Kornfeld D: A "new" drug for treating agitation and psychosis in the general hospital: chlorpromazine: Gen Hosp Psychiatry 1986; 8:404-410
  14. Rosen H: Double-blind comparison of haloperidol and thioridazine in geriatric patients. J Clin Psychiatry 1979; 40:17-20
  15. Smith G, Taylor C, Linkous P: Haloperidol versus thioridazine for the treatment of psychogeriatric patients: a double-blind clinical trial. Psychosomatics 1974; 15:134-138[Abstract/Free Full Text]
  16. Tsuang MM, Lu LM, Stotsky BA, et al: Haloperidol versus thioridazine for hospitalized psychogeriatric patients: double-blind study. J Am Geriatr Soc 1971; 19:593-600[Medline]
  17. Kirven LE, Montero EF: Comparison of thioridazine and diazepam in the control of nonpsychotic symptoms associated with senility: double-blind study. J Am Geriatr 1973; 12:546-551
  18. Thomas H, Schwartz E, Petrilli R: Droperidol versus haloperidol for chemical restraint of agitated and combative patients. Ann Emerg Med 1992; 21:407-413[CrossRef][Medline]
  19. van Leeuwen A, Molders J, Sterkmans P, et al: Droperidol in acutely agitated patients. J Nerv Ment Dis 1977; 164:280-283[Medline]
  20. Resnick M, Burton B: Droperidol vs haloperidol in the initial management of acutely agitated patients. J Clin Psychiatry 1984; 45:298-299[Medline]
  21. Devanand DP, Marder K, Michaels KS, et al: A randomized, placebo-controlled dose-comparison trial of haloperidol for psychoses and disruptive behaviors in Alzheimer's disease. Am J Psychiatry 1998; 155:1512-1520[Abstract/Free Full Text]
  22. De Deyn PP, Rabheru K, Rasmussen A, et al: A randomized trial of risperidone, placebo and haloperidol for behavioral symptoms of dementia. Neurology 1999; 53:946-955[Abstract/Free Full Text]
  23. Katz IR, Jeste DV, Mintzer JE, et al: Comparison of risperidone and placebo for psychosis and behavioral disturbances associated with dementia: a randomized double-blind trial. J Clin Psychiatry 1999; 60:107-115[Medline]
  24. Kinon BJ, Tragum SD, Basson BR, et al: Olanzapine in the management of behavioral disturbances and/or psychosis in demented nursing home patients. Poster presentation, 12th European College of Neuropsychopharmacology, London, 1999
  25. Street JS, Clark WS, Gannon KS, et al: Olanzapine treatment of psychotic and behavioral symptoms in patients with Alzheimer's disease in nursing care facilities. Arch Gen Psychiatry 2000; 57:968-976[Abstract/Free Full Text]
  26. Solomons K, Geiger O: Olanzapine use in the elderly: a retrospective analysis. Can J Psychiatry 2000; 45:151-155[Medline]
  27. Anand HS: Olanzapine in an intensive care unit. Can J Psychiatry 1999; 44:397[Medline]
  28. Passik SD, Cooper M: Complicated delirium in a cancer patient successfully treated with olanzapine. J Pain Symptom Manage 1999; 17; 219-223
  29. Ravona-Springer R, Dolberg OT, Hirschmann S, et al: Delirium in elderly patients treated with risperidone: a report of three cases. J Clin Psychopharmacol 1998; 18:171-172[CrossRef][Medline]
  30. Sipahimalani A, Masand PS: Use of risperidone in delirium: case reports. Ann Clin Psychiatry 1997; 9:105-107[CrossRef][Medline]
  31. Sipahimalani A, Prakash M: Olanzapine in the treatment of delirium. Psychosomatics 1998; 39:422-430[Abstract/Free Full Text]
  32. Sipahimalani A, Sime RM, Masand PS: Treatment of delirium with risperidone. Int J Geriatr Psychopharmacol 1997; 1:24-26
  33. Zayas EM, Grossberg GT: The treatment of psychosis in late life. J Clin Psychiatry 1998; 59(suppl 1):5-12
  34. Lerner MD, Schuetz L, Holland S, et al: low-dose risperidone for the irritable medically ill patient. Psychosomatics 2000; 41:69-71[Free Full Text]
  35. Goodnick PJ, Barrios CA: Use of olanzapine in non-psychotic psychiatric disorders. Exp Opin Pharmacother 2001; 2:667-680
  36. Breitbart W, Rosenfeld B, Roth A, et al: The Memorial Delirium Assesment Scale. J Pain Symptom Manage 1997; 13:128-137[CrossRef][Medline]
  37. Lawlor PG, Nekolaichuk C, Gagnon B, et al: Clinical utility, factor analysis, and further validation of the Memorial Delirium Assessment Scale in patients with advanced cancer. Assessing delirium in advanced cancer. Cancer 2000; 88:2859-2867[CrossRef][Medline]
  38. Matsuoka Y, Miyake Y, Arakaki H, et al: Clinical utility and validation of the Japanese version of Memorial Delirium Assessment Scale in a psychogeriatric inpatient setting. Gen Hosp Psychiatry 2001; 23:36-40[CrossRef][Medline]
  39. Karnofsky DA, Burchenal JH: The clinical evaluation of chemotherapeutic agents in cancer, in Evaluation of Chemotherapeutic Agents. Edited by Macleod CM. New York, Columbia University Press, 1949, pp 191-205
  40. Jibson MD, Tandon R; New atypical antipsychotic medications. J Psychiatr Res 1998; 215-228
  41. Lawlor PG, Gagnon B, Mancini IL, et al: Occurrence, causes, and outcome of delirium in patients with advanced cancer. Arch Intern Med 2000; 160:786-794[Abstract/Free Full Text]
  42. Inouye SK, Viscoli CM, Horwitz RI, et al: A predictive model for delirium in hospitalized elderly medical patients based on admission characteristics. Ann Intern Med 1993; 119:478-481
  43. Platt M, Breitbart W, Smith M, et al: Efficacy of neuroleptics for hypoactive delirium. J Neuropsychiatry Clin Neurosci 1994; 6:66-67[Free Full Text]



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