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Keywords:

  • delirium;
  • Delirium Rating Scale (DRS);
  • elderly;
  • risperidone

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Background:  Despite increasing recognition of delirium as a serious complication of physical illness, little has been reported in this area. Interest has been raised in treatment options other than haloperidol, such as atypical antipsychotic agents.

Methods:  A 2-week open-label trial of risperidone for the treatment of delirium was conducted to assess the efficacy and tolerance of this medication in elderly patients. Twenty-two patients with DSM-IV-defined delirium were investigated. All patients had the hyperactive–hyperalert variant of delirium. Patients received a fixed dose of risperidone (mean 1.5 ± 0.7 mg; range 0.5–3 mg). Delirium was assessed using the Delirium Rating Scale (DRS) at baseline and on Days 1, 3, 5, 7, and 14 after the initiation of risperidone treatment. Clinical and demographic data, as well as risperidone therapy related information, were collected.

Results:  Delirium resolved in all patients over the course of treatment. The mean period over which delirium resolved was 4.0 ± 2.9 days. The mean DRS score at baseline was 20.7 ± 3.0. The DRS score improved from baseline to Day 1 of treatment and continued to improve until the study end-point. Mild side-effects were present in 27.3% of patients. Stepwise logistic regression identified a decrease of 2 points or higher on the DRS on Day 1 associated with side-effects. There were no significant differences in the response to treatment with the different doses of risperidone used.

Conclusion:  Our findings indicate that low-dose risperidone (0.5–3.0 mg/day) is effective and safe for the treatment of delirium in elderly patients, and that an early response on Day 1 of treatment may be associated with side-effects in these patients.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

In general hospitals, delirium is a common psychiatric disorder among medically ill patients. Inappropriate management of delirium often causes prolonged hospitalization, increasing costs, and severe discomfort to the patient. Thus, the early and effective treatment of delirium, including environmental interventions and drug therapy, is of considerable importance.

Despite frequent side-effects, haloperidol and other typical antipsychotics have been used conventionally as the first choice in the treatment of patients with delirium. However, there is recent evidence for the efficacy and low burden of side-effects of atypical antipsychotics, such as risperidone, in patients with this condition.1–7 Thus, particularly the elderly and severely ill, who are more prone to adverse effects, may benefit from this type of medication for the treatment of symptoms of delirium.2

In the present study, we conducted a prospective, open-label trial of fixed-dose risperidone for the treatment of delirium in elderly patients to determine the efficacy of this medication in the treatment of delirium, as well as to identify factors associated with the incidence of side-effects.

METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Subjects

The present study was conducted on 30 patients diagnosed with delirium according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edn (DSM-IV).8 All patients were seen at Osaka Koseinenkin Hospital from March 1998 to December 1999. Patients with any substance abuse and psychiatric comorbidities were excluded from the study. Eight patients were withdrawn from the trial because two refused to take neuroleptic drugs and six presented with psychomotor excitement that was too severe to enable them to take any oral medication. Rapid sedation using other drugs and methods was required in these patients. Consequently, the remaining 22 patients diagnosed with the hyperactive–hyperalert variant type of delirium9 were enrolled in the study. Informed consent was obtained from the family of all patients. The experimental procedure was conducted in accordance with the policies and principles contained in the Declaration of Helsinki. Although in 2005 the Food and Drug Administration (FDA) issued an advisory stating that atypical antipsychotic medications may increase mortal adverse events in elderly patients (http://www.fda.gov/cder/drug/advisory/antipsychotics.htm), the present study was performed before the release of this statement and so no ethical problems need to be addressed.

Procedure

The severity of delirium was evaluated by two psychiatrists (KI, YT) using the Delirium Rating Scale (DRS).10 The DRS was assessed in patients in the morning at their bedside prior to risperidone treatment (baseline) and then again 1, 3, 5, 7, and 14 days after the initiation of treatment. Risperidone was administered orally at a fixed daily dose of 0.5–3.0 mg once or twice a day in monotherapy. The dose and titration of risperidone were based on clinical judgment, taking into consideration essentially the severity of the delirium. In addition, psychomotor excitement, age, blood pressure, physical state, and the body weight of patients were also considered. We administered, in principle, 0.5–1.0 mg/day risperidone to patients with a baseline DRS score of 20 or less, and 2.0–3.0 mg/day risperidone when the DRS score was higher than 21. Antipsychotic drugs other than risperidone were not administered. Resolution of delirium was defined as a score of 12 points or less on the DRS after the initiation of treatment.10 The day of the initial response to treatment was considered when the patient showed any decrease in the DRS score from baseline.5 Delirium resolution occurring before 5 days of treatment (on Days 1 or 3) was deemed fast resolution.6,7 All patients in whom symptoms of delirium resolved within the first week of treatment were allowed to discontinue risperidone on Day 7, without reaching 14 days therapy. In addition to DRS ratings, data on the etiology of the delirium (malignancy related, hepatic or renal failure, postoperative, toxic, or cerebrovascular disease), treatment-related side-effects, and patient demographics (age and gender) were also collected.

Statistical analysis

Statistical analyses were performed using spss version 10 (SPSS, Chicago, IL, USA), and EXCEL TOUKEI version 6.0 (ESUMI, Tokyo, Japan). Data were analyzed using the Friedman test, Steel procedure (Non-parametric multiple comparison), Mann–Whitney test, Spearman correlation, and χ2. In addition, two stepwise logistic regression models were developed to identify possible predictors of fast delirium resolution and treatment-related side-effects. The independent variables used in the analyses were age, gender, dose, and those variables related to delirium etiology. In addition, a 2-point or higher decrease in the DRS scores on Day 1 was used in the model concerning side-effects. The level of significance was set at P < 0.05.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

The demographic and clinical characteristics of the elderly patients with delirium in the present study are given in Table 1. Mean (± SD) patient age was 73.6 ± 7.8 years (range 60–86 years). The mean dose of risperidone administered was 1.5 ± 0.7 mg (range 0.5–3 mg) and the mean period of risperidone treatment was 11.7 ± 3.5 days. The DRS time-course is shown in Fig. 1. The mean times until an initial response to treatment and the resolution of delirium were 1.3 ± 0.9 and 4.0 ± 2.9 days, respectively. Fifteen patients were found to respond initially to risperidone on Day 1 of treatment. Delirium resolved within 7 days in most patients (n = 21; 95.5%). Significant differences between DRS scores at baseline and after risperidone treatment were observed as early as Day 1 (P < 0.001) and the DRS scores continued to improve until the study end-point. All patients completed at least 7 days treatment. There were no significant differences in the time until delirium resolution and DRS scores at end-point between patients with baseline DRS scores of 20 or less (receiving, in principle, 0.5–1.0 mg/day risperidone) and those with baseline DRS scores higher than 20 (receiving, in principle, 2.0–3.0 mg/day risperidone; P = 0.97 and P = 0.23, respectively). No correlations were found between the time until delirium resolution and any of the variables in the analyses using Spearman's coefficient. Similarly, no predictors of fast delirium resolution were found using logistic regression analysis, even though risperidone dose approached statistical significance (P = 0.073). Risperidone treatment-related side-effects were present in six patients (27.3%). The most common symptom was somnolence (n = 4; 18.2%), followed by fatigue (n = 2, 9.1%), limb weakness (n = 1; 4.5%), and extrapyramidal effects (n = 1; 4.5%). Because these symptoms were mild in severity, there was no need for either discontinuation of the medication or a decrease in dose. Furthermore, all symptoms disappeared within several days after the termination of risperidone treatment. Another logistic regression model (χ2 = 11.7; P = 0.008) with side-effects as the dependent variable identified a decrease in 2 points or higher on the DRS score on Day1 (odds ratio = 5.6; 95% confidence interval = 1.1–28.1; P = 0.037) as a predictor of risperidone-related side-effects in this sample of elderly patients. The severity of the delirium was not found to be significantly associated with either fast delirium resolution or the development of side-effects. The presence of malignancies (brain, pancreas, stomach, lung, and lymphoma) approached statistical significance (P = 0.089).

Table 1.  Demographic and clinical characteristics of the patients in the present study (n = 22)
  • Unless indicated otherwise, data show the number of patients, with percentages given in parentheses.

  • Four patients with malignancies are also included in the postoperative delirium group.

Mean (±SD) age (years)73.6 ± 7.8
Gender
 Male8 (36.4%)
 Female14 (63.6%)
Patient's type
 Inpatients18 (81.8%)
 Outpatients4 (18.2%)
Delirium etiology
 Cerebral vascular disease6 (27.3%)
 Malignancy related5 (22.7%)
 Hepatic or renal failure4 (18.2%)
 Postoperative9 (40.9%)
 Antiparkinsonian drugs1 (4.5%)
Treatment-related side-effects
 Somnolence4 (18.2%)
 Fatigue2 (9.1%)
 Limbs weakness1 (4.5%)
 New-onset extrapyramidal effects1 (4.5%)
image

Figure 1. Time-course of Delirium Rating Scale (DRS) over the treatment period. Mean (± SD) DRS scores decreased over 14 days treatment with risperidone. *P < 0.01 compared with DRS scores on Days 1, 3, 5, 7, and 14; P < 0.01 compared with DRS scores on Days 5, 7, and 14.

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DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

The findings of the present study indicate that fixed-dose risperidone treatment was well tolerated and effective in resolving delirium in all 22 elderly patients. Interestingly, the use of a relatively low-dose risperidone regimen (1.5 mg/day on average) in the present study significantly improved the DRS score from baseline to Days 1 and 3 of treatment. Furthermore, the improvement continued until the end of treatment. The severity of delirium in our patients, as indicated by the mean DRS baseline score, was similar to that in previous reports.3,4,6,7 However, the mean time until delirium resolution in the present study (4 days) was found to be shorter and the initial response to treatment (1.3 days) faster compared with results from another study of risperidone (7.1 and 3.3 days, respectively).5 We speculate that the difference in the findings may be due to the use of an optimal fixed dose of risperidone based on the severity of the delirium in the present study compared with the flexible-dose methodology applied in the other study, because the flexible-dose regimen starts with a low dose and increases to the maximum tolerated dose. Moreover, consistent with findings from other investigations,5,6 the incidence of side-effects in our sample (27.3%) was relatively low compared with that reported by previous studies on haloperidol in delirium.11,12

A striking finding of the present study with clinical implications is that a decrease in 2 points or higher on the DRS score on Day 1 in the elderly was identified as a predictor for the development of side-effects. This seems to be unrelated to risperidone dose. Furthermore, dose was not associated with either the delirium resolution period or the development of side-effects. Although hepatic and renal disease were not identified as predictors of side-effects in the present study, the fact that an early response to the antipsychotic treatment (on Day 1) was associated with side-effects may reflect changes in the pharmacokinetics of risperidone related to decreased renal clearance and hepatic metabolizing capacity in elderly individuals.13

The findings of the present study suggest that risperidone is effective and safe for the management of delirium. Thus, it is strongly recommended an optimal dose risperidone is used, rather than typical antipsychotics, in the treatment of delirium in the elderly, who are more prone to side-effects following treatment with antipsychotics.

The main limitations of the present preliminary study lie in its small sample size, the lack of a control group, and the administration of risperidone only to patients with a mild or moderate hyperactive–hyperalert variant of delirium. Thus, our findings should be interpreted with caution and cannot be applied to the severe and hypoactive variant of delirium. Despite these limitations, the findings support the increasing evidence for the use of risperidone as an effective and safe medication in the treatment of delirium in the elderly and the severely ill. Further larger systematic studies are necessary.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES