Original articleA randomized controlled trial of quetiapine versus placebo in the treatment of delirium☆
Introduction
Delirium is a common disorder that occurs in 11–42% of general medical inpatients [1] and up to 50% of the hospitalized elderly [2]. It is a complex neuropsychiatric syndrome that includes a broad range of cognitive and noncognitive symptoms. Historically, treatment has focused on underlying causes. It is also increasingly appreciated that delirium can be persistent with an independent impact on functional capacity, morbidity, and mortality. Delirium remains understudied, especially in relation to pathophysiology and treatment.
With detection and correction of the underlying cause, the standard management of delirium includes nonpharmacological and pharmacological treatment [3], but when and what drugs to use remains uncertain, reflecting a lack of well-designed efficacy studies. A small open label study suggests that haloperidol and olanzapine may be effective in the treatment of delirium [4]. In two RCTs, olanzapine was recommended as a safe alternative to haloperidol in intensive care for managing delirium [5], [6]. In a case series of 12 patients, quetiapine was found to be beneficial with improvement shown on Delirium Rating Scale scores along with improvement in scores of the Mini-Mental State Examination (MMSE) and Clock Drawing Test [7]. An open-labeled randomized prospective flexible dosing study found similar responses for amisulpride and quetiapine [8]. The mean daily dose for the quetiapine group was 113 mg/day [8]. In a more recent case series of 22 patients, a mean (S.D.) dose of quetiapine was 45.7 (28.7) mg/day [9].
Prophylactic effects of haloperidol [10] and donepezil [11] have been studied in placebo-controlled studies as well. The fluctuating nature of delirium and its potential for spontaneous recovery as medical problems improve make placebo-controlled studies especially important in ascertaining the efficacy of drug-treatments.
We report a double blind randomized, placebo-controlled trial to determine the efficacy and acceptability of quetiapine in the treatment of incident delirium in general hospital inpatients with or without minor pre-existing cognitive deficits.
Full ethics committee approval was obtained for this investigator initiated study to include participants without mental capacity subject to relative's assent. The South East Wales Research and Ethics Committee and the Cardiff and Vale National Health Service (NHS) Trust Research and Development department formally approved the trial. AstraZeneca UK sponsored the study and provided funding for a research assistant, trial medication, and the randomization codes.
Sample size calculations indicated that 34 patients in each treatment group were required to have a 95% power to detect a mean five-point difference on the Delirium Rating Scale Revised 98 (DRS-R-98) [12] between the two groups at the 0.05 confidence level assuming a standard deviation of 5.6 at a specific time point.
Screening for delirium was conducted by daily contact with medical, surgical and orthopedic wards at the University Hospital of Wales by a research assistant. An attempt was made to recruit those who met the DSM-IV criteria for delirium on the same day if they had a DRS-R-98 total score of 15 or more. Individuals with major pre-existing cognitive deficits, alcohol withdrawal, pre-existing psychosis, substance dependence, inability to comply with the constraints of the trial, or who were on medication that interacted with quetiapine were excluded from the study. The nature and degree of any pre-existing cognitive deficits were determined by reviewing clinical notes and by obtaining information from a reliable informant. Informed consent was obtained from participants with mental capacity.
The DRS-R-98 total mean score was the primary outcome measure. This score was used to evaluate improvement at each contact. Secondary outcome measures included the MMSE, the Brief Psychiatric Rating Scale (BPRS) and the Clinical Global Improvement (CGI). Tolerability was assessed by using the Abnormal Involuntary Movements Scale (AIMS) and clinical examination. The participants were assessed on Days 1, 2, 3, 4, 7, and 10. A follow-up assessment was also undertaken on Day 30. Physical status and investigations were considered at each time point by reviewing the medical case notes.
After collecting baseline data, participants were blindly randomized to a flexible dosing regime of 25 mg once daily oral quetiapine or a matching placebo tablet with dose titration of 25 mg/day to a maximum daily dose of 175 mg in divided doses. Computer-generated randomization codes were kept in sealed envelopes at the University Hospital of Wales' Pharmacy. In addition, a set of individual treatment codes was kept by the Scottish Poisons Information Bureau, Royal Infirmary Edinburgh, for emergency out-of-hours use only. The dose of quetiapine was only increased if the DRS-R-98 and clinical condition did not show any improvement. In addition to the clinical response and tolerability, information from nursing and medical staff was also considered prior to dose changes. The decision to increase the dose was taken by the clinicians involved in the trial up to a maximum of 10 days after recruitment. If the treatment was successful and symptoms were resolved as shown by improvement in the DRS-R-98 and clinical condition, the dose was down-titrated in the reverse pattern from initial titration.
To account for the noncompleters, due to various reasons given below, it was important to take into account missing data and the improvement in delirium with or without medication; we used non-linear, mixed-effects model to estimate differences in recovery trajectories between treatment groups. Initially, we considered models that allowed different starting and long-term mean values in the two treatment groups; however, no significant evidence of such differences was found. The final models therefore took the form
where s0 is the overall mean starting value; si is a subject-specific deviation from this starting value for the ith individual; f0 and fi are the equivalent parameters describing the overall mean and subject-specific deviation from the long-term prognosis; t represents the elapsed (calendar) time from the Day 1 of inclusion in the trial; r describes the rate at which the placebo group progresses from starting value to long-term prognosis; xi indicates the treatment group of subject i; and a describes the difference in recovery rate in the quetiapine group. If a>0, the quetiapine group recovers more quickly; if a=0, there is no difference in recovery trajectories, and if a<0 the quetiapine group recovers more slowly. For instance, if a=1, then the quetiapine group would recover twice as quickly as the placebo group.
We reiterate that, following nonsignificant tests of inequality, the quetiapine and placebo groups were assumed to have the same mean response at baseline in all nonlinear models. Note, however, that as the BPRS and CGI measurements were only made at three time points, they were not suitable for analysis using non-linear models. For BPRS and CGI, therefore, the treatment groups were compared on the three available measurements occasions.
Statistical Package R and SPSS (Version 16) were used for the analyses.
Section snippets
Results
Between June 2003 and April 2005, 372 patients were screened to recruit 42 (21 in each group) patients for this study. Reasons for exclusion were a score less than 15 on the DRS-R-98, inability to obtain relative's assent, physical illness of a severity preventing recruitment into the study, and impairment of mental capacity. Only one patient was able to consent.
Nineteen of the recruited sample had undergone a surgical operation. Others had a medical cause for admission. Of the 19 who had
Discussion
This is the first placebo-controlled RCT of quetiapine in delirium. The trial was stopped early at the request of the manufacturer due to the Food and Drug Administration's concerns on the use of antipsychotic medication in the elderly. Even though the study was underpowered and can be considered a failed study due to the small sample size, a significantly faster response for quetiapine was shown on DRS-R-98 severity score. In addition, a statistically significant improvement in noncognitive
Acknowledgments
The authors thank Dr. A. Johansen for facilitating recruitment of patients for this RCT.
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Declaration of interest: This is an investigator initiated study. In terms of the Clinical Trials Directive, AstraZeneca UK has legally sponsored and provided funding for recruitment of a research assistant and trial medication.