An open-label study of quetiapine for delirium.

Abstract

To evaluate the effects of quetiapine treatment in patients with delirium.
All patients with delirium were assessed. The diagnosis of delirium was confirmed by using the Confusion Assessment Method (CAM). Quetiapine at the dose between 25 and 100 mg/day was given for 7 days. The efficacy of quetiapine on delirium was evaluated by using the Delirium Rating Scale (DRS) and the Clinical Global Impression-Severity scale (CGI-S). The extrapyramidal side effects were assessed by using the Modified (9-item) Simpson-Angus Scale (MSAS).
Twenty-two patients had delirium. Seventeen (10 males and 7 females) subjects with a mean age (SD) of 55.6 (18.6) years were included in the present study. Means (SDs) dose and duration (SD) of quetiapine treatment were 45.7 (28.7) mg/day and 6.5 (2.0) days, respectively. The DRS and CGI-S scores of days 2-7 were significantly lower than those of day 0 (p < 0. 001) for all comparisons). Only two subjects were shown to have mild tremor.
Quetiapine within the range of 25-100 mg/day improves delirious condition within 24 hours of treatment. It is well-tolerated and has a very low propensity to induce extrapyramidal side effects. Further randomized, placebo-controlled trials are warranted.

Full text

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2158 J Med Assoc Thai Vol. 90 No. 10 2007
Correspondence to : Maneeton B, Department of Psychiatry,
Chiang Mai University, 110 Intawaroros Rd, Sriphum, Amphur
Muang, Chiang Mai 50200, Thailand. Phone: 053-945-422,
Fax: 053-945-426, E-mail: bkhongsa@mail.med.cmu.ac.th
Delirium is a common neuropsychiatric syn-
drome with a prevalence of 10% to 20% among hospi-
talized patients in medical and surgical wards(1). Its
symptoms include disturbances of consciousness,
attention, cognition, and perception. This condition
develops over a short period of time and tends to fluc-
tuate during the course of the day, and it is caused by
one or more physical conditions(2). Delirium is tradi-
tionally considered as a transient syndrome that ends
in recovery after 10-12 days(3). Disorganized behavior
in delirious patients, such as aggression, agitation,
restlessness, insomnia, liability of mood, and delusion
usually disturb treatment settings and may be danger-
ous to patients and others. In addition, hospital mor-
tality estimates range from 10% to 65%(4).
Management of delirium includes early de-
tection, environmental manipulation, and treatment for
the underlying physical conditions contributing to de-
Preliminary Report
lirium. However, psychopharmacological treatment is a
major component of all interventions for moderate to
severe cases. As a condition that impairs global cere-
bral function and decreases function of the cholinergic
system(5), any medications with considerable anticho-
linergic effect, such as low-potency, conventional
antipsychotics, should be avoided(6). Due to their less
anticholinergic effects, high-potency, conventional
antipsychotics (e.g., haloperidol) have been used as
first-line treatment for the neuropsychiatric symptoms
of delirium(7). However, these medications are also fre-
quently associated with extrapyramidal side effects
(EPS).
Atypical antipsychotic medications, which
are less likely to induce EPS, may be an alternative to
high-potency conventional antipsychotics for the
treatment of delirium. Recently, several lines of evi-
dence have shown that risperidone and olanzapine are
effective and safe for patients with delirium(8).
In schizophrenic patients, quetiapine is an
atypical antipsychotic with a very low propensity to
induce EPS(9). Due to its relatively low affinity to
An Open-Label Study of Quetiapine for Delirium
Benchalak Maneeton MD*,
Narong Maneeton MD*, Manit Srisurapanont MD*
* Department of Psychiatry, Chiang Mai University, Chiang Mai
Objective: To evaluate the effects of quetiapine treatment in patients with delirium.
Material and Method: All patients with delirium were assessed. The diagnosis of delirium was confirmed by
using the Confusion Assessment Method (CAM). Quetiapine at the dose between 25 and 100 mg /day was
given for 7 days. The efficacy of quetiapine on delirium was evaluated by using the Delirium Rating Scale
(DRS) and the Clinical Global Impression-Severity scale (CGI-S). The extrapyramidal side effects were assessed
by using the Modified (9-item) Simpson-Angus Scale (MSAS).
Results: Twenty-two patients had delirium. Seventeen (10 males and 7 females) subjects with a mean age (SD)
of 55.6 (18.6) years were included in the present study. Means (SDs) dose and duration (SD) of quetiapine
treatment were 45.7 (28.7) mg/day and 6.5 (2.0) days, respectively. The DRS and CGI-S scores of days 2-7 were
significantly lower than those of day 0 (p < 0.001) for all comparisons). Only two subjects were shown to have
mild tremor.
Conclusion: Quetiapine within the range of 25-100 mg/day improves delirious condition within 24 hours of
treatment. It is well-tolerated and has a very low propensity to induce extrapyramidal side effects. Further
randomized, placebo-controlled trials are warranted.
Keywords: Delirium, Quetiapine, Extrapyramidal side effects, Treatment outcome
J Med Assoc Thai 2007; 90 (10): 2158-63
Full text. e-Journal: http://www.medassocthai.org/journal

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J Med Assoc Thai Vol. 90 No. 10 20072159
muscarinic (M1) receptors(10), quetiapine may be less
likely to worsen the delirious condition. Due to the
above-mentioned safety profile, a number of quetiapine
studies have been carried out in patients with delirium.
Although most study findings suggest that quetiapine
is effective and safe in this population, none of the
studies used an objective measure to examine antipsy-
chotic-induced EPS, which may be the main benefit of
this medication.
The present study aimed to examine the
therapeutic effects and adverse events, in particular
EPS, of quetiapine in patients with delirium.
Material and Method
This 7-day prospective study of quetiapine
was carried out in physically ill patients admitted to
Chiang Mai University Hospital, a tertiary care setting
in northern Thailand. The research proposal was ap-
proved by the Ethics Committee of the Faculty of Medi-
cine, Chiang Mai University. Prior to the study partici-
pation, written informed consent was obtained from a
1st degree relative of each subject after the study de-
tails had been fully explained.
Subjects
All physically ill in-patients, whose primary
physicians consulted the psychiatrists for assessing
and treating delirium, were considered as potential
subjects. The inclusion criteria for the subjects were:
i) physically ill patients meeting the DSM-IV diagnos-
tic criteria of delirium, due to a medical condition, or
delirium due to multiple etiologies and ii) male or female
patients aged 18 years old or more. The diagnosis of
delirium was reconfirmed by use of the Confusion
Assessment Method (CAM)(11). The exclusion criteria
were: i) delirium tremens, ii) history of psychotic dis-
orders, iii) being on narcotic medications, and iv) preg-
nant and nursing women. To ensure that the process
of consent obtained would not be a cause of treatment
delay, the authors also excluded patients who were not
accompanied by a 1st degree relative during the first
psychiatric assessment.
Procedures
The patients were given quetiapine at doses
between 25 and 100 mg/day. Patients received quetiapine
once (bedtime) or twice a day (morning and bedtime).
Quetiapine dosage was assessed after the present study
had ended, the primary physician made a decision about
the appropriate antipsychotic to use for each patient.
During the present study, lorazepam at the maximum
dose of 2 mg/day was an additional medication that
could be used if needed. The patients were not allowed
to receive other psychotropic medications, including
antidepressants, mood stabilizers, other anxiolytics/
hypnotics, or other antipsychotic medications.
Clinical measures and safety assessment
The authors assessed the severity of delirium
by using the Delirium Rating Scale (DRS), which has a
maximum score of 32 points(12) and the Clinical Global
Impression-Severity scale (CGI-S) which comprises
7 score(13). Clinically significant improvement was
defined as a DRS score reduction of 50% or more.
The authors assessed the EPS by using the Modified
(9-item) Simpson-Angus Scale (MSAS)(14). The MSAS
is a 5-point scale of 9 items (arm dropping, shoulder
shaking, elbow rigidity, wrist rigidity, leg pendulous-
ness, head dropping, glabellar tap, tremor, and saliva-
tion). Score 0 = normal, 1 = slightly, 2 = moderate, 3 =
marked, 4 = extreme, and 9 = not ratable, which has a
maximum score of 81 points. The item of gait stability
was excluded because the patients might not cooperate
properly or have injuries during the assessment. All
measures were applied at baseline (day 0, prior to the
commencement of quetiapine treatment) and daily
throughout the present study (days 1-7).The higher
the score, the greater the functional impairment.
Statistical analysis
Data were expressed as number, present,
mean, and standard deviation (SD). The DRS and CGI-
S scores measured on day 0 were compared with those
assessed on days 1-7 by the use of repeated measure-
ment ANOVA of. All p-values of less than.05 were con-
sidered as significant differences. The data analyses
were performed on an intention-to-treatment basis by
the use of last-observation-carried-forward analysis.
A p-value of less than 0.05 was considered statistical
significance.
Results
From June to December 2005, 22 delirious
patients were consulted for psychiatric assessment and
treatment. Of those, five did not meet the inclusion/
exclusion criteria or gave written informed consent.
Seventeen patients (10 males and 7 females) with DSM-
IV delirium participated in the present study. None of
them had a history of psychiatric illness. Their mean
(SD) age was 55.6 (18.6) years old. Mean (SD) duration
of delirium before treatment were 7.9 (7.2) days. Most
subjects had varies diagnoses and multiple etiologies

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2160J Med Assoc Thai Vol. 90 No. 10 2007
of delirium. One patient had about six (1.4) causes of
delirium. (Table 1). No patient received lorazepam (the
rescue medication). The mean (SD) of quetiapine doses
was 45.7 (28.7) mg/day.
Efficacy and adverse events
Five patients who had much improvement
were discharged before the present study ended. How-
ever, these patients accepted to continue the same
dosage of quetiapine at home until 8 days. Two patients
discontinued quetiapine within 3 and 6 days of treat-
ment respectively. One subject (multiple myeloma)
refused to take medication after the 6th day of treat-
ment. The authors discontinued quetiapine in one
patient with dilated cardiomyopathy with sepsis due
to hypotension.
Of 17 subjects participating in the present
study, 15 (88.2%) had clinically significant improve-
ment (> 50% reduction of the DRS scores). The mean
(SD) days of treatment until improvement was 3.9 (2.1).
A mean (SD) DRS score of 24.5 (3.2) at baseline (day 0)
was decreased to a mean (SD) of 9.6 (6.0) on day 7. All
DRS scores obtained on days 1-7 were significantly
lower than those at day 0 (Table 2). A mean (SD) CGI-S
score of 4.9 (0.9) at baseline (day 0) was lowered to a
mean (SD) of 1.6 (1.3) on day 7. All CGI-S score assessed
at days 1-7 were significantly lower than those of day 0
(Table 2). DRS and CGI-S scores were decreased by
time (Fig. 1).
Of all subjects, only two had MSAS scores of
1 on the item of tremor. The first one was a 33-year-old
woman with seizures, due to neuropsychiatric compli-
cations of systemic lupus erythematosus. Valproate-
induced tremor was suspected because her tremor
was found on day 0 (prior to the start of quetiapine)
and subsided on day 6 after the discontinuation of
valproate. The second participant was a 68 years old man
with dilated cardiomyopathy who also had multiples
organ failure, sepsis, and cerebral infarct. Right hand
tremor of this patient was increased from 0 to 1 during
the present study. Other adverse effects found during
treatment are shown in Table 3.
Table 1. Patients details characteristics
Characteristic
Mean age (years) (SD)
Gender
Male
Female
Physical disease (n = 17)
Dilated cardiomyopathy
SLE
Multiple sclerosis
Acquired immune deficiency syndrome
Carcinoma
Fracture or head injury
DKA
Causes of delirium (n = 17)
Infection
Acute metabolic
Trauma*
CNS pathology
Hypoxia
Malnutrition
Toxin or drug intoxication
Others
Dosages
Starting dose (mg/day)
Mean dose (mg/day) (n = 17)
Mean dose daytime (n = 10)
Mean dose bedtime (n = 17)
Mean dose prn agitation (n = 9)
55.6 (18.6)
10 (58.8%)
7 (41.2%)
2 (11.8%)
3 (17.6%)
1 (5.9%)
1 (5.9%)
4 (23.5%)
5 (29.4%)
1 (5.9%)
11 (64.7%)
12 (70.6%)
7 (41.1%)
14 (82.4%)
11 (64.7%)
11 (64.7%)
12 (70.6%)
8 (47.1%)
36.8 (24.8)
45.7 (28.7)
15.0 (5.5)
35.0 (21.9)
6.6 (4.3)
Data are n (%) or mean (SD)
* Fracture femur (n = 1), subtrochanteric fracture (n = 1),
intertrochanteric fracture (n = 1), postoperative trauma (n =
1), C-spine injury (n = 1) and closed head injury (n = 2)
Table 2. Delirium rating scales (DRS)
Scale Baseline (d0) d1 d2d3 d4d5 d6 d7
DRS
CGI-S 4.9 (0.9)
24.5 (3.2) 18.2 (5.7)*
2.9 (0.8)*
14.6(6.3)**
2.6 (0.9)** 2.2 (1.1)** 2.2 (1.7) ** 1.9 (1.4)** 1.9 (1.3)** 1.6 (1.3)**
12.6 (6.5)** 11.7 (7.0)** 10.7 (6.3)** 10.5 (6.0)** 9.6 (6.0)**
Data are expressed as mean (SD)
* p < .01, ** p < .001 based on within-treatment changes
Discussion
The present study findings showed that
quetiapine at a mean dose of 45.7 mg/day may rapidly
decrease neuropsychiatric symptoms of delirium.
Quetiapine treatment is well-tolerated by patients with
delirium. By the use of a standard measure, the com-
prehensive physical examination for EPS could find
only mild tremor in two patients.

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J Med Assoc Thai Vol. 90 No. 10 20072161
Fig. 1
Mean of DRS and CGI-S scores from day 0 to day 7 in 17 patients with DSM-IV delirium (n = 17)
Abbreviation: DRS = Delirium rating scale; CGI-S = Clinical global impression-severity scale
Table 3. Adverse effects of quetiapine
Adverse effects n = 17
Extrapyramidal side effect
Tremor
Other adverse effect+
Hypotension
Daytime sleepiness
Nightmare
Dry mouth
Nausea
2 (11.8)
2 (11.8)
13 (76.5)
3 (17.6)
2 (11.8)
1 (5.9)
Data are n (%)
+ One case with more than one adverse effect
The results of the present study confirm the
previous findings that quetiapine is effective and safe
for individuals with delirium. The mean daily dose of
quetiapine in the present study (45.7 mg/day) was rela-
tively lower than those in previous ones (93.8-211.4
mg/day)(15-18). It is possible that the metabolism of Thai
patients was slower than those of Caucasian(15) and
Asian subjects(16-18). The correlation of the mean daily
dose of quetiapine and the change in the DRS score
was not significant in our study (p = 0.667), which is
similar to that of previous studies (p = 0.618 and p =
0.336)(15,17), indicating that the effect of quetiapine for
treating delirium is not associated with a dose incre-
ment.
To the authors’ knowledge, this is the first
study of quetiapine to use a low dose of medication
in patients with delirium. However, there were some
limitations. The open-label study design may be prone
to bias. Because delirium is self-limited in most patients,
self-improvement cannot be ruled out. The small
sample size was also another important limitation.
In conclusion, quetiapine treatment may
rapidly decrease neuropsychiatric symptoms of deli-
rium. It is well tolerated and has a very low propensity
to induce EPS in patients with delirium. Further ran-
domized, placebo-controlled trials with large sample
sizes are warranted.
Acknowledgements
There was no grant support for the present
study. The quetiapine tablets used in the present study
were donated by Astra Zeneca (Thailand).
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J Med Assoc Thai Vol. 90 No. 10 2007 2163
การศึกษาแบบเปิดฉลากของ quetiapine สำหรับภาวะเพ้อ
เบญจลักษณ์ มณีทอน, ณรงค์ มณีทอน, มานิต ศรีสุรภานนท์
วัตถุประสงค์: เพื่อประเมินประสิทธิภาพของยาคิวไทอาปีน ในการรักษาผู้ป่วยที่มีภาวะเพ้อ
วัสดุและวิธีการ: ทำการศึกษาในผู้ป่วยที่มีภาวะเพ้อ ตามเกณฑ์วินิจฉัยแบบ diagnostic และ statistical manual
of mental disorders, fourth edition diagnosis (DSM-IV) โดยยืนยันการวินิจฉัยด้วยเครื่องมือ the confusion as-
sessment method (CAM) ผู้รายงานได้ให้ยาคิวไทอาปีนขนาด 25-100 มิลลิกรัมต่อวัน เป็นเวลาประมาณ 7 วัน
แก่ผู้ป่วยที่มีภาวะเพ้อและประเมินประสิทธิภาพในการรักษาด้วยเครื่องมือ the delirium rating scale (DRS) และ
the clinical global impression-severity scale (CGI-S) นอกจากนี้ยังประเมินผลข้างเคียงชนิด extrapyramidal
ด้วยเครื่องมือ the modified (9-item) Simpson-Angus scale (MSAS)
ผลการศึกษา: มีผู้ป่วยจำนวน 22 ราย ที่ได้รับการวินิจฉัยว่ามีภาวะเพ้อ โดยมีผู้ป่วยจำนวน 17 รายเข้าร่วมการศึกษา
เป็นเพศชาย 10 รายและเพศหญิง 7 ราย มีอายุเฉลี่ย (ค่าเบี่ยงเบนมาตรฐาน) เท่ากับ 55.6 (18.6) ปี ผู้ป่วยกลุ่มนี้
ได้รับยาเฉลี่ย (ค่าเบี่ยงเบนมาตรฐาน) เท่ากับ 47.0 (27.3) มิลลิกรัมต่อวัน เป็นเวลาเฉลี่ย (ค่าเบี่ยงเบนมาตรฐาน)
เท่ากับ 6.5 (2.0) วัน พบว่าผู้ป่วยมีการตอบสนองต่อยาดี โดยคะแนน DRS และ CGI-S มีค่าลดลงเมื่อเทียบกับคะแนน
ก่อนการรักษาในวันที่ 2 หลังการรักษาเป็นต้นไป อย่างมีนัยสำคัญ (p < 0.001) นอกจากนี้พบว่าผู้ป่วย 2 ราย
มีอาการมือสั่นเพียงเล็กน้อย
สรุป: ยาคิวไทอาปีนขนาด 25-100 มิลลิกรัมต่อวัน สามารถช่วยรักษาภาวะเพ้อได้ดีภายในเวลา 24 ชั่วโมง
หลังเริ่มรักษา ทั้งยังทำให้เกิดผลข้างเคียงในกลุ่ม extrapyramidal ค่อนข้างน้อย อย่างไรก็ตามควรมีการศึกษาเพิ่มเติม
โดยใช้กลุ่มควบคุมต่อไป