Paliperidone in the treatment of delirium: results of a prospective open‐label pilot trial

Abstract

Yoon H-K, Kim Y-K, Han C, Ko Y-H, Lee H-J, Kwon D-Y, Kim L. Paliperidone in the treatment of delirium: results of a prospective open-label pilot trial.Objective: Delirium is a life-threatening neuropsychiatric syndrome characterised by disturbances in consciousness, attention, cognition and perception. Antipsychotics are considered the drugs of choice in managing the symptoms of delirium. Paliperidone is a benzisoxazole derivative and the principal active metabolite of risperidone. In this study, we aimed to evaluate the efficacy of paliperidone for the treatment of delirium.Methods: A prospective open-label study of paliperidone for delirium treatment was performed with 6-day follow-up. Fifteen patients who met Diagnostic and Statistical Manual of Mental disorders, Fourth Edition criteria for delirium and had a score of 13 on the Delirium Rating Scale were recruited. The starting dose was 3 mg once a day and the dose was adjusted depending on the status of delirium. Daily assessments of the severity of delirium were evaluated using Memorial Delirium Assessment Scale (MDAS).Results: The mean daily maintenance dose of paliperidone was 3.75 ± 1.06. The MDAS scores before and after treatment (day 7) were 23.60 ± 6.31 and 11.33 ± 5.45 (t = 6.78, p < 0.001), respectively. The intensity of delirium showed a statistically significant reduction in MDAS scores from the first day of treatment. No serious adverse effects were observed, and none of the patients discontinued paliperidone because of adverse effects.Conclusions: This study shows that low-dose paliperidone is effective in reducing behavioural disturbances and symptoms in delirium and is well tolerated in delirious patients. This trial is an open-label study with a small sample size, and further controlled studies will be necessary.

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Acta Neuropsychiatrica 2011: 23: 179–183
All rights reserved
DOI: 10.1111/j.1601-5215.2011.00568.x
© 2011 John Wiley & Sons A/S
ACTA NEUROPSYCHIATRICA
Paliperidone in the treatment of delirium:
results of a prospective open-label pilot trial
Yoon H-K, Kim Y-K, Han C, Ko Y-H, Lee H-J, Kwon D-Y, Kim L.
Paliperidone in the treatment of delirium: results of a prospective
open-label pilot trial.
Objective: Delirium is a life-threatening neuropsychiatric syndrome
characterised by disturbances in consciousness, attention, cognition and
perception. Antipsychotics are considered the drugs of choice in managing
the symptoms of delirium. Paliperidone is a benzisoxazole derivative and
the principal active metabolite of risperidone. In this study, we aimed to
evaluate the efficacy of paliperidone for the treatment of delirium.
Methods: A prospective open-label study of paliperidone for delirium
treatment was performed with 6-day follow-up. Fifteen patients who met
Diagnostic and Statistical Manual of Mental disorders, Fourth Edition
criteria for delirium and had a score of 13 on the Delirium Rating Scale
were recruited. The starting dose was 3 mg once a day and the dose was
adjusted depending on the status of delirium. Daily assessments of the
severity of delirium were evaluated using Memorial Delirium Assessment
Scale (MDAS).
Results: The mean daily maintenance dose of paliperidone was
3.75 ± 1.06. The MDAS scores before and after treatment (day 7) were
23.60 ± 6.31 and 11.33 ± 5.45 (t = 6.78, p < 0.001), respectively. The
intensity of delirium showed a statistically significant reduction in MDAS
scores from the first day of treatment. No serious adverse effects were
observed, and none of the patients discontinued paliperidone because of
adverse effects.
Conclusions: This study shows that low-dose paliperidone is effective in
reducing behavioural disturbances and symptoms in delirium and is well
tolerated in delirious patients. This trial is an open-label study with a small
sample size, and further controlled studies will be necessary.
Ho-Kyoung Yoon1, Yong-Ku
Kim1, Changsu Han1,
Young-Hoon Ko1, Heon-Jeong
Lee1, Do-Young Kwon2,
Leen Kim1
1Department of Psychiatry, College of Medicine,
Korea University, Seoul, South Korea; and
2Department of Neurology, College of Medicine,
Korea University, Seoul, South Korea
Keywords: delirium; DRS; MDAS; paliperidone
Professor Leen Kim, Department of Psychiatry,
College of Medicine, Korea University Anam
Hospital, Anam-Dong, Sungbuk-Gu, Seoul
136-705, South Korea.
Tel: +82 2 920 5815;
Fax: +82 2 927 2836;
E-mail: because@naver.com
Introduction
Delirium is an acute neuropsychiatric syndrome char-
acterised by disturbance of consciousness and atten-
tion, cognition and perception for a brief period of
time and tends to fluctuate during the course of
the day. It occurs in 10–30% of the hospitalised
medically ill patients, and it is associated with both
increased mortality and longer hospitalisation (1,2).
The management of delirium is challenging for clini-
cians and involves both aetiological and symptomatic
treatment. Although supportive and environmental
measures are useful, the cornerstone of treatment is
drug administration (3).
High-potency typical antipsychotics such as hal-
operidol have been used as the first choice in
the treatment of delirium. Haloperidol is the most
studied agent and is commonly used by clinicians
in all medical settings. It has the advantage of
intravenous administration. However, haloperidol is
frequently associated with adverse effects such as
extrapyramidal symptoms, which are more frequent
in the elderly and seriously medically ill patients,
who are most vulnerable to delirium.
Atypical antipsychotics including risperidone, que-
tiapine and olanzapine have been widely used for
treatment not only for schizophrenia symptoms
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Yoon et al.
but also delirium, because they are at least as
effective as haloperidol and they are clearly better
tolerated (4–7).
Paliperidone is the 9-hydroxy, active metabolite
of risperidone, and shares some similarities in its
receptor-binding profile with that of risperidone (8).
Paliperidone has no affinity for cholinergic mus-
carinic receptors and would not be expected to cause
anticholinergic adverse effects such as dry mouth and
constipation (9) and, therefore, is expected to have an
advantage on the treatment of delirium.
In several studies, risperidone was proved effective
and safe in the treatment of delirium (5,10,11).
However, clinical trial of paliperidone for the
treatment of the patients with delirium has yet to
be published. Therefore, this prospective open-label
trial aimed to determine the efficacy of paliperidone
in the treatment of delirium.
Methods
Subjects
Male and female patients aged over 18 who were
referred to psychiatrists at Korea University Ansan
Hospital between October and December 2009 were
eligible to enter the study if they had delirium symp-
toms according the Diagnostic and Statistical Manual
of Mental disorders, Fourth Edition (DSM-IV) (12),
had a score of 13 on the Delirium Rating Scale
(DRS) (13).
Each patient was examined by trained psychiatrists
using the Structured Clinical Interview for DSM-IV
Axis I Disorders. Patients with previous diagnosis
of dementia, severe psychiatric pathology (psychotic
disorders, bipolar depression and severe recurrent
major depression), pregnant women, drug or alcohol-
dependent and abstinent patients, those treated with
antipsychotics over 3 weeks before recruitment, those
had a history of a prior hypersensitivity to paliperi-
done or risperidone and those aged below 18 years,
were excluded. We also excluded patients with phys-
ical restraint because of severe agitation, as paliperi-
done is available only through oral administration
that makes it difficult to guarantee drug compliance
in these cases. Patients signed the informed con-
sent previously approved by the Institutional Review
Board, or in those cases they were unable to do so,
the consent was signed by their legal representatives.
Measurements
The severity of delirium was evaluated using the
DRS (13) and the Memorial Delirium Assessment
Scale (MDAS) (14). The DRS is a 10-item, clinician-
rated symptom scale to identify delirium in the med-
ically ill patients. Items are scored from 0 to 3 or 0
to 4, and the temporal onset of symptoms, perceptual
disturbances, hallucinations, delusions, psychomotor
behaviour, cognitive status, presence of an underly-
ing organic pathology, sleep-wake disturbances and
fluctuation of symptoms are evaluated. Cut-off scores
of 10 and 12 have been suggested to distinguish
patients with delirium from patients with other neu-
ropsychiatric diseases (15). The cut-off score in this
study was 13. The DRS was used as a screening tool
in this study. The MDAS is a physician-rated instru-
ment designed to measure the severity of delirium.
Behavioural manifestations and cognitive deficit can
be evaluated using this scale. The MDAS yields a
global score ranging from 0 to 30, with a suggested
cut-off score of 13 for delirium.
Procedure
Each patient was evaluated at baseline using the
DRS and MDAS. Paliperidone was started at a dose
of 3 mg/day, and administered orally once per day,
in the evening. No other psychotropic drugs were
used. The dosage was increased up to 9 mg/day
depending on the status of delirium during the
7 days. The patients were examined at the same
time everyday for 7 days. Day 7 of treatment was
considered the endpoint of the study. If the dose
could not be increased because of adverse effects or
the patient’s poor physical condition, the dose was
continued for 7 days and the study was terminated
after confirming the absence of a marked change
of symptoms. A marked improvement was defined
as >50% reduction in the baseline severity score
of MDAS, a moderate improvement as 25–50%
reduction and no improvement as 0–25% change
in the score. Adverse effects were also investigated
during the study. The period of onset of effect was
defined as the time from the start of paliperidone to
any reduction in the baseline MDAS score.
For statistical analysis, Student’s t-test (paired
and two-tailed) and repeated measures analysis
of variance were performed, and the difference
was considered to be significant at p < 0.05. The
study protocol was reviewed and approved by the
Institutional Review Board.
Results
A total of 15 of 30 patients evaluated were enrolled
in this study. Fifteen patients were excluded for
the following reasons: oral administration of med-
ication was not suitable for six patients, four
patients required physical restraints, two patients
were diagnosed as Alzheimer’s dementia, the aeti-
ology of delirium in two patients was alcohol absti-
nence and one patient was experiencing a terminal
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Paliperidone and delirium
event. The subjects consisted of eight males and
seven females. The age of subjects was 66.09 ±
20.69 years. Medical diagnoses of subjects included:
pneumonia (n = 3), traumatic brain injury (n = 2),
cerebrovascular attack (n = 2), postoperative state
because of orthopaedic problems (n = 4), post-
operative state because of gastrointestinal prob-
lems (n = 3) and coronary heart disease (n = 1).
Mean maintenance dose of paliperidone was 3.75 ±
1.06 mg/day (Table 1).
Paliperidone was associated with a significant
improvement on MDAS from baseline to endpoint
(Fig. 1). The mean MDAS scores for the total sam-
ples were 23.60 ± 6.31 at baseline and 11.33 ± 5.45
at the end of the study. There was a significant
decrease from baseline throughout the study period
(F = 9.638, p = 0.002) and from baseline to end-
point (t = 6.78, p < 0.001). Nine of 15 patients
(60%) showed a marked improvement, 4 (26.7%)
a moderate improvement and 2 (13.3%) showed no
improvement. The appropriate dose in the 11 patients
who were assessed as having experienced a marked
or moderate improvement averaged 3.36 mg/day.
There was no correlation between the symptom
severity and efficacy.
No serious adverse effects were observed, and
none of the patients discontinued paliperidone
because of adverse effects. Two patients experienced
akathisia at a paliperidone dose of 6 mg/day, which
disappeared when treatment was combined with
β-blocker. No changes in biochemical and haema-
tological examinations, urinalysis or blood pressure
were noted.
Table 1. Characteristics of subjects and changes of MDAS
Number of subjectsMean ± SD
Sex
Males
Females
Age
Diagnosis
Postoperative state
Pneumonia
Traumatic brain injury
Cerebrovascular attack
Coronary heart disease
Mean dose
DRS of pretreatment
MDAS of first day treatment
MDAS of second day treatment
MDAS of third day treatment
MDAS of fourth day treatment
MDAS of fifth day treatment
MDAS of sixth day treatment
MDAS of seventh day treatment
8
7
—
—
— 66.09 ± 20.69
7
3
2
2
1
—
—
—
—
—
—
—
—
—
—
—
—
—
—
3.75 ± 1.06
23.15 ± 3.67
23.60 ± 6.31
20.20 ± 6.33
17.00 ± 6.68
15.40 ± 6.48
14.07 ± 6.07
12.93 ± 5.97
11.33 ± 5.45
DRS, Delirium Rating Scale; MDAS, Memorial Delirium Assessment Scale.
Fig. 1. Change in Memorial Delirium Assessment Scale scores.
A post hoc
G*Power 3.1.2 (GPower Software Inc., Kiel, Ger-
many). The power of this study was 0.99 (t-test, two-
tailed, α = 0.05; correlation between groups = 0.493
and effect size = 2.056).
power analysis was performed
Discussion
This prospective, open-label study shows that treat-
ment of hospitalised patients with low-dose paliperi-
done for 7 days is associated with a decrease in
symptoms of delirium and improvement in patient
functioning. To the best our knowledge, this study is
the first report on the paliperidone use for delirium
treatment.
Thirteen of 15 patients improved on most measures
of delirium. These findings were considered to have
occurred in response to treatment with paliperidone
because patients in whom the aetiological factors
of delirium could be eliminated and those whose
delirium was quite likely to resolve spontaneously
were excluded from the study. The dose of paliperi-
done was lower than those generally used to treat
schizophrenia (16–18). The mean appropriate dose
averaged 3.75 ± 1.06 mg/day.
No serious adverse effects were noted. Two
patients experienced akathisia, but it is easily treated
with β-blocker. Atypical antipsychotics have the
obvious advantage of low potential adverse effects.
Delirious patients, in general, are more sensitive
to medication adverse effects including anticholin-
ergic effects, orthostatic hypotension, parkinson-
ism, tardive dyskinesia and cognitive impairment
than patients with general psychotic conditions (19).
Drug-induced movement disorder may not only add
to medical morbidity but can further confuse an
already complicated clinical picture (20). Another
consideration in the choice of an antipsychotic in
the treatment of delirium is its anticholinergic pro-
file. The cumulative anticholinergic burden from var-
ious concomitant medications has been implicated
in the development of delirium (20,21). Therefore,
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Yoon et al.
choosing an atypical antipsychotics with no or low
affinity for muscarinic receptors, such as paliperi-
done, might provide an advantage over agent with
greater anticholinergic properties. In this aspect of
tolerability, no subject in this study discontinued
paliperidone, and there were no reported serious
side-effects, and only two patients complained of
akathisia, which suggests satisfactory tolerability of
this drug in patients with delirium.
Paliperidone is a benzisoxazole derivative and
is considered to be the major active metabo-
lite of risperidone. Similar to risperidone, paliperi-
done has an affinity for 5-HT1D, 5-HT2B, 5-HT7
and D3 receptors (8,22,23). However, the inhibi-
tion constant values for binding to D2 and 5-HT2A
receptors are lower for paliperidone than risperi-
done (0.16 vs. 5.9 nmol/l and 0.25 vs. 4.8 nmol/l,
respectively) (22–24). Also, paliperidone has shown
weaker affinity for α1- or α2-adrenergic receptors
compared with that of risperidone in vitro; there-
fore, hypothetically, it may cause less orthostasis
compared with risperidone (8). In addition, paliperi-
done has no affinity for cholinergic, muscarinic and
β1- or β2-adrenergic receptors. As a result, it may
be hypothesised that paliperidone causes less weight
gain compared with other second-generation antipsy-
chotics (9,25,26).
In contrast to risperidone and other antipsychotics,
paliperidone undergoes limited hepatic metabolism.
Four metabolic pathways were identified as being
involved in the elimination of paliperidone, each of
which accounted for up to a maximum of 6.5%
of the biotransformation of the total dose. Renal
excretion was the major route of elimination with
59% of the dose excreted unchanged in urine.
About half of the renal excretion occurred by
active secretion (27). As the cytochrome P450 2D6
pathway is minimally involved in the metabolism of
paliperidone, clinically significant pharmacokinetic
drug interactions with drugs that inhibit this enzyme
are unlikely. Risperidone, by comparison, has known
drug–drug interactions with the cytochrome P450
2D6 inhibitors, fluoxetine and paroxetine.
This study has some limitations. First, it was a
prospective open-label study with small sample size.
For the assessment of the efficacy of treatment,
randomised double blind case–control study using
the larger sample is crucial. Second, the patients
who required physical restraint and unable to use
oral medications were excluded because paliperi-
done is available only through oral administration
that makes it difficult to guarantee drug compli-
ance. These exclusion criteria may have created a
selection bias. Third, the observation period was too
short to evaluate the long-term efficacy and adverse
effects of paliperidone in delirium patients. Finally,
although the patients treated with antipsychotics were
excluded from the study, most of the patients were
very ill and were treated with several concurrent
medications, which may have resulted in confound-
ing factor. The validity of generalising these results
to a wider population of patients with pre-existing
delirium remains to be confirmed in larger double
blind studies.
In conclusion, this small open-label pilot study
indicates that low-dose paliperidone is effective in
reducing behavioural disturbances and symptoms in
delirium and is well tolerated in delirious patients.
Although it is too early to tell whether paliperidone
might be the treatment choice of delirium, further
systematic controlled studies should be warranted.
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