Treatment of behavioural, cognitive and
circadian rest-activity cycle disturbances in
Alzheimer’s disease: haloperidol vs. quetiapine
Egemen Savaskan1, Corina Schnitzler2, Carmen Schro ¨der2, Christian Cajochen2,
Franz Mu ¨ller-Spahn1and Anna Wirz-Justice2
1Geriatric Psychiatry and2Centre for Chronobiology, University Psychiatric Hospitals, CH-4025 Basel, Switzerland
This 5-wk, open-label, comparative study investigated the effects of quetiapine and haloperidol on
behavioural, cognitive and circadian rest–activity cycle disturbances in patients with Alzheimer’s disease
(AD). Out of a total of 30 patients enrolled in the study, there were 22 completers, 11 in the quetiapine
group (mean age 81.9¡1.8 yr, mean baseline MMSE 19.9¡1.3, mean dose 125 mg) and 11 in the
haloperidol group (mean age 82.3¡2.5 yr, mean baseline MMSE 18.1¡1.3, mean dose 1.9 mg). As shown
in the Neuropsychiatric Inventory, both medications reduced delusion and agitation, whereas quetiapine
additionally improved depression and anxiety. Haloperidol worsened aberrant motor behaviour and
caused extrapyramidal symptoms. In the Consortium to Establish a Registry for Alzheimer’s Disease
(CERAD) neuropsychological test battery which assessed cognitive parameters, quetiapine improved
word recall; significant interaction terms revealed differences between quetiapine and haloperidol in
word-list memory and constructional praxis. According to the Nurses’ Observation Scale for Geriatric
Patients (NOSGER) quetiapine improved instrumental activities of daily living. Actimetry documented
the circadian rest–activity cycle before and after treatment. Sleep analysis revealed that patients receiving
quetiapine had shorter wake bouts during the night, whereas patients receiving haloperidol had fewer
though longer immobile phases. The study provides evidence that quetiapine at a moderate dose may be
efficacious in treating behavioural disturbances in AD, with better tolerability than haloperidol.
Received 12 April 2005; Reviewed 29 May 2005; Revised 4 July 2005; Accepted 7 July 2005;
First published online 5 September 2005
Key words: Actimetry, Alzheimer’s disease, behavioural symptoms, haloperidol, quetiapine.
Alzheimer’s disease (AD) is the most common cause
of dementia in the elderly population, causing
progressive cognitive decline often accompanied by
affective, behavioural and circadian sleep–wake cycle
disturbances. These can be manifested as agitation,
aggression, purposeless activity, wandering, pacing,
nocturnal restlessness, depressive features and psy-
chotic symptoms such as hallucinations and delusions
(Van Someren et al., 1996; Vitiello and Borson, 2001).
At least one of these neuropsychiatric disturbances is
found in 60% of AD patients (Lyketsos et al., 2000).
The behavioural and sleep–wake cycle disturbances of
AD have a severe impact on the patient’s and care-
giver’s quality of life, often being the reason for the
decision to institutionalize these patients (Pollak and
Stokes, 1997). Therefore, effective treatment of these
symptoms may help to reduce social and economic
costs. Unfortunately, most of the agents used in
this polymorbid population, such as benzodiazepines,
anxiolytics or anticonvulsants cause severe side-effects
and interact with internistic diseases also present,
as well as with other medication.
Neuroleptics are commonly used to treat be-
havioural symptoms in AD patients (Motsinger
et al., 2003; Profenno and Tariot, 2004; Salzman, 2001).
However, because of their anticholinergic side-effects
and tendency to induce extrapyramidal symptoms
(EPS), classical neuroleptics are disadvantageous and
atypical neuroleptics are receiving more attention in
the management of these behavioural disturbances.
In a previous single case study, we showed that
Address for correspondence: E. Savaskan, M.D., University
Psychiatric Hospitals, Wilhelm Klein-Str.27, CH-4025 Basel,
Tel.: + +41-61-3255319 Fax:
International Journal of Neuropsychopharmacology (2006), 9, 507–516. Copyright f 2005 CINP
haloperidol, a conventional neuroleptic, disrupted the
circadian rest–activity cycle of an early-onset AD
patient, whereas clozapine improved it (Wirz-Justice
et al., 2000).
Quetiapine (Seroquel1), a new atypical neuroleptic,
is a dibenzothiazine derivative that has been eval-
uated for the treatment of patients with psychotic
symptoms (DeVane and Nemeroff, 2001). It exhibits
strong binding properties for serotonin 5-HT2A,
histamine H1and a1adrenergic receptors, some a2
adrenergic receptor-blocking qualities, but markedly
low affinity to dopamine D2 and D1 receptors
when compared with classical antipsychotic agents
(Richelson and Souder, 2000; Saller and Salama, 1993).
In addition, as shown by electrophysiological studies,
it has high selectivity for mesolimbic dopamine
receptors (Saller and Salama, 1993). The weak anti-
cholinergic effects and low incidence of EPS after
quetiapine have been postulated to be related to this
receptor-binding profile, and would thus be advan-
tageous for treating patients with impaired cholinergic
function such as present in AD (Tariot and Ismail,
Quetiapine has been found to be both effective and
well tolerated in elderly patients with AD (Fujikawa
et al., 2004; Salzman, 2001; Scharre and Chang, 2002;
Tariot and Ismail, 2002; Tariot et al., 2000), as well
as being effective in treating psychotic symptoms
and disruptive behaviour in other causes of dementia,
for example in Lewy body dementia (LBD) (Davis
and Baskys, 2002; Fernandez et al., 1999, 2002, 2003;
Takahashi et al., 2003). In AD, an 8-wk treatment of
behavioural symptoms with quetiapine significantly
improved agitation, delusions, activity disturbances,
aggressiveness and diurnal rhythm disturbances
(Fujikawa et al., 2004). Quetiapine does not appear
to worsen cognition (Scharre and Chang, 2002), this
being an additional limiting factor for the use of
classical neuroleptics in a cognitively disabled popu-
lation. The aim of the present study was the com-
parative evaluation of quetiapine and haloperidol
effects on behavioural and cognitive symptoms in
AD patients. In addition, actimetry was carried out to
detect possible differential neuroleptic modification of
the circadian sleep–wake cycle disturbances.
The present study was a 5-wk, single centre, com-
parative, randomized, open-label trial to assess the
improvement of behavioural symptoms, cognitive
state and the circadian rest–activity cycle in AD
patients treated with either quetiapine or haloperidol.
The protocol was approved by the local Ethical
Commitee. Full and adequate oral and written infor-
mation about objectives and goals of the study,
possible therapeutical advantages and side-effects
was given to the subjects and their caregivers. After
informed consent and a maximum 7 d run-in period
for baseline assessments, eligible subjects diagnosed
as probable AD patients with behavioural symptoms
were randomized to one of the two treatment groups.
Screening and demographic measurements included:
date of birth, sex, race, weight, height, tobacco and
alcohol consumption, significant medical and surgical
history, physical and laboratory examination, electro-
cardiogram and the diagnosis of AD according to the
criteria of ICD-10.
The inclusion criteria included confirmed diagnosis
of AD, behavioural symptoms (at least three of the
following: aggression, psychotic symptoms, sleep–
wake cycle disturbances, agitation, restlessness or
sundowning), permanent medical or social care avail-
able during the study, written informed consent
and age over 65 yr. The exclusion criteria included
known sensitivity to study drugs, evidence of
chronic and/or severe renal, hepatic, cardiovascular,
pulmonary or gastrointestinal impairment or cancer,
other antipsychotic medication than the study drugs,
participation in any other drug trial and contra-
indications as detailed in the country-specific pre-
scribing information for the study drugs. Subjects
were free to withdraw their informed consent at any
time, without prejudice to further treatment.
Patient data was collected during three visits: Visit
1 during the run-in period for baseline assessments;
Visit 2, 1 d prior to commencing study drugs and
Visit 3 at the end of the fifth week of treatment. During
the treatment period the patients received either
quetiapine (25–200 mg) or haloperidol (0.5–4 mg), and
no other neuroleptic. Initial dosage was 25 mg for
quetiapine and 0.5 mg for haloperidol. The dosage
was increased weekly by 25 mg for quetiapine and
0.5 mg for haloperidol. All other concomitant medi-
cation was continued and was documented. All AD
patients received a cholinesterase inhibitor as co-
medication (galantamine 2r8 mg). The protocol was
planned in 2001 and patients entered the study from
2002 to 2004.
Thirty AD in-patients hospitalized on the geronto-
psychiatric ward entered the study. No patients
508E. Savaskan et al.
had any prior history of psychiatric diagnosis. Four
patients dropped out in the course of the study. Owing
to an unforeseen rater change, the last four patients
were not included in the analysis. Thus, a total of
22 AD patients finished the 5-wk treatment period
and could be evaluated: 11 in the haloperidol group
[Table 1: 6 females and 5 males, mean age ( ¡S.E.M.)
82.3¡2.5 yr; mean baseline MMSE 18.1¡1.3; mean
dose at the end of the study 1.9 mg; starting dose
0.5–1 mg] and 11 in the quetiapine group (Table 1: 9
females and 2 males, mean age 81.9¡1.8 yr; mean
baseline MMSE 19.9¡1.3; mean dose at the end of the
study 125 mg; starting dose 25 mg).
Psychometric test battery
The following test battery was used twice, at baseline
and at the end of the 5-wk treatment period (Visits 1
and 3), to assess behavioural and cognitive symptoms
and activities of daily living.
Neuropsychiatric Inventory (NPI)
The NPI is a brief interview assessing behavioural
disturbances (subscales: delusions, hallucinations,
dysphoria, anxiety, agitation/aggression, euphoria,
disinhibition, irritability/lability, apathy and aberrant
motor behaviour) in dementia (Cummings et al., 1994).
The Nursing Home version was used in the present
study to assess two additional subscales: appetite and
night-time behavioural disturbances. Each subscale
consits of a frequency rating (1–4) and a severity rating
(1–3), and the subscale score is the product of the
frequencyrthe severity (raw score) for each domain.
comparing the NPI subscale with subscales of the
BEHAVE-D and the Hamilton Depression Rating
Scale. Highly significant correlations were found.
The NPI is thus a suitable test battery for assessing
behavioural symptoms in AD (Cummings et al., 1994).
For each symptom subscale the difference from
Table 1. Demographic data and outcome measures of behavioural and cognitive assessments
of 22 AD patients who finished the 5-wk treatment period with haloperidol or quetiapine
CaseMax. dose Sex Age
Baseline Week 5Baseline Week 5
M, male; F, female; NPI, Neuropsychiatric Inventory (total score of all subscales, each fre-
quency times the severity); MMSE, Mini-Mental State Examination.
Quetiapine treatment in Alzheimer’s disease509
baseline to post-testing was calculated with raw
Consortium to Establish a Registry for Alzheimer’s
Disease (CERAD) neuropsychological test battery
CERAD, established in 1986 by the National Institute
of Aging, developed a battery of standardized instru-
ments for the evaluation of AD patients (Heyman
et al., 1990; Morris et al., 1988). Three primary assess-
ments include a clinical battery, a neuropsychological
battery and a neuropathological assessment. The
neuropsychological battery used in the present study
to assess cognition included the following tests: verbal
fluency, modified Boston Naming Test, Mini-Mental
State Examination (MMSE), constructional praxis and
recall, word-list memory, word-list recognition and
Nurses’ Observation Scale for Geriatric Patients
NOSGER is an assessment scale for behaviour and
functioning in elderly patients (Spiegel et al., 1991).
It has 30 items coinciding with one of the following
six assessment areas: memory, instrumental activities
of daily living, social behaviour, self-care, mood and
To investigate the circadian rest–activity cycle, the
patients were asked to wear a small activity monitor
(Actiwatch-L1, Cambridge Neurotechnology Ltd,
Cambridge, UK) on the non-dominant wrist con-
tinously for 7 consecutive days, twice, prior to the
start of neuroleptic medication and during week 5 of
treatment. Actimetry in patients with AD has been
approved by the Ethical Committee of the Department
of Medicine, University Hospital Basel, and has been
successfully employed in our previous clinical trials
(Fontana-Gasio et al., 2003; Werth et al., 2002; Wirz-
Justice et al., 2000). The actigraph measures locomotor
activity by a piezoelectric element and activity counts
are accumulated in 1-min epochs. Concurrent with
activity monitoring, light exposure is measured by an
implemented light sensor. This non-invasive method
allows patients to continue their daily activities and
choose their own bedtimes.
Actimetry data analysis
The detailed data analysis procedure has been
previously reported (Werth et al., 2002). Patients’ raw
motor activity was documented as consecutive daily
activity plots. After checking for artefacts and
removing/interpolating missing data, mean values for
selected time episodes were analysed as 24-h patterns
to compare changes in the rest–activity cycle longi-
software (Sleep Analysis
Software version 4.12; Cambridge Neurotechnology,
Cambridge, UK) provides estimates of ‘sleep’ from
the rest–activity cycle data (with reasonable validation
when compared with polysomnography). The follow-
ing variables from the activity data of the selected time
segments were extracted: mean diurnal (=daytime
episode between lights on and lights off), nocturnal
(=night-time episode between lights off and lights
on), and 24-h activity; total wakefulness during the
sleep period; total sleep during the wake period and
number of nocturnal wake bouts. Sensitive variables
that quantify the circadian rhythm aspects of the
activity pattern were also extracted: (1) inter-daily
stability gives an indication of the degree of synchron-
ization of the rest–activity cycle to environmental
timing cues; (2) intra-daily variability is a measure of
the fragmentation of the rest–activity cycle; (3) relative
amplitude is the difference between the most active
10 h during the day and the least active 5 h during the
Changes over time in the variables described above
were analysed using analysis of variance for repeated
measures (ANOVAs) followed by Duncan’s multiple-
range tests when the interaction term of the ANOVA
Patients’ demographic data and the results of NPI and
MMSE assessments are summarized in Table 1. In
each group two dropouts were registered because of
adverse events or coincidential diseases: in the halo-
peridol group one patient discontinued the study
because of EPS and one patient because of a transient
ischaemic attack; in the quetiapine group one patient
dropped out because of postural hypotonia and one
because of myocardial infarction, early in the second
week of the treatment period, which might be not
related to the treatment. The otherwise observed
adverse events were: in the haloperidol group, two
patients had EPS (Table 1, cases 2 and 11), one patient
had an infection of unknown origin (Table 1, case 1)
and one patient showed arterial hypertonia (Table 1,
case 3); in the quetiapine group one patient showed
reversible syncope (Table 1, case 2) and one patient
had gastroenteritis (Table 1, case 7).
510E. Savaskan et al.
Analysis of NPI scores, which assessed the behav-
ioural effects of treatment revealed similar effects
both for haloperidol and quetiapine in two subscales:
both medications reduced delusions (p=0.017) and
agitation (p=0.016) at the end of the 5-wk treatment
period (Figure 1, main effect). Statistically significant
interaction terms showed that there was a difference
between haloperidol and quetiapine at the end of
week 5 from baseline in the subscales depression
(p=0.042), anxiety (p=0.046), and aberrant motor
behaviour (p=0.01) (Figure 1): post-hoc analysis
(p=0.031) and anxiety (p=0.052) at week 5 relative
to baseline, and, in contrast, haloperidol treatment
significantly increased aberrant motor activity relative
to baseline (p=0.035) (Figure 1).
In the CERAD, assessing the cognitive parameters,
in improving word recall (p=0.031, main effect)
(Figure 2). Significant interaction terms revealed
differences between quetiapine and haloperidol in
word-list memory (p=0.03), and constructional praxis
(p=0.038) (Figure 3a, b). Post-hoc analyses showed
memory (p=0.006) relative to baseline (Figure 3a).
Interestingly, at the end of the 5-wk treatment,
quetiapine-treated patients showed a non-significant
2-point improvement in the mean MMSE score
when compared with baseline (baseline: 19.9¡1.3;
end of week 5: 22.2¡1.6; Table 1, Figure 2).
(p=0.04) revealed differences between quetiapine and
haloperidol treatments: post-hoc analysis demon-
strated that quetiapine improved instrumental activi-
ties of daily living in AD patients (Figure 3c).
Actimetry revealed what the clinical observation
have highly disturbed sleep–wake cycles. No drug
effects on the circadian rest–activity cycle were found.
However, in the sleep analysis, quetiapine or halo-
peridol treatment differentially effected sleep consoli-
dation as shown by the actimetry data: quetiapine
improved sleep patterns in AD patients, with patients
experiencing shorter wake bouts (p=0.023) at the end
of week 5 compared with baseline (Figure 4a) indicat-
ing a more consolidated sleep episode. Patients in
the haloperidol-treatment group showed a different
effect, of fewer (p=0.053) though longer (p=0.01)
immobile phases during sleep compared with baseline
(Figure 4b, c).
The present study revealed that quetiapine was su-
perior to haloperidol in controlling behavioural, cog-
nitive and circadian rest–activity cycle disturbances
Aberrant motor behaviour
NPI score at week 5
(mean change from baseline)
Figure 1. Effect of quetiapine (%) and haloperidol (&) on NPI subscales. Delusions: * p=0.017 vs. baseline (main effect);
agitation: ** p=0.016 vs. baseline (main effect); depression: *** p=0.031 quetiapine vs. baseline (post-hoc analysis); anxiety:
# p=0.052 quetiapine vs. baseline (post-hoc analysis); abnormal motor behaviour: ## p=0.035 haloperidol vs. baseline
Quetiapine treatment in Alzheimer’s disease511
in AD patients. Whereas both quetiapine and halo-
peridol were effective in reducing delusions and
agitation (NPI), quetiapine additionally improved
depression and anxiety. The cognitive advantages of
quetiapine may be reflected in the improvement of
word-list memory and word recall in the CERAD, as
well as the lack of worsening in the MMSE over this
time period. These individual effects of quetiapine
probably contributed to an improvement in the
activities of daily living (NOSGER). Finally, the
actimetry data revealed that quetiapine treatment
resulted in more consolidated night-time sleep.
Adverse events observed in the study patients
were EPS, infection and arterial hypertonia in the
haloperidol group and, syncope and gastroenteritis in
the quetiapine group. Whereas infectious diseases
may not reflect medication-related side-effects, we
should pay attention to EPS and syncope. Two
patients in the haloperidol group showed EPS, in
accordance with previous data revealing EPS as a
common side-effect of haloperidol treatment in AD
patients, whereas quetiapine-treated patients experi-
ence significantly fewer EPS (Tariot and Ismail,
2002; Tariot et al., 2000). Thus, the worsening in
the NPI subscale – aberrant motor behaviour – in the
CERAD no. of words
NOSGER mean score
CERAD no. of points
Figure 3. Effect of quetiapine and haloperidol on (a) word-list
memory, and (b) constructional praxis in CERAD at baseline
and at the end of the fifth treatment week. (c) Effect of
quetiapine and haloperidol on instrumental activities of daily
living in NOSGER.
CERAD score at week 5
(mean change from baseline)
Word-list positive recognition
Word-list negative recognition
Constructive praxis (recall)
Figure 2. Effect of quetiapine (%) and haloperidol (&) on
cognitive performance in CERAD scores. Word-list recall:
* p=0.031 vs. baseline (main effect); word-list memory:
** p=0.006 quetiapine vs. baseline (post-hoc analysis).
Total wake time/
No. of immobile phases/
Figure 4. Actimetry data: effect of quetiapine and haloperidol
on (a) mean wake bout time, (b) number of immobile
phases, and (c) mean length immobile.
512E. Savaskan et al.
negative effects on motor symptoms.
Because of its effect on improving psychosis with-
out exacerbating movement disorders, quetiapine
has been recommended for treatment of psychotic
symptoms in Parkinson’s
Quetiapine has also been used for the treatment of
behavioural and psychotic symptoms in patients with
LBD with no significant changes in EPS (Davis and
Baskys, 2002; Takahashi et al., 2003). The most com-
mon side-effects of quetiapine noted in the elderly
have been somnolence (30%), dizziness (17%), and
postural hypotension (15%) (Tariot et al., 2000).
Syncope was an adverse event in one patient in the
quetiapine treatment group in our study, probably
due to postural hypotension. In the quetiapine group
one patient dropped out because of myocardial
infarction very early in the treatment phase, which is
unlikely to be related to treatment. Nevertheless, an
excess of cerebrovascular and cardiovascular events
has been reported with several atypical neuroleptics
other than quetiapine (Lee et al., 2004). Although
AD patients have been found to predispose to
cerebrovascular events and have to be taken in con-
sideration when prescribing atypical antipsychotics,
presently can it not be excluded that this is a class
effect which is not constrained to the three drugs
that have been studied in this respect so far.
To avoid side-effects, quetiapine has been rec-
ommended to be initiated at a very low dose of 25 mg
(McManus et al., 1999), or even 12.5 mg (Motsinger
et al., 2003), and to be increased slowly. The starting
dose in our study was 25 mg which may account for
the low incidence of side-effects. The optimal quetia-
pine dose for AD patients has been suggested to vary
between 25 and 200 mg/d (Sultzer, 2004), and the
mean dose of 125 mg attained in the present study is
comparable with analogous studies in the literature
(Tariot et al., 2000). The patient showing syncope as an
adverse event (Table 1, case 2, 175 mg) was one of the
four cases receiving quetiapine doses greater than the
mean dose (Table 1, cases 2, 4, 5 and 7) which again
may point to the necessity of careful dosage in this
Both quetiapine and haloperidol were effective in
reducing delusions and agitation, whereas additional
positive effects on depression and anxiety were
observed in the quetiapine-treated AD patients. The
effects of quetiapine to improve psychotic symptoms,
aggression and agitation have been well documented
in LBD (Davis and Baskys, 2002; Fernandez et al.,
1999, 2002, 2003; Takahashi et al., 2003). In an open-
label, multicentre trial in 184 elderly patients with
significant improvement in the Brief Psychiatric
Rating Scale (BPRS) total score and the Clinical Global
Impressions severity of illness item score (Tariot et al.,
2000). The same authors also reported a double-blind,
placebo-controlled, 10-wk, randomized trial in 284 AD
patients with flexible dosing of quetiapine or halo-
peridol (Tariot and Ismail, 2002). Whereas both
quetiapine and haloperidol treatment significantly
improved agitation, patients in the quetiapine group
had also significantly better functional status as
assessed by the BPRS anergia factor, the Physical
Self-Maintenance Scale, and the Multidimensional
Observation Scale for Elderly Subjects (Tariot and
Ismail, 2002). Finally, in an open-label, 12-wk study in
AD patients receiving doses from 50 to 150 mg, que-
tiapine significantly decreased delusions, aggression,
and overall behaviours based on NPI scores (Scharre
and Chang, 2002). These previous findings support
our results that quetiapine is effective in the treatment
of psychotic and behavioural symptoms in AD.
Although there is still limited evidence, additional
data from a Cochrane-based review evaluating the
effects of atypical antipsychotics (risperidone and
olanzapine) on behavioural symptoms in dementia
in randomized trials concluded that atypical anti-
psychotics in general improve efficacy and adverse-
event profiles compared with typical antipsychotic
drugs (Lee et al., 2004). Treatment with atypical anti-
psychotic drugs was superior to placebo for the pri-
mary end-point in three of the five trials. However,
adverse events were common and included EPS,
somnolence, and abnormal gait (Lee et al., 2004).
Our results showed additional quetiapine effects
on affective symptoms, improving depression and
anxiety in AD. Quetiapine has been found to be a
useful agent in the management of depressive symp-
toms in psychosis (Sajatovic et al., 2002), and in mood
disorders including bipolar and schizoaffective dis-
orders (Sajatovic et al., 2001). Thus, because of its
sedative effects, quetiapine has been recommended for
the treatment of therapy-resistant bipolar disorder
(Ghaemi and Katzow, 1999). Nevertheless, it has to be
taken in consideration that atypical neuroleptics can,
as a rare side-effect, also induce mania (Fahy and
The positive effects of quetiapine treatment on
cognitive parameters in our AD patients are in
accordance with previous data showing that quetia-
pine, relative to haloperidol, has a positive impact
on cognitive performance in schizophrenia patients
Quetiapine treatment in Alzheimer’s disease513
(Velligan et al., 2002). Quetiapine, after a 24-wk treat-
ment period, improved overall cognitive function,
especially in verbal fluency test, verbal memory and
attention (Velligan et al., 2002). In AD patients,
quetiapine was found to improve psychotic and
behavioural symptoms without worsening cognition
(Scharre and Chang, 2002). In our series, quetiapine-
treated patients showed obvious improvement in
word-list memory, word recall and constructional
praxis, and, in addition, a non-significant improve-
ment in MMSE scores. In schizophrenia patients,
been found not to be attributable solely to changes in
positive symptoms of psychosis, negative symptoms,
side-effects, or to additional medication use, but rather
to be a direct effect of quetiapine (Velligan et al.,
2002). However, the positive effect on cognition was
found for the high-dose quetiapine treatment with
600 mg/d, and not for the low-dose 300 mg/d treat-
ment group. Since a relatively low quetiapine dose
was used in our study and the treatment period was
relatively short, the effect on cognitive parameters
may also be a consequence of the improvement in
behavioural and circadian rest–activity cycle symp-
toms. Nevertheless, because of their 5-HT2Areceptor-
binding profile, atypical antipsychotics like quetiapine
have been shown to have a positive impact on cog-
nition (Tyson et al., 2004). After a 6-wk quetiapine
treatment period patients with schizophrenia showed
a beneficial influence on auditory short-term memory
and recognition memory for patterns and spatial
information (Tyson et al., 2004). In addition, the
thinking time in planning tasks over repeated testing
was decreased. The authors suggested that the action
through the 5-HT2Areceptors may change dopamine
levels in the prefrontal cortex which may be respon-
sible for cognitive effects.
The sleep–wake cycle in these elderly AD patients
was highly disturbed. Thus, at this late stage of
the disease one can not expect major improvements
by any treatment. Nonetheless, actimetry analyses
revealed that AD patients receiving quetiapine had a
more consolidated sleep phase with shorter wake
bouts. The sleep-promoting effects of quetiapine are
well documented polysomnographically in schizo-
phrenia patients showing that quetiapine significantly
improved sleep induction and continuity under
standard and acoustic stress conditions (Cohrs et al.,
2004). Increases in total sleep time, sleep efficiency,
percentage sleep stage 2 and subjective sleep quality
were observed by polysomnographic sleep recording
(Cohrs et al., 2004). These sleep-inducing and sleep-
modifying effects have been postulated to be related
to quetiapine‘s antihistaminergic, antidopaminergic
and antiadrenergic properties. Whereas some of the
observed effects of quetiapine on sleep, such as the
increased total sleep time and transient reduction in
REM sleep have been postulated to be related to its
antihistaminergic effects, the dopamine D1blocking
qualities of quetiapine have been postulated to be
responsible for its sleep-inducing properties (Cohrs
et al., 2004).
In contrast, patients in the haloperidol treatment
group showed a decrease in the number of immobile
phases. These disruptive effects on sleep are in line
with our previous findings in AD where haloperidol
was shown to induce disruption of the circadian
rest–activity cycle parallel to worsening of cognitive
state (Wirz-Justice et al., 2000), indicating that classical
neuroleptics may aggravate sleep disturbances and
not be favourable in AD patients.
In conclusion, quetiapine was effective in treating
behavioural and sleep disturbances in AD patients,
thus improving cognitive state. Nevertheless, the
limitation of small sample size in the present study
requires larger double-blind trials to confirm the pre-
liminary results presented here. In addition, the use of
neuroleptics in this handicapped population requires
the detailed and individual consideration of dosage,
possible side-effects and interactions with concomitant
medication and diseases.
C. Schnitzler and C. Schro ¨der were supported by a
grant from AstraZeneca (Switzerland), C. Cajochen
by a Swiss National Science Foundation Research
Professorship (SNF grants START no. 3130-054991 and
Statement of Interest
Cohrs S, Rodenbeck A, Guan Z, Pohlmann K, Jordan W,
Meier A, Ruther E (2004). Sleep-promoting properties of
quetiapine in healthy subjects. Psychopharmacology 174,
Cummings JL, Mega M, Gray K, Rosenberg-Thomson S,
Carusi DA, Gornbein J (1994). The Neuropsychiatric
Inventory: comprehensive assessment of psychopathology
in dementia. Neurology 44, 2308–2314.
Davis P, Baskys A (2002). Quetiapine effectively reduces
psychotic symptoms in patients with Lewy body
dementia: an advantage of the unique pharmacological
profile? Brain Aging 2, 49–53.
514E. Savaskan et al.
DeVane CL, Nemeroff CB (2001). Clinical pharmacokinetics
of quetiapine: an atypical neuroleptic. Clinical
Pharmacokinetics 40, 509–522.
Dewey Jr. RB, O’Suilleabhain PE (2000). Treatment of
drug-induced psychosis with quetiapine and clozapine
in Parkinson’s disease. Neurology 55, 1753–1754.
Fahy S, Fahy TJ (2000). Induction of manic symptoms by
novel antipsychotics. British Journal of Psychiatry 176, 597.
Fernandez HH, Friedman JH, Jacques C, Rosenfeld M
(1999). Quetiapine for the treatment of drug-induced
psychosis in Parkinson’s disease. Movement Disorders 14,
Fernandez HH, Trieschmann ME, Burke MA, Friedman JH
(2002). Quetiapine for psychosis in Parkinson’s disease
versus dementia with Lewy bodies. Journal of Clinical
Psychiatry 63, 513–515.
Fernandez HH, Wu C-K, Ott BR (2003). Pharmacotherapy
of dementia with Lewy bodies. Expert Opinion on
Pharmacotherapy 4, 2027–2037.
Fontana-Gasio P, Kra ¨uchi K, Cajochen C, Van Sommeren E,
Amrhein I, Pache M, Savaskan E, Wirz-Justice A (2003).
Dawn-dusk simulation light therapy of disturbed
circadian rest-activity cycles in demented elderly.
Experimental Gerontology 38, 207–216.
Fujikawa T, Takahashi T, Kinoshita A, Kajiyama H,
Kurata A, Yamashita H, Yamawaki S (2004). Quetiapine
treatment for behavioral and psychological symptoms
in patients with senile dementia of Alzheimer type.
Pharmacopsychiatry 49, 201–204.
Ghaemi SN, Katzow JJ (1999). The use of quetiapine for
treatment-resistant bipolar disorder: a case series.
Annals of Clinical Psychiatry 11, 137–140.
Heyman A, Fillenbaum GG, Mirra SS (1990). Consortium to
Establish a Registry for Alzheimer’s Disease (CERAD):
clinical, neuropsychological, and neuropathological
components. Aging 2, 415–424.
Lee PE, Gill SS, Freedman M, Bronskill SE, Hillmer MP,
Rochon PA (2004). Atypical antipsychotic drugs in the
treatment of behavioural and psychological symptoms of
dementia: systematic review. British Medical Journal 329,
Lyketsos CG, Steinberg M, Tschanz JT, Norton MC,
Steffens DC, Breitner JC (2000). Mental and behavioral
disturbances in dementia: findings from the Cache County
Study on Memory in Aging. American Journal of Psychiatry
McManus DQ, Arvanitis LA, Kowalcyk BB (1999).
Quetiapine, a novel antipsychotic: experience in elderly
patients with psychotic disorders. Seroquel Trial 48 Study
Group. Journal of Clinical Psychiatry 60, 292–298.
Morris JC, Mohs RC, Rogers H, Fillenbaum G, Heyman A
(1988). Consortium to establish a registry for Alzheimer’s
disease (CERAD) clinical and neuropsychologocal
assessment of Alzheimer’s disease. Psychopharmacology
Bulletin 24, 641–652.
Motsinger CD, Perron GA, Lacy TJ (2003). Use of atypical
antipsychotic drugs in patients with dementia. American
Family Physician 67, 2335–2340.
Pollak CP, Stokes PE (1997). Circadian rest-activity rhythms
in demented and nondemented older community residents
and their caregivers. Journal of the American Geriatrics
Society 45, 446–452.
Profenno LA, Tariot PN (2004). Pharmacologic management
of gitation in Alzheimer’s disease. Dementia and Geriatric
Cognitive Disorders 17, 65–77.
Richelson E, Souder T (2000). Binding of antipsychotic drugs
to human brain receptors: focus on newer generation
compounds. Life Sciences 68, 29–39.
Sajatovic M, Brescan DW, Perez DE, DiGiovanni SK,
Hattb H, Ray JB, Bingham CR (2001). Quetiapine alone
and added to a mood stabilizer for serious mood disorders.
Journal of Clinical Psychiatry 62, 728–732.
Sajatovic M, Mullen JA, Sweitzer DE (2002). Efficacy of
quetiapine and risperidone against depressive symptoms
in outpatients with psychosis. Journal of Clinical Psychiatry
Saller CF, Salama AI (1993). Seroquel: biochemical profile
of a potential atypical antipsychotic. Psychopharmacology
Salzman C (2001). Treatment of the agitation of late-life
psychosis and Alzheimer’s disease. European Psychiatry
16 (Suppl. 1), 25–28.
Scharre DW, Chang S-I (2002). Cognitive and behavioral
effects of quetiapine in Alzheimer disease patients.
Alzheimer Disease and Associated Disorders 16, 128–130.
Spiegel R, Brunner C, Ermini-Fu ¨nfschilling D, Monsch A,
Notter M, Puxty J, Tremmel L (1991). A new behavioural
assessment for geriatric out- and in-patients: the NOSGER
(Nurses’ Observation Scale for Geriatric Patients). Journal of
the American Geriatric Society 39, 339–347.
Sultzer DL (2004). Psychosis and antipsychotic medications
in Alzheimer’s disease: clinical management and research
perspectives. Dementia and Geriatric Cognitive Disorders 17,
Takahashi H, Yoshida K, Sugita T, Higuchi H, Shimizu T
(2003). Quetiapine treatment of psychotic symptoms and
aggressive behavior in patients with dementia with Lewy
boides: a case series. Progress in Neuro-Psychopharmacology
& Biological Psychiatry 27, 549–553.
Tariot PN, Ismail MS (2002). Use of quetiapine in elderly
patients. Journal of Clinical Psychiatry 63, 21–26.
Tariot PN, Salzman C, Yeung PP, Pultz J, Rak IW (2000).
Long-term use of quetiapine in elderly patients with
psychotic disorders. Clinical Therapeutics 22, 1068–1084.
Tyson PJ, Roberts KH, Mortimer AM (2004). Are the
cognitive effects of atypical antipsychotics influenced by
their affinity to 5HT-2A receptors? International Journal of
Neuroscience 114, 593–611.
Van Someren EJW, Hagebeuk EE, Lijzenga C, Scheltens P,
de Rooij SE, Jonker C, Pot AM, Mirmiran M, Swaab DF
(1996). Circadian rest-activity rhythm disturbances in
Alzheimer’s disease. Biological Psychiatry 40, 259–270.
Velligan DI, Newcomer J, Pultz J, Csernansky J, Hoff AL,
Mahurin R, Miller AL (2002). Does cognitive function
improve with quetiapine in comparison to haloperidol?
Schizophrenia Research 53, 239–248.
Quetiapine treatment in Alzheimer’s disease515
Vitiello MV, Borson S (2001). Sleep disturbances in Download full-text
patients with Alzheimer’s disease: epidemiology,
pathophysiology and treatment. CNS Drugs 15,
Werth E, Savaskan E, Knoblauch V, Fontana-Gasio P,
Van Sommeren EJW, Hock C, Wirz-Justice A (2002).
Decline in long-term circadian rest-activity cycle
organization in a patient with dementia. Journal of
Geriatric Psychiatry and Neurology 15, 55–59.
Wirz-Justice A, Werth E, Savaskan E, Knoblauch V,
Fontana-Gasio P, Mu ¨ller-Spahn F (2000). Haloperidol
disrupts, clozapine reinstates the circadian rest-activity
cycle in a patient with early-onset Alzheimer disease.
Alzheimer Disease and Associated Disorders 14, 212–215.
516E. Savaskan et al.