ORIGINAL CONTRIBUTION

Association of the Serotonin Transporter

and Receptor Gene Polymorphisms in
Neuropsychiatric Symptoms in Alzheimer Disease
Frédéric Assal, MD; Maricela Alarcón, PhD; Esther C. Solomon, BS; Donna Masterman, MD;
Daniel H. Geschwind, MD, PhD; Jeffrey L. Cummings, MD

Background: Serotonin has been linked to neuropsy-
chiatric symptoms in Alzheimer disease, mainly
agitation/aggression, depression, and psychosis. Neu-
ropsychiatric symptoms have been associated with
polymorphisms of the promoter region (5-HTTPR)
and intron 2 of the serotonin transporter gene
(5-HTTVNTR) or the 5-HT2A and 5-HT2C receptor
genes in some but not all studies.
Objective: To examine the association of the seroto-
nin promoter, transporter, and receptor genes with
neuropyschiatric symptoms in patients with Alzheimer
disease.
Methods: The sample included 96 patients with Alz-
heimer disease from the outpatient clinic of the Univer-
sity of California Los Angeles Alzheimer’s Disease Re-
search Center, Los Angeles. The Neuropsychiatric
Inventory was used to measure neuropsychiatric symp-
toms, and blood samples were available for genetic analy-
sis. Based on the literature, we hypothesized that the
5-HT2A and 5-HT2C receptor polymorphisms would be
associated with agitation/aggression and psychosis and
the 5-HTTPR or 5-HTTVNTR polymorphisms, with agi-
tation/aggression or depression and anxiety. One-way
analyses of variance were performed with age, ethnicity,
sex, or education as covariates.
Results: The 102T genotype of the 5-HT2A receptor
was significantly associated with delusions (P = .045)
and agitation/aggression (P = .002). We did not repli-
cate previous associations of the 5-HT2C receptor
polymorphism with psychosis or of the 5-HTTPR poly-
morphism with agitation/aggression, psychosis, or
depression. We did not find any associations with the
5-HTTVNTR polymorphism and agitation/aggression,
depression, or anxiety.
Conclusions: The 5-HT2A receptor polymorphism may
contribute to the expression of psychosis and agitation/
aggression in patients with Alzheimer disease. Absence
of other positive associations may be due to the rela-
tively small sample size and/or potentially small effect size
of the polymorphisms and requires further study.
Arch Neurol. 2004;61:1249-1253

Author Affiliations:
Departments of Neurology
(Drs Assal, Alarcón, Masterman,
Geschwind, and Cummings)
and Psychiatry and
Biobehavioral Sciences
(Dr Cummings), the Center
for Neurobehavioral Genetics
Program (Drs Alarcón,
Solomon, and Geschwind) and
the Kagan Treatment Program
(Drs Masterman and
Cummings), The David Geffen
School of Medicine at UCLA,
Los Angeles, Calif; and
the Department of Neurology,
Hôpitaux Universitaires
de Genève, Geneva, Switzerland
(Dr Assal).
S
EROTONIN HAS BEEN ASSOCI-
ated with various neuropsy-
chiatric symptoms in Alzhei-
mer disease (AD), such as
agitation/aggression, depres-
sion, or psychosis.1 These noncognitive
symptoms, and in particular agitation, con-
stitute a major source of distress for the
patient’s caregiver and increase the like-
lihood of nursing home placement.2,3 Re-
cent genetic studies in AD showed asso-
ciations between several polymorphisms
of the serotonin neurotransmitter genes
and some neuropsychiatric symptoms. A
102T/C polymorphism in the 5-HT2A re-
ceptor (5-HT2AR) gene was associated with
visual and auditory hallucinations4 or psy-
chosis5 in patients with AD. The Cys23Ser
polymorphism in the 5-HT2C receptor
(5-HT2CR) gene was significantly associ-
ated with visual hallucinations and hy-
perphagia in another sample of patients
with AD.4 A 44–base pair (bp) insertion
(the long form or l form) of the 5-HTT pro-
moter region (5-HTTPR) was reported to
be associated with psychosis and aggres-
sion.6,7 A variable number tandem repeat
(VNTR) polymorphism in intron 2 of the
5-HTT gene was also associated with sus-
ceptibility to unipolar or bipolar depres-
sion,8 but this association was not found
in patients with AD with depression.9 The
purpose of this brief study was to exam-
ine whether variations in serotonin genes
were related to neuropsychiatric symp-
toms in a sample of patients with AD.
Based on the literature, we addressed the
following questions: (1) Are 5-HT2AR and

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 5-HT2CR polymorphisms associated with psychosis (de-
lusions, hallucinations)? (2) Are these polymorphisms
related to agitation/aggression? and (3) Are 5-HTTPR and
5-HTTVNTR polymorphisms associated with anxiety, de-
pression, or agitation/aggression in patients with AD?
METHODS
PATIENTS
The sample included 96 patients with AD from the Alzhei-
mer’s Disease Research Center of the University of California
in Los Angeles evaluated between 1996 and 2000. Since our
aim was to test the association of abnormal behaviors with can-
didate genes in patients with AD, we did not include healthy
controls in the study. Inclusion criteria were (1) diagnosis of
probable or possible AD according to the criteria of the Na-
tional Institute of Neurological and Communicative Disor-
ders and Stroke and the Alzheimer’s Disease and Related Dis-
orders Associations10; (2) evaluation of the neuropsychiatric
symptoms with the Neuropsychiatric Inventory (NPI)11; and
(3) presence of a blood sample stored in the genetic database.
Patients with a major psychiatric disorder or a history of alco-
hol or drug abuse were excluded. We used the total NPI sub-
scale scores as measures of each symptom including delu-
sions, hallucinations, agitation/aggression, depression, and
anxiety. Demographic data also were collected, and subjects were
assessed for the severity of cognitive impairment using the Mini-
Mental State Examination (MMSE).12 All clinical and genetic
data were obtained with protocols approved by the University
of California Los Angeles medical institutional review board.
GENOTYPING
DNA was extracted from peripheral blood using the Easy-
DNA kit (Invitrogen, Carlsbad, Calif) , and coded samples were
stored in a –70°C freezer. An MJ Research PTC-200 Pertier ther-
mocycler (Watertown, Mass) was used for all polymerase chain
reaction (PCR) amplifications. All PCR reactions included 30
to 80 ng of genomic DNA, 1 U Taq polymerase (Qiagen, Va-
lencia, Calif ), 0.3X corresponding Qiagen PCR buffer, 3.75 µg
of sense and antisense primers, and 2.5mM dinucleoside tri-
phosphate (dNTP) in a final volume of 50 µL. All PCR prod-
ucts were electrophoresed in a 3% MetaPhor agarose gel (Cam-
brex, Rockland, Me) in Tris-borate/ethylenediaminetetraacetic
acid buffer (TBE ), stained with ethidium bromide, and viewed
by UV light. Four variants were genotyped: 5-HTTPR in the pro-
moter region, 5-HTTVNTR in intron 2 of the transporter gene,
and 5-HT2AR and 5-HT2CR in the receptor gene.
5-HTTPR POLYMORPHISM
The 5-HTTPR polymorphism had a long allele that was 529 bp
and a short allele with a 44-bp deletion.13 The following primer
pairs were designed for PCR amplification: 5⬘-GGCGTTGC-
CGCTCTGAATGC-3⬘ and 5⬘-GAGGGACTGAGCTGGA-
CAACCA-3⬘. The PCR cycling conditions were 94°C for 5 min-
utes, 35 cycles of 94°C for 30 seconds, 60°C for 30 seconds,
and 72°C for 60 seconds followed by a final extension at 72°C
for 10 minutes.
5-HTTVNTR POLYMORPHISM
The 5-HTTVNTR had 3 alleles that were 250 bp, 267 bp, and
300 bp that corresponded to 9, 10, and 12 repeats, respec-
tively. The following primer pairs were modified from Li et
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al9: 5⬘-GTCAGTATCACAGGCTGCGAG-3⬘ and
5⬘-TGTTCCTAGTCTTACGCCAGTG-3⬘. The cycling condi-
tions were 94°C for 5 minutes, 35 cycles of 94°C for 30 sec-
onds, 58°C for 30 seconds, and 72°C for 60 seconds fol-
lowed by a final extension at 72°C for 10 minutes.
5-HT2AR POLYMORPHISM
The 5-HT2AR polymorphism, 102T/C, allowed the MspI re-
striction enzyme to cleave a 342-bp product and produced 2
short fragments (126 and 216 bp in length). The primer pairs
were adapted from Warren et al14: 5⬘-TCTGCTACAAGTTC-
TGGCTT-3⬘ and 5⬘-CTGCAGCTTTTTCTCTAGGG-3⬘. The 3
initial cycles had the following conditions: 94°C for 3 min-
utes, 55°C for 45 seconds, and 72°C for 1.5 minutes. These were
followed by 35 cycles of 94°C for 1 minute, 55°C for 45 sec-
onds, 72°C for 1.5 minutes, and a final 10-minute extension
step at 72°C. The PCR product was digested with MspI.
5-HT2CR POLYMORPHISM
The 5-HT2CR Cys23Ser polymorphism, C/G, was detectable by
the introduction of a restriction site upstream of the change. If
the polymorphism was unchanged (ie, C), then the PCR prod-
uct was digested producing 2 small fragments of 18 bp and 86
bp. If the polymorphism was changed, then the PCR product
remained uncut and was 104 bp long. The following primer
pairs were modified from Sodhi et al15: 5⬘-TTGGCCTATTG-
GTTTGGGAATGTG-3⬘ and 5⬘-GTCTGGGAATTTGAAGC-
GTCCAC -3⬘. The first primer introduced a C-to-G substitu-
tion 4 bp upstream from the polymorphism. The cycling
conditions were 95°C for 5 minutes, 35 cycles of 95°C for 1
minute, 55°C for 2 minutes, and 72°C for 3 minutes. The PCR
product was digested with HinfI.
STATISTICAL ANALYSIS
Data were analyzed using the SPSS computer software pro-
gram.16 To test our hypotheses, we used 1-way analysis of vari-
ance (ANOVA) for each NPI subscale score. Prior to the
ANOVAs, independent t tests were performed to compare the
patient groups (neuropsychiatric symptoms present vs neuro-
psychiatric symptoms absent) by age, sex, education, and se-
verity of disease (using the MMSE). Then, variables with sta-
tistically significant differences (age, sex, ethnicity, or education)
were used as covariates in the 1-way ANOVA. All tests were
2-tailed, and we chose a significance level of P=.05.
RESULTS
The total sample consisted of 96 subjects with AD, of
whom 59 (61.5%) were women and 37 (38.5%) were men.
The average age was 76.7± 7.4 years, and the average edu-
cational level was 13.8 ± 3.3 years. The ethnic compo-
sition was 70 white non-Hispanic subjects (72.9%), 17
African American subjects (17.7%), 5 Asian/Pacific Is-
lander subjects (5.2%), 1 Hispanic/Latino subject (1.0%),
and 2 subjects of “other” race (2.1%); there was 1 sub-
ject missing data (1%). The allele frequencies for the
sample are shown in Table 1. They did not vary as a
function of ethnicity.
The number of patients with the neuropsychiatric
symptoms that we tested were: 24 (25%) with delu-
sions, 12 (12.6%) with hallucinations, 39 (40.6%) with
agitation, 49 (51%) with depression, and 38 (39.6%) with
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 Table 1. Genotypic Distribution and Allele Frequencies Table 2. One-way Analysis of Variance, 5-HT2A Receptor
of the Serotonin Transporter and Receptor Genotype Frequencies by Agitation/Aggression
Gene Polymorphisms Neuropsychiatric Inventory (NPI) Scores, 5-HT2A Receptor
Genotype Frequencies by Delusions NPI Scores
5-HTT Promoter Region (n = 85)
Genotype, No. (%) of patients Sample Agitation/Aggression Delusions NPI Score,
Long/long 28 (33) Genotype Size NPI Score, Mean ± SD Mean ± SD
Long/short 25 (29) CC 22 0.36 ± 0.73 0.18 ± 0.50
Short/short 32 (38) TC 40 1.25 ± 2.23 1.40 ± 2.94
Long/short + short/short* 57 (66) TT 30 3.03 ± 3.47 1.13 ± 2.37
Allele frequency Total 92 1.62 ± 2.68 1.02 ± 2.41
f(long) 0.48 F score NA 6.343 2.554
f(short) 0.52 Covariates NA Ethnicity Ethnicity, age
5-HT2A Receptor Gene (n = 93) P value NA .002 .045
Genotypes, No. (%) of patients
C/C 22 (23.7) Abbreviation: NA, not applicable.
T/C 41 (44.1)
T/T 30 (32.3)
Allele frequency
f(T) 0.46 a computed P⬍.004 was significant. The association be-
f(C) 0.54 tween the 5-HT2AR polymorphism and agitation/
5-HT2C Receptor Gene (n = 88)
aggression remained significant, although the corre-
Genotype, No. (%) of patients sponding association with delusions was not. However,
C/C 60 (68.2) we consider the Bonferroni method too conservative in
C/S 18 (20.5) our case because of its assumption of the independence
S/S 10 (11.4) of the variables. Moreover, post hoc power for the asso-
Allele frequency ciation test of the polymorphism with agitation/
f(C) 0.78
aggression was 90%, as opposed to the corresponding
f(S) 0.22
value of 60% for the test of delusions. Thus, the lack of
5-HTT Variable Number Tandem Repeat (n = 71) power to test the association of the 5-HT2AR polymor-
Genotype, No. (%) of patients
phism with delusions in this sample suggests that our re-
9/12 2 (2.8)
10/10 15 (21.1) sult is not conclusive and further investigation is war-
10/12 28 (39.4) ranted in a larger AD sample. Patients with 1 or 2 copies
12/12 26 (36.6) of the 102T polymorphism had higher NPI subscale scores
Allele frequency than those homozygous for 102C.
f(9) 0.01 Associations were not significant for other hypoth-
f(10) 0.40
eses tested using 1-way ANOVA: hallucinations and the
f(12) 0.58
5-HT2AR polymorphisms; delusions and hallucinations
*Patients homozygous for the long genotype vs patients with either 1 or 2
and the 5-HT2CR polymorphisms; affective symptoms (de-
copies of the short genotype.13 pression, anxiety) or agitation/aggression and the 5-HTTPR
polymorphisms. Nonsignificant associations are pre-
anxiety. The average MMSE score was 19.1 ± 6.9, indi- sented in Table 3. Post hoc analyses showed that we
cating that our sample was in the moderate stage of de- had less than 80% power to test these associations in our
mentia severity. Differences of MMSE scores as a func- study. Since preliminary power calculations showed we
tion of the presence (or absence) of neuropsychiatric had enough power to detect an association with a mod-
symptoms were not significant using independent t tests erate to high effect size, the modest observed power es-
(results not shown). Age, sex, or ethnicity were used as timates suggest that the effect sizes were small and a larger
covariates in the 1-way ANOVA as appropriate based on sample is necessary to address our hypotheses.
the preliminary results. Initial power calculations for a
1-way ANOVA assuming equal sample sizes for the 3 COMMENT
genotype groups (N = 25), an ␣=.05, and a fixed-effects
model suggested that we had between 61% and 88% power We found positive associations with the 5-HT2AR 102T/C
to detect a medium effect size and at least 98% power to polymorphism and patients with AD with agitation/
detect a large effect size. These power estimates varied aggression and delusions. Although the Bonferroni cor-
according to the assumed within-group standard devia- rection for multiple comparisons is not appropriate in
tions and sample sizes. our case because of nonindependence of the neuropsy-
Significant associations between neuropsychiatric chiatric symptoms, the association with agitation/
symptoms and genotypes are shown in Table 2. In our aggression remained significant after the excessively strin-
sample, there were significant associations between the gent correction. Interestingly, the patients with AD who
5-HT2AR polymorphism and NPI subscale score for agi- were homozygous for the 102T genotype had higher agi-
tation/aggression (F3 = 6.34; P = .002) and for delusions tation/aggression or delusions scores than those who were
(F4 =2.55; P=.045). Bonferroni correction of the initial heterozygous. The latter had higher agitation scores than
P=.05 for the 12 tests that we performed suggested that those who were homozygous for the 102C form. A type

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 Table 3. One-way Analysis of Variance, 5-HT2A Receptor, 5-HT2C Receptor, 5-HTT Promoter Region,
5-HTT Variable Number Tandem Repeat Genotype Frequencies ⴛ Neuropsychiatric Inventory Scores

Genotype Sample Size Neuropsychiatric Symptoms Covariates P Value

5-HT2A receptor (CC, TC, TT) 93 Hallucinations None .55
5-HT2C receptor (CC, CS, SS) 87 Delusions Ethnicity, age .18
87 Hallucinations None .70
5-HTT promoter region (ll, ls, ss) 85 Depression Age, sex .53
85 Anxiety Ethnicity .46
85 Agitation/aggression Ethnicity .75
5-HTT promoter region (ll, ls + ss)* 85 Depression Age, sex .39
85 Anxiety Age, sex .62
85 Agitation/aggression Ethnicity .55
5-HTT variable number tandem repeat (9/12, 10/10, 10/12, 12/12) 71 Depression Age, sex .36
71 Anxiety Ethnicity .77
71 Agitation/aggression Ethnicity, sex .43

Abbreviations: l, long; s, short.

*Patients homozygous for the l genotype vs patients with either 1 or 2 copies of the s genotype.13

I error is possible with such a sample, but indirect evi-
dence points to a possible involvement of 5-HT2AR
and agitation even if it is still not known if the
5-HT2AR 102T/C polymorphism is functional or
silent. Postmortem studies of patients with AD showed
that lower serotonin levels were correlated with
aggression in the orbitofrontal cortex.17 Randomized,
placebo-controlled clinical trials demonstrated that
risperidone and olanzapine, which are atypical anti-
psychotic agents acting on the 5-HT2AR receptor,
decreased agitation and psychosis in patients with
AD.18,19 Indirectly, in patients with schizophrenia, a
combination of those polymorphisms showed a strong
association with pharmacological response to cloza-
pine, another atypical antipsychotic agent linked to
5-HT2AR. 20 Thus, a genetic risk factor with this
5-HT2AR polymorphism may predispose to the clinical
expression of agitation in AD. The 5-HT2AR polymor-
phism was significantly associated with delusions but
not with hallucinations. That may be because halluci-
nations were not frequently observed in our sample.
Moreover, delusions are more common than halluci-
nations in AD, and the latter are usually more com-
mon in more advanced stages of the disease.21 We did
not find associations of the 5-HT2CR polymorphism
with hallucinations or with delusions and, thus, did
not confirm previous findings.4,5
For the 5-HTTPR polymorphism and affective
symptoms (depression and anxiety) or agitation/
aggression, no statistical associations were found in
our sample. Our results may suggest that these poly-
morphisms are not major susceptibility factors for the
expression of delusions, hallucinations, anxiety, or
depression. However, results of our post hoc calcula-
tions suggest that we had less than 80% power to
detect these associations given the unequal sample
sizes of our groups, our large neuropsychiatric symp-
toms standard deviations, and, possibly, the small
effect sizes of the polymorphisms. Thus, a larger
sample is needed to examine these associations more
definitively. The NPI has the advantage to screen for
10 different behaviors and may be particularly accu-
rate in revealing neuropsychiatric symptoms in a given
patient.21,22 Finally, although our patients did not have
significant differences in their cognitive impairment
and we did not need to covary for the MMSE, our
sample was a cross-sectional assessment and did not
follow behaviors across time. Since neuropsychiatric
symptoms are expressed preferentially for a given
patient at a critical window during the evolution of the
disease, such a genetic predisposition could be missed
because the neuropsychiatric symptoms would not be
expressed during the time of assessment. Future asso-
ciation studies of neuropsychiatric symptoms should
measure these repeatedly across the course of the dis-
ease. Combining behavioral neurogenetics and phar-
macogenomics with pharmacoimaging may allow
greater specificity in understanding the pathophysi-
ological features of neuropsychiatric symptoms in AD
and optimizing treatment.
Accepted for Publication: March 18, 2004.
Correspondence: Jeffrey L. Cummings, MD, Reed Neu-
rological Research Center 2-238, UCLA Alzheimer’s Dis-
ease Center, 710 Westwood Plaza, Los Angeles, CA 90095-
1769 (cummings@ucla.edu).
Author Contributions: Study concept and design: Assal,
Alarcón, Geschwind, and Cummings. Acquisition of data:
Assal, Solomon, and Masterman. Analysis and interpre-
tation of data: Assal and Alarcón. Drafting of the manu-
script: Assal. Critical revision of the manuscript for impor-
tant intellectual content: Alarcón, Solomon, Masterman,
Geschwind, and Cummings. Statistical expertise: Assal and
Alarcón. Obtained funding: Cummings. Administrative,
technical, and material support: Geschwind and Cum-
mings. Study supervision: Geschwind and Cummings.
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