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Schizophrenia Research
j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / s c h r e s
Nathan Kline Institute for Psychiatric Research, 140 Old Orangeburg Road, Orangeburg, NY 10962, United States
New York University School of Medicine, 550 First Avenue, New York, NY 10016, United States
Department of Psychiatry and Psychotherapy, Semmelweis Medical University, Budapest, Hungary
a r t i c l e
i n f o
Article history:
Received 1 December 2010
Received in revised form 30 March 2011
Accepted 5 April 2011
Available online 6 May 2011
Keywords:
Cholesterol
Cognition
Clozapine
Olanzapine
Haloperidol
a b s t r a c t
Objective: A positive relationship between cholesterol levels and cognition has been reported in various
human and animal studies, but has never been investigated in schizophrenia. The goal of this study was to
examine this relationship in schizophrenic patients randomized to clozapine, olanzapine or haloperidol.
Method: This was a double-blind randomized prospective 12-week study. Participants received a baseline
evaluation including a cognitive battery consisting of an evaluation of psychomotor function, general
executive function, visual and verbal memory, and visuospatial ability. Their fasting serum cholesterol level
was also assessed. The participants were then randomized to clozapine, olanzapine, or haloperidol. They were
evaluated at the end of 12 weeks. A general cognitive index (GCI) derived from the cognitive battery was the
primary variable.
Results: 82 patients had both baseline and endpoint neurocognitive assessments and cholesterol levels. There
was a statistically and clinically signicant positive association between change in cholesterol levels and
change in GCI. This association was especially pronounced for verbal memory. There was no interaction
between medication grouping and cholesterol level; the positive association was observable separately in
each medication group. It was very robust and remained signicant after we controlled for glucose and
triglyceride levels, anticholinergic side effects, medication serum levels, cholesterol lowering medications,
and pre-study antipsychotic medications.
Conclusions: Cholesterol levels show a strong association with cognition in schizophrenia in all medication
groups. Further research on the role of lipid metabolism in cognition may suggest new treatments for this core
decit of schizophrenia.
2011 Elsevier B.V. All rights reserved.
1. Introduction
Cognitive impairment is a core feature of schizophrenic illness and
an important predictor of functional outcome (Green, 1996). Yet, little
progress has been made in treating it. A positive relationship between
cholesterol levels and various cognitive measures has been reported
in human and animal studies, but has not been investigated in
schizophrenia.
A cholesterol-rich diet improves performance on various learning
tasks, enhances memory acquisition and retention (Sparks and
Schreurs, 2003; Dufour et al., 2006), and facilitates classical
conditioning in diverse animal species (Schreurs et al., 2007).
Addition of cholesterol to the diet of animals decient in cholesterol
or animals that have cholesterol synthesis blocked reverses the
Corresponding author at: Nathan Kline Institute for Psychiatric Research, 140 Old
Orangeburg Road, Orangeburg, NY 10962, United States. Tel.: + 1 845 398 6542; fax: + 1
845 398 6545.
E-mail address: Krakow@nki.rfmh.org (M. Krakowski).
0920-9964/$ see front matter 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.schres.2011.04.005
learning and memory decits (Endo et al., 1996; O'Brien et al., 2002;
Voikar et al., 2002).
In humans there are both observational and randomized treatment
studies which indicate that total cholesterol level (TC) correlates
positively with cognitive abilities. There was a signicant positive
linear association between TC and a composite score measuring
multiple cognitive domains (Elias et al., 2005). Lower TC levels were
associated with poorer performance on choice reaction time task
(Benton, 1997), block design (Muldoon et al., 2001), attention/
concentration, executive function tests (Elias et al., 2005), and
visuomotor tasks (Zhang et al., 2004). Cholesterol-lowering interventions, such as treatment with statins (Muldoon et al., 2000) or diet
(Wardle et al., 2000), have been associated with poorer performance
on neurocognitive measures.
Though the blood brain barrier limits cholesterol inux from the
blood into the brain (Hibbeln et al., 2000; Bjorkhem and Meaney,
2004), changes in cholesterol in the diet or blood result in changes in
brain cholesterol content (Schoknecht et al., 1994; Sparks et al., 1995),
and are accompanied by changes in brain activity (Schoknecht et al.,
1994; Dufour et al., 2006). Some cholesterol metabolites, such as 27-
28
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Table 1
Baseline characteristics of patients assigned to receive clozapine, olanzapine and
haloperidola.
Characteristics
Categorical variables N (%)
Demographic
Male, no. (%)
Race/ethnicity, no. (%)
White
African American
Hispanic
Other
Diagnosis, no (%)
Schizophrenia
Schizoaffective disorder
Median length of
hospitalizationb
Clozapine
(N = 30)
Olanzapine
(N = 30)
Haloperidol
(N = 22)
25 (83.3)
24 (80.0)
19 (86.4) 0.4
7 (23.3)
14 (46.7)
7 (23.3)
2 (6.7)
4 (13.3)
22 (73.3)
4 (13.3)
0 (0.0)
3 (13.6)
13 (59.1) 7.7
6 (27.3)
0 (0.0)
21 (70.0)
9 (30.0)
45
18 (60.0)
12 (40.0)
48
15 (68.2) 0.7
7 (31.8)
36
1.2
0.83
0.46
0.69
0.54
34.6 (11.3)
34.6 (8.9)
0.62
14.9 (8.7)
11.8 (9.4)
16.3 (10.7)
12.0 (10.2)
0.74
0.53
.09
.06
.03
.26
.40
25.5
81.0
(.57)
(.68)
(.57)
(.78)
(.87)
(3.5)
(13.7)
.06
.11
.09
.16
.08
25.8
85.2
(.52)
(.51)
(.73)
(1.04)
(.97)
(2.8)
(12.4)
0.25
0.46
0.41
1.21
2.42
0.4
1.59
0.78
0.63
0.66
.30
.10
.70
0.21
a
For categorical variables data are presented as relative frequencies and for
continuous variables means and SD's are provided.
b
Median length of hospitalization in days upon study entry.
c
The Global Cognitive Index and the neurocognitive domain scores are based on ztransformed values of the constituting variables. The Global Cognitive Index reects the
equally weighted mean of all scores on the different neurocognitive domains.
30
Table 2
Changes in total cholesterol levels and changes in cognitive function over treatment in patients assigned to the olanzapine, clozapine or haloperidol groupsa.
Clozapine N = 30
Olanzapine N = 30
Haloperidol N = 22
Change in:
Mean
SD
Mean
SD
Mean
SD
7.43
.10
38.2
.39
1.07
1.41
.30
.17
2.13
.34
34.7
.72
.34
2.61
.74
.01
5.55
.17
25.0
.49
1.04
1.64
.31
.12
a
The values in the table are based on paired t-tests for the change between baseline and endpoint values. Positive signs for the total cholesterol levels indicate increases and
positive signs for the Global Cognitive Index indicate improvement.
b
The Global Cognitive Index reects the equally weighted mean of all scores on the different neurocognitive domains, based on z-transformed values of the constituting variables.
Table 3
Baseline and endpoint values for weight, triglycerides and glucose in the 82 subjects of
the studya.
Weight (kgs)
Triglyceride (mg/dl)
Glucose (mg/dl)
Baseline values
Endpoint values
Mean
SD
Mean
SD
91.3
160.9
92.7
17.6
92.1
24.9
93.5
177.0
99.5
19.1
101.4
42.0
2.97
1.88
1.57
.004
.06
.12
a
The table provides information about the observed mean values at baseline and at
endpoint for body weight, serum triglycerides and serum glucose in the total group of
subjects. Standard deviations and paired t-test values are also provided in the table.
31
32
Cholesterol may inuence serotonergic and cholinergic neurotransmission. A reduction in serum cholesterol may result in decreased brain
serotonergic activity, as cholesterol concentration determines availability of serotonin receptors and transporters (Engelberg, 1992). As noted
above, cholesterol may be a marker for PUFAs which are also linked to
serotonergic and cholinergic function (Hibbeln et al., 2000). Other
factors should also be considered, as a complex regulatory network is
implicated in metabolic changes in patients with schizophrenia. Leptins,
for example, may also play a role. Studies have shown that leptin
enhances cognition (Li et al., 2002; Farr et al., 2006) and that atypical
antipsychotic medications, especially clozapine and olanzapine, increase leptin blood levels (Kraus et al., 1999).
The positive association between cholesterol and cognition does
not necessarily mean that cholesterol exerts a procognitive effect.
Other explanations for this association should be considered. Improvement in performance on cognitive tests may represent a practice
(learning) effect. Increases in cholesterol may allow patients to prot
more from previous practice, as has been pointed out in the literature
with regard to cognitive improvements that occur with antipsychotic
treatment (Harvey et al., 2000; Harvey and Keefe, 2001).
There are limitations in the generalizability of our results to other
schizophrenic patients in that the length of hospitalization in our
study is longer than that reported for non-state facilities; these
patients may represent a more chronic population. There was also a
high percentage of AfricanAmerican patients. In addition, our results
were based on only two time points; future studies may investigate
more extensively the time course of this association. In the future, the
use of standardized batteries, such as the MATRICS, might also
facilitate comparisons across studies.
5. Conclusions
We found a positive longitudinal association between change in
cholesterol and change in cognition in each of three medication
groups. These results were robust, as they remained highly signicant
when we controlled for many different confounders. A more extensive
investigation of lipid metabolism and its role in cognition may open
the way for new treatments of cognitive decits in schizophrenia.
Role of funding source
The project was supported by NIMH grant MH74767 and MH85322. The National
Institute of Mental Health had no role in the study design, data collection, analysis and
interpretation; the writing of the report and in the decision to submit the article for
publication.
Contributors
Dr. Krakowski was responsible for the design of the study, data collection and
analyses, and manuscript preparation. Dr. Czobor helped with the design of the study
and the interpretation of the results; he also conducted the statistical analyses. All
authors contributed to and have approved the nal manuscript.
Conict of interest
The authors have no conict of interest.
Acknowledgements
The authors thank Linda Kline, R.N., M.S., C.S., the chief coordinator of the project,
the CREF psychiatrists, Dr. Leslie Citrome, Dr. Biman Roy, Dr. Angel Cienfuegos, Dr.
William Greenberg, Dr. Fabien Tremeau and Dr. Narenda Patel, the CREF internist, Dr.
Surgit Dhami; Mike Hill and Henry Epstein, the CREF nursing staff and the Nathan Kline
Institute research staff: Melissa Benedict, Elsie Andrade, Faye Greenebaum, Gabriel
Goldfedder, Yakov Frances, Susan Grencer, Michael Radosta, Lorraine O'Donnell and the
Nathan Kline Institute research nurses: Sathamma Vaidian and Eunide Joseph. They
thank also Dr. Joseph Battaglia, Stephen Tomor and Stuart Moss.
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