International Journal of Clinical Medicine, 2012, 3, 368-376
http://dx.doi.org/10.4236/ijcm.2012.35070 Published Online September 2012 (http://www.SciRP.org/journal/ijcm)
1
Increased Oxidant Stress and Inflammation in Patients
with Chronic Schizophrenia
Aysenur Yegin1*, Nurullah Ay1, Ozgur Aydin1, Nedim Yargici2, Esin Eren3, Necat Yilmaz1
1Central Laboratory, Department of Biochemistry, Antalya Educational and Research Hospital, Antalya, Turkey; 2Department of
Psychiatry, Antalya Educational and Research Hospital, Antalya, Turkey; 3Central Laboratory, Ataturk Hospital of Ministry of
Health, Antalya, Turkey.
Received June 22nd, 2012; revised July 24th, 2012; accepted August 6th, 2012
ABSTRACT
Background: Several lines of evidence, including postmortem studies, suggest increased oxidative stress and
inflammation in patients with schizophrenia. Alteration of oxidative stress markers has been reported in schizoprenia
studies, but with inconsistent results. Oxidized low-density lipoproteins (oxLDL) have been reported to be capable of
eliciting neurocytotoxicity. On the other hand, paraoxonase (PON1), an arylesterase(ARE), plays a role in protection
against oxidative modifications of LDL and is considered to be one of the antioxidant enzymes. There are no studies
showing the changes in oxidative stress and inflammation together, nor the activities of PON1 and ARE in
schizophrenic patients. In this study, we examined PON1, ARE activities and oxidative/anti-oxidative markers in
patients with chronic schizophrenia and healthy controls. Methods: We recruited 30 male chronic schizophrenic
patients and 30 male healthy control subjects and examined C-reactive protein(CRP), fibrinogen, PON1, ARE and
plasma total antioxidant status (TAS) and total oxidant status (TOS), oxidative stress index(OSI) in both groups.
Schizophrenia symptoms were assessed using the positive and negative syndrome scale (PANSS). The related routine
lipid profile parameters including HDL were also examined. Resu lts: Patients had significantly higher CRP, fibrinogen,
TOS and OSI levels; but the patients and control subjects did not differ on activities of the antioxidant enzymes PON1
and ARE. Interestingly, there were not any group differences in the lipid profile parameters except the triglyceride
levels, that increased significantly in the patient group. Conclusions: In the present study, reporting the ARE activities
besides the PON1 activities in schizophrenic patients for the first time, we showed that PON1 and ARE enzyme
activities were not statistically different in patients with chronic schizophrenia. This study provides additional evidence
of increased oxidative stress and inflammation in chronic schizophrenia, but no alterations in the antioxidant status were
observed. Our results suggest that other mechanisms than the high density lipoprotein(HDL)-disfunctionality, namely
decreases in PON1 or ARE enzyme activities, are more important in oxidative or antioxidative pathophysiological
processes in schizophrenia.
Keywords: Oxidative Stress; Antioxidant Status; Inflammation; Paraoxonase; Schizophrenia
1. Introduction
“Schizophrenia is still one of the most mysterious and
costliest mental disorders in terms of human suffering
and societal expenditure” [1]. Accumulating evidence
points to many interrelated mechanisms that increase
production of reactive oxygen or decrease antioxidant
protection in schizophrenic patients [2]. However, the
reports regarding the status of oxidative stress markers in
schizophrenia are very inconsistent, with various authors
stating both increased and decreased activities of the
main antioxidant enzymes, while others did not observe
any significant modifications, as compared to control
groups [3].
The chief cause of excess premature mortality among
patients with schizophrenia is cardiovascular heart dis-
ease, caused mainly by their adverse risk factor profile
[4]. Schizophrenia patients have a higher chance (pre-
valence of 36%) of developing metabolic syndrome,
even without antipsychotic medication [5]. Not only
diabetes mellitus but multiple risk factors for car-
diovascular diseases are significantly increased in this
patient group [6]. Schizophrenic patients have a higher
risk of raised cholesterol/HDL ratio, and also smoke
more often. Some risk factors are already present at the
onset of the psychotic disorder [5]. Low levels of HDL
are typical of the biochemical cluster defining metabolic
*Corresponding author.

Increased Oxidant Stress and Inflammation in Patients with Chronic Schizophrenia 369
syndrome. Disturbances in the concentrations of apo-
proteins, function of enzymes, transport proteins, re-
ceptors, other lipoproteins, and their clearance from
plasma can have a major impact on the anti-atherogenic
properties in HDL. Furthermore, HDLs are one of the
most important antioxidant defence systems in plasma.
They are well known to prevent LDL oxidation and
protect against LDL-induced cytotoxicity [7-10]. HDLs
also possess anti-inflammatory properties, including the
ability of suppressing cytokine-induced endothelial cell
adhesion molecules function [11-13].
The antioxidant properties of HDLs are, at least to
some extent, attributable to serum PON1. PON1, an ARE,
plays a role in protection against oxidative modifications
of LDL and is considered to be one of the antioxidant
enzymes [14]. Taken together, these data suggest that
PON1, an antioxidant enzyme, may be involved in the
pathophysiology of schizophrenia. The present study was
therefore undertaken to investigate the PON1 and ARE
activities besides the oxidant stress index and inflam-
mation markers, in a cohort of patients diagnosed as
chronic schizophrenia.
2. Materials and Methods
2.1. Subjects
Blood from 30 selected male patients with chronic
schizophrenia and 30 normal healthy age matched male
controls was assayed in this study. The patients were
enrolled from the Psychiatric Clinic, Research and Edu-
cation Hospital, Antalya, Turkey. Healthy controls were
recruited from the hospital staff and were also assessed
by a semistructured psychiatric interview. The study was
approved by the local ethics committee. The trial pro-
cedure was in accordance with the guidelines of 2002
Declaration of Helsinki.
A Diagnostic and Statistical Manual of Mental Dis-
orders (DSM-IV) diagnosis of chronic schizophrenia was
established on the basis of independent clinical inter-
views; and reviews of the patient records by two
psychiatrists using the Brief Psychiatric Rating Scale
(BPRS), the Scale for the Assessment of Negative
Symptoms (SANS), and the Scale for the Assessment of
Positive Symptoms (SAPS) [15]. Study criteria for
patients with schizophrenia were as follows: 1) diagnosis
of schizophrenia according to Diagnostic and Statistical
Manual (DSMIV); 2) no other DSM-IV axis I diagnosis;
3) no history of alcohol or substance abuse or de-
pendence; 4) absence of antioxidant administration for at
least one year; 5) no concomitant or past severe medical
conditions; 6) nonsmoking; 7) ability to provide in-
formed consent. All patients presented the typical symp-
toms of schizophrenia, that were divided into positive
and negative, through the defined guidelines. Positive
symptoms were those that appeared to reflect an excess
or distortion of normal functions, like delusions, hal-
lucinations, disorganized speech and thinking, grossly
disorganized behavior, catatonic behaviors. Negative
symptoms were those that appeared to reflect a diminution
or loss of normal functions, like affective flattening,
alogia, and avolition. The absence of medical or neuro-
logical illness was verified by means of physical and
neurological examination, routine laboratory investi-
gation, treating physician reports, and medical records.
Individuals without any clearly evident psychiatric ill-
ness or substance abuse were recruited as control sub-
jects for the study. Study criteria for healthy controls
were: 1) absence of past or present neurological or
psychiatric illnesses; 2) absence of concomitant or past
severe medical conditions; and 3) informed consent.
Healthy controls were group matched to patients for age,
gender and race.
The patients were treated with various antipsychotic
drugs (>60 months), 19 with second generation anti-
psychotics (nine with risperidone, five with olanzapine,
five with clozapine) and 11 with classic antipsychotics
(haloperidol).
2.2. Analytical Methods
2.2.1. Blood Sample Collection
Blood samples were obtained after an overnight fasting
state. Serum samples were then separated from the cells
by centrifugation at 3000 rpm for 10 minutes, and lipid
parameters were measured freshly. Remaining serum
portions were stored at –80˚C and used to analyze PON1
and ARE enzyme activities and TOS and TAS levels.
2.2.2. Measurement of Paraoxonase and Aryles terase
Activities of Serum
PON1 and ARE activities were measured using comer-
cially available kits (Relassay®, Turkey). Fully auto-
mated PON1 activity measurement method consists of
two different sequential reagents. The first reagent is an
appropriate Tris buffer and it also contains calcium ion,
which is a cofactor of PON1 enzyme. Linear increase of
the absorbance of p-nitrophenol, produced from para-
oxon, is followed at kinetic measurement mode. Nonen-
zymatic hydrolysis of paraoxon was substracted from the
total rate of hydrolysis. The molar absorptivity of p-ni-
trophenol is 18,290 M–1·cm–1 and one unit of para-
oxonase activity is equal to 1 mol of paraoxon hydro-
lyzed per liter per minute at 37˚C [16].
Phenylacetate was used as a substrate to measure the
ARE activity. PON1, present in the sample, hydrolyses
phenylacetate to its products, which are phenol and acetic
acid. The produced phenol is colorimetrically measured
via oxidative coupling with 4-aminoantipyrine and po-
tassium ferricyanide. Nonenzymatic hydrolysis of phenyl

Increased Oxidant Stress and Inflammation in Patients with Chronic Schizophrenia
370
acetate was subtracted from the total rate of hydrolysis.
The molar absorptivity of colored complex is 4000
M–1·cm–1 and one unit of arylesterase activity is equal to
1 mmol of phenylacetate hydrolyzed per liter per minute
at 37˚C [17].
2.2.3. Measurement of the Total Antioxidant Status of
Serum
The TAS of the serum was measured using a novel
automated colorimetric measurement method for TAS
developed by Erel [18]. In TAS method, antioxidants in
the sample reduce dark blue-green colored 2,2’-azino-
bis (3-ethylbenzthiazoline-6-sulphonic acid) (ABTS)
radical to colorless reduced ABTS form. The change of
absorbance at 660 nm is related with total antioxidant
level of the sample. Using this method, the antioxidative
effect of the sample against the potent free radical reac-
tions initiated by the produced hydroxyl radical, is meas-
ured. The results are expressed as micromolar trolox
equivalent per liter.
2.2.4. Measurement of the Total Oxidant Status of
Serum
The TOS of the plasma was measured using a novel
automated colorimetric measurement method for TOS
developed by Erel [19]. In TOS method; oxidants present
in the sample oxidize the ferrous ion-chelator complex to
ferric ion. The ferric ion makes a colored complex with
chromogen in an acidic medium. The color intensity,
which can be measured spectrophotometrically, is related
to the total amount of oxidant molecules present in the
sample. The results are expressed in terms of micromolar
hydrogen peroxide equivalent per liter (μmol H2O2 Equiv.
/L).
2.2.5. Oxidative Stress Index
The percentage ratio of TOS level to TAS level was ac-
cepted as oxidative stress index (OSI) [20]. For calcula-
tion, the resulting unit of TAS was changed to millimoles
per liter, and the OSI value was calculated according to
the following formula: OSI (arbitrary unit) = TOS (mi-
cromolar hydrogen peroxide equivalent per liter)/TAS
(micromolar trolox equivalent per liter) [19].
2.2.6. Routine Parameters
The levels of triglycerides (TG), total cholesterol (TC),
high-density lipoprotein cholesterol (HDL-C), and Low-
density lipoprotein cholesterol (LDL-C) were determined
by using commercially available assay kits (Abbott) with
an autoanalyzer (Architect® c16000, Abbott Diagnos-
tics). A nephelometric method was used for measuring
CRP levels (Delta Array® Protein System, SEAC Diag-
nostics) and fibrinogen was measured with a coagulome-
ter (Trombolyzer® XRC, Behnk Elektronik). Vitamin
B12 and folate levels were determined by using the in-
strument Beckman Coulter DXI 800. The Access Vita-
min B12 assay was a competitive-binding immunoenzy-
matic assay and the Access Folate assay was a compete-
tive-binding receptor assay. Non-HDL-C levels were
calculated using the formula: Non-HDL-C Level = Total
Cholesterol Level-HDL-C Level.
2.3. Stati stical An alysis
Statistical analyses were carried out using the MedCalc
statistical software (MedCalc, Mariakerke, Belgium).
The results were expressed as mean ± SD. The signifi-
cance of the differences between groups was determined
by student’s unpaired t-test and the Wilcoxon test. Pear-
son correlation coefficient was used to test the strength of
any associations between different variables. P values
less than 0.05 was accepted as the significance level. The
c statistic was used to observe the optimal cut-off levels
and associated diagnostic performances (sensivity, speci-
ficity, and diagnostic value) of PON, ARE, TAS, TOS,
and OSI, based on area under the receiver operating
characteristic (ROC) curve (AUC) analysis.
3. Results
Clinical data of patients and age-matched controls are
summarized in Table 1. The means of BMI of the groups
did not differ significantly. There were no differences
between cases and controls with regard to body mass
index and age.
Mean of total cholesterol (TC) in schizophrenic pa-
tients was 187.8 ± 43.3 mg/dL which was not statistically
any different compared to the control subjects (177.5 ±
32.4 mg/dL) as shown in Table 2. Similarly, neither of
means of serum HDL-C and serum LDL-C were signify-
cantly different between the patients and the controls
(Table 2). However, mean of serum TG in patients
(180.6 ± 85.3 mg/dL) was significantly higher compared
to the controls (109.7 ± 51.4 mg/dL) (p = 0.0003) (Table
2). Patients did not differ from controls in terms of the
nutritionalparameters, plasma folate and vitamin B12
levels. On the contrary, the inflammation markers CRP
and fibrinogen were higher in the patient group (Table
2).
Table 1. Sample demographics.
Parameter (mean ± SD) Patients (n = 30) Controls (n = 30)P
Age 36.7 ± 9.4 38.3 ± 15.3 0.643
Weight 73.4 ± 10 74 ± 9.7 0.65
Gender All males All males
BMI (kg/m2), mean ± SD25.54 ± 2.54 25.15 ± 4.0 0.646
BPRS total score 18.79 ± 9.30 -
SANS total scores 57.87 ± 27.18 -
SAPS total scores 34.00 ± 29.75 -

Increased Oxidant Stress and Inflammation in Patients with Chronic Schizophrenia
371
curves for all the parameters in Figure 1. The sensitivity
and specificity of TOS were 80% and 93.3%, res-
pectively, and the AUC was 0.893 (Figure 2). According
to the ROC curve for OSI, the diagnostic sensitivity and
specificity were 80.0% and 93.3%, respectively, and the
AUC was 0.878 (Figure 3). The AUC for the PON and
ARE were 0.504 and 0.549 respectively, and these values
were lower than that of TOS and OSI.
We also investigated the serum TAS, TOS and OSI
levels of schizophrenia patients and the controls. We
found TOS and OSI higher in patients compared to con-
trols, but no significant difference was observed in TAS
levels. PON1 and ARE enzyme activities were not either
different between the patients and the control group. The
results are presented in Table 3. Table 4 shows the
significant correlation between OSI and CRP.
Optimal cut-off levels and associated diagnostic
performances (sensivity, specificity, and diagnostic value)
of PON, ARE, TAS, TOS, and OSI, based on ROC
analysis, are given in Table 5. We presented the ROC
4. Discussion
Since over a century that schizophrenia has been
conceptualized there have been wide-ranging variety of
pathophysiological models and causal hypotheses of
schizophrenia [21]. One among these is the role for free
radical-mediated pathology in schizophrenia that was
proposed more than half century ago [22]. Brain is
particularly vulnerable to oxidative stress as a result of
the relatively low levels of antioxidants, high levels of
Table 2. Blood lipid, inflammation and nutritional para-
meters in schizophrenia patients and controls.
Serum Parameters
(mean ± SD)
Patients
(n = 30)
Controls
(n = 30) P values
Total Cholesterol (mg/dL) 187.8 ± 43.3 177.5 ± 32.4 0.302
Triglyceride (mg/dL) 180.6 ± 85.3 109.7 ± 51.4 0.0003
HDL Cholesterol (mg/dL) 41.5 ± 10.4 45.9 ± 10.7 0.107
LDL Cholesterol (mg/dL) 110.1 ± 41.0 109.5 ± 31.3 0.950
Non-HDL Cholesterol
(mg/dL) 146 ± 42 131 ± 32 0.13
Folic Acid (ng/mL) 5.31 ± 2.31 5.94 ± 1.9 0.21
Vitamin B12 (pg/mL) 182 ± 83 152 ± 62 0.12
Fibrinogen (mg/dL) 358.9 ± 121 292.4 ± 97 0.0094
CRP* (mg/L) 5.0987 ± 4.74* 2.84 ± 1.03 0.017
Table 4. Correlation Coefficients in schizoprenia group.
CRP
OSI R = 0.4552 P = 0.01
weight r = 0.3597 P = 0.05
ARES
OSI
PON
TAS
TOS
0 20 40 60 80 100
100-S
p
ecificit
y
10
0
80
60
40
20
Sensitivity
*Wilcoxon test.
Table 3. Serum PON1, ARE, TAS, TOS and OSI levels of
schizophrenia patients compared to the controls.
Parameter (mean ± SD) Patients (n = 30) Controls (n = 30)P
PON1(U/L) 99.9 ± 61.6 93.7 ± 44.5 0.660
ARE(kU/L) 150.1 ± 59.3 163.8 ± 66.1 0.402
TAS (nmol Troloks/L) 1.44 ± 0.33 1.52 ± 0.30 0.327
TOS
(μmol H2O2 Equiv./L) 67.4 ±60.1 8.69 ± 2.91 0.0001
OSI 12297.3 ± 3963.8 564.7 ± 121.3 0.0001
PON/ARE* 0.66 ± 0.29 0.61 ± 0.27 0.51Figure 1. The figure compares the diagnostic performances
(sensitivity and specificity) of PON, ARE, TAS, TOS and
OSI based on ROC analysis.
*Wilcoxon test.
Table 5. Optimal cut-off levels and associated diagnostic performances (sensitivity, specificity, and diagnostic value) of PON,
ARE, TAS, TOS and OSI based on ROC analysis, are given in the table. The AUC for the PON, and ARE were 0.504 and
0.549, respectively, and these values were lower than those of TOS (0.897) and OSI (0.878).
Biomarker Cut-off levelSensitivity (%) Specificity (%) Diagnostic value (AUC) +LR –LR
PON1 47.0 26.7 90.0 0.504 2.67 0.81
ARE 204.3 90.0 26.7 0.549 1.23 0.37
TAS 1.2 36.7 86.7 0.576 2.75 0.73
TOS 15.0 76.7 93.3 0.897 11.50 0.25
OSI 788.1 80.0 93.3 0.878 24.00 0.21
+LR = Positive likelihood ratio; –LR = Negative likelihood ratio.

Increased Oxidant Stress and Inflammation in Patients with Chronic Schizophrenia
372
1 0
patient
TOS
>15.0
Sens: 76.7
Sec: 93.3
250
200
150
100
50
0
Figure 2. The sensitivity and specificity of TOS were 76.7% and 93.3%, respectively, and the AUC was 0.897 (1: schizophre-
nia patients; 0: controls).
1 0
patient
OSI
>788.1
Sens: 80.0
Sec: 93.3
14000
12000
10000
8000
6000
4000
2000
0
Figure 3. The sensitivity and specificity of OSI were 80.0% and 93.3%, respectively, and the AUC was 0.878 (1: schizophrenia
patients; 0: controls).
polyunsaturated fatty acids and increased need of oxygen
[23,24]. In the intervening decades there has been a
steady stream of evidence demonstrating the presence of
oxidative stress in patients with schizophrenia [21]. In
accordance with these implications, our results showed
that TOS and OSI increased in our patient group
compared to the controls, providing additional evidence
of increased oxidative stress in schizophrenia (Tables 3
and 5). Moreover, ROC analysis revealed high diagnostic
values for TOS and OSI with respect to male patients
with schizophrenia, with an area under curve (AUC) of
0.897 and 0.878, respectively as shown in the Figures
1-3.
Additionally, our results for CRP, a prototypic marker
of inflammation, and fibrinogen suggest that inflam-
mation is enhanced in the schizophrenic patients in our
study group (Table 2). Fibrin (ogen) has been shown to
cause an inflammatory response in peripheral blood
mononuclear cells induced by high levels of reactive
oxygen species, increased cytokine and chemokine ex-
pression and macrophage chemoattractant protein-1 [25].
In their review, Leonard et al. stated that inflammatory
mediators including CRP and fibrinogen, are raised in the
serum of patients with schizophrenia. Thus they con-
cluded that there is a chronic, low-grade inflammatory
change associated with the active phase of schizophrenia
[26]. Oxidative stress and inflammation are inextricably
tied processes. Chronic inflammation is associated with
elevated reactive oxygen species levels; anti-inflam-
matory cascades are linked to diminished reactive oxy-
gen species concentrations. And the converse is true-
elevated oxidative stress triggers inflammation, whereas
redox balance inhibits the cellular response. Thus, oxi-
dative stress and inflammation may be seen as both
causes and consequences of cellular pathology in many
disorders [27], probably in degenarative diseases such as
schizophrenia.
Schizophrenic patients are in general expected to be an
undernourished group and, as a consequence, may show
low vitamin levels; however there was no significant

Increased Oxidant Stress and Inflammation in Patients with Chronic Schizophrenia 373
difference in folate and B12 levels between the patient
and control groups in this study (Table 2). In agreement
with our findings, other authors reported that schizo-
phrenic patients in their study groups also had folate and
B12 levels within normal limits [28]. These findings
suggest that the patients in our study group were not
undernourished.
The potential toxicity of free radicals is counteracted
by a number of cytoprotective antioxidant enzymes that
limit the damage, such as superoxide dismutase and
glutathione peroxidase. However, the reports regarding
the status of antioxidant defence system in schizophrenia
are very inconsistent, with various authors stating both
increased and decreased activities of the main antioxidant
enzymes, while others did not observe any significant
modifications, as compared to control groups [29]. Stud-
ies performed in schizophrenia patients have generally
suggested a compromised antioxidant system, but this is
not always consistent with specific observed parameters,
which on the whole, show evidences of dysregulation.
Reduced levels of the antioxidant enzymes are generally
reported in patients with schizophrenia compared with
controls [30-33]. However, some studies have advocated
a strengthening of antioxidant status in schizophrenia
[34-37]. In our study, we observed no significant dif-
ference in TAS values of our study groups. As our
understanding of the interrelations of the components of
the antioxidant defence system enlarges, it becomes
obvious that examining one enzyme in isolation may
have limited value for elucidating the role of impaired
antioxidant defence system in neuropsychiatric disease
processes, suggesting that the dynamic aspects of the
antioxidant defence system likely have more salience to
understanding the pathophysiology of schizophrenia [38].
It is generally believed that the equivocal results men-
tioned above may be due to different tissue studies,
different species or the administrated treatment and the
duration of the disease/treatment [3]. On the other hand,
changes in antioxidant defense system such as decreased
plasma TAS do not necessarily reflect an increased
oxidative stress and subsequent membrane lipid damage
[29].
Patients with major mental illnesses such as schi-
zophrenia and bipolar disorder have increased risks of
morbidity and mortality compared with the general
population, with a 25- to 30-year shorter life span due
primarily to premature cardiovascular disease [39]. Oxi-
dative stress, owing to increased lipid and protein oxi-
dation products, is associated with cardiovascular dis-
eases and affects PON1 expression and activities [40].
Although the primary physiological role of PON1 is still
uncertain, a recent study has shown that PON1 is located
on HDL and plays a role in protection against oxidative
modification of LDL; that is, lipid peroxidation [41].
PON1 enzyme activity is associated with HDL func-
tionality and it is reported to be responsible for the
antioxidant properties of HDL [42]. In the present study,
we showed that PON1 and ARE enzyme activities were
not statistically different in patients with chronic schi-
zophrenia. To our knowledge, this is the first paper
reporting the ARE activities besides the PON1 activities
in schizophrenic patients. Although PON1 and ARE are
considered to be two different enzymes, previous studies
have shown that a single gene product in human serum
has both ARE and PON1 activities [43]. PON1 is located
on Chr 7q21.3 and the Gln192Arg polymorphism is
associated with PON1 activity to protect LDL against
oxidative modification [14]. Matsumoto et al. [14] did
not observe a significant association between schizoph-
renia and one nonsynonymous polymorphism (Gln192Arg).
Comparison of the ability of HDL to protect LDL from
oxidation between PON1 192Gln/Gln genotype and PON1
192Arg/Arg genotype demonstrated that the 192Gln/Gln
genotype exhibited approximately 6-fold higher efficien-
cy than the 192Arg/Arg genotype [44].
The only lipid profile parameter that significantly
differed from those of the control subjects was the serum
triglyceride levels in our patient group (Table 2). On the
other hand, it was interesting to observe that HDL-
cholesterol levels seemed to be lower, but not signi-
ficantly different in the shizophrenic patients compared
to the control subjects (Table 2). In the context of high
triglycerides, low HDL cholesterol is not only an early
symptom, but also provides a very sensitive marker of
impaired glucose tolerance and increased lipolysis. These
examples reflect the very heterogeneous nature of HDL
which makes HDL genetics very complex [45]. Although
high-density lipoprotein-cholesterol levels in large epide-
miological studies are inversely related to the risk of
coronary heart disease (CHD), increasing the level of
circulating HDL does not necessarily decrease the risk of
CHD events, CHD deaths, or mortality [46]. Typically,
total plasma HDL contains 20% - 30% (wt/wt) phos-
pholipids, 3% - 5% free cholesterol, 14% - 18% choles-
teryl ester and 3% - 6 % triglycerides. Another factor that
might make HDL dysfunctional is a change in the HDL
associated lipids. Enrichment in triglyceride with de-
pletion of cholesteryl ester in the HDL core is the most
frequent abnormality of HDL lipid composition and
occurs in hypertriglyceridemic states associated with
decreased activity of lipoprotein lipase, hepatic lipase,
LCAT, or a combination of these. In addition, HDL
triglyceride content can also be increased in hyper-
triglyceridemia as a consequence of elevated cholesteryl
ester transfer protein activity [47]. Because low plasma
HDL concentration sometimes is associated with in-
creased risk of cardiovascular diseases, whereas other
conditions with low plasma HDL concentration are as-

Increased Oxidant Stress and Inflammation in Patients with Chronic Schizophrenia
374
sociated with improved prognosis, it seems that it is not
only the concentration per se but also the function of the
HDL particles that is important for its antiatherogenic
effects. HDL particles are susceptible to structural mo-
difications mediated by various mechanisms, including
oxidation, glycation, or enzymatic degradation, affecting
their functional properties. Moreover, in vitro studies
have shown that homocysteinylation of HDL may reduce
the activity of the enzyme PON1, which is associated
with human HDL, thus rendering the HDL particle more
susceptible to oxidative damage [48,49].
All the patients in our patient group were under
treatment with various antipsychotic drugs. In the pre-
vious studies, it was shown that neither individual anti-
oxidant levels nor total antioxidant status were signi-
ficantly affected by antipsychotic treatment [25,50-52].
More importantly, the altered antioxidants observed were
independent of treatment since patients were antipsy-
chotic drug-naive at entry into the study [29,50,51].
Therefore, we could suggest that the antioxidant enzyme
activities of PON1 and ARE were not affected by the
antipsychotic drugs used to treat our patient group.
5. Conclusion
This study provides additional evidence of increased
oxidative stress and inflammation in chronic schizo-
phrenia, but no alterations in the antioxidant status nor in
the enzymatic activities of PON1 and ARE were ob-
served. Our results suggest that other mechanisms than
the HDL-disfunctionality, namely decreases in PON1 or
ARE enzyme activities, are more important in oxidative
or antioxidative pathophysiological processes in schizo-
phrenia.
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