Chaque forme pharmaceutique présente ses propres avantages et inconvénients acheter du amoxil
mais n'ont pas d'effets néfastes pour l'organisme dans son ensemble.
Elevated plasma superoxide dismutase in first-episode and drug naive patients with schizophrenia: inverse association with positive symptoms
Contents lists available at
Progress in Neuro-Psychopharmacology & Biological
Elevated plasma superoxide dismutase in ﬁrst-episode and drug naive patients withschizophrenia: Inverse association with positive symptoms
Zhiwei Wu , Xiang Yang Zhang Huanhuan Wang , Wei Tang Yu Xia FeiXue Zhang , Jiahong Liu ,Ye Fu , Jianjun Hu Yuanling Chen Linjing Liu Da Chun Chen Mei Hong Xiu Thomas R. Kosten ,Jincai He ,
a The First Afﬁliated Hospital, Wenzhou Medical College, Wenzhou, Chinab Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, USAc Center for Psychiatric Research, Beijing Huilongguan Hospital, Beijing, Chinad Department of Psychiatry, Kangning Hospital, Wenzhou, China
Excessive free radical production or oxidative stress may be involved in the pathophysiology of schizophrenia
Received 9 June 2011
as evidenced by increased superoxide dismutase (SOD) activities, a critical enzyme in the detoxiﬁcation of
Received in revised form 17 August 2011
superoxide radicals. This study compared plasma SOD activities in 78 never-medicated ﬁrst-episode and
Accepted 22 August 2011
100 medicated chronic schizophrenia patients to 100 healthy control subjects and correlated these SOD ac-
Available online 30 August 2011
tivities with the Positive and Negative Syndrome Scale (PANSS) among the schizophrenic patients. Wefound that both ﬁrst-episode and chronic patients had signiﬁcantly increased plasma SOD activities com-
pared to controls, and that chronic schizophrenic patients on antipsychotic medication had signiﬁcantly
higher SOD activities than ﬁrst episode schizophrenic patients. Plasma SOD activities were also negatively
correlated with positive symptoms of schizophrenia, but only in ﬁrst-episode patients. Thus, oxidative stress
appears to be greater in ﬁrst episode schizophrenic patients with fewer positive symptoms and may become
greater as schizophrenia becomes more chronic, although we cannot exclude the possibility that chronic an-tipsychotic treatment may increase SOD activities and presumed oxidative stress in schizophrenia.
2011 Elsevier Inc. All rights reserved.
). For example, superoxide dismutase
Schizophrenia is associated with altered antioxidant enzymes and
(SOD), one of the critical scavenging enzymes that detoxiﬁes super-
oxidative stress as part of its pathophysiology
oxide radicals, has been consistently elevated in chronic schizophren-
). Numerous studies in patients with schizophre-
nia have shown abnormally high activities of critical antioxidant en-
) and to be low in neuroleptic naive, ﬁrst-episode
zymes reduced levels of
schizophrenic patients with a few excep-
tions to these ﬁndings (Antioxidant enzymes and
lipid peroxidation alterations also have been associated with negative
), and increased levels of
symptoms (with positive symptoms
lipid peroxidation in plasma, red blood cells, and cerebrospinal ﬂuid
) and with tardive dyskinesia
). Most recently, we found that total antioxidant status(TAS) levels were signiﬁcantly lower in ﬁrst-episode patients withschizophrenia than in healthy control subjects. Moreover, a trend to-
Abbreviations: ANCOVA, analysis of covariance; ANOVA, analysis of variance; CSF,
ward signiﬁcant inverse correlation between TAS levels and PANSS
central spinal ﬂuid; FEP, ﬁrst-episode psychosis; HAMD, Hamilton rating scale for de-
negative subscore was observed in patients (These
pression; LSD, least signiﬁcant difference; PANSS, positive and negative syndromescale; SOD, superoxide dismutase; SCID, Structured Clinical Interview for DSM-IV.
ﬁndings support oxidative stress as a component in the psychopa-
⁎ Corresponding authors at: VA Medical Center, Research Building 110, 2002 Holcombe
thology of schizophrenia.
Boulevard, Houston, TX 77030, USA. Tel.: +1 713 794 7032; fax: +1 713 7947 938.
Studies of ﬁrst-episode schizophrenic patients allow us to mini-
⁎⁎ Correspondence to: J.C. He, Sleep Center, the First Afﬁliated Hospital, Wenzhou
mize confounds, such as illness duration, medication effects, and the
Medical College, Wenzhou 325000, China. Tel.: +86 577 88069799.
E-mail addresses: (X.Y. Zhang), (T.R. Kosten),
psychiatric and medical comorbidities that are associated with chro-
nic illness The few studies about oxidative
0278-5846/$ – see front matter 2011 Elsevier Inc. All rights reserved.
Z. Wu et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 36 (2012) 34–38
stress in ﬁrst-episode patients with schizophrenia have all had small
2.4. Statistical analysis
sample sizes ). Thus the present study has a larger sample of never-
We compared the SOD activities in the patient and control groups
medicated ﬁrst-episode psychotic (FEP) patients and a direct compar-
using a univariate analysis of covariance (ANCOVA) with gender, age
ison to chronic patients in assessing plasma SOD activities and relat-
and smoking as covariates. Post hoc comparisons between groups
ing SOD activities to symptoms in these schizophrenic patients.
used Fisher's least signiﬁcant difference (LSD) procedure. Univariateanalysis of variance (ANOVA) was also used to compare nicotineusers with nonusers. Psychopathology on the PANSS was compared
between the patient groups by one-way ANOVA and correlated withSOD activities within patient groups by calculating Pearson correla-
tion coefﬁcients. Bonferroni corrections were applied to adjust formultiple testing. Stepwise multiple regression analysis using SOD as
First-episode, never-medicated patients (FEP) (n = 78; male/
the dependent variable examined the impact of age, gender, duration
female = 42/36) who met DSM-IV criteria for schizophrenia were
of illness, age of onset and psychopathological symptoms as assessed
recruited from consecutive admissions at the inpatient unit of Beijing
by the PANSS and its subscales. We used two-tailed signiﬁcance
HuiLongGuan hospital, a Beijing city owned psychiatric hospital. All pa-
values set at 0.05.
tients were reassessed about 3 months after follow-up during subsequenthospitalization. Two independent experienced psychiatrists made diag-
noses using the Structured Clinical Interview for DSM-IV (SCID).
Chronic medicated schizophrenic patients (n=100; male/female=
shows the subjects' demographic data. First-episode, chronic
68/32) were enrolled at the same hospital. Diagnoses and clinical assess-
patients and control subjects signiﬁcantly differed in age (pb0.001) and
ment of these patients were also done using the same methodologies
smoking (pb 0.001), and duration of illness differed between FEP and
used for FEP patients. These patients had been receiving stable dose of
chronic patients (pb 0.001). We found no correlation of age with SOD
oral neuroleptics for at least 12 months which included clozapine
activities in normal controls (r= −0.06, ns). The SOD activities differed
(n=46), risperidone (n=26), haloperidol (n=12), perphenazine
between male and female normal controls (68.6 ± 3.0 U/ml vs 61.9 ±
(n=11) and chlorpromazine (n =5).
3.5 U/ml, F = 3.13, p b0.05); however, SOD activities did not differ be-
Normal controls (n = 100; male/female = 65/35) were recruited
tween male and female patients in the combined groups (F= 1.14,
from the local community. Current mental status and personal or
p N 0.05) or when the ﬁrst-episode (F=0.19, pN 0.05) and chronic pa-
family history of any mental disorder were assessed by unstructured
tients (F= 1.46, p N 0.05) were examined separately.
interviews. None of the healthy control subjects presented a personalor family history of psychiatric disorder. All subjects were Han Chi-
3.1. Plasma SOD activities
nese recruited at the same period from the Beijing area.
A complete medical history, physical examination and laboratory
Plasma SOD activities signiﬁcantly differed among ﬁrst episode pa-
tests were obtained from patients and control subjects. All were in
tients, chronic patients and normal controls [F(2,278) = 39.95,
good physical health and any subjects with abnormalities were ex-
p b 0.001] ). When age, gender and smoking were added as po-
cluded. Neither schizophrenic patients nor control subjects suffered
tentially confounding covariate terms, the differences between the pa-
from drug or alcohol abuse/dependence. All subjects gave signed, in-
tients and controls remained signiﬁcant [F(5,273)=18.18, pb 0.001].
formed consent to participate in the study, approved by the Institu-
Post hoc comparisons showed signiﬁcantly increased SOD in
tional Review Board, Beijing HuiLongGuan hospital.
chronic patients and ﬁrst-episode patients compared to normal con-trols (both p b 0.001), and chronic patients had higher SOD activitiesthan ﬁrst-episode patients [F(1,124)= 24.7, p b 0.001]. When age,
2.2. Psychopathological assessment in patients
sex, duration of illness and smoking were added as covariates, the dif-ferences between the patients and controls remained signiﬁcant
Four psychiatrists who were blind to the clinical status and treat-
(p b0.001). Neither age nor duration of illness were associated with
ment conditions assessed the patient's psychopathology using the
SOD activities in ﬁrst-episode or chronic patients (all p N 0.05).
Positive and Negative Syndrome Scale (PANSS) () on
In addition, since there were no age-matched control samples to
the day of the blood sampling. To ensure consistency and reliability
those of chronic schizophrenia patients in the analysis above, a new
of rating across the study, these four psychiatrists who had worked
sex-, age- and smoking matched normal control group (Male/Fe-
at least 5 years in clinical practice simultaneously attended a training
male = 57/17; age: 55.6 ± 7.5 years; smoker = 67.6%) was measured
session in the use of the PANSS before the start of the study. After
with SOD activities to make a better comparison thereby minimally
training the four psychiatrists maintained an inter-rater correlationcoefﬁcient greater than 0.8 for the PANSS total score at repeated as-
sessments during the course of the study.
Demographic data in ﬁrst-episode (EFP), chronic patients and control groups.
2.3. SOD activity measurement in plasma
We determined plasma total SOD activities using a standard spec-
trophotometric assay of the inhibition of superoxide-induced forma-
tion of nitrite from hydroxylamine, as described by
Duration of illness
. Xanthine–xanthine oxidase provided the
superoxide source. One unit is deﬁned as the amount of SOD that in-
hibits 50% of nitrite formation under the assay conditions with activ-
ity expressed as Units per milliliter plasma (U/ml). The inter- and
intra-assay coefﬁcient of variation for SOD activity was 4.8% (n = 6)
and 3.9% (n = 6), respectively.
*** Indicate comparison between ﬁrst-episode and chronic patients. *** p b 0.001
Z. Wu et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 36 (2012) 34–38
reducing the effect of age. The results still showed signiﬁcantly in-
differences in techniques of measuring SOD activities, differences in
creased SOD in chronic patients than this older normal control group
testing material (red blood cells vs. plasma vs. serum), exposure to
[67.2 ± 9.9 U/ml; F(1,172)= 75.6, p b0.001]. Furthermore, there was
neuroleptic treatment (drug withdrawal vs. medicated), sampling of
no signiﬁcant difference in SOD between the older and younger normal
patients in different stages of disease progression (chronic active
control groups (pN0.05).
phase vs. remission), different illness courses of patients or differentethnic origin, lifestyle and dietary patterns (),
3.2. Psychopathology and SOD
may be responsible for the discrepancy (In addi-tion, as polymorphisms in the genes encoding isoforms of SOD have
PANSS total scores, positive and general psychopathology subscores
been proposed as a factor that could result in predisposition to
were signiﬁcantly higher while negative subscores were lower in FEP
schizophrenia (), interethnic differences in the alle-
compared to chronic patients (all p b 0.05) (see
lic frequencies of the SOD gene polymorphisms may play an impor-
The SOD activities and PANSS positive symptom subscores showed a
tant role. For example, the Ala–9Val polymorphism in exon 2 of the
signiﬁcantly negative association (r=−0.24, df=78, pb0.05) in FEP
manganese (Mn) isoform (MnSOD) gene is the most extensively stud-
patients (. Stepwise multiple regression analysis in the FEP pa-
ied polymorphism, with the Ala-to-Val substitution possibly resulting
tients that included the PANSS and its subscales, age, gender, duration
in the alteration of MnSOD activity in human mitochondria (
of illness, age of onset and smoking and SOD activities (as dependent
Genotype frequencies of MnSOD Ala-9Val
variable) also identiﬁed only the PANSS positive subscore as signiﬁcant-
polymorphism were signiﬁcantly different between Easter and Western
ly associated with SOD activities (beta= −0.25, t=2.23, pb 0.04). The
population, with lower (11–30%) Ala allelic frequencies reported in
chronic patients showed no signiﬁcant association with the PANSS.
Japanese and Chinese population than the 41–62% in Europeans(Taken together, these fac-tors, together with some other unknown factors might account for
3.3. Other confounding factors
such difference in SOD activities.
We do not know the reasons for increased SOD activities in schizo-
Other possible confounding factors accounting for the differences
phrenic patients. However, the elaborate antioxidant defense system
in SOD activities included cigarette smoking, and antipsychotic
that protects against oxidative damage may be overstressed in
agent type, dose and duration of treatment. Cigarette smoking dif-
schizophrenia. Since SOD is the ﬁrst line of defense against oxidative
fered among groups (p b 0.001; ), with more smoking among
stress to detoxify superoxide, an increase in SOD activity may be in-
chronic patients (69%) than normal controls (32%) or ﬁrst-episode
duced in response to increased oxidative tone as a compensatory
patients (35%). However, SOD activities did not differ between ciga-
mechanism (Thus, elevated
rette smokers and non-smokers in the combined three groups or
SOD activities in the ﬁrst episode and chronic patients with schizo-
when the normal controls and patients (ﬁrst-episode and chronic)
phrenia suggest that oxidative stress may occur in the initial phase
were examined separately. Among the chronic patients SOD activities
of schizophrenia, and then worsen with chronicity of the disorder.
were not signiﬁcantly affected by typical vs atypical neuroleptics,
However, we measured SOD activity in plasma not in cerebral spinal
dose or duration of antipsychotic treatment.
ﬂuid (CSF), and peripheral SOD may not reﬂect similar activities inthe brain. The relationships between peripheral and brain SOD activ-
ities, and between antioxidant enzyme alterations and other systems(i.e., membrane structure, immune function, and neurotransmission),
We found that (1) plasma SOD activities were signiﬁcantly greater
and clinical implications need further investigation.
in both FEP and chronic schizophrenic patients compared to normal
The modest correlation between lower SOD activities and larger
controls and greater in chronic than FEP patients; (2) modest correla-
PANSS positive subscores in FEP patients is a new ﬁnding that has
tions between SOD activities and positive symptoms in FEP patients.
not been reported in previous studies. This inverse association sug-
Increased activities of SOD in patients with chronic medicated
gests that the FEP patients who present with few positive symptoms
schizophrenia agree with most previous studies in chronic medicated
of schizophrenia and thereby more of the negative symptoms and as-
pects of schizophrenia are at risk for greater oxidative stress as a part
of their illness. Whether these patients with higher levels of oxidative
but not all studies
stress go on to a course of more chronic deterioration (classic demen-
tia precox) rather than multiple acute psychotic episodes is an inter-
). Several factors, such as
esting question to be examined in our longitudinal studies. Ourﬁnding of even greater SOD activities in the chronic patients would
be consistent with this hypothesis. Interestingly, our recent studyshowed a trend toward inverse association between negative symp-toms and TAS levels in FEP patients Taken together,these results suggest a biological active process of oxidative damageinvolved in the initial phase of psychotic disorder and a role of oxida-tive stress in the symptomatology of schizophrenia. On the other
hand, it is generally assumed that the positive symptoms of schizo-phrenia are associated with hyperactivity of dopaminergic systems,and the negative symptoms with hypo activity of dopaminergic sys-tems, especially in subcortical cortex (). Moreover,
Plasma SOD activity (U/ml)
several studies have revealed that the metabolism of catecholamines,
especially DA, is associated with free radical generation. Catechol-
amines can auto-oxidize to form radicals or contribute to radical for-
PANSS positive subscore
mation through the metabolization of the enzyme monoamineoxidase Hence, conditions as-
Fig. 1. The SOD activities and PANSS positive symptom subscore showed a signiﬁcantly
sociated with increased catecholamine metabolism may increase the
negative association (r = −0.24, df = 78, p b 0.05) in ﬁrst-episode and drug naive pa-tients with schizophrenia.
radical burden. Therefore, we postulate that the correlation observed
Z. Wu et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 36 (2012) 34–38
between SOD activities and positive symptom in the present study, or
relationship between SOD and prolactin (PRL) in the schizophrenic
between TAS levels and negative symptom in the previous study
group ), suggesting that gender differences in ox-
might be associated with abnormal interaction between
idative stress may be related to hormone differences between males
free radical production and DA systems. However, this explanation
and females, which deserves further investigation.
is quite speculative; interaction between free radical metabolism
In summary, our data show that SOD activity is increased in the
and dopamine system and how they relate to positive or negative
acute early phase of schizophrenia, but greater positive symptoms
symptoms of schizophrenia need to be explored with further detailed
are associated with relatively normal SOD activity. Since SOD activi-
ties are also increased in chronic schizophrenic patients, this supports
Furthermore, we found higher SOD activities in chronic schizophren-
a hypothesis that oxidative stress may be involved in the pathogene-
ic patients treated with antipsychotics compared to never-medicated
sis of a chronic schizophrenia with more of a cognitive and negative
early-stage patients. Probably, there are two main mechanisms for this
symptom deterioration. Interestingly, these negative and cognitive
result: aging and antipsychotic treatment. There are few reports on
symptoms tend to not respond to long-term antipsychotic pharmaco-
plasma SOD activity of healthy human subjects with aging. Some papers
therapy, which is best for reducing positive symptoms of schizophre-
show a slight negative correlation of aging to human erythrocyte or
nia. Whether the higher SOD activity in chronic patients is associated
blood SOD activity ). On
with medication or a natural progression of the disease in this hy-
the other hand, another paper shows tendency of slight increase with
pothesized subgroup of patients will be an important area for our fu-
aging In our present study, however, we did
not ﬁnd a correlation between age and SOD activity in the normal con-trols or in patients. To further conﬁrm this result, an age-matched older
normal control group was recruited and SOD activity was analyzed.
Still, chronic patients showed signiﬁcantly increased SOD than these
Funding for this study was provided by grants from the Stanley
age-matched controls. These results suggest that aging may not be asso-
Medical Research Institute (03T-459 and 05T-726), and the Department
ciated with the increased SOD in patients. On the other hand, one possi-
of Veterans Affairs, VISN 16, Mental Illness Research Education and
bility to explain our results of increased SOD would be due to
Clinical Center (MIRECC), United States National Institute of Health
antipsychotic treatment ). In our present study, the
K05-DA0454, P50-DA18827 and U01-MH79639.
chronic patients had a long duration of illness and had been treatedwith antipsychotic drugs for a long-term period. It is presumed that an-
tipsychotic medication treatment is related to increased SOD activitiesbecause all appropriate confounding variables had been controlled for.
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Elaboración de la GuíaManuel Praena Crespo, Coordinador ProyeCto de eduCaCión en asma en Centros de eduCaCión seCundaria. GruPo de eduCaCión y salud en asma (Gesa). Pediatra. Centro de salud de la Candelaria. sevillaLeandro Castro Gómez, médiCo esColar. equiPo de orientaCión eduCativa san Pablo santa Justa. deleGaCión de sevillaJosé Manuel Cenizo Benjumea, maestro esPeCialista de eduCaCión FísiCa. C.e.i.P. Padre marChena (marChena -sevilla)Juan Carlos Fernández Truan, ProFesor FaCultad del dePorte. universidad Pablo de olavideJavier Gálvez González, ProFesor FaCultad del dePorte. universidad Pablo de olavideJuan Antonio Morales Lozano, ProFesor titular. FaCultad de CienCias de la eduCaCión. universidad de sevillaAlfonso Murillo Fuentes, ProFesor del Ces Cardenal sPínola. FundaCión san Pablo andaluCía-CeuFrancisco Javier Velasco Fano, ProFesor de enseñanza Primaria. málaGa
Fall 2012 Edition Website Updates Personalizing Tamoxifen Therapy in London The Lawson Translational Cancer Research Team (LTCRT) based in London has been facilitating the development and adoption of personalized cancer medicine using pharmacogenomics. Dr. Richard Kim, a recipient of the Cancer Care Ontario (CCO) Research Chair (Tier-1) Award in 2010 and leader of a program of Personalized Medicine at the London Health Sciences Centre, has been working closely with a team of oncologists and the LTCRT to ensure a group of breast cancer patients experience the best outcomes possible. Tamoxifen is an important drug for the treatment and prevention of certain breast cancers, and is metabolized in the liver by a drug metabolizing enzyme called CYP2D6. This enzyme is responsible for converting tamoxifen to its active form, endoxifen. The CYP2D6 enyzme occurs in different forms in human beings (called "polymorphisms") which may metabolize the same drugs differently. There is compelling research that shows that women with less active variants of CYP2D6 are at greater risk for breast cancer recurrence compared to those without such polymorphisms when treated with tamoxifen. In March of 2010, Dr. Kim started a personalized medicine clinic for breast cancer patients on tamoxifen therapy using the research funds available through his CCO Chair award. Patients referred to his clinic have their CYP2D6 genotyped as well as tamoxifen and endoxifen blood levels assessed using state-of-the-art genotyping and drug level analysis technologies. Dr. Kim then provides a detailed report to the referring oncologist in terms of the patient's ability to metabolize tamoxifen. He now has data from over 200 patients that show not only are CYP2D6 polymorphisms important to tamoxifen bioactivation to endoxifen, but so are polymorphisms in a another enzyme (CYP3A4) and the patient's vitamin D level.