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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- Keywords:Free radical 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 Superoxide dismutase 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.
doi: 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- Cigarette smoking 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- schizophrenic patients 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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