Psychiatry and Clinical Neurosciences 2015; 69: 699–707

doi:10.1111/pcn.12333

Regular Article

First-episode psychosis is associated with oxidative stress: Effects of short-term antipsychotic treatment Asli Sarandol, MD,1* Emre Sarandol, MD,2 Hacer Ebru Acikgoz, Cengiz Akkaya, MD1 and Melehat Dirican, MD2

MD,2

Salih Saygin Eker,

MD,1

Departments of 1Psychiatry and 2Clinical Biochemistry, Uludag University Medical Faculty, Bursa, Turkey

Aims: In the present study, our aim was to investigate the oxidative–antioxidative systems in unmedicated first-episode psychosis (FEP) patients at the beginning and after short-term treatment. Methods: This study consisted of 29 patients who experienced an FEP and 25 control subjects. In order to investigate the oxidative status, we determined plasma malondialdehyde (MDA) levels, oxidizability of red blood cells, oxidation and oxidizability of apolipoprotein B-containing lipoproteins (apo B-basal MDA and apo B-ΔMDA). In order to evaluate the antioxidative defense, we measured serum total antioxidative capacity, uric acid, albumin, total bilirubin and vitamin E levels and serum paraoxonase/ arylesterase, whole blood glutathione peroxidase (GPx) and red blood cell superoxide dismutase activities before and after 6 weeks of treatment in patients with FEP. Results: Plasma MDA and apo B-basal MDA levels and red blood cell superoxide dismutase activity were

N THE HUMAN body, there is a physiologic struggle between the naturally occurring oxidative molecules and antioxidative defense forces. Oxidative stress is the unequilibrium between these two systems in favor of the former, which is responsible for the physiopathologic mechanisms of several diseases. There is accumulating evidence that oxidative stress plays a role in the etiopathogenesis of mental disorders, particularly schizophrenia and bipolar dis-

I

*Correspondence: Asli Sarandol, MD, Department of Psychiatry, Uludag University Medical Faculty, Gorukle, Bursa 16059, Turkey. Email: [email protected]; [email protected] Received 9 January 2015; revised 12 June 2015; accepted 3 July 2015.

significantly higher and serum arylesterase and whole blood-GPx activities were lower in the FEP group than those of the healthy control group. There were not any significant changes in the oxidative and antioxidative system parameters (except increased vitamin E levels) after treatment.

Conclusions: The results of this study suggest that FEP is accompanied by oxidative stress. However, further studies are needed to clarify the role of oxidative stress in the physiopathologic mechanisms of FEP, so that oxidative and antioxidative system parameters can be used in the management of these patients. In accordance with psychiatric evaluation, for a better management, patients with FEP may require a multidisciplinary approach, including oxidative and antioxidative system parameters. Key words: affective disorders, antioxidant, firstepisode psychosis, oxidative stress, schizophrenia.

order (BPD),1 which commonly start at early ages2,3 with a first-episode psychosis (FEP). Some authors,4,5 but not all,6,7 suggest that oxidative injury occurs at the onset of psychosis and they also propose that oxidative stress is a feature of the disease process itself. FEP is an intermediate diagnosis until the clinical picture stabilizes.8 Most patients with FEP will eventually be diagnosed as having schizophrenia, BPD or major depression with psychotic features. Some authors point out the importance of determining people who are vulnerable to psychosis, which could allow for preventive interventions.9–11 There are several problems in the management of patients with FEP. Accurate diagnosis at first episode is important

© 2015 The Authors Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology

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for planning proper treatment; however, it was reported that more than one-fifth of patients who presented with FEP were given a different diagnosis upon recurrence.12 The diagnosis performed in the first episode has important therapeutic and prognostic implications, considering that patients with mood disorder and those with schizophrenia spectrum disorders are likely to require different medical and psychosocial treatment. Furthermore, FEP patients should be diagnosed and treated urgently, as prolongation of the untreated period results in a poorer prognosis.9 Early initiation of optimal therapy may reduce the disability associated with the disease progression, and may modify the course of the disorder into a less malignant and more treatment-responsive pattern.13 However, patients with moderate to severe impairment at onset do not obtain full remission from pharmacotherapy, and develop relapse and chronicity.14 The incidence of resistance to treatment is around 10–30%.15 Adverse metabolic effects of antipsychotics is another major health problem, which raises questions about medication discontinuation or low-dose strategies.16 It is important to identify patients who may not need antipsychotic treatment continuation. In order to personalize and optimize treatment, there is also a trend in research for development of alternative strategies to improve current treatment modalities, ranging from adjunct treatment to electroconvulsive therapy.1,17–20 For example, Mahadik et al.21 proposed that a combination of antioxidants and omega-3 polyunsaturated fatty acids may be effective for long-term improved outcome, particularly in the early stages of illness, as at that stage the brain has a high degree of neuroplasticity. There is also a demand for reliable neurobiological markers to improve the determination of high-risk people,9–11 to diagnose correctly22 and to follow up the course of the disease and response to treatment.19,23 Understanding the physiopathologic mechanisms underlying FEP may provide alternatives for treatment strategies and neurobiological markers, as these patients have not been under the effect of antipsychotic medication. Data concerning the oxidative stress parameters may be helpful in understanding the etiopathogenesis of FEP, so that we can determine people who are at risk for FEP or we can more effectively diagnose and/or treat and/or follow the progress of the disease. However, there is limited and conflicting data about oxidative–antioxidative system parameters in patients

with FEP. In the present study, our aim was to investigate the oxidative–antioxidative systems in unmedicated FEP patients at the beginning and after short-term (6 weeks’) treatment. We also aimed to investigate if there were any differences in those parameters between the FEP patients in those latterly diagnosed as having schizophrenia or BPD. For this purpose, in order to investigate the oxidative status of those patients, we determined plasma malondialdehyde (MDA) levels, oxidizability of red blood cells (expressed as RBC-MDA), oxidation and oxidizability of apolipoprotein B-containing lipoproteins (expressed as apo B-basal MDA and apo B-ΔMDA, respectively). Also, in order to evaluate the antioxidative defense, we measured serum total antioxidative capacity (TAOC), uric acid, albumin, total bilirubin and vitamin E levels and serum paraoxonase/arylesterase, whole blood glutathione peroxidase (GPx) and red blood cell superoxide dismutase (RBC-SOD) activities before and after 6 weeks of treatment in patients with FEP.

METHODS This study consisted of 29 patients who experienced an FEP. FEP was defined as the first time a patient displayed positive psychotic symptoms of delusions or hallucinations. The Semi-structured Clinical Interview for DSM-IV was used for the diagnosis. All patients met the criteria for schizophrenia or BPD at 6 months after their acute episode. The patients were subsequently diagnosed with schizophrenia (11 patients) or BPD (15 patients) at 6 months after FEP. Subjects who were free of psychotic symptoms and had at least one mood episode in the last 6 months were defined as BPD patients. By the end of 6 months, one patient with schizophrenia and two patients with BPD were dropped out of the study and their data were excluded. Exclusion criteria were: mental retardation, neurological disorders, history of head trauma with loss of consciousness, other concomitant illnesses (including active inflammatory illness), taking anti-inflammatory medication, and pregnancy or breast-feeding. All study participants gave written informed consent and the study was approved by the Ethics Committee of Uludag University. In order to provide a convenient sample, 25 control subjects who were matched according to age, sex and smoking status were recruited among the

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university staff. The control group consisted of 15 women and 10 men (mean age ± SD: 23.5 ± 9.2 years, range: 19–44). They were assessed by a semistructured psychiatric interview and the same laboratory test protocol was applied to the control subjects as was applied to the patient group. The control subjects were free of any medication for at least 3 weeks prior to blood sampling. Exclusion criteria for the control group were: having a physical or psychiatric disorder as judged from their clinical and laboratory examinations. None of the control subjects were drinkers or had ever taken psychotropic drugs. They had no family history of psychiatric disorder. The patients were treated with various antipsychotic drugs: 15 with second-generation antipsychotics (five with risperidone, three with olanzapine, three with clozapine, two with quetiapine and two with amisulpride), seven with classic antipsychotics (haloperidol) and four with long-acting antipsychotics (long-acting risperidone) in standard doses. Blood samples were drawn after an overnight fasting from the antecubital vein in heparin-coated, ethylenediaminetetraacetic acid (EDTA)-containing and non-additive tubes. Sera and plasma were separated by centrifugation at 1500 g for 10 min. Plasma of the EDTA-containing blood sample was used for separating apolipoprotein B-containing lipoproteins (low-density lipoproteins [LDL] and very low-density lipoproteins) and MDA measurement, and the remainder of the blood sample was used for investigating oxidizability of RBC. A part of heparinized whole blood was frozen for GPx determination. Erythrocytes for SOD determination were washed by saline and frozen after hemolysis. Plasma aliquots for vitamin E measurements were kept at −80°C until the analyses were performed. Tubes for vitamin E determination were protected against light exposure. Plasma aliquots, separated for MDA measurements, were kept at −20°C and analyzed within 2 months. Plasma obtained for determination of apo B-containing lipoproteins was kept at 4°C and analyzed within 24 h. Oxidizability of RBC and serum lipid and apolipoprotein levels and other routine biochemical parameters were measured on the day of blood collection. The same procedures were performed to the patient group after 6 weeks of treatment. Serum levels of total cholesterol, high-density lipoprotein (HDL) cholesterol, triglyceride, glucose, urea, creatinine, uric acid, albumin, total bilirubin, apo A1,

apo B, lipoprotein (a) and thyroid stimulating hormone (TSH) levels were determined using routine laboratory methods on analyzers Architect c 16 000 and Architect i2000 (Abbott Lab., Dallas, TX, USA). Plasma MDA concentrations were determined by reaction with thiobarbituric acid (TBA) and highperformance liquid chromatography (HPLC) separation of the MDA-TBA conjugate.24 We analyzed oxidizability of apo B-containing lipoproteins as described by Zhang et al.25 After precipitating apo B-containing lipoproteins with dextran sulfatemagnesium chloride, HDL containing supernatant was discarded and the precipitate apo B-containing lipoproteins were suspended in phosphate-buffered saline. Cholesterol content of apo B-containing lipoprotein fraction was adjusted to 200 μg/mL with phosphate-buffered saline. MDA level of apo B-containing lipoprotein fraction was measured before (without any incubation, basal value) and after 3 h following incubation with copper sulfate (final concentration 50 μmol/L) at 37°C. The 3-h value was subtracted from the basal value to obtain ΔMDA, which represents the capacity for peroxidation.26 MDA levels of this fraction were determined by the TBA reactive substances (TBARS) assay. Concentration of TBARS in the sample was estimated from a standard curve prepared by 1,1’,3,3’ tetramethoxypropane and expressed as nmol MDA/mg non-HDL cholesterol.27 RBC susceptibility to lipid peroxidation was determined by MDA formation, using the technique of Stocks et al.28 in which RBC suspension was incubated with hydrogen peroxide for 2 h at 37°C in the presence of sodium azide (a potent inhibitor of RBC catalase). Results were expressed in terms of nmol MDA/g hemoglobin (Hb). Hb concentration was determined by the cyanmethemoglobin method.29 TAOC was measured in serum by means of a commercial kit (Randox Laboratories, Antrim, UK). The assay is based on the incubation of 2,2’-azino-di-(3ethylbenzthiazoline-6-sulphonic acid) (ABTS) with a peroxidase (metmyoglobin) and hydrogen peroxide to produce the radical cation ABTS+, which has a relatively stable blue-green color, measured at 600 nm. When the colored ABTS+ is mixed with an antioxidant substance, it is reduced to its original colorless ABTS form. Antioxidants in the added sample cause suppression of this color production to a degree that is proportional to their concentration. The suppression of the color is compared with that of the Trolox, which is widely used as a traditional stan-

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dard for TAOC measurement assays, and the assay results are expressed as Trolox equivalent (mmol/L). Erythrocyte SOD and whole blood GPx activities were determined using Randox kits (Antrim, Ulster, UK). Briefly, the determination of SOD activity was based on the production of O2− anions by the xanthine/xanthine oxidase system. GPx catalyzed by the oxidation of reduced glutathione in the presence of cumene hydroperoxide. The depletion of nicotinamide adenine dinucleotide phosphate was measured spectrophotometrically at 340 nm. Vitamin E (α-tocopherol) concentrations were quantified by the HPLC procedure using UV detection at 292 nm as previously described.30 Paraoxonase activity was determined as described by Eckerson et al.31 The rate of hydrolysis of paraoxon was measured by monitoring the increase in absorbance at 412 nm and 25°C. The amount of p-nitrophenol generated was calculated from the molar extinction coefficient at pH: 10.5, which was 18 290 M−1 cm−1. Paraoxonase activity is expressed in U/L serum. Arylesterase activity was determined by using phenylacetate as the substrate. Enzymatic activity was calculated from the molar extinction coefficient at pH: 8.0, which was 1 310 M−1 cm−1. One unit of arylesterase activity is defined as 1 μmol phenol generated per min under the above conditions and expressed as kU/L.32 All data were expressed as mean ± SD. The FEP patient group was compared with the control group by using the t-test for independent groups and the χ2-test. Pre- and post-treatment values of the FEP patient groups were compared with the use of the paired sample t-test. We also performed the Mann– Whitney U-test or the Kruskal–Wallis test to compare the pretreatment values or percent changes of the parameters between the subgroups categorized according to the latter follow-up diagnosis (BPD [n = 15] and schizophrenia [n = 11]) of the patients. Pearson correlation test was performed to analyze the correlation between study parameters. A P-value < 0.05 was considered significant.

significant differences in the other parameters between the two groups. Plasma MDA and apo B-basal MDA levels and RBC-SOD activity were significantly higher and serum arylesterase and whole blood-GPx activities were lower in the FEP group than those of the healthy control group (Table 2). There were not any significant differences in the rest of the oxidative stress parameters between the two groups. After 6 weeks of treatment, serum total cholesterol, LDL-cholesterol, apo A1, apo B and vitamin E values were significantly increased in the FEP patients (Tables 1 and 2). We investigated the patients according to their follow-up diagnosis and observed that serum total cholesterol, LDL cholesterol, apo B and vitamin E levels were significantly increased in the patients diagnosed with BPD after 6 weeks of treatment, but there were not any changes in the FEP patients diagnosed with schizophrenia (Table 3). Furthermore, there were not any significant changes in the percent changes of the parameters between the FEP patients diagnosed with BPD or schizophrenia (data not shown). Correlations of the study parameters were analyzed and the correlation coefficients of oxidative and antioxidative system parameters that differ between the control and FEP pretreatment groups or FEP pre- and posttreatment values are displayed in Table 4 (please see Table 2 for significantly different parameters).

RESULTS Demographic data and biochemical parameters of the FEP group and the healthy controls are given in Table 1. Systolic and diastolic blood pressure values were significantly higher and apo A1 levels were significantly lower in the FEP patients compared to those of the healthy controls. There were not any

DISCUSSION In the present study, we demonstrated oxidative stress, as reflected by increased plasma MDA levels, which is one of the most used parameters of lipid peroxidation and oxidative stress. In parallel to our findings, several authors4,33,34 reported increased plasma MDA levels in FEP patients; however others6,7 did not find any significant difference between the FEP patients and the controls. Increased apo B-basal MDA levels, observed in our study, reflect the oxidative status of apo B-containing lipoproteins and are another accurate indicator of oxidative stress. We did not observe any significant changes in the oxidative and antioxidative system parameters (except increased vitamin E levels) after 6 weeks of treatment. However, Petronijevic et al.34 reported that plasma MDA, but not RBC-MDA, levels were reduced after 3 weeks of treatment in patients with FEP and in another study, Ruiz-Litago et al.35 found increased plasma TBARS levels after 1 month of treatment in patients with FEP. According to our literature search,

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Table 1. Demographic data and biochemical parameters of FEP patients and healthy controls

Age (years) Sex (female/male) BMI (kg/m2) Smokers/non-smokers Systolic pressure (mmHg) Diastolic pressure (mmHg) Total cholesterol (mg/dL) HDL cholesterol (mg/dL) LDL cholesterol (mg/dL) Triglyceride (mg/dL) Apo A1 (mg/dL) Apo B (mg/dL) Lp(a) (mg/dL) Glucose (mg/dL) Urea (mg/dL) Creatinine (mg/dL) Uric acid (mg/dL) Albumin (g/dL) Total bilirubin (mg/dL) TSH (μIU/mL)

Control (n = 25)

FEP (n = 26) Pretreatment

FEP (n = 26) Post-treatment

23.5 ± 9.2 15/10 22.7 ± 3.0 19/6 105 ± 11 64 ± 7 167 ± 25 48 ± 10 102 ± 25 82 ± 44 162 ± 22 79 ± 19 13.3 ± 12.5 75 ± 8 26.0 ± 7.6 0.94 ± 0.15 4.62 ± 1.46 4.7 ± 0.2 0.76 ± 0.27 1.95 ± 1.20

25.6 ± 7.0 16/10 22.0 ± 3.3 19/7 116 ± 13†* 75 ± 10†** 155 ± 29 45 ± 7 92 ± 26 83 ± 40 134 ± 20†*** 78 ± 20 21.7 ± 23.9 84 ± 17 24.6 ± 8.9 0.81 ± 0.21 5.41 ± 1.80 4.5 ± 0.5 0.81 ± 0.37 1.76 ± 0.84

— — 23.1 ± 3.3‡* — 118 ± 12 76 ± 10 186 ± 46‡** 48 ± 10 118 ± 29‡** 102 ± 39 157 ± 33‡* 99 ± 31‡** 33.9 ± 32.3 79 ± 10 24.4 ± 7.8 0.82 ± 0.18 5.02 ± 1.68 5.1 ± 0.9 1.06 ± 0.44 1.88 ± 0.89

*P < 0.05; **P < 0.01; ***P < 0.001. † Compared with the control group. ‡Compared with the pretreatment values. Apo, apolipoprotein; BMI, body mass index; FEP, first-episode psychoses; HDL, high-density lipoprotein; LDL, low-density lipoprotein; Lp, lipoprotein; TSH, thyroid-stimulating hormone.

Table 2. Oxidative and antioxidative system parameters of FEP patients and healthy controls

Plasma MDA (nmol/mL) RBC-MDA (nmol/g Hb) Apo B-basal MDA (nmol/mg non-HDL cholesterol) Apo B-ΔMDA (nmol/mg non-HDL cholesterol) Serum TAOC (mmol/L) RBC-SOD (U/mL) Whole blood GPx (U/mL) Serum paraoxonase (U/L) Serum arylesterase (kU/L) Plasma vitamin E (μmol/L)

Control (n = 25)

FEP (n = 26) Pretreatment

FEP (n = 26) Post-treatment

0.56 ± 0.21 95.8 ± 26.4 6.82 ± 0.82 36.4 ± 18.7 1.23 ± .0.22 82 ± 50 5116 ± 1635 186 ± 75 89.7 ± 37.2 12.1 ± 3.9

1.13 ± 0.64†*** 96.5 ± 22.4 8.56 ± 0.82†* 43.7 ± 15.5 1.12 ± 0.42 560 ± 279†*** 2692 ± 2483†** 198 ± 107 64.4 ± 36.7†* 13.1 ± 2.9

0.99 ± 0.43 122.6 ± 60.0 8.05 ± 1.82 39.1 ± 15.9 Not available 445 ± 236 2932 ± 2880 209 ± 107 59.9 ± 28.3 15.2 ± 4.3‡*

*P < 0.05; **P < 0.01; ***P < 0.001. † Compared with the control group. ‡Compared with the pretreatment values. Apo, apolipoprotein; FEP, first-episode psychoses; GPx, glutathione peroxidase; MDA, malondialdehyde; RBC, red blood cell; SOD, superoxide dismutase; TAOC, total antioxidant capacity.

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Table 3. Oxidative and antioxidative system parameters and the lipid profile of the FEP patients who were latterly diagnosed as schizophrenia or bipolar disorder Schizophrenia Schizophrenia Bipolar disorder Bipolar disorder (n = 11) (n = 11) (n = 15) (n = 15) Pretreatment Post-treatment Pretreatment Post-treatment Plasma MDA (nmol/mL) 1.20 ± 0.68 RBC-MDA (nmol/g Hb) 97.3 ± 12.6 Apo B- basal MDA (nmol/mg non-HDL cholesterol) 9.29 ± 2.73 Apo B-ΔMDA (nmol/mg non-HDL cholesterol) 43.3 ± 22.2 Serum TAOC (mmol/L) 0.88 ± 0.13 RBC-SOD (U/mL) 485 ± 145 Whole blood GPx (U/mL) 3442 ± 1901 Serum paraoxonase (U/L) 214 ± 129 Serum arylesterase (kU/L) 73.0 ± 42.0 Plasma vitamin E (μmol/L) 14.8 ± 2.5 Total cholesterol (mg/dL) 161 ± 41 HDL cholesterol (mg/dL) 44.4 ± 8.1 LDL cholesterol (mg/dL) 92.6 ± 31.4 Triglyceride (mg/dL) 93.3 ± 45.1 Apo A1 (mg/dL) 137 ± 22 Apo B (mg/dL) 80.7 ± 29.1 Lp(a) (mg/dL) 16.5 ± 7.4

1.03 ± 0.36 99.4 ± 27.1 8.81 ± 2.03 33.0 ± 19.4 Not available 411 ± 287 2793 ± 1619 189 ± 87 51.0 ± 13.5 14.5 ± 3.1 203 ± 70 51.4 ± 12.9 95.5 ± 23.4 121 ± 43 157 ± 33 98.2 ± 29.4 36.0 ± 32.6

1.16 ± 1.26 96.1 ± 27.0 7.97 ± 1.71 43.9 ± 10.7 1.22 ± 0.46 613 ± 348 2351 ± 2119 190 ± 97 59.4 ± 34.0 11.9 ± 2.7 152 ± 23 45.5 ± 7.2 91.5 ± 17.1 78.2 ± 38.5 133 ± 19 76.9 ± 16.2 28.3 ± 23.9

0.96 ± 0.49 105.7 31.8 7.42 ± 1.53 42.4 ± 13.7 Not available 471 ± 219 2902 ± 2368 220 ± 120 65.3 ± 33.8 15.5 ± 5.0†* 175 ± 23†** 45.7 ± 7.8 110.9 ± 18.7†** 90.8 ± 33.5 157 ± 35 100 ± 33†* 32.8

*P < 0.05; **P < 0.01. † Compared with the pretreatment values. Apo, apolipoprotein; FEP, first-episode psychoses; GPx, glutathione peroxidase; MDA, malondialdehyde; RBC, red blood cell; SOD, superoxide dismutase; TAOC, total antioxidant capacity.

there are not any other data that we could compare to our short-term post-treatment results concerning the oxidative–antioxidative system parameters of our study. The antioxidant defense system consists of enzymatic and non-enzymatic elements. In this study, serum levels of antioxidant compounds, albumin, total bilirubin, uric acid, vitamin E and TAOC (which reflects the total antioxidant capacity of all molecules in the serum), were not different from those of the control group. This might suggest that oxidative stress, observed in this study, arises from an increment in free radical production other than an insufficiency in the levels of serum antioxidant molecules. Furthermore, plasma MDA and apo B- basal MDA levels were significantly correlated with TAOC in the pretreatment FEP group, which might also reflect an inefficient defensive response to oxidative stress (Table 4). However, Martínez-Cengotitabengoa et al.6,36 and Mico et al.18 reported that plasma TAOC was reduced in patients with FEP. In a study by Reddy et al.,37 FEP patients were separated as ‘schizophrenics’ and ‘bipolar or depressive

disorder’ groups based on their 6-month diagnosis. Those authors investigated plasma albumin, total bilirubin and uric acid, which are the major contributors of plasma antioxidant activity. Reddy et al. found that those parameters were lower in the schizophrenics group but not in the bipolar or depressive disorder group compared to those of the healthy controls. We also separated our patients according to their latter diagnosis and compared their basal pretreatment values. There were not any significant differences in the basal pretreatment values investigated in this study between the patients that were latterly diagnosed as having schizophrenia or BPD and the healthy controls (Table 3), which might be related to the limited number of subjects in these patient subgroups. In this study, in order to evaluate the enzymatic component of the antioxidant system, we measured RBC-SOD and whole blood-GPx activities. SOD dismutases superoxide to H2O2 and oxygen. H2O2 is neutralized to H2O by Gpx or catalase. Gpx activity is dependent on reduced glutathione (GSH) levels. Glutathione reductase recycles oxidized glutathione to

© 2015 The Authors Psychiatry and Clinical Neurosciences © 2015 Japanese Society of Psychiatry and Neurology

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Table 4. Correlations of oxidative and antioxidative system markers

Control (n = 25)

Pearson correlation, significance (2-tailed)

Apo B- basal MDA – Apo B-ΔMDA Apo B- basal MDA – serum arylesterase Whole Blood GPx – serum TAOC Whole Blood GPx – Apo B Whole Blood GPx – total bilirubin Serum Arylesterase – triglyceride

0.945, 0.000 −0.618, 0.008 −0.578, 0.019 −0.587, 0.021 0.560, 0.024 −0.715, 0.001

FEP: Pretreatment (n = 26) Plasma MDA – TAOC Apo B- basal MDA – serum TAOC Apo B- basal MDA – total cholesterol Apo B- basal MDA – LDL cholesterol Whole blood GPx – TAOC Serum arylesterase – serum paraoxonase Serum arylesterase – Lp(a)

0.784, 0.004 −0.667, 0.015 −0.561, 0.019 −0.520, 0.033 −0.629, 0.029 0.684, 0.000 0.552, 0.029

FEP: Post-treatment (n = 26) Plasma vitamin E – total cholesterol

0.625, 0.022

Apo, apolipoprotein; FEP, first-episode psychoses; GPx, glutathione peroxidase; MDA, malondialdehyde; TAOC, total antioxidant capacity.

GSH by using nicotinamide adenine dinucleotide phosphate (NADPH) as the reducing power. Increased free radical production may result in a responsive increase in SOD activity.38 However, after a critical level, related to the limitation of NADPH and GSH supply, Gpx activity may be inadequate to buffer excessive production of H2O2. In this situation, the production of hydroxyl radical, which destroys all molecules in the human body, increases and the organism faces the oxidative stress. Increased RBCSOD activity, observed in our study, may be the reflection of an antioxidant response to increased free radical production and reduced whole blood-GPx activity may be the result of insufficiency in NADPH and GSH supply, as mentioned above.38 The unchanged RBC-MDA levels, observed in this study, might partly be related to increased defense of RBC as reflected by increased SOD activity. Furthermore, significant negative correlations between the whole blood GPx activity and TAOC observed both in the

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control and the FEP pretreatment groups might also indicate the antioxidant defense system attempt to overwhelm the reduced GPx activity. In parallel to our finding, Petronijevic et al.34 did not observe any difference in RBC-MDA levels between the patients with FEP and healthy controls. However, concerning oxidative stress parameters, there are discrepancies in the findings of several studies investigating patients with FEP. Martínez-Cengotitabengoa et al.6 reported that total glutathione levels were comparable to those of the control group whereas in another study, the same author group36 reported reduced levels of total glutathione in erythrocyte hemolysates of patients with FEP. In contrast to our findings, Gpx activity was reported as increased18,39 and unchanged6 and SOD activity was reported as unchanged6,18,39 in the RBC of patients with FEP. We did not observe any changes in Gpx or SOD activity after 6 weeks of treatment, whereas Ruiz-Litago et al.,35 in their follow-up study, reported reduced plasma Gpx and SOD activity after 1 month of treatment in patients with FEP. Serum paraoxonase is an HDL-associated antioxidant enzyme that protects lipoproteins and cells from oxidation. The enzyme exerts several enzymatic activities towards several substrates, such as paraoxon (paraoxonase activity), and phenylacetate (arylesterase activity). FEP patients of this study showed decreased arylesterase activity, which could also be related to diminished antioxidative defense in these patients. Cardiometabolic abnormalities in the early phase of psychoses40,41 have become a major concern as this condition is associated with a lower functional outcome, poorer quality of life and non-compliance to antipsychotic medication. However, there are limited and conflicting data and, as stated by Foley et al.,8 more research is needed to understand the magnitude and nature of CVD risk factors associated with psychoses in the early phase of illness. In line with our results, the Scottish Research Group7 reported that total cholesterol and vitamin E levels were not different between the FEP patients and the controls. However, in the present study, 6 weeks of treatment resulted in increment in body mass index (BMI), serum total cholesterol, LDL cholesterol, apo A1, apo B and plasma vitamin E levels in patients with FEP. In parallel to our findings, Basoglu et al.42 reported that BMI, LDL cholesterol and triglyceride levels were increased after 6 weeks of treatment in drug-naive, nonobese, young adult, male patients with newly diagnosed FEP.

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There are several limitations of this study. We would like to point that there are some difficulties in interpretation of the data concerning oxidative stress, as there are several parameters of the oxidative and antioxidative systems that may be investigated by several different methods. Furthermore, several kinds of samples, such as whole blood, plasma, serum, spinal fluid and cell cultures, can be used for the investigation of oxidative stress. These parameters may also vary according to ethnicity and lifestyle factors, such as smoking, diet, exercise and emotional or physical stress. Also, it must be taken into consideration that psychiatric disorders are heterogeneous in etiopathogenesis and study populations may vary according to the stage or duration of the disease, treatment modalities, and supportive treatments. The results of this study suggest that FEP is accompanied by oxidative stress. However, further studies are needed to clarify the role of oxidative stress in the physiopathologic mechanisms of FEP, so that oxidative and antioxidative system parameters can be used in the management of these patients. In accordance with psychiatric evaluation, for a better management, patients with FEP may require a multidisciplinary approach, including psychological tests, radiologic examination and oxidative and antioxidative system parameters.

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ACKNOWLEDGMENTS There is no conflict of interest and none of the authors has anything to disclose.

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