Original research paper
Vitamin E and essential polyunsaturated fatty acids supplementation in schizophrenia patients treated with haloperidol Marija Bošković 1, Tomaž Vovk1, Jure Koprivšek 2, Blanka Kores Plesnicˇ ar3, Iztok Grabnar1 1
Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia, 2Department of Psychiatry, University Clinical Centre Maribor, Maribor, Slovenia, 3University Psychiatric Clinic Ljubljana, Ljubljana, Slovenia Objectives: Previously, oxidative damage has been associated with severity of clinical symptoms and supplementation with antioxidants and essential polyunsaturated fatty acids (EPUFAs) was proposed to have beneficial effects in schizophrenia. We evaluated the effects of supplementation with EPUFAs and vitamin E in patients treated with haloperidol depot injection. Design: This was a double-blind randomized placebo-controlled study with four arms (Placebo, vitamin E, EPUFAs, and vitamin E + EPUFAs). Biomarkers of oxidative stress, neurochemistry, psychopathology, and extrapyramidal symptoms were assessed at baseline and after 4 months. Results: In EPUFAs group of patients, reduced glutathione concentration was increased compared to placebo. Concentration of oxidized glutathione was decreased in patients receiving vitamin E. In addition, compared to placebo a non-significant trend of increased activity of catalase and superoxide dismutase was observed in all three treatment groups. Patients receiving vitamin E experienced less motor retardation. No difference in extrapyramidal symptoms was found. Discussion: Our study indicates that supplementation with vitamin E and EPUFAs may improve the antioxidative defense, especially glutathione system, while there is no major effect on symptoms severity. Supplemental treatment with EPUFAs and vitamin E in schizophrenia patients treated with haloperidol is potentially beneficial and a larger independent study appears warranted. Keywords: Schizophrenia, Essential polyunsaturated fatty acids, Vitamin E, Haloperidol, Oxidative stress
Introduction Oxidative stress is involved in pathophysiology of schizophrenia.1 Potential mechanisms include dopamine oxidation, mitochondrial electron transport chain, genetic factors, and antipsychotic treatment.2 Reactive species (RS) mediated abnormalities may contribute to the development of clinically significant consequences, like worsening of psychopathology and extrapyramidal symptoms.3 Involvement of oxidative stress in schizophrenia suggests potential benefits of supplementation with antioxidants, such as vitamin E.1 In addition, reduced levels of essential polyunsaturated fatty acids (EPUFAs) were found in the brain and red blood cell membranes of schizophrenia patients, indicating that dysfunctional fatty acid Correspondence to: Iztok Grabnar, Faculty of Pharmacy, University of Ljubljana, Asˇ kercˇ eva cesta 7, Ljubljana SI-1000, Slovenia. Email: [email protected]
© W. S. Maney & Son Ltd 2014 DOI 10.1179/1476830514Y.0000000139
metabolism could be involved in the etiology of the disorder.4 Previous studies on the effects of vitamin E and EPUFAs supplementation in schizophrenia are inconclusive.2 We have previously investigated the role of oxidative stress in schizophrenia and involvement of genetic factors.5,6 Here, we report on a pilot randomized double-blind, placebo-controlled study in the same patients, which aimed to assess the benefits of supplementation with EPUFAs, vitamin E, and their combination. Biomarkers of oxidative stress, neurochemistry, psychopathology, and extrapyramidal symptoms were evaluated at baseline and after 4 months of supplementation. According to our knowledge, there was no previously published study with this design in a treatment homogeneous group of patients, which would evaluate such variety of biomarkers and psychiatric rating scales in schizophrenia patients.
Nutritional Neuroscience
2014
VOL.
0
NO.
0
1
Bošković et al.
Vitamin E and EPUFAs supplementation in schizophrenia patients
Methods Patients
noradrenaline, adrenaline, dopamine, and serotonin were performed as previously described.6
Fifty-two schizophrenia outpatients of the Caucasian origin with a minimum 3-year duration of illness were recruited. All patients were diagnosed based on a structured clinical interview according to Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV). Patients were receiving their regular therapy of intramuscular haloperidol decanoate (4.2–50 mg/week) for at least 6 months, and concomitantly 14 patients were given oral dose of haloperidol (2–30 mg/day). Based on complete medical history and physical examination, all subjects were physically healthy. The available hospital records and patient interviews were used to determine demographic data, concomitant medication, smoking status, alcohol consumption data, and use of food supplements. The study was approved by the National Medical Ethics Committee of the Republic of Slovenia and was performed in accordance with the ethical standards set by Declaration of Helsinki. The study was registered in EU Clinical Trials Register (EudraCT number: 2009-018054-33).
Study design This was a double-blind randomized placebo-controlled study with four arms (placebo, vitamin E, EPUFAs, and vitamin E + EPUFAs). Vitamin E group of patients was treated with Apozema®, Vitamin E 600 IU soft gelatin capsules (Apomedica, Graz, Austria) twice daily. Patients in the EPUFAs group were treated with Omega-3 Forte soft gelatin capsules, Dr Böhm®, Apomedica (eicosapentaenoic acid (EPA) 132 mg, docosahexaenoic acid 88 mg, alpha-linoleic acid 94 mg, and oleic acid 52 mg) three capsules per day. Patients were instructed to take two capsules in the morning and one in the evening after a meal. Patients from vitamin E + EPUFAs group received both treatments as described above. Lactose (500 mg) hard gelatin capsules were used as placebo. Patients were instructed to return their unused capsules at monthly visits for assessment of compliance and were reassessed after 4 months of treatment. Study intervention did not influence the usual antipsychotic therapy in any way other than explained above.
Sample collection and biochemical measurements At baseline and after 4 months, venous blood sample was drawn and plasma was prepared immediately by centrifugation. Biochemical measurements, including superoxide dismutase (SOD), glutathione peroxidase (GpX), glutathione reductase (GR), catalase (CAT), reduced (GSH) and oxidized (GSSG) forms of glutathione, protein carbonyls (PC), malondialdehyde (MDA), nitrates (NO3) and nitrites (NO2), 2
Nutritional Neuroscience
2014
VOL.
0
NO.
0
Clinical assessment Psychopathology was evaluated by experienced psychiatrists by positive and negative symptoms scale (PANSS). Extrapyramidal symptoms were assessed with abnormal involuntary movement scale (AIMS) for tardive dyskinesia, Simpson Angus scale (SAS) for Parkinsonism, and Barnes akathisia rating scale (BARS) for akathisia.
Statistical analysis Differences between parameter values after 4 months of treatment and at baseline were used for comparison of treatment effects. Significance level was set at P < 0.05. Between-group differences in continuous variables were evaluated by one-way analysis of variance (ANOVA), followed by Dunnett’s test for post hoc pairwise comparisons. In addition, analysis of covariance (ANCOVA) controlling for baseline parameter values was used. Kruskal–Wallis tests were used for comparison of psychopathology and extrapyramidal symptoms data. Mann–Whitney U tests with Holm’s sequential method for control of type I error were conducted for subsequent pairwise comparisons. Between-group differences in categorical data were assessed by Chisquare test. Statistical analyses were carried out using SPSS version 20 (IBM SPSS, Chicago, IL, USA). The sample size was calculated using G*Power 3.1.6 (Institute for Experimental Psychology, Heinrich Heine University Dusseldorf, Germany, http:// www.psycho.uni-duesseldorf.de/abteilungen/aap/ gpower3/). A sample size of 60 subjects randomly assigned to four groups was calculated for one-way ANOVA using an effect size of 0.4 to provide 0.7 power with α error probability set at 0.05.
Results Characterization of patients Of the 52 patients included in the study, 34 completed the supplementation treatment and were included in statistical evaluation (Table 1). At initiation of the study, no significant difference was found between the groups in regard to age, gender, smoking status, weight, duration of illness, and dose of haloperidol (assuming relative oral bioavailability of 65%). In addition, at baseline the four groups did not differ in psychopathology and extrapyramidal symptoms. Summary of biomarkers of oxidative stress and neurotransmitters are presented in Table 2. Biomarkers of oxidative stress and neurotransmitters at baseline were comparable between the groups of patients, except for GSSG and GR. Mean (SD) compliance for all four groups was 92 (13) %.
Bošković et al.
Vitamin E and EPUFAs supplementation in schizophrenia patients
Table 1 Demographic and clinical characteristics of the patients
Age (years)* Gender M/F (n, %)† Smokers (n, %)† Number of cigarettes per day*,‡ Weight (kg)* Duration of illness (months)* Haloperidol dose (mg/week)* PANSS§ Positive subscale Negative subscale General subscale Total score SAS§ AIMS§ BARS§
Total (n = 34)
Placebo (n = 11)
Vitamin E (n = 5)
EPUFAs (n = 9)
Vitamin E + EPUFAs (n = 9)
P- value
50.2 (9.2) 17/17, 50/50 15, 44 14 (14) 81.6 (24.4) 186 (87) 36.5 (38.9)
45.6 (8.7) 4/7, 36/64 4, 36 15 (14) 82.4 (18.2) 190 (116) 37.2 (26.1)
45.8 (4.1) 3/2, 60/40 3, 60 13 (19) 88.1 (26.2) 132 (136) 21.7 (10.8)
53.6 (8.7) 4/5, 44/56 4, 44 16 (17) 79.1 (40.0) 201 (94) 30.0 (38.9)
54.8 (9.6) 6/3, 67/33 4, 44 12 (12) 79.6 (8.1) 184 (18) 50.3 (58.4)
0.055 0.546 0.854 0.932 0.922 0.826 0.568
9 (7, 23) 18 (7, 30) 27 (16, 52) 56 (34, 99) 3 (0, 14) 0 (0, 12) 0 (0, 5)
11 (7, 20) 18 (7, 28) 28 (20, 43) 56 (35, 84) 3 (2, 11) 0 (0, 12) 0 (0, 5)
7 (7, 10) 16 (7, 22) 21 (19, 33) 44 (34, 65) 1 (0, 12) 0 (0, 2) 1 (0, 3)
9 (7, 23) 22 (8, 30) 27 (19, 52) 58 (34, 99) 3 (0, 14) 0 (0, 10) 0 (0, 5)
9 (7, 20) 14 (9, 29) 22 (16, 43) 43 (35, 90) 3 (0, 12) 1 (0, 11) 1 (0, 5)
0.228 0.716 0.787 0.670 0.906 0.559 0.660
*Continuous data are presented as mean (SD), P-value indicates one-way significance by ANOVA. Categorical data reported as number, percentage of patients, P-value indicates between-group significance by Chi-square test. ‡ Subgroup of patients who smoke. § Ordinal data presented as median (range), P-value indicates between-group significance by Kruskal–Wallis test. AIMS, abnormal involuntary movements scale; BARS, Barnes akathisia rating scale; PANSS, positive and negative symptoms scale; SAS, Simpson Angus scale. †
Treatment effect on biomarkers of oxidative stress and neurochemistry Treatment effect on biomarkers of oxidative stress and neurotransmitters are presented in Table 3. Compared to placebo group of patients, blood concentration of GSH was significantly increased in EPUFAs-treated patients (P = 0.044). Similar non-significant trend of increase was also observed in vitamin E (P = 0.115) and vitamin E + EPUFAs (P = 0.075) groups of patients. Furthermore, compared to placebo, blood concentration of GSSG was reduced in patients receiving vitamin E (P = 0.004). This difference remained significant (P = 0.004), when the effect was evaluated by ANCOVA corrected for baseline GSSG concentration. Similar non-significant trends were observed for SOD and CAT. After 4 months of treatment, activities of both of these enzymes decreased in
placebo group of patients, while there was an increase in groups of patients treated with vitamin E, EPUFAs, and their combination (Table 3). In addition, we observed a significant effect of treatment on plasma serotonin concentration (Table 3). Mean concentration of serotonin was decreased in group of patients treated with vitamin E, while in patients treated with EPUFAs concentration of serotonin was increased (Bonferroni test P = 0.027). However, compared to placebo treatment the differences in both groups were non-significant.
Treatment effect on psychopathology of schizophrenia and extrapyramidal symptoms No effect of treatment was found on PANSS total score, as well as on PANSS positive, negative, and general subscores. However, comparison of motor
Table 2 Summary of baseline biomarkers of oxidative stress and neurotransmitters according to treatment groups
SOD (U/g Hb) CAT (U/g Hb) MDA (μmol/l) PC (nmol/mg protein) NO2 (μmol/l) NO2 + NO3 (μmol/l) GSH (μmol/l) GSSG (μmol/l) GpX (U/g Hb) GR (U/g Hb) Dopamine (ng/l) Adrenaline (ng/l) Noradrenaline (ng/l) Serotonin (μg/l)
Total (n = 34)
Placebo (n = 11)
Vitamin E (n = 5)
EPUFAs (n = 9)
Vitamin E + EPUFAs (n = 9)
P- value
2161 (629) 68.1 (27.8) 0.252 (0.066) 1.23 (1.14) 1.15 (0.88) 69.21 (44.10) 1127 (540) 168.4 (63.0) 23.17 (7.96) 3.62 (1.19) 88.7 (51.9) 71.1 (69.0) 718.2 (297.7) 4.74 (5.40)
2321 (450) 80.9 (34.3) 0.244 (0.053) 1.54 (1.37) 1.14 (0.69) 92.53 (68.22) 1364 (730) 117.5 (43.5) 25.82 (9,56) 4.03 (0.76) 103.5 (69.9) 69.7 (27.4) 772.9 (334.0) 3.65 (2.10)
1841 (1082) 70.1 (23.2) 0.228 (0.047) 0.55 (0.18) 1.30 (0.79) 69.51 (29.99) 1034 (362) 220.1 (52.5)# 21.24 (9.55) 3.85 (1.11) 95.8 (22.9) 70.5 (35.4) 742.0 (303.2) 10.53 (12.67)
2256 (686) 58.5 (13.4) 0.241 (0.049) 0.81 (0.54) 1.44 (1.31) 55.54 (17.71) 939 (551) 158.7 (55.1) 22.83 (8.41) 3.92 (1.58) 67.7 (29.8) 87.1 (128.6) 685.5 (291.0) 3.82 (2.17)
2047 (444) 60.9 (29.5) 0.287 (0.095) 1.63 (1.37) 0.77 (0.54) 54.24 (15.19) 1076 (201) 211.6 (46.2)# 21.36 (3.88) 2.69 (0.80)# 87.8 (55.1) 57.3 (32.1) 670.7 (295.3) 3.78 (2.30)
0.492 0.262 0.323 0.181 0.442 0.173 0.173
Vitamin E and essential polyunsaturated fatty acids supplementation in schizophrenia patients treated with haloperidol Marija Bošković 1, Tomaž Vovk1, Jure Koprivšek 2, Blanka Kores Plesnicˇ ar3, Iztok Grabnar1 1
Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia, 2Department of Psychiatry, University Clinical Centre Maribor, Maribor, Slovenia, 3University Psychiatric Clinic Ljubljana, Ljubljana, Slovenia Objectives: Previously, oxidative damage has been associated with severity of clinical symptoms and supplementation with antioxidants and essential polyunsaturated fatty acids (EPUFAs) was proposed to have beneficial effects in schizophrenia. We evaluated the effects of supplementation with EPUFAs and vitamin E in patients treated with haloperidol depot injection. Design: This was a double-blind randomized placebo-controlled study with four arms (Placebo, vitamin E, EPUFAs, and vitamin E + EPUFAs). Biomarkers of oxidative stress, neurochemistry, psychopathology, and extrapyramidal symptoms were assessed at baseline and after 4 months. Results: In EPUFAs group of patients, reduced glutathione concentration was increased compared to placebo. Concentration of oxidized glutathione was decreased in patients receiving vitamin E. In addition, compared to placebo a non-significant trend of increased activity of catalase and superoxide dismutase was observed in all three treatment groups. Patients receiving vitamin E experienced less motor retardation. No difference in extrapyramidal symptoms was found. Discussion: Our study indicates that supplementation with vitamin E and EPUFAs may improve the antioxidative defense, especially glutathione system, while there is no major effect on symptoms severity. Supplemental treatment with EPUFAs and vitamin E in schizophrenia patients treated with haloperidol is potentially beneficial and a larger independent study appears warranted. Keywords: Schizophrenia, Essential polyunsaturated fatty acids, Vitamin E, Haloperidol, Oxidative stress
Introduction Oxidative stress is involved in pathophysiology of schizophrenia.1 Potential mechanisms include dopamine oxidation, mitochondrial electron transport chain, genetic factors, and antipsychotic treatment.2 Reactive species (RS) mediated abnormalities may contribute to the development of clinically significant consequences, like worsening of psychopathology and extrapyramidal symptoms.3 Involvement of oxidative stress in schizophrenia suggests potential benefits of supplementation with antioxidants, such as vitamin E.1 In addition, reduced levels of essential polyunsaturated fatty acids (EPUFAs) were found in the brain and red blood cell membranes of schizophrenia patients, indicating that dysfunctional fatty acid Correspondence to: Iztok Grabnar, Faculty of Pharmacy, University of Ljubljana, Asˇ kercˇ eva cesta 7, Ljubljana SI-1000, Slovenia. Email: [email protected]
© W. S. Maney & Son Ltd 2014 DOI 10.1179/1476830514Y.0000000139
metabolism could be involved in the etiology of the disorder.4 Previous studies on the effects of vitamin E and EPUFAs supplementation in schizophrenia are inconclusive.2 We have previously investigated the role of oxidative stress in schizophrenia and involvement of genetic factors.5,6 Here, we report on a pilot randomized double-blind, placebo-controlled study in the same patients, which aimed to assess the benefits of supplementation with EPUFAs, vitamin E, and their combination. Biomarkers of oxidative stress, neurochemistry, psychopathology, and extrapyramidal symptoms were evaluated at baseline and after 4 months of supplementation. According to our knowledge, there was no previously published study with this design in a treatment homogeneous group of patients, which would evaluate such variety of biomarkers and psychiatric rating scales in schizophrenia patients.
Nutritional Neuroscience
2014
VOL.
0
NO.
0
1
Bošković et al.
Vitamin E and EPUFAs supplementation in schizophrenia patients
Methods Patients
noradrenaline, adrenaline, dopamine, and serotonin were performed as previously described.6
Fifty-two schizophrenia outpatients of the Caucasian origin with a minimum 3-year duration of illness were recruited. All patients were diagnosed based on a structured clinical interview according to Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV). Patients were receiving their regular therapy of intramuscular haloperidol decanoate (4.2–50 mg/week) for at least 6 months, and concomitantly 14 patients were given oral dose of haloperidol (2–30 mg/day). Based on complete medical history and physical examination, all subjects were physically healthy. The available hospital records and patient interviews were used to determine demographic data, concomitant medication, smoking status, alcohol consumption data, and use of food supplements. The study was approved by the National Medical Ethics Committee of the Republic of Slovenia and was performed in accordance with the ethical standards set by Declaration of Helsinki. The study was registered in EU Clinical Trials Register (EudraCT number: 2009-018054-33).
Study design This was a double-blind randomized placebo-controlled study with four arms (placebo, vitamin E, EPUFAs, and vitamin E + EPUFAs). Vitamin E group of patients was treated with Apozema®, Vitamin E 600 IU soft gelatin capsules (Apomedica, Graz, Austria) twice daily. Patients in the EPUFAs group were treated with Omega-3 Forte soft gelatin capsules, Dr Böhm®, Apomedica (eicosapentaenoic acid (EPA) 132 mg, docosahexaenoic acid 88 mg, alpha-linoleic acid 94 mg, and oleic acid 52 mg) three capsules per day. Patients were instructed to take two capsules in the morning and one in the evening after a meal. Patients from vitamin E + EPUFAs group received both treatments as described above. Lactose (500 mg) hard gelatin capsules were used as placebo. Patients were instructed to return their unused capsules at monthly visits for assessment of compliance and were reassessed after 4 months of treatment. Study intervention did not influence the usual antipsychotic therapy in any way other than explained above.
Sample collection and biochemical measurements At baseline and after 4 months, venous blood sample was drawn and plasma was prepared immediately by centrifugation. Biochemical measurements, including superoxide dismutase (SOD), glutathione peroxidase (GpX), glutathione reductase (GR), catalase (CAT), reduced (GSH) and oxidized (GSSG) forms of glutathione, protein carbonyls (PC), malondialdehyde (MDA), nitrates (NO3) and nitrites (NO2), 2
Nutritional Neuroscience
2014
VOL.
0
NO.
0
Clinical assessment Psychopathology was evaluated by experienced psychiatrists by positive and negative symptoms scale (PANSS). Extrapyramidal symptoms were assessed with abnormal involuntary movement scale (AIMS) for tardive dyskinesia, Simpson Angus scale (SAS) for Parkinsonism, and Barnes akathisia rating scale (BARS) for akathisia.
Statistical analysis Differences between parameter values after 4 months of treatment and at baseline were used for comparison of treatment effects. Significance level was set at P < 0.05. Between-group differences in continuous variables were evaluated by one-way analysis of variance (ANOVA), followed by Dunnett’s test for post hoc pairwise comparisons. In addition, analysis of covariance (ANCOVA) controlling for baseline parameter values was used. Kruskal–Wallis tests were used for comparison of psychopathology and extrapyramidal symptoms data. Mann–Whitney U tests with Holm’s sequential method for control of type I error were conducted for subsequent pairwise comparisons. Between-group differences in categorical data were assessed by Chisquare test. Statistical analyses were carried out using SPSS version 20 (IBM SPSS, Chicago, IL, USA). The sample size was calculated using G*Power 3.1.6 (Institute for Experimental Psychology, Heinrich Heine University Dusseldorf, Germany, http:// www.psycho.uni-duesseldorf.de/abteilungen/aap/ gpower3/). A sample size of 60 subjects randomly assigned to four groups was calculated for one-way ANOVA using an effect size of 0.4 to provide 0.7 power with α error probability set at 0.05.
Results Characterization of patients Of the 52 patients included in the study, 34 completed the supplementation treatment and were included in statistical evaluation (Table 1). At initiation of the study, no significant difference was found between the groups in regard to age, gender, smoking status, weight, duration of illness, and dose of haloperidol (assuming relative oral bioavailability of 65%). In addition, at baseline the four groups did not differ in psychopathology and extrapyramidal symptoms. Summary of biomarkers of oxidative stress and neurotransmitters are presented in Table 2. Biomarkers of oxidative stress and neurotransmitters at baseline were comparable between the groups of patients, except for GSSG and GR. Mean (SD) compliance for all four groups was 92 (13) %.
Bošković et al.
Vitamin E and EPUFAs supplementation in schizophrenia patients
Table 1 Demographic and clinical characteristics of the patients
Age (years)* Gender M/F (n, %)† Smokers (n, %)† Number of cigarettes per day*,‡ Weight (kg)* Duration of illness (months)* Haloperidol dose (mg/week)* PANSS§ Positive subscale Negative subscale General subscale Total score SAS§ AIMS§ BARS§
Total (n = 34)
Placebo (n = 11)
Vitamin E (n = 5)
EPUFAs (n = 9)
Vitamin E + EPUFAs (n = 9)
P- value
50.2 (9.2) 17/17, 50/50 15, 44 14 (14) 81.6 (24.4) 186 (87) 36.5 (38.9)
45.6 (8.7) 4/7, 36/64 4, 36 15 (14) 82.4 (18.2) 190 (116) 37.2 (26.1)
45.8 (4.1) 3/2, 60/40 3, 60 13 (19) 88.1 (26.2) 132 (136) 21.7 (10.8)
53.6 (8.7) 4/5, 44/56 4, 44 16 (17) 79.1 (40.0) 201 (94) 30.0 (38.9)
54.8 (9.6) 6/3, 67/33 4, 44 12 (12) 79.6 (8.1) 184 (18) 50.3 (58.4)
0.055 0.546 0.854 0.932 0.922 0.826 0.568
9 (7, 23) 18 (7, 30) 27 (16, 52) 56 (34, 99) 3 (0, 14) 0 (0, 12) 0 (0, 5)
11 (7, 20) 18 (7, 28) 28 (20, 43) 56 (35, 84) 3 (2, 11) 0 (0, 12) 0 (0, 5)
7 (7, 10) 16 (7, 22) 21 (19, 33) 44 (34, 65) 1 (0, 12) 0 (0, 2) 1 (0, 3)
9 (7, 23) 22 (8, 30) 27 (19, 52) 58 (34, 99) 3 (0, 14) 0 (0, 10) 0 (0, 5)
9 (7, 20) 14 (9, 29) 22 (16, 43) 43 (35, 90) 3 (0, 12) 1 (0, 11) 1 (0, 5)
0.228 0.716 0.787 0.670 0.906 0.559 0.660
*Continuous data are presented as mean (SD), P-value indicates one-way significance by ANOVA. Categorical data reported as number, percentage of patients, P-value indicates between-group significance by Chi-square test. ‡ Subgroup of patients who smoke. § Ordinal data presented as median (range), P-value indicates between-group significance by Kruskal–Wallis test. AIMS, abnormal involuntary movements scale; BARS, Barnes akathisia rating scale; PANSS, positive and negative symptoms scale; SAS, Simpson Angus scale. †
Treatment effect on biomarkers of oxidative stress and neurochemistry Treatment effect on biomarkers of oxidative stress and neurotransmitters are presented in Table 3. Compared to placebo group of patients, blood concentration of GSH was significantly increased in EPUFAs-treated patients (P = 0.044). Similar non-significant trend of increase was also observed in vitamin E (P = 0.115) and vitamin E + EPUFAs (P = 0.075) groups of patients. Furthermore, compared to placebo, blood concentration of GSSG was reduced in patients receiving vitamin E (P = 0.004). This difference remained significant (P = 0.004), when the effect was evaluated by ANCOVA corrected for baseline GSSG concentration. Similar non-significant trends were observed for SOD and CAT. After 4 months of treatment, activities of both of these enzymes decreased in
placebo group of patients, while there was an increase in groups of patients treated with vitamin E, EPUFAs, and their combination (Table 3). In addition, we observed a significant effect of treatment on plasma serotonin concentration (Table 3). Mean concentration of serotonin was decreased in group of patients treated with vitamin E, while in patients treated with EPUFAs concentration of serotonin was increased (Bonferroni test P = 0.027). However, compared to placebo treatment the differences in both groups were non-significant.
Treatment effect on psychopathology of schizophrenia and extrapyramidal symptoms No effect of treatment was found on PANSS total score, as well as on PANSS positive, negative, and general subscores. However, comparison of motor
Table 2 Summary of baseline biomarkers of oxidative stress and neurotransmitters according to treatment groups
SOD (U/g Hb) CAT (U/g Hb) MDA (μmol/l) PC (nmol/mg protein) NO2 (μmol/l) NO2 + NO3 (μmol/l) GSH (μmol/l) GSSG (μmol/l) GpX (U/g Hb) GR (U/g Hb) Dopamine (ng/l) Adrenaline (ng/l) Noradrenaline (ng/l) Serotonin (μg/l)
Total (n = 34)
Placebo (n = 11)
Vitamin E (n = 5)
EPUFAs (n = 9)
Vitamin E + EPUFAs (n = 9)
P- value
2161 (629) 68.1 (27.8) 0.252 (0.066) 1.23 (1.14) 1.15 (0.88) 69.21 (44.10) 1127 (540) 168.4 (63.0) 23.17 (7.96) 3.62 (1.19) 88.7 (51.9) 71.1 (69.0) 718.2 (297.7) 4.74 (5.40)
2321 (450) 80.9 (34.3) 0.244 (0.053) 1.54 (1.37) 1.14 (0.69) 92.53 (68.22) 1364 (730) 117.5 (43.5) 25.82 (9,56) 4.03 (0.76) 103.5 (69.9) 69.7 (27.4) 772.9 (334.0) 3.65 (2.10)
1841 (1082) 70.1 (23.2) 0.228 (0.047) 0.55 (0.18) 1.30 (0.79) 69.51 (29.99) 1034 (362) 220.1 (52.5)# 21.24 (9.55) 3.85 (1.11) 95.8 (22.9) 70.5 (35.4) 742.0 (303.2) 10.53 (12.67)
2256 (686) 58.5 (13.4) 0.241 (0.049) 0.81 (0.54) 1.44 (1.31) 55.54 (17.71) 939 (551) 158.7 (55.1) 22.83 (8.41) 3.92 (1.58) 67.7 (29.8) 87.1 (128.6) 685.5 (291.0) 3.82 (2.17)
2047 (444) 60.9 (29.5) 0.287 (0.095) 1.63 (1.37) 0.77 (0.54) 54.24 (15.19) 1076 (201) 211.6 (46.2)# 21.36 (3.88) 2.69 (0.80)# 87.8 (55.1) 57.3 (32.1) 670.7 (295.3) 3.78 (2.30)
0.492 0.262 0.323 0.181 0.442 0.173 0.173
