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Dr. Bob is Robert Hsiung, MD,
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Posted by jrbecker on October 19, 2005, at 12:02:19
Psychopharmacology
© Springer-Verlag 2005
10.1007/s00213-005-0117-1
Supplementation of vitamin C with atypical antipsychotics reduces oxidative stress and improves the outcome of schizophreniaG. N. Dakhale1, S. D. Khanzode1, 2 , S. S. Khanzode3 and A. Saoji4
(1) Department of Pharmacology, Government Medical College, Nagpur, India
(2) 46, S.E. Rly Colony (1), Venkatesh Apartment, Pratap Nagar, Nagpur, Maharashtra, 440 022, India
(3) Biochemist in Medicine, Government Medical College, Nagpur, India
(4) Department of Psychiatry, Government Medical College, Nagpur, IndiaReceived: 3 February 2005 Accepted: 27 June 2005 Published online: 19 October 2005
Abstract
Rationale Several investigators implicated role of free radical-mediated pathology in schizophrenia. No study has ever examined the effect of vitamin C with atypical antipsychotics in the treatment of schizophrenia.
Objective The aim of this study was to examine the effect of oral vitamin C with atypical antipsychotics on serum malondialdehyde (MDA), plasma ascorbic acid levels, and brief psychiatric rating scale (BPRS) score in schizophrenic patients.
Method Forty schizophrenic patients participated in a prospective, double-blind, placebo-controlled, noncrossover, 8-week study. The patients with schizophrenia were divided randomly into placebo and vitamin C group of 20 each. Serum MDA and plasma ascorbic acid were estimated by methods of Nischal and Aye, respectively.
Result Increased serum MDA and decreased plasma ascorbic acid levels were found in schizophrenic patients. These levels were reversed significantly after treatment with vitamin C along with atypical antipsychotics compared to placebo with atypical antipsychotics. BPRS change scores at 8 weeks improved statistically significant with vitamin C as compared to placebo.
Conclusion Oral supplementation of vitamin C with atypical antipsychotic reverses ascorbic acid levels, reduces oxidative stress, and improves BPRS score, hence both the drugs in combination can be used in the treatment of schizophrenia.
Keywords Schizophrenia - Vitamin C - Atypical antipsychotics - Oxidative stress - BPRS score
--------------------------------------------------------------------------------Introduction
Schizophrenia is one of the major mental disorders associated with great deal of morbidity and economic cost. The illness has a poor outcome in spite of the best currently available treatments. Hence, development of novel strategies to improve outcome will be of great benefit. Several investigators have implicated role of free radical-mediated pathology in schizophrenia. Abnormal activities of critical antioxidant enzymes (Altuntas et al. 2000; Vaiva et al. 1994; Reddy et al. 1991) and other indices of lipid peroxidation (Kuloghi et al. 2002; Mahadik et al. 1995) in plasma and RBCs have been detected in schizophrenic patients. Brain contains large amount of unsaturated fatty acids, catecholamines and monoamines, which are the target molecules for lipid peroxidation (Arvindakshan et al. 2003a). It is rich in iron and produces highly damaging hydroxyl radicals to begin lipid peroxidation. Monoamine and catecholamine oxidation also produces superoxide anions in the brain (Fridovich 1983).Ascorbic acid, an antioxidant vitamin, plays an important role in protecting free radical-induced damage in the brain. It is present in the brain tissue and dopamine-dominant areas at high concentrations compared to other organs (Seregi et al. 1978; Oke et al. 1987). Recently, Arvindakshan et al. (2003b) reported reduction in brief psychiatric rating scale (BPRS) and positive and negative syndrome scale (PANSS) score after supplementation with omega-3 fatty acids, vitamin C, and vitamin E. However, no study has ever examined the effect of vitamin C with atypical antipsychotics in the treatment of schizophrenia. Thus, the main objective of this study is to evaluate whether the oral supplementation of vitamin C with atypical antipsychotics would improve clinical symptoms and reduces the imbalance between reactive oxygen species and antioxidant defense in schizophrenic patients. Therefore, the present study was designed to measure the effect of vitamin C along with atypical antipsychotics on levels of serum malondialdehyde (MDA), plasma ascorbic acid, and BPRS score in schizophrenic patients.
--------------------------------------------------------------------------------Materials and methods
Patients
Forty schizophrenic patients participated in a prospective, double-blind, placebo-controlled, noncrossover, 8-week study approved by Institutional Ethics Committee of Government Medical College and Hospital, Nagpur, India (GMCHNI). The trial procedure was in accordance with the guidelines of 1964 Declaration of Helsinki. All patients gave their informed consent prior to their inclusion in the study.The inclusion criteria were patients from Outpatient Department of Psychiatry, GMCHNI. All patients were newly diagnosed, and none of them were in acute severe state and required hospitalization. Diagnosis of schizophrenia was made using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria. Each patient underwent diagnostic evaluation by one trained psychiatrist on the basis of a semistructured interview to determine DSM-IV diagnosis. The 18 item BPRS for schizophrenia was used to measure the severity of schizophrenia (Overall and Gorham 1962). Scoring system used was 06. None of the subjects was a regular drinker, heavy smoker, or had been taking any psychotropic drug. Exclusion criteria for patients were medical illnesses including endocrine, metabolic or autoimmune disorders known to affect free radical status. Routine investigations like lipid profile, electrocardiogram, serum electrolytes, blood urea, serum creatinine, and liver function tests were performed to rule out active medical problems in all patients.
Schizophrenic patients were divided randomly into two groups, A and B, of 20 each. Randomization was blocked and done by using computer program to generate sequence of random numbers and assign each patient randomly to either group A or group B. Patients were given medicine in coded form as capsule, to be taken one capsule a day, preferably in the morning for 8 weeks. All medicines were identical in formulation, shape, size, weight, color, and packing. The drug was issued to patients for duration of 30 days at a time. The patients were asked to bring the unused drugs and container during the follow up. Eighty percent consumption was considered to be compliant. The returned drugs were discarded. The drugs were decoded at end of the trial. Group A received placebo with atypical antipsychotics, and group B received vitamin C along with atypical antipsychotics. The dose of vitamin C was 500 mg/day and decided on the basis of previous study.
All the patients received atypical antipsychotics: olanzapine (10 mg/day) or quetiapine (200 mg/day) or ziprasidone (40 mg/day) along with coded drug, as it is unethical to give either placebo or vitamin C only to schizophrenic patients. In our preliminary experiment, it was determined that subjects reached a new lower steady-state plasma concentration after 1 week on controlled diet. Placebo or vitamin C supplementation was started after 1 week of vitamin C restricted diet. Patients were given a new supply of capsule at the end of each 4-week. Of the 40 patients entered in the trial, 5 were withdrawn (4 in placebo group, 1 in vitamin C group). The most common cause was failure to reattend and increase in dose of the drug. One patient was dropped out in placebo group because of nonresponse to the ziprasidone at the end of 4 weeks and was shifted to the other drug. Same doses were maintained throughout the study.
All patients were maintained on their usual dietary pattern while limiting their consumption of vitamin C-rich foods throughout the study. As patients were on self-selected diets, each patient was instructed by a dietician to use comprehensive food list that contained food items by type, portion size, method of preparation, and vitamin C content. This enabled patients to substitute foods with low-vitamin C content for those they might normally consume containing higher levels of vitamin C and also to ensure that their daily intake from dietary sources would remain the same. Compliance to the dietary restriction of ascorbic acid was determined by obtaining a 24-h dietary recall from the subjects on two occasions during each 1-month period.
Hematology, blood chemistry, and liver and kidney function tests were repeated after 4 and 8 weeks. Fasting blood samples for the assessment of serum MDA and plasma ascorbic acid were obtained at baseline (1 week after vitamin C-restricted diet) and after 4 and 8 weeks. No serious adverse event was reported, and no abnormalities in laboratory test were found during trial period. Serum MDA estimation was carried out using clear serum incubated in trichloroacetic acid and thiobarbituric acid, and the mixture was heated in boiling water bath for 30 min (Kei 1978). Resulting chromogen was extracted with n-butanol, the absorbance of which was measured at 530 nm. MDA was expressed as micromoles per liter of serum. Plasma ascorbic acid was estimated by a single-step-colorimetric method using modified acid phosphotungstate reagent (Aye 1978). Fresh plasma was slowly mixed with the modified acid phosphotungstate and incubated at room temperature for 30 min and then centrifuged. Supernatant was used to measure absorbance at 700 nm. Standards of pure ascorbic acid obtained from Sigma Company, USA, in the range of 0.10 to 0.90 mg% were prepared in 0.5% oxalic acid solution. For every set, standard and blanks were run throughout the procedure. For all the investigations, chemicals used were of analytical reagent grade.
Results were expressed as Mean±SD. Intention to treat analysis was performed. Group differences were ascertained by unpaired t test or repeated measures one-way ANOVA followed by NewmanKeuls post-hoc test. Relationship between variables was determined by means of either Pearson's or Spearman's correlation coefficient depending on distribution of the data. Chi-square test was used for analysis of demographic data. Two-tailed p value was used throughout, and the p value less than 0.05 was adjudged statistically significant. Statistical calculations were done using Graph Pad Prism, Version 3.02.
--------------------------------------------------------------------------------Results
The mean age of the schizophrenic patients in placebo group (36.3±12.8 years) and vitamin C group (40.8±10.2 years) was not significantly different from each other. BPRS score, serum MDA, and plasma ascorbic acid levels did not differ among subjects before receiving placebo and vitamin C treatment (p>0.05). Commonly observed items in BPRS scores were suspiciousness, hostility, excitement, and somatic concern.In placebo group, levels of serum MDA reduced significantly (p<0.05) and at the same time, levels of plasma ascorbic acid increased significantly (p<0.05) after 8 weeks of treatment compared to pretreatment levels. Reductions in BPRS scores were first apparent and significant by week 4 (p<0.01) and continued progressively throughout the 8-week treatment period (Table 1).
Table 1 Effect of atypical antipsychotics with placebo and vitamin C on serum MDA, plasma ascorbic acid, and BPRS score in patients of schizophrenia at different treatment intervals
Parameter
Before treatment (I)
After treatment
df
F ratio
p (ANOVA)
4 weeks (II)
8 weeks (III)
Group A
Serum MDA
6.66±1.37
6.35±1.12
6.10±0.81*
2,57
4.35
<0.05
Plasma AA
20.41±2.84
21.08±2.27
22.79±2.27*
2,57
3.61
<0.05
BPRS score
35.90±5.41
31.76±5.82**
28.96±6.16***
2,57
18.34
<0.001
Group B
Serum MDA
6.30±0.76
5.60±0.56
4.33±0.78
2,57
38.02
<0.001
Plasma AA
21.51±2.84
24.29±3.95
33.54±2.84
2,57
69.45
<0.0001
BPRS score
36.65±5.78
33.23±5.25
19.30±5.46
2,57
63.36
<0.0001
Group A, placebo with atypical antipsychotics; Group B, vitamin C with atypical antipsychotics. MDA and ascorbic acid are measured in micromoles per liter
n=20 in each group
df degree of freedom
*<0.05 (I vs. III), **<0.01 (I vs. II), ***<0.001 (I vs. III) by using NeumanKeuls post-hoc test
<0.05(I vs. II); <0.01 (I vs. II); <0.001 (I vs. III) by using NeumanKeuls post-hoc test
In patients receiving vitamin C, reduction in serum MDA levels was significant at week 4 (p<0.05) and decreased progressively at week 8. However, highly significant difference was observed in plasma ascorbic acid levels (p<0.01) after 4 weeks. This improvement with vitamin C treatment was maintained during the subsequent 8 weeks of the study (p<0.001) (Table 1). BPRS scores improved significantly after 4 (p<0.01) and 8 weeks (p<0.001) with vitamin C treatment.To test whether oral supplementation of vitamin C is better in reversing symptoms and biochemical parameters as compared to placebo, we compared effects of drugs in placebo group and vitamin C group after 8 weeks of treatment, taking into consideration the change from baseline values of these parameters. Decrease in serum MDA levels (p<0.01) and reduction in BPRS score (p<0.01) was significant after 8 weeks in vitamin C group compared to placebo group. In contrast, supplementation of vitamin C increased plasma ascorbic acid significantly in vitamin C group (p<0.001) compared to placebo group (Table 2).
Table 2 Comparison of effects of atypical antipsychotics with placebo and in combination with vitamin C on serum MDA, plasma ascorbic acid, and BPRS score at 8 weeks in schizophrenia taking into account the change from baseline
Parameter
Change from baseline at 8 weeks
p (unpaired)
Placebo
Vitamin C
Serum MDA
−0.67±1.03
−1.96±1.22
<0.01
Plasma AA
3.40±1.13
11.36±3.40
<0.001
BPRS score
−6.93±4.82
−14.79±4.87
<0.01
MDA and ascorbic acid are measured in micromoles per liter
n=20 in each group
Significant and negative correlation was found between plasma ascorbic acid levels and BPRS score (r=−0.38, p<0.05). However, no correlation existed between serum MDA and plasma ascorbic acid levels and serum MDA and BPRS score.
--------------------------------------------------------------------------------Discussion
The results of this study are in agreement with our previously published data showing that atypical antipsychotics decreased serum MDA and increased plasma ascorbic acid levels in schizophrenic patients (Dakhale et al. 2004). Although exact mechanism is not known, direct effect of drugs on lipid peroxidation or indirect effect through alteration in superoxide and hydroxy radical formation could not be ruled out. Atypical antipsychotic like clozapine seems to increase 5-hydroxyindol acetic acid (5-HIAA), which is excellent scavenger of hydroxyl and superoxide radicals (Blakely et al. 1984; Liu and Mori 1993). 5-HIAA is also known to inhibit ascorbate-induced lipid peroxidation in rat brain homogenate (Sen and Hanninen 1994). These metabolites chelate iron ion to stop or slowdown iron participation in lipid peroxidation and iron catalyzed Haber Hess reaction (Liu and Mori 1993). Increase in ascorbic acid levels could be attributed to inhibition of lipid peroxidation and decreased formation of MDA; as a result, less ascorbic acid is required to scavenge free radicals.Primary finding of the present study is significant decrease in serum MDA and increase in plasma ascorbic acid levels after vitamin C supplementation along with atypical antipsychotics as compared to placebo with atypical antipsychotics. To the best of our knowledge, this is the first report related to lipid peroxidation and plasma ascorbic levels in schizophrenic patients after concomitant use of atypical antipsychotics and vitamin C. BPRS score is significantly reduced after supplementation of vitamin C compared to placebo as substantiated by significant and negative correlation between BPRS score and plasma ascorbic acid levels in the present study. Recently, one study demonstrated reduction in BPRS and PANSS and increase in Henrich's quality of life scale score after supplementation with omega-3 fatty acids, vitamin C, and vitamin E (Arvindakshan et al. 2003b). Moreover, the present study provides evidence of relationship between plasma ascorbic acid levels and clinical response prior to and after the treatment with vitamin C along with atypical antipsychotics. Because patients receiving atypical antipsychotics also claimed similar improvements, it is difficult to say whether this beneficial effect of ascorbic acid supplements could be attributed to its effects on the underlying disease or rather to the correction of the inadequate vitamin C nutrition status. The exact mechanism by which vitamin C brings about these changes is not known. Ascorbic acid inhibits binding at the agonist site of dopamine receptor (Hadjiconstanttinou and Neff 1983). If this is the case, a high concentration of ascorbic acid should reduce the action of dopamine and, at the same time, potentiate the effects of drugs that act at an antagonist site. Our results with atypical antipsychotics support this view. Thus, an ascorbic acid-induced regulation of the dopamine receptor may have functional consequences. Our results do not rule out a metabolic or pharmacokinetic interaction between ascorbic acid and atypical antipsychotics. In either case, results of the present study point to ascorbic acid as critical in modulating behavioral effects of atypical antipsychotics. Ascorbic acid may inhibit peroxidation of membrane phospholipids and acts as a scavenger of free radicals (Englard and Seifter 1986; Padh 1990). Ascorbic acid is a water-soluble ketoacetone. It plays a crucial role in the suppression of superoxide radicals by blocking catecholamine autooxidation (Cadet and Brannock 1997) thereby inhibiting formation of potential toxic by-products such as 6-hydroxy dopamine (6-OHDA), semiquinone, hydrogen peroxide, and hydroxyl radical, eventually leading to neuronal damage in the brain and development of defect symptoms (Cadet and Lohr 1987). This could be one of the reasons for reduction in BPRS score after vitamin C supplementation.
Although the mechanism of ascorbic acid transport is unknown, it has been proposed that after oxidation, dehydroascorbic acid enters the cell and is reduced intracellularly to ascorbic acid (Vera et al. 1993; Washko et al. 1993). In brain cells, dehydroascorbic acid is immediately reduced to ascorbic acid, which acts as an antioxidant. The present study has few limitations (a) sample size is small and (b) the study only examined peripheral biochemical indices.
Treatment with vitamin C with atypical antipsychotics was well tolerated and devoid of any side effect. The absence of any substantial side-effects, cheaper cost, improvement in BPRS score, and the fact that plasma ascorbic acid levels are decreased in schizophrenia and increases after oral supplementation make it a particularly attractive therapeutic adjuvant in the treatment of schizophrenia.
The study complies with current laws of the country.
--------------------------------------------------------------------------------
References
Altuntas I, Aksoy H, Coskun I, Caykoylu A, Akcay F (2000) Erythrocyte superoxide dismutase and glutathion paraoxidase activities and malondealdehyde and reduced glutathione levels in schizophrenic patients. Clin Chem Lab Med 38:12771281
Arvindakshan M, Sitasawad S, Debsikdar V, Ghate M, Evans D, Horrobin DF, Bennett C, Ranjekar PK, Mahadik SP (2003a) Essential polyunsaturated fatty acid and lipid peroxide levels in never-medicated and medicated schizophrenia patients. Biol Psychiatry 53:5664
Arvindakshan M, Ghate M, Ranjekar PK, Evans DR, Mahadik SP (2003b) Supplementation with a combination of omega 3 fatty acids and antioxidants (vitamin E and C) improves the outcome of schizophrenia. Schizophr Res 62:195204
Aye K (1978) A simple colorimetric method for ascorbic acid determination in blood plasma. Clin Chim Acta 86:153157
Blakely RD, Wages SA, Justice JB, Hernbon JB, Neill DB (1984) Neuroleptics increase striatal catecholamines metabolites but not ascorbic acid in dialyzed perfusate. Brain Res 308:16
Cadet JL, Brannock C (1997) Invited review-free radicals and pathobiology of brain dopamine system. Neurochem Int 32:117131
Cadet JL, Lohr JB (1987) Free radicals and developmental biopathology of schizophrenic burnout. Integr Psychiatr 51:4048
Dakhale G, Khanzode SD, Khanzode SS, Saoji A, Khobragade L, Turankar A (2004) Oxidative damage and schizophrenia: the potential benefit by atypical antipsychotics. Neuropsychobiology 49:205209
Englard S, Seifter S (1986) The biochemical functions of ascorbic acid. Annu Rev Nutr 6:365406
Fridovich I (1983) Superoxide radical: an endogenous toxicant. Annu Rev Pharmacol Toxicol 23:239257
Hadjiconstanttinou M, Neff NH (1983) Ascorbic acid could be hazardous to your experiments: a commentary on dopamine receptor binding studies with speculation on a role for ascorbic acid in neuronal function. Neuropharmacology 22:939946
Kei S (1978) Lipid peroxides in cerebrovascular disorders determined by new colorimetric method. Clin Chim Acta 90:3743
Kuloghi M, Ustundag B, Atmaca M, Canatan H, Tezean AE, Cinkiline N (2002) Lipid peroxidation and antioxidant enzyme levels in patients with schizophrenia and bipolar disorder. Cell Biochem Funct 20:171175
Liu J, Mori A (1993) Monoamine metabolism provides an antioxidant defense in the brain against oxidant and free radical induced damage. Arch Biochem Biophys 302:118127
Mahadik SP, Mukherjee S, Correnti I, Sheffer R (1995) Elevated levels of lipid peroxidation products in plasma from drug-naive patients at onset of psychosis. Schizophr Res 15:6670
Oke AI, May L, Adams RN (1987) Ascorbic acid distribution pattern in human brain. In: Bums JJ, Reverse JM, Machlin LJ (eds) Third conference on Vit C. Ann NY Acad Sci pp 112
Overall JE, Gorham DR (1962) The brief psychiatric rating scale. Psychol Rep 10:799812
Padh H (1990) Cellular functions of ascorbic acid. Biochem Cell Biol 68:11661173
Reddy R, Mahadik SP, Mukherjee M, Murty JN (1991) Enzymes of the antioxidant system in chronic schizophrenic patients. Biol Psychiatry 30:409412
Sen CK, Hanninen O (1994) Physiological antioxidants. In: Sen CK, Packer L, Hanninen O (eds) Exercise and oxygen toxicity. Elsevier Science Publishers, B.V., Amsterdam
Seregi A, Schaefer A, Komlos M (1978) Protective role of brain ascorbic acid content against lipid peroxidation. Experientia 34:10561057
Vaiva G, Thomas P, Leroux JM (1994) Erythrocyte superoxide dismutase determination in positive moments of psychosis. Therapie 49:343348
Vera JC, Rivas CI, Fischbarg J (1993) Mammalian facilitative hexose transporters mediate the transport of dehydroascorbic acid. Nature 364:7982
Washko PW, Wanw Y, Levine M (1993) Ascorbic acid recycling in human neutrophils. J Biol Chem 268:1553115535
Posted by linkadge on October 25, 2005, at 11:35:11
In reply to Vit C Supplementation Improves Outcome in Schizoph, posted by jrbecker on October 19, 2005, at 12:02:19
We need more studys like this.
One of the main alternative treatments for schitsophrenia is vitamin C, and Niacin.
Vitamin C, alone, has antipsychotic properties that need to be investegated further.
Linkadge
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