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Meta-Analysis
. 2016 Feb 5;2(2):CD008919.
doi: 10.1002/14651858.CD008919.pub2.

Antioxidant treatments for schizophrenia

Pedro V S Magalhães  1 , Olivia Dean, Ana C Andreazza, Michael Berk, Flávio Kapczinski
Affiliations
Meta-Analysis

Antioxidant treatments for schizophrenia

Pedro V S Magalhães et al. Cochrane Database Syst Rev. .

Abstract

Background: There is accumulating evidence that progressive changes in brain structure and function take place as schizophrenia unfolds. Among many possible candidates, oxidative stress may be one of the mediators of neuroprogression, grey matter loss and subsequent cognitive and functional impairment. Antioxidants are exogenous or endogenous molecules that mitigate any form of oxidative stress or its consequences. They may act from directly scavenging free radicals to increasing anti-oxidative defences. There is evidence that current treatments impact oxidative pathways and may to some extent reverse pro-oxidative states in schizophrenia. The existing literature, however, indicates that these treatments do not fully restore the deficits in antioxidant levels or restore levels of oxidants in schizophrenia. As such, there has been interest in developing interventions aimed at restoring this oxidative balance beyond the benefits of antipsychotics in this direction. If antioxidants are to have a place in the treatment of this serious condition, the relevant and up-to-date information should be available to clinicians and investigators.

Objectives: To evaluate the effect of antioxidants as add-on treatments to standard antipsychotic medication for improving acute psychotic episodes and core symptoms, and preventing relapse in people with schizophrenia.

Search methods: We searched the Cochrane Schizophrenia Group's Study-Based Register of Trials which is based on regular searches of CINAHL, BIOSIS, AMED, Embase, PubMed, MEDLINE, PsycINFO, and registries of clinical trials. There are no language, time, document type, or publication status limitations for inclusion of records in the register. We ran this search in November 2010, and again on 8 January 2015. We also inspected references of all identified studies for further trials and contacted authors of trials for additional information.

Selection criteria: We included reports if they were randomised controlled trials (RCTs) involving people with schizophrenia who had been allocated to either a substance with antioxidant potential or to a placebo as an adjunct to standard antipsychotic treatment.

Data collection and analysis: We independently extracted data from these trials and we estimated risk ratios (RR) or mean differences (MD), with 95% confidence intervals (CI). We assessed risk of bias for included studies and created a 'Summary of findings' table using GRADE.

Main results: The review includes 22 RCTs of varying quality and sample size studying Ginkgo biloba, N-acetyl cysteine (NAC), allopurinol, dehydroepiandrosterone (DHEA), vitamin C, vitamin E or selegiline. Median follow-up was eight weeks. Only three studies including a minority of the participants reported our a priori selected primary outcome of clinically important response. Short-term data for this outcome (measured as at least 20% improvement in scores on Positive and Negative Syndrome Scale (PANSS)) were similar (3 RCTs, n = 229, RR 0.77, 95% CI 0.53 to 1.12, low quality evidence). Studies usually reported only endpoint psychopathology rating scale scores. Psychotic symptoms were lower in those using an adjunctive antioxidant according to the PANSS ( 7 RCTS, n = 584, MD -6.00, 95% CI -10.35 to -1.65, very low quality evidence) and the Brief Psychiatric Rating Scale (BPRS) (8 RCTS, n = 843, MD -3.20, 95% CI -5.63 to -0.78, low quality evidence). There was no overall short-term difference in leaving the study early (16 RCTs, n = 1584, RR 0.73, 95% CI 0.48 to 1.11, moderate quality evidence), or in general functioning (2 RCTs, n = 52, MD -1.11, 95% CI -8.07 to 5.86, low quality evidence). Adverse events were generally poorly reported. Three studies reported useable data for 'any serious adverse effect', results were equivocal (3 RCTs, n = 234, RR 0.65, 95% CI 0.19 to 2.27, low quality evidence). No evidence was available for relapse, quality of life or service use.

Authors' conclusions: Although 22 trials could be included in this review, the evidence provided is limited and mostly not relevant to clinicians or consumers. Overall, although there was low risk of attrition and selective data reporting bias within the trials, the trials themselves were not adequately powered and need more substantial follow-up periods. There is a need for larger trials with longer periods of follow-up to be conducted. Outcomes should be meaningful for those with schizophrenia, and include measures of improvement and relapse (not just rating scale scores), functioning and quality of life and acceptability and, importantly, safety data.

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Conflict of interest statement

Pedro Magalhães has no conflicts of interest. Olivia Dean has received grant support from the Brain and Behavior Foundation, Simons Autism Foundation, Stanley Medical Research Institute, Lilly, NHMRC and an ASBD/Servier grant. Anna Andreazza has no conflicts of interest. Michael Berk was the lead investigator for one potentially relevant study for the review (Berk 2008; Berk 2008a) , but did not extract data from these trials for this review. He has received grant/research support from the Stanley Medical Research Foundation, MBF, NHMRC, beyondblue, Geelong Medical Research Foundation, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Organon, Novartis, Mayne Pharma, Servier; has been a consultant/speaker for: Astra Zeneca, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Janssen Cilag, Lundbeck, Pfizer, Sanofi Synthelabo, Servier, Solvay, Wyeth. Professor Berk is co‐inventor on two provisional patents regarding the use of NAC and related compounds for psychiatric indications, which, whilst assigned to the Mental Health Research Institute, could lead to personal remuneration upon a commercialisation event. Flávio Kapczinski has received grant/research support from Astra‐Zeneca, Eli Lilly, the Janssen‐Cilag, Servier, CNPq, CAPES, NARSAD and the Stanley Medical Research Institute; has been a member of the speakers’ boards for Astra‐Zeneca, Eli Lilly, Janssen and Servier; and has served as a consultant for Servier.

Figures

1
1
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
2
2
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
3
3
Study flow diagram.
1.1
1.1. Analysis
Comparison 1 ADJUNCTIVE ANTIOXIDANTS versus PLACEBO, Outcome 1 Global state: No clinically important response (20% improvement PANSS).
1.2
1.2. Analysis
Comparison 1 ADJUNCTIVE ANTIOXIDANTS versus PLACEBO, Outcome 2 Leaving the study early: 1a. Short term.
1.3
1.3. Analysis
Comparison 1 ADJUNCTIVE ANTIOXIDANTS versus PLACEBO, Outcome 3 Leaving the study early: 1b. Medium term.
1.4
1.4. Analysis
Comparison 1 ADJUNCTIVE ANTIOXIDANTS versus PLACEBO, Outcome 4 Leaving the study early: 1c. Long term.
1.5
1.5. Analysis
Comparison 1 ADJUNCTIVE ANTIOXIDANTS versus PLACEBO, Outcome 5 Mental state: 1a. General ‐ average overall endpoint score ‐ short term (BPRS total, high = worse).
1.6
1.6. Analysis
Comparison 1 ADJUNCTIVE ANTIOXIDANTS versus PLACEBO, Outcome 6 Mental state: 1b. General ‐ average overall endpoint score ‐ short term (PANSS total, high = worse).
1.7
1.7. Analysis
Comparison 1 ADJUNCTIVE ANTIOXIDANTS versus PLACEBO, Outcome 7 Mental state: 1c. General ‐ average overall endpoint score ‐ medium term (PANSS total, high = worse).
1.8
1.8. Analysis
Comparison 1 ADJUNCTIVE ANTIOXIDANTS versus PLACEBO, Outcome 8 Mental state: 1d. General ‐ average overall endpoint score ‐ long term (BPRS total, high = worse).
1.9
1.9. Analysis
Comparison 1 ADJUNCTIVE ANTIOXIDANTS versus PLACEBO, Outcome 9 Mental state: 2a. Specific ‐ average negative symptom endpoint score ‐ short term (PANSS negative, high = worse).
1.10
1.10. Analysis
Comparison 1 ADJUNCTIVE ANTIOXIDANTS versus PLACEBO, Outcome 10 Mental state: 2b. Specific ‐ average negative symptom endpoint score ‐ short term (SANS, high = worse).
1.11
1.11. Analysis
Comparison 1 ADJUNCTIVE ANTIOXIDANTS versus PLACEBO, Outcome 11 Mental state: 2c. Specific ‐ average negative symptom endpoint score ‐ medium term (PANSS negative, high = worse).
1.12
1.12. Analysis
Comparison 1 ADJUNCTIVE ANTIOXIDANTS versus PLACEBO, Outcome 12 Mental state: 2d. Specific ‐ average positive symptom endpoint score ‐ short term (PANSS positive, high = worse).
1.13
1.13. Analysis
Comparison 1 ADJUNCTIVE ANTIOXIDANTS versus PLACEBO, Outcome 13 Mental state: 2e. Specific ‐ average positive symptom endpoint score ‐ short term (SAPS, high = worse).
1.14
1.14. Analysis
Comparison 1 ADJUNCTIVE ANTIOXIDANTS versus PLACEBO, Outcome 14 Mental state: 2f. Secific ‐ average positive symptom endpoint score ‐ medium term (PANSS positive, high = worse).
1.15
1.15. Analysis
Comparison 1 ADJUNCTIVE ANTIOXIDANTS versus PLACEBO, Outcome 15 General functioning: 1a. General ‐ average overall endpoint score ‐ short term (GAS total, high = worse).
1.16
1.16. Analysis
Comparison 1 ADJUNCTIVE ANTIOXIDANTS versus PLACEBO, Outcome 16 General functioning: 1b. General ‐ average overall endpoint score ‐ medium term (GAS total, high = worse).
1.17
1.17. Analysis
Comparison 1 ADJUNCTIVE ANTIOXIDANTS versus PLACEBO, Outcome 17 General functioning: 1c. General ‐ average overall endpoint score ‐ long term (GAS total, high = worse).
1.18
1.18. Analysis
Comparison 1 ADJUNCTIVE ANTIOXIDANTS versus PLACEBO, Outcome 18 Adverse effects: 1. Serious (any time point).
1.19
1.19. Analysis
Comparison 1 ADJUNCTIVE ANTIOXIDANTS versus PLACEBO, Outcome 19 Adverse effects: 2. Various ‐ less serious.
1.20
1.20. Analysis
Comparison 1 ADJUNCTIVE ANTIOXIDANTS versus PLACEBO, Outcome 20 Adverse effects: 3. Average score (TESS endpoint, high = worse).
1.21
1.21. Analysis
Comparison 1 ADJUNCTIVE ANTIOXIDANTS versus PLACEBO, Outcome 21 Laboratory data (serum tests) ‐ short term.
See this image and copyright information in PMC

Comment in

References

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