Antioxidants as add-on treatment for people with schizophrenia

Antioxidants are substances that protect cells from the damage caused by unstable molecules known as free radicals (causing oxidative stress). It is well known that adding antioxidant-rich fruits and vegetables to your daily diet will strengthen your ability to fight infection and disease. There is recent evidence that progressive brain changes take place as schizophrenia unfolds. Among many possible explanations, oxidative stress may be one of the factors contributing to the deterioration of the brain and its grey matter, leading to difficulties in people’s thinking and everyday functioning. The aim of this review is to evaluate the effect of antioxidants as an add-on treatment to standard antipsychotic medication. In particular, by reducing (or lessening) psychotic episodes and core symptoms, and preventing relapse

Searches for randomised trials were run in 2010 and 2012, review authors found 22 relevant trials that randomised a total of 2041 people with schizophrenia. The trials compared the effects of taking a variety of antioxidants (allopurinol, Ginkgo biloba, N-acetyl cysteine (NAC), selegiline, vitamins C and E) compared with placebo. Most results showed no real differences between the antioxidants and placebo although there was evidence Ginkgo biloba had a positive effect on psychotic symptoms in the short term. The quality of this evidence was moderate.

However, overall, the trials suffered from a lack of real-world outcomes, such as clinical response, rates of relapse, quality of life, functioning, safety and satisfaction or acceptability of treatment. Adverse effects were also poorly reported with some studies not providing any data for adverse effects.

Ginkgo biloba and NAC emerged from the trials as the most promising, so should have priority in the design of future trials that are larger, longer and better reported than the 22 studies available at the present time.

Ben Gray, Senior Peer Researcher, McPin Foundation:

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.

Read the full abstract...

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.


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 strategy: 

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.