Results of the Review

Most trials showed no significant differences between antioxidants and placebo. In general, there was a great deal of heterogeneity in the studies, in terms of the primary outcomes. Most studies did not include a categorical measure of response in global state (ie, 20% improvement on PANSS) and therefore did not demonstrate an advantage for adjunctive antioxidants. Only two short-term and one medium-term study (of allopurinol and NCC respectively) reported clinical response as a 20% reduction in the PANSS.

Other findings are summarized in Table 2.

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The researchers noted that the studies were “mostly underpowered” and did not “offer data on the most clinically meaningful outcomes.” Additionally, they were of “low quality” and “highly heterogeneous.” While safety was not a concern in the use of antioxidants, the overall findings “make it difficult to interpret the effect of adding an antioxidant to the standard treatment of schizophrenia.” Additionally, the trials “suffered from lack of real-world outcomes, such as clinical response, rates of relapse, quality of life, functioning, safety and satisfactions, or acceptability of treatment.”

Ginkgo biloba was the most studied agent, particularly in Chinese inpatients, with a lower rate of patients leaving the study early and reduced scores for positive symptoms. Both Ginkgo biloba and NAC were promising agents and “should have priority in the design of future trials that are larger, longer, and better reported than the 22 studies made available at the present time.”


1.      Magalhães PV, Dean O, Andreazza AC, Berk M, Kapczinski F. Antioxidant treatments for schizophrenia. Cochrane Database Syst Rev. 2016 Feb 5;2:CD008919.

2.      Wood SJ, Yücel M, Pantelis C, Berk M. Neurobiology of schizophrenia spectrum disorders: the role of oxidative stress. Ann Acad Med Singapore. 2009 May;38(5):396-6.

3.      Ng F, Berk M, Dean O, Bush AI. Oxidative stress in psychiatric disorders: evidence base and therapeutic implications. Int J Neuropsychopharmacol. 2008 Sep;11(6):851-76.

Table 1

Secondary Trial Outcomes

  • Leaving the study early
  • Global state
  • Mental state
  • General functioning
  • Quality of life/satisfaction with treatment
  • Cognitive functioning
  • Service use
  • Adverse effects
  • Laboratory data

Table 2

Study Results

Outcome Study Finding

Leaving the study early

  • Use of antioxidants did not change the risk of leaving the study early in the short term (16 RCTs, 1584 people)
  • Substantial heterogeneity
Mental state: general–short-term BPRS)
  • Favorable effect (8 RCTs, n=843)
  • Substantial heterogeneity
  • In three short-term studies (n=663), Ginkgo biloba showed favorable effect
Mental state: general–short-term PANSS)
  • Favorable effect (7 RCTs, n= 584)
  • Substantial heterogeneity
  • In one trial (n-157), Ginkgo biloba showed favorable effect
  • In one trial (n=42), NAC showed favorable effect
Mental state: specific–short-term PANSS negative)
  • No effect, compared to placebo (9 RCTs, n=653)
  • Substantial heterogeneity
  • Statistically significant difference: selegiline (3 RCTs, n=111), Ginkgo biloba (1 RCT, n=157), NAC (1 RCT, n=44)
Mental state: specific–short-term SANS negative)
  • Statistically significant difference between Ginkgo biloba and placebo (RCTs, n=667)
Mental state: specific–medium-term PANSS negative)
  • Statistically significant difference between NAC (1 RCT, n=135)
Mental state: general–short-term SAPS positive
  • Statistically significant difference between Ginkgo biloba and placebo (1 RCTs, n=151)
Adverse effects
  • No statistical difference between antioxidants and placebo