Reviewed: Chen X, Hong Y, Zheng P. Efficacy and safety of extract of Ginkgo biloba as an adjunct therapy in chronic schizophrenia: a systematic review of randomized, double-blind, placebo-controlled studies with meta-analysis. Psychiatry Res. 2015;228(1):121-127.

The exact cause of schizophrenia is unknown. One theory is that excessive production of free radicals, oxidative stress, and an increase in lipid peroxides may be involved in the pathogenesis. Therefore, free radical scavengers (e.g., antioxidants) may be useful as a treatment for schizophrenia. Ginkgo (Ginkgo biloba, Ginkgoaceae) leaf standardized extract is a free radical scavenger that has been evaluated as a treatment for schizophrenia with mixed results. However, according to the authors of this review, previous meta-analyses1,2 have failed to take into account the numerous studies available only in Chinese. Hence, the purpose of this meta-analysis was to compile, without restricting language, studies that evaluated the safety and efficacy of ginkgo extract as an adjunct therapy for patients with schizophrenia. Curiously, only Chinese-language studies were ultimately included.

The following electronic databases were searched from inception through March 23, 2014: PubMed/MEDLINE, EMBASE, PsycINFO, the Cochrane Library, China National Knowledge Infrastructure, WanFang Data Digital Periodicals, and Chinese Scientific Journals Database. Studies were included if they had a randomized, double-blind, placebo-controlled design with complete data analysis; involved participants with chronic schizophrenia; and used ginkgo as an adjunct therapy. The included studies did not restrict race or nationality of patients.

The primary outcome variables of the included studies were based on the Brief Psychiatric Rating Scale (BPRS), the Scale for the Assessment of Negative Symptoms (SANS), and/or the Positive and Negative Syndrome Scale (PANSS). These are all scales used to quantitatively measure the severity of different schizophrenia symptoms. The secondary outcome variables were adverse reactions, measured using the Treatment Emergent Symptom Scale (TESS) and the Rating Scale for Extrapyramidal Side Effects (RSESE). The methodological quality of the studies was evaluated according to the Cochrane Handbook. Repeated data articles and duplicate studies were excluded.

A total of 339 studies were retrieved from the initial search, but only eight Chinese articles met all of the inclusion criteria. Together, the studies included 1033 patients (571 treated with ginkgo and 462 treated with placebo) who had been diagnosed with schizophrenia at least three years prior to the study. The average onset age ranged from 30-50 years, and the number of participants ranged from 29 to 512.

Patients were treated with either 240 mg/day ginkgo extract (four studies) or 360 mg/day ginkgo extract (four studies), for eight weeks (one study), 12 weeks (three studies), or 16 weeks (four studies), while continuing to take their original antipsychotic medication. All studies report having used the standardized ginkgo extract product EGb 761® (Dr. Willmar Schwabe; Karlsruhe, Germany).

The authors stated that the pooled studies had a low overall risk of bias. However, only one randomized controlled trial out of eight reported its randomization method clearly and used allocation concealments, which indicates that the risk of bias was underestimated. Seven of the eight studies were combined into a meta-analysis to determine the effect of ginkgo as an adjunct therapy for total symptoms of chronic schizophrenia (e.g., delusion, disorganized thinking, and hallucinations), and all eight studies were included in the meta-analysis to determine the effect of ginkgo on negative symptoms of schizophrenia (e.g., avolition [lack of interest] and psychomotor poverty [lack of speech, decreased spontaneous movements, and blunting of emotion]3). There was no statistical heterogeneity for either endpoint, which suggests consistent methodology among the studies. The ginkgo groups had significantly greater improvements in total symptoms and negative symptoms compared with placebo groups (P < 0.01 for both). However, the study with the largest sample size (n = 512) — which reported a benefit of ginkgo — contributed more heavily to these outcomes (28.5% and 48.5%, respectively).

Five of the studies reported adverse events (AEs). The adverse event scores (e.g., for behavioral toxicity, thirst, tachyarrhythmia, etc.) were similar among treatment and placebo groups. The AEs were scored lower in the ginkgo group, but the difference among groups was not significantly different. One study reported that two placebo-treated patients received 480 mg/day of ginkgo extract (after the end of the study) as an adjunct to their psychiatric treatment in an attempt to improve negative symptoms that were not responding to therapy. Both patients had severe persecutory delusions after 12 and 14 days of ginkgo use, a symptom that resolved after stopping ginkgo treatment and receiving additional antipsychotic drugs. The authors conclude that the safety of ginkgo as an adjunct therapy for schizophrenia may be related to its dose, and that additional research is needed.

The authors state that ginkgo adjunct therapy may be more beneficial than antipsychotics alone in people with chronic schizophrenia. The severity of adverse side effects associated with ginkgo may be related to the relatively higher dose of the herb that was administered to certain patients. The authors acknowledge that the meta-analysis was limited by the inclusion of only eight studies with Chinese participants. However, the authors note that the study is valuable because it fills a gap in Western-centered research publications.

—Heather S. Oliff, PhD

References

1. Singh V, Singh SP, Chan K. Review and meta-analysis of usage of ginkgo as an adjunct therapy in chronic schizophrenia. Int J Neuropsychopharmacol. 2010;13(2):257-271.
2. Brondino N, DeSilvestri A, Re S, et al. A systematic review and meta-analysis of Ginkgo biloba in neuropsychiatric disorders: from ancient tradition to modern-day medicine. Evid Based Complement Alternat Med. 2013;2013:915691.
3. Morrens M, Hulstijn W, Sabbe B. Psychomotor slowing in schizophrenia. National Institutes of Health website. Available at: www.ncbi.nlm.nih.gov/pmc/articles/PMC2632327/. Accessed September 23, 2015.