Lack of scientific rationale for use of valproic acid for retinitis pigmentosa

Michael A. Sandberg, Associate Professor of Ophthalmology,

Other Contributors:

November 24, 2010

Lack of Scientific Rationale for Use of Valproic Acid for Retinitis Pigmentosa

Michael A. Sandberg, Ph.D., Bernard Rosner, Ph.D., Carol Weigel- DiFranco, Eliot L. Berson, M.D.

Corresponding author: Michael A. Sandberg, Ph.D. Berman-Gund Laboratory, Harvard Medical School 243 Charles Street Boston, Massachusetts 02114 USA Email: Telephone: 617-573-3605 FAX: 617-573-3216

Author affiliations: Berman-Gund Laboratory for the Study of Retinal Degenerations, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA

The Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all authors, an exclusive licence on a worldwide basis to the BMJ Publishing Group Ltd and its Licensees to permit this article (if accepted) to be published in BJO editions and any other BMJPGL products to exploit all subsidiary rights, as set out in our licence.

Competing Interest: None to declare

Key words: retinitis pigmentosa, valproic acid

Word count for text: 273

"Therapeutic potential of valproic acid for retinitis pigmentosa," by CM Clemson, R Tzekov, M Krebs, JM Checchi, C Bigelow, and S Kaushal has significant flaws that mitigate against their conclusion that short-term valproic acid improved the vision of patients with retinitis pigmentosa (RP).

The investigators should have performed a case-control study, comparing patients taking valproic acid to control patients matched for baseline field and acuity. This would have allowed for possible floor effects due to the low baseline function of some of the treated patients (i.e., who might be more likely to improve rather than decline over follow -up by chance variability) and avoided their use of historical rates of change drawn from different populations tested by others with different methods.

Statistical analyses should have been performed on patients, instead of eyes, unless controlling for the intraclass correlation between fellow eyes of the same patient. A reanalysis of their results by the signed-rank test for cluster-correlated data1 reveals weaker effects for visual field improvement (e.g., p = 0.14 versus no change) and visual acuity improvement (e.g., p = 0.06 versus no change) in their cohort. In fact, none of the presented comparisons was statistically significant with this test.

The authors did not cite published side effects of valproic acid (e.g., constipation, diarrhea, and hearing loss). Among patients given valproic acid elsewhere, one reported to us a further impairment of hearing and no visual improvement after taking this drug for several weeks. Another showed decline in retinal function while on this drug for one year.

We believe that the above-named report does not provide a scientific rationale for the clinical trial that the authors recommend.

Michael A. Sandberg, Ph.D. Bernard Rosner, Ph.D. Carol Weigel-DiFranco, M.A. Eliot L. Berson, M.D.


1Rosner B, Glynn RJ, Lee ML. The Wilcoxon signed rank test for paired comparisons of clustered data. Biometrics 2006;62:185-192.

Conflict of Interest:

None declared

Conflict of Interest

None declared