Journal of Neuro-Ophthalmology, December 1999, Volume 19, Issue 4

Toxic Optic Neuropathy after Concomitant Use of Melatonin, Zoloft, and a High-Protein Diet

Melatonin is a neuromodulating hormone found in the pineal gland and retina. It is involved in light-dark circadian rhythms and mediates retinal processes in a manner antagonistic to that of dopamine. Zoloft (sertraline) is an antidepressant drug that blocks the reuptake of serotonin at the neural synapse. Serotonin is the natural precursor of melatonin. A 42-year-old woman sought treatment for visual acuity loss, dyschromatopsia, and altered light adaptation. Neuro-ophthalmologic examination was otherwise normal except for evolving bilateral cecocentral scotomas. She had taken Zoloft for 4 years and began a high-protein diet with melatonin supplementation 2 weeks before onset of visual symptoms. Visual acuity and color vision improved within 2 months after melatonin and the high-protein diet were discontinued. Combined use of melatonin, Zoloft, and a high-protein diet may have resulted in melatonin/dopamine imbalance in the retina, manifesting as a toxic optic neuropathy. Physicians and patients should be alerted to this potential drug interaction.

Journal of Neuro- Ophihalmology 19( 4): 232- 234, 1999. © 1999 Lippincott Williams & Wilkins, Inc., Philadelphia Toxic Optic Neuropathy After Concomitant Use of Melatonin, Zoloft, and a High- Protein Diet Norman L. Lehman, M. D., Ph. D., and Lenworth N. Johnson, M. D. Melatonin is a neuromodulating hormone found in the pineal gland and retina. It is involved in light- dark circadian rhythms and mediates retinal processes in a manner antagonistic to that of dopamine. Zoloft ( sertraline) is an antidepressant drug that blocks the reuptake of serotonin at the neural synapse. Seroto­nin is the natural precursor of melatonin. A 42- year- old woman sought treatment for visual acuity loss, dyschromatopsia, and altered light adaptation. Neuro- ophthalmologic examination was otherwise normal except for evolving bilateral cecocentral scotomas. She had taken Zoloft for 4 years and began a high-protein diet with melatonin supplementation 2 weeks before onset of visual symptoms. Visual acuity and color vision im­proved within 2 months after melatonin and the high- protein diet were discontinued. Combined use of melatonin, Zoloft, and a high- protein diet may have resulted in melatonin/ dopamine imbalance in the retina, manifesting as a toxic optic neuropa­thy. Physicians and patients should be alerted to this potential drug interaction. Key Words: Dopamine- Melatonin- Retina- Sertraline- Toxic optic neuropathy. Melatonin is a hormone produced by the pineal gland and retina, and is involved in light- dark circadian rhythms ( 1). It is used as a holistic sleep aid and touted cure for several ailments ( 2). Some researchers have cau­tioned against possible side effects of melatonin supple­mentation including cerebral and coronary vasoconstric­tion, infertility, and retinal damage ( 2). Zoloft ( sertraline; Pfizer Inc., New York, NY) is a commonly used antide­pressant drug belonging to the selective serotonin re­uptake inhibitor ( SSRI) category. We report a case of possible toxic optic neuropathy associated with concomi­tant use of Zoloft and supplemental melatonin. CASE REPORT A 42- year- old woman developed blurred vision, re­duced color vision, decreased brightness sensation when Manuscript received December 21, 1998; accepted August 24, 1999. From the Neuro- ophthalmology Unit, Mason Eye Institute, Univer­sity of Missouri- Columbia, Columbia, Missouri, U. S. A. The authors have no proprietary interest in any product listed. Address correspondence to Dr. Norman L. Lehman, Department of Pathology, Creighton University/ St. Joseph Hospital, 601 North 30th Street, Omaha, NE 68131. indoors, and outdoor photosensitivity 2 weeks after ini­tiating a high- protein diet with melatonin supplementa­tion ( 1 mg daily). Additionally, she reported imbalance and restless sleep. She previously enjoyed excellent health apart from depression, for which she had taken Zoloft 100 mg daily for 4 years. Her best corrected visual acuity was 20/ 50 OD and 20/ 60 OS. Automated perim­etry ( Humphrey 120- point screen) initially was normal for the left eye, but showed a central scotoma for the right eye. Twelve days after discontinuing melatonin and resuming a normal diet, her visual acuity improved to 20/ 30 in each eye ( OU). She correctly identified only 1 and 5 of 17 Ishihara color plates with the right and left eyes, respectively. Humphrey automated perimetry ( pro­gram 24- 2) showed a cecocentral scotoma OD and cen­tral scotoma OS ( Fig. 1A). The remainder of the neuro-ophthalmologic examination including pupillary exami­nation, slit- lamp biomicroscopy, and fundoscopic examination were normal. A magnetic resonance imag­ing scan of the cranium and orbits was normal. One month later, her visual acuity was 20/ 30 OD and 20/ 25 OS. Automated perimetry showed cecocentral scotoma OU ( Fig. IB). Color vision was unchanged. The neurologic examination was normal. Two months after stopping melatonin and the high- protein diet her visual acuity was 20/ 25 OU. Her color vision improved to cor­rectly identifying 12 of 17 color plates with the right eye and all 17 color plates with the left eye. Automated pe­rimetry performed 6 months after the initial visit showed normal results ( Fig. 1C). DISCUSSION Bilateral visual acuity loss, cecocentral scotomas, and dyschromatopsia suggest toxic, hereditary, demyelinat-ing, compressive, or infiltrating optic neuropathy. Al­though mitochondrial DNA analysis was not performed, the absence of optic disc telangiectasia, lack of family history, and rapid recovery of vision renders Leber's he­reditary optic neuropathy unlikely. Absence of retrobul­bar pain, normal neuroimaging, and rapid resolution of signs and symptoms after discontinuation of melatonin and the high- protein diet are most consistent with toxic optic neuropathy. 232 TOXIC OPTIC NEUROPATHY 233 Left Eye TOM DEVIATION PATTERN DEVIATION Right Eye TOTAl DEVIATION PATTERN DEVIATION 3* 8 FH: 1/ 12 SF: 1.63 FOVEA: 27 OB • HO: - 4.85 DB P < 5Z 8 £ 8 8 FP: 2/ 13 CPSO: 2.35 08 P ( 5'/ £ • m & • # . • 8 • • • • • • • FOVEA: 26 DO • NO: - 6.2? DB P ( 8.5X 8 :: ... • • • #. £ " 88 • • • • • xf. • • • & • • & • 8 • • FN: 2/ 11 SF: 2.40 DB P ( 1BZ FP: 1/ 12 CPSO: 5.54 DB P ( 8.5X B :: • &. s?. FOVEA: 26 OB • NO: - 5.48 DB P < 8.5'/ * • • • • & • • • • • • • 8 • • 8 • 8 • • & • 8 • : 5.7 m FN: 1/ 12 SFS 2.64 DB P < 5Z FP: 2/ 13 CPSDi 2.54 OB P < 5X • £ • • 8 • £ s* 8 • • 8 8 • • 8 LOU PATIENT RELIABILITY 8 • • II • • • 8 8 8 • • 8 FOVEA « D: - & £ :: • &. • 21 DB • 8.41 DB P ( 8.5X- • • • • #. *?. u • 8 5.3 HK £ 8 FN: / 12 SF: 2.7? OB P < V/. FP: 9815 CPSO: 3.87 DB P < B. 5'<< FOVEA: 33 OB •• m: - 1.25 DB 5.5 NN FOVEA: 38 DB I ND: - 1.73 OB 6.1 NN FN! 1/ 9 SF: 8.81 DB FP: 2/ 11 CPSO: 1. B6 DB P < W. FN: 8/ 8 SF: 1.29 I FP: 8/ 18 CPSO: 1.22 FIG. 1. Humphrey automated perimetry ( program 24- 2) shows left central scotoma and right cecocentral scotoma at 1 month ( A), bilateral cecocentral scotomas at 2 months ( B), and resolution of scotomas at 6 months ( C) after discontinuation of melatonin supplementation and the high- protein diet. Melatonin and the neurotransmitter- neuromodulator dopamine both undergo diurnal release in the retina. Retinal melatonin levels peak under dark conditions, whereas dopamine peaks during light ( 1). Dopamine is important in visual acuity, color vision, and contrast sen­sitivity ( 3- 5). Dopamine, which is produced by retinal amacrine and interplexiform cells, affects photoreceptors and horizontal cells, and reduces spontaneous firing rates and light- evoked responses of ganglion cells ( 6). Mela­tonin is involved in light- dark adaptation. Melatonin in­hibits both dopamine release and dopamine function at Dj receptors ( 3). The melatonin antagonist luzindole in- J Neuro- Ophthalmol, Vol. 19, No. 4, 1999 234 N L. LEHMAN AND L. N. JOHNSON hibits melatonin's ability to decrease dopamine release and protects dark- adapted rat photoreceptor cells from light damage ( 7). Dopamine action at D2- receptor sites results in reduced melatonin via inhibition of the expres­sion of the key regulatory enzyme in the conversion of serotonin to melatonin, serotonin / V- acetyltransferase ( 1). Thus, dopamine and melatonin mediate retinal processes in a reciprocal manner. SSRIs increase levels of serotonin at the neural synapse. Exogenous administration of the amino acid precursors of serotonin, namely, tryptophan and 5- hy-droxytryptophan, increase central nervous system sero­tonin levels ( 8) and retinal melatonin levels ( 9), respec­tively. A diet depleted in tryptophan decreases brain serotonin. Depending on its composition, a high- protein diet may also decrease brain serotonin because of pref­erential absorption of competitive neutral amino acids in the brain ( 10), although to our knowledge, a similar ef­fect in the retina has not been described. Inhibition of serotonin axonal reuptake by a SSRI may result in an increased supply of serotonin as a melatonin precursor for neighboring cells. We suspect that our patient had relatively high retinal melatonin levels because of the combined effects of Zoloft, the high- protein diet, and exogenous melatonin supplementation, resulting in decreased dopamine- medi-ated retinal activity with resultant indirect and direct ef­fects on ganglion cells. Because an electroretinogram, pattern and standard visual evoked potentials were not performed, it remains uncertain whether the initial dys­function was caused by a nonspecific retinal disorder or specific retinal ganglion cell damage ( optic neuropathy). The patient could have been rechallenged with melatonin to confirm the toxic reaction; however, the risk of in­complete recovery renders such testing unethical. In summary, the combined use of melatonin and Zoloft, and possibly a high- protein diet, may be associ­ated with retinal melatonin/ dopamine imbalance mani­festing as possible toxic optic neuropathy. Physicians and patients should be alerted to this potential drag in­teraction. Acknowledgment: Supported in part by an unrestricted grant from Research to Prevent Blindness, Inc. ( New York, New York) to the Mason Eye Institute, University of Missouri- Columbia. REFERENCES 1. Iuvone PM, Avendano G, Butler BJ, Adler R. 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