Progress in neuro-psychopharmacology and biological psychiatry

Progress in Neuro-Psychopharmacology & Biological Psychiatry 31 (2007) 972 – 973 www.elsevier.com/locate/pnpbp

Letter to the Editor (Comment) Progress in neuro-psychopharmacology and biological psychiatry Re.: Omega-3 fatty acids and sudden unexpected death in epilepsy: What does the evidence tell us?

Dear Sir, The elegant review article by Mazza et al. (2007) encouraged us to write this short commentary article. The epilepsies are the most common serious neurological condition, affecting cognitive, emotional, and behavioral conditions, ability to work, social functioning, family stability and self-esteem of the patient (Duncan et al., 2006). Moreover, people with epilepsy has a two- to three-fold increased risk of dying prematurely than those without epilepsy and the most common epilepsy-related category of death is sudden unexpected death in epilepsy (SUDEP) (Tomson et al., 2005). Information concerning risk factors for SUDEP is conflicting, but potential risk factors include: age, early onset of epilepsy, duration of epilepsy, uncontrolled seizures, seizure frequency, seizure type and antiepileptic drugs number (Stollberger and Finsterer, 2004). The exact pathophysiological causes of SUDEP is unknown, but it is very probable that cardiac arrhythmia during and between seizures play a potential role (Stollberger and Finsterer, 2004). Although the availability of pharmacological treatment of epilepsies has expanded, the antiepileptic drugs are still limited in clinic efficacy. In this line, several factors such as genetic, environmental and social can contribute to the inefficacy of therapeutic outcome in epileptic patients. Among these factors, nutritional aspects, i.e., omega-3 fatty acids deficiency should also have an interesting role in this scenario. In this way, some animal and clinical studies have been shown that omega-3 fatty acids could be useful in the prevention and treatment of epilepsy. In 1998, Voskuyl et al., using the cortical stimulation seizure model in rats, demonstrated a modest anticonvulsant effect but of long duration with the polyunsaturated fatty acids. Moreover, pharmacological studies have shown that polyunsaturated fatty acids applied extracellularly raise the stimulatory thresholds of CA1 neurons in hippocampal slices (Xiao and Li, 1999). Recently, our group showed that a chronic treatment with omega-3 fatty acids promote neuroprotection and increase parvalbumin-positive neurons in the hippocampal formation of rats with epilepsy, suggest that omega-3 fatty acids leads to prominent plastic changes in the hippocampal formation of rats with epilepsy (Scorza et al., 2006). From the clinical point of 0278-5846/$ - see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2007.02.001

view, Schlanger et al. (2002) reported on an open clinical trial in which omega-3 fatty acids supplements were given to 5 adult people with epilepsy by addition of a special spread containing 65% of omega-3 fatty acids to their daily diet. The patients consumed 5 g of this spread at every breakfast for 6 months and all of them showed a marked reduction in both frequency and strength of the epileptic seizures, suggesting that a dietary supplement containing omega-3 fatty acids may be beneficial in suppressing some types of epileptic seizures. Recently, in the first randomized, placebo-controlled parallel group trial of omega-3 fatty acids supplementation, seizure frequency was reduced over the first 6 weeks of treatment in the supplement group, but this effect was not sustained (Yuen et al., 2005). The authors believe that the loss of effect following the initial 6 weeks was a result of omega-3 fatty acids preparations, doses, treatment duration, and sample sizes. As mentioned above, SUDEP is the most important direct epilepsy-related cause of death in people with epilepsy and cardiac arrhythmia during and between seizures has been hypothesized as its underlying substrate (Stollberger and Finsterer, 2004). As omega-3 fatty acids per se have been shown to reduce cardiac arrhythmias in animal studies and to reduce sudden cardiac deaths, Yuen and Sander (2004) proposed the interesting hypothesis that omega-3 fatty acids fatty acid supplementation in patients with refractory seizures may reduce seizures and seizure associated cardiac arrhythmias and hence SUDEP. In accordance to this reasoning, our group started some studies aimed to explore this question. Firstly, we evaluated the heart rate (in vivo and in vitro) and ventricular pressure in vitro of rats with epilepsy (Colugnati et al., 2005). Our results showed a significant increase of heart rate in vivo in the animals with epilepsy when compared with control group. In contrast, we did not find differences during in vitro experiments, suggesting a central nervous system modulation on the heart, which could explain the sudden unexpected death in epilepsy. In the second step and quite interesting, Scorza et al. (unpublished data) evaluated the heart rate in vivo of rats with epilepsy before and after chronic omega-3 fatty acids fatty acids administration. The results showed a decrease of heart rate in vivo in the omega-3 fatty acids-treated animals. In this way, our experimental studies are in accordance with previous reports (Yuen and Sander, 2004), suggesting that omega-3 fatty acids fatty acids is effective in preventing heart arrhythmias and hence SUDEP. As a whole, the development of new purposes and therapeutic strategies should be developed with the aim to prevent and treat people with epilepsy. Actually, it has long been believed

Letter to the Editor (Comment)

that a daily intake of 3000 to 4000 mg of fish oil supplements or 2 to 3 servings of fatty fish per week are safe and effective to adults in general, included those with neurological diseases (to review see Mazza et al., 2007). In this way, new considerations and experimental, epidemiological and clinical studies should be evaluated to establish with precision the relationship between omega-3 fatty acids and epilepsy. References Colugnati DB, Gomes PA, Arida RM, de Albuquerque M, Cysneiros RM, Cavalheiro EA, et al. Analysis of cardiac parameters in animals with epilepsy: possible cause of sudden death? Arq Neuropsiquiatr 2005;63(4): 1035–41. Duncan JS, Sander JW, Sisodiya SM, Walker MC. Adult epilepsy. Lancet 2006;367(9516):1087–100. Mazza M, Pomponi M, Janiri L, Bria P, Mazza S. Omega-3 fatty acids and antioxidants in neurological and psychiatric diseases: an overview. Prog Neuropsychopharmacol Biol Psychiatry 2007;31(1):12–26. Schlanger S, Shinitzky M, Yam D. Diet enriched with omega-3 fatty acids alleviates convulsion symptoms in epilepsy patients. Epilepsia 2002;43(1): 103–4. Scorza FA, Ferrari D, Scorza CA, Pansani A, Arida RM, Cavalheiro EA, et al. Neuroproteção produzida pelo omega-3 no modelo de epilepsia induzido pela pilocarpina. J Epilepsy Clin Neurophysiol 2006;12:16. Stollberger C, Finsterer J. Cardiorespiratory findings in sudden unexplained/ unexpected death in epilepsy (SUDEP). Epilepsy Res 2004;59(1):51–60. Tomson T, Walczak T, Sillanpaa M, Sander JW. Sudden unexpected death in epilepsy: a review of incidence and risk factors. Epilepsia 2005;46 (Suppl 11):54–61. Voskuyl RA, Vreugdenhil M, Kang JX, Leaf A. Anticonvulsant effect of polyunsaturated fatty acids in rats, using the cortical stimulation model. Eur J Pharmacol 1998;341(2–3):145–52.

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Xiao Y, Li X. Polyunsaturated fatty acids modify mouse hippocampal neuronal excitability during excitotoxic or convulsant stimulation. Brain Res 1999;846(1):112–21. Yuen AW, Sander JW. Is omega-3 fatty acid deficiency a factor contributing to refractory seizures and SUDEP? A hypothesis. Seizure 2004;13(2):104–7. Yuen AW, Sander JW, Fluegel D, Patsalos PN, Bell GS, Johnson T, et al. Omega-3 fatty acid supplementation in patients with chronic epilepsy: a randomized trial. Epilepsy Behav 2005;7(2):253–8.

Fulvio A. Scorza* Roberta M. Cysneiros Esper A. Cavalheiro Disciplina de Neurologia Experimental, Universidade Federal de São Paulo/Escola Paulista de Medicina (UNIFESP/EPM), São Paulo, Brazil *Corresponding author.

Ricardo M. Arida Departamento de Fisiologia, Universidade Federal de São Paulo/Escola Paulista de Medicina (UNIFESP/EPM), São Paulo, Brazil

Marly de Albuquerque Núcleo de Pesquisas Tecnológicas, Universidade de Mogi das Cruzes, São Paulo, Brazil 30 January 2007