Hostname: page-component-788cddb947-m6qld Total loading time: 0 Render date: 2024-10-10T12:18:07.791Z Has data issue: false hasContentIssue false

Efficacy of ethyl-EPA as a treatment for Huntington disease: a systematic review and meta-analysis

Published online by Cambridge University Press:  19 June 2019

Sara Morsy
Affiliation:
Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Tanta University, Tanta, Egypt Nagasaki University, Nagasaki, Japan (http://www.onlineresearchclub.org)
Samar Morsy Khalil
Affiliation:
Nagasaki University, Nagasaki, Japan (http://www.onlineresearchclub.org) National Institute of Neuromotor System, Cairo, Egypt
Mohamed Fahmy Doheim
Affiliation:
Nagasaki University, Nagasaki, Japan (http://www.onlineresearchclub.org) Faculty of Medicine, Alexandria University, Alexandria, Egypt
Mohamed Gomaa Kamel
Affiliation:
Nagasaki University, Nagasaki, Japan (http://www.onlineresearchclub.org) Faculty of Medicine, Minia University, Minia, Egypt
Doaa Saeed Mahmoud El-Basiony
Affiliation:
Nagasaki University, Nagasaki, Japan (http://www.onlineresearchclub.org) Faculty of Medicine, Menoufia University, Menoufia, Egypt
Hossam Idrees Ahmed Hassan
Affiliation:
Nagasaki University, Nagasaki, Japan (http://www.onlineresearchclub.org) Faculty of Medicine, Assiut University, Assiut, Egypt
Ahmed Abdelaziz Eisa
Affiliation:
Nagasaki University, Nagasaki, Japan (http://www.onlineresearchclub.org) Faculty of Medicine, Alexandria University, Alexandria, Egypt
Cao Thị Anh Ngoc
Affiliation:
Nagasaki University, Nagasaki, Japan (http://www.onlineresearchclub.org) University of Medicine and Pharmacy, Ho Chi Minh City, Vietnam
Nguyen Phu Dang
Affiliation:
Nagasaki University, Nagasaki, Japan (http://www.onlineresearchclub.org) University of Medicine and Pharmacy, Ho Chi Minh City, Vietnam
Kenji Hirayama
Affiliation:
Department of Immunogenetics, Institute of Tropical Medicine (NEKKEN), Leading Graduate School Program, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
Nguyen Tien Huy*
Affiliation:
Evidence-Based Medicine Research Group, Ton Duc Thang University, Ho Chi Minh City, Vietnam Faculty of Applied Sciences, Ton Duc Thang University, Ho Chi Minh City, Vietnam Department of Clinical Product Development, Institute of Tropical Medicine (NEKKEN), School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki, Japan
*
Author for correspondence: Nguyen Tien Huy, Email: nguyentienhuy@tdtu.edu.vn

Abstract

Objective:

After MRI studies suggested the efficacy of ethyl-EPA in reducing the progressive brain atrophy in Huntington disease (HD), trials were conducted to test its efficacy as a treatment for HD. Trials that continued for 6 months did not find any significant improvement, urging discontinuation of the drug. However, trials that continued for 12 months indicated improvement of motor functions in these patients.

Methods:

We searched 12 electronic databases to find randomised clinical trials relevant to our inclusion criteria. After screening, only five papers were included. Continuous and binary variables were analysed to compute the pooled mean difference (MD) and risk ratio (RR), respectively. Quality effect model meta-analysis was used as a post hoc analysis for studies at 12 months.

Findings:

Meta-analysis indicated that ethyl-eicosapentaenoic acid (EPA) has no significant effect on any scale of HD at 6 months. At 12 months, two studies suggested significant improvements of the Total Motor Score and Total Motor Score–4 in both fixed and quality effect models [MD = −2.720, 95% CI (−4.76, –.68), p = 0.009; MD = −2.225, 95% CI (−3.842, −0.607), p = 0.007], respectively. Maximal chorea score showed significant results [MD = −1.013, 95% CI (−1.793, −0.233), p = 0.011] in only fixed-effect model, while no improvement was detected for Stroop colour naming test or symbol digit modality.

Conclusion:

Meta-analysis indicated a significant improvement of motor scores only after 12 months. These results should be interpreted cautiously because only two studies had assessed the efficacy of ethyl-EPA after 12 months with one of them having a 6-month open-label phase.

Type
Review Article
Copyright
© Scandinavian College of Neuropsychopharmacology 2019 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Bauer, I, Crewther, S, Pipingas, A, Sellick, L and Crewther, D (2014) Does omega-3 fatty acid supplementation enhance neural efficiency? A review of the literature. Human Psychopharmacology 29(1), 818.CrossRefGoogle ScholarPubMed
Biglan, KM, Ross, CA, Langbehn, DR, Aylward, EH, Stout, JC, Queller, S, Carlozzi, N, Duff, K, Beglinger, LJ and Paulsen, JS (2009) Motor abnormalities in premanifest persons with Huntington’s disease: the PREDICT-HD study. Movement Disorders 24(12), 17631772.CrossRefGoogle ScholarPubMed
Block, RC, Dorsey, ER, Beck, CA, Brenna, JT and Shoulson, I (2010) Altered cholesterol and fatty acid metabolism in Huntington disease. Journal of Clinical Lipidology 4(1), 1723.CrossRefGoogle ScholarPubMed
Bos, DJ, van Montfort, SJT, Oranje, B, Durston, S and Smeets, PAM (2016) Effects of omega-3 polyunsaturated fatty acids on human brain morphology and function: what is the evidence? European Neuropsychopharmacology 26(3), 546561.CrossRefGoogle ScholarPubMed
Carlozzi, NE, Hahn, EA, Goodnight, SM, Kratz, AL, Paulsen, JS, Stout, JC, Frank, S, Miner, JA, Cella, D, Gershon, RC, Schilling, SG and Ready, RE (2017) Patient-reported outcome measures in Huntington disease: quality of life in neurological disorders (Neuro-QoL) social functioning measures. Psychological Assessment. 30(4), 450458.CrossRefGoogle ScholarPubMed
Clifford, JJ, Drago, J, Natoli, AL, Wong, JY, Kinsella, A, Waddington, JL and Vaddadi, KS (2002) Essential fatty acids given from conception prevent topographies of motor deficit in a transgenic model of Huntington’s disease. Neuroscience 109(1), 8188.CrossRefGoogle Scholar
Cowan, CM and Raymond, LA (2006) Selective neuronal degeneration in Huntington’s disease. Current Topics in Developmental Biology 75, 2571.CrossRefGoogle ScholarPubMed
DerSimonian, R and Laird, N (1986) Meta-analysis in clinical trials. Controlled Clinical Trials 7(3), 177188.CrossRefGoogle ScholarPubMed
Divino, V, Dekoven, M, Warner, JH, Giuliano, J, Anderson, KE, Langbehn, D, and Lee, WC (2013) The direct medical costs of Huntington’s disease by stage. a retrospective commercial and Medicaid claims data analysis. Journal of Medical Economics 16(8), 10431050.CrossRefGoogle Scholar
Doi, SAR and Thalib, L (2008) A quality-effects model for meta-analysis. Epidemiology 19(1), 94100.CrossRefGoogle ScholarPubMed
Estrada Sanchez, AM, Mejia-Toiber, J and Massieu, L (2008) Excitotoxic neuronal death and the pathogenesis of Huntington’s disease. Archives of Medical Research 39(3), 265276.CrossRefGoogle ScholarPubMed
Ferreira, JJ, Rosser, A, Craufurd, D, Squitieri, F, Mallard, N and Landwehrmeyer, B (2015) Ethyl-eicosapentaenoic acid treatment in Huntington’s disease: a placebo-controlled clinical trial. Movement Disorders 30(10), 14261429.CrossRefGoogle ScholarPubMed
Follmann, D, Elliott, P, Suh, I and Cutler, J (1992) Variance imputation for overviews of clinical trials with continuous response. Journal of Clinical Epidemiology 45(7), 769773.CrossRefGoogle ScholarPubMed
Frank, S (2014) Treatment of Huntington’s disease. Neurotherapeutics 11(1), 153160.CrossRefGoogle ScholarPubMed
Frank, S, Testa, CM, Stamler, D, Kayson, E, Davis, C, Edmondson, MC, Kinel, S, Leavitt, B, Oakes, D, O’Neill, C, Vaughan, C, Goldstein, J, Herzog, M, Snively, V, Whaley, J, Wong, C, Suter, G, Jankovic, J, Jimenez-Shahed, J, Hunter, C, Claassen, DO, Roman, OC, Sung, V, Smith, J, Janicki, S, Clouse, R, Saint-Hilaire, M, Hohler, A, Turpin, D, James, RC, Rodriguez, R, Rizer, K, Anderson, KE, Heller, H, Carlson, A, Criswell, S, Racette, BA, Revilla, FJ, Nucifora, F Jr, Margolis, RL, Ong, M, Mendis, T, Mendis, N, Singer, C, Quesada, M, Paulsen, JS, Brashers-Krug, T, Miller, A, Kerr, J, Dubinsky, RM, Gray, C, Factor, SA, Sperin, E, Molho, E, Eglow, M, Evans, S, Kumar, R, Reeves, C, Samii, A, Chouinard, S, Beland, M, Scott, BL, Hickey, PT, Esmail, S, Fung, WL, Gibbons, C, Qi, L, Colcher, A, Hackmyer, C, McGarry, A, Klos, K, Gudesblatt, M, Fafard, L, Graffitti, L, Schneider, DP, Dhall, R, Wojcieszek, JM, LaFaver, K, Duker, A, Neefus, E, Wilson-Perez, H, Shprecher, D, Wall, P, Blindauer, KA, Wheeler, L, Boyd, JT, Houston, E, Farbman, ES, Agarwal, P, Eberly, SW, Watts, A, Tariot, PN, Feigin, A, Evans, S, Beck, C, Orme, C, Edicola, J, Christopher, E (2016) Effect of deutetrabenazine on chorea among patients with Huntington disease: a randomized clinical trial. The Journal of the American Medical Association 316(1), 4050.Google ScholarPubMed
Fu, R, Vandermeer, BW, Shamliyan, TA, O’Neil, ME, Yazdi, F, Fox, SH and Morton, SC (2008) Handling continuous outcomes in quantitative synthesis. In Rockville (MD).Google Scholar
Gusella, JF, MacDonald, ME, Ambrose, CM and Duyao, MP (1993) Molecular genetics of Huntington’s disease. Archives of Neurology 50(11), 11571163.CrossRefGoogle ScholarPubMed
Higgins, JP, Altman, DG, Gøtzsche, PC, Jüni, P, Moher, D, Oxman, AD, Savovic, J, Schulz, KF, Weeks, L and Sterne, JA (2011) The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. The British Medical Journal 343, d5928.CrossRefGoogle ScholarPubMed
Hsu, Y-M and Yin, M-C (2016) EPA or DHA enhanced oxidative stress and aging protein expression in brain of d-galactose treated mice. BioMedicine 6(3), 17.CrossRefGoogle ScholarPubMed
Huntington Study Group (1996) Unified Huntington’s Disease Rating Scale: reliability and consistency. Movement Disorders 11(2), 136142.CrossRefGoogle Scholar
Huntington Study Group TREND-HD Investigators (2008) Randomized controlled trial of ethyl-eicosapentaenoic acid in Huntington disease: the TREND-HD study. Archives of Neurology 65(12), 15821589.Google Scholar
Jones, C, Busse, M, Quinn, L, Dawes, H, Drew, C, Kelson, M, Hood, K, Rosser, A and Edwards, RT (2016) The societal cost of Huntington’s disease: are we underestimating the burden? European Journal of Neurology 23(10), 15881590.CrossRefGoogle ScholarPubMed
Katsuno, M, Banno, H, Suzuki, K, Takeuchi, Y, Kawashima, M, Tanaka, F, Adachi, H and Sobue, G (2008) Molecular genetics and biomarkers of polyglutamine diseases. Current Molecular Medicine 8(3), 221234.CrossRefGoogle ScholarPubMed
Kawashima, A, Harada, T, Kami, H, Yano, T, Imada, K and Mizuguchi, K (2010) Effects of eicosapentaenoic acid on synaptic plasticity, fatty acid profile and phosphoinositide 3-kinase signaling in rat hippocampus and differentiated PC12 cells. Journal of Nutritional Biochemistry 21(4), 268277.CrossRefGoogle ScholarPubMed
Kenney, C, Hunter, C, Davidson, A and Jankovic, J (2007) Short-term effects of tetrabenazine on chorea associated with Huntington’s disease. Movement Disorder 22(1), 1013.CrossRefGoogle ScholarPubMed
Kirkwood, SC, Siemers, E, Bond, C, Conneally, PM, Christian, JC and Foroud, T (2000) Confirmation of subtle motor changes among presymptomatic carriers of the Huntington disease gene. Archives of Neurology 57(7), 10401044.CrossRefGoogle ScholarPubMed
Klempir, J,Klempirova, O, Spackova, N, Zidovska, J and Roth, J. (2006) Unified Huntington’s disease rating scale: clinical practice and a critical approach. Funct Neurol 21(4), 217221.Google Scholar
Langbehn, DR, Hayden, M, Paulsen, JS and Group the P-HI of the HS (2010) CAG-repeat length and the age of onset in Huntington Disease (HD): a review and validation study of statistical approaches. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 153B(2) , 397408. Available at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3048807/.CrossRefGoogle ScholarPubMed
Liberati, A, Altman, DG, Tetzlaff, J, Mulrow, C, Gøtzsche, PC, Ioannidis, JP, Clarke, M, Devereaux, PJ, Kleijnen, J and Moher, D (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. The British Medical Journal 339, b2700.CrossRefGoogle ScholarPubMed
Liu, G, Bibus, DM, Bode, AM, Ma, W-Y, Holman, RT, Dong, Z. (2001) Omega 3 but not omega 6 fatty acids inhibit AP-1 activity and cell transformation in JB6 cells. Proceedings of the National Academy of Sciences of the United States of America 98(13), 75107515.CrossRefGoogle Scholar
Liu, YF (1998) Expression of polyglutamine-expanded Huntingtin activates the SEK1-JNK pathway and induces apoptosis in a hippocampal neuronal cell line. Journal of Biological Chemistry 273(44), 2887328877.CrossRefGoogle Scholar
Louis, ED, Lee, P, Quinn, L and Marder, K (1999) Dystonia in Huntington’s disease: prevalence and clinical characteristics. Movement Disorders 14(1), 95101.3.0.CO;2-8>CrossRefGoogle ScholarPubMed
Loy, CT and McCusker, EA (2013) Is a motor Criterion Essential for the Diagnosis of Clinical Huntington Disease? PLoS Currents 5, ecurrents.hd.f4c66bd51e8db11f55e1701af937a419. Available at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3644296/.Google Scholar
Lynch, AM, Moore, M, Craig, S, Lonergan, PE, Martin, DS andLynch, MA (2003) Analysis of interleukin-1 beta-induced cell signaling activation in rat hippocampus following exposure to gamma irradiation. Protective effect of eicosapentaenoic acid. Journal of Biological Chemistry 278(51), 5107551084.CrossRefGoogle ScholarPubMed
Mantel, N and Haenszel, W (1959) Statistical aspects of the analysis of data from retrospective studies of disease. Journal of the National Cancer Institute 22(4), 719748.Google Scholar
Murck, H and Manku, M (2007) Ethyl-EPA in Huntington disease: potentially relevant mechanism of action. Brain Research Bulletin 72(2–3), 159164.CrossRefGoogle ScholarPubMed
Paulsen, JS (2011) Cognitive impairment in Huntington disease: diagnosis and treatment. Current Neurology and Neuroscience Reports 11(5), 474483.CrossRefGoogle ScholarPubMed
Paulsen, JS, Langbehn, DR, Stout, JC, Aylward, E, Ross, CA, Nance, M, Guttman, M, Johnson, S, MacDonald, M, Beglinger, LJ, Duff, K, Kayson, E, Biglan, K, Shoulson, I, Oakes, D and Hayden, M (2008) Detection of Huntington’s disease decades before diagnosis: the Predict-HD study. Journal of Neurology, Neurosurgery, and Psychiatry 79(8), 874880.CrossRefGoogle ScholarPubMed
Penney, JB Jr, Young, AB, Shoulson, I, Starosta-Rubenstein, S, Snodgrass, SR, Sanchez-Ramos, J, Ramos-Arroyo, M, Gomez, F, Penchaszadeh, G, Alvir, J, and Esteves, J (1990) Huntington’s disease in Venezuela: 7 years of follow-up on symptomatic and asymptomatic individuals. Movement Disorders 5(2), 9399.CrossRefGoogle ScholarPubMed
Philbrick, DJ, Mahadevappa, VG, Ackman, RG and Holub, BJ (1987) Ingestion of fish oil or a derived n-3 fatty acid concentrate containing eicosapentaenoic acid (EPA) affects fatty acid compositions of individual phospholipids of rat brain, sciatic nerve and retina. Journal of Nutrition 117(10), 16631670.CrossRefGoogle ScholarPubMed
Pringsheim, T, Wiltshire, K, Day, L, Dykeman, J, Steeves, T and Jette, N (2012) The incidence and prevalence of Huntington’s disease: a systematic review and meta-analysis. Movement Disorders 27(9), 10831091.CrossRefGoogle ScholarPubMed
Puri, BK, Bydder, GM, Counsell, SJ, Corridan, BJ, Richardson, AJ, Hajnal, JV, Appel, C, Mckee, HM, Vaddadi, KS and Horrobin, DF (2002) MRI and neuropsychological improvement in Huntington disease following ethyl-EPA treatment. NeuroReport 13(1), 123126.CrossRefGoogle ScholarPubMed
Puri, BK, Bydder, GM, Manku, MS, Clarke, A, Waldman, AD and Beckmann, CF (2008) Reduction in cerebral atrophy associated with ethyl-eicosapentaenoic acid treatment in patients with Huntington’s disease. Journal of International Medical Research 36(5), 896905.CrossRefGoogle ScholarPubMed
Puri, BK, Leavitt, BR, Hayden, MR, Ross, CA, Rosenblatt, A, Greenamyre, JT, Hersch, S, Vaddadi, KS, Sword, A, Horrobin, DF, Manku, M and Murck, H (2005) Ethyl-EPA in Huntington disease: a double-blind, randomized, placebo-controlled trial. Neurology 65(2), 286292.CrossRefGoogle ScholarPubMed
Pusceddu, MM, Kelly, P, Stanton, C, Cryan, JF and Dinan, TG (2016) N-3 Polyunsaturated fatty acids through the lifespan: implication for psychopathology. The International Journal of Neuropsychopharmacology 19(12), pyw078.CrossRefGoogle ScholarPubMed
Shah, PB (2011) Intention-to-treat and per-protocol analysis. Canadian Medical Association Journal 183(6), 696. Available at https://www.ncbi.nlm.nih.gov/pubmed/21464181 CrossRefGoogle ScholarPubMed
Siesling, S, van Vugt, JP, Zwinderman, KA, Kieburtz, K and Roos, RA (1998) Unified Huntington’s disease rating scale: a follow up. Movement Disorders 13(6), 915919.CrossRefGoogle ScholarPubMed
Siesling, S, Zwinderman, AH, van Vugt, JP, Kieburtz, K and Roos, RA (1997) A shortened version of the motor section of the Unified Huntington’s Disease Rating Scale. Movement Disorders 12(2), 229234.CrossRefGoogle ScholarPubMed
Titova, OE, Sjögren, P, Brooks, SJ, Kullberg, J, Ax, E, Kilander, L, Riserus, U, Cederholm, T, Larsson, EM, Johansson, L and Ahlström, H (2013) Dietary intake of eicosapentaenoic and docosahexaenoic acids is linked to gray matter volume and cognitive function in elderly. Age (Dordr) 35(4), 14951505.CrossRefGoogle ScholarPubMed
Vaccarino, AL, Anderson, K, Borowsky, B, Duff, K, Giuliano, J, Guttman, M, Ho, AK, Orth, M, Paulsen, JS, Sills, T and Van Kammen, DP (2011) An item response analysis of the motor and behavioral subscales of the unified Huntington’s disease rating scale in huntington disease gene expansion carriers. Movement Disorders 26(5), 877884.CrossRefGoogle ScholarPubMed
Van Raamsdonk, JM, Pearson, J, Rogers, DA, Lu, G, Barakauskas, VE, Barr, AM, Honer, WG, Hayden, MR and Leavitt, BR (2005) Ethyl-EPA treatment improves motor dysfunction, but not neurodegeneration in the YAC128 mouse model of Huntington disease. Experimental Neurology 196(2), 266272.CrossRefGoogle Scholar
van Rijkom, HM, Truin, GJ and van ‘t Hof, MA (1998) A meta-analysis of clinical studies on the caries-inhibiting effect of fluoride gel treatment. Caries Research 32(2), 8392.CrossRefGoogle ScholarPubMed
Waitzberg, DL and Garla, P (2014). Nutrición Hospitalaria 30(3), 467477.Google Scholar
Walker, FO (2017) Huntington’s disease. Lancet 369(9557), 218228.CrossRefGoogle Scholar
Yasuda, S, Inoue, K, Hirabayashi, M, Higashiyama, H, Yamamoto, Y, Fuyuhiro, H, Komure, O, Tanaka, F, Sobue, G, Tsuchiya, K, Hamada, K, Sasaki, H, Takeda, K, Ichijo, H and Kakizuka, A (1999) Triggering of neuronal cell death by accumulation of activated SEK1 on nuclear polyglutamine aggregations in PML bodies. Genes to Cells 4(12), 743756.CrossRefGoogle ScholarPubMed
Zhao, Y and Chen, LH. (2005) Eicosapentaenoic acid prevents lipopolysaccharide-stimulated DNA binding of activator protein-1 and c-Jun N-terminal kinase activity. Journal of Nutritional Biochemistry 16(2), 7884.CrossRefGoogle ScholarPubMed