Huperzine A for the treatment of cognitive, mood, and functional deficits after moderate and severe TBI (HUP-TBI): results of a Phase II randomized controlled pilot study: implications for understanding the placebo effect

References

• Centers for Disease Control and Prevention. Report to Congress on Traumatic Brain Injury in the United States: Epidemiology and Rehabilitation. Atlanta (GA): National Center for Injury Prevention and Control; Division of Unintentional Injury Prevention; 2015. [accessed 2019 Apr 2]. https://www.cdc.gov/traumaticbraininjury/pubs/congress_epi_rehab.html.
   Google Scholar
• Warden DL, Gordon B, McAllister TW, Silver JM, Barth JT, Bruns J, Drake A, Gentry T, Jagoda A, Katz DI, et al. Guidelines for the pharmacologic treatment of neurobehavioral sequelae of traumatic brain injury. J Neurotrauma. 2006;23(10):1468–501. doi:10.1089/neu.2006.23.1468.
   PubMed Web of Science ®Google Scholar
• Zhang YG, Zhao XY, Chen XQ, Wang Y, Yang HH, Hu GY.Spermidine antagonizes the inhibitory effect of Huperzine A on [3H]dizocilpine (MK-801) binding in synaptic membrane of rat cerebral cortex. Neurosci Lett. 2002;319(2):107–10. doi:10.1016/s0304-3940(01)02565-4.
   PubMed Web of Science ®Google Scholar
• Gordon RK, Nigam SV, Weitz JA, Dave JR, Doctor BP, Ved HS. The NMDA receptor ion channel: a site for binding of Huperzine A. J Appl Toxicol. 2001;21:S47–51. doi:10.1002/jat.805.
   PubMed Web of Science ®Google Scholar
• Peng Y, Jiang L, Lee DY, Schachter SC, Ma Z, Lemere CA. 2006. Effects of huperzine A on amyloid precursor protein processing and beta-amyloid generation in human embryonic kidney 293 APP Swedish mutant cells. J Neurosci Res. 84(4):903–11. doi:10.1002/jnr.20987.
   PubMed Web of Science ®Google Scholar
• Wang R, Yan H, Tang XC. 2006. Progress in studies of huperzine A, a natural cholinesterase inhibitor from Chinese herbal medicine. Acta Pharmacol Sin. 27(1):1–26. doi:10.1111/j.1745-7254.2006.00255.x.
   PubMed Web of Science ®Google Scholar
• Chu D, Liu W, Li Y, Li P, Gu J, Liu K. 2006. Pharmacokinetics of Huperzine A in dogs following single intravenous and oral administrations. Planta Med. 72(6):552–55. doi:10.1055/s-2006-931566.
   PubMed Web of Science ®Google Scholar
• Garcia GE, Hicks RP, Skanchy D, Moorad-Doctor DR, Doctor BP, Ved HS.Identification and characterization of the major Huperzine A metabolite in rat blood. J Anal Toxicol. 2004;28(5):379–83. doi:10.1093/jat/28.5.379.
   PubMed Web of Science ®Google Scholar
• Zhu XD, Giacobini E. 1995. Second generation cholinesterase inhibitors: effect of (L)-Huperzine-A on cortical biogenic amines. J Neurosci Res. 41(6):828–35. doi:10.1002/jnr.490410613.
   PubMed Web of Science ®Google Scholar
• Tian GX, Zhu XQ, Chen Y, Wu GC, Wang J. 2013. Huperzine A inhibits CCL2 production in experimental autoimmune encephalomyelitis mice and in cultured astrocyte. Int J Immunopathol Pharmacol. 26(3):757–64. doi:10.1177/039463201302600320.
   PubMed Web of Science ®Google Scholar
• Qian ZM, Ke Y. Huperzine A: is it an effective disease-modifying drug for Alzheimer’s disease? Front Aging Neurosci. 2014;6:216. doi:10.3389/fnagi.2014.00216.
   PubMed Web of Science ®Google Scholar
• Mei Z, Zheng P, Tan X, Wang Y, Situ B. 2017. Huperzine A alleviates neuroinflammation, oxidative stress and improves cognitive function after repetitive traumatic brain injury. Metab Brain Dis. 32(6):1861–69. doi:10.1007/s11011-017-0075-4.
   PubMed Web of Science ®Google Scholar
• Damar U, Gersner R, Johnstone JT, Kapur K, Collins S, Schachter S, Rotenberg A. 2018. Alterations in the timing of Huperzine A cerebral pharmacodynamics in the acute traumatic brain injury setting. J Neurotrauma. 35(2):393–97. doi:10.1089/neu.2017.5258.
   PubMed Web of Science ®Google Scholar
• Tenovuo O. 2005. Central acetylcholinesterase inhibitors in the treatment of chronic traumatic brain injury-clinical experience in 111 patients. Prog Neuropsychopharmacol Biol Psychiatry. 29(1):61–67. doi:10.1016/j.pnpbp.2004.10.006.
   PubMed Web of Science ®Google Scholar
• Zangara A.The psychopharmacology of huperzine A: an alkaloid with cognitive enhancing and neuroprotective properties of interest in the treatment of Alzheimer’s disease. Pharmacol Biochem Behav. 2003;75(3):675–86. doi:10.1016/s0091-3057(03)00111-4.
   PubMed Web of Science ®Google Scholar
• Xu ZQ, Liang XM, Juan-Wu ZYF, Zhu CX, Jiang XJ. 2012. Treatment with Huperzine A improves cognition in vascular dementia patients. Cell Biochem Biophys. 62(1):55–58. doi:10.1007/s12013-011-9258-5.
   PubMed Web of Science ®Google Scholar
• Yang G, Wang Y, Tian J, Liu JP. 2013. Huperzine A for Alzheimer’s disease: a systematic review and meta-analysis of randomized clinical trials. PLoS One. 8(9):e74916. doi:10.1371/journal.pone.0074916.
   PubMed Web of Science ®Google Scholar
• Meeusen R, Decroix L. 2018. Nutritional supplements and the brain. Int J Sport Nutr Exerc Metab. 28(2):200–11. doi:10.1123/ijsnem.2017-0314.
   PubMed Web of Science ®Google Scholar
• Xu SS, Gao ZX, Weng Z, Du ZM, Xu WA, Yang JS, Zhang ML, Tong ZH, Fang YS, Chai XS.Efficacy of tablet Huperzine-A on memory, cognition, and behavior in Alzheimer’s disease. Zhongguo Yao Li Xue Bao. 1995;16(5):391–95.
   PubMed Web of Science ®Google Scholar
• Rafii MS, Walsh S, Little JT, Behan K, Reynolds B, Ward C, Jin S, Thomas R, Aisen PS.Alzheimer’s disease cooperative study. A phase II trial of Huperzine A in mild to moderate Alzheimer disease. Neurology. 2011;76(16):1389–94. doi:10.1212/WNL.0b013e318216eb7b.
   PubMed Web of Science ®Google Scholar
• Edgington ES, Onghena P. Randomization tests. 4th ed. Boca Raton (FL): Chapman and Hall/CRC Press; 2007.
   Google Scholar
• Todman JB, Dugard P. Single-case and small-n experimental designs. Mahwah (NJ): Lawrence Erlbaum Associates; 2001.
   Google Scholar
• Kaiser J, Lacy MG.A general-purpose method for two group randomization tests. Stata J. 2009;9(1):70–85. doi:10.1177/1536867X0900900105.
   Web of Science ®Google Scholar
• Button KS, Kounali D, Thomas L, Wiles NJ, Peters TJ, Welton NJ, Ades AE, Lewis G.Minimal clinically important difference on the beck depression inventory-II according to the patient’s perspective. Psychol Med. 2015;45(15):3269–79.doi:10.1017/S0033291715001270.
   PubMed Web of Science ®Google Scholar
• Polich G, Iaccarino MA, Kaptchuk TJ, Morales-Quezada L, Zafonte R. 2018. Placebo effects in traumatic brain injury. J Neurotrauma. 35(11):1205–12. doi:10.1089/neu.2017.5506.
   PubMed Web of Science ®Google Scholar
• Ongaro G, Kaptchuk TJ. 2019. Symptom perception, placebo effects, and the Bayesian brain. Pain. 160(1):1–4. doi:10.1097/j.pain.0000000000001367.
   PubMed Web of Science ®Google Scholar
• Hall KT, Loscalzo J, Kaptchuk TJ. 2015. Genetics and the placebo effect: the placebome. Trends Mol Med. 21(5):285–94. doi:10.1016/j.molmed.2015.02.009.
   PubMed Web of Science ®Google Scholar
• Evers AWM, Colloca L, Blease C, Annoni M, Atlas LY, Benedetti F, Bingel U, Büchel C, Carvalho C, Colagiuri B, et al. Implications of placebo and nocebo effects for clinical practice: expert consensus. Psychother Psychosom. 2018;87(4):204–10. doi:10.1159/000490354.
   PubMed Web of Science ®Google Scholar
• Ashman TA, Cantor JB, Gordon WA, Spielman L, Flanagan S, Ginsberg A, Engmann C, Egan M, Ambrose F, Greenwald B. 2009. A randomized controlled trial of sertraline for the treatment of depression in persons with traumatic brain injury. Arch Phys Med Rehabil. 90(5):733–40. doi:10.1016/j.apmr.2008.11.005.
   PubMed Web of Science ®Google Scholar
• Hammond FM, Sherer M, Malec JF, Zafonte RD, Whitney M, Bell K, Dikmen S, Bogner J, Mysiw J, Pershad R. 2015. Amantadine effect on perceptions of irritability after traumatic brain injury: results of the amantadine irritability multisite study. J Neurotrauma. 32(16):1230–38. doi:10.1089/neu/2014.3803.
   PubMed Web of Science ®Google Scholar
• Kam-Hansen S, Jakubowski M, Kelley JM, Kirsch I, Hoaglin DC, Kaptchuk TJ, Burstein R. 2014. Altered placebo and drug labeling changes the outcome of episodic migraine attacks. Sci Transl Med. 6(218):218ra5. doi:10.1126/scitranslmed.3006175.
   PubMed Web of Science ®Google Scholar
• Kaptchuk TJ, Miller FG. Open label placebo: can honestly prescribed placebos evoke meaningful therapeutic benefits? BMJ. 2018;363:k3889. doi:10.1136/bmj.k3889.
   PubMed Web of Science ®Google Scholar
• Carvalho C, Caetano JM, Cunha L, Rebouta P, Kaptchuk TJ, Kirsch I. Open-label placebo treatment in chronic low back pain: a randomized controlled trial. Pain. 2016; 157(12):2766–72. Erratum in: Pain. 2017;158(2):365. doi:10.1097/j.pain.0000000000000700.
   PubMed Web of Science ®Google Scholar
• Ballou S, Kaptchuk TJ, Hirsch W, Nee J, Iturrino J, Hall KT, Kelley JM, Cheng V, Kirsch I, Jacobson E, et al. Open-label versus double-blind placebo treatment in irritable bowel syndrome: study protocol for a randomized controlled trial. Trials. 2017;18(1):234. doi:10.1186/s13063-017-1964-x.
   PubMed Web of Science ®Google Scholar
• Kelley JM, Kaptchuk TJ, Cusin C, Lipkin S, Fava M. 2012. Open-label placebo for major depressive disorder: a pilot randomized controlled trial. Psychother Psychosom. 81(5):312–14. doi:10.1159/000337053.
   PubMed Web of Science ®Google Scholar
• Lamm AG, Goldstein R, Giacino J, Niewczyk P, Schneider JC, Zafonte RD. Changes in patient demographics and outcomes in the inpatient rehabilitation facility traumatic brain injury population from 2002 to 2016: implications for patient care & clinical trials. Neurotrauma. [accessed 2019 Apr 2];36:2513–20. Epub ahead of print. doi:10.1089/neu.2018.6014.
   PubMed Web of Science ®Google Scholar
• Silver JM, Koumaras B, Chen M, Mirski D, Potkin SG, Reyes P, Warden D, Harvey PD, Arciniegas D, Katz DI. 2006. Effects of rivastigmine on cognitive function in patients with traumatic brain injury. Neurology. 67(5):748–55. doi:10.1212/01.wnl.0000234062.98062.e9.
   PubMed Web of Science ®Google Scholar
• Rybin D, Doros G, Pencina MJ, Fava M. 2015. Placebo non-response measure in sequential parallel comparison design studies. Stat Med. 34(15):2281–93. doi:10.1002/sim.6494.
   PubMed Web of Science ®Google Scholar
• Fava M, Evins AE, Dorer DJ, Schoenfeld DA. 2003. The problem of the placebo response in clinical trials for psychiatric disorders: culprits, possible remedies, and a novel study design approach. Psychother Psychosom. 72(3):115–27. doi:10.1159/000069738.
   PubMed Web of Science ®Google Scholar