The purpose of this review study is to reveal a potential threat of one type of such widely used and freely distributed drugs, which are proton pump inhibitors that might be the cause of the onset of both dementia and depression. The authors performed a literature review of available studies on the research topic describing the adverse effect of proton pum inhibitors (PPIs) (omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, pantoprazole, dexrabeprazole, ilaprazole). For a long time, PPIs were considered to be completely safe drug substances for both short and long-term use. In recent years, there have been a few contradictory studis of absolute safety, especially in patients, who have long been using PPIs. At this time when depression and dementia are rising in the population, this is a very worrying fact that needs to be highlighted, and which needs to be carefully studied and evaluated, ideally trying to prevent it. The findings of most research studies described in this review indicate that there is a direct association between the onset of dementia and depression on one side and the long-term use of PPIs on the other.

Biomedical Research Centrum University Hospital Hradec Králové Hradec Králové Czechia

Department of Neurology University Hospital Hradec Kralove Hradec Králové Czechia

Zobrazit více v PubMed

Maresova P, Klimova B, Novotny M, Kuca K. Alzheimer's disease and Parkinson's diseases: expected economic impact on Europe – a call for a uniform European strategy. J. Alzheimer's Dis. (2016) 54:1123–33. 10.3233/JAD-160484 PubMed DOI

WHO Mental Health of Older Adults. (2017). Available online at: http://www.who.int/news-room/fact-sheets/detail/mental-health-of-older-adults (Accessed September 10, 2018).

Langa KM. Is the risk of Alzheimer's disease and dementia declining? Alzheimer's Res. Ther. (2015) 7:1–4. 10.1186/s13195-015-0118-1 PubMed DOI PMC

WHO Depression. Key Facts. (2016) Available online at: http://www.who.int/mediacentre/factsheets/fs369/en/ (Accessed September, 10, 2018).

MHF Mental Health Statistics: Older People (2018). Available online at: https://www.mentalhealth.org.uk/statistics/mental-health-statistics-older-people (Accessed September 10, 2018).

MHF Fundamental Facts About Mental Health (2015). Available online at: https://www.mentalhealth.org.uk/sites/default/files/fundamental-facts-15.pdf (Accessed September 10, 2018).

Klimova B, Valis M, Kuca K. Dancing as an intervention tool for people with dementia: a mini-review. Curr Alzheimer Res. (2017) 14:1264–9. 10.2174/1567205014666170713161422 PubMed DOI

Maresova P, Klimova B. Non-Pharmacological Approaches in the Depression Treatment - Strengths and Weaknesses of Mobile Applications Use. In: Lecture Notes of the Institute for Computer Sciences, Social Informatics and Telecommunications Engineering 207. Cham: Springer; (2018).

NIH Depression and Older People (2017). Available online at: https://www.nia.nih.gov/health/depression-and-older-adults (Accessed September 10, 2018).

Klimova B, Maresova P, Valis M, Hort J, Kuca K. Alzheimer's disease and language impairments: social intervention and medical treatment. Clin Interv Aging (2015) 10:1401–8. 10.2147/CIA.S89714 PubMed DOI PMC

Imhann F, Bonder MJ, Vich Vila A, Fu J, Mujagic Z, Vork L, et al. . Proton pump inhibitors affect the gut microbiome. Gut (2015) 65:740–8. 10.1136/gutjnl-2015-310376 PubMed DOI PMC

Laudisio A, Antonelli Incalzi R, Gemma A, Giovannini S, Lo Monaco MR, Vetrano DL, et al. . Use of proton-pump inhibitors is associated with depression: a population-based study. Int Psychogeriatr (2018) 30:153–9. 10.1017/S1041610217001715 PubMed DOI

Targownik L. Discontinuing long-term ppi therapy: why, with whom, and how? Am J Gastroenterol. (2018) 113:519–28. 10.1038/ajg.2018.29 PubMed DOI

Cardona-Ospina JA, Medina-Morales DA, Rodríguez-Morales AJ, Machado-Alba JE. Evidence based medicine perspective on long-term adverse effects of proton pump inhibitors. Rev Col Gastroenterol. (2016) 31:403–8. Available online at: http://www.scielo.org.co/scielo.php?script=sci_abstract&pid=S0120-99572016000400010&lng=en&nrm=iso&tlng=en

Strand DS, Kim D, Peura DA. 25 Years of proton pump inhibitors: a comprehensive review. Gut Liver (2017) 11:27–37. 10.5009/gnl15502 PubMed DOI PMC

WHO ATC/DDD Index 2018. (2018). Available online at: https://www.whocc.no/atc_ddd_index/ (Accessed November 30, 2018).

WHO Global Guidelines (2018) WHO Global Guidelines,. Available online at: http://www.worldgastroenterology.org/guidelines/global-guidelines/gastroesophageal-reflux-disease/gastroesophageal-reflux-disease-english (Accessed November 30, 2018).

Nice Guidance. (2014). Nice Guidance Available online at: https://www.nice.org.uk/guidance/cg184 (Accessed November 30, 2018).

Gomm W, von Holt K, Thomé F, Broich K, Maier W, Fink A, et al. . Association of proton pump inhibitors with risk of dementia: a pharmacoepidemiological claims data analysis. JAMA Neurol. (2016) 73:410–6. 10.1001/jamaneurol.2015.4791 PubMed DOI

Eusebi LH, Rabitti S, Artesiani ML, Gelli D, Montagnani M, Zagari RM, et al. . Proton pump inhibitors: Risks of long-term use. J Gastroenterol Hepatol. (2017) 32:1295–302. 10.1111/jgh.13737 PubMed DOI

Martin RM, Dunn NR, Freemantle S, Shakir S. The rates of common adverse events reported during treatment with proton pump inhibitors used in general practice in England: cohort studies. Br J Clin Pharmacol. (2000) 50:366–72. 10.1046/j.1365-2125.2000.00262.x PubMed DOI PMC

Kinoshita Y, Ishimura N, Ishihara S. Advantages and disadvantages of long-term proton pump inhibitor use. J Neurogastroenterol Motil. (2018) 24:182–96. 10.5056/jnm18001 PubMed DOI PMC

EUDRAVIGILANCE - European Database of Suspected Adverse Drug Reaction Reports,. EUDRAVIGILANCE. (2018). Available online at: http://www.adrreports.eu/ (Accessed November 30, 2018).

Laine L, Nagar A. Long-term PPI use: balancing potential harms and documented benefits. Am J Gastroenterol. (2016) 111:913–5. 10.1038/ajg.2016.156 PubMed DOI

Freedberg DE, Kim LS, Yang YX. The risks and benefits of long-term use of proton pump inhibitors: expert review and best practice advice from the American gastroenterological association. Gastroenterology (2017) 152:706–15. 10.1053/j.gastro.2017.01.031 PubMed DOI

Lam JR, Schneider JL, Zhao W, Corley DA. Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B12 deficiency. JAMA (2013) 310:2435–42. 10.1001/jama.2013.280490 PubMed DOI

den Elzen WP, Groeneveld Y, de Ruijter W, Souverijn JH, le Cessie S, Assendelft WJ, et al. Long-term use of proton pump inhibitors and vitamin B12 status in elderly individuals. Aliment Pharmacol Ther. (2008) 27:491–7. 10.1111/j.1365-2036.2008.03601.x PubMed DOI

Sarzynski E, Puttarajappa C, Xie Y, Grover M, Laird-Fick H. Association between proton pump inhibitor use and anemia: a retrospective cohort study. Dig Dis Sci. (2011) 56:2349–53. 10.1007/s10620-011-1589-y PubMed DOI

Ajmera AV, Shastri GS, Gajera MJ, Judge TA. Suboptimal response to ferrous sulfate in iron-deficient patients taking omeprazole. Am J Ther. (2012) 19:185–9. 10.1097/MJT.0b013e3181f9f6d2 PubMed DOI

Stewart CA, Termanini B, Sutliff VE, Serrano J, Yu F, Gibril F, et al. . Iron absorption in patients with Zollinger-Ellison syndrome treated with long-term gastric acid antisecretory therapy. Aliment Pharmacol Ther. (1998) 12:83–98. 10.1046/j.1365-2036.1998.00274.x PubMed DOI

Epstein M, McGrath S, Law F. Proton-pump inhibitors and hypomagnesemic hypoparathyroidism. N Engl J Med. (2006) 355:1834–6. 10.1056/NEJMc066308 PubMed DOI

Cheungpasitporn W, Thongprayoon C, Kittanamongkolchai W, Srivali N, Edmonds PJ, Ungprasert P, et al. . Proton pump inhibitors linked to hypomagnesemia: a systematic review and meta-analysis of observational studies. Ren Fail (2015) 37:1237–41. 10.3109/0886022X.2015.1057800 PubMed DOI

Yang YX, Lewis JD, Epstein S, Metz DC. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA (2006) 296:2947–53. 10.1001/jama.296.24.2947 PubMed DOI

Vestergaard P, Rejnmark L, Mosekilde L. Proton pump inhibitors, histamine H2 receptor antagonists, and other antacid medications and the risk of fracture. Calcif Tissue Int. (2006) 79:76–83. 10.1007/s00223-006-0021-7 PubMed DOI

Targownik LE, Lix LM, Metge CJ, Prior HJ, Leung S, Leslie WD. Use of proton pump inhibitors and risk of osteoporosis-related fractures. CMAJ (2008) 179:319–26. 10.1503/cmaj.071330 PubMed DOI PMC

Corley DA, Kubo A, Zhao W, Quesenberry C. Proton pump inhibitors and histamine-2 receptor antagonists are associated with hip fractures among at-risk patients. Gastroenterology (2010) 139:93–101. 10.1053/j.gastro.2010.03.055 PubMed DOI PMC

Lewis SJ, Franco S, Young G, O'Keefe SJ. Altered bowel function and duodenal bacterial overgrowth in patients treated with omeprazole. Aliment Pharmacol Ther. (1996) 10:557–61. 10.1046/j.1365-2036.1996.d01-506.x PubMed DOI

Pereira SP, Gainsborough N, Dowling RH. Drug-induced hypochlorhydria causes high duodenal bacterial counts in the elderly. Aliment Pharmacol Ther. (1998) 12:99–104. 10.1046/j.1365-2036.1998.00275.x PubMed DOI

Lo WK, Chan WW. Proton pump inhibitor use and the risk of small intestinal bacterial overgrowth: a meta-analysis. Clin Gastroenterol Hepatol. (2012) 11:483–90. 10.1016/j.cgh.2012.12.011 PubMed DOI

Bavishi C, Dupont HL. Systematic review: the use of proton pump inhibitors and increased susceptibility to enteric infection. Aliment Pharmacol Ther. (2011) 34:1269–181. 10.1111/j.1365-2036.2011.04874.x PubMed DOI

Sheen E, Triadafilopoulos G. Adverse effects of long-term proton pump inhibitor therapy. Dig Dis Sci. (2011) 56:931–50. 10.1007/s10620-010-1560-3 PubMed DOI

Fireman Z, Kopelman Y, Sternberg A. Central nervous system side effects after proton pump inhibitor treatment. J Clin Gastroenterol. (1997) 25:718. 10.1097/00004836-199712000-00047 PubMed DOI

Akter S, Hassan MR, Shahriar M, Akter N, Abbas MG, Bhuiyan MA. Cognitive impact after short-term exposure to different proton pump inhibitors: assessment using CANTAB software. Alzheimers Res Ther. (2015) 7:79. 10.1186/s13195-015-0164-8 PubMed DOI PMC

Haenisch B, von Holt K, Wiese B, Prokein J, Lange C, Ernst A, et al. . Risk of dementia in elderly patients with the use of proton pump inhibitors. Eur Arch Psychiatry Clin Neurosci. (2015) 265:419–28. 10.1007/s00406-014-0554-0 PubMed DOI

Tai SY, Chien CY, Wu DC, Lin KD, Ho BL, Chang YH, et al. . Risk of dementia from proton pump inhibitor use in Asian population: a nationwide cohort study in Taiwan. PLoS ONE (2017) 12:e0171006. 10.1371/journal.pone.0171006 PubMed DOI PMC

Batchelor R, Gilmartin JF, Kemp W, Hopper I, Liew D. Dementia, cognitive impairment and proton pump inhibitor therapy: a systematic review. J Gastroenterol Hepatol. (2017) 32:1426–35. 10.1111/jgh.13750 PubMed DOI

Booker A, Jacob LE, Rapp M, Bohlken J, Kostev K. Risk factors for dementia diagnosis in German primary care practices. Int Psychogeriatr. (2016) 28:1059–65. 10.1017/S1041610215002082 PubMed DOI

Goldstein FC, Steenland K, Zhao L, Wharton W, Levey AI, Hajjar I. Proton pump inhibitors and risk of mild cognitive impairment and dementia. J Am Geriatr Soc. (2017) 65:1969–74. 10.1111/jgs.14956 PubMed DOI PMC

Otremba I, Wilczynski K, Szewieczek J. Delirium in the geriatric unit: proton-pump inhibitors and other risk factors. Clin Interv Aging (2016) 11:397–405. 10.2147/CIA.S103349 PubMed DOI PMC

Galatti L, Giustini SE, Sessa A, Polimeni G, Salvo F, Spina E, et al. . Neuropsychiatric reactions to drugs: an analysis of spontaneous reports from general practitioners in Italy. Pharmacol Res. (2005) 51:211–6. 10.1016/j.phrs.2004.08.003 PubMed DOI

Polimeni G, Cutroneo P, Gallo A, Gallo S, Spina E, Caputi AP. Rabeprazole and psychiatric symptoms. Ann Pharmacother. (2007) 41:1315–7. 10.1345/aph.1K134 PubMed DOI

Abela M, Aquilina N, Attard A. Omeprazole-induced delirium. Synapse (2014) 13:18–9. Available online at: https://www.um.edu.mt/library/oar//handle/123456789/13967

Heckmann JG, Birklein F, Neundörfer B. Omeprazole-induced delirium. J Neurol. (2000) 247:56–7. 10.1007/s004150050011 PubMed DOI

Badiola N, Alcalde V, Pujol A, Münter LM, Multhaup G, Lleó A, et al. . The proton-pump inhibitor lansoprazole enhances amyloid beta production. PLoS ONE (2013) 8:e58837. 10.1371/journal.pone.0058837 PubMed DOI PMC

Fujii S, Tanimukai H, Kashiwagi Y. Comparison and analysis of delirium induced by histamine H2 receptor antagonists and proton pump inhibitors in cancer patients. Case Rep Oncol. (2012) 5:409–12. 10.1159/000341873 PubMed DOI PMC

Fallahzadeh MK, Borhani Haghighi A, Namazi MR. Proton pump inhibitors: predisposers to Alzheimer disease? J Clin Pharm Ther. (2010) 35:125–6. 10.1111/j.1365-2710.2009.01100.x PubMed DOI