Advertisement

Current Psychiatry Reports

, 20:117 | Cite as

Diagnosis and Management of Neuropsychiatric Symptoms in Alzheimer’s Disease

  • David Wolinsky
  • Karina Drake
  • Jolene Bostwick
Complex Medical-Psychiatric Issues (MB Riba, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Complex Medical-Psychiatric Issues

Abstract

Purpose of Review

To explore the most recent developments in the effective diagnosis and treatment of neuropsychiatric symptoms (NPS) in Alzheimer’s disease (AD).

Recent Findings

The clinical diagnosis of NPS in AD is facilitated by the use of the Neuropsychiatric Inventory (NPI). CT and MRI scans can be useful for detecting structural changes indicating AD. Other promising diagnostic methodologies that are less frequently used in the clinical setting include positron emission tomography (PET) scans for detecting amyloid and blood tests for detecting serum biomarkers. Numerous pharmaceutical agents have been studied for their use in managing NPS, with antipsychotics being popular for managing agitation but also having significant side effects. Non-pharmacological interventions, such as reminiscence therapy and the Describe, Investigate, Create, Evaluate (DICE) approach may be able to provide treatment without such adverse effects.

Summary

Diagnosing AD and the comorbid NPS remains primarily a clinical endeavor with CT and MRI scans sometimes used, but evidence is amassing for the use of other imaging modalities and different lab tests for convenient and empiric diagnosis of AD to distinguish it from other psychiatric illnesses. The number of pharmacologic treatments for NPS that are safe as well as efficacious remains limited, yet non-pharmacologic interventions have clear clinical utility. In addition to searching for more successful pharmacological treatments, further research should focus on novel diagnostic tests and non-pharmacologic therapies.

Keywords

Neuropsychiatric symptoms Alzheimer’s disease Antipsychotics Brain imaging DICE method Acetylcholinesterase inhibitors 

Notes

Acknowledgments

The editors would like to thank Dr. Madhavi Nagalla for taking the time to review this manuscript.

Compliance with Ethical Standards

Conflict of Interest

David Wolinsky, Karina Drake, and Jolene Bostwick each declare no potential conflicts of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    No Author (2018) 2018 Alzheimer’s disease facts and figures. https://www.alz.org/facts/. Accessed 4 Apr 2018.
  2. 2.
    No Author (2018) Fact sheet. Alzheimer’s association. http://act.alz.org/site/DocServer/2012_Costs_Fact_Sheet_version_2.pdf?docID=7161. Accessed July 20th, 2018.
  3. 3.
    •• Zhao QF, Tan L, Wang HF, Jiang T, Tan MS, Tan L, et al. The prevalence of neuropsychiatric symptoms in Alzheimer’s disease: systematic review and meta-analysis. J Affect Disord. 2016;190:264–71 This recent meta-analysis looks at pertinent studies of AD from 1964 to 2014 to determine the most frequent NPS in AD patients.CrossRefPubMedGoogle Scholar
  4. 4.
    Steinberg M, Shao H, Zandi P, Lyketsos CG, Welsh-Bohmer KA, Norton MC, et al. Point and 5-year period prevalence of neuropsychiatric symptoms in dementia: the Cache County study. International journal of geriatric psychiatry. 2008;23(2):170–7.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    •• Peters ME, Schwartz S, Han D, Rabins PV, Steinberg M, Tschanz JT, et al. Neuropsychiatric symptoms as predictors of progression to severe Alzheimer’s dementia and death: the Cache County Dementia Progression Study. Am J Psychiatry. 2015;172(5):460–5 This cluster analysis of the different NPS identifies which ones can herald a more rapid decline and increased mortality in AD patients.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Hampel H, Mesulam MM, Cuello AC, Farlow MR, Giacobini E, Grossberg GT, et al. The cholinergic system in the pathophysiology and treatment of Alzheimer’s disease. Brain. 2018;141(7):1917–33.CrossRefPubMedGoogle Scholar
  7. 7.
    Polvikoski T, Sulkava R, Haltia M, Kainulainen K, Vuorio A, Verkkoniemi A, et al. Apolipoprotein E, dementia, and cortical deposition of β-amyloid protein. N Engl J Med. 1995;333(19):1242–8.CrossRefPubMedGoogle Scholar
  8. 8.
    Iqbal K, Alonso AD, Chen S, Chohan MO, El-Akkad E, Gong CX, et al. Tau pathology in Alzheimer disease and other tauopathies. Biochim Biophys Acta (BBA) - Mol Basis Dis. 2005;1739(2–3):198–210.CrossRefGoogle Scholar
  9. 9.
    Johnson KA, Fox NC, Sperling RA, Klunk WE. Brain imaging in Alzheimer disease. Cold Spring Harbor perspectives in medicine. 2012;2(4):a006213.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    •• Nowrangi MA, Lyketsos CG, Rosenberg PB. Principles and management of neuropsychiatric symptoms in Alzheimer’s dementia. Alzheimers Res Ther. 2015;7(1):12 This review article posits that NPS in AD are related to the damage in discrete brain regions that together are essential for adequate attention, mood regulation, and behavior control.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    • Sampath D, Sathyanesan M, Newton SS. Cognitive dysfunction in major depression and Alzheimer’s disease is associated with hippocampal–prefrontal cortex dysconnectivity. Neuropsychiatr Dis Treat. 2017;13:1509 This review of fMRI studies in AD patients illustrates the role of the hypothalamic-prefrontal cortex in AD and major depressive disorder (MDD), and also identifies the different fMRI features between these illnesses.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Braak H, Braak E, Bohl J. Staging of Alzheimer-related cortical destruction. Eur Neurol. 1993;33(6):403–8.CrossRefPubMedGoogle Scholar
  13. 13.
    • Šimić G, Leko MB, Wray S, Harrington CR, Delalle I, Jovanov-Milošević N, et al. Monoaminergic neuropathology in Alzheimer’s disease. Prog Neurobiol. 2017;151:101–38 This comprehensive review article focuses on the monoamine changes in AD and the evidence for how changes in the levels of monoamines such as dopamine and serotonin can yield NPS.CrossRefPubMedGoogle Scholar
  14. 14.
    Ramirez MJ, Lai MK, Tordera RM, Francis PT. Serotonergic therapies for cognitive symptoms in Alzheimer’s disease: rationale and current status. Drugs. 2014;74(7):729–36.CrossRefPubMedGoogle Scholar
  15. 15.
    Lai MK, Tsang SW, Francis PT, Esiri MM, Keene J, Hope T, et al. Reduced serotonin 5-HT1A receptor binding in the temporal cortex correlates with aggressive behavior in Alzheimer disease. Brain Res. 2003;974(1–2):82–7.CrossRefPubMedGoogle Scholar
  16. 16.
    Le Heron C, Apps MA, Husain M. The anatomy of apathy: a neurocognitive framework for amotivated behaviour. Neuropsychologia. 2017.Google Scholar
  17. 17.
    Lei S. Serotonergic modulation of neural activities in the entorhinal cortex. International journal of physiology, pathophysiology and pharmacology. 2012;4(4):201.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Ouchi Y, Yoshikawa E, Futatsubashi M, Yagi S, Ueki T, Nakamura K. Altered brain serotonin transporter and associated glucose metabolism in Alzheimer disease. J Nucl Med. 2009;50(8):1260–6.CrossRefPubMedGoogle Scholar
  19. 19.
    Baune BT, Smith E, Reppermund S, Air T, Samaras K, Lux O, et al. Inflammatory biomarkers predict depressive, but not anxiety symptoms during aging: the prospective Sydney Memory and Aging Study. Psychoneuroendocrinology. 2012;37(9):1521–30.CrossRefPubMedGoogle Scholar
  20. 20.
    Torres-Platas SG, Cruceanu C, Chen GG, Turecki G, Mechawar N. Evidence for increased microglial priming and macrophage recruitment in the dorsal anterior cingulate white matter of depressed suicides. Brain Behav Immun. 2014;42:50–9.CrossRefPubMedGoogle Scholar
  21. 21.
    • Barron H, Hafizi S, Andreazza AC, Mizrahi R. Neuroinflammation and oxidative stress in psychosis and psychosis risk. Int J Mol Sci. 2017;18(3):651 An updated look at the evidence for how neuroinflammation can lead to schizophrenia and the clinical implications for this information.CrossRefPubMedCentralGoogle Scholar
  22. 22.
    Banerjee A, Khemka VK, Roy D, Dhar A, Roy TK, Biswas A, et al. Role of pro-inflammatory cytokines and vitamin D in probable Alzheimer’s disease with depression. Aging and disease. 2017;8(3):267.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Deane R, Singh I, Sagare AP, Bell RD, Ross NT, LaRue B, et al. A multimodal RAGE-specific inhibitor reduces amyloid β–mediated brain disorder in a mouse model of Alzheimer disease. J Clin Invest. 2012;122(4):1377–92.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Chen WW, Zhang X, Huang WJ. Role of neuroinflammation in neurodegenerative diseases. Mol Med Rep. 2016;13(4):3391–6.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Bu XL, Yao XQ, Jiao SS, Zeng F, Liu YH, Xiang Y, et al. A study on the association between infectious burden and Alzheimer’s disease. Eur J Neurol. 2015;22(12):1519–25.CrossRefPubMedGoogle Scholar
  26. 26.
    Wallin K, Solomon A, Kåreholt I, Tuomilehto J, Soininen H, Kivipelto M. Midlife rheumatoid arthritis increases the risk of cognitive impairment two decades later: a population-based study. J Alzheimers Dis. 2012;31(3):669–76.CrossRefPubMedGoogle Scholar
  27. 27.
    Diniz BS, Butters MA, Albert SM, Dew MA, Reynolds CF. Late-life depression and risk of vascular dementia and Alzheimer’s disease: systematic review and meta-analysis of community-based cohort studies. Br J Psychiatry. 2013;202(5):329–35.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    •• Wang J, Tan L, Wang HF, Tan CC, Meng XF, Wang C, et al. Anti-inflammatory drugs and risk of Alzheimer’s disease: an updated systematic review and meta-analysis. J Alzheimers Dis. 2015;44(2):385–96 Meta-analysis finding the capacity for NSAID use to decrease the risk of Alzheimer’s disease, further illustrating a link between inflammation and AD as well as arguing for more established studies to look into the role of anti-inflammatory agents to reduce the risk of dementia.CrossRefPubMedGoogle Scholar
  29. 29.
    • Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The Neuropsychiatric Inventory comprehensive assessment of psychopathology in dementia. Neurology. 1994;44(12):2308 This seminal article proposed the NPI for diagnosing psychiatric symptoms in patients with dementia. CrossRefPubMedGoogle Scholar
  30. 30.
    De Medeiros K, Robert P, Gauthier S, Stella F, Politis A, Leoutsakos J, et al. The Neuropsychiatric Inventory-Clinician rating scale (NPI-C): reliability and validity of a revised assessment of neuropsychiatric symptoms in dementia. Int Psychogeriatr. 2010;22(6):984–94.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Wood S, Cummings JL, Hsu MA, Barclay T, Wheatley MV, Yarema KT, et al. The use of the neuropsychiatric inventory in nursing home residents: characterization and measurement. Am J Geriatr Psychiatry. 2000;8(1):75–83.CrossRefPubMedGoogle Scholar
  32. 32.
    Kaufer DI, Cummings JL, Ketchel P, Smith V, MacMillan A, Shelley T, et al. Validation of the NPI-Q, a brief clinical form of the Neuropsychiatric Inventory. The Journal of neuropsychiatry and clinical neurosciences. 2000;12(2):233–9.CrossRefPubMedGoogle Scholar
  33. 33.
    David R, Koulibaly M, Benoit M, Garcia R, Caci H, Darcourt J, et al. Striatal dopamine transporter levels correlate with apathy in neurodegenerative diseases: a SPECT study with partial volume effect correction. Clin Neurol Neurosurg. 2008;110(1):19–24.CrossRefPubMedGoogle Scholar
  34. 34.
    Sultzer DL, Melrose R, Campa OR, Achamallah N, Harwood D, Brody A, et al. Cholinergic receptor imaging in Alzheimer’s disease: method and early results, in annual meeting of the American Association for Geriatric Psychiatry. Am J Geriatr Psychiatry. 2010;18:S71–2.CrossRefGoogle Scholar
  35. 35.
    Richard E, Schmand B, Eikelenboom P, Yang SC, Ligthart SA, Van Charante EM, et al. Symptoms of apathy are associated with progression from mild cognitive impairment to Alzheimer’s disease in non-depressed subjects. Dement Geriatr Cogn Disord. 2012;33(2–3):204–9.CrossRefPubMedGoogle Scholar
  36. 36.
    Gonfrier S, Andrieu S, Renaud D, Vellas B, Robert PH. Course of neuropsychiatric symptoms during a 4-year follow up in the REAL-FR cohort. J Nutr Health Aging. 2012;16(2):134–7.CrossRefPubMedGoogle Scholar
  37. 37.
    • Sahin S, Önal TO, Cinar N, Bozdemir M, Çubuk R, Karsidag S. Distinguishing depressive pseudodementia from Alzheimer disease: a comparative study of hippocampal volumetry and cognitive tests. Dementia and geriatric cognitive disorders extra. 2017;7(2):230–9 A recent study of patients with AD that detected imaging changes to act as biomarkers for distinguishing pseudodementia from AD. CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Kang H, Zhao F, You L, Giorgetta C. Pseudo-dementia: a neuropsychological review. Annals of Indian Academy of Neurology. 2014;17(2):147.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Small GW, Jarvik LF, Liston EH. Diagnosis and treatment of dementia in the aged. West J Med. 1981;135(6):469.PubMedPubMedCentralGoogle Scholar
  40. 40.
    • Van der Mussele S, Mariën P, Saerens J, Somers N, Goeman J, De Deyn PP, et al. Psychosis associated behavioral and psychological signs and symptoms in mild cognitive impairment and Alzheimer’s dementia. Aging Ment Health. 2015;19(9):818–28 This study of patients with AD and mild cognitive impairment found that psychotic symptoms were far more prevalent in patients with full-blown dementia than those with MCI. CrossRefPubMedGoogle Scholar
  41. 41.
    Jeste DV, Finkel SI. Psychosis of Alzheimer’s disease and related dementias. Am J Geriatr Psychiatry. 2000;8:29–34.CrossRefPubMedGoogle Scholar
  42. 42.
    Murray PS, Kumar S, DeMichele-Sweet MA, Sweet RA. Psychosis in Alzheimer’s disease. Biol Psychiatry. 2014;75(7):542–52.CrossRefPubMedGoogle Scholar
  43. 43.
    Ropacki SA, Jeste DV. Epidemiology of and risk factors for psychosis of Alzheimer’s disease: a review of 55 studies published from 1990 to 2003. Am J Psychiatr. 2005;162(11):2022–30.CrossRefPubMedGoogle Scholar
  44. 44.
    Scharre DW, Chang SI, Nagaraja HN, Park A, Adeli A, Agrawal P, et al. Paired studies comparing clinical profiles of Lewy body dementia with Alzheimer’s and Parkinson’s diseases. J Alzheimers Dis. 2016;54(3):995–1004.CrossRefPubMedGoogle Scholar
  45. 45.
    Ballard C, Holmes C, McKeith I, Neill D, O’Brien J, Cairns N, et al. Psychiatric morbidity in dementia with Lewy bodies: a prospective clinical and neuropathological comparative study with Alzheimer’s disease. Am J Psychiatr. 1999;156(7):1039–45.PubMedGoogle Scholar
  46. 46.
    McKeith IG, Boeve BF, Dickson DW, Halliday G, Taylor JP, Weintraub D, et al. Diagnosis and management of dementia with Lewy bodies fourth consensus report of the DLB consortium. Neurology. 2017;89(1):88–100.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Yaffe K, Freimer D, Chen H, Asao K, Rosso A, Rubin S, et al. Olfaction and risk of dementia in a biracial cohort of older adults. Neurology. 2017;88(5):456–62.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Lafaille-Magnan ME, Poirier J, Etienne P, Tremblay-Mercier J, Frenette J, Rosa-Neto P, et al. Odor identification as a biomarker of preclinical AD in older adults at risk. Neurology. 2017;89(4):327–35.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Price JL Olfactory higher centers anatomy. In Encyclopedia of neuroscience. Squire LR, editor. Elsevier; 2009.Google Scholar
  50. 50.
    Cerejeira J, Lagarto L, Mukaetova-Ladinska E. Behavioral and psychological symptoms of dementia. Front Neurol. 2012;3:73.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Romero AP, Garrido SG. The importance of behavioural and pyschological symptoms in Alzheimer disease. Neurología (English Edition) 2018.Google Scholar
  52. 52.
    Atri A Imaging of neurodegenerative cognitive and behavioral disorders: practical considerations for dementia clinical practice. In Handbook of clinical neurology 2016 (Vol. 136, pp. 971–984). Elsevier.Google Scholar
  53. 53.
    Maruszak A, Thuret S. Why looking at the whole hippocampus is not enough—a critical role for anteroposterior axis, subfield and activation analyses to enhance predictive value of hippocampal changes for Alzheimer’s disease diagnosis. Front Cell Neurosci. 2014;8:95.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    •• Lui S, Zhou XJ, Sweeney JA, Gong Q. Psychoradiology: the frontier of neuroimaging in psychiatry. Radiology. 2016;281(2):357–72 Recent overview of neurologic imaging for diagnosis psychiatric disorders. CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Haukvik UK, Hartberg CB, Agartz I. Schizophrenia--what does structural MRI show? Tidsskrift for den Norske laegeforening: tidsskrift for praktisk medicin, ny raekke. 2013;133(8):850–3.CrossRefGoogle Scholar
  56. 56.
    Wang X, Wang J, He Y, Li H, Yuan H, Evans A, et al. Apolipoprotein E ε4 modulates cognitive profiles, hippocampal volume, and resting-state functional connectivity in Alzheimer’s disease. J Alzheimers Dis. 2015;45(3):781–95.CrossRefPubMedGoogle Scholar
  57. 57.
    Xiang Q, Wang Y, Zhang J, Li Y, Xiao Z, Jiang K, et al. Progressive brain changes in the early stage of schizophrenia: a combined structural MRI and DTI study. Neuropsychiatry (London). 2018;8(2):523–32.Google Scholar
  58. 58.
    • Amen DG, Krishnamani P, Meysami S, Newberg A, Raji CA. Classification of depression, cognitive disorders, and co-morbid depression and cognitive disorders with perfusion SPECT neuroimaging. J Alzheimers Dis. 2017;57(1):253–66 This retrospective study of SPECT scans in patients with depression and cognitive disorders is one of the first to not only show the clinical utility of SPECT scans in diagnosing dementia but also to isolate which brain regions are most hypoperfused. CrossRefPubMedGoogle Scholar
  59. 59.
    Salmon E. Functional brain imaging applications to differential diagnosis in the dementias. Curr Opin Neurol. 2002;15(4):439–44.CrossRefPubMedGoogle Scholar
  60. 60.
    Trzepacz PT, Yu P, Sun J, Schuh K, Case M, Witte MM, et al. Comparison of neuroimaging modalities for the prediction of conversion from mild cognitive impairment to Alzheimer’s dementia. Neurobiol Aging. 2014;35(1):143–51.CrossRefPubMedGoogle Scholar
  61. 61.
  62. 62.
    Rogers MB In Clinical use, amyloid scans change two-thirds of treatment plans [Internet]. Alzforum. 2017 [cited 2018May7]. Available from: https://www.alzforum.org/news/conference-coverage/clinical-use-amyloid-scans-change-two-thirds-treatment-plans
  63. 63.
    •• Sharma N, Singh AN. Exploring biomarkers for Alzheimer’s disease. J Clin Diagn Res. 2016;10(7):KE01 A thorough and up-to-date overview of the laboratory findings that can unearth potential biomarkers for Alzheimer’s disease. PubMedPubMedCentralGoogle Scholar
  64. 64.
    Koyama A, Okereke OI, Yang T, Blacker D, Selkoe DJ, Grodstein F. Plasma amyloid-β as a predictor of dementia and cognitive decline: a systematic review and meta-analysis. Arch Neurol. 2012;69(7):824–31.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Nakamura A, Kaneko N, Villemagne VL, Kato T, Doecke J, Doré V, et al. High performance plasma amyloid-β biomarkers for Alzheimer’s disease. Nature. 2018;554(7691):249–54.CrossRefGoogle Scholar
  66. 66.
    Lövheim H, Elgh F, Johansson A, Zetterberg H, Blennow K, Hallmans G, et al. Plasma concentrations of free amyloid β cannot predict the development of Alzheimer’s disease. Alzheimers Dement. 2017;13(7):778–82.CrossRefGoogle Scholar
  67. 67.
    Popp J, Oikonomidi A, Tautvydaitė D, Dayon L, Bacher M, Migliavacca E, et al. Markers of neuroinflammation associated with Alzheimer’s disease pathology in older adults. Brain Behav Immun. 2017;62:203–11.CrossRefPubMedGoogle Scholar
  68. 68.
    King E, O’Brien JT, Donaghy P, Morris C, Barnett N, Olsen K, et al. Peripheral inflammation in prodromal Alzheimer’s and Lewy body dementias. J Neurol Neurosurg Psychiatry. 2018;89(4):339–45.CrossRefPubMedGoogle Scholar
  69. 69.
    Cheng L, Doecke JD, Sharples RA, Villemagne VL, Fowler CJ, Rembach A, et al. Prognostic serum miRNA biomarkers associated with Alzheimer’s disease shows concordance with neuropsychological and neuroimaging assessment. Mol Psychiatry. 2015;20(10):1188–96.CrossRefPubMedGoogle Scholar
  70. 70.
    Pogue AI, Lukiw WJ. Up-regulated pro-inflammatory microRNAs (miRNAs) in Alzheimer’s disease (AD) and age-related macular degeneration (AMD). Cell Mol Neurobiol. 2018;38(5):1021–31.CrossRefPubMedGoogle Scholar
  71. 71.
    • Moradifard S, Hoseinbeyki M, Ganji SM, Minuchehr Z. Analysis of microRNA and gene expression profiles in Alzheimer’s disease: a meta-analysis approach. Sci Rep. 2018;8(1):4767 In addition to summarizing the miRNAs with expressions that correlate with AD, this meta-analysis also identifies which miRNAs are upregulated and which are downregulated, as well as the genes transcribed from these miRNAs. CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Schneider LS, Tariot PN, Dagerman KS, Davis SM, Hsiao JK, Ismail MS, et al. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer’s disease. N Engl J Med. 2006;355(15):1525–38.CrossRefPubMedGoogle Scholar
  73. 73.
    Maust DT, Kim HM, Seyfried LS, Chiang C, Kavanagh J, Schneider LS, et al. Antipsychotics, other psychotropics, and the risk of death in patients with dementia: number needed to harm. JAMA psychiatry. 2015;72(5):438–45.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Corbett A, Burns A, Ballard C. Don’t use antipsychotics routinely to treat agitation and aggression in people with dementia. BMJ. 2014;349(g6420):25368388.Google Scholar
  75. 75.
    Gerhard T, Huybrechts K, Olfson M, Schneeweiss S, Bobo WV, Doraiswamy PM, et al. Comparative mortality risks of antipsychotic medications in community-dwelling older adults. Br J Psychiatry. 2014;205(1):44–51.CrossRefPubMedGoogle Scholar
  76. 76.
    Kales HC, Kim HM, Zivin K, Valenstein M, Seyfried LS, Chiang C, et al. Risk of mortality among individual antipsychotics in patients with dementia. Am J Psychiatr. 2012;169(1):71–9.CrossRefPubMedGoogle Scholar
  77. 77.
    Huybrechts KF, Gerhard T, Crystal S, Olfson M, Avorn J, Levin R, et al. Differential risk of death in older residents in nursing homes prescribed specific antipsychotic drugs: population based cohort study. BMJ. 2012;344:e977.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Rossom RC, Rector TS, Lederle FA, Dysken MW. Are all commonly prescribed antipsychotics associated with greater mortality in elderly male veterans with dementia? J Am Geriatr Soc. 2010;58(6):1027–34.CrossRefPubMedGoogle Scholar
  79. 79.
    Schneider LS, Dagerman K, Insel PS. Efficacy and adverse effects of atypical antipsychotics for dementia: meta-analysis of randomized, placebo-controlled trials. Am J Geriatr Psychiatry. 2006;14(3):191–210.CrossRefPubMedGoogle Scholar
  80. 80.
    Sultzer DL, Davis SM, Tariot PN, Dagerman KS, Lebowitz BD, Lyketsos CG, et al. Clinical symptom responses to atypical antipsychotic medications in Alzheimer’s disease: phase 1 outcomes from the CATIE-AD effectiveness trial. Am J Psychiatr. 2008;165(7):844–54.CrossRefPubMedGoogle Scholar
  81. 81.
    De Deyn P, Jeste DV, Swanink R, Kostic D, Breder C, Carson WH, et al. Aripiprazole for the treatment of psychosis in patients with Alzheimer’s disease: a randomized, placebo-controlled study. J Clin Psychopharmacol. 2005;25(5):463–7.CrossRefPubMedGoogle Scholar
  82. 82.
    •• Wang J, Yu JT, Wang HF, Meng XF, Wang C, Tan CC, et al. Pharmacological treatment of neuropsychiatric symptoms in Alzheimer’s disease: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry. 2015;86:101–9 A very helpful meta-analysis that compares and contrasts different classes of pharmacologics for the management of NPS in AD. CrossRefPubMedGoogle Scholar
  83. 83.
    Mintzer JE, Tune LE, Breder CD, Swanink R, Marcus RN, McQuade RD, et al. Aripiprazole for the treatment of psychoses in institutionalized patients with Alzheimer dementia: a multicenter, randomized, double-blind, placebo-controlled assessment of three fixed doses. Am J Geriatr Psychiatry. 2007;15(11):918–31.CrossRefPubMedGoogle Scholar
  84. 84.
    Yohanna D, Cifu AS. Antipsychotics to treat agitation or psychosis in patients with dementia. JAMA. 2017;318(11):1057–8.CrossRefPubMedGoogle Scholar
  85. 85.
    •• Reus VI, Fochtmann LJ, Eyler AE, Hilty DM, Horvitz-Lennon M, Jibson MD, et al. The American Psychiatric Association practice guideline on the use of antipsychotics to treat agitation or psychosis in patients with dementia. Am J Psychiatr. 2016;173(5):543–6 The most recent APA guidelines on using antipsychotics in patients with Alzheimer’s dementia. CrossRefPubMedGoogle Scholar
  86. 86.
    • Tampi RR, Tampi DJ, Balachandran S. Antipsychotics, antidepressants, anticonvulsants, melatonin, and benzodiazepines for behavioral and psychological symptoms of dementia: a systematic review of meta-analyses. Current Treatment Options in Psychiatry. 2017;4(1):55–79 An especially helpful look at the many different medications proposed for treating NPS. CrossRefGoogle Scholar
  87. 87.
    Di Santo SG, Prinelli F, Adorni F, Caltagirone C, Musicco M. A meta-analysis of the efficacy of donepezil, rivastigmine, galantamine, and memantine in relation to severity of Alzheimer’s disease. J Alzheimers Dis. 2013;35(2):349–61.CrossRefPubMedGoogle Scholar
  88. 88.
    Tan CC, Yu JT, Wang HF, Tan MS, Meng XF, Wang C, et al. Efficacy and safety of donepezil, galantamine, rivastigmine, and memantine for the treatment of Alzheimer’s disease: a systematic review and meta-analysis. J Alzheimers Dis. 2014;41(2):615–31.CrossRefPubMedGoogle Scholar
  89. 89.
    Gauthier S, Loft H, Cummings J. Improvement in behavioural symptoms in patients with moderate to severe Alzheimer’s disease by memantine: a pooled data analysis. International journal of geriatric psychiatry. 2008;23(5):537–45.CrossRefPubMedGoogle Scholar
  90. 90.
    Orgeta V, Tabet N, Nilforooshan R, Howard R. Efficacy of antidepressants for depression in Alzheimer’s disease: systematic review and meta-analysis. J Alzheimers Dis. 2017;58(3):725–33.CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Porsteinsson AP, Drye LT, Pollock BG, Devanand DP, Frangakis C, Ismail Z, et al. Effect of citalopram on agitation in Alzheimer disease: the CitAD randomized clinical trial. JAMA. 2014;311(7):682–91.CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Leonpacher AK, Peters ME, Drye LT, Makino KM, Newell JA, Devanand DP, et al. Effects of citalopram on neuropsychiatric symptoms in Alzheimer’s dementia: evidence from the CitAD study. Am J Psychiatr. 2016;173(5):473–80.CrossRefPubMedGoogle Scholar
  93. 93.
    Xiao H, Su Y, Cao X, Sun S, Liang Z. A meta-analysis of mood stabilizers for Alzheimer’s disease. Journal of Huazhong University of Science and Technology [Medical Sciences]. 2010;30(5):652–8.CrossRefGoogle Scholar
  94. 94.
    Forlenza OV, De-Paula VD, Diniz BS. Neuroprotective effects of lithium: implications for the treatment of Alzheimer’s disease and related neurodegenerative disorders. ACS Chem Neurosci. 2014;5(6):443–50.CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Padala PR, Padala KP, Lensing SY, Ramirez D, Monga V, Bopp MM, et al. Methylphenidate for apathy in community-dwelling older veterans with mild Alzheimer’s disease: a double-blind, randomized, placebo-controlled trial. Am J Psychiatr. 2017;175(2):159–68.CrossRefPubMedGoogle Scholar
  96. 96.
    Rosenberg PB, Lanctôt KL, Drye LT, Herrmann N, Scherer RW, Bachman DL, et al. Safety and efficacy of methylphenidate for apathy in Alzheimer’s disease: a randomized, placebo-controlled trial. The Journal of clinical psychiatry. 2013;74(8):810–6.CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Sepehry AA, Sarai M, Hsiung GY. Pharmacological therapy for apathy in Alzheimer’s disease: a systematic review and meta-analysis. Can J Neurol Sci. 2017;44(3):267–75.CrossRefPubMedGoogle Scholar
  98. 98.
    Scherer RW, Drye L, Mintzer J, Lanctôt K, Rosenberg P, Herrmann N, et al. The Apathy in Dementia Methylphenidate Trial 2 (ADMET 2): study protocol for a randomized controlled trial. Trials. 2018;19(1):46.CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Song C, Shieh CH, Wu YS, Kalueff A, Gaikwad S, Su KP. The role of omega-3 polyunsaturated fatty acids eicosapentaenoic and docosahexaenoic acids in the treatment of major depression and Alzheimer’s disease: acting separately or synergistically? Prog Lipid Res. 2016;62:41–54.CrossRefPubMedGoogle Scholar
  100. 100.
    Bergantin LB, Caricati-Neto A. Challenges for the pharmacological treatment of neurological and psychiatric disorders: implications of the Ca2+/cAMP intracellular signalling interaction. Eur J Pharmacol. 2016;788:255–60.CrossRefPubMedGoogle Scholar
  101. 101.
    van den Berg JF, Kruithof HC, Kok RM, Verwijk E, Spaans HP. Electroconvulsive therapy for agitation and aggression in dementia: a systematic review. Am J Geriatr Psychiatry. 2018;26(4):419–34.CrossRefPubMedGoogle Scholar
  102. 102.
    Teri L, Logsdon RG, Peskind E, Raskind M, Weiner MF, Tractenberg RE, et al. Treatment of agitation in AD A randomized, placebo-controlled clinical trial. Neurology. 2000;55(9):1271–8 This trial found that, contrary to its own hypothesis, behavioral management techniques were just as effective as haloperidol in managing agitation.CrossRefPubMedGoogle Scholar
  103. 103.
    Teri L, Gibbons LE, McCurry SM, Logsdon RG, Buchner DM, Barlow WE, et al. Exercise plus behavioral management in patients with Alzheimer disease: a randomized controlled trial. JAMA. 2003;290(15):2015–22.CrossRefPubMedGoogle Scholar
  104. 104.
    Kurz A, Thöne-Otto A, Cramer B, Egert S, Frölich L, Gertz HJ, et al. CORDIAL: cognitive rehabilitation and cognitive-behavioral treatment for early dementia in Alzheimer disease: a multicenter, randomized, controlled trial. Alzheimer Dis Assoc Disord. 2012;26(3):246–53.CrossRefPubMedGoogle Scholar
  105. 105.
    Guetin S, Portet F, Picot MC, Pommié C, Messaoudi M, Djabelkir L, et al. Effect of music therapy on anxiety and depression in patients with Alzheimer’s type dementia: randomised, controlled study. Dement Geriatr Cogn Disord. 2009;28(1):36–46.CrossRefPubMedGoogle Scholar
  106. 106.
    Cotelli M, Manenti R, Zanetti O. Reminiscence therapy in dementia: a review. Maturitas. 2012;72(3):203–5.CrossRefPubMedGoogle Scholar
  107. 107.
    Duru Aşiret G, Kapucu S. The effect of reminiscence therapy on cognition, depression, and activities of daily living for patients with Alzheimer disease. J Geriatr Psychiatry Neurol. 2016;29(1):31–7.CrossRefPubMedGoogle Scholar
  108. 108.
    Kaymaz TT, Ozdemir L. Effects of aromatherapy on agitation and related caregiver burden in patients with moderate to severe dementia: a pilot study. Geriatr Nurs. 2017;38(3):231–7.CrossRefGoogle Scholar
  109. 109.
    Yang YP, Lee FP, Chao HC, Hsu FY, Wang JJ. Comparing the effects of cognitive stimulation, reminiscence, and aroma-massage on agitation and depressive mood in people with dementia. J Am Med Dir Assoc. 2016;17(8):719–24.CrossRefPubMedGoogle Scholar
  110. 110.
    •• Kales HC, Gitlin LN, Lyketsos CG. Detroit expert panel on the assessment and management of the neuropsychiatric symptoms of dementia. Management of neuropsychiatric symptoms of dementia in clinical settings: recommendations from a multidisciplinary expert panel. J Am Geriatr Soc. 2014;62(4):762–9 This article explains the DICE approach and includes a large table with questions that can help clinicians apply the DICE approach. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of PsychiatryUniversity of MichiganAnn ArborUSA

Personalised recommendations