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J Prev Alzheimers Dis. Author manuscript; available in PMC 2016 September 01. Published in final edited form as: J Prev Alzheimers Dis. 2015 September ; 2(3): 155–156. doi:10.14283/jpad.2015.60.
Neuropsychiatric Symptoms in Dementia: Overview and Measurement Challenges C.G. Lyketsos Johns Hopkins Bayview and Johns Hopkins University, Baltimore, MD, USA
Author Manuscript
Introduction Neuropsychiatric symptoms (NPS) are now known to occur almost universally over the course of dementia, Alzheimer’s in particular (1, 2). They also occur with higher-thanexpected frequency in the dementia prodrome of mild cognitive impairment (3). Further, NPS in the form of “mild behavioral impairment,” in the absence of cognitive impairment, may constitute a dementia prodrome (4). NPS are associated with a number of adverse outcomes including accelerated transition from prodrome to dementia (4), and faster progression from early dementia to severe dementia or death [Peters et al, Am J Psychiatry, in press], as well as serious adverse effects for patients and caregivers such as greater disability, worse quality of life, earlier institutionalization, increased burden, and higher health care costs (2). Given their central importance, NPS are increasingly a focus of study with an eye to the development of effective treatments.
Author Manuscript Author Manuscript
The heterogeneity of NPS complicates treatment development; they are heterogeneous in both phenomenology and cause. A wide range of symptoms has been reported although they tend to aggregate into predictable groups, especially in milder disease (5). The most reproducible groupings have been: depression, apathy, psychosis, agitation, and sleep disturbances [6]. Recent treatment development has targeted presumptive or proposed syndromes in these areas (7, 8). From the point of view of cause, NPS likely result from several interacting factors. The brain neurodegenerative process, through disruption of brain circuits involved in affect, behavior, motivation, or perception, is central to their emergence either through direct damage to circuits, or through creating vulnerabilities acted on by the environment. Additionally, NPS may result because of difficulties individuals face adapting to the surroundings as they lose cognitive abilities. Further, NPS may arise because of unmet needs, acute comorbid illnesses causing confusional states akin to delirium, or environments and caregiving that are mismatched with the patient’s current capabilities and skills [Kales et al, BMJ, under review). Treatment development for NPS has to grapple with a number of issues concurrently. Efforts have included the development of nonpharmacologic approaches (9), as well as pharmacologic approaches. The latter initially involved importation of psychopharmaca developed for the treatment of psychiatric disorders into this setting with mixed results (2,
Corresponding Author: Constantine G. Lyketsos, 5300 Alpha Commons Blvd, Baltimore, MD 21224, USA, Tel: 410-550-0062, Fax: 410-550-1407, [email protected].
Lyketsos
Page 2
Author Manuscript
6). Of particular concern has been unexpected serious risks associated with these medications, antipsychotics in particular (6).
Author Manuscript
Central to treatment development for NPS is clinical measurement. As there are no specific “direct” measures of NPS, as with measures of cognitive functioning, measurement relies on reporting of observable behaviors and mental states by patients and others. Measurement is affected by a number of variables. These include aspects of the cognitive disorder that limit patient ability to reveal mental state, or lead to forgetting prior experiences and behaviors. As a result, measurement depends on input from caregivers who themselves are “filters,” leading at times to biased reporting in particular when caregivers suffer from psychological disturbances—a common finding in dementia caregivers (10). Further, because NPS are episodic, relapsing and remitting frequently, often “real-time” in response to environmental situations, the quantification of NPS frequency and severity over longer time frames is difficult. In the last several decades a number of measures have been developed for the study of NPS. The most widely used are discussed in the most recent Handbook of Psychiatric Measures (11). They include “broad spectrum” measures to quantify the occurrence, frequency, severity, or other attributes of NPS (e.g., associated caregiver distress), without going into depth for individual disturbances. Other measures are “narrow spectrum” focused on individual disturbances such as depression, apathy, or agitation.
Author Manuscript
Some measures acquire information about the NPS entirely from structured caregiver interviews. Other measures use structured patient interviews, and yet others combinations of these approaches. The introduction of rating judgments from experienced clinicians, following the LED standard (longitudinal, expert, all data) is the optimal way of quantifying NPS; it is also the most complicated, costly, and time-consuming (12). Development of the Neuropsychiatric Inventory-clinician rating (NPI-C) (13), has produced a versatile measure that can be used as a broad spectrum measure based entirely on caregiver report or as a narrow spectrum measure of a particular domain, such as agitation. In the latter case NPI-C incorporates information from patient, caregiver and other sources and applies clinician judgment in making final ratings. NPI-C has better inter-rater reliability then the conventional NPI (13) perhaps because the latter is highly structured, based only on caregiver report, and not very sensitive to change (14). Rating judgments from well-trained clinicians are least affected by biases related to caregiver report.
Author Manuscript
In summary, NPS are a central focus of study and treatment development in the context of Alzheimer’s and other neurodegenerative brain diseases. It should be no surprise that such symptoms are universal in diseases that affect key brain areas regulating behavior, or disrupt multiple brain areas over time. Despite heterogeneity in phenomenology and etiology, treatment development for NPS has accelerated in the last few years (15) with the promise of more effective novel treatments on the immediate horizon.
Acknowledgement Supported by grant P5O-AG042350 from the National Institute on Aging to the Johns Hopkins Alzheimer’s Disease Research Center.
J Prev Alzheimers Dis. Author manuscript; available in PMC 2016 September 01.
Lyketsos
Page 3
Author Manuscript
Disclosures: Dr. Lyketsos has received Grant support (research or CME) from NIMH, NIA, Associated Jewish Federation of Baltimore, Weinberg Foundation, Forest, Glaxo-Smith-Kline, Eisai, Pfizer, Astra-Zeneca, Lilly, Ortho-McNeil, Bristol-Myers, Novartis, National Football League, Elan, Functional Neuromodulation; he has been Consultant/Advisor to Astra-Zeneca, Glaxo-Smith Kline, Eisai, Novartis, Forest, Supernus, Adlyfe, Takeda, Wyeth, Lundbeck, Merz, Lilly, Pfizer, Genentech, Elan, NFL Players Association, NFL Benefits Office, Avanir, Zinfandel, BMS, Abvie, Janssen, Orion, Otsuka; and has received honorarium or travel support from Pfizer, Forest, GlaxoSmith Kline, Health Monitor.
References
Author Manuscript Author Manuscript Author Manuscript
1. Steinberg M, Shao H, Zandi P, Lyketsos CG, Welsh-Bohmer KA, Norton MC, Breitner JCS, Steffens DC, Tschanz JT. Cache County Investigators. Point and 5-year period prevalence of neuropsychiatric symptoms in dementia: the Cache County Study. Int J Geriatr Psychiatry. 2008; 23:170–177. [PubMed: 17607801] 2. Lyketsos CG, Carrillo MC, Ryan JM, Khachaturian AS, Trzepacz P, Amatniek J, Cedarbaum J, Brashear R, Miller DS. Neuropsychiatric symptoms in Alzheimer’s disease. Alzheimer’s & Dementia. 2011; 7:532–539. 3. Lyketsos CG, Lopez O, Jones B, Fitzpatrick AL, Breitner J, DeKosky S. Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study. Jama : the journal of the American Medical Association. 2002; 288:1475–1483. [PubMed: 12243634] 4. Taragano FE, Allegri RF, Krupitzki H, Sarasola DR, Serrano CM, Loñ L, Lyketsos CG. Mild behavioral impairment and risk of dementia: a prospective cohort study of 358 patients. J Clin Psychiatry. 2009; 70:584–592. [PubMed: 19323967] 5. Lyketsos CG, Sheppard JM, Steinberg M, Tschanz JA, Norton MC, Steffens DC, Breitner JC. Neuropsychiatric disturbance in Alzheimer’s disease clusters into three groups: the Cache County study. Int J Geriatr Psychiatry. 2001; 16:1043–1053. [PubMed: 11746650] 6. Geda YE, Schneider LS, Gitlin LN, Miller DS, Smith GS, Bell J, Evans J, Lee M, Porsteinsson A, Lanctôt KL, Rosenberg PB, Sultzer DL, Francis PT, Brodaty H, Padala PP, Onyike CU, Ortiz LA, Ancoli-Israel S, Bliwise DL, Martin JL, Vitiello MV, Yaffe K, Zee PC, Herrmann N, Sweet RA, Ballard C, Kin NA, Alfaro C, Murray PS, Schultz S, et al. Neuropsychiatric symptoms in Alzheimer’s disease: Past progress and anticipation of the future. Alzheimers Dement. 2013 7. Robert P, Onyike CU, Leentjens AFG, Dujardin K, Aalten P, Starkstein S, Verhey FRJ, Yessavage J, Clement JP, Drapier D, Bayle F, Benoit M, Boyer P, Lorca PM, Thibaut F, r SG, Grossberg G, Vellas B, Byrne J. Proposed diagnostic criteria for apathy in Alzheimer’s disease and other neuropsychiatric disorders. European Psychiatry. 2009:1–7. 8. Olin JT, Schneider LS, Katz IR, Meyers BS, Alexopoulos GS, Breitner JC, Bruce ML, Caine ED, Cummings JL, Devanand DP, Krishnan KRR, Lyketsos CG, Lyness JM, Rabins PV, Reynolds CF, Rovner BW, Steffens DC, Tariot PN, Lebowitz BD. Provisional diagnostic criteria for depression of Alzheimer disease. Am J Geriatr Psychiatry. 2002; 10:125–128. [PubMed: 11925273] 9. Kales HC, Gitlin LN, Lyketsos CG. Detroit Expert Panel on Assessment and Management of Neuropsychiatric Symptoms of Dementia. Management of neuropsychiatric symptoms of dementia in clinical settings: recommendations from a multidisciplinary expert panel. J Am Geriatr Soc. 2014; 62:762–769. [PubMed: 24635665] 10. Rosenberg PB, Mielke MM, Lyketsos CG. Caregiver assessment of patients’ depression in Alzheimer disease: longitudinal analysis in a drug treatment study. Am J Geriatr Psychiatry. 2005; 13:822–826. [PubMed: 16166413] 11. Rush, AJ.; First, MB.; Blacker, D. Handbook of Psychiatric Measures. American Psychiatric Pub; 2008. 12. Lyketsos CG. Neuropsychiatric symptoms (behavioral and psychological symptoms of dementia) and the development of dementia treatments. Int Psychogeriatr. 2007; 19:409–420. [PubMed: 17346363] 13. de Medeiros K, Robert P, Gauthier S, Stella F, Politis A, Leoutsakos J, Taragano F, Kremer J, Brugnolo A, Porsteinsson AP, Geda YE, Brodaty H, Gazdag G, Cummings J, Lyketsos C. The Neuropsychiatric Inventory-Clinician rating scale (NPI-C): reliability and validity of a revised
J Prev Alzheimers Dis. Author manuscript; available in PMC 2016 September 01.
Lyketsos
Page 4
Author Manuscript
assessment of neuropsychiatric symptoms in dementia. Int Psychogeriatr. 2010; 22:984–994. [PubMed: 20594384] 14. Mayer LS, Bay RC, Politis A, Steinberg M, Steele C, Baker AS, Rabins PV, Lyketsos CG. Comparison of three rating scales as outcome measures for treatment trials of depression in Alzheimer disease: findings from DIADS. Int J Geriatr Psychiatry. 2006; 21:930–936. [PubMed: 16955427] 15. Soto M, Andrieu S, Nourhashemi F, Ousset PJ, Ballard C, Robert P, Vellas B, Lyketsos CG, Rosenberg PB. Medication development for agitation and aggression in Alzheimer disease: review and discussion of recent randomized clinical trial design. Int Psychogeriatr. 2014:1–17. [PubMed: 25226218]
Author Manuscript Author Manuscript Author Manuscript J Prev Alzheimers Dis. Author manuscript; available in PMC 2016 September 01.
J Prev Alzheimers Dis. Author manuscript; available in PMC 2016 September 01. Published in final edited form as: J Prev Alzheimers Dis. 2015 September ; 2(3): 155–156. doi:10.14283/jpad.2015.60.
Neuropsychiatric Symptoms in Dementia: Overview and Measurement Challenges C.G. Lyketsos Johns Hopkins Bayview and Johns Hopkins University, Baltimore, MD, USA
Author Manuscript
Introduction Neuropsychiatric symptoms (NPS) are now known to occur almost universally over the course of dementia, Alzheimer’s in particular (1, 2). They also occur with higher-thanexpected frequency in the dementia prodrome of mild cognitive impairment (3). Further, NPS in the form of “mild behavioral impairment,” in the absence of cognitive impairment, may constitute a dementia prodrome (4). NPS are associated with a number of adverse outcomes including accelerated transition from prodrome to dementia (4), and faster progression from early dementia to severe dementia or death [Peters et al, Am J Psychiatry, in press], as well as serious adverse effects for patients and caregivers such as greater disability, worse quality of life, earlier institutionalization, increased burden, and higher health care costs (2). Given their central importance, NPS are increasingly a focus of study with an eye to the development of effective treatments.
Author Manuscript Author Manuscript
The heterogeneity of NPS complicates treatment development; they are heterogeneous in both phenomenology and cause. A wide range of symptoms has been reported although they tend to aggregate into predictable groups, especially in milder disease (5). The most reproducible groupings have been: depression, apathy, psychosis, agitation, and sleep disturbances [6]. Recent treatment development has targeted presumptive or proposed syndromes in these areas (7, 8). From the point of view of cause, NPS likely result from several interacting factors. The brain neurodegenerative process, through disruption of brain circuits involved in affect, behavior, motivation, or perception, is central to their emergence either through direct damage to circuits, or through creating vulnerabilities acted on by the environment. Additionally, NPS may result because of difficulties individuals face adapting to the surroundings as they lose cognitive abilities. Further, NPS may arise because of unmet needs, acute comorbid illnesses causing confusional states akin to delirium, or environments and caregiving that are mismatched with the patient’s current capabilities and skills [Kales et al, BMJ, under review). Treatment development for NPS has to grapple with a number of issues concurrently. Efforts have included the development of nonpharmacologic approaches (9), as well as pharmacologic approaches. The latter initially involved importation of psychopharmaca developed for the treatment of psychiatric disorders into this setting with mixed results (2,
Corresponding Author: Constantine G. Lyketsos, 5300 Alpha Commons Blvd, Baltimore, MD 21224, USA, Tel: 410-550-0062, Fax: 410-550-1407, [email protected].
Lyketsos
Page 2
Author Manuscript
6). Of particular concern has been unexpected serious risks associated with these medications, antipsychotics in particular (6).
Author Manuscript
Central to treatment development for NPS is clinical measurement. As there are no specific “direct” measures of NPS, as with measures of cognitive functioning, measurement relies on reporting of observable behaviors and mental states by patients and others. Measurement is affected by a number of variables. These include aspects of the cognitive disorder that limit patient ability to reveal mental state, or lead to forgetting prior experiences and behaviors. As a result, measurement depends on input from caregivers who themselves are “filters,” leading at times to biased reporting in particular when caregivers suffer from psychological disturbances—a common finding in dementia caregivers (10). Further, because NPS are episodic, relapsing and remitting frequently, often “real-time” in response to environmental situations, the quantification of NPS frequency and severity over longer time frames is difficult. In the last several decades a number of measures have been developed for the study of NPS. The most widely used are discussed in the most recent Handbook of Psychiatric Measures (11). They include “broad spectrum” measures to quantify the occurrence, frequency, severity, or other attributes of NPS (e.g., associated caregiver distress), without going into depth for individual disturbances. Other measures are “narrow spectrum” focused on individual disturbances such as depression, apathy, or agitation.
Author Manuscript
Some measures acquire information about the NPS entirely from structured caregiver interviews. Other measures use structured patient interviews, and yet others combinations of these approaches. The introduction of rating judgments from experienced clinicians, following the LED standard (longitudinal, expert, all data) is the optimal way of quantifying NPS; it is also the most complicated, costly, and time-consuming (12). Development of the Neuropsychiatric Inventory-clinician rating (NPI-C) (13), has produced a versatile measure that can be used as a broad spectrum measure based entirely on caregiver report or as a narrow spectrum measure of a particular domain, such as agitation. In the latter case NPI-C incorporates information from patient, caregiver and other sources and applies clinician judgment in making final ratings. NPI-C has better inter-rater reliability then the conventional NPI (13) perhaps because the latter is highly structured, based only on caregiver report, and not very sensitive to change (14). Rating judgments from well-trained clinicians are least affected by biases related to caregiver report.
Author Manuscript
In summary, NPS are a central focus of study and treatment development in the context of Alzheimer’s and other neurodegenerative brain diseases. It should be no surprise that such symptoms are universal in diseases that affect key brain areas regulating behavior, or disrupt multiple brain areas over time. Despite heterogeneity in phenomenology and etiology, treatment development for NPS has accelerated in the last few years (15) with the promise of more effective novel treatments on the immediate horizon.
Acknowledgement Supported by grant P5O-AG042350 from the National Institute on Aging to the Johns Hopkins Alzheimer’s Disease Research Center.
J Prev Alzheimers Dis. Author manuscript; available in PMC 2016 September 01.
Lyketsos
Page 3
Author Manuscript
Disclosures: Dr. Lyketsos has received Grant support (research or CME) from NIMH, NIA, Associated Jewish Federation of Baltimore, Weinberg Foundation, Forest, Glaxo-Smith-Kline, Eisai, Pfizer, Astra-Zeneca, Lilly, Ortho-McNeil, Bristol-Myers, Novartis, National Football League, Elan, Functional Neuromodulation; he has been Consultant/Advisor to Astra-Zeneca, Glaxo-Smith Kline, Eisai, Novartis, Forest, Supernus, Adlyfe, Takeda, Wyeth, Lundbeck, Merz, Lilly, Pfizer, Genentech, Elan, NFL Players Association, NFL Benefits Office, Avanir, Zinfandel, BMS, Abvie, Janssen, Orion, Otsuka; and has received honorarium or travel support from Pfizer, Forest, GlaxoSmith Kline, Health Monitor.
References
Author Manuscript Author Manuscript Author Manuscript
1. Steinberg M, Shao H, Zandi P, Lyketsos CG, Welsh-Bohmer KA, Norton MC, Breitner JCS, Steffens DC, Tschanz JT. Cache County Investigators. Point and 5-year period prevalence of neuropsychiatric symptoms in dementia: the Cache County Study. Int J Geriatr Psychiatry. 2008; 23:170–177. [PubMed: 17607801] 2. Lyketsos CG, Carrillo MC, Ryan JM, Khachaturian AS, Trzepacz P, Amatniek J, Cedarbaum J, Brashear R, Miller DS. Neuropsychiatric symptoms in Alzheimer’s disease. Alzheimer’s & Dementia. 2011; 7:532–539. 3. Lyketsos CG, Lopez O, Jones B, Fitzpatrick AL, Breitner J, DeKosky S. Prevalence of neuropsychiatric symptoms in dementia and mild cognitive impairment: results from the cardiovascular health study. Jama : the journal of the American Medical Association. 2002; 288:1475–1483. [PubMed: 12243634] 4. Taragano FE, Allegri RF, Krupitzki H, Sarasola DR, Serrano CM, Loñ L, Lyketsos CG. Mild behavioral impairment and risk of dementia: a prospective cohort study of 358 patients. J Clin Psychiatry. 2009; 70:584–592. [PubMed: 19323967] 5. Lyketsos CG, Sheppard JM, Steinberg M, Tschanz JA, Norton MC, Steffens DC, Breitner JC. Neuropsychiatric disturbance in Alzheimer’s disease clusters into three groups: the Cache County study. Int J Geriatr Psychiatry. 2001; 16:1043–1053. [PubMed: 11746650] 6. Geda YE, Schneider LS, Gitlin LN, Miller DS, Smith GS, Bell J, Evans J, Lee M, Porsteinsson A, Lanctôt KL, Rosenberg PB, Sultzer DL, Francis PT, Brodaty H, Padala PP, Onyike CU, Ortiz LA, Ancoli-Israel S, Bliwise DL, Martin JL, Vitiello MV, Yaffe K, Zee PC, Herrmann N, Sweet RA, Ballard C, Kin NA, Alfaro C, Murray PS, Schultz S, et al. Neuropsychiatric symptoms in Alzheimer’s disease: Past progress and anticipation of the future. Alzheimers Dement. 2013 7. Robert P, Onyike CU, Leentjens AFG, Dujardin K, Aalten P, Starkstein S, Verhey FRJ, Yessavage J, Clement JP, Drapier D, Bayle F, Benoit M, Boyer P, Lorca PM, Thibaut F, r SG, Grossberg G, Vellas B, Byrne J. Proposed diagnostic criteria for apathy in Alzheimer’s disease and other neuropsychiatric disorders. European Psychiatry. 2009:1–7. 8. Olin JT, Schneider LS, Katz IR, Meyers BS, Alexopoulos GS, Breitner JC, Bruce ML, Caine ED, Cummings JL, Devanand DP, Krishnan KRR, Lyketsos CG, Lyness JM, Rabins PV, Reynolds CF, Rovner BW, Steffens DC, Tariot PN, Lebowitz BD. Provisional diagnostic criteria for depression of Alzheimer disease. Am J Geriatr Psychiatry. 2002; 10:125–128. [PubMed: 11925273] 9. Kales HC, Gitlin LN, Lyketsos CG. Detroit Expert Panel on Assessment and Management of Neuropsychiatric Symptoms of Dementia. Management of neuropsychiatric symptoms of dementia in clinical settings: recommendations from a multidisciplinary expert panel. J Am Geriatr Soc. 2014; 62:762–769. [PubMed: 24635665] 10. Rosenberg PB, Mielke MM, Lyketsos CG. Caregiver assessment of patients’ depression in Alzheimer disease: longitudinal analysis in a drug treatment study. Am J Geriatr Psychiatry. 2005; 13:822–826. [PubMed: 16166413] 11. Rush, AJ.; First, MB.; Blacker, D. Handbook of Psychiatric Measures. American Psychiatric Pub; 2008. 12. Lyketsos CG. Neuropsychiatric symptoms (behavioral and psychological symptoms of dementia) and the development of dementia treatments. Int Psychogeriatr. 2007; 19:409–420. [PubMed: 17346363] 13. de Medeiros K, Robert P, Gauthier S, Stella F, Politis A, Leoutsakos J, Taragano F, Kremer J, Brugnolo A, Porsteinsson AP, Geda YE, Brodaty H, Gazdag G, Cummings J, Lyketsos C. The Neuropsychiatric Inventory-Clinician rating scale (NPI-C): reliability and validity of a revised
J Prev Alzheimers Dis. Author manuscript; available in PMC 2016 September 01.
Lyketsos
Page 4
Author Manuscript
assessment of neuropsychiatric symptoms in dementia. Int Psychogeriatr. 2010; 22:984–994. [PubMed: 20594384] 14. Mayer LS, Bay RC, Politis A, Steinberg M, Steele C, Baker AS, Rabins PV, Lyketsos CG. Comparison of three rating scales as outcome measures for treatment trials of depression in Alzheimer disease: findings from DIADS. Int J Geriatr Psychiatry. 2006; 21:930–936. [PubMed: 16955427] 15. Soto M, Andrieu S, Nourhashemi F, Ousset PJ, Ballard C, Robert P, Vellas B, Lyketsos CG, Rosenberg PB. Medication development for agitation and aggression in Alzheimer disease: review and discussion of recent randomized clinical trial design. Int Psychogeriatr. 2014:1–17. [PubMed: 25226218]
Author Manuscript Author Manuscript Author Manuscript J Prev Alzheimers Dis. Author manuscript; available in PMC 2016 September 01.
