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Antipsychotic Drug Use and Mortality in Older Adults with Dementia

Sudeep S. Gill, MD, MSc; Susan E. Bronskill, PhD; Sharon-Lise T. Normand, PhD; Geoffrey M. Anderson, MD, PhD; Kathy Sykora, MSc; Kelvin Lam, MSc; Chaim M. Bell, MD, PhD; Philip E. Lee, MD; Hadas D. Fischer, MD; Nathan Herrmann, MD; Jerry H. Gurwitz, MD; and Paula A. Rochon, MD, MPH
[+] Article and Author Information

From Queen's University, Kingston, Ontario, Canada; Institute for Clinical Evaluative Sciences and University of Toronto, Toronto, Ontario, Canada; Harvard Medical School and Harvard School of Public Health, Boston, Massachusetts; University of British Columbia, Vancouver, British Columbia, Canada; and Meyers Primary Care Institute of the University of Massachusetts Medical School, Fallon Clinic Foundation, and Fallon Community Health Plan, Worcester, Massachusetts.


Grant Support: By a Canadian Institutes for Health Research operating grant (no. 53124) and a Chronic Disease New Emerging Team program grant (no. 54010). The New Emerging Team program receives joint sponsorship from the Canadian Diabetes Association, the Kidney Foundation of Canada, the Heart and Stroke Foundation of Canada and the Canadian Institutes for Health Research Institutes of Nutrition, Metabolism & Diabetes and Circulatory & Respiratory Health. Dr. Gill is supported by an Ontario Ministry of Health and Long-Term Care Career Scientist Award. Dr. Bronskill is supported by a New Investigator Award through the New Emerging Team program. Dr. Anderson is supported by a Chair in Health Management Strategies from the University of Toronto. Dr. Rochon is supported by a Canadian Institutes for Health Research Investigator Award. Dr. Lee is supported by a fellowship grant from Eli Lilly.

Potential Financial Conflicts of Interest: Consultancies: P.E. Lee (Pfizer Canada, Janssen-Ortho), N. Herrmann (Janssen, Novartis, Pfizer Inc.); Honoraria: P.E. Lee (Pfizer Inc., Janssen-Ortho, Novartis), N. Herrmann (Janssen, Eli Lilly, Novartis, AstraZeneca); Expert testimony: N. Herrmann (Janssen); Grants received: P.E. Lee (Eli Lilly), N. Herrmann (Janssen).

Requests for Single Reprints: Sudeep S. Gill, MD, MSc, St. Mary's of the Lake Hospital, 340 Union Street, Kingston, Ontario K7L 5A2, Canada.

Current Author Addresses: Dr. Gill: St. Mary's of the Lake Hospital, 340 Union Street, Kingston, Ontario K7L 5A2, Canada.

Drs. Bronskill, Anderson, Bell, Fischer, and Rochon; Ms. Sykora; and Mr. Lam: Institute for Clinical Evaluative Sciences, G Wing, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada.

Dr. Normand: Department of Health Care Policy, Harvard Medical School, 180 Longwood Avenue, Boston, MA 02115-5899.

Dr. Lee: St. Paul's Hospital, 1081 Burrard Street, 9th Floor, Providence Building, Vancouver, British Columbia V6T 2B5, Canada.

Dr. Herrmann: Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada.

Dr. Gurwitz: Meyers Primary Care Institute, 630 Plantation Street, Worcester, MA 01605.

Author Contributions: Conception and design: S.S. Gill, S.E. Bronskill, S.-L.T. Normand, G.M. Anderson, C.M. Bell, P.E. Lee, N. Herrmann, J.H. Gurwitz, P.A. Rochon.

Analysis and interpretation of the data: S.S. Gill, S.E. Bronskill, S.-L.T. Normand, G.M. Anderson, K. Sykora, K. Lam, C.M. Bell, P.E. Lee, H.D. Fischer, N. Herrmann, J.H. Gurwitz, P.A. Rochon.

Drafting of the article: S.S. Gill, S.E. Bronskill.

Critical revision of the article for important intellectual content: S.S. Gill, S.E. Bronskill, G.M. Anderson, K. Sykora, K. Lam, C.M. Bell, P.E. Lee, H.D. Fischer, N. Herrmann, J.H. Gurwitz, P.A. Rochon.

Final approval of the article: S.S. Gill, C.M. Bell, N. Herrmann, J.H. Gurwitz, P.A. Rochon.

Statistical expertise: S.S. Gill, S.E. Bronskill, S.-L.T. Normand, K. Sykora, K. Lam.

Administrative, technical, or logistic support: K. Sykora, K. Lam, H.D. Fischer.


Ann Intern Med. 2007;146(11):775-786. doi:10.7326/0003-4819-146-11-200706050-00006
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Our study provides further evidence that use of atypical antipsychotics is associated with a small but significant increase in mortality among older adults with dementia. In addition, the risk for death associated with antipsychotics is apparent after as little as 1 month of use and may persist for 6 months. Finally, these data provide independent confirmation of reports that use of conventional antipsychotics confers an even greater risk for death than does use of atypical antipsychotics (15, 18).

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Figures

Grahic Jump Location
Figure 1.
Cumulative mortality in atypical antipsychotic users and nonusers.
Grahic Jump Location
Grahic Jump Location
Figure 2.
Cumulative mortality in conventional antipsychotic users and atypical antipsychotic users.
Grahic Jump Location

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Comments

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Is medication or the need for medication the root cause?
Posted on June 6, 2007
Trevor W Rimmer
East Cheshire NHS Trust
Conflict of Interest: None Declared

This article reinforces the point that one should always attempt non- pharmacological methods of managing challenging behaviour in those with dementia. However, I was not entirely sure if like was being compared with like in the comparison of mortality between those given antipsychotic drugs and those not. Was the incidence and nature of challenging behaviour the same in both groups? Behavioural disturbance may be a feature of more advanced dementia. It may also worsen in the presence of other pathology - so difficult to identify in this group of patients. Might the higher incidence in mortality be expalined by a greater incidence of unidentified intercurrent patholgy causing diturbed behaviour, rather than a reaction to the drugs themselves?

Confounding Factor
Posted on June 6, 2007
Thomans A. Barley
No Affiliation
Conflict of Interest: None Declared

The confounding factor not addressed by the antipsychotic drug use review article is who is being treated and why. I do not give antipsychotics to patients doing well. They are reserved for those having the most problems. They are the highest risk group for falls, poor eating, an inability to care for their physical needs, refusing their meds, etc. I use typical antipsychotics only in patients I consider terminally ill due to the long term side effects. Until you treat a large group of patients with antipsychotics who don't need them you cannot prove harm or increased mortality. I know they relieve frightful distress and allow safety of the staff and facility to be enhanced. Thomas Barley MD

Conflict of Interest:

None declared

This could be due to lower DHEA levels...
Posted on June 10, 2007
James M. Howard
independent
Conflict of Interest: None Declared

I suggest these findings may be explained by reductions in DHEA caused by antipsychotic medications in individuals whose DHEA already is low.

A case may be made that dementia is due to low DHEA. DHEA naturally declines in old age and is probably lower in individuals exhibiting dementia.

A case may be made that antipsychotic medication reduces DHEA. The effect of reducing DHEA is to reduce activity in lower parts of the brain that are active without executive, or upper level, control. Reducing DHEA reduces lower brain activity and makes the treated individual more manageable.

Antipsychotic medications, old and new, increase prolactin. Prolactin specifically and directly stimulates the production of DHEA. I suggest high prolactin indicates that DHEA is not being produced, thereby reducing DHEA feedback of prolactin production. Increased prolactin levels caused by antipsychotic medications may indicate that DHEA is being reduced, therefore, reducing lower brain activity.

Low DHEA of dementia and in older individuals, who are in the natural decline of DHEA, are vulnerable to further low DHEA levels which may result in death. I suggest lowering DHEA in these individuals via antipsychotic medications may explain the findings of Gill, et al.

Conflict of Interest:

None declared

Antipsychotic use and mortality rate in dementia
Posted on July 4, 2007
Abid Iraqi
Syracuse VA Medical Center, Syracuse, NY
Conflict of Interest: None Declared

To The Editor:

Gill and colleagues (1) highlight the substantial difference in the mortality rate of dementia patients who took antipsychotics as compared to those who did not take antipsychotics. However, it does not seem that their study took into consideration as to how long these patients had dementia. Dementia has shown to shorten life expectancy. In the earlier studies, estimates of median survival from the onset of symptoms vary from 5 years (range, 1 to 13) (2) to 9.3 years (range, 1.8 to 16 or more) (3), and the later study showed unadjusted overall median survival of 6.60 years, with an adjusted median survival of 3.33 years after the onset of dementia (4). If patients in antipsychotic group had dementia for a longer duration then they were anticipated to have a shorter life expectancy to begin with. Additionally, initiation and/or use of antipsychotic use in dementia patients may have been an indication that their dementia was getting worse as usually incidence of behavioral disturbances increases with the advancement in the stages of dementia. Is it possible that due to progression in dementia, their life expectancy was shorter and was not necessarily due to antipsychotic use?.

We agree that antipsychotics should be used cautiously and perhaps may be used, as mandated in the OBRA regulations of 1987, as a last resort and not as the first option.

References:

1. Gill SS, Bronskill SE, Normand ST, et al. Antipsychotic Drug Use and Mortality in Older Adults with Dementia. Ann Intern Med.2007; 146: 775- 786.

2. Molsa PK, Marttila RJ, Rinne UK. Survival and cause of death in Alzheimer's disease and multi-infarct dementia. Acta Neurol Scand 1986; 74:103-107

3. Walsh JS, Welch HG, Larson EB. Survival of outpatients with Alzheimer- type dementia. Ann Internal Med 1990; 113:429-434.

4. Wolfson C, Wolfson DB, Asgharian M, et al. A reevaluation of the duration of

survival after the onset of dementia. N Eng J Med 2001; 344:1111- 1116.

Conflict of Interest:

None declared

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Summary for Patients

Antipsychotic Drug Use and Death in Older Adults with Dementia

The summary below is from the full report titled “Antipsychotic Drug Use and Mortality in Older Adults with Dementia.” It is in the 5 June 2007 issue of Annals of Internal Medicine (volume 146, pages 775-786). The authors are S.S. Gill, S.E. Bronskill, S.-L.T. Normand, G.M. Anderson, K. Sykora, K. Lam, C.M. Bell, P.E. Lee, H.D. Fischer, N. Herrmann, J.H. Gurwitz, and P.A. Rochon.

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