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Comparative mortality risks of antipsychotic medications in community-dwelling older adults

  • T. Gerhard (a1), K. Huybrechts (a2), M. Olfson (a3), S. Schneeweiss (a2), W. V. Bobo (a4), P. M. Doraiswamy (a5), D. P. Devanand (a3), J. A. Lucas (a6), C. Huang (a6), E. S. Malka (a6), R. Levin (a2) and S. Crystal (a7)...

All antipsychotic medications carry warnings of increased mortality for older adults, but little is known about comparative mortality risks between individual agents.


To estimate the comparative mortality risks of commonly prescribed antipsychotic agents in older people living in the community.


A retrospective, claims-based cohort study was conducted of people over 65 years old living in the community who had been newly prescribed risperidone, olanzapine, quetiapine, haloperidol, aripiprazole or ziprasidone (n = 136 393). Propensity score-adjusted Cox proportional hazards models assessed the 180-day mortality risk of each antipsychotic compared with risperidone.


Risperidone, olanzapine and haloperidol showed a dose–response relation in mortality risk. After controlling for propensity score and dose, mortality risk was found to be increased for haloperidol (hazard ratio (HR) = 1.18, 95% CI 1.06–1.33) and decreased for quetiapine (HR = 0.81, 95% CI 0.73–0.89) and olanzapine (HR = 0.82, 95% CI 0.74–0.90).


Significant variation in mortality risk across commonly prescribed antipsychotics suggests that antipsychotic selection and dosing may affect survival of older people living in the community.

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Corresponding author
Professor Tobias Gerhard, Ernest Mario School of Pharmacy, Rutgers University, 112 Paterson Street, New Brunswick, NJ 08901, USA. Email:
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Parts of this paper were presented on 17 August 2011 at the 27th International Conference of the International Society for Pharmacoepidemiology in Chicago, Illinois, USA.

See editorial, pp. 4–5, this issue.

This work was supported by Agency for Healthcare Research and Quality/Food and Drug Administration (AHRQ/FDA) award HS017918 and AHRQ award HS016097.

Declaration of interest

P.M.D. has received research grants and advisory/speaking fees from several pharmaceutical companies, including antipsychotic manufacturers, for other research. He owns stock in AdverseEvents Inc. which was not involved in this project. D.P.D. has received research support from Novartis AG and Eli Lilly and has served as a consultant to Bristol-Myers Squibb.

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Comparative mortality risks of antipsychotic medications in community-dwelling older adults

  • T. Gerhard (a1), K. Huybrechts (a2), M. Olfson (a3), S. Schneeweiss (a2), W. V. Bobo (a4), P. M. Doraiswamy (a5), D. P. Devanand (a3), J. A. Lucas (a6), C. Huang (a6), E. S. Malka (a6), R. Levin (a2) and S. Crystal (a7)...
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Do antipsychotics have a role in reducing mortality risk?

Natalie M. Da Silva, CT1 Doctor
12 August 2014

We found Gerhard et al's article (1) highly relevant to our practise and the study cohort of 136,393 patients with new antipsychotic treatment episodes gives it considerable weight.

We would like to draw the reader's attention to Ray et al.'s paper (2) which compared cohort arms of more than 40,000 patients each. It does not focus on the mortality effect in the dementia or even older populationbut does suggest that typical and atypical antipsychotic drugs have a similar dose-related increased risk of sudden cardiac death in patients with psychosis and bipolar affective disorder. This is higher than non-users of antipsychotic drugs. Further in support of this is ZYPADHERA's summary of product characteristics (3) which documents the incidence of death to be higher in olanzapine versus the placebo group, independent of risk factors such as age > 65 years, dysphagia, sedation, malnutrition and dehydration, pulmonary conditions or concomitant use of benzodiazepines.

However, Tiihonen's 11-year follow-up of mortality in patients with schizophrenia (4), concludes that long-term treatment with antipsychotic drugs is associated with lower mortality compared with no antipsychotic use.

We wonder what trends one would observe were we to look at the same for antipsychotic use for behavioural problems versus licensed indications. Clearly the risks will be higher in patients with behaviouraldisturbances and to do nothing is unacceptable.

In the article, we do appreciate that the dose-response findings are consistent with an increased absolute mortality risk associated with antipsychotic medications but that is not controlled for by other medication or pre-existing cardiac status. Moreover, exclusion of patientson antipsychotic and antidepressant combinations is stated yet haloperidolwas selectively used in patients not suffering from depression! The SPC for haloperidol has a requirement of pre-treatment ECG and we wonder if this had been carried out whether it would have eliminated one of the confounding factors.

Gerhard's paper again clearly identified that only a third of patients had dementia and, as raised by the authors, that there was no inclusion of an untreated comparison group. Hence this leaves the findingsdifficult to apply on a day- to-day basis.

We wonder whether the conclusions drawn by the authors are perhaps too wide due to factors such as uncertainty of diagnosis, co-prescription and severity of behavioural disturbance, which has not been controlled for. Perhaps to have a more meaningful outcome it would be interesting to further analyse data in the third of patients with dementia and look at the dose-response relationship when co-prescribing is controlled for. We would welcome that information particularly if it included a comparison group of patients suffering from dementia (with behavioural problems) who were not treated with antipsychotic medication.

REFERENCES1. Gerhard T, Huybrechts K, Olfson M, Schneeweiss S, Bobo WV, Doraiswamy PM,Devanand DP, Lucas JA, Huang C, Malka ES, Levin R, Crystal S. Comparative mortality risks of antipsychotic medications in community-dwelling older adults. Br J Psychiatry. 2014 Jul;205(1):44-51

2. Wayne A. Ray, Ph.D., Cecilia P. Chung, M.D., M.P.H., Katherine T.Murray, M.D., Kathi Hall, B.S., and C. Michael Stein, M.B., Ch.B. AtypicalAntipsychotic Drugs and the Risk of Sudden Cardiac Death, N Engl J Med 2009; 360:225-235

3. ZYPADHERA 210 mg, 300 mg, and 405 mg, powder and solvent for prolonged release suspension for injection - Summary of Product Characteristics (SPC) - (eMC)

4. Tiihonen J1, Lannqvist J, Wahlbeck K, Klaukka T, Niskanen L, Tanskanen A, Haukka J). 11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study). Lancet. 2009Aug 22;374(9690):620-7.

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