C O M PA R A T I V E M O R TA L I T Y R I S K S OF ANTIPSYCHOT IC MEDICATIONS IN COMMUNITY-DWELLING OLDER ADULTS

JOURNAL READING

BACKGROUND
All antipsychotic medications carry warnings of increased mortality for older adults In 2005 a meta-analysis of 15 clinical trials in patients with Alzheimers disease or dementia reported a more than 50% increase in mortality for second-generation antipsychotics above placebo
There are reports on increasing use of off-label antipsychotic use of first- and second-generation antipsychotics in elderly patients with dementia

AIM

METHOD

A 180 days retrospective, observational cohort study Propensity score-adjusted. Cox proportional hazards models assessed the 180-day mortality risk of each antipsychotic compared with risperidone.

Subjects: People 65 y.o; in 45 states around U.S Observed: January 1st 2001December 31st 2005

CRITERIA OF INCLUSION
People aged 65 y.o New antipsychotic treatment episode
INCLUDED

Exclusion criteria Schizofrenia Bipolar disorder Cancer

Censored criteria
Discontinuation Drug switch or augmentation 10 days of hospitalization 180 days after prescription claim Died

30 days were added tot the last day of follow up for patients who discontinued anti-psychothic therapy

Informed consent was obtained from each patient.

The study was approved by the Rutgers University institutional review board

For patients who were impaired, the consent of one or more guardians was also obtained.

MEDICAL ETHICS

STATISTICAL ANALYSIS
Crude and adjusted Cox proportional hazard regressions models were fitted at several level of adjustment::
Unadjusted Adjusted for gender, etchnicity, age and calendar year Adjusted for propensity score Adjusted for high demensional propensity score

RESULTS

MORTALITY HAZARD RATIOS

 In analyses adjusted for high-dimensional propensity score, haloperidol demonstrated a 45% increase in risk and only quetiapine exhibited a statistically significant reduction in risk below risperidone

DOSE RESPONSE ANALYSIS

 Doseresponse relationship was apparent with hazard ratios of;

1.36 (95% CI 1.241.49) for high v. low dose 1.19 (95% CI 1.101.27) for medium v.low dose

Among the four most widely used agents, all but quetiapine showed significant dose response. Haloperidol demonstrated the strongest doseresponse effect. Aripiprazole and ziprasidone were not used with sufficient frequency to permit meaningful evaluation of doseresponse risk of mortality.

RESULT

Risperidone, olanzapine and haloperidol showed a dose response relation in mortality risk.

Mortality risk was found to be increased for haloperidol (hazard ratio (HR)=1.18, 95% CI 1.061.33

Mortality risk was found to be decreased for quetiapine (HR=0.81, 95% CI 0.73 0.89) and olanzapine (HR=0.82, 95% CI 0.74 0.90).

DISCUSSION
In several respects the results confirm those from previous studies that directly compared individual antipsychotic agents. Hazard ratio point estimates for comparisons with risperidone across the three studies ranged from
1.45 to 1.81 for haloperidol 0.99 to 1.06 for olanzapine 0.74 to 0.83 for quetiapine.

DISCUSSION
Adjustment for dose in the analysis markedly altered the magnitude and for some medications the direction of the individual agent mortality effect estimates.

Particularly, the excess mortality risk of haloperidol compared with risperidone

may be at least partially due to more aggressive dosing. Previous studies did not report significant changes in their findings after dose adjustment. The differences among studies in individual agent dose-adjusted mortality

effect estimates could be due to differences in dose-adjustment methods or patient

populations.

STUDY LIMITATION
Severity of dementia and dementia-related behavioural symptoms, which are not directly observable in claims data, may have confounded the observed associations The chlorpromazine dose equivalency schedule, which was developed for schizophrenia treatment, has uncertain applicability to the lower antipsychotic doses used in older patients without psychosis

STUDY LIMITATIONS
Dose analyses were based on the antipsychotic dose of the index prescription and might therefore have introduced dose misclassification if titration schedules varied across agents Underascertainment of dementia in claims data is well recognisedunderdiagnosis of dementia in clinical practice (particularly in the early stage of the disease, where diagnostic sensitivity has been

estimated at 941%),41 and incomplete coding of diagnosed dementia

STUDY LIMITATIONS
This study was limited to comparisons between antipsychotic agents commonly used in the USA during the years 20012005 and therefore could not provide estimates of the comparative mortality risk associated

with newer agents or agents not approved in the USA such as amisulpride
Results are limited to the first 6 months of treatment and therefore do not inform the long-term comparative safety of antipsychotic treatment, and no comparison is presented with patients not receiving antipsychotic medication

JOURNAL IDENTITY
The study come from :
Ernest Mario School of Pharmacy, Rutgers University Authors: T. Gerhard

K. Huybrechts
M. Olfson S. Schneeweiss W. V. Bobo

P. M. Doraiswamy
D. P. Devanand

 Published by The Royal College of Psychiatrists, on 8th August 2013 Available at: http://bjp.rcpsych.org/

TITLE
Comparative mortality risks of antipsychotic medications in community-dwelling older adults Positive: Clearly shows that variables that were investigated Bold written There is no abbreviation Less than 12 words Negative: No location No time Without a capital letter at the beginning of the word

ABSTRACT
Consist of 5 sections Background Aims

Method
Results Conclusion Declaration of Interest > 250 words

METHODS
Positive:
Participant of study is clear, followed by the inclusion and exclusion criteria Analysis tools mentioned clearly Measurable outcomes are clear Technique sampling is randomized

Negative:
None

RESULTS
Positive Tables are presented in accordance with the international journal writing format (without the vertical and horizontal lines in a table) with serial number and table title and description of the contents of the table - Negative : Some drugs used as comparison are not suitable because they are rarely used in USA.

DISCUSSION
Positive There are advantages of the mentioned research results that have been achieved There is an emphasis if the results of the research will be applied Several respects of the results confirm those from previous studies that directly compared individual antipsychotic agents. Negative : There are several limitations in the study, such as, the results are limited to the first 6 months of treatment only and there is no comparison presented with patients not receiving antipsychotics medication.

PICO ANALYSIS
POPULATION People aged 65 years old or older Living in the community and had recently begun antipsychotics treatment. INTERVENTION Antipsychotics medication, included risperidone, olanzapine, quetiapine, haloperidol, aripiprazole and ziprasidone

 COMPARISON To compare non-cancer and cause-specific mortality risks between the individual antipsychotics medications

OUTCOME
Risperidone, olanzapine and haloperidol showed a doseresponse relation in mortality risk. After controlling for propensity score

and dose, mortality risk was found to be increased for haloperidol

and decreased for quetiapine and olanzapine.

VALID EVIDENCE
QUESTIONS
Is the allocation of patients in the study randomized? Is patient observation done quite long and complete? Are all patients in the randomized, analyzed?

YES NO YES

Whether patients and physicians remain blind in doing therapy, apart from the therapy being tested?

YES

APPLICABILITY OF TEST
QUESTIONS Whether such therapy may be applied to our patients? Does the patient have a potential beneficial or detrimental when the program implemented? YES Profitable

CONCLUSION
1

Clinical study is valid

Clinical study is applicable