Background:
Antipsychotics are frequently and increasingly prescribed to treat the behavioural symptomsassociated with dementia despite their modest efficacy. Evidence regarding the potentialadverse events of antipsychotics is limited and little is known about the longer-term safety ofthese medicines in the elderly. The aim of this review was to determine the impact of the choice of observational study design and methods used to control for confounding on the measurement of antipsychotic risks in elderly patients.
Methods:
We searched PUBMED and the Cochrane controlled trials register for double-blindrandomised controlled trials (RCTs), meta-analyses and published observational studies ofantipsychotics.
Results:
Forty four studies were identified for the endpoints; death, cerebrovascular events, hipfracture and pneumonia. RCTs found a 20% to 30% increased risk of death, or an absoluteincrease of 1extra death per 100 patients with atypical antipsychotics compared to non-use.Cohort and instrumental variable analyses estimated between 2 to 7 extra deaths per 100patients with conventional compared to atypical antipsychotics. RCTs found a 2 to 3 timesincreased risk of all cerebrovascular events with atypical antipsychotics compared to placeboand no association with serious stroke that required hospitalisation. Observational studiesusing cohort and self-controlled case-series designs reported similar results; no associationwhere the endpoint was stroke causing hospitalisation and a doubling of risk when minorstroke was included. No RCTs were available for the outcome of hip fracture or pneumonia.Observational studies reported a 20% to 40% increased risk of hip fracture with bothantipsychotic classes compared to non-use. The risk of pneumonia was a 2 to 3 times greaterwith both classes compared to non-use while a self-controlled case-series study estimated a60% increased risk. Conventional antipsychotics were associated with a 50% greater hipfracture risk than atypical antipsychotics, while the risk of pneumonia was similar betweenthe classes.
Conclusions:
Choice of observational study design is critical in studying the adverse effects ofantispychotics. Cohort and instrumental variable analyses gave more consistent results toclinical studies for mortality outcomes as have self-controlled case-series for the risk ofcerebrovascular events and stroke. Observational evidence has highlighted the potential forantipsychotics to be associated with serious adverse events that were not reported in RCTsincluding hip fracture and pneumonia. Good quality observational studies are required, thatemploy appropriate study designs that are robust towards unmeasured confounding, toconfirm the potential excess risk of hip fracture and pneumonia with antipsychotics.