Antipsychotics, Other Psychotropics, and the Risk of Death in Patients with Dementia: Number Needed to Harm

Importance: Antipsychotic medications are associated with increased mortality in older adults with dementia, yet their absolute effect on risk relative to no treatment or an alternative psychotropic is unclear.

Objective: To determine the absolute mortality risk increase and number needed to harm (NNH) (ie, number of patients who receive treatment that would be associated with 1 death) of antipsychotic, valproic acid and its derivatives, and antidepressant use in patients with dementia relative to either no treatment or antidepressant treatment.

Design, Setting, And Participants: A retrospective case-control study was conducted in the Veterans Health Administration from October 1, 1998, through September 30, 2009. Participants included 90,786 patients 65 years or older with a diagnosis of dementia. Final analyses were conducted in August 2014.

Exposures: A new prescription for an antipsychotic (haloperidol, olanzapine, quetiapine, and risperidone), valproic acid and its derivatives, or an antidepressant (46,008 medication users).

Main Outcomes And Measures: Absolute change in mortality risk and NNH over 180 days of follow-up in medication users compared with nonmedication users matched on several risk factors. Among patients in whom a treatment with medication was initiated, mortality risk associated with each agent was also compared using the antidepressant group as the reference, adjusting for age, sex, years with dementia, presence of delirium, and other clinical and demographic characteristics. Secondary analyses compared dose-adjusted absolute change in mortality risk for olanzapine, quetiapine, and risperidone.

Results: Compared with respective matched nonusers, individuals receiving haloperidol had an increased mortality risk of 3.8% (95% CI, 1.0%-6.6%; P < .01) with an NNH of 26 (95% CI, 15-99); followed by risperidone, 3.7% (95% CI, 2.2%-5.3%; P < .01) with an NNH of 27 (95% CI, 19-46); olanzapine, 2.5% (95% CI, 0.3%-4.7%; P = .02) with an NNH of 40 (95% CI, 21-312); and quetiapine, 2.0% (95% CI, 0.7%-3.3%; P < .01) with an NNH of 50 (95% CI, 30-150). Compared with antidepressant users, mortality risk ranged from 12.3% (95% CI, 8.6%-16.0%; P < .01) with an NNH of 8 (95% CI, 6-12) for haloperidol users to 3.2% (95% CI, 1.6%-4.9%; P < .01) with an NNH of 31 (95% CI, 21-62) for quetiapine users. As a group, the atypical antipsychotics (olanzapine, quetiapine, and risperidone) showed a dose-response increase in mortality risk, with 3.5% greater mortality (95% CI, 0.5%-6.5%; P = .02) in the high-dose subgroup relative to the low-dose group. When compared directly with quetiapine, dose-adjusted mortality risk was increased with both risperidone (1.7%; 95% CI, 0.6%-2.8%; P = .003) and olanzapine (1.5%; 95% CI, 0.02%-3.0%; P = .047).

Conclusions And Relevance: The absolute effect of antipsychotics on mortality in elderly patients with dementia may be higher than previously reported and increases with dose.