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

Individual clinical trials and meta-analyses have suggested modest benefit from some antipsychotic agents over placebo for the treatment of psychosis and aggression in patients with dementia1–3 and that these symptoms may return when a medication is discontinued.4 Potential harms anticipated with use of these medications include known adverse effects such as metabolic changes and extrapyramidal symptoms.1,5,6 However, evidence pooled across randomized, placebo-controlled trials (RCTs) of atypical antipsychotics, such as risperidone and olanzapine, demonstrated an increased risk of cerebrovascular adverse events for which the US Food and Drug Administration (FDA) issued a warning in 2003.7 Subsequent analyses of published and unpublished clinical trial data on atypical antipsychotics by the FDA and a meta-analysis of 15 RCTs by Schneider et al8 demonstrated an increased mortality risk. In April 2005, the FDA9 issued a black box warning that the use of atypical antipsychotics leads to increased all-cause mortality when used for behavioral disturbances in patients with dementia. Additional observational analyses10,11 have demonstrated that first-generation antipsychotic agents confer an even higher mortality risk than do the atypical agents, leading to another FDA12 black box warning in 2008. However, at the time the warnings were issued, the available evidence described class-wide effects on mortality without clear delineation of the risks associated with individual medications. Using a large national registry of Veterans Affairs (VA) patients with dementia, Kales et al13 published the first analyses that provided estimates of the head-to-head mortality risk over 180 days, comparing individual antipsychotic agents and valproic acid and its derivatives (hereafter referred to as valproic acid), which are frequently used alternatives14 for behavioral disturbances in dementia. Subsequent analyses of elderly community-dwelling15 and nursing home16 patients have generally confirmed the initial findings that individual antipsychotic agents vary in their mortality risk, ranging from quetiapine (lowest) to haloperidol (highest). The decision to use any intervention in medicine requires balancing potential benefits with potential harms, but it can be difficult for clinicians to interpret the clinical significance of absolute changes in risk or benefit. The number needed to harm (NNH) is a useful metric for clinicians to understand a treatment’s potential for harm, expressing the number of patients who have to receive treatment for a particular harmful outcome to occur with the intervention.17 The NNH is formally defined as the reciprocal of the change in absolute risk. Two sets of meta-analyses of atypical RCTs by Schneider et al1,8 provided key preliminary evidence for clinicians to help weigh the relative benefits and risks of using antipsychotics. First, this group demonstrated the increased mortality risk of atypical antipsychotics relative to placebo in patients with dementia,8 showing an absolute mortality risk increase of 1% over 8 to 12 weeks of treatment, or an NNH of 100 (1/.01). The authors suggested that this degree of risk may be similar to that of other types of medications used in frail, elderly patients, although subsequent work18 has demonstrated that the mortality risk associated with antipsychotic treatment is greater than that with other psychotropic medications. In a second set of analyses, Schneider et al1 examined the potential benefits of treatment with antipsychotics. Depending on the outcome measure and criterion for improvement, the number needed to treat ranged from 5 to 14, in contrast to the NNH of 100. Over the past several years, investigators have consistently demonstrated both class- and agent-specific associations with increased mortality risk when these agents are used to treat dementia-related behavioral disturbances. However, when faced with the clinical decision of whether to prescribe a given medication for a given patient, physicians may have difficulty quantifying and comparing the risk. Here, we build on previous observational analyses of a cohort of patients with dementia newly treated with an antipsychotic (haloperidol, olanzapine, quetiapine, and risperidone) to estimate the increased absolute mortality risk and corresponding NNH during 180 days of follow-up relative to no treatment. Similar analyses are included for valproic acid and antidepressants since they are commonly used as alternatives to antipsychotics for aggression/agitation in dementia.14 Then, given the interest in antidepressant agents as more benign alternatives to antipsychotics19,20 and their increased use following the FDA warnings,14 we describe the mortality risk and NNH of anti-psychotics and valproic acid relative to antidepressants. Finally, we provide estimates of the increased risk across atypical antipsychotics by agent and by dose.