Commentary on Kales study Am J Psychiatry 2012;169:71-79
The study examined the relative risk of mortality associated with newly commenced prescriptions of olanzapine, quetiapine, and haloperidol, compared with risperidone as the reference compound, in a cohort of more than 30,000 veterans with dementia, ages 65 years and older.
Which antipsychotic has the highest and lowest risk of mortality?
Haloperidol was associated with significantly greater mortality than risperidone (relative risk=1.54).
Several studies have suggested that haloperidol confers a greater mortality risk than atypical antipsychotics (9), but the Kales et al. report is one of the few to have systematically compared mortality risk between different atypical antipsychotic agents.
Olanzapine and risperidone had similar mortality risk, while the risk for quetiapine was significantly lower (relative risk=0.73).
A key observation is that the highest increase in mortality risk was in the first 120 days, particularly in the first 30 days for haloperidol.
Which antipsychotic is best for aggression, agitation, or psychosis?
...three randomized controlled trials of quetiapine did not demonstrate any effectiveness in the treatment of aggression, agitation, or psychosis (4, 5).
The best evidence of efficacy is for risperidone, with consistent evidence of a modest but significant benefit over 12 weeks in the treatment of both aggression and psychosis.
There is also evidence of a similar level of benefit with aripiprazole, olanzapine, and haloperiodol, but only a few studies have examined other agents.
Through balancing the mortality data from this study and efficacy data from previous randomized controlled trials, risperidone and olanzapine emerge as the best evidence-based options.
What harms are associated with antipsychotic use?
...extrapyramidal symptoms, sedation, gait disturbances, and falls.
Many agents also lead to anticholinergic side effects, including delirium (4).
Tardive dyskinesia with atypical antipsychotics appears to occur less frequently than with typical antipsychotics, but QTc prolongation has been reported as a significant problem associated with several atypical antipsychotics.
A meta-analysis also identified a significant increase in respiratory and urinary tract infections as well as peripheral edema in people treated with risperidone, compared with placebo (4). These are likely to be class effects of atypical antipsychotics.
It has also become clear that other, more serious adverse outcomes, such as stroke and related cerebrovascular events, accelerated cognitive decline, and death, are significantly increased in people with dementia who are prescribed antipsychotics, compared with people with dementia not treated with these agents.
Deaths related to bronchopneumonia, thrombo-embolic events (including stroke and pulmonary embolism), and sudden cardiac arrhythmias are all significantly increased in people with dementia receiving antipsychotic treatment (6).
...meta-analyses of randomized controlled trials have reported significant incidence of sedation, chest-infection, and dehydration (4)
1.5- to 1.7-fold increase in mortality risk for people with Alzheimer's disease receiving antipsychotics
What can we do to reduce the harms associated with antipsychotic use?
...monitoring fluid intake and promoting vigilance for early detection and treatment of chest infections, may offer important potential opportunities to reduce excess mortality.
The potential role of ECG monitoring for prolonged QTc interval should perhaps also be considered
What about the use of non-psychotics like valproic acid?
The mortality risk for valproic acid and its derivatives, which were included as a nonantipsychotic comparison, was generally higher than the risk for quetiapine and similar to that for risperidone.
See guidelines below from UK Alzheimer's Society:
