This study provides preliminary support for the efficacy of the alpha-1 AR antagonist prazosin as a novel treatment for behavioral symptoms in AD patients with agitation and aggression. Improvements in both the NPI and BPRS were significantly and substantially greater with prazosin than placebo. The onset of improvement with prazosin was rapid and the clinical significance of improvement was supported by CGIC ratings. The magnitude of behavioral improvement with prazosin in this study was comparable to that of atypical antipsychotics in previous randomized controlled trials.(10
Because there is substantial loss of NE producing locus ceruleus (LC) neurons in AD, it may seem counterintuitive that reducing the CNS postsynaptic response to NE by prazosin would produce behavioral improvement. However, compensatory upregulation of surviving LC neurons that sustain age-appropriate enhanced levels of CNS NE outflow in AD is supported by multiple postmortem brain tissue as well as clinical studies.(19
) In addition to the compensatory upregulation of presynaptic noradrenergic outflow in AD, there is also increased density of postsynaptic alpha-1 AR in LC projection areas in prefrontal cortex and hippocampus.(21
) This upregulation of postsynaptic alpha-1 AR is associated with aggressive behavior antemortem.(35
) That antagonism of brain alpha-1 AR by prazosin reduces behavioral symptoms in AD is therefore consistent with the complex neurobiology of brain adrenergic system changes in AD.
The potential contribution of increased NE responsiveness at CNS alpha-1 AR to the pathophysiology of behavioral symptoms in AD may explain the efficacy of atypical antipsychotics for agitation and aggression. In vitro studies in human postmortem brain tissue demonstrate that alpha-1 AR antagonism of the atypical antipsychotics is more potent or similarly potent to dopamine D2 receptor antagonism. Quetiapine is clearly more potent at the alpha-1 AR than at the dopamine D2 receptor (Kd = 8.1 for the alpha-1 AR versus 770 for the D2 receptor, with lower Kd values indicating higher potency).(36
) Olanzapine, risperidone and ziprasidone are comparably potent at the alpha-1 AR and dopamine D2 receptor.(36
Recently, representatives from academic medical centers, the pharmaceutical industry, the FDA, the NIH, the nursing home industry, and patient advocacy groups created a consensus statement stressing the need for medications to treat agitation related to dementia and the drawbacks of current off-label atypical antipsychotic use.(18
) Several consensus guidelines and position statements recommend using atypical antipsychotics when nonpharmacological approaches have failed, but they caution prescribers about the increased side effect burden and risks involved, including the FDA “black box warning” for risk of cerebrovascular events and mortality in patients with dementia.(7
) The CATIE-AD study showed that side effects, such as sedation, extrapyramidal symptoms, and confusion, often offset efficacy of atypical antipsychotics for patients with AD with agitation and aggression.(12
) It has been hypothesized that sedation caused by antipsychotics may increase morbidity and mortality in frail elderly dementia patients.(11
) Prazosin is a promising treatment alternative because it is rarely sedating.
Interpretation of the results in this study is limited by the small sample size and the high dropout rate during follow-up. For these reasons, we presented data at each time-point, avoided last observation carried forward summaries for primary outcome measures, and did not perform a formal exploratory analysis of subitems in the NPI and BPRS. In the prazosin group, many NPI subitems had lower mean scores at last observation than at baseline, suggesting that not only agitation and aggression, but other behavioral symptoms might respond. However, without a formal NPI and BPRS subitem statistical analysis, we can not conclude which specific psychiatric or behavioral symptoms improved with prazosin. The improvements in total NPI and BPRS scores, however, do suggest overall behaviors improve with prazosin, providing rationale for future larger studies where efficacy can be more clearly demonstrated and the needed analysis of specific behavioral domains can be undertaken.
Another potential limitation to this study is that the optimal dose for prazosin was not clearly established, since most participants tolerated well the highest dose provided in this study. Future trials can investigate whether doses higher than 6mg/day may be optimal. Follow-up in this study also ended after eight weeks. Previous studies of propranolol and atypical antipsychotics that include longer observational periods indicate that behavioral improvements may not persist long-term.(39
) Longer follow-up in future studies would better establish long-term efficacy.
In summary, this study showed statistically and clinically significant differences favoring prazosin over placebo in behavioral outcome measures, and prazosin was well-tolerated. These data suggest that this medication may be effective for behavioral symptoms in patients with dementia-related agitation and aggression, and support the need for future studies to establish efficacy of prazosin.