Background

Prazosin is an α-blocker, that is, an antagonist selective for α-1 adrenergic receptors. These receptors are expressed throughout the brain on vascular smooth muscle cells, where they mediate the vasoconstrictive effect of norepinephrine/adrenaline. Prazosin went off patent in 2013 and is available as a generic. Prazosin's side effects include weakness, fatigue, headache, and nausea, among others, but it is generally well-tolerated and not sedating. Besides hypertension, it is being prescribed for other indications, such as benign hypertrophy of the prostate and post-traumatic stress disorder. Prazosin may be considered to treat agitation in people with Alzheimer’s disease when other medication classes are ineffective or not tolerated (Tampi et al., 2022).

Prazosin started drawing interest in Alzheimer's disease research in the early 2000s as a potential alternative to antipsychotic medications for the treatment of aggressive agitation in the moderate stages of the disease. Aggression in AD is distressing to caregivers and frequently precipitates placement in a nursing home. Pathology studies showed that in AD, α-1 adrenergic receptors undergo region-specific changes, and that degeneration of adrenergic neurons in the locus coeruleus is accompanied by compensatory increases in both norepinephrine and the postsynaptic α-1 receptor (e.g. Shimohama et al., 1986; Szot et al., 2006).

Prazosin has been reported to reduce Aβ generation in neuronal cultures, and to improve behavioral and inflammatory outcome measures in APP23 mice (Katsouri et al., 2013). Growing interest in the connection between hypertension, neurovascular function, and Alzheimer's disease has led to the concept of increased postsynaptic responsiveness to adrenaline, perhaps aided by Aβ. Prazosin has been suggested to counteract Aβ-induced vasoconstriction mediated via α-1 adrenergic receptor signaling (e.g., Haase et al., 2013).

Findings

In an initial study conducted through the University of Washington in Seattle, 22 people with AD and aggressive agitation were randomized to take up to 6 mg/day of prazosin or placebo a day for eight weeks and evaluated on overall global impression of change and the neuropsychiatric inventory (NPI). Prazosin outperformed placebo in this pilot study (Wang et al., 2009). 

In 2010, a second NIH-funded study at the University of Washington started to recruit 120 patients with AD and disruptive agitation to compare a 12-week course of 8 mg/day of prazosin to placebo followed by 12 weeks of prazosin offered open-label. The study ended in March 2014 after enrolling just 20 participants. Results posted on clinicaltrials.gov report a small improvement in the primary outcome of the NPI, but no change in in the Clinical Global Impression of Change (CGIC).

In 2013, the NIH announced that it would fund a multicenter North American study of prazosin through the Alzheimer's Disease Cooperative Study’s national consortium of academic medical centers (ADCS) (Jan 2013 news story). The PEACE-AD study began in 2018, intending to recruit 186 AD patients with moderate to severe disruptive behavior living in nursing homes. They were to be randomized 2:1 to prazosin or placebo for 12 weeks, against a primary outcome of the CGIC-Agitation. According to a presentation at the December 2022 CTAD conference, the study had difficulty enrolling people in long-term care, and then was further delayed by the COVID pandemic. After modifications to include home-based participants, remote assessment, and a reduced enrollment, the trial ended in January 2022 with 35 participants. Twenty finished the study. The primary outcome and key secondaries of the NPI and ADCS-ADL favored drug but the difference did not reach significance. One exploratory outcome, the Cohen-Mansfield Agitation Index, was significantly improved on drug compared to placebo. Side effects were as expected, including fainting, nausea, and dizziness. One severe adverse event of fainting was deemed related to drug.

In December 2016, the Veteran’s Administration began a study involving 120 participants with a history of mild traumatic brain injury and posttraumatic stress disorder, who have a higher than normal risk of developing Alzheimer’s disease and other forms of dementia. TBI and PTSD are believed to slow Aβ and tau efflux from the brain, due to loss of noradrenergic signaling and poor sleep. The study will determine if 10 weeks of prazosin can increase Aβ and tau removal, as measured by CSF Aβ42, total tau and p-tau 181. Recruitment was halted due to COVID, but as of January 2022 the study is active, and expected to finish by the end of 2024.

For details of prazosin trials, see clinicaltrials.gov