Therapeutics

Prazosin

Overview

Name: Prazosin
Synonyms: Prazosin hydrochloride, Minipress, Hypovase, Vasoflex
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 4)
Approved for: Hypertension

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 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 changes (e.g., Shimohama et al., 1986Szot 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. 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). 

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References

News Citations

  1. NIH Funds Four Clinical Trials in ADCS Renewal

Research Models Citations

  1. APP23

Paper Citations

  1. . Prazosin for the treatment of behavioral symptoms in patients with Alzheimer disease with agitation and aggression. Am J Geriatr Psychiatry. 2009 Sep;17(9):744-51. PubMed.
  2. . Biochemical characterization of alpha-adrenergic receptors in human brain and changes in Alzheimer-type dementia. J Neurochem. 1986 Oct;47(4):1295-301. PubMed.
  3. . Compensatory changes in the noradrenergic nervous system in the locus ceruleus and hippocampus of postmortem subjects with Alzheimer's disease and dementia with Lewy bodies. J Neurosci. 2006 Jan 11;26(2):467-78. PubMed.
  4. . Prazosin, an α(1)-adrenoceptor antagonist, prevents memory deterioration in the APP23 transgenic mouse model of Alzheimer's disease. Neurobiol Aging. 2013 Apr;34(4):1105-15. Epub 2012 Oct 11 PubMed.
  5. . Amyloid-β peptides activate α1-adrenergic cardiovascular receptors. Hypertension. 2013 Nov;62(5):966-72. Epub 2013 Sep 3 PubMed.

Further Reading