Background

This drug is an α2A adrenergic receptor agonist. It acts in the central nervous system and is used to treat high blood pressure and attention-deficit/hyperactivity disorder (ADHD). An extended-release formulation, approved as a once-a-day medication for ADHD in children, is available as a generic. Side effects include blurred vision, confusion, faintness, sweating, fatigue, and others.

Guanfacine works in the prefrontal cortex to increase attention and cognition by activating postsynaptic norepinephrine receptors. In preclinical studies, the drug improved working memory of aged rodents and monkeys (Arnsten and Jin, 2012). People with AD show impairment in attention, which may contribute to memory problems (Malhotra, 2018). In addition, degeneration of norepinephrine-producing locus coeruleus neurons, and noradrenergic dysfunction, are recognized features of Alzheimer’s and Parkinson’s diseases (Weinshenker, 2018; Jacobs et al., 2019).

Findings

The idea that guanfacine might boost cognition in Alzheimer’s disease has been around for two decades, but not supported by trial data. The first small studies using guanfacine alone in people with AD were negative (Crook et al., 1992; Schlegel et al., 1989). Likewise, a larger trial in people with age-associated memory impairment found no benefit on learning or memory (McEntee et al., 1991). In more recent work, three months of treatment with extended-release guanfacine at one-half, and one-tenth, the dose used for ADHD did not improve attention or cognitive function in 154 healthy elderly controls (Barcelos et al., 2018).

In January 2019, a study began to evaluae guanfacine as an add-on to cholinergic treatment in people with AD. The single-center Phase 3 trial at Imperial College London is enrolling 160 participants who meet clinical criteria for probable AD and have been taking a stable dose of donepezil, galantamine, or rivastigmine for three months. They will receive 2 mg per day of extended-release guanfacine or placebo for three months. The primary outcome is performance on the ADAS-Cog; secondary outcomes include additional cognitive tests focusing on attention, plus neuropsychiatric symptoms, daily activities, and caregiver burden. Blood pressure and sleepiness will be tracked. The trial will end in early 2021. 

Guanfacine is also being studied for stress disorders, Tourette’s syndrome, and for alcohol, opioid, nicotine, or cannabis withdrawal. 

For details on guanfacine trials, see clinicaltrials.gov.

Clinical Trial Timeline